Brazilian guidelines on antiplatelet and anticoagulant agents in cardiology

GUIDELINES

Brazilian guidelines on antiplatelet and anticoagulant agents in cardiology

Serrano Jr CV; Fenelon G; Soeiro AM; Nicolau JC; Piegas LS; Montenegro ST; Lorga Filho AM; Azmus AD; Quadros AS; Avezum Junior A; Marques AC; Franci A; Manica ALL; Volschan A; De Paola AAV; Greco AIL; Ferreira ACN; Sousa ACS; Pesaro AEP; Simão AF; Lopes ASSA; Carvalho ACC; Timerman A; Ramos AIO; Alves BR; Caramelli B; Mendes BA; Polanczyk CA; Montenegro CEL; Barbosa CJDG; Melo CCL; Pinho C; Moreira DAR; Calderaro D; Gualandro DM; Armaganijan D; Machado Neto EA; Bocchi EA; Paiva EF; Stefanini E; D'Amico E; Evaristo EF; Silva EER; Fernandes F; Brito Junior FS; Bacal F; Ganem F; Gomes FLT; Mattos FR; Moraes Neto FR; Tarasoutchi F; Darrieux FCC; Feitosa GS; Morais GR; Correa Filho H; Castro I; Gonçalves Junior I; Atié J; Souza Neto JD; Ferreira JFM; Faria Neto JR; Annichino-Bizzacchi JM; Zimerman LI; Pires LJT; Baracioli LM; Silva LB; Mattos LAP; Lisboa LAF; Magalhães LPM; Lopes MACQ; Montera MW; Figueiredo MJO; Malachias MVB; Gaz MVB; Andrade MD; Bacellar MSC; Barbosa MR; Clausell NO; Dutra OP; Coelho OR; Yu PC; Lavítola PL; Lemos Neto PA; Andrade PB; Farsky PS; Franco RA; Kalil RAK; Lopes RD; Esporcatte R; Heinisch RH; Kalil Filho R; Giraldez RRCV; Alves RC; Leite REGS; Gagliardi RJ; Ramos RF; Accorsi TAD; Jardim TSV; Scudeler TL; Moisés VA; Portal VL

^{Mailing Address}

1. Introduction

In the past 10 years, we have observed an exponential development of anticoagulant and antiplatelet agents for replacing heparin and vitamin K antagonists and/or aiding in the treatment of coronary artery disease. Scientific literature has increasingly shown new applications for these agents. Some of these are already approved for use by ANVISA in Brazil, such as dabigratan, rivaroxaban, apixaban, prasugrel, and ticagrelor. These new alternative drugs require recommendations on specific restrictions and risks that must be considered before administration to patients. During the development of new medications, the safety of patients is being increasingly valued and includes a greater use of bleeding risk scores.

Various multicenter randomized studies have been developed to validate the use of these drugs in acute coronary syndrome (ACS), venous thromboembolism (VTE), and pulmonary thromboembolism (PTE) and in the prevention of thrombotic events. Brazil has participated in some of the main trials and, the country's experience in the use and management of these drugs is increasing.

The Board of the Brazilian Heart Society (Sociedade Brasileira de Cardiologia, SBC) proposed to develop a guideline on recommendations regarding the use of anticoagulant and antiplatelet drugs owing to the importance of this fact in the field of cardiology in Brazil.

This guideline was prepared by an editorial board consisting of Brazilian cardiologists with recognized experience and qualifications in the area. The document is a compilation of many national and international findings and opinions of Brazilian specialists and aims to help physicians in making decisions regarding patients in various clinical situations. Didactically, antithrombotic drugs are classified as antiplatelet and anticoagulant agents.

SBC, the editors, and the group that collaborated in the preparation of this guideline hope that its dissemination will contribute to a better standardization of anticoagulant and antiplatelet drug management and will increase the effectiveness of their use and patient safety.

1.1. Methods and scientific evidence

The editorial board selected to write these recommendations consists of physicians with extensive experience in this area. These professionals are involved in the management and treatment of various clinical situations in which these drugs are widely used and work in major teaching and research centers in Latin America.

We selected relevant studies published up to 2012, according to the evidence pyramid, the organization into levels of recommendation (Classes I, IIa, IIb, and III; Table 1), and the impact of the evidence levels (A, B, and C; Table 2).

1.2. Presentation of the text

The guidelines in this document are presented in two manners. The first consists of a full text that includes the description of the pertaining to each agent, the recommendations, and the evidence levels shown in tables, together with the citations. This text is available on the website of Arquivos Brasileiros de Cardiologia.

The second consists of the executive summary, which contains only the tables with the recommendations and the evidence levels. The executive summary will be available in the publications of Arquivos.

2. Use of antiplatelet and anticoagulant agents in ST-segment elevation myocardial infarction (STEMI)

2.1. Introduction

ST-segment elevation myocardial infarction (STEMI) is the most severe form of unstable myocardial ischemia; its incidence varies between 29% and 47% of cases of acute coronary syndrome (ACS), and it is associated with high morbidity and mortality. Data from the Center for Disease Control and Prevention (CDC)¹ in the US show that in 2010, the main cause of mortality was cardiovascular disease and that acute myocardial infarction (AMI) accounted for approximately 5% of the overall mortality. In addition to the high impact on mortality in the general population, AMI has also an important economic impact because it involves a large number of hospitalizations. According to data from the Heart Diseases and Stroke Statistics², it is estimated that in 2006, the US spent 11.7 billion dollars on hospital expenses related to AMI.

In Brazil, according to data from DATASUS for 2003³, cardiovascular diseases accounted for 11% of hospitalizations and approximately 19.5% of resources spent by SUS on hospitalizations in general. AMI accounted for 4.2% of all hospitalizations, which demonstrates the importance of this condition in terms of morbidity and hospital costs.

With regard to the treatment of this clinical entity, in addition to reperfusion therapies (pharmacological, thrombolytic, or percutaneous therapy via primary angioplasty), antiplatelet and anticoagulant therapy is essential to reduce mortality and recurrence of cardiovascular events⁴.

This section aims to assess the use of antiplatelet and anticoagulant agents in the treatment of STEMI.

2.2. Antiplatelet therapy in STEMI

2.2.1. ASA

The use of acetylsalicylic acid (ASA, aspirin) in STEMI is based on solid evidence; its use is deemed to be essential. The Second International Study of Infarct Survival (ISIS-2)⁵ assessed the use of ASA and streptokinase alone and in combination. The use of ASA alone led to a 23% reduction in all-cause mortality, and combined use of the drugs led to a 42% reduction in all-cause mortality. A 25 ± 7%, 21 ± 7%, and 21 ± 12% reductions in mortality were observed when used within 0-4 h, 5-12 h, and 13-24 h of the initial symptoms, respectively.

Subsequent meta-analyses reinforced the fundamental role of ASA in the reduction of mortality and cardiovascular events, when used at an early stage and in the long term. A study by the "Antiplatelet Trialists Collaboration"⁶ group demonstrated a 29% reduction in the relative risk for the incidence of vascular events (nonfatal infarction, stroke, or vascular death). A more recent publication⁷, which analyzed the same outcomes, revealed a reduction of 36 vascular events per 1,000 patients with previous myocardial infarction.

With regard to the ASA dose, the CURRENT-OASIS-7 study⁸ evaluated the hypothesis of using a double maintenance dose of ASA in patients with ACS; 29% of them had STEMI and were undergoing primary percutaneous coronary intervention (PPCI). This study did not show any difference between the standard-dose regimen (75-100 mg/day) and the high-dose regimen (300-325 mg/day) in preventing cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or stroke) over 30 days (p = 0.61, 95% CI 0.86-1.09). Moreover, there was no difference in terms of the incidence of major bleeding (p = 0.90, 95% CI 0.84-1.17).

The use of ASA should be contraindicated in some exceptional situations, e.g., known hypersensitivity (hives, bronchospasm, or anaphylaxis), active peptic ulcers, blood dyscrasia, and severe hepatopathy.

Based on these findings, the use of ASA in patients with STEMI is essential in the prevention of mortality and cardiovascular events, both in the short and long term, and it should be indefinitely continued after the acute event (secondary prevention).

2.2.2. Clopidogrel

The use of clopidogrel, a thienopyridine derivative and inhibitor of adenosine diphosphate (ADP), in ACS began with the CURE study⁹, which compared the use of ASA alone and in combination with clopidogrel in a situation of intermediate- or high-risk unstable angina as well as non-STEMI (NSTEMI). This study showed a 20% reduction in the relative risk for cardiovascular death, stroke, and nonfatal AMI.

In the context of STEMI, two important studies should be highlighted. The first study is the CLARITY-TIMI 28 study¹⁰ that included 3,491 patients diagnosed with STEMI who were aged < 75 years and were undergoing thrombolytic therapy (99.7% undergoing thrombolysis). These patients were assigned to ASA or ASA combined with clopidogrel groups; the study design envisaged the use of a 300 g loading dose of clopidogrel and a 75 mg maintenance dose/day. This study showed a 36% reduction in the combined outcome of death, nonfatal myocardial infarction, or revascularization of the target vessel; no difference was observed in terms of bleeding between the groups. In this study, the age limit for inclusion was 75 years and the mean time of clopidogrel use was 4 days.

The second study is the COMMIT study¹¹ that randomly assigned 45,852 patients with suspected STEMI in 1,250 centers in China to receive 162 mg of ASA/day or ASA (same dose) combined with 75 mg of clopidogrel/day, without the administration of a loading dose. This study included 26% of patients aged > 70 years (without a maximum age limit). In addition, 50% of patients were subjected to thrombolysis. In this study, a 9% reduction in the combined outcome (death, reinfarction, or stroke) was observed; no difference was observed in terms of bleeding. The mean time of clopidogrel use was 28 days. Clopidogrel was beneficial for patients who received thrombolytic therapy and those who did not undergo reperfusion. There was a 7% reduction in the overall mortality (RR 0.93, 95% CI 0.87-0.99).

In addition, the CURRENT-OASIS-7 study⁷, which assessed 25,086 patients, tested two hypotheses: the use of a high-maintenance dose of ASA (described in section 2.2.1) and the use of a double loading dose of 600 mg of clopidogrel, followed by a dose of 150 mg/day for 7 days and a dose of 75 mg/day thereafter, as opposed to the standard regimen (a loading dose of 300 mg, followed by 75 mg/day), in patients with ACS (29% of patients with STEMI). This study did not show any effect of the higher dose regimen on the prevention of cardiovascular events (cardiovascular deaths, nonfatal myocardial infarction, or stroke) over 30 days (p = 0.30). With regard to major bleeding, the group that received higher doses of clopidogrel exhibited a higher incidence of this event (2.5% × 2.0%, p = 0.01). Analysis of secondary outcomes revealed a significant decrease in the incidence of stent thrombosis (1.6% × 2.3%, p = 0.001) in the group subjected to PCI (17,263 patients). It should be noted that clopidogrel was never compared with a placebo in patients undergoing PPCI. The CURRENT-OASIS-7 study only compared the use of two doses of clopidogrel in patients with STEMI subjected to PPCI. A double dose of clopidogrel was also not assessed in patients who received thrombolytic therapy or those who were treated without reperfusion and should not be used in these patients.

A loading dose of 600 mg of clopidogrel is used in patients subjected to PPCI because it enables faster inhibition of the ADP receptor. This fact has been demonstrated in various observational studies^12,13.

Clopidogrel should be administered during 12 months after STEMI, particularly if the patient has undergone PPCI. This conclusion resulted from the extrapolation of studies on Non-ST-segment elevation ACS (NSTEACS), including the CURE study⁸ described above.

Therefore, the use of clopidogrel is justified in the context of STEMI, with a loading dose of 300 mg, followed by 75 mg/day, from the acute phase up to 12 months after the event. It should be noted that the loading dose of 300 mg should not be administered to patients subjected to thrombolysis who are aged over 75 years. In patients undergoing PPCI, the loading dose should be 600 mg. A double dose of 150 mg/day should be restricted to patients at low risk for bleeding. In the case of surgical intervention, the administration of clopidogrel should be discontinued 5 days before the procedure.

Table 1

2.2.3. Prasugrel

Prasugrel, an inhibitor of platelet aggregation induced by ADP via the irreversible blocking of the P2Y12 receptors, was developed to inhibit platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel, thereby avoiding the well-known resistance to clopidogrel exhibited by a portion of the population.

The TRITON-TIMI 38 study¹⁴, published in 2007, randomly assigned 13,608 patients with ACS, known as coronary anatomy, and planned PCI with clopidogrel or prasugrel, associated with standard therapy (including ASA). Within the sample, STEMI accounted for 26% of patients. In the general cohort, the group that used prasugrel exhibited a 19% reduction (p < 0.001) in the combined outcome of death from cardiovascular causes, nonfatal infarction, or stroke, particularly due to the reduction in cases of nonfatal infarction. With regard to bleeding, the prasugrel group exhibited a 32% increase (p = 0.03) in the risk for major bleeding (according to the TIMI score). Post hoc analyses identified three groups at higher risk for bleeding: age > 75 years, weight < 60 kg, or previous stroke/transient ischemic attack (TIA).

Of the 3,534 patients with STEMI, 2,438 were subjected to PPCI and 1,096 were subjected to secondary PCI (patients referred to PCI approximately 38 h after AMI). The primary outcome of cardiovascular death, nonfatal AMI with stroke, was significantly less frequent in the prasugrel group than in the clopidogrel group (RC 0.79, 95% CI 0.65-0.97) over 15 months. A reduction in stent thrombosis from 2.8% to 1.6% was observed in the prasugrel group. There was no difference in the bleeding rate between the two groups¹⁵.

Therefore, the use of prasugrel in STEMI is indicated for cases of PPCI, after knowing the coronary anatomy. Prasugrel should be administered at a loading dose of 60 mg and a maintenance dose of 10 mg/day for 12 months. A lower maintenance dose (5 mg) may be considered for individuals weighing less than 60 kg and aged older than 75 years; however, such a dose has not been prospectively tested in STEMI clinical studies. The drug is contraindicated in the following cases: in combination with thrombolytic therapy and in patients without reperfusion (not studied in this population), in patients aged > 75 years or in patients with previous stroke/TIA. In case of surgical intervention, the administration of prasugrel should be discontinued 7 days before the procedure.

2.2.4. Ticagrelor

Ticagrelor, another ADP inhibitor antiplatelet agent, is a reversible inhibitor of the P2Y12 receptors of ADP. It does not depend on primary metabolism (it is therefore not a pro-drug) and inhibits aggregation more intensely, more rapidly, and more consistently than clopidogrel.

In ACS, the PLATO study¹⁶ randomly assigned 18,624 patients to ticagrelor or clopidogrel, associated with the standard treatment (including ASA). In this study, clopidogrel or ticagrelor were administered during the initial treatment in the emergency room, without knowledge of the coronary anatomy. The prevalence of STEMI in the sample was approximately 38%. The group that used ticagrelor exhibited a 16% reduction in the incidence of the combined outcome of death from vascular causes, nonfatal infarction, or stroke (p < 0.001). Analysis of secondary outcomes revealed that in the ticagrelor group, there was a 21% (p < 0.001) reduction in mortality by vascular causes and a 22% (p < 0.001) reduction in all-cause mortality. With regard to the occurrence of major bleeding, ticagrelor was not significantly different from clopidogrel for the various criteria used (including the TIMI score). However, the ticagrelor group had a higher incidence of dyspnea, usually transient, which forced discontinuation in a higher number of individuals in this group. Moreover, this group exhibited a higher incidence of bradycardia, also usually transient and not leading to differences in clinical repercussions between the groups (pacemaker implant or symptoms).

Therefore, the use of ticagrelor is indicated for patients with ACS with or without ST-segment elevation, regardless of the knowledge of the coronary anatomy. Ticagrelor should be administered at a loading dose of 180 mg and a maintenance dose of 90 mg twice a day, and its use should be continued for 12 months. The drug combined with thrombolytic therapy is contraindicated as well as in patients without reperfusion (not studied in this population). In case of surgical intervention, ticagrelor should be discontinued 5 days before the procedure.

2.2.5. Glycoprotein (GP) IIb/IIIa inhibitors

Studies with GP IIb/IIIa inhibitors, conducted prior to the current regimens of double antiplatelet therapy, revealed a significant reduction in the incidence of reinfarction, both in the context of PPCI and the use of thrombolytic agents. In the former situation, there was no increase in hemorrhage complications; however, there was a significant increase in bleeding in the context of thrombolysis¹⁷.

With the routine use of clopidogrel and the advent of PCI with stent, doubts have arisen regarding the use of GP IIb/IIIa inhibitors in STEMI. Since then, physicians have been unsure about using them routinely or selectively and about the best administration route (intracoronary or intravenous).

The Relax-AMI study¹⁸, which included 210 patients, compared the early use of abciximab and its use just before PCI in the hemodynamics laboratory, and the results revealed improved perfusion parameters and recovery of ventricular function over 30 days. The On-TIME 2 study¹⁹, which randomly assigned 984 patients with STEMI to a prehospital high bolus dose of tirofiban or use during ICPP, showed a higher decrease in ST-segment elevation without a significant increase in major bleeding.

The FINESSE study randomly assigned patients to three groups: PPCI, PCI facilitated with abciximab, and PCI facilitated with a small dose of reteplase and abciximab. There was no reduction in the ischemic outcomes, and there was an increase in hemorrhagic events with the use of the GP IIb/IIIa inhibitor. After 12 months of follow-up, the subgroup with previous AMI exhibited reduced mortality with the use of reteplase and abciximab (p = 0.093). The BRAVE-3 study randomly assigned patients with STEMI to a 600 mg loading dose of clopidogrel for routine use of abciximab or placebo, and there was no reduction in the size of the infarction area with this strategy^20,21.

Therefore, the routine use of GP IIb/IIIa inhibitors in STEMI is not beneficial and may involve higher bleeding rates. The use of GP IIb/IIIa inhibitors alone during PPCI (high incidence of thrombi, no reflow, and other thrombotic complications) may be considered despite the absence of strong evidence. The best way to use tirofiban and abciximab together with the new antiplatelet drugs (prasugrel and clopidogrel) still remains unclear.

Another question is whether intracoronary administration of GP IIb/IIIa inhibitors is better than intravenous administration. Several small studies have evaluated this strategy; the majority evaluated abciximab and suggested that intracoronary administration leads to better perfusion after PCI, lesser need for new revascularization, and decreased early deaths²².

The only large study on this subject is the AINDA study, which randomly assigned 2,065 patients with STEMI to intracoronary or intravenous (0.25 mg/kg) administration of abciximab and intravenous administration of a maintenance dose of 0.125 mg/kg/min for 12 h. There was no difference in the primary outcome of death, AMI, and heart failure over 90 days, and there were no significant differences between the groups with regard to safety outcomes. However, analysis of secondary outcomes revealed that the group with intracoronary bolus exhibited a 43% reduction in the incidence of heart failure over 90 days. Based on these data, the intracoronary administration of GP IIb/IIIa inhibitors may be considered; however, the intravenous route remains the route of choice²³.

2.3. Anticoagulant therapy in STEMI

2.3.1. Unfractionated heparin (UH)

The advantage of using UH in ACS was recognized even before using ASA and thrombolytic therapy²⁴. Studies such as the GISSI-2²⁵ and ISIS-3 studies²⁶, wherein the use of UH during treatment with ASA and thrombolytic agents was assessed, revealed that it was not associated with a significant reduction in clinically relevant outcomes. However, in these studies, UH was subcutaneously administered 4-12 h after the administration of thrombolytic therapy.

The GUSTO-I study²⁷, published in 1993, evaluated the intravenous administration of UH using a 5,000 IU bolus, followed by initial continuous infusion of 1,000 or 1,200 IU/h, in patients weighing > 80 kg. The UH dose was adjusted to maintain an activated partial thromboplastin time (aPTT) between 60 and 85 s in patients with STEMI receiving ASA and subjected to various thrombolytic therapies. Among the 41,021 randomized patients, the group that was administered UH intravenously combined with thrombolytic therapy with r-TPA exhibited the lowest mortality (6.3%) over 30 days.

The ASSENT-3 study²⁸ assessed the efficacy and safety of tenecteplase in combination with enoxaparin, UH, or abciximab. In this study, a 60 IU/kg bolus of UH was intravenously administered (maximum 4.000 IU), followed by continuous infusion of 12 IU/kg/h (maximum 1.000 IU/h, initially), and adjusted to maintain aPTT between 50 and 70 s. The occurrence of death, reinfarction, or recurrent ischemia over 30 days was lower in the UH group than in the enoxaparin group; however, no difference in mortality was observed over 30 days. This UH administration regimen is associated with a lower incidence of hemorrhagic events (major bleeding and need for transfusions); however, it was not statistically different from enoxaparin.

2.3.2. Low-molecular-weight heparin (LMWH)

The above mentioned ASSENT-3 study²⁴ was one of the first large studies to compare LMWH and UH. Among 6,095 patients with STEMI or new left branch block (LBB) within 6 h of the onset of ischemic symptoms, the patients that received enoxaparin combined with thrombolytic therapy using tenecteplase exhibited a significant 26% reduction in the relative risk for death, reinfarction, or refractory ischemia over 30 days in comparison with those who received UH combined with tenecteplase, with the number of treated patients required to avoid an outcome (NNT) being 25.

However, the strongest data on efficacy and safety of enoxaparin in patients with STEMI were obtained from the ExTRACT TIMI 25 study^29-31, published in 2006. This was an international, multicenter, randomized, and double-blinded study that included 20,506 patients within 6 h of the onset of ischemic symptoms. ECG revealed ST-segment elevation in at least two contiguous leads or new LBB. Thrombolytic therapy was programmed. The patients were randomly assigned to UH for a minimum period of 48 h or enoxaparin for 8 days or until discharged. The enoxaparin regimen consisted of a 30 mg bolus intravenously administered 15 min before or up to 30 min after the onset of thrombolysis, followed by a subcutaneous injection of 1.0 mg/kg every 12 h (maximum 100 mg in the two first doses). Patients aged > 75 years were not administered the bolus, and the dose of enoxaparin was adjusted to 0.75 mg/kg every 12 h (maximum 75 mg in the two first doses). In patients with an estimated creatinine clearance (CrCl) of < 30 ml/min, the dose was adjusted to 1.0 mg/kg every 24 h. A 60 IU/kg bolus of UH was intravenously administered (maximum 4,000 UI), followed by continuous infusion of 12 IU/kg/h (maximum 1.000 IU/h, initially). The results revealed a significant 17% reduction in the relative risk for death or nonfatal infarction over 30 days in the group assigned to enoxaparin, with NNT of 48. Safety analysis revealed that there was a significant 53% increase in the relative risk for major bleeding in the group that received enoxaparin; however, there was no significant increase in the occurrence of intracranial bleeding. In the prespecified evaluations of the clinical advantages of the drugs, wherein the occurrence of death, nonfatal AMI, stroke with severe sequelae, nonfatal major bleeding, or intracranial hemorrhage was analyzed, the results obtained for enoxaparin were better.

The use of enoxaparin in patients with STEMI subjected to PPCI was assessed in the ATOLL study, published in 2011. The study included 910 patients who were randomly assigned to receive 0.5 mg/kg of enoxaparin intravenously or 70-100 IU/kg of UH intravenously (in case of patients who did not receive GP IIb/IIIa inhibitors) and 50 -70 IU/kg of UH intravenously (in case of patients who received GP IIb/IIIa inhibitors). The UH dose was adjusted by TCA during the procedure. In this study, there was no significant difference in the outcome of death, infarction, failure to perform the procedure, or major bleeding over 30 days (p = 0.063)³². In Brazil, physicians prefer to use UH over enoxaparin after PPCI in the hemodynamics room.

A meta-analysis with six studies, published in 2007, compared enoxaparin with UH in 27,131 patients with STEMI. A significant 16% reduction in the clinical outcome of death, nonfatal infarction, or nonfatal major bleeding was observed in the patients treated with enoxaparin over 30 days³³.

2.3.4. Fondaparinux

Fondaparinux is an antithrombotic agent that indirectly inhibits the Xa factor via selective bonding to antithrombin, inhibiting thrombin generation. The administration of fondaparinux in patients with STEMI was assessed in only one large clinical study. The OASIS-6 study³⁴, published in 2006, included more than 12,000 patients assigned to receive fondaparinux for 8 days or until discharge or to receive UH or placebo according to the researcher's indication. The patients were treated with thrombolytic therapy or PPCI or did not receive reperfusion therapy. In this study, compared with the group that received UH or the placebo, a slight reduction in the incidence of death or reinfarction was observed over 30 days in the group that received fondaparinux (2.5 mg, first intravenous dose, followed by a subcutaneous dose of 2.5 mg/day). This advantage was obvious in the patients who received thrombolytic therapy (RR 0.79, p = 0.003) and in those who did not receive reperfusion therapy (RR 0.80, p = 0.03). However, this advantage was not observed in the patients undergoing PPCI because there was an increase in the incidence of catheter-related thrombosis and complications during the procedure and fondaparinux should not be used in these patients. There was no significant difference between the groups with regard to the incidence of major bleeding over 9 days.

2.3.5. Bivalirudin

In the HORIZONS-AMI study^35,36, published in 2008, 3,602 patients with STEMI within 12 h before the onset of symptoms who were referred for ICPP were randomly assigned to bivalirudin or UH combined with GP IIb/IIIa inhibitors. In this study, a 24% reduction in the relative risk for the primary outcome of death, reinfarction, and need for revascularization of the target vessel due to ischemia or stroke was observed in the group treated with bivalirudin over 30 days. In addition, there was a 40% reduction in the occurrence of major bleeding. Analysis of the secondary outcomes revealed that there was a 38% reduction in the occurrence of deaths caused by cardiovascular events and a 36% reduction in all-cause mortality. Despite the clear advantage of the use of this drug in treating patients with STEMI who will be subjected to PPCI, bivalirudin is still not available in Brazil.

Table 2

Table 3

3. Use of antiplatelet and anticoagulant agents in non-ST-segment elevation acute coronary syndrome (NSTEACS)

3.1. Introduction

NSTEACS is the most common form of acute coronary disease. These include low-, intermediate-, and high-risk unstable angina and non-ST elevation myocardial infarction (NSTEMI), which are characterized by changes in myocardial necrosis markers such as troponin and the absence of ST-segment elevation on the electrocardiogram.

In a large North American register with more than 46,000 patients¹, the mean prevalence of NSTEACS between 1999 and 2008 was approximately 67% among patients hospitalized for ACS. A recent study conducted in developing countries revealed that this percentage was similar to that of patients with STEMI; there were clear regional differences in terms of treatments used^2,3. Moreover, the North American register shows that during the period under analysis, the incidence of hospitalizations due to ACS decreased, mainly because of the persistent reduction in the occurrence of STEMI. On the other hand, the incidence of NSTEMI increased up to 2004 and began to decrease thereafter. This increase may be attributed to the improvement in myocardial necrosis detection techniques, particularly with the advent and dissemination of increasingly sensitive troponin tests. In addition, the register shows a reduction in mortality over 30 days, between 1999 and 2008, in patients hospitalized due to ACS. Interestingly, patients with NSTEMI exhibited an 18% (HR 0.82, 95% CI, 0.67-0.99) reduction in the relative risk for death; on the other hand, mortality in patients with STEMI did not change significantly during this period (HR 0.93, 95% CI 0.71-1.20) despite the increase in the number of patients undergoing revascularization. It has been suggested that the increasing use of cardioprotective medications prior to coronary events (statins, angiotensin-converting enzyme inhibitors, angiotensin II type I receptor blockers, and beta blockers) is responsible for the reduction in the incidence of death in this population. Moreover, the use of troponin (and consequently, the increased sensitivity of NSTEMI diagnosis) has led to the inclusion of patients experiencing a less severe course of the disease and with better prognosis.

Intrahospital mortality among patients with NSTEACS is lower than that among those with STEMI (3%-5% vs. 7%). However, 6-month mortality is similar (13% vs. 12%), and after 4 years, the risk for death in patients with NSTEACS is twofold higher than that in patients with STEMI. This difference in the medium- to long-term evolution may be explained by some differences between the patients' profiles because patients with NSTEACS are older and have more comorbidities, namely diabetes and renal impairment, in addition to higher incidence of previous arteries, which increase the likelihood of reinfarction⁴.

Because NSTEACS includes patients with distinct forms of clinical presentation and evolution, it is essential to adequately stratify the patients' risk when making therapeutic decisions, both in terms of ischemic events and bleeding. The "occasional" stratification initially proposed by Braunwald⁵ and the various previously published scores enable careful analysis of ischemic events. The most commonly used risk scores are probably the TIMI risk score⁶ and the GRACE score^7-9, each with their qualities and limitations^10,11. It should be noted that the same patient is often at low, intermediate, or high risk according to different methods; in this situation, the worst scenario should be taken into account when making a decision. With regard to bleeding, other scores have been proposed, such as the one that resulted from the CRUSADE study¹² and the one proposed by Mehran et al.¹³. Many guidelines on antiplatelet and anticoagulant therapy presented in this section are directly associated with the risk group in which the patient was included; this demonstrates the importance of this step in the evaluation of patients with NSTEACS.

3.2. Antiplatelet therapy in NSTEACS

There are two well-established indications for the use of double antiplatelet therapy in patients with coronary artery disease: coronary stent implant (to prevent stent thrombosis) and after ACS (to prevent the recurrence of ischemic events).

3.2.1. ASA

The importance of ASA in the treatment of NSTEACS is based on studies published since the 1980s. One of the first studies published by Cairns et al.¹⁴ in 1985 assigned groups to ASA, sulfinpyrazone [a uricosuric agent with anti-inflammatory activity via cyclooxygenase (COX) blocking], both drugs, or no drugs, in the context of unstable angina. This study included 555 patients and found a significant 51% (p = 0.008) reduction in the combined outcome of death and nonfatal acute myocardial infarction (AMI) in individuals who received ASA.

Soon after this, in 1988, a study was published that compared the use of ASA, heparin, or both in the treatment of unstable angina in 479 patients¹⁵. A significant reduction in the incidence of nonfatal AMI was observed in the groups that received ASA, both when used alone (3% vs. 12% in the placebo group, p = 0.01) and in combination with heparin (3% vs. 1.6% in the placebo group, p = 0.003); a low incidence of mortality was observed in this study, and it was not possible to identify differences between the groups. In 1993, the same group published a study comparing the use of ASA and heparin in unstable angina, with the aim of preventing the occurrence of infarction¹⁶. This study included 484 patients; there were only nine cases of infarction in the group that received ASA (244 patients) and only two cases of infarction in the group that received heparin (240 patients); the results of this study favored the isolated use of heparin over ASA (p = 0.035).

With regard to the dosage, ASA should be initially administered at a loading dose of 150-300 mg^17-19, followed by a maintenance dose of 75-100 mg/day. The CURRENT OASIS-7 study²⁰ tested the hypothesis of using a double maintenance dose of ASA in patients with ACS (approximately 71% of patients with NSTEACS). This study did not show any difference between the standard maintenance dose (75-100 mg/day) and the high dose (300-325 mg/day) in the prevention of cardiovascular events (mortality, nonfatal myocardial infarction, or stroke; p = 0.61, 95% CI 0.86-1.09); in addition, no difference was observed with regard to major bleeding (p = 0.90, 95% CI 0.84-1.17).

Furthermore, it should be noted that the use of nonsteroidal anti-inflammatory drugs (such as rofecoxib, celecoxib, ibuprofen, and diclofenac) is associated with increased risk for ischemic events (these compounds cause transient blocking of COX-1, thereby inhibiting the irreversible blocking by ASA). Therefore, their combination with ASA should be avoided²¹.

Therefore, the use of ASA in the context of NSTEACS, at the previously mentioned doses, is well established and is fundamental in this context. ASA should not be administered to patients with known allergy to the compound (a rare condition; the estimated prevalence is less than 0.5% of the population) and in cases of active bleeding in the digestive tract, particularly those related to gastric ulcers (due to the direct irritant effect of the compound associated with the antiplatelet effect on the stomach).

3.2.2. Clopidogrel

Clopidogrel, a thienopyridine derivative, inhibits the P2Y12 receptor for ADP, and it consequently inhibits the platelet aggregation process, which is mediated by this path. Clopidogrel is a pro-drug and is dependent on its first passage through the liver (and two modifications in this organ) for the formation of the active metabolite via metabolism by cytochrome P450 enzymes.

This agent was first studied in the context of NSTEACS during the CURE study²², in which the isolated use of ASA (75-325 mg/day) was compared with the combined use of ASA and clopidogrel (loading dose of 300 mg, followed by a daily maintenance dose of 75 mg), in the context of intermediate- or high-risk unstable angina and NSTEMI. This study included 12,562 patients and revealed a 20% (9.3% vs. 11.4%, p < 0.001, NNT 48) reduction in the relative risk for the combined outcome of cardiovascular death, stroke, and nonfatal acute myocardial reinfarction. This advantage was the result of the reduction in the incidence of reinfarction. With regard to safety outcomes, the group that received clopidogrel exhibited a 38% increase in the incidence of major bleeding (3.7% vs. 2.7%, p = 0.001, NND 100); however, there was no difference in the incidence of life-threatening bleeding (2.1% vs. 1.8%, p = 0.13). In this study, 43.7% of patients (5,491 patients) underwent cine coronary angiography, 16.5% (2,072 patients) underwent myocardial revascularization surgery, and 21.2% (2,658 patients) underwent PCI. Clopidogrel was used during 12 months, with a mean use time of 9 months.

Substudies of CURE revealed that adding clopidogrel to ASA remained advantageous regardless of the subsequent treatment received (clinical, percutaneous, or surgical). The PCI-CURE study²³ revealed a 30% reduction in the relative risk for the combined outcome of cardiovascular death, stroke, and nonfatal AMI (4.5% vs. 6.4%, p = 0.03, NNT 48); there was no significant difference between the groups in terms of major bleeding (p = 0.64). In the portion of the sample exclusively subjected to clinical treatment, the group that received clopidogrel exhibited a 20% reduction in the relative risk for the combined outcome of cardiovascular death, stroke, and nonfatal AMI (8.1% vs. 10%, 95% CI 0.69-0.92, NNT 53). In the group subjected to myocardial revascularization surgery, this advantage was less clear; the group that received clopidogrel exhibited a 11% reduction in the relative risk for the combined outcome of cardiovascular death, stroke, and nonfatal AMI (14.5% vs. 16.2%, 95% CI 0.71-1.11); however, this difference was not statistically significant²⁴.

Another peculiarity of this drug is how quickly it produces beneficial effects. Temporal analysis in the CURE study²⁵ demonstrated that the reduction in the combined outcome of cardiovascular death, stroke, nonfatal AMI, and refractory ischemia occurred within the first 24 h of the administration of clopidogrel combined with ASA, with a 34% decrease in the relative risk (p < 0.01); in addition, this effect lasted for at least 12 months when a stent was placed.

With regard to the dose regimen, the CURRENT OASIS-7 study²⁰ assessed 25,086 patients and tested two hypotheses the use of a double maintenance dose of ASA (results previously discussed in this document) and the use of a 600 mg loading dose of clopidogrel, followed by a dose of 150 mg/day for 7 days and 75 mg/day thereafter. This regimen was compared with the standard regimen (300 mg loading dose, followed by 75 mg/day) in patients with acute coronary disease (approximately 70% of patients with NSTEACS). This study did not show any difference between the high dose and the standard regimen in terms of preventing cardiovascular events (cardiovascular deaths, nonfatal myocardial infarction, or stroke) over 30 days (p = 0.30). With regard to major bleeding, the group that received higher doses of clopidogrel exhibited a higher incidence of major bleeding (2.5% vs. 2.0%, p = 0.01). Analysis of secondary outcomes revealed a significant reduction in the incidence of stent thrombosis (1.6% vs. 2.3%, p = 0.001) in the group subjected to PCI (17,263 patients). This subpopulation deserved a specific study²⁶, wherein a 14% reduction in the incidence of cardiovascular deaths, nonfatal myocardial infarction, or stroke was observed over 30 days (p = 0.039, NNT 167), in addition to a significant reduction in definite stent thrombosis (0.7% vs. 1.3%, p = 0.0001), owing to a higher incidence of major bleeding (1.6% vs. 1.1%, p = 0.009, NNH 200).

Another important point is the high intra- and interindividual variability in the response to this compound, which is not observed with the more modern antiplatelet drugs. These limitations can be explained by genetic variability, such as differences related to the process of liver metabolism by cytochrome P450 enzymes (polymorphisms related to CYP3A4 and mainly to CYP2C19)²⁷ and to the process of intestinal drug absorption, which is associated with the expression of P-glycoprotein (Pgp), a product of the ABCB1 gene, in intestinal epithelial cells²⁸. The routine use of genetic tests is not indicated in clinical practice because they only partially explain the poor response to clopidogrel²⁹; however, platelet aggregation tests have been increasingly used. The GRAVITAS study³⁰ assessed 2,214 patients with poor response to clopidogrel (as determined by VerifyNow^® 12-24 h after elective angioplasty with pharmacological stents) who were randomly assigned to receive a high dose of the drug (loading dose of 600 mg and maintenance dose of 150 mg/day) or standard dose, without a loading dose and with a maintenance dose of 75 mg/day (both regimens administered for 6 months). At the end of the follow-up period, no difference was observed between the two groups in terms of events (2.3% vs. 2.3%, p = 0.97). On the other hand, another study³¹ compared > 100 patients subjected to elective PCI and followed them for 1 year; the results revealed that at the end of the follow-up period, most tests significantly correlated with events; however, the predictive capacity was poor or moderate at best. Thus, the use of platelet aggregation tests to guide therapy still does not have a defined place in clinical practice, and its routine use in NSTEACS is not recommended, with the exception of cases of patients with acute coronary disease receiving appropriate treatment with ASA in combination with clopidogrel.

Furthermore, various drugs that interfere with liver metabolism mediated by cytochrome P450 enzymes affect the action of clopidogrel, such as ketoconazole (by inhibiting cytochrome P450 and reducing the action of clopidogrel) and rifampicin (by inducing cytochrome P450 and promoting the action of clopidogrel). The combined use of proton pump inhibitors (PPI) and clopidogrel, an important point in clinical practice, has not been completely clarified till date. Several in vitro studies have revealed a reduction in platelet inhibition induced by clopidogrel when used in combination with PPI, particularly omeprazole. Small clinical studies have suggested an increase in the incidence of ischemic events when this combination is used; however, only one randomized clinical study has tested this hypothesis: the COGENT study³², which assessed 3,761 patients with indication for double antiplatelet therapy for at least 12 months (one group received clopidogrel and omeprazole and another group received clopidogrel and placebo). This study was prematurely terminated for funding reasons; however, no differences were observed in the incidence of ischemic events between the patients (4.9% in the omeprazole group × 5.7% in the placebo group, p = 0.96). In addition, the placebo group exhibited a higher incidence of bleeding in the digestive tract (2.9% vs. 1.1%, p < 0.001). Thus, the use of PPI (particularly omeprazole) in combination with clopidogrel should be restricted to groups at higher risk for gastrointestinal bleeding (history of hemorrhage in the digestive tract, peptic ulcer, infection by Helicobacter pylori in individuals aged > 65 years, concomitant use of anticoagulant agents or steroids). On the other hand, H2 blockers (ranitidine, cimetidine) may be used as an alternative.

Therefore, the use of clopidogrel is indicated for individuals with NSTEACS at moderate and high risk for ischemic events; a loading dose of 300 mg and a daily maintenance dose of 75 mg should be administered. In patients at low risk for bleeding and undergoing PCI, a loading dose of 600 mg may be considered, followed by a maintenance dose of 150 mg in the first 7 days and a dose of 7-5 mg/day thereafter. The ideal time of clopidogrel use is 12 months, regardless of the subsequent treatment (clinical, percutaneous, or surgical). In case of surgical procedure, clopidogrel should be discontinued for at least 5 days before the procedure.

In patients with indication for triple antithrombotic therapy, the use of clopidogrel is recommended in addition to P2Y12 receptor blockers; the concomitant use of clopidogrel and anticoagulant agents has not yet been tested in these patients.

3.2.3. Prasugrel

Prasugrel, a new generation thienopyridine, was developed to inhibit platelet aggregation more effectively than clopidogrel, thereby minimizing its limitations. Its active metabolite is similar to the active metabolite derived from clopidogrel; however, their metabolism differs: prasugrel solely depends on one oxidation phase in the liver; the first phase occurs via plasma esterases. Consequently, the antiaggregation effect occurs faster and more consistently and is less affected by agents that act on cytochrome P450.

The TRITON-TIMI 38 study³³, published in 2007, randomly assigned 13,608 patients with ACS (who had not previously received clopidogrel and those with known coronary anatomy and planned PCI) to clopidogrel or prasugrel combined with the standard therapy (including ASA). NSTEACS accounted for 74% of the sample. In the general cohort, the group that used prasugrel exhibited a 19% (9.9% vs. 12.1%, p < 0.001) reduction in the combined outcome of cardiovascular death, nonfatal infarction, or stroke (primary efficacy outcome), mainly due to the reduction in cases of nonfatal infarction (7.3% vs. 9.5%, p < 0.001); there were no significant differences in terms of cardiovascular deaths and stroke; the results of using the AMI universal classification³⁴ revealed that the decrease in the incidence of reinfarction occurred in all five types of infarction³⁵. With regard to bleeding, the prasugrel group exhibited a 32% increase in the risk for major bleeding according to the TIMI score, which is the main safety outcome (2.4% vs. 1.8%, p = 0.03). In addition, there was a significant increase in the incidence of life-threatening bleeding (1.4% vs. 0.9%, p = 0.01). When evaluating the benefit-harm relation, a clear benefit of 13% (p = 0.004) in favor of clopidogrel was observed. Post hoc analyses identified three groups at higher risk for bleeding: individuals aged > 75 years, weighing less < 60 kg (in these two subgroups, there was no clear benefit), and with a history of stroke/TIA (in which the net benefit was significantly favorable to clopidogrel). Prespecified subanalyses revealed that prasugrel was more effective than clopidogrel in several subgroups and that there was a special benefit for diabetic patients, although a significant interaction between diabetes and the results obtained in the prasugrel and clopidogrel groups was not demonstrated³⁶.

In conclusion, after determination of the coronary anatomy, the use of prasugrel in NSTEACS is indicated in cases of intermediate- and high-risk unstable angina and NSTEMI that have been referred for PCI. Prasugrel should be administered at a loading dose of 60 mg and at a maintenance dose of 10 mg/day, and its use should be continued for 12 months. A lower maintenance dose (5 mg) can be considered for individuals weighing less than 60 kg; however, such a dose has not been prospectively tested in clinical studies. The drug should be avoided in patients aged > 75 years; if it is used, the recommended dose is 5 mg/day. The medication is contraindicated in the case of patients with a history of stroke/TIA. In case of surgical intervention, prasugrel should be discontinued for at least 7 days before the procedure.

3.2.4. Ticagrelor

Ticagrelor also inhibits the action of ADP via P2Y12 receptor blocking; however, unlike clopidogrel and prasugrel, it is not a thienopyridine; it is a cyclopentyl-triazolo-pyrimidine (CPTP). The characteristics of this chemical class are very different from those of thienopyridine drugs, e.g., the fact that it inhibits P2Y12 receptors in a reversible manner. Because this drug does not depend on primary metabolism (it is therefore not a pro-drug and its main effect is mediated by ticagrelor itself and, to a lesser extent, by an active metabolite), it inhibits platelet aggregation more rapidly, more consistently, and to a greater extent than clopidogrel. It has a relatively short half-life (approximately 12 h).

In particular, in acute coronary disease, ticagrelor was tested in the PLATO study³⁷, which randomly assigned 18,624 to ticagrelor or clopidogrel. The study design was very interesting because it included all types of acute coronary disease (with the exception of STEMI treated with a fibrinolytic drug), the possibility of using clopidogrel before patient randomization, or the possibility of using an additional dose of clopidogrel before PCI. In this study, clopidogrel or ticagrelor was administered during the initial treatment, without determining the coronary anatomy, and the patients were followed during the period of 1 year. In the sample, the prevalence of NSTEACS was approximately 60% (intermediate- and high-risk unstable angina, in addition to NSTEMI). During the intrahospital phase, 61% of individuals received percutaneous treatment, approximately 10% underwent myocardial revascularization surgery, and the remaining received only clinical treatment.

The use of ticagrelor resulted in a 16% reduction in the incidence of the primary efficacy outcome, death from vascular causes, nonfatal reinfarction, or stroke (9.8% vs. 11.7%, p < 0.001). Separate analysis of the components of the combined outcome revealed a significant reduction in the incidence of reinfarction (5.8% vs. 6.9%, p = 0.005) and cardiovascular deaths (4.0% vs. 5.1%, p < 0.001), and there were no significant differences with regard to the incidence of stroke. In addition, a significant 22% reduction in the incidence of all-cause mortality (4.5 vs. 5.9%, p < 0.001) was observed. With regard to safety outcomes, there were no significant differences in the incidence of major bleeding (according to different definitions) or need for transfusions in the overall population. Other secondary effects that exhibited a higher incidence in the ticagrelor group included dyspnea (13.8% vs. 7.8%, p < 0.001), usually transient and leading to discontinuation of the drug in 0.9% vs. 0.1% (p < 0.001); bradycardia was also usually transient did not differ between the groups in terms of clinical repercussions (pacemaker implant, syncope, or heart block). This was noted on Holter monitoring, which revealed a significant increase in the incidence of ventricular pauses of more than 3 s in the first 7 days of ticagrelor use (5.8% × 3.6%, p = 0.01) but was less significant after 30 days of drug use (2.1% vs. 1.7%, p < 0.52)³⁸. Finally, a significant increase in creatinine (10% vs. 8%) and uric acid (14% vs. 7%) levels was observed; however, there were no significant differences between the groups 1 month after the end of the treatment.

The PLATO database resulted in the publication of several analyses of prespecified subgroups of patients, such as diabetic and nondiabetic³⁹, with or without renal impairment⁴⁰, with or without previous stroke⁴¹, on or not on proton-pump blockers⁴², referred for invasive or noninvasive treatment⁴³, and undergoing myocardial revascularization surgery⁴⁴. In general, the results were very similar to those described in the original publication, in which the entire population was studied.

Therefore, the use of ticagrelor in NSTEACS is indicated in cases of moderate- or high-risk unstable angina and NSTEMI, regardless of the subsequent treatment strategy. Ticagrelor should be administered at a loading dose of 180 mg and a maintenance dose of 90 mg twice a day, and its use should be continued for 12 months. This medication can be administered in the emergency room, even without the determination of the coronary anatomy. In case of surgical intervention, ticagrelor should be discontinued 5 days before the procedure. Among other precautions (see package insert), the use of the drug should be avoided in patients with uremic nephrotic syndrome and care should be taken when administering to patients with bradycardia.

3.2.5. Glycoprotein (GP) IIb/IIIa inhibitors

The use of GP IIb/IIIa inhibitors is well established in patients with high ischemic risk (diabetic patients, patients with positive myocardial necrosis markers) subjected to PCI. This evidence mainly stems from studies in which the early invasive strategy and double oral antiplatelet treatment were not used^45-47. However, a meta-analysis with more than 20,000 patients subjected to PCI revealed a 31% decrease in mortality at 30 days of follow-up, when the drug was used⁴⁸.

No studies have compared the use of double antiplatelet therapy with ASA and GP IIb/IIIa inhibitors with that of double oral antiplatelet therapy (ASA with clopidogrel, prasugrel or ticagrelor). Recent studies have assessed the use of triple antiplatelet therapy (double antiplatelet therapy and GP IIb/IIIa inhibitors), with the aim of determining when and in which patients this therapy should be used.

The EARLY ACS study⁴⁹ evaluated 9,492 patients with NSTEACS receiving double antiplatelet therapy (ASA and clopidogrel) and randomly assigned them to additional routine use of the GP IIb/IIIa inhibitor before PCI or its use in selected cases during PCI (presence of thrombi, diffuse disease, thrombotic complications). In this study, the GP IIb/IIIa inhibitor used was eptifibatide, a synthetic cyclic heptapeptide, not commercially available in Brazil. The results of EARLY ACS revealed that the routine use of the GP IIb/IIIa inhibitor did not significantly reduce the combined outcome of death, AMI, recurrent ischemia, and thrombotic complications in PCI (9.3% in the routine group vs. 10% in the selective group, RR 0.92, p = 0.23). On the other hand, routine triple antiplatelet therapy led to a significant increase in the outcome of major hemorrhage according to the TIMI criterion (2.6% vs. 1.8%, RR 1.42, p = 0.015).

The ACUITY study assessed the best moment to use GP IIb/IIIa inhibitors. It included 9,207 patients and a 2 × 2 factorial design: in addition to evaluating three antithrombotic regimens (heparin with the GP IIb/IIIa inhibitor, bivalirudin with the GP IIb/IIIa inhibitor, or only bivalirudin), it randomly assigned patients from the GP IIb/IIIa inhibitors groups to routine use before PCI or use in selected cases during PCI. The routine use of triple antiplatelet therapy did not significantly reduce the primary combined outcome of death, AMI, and new revascularization over 30 days (7.1% vs. 7.9%, RR 1.12, p = 0.13). On the other hand, the use of GP IIb/IIIa inhibitors in selected cases resulted in a lower incidence of major hemorrhagic events (4.9% vs. 6.1%, RR 0.8, p = 0.009)⁵⁰.

Therefore, GP IIb/IIIa inhibitors should be used as a third antiplatelet agent in patients who are not at high risk for hemorrhage and who, on the other hand, are at high risk for clinical ischemia (positive necrosis markers, recurrent ischemia, ST-segment depression), only after confirmation by angiography (severe atheromatosis, presence of thrombi, and thrombotic complications of PCI).

It has been shown that when the drug is concomitantly used with the new oral antiplatelet drugs (prasugrel and ticagrelor), the benefits of the latter (see relevant chapter) occur regardless of using GP IIb/IIIa inhibitors, e.g., both the TRITON study and the PLATO study showed nonsignificant p values for the interaction with prasugrel (or ticagrelor) vs. the interaction with clopidogrel in patients also using or not using GP IIb/IIIa inhibitors^37,51.

The GP IIb/IIIa inhibitors that are commercially available in Brazil are abciximab and tirofiban. The meta-analysis published in 2010 revealed that in the studies wherein a higher loading dose of tirofiban (25 µg/kg) was used, this compound was equivalent to abciximab in terms of ischemic outcomes^52,53.

3.3. Anticoagulant therapy in NSTEACS

3.3.1. Fondaparinux

This is a synthetic pentasaccharide that selectively binds to antithrombin, indirectly causing the inhibition of factor Xa. It does not interact with many plasma components and therefore acts in a predictable manner with low individual variability. It has a half-life of 17 h and renal excretion [contraindicated in CrCl < 20 ml/min). It does not induce thrombocytopnea and does not need to be monitored.

Fondaparinux was initially evaluated in NSTEACS in the PENTUA study⁵⁴, which randomly assigned 1,138 patients to different doses of fondaparinux or enoxaparin. This phase II study concluded that the subcutaneous administration of 2.5 mg/day was safe and as effective as enoxaparin in preventing death, AMI, and recurrent ischemia.

The use of fondaparinux in the context of NSTEACS was assessed in the OASIS 5 study⁵⁵, which randomly assigned 20,078 patients to a fondaparinux group (2.5 mg subcutaneously once a day) or enoxaparin group (1 mg/kg every 12 h or every 24 h if CrCl < 30 ml/min). Fondaparinux was not inferior to enoxaparin with regard to the combined outcome of death and refractory ischemia over 9 days (RR 1.01, 95% CI 0.9-1.13, p = 0.007 for noninferiority), which was the main aim of the study. Moreover, the incidence of the main secondary outcome (death and infarction over 9 days) did not differ significantly between the groups. During the 30-day and 90-day follow-up, a significant reduction in mortality was observed (RR 0.83, p = 0.02 and RR 0.89, p = 0.05, respectively), mainly due to clinical treatment of patients, because there were no significant differences between the groups of patients subjected to PCI (RR 0.94 and 0.92 at 30 days and 180 days, respectively, p = NS).

Table 1

The results of hemorrhagic outcomes were as follows: a significant reduction in major bleeding (2.2% vs. 4.1%, RR 0.52, p < 0.001) and a significant reduction in fatal bleeding in the population using fondaparinux owing to the significant increase in the incidence of catheter thrombosis (RR 3.59, p = 0.001). On the other hand, subanalysis of the OASIS 5 study⁵⁶ revealed that a reduction in major bleeding occurred in the group treated with fondaparinux, regardless of the use of GP IIb/IIIa inhibitors or thienopyridine drugs.

A possible explanation for this reduction in hemorrhagic events is that fondaparinux has a lower anticoagulation potential than enoxaparin. This conclusion stems from the fact that anti-Xa levels in individuals treated with fondaparinux are 50% lower than those in individuals treated with enoxaparin, which explains the increase in the incidence of catheter thrombosis in patients undergoing PCI, observed in the abovementioned OASIS 5 study⁵⁷. Subananalysis including only the patients subjected to PCI (approximately 40% of the population in the OASIS 5 study) revealed that even in this subpopulation, the fondaparinux group had a significantly lower incidence of bleeding; however, there were no significant differences between the fondaparinux and enoxaparin groups in terms of the main outcome of the study (death, reinfarction, or stroke) or any of its components at 9, 30, or 180 days of follow-up⁵⁸.

The increase in the incidence of catheter thrombosis led to the modification of the protocol during the course of the OASIS 5 study, with the incorporation of a bolus of UH in the fondaparinux group. However, the ideal dose of a bolus of UH to be administered to the patients treated with fondaparinux during PCI was subsequently determined in the FUTURA OASIS 8 study. In this study, 2,026 patients initially treated with fondaparinux were randomly assigned to receive distinct doses of a bolus of UH during PCI. The patients would receive 50 IU/kg (regardless of the use of GP IIb/IIIa inhibitors) or 85 IU/kg (reduced to 60 IU/kg in the case of concomitant use with GP IIb/IIIa inhibitors). There was no significant difference between the groups in terms of the combined primary outcome of major bleeding, minor bleeding, or vascular complications. However, the net benefit in terms of major bleeding over 48 h and revascularization of the target vessel over 30 days was favorable in the group receiving a dose of 85 IU/kg (RR 1.51, p = 0.05). It should be noted that in this study, the incidence of catheter thrombosis while using the 85 IU/kg bolus was only 0.1%⁵⁹.

Therefore, the use of fondaparinux (2.5 mg subcutaneously once a day) has been proven to be a similarly effective alternative; however, its safety profile is better than that of enoxaparin in patients with NSTEACS, and the concomitant use of a bolus of UH in patients undergoing PCI is mandatory.

3.3.2. Unfractionated heparin (UH)

UH is a heterogeneous mixture of polysaccharide molecules (mean molecular weight between 15,000 and 18,000 Da). In general, only one-third of the molecules found in a solution of heparin have the necessary pentasaccharide sequence to bind to antithrombin and establish anticoagulant activity.

A study by Théroux et al.¹⁵ compared the isolated use of ASA or UH with the combined use of the two drugs or the use of a placebo. This was a randomized and double-blind study with 479 patients with unstable angina who were evaluated for the occurrence of refractory angina, AMI, or death. Compared with the placebo group, the isolated use of ASA and UH led to a significant reduction in the occurrence of IAM, with UH showing better results. Moreover, there was a marked reduction in the occurrence of recurrent angina in the group treated with UH. In this study, the combined use of ASA and UH did not confer additional protection against the risk for ischemic events and was associated with a slight increase in the risk for bleeding.

The ATACS study^19,60, published in 1994, randomly assigned 214 patients with unstable angina or NSTEMI to UH in addition to ASA or no therapy. A significant reduction in the occurrence of ischemic events was observed at 14 days of follow-up in the patients who received the combination of ASA and UH (10.5% vs. 27%, p = 0.004); however, this difference was not statistically significant in the 12-week evaluation (19% vs. 28%, p = 0.09). In addition, there was a slight increase in the incidence of bleeding in the group that received UH.

Analysis of the most relevant clinical studies comparing the benefits of UH and ASA in patients with unstable angina and NSTEMI revealed a significant reduction in the risk for AMI or death in the patients who received combined therapy (ASA) and UH compared with that in the patients who received only ASA (RR 0.44, 95% CI 0.21-0.93)⁶¹.

With the advent of LMWH, several studies were conducted to compare the efficacy of UH with that of the new drugs in reducing the risk for ischemic events, associated with better results in terms of bleeding risk-related safety. In a meta-analysis published in 2000, involving 17,157 patients with NSTEACS included in 12 clinical studies, there was no significant difference in the occurrence of death or AMI between therapy with LMWH or UH (RR 0.88, p = 0.34). On the other hand, both were highly effective in reducing the risk for AMI or death in comparison with the placebo or untreated controls (RR 0.53, p = 0.0001)⁶².

3.3.3. Low-molecular-weight heparin (LMWH)

LMWH is a heterogeneous group of compounds derived from heparin, and its molecular weights vary between 2,000 and 10,000 Da. This group of compounds exhibits some very important advantages over UH⁶¹; these include convenient dosage and administration route (i.e., intermittent use and subcutaneous administration); no need to monitor the anticoagulant effect, with the exception of special situations (such as obesity and renal failure) wherein anti-Xa activity should be monitored whenever possible (therapeutic target between 0.6 and 1.0 IU/ml)⁶³; almost complete absorption via the subcutaneous route; lower binding to proteins; lower platelet activation; and, most importantly, a more predictable dose-effect relation.

Compared with the use of UH, there was a nonsignificant 12% reduction in the occurrence of death or AMI during the initial phase of LMWH use. On the other hand, the main representative of LMWH is enoxaparin, and it is the most used in clinical practice. Enoxaparin was compared with UH in the context of NSTEACS in several studies. The ESSENCE and TIMI 11B studies showed, for the first time, the superiority of LMWH over UH⁶⁴. However, because these studies were conducted at a time when the invasive strategy was not used and certain antithrombotic agents (such as GP IIb/IIIa inhibitors) still did not exist, further studies on the subject were required, and the SYNERGY study was therefore conducted⁶⁵. This study randomly assigned 10,027 high-risk NSTEACS patients, allocated to early invasive strategy, to receive enoxaparin or UH. The primary aim of the study was to analyze the combined outcome of all-cause death or myocardial infarction in the first 30 days after randomization. Of the total sample, 92% of the patients were underwent cine coronary angiography, 47% underwent percutaneous revascularization, and 19% underwent surgical revascularization, distributed equally between the enoxaparin or UH groups. With regard to the primary outcome, there was no difference between the LMWH and UH groups (14% vs. 14.5%, p = 0.4). A similar result was observed at 48 h and at 14 days (p = 0.10 and 0.38, respectively). With regard to safety outcomes, the enoxaparin group exhibited a higher incidence of major bleeding according to the TIMI score (p = 0.008); however, no significant difference was observed according to the GUSTO score (p = 0.08) or when the number of transfusions was used as parameter (p = 0.15). In the population subjected to PCI, the incidence of any unsuccessful PCI, threat of acute occlusion, acute occlusion, and emergency myocardial revascularization surgery was similar between the groups. This study showed very relevant results regarding the crossover of heparin during the treatment of these patients. Of the total population, approximately 6,000 patients used only one heparin during hospitalization, and in this population receiving a "consistent therapy," post hoc analysis revealed a significant reduction in the incidence of the primary outcome of death or AMI over 30 days of evolution with the use of LMWH (12.8% vs. 15.6%, RR 0.81, p = 0.003).

A meta-analysis that included approximately 22,000 patients with NSTEACS treated with enoxaparin or UH⁶⁶ revealed the following: a significant reduction in the combined outcome of death and myocardial infarction over 30 days in the enoxaparin group (RR 0.91, 95% CI 0.83-0.99) and nonsignificant differences in the incidence of major bleeding (RR 1.04, CI 0.83-1.30) or need for transfusions (RR 1.01, 95% CI 0.89-1.14); in the subpopulation without heparin therapy before randomization, the benefits of enoxaparin with regard to death or AMI were amplified when compared with UH (HR 0.81; 95% 95% CI 0.70-0.94).

The recommended dose of enoxaparin to be used is 1 mg/kg every 12 h; this dose should be adjusted to 1 mg/kg once a day in case of renal failure with CrCl < 30 ml/min and to 0.75 mg every 12 h in elderly patients aged > 75 years. If a percutaneous procedure (angioplasty) is performed within 8 h of the last dose of enoxaparin, there is no need for an additional dose of enoxaparin; if the angioplasty is performed more than 8 h after the last dose of enoxaparin, an additional dose of 0.3 mg/kg should be intravenously administered. The concomitant use of enoxaparin and UH during hospitalization should be avoided⁶⁷.

Therefore, LMWH should be used in patients with high- and intermediate-risk NSTEACS in addition to NSTEMI, at the described doses, until PCI or myocardial revascularization surgery is performed; in case of clinical treatment, it should be used for 8 days or until the patient is discharged; its use for a longer period than this is associated with increased risk for bleeding without significant reduction in ischemic events^68,69.

3.3.4. New anticoagulant agents

Phase III studies have analyzed two oral Xa factor inhibitors (apixaban and rivaroxaban) combined with double antiplatelet therapy in the context of acute coronary disease. The APRAISE-2 study randomly assigned 7,392 patients to apixaban (5 mg every 12 h) or placebo, 6 days (on average) after the onset of symptoms compatible with ACS. The study was prematurely terminated owing to a significant increase in major bleeding according to the TIMI criterion (HR 2.59, p = 0.001), without the observation of significant benefits in terms of ischemic events⁷⁰. The dose of apixaban used was the same as that tested in the context of atrial fibrillation (AF), which would explain the excessive severe bleeding.

The use of rivaroxaban in a similar population (4.7 days on average after an acute ischemic event) was assessed in the ATLAS ACS 2 study⁷¹, in which > 15,000 patients were randomly assigned to three groups: rivaroxaban 2.5 mg every 12 h, rivaroxaban 5 mg every 12 h, and placebo (both doses were much lower than those tested in the context of AF). The 2.5 mg dose resulted in better results, with a relative 16% reduction in the primary goal of the study, the combined outcome of cardiovascular death, AMI , and stroke (p = 0.007), at the end of a 2-year follow-up; moreover, there was a significant reduction in cardiovascular death (HR 0.66, p = 0.005) and all-cause death (HR 0.68, p = 0.004). With regard to safety, the rivaroxaban group exhibited a significant increase in the incidence of nonsurgery-related bleeding (HR 3.46, p < 0.001), as expected; however, there was no significant increase in the incidence of fatal bleeding (p = 0.45).

With regard to thrombin inhibitors, the concomitant use of dabigratan and double antiplatelet therapy was evaluated after ACS in the REDEEM study⁷². In this study, there was a marked increase in the incidence of bleeding at the different doses tested (50, 75, 110, and 150 mg).

Table 2

4. Use of antiplatelet and anticoagulant agents in stroke and transient ischemic attack (TIA)

4.1. Introduction

Stroke is the second main cause of morbidity and mortality in Brazil. Data from the DATASUS of 2010 revealed that stroke accounted for deaths in 99,732 patients (http://tabnet.datasus.gov.br/cgi/tabcgi.e.,xe?sim/cnv/obt10uf.def)¹; the leading cause is ischemic heart disease. In addition, it is essential to recognize TIA because it is a strong predictor of stroke.

Furthermore, it should be noted that of the patients who survived the first event, many will have recurrent stroke. Therefore, the secondary prevention of new events is fundamental.

This section aims to evaluate the use of antiplatelet and anticoagulant drugs in the secondary prevention of noncardioembolic stroke (described in section 5, "Use of antiplatelet and anticoagulant agents in atrial fibrillation"), particularly cases of atherosclerotic origin.

4.2. Antiplatelet therapy in stroke

The main mechanisms involved in the pathophysiology of stroke are arterial thrombosis, particularly related to atherosclerotic disease, and cardioembolic events, which confirms that platelet aggregation plays an important role in the development of stroke. Thus, the use of medications that act by blocking platelet aggregation reduces the rate of vascular events (including new stroke, acute myocardial infarction, and death).

Most studies involving antiplatelet agents in the secondary prevention of stroke analyze combined cardiovascular events; this prevents an effective determination of the rate of stroke recurrence.

Next, we describe the existing evidence in favor of prescribing antiplatelet agents for the secondary prevention of stroke /TIA after the acute 48-h phase.

4.2.1. ASA

The use of ASA is the standard secondary prevention against stroke and TIA. A meta-analysis published in 1999² assessed the efficacy of ASA in the prevention of new cerebrovascular events. In total, 11 studies were included in the analysis (with a total of over 9,500 patients), wherein ASA was compared with a placebo with regard to the prevention of de novo stroke in patients who had already suffered a previous episode of ischemic stroke/TIA. The results of this meta-analysis revealed that there was an approximately 15% reduction in the occurrence of de novo cerebrovascular events with the use of ASA and the difference was statistically significant. An important aspect of this study was the observation that the reduction in risk did not depend on higher doses of ASA, which suggests that even lower doses are effective in secondary prevention. Another factor to be taken into account is that higher doses of ASA are associated with a higher number of hemorrhagic events, particularly in the gastrointestinal tract. Therefore, the use of ASA at low doses (e.g., 100 mg) seems to be effective in the secondary prevention of stroke/TIA, with less adverse effects.

4.2.2. ASA in combination with dipiridamol

The effectiveness of dipiridamol compared with that of ASA in the secondary prevention of ischemic stroke was evaluated in four major clinical trials. Among these, the ESPS-2 study³ randomly assigned more than 6,000 patients who had ischemic stroke or TIA to ASA (25 mg twice a day), sustained-release dipiridamol (200 mg twice a day), ASA in addition to sustained-release dipiridamol (25/200 mg twice a day), or placebo. The primary outcomes assessed were stroke and death. The group that received the combined therapy exhibited a 23.1% and 24.7% reduction in the relative risk for ischemic stroke and TIA, respectively, compared with the groups that received ASA and dipiridamol alone, and the difference was statistically significant. However, the dose of ASA used in this study was low. With regard to adverse effects, the incidence of bleeding was higher in patients who used ASA, both in the ASA group and in the group receiving ASA and dipiridamol. The patients who used dipiridamol experienced more headaches and gastrointestinal symptoms, particularly diarrhea.

The ESPRIT study⁴ randomly assigned more than 2,500 patients with stroke or TIA to ASA (the dose varied between 30 and 325 mg/day and the average dose was 75 mg/day) or ASA combined with sustained-release dipiridamol (the dose of dipiridamol was 200 mg twice a day). The primary outcome assessed was a combination of acute myocardial infarction (AMI), stroke, and death from cardiovascular causes or bleeding. These events occurred in 13% of patients under double therapy and in 16% of patients in the group under monotherapy. However, an intriguing fact observed in this study was that there was a higher occurrence of hemorrhagic events in the patients receiving only ASA than in those receiving double therapy. Therefore, ASA combined with sustained-release dipiridamol (200 mg twice a day) is an interesting option for secondary prevention in patients with ischemic stroke or TIA. However, this form of dipiridamol is still not available in Brazil.

In general, the studies showed that dipiridamol combined with ASA was as effective as ASA alone, although the patients less tolerated it.

4.2.4. Ticlopidine

The CATS study⁵ involved more than 1,000 patients who had stroke; they were randomly assigned to ticlopidine (250 mg twice a day) or placebo to determine the reduction in de novo stroke, AMI, or death from vascular causes. Compared with the placebo group, the ticlopidine group (assessed by intention to treat) exhibited a 23.3% reduction in the relative risk for events, and the difference was statistically significant. The most common adverse effects related to the use of ticlopidine were neutropenia, skin rash, and diarrhea (all were reversible after drug discontinuation).

The TASS study⁶ randomly assigned more than 3,000 patients who had stroke or TIA to ticlopidine (250 mg twice a day) or ASA (625 mg twice a day). The primary outcome assessed was de novo stroke or all-cause mortality. There was a 12% reduction in the relative risk as a result of using ticlopidine. However, the incidence of side effects when ticlopidine was used (similar to the CATS study) was higher than when ASA was used.

The AAASPS study⁷ selected almost 2,000 African-American patients who recently had a stroke. The patients were randomly assigned to ticlopidine (250 mg twice a day) or ASA (325 mg twice a day). The outcomes assessed were de novo stroke, AMI, or death from cardiovascular causes. The incidence of stroke and TIA in the ticlopidine group was 14.7% and 12.3% in the ASA group; however, the difference was not statistically significant. The side effects of using ticlopidine were similar to those observed in the previous studies.

Considering that the number of severe adverse events observed with the use of ticlopidine is higher than that observed with the use of a similar drug, clopidogrel, the use of ticlopidine has no longer been considered as an alternative to ASA.

4.2.5. Clopidogrel

No studies have compared clopidogrel with a placebo in the secondary prevention of stroke.

The CAPRIE study⁸ involved more than 19,000 patients with manifest atherosclerotic disease (ischemic stroke, acute myocardial infarction [AMI], and symptomatic peripheral vascular disease). The patients were randomly assigned to ASA (325 mg/day) or clopidogrel (75 mg/day). The primary outcome was a combination of ischemic stroke, AMI, intracranial hemorrhage, leg amputation, and death. There was a relative 8.7% reduction in risk for events with the use of clopidogrel. If we only consider patients with ischemic stroke, there was a relative 7.3% reduction in the risk for events with the use of clopidogrel; however, the difference was not statistically significant. It should be noted that this study was not designed to assess events only in patients with previous ischemic stroke.

The PRoFESS study⁹ randomly assigned more than 20,000 patients with a history of stroke to clopidogrel (75 mg/day) or ASA in addition to sustained-release dipiridamol (25/200 mg twice a day). The primary outcome assessed was recurrent stroke. The rate of primary events in the patients who received clopidogrel was 8.8%, whereas that in the patients who received ASA in combination with sustained-release dipiridamol was 9.0%. This was a noninferiority study; however, the treatment regimens were found to be equivalent. Moreover, the number of hemorrhagic events was higher in the patients who received ASA in combination with sustained-release dipiridamol than in those who received clopidogrel.

4.2.6. ASA plus clopidogrel

The MATCH study¹⁰ selected more than 7,500 patients who were using clopidogrel and had stroke or TIA to receive ASA (75 mg/day) or a placebo. The primary outcome assessed was stroke, AMI, death from vascular causes, or rehospitalization for acute ischemia. There was a 9.5% reduction in the relative risk for events in the patients who received clopidogrel in addition to ASA; however, the difference was not statistically significant. The group that received the combined therapy exhibited more hemorrhagic events.

The CHARISMA study¹¹ randomly assigned more than 15,000 patients with manifest atherosclerotic disease or with multiple risk factors to ASA combined with placebo or ASA combined with clopidogrel for determining whether the association of antiplatelet agents was more effective in reducing AMI, stroke, or death from cardiovascular causes than the use of ASA alone. The results demonstrated a reduction in the risk for events with the use of the antiplatelet drug combination; however, the difference was not statistically significant. The combination of ASA with clopidogrel increased the rate of bleeding. In subgroup analysis that included only the patients with manifest atherosclerotic disease (excluding the patients who only exhibited risk factors for atherosclerotic disease), a statistically significant reduction in the primary outcome was observed. However, analysis that only included the poststroke patients did not reveal a statistically significant reduction in primary outcomes with the combination of ASA and clopidogrel.

The FASTER study¹² aimed to assess the potential benefits of adding clopidogrel to ASA in terms of reducing the primary outcome (stroke, TIA, AMI, or all-cause mortality). However, the recruitment of patients failed and the study was prematurely terminated. The results of this study suggest that the combination of ASA (a loading dose of 162 mg, followed by a maintenance dose of 81 mg/day) and clopidogrel (a loading dose of 300 mg, followed by a maintenance dose of 75 mg/day) was not effective in reducing events and increased the bleeding rate.

4.2.7. Cilostazol

A Chinese pilot study (CASISP)¹³ randomly assigned 720 postischemic patients to ASA or cilostazol; the dose used in each group of patients was not indicated. The primary outcome assessed was the recurrence of ischemic and hemorrhagic stroke. A 38% reduction in the relative risk for events was observed in the group that received cilostazol, and the event curves began to diverge 6 months after the use of medication. However, there was no statistically significant difference. Headaches, tachycardia, palpitations, and dizziness were the most common side effects among the patients who used cilostazol.

In the Japanese CSPS-2 study¹⁴ (a noninferiority study), more than 2,500 postischemic stroke patients were randomly assigned to ASA (81 mg/day) or cilostazol (100 mg twice a day). The primary outcomes assessed were similar to those assessed in the CASISP study. Cilostazol reduced the likelihood of primary events in 25% patients and was thus not lesser effective than ASA in preventing postischemic stroke events. Another advantage of using cilostazol was the lower incidence of hemorrhagic events. However, it should be noted that patients in the ASA group used more antidiabetic, antihypertensive, and lipid-lowering medications, which confirmed the higher severity of the disease in this group. The adverse effects of using cilostazol were similar to those observed in the CASISP study.

4.2.8. Glycoprotein (GP) IIb/IIIa inhibitors

Abciximab was tested in a phase II study in postacute ischemic stroke patients and was shown to be safe if administered within 24 h after the event¹⁵.

On the other hand, the AbESTT-II study16, a multicenter phase III study with a higher number of patients, did not show abciximab to be safe or effective in patients with ischemic stroke. The study was prematurely terminated owing to the higher incidence of bleeding in the group that received abciximab.

4.3. Anticoagulant therapy in stroke

Arterial thromboembolism is an important mechanism in the pathophysiology of ischemic stroke. In general, multicenter studies have not demonstrated that anticoagulant agents are beneficial in the secondary prevention of noncardioembolic ischemic stroke.

Next, we describe these studies and address the use of heparin after acute stroke.

4.3.1. Warfarin

The SPIRIT study¹⁷ randomly assigned more than 1,700 poststroke or TIA patients to ASA 300 mg/day or warfarin (target INR [international normalization ratio] between 3.0 and 4.5). The primary outcome assessed was a combination of death from cardiovascular causes, stroke, AMI, or major hemorrhagic complications. This study was prematurely terminated owing to the statistically higher incidence of events in the group that received warfarin (RR 2.3). The occurrence of events was most influenced by hemorrhagic complications, including those that led to death. Therefore, the use of warfarin to keep INR between 3.0 and 4.5 is not safe in patients with ischemic stroke or TIA.

The WARSS study¹⁸ involved more than 2,200 postischemic stroke patients who were randomly assigned to ASA (325 mg/day) or warfarin (target INR between 1.4 and 2.8). The primary outcomes assessed were all-cause mortality and recurrent ischemic stroke. The group that received warfarin exhibited a 1.13-fold higher risk for primary events than the group that received ASA, without a statistically significant difference. The risk for major bleeding was 1.48-fold higher in the warfarin group, without a statistically significant difference.

The ESPRIT study³ randomly assigned postischemic stroke or TIA patients to warfarin (target INR between 2.0 and 3.0) or ASA (doses varying between 30 and 325 mg/day). The primary outcome assessed was similar to that evaluated in the SPIRIT study. Furthermore, post hoc analysis was performed to compare the use of warfarin with the combination of ASA and sustained-release dipiridamol (200 mg twice a day); the same outcome was assessed in both the cases. The incidence of events was 19% in the warfarin group and 18% in the ASA group, without a statistically significant difference. Considering only ischemic events, there was a 27% reduction in the relative risk for events with the use of warfarin; however, the difference was not statistically significant. The risk for major bleeding was 2.56-fold higher in the group that received warfarin; the difference was statistically significant. It is important to note that in post hoc analysis, the risk for primary events was 1.31-fold higher in the warfarin group than in the group using the combination of ASA with sustained-release dipiridamol, although there was no statistically significant difference.

The chronic use of oral anticoagulant drugs is recommended in some specific clinical conditions, such as stroke due to cerebral artery dissection, acquired thrombophilia, and antiphospholipid antibody syndrome, according to indirect evidence from clinical trial subgroups, series of cases, and the opinion of specialists. It is not within the scope of this review to address these conditions.

4.3.2. Unfractionated heparin (UH)

The number of studies on the use of UH in the acute phase of stroke is small.

A single-center study¹⁹ randomly assigned more than 400 patients in the first 3 h after lacunar ischemic stroke to endovenous UH (target aPTT between 2.0 and 2.5) or saline solution. The primary outcome assessed was the autonomy in daily activities 90 days after the acute event. The safety outcomes were death, symptomatic intracranial hemorrhage, and other major bleeding. After 90 days, the percentage of patients who received heparin with primary outcome was 38.9% and that of patients who received saline solution was 28.6%; the difference was statistically significant. However, symptomatic intracranial hemorrhage occurred in 6.2% of patients in the treatment group and 1.4% of patients in the control group; the difference was also statistically significant.

Table 1

A meta-analysis²⁰ assessed the use of anticoagulant drugs (including heparin and oral anticoagulant agents) in acute ischemic stroke. The results showed that the use of anticoagulant drugs did not reduce mortality or improve the patients' autonomy.

4.3.3. Low-molecular-weight heparin (LMWH)

A study conducted in Hong Kong²¹ randomly assigned approximately 300 patients within 48 h after acute stroke to receive nadroparin at high doses (4,000 IU twice a day), nadroparin at low doses (4,000 IU once a day), or a placebo for 10 days. The primary outcome assessed was death or autonomy in daily activities. At 3 months of follow-up, no difference was observed between the groups. However, in 6-month analysis, the percentages of patients with the primary outcome were as follows: 45% in the group that received high-dose nadroparin, 52% in the group that received low-dose nadroparin, and 65% in the placebo group, without any increase in hemorrhagic transformation. It is important to note that this study included patients with cardioembolic stroke.

Another study²² on nadroparin did not show any advantages of using this medication and demonstrated that higher doses are associated with higher bleeding rates.

It should be noted that the use of any antiplatelet or anticoagulant drug is contraindicated within 24 h after intravenous thrombolytic treatment of ischemic stroke with alteplase²³.

4.3.4. Anticoagulation following a hemorrhagic cerebral event

Deciding the best time to return to full anticoagulation therapy after a hemorrhagic cerebral event in previously anticoagulated patients is a great challenge. The evaluation of the risk for thrombotic events and new hemorrhagic events is important. Therefore, some factors must be taken into account in this assessment: the motive for which the patient is anticoagulated, age, presence of systemic arterial hypertension, level of anticoagulation, presence of small bleeding areas on magnetic resonance, dialysis, and presence of lobar hemorrhage.

A study²⁴ assessed more than 230 patients who presented acute cerebral hemorrhage and used anticoagulant drugs. Of these patients, 177 survived the first week. Only 33% of patients restarted anticoagulation therapy after the hemorrhagic event. Recurrence of hemorrhagic events occurred in eight patients who restarted anticoagulant therapy and in 10 patients who did not receive anticoagulant therapy. The risk for embolic events was higher in the group that was not anticoagulated. After a statistical model was applied, the authors determined that the ideal time to restart anticoagulation therapy was between 10 and 30 weeks after the event.

In another study²⁵, in which more than 700 patients were followed after intracranial hemorrhage, Hanger et al. observed that the risk for a new hemorrhagic event was 2.1% in the first year of follow-up and the risk for ischemic stroke was 1.3%.

Overall, it is important to note that if there is a need to start the patient on anticoagulant therapy, the administration of UH using a continuous infusion pump should be preferred because titration and reversal are easier with this medication²⁶.

Table 2

5. Use of antiplatelet and anticoagulant agents in atrial fibrillation (AF)

5.1. Introduction

AF is the most common form of sustained arrhythmia in clinical practice. Its incidence and prevalence increase as the population ages, doubling every decade of life after 50 years of age. AF is associated with an increase in the risk for stroke, heart failure and overall mortality^1-6.

Stroke is the third cause of death in developed countries and the main cause of severe long-term incapacity; it has a negative impact on treatment costs. At least one in every five strokes is caused by AF^5,7-10. In addition, stroke secondary to a thromboembolic event in a patient with AF is usually more severe and disabling than ischemic stroke^9,10. Furthermore, it is important to highlight the increased risk for cognitive disorders in the population with AF. Small observational studies have shown that asymptomatic embolic events can contribute to cognitive deficit in patients with AF in the absence of clinically diagnosed stroke¹¹.

This document focuses on the update of antithrombotic therapy in AF in view of the main advances in risk stratification in the prevention of thromboembolic phenomena and the incorporation of new antithrombotic therapies, such as dabigatran, rivaroxaban, and apixaban.

5.2. Application of thromboembolic risk scores in patients with AF

The main AF treatment strategies include the improvement of symptoms (via rhythm or heart rate control) and prevention of thromboembolic phenomena. However, AF can be silent in the preclinical and clinical phases or after invasive interventions. In the presence of risk factors, the prevention of thromboembolic phenomena is considered most important for the treatment of AF, regardless of the adopted strategy (rhythm or heart rate control)^12,13. In addition, the paroxysmal form of AF exhibits the same risk for stroke as the persistent and permanent forms.

The risk for thromboembolic phenomena can be determined using the CHADS₂ score^14-16 as well as the recent CHA₂DS₂-VASc score¹⁷ (Chart 1 and Table 1). This new score resulted in a "real" separation between uncertain low risk and certain low risk. Moreover, several patients previously classified as being at intermediate risk according to the old score were now part of high-risk groups according to the new risk score, with a clinical impact (less thromboembolic events). New risk factors were incorporated in the score, such as female gender, presence of arterial vascular disease (such as coronary artery disease, peripheral vascular disease, or plaque in the aorta), and intermediate age (between 65 and 74 years). Age > 75 years now correspond to a score of 2 points because of the high risk associated with this factor. Thus, the CHA₂DS₂-VASc score is a refinement of the CHADS₂ score, when the latter is 0 or 1. Because the CHA₂DS₂-VASc score automatically includes the risk factors of the old CHADS₂ score, it is simpler and more accurate to assess the risk thromboembolic phenomena in AF using the CHA₂DS₂-VASc score. CHA₂DS₂-VASc scores above 1 indicate anticoagulant therapy (Table 2).

The customary indications for anticoagulation, based on the CHA₂DS₂-VASc score, are shown in Tables 2 and 3.

5.3. Risk for hemorrhagic phenomena during oral anticoagulation therapy

Strong evidence indicates a beneficial action of chronic oral anticoagulation (COA) therapy in patients at risk. On the other hand, this therapy is associated with hemorrhagic complications^18-22, one of the most feared complications being intracranial hemorrhage, which is almost always related to levels of INR above the therapeutic range (INR > 3.5-4.0). Because the therapeutic range of INR is very narrow, several scores have been developed to assess the hemorrhagic risk; the HAS-BLED risk score [Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly (> 65 years), Drugs/Alcohol Concomitantly]²³ is the most used in patients with AF. If the score is > 3, COA should be administered very carefully and all efforts should be made to control the risk factors, such as arterial hypertension and alcohol consumption.

5.4. Use of new anticoagulant agents in patients with AF

5.4.1. Results from large studies

Warfarin, at adjusted doses, is highly effective in the prevention of thromboembolic phenomena in AF by reducing this risk by 64% in adequately treated patients^24-26. Despite this success, 50% of patients who are supposed to be treated are not indeed, owing to several reasons that include the need for frequent evaluation of the anticoagulation rate (periodical INR monitoring) and hemorrhagic risk^24,25. On the other hand, patients treated with this medication are not always within the appropriate therapeutic range. This is because of the irregular use of the medication, the interaction between warfarin and foods (particularly "greens") and other medications such as antibiotics and anti-inflammatory drugs. The likelihood of anticoagulation being outside the therapeutic range is particularly noteworthy in the elderly, who usually take other drugs for the treatment of associated conditions. Furthermore, there is the possibility of resistance to the drug owing to individual genetic characteristics. Thus, although anticoagulant therapy is highly effective, it has some disadvantages and does not benefit the population that needs it the most.

In recent years, the discovery of thrombin or factor Xa inhibitor drugs has brought a new perspective on anticoagulant therapy²⁷. These drugs do not require anticoagulation monitoring (INR) and have little interaction with medications and foods. Owing to these characteristics as well as their high efficacy and safety, these new drugs have the potential to increase adherence to treatment with COA as well as the number of treated patients. Three new generation anticoagulant drugs had a phase III clinical trial approval: dabigatran, rivaroxaban, and apixaban. Dabigatran is a direct thrombin competitive inhibitor and the remaining are factor Xa inhibitors.

Dabigatran was compared to warfarin in the prevention of systemic thromboembolism (STE) in a study involving approximately 18,000 patients with paroxysmal or permanent AF. Patients were aged > 75 years; in the latter case, patients had more than one associated risk factor such as heart failure, diabetes, arterial hypertension, or a previous history of stroke. Patients were randomly assigned to warfarin at doses adjusted according to INR or fixed doses of dabigatran (110 mg and 150 mg twice a day). This was an open study, based on intention to treat analysis, with a maximum follow-up period of 3 years. The mean CHADS₂ risk score of the assessed population was 2.3, and the time in therapeutic range for patients who used warfarin was 64%. The RE-LY study used the criterion of noninferiority of the new anticoagulant agent relative to warfarin, i.e., the criterion that the efficacy and safety of the new agent are at least equal to those of warfarin^28,29.

In the RE-LY study, the annual rate of stroke or systemic embolism was 1.71% for warfarin, 1.54% for the 110 mg dose of dabigatran (RR 0.90; 95% CI 0.74-1.10), and 1.11% for the 150 mg dose of dabigatran (RR 0.65; 95% CI 0.52-0.81). Hemorrhagic stroke rate was lower with the use of both doses of dabigatran [150 mg (0.10%) and 110 mg (0.12%)] than with the use of warfarin (0.38%) (p < 0.001 for both doses). Major bleeding rate was 3.57% with the use of warfarin, 2.8% with the use of 110 mg of dabigatran (p = 0.003), and 3.22% with the use of 150 mg of dabigatran (p = 0.31).

Regarding to side effects, there was a higher rate of dyspepsia in the group that received dabigatran and a slight increase in the risk for gastrointestinal bleeding at a dose of 150 mg. A higher numeric risk for myocardial infarction was observed in patients receiving dabigatran (0.82% and 0.81% for 110 mg and 150 mg, respectively) than in those receiving warfarin (0.64%/year; p = 0.09 and 0.12, respectively), but with no statistical significance.

These findings revealed that dabigatran was safe and effective in preventing TE in patients with AF. The 150 mg dose of dabigatran was superior to warfarin (with similar bleeding rate), while the 110 mg dose of dabigatran had a similar efficacy and lower bleeding rate.

The ROCKET-AF study³⁰ compared rivaroxaban with warfarin in the prevention of TE in 14,264 patients with nonvalvular AF and with risk factors for thromboembolism (mean CHADS₂ = 3.47). A 20 mg fixed dose of rivaroxaban once a day (dose of 15 mg for patients with renal clearance between 30 and 49 ml/min) was compared with warfarin in a double-blind manner using the criterion of noninferiority In a per protocol analysis, the annual rate of stroke was 1.7% for rivaroxaban and 2.2% for warfarin [the relative risk (RR) in the rivaroxaban group was 0.79; 95% CI 0.66-0.96, p < 0.001 for noninferiority]. Based on the intention to treat analysis, thromboembolic events occurred in 2.1% (per year) of patients who received rivaroxaban and in 2.4% of patients who received warfarin (RR 0.88, 95% CI 0.74-1.03, p < 0.001 for noninferiority; p = 0.12 for superiority). The rates of major and clinically nonmajor bleeding were similar in both groups (14.9% vs. 14.5%, RR 1.03, 95% CI 0.96-1.11, p = 0.44); however, the rates of hemorrhagic stroke were lower with rivaroxaban than with warfarin (0.5% vs. 0.7%, p = 0.02) and the same trend was observed in fatal bleeding rates (0.2% with rivaroxaban and 0.5% with warfarin, p = 0003).

Regarding to secondary prevention, a recent presentation confirmed the noninferiority of rivaroxaban relative to warfarin. In a prospective evaluation of 7,468 patients with a previous history of stroke/TIA (CHADS2 score of 3.93), the rate of stroke recurrence was 13% lower in the group that received rivaroxaban than in the group that received warfarin (2.26% in the rivaroxaban group and 2.60% in the warfarin group; RR 0.87, 95% CI 0.69-1.10)³¹.

Apixaban was assessed in two large studies. The double-blind AVERROES study³² compared apixaban (at a dose of 5 mg twice a day) with aspirin in 5,599 patients with AF and at risk for stroke, who, for some reason, could not use warfarin³². The study was prematurely stopped because there was a clear reduction in TE and stroke with the use of apixaban (1.6% for apixaban and 3.7% for aspirin, RR 0.45, 95% CI 0.32-0.62), with similar rates of major hemorrhage (1.4% for apixaban and 1.2% for aspirin, RR 1.13, 95% CI 0.74-1.75). Death rate was 3.5% in the apixaban group and 4.4% in the aspirin group (RR 0.79, 95% CI 0.62-1.02, p < 0.07).

The ARISTOTLE study^33,34 compared apixaban at a dose of 5 mg twice a day with warfarin (INR between 2 and 3) in a double-blind manner using the criterion of noninferiority in 18,201 patients with AF and with at least one additional risk factor for stroke. In a 1.8-year follow-up, the annual rate of primary events was 1.27% in the apixaban group and 1.60% in the warfarin group (RR with apixaban 0.79, 95% CI 0.66-0.95, p < 0.001 for noninferiority; p < 0.01 for superiority). Major bleeding rate was 2.13% in the apixaban group and 3.09% in the warfarin group (RR 0.69, 95% CI 0.60-0.80, p < 0.001). The annual rate of all-cause mortality was 3.52% for apixaban and 3.94% for warfarin (RR 0.89, 95% CI 0.80-0.99, p = 0.047). Hemorrhagic stroke rate was 0.24% in the apixaban group and 0.47% in the warfarin group (RR 0.51, 95% CI 0.35-0.75, p < 0.001). The annual rate of ischemic stroke or stroke of undetermined cause was 0.97% in the apixaban group and 1.05% in the warfarin group (RR 0.92, 95% CI 0.74-1.13, p = 0.42). Therefore, apixaban was superior to warfarin in reducing stroke and TE and exhibited a lower risk for hemorrhage and mortality³⁴.

5.5. Considerations on electrical cardioversion with the new oral anticoagulant agents

The use of new oral anticoagulant drugs for the prevention of thromboembolic phenomena in patients with AF leads us to an important topic regarding the strategy to be used in case these patients need to undergo electrical cardioversion. Data are still scarce in the literature; however, subgroup analysis resulting from the RE-LY study revealed that cardioversion could be performed without major risk for thromboembolic phenomena, provided the patients were on chronic dabigatran therapy³⁵. Data on rivaroxaban and apixaban are still not available.

5.6. Recommendations on the use of the new oral anticoagulant agents

The results of the studies on the new oral anticoagulant drugs (NOACs) reinforce the new indications for their use (dabigatran, rivaroxaban, and apixaban) in patients with AF and risk factors for thromboembolic events. However, until the end of this paper, we will limit the recommendations to the drugs currently available in Brazil: dabigatran and rivaroxaban.

Pharmacovigilance is of utmost importance as the use of these new drugs in the "real world" increases. Till date, there is no specific antidote for dabigatran, whose half-life is short (between 12 and 17 h). In case of bleeding, treatment may vary from basic care (minor bleeding) to transfusion of blood derivatives, oral administration of activated charcoal, hemodialysis, and surgical intervention (major bleeding). In case of minor bleeding, interrupting the dose for 12-24 h or, if appropriate, reducing the subsequent dose (e.g., from 150 mg to 110 mg) may be sufficient. Although not a specific antidote, the prothrombin complex can be used to reverse the anticoagulant activity of factor Xa inhibitors³⁶. The recommendations on the use of dabigatran and rivaroxaban in AF are shown in Tables 4 and 5, respectively.

5.7. Use of heparin in patients with AF

UH is mainly used in the prevention of thromboembolic phenomena in patients subjected to electrical or chemical cardioversion of AF; however, it has lost prominence to LMWH. The type of heparin preferred for the maintenance of anticoagulation in patients with AF is LMWH, which is administered when the ideal adjustment of ACO has not been achieved or when its use must be temporarily interrupted because of diagnostic or therapeutic procedures that carry risk for hemorrhage. Although there are three types of LMWH (dalteparin, enoxaparin, and nadroparin), enoxaparin is the most used in clinical practice. The indications for the use of heparin in AF are shown in Tables 6 and 7³⁷.

5.8. Summary of the international guidelines

In addition to Diretrizes Brasileiras de Fibrilação Atrial³⁸, various international guidelines have been published regarding anticoagulation in AF, with a clear preference for the new anticoagulant drugs as anticoagulation agents in patients with nonvalvular AF^39-42. However, other topics remain controversial, and consensus has not been reached with regard to recommendations such as which agent to use (and for how long) after AF ablation.

6. Use of antiplatelet and anticoagulant agents in valvular disease

6.1. Introduction

It is well documented that valvular dysfunctions, regardless of the cardiac rhythm and mainly in the presence of atrial fibrillation (AF), put patients at increased risk for embolic events¹. Systemic thrombolism (STE) has been shown to be one of the severe complications following the formation of a thrombus in the atrial chamber. Thromboembolic phenomena can significantly modify the natural history of valvular disease, and its prevention should be considered during disease follow-up².

In practice, two groups of antithrombotic agents are available:

• Oral anticoagulant drugs. This group includes phenprocumon (Marcoumar^®), acenocoumarol (Sintrom^®), phenindione (Dindevan^®), crystalline sodium warfarin (Cumadin^®), and sodium warfarin (Marevan^®). Of the four compounds, sodium warfarin is the most used in clinical practice.

• Anticoagulant agents for parenteral use: heparin. This group includes UH (Liquemin^®) and LMWH: dalteparin (Fragmin^®), nadroparin (Fraxiparine^®), and enoxaparin (Clexane^®).

Treatment of valvular dysfunctions with oral anticoagulant agents is prolonged and oral administration is therefore preferred. The use of heparin (via endovenous or subcutaneous administration) is indicated for special treatment situations.

6.2. Oral anticoagulation with warfarin

Of the anticoagulant compounds that are administered orally, both forms of warfarin (sodium warfarin and crystalline sodium warfarin) are the most used because of their advantageous characteristics, namely good availability, predictable onset and duration of action^3,4.

Warfarin has been used in clinical practice for more than half a century. Despite this fact, it is still underused because of difficulties in controlling coagulation, drug interactions, and lack of compliance.

6.3. Parenteral anticoagulant agents

Of the injectable anticoagulant compounds, LMWH is the drug of choice because of its anticoagulation efficacy and practicality of use.

The isolated or combined use of both forms of anticoagulant drugs depends on their half-life. If the aim is to rapidly achieve antithrombotic protection, heparin is used concomitantly with oral warfarin⁴.

Heparin, particularly LMWH, can be used after implanting a mechanical valvular prosthesis if the risk for bleeding is considered until oral anticoagulation is initiated and INR is within the appropriate range^5-15. Moreover, it is useful in the transition between oral anticoagulation discontinuation and a surgical/intervention procedure ("heparin bridge") in patients with valvular disease and indication for permanent anticoagulation therapy^16-18, in pregnant women (from pregnancy diagnosis to week 12 of gestation), and in women with valvular disease and with indication for permanent anticoagulation therapy (from week 36 of gestation)^16,19,20.

6.4. Initial and maintenance doses of oral anticoagulant agents

The initial and maintenance doses should be guided by INR (international normalization ratio) values. The initial dose is 2.5 mg/day in patients aged > 65 years and 5 mg/day in the remaining patients. Laboratory monitoring of INR should be performed after 5 days. Following dose adjustment, the adequate dose is achieved when the values of three blood samples collected at 5-day intervals are within the desired range. It has been suggested that patients aged > 65 years are more sensitive to warfarin because of lower liver metabolism. Liver cells that form the sarcoplasmic reticulum of the P450 system, where warfarin is metabolized, secrete less enzyme¹⁸. Achievement of target values of INR throughout the treatment is difficult because of numerous external factors such as fluctuation of the vitamin K dose (the intake of this vitamin varies with frequently modified diets), use of multiple drugs with agonist or antagonist effects, and gastric mucosa edema resulting in lower drug absorption. It is recommended that the patient follows a balanced diet without great restrictions and anticipates blood collection for INR monitoring when there is a need to start a new medication. Once the correct dose is achieved, INR monitoring can be performed every 30 days¹⁹.

The best moment for warfarin administration is open for debate. One study has reported that absorption is greater at the proximal level (stomach and duodenum) of the gastrointestinal tract¹⁹, while another study has added that the absorption rate depends on the presence of food²⁰. Based on reports, it is suggested that the drug should be taken in the morning, after fasting, to avoid the influence of gastric pH, which is modified by ingested foods. In clinical practice, no differences have been observed as a result of distinct times of drug intake.

6.5. Anticoagulation in valvular disease with native valve

Rheumatic mitral valve disease (RMVD) is more thrombogenic than aortic lesions, and it results in a fivefold increase in the incidence of embolic events. STE is not frequent among patients with aortic valve disease, particularly stenosis from calcification and sinus rhythm. Holley et al.²¹ attribute the presence of microemboli, particularly renal microemboli, to aortic degeneration.

AF is the most common arrhythmia in mitral dysfunctions; it occurs in 26% of patients with mitral stenosis and in 16% of patients with mitral insufficiency. In aortic dysfunction, AF is also more common in stenotic lesions (5%). The presence of AF results in a 17.5-fold increase in TE²².

Studies have failed to show that left atrial dilatation (55 mm) is associated with higher risk for STE per se. However, patients with left atrial diameter > 55 mm and associated risk factors such as advanced age, presence of intracavitary thrombus, or even spontaneous contrast are candidates for thromboembolism prevention⁵.

Coulshed et al.²² revealed that in mitral valve dysfunction (mitral stenosis and mitral insufficiency, even in sinus rhythm), the incidence of STE varies from 7.7% to 8%. In the presence of AF, this incidence is three- to fourfold higher (21.1% vs. 31.5%).

In patients who exhibit aortic calcification and sinus rhythm, without a previous history of thromboembolic events, anticoagulation is not recommended.

Oral anticoagulation is recommended in patients with aortic stenosis or insufficiency who develop AF^5,6.

Aspirin can be used as an alternative for STE prevention in patients in unfavorable economic conditions, at a dose of 200-300 mg/day².

6.6. Anticoagulation in patients with a mechanical prosthesis

It is generally agreed that a mechanical prosthesis exposes the patients to an increased risk for STE, regardless of the cardiac rhythm. This risk is estimated to be 12%/year for a prosthesis in the aortic position and 22% for a prosthesis in the mitral position, in the absence of oral anticoagulation therapy⁷.

Patients with a mechanical prosthesis, regardless of their mitral/aortic position and cardiac rhythm, require antithrombotic prevention treatment. When they are implanted in the aortic position and the cardiac rhythm is sinusal, in the absence of other risk factors for STE, INR should be between 2.0 and 3.0³. Mechanical prostheses in the aortic position are less thrombogenic because this is a site of high flow and pressure where fibrin deposition is reduced. However, even with a prosthesis in the aortic position, if the patient has AF rhythm, it is recommended to maintain INR between 2.5 and 3.5. Because bleeding in elderly patients is a relatively common complication⁸, it is recommended to keep INR between 2.0 and 2.5 and to monitor this parameter more frequently⁹.

In patients with a mechanical prosthesis implanted in the mitral position, regardless of the cardiac rhythm, prophylactic care against thromboembolism should be greater and mean INR of 3.0 (2.5-3.5) is recommended.

In patients with a mechanical prosthesis, in the presence of any risk factor for STE, such as blood hypercoagulability, previous thromboembolism in the presence of adequate anticoagulation, or compromised ventricular function, it is recommended to add oral aspirin at a dose of 50-100 mg/day to the anticoagulation therapy. The exceptions are as follows: elderly patients aged > 80 years or those with a tendency for gastrointestinal bleeding¹⁰.

6.7. Anticoagulation in patients with a biological prosthesis

Bioprostheses are less thrombogenic. However, some authors believe that the risk for STE is higher in the first 3 months after implantating a prosthesis. Thrombogenicity may be associated with suture stitches and nonendothelized traumatized perivalvular tissues¹¹.

In patients with a biological prosthesis implanted in the mitral and aortic positions, even in sinus rhythm, the recommended oral anticoagulant agent for use in the first 3 months after surgery is class IIb (Table 3).

Regardless of the position of the bioprosthesis, in the presence of AF or hypercoagulability, oral anticoagulation should be prolonged and INR should be maintained at approximately 2.5.

The presence of an intracavitary thrombus found during the surgical procedure requires anticoagulation for a minimum period of 3 months after surgery. Even if the thrombus is removed during the procedure, INR should be kept at approximately 2.5 (2.0-3.0).

These recommendations are based on studies^13,14 in which the authors observed a high incidence of embolic events (6.9%) among patients who did not receive antithrombotic prevention treatment in the first 3 months after surgery.

Table 1

Table 2

Table 3

7. Use of antiplatelet and anticoagulant agents in venous thromboembolism (VTE)

7.1. Introduction

VTE has a high impact on morbidity and mortality in the general population; however, it can be prevented in most cases. Thus, its treatment and prevention through the use of specific medication is very important. Until recently, the anticoagulant drugs used in clinical practice were fractioned heparin and UH, fondaparinux, and warfarin. However, these drugs exhibit limitations, such as its injectable use (heparin and fondaparinux) and a narrow therapeutic window associated with a strong interaction with various drugs and foods (warfarin). Therefore, new anticoagulant agents were developed to overcome these limitations and enable oral treatment with fixed doses, without the need for routine laboratory monitoring.

These drugs have been tested in randomized controlled studies that included a large number of patients. However, clinical studies do not represent the "real world" because patients at high risk for hemorrhage or with more clinical complications are usually excluded. Didactically, we will consider that VTE encompasses deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE).

Most studies comparing enoxaparin with the new anticoagulant drugs for primary prevention in case of knee and hip prostheses surgeries focus on the occurrence of asymptomatic DVT; however, cost/benefit analysis requires the assessment of the occurrence of symptomatic VTE and bleeding.

7.2. Assessment of the risk for VTE and prevention

The prevention of VTE is indicated for hospitalized medical patients who are aged > 40 years, have an expected duration of limited mobility of 3 days or more, have at least one risk factor for TEV, and are not at increased risk for bleeding; prophylactic therapy should be maintained at least until hospital discharge. All patients hospitalized in intensive care units are deemed at high risk for VTE.

Risk factors for VTE are as follows: previous VTE, advanced age (particularly > 55 years), surgery, major trauma or lower limb injury, immobility, lower limb paresis, varicose veins, cancer, cancer therapy (hormone therapy, chemotherapy, radiotherapy, angiogenesis inhibitors), myeloproliferative disorders, venous compression (hematoma, tumor, arterial abnormality), pregnancy and puerperium, estrogen therapy, estrogen receptor modulators, erythropoiesis-stimulating agents, acute disease, acute infectious disease, class III or IV congestive heart failure, AMI, acute respiratory disease, stroke, rheumatic disease, inflammatory bowel disease, nephrotic syndrome, renal failure, nocturnal paroxystic hemoglobinuria, obesity, central venous catheter, and inherited or acquired thrombophilia^1,2.

The indication for prevention using anticoagulant agents should take into account cost/benefit analysis of using these drugs with the potential risk for bleeding. In practice, it is difficult to determine when medical patients are at high or low risk for developing DVT on the basis of studies with very heterogeneous populations.

In an observational prospective study that included 1,180 patients hospitalized for medical treatment, 11 risk factors for DVT with different weights were established and scores were defined for risk for DVT on the basis of the total number of points considered for the presence of each one of these factors (see Table 1 for the Padua risk score)³.

Patients were deemed to be at high risk when the score was > 4 (39.7% of patients) and low risk when it was < 4 points (60.3%). After a 90-day follow-up, DVT occurred in 11% of high-risk patients and in 0.3% of low-risk patients. Despite the limitations of this study, the Padua risk score is a good means of determining risk for DVT in hospitalized patients. In surgical patients, preventive anticoagulation is recommended for patients deemed at moderate risk (patients undergoing gynecological, urological, or thoracic surgery or neurosurgery; patients undergoing small surgical procedures who exhibit an additional risk factor; patients aged between 40 and 60 years who will receive general anesthesia for more than 30 min without additional risk factors) or at high risk (patients aged > 60 years undergoing major surgical procedures; patients aged between 40 and 60 years with additional risk factors; patients undergoing hip or knee arthroplasty, pelvic or hip fracture surgery, colorectal surgery, major trauma, spinal cord surgery, or cancer surgery). Risk factors for the development of VTE in surgical patients also include the type and extent of the surgery or trauma as well as the duration of hospitalization. Prevention should be continued until hospital discharge. In some subgroups of patients, it may be advisable to maintain prevention for an extended period of time after discharge, e.g., patients undergoing major cancer surgery or having experienced a previous thromboembolic event (up to 28 days) and patients undergoing hip or knee prosthesis surgery or hip fracture surgery (up to 35 days)⁴.

7.3. Risk for bleeding

Till date, there is no prospectively validated model for assessing the risk for bleeding in hospitalized medical patients. A retrospective study including more than 15,000 patients presented the following risk factors for bleeding: active gastroduodenal ulcer, bleeding over the last 3 months, platelet count < 50,000/µl, older age, liver or kidney failure, prolonged stay in an intensive care unit, presence of a central venous catheter, rheumatic disease, cancer, and male gender⁵.

7.4. Anticoagulant therapy in VTE

7.4.1. Unfractionated heparin (UH)

7.4.1.1. Prevention

The use of UH at low doses (5,000 IU subcutaneously every 8 or 12 h) for the prevention of thromboembolism in medical and surgical patients at risk is effective and safe and reduces the risk for VTE and fatal pulmonary embolism (in 60%-70% of patients)⁶. On the other hand, its use is associated with a slight increase in the incidence of wound hematoma and a nonstatistically significant increase in major bleeding (without an increase in fatal bleeding).

Patients hospitalized for stroke who exhibit reduced mobility should receive prophylactic treatment with low-dose anticoagulant drugs; however, these drugs should not be used during 24 h after the administration of thrombolytic drugs^9,10. Patients hospitalized for hemorrhagic stroke should receive mechanical prophylactic treatment using pneumatic compression intermittent devices¹¹. The use of heparin at low doses should be considered for high-risk patients, particularly bedridden patients, after bleeding cessation has been observed, on the second to fourth day following the onset of hemorrhagic stroke¹².

Platelet count should be performed every 2-3 days within 4-14 days or until the end of heparin treatment, whichever occurs first, in patients who are on prophylactic UH and on alternate days in patients who are on postoperative prophylactic UH because they represent the group at higher risk for thrombocytopenia induced by heparin. In patients who will start UH or LMWH therapy and who have received UH in the last 100 days, basal platelet count should be performed and repeated 24 h after the start of heparin therapy. Platelet count is not necessary in medical patients who are solely on UH catheter flush¹³.

7.4.1.2. Treatment

UH is an effective drug in the treatment of DVT. It should be started as soon as the diagnosis is confirmed (or in case of high medical suspicion, until the diagnostic tests are performed) because pulmonary embolism occurs in approximately 50% of patients with symptomatic DVT in untreated lower limbs¹⁴.

There are three forms of using UH in the initial treatment of DVT: intravenous administration with coagulation monitoring, subcutaneous administration with coagulation monitoring, and subcutaneous administration adjusted for weight without coagulation monitoring.

Intravenous administration with coagulation monitoring. Two administration regimens of intravenous UH are recommended for the treatment of DVT: a 5.000 IU bolus followed by continuous infusion of at least 30.000 IU in the first 24 h (1,250 IU/h) or a 80 IU kg bolus followed by 18 IU/kg/h (specific protocols are available to reach and maintain adequate aPTT levels, i.e., 1.5- to 2.5-fold the control value)¹⁵. Intravenous administration of heparin is difficult and can often result in inadequate treatment, with up to 60% of patients not reaching an adequate aPTT in the first 24 h¹⁶. The creation of specific protocols, such as the administration of weight-adjusted doses, aims to avoid incorrect dosing.

Subcutaneous administration with coagulation monitoring. A meta-analysis of eight clinical studies on the initial treatment of patients with DVT revealed that subcutaneous administration of UH twice a day is more effective (RR of extent or recurrence of thromboembolism: 0.62, 95% CI 0.39-0.98) and at least as safe (RR of major bleeding: 0.79, 95% CI 0.42-1.48) as continuous intravenous administration¹⁷, which facilitates dosage and enables home treatment. The usual regimen in these studies included an initial intravenous bolus of approximately 5,000 IU and a subsequent subcutaneous dose of 17,500 IU twice a day in the first day, followed by adjustments to reach aPTT that is 1.5- to 2.5-fold the laboratory control value.

Subcutaneous administration of UH with aPTT adjustment was also as effective and safe as that of a fixed dose of LMWH in the initial treatment of patients with VTE, including patients with pulmonary embolism¹⁸. In this case, heparin therapy was initiated at a dose adjusted for weight (< 50 kg, 4,000 IU intravenously + 12,500 IU subcutaneously; 50-70 kg, 5,000 IU intravenously + 15,000 IU subcutaneously; > 70 kg, 6,000 IU intravenously + 17,500 IU subcutaneously) and the dose was adjusted according to the result of aPTT every 6 h.

Table 2

Subcutaneous administration adjusted for weight without coagulation monitoring. The rates of recurrent VTE, major bleeding, and death after subcutaneous administration of UH at an initial dose of 333 IU/kg, followed by a fixed dose of 250 IU/kg twice a day, without coagulation monitoring were similar to those after the administration of LMWH¹⁹.

The efficacy of treatment with UH depends on reaching a critical therapeutic level of heparin in the first 24 h (aPTT 1.5-fold higher than the control value or the upper limit of the normal variation of aPTT)²⁰; the risk for thromboembolism recurrence in patients who do not attain this level is increased. The use of a dose adjusted to weight (initial bolus of 80 IU/kg, followed by a continuous infusion of 18 IU/kg/h) results in a higher number of patients (97% vs. 77%) reaching aPTT within the therapeutic range in the first 24 h and in a lower incidence of thromboembolism recurrence¹⁵. In the case of subcutaneous administration, the initial dose should be high to obtain an adequate response within the first 24 h²¹.

At present, the simultaneous introduction of heparin and vitamin K antagonist, followed by heparin discontinuation after 5 days, is recommended, provided that INR is > 2.0 for at least 24 h. In addition to the reduction in the risk for thrombocytopenia induced by heparin, two randomized clinical studies including patients with proximal DVT showed a similar efficacy in the use of intravenous UH for 5-7 days and 10-14 days^22,23. Platelet counts should be regularly performed to monitor thrombocytopenia induced by heparin, which should be discontinued if there is a sharp or sustained platelet drop or a platelet count < 100,000.

7.4.2. Low-molecular-weight heparin (LMWH)

7.4.2.1. Prevention

The use of LMWH in the prevention of DVT is determined by the patient's risk for experiencing a medical event. Within this risk stratification, certain medical situations are differently assessed. In this context, patients are divided into three groups: nonsurgical patients, patients undergoing orthopedic surgeries, and patients undergoing nonorthopedic surgeries. In this section, we will focus on nonsurgical patients.

The use of heparin significantly reduces the incidence of VTE, with better efficacy obtained with LMWH, which can be administered once a day and exhibits a lower tendency for trombocytopenia²⁴.

Data from three systematic literature reviews were used to determine the indication for prophylaxis of thromboembolic phenomena in patients hospitalized for acute diseases. The results show that thromboprophylaxis is associated with a significant reduction in the risk for thromboembolic phenomena, particularly in patients deemed at higher risk for these events. Moreover, the risk for major bleeding was not significant^25,26.

Therefore, tromboprophylaxis with LMWH is recommended for high-risk individuals until mobility is recovered or until hospital discharge (whichever occurs first). In low-risk individuals, the incidence of events is very low and does not justify prophylaxis²⁷.

Interestingly, in the LIFENOX study²⁸ was a double-blind, placebo-controlled, randomized study that compared the effect of subcutaneous enoxaparin (40 mg/day) with that of a placebo (both administered for 10 ± 4 days in patients who wore elastic graduated compression stockings) as well as the rate of all-cause mortality among acute hospitalized patients. The results revealed that compared with the use of elastic graduated compression stockings alone, combined use of enoxaparin and elastic graduated compression stockings was not associated with a reduction in the rate of all-cause mortality.

Prevention of DVT in long-distance travel. Prophylaxis with LMWH or ASA has been discussed and often indicated in individuals who return from long-distance flights. Symptomatic VTE is rare in this specific group of patients.

High-risk patients are recommended to walk frequently, exercise, and massage the muscles. In addition, these patients should consider wearing below-the-knee elastic stockings with compression of 15-30 mmHg.

Table 3

Till date, no studies have been conducted using an adequate methodology to test the potential benefits of LMWH in this group of patients. In high-risk individuals, i.e., those with previous thromboembolism, known thrombophilia, body mass index above 40 kg/m² (third-degree obesity), active cancer, recent major surgery (less than 1 month), as well as those traveling for more than 6 h, the use of thromboprophylactic medications should be decided on a case-by-case basis, always taking into account that adverse events may outweigh any benefit²⁹.

The usual practice in this case is the use of 20-40 mg of enoxaparin (subcutaneously) 1 h before boarding a flight of more than 6 h, although this has not been scientifically demonstrated. Other drug options (also not tested under these conditions) include dabigatran (110 mg) or rivaroxaban (10 mg).

7.4.2.2. Treatment

The use of LMWH for initial anticoagulation after a diagnosis of DVT is associated with lower mortality, lower DVT recurrence, and a lower incidence of major bleeding. Moreover, there is a lower incidence of thrombocytopenia induced by heparin and its use is simple. Care should be taken when administering the drug to individuals with significantly impaired renal function (CrCl < 30 ml/min). The dose is adjusted according to the patient's age, with a predictable therapeutic effect. aPTT monitoring is unnecessary. LMWH exhibits better bioavailability than UH. The prolonged therapeutic activity of LMWH enables one or two daily administrations^30,31.

Therefore, combined use of LMWH and a vitamin K antagonist is recommended until INR monitoring reveals that the patient is adequately anticoagulated^32,33.

7.4.3. Warfarin

7.4.3.1. Prevention

In patients who underwent major orthopedic surgery and who do not accept or tolerate injections, warfarin can be used as an alternative to apixaban, dabigratan, or intermittent pneumatic compression devices for the prevention of DVT³⁴.

7.4.3.2. Treatment

In patients with acute DVT, warfarin must be started on the same day as that of the onset of the administration of LMWH or UH. Parenteral anticoagulation must be maintained for a minimum of 5 days or until INR of 2.0 is reached³⁵.

In patients with DVT treated with warfarin, the dose must be adjusted in view of reaching INR between 2.0 and 3.0 (target INR: 2.5)^36,37.

The anticoagulation period will depend on the existence of a thrombosis-predisposing factor, which may be transient such as surgery or definitive such as thrombophylic syndrome. A minimum period of 3 months is recommended, which can be extended in the presence of a causative factor. In patients with proximal lower-extremity DVT caused by surgery ^38,39, proximal lower-extremity DVT caused by a transient risk factor not related to surgery, or an isolated episode of distal lower-extremity DVT caused by a transient risk factor or caused by surgery ⁴⁰,the recommended period of anticoagulation with warfarin is also 3 months.

In patients with spontaneous DVT (without a known triggering factor) in the lower extremities, the minimum recommended period of anticoagulation with warfarin is 3 months. After this period, patients must be evaluated with regard to the risk/benefit of extending the anticoagulation treatment. In patients who present with a first episode of proximal lower-extremity DVT without a known risk factor, anticoagulation for a period greater than 3 months is recommended. Anticoagulation for 3 months is recommended for individuals who exhibit a first episode of proximal lower-extremity DVT without a known risk factor and with a high risk of bleeding. In patients who present with a first episode of proximal lower-extremity DVT without a known risk factor, regardless of the risk for bleeding, anticoagulation with warfarin for 3 months is recommended^41,42.

Table 4

Table 5

Another factor that should be considered with regard to anticoagulation time is the nature of the DVT episode: first episode or recurrent episode. Furthermore, the risk for bleeding should be evaluated.

In patients with a recurrent DVT episode without a known risk factor, the period of anticoagulation with warfarin should be extended beyond 3 months in individuals at low risk for bleeding^43,44.

In patients with a recurrent DVT episode without a known risk factor, it is suggested that the period of anticoagulation with warfarin should be extended beyond 3 months in individuals at moderate risk for bleeding. In patients with a recurrent DVT episode without a known risk factor, the period of anticoagulation with warfarin should be 3 months in individuals at high risk for bleeding^45,46.

In patients with active cancer, the period of anticoagulation with warfarin for lower-extremity DVT should be extended beyond 3 months in individuals not at high risk for bleeding. In patients with active cancer, the period of anticoagulation with warfarin for lower-extremity DVT should be 3 months in individuals at high risk for bleeding. Warfarin treatment for asymptomatic lower-extremity DVT should follow the same recommendations with regard to the INR therapeutic level and duration⁴⁷.

The ARTEMIS double-blind, randomized, placebo-controlled study was designed to evaluate the efficacy and safety of the use of fondaparinux in the prevention of DVT in 849 patients aged > 60 years who had been hospitalized for acute cardiac, respiratory, infectious, or inflammatory disease and who needed to be bedridden for at least 4 days and had moderate risk for DVT.

Subcutaneous administration of fondaparinux 2.5 mg/day (with an onset within the first 48 h after hospital admission and maintained for 6-14 days) significantly reduced the risk for DVT, from 10.5% in the placebo group to 5.6% (reduction in RR 47%, 95% CI 8-69). Major bleeding occurred in one patient in each group (0.2%)⁴⁸.

In the PEGASUS study, patients who underwent elective abdominal surgery were randomly assigned to receive fondaparinux 2.5 mg daily for 5-9 days, with treatment beginning 6 h after the surgery, or subcutaneously administered 2,500 U dalteparin 2 h before and 12 h after the preoperative dose, followed by 5,000 U daily for 5-9 days. Among the 2,048 patients, the rate of DVT was 4.6% in the fondaparinux group and 6.1% in the group that received dalteparin, which represented a 25% reduction in RR (95% CI -9-48). The goal of noninferiority of fondaparinux was reached, and the rate of major bleeding was similar (3.4% in the fondaparinux group vs. 2.4% in the dalteparin group)⁴⁹.

Based on the presence of a composite endpoint in bilateral ascending venography, phase III randomized studies revealed that compared with LMWH (enoxaparin), fondaparinux therapy, when started within 4-8 h postoperatively, exhibited a superior efficacy in the prevention of DVT in patients who underwent orthopedic surgery, such as total hip replacement, knee replacement, and hip fracture surgery, and objectively documented symptomatic events⁵⁰.

Table 6

Table 7

A meta-analysis of four multicenter, double-blind, randomized studies on the prevention of DVT that compared fondaparinux with enoxaparin in patients who underwent major orthopedic surgery confirmed those findings in favor of fondaparinux⁵¹.

Prolonged thromboprophylaxis was evaluated in a phase III study entitled PENTPHIRA-Plus, which evaluated patients who underwent hip fracture surgery. Prolongation of the duration of prophylaxis with subcutaneous administration of fondaparinux 2.5 mg once a day starting 1 to 4 weeks after the fracture considerably lowered the frequency of venographically confirmed DVT [from 35% to 1.4% (p = 0.0001)] as well as that of symptomatic DVT [from 2.7% to 0.3% (p = 0.0021)]⁵².

Studies that evaluated treatments for DVT revealed that fondaparinux was as effective and safe as enoxaparin and UH in treating DVT and PTE.

The double-blind MATISSE study randomly assigned 2,205 patients with acute symptomatic DVT and weight < 50 kg, from 50 to 100 kg, and > 100 kg to receive an initial treatment with 5, 7.5, and 10 mg/day of fondaparinux, respectively, or with 1 mg/kg enoxaparin twice a day, for at least 5 days or until vitamin K inhibitors induced INR greater than 2.0. The main outcome, i.e., the recurrence of symptomatic DVT within 3 months, was 3.9% in the fondaparinux group and 4.1% in the enoxaparin group. The incidence of major bleeding during the initial period (1.1% and 1.2%, respectively) was also similar; the same was observed in case of the overall mortality (3.8% and 3.0%, respectively). It was concluded that the administration of fondaparinux once daily was at least as effective and safe as that of enoxaparin in the initial treatment of symptomatic DVT⁵³.

The CALISTO study, which was a randomized trial that included more than 3,000 patients with superficial vein thrombosis of the lower extremities, compared the administration of fondaparinux at a dose of 2.5 mg subcutaneously once daily for 45 days with the administration of a placebo. This study showed that the active treatment reduced the incidence of composite endpoints of symptomatic DVT, PTE, the spread of thrombosis into the sapheno-femoral junction, the recurrence of superficial vein thrombosis, and death (0.9% in the active treatment group vs. 5.9% in the placebo group), with an 85% reduction in RR in favor of fondaparinux (p < 0.001). No statistically significant difference was observed with regard to hemorrhagic complications between the two groups⁵⁴.

7.4.5. Dabigatran

7.4.5.1. Prevention

Four randomized, controlled, double-blind studies evaluated the efficacy and safety of dabigratan for the prophylaxis of VTE during knee or hip replacement surgery. The primary event was total VTE (including PTE and proximal and distal, symptomatic and asymptomatic DVT, as assessed by venography) and all-cause mortality.

The RE-NOVATE study included 3,494 patients who underwent hip replacement surgery and compared dabigratan at a dose of 150 or 220 mg once daily with enoxaparin at a dose of 40 mg/day, with a duration of 28-35 days. The frequency of the primary event after 220 mg of dabigratan, 150 mg of dabigratan, and enoxaparin was 6%, 8.6%, and 6.7%, respectively. These results revealed that dabigratan is not inferior to enoxaparin. In the same groups, the incidence of major bleeding was 2%, 1.3%, and 1.6%, respectively. Therefore, there was no difference between the groups⁵⁵.

The RE-NOVATE II study evaluated only a dose of 220 mg of dabigratan in 2,055 patients who underwent hip replacement surgery. In the dabigratan and enoxaparin groups, the primary event occurred with a frequency of 7.7% and 8.8%, respectively, and major bleeding occurred in 1.4% and 0.9%, respectively. Therefore, there was no difference between the groups with regard to both safety and efficacy⁵⁶.

Table 8

Table 9

Table 10

The RE-MOBILIZE study included 2,615 patients and compared dabigratan 150 or 220 mg once daily with enoxaparin 30 mg twice daily for a period of 12-15 days in the context of knee replacement surgery. In the dabigratan 150 mg, dabigratan 220 mg, and enoxaparin 30 mg groups, the frequency of the primary event was 33.7%, 31.1%, and 25.3%, respectively. Major bleeding occurred in 0.6%, 0.6%, and 1.4% of cases, respectively. Therefore, these results revealed that despite having the same safety, the efficacy of debigratan was lower⁵⁷.

The RE-MODEL study included 2,076 patients who received debigratan 150 or 220 mg once daily or enoxaparin 40 mg once daily for 6-10 days. In the dabigratan 150 mg, dabigratan 220 mg, and enoxaparin 40 mg groups, the primary event occurred in 40.5%, 36.4%, and 37.7% of cases, respectively. The frequency of major bleeding was 1.3%, 1.5%, and 1.3%, respectively. Therefore, dabigratan was not inferior to enoxaparin, and it exhibited the same safety⁵⁸.

A meta-analysis that evaluated only 220 mg of dabigratan in the RE-MODEL, RE-NOVATE, and RE-MOBILIZE trials demonstrated a lack of inferiority and a similar hemorrhagic risk for dabigratan relative to enoxaparin⁵⁹.

Another meta-analysis that included the four studies revealed that the frequency of the occurrence of VTE or mortality associated with VTE was 3%, 3.8%, and 3.3% in the dabigatran 220 mg, dabigatran 150 mg, and enoxaparin groups, respectively. Major bleeding occurred in 1.4%, 1.1%, and 1.4% of cases, respectively. Therefore, dabigratan was as effective as enoxaparin and exhibited the same hemorrhagic risk⁶⁰.

No study has compared the presence thromboprophylaxis with dabigratan vs. absence of thromboprophylaxis in knee and hip replacement surgeries.

The NICE Guidance considers that dabigratan is safe and adequate for primary prophylaxis in knee and hip replacement surgery, with an adequate cost/effectiveness, while emphasizing on the lack of an antidote and the fact that a dose of 150 mg/day would be more adequate for patients with renal failure or elderly patients. Dabigratan may be considered as an alternative in situations in which enoxaparin is indicated⁶¹.

The 9th ACCP Guideline, which uses the data obtained in the four studies described above, considered that dabigratan at a dose of 220 mg was similar to enoxaparin with regard to the occurrence of symptomatic VTE (PTE: RR 1.22, 95% CI, 0.52-2.85; DVT: RR 0.7, 95% CI 0.12-3.91) and major bleeding (RR 1.06, 95% CI 0.66-1.72). The absolute risk for bleeding and VTE was similar, with one event/1,000 patients. At a dose of 150 mg, dabigratan failed to demonstrate or exclude a beneficial VTE-preventive effect in comparison with enoxaparin (PTE: RR 0.31, 95% CI 0.04-2.48; symptomatic DVT: RR 1.52, 95% CI 0.45-5.05). Therefore, based on evidence with moderate quality, dabigratan may be considered to be similar to enoxaparin with regard to efficacy and safety; however, given the greater amount of experience with enoxaparin, this drug is indicated as the first choice⁶².

For the prophylaxis of VTE in knee and hip replacement surgeries, a dose of 150 or 220 mg once daily for a period of 28-35 or 14 days is recommended. The administration of the drug should begin 1-4 h after the surgical procedure, with hemostasis established with half dose. The choice of dose is left to the discretion of the physician taking into consideration the age of the patient, CrCl, and the use of other drugs that interact with dabigratan.

Studies conducted on patients with acute or chronic DVT were analyzed for comparing the noninferiority and safety of dabigratan and warfarin, considering the occurrence of symptomatic VTE.

The RE-COVER study was a phase III, double-blind, randomized, and controlled study on the treatment of acute VTE. After conventional treatment with enoxaparin for a minimum of 5 days, a total of 2,539 patients received 150 mg of dabigratan twice daily or warfarin at a dose adjusted for INR between 2.0 and 3.0 for 6 months. The results revealed that the recurrence of VTE (2.4% vs. 2.1%, RR 1.10, 95% CI 0.65-1.84) and major bleeding (1.6% vs. 1.9%, RR 0.83, 95% CI 0.46-1.49) was similar. During the study-inclusion period, 786 patients (31%) exhibited symptoms of TPE. The results showed no differences in the response to dabigratan with regard to the recurrence of VTE or bleeding in that subgroup of patients⁶³.

The RE-MEDY study compared the use of 150 mg of dabigratan twice daily with that of warfarin at a dose adjusted for INR between 2.0 and 3.0 for 6-36 months after a period of conventional treatment for VTE of 3-12 months. The study included 2,856 patients; the recurrence of VTE occurred in 1.8% and 1.3% of cases, respectively (RR 1.44, 95% CI 0.79-2.62), and the recurrence of major bleeding occurred in 0.9% and 1.8% of cases, respectively (RR 0.56, 95% CI 0.27-1.01). These results revealed that the efficacy of dabigratan is similar to that of warfarin, with the same hemorrhagic risk. An increased incidence of acute coronary events was observed. The results of this study have not been published till date.

Table 11

The RE-SONATE study was started in 2011 for evaluating the noninferiority of dabigratan and the placebo with regard to the recurrence of symptomatic VTE. After a conventional treatment period of 6-18 months, the patients will be included in the study for an additional treatment of 6 months.

The 9th ACCP, which was cited above, considers that the indication of dabigratan for the treatment of acute VTE is based on moderate-quality evidence because of serious imprecision regarding various occurrences and the lack of data on long-term safety. Because very few patients with cancer were included, the results cannot be extrapolated to that group of patients.

Some aspects that need to be evaluated when choosing an anticoagulant include the patient's tolerance to daily injections, history of heparin-induced thrombocytopenia, renal function, need for laboratory control, cost of treatment, and availability of an antidote to treat intoxication. Dabigratan can be very unpleasant for patients; however, no phase IV studies substantiate the safety of this drug in a better manner, particularly with regard to bleeding and hepatic complications.

In addition, there is a limitation in the use of this drug in patients with renal impairment as well as the lack of an antidote. In patients with CrCl between 30 and 50 ml/min or those older than 75 years, the dose can be reduced to 150 mg/day. Similarly, as mentioned in the RE-COVER study, the dose should be reduced to 150 mg/day in the presence of the concomitant administration of potent inhibitors of glycoprotein P, such as amiodarone or verapamil.

7.4.6. Rivaroxaban

7.4.6.1. Prevention

The most important studies that analyzed the efficacy and safety of rivaroxaban for the primary prophylaxis of VTE in knee and hip replacement surgeries are the RECORD 1-4 controlled, randomized, double-blind, phase III studies. The primary event was total VTE, including PTE, proximal and distal, symptomatic and asymptomatic DVT (as assessed by venography), and all-cause mortality.

In the RECORD 1 study, which included 4,541 patients who underwent hip replacement surgery, rivaroxaban was administered at a dose of 10 mg once daily, started on the day of surgery, and it was compared with enoxaparin 40 mg once daily, started 2 days before the surgery, for 35 days. Rivaroxaban was superior to enoxaparin with regard to the primary event (1.1% vs. 3.7%, RR 0.3, 95% CI 0.18-0.51, p < 0.001) and the occurrence of VTE (0.2% vs. 2.0%, RR 0.12, 95% CI 0.04-0.34, p < 0.001). Major bleeding was similar between the two groups (0.3% vs. 0.1%, RR 3.02, 95% CI 0.61-14.95, p = 0.18). These results revealed that rivaroxaban was more effective than enoxaparin, and it exhibited the same safety⁶⁴.

The RECORD 2 study compared 2,509 patients who received prophylaxis with rivaroxaban 10 mg once daily for 35 days or enoxaparin 40 mg once daily for 15 days. The primary event had a lower incidence in the rivaroxaban group than in the enoxaparin group (2.0% vs. 9.3%, RR 0.21, 95% CI 0.13-0.35, p < 0.001); the same was observed in case of VTE (0.6% vs. 5.1%, RR 0.12, 95% CI 0.04-0.34, p < 0.001). The incidence of major or clinically significant bleeding was similar in the two groups (0.1% vs. 0.1%, RR 1.0, 95% CI 0.06-15.98 and 9.9% vs. 8.21%; RR 1.20, 95% CI 0.93-1.54, respectively)⁶⁵. Therefore, rivaroxaban was more effective and had the same safety as enoxaparin. However, it is important to stress that enoxaparin was used for 15 days only, whereas rivaroxaban was used for 35 days.

The RECORD 3 study (n = 2,531) compared patients who underwent knee replacement surgery and received 10 mg of rivaroxaban once daily or 40 mg of enoxaparin/day for 10-14 days. Rivaroxaban was superior to enoxaparin with regard to the prevention of the primary event (1.1% vs. 3.7%, RR 0.3, 95% CI 0.18-0.51, p < 0.001) and VTE (0.2% vs. 2.0%, RR 0.12, 95% CI 0.04-0.34). Major bleeding was similar in the two groups (0.3% vs. 0.1%, RR 3.02, 95% CI 0.61-14.95)⁶⁶. Therefore, rivaroxaban was more effective and had the same safety as enoxaparin.

In the RECORD 4 study (n = 3,148), rivaroxaban was used at a dose of 10 mg once daily and was compared with enoxaparin 30 mg twice daily for knee replacement surgery. The primary event was less prevalent in the rivaroxaban group (6.9% vs. 10.1%, RR 0.69, 95% CI 0.51-0.92, p < 0.001); the same was observed in case of VTE (1.2% vs. 2.0%, RR 0.59, 95% CI 0.30-1.16). Bleeding was similar in the two groups (0.7% vs. 0.3%, RR 2.47, 95% CI 0.78-7.86)⁶⁷. Therefore, these results confirmed those obtained in the RECORD 3 study.

The incidence of clinically significant bleeding was also low in all these studies: RECORD 1: 5.8% vs. 5.8%; RECORD 2: 6.5% vs. 5.5%; RECORD 3: 4.3% vs. 4.4%; and RECORD 4: 10.2% vs. 9.2%.

A meta-analysis of eight randomized clinical studies that included 15,586 patients who underwent knee or hip replacement surgery revealed that the use of rivaroxaban was associated with a lower incidence of VTE and all-cause mortality (9,244 patients, RR 0.56, 95% CI 0.39-0.80) and with a similar incidence of bleeding (major bleeding: 13,384 patients, RR 1.65, 95% CI 0.93-2.93; clinically significant bleeding: 13,384 patients, RR 1.21, 95% CI 0.98-1,50; total hemorrhagic events: 13,384 patients, RR 1.10, 95% CI 0.97-1.24)⁶⁸.

Table 12

However, a limitation of the bleeding evaluation method used in those studies was that only bleeding that required reoperation was considered and bleeding at the surgical site was not and that the drop in hemoglobin was compared with the first postoperative day and not with the preoperative value.

Furthermore, approximately 30%-39% of patients included in the RECORD studies were excluded from analysis of the intention-to-treat because of inadequate evaluation of DVT. Moreover, the RECORD 4 study was completely excluded from the approval decision of FDA. Inadequate monitoring and loss of data compromised analyses and prevented the confirmation of the superiority of rivaroxaban over enoxaparin. In addition, the bleeding was considered to be similar.

The NICE Guidance considers that rivaroxaban is more effective than enoxaparin for the prevention of VTE; however, the risk for major bleeding is greater (when considering RR of the studies), and the drug can be considered in situations in which enoxaparin is indicated. With regard to the direct comparison between rivaroxaban and dabigatran, the former significantly reduced the risk of VTE, whereas the risk of bleeding favored dabigatran; therefore, these drugs were considered as being similar.

The 9th ACCP Guidelines included seven randomized clinical studies that included more than 10,000 patients to evaluate the indication of the use of rivaroxaban for the thromboprophylaxis of knee and hip replacement surgery. Rivaroxaban reduced symptomatic DVT by 50% (RR 0.41, 95% CI 0.20-0.83), with an increase in major bleeding or bleeding that required reoperation (major bleeding: RR 1.58, 95% CI 0.84-2.97; bleeding that required reoperation: RR 2.0, 95% CI 0.86-4.83; both: RR 1.73, 95% CI 0.94-3.17). The absolute risk for major bleeding was low; however, the criteria used for evaluating bleeding mentioned earlier were not adequate. It was estimated that the reduction of five symptomatic DVT among 1,000 patients would lead to nine major bleedings.

With regard to prolonged thromboprophylaxis in hip replacement surgery, which included more than 2,400 patients, rivaroxaban significantly reduced symptomatic VTE (symptomatic DVT: RR 0.18, 95% CI 0.04-0.82; PTE: RR 0.25, 95% CI 0.02-2.2). However, it is important to stress that enoxaparin was only used in the first 12 days. Analysis of bleeding also had the same limitations as those mentioned for the previous studies, and there was only one case of bleeding in the two groups. It is estimated that among 1,000 patients, 12 less DVTs will occur in the rivaroxaban group. However, given the uncertain results regarding bleeding, it remains unclear whether the beneficial effects will be overcome by the increase in the hemorrhagic risk.

Based on these studies (which are considered to provide moderate quality evidence), the increased hemorrhagic risk, and the lack of data on long-term safety, ACCP still recommends enoxaparin as the first choice for the thromboprophylaxis of knee and hip replacement surgery, even considering the inconvenience of subcutaneous injections.

The randomized, double-blind MAGELLAN study⁶⁹ evaluated rivaroxaban for the prevention of VTE in hospitalized medical patients. The study included 5,932 patients who were administered 10 mg of rivaroxaban/day for 35 days or 40 mg of enoxaparin/day for 10 days. Patients were also administered a placebo orally for 35 days or subcutaneously for 10 days. The risk factors were infectious disease, congestive heart failure, respiratory insufficiency, cancer, ischemic stroke, and inflammatory or rheumatologic disease. The results revealed that rivaroxaban reduced the incidence of VTE at 35 days (4.4% vs. 5.7%, RR 0.77, 95% CI 0.62-0.96, p = 0.02), albeit with a significant increase in bleeding (1.9% vs. 0.6%, RR 0.77, 95% CI 0.62-0.96, p = 0.02), which overcame the benefits of its use. The debate regarding this study includes the possibility that the heterogeneity of the patients and comparison with the placebo explain the findings and that subgroup analysis and long-term comparison with enoxaparin may be important because VTE is also common in hospitalized medical patients. The results of this study have not been published. For the prevention of VTE in knee and hip replacement surgeries, a dose of 10 mg once daily is recommended for a period of 35 and 14 days, respectively. The administration of the drug should be started 6-8 h after the surgical procedure, after hemostasis has been re-established.

The efficacy and safety of rivaroxaban for the treatment of acute- and long-term VTE have been evaluated in more than 4,600 patients in two controlled, randomized, phase III clinical studies, EINSTEIN DVT⁷⁰ and EINSTEIN EXTENSION⁷¹. These two studies used the same primary (recurrent symptomatic VTE, defined as recurrent DVT or fatal or nonfatal PTE) and secondary (recurrent DVT, nonfatal PTE, and all-cause mortality) events for the evaluation of efficacy. In those studies, patients with moderate renal failure (CrCl 30-49 ml/min) were treated with the same dose as patients with CrCl greater than 50 ml/min.

One of A difference between the EINSTEIN DVT and RE-COVER studies was that rivaroxaban was started immediately after the diagnosis of VTE and not after the administration of enoxaparin.

Table 13

In the EINSTEIN study (n = 3,449), rivaroxaban was administered at a dose of 15 mg twice daily for 3 weeks, followed by 20 mg/day for 3, 6, or 12 months, and it was compared with enoxaparin for a minimum of 5 days and with warfarin at a dose adjusted for INR between 2.0 and 3.0. Only patients with proximal symptomatic DVT were included, and those with symptomatic PTE were excluded. The results revealed that the recurrence of VTE (2.1% vs. 3.0%, RR 0.70, 95% CI 0.46-1.07) and that of major bleeding (0.8% vs. 1.2%, RR 0.70, 95% CI 0.35-1.38, p = 0.21) were similar to those observed for enoxaparin and warfarin in the treatment of acute-stage VTE.

In the EINSTEIN EXTENSION study (n = 1,196), patients with proximal DVT who were previously treated with rivaroxaban or enoxaparin and warfarin for 6-12 months were administered rivaroxaban 20 mg/day or placebo for treatment over an additional 6-12 months. The results revealed that rivaroxaban was superior to the placebo with regard to the primary and secondary efficacy events (1.3% vs. 7.1%, RR 0.19, 95% CI 0.09-0.40, p < 0.001), with a nonsignificant increase in bleeding (0.7% vs. 0%, RR 7.89, 95% CI 0.42-148.99).

The 9th ACCP considers that the indication of rivaroxaban for the treatment of acute- and long-term DVT stems from moderate quality evidence resulting from serious imprecision regarding various events and the lack of data regarding long-term safety. Because very few patients with cancer were included, the results cannot be extrapolated to that group of patients.

Some aspects that need to be evaluated when choosing an anticoagulant include the patient's tolerance to daily injections, history of heparin-induced thrombocytopenia, renal function, need for laboratory control, cost of treatment, and availability of an antidote to treat intoxication. Rivaroxaban can be lesser unpleasant for patients; however, it was associated with greater bleeding in studies of primary thromboprophylaxis. At present, there are no phase IV studies to substantiate the safety of this drug in a better manner, particularly with regard to bleeding and hepatic complications. In addition, there is a limitation in the use of this drug in patients with renal impairment as well as the lack of an antidote. Although this has not been well established, there should be some precaution with regard to the administration of rivaroxaban to patients with CrCl between 15 and 30 ml/min, liver disease (Child-Pugh classes B and C), concomitant use of inhibitors/enhancers of CYP3A4 or glycoprotein P (amiodarone, verapamil, macrolides, rifampicin, phenytoin, carbamazepine, and phenobarbital), and use of nonsteroidal anti-inflammatory drugs and platelet inhibitors.

7.4.7. Apixaban

7.4.7.1. Prevention

The efficacy and safety of apixaban in the primary prevention of VTE in patients who underwent hip and knee prosthesis were assessed in three controlled, randomized, double-blind, phase III clinical studies, entitled ADVANCE 1-3. The primary event was total VTE (including PTE, proximal and distal DVT, symptomatic and asymptomatic, as assessed by venography) and all-cause mortality.

In the ADVANCE 1 study, 3,195 patients who underwent knee prosthesis received apixaban at a dose of 2.5 mg twice daily, starting on the day of the surgery, or anoxaparin at a dose of 30 mg twice daily, starting one day before the surgery, for 10-14 days. Apixaban was similar to enoxaparin with regard to the incidence of total VTE and death (9.9% vs. 8.8%, RR 1.02, 95% CI 0.78-1.32, p = 0.06). The incidence of major or clinically significant bleeding was lower in the apixaban group (2.9% vs. 4.3%, RR 0.67, 95% CI 0.47-0.97, p = 0.03)⁷².

The ADVANCE 2 study⁷³ compared 3,057 patients who underwent knee arthroplasty and received 2.5 mg of apixaban twice daily or 40 mg of enoxaparin once daily for 10-14 days. The first dose of apixaban was administered between 12-24 h after the surgery, and enoxaparin was started between 9-15 h before the surgery. The incidence of the primary event was lower in the apixaban group (15.06% vs. 24.37%, RR 0.62, 95% CI 0.51-0.34, p < 0.0001), and major or clinically significant bleeding was similar in both the groups (4% vs. 5%, RR 0.74, 95% CI 0.52-1.05, p = 0.08).

The ADVANCE 3 study⁷⁴ (n = 5,407) compared the effect of 2.5 mg of apixaban twice daily with 40 mg of enoxaparin administered for 35 days in hip prosthesis surgery. Apixaban was superior to enoxaparin with regard to the primary event (1.4% vs. 3.9%, RR 0.36, 95% CI 0.22-0.54, p < 0.001). Major or clinically significant bleeding was similar in both the groups (4.8% vs. 5.0%, RR 0.96, 95% CI 0.76-1.21, p = 0.68).

One meta-analysis⁷⁵ included the three studies (n = 7,337) that compared the use of apixaban 2.5 mg twice daily with that of enoxaparin 40 mg/day or 30 mg twice daily for the prevention of VTE in knee prosthesis surgery. The risk for VTE when using apixaban and enoxaparin was 0.47 (95% CI 0.27-0.82, 0.6% vs. 1.2%) and 2.09 (95% CI 0.99-4.45, 0.6% vs. 0.3%), respectively. Death occurred in 0.2% of patients in the apixaban group and in 0.09% of patients in the enoxaparin group (OR 1.74, 95% CI 0.51-5.95). Apixaban was associated with a lower hemorrhagic risk (OR 0.55, 95% CI 0.32-0.96). These data demonstrated that in knee prosthesis surgery, apixaban is more effective and safe than enoxaparin.

Table 14

The NICE Guidance considered that apixaban was more effective than enoxaparin and exhibited lower hemorrhagic risk, although the difference was not statistically significant. However, it also points out that the observation period with regard to adverse events was short.

The 9th ACCP assessed four studies that included more than 12,000 patients using apixaban for prevention in case of knee or hip prosthesis surgery. Apixaban reduced the occurrence of symptomatic PVT by 59% (RR 0.41, 95% CI 0.18-0.95) and had little or no effect on the occurrence of major bleeding (RR 0.76, 95% CI 0.44-1.32) or bleeding that required reoperation (RR 0.82 95% CI 0.15-4.58) in comparison with enoxaparin. However, the criticism that was made in relation to the two studies with rivaroxaban is also applicable to the ADVANCE 2 and 3 studies because the drop in hemoglobin was compared with the hemoglobin value on the first postoperative day and not with the preoperative value, which may underestimate the rate of major bleeding. The results failed to show a beneficial or deleterious effect of apixaban with regard to nonfatal PTE (RR 1.09, 95% CI 0.31-3.88) and overall mortality (RR 1.87, 95% CI 0.61-5.74). The five deaths occurred in the apixaban group. The best estimations suggest that apixaban prevents seven symptomatic PVTs in 1,000 patients, without a significant increase in major bleeding (at least eight major bleedings or more less in five cases). However, the results failed to demonstrate a difference when all fatal and nonfatal VTEs were included. Therefore, based on moderate-quality evidence, the safety of apixaban was deemed to be similar to that of enoxaparin with regard to the occurrence of symptomatic VTE and hemorrhagic risk, which was infrequent. However, because of the lack of results on long-term safety in phase IV studies, there is still no indication for the preferential use of enoxaparin.

The ADOPT study⁷⁶ assessed apixaban for the prevention of VTE in hospitalized patients with acute disease, congestive heart failure, respiratory failure or other acute condition, and at least one more risk factor for VTE. The study included 6,528 patients who used 2.5 mg of apixaban twice daily for 30 days or 40 mg of enoxaparin once daily for 6-14 days. The occurrence of VTE was similar in both the groups (2.71% vs. 3.06%, RR 0.87, 95% CI 0.62-1.23), with a higher bleeding rate in the apixaban group (2.7% vs. 2.1%, RR 1.28, 95% CI 0.93-1.76). Therefore, these results revealed that apixaban was not superior to enoxaparin with regard to the prevention of VTE in hospitalized medical patients and was associated with higher bleeding; its use is not indicated in this situation.

A dose of 2.5 mg twice daily for a period of 32-38 days and 10-14 days is recommended for the prevention of VTE in hip and knee prosthesis surgery, respectively. The medication should begin 12-24 h after the surgical procedure and after hemostasis has been achieved.

Some aspects that need to be evaluated when choosing an anticoagulant include the patient's tolerance to daily injections, history of thrombocytopenia induced by heparin, renal function, need for laboratory monitoring, cost of treatment, and availability of an antidote to treat intoxication. Apixaban can be lesser unpleasant for patients and its efficacy and safety are similar to or better than those of enoxaparin in the thromboprophylaxis of knee and hip prosthesis surgery. At present, there are no phase IV studies to substantiate the safety of this drug in a better manner, particularly with regard to bleeding and hepatic complications. Compared with dabigatran and rivaroxaban, there are lesser limitations in patients with renal impairment, and there is no antidote. Although this has not been well established, there should be some precaution with regard to the administration of apixaban to patients with CrCl between 15 and 30 ml/min, liver disease (Child-Pugh class A and B), concomitant use of inhibitors/inducers of CYP3A4 or glycoprotein P (amiodarone, verapamil, macrolides, rifampicin, phenytoin, carbamazepine, and phenobarbital), and use of nonsteroidal anti-inflammatory drugs and platelet inhibitors in patients with increased liver transaminase.

7.4.7.2. Treatment

There are no recommendations for the use of apixaban in the treatment of VTE. Studies are still ongoing.

7.5. Comparison between the new anticoagulant agents

Comparison between the use of apixaban, dabigatran, and rivaroxaban for the prevention of VTE in knee or hip prosthesis was indirectly performed through the various studies that compared these new drugs with enoxaparin. One of the criticisms to this type of comparison is that there may be differences in the design of the studies and the centers where they were developed may also have been different.

A review⁷⁷ that only included randomized studies comparing the safety and efficacy of apixaban with those of other anticoagulant drugs in the prevention of VTE in knee and hip prosthesis surgery revealed that VTE and death are more frequent with dabigatran than with apixaban in hip (OR 2.51, 95% CI 1.50-4.21) and knee (OR 1.72, 95% CI 1.22-2.42) surgery. Rivaroxaban was similar to apixaban in hip and knee surgery (OR 0.69, 95% CI 0.38-1.25 and OR 0.83, 95% CI 0.57-1.19, respectively). There was no difference with regard to major bleeding.

Another meta-analysis⁷⁸ that included 12 studies comparing rivaroxaban or apixaban with enoxaparin revealed that apixaban was associated with a lower incidence of bleeding in knee prosthesis surgery (6,496 patients, RR 0.56, 95% CI 0.32-0.96) and that the number of major bleeding cases was similar (5,699 patients, RR 1.40, 95% CI 0.56-3.52). There was no difference in bleeding in hip prosthesis.

Maratea et al.⁷⁹ analyzed eight studies comparing the new anticoagulant agents in the prevention of VTE in knee and hip prosthesis surgery. Dabigatran at a dose of 150 mg/day was less effective than apixaban at a dose of 2.5 mg twice daily (RR 2.0, 95% CI 1.61-2.50) and rivaroxaban at a dose of 10 mg/day (RR 2.38, 95% CI 1.85-3.03). Dabigatran at a dose of 220 mg/day was also less effective than apixaban at a dose of 2.5 mg twice daily (RR 1.66, 95% CI 1.33-2.08) and rivaroxaban at a dose of 10 mg/day (RR 2.38, 95% CI 1.85-3.03). There was no difference in the efficacy of dabigatran at doses of 150 mg and 220 mg/day (RR 0.83, 95% CI 0.67-1.02). Rrivaroxabana at 10 mg/day was superior to apixaban at 2.5 mg twice daily (RR 0.70, 95% CI 0.53-0.90). Indirect comparison between rivaroxaban and dabigatran with regard to primary thromboprofilaxys in knee and hip prosthesis revealed that rivaroxaban was superior to dabigatran in the prevention of VTE (RR 0.50, 95% CI 0.37-0.68); however, the hemorrhagic risk was higher with rivaroxaban (RR 1.14, 95% CI 0.80-1.64).

Recently, a meta-analysis⁸⁰ revealed that compared with mechanical methods and warfarin, the use of powerful anticoagulant agents, including dabigatran and rivaroxaban, was associated with higher mortality. However, as noted by Eriksson et al.⁸¹, this study had numerous flaws, from the inclusion of studies with distinct designs to the generalization of the results obtained for one anticoagulant to the entire group, different periods of prophylaxis, and lack of results corrected by interference factors.

7.6. Bivalirudin

We identified a single phase II open study⁸², with 222 patients, which assessed the efficacy and safety of various doses of bivalirudin for the prevention of VTE in patients who underwent major hip and knee orthopedic surgery. Six different regimens were evaluated, varying from 0.3 mg/kg every 12 h to 1.0 mg/kg every 8 h, via subcutaneous administration. On discharge, patients were subjected to bilateral venography and the highest dose resulted in the lowest rates of total (17%) and proximal DVT (2%), which were significantly different from those observed at lower doses (overall incidences: 43% for total DVT and 20% for proximal DVT (p = 0.01 and p = 0.023, respectively). It is not possible to make recommendations regarding the use of bivalirudin for the treatment and prevention of DVT because of the lack of studies on the subject.

7.7. Antiplatelet therapy in VTE

Arterial and venous thromboses are considered to be distinct pathophysiological entities. Arterial thrombosis mainly involves platelets (white clot), and venous thrombosis is caused by the formation of fibrin and deposition of erythrocytes (red thrombus). However, some characteristics are common to arterial and venous events. In fact, platelets, fibrin, and erythrocytes are present in both arterial and venous thrombi, although in different proportions. Moreover, there is evidence that platelet activation occurs in venous thrombi and that the inhibition of P-selectin, a protein on the surface of activated platelets, can lead to the resolution of venous thrombosis⁸³. These facts explain some effect of antiplatelet therapy on the prevention of venous events.

Although there is strong evidence regarding the beneficial effect of antiplatelet therapy on the secondary prevention of arterial events, these drugs have not been tested with regard to the treatment of DVT or PTE, and data related to the prevention of VTE are not very consistent. Some studies suggest that there is an approximately 25% reduction in the risk for VTE after surgical procedures; however, there is no indication that this is an ideal prophylactic method and there are no well-designed studies directly comparing this method with heparins or coumarin derivatives⁸⁴.

Two meta-analyses, one with general surgery patients published in 1988⁶ and another with patients subjected to total hip arthroplasty published in 1994⁸⁵, did not demonstrate a beneficial effect of aspirin on the reduction of VTE. On the other hand, in a systematic review also published in 1994, which included data from 9,623 patients, 814 of which were medical patients and 8,809 were surgical patients, the authors concluded that antiplatelet drugs reduced the incidence of DVT by 39% and the incidence of PTE by 64% and that the effect was detected both in the groups of high-risk surgical and medical patients⁸⁶. However, the validity of these conclusions has been widely questioned; most studies included in this systematic review were not blind and had been published in the 1970s and 1980s, and n was < 200. Moreover, a wide range of drugs were used, including ASA at various doses, dipiridamol, suloctidil, hydroxychloroquine, ticlopidine, and sulfinopyrazone, either isolated or in combination. The VTE detection method considerably varied, and in five studies, there was concomitant use of UH. Lastly, analysis of the various subgroups did not show any reduction in the risk for VTE in high-risk medical patients.

A large randomized prospective study ⁸⁷ with 17,444 patients compared the effect of aspirin with that of a placebo with regard to the incidence of VTE after orthopedic surgery (13,356 hip fractures, 2,648 hip arthroplasties, and 1,440 knee arthroplasties). ASA at a dose of 160 mg or placebo was used for 35 days, and the aim was to assess morbidity and intrahospital mortality at 35 days. It should be noted that 18% of patients received UH, 26% received LMWH, and 30% wore elastic gradual compression stockings. A significant reduction in the incidence of total VTE was observed in the group that used ASA (HR 0.71, 95% CI 0.54-0.94), DVT (HR 0.71, 95% CI 0.52-0.97), and fatal PTE (HR 0.42, 95% CI 0.24-0.73). This reduction in risk was observed in patients who were not on heparin or UH but was not detected in those who also used LMWH. In patients subjected to hip or knee arthroplasty, the use of ASA did not reduce the incidence of DVT or PTE.

We only identified three small studies that performed a direct comparison between ASA and drugs normally used for preventing VTE. One of these studies compared the efficacy and safety of ASA with those of danaparoid in 251 patients subjected to hip fracture surgery. This was a randomized, blind study, and the dose of ASA used was 100 mg twice daily for 14 days. All the patients underwent labeled fibrinogen scanning or pletismography, and suspected cases of DVT were confirmed by venography. The incidence of VTE was significantly lower in the danaparoid group [27.8% vs. 44.3% in the ASA group, RRR 37.3 (95% CI 3.7-59.7)], and the incidence of hemorrhages was 1.6% in the danaparoid group and 6.4% in the placebo group (p = NS)⁸⁸.

In another study, 312 patients subjected to hip or knee arthroplasty were randomly assigned to ASA (325 mg twice daily) or warfarin. The incidence of VTE was 33.1% in the aspirin group and 24.7% in the warfarin group (p = NS)⁸⁹. In the last study on knee arthroplasty, Westrich et al.⁹⁰ randomly assigned 275 patients to 325 mg of ASA, which was started on the day of the surgery, or enoxaparin (30 mg twice daily), which was only started 48 h after the surgery. The drugs were maintained for 3 weeks and the dose of enoxaparin was reduced to 40 mg once daily after discharge. The incidence of VTE was 17.8% in the ASA group and 14.1% in the enoxaparin group (p = NS). In both studies, the small size of the sample and the lack of power of the study may explain why the differences observed between the ASA group and the control group were not statistically significant. In addition, the delayed administration of enoxaparin in Westrich's study may have contributed to the VTE events observed in this group.

Analysis of the data of two recent studies^91,92 suggests a beneficial effect of ASA (100 mg/day) in patients who discontinue oral anticoagulation after 3-6 months of DVT treatment. In these patients, a reduction of at least 30% was observed in the recurrence of VTE episodes and a 42% reduction was observed in the recurrence of other vascular events.

Table 15

8. Use of antiplatelet and anticoagulant agents in heart failure (HF)

8.1. Introduction

Full anticoagulation in patients with HF has been the subject of various studies over recent years. Its wide use has been criticized, and it is only indicated for specific situations. New drugs have been recently developed; however, their function has not been definitely established in this context. As shown below, this guideline focuses on reporting the indications for antithrombosis, particularly in HF, taking into account the main studies that have been developed in the area.

8.2. Anticoagulation in patients with atrial fibrillation (AF)

Decreased left ventricular ejection fraction and nonrheumatic AF are independent predictors of stroke^1,2. However, there are conflicting data with regard to the predictive value of history of HF because antithrombotic prevention is associated with increased risk for bleeding^3-5. In addition, ASA can, in theory, interact with angiotensin-converting enzyme inhibitors and decrease their beneficial effect⁴. Recommendations for prophylaxis are based on the clinical effect by taking into account the risk for stroke and the risk for bleeding⁵.

8.2.1. Application of thromboembolism risk scores in AF

Risk scores are applied to guide the use of drugs that reduce the incidence of thromboembolic phenomena. However, all scores that have been published only exhibit moderate ability to predict stroke in AF (statistic between 0.55 and 0.70)⁶. The most validated score is the CHADS₂ score for risk stratification (C, deterioration of heart failure; H, history of hypertension; A, age > 75 years; D, diabetes; S, stroke or transient ischemic episode)⁷. Each risk factor has a weight of 1 point, with the exception of S, which has a weight of 2 points, and anticoagulation therapy with warfarin is recommended if the score is > 2. Recently, the CHA₂DS₂VASc score, which includes new risk factors, has been used⁸. Age > 75 years now weighs 2 points; moreover, V means previous AMI, peripheral vascular disease, or plaque in the aorta and weighs 1 point; A, age between 65 and 74 years adds a point; the female gender is represented by the letters Sc. Considering the previous version of the score, the absence of risk factor is considered to indicate low risk for AF and a score of 1 is considered to indicate intermediate risk. A score > 2 indicates high risk. There are no specific prospective studies considering HF. (section 4, "Use of antiplatelet and anticoagulant agents in atrial fibrillation," also addresses the CHADS₂ and CHA₂DS₂VASc scores.)

Table 1

The indication for medications should also be assessed taking into account the risk for the bleeding score HAS-BLED (H, arterial hypertension with systolic > 160 mmHg weighing 1 point; A, impaired liver or renal function weighing 1 point each; S, stroke weighing 1 point; B, bleeding weighing 1 point; L, unstable INR weighing 1 point; E, elderly (> 75 years) weighing 1 point; D, drugs or alcohol weighing 1 point each)⁹. Three or more points indicate high annual risk for bleeding, and the use of medication for the prevention of thromboembolism needs to be weighed against the risk. To justify the use of medications that are not associated with the reduction of mortality, the number of avoided nonfatal strokes should be higher than 1/3 of the number of major extracranial bleeding episodes⁶. (section 4, "Use of antiplatelet and anticoagulant agents in atrial fibrillation," also addresses the HAS-BLED score.)

8.3. Anticoagulation therapy in patients with HF and sinus rhythm

The WATCH study assessed patients with heart failure and sinus rhythm who were using vitamin K antagonist (dose adjusted according to INR) over 23 months. The incidence of stroke was 0.7% with vitamin K antagonist, 2.1%, with the use of ASA 162 mg, and 2.5% with clopidogrel 75 mg (p < 0.05)¹⁰. The number of hospitalizations was higher in the ASA group (22.2%) than in the group receiving the vitamin K antagonist. There was no difference in mortality. However, there was no placebo group. The WASH study, with a limited number of patients with heart failure and sinus rhythm, did not show a beneficial effect of the vitamin K antagonist with regard to mortality: however, the incidence of stroke was lower in the vitamin K antagonist group than in the placebo and ASA groups. Hospitalization was more frequent in the ASA 300 mg group (58%) than in the vitamin K antagonist group (42%) and the group without prophylaxis (48%) (p = 0.05)¹¹. The recently published WARCEF study¹² assessed 2,305 patients from 176 centers in 11 countries, with LVEF lower than 35%, with sinus rhythm. This double-blind study compared treatment with warfarin and target INR of 2-3.5 with treatment with aspirin at a dose of 325 mg/day. The mean follow-up of the study was 3.5 years. Compared with ASA, warfarin did not significantly reduce the rate of the primary outcome (7.47 events/100 person-years in the warfarin group and 7.93 in the aspirin group).

Therefore, at present, full anticoagulation is indicated for patients with heart failure and sinus rhythm, only as secondary prevention of thromboembolic events.

8.4. New anticoagulant agents for HF

New anticoagulant drugs have been recently proposed in the context of AF. The RE-LY, ROCKET AF, and ARISTOTLE clinical trials were recently published and compared warfarin with dabigatran, rivaroxaban, and apixaban with regard to the prevention of the primary outcome of stroke or systemic embolism. In the RE-LY trial, which tested dabigatran, a competitive thrombin inhibitor, of the 18,113 patients with AF, 5,793 had heart failure (32%)¹³. In the prespecified subgroup analysis of patients symptomatic for HF, dabigatran at the doses of 110 mg and 150 mg twice daily was not inferior or superior to warfarin in the prevention of the primary outcome, although at a dose of 150 mg, it reduced the primary outcome from 1.53% to 1.11% (p < 0.001 for superiority) in the overall group. There was no difference in mortality. Patients with CrCl < 30 ml/min should not receive dabigatran, and patients with some degree of renal impairment or low weight should receive a lower dose¹⁴. In the ROCKET study, rivaroxaban, a direct inhibitor of the activated factor X, was tested. It included 14,264 patients, 8,851 of which had heart failure (62%). Rivaroxaban was not inferior to warfarin in the overall group and in patients with heart failure with regard to the prevention of stroke or systemic embolism¹⁵. The ARISTOTLE study tested apixaban, an inhibitor of the activated factor X. It included 18,201 patients, 6,451 of which had heart failure¹⁶. In the overall group, compared with warfarin, apixaban reduced the primary outcome from 1.6% to 1.27% (p = 0.01 for superiority) and major bleeding from 3.09% to 2.13% (p < 0.001); however, there was a reduction in mortality from 3.95% to 3.52%, with p = 0.047, i.e., close to 0.05 despite the inclusion of a high number of patients. In the subgroup analysis of patients with HF, apixaban was not superior to warfarin. The disadvantages of using these new anticoagulant agents are the higher cost and the limitations in the treatment of bleeding episodes. The advantage is that there is no need to monitor INR, which is important in patients who do not adhere to an adequate control protocol. However, the main limitations are the lack of phase IV studies to assess safety in the "real world" and the lack of specific studies on HF. Moreover, there are no publications that include patients with heart failure caused by Chagas disease, which would be important because studies suggest that microembolism is more frequent in patients with this disease¹⁷.

Table 2

Table 3

8.5. Anticoagulation in HF due to Chagas disease

Chagas disease remains a serious public health problem in Brazil, with approximately 5 million infected individuals. It is estimated that 30% of these patients will develop the symptomatic clinical form of the disease, chronic chagasic cardiopathy (CCC), which is the most severe stage of the disease. Its most common clinical manifestations are tachycardia, bradyarrhythmia, thromboembolic phenomena, and HF¹⁸.

Thromboembolic phenomena are common complications because of the presence of dyskinesia and ventricular aneurysm, cardiac chamber dilatation, venous stasis, and AF¹⁹.

The presence of these factors favors the formation of intracavitary thrombi with subsequent systemic or pulmonary embolism. Chagas disease is the third cause of heart failure in Brazil²⁰. The annual incidence of thromboembolic phenomena is 1%-2% in CCC, and they are associated with aneurysm of the left ventricular apex and mural thrombosis.

In view of the specificities of Chagas disease, the most recent update of the Brazilian guideline on chronic heart failure considers that the treatment of heart failure of chagasic origin is similar to that of other etiologies, the only difference being the level of evidence⁵.

8.5.1. Application of thromboembolism risk scores in Chagas disease

The CHADS₂ scoreand more recently the CHA₂DS₂VASCscore are used for risk stratification in the treatment to reduce thromboembolic phenomena in HF in the presence of AF. The recommendation made for the use of warfarin in other forms of heart failure is applicable.

A Brazilian study published in 2008²¹ presented the development of a score (IPEC/FIOCRUZ - Instituto de Pesquisa Clínica Evandro Chagas/Fundação Osvaldo Cruz) for risk assessment and the prevention of stroke in Chagas disease, in particular. The presence of left ventricular systolic dysfunction contributed with 2 points, and apical aneurysm, ventricular repolarization alteration, and age > 48 years contributed 1 point each. Risk/benefit analysis revealed that warfarin is indicated for patients with 4-5 points (in this subgroup, the annual incidence of stroke was 4.4% and the annual incidence of major bleeding was 2%). In the subgroup with a score of 3 points, the rates of events and bleeding with anticoagulant agent are balanced, and both warfarin and ASA are indicated. In patients with 2 points, ASA or no prophylaxis is recommended because of the low incidence of stroke.

See Tables 4 and 5.

8.5.2. Anticoagulation with heparin in patients with Chagas disease

Anticoagulant drugs such as UH or LMWH can be used in this group of patients. Other antiplatelet and anticoagulant drugs have not been tested in the chagasic population; therefore, its use is not recommended. Recommendations follow the same line as those for patients with heart failure of other etiologies.

8.5.3. Use of new oral anticoagulant agents in patients with Chagas disease

Recent clinical trials such as the RE-LY, ROCKET AF, and the ARISTOTLE trials compared dabigatran, rivaroxaban, and apixaban with warfarin in the prevention of systemic thromboembolism. However, patients with Chagas disease were not included in this studies; therefore, there is no evidence in favor of its use in this group of patients^13,15,16.

9. Use of antiplatelet and anticoagulant agents in the perioperative period of cardiac and noncardiac surgeries

9.1. Introduction

Certain cardiovascular diseases often present some thromboembolic complications. Consequently, their treatment includes the use of drugs that inhibit platelet aggregation and delay blood coagulation. However, in the perioperative period, this activity may be inconvenient because blood coagulation needs to be partially or entirely completed for the surgical procedure to be successful. This creates a paradox that the involved professionals have to address during perioperative procedures using evidence to weigh the risk for bleeding against the risk for thromboembolic event and ensure patients' safety. We hope that the following recommendations help these professionals determine the lowest risk:

9.2. Indications for antiplatelet agents in cardiac surgery

9.2.1. ASA

The effect of ASA on the reduction of mortality, myocardial infarction, and cerebral thromboembolism in patients at risk for thromboembolic events, at the cost of higher risk for bleeding, has been demonstrated¹. Doses of 75-100 mg are as effective as doses >300 mg, with lower risk for bleeding². On the other hand, the variability of individual response to ASA and other antiplatelet agents has been shown. However, there is no practical clinical way of individualizing its administration and dosage.

In patients who are scheduled for cardiac surgery, the risk-benefit analysis of maintaining ASA in the preoperative period depends on the urgency of the situation, patient's cardiovascular risk, associated antithrombotic medications, and risk for bleeding³.

Although in the past, the recommendation was to discontinue the use of ASA for 3-5 days before cardiac surgery, this practice has not been in use for some years in most healthcare centers⁴. The current guidelines of the American Heart Association/American College of Cardiology regarding revascularization surgery recommend the administration of ASA before the surgical procedure (as Class I) because there is evidence of an association with better postoperative outcomes⁵. In modern perioperative management, potential bleeding is rarely associated with continued administration of ASA (Table 1).

9.2.2. Thienopyridines

Ticlopidine is the first-generation thienopyridine. In the second generation, clopidogrel was introduced; it became the preferred agent for the associated lower incidence of blood dyscrasias and bone marrow toxicity⁶. More recently, prasugrel was introduced. Antiplatelet drugs of this class are associated with major bleeding in the postoperative period and should be avoided or specific measures should be taken in perioperative management. All these agents irreversibly inhibit platelet aggregation, and antidotes are not available. Thus, to restore platelet function, the use of these drugs needs to be discontinued, and one should wait for 5-7 days for the circulating platelet population to be renewed.

These drugs should receive separate comments because they exhibit specific characteristics (Table 2).

9.2.2.1. Ticlopidine

This first-generation thienopyridine reduces the incidence of stroke, myocardial infarction, and death by vascular causes and is more effective than ASA. The maximum effect occurs after 3-5 days and lasts for up to 10 days after discontinuation. The adverse effects include diarrhea, allergic reaction, urticaria and erythema, and hemorrhagic (epistaxis, ecchymosis, menorrhagia) and hematolological (leucopenia, thrombocytopenia, pancytopenia) disorders⁷.

In systematic reviews of large clinical trials, it was considered to be as effective as or more effective than ASA in preventing cardiovascular events. However, with the advent of clopidogrel, a drug of the same class and with less side effects, its use became secondary in clinical practice, mainly because of the occurrence of diarrhea and neutropenia⁸.

9.2.2.2. Clopidogrel

This thienopyridine agent, a ADP P2Y12 receptor inhibitor, is the most widely used. It irreversibly inhibits platelet aggregation and should be discontinued 5-7 days before a surgical procedure to enable platelet renewal.

A recent multicenter analysis assessed the impact of exposure to clopidogrel for < 5 days before myocardial revascularization surgery on the outcomes of reoperation, major bleeding, and hospitalization time in patients with ACS. The risk-adjusted reoperation rate (OR) was 9.80%, (95% CI 2.18-43.95, p = 0.01) in the clopidogrel group, in which the rate of reoperations was 6.4%, compared with 1.7% in the group without clopidogrel (p = 0.004)⁹.

On the other hand, another recent analysis that compared the results obtained during three decades revealed that the management of surgical patients receiving clopidogrel had improved, which was demonstrated by the significant reduction in the occurrence of bleeding and mortality in recent years¹⁰.

There is individual variability in the response to clopidogrel as a result of the genetic characteristics of patients. Therefore, a laboratory assessment should be performed (point of care testing) to determine its action in a specific patient³.

In patients with recent ACS, stabilized with drug-based treatment, the preferred strategy is discontinuation for 5 days before the surgery, as mentioned above. During this period, the administration of ASA 100 mg/day and heparin is recommended. In patients at high risk for severe ischemic events (previous myocardial revascularization surgery, complex procedures, or with noncardiac comorbidities), the recommendation, which is rarely followed, is to perform antiplatelet therapy as "bridge to surgery" with drugs of short duration, i.e., GP IIb/IIIa inhibitors such as eptifibatide and tirofiban.

9.2.3. Glycoprotein (GP) IIb/IIIa inhibitors

This class of drugs inhibits the final step of platelet aggregation, preventing fibrinogen from binding to GP IIb/IIIa receptors and its conversion to fibrin. The available drugs are tirofiban, abciximab, and eptifibatide, all of which are intravenously administered. Their rapid activity onset, which occurs minutes after administration, and potency make them particularly effective for use in percutaneous coronary angioplasty and ACS but at the cost of higher risk for bleeding¹¹. They vary with regard to the mechanism of action and duration of the effect.

Tirofiban and eptifibatide. These agents have short duration and a reversible effect. Tirofiban is a peptidomimetic, with an amino acid sequence similar to that of fibrinogen. Eptifibatide is a hexapeptide that has a three-amino-acid sequence similar to the bothropic ophidic venom¹².

Abciximab. This is a long-acting monoclonal antibody that inhibits thrombin generation. It has a short half-life in plasma and exhibits cross-reactivity with leukocyte receptors. It has a potent platelet-inhibiting activity, with gradual recovery 24-48 h after discontinuation¹².

The use of these agents combined with UH is recommended for a short preoperative period of time as "bridge to surgery" in patients with ACS who were using clopidogrel. The latter should be discontinued at least 5 days before the surgery. During this period, the use of ASA at a low dose (up to 100 mg) and heparin is recommended. An alternative, although not very much used, could be the administration of GP IIb/IIIa inhibitors to prevent ischemic events during the preoperative period but at the cost of higher risk for bleeding. In patients at high risk for bleeding, the alternative is to form this bridge using an intra-aortico balloon for 48-72 h before the surgical procedure⁴. In Brazil, the postclopidogrel bridge has been preferentially used with UH and ASA.

Patients who undergo surgery with the use of GP IIb/IIIa inhibitors require special measures and discontinuation of the medication at the time of the procedure, if not before. Eptifibatide and tirofiban have short half-lives of approximately 2 h, and there may be platelet aggregation recovery at the end of the revascularization surgery. With regard to abciximab, although it has a short half-life in plasma (10 min), dissociation from platelets gradually occurs, and with a half-life of 4 h, platelet function returns to normal after 24-48 h and a rebound effect may occur. If excessive bleeding occurs, the recommendations include fresh platelet transfusion and fibrinogen supplementation with fresh plasma or cryoprecipitate; these measures may be applied alone or in combination¹³ (Table 3).

9.2.4. P2Y12 receptor inhibitors

For complete aggregation to occur, both receptors (P2Y1 and P2Y12) have to be inhibited; however, P2Y12 is predominant, and its binding to adenosin results in increased production of thromboxane and prolonged antiplatelet activity^14-18.

The antiplatelet therapy recommended for patients with ACS and for those undergoing a coronary stent implant comprises ASA and a P2Y12 receptor inhibitor^19,20.

The new P2Y12 receptor inhibitors alter the conformation of this receptor, resulting in its reversible inhibition, unlike old platelet inhibitors such as ticlopidine and clopidogrel that irreversibly bind to platelets^21,22. Platelet inhibition achieved by the new inhibitors prasugrel and ticagrelor has an earlier onset, on average 15-30 min after the initial dose vs. 1-2 h after the initial dose of clopidogrel, which has a higher effect (between 60% and 70% of inhibition 2-4 h after the initial dose vs. 30% 5 h after the initial dose of clopidogrel). Moreover, it exhibits a higher duration of action (up to 10 days vs. 7 days with clopidogrel)^23-30. Patients with ACS treated with prasugrel are more protected against ischemic events than patients treated with clopidogrel. However, they exhibit higher risk for bleeding³¹.

In the literature, some factors are associated with increased risk for postoperative bleeding, such as advanced age, preoperative anemia, emergency surgery, surgery with long extracorporeal circulation, and other comorbidities such as congestive heart failure, chronic obstructive pulmonary disease, and renal failure. In addition, one important factor associated with bleeding is the use of antiplatelet agents in the preoperative period. This type of drug is common in patients with coronary disease, particularly those with ACS. A series of studies have indicated that the use of P2Y12 receptor inhibitor is associated with major bleeding and that not even surgery without extracorporeal circulation seems to prevent this^9,32-34. Three studies suggest that the use of P2Y12 receptor inhibitors associated with ASA decreases the incidence of ischemic events and does not increase the rate of bleeding, provided that the P2Y12 receptor inhibitors are discontinued at least 5 days before surgery^35-37. Two recent studies have revealed that discontinuation 3 days before coronary surgery is sufficient^38,39.

In some series of studies, compared with clopidogrel, the two new P2Y12 receptor inhibitor agents prasugrel and ticagrelor did not exhibit an excessive increase in bleeding^40,41. However, this fact is not associated with coronary surgeries, i.e., even if the increase in the incidence of bleeding with the use of these drugs has not been demonstrated, bleeding associated with myocardial revascularization surgery in patients using these new antiplatelet agents is increased⁴¹. Studies have shown up to fourfold higher likelihood of bleeding with the use of prasugrel than with the use of clopidogrel, and both ticagrelor and clopidogrel have been shown to exhibit the same risk for bleeding during surgery if the drug is administered up to 72 h before surgery^31,42.

The Society of Thoracic Surgery (STS), in a guideline published in 2011³, recommends the discontinuation of P2Y12 receptor inhibitor agents at least 3 days before the surgical procedure. The previous recommendation was to wait for 5-7 days after the discontinuation of these drugs to perform surgery. However, many surgeons did not wait for this long³⁷, and because some studies^38,39 suggest that 3 days are sufficient, this is the current recommendation of STS.

ASA decreased the incidence of occlusion of venous grafts in the postoperative period. In the literature, there is a systematic review on the expansion of this concept to antiplatelet drugs⁴³. Their systematic use after myocardial revascularization increases the incidence of reoperation caused by bleeding, and in view of currently available evidence, is not indicated. The use of P2Y12 receptor inhibitors is indicated in patients with some contraindication for the use of ASA in the postoperative period⁴⁴. When its use is mandatory, it should be reintroduced 48 h after the end of surgery.

The American Heart Association, together with the American Association for Thoracic Surgery and STS, in their 2011 guideline for the management of antiplatelet drugs in myocardial revascularization surgery, recommend the discontinuation of ticagrelor 5 days before the surgery and discontinuation of prasugrel 7 days before the procedure. In cases of emergency reoperations, it is recommended that, if possible, these drugs be discontinued at least 24 h before surgery⁵ (Table 4).

9.2.5. Cilostazol

This is a cAMP inhibitor with antiplatelet and vasodilating functions. It has been used with good results in patients with severe peripheral vascular disease and intermittent claudication⁴⁵ for the secondary prevention of stroke⁴⁶ and helps reduce intrastent restenosis in coronary disease^47,48. It is used as part of the triple therapy associated with ASA and clopidogrel, and it decreases platelet aggregation in patients with AMI who undergo primary angioplasty⁴⁹. Some studies have revealed that its combination with ASA does not increase the bleeding time⁵⁰.

Moreover, cilostazol affects the smooth muscle of vessels that appears to prevent the occurrence of hyperplasia^51,52. This effect, in addition to preventing intrastent restenosis, decreases potential intimal hyperplasia that occurs at coronary anastomoses sites⁵³.

Onoda K et al.⁵⁴ revealed the benefits of combining cilostazol with ASA in patients undergoing myocardial revascularization without extracorporeal circulation. The authors mention that in surgeries without extracorporeal circulation, a state of hypercoagulation^55,56 occurs and that cilostazol is beneficial in the immediate postoperative period. In this study, both cilostazol and ASA were discontinued 7 days before the surgery (Table 5).

9.2.6. Dipiridamol and triple therapy

The articles on dipiridamol are outdated; the most recent publications are approximately 20 years old. In 1988, Teoh KH et al.⁵⁷ published a prospective and randomized study with 58 patients who underwent cardiac surgery with extracorporeal circulation. Forty patients who received dipiridamol, pre- and postoperatively, were compared with a control group of 18 patients. The preoperative administration of dipiridamol resulted in a significantly lower blood loss and lesser need for transfusion of blood concentrates. The authors concluded that dipiridamol leads to an increase in the number of platelets and reduces the postoperative risk for bleeding.

In 1975, another study⁵⁸ compared 12 patients who underwent cardiac surgery with extracorporeal circulation and were treated with dipiridamol in the pre- and postoperative periods, with a control group of 38 patients. As observed in the first study, the results revealed an increase in the number of platelets, and increased bleeding in the postoperative period was not observed.

In 1986, Chesebro and Fuster⁵⁹ conducted a study wherein the efficacy of dipiridamol in preventing early occlusion of the saphenous vein bridge was assessed. The authors reported that the agent decreased platelet deposition in the graft during surgery and that its use in the preoperative period is important. Similar to other studies, they did not observe increased postoperative bleeding.

In 1978, another study⁶⁰ evaluated antithrombotic therapy in patients subjected to myocardial revascularization with the saphenous bridge and internal thoracic artery. In this series, the authors reported that there was a clear advantage in terms of reduction in the graft occlusion rate a year after the surgery in patients who received dipiridamol, without an increase in the incidence of bleeding immediately after the surgery^60,61.

The most recent article was published in 1993, and it refers to positive results in terms of reduction in the graft occlusion rate in the late postoperative period in patients who used dipiridamol. An increase in bleeding in the immediate postoperative period was not reported. In the 2011 guideline of STS^62,63 and the American Society of Anesthesiologists³, dipiridamol is not mentioned as an agent responsible for increased postoperative bleeding.

With regard to triple therapy, there is no strong evidence to be considered; therefore, evidence regarding the individual drugs should be considered (Table 6).

9.3. Indications for anticoagulant agents in cardiac surgery

9.3.1. Heparin

Patients with ACS may require surgical treatment for myocardial revascularization. When they are administered heparin, they exhibit higher risk for postoperative bleeding and higher need for revision surgery and blood transfusion^64-73. Therefore, the potential clinical benefit of using heparin in the preoperative period should be weighed against the risk for major postoperative bleeding and higher need for blood transfusion that may lead to an increase in clinical complications and death at 30 days^74,75. Both blood derivative transfusion and revision surgery result in deterioration of the patient's clinical evolution and in increased costs and hospitalization time (Table 7).

The management of patients who use anticoagulant drugs in the perioperative period depends on the patient's risk for developing thromboembolic events when the use of the drug is discontinued and on the bleeding risk if anticoagulation therapy is not interrupted. Anticoagulation in the perioperative period is associated with a 3.0% increase in severe bleeding. It has been shown that INR (international normalization ratio) < 1.5 is not associated with perioperative major bleeding^76-78. Adequate adjustment of anticoagulation therapy is important to minimize thrombotic and hemorrhagic events.

Discontinuation of anticoagulant therapy increases the risk for embolic phenomena such as stroke and thrombosis of mechanical prostheses, and this risk varies according to the presence of other comorbidities. These events can have devastating clinical consequences: stroke can lead to significant incapacity or death in 70% of patients; mechanical prosthesis thrombosis can be fatal in 15% of patients⁷⁶.

According to risks for embolic events in the perioperative period and the associated comorbidities, the risk will be stratified into high, moderate, and low⁷⁸ (Tables 8 and 9).

When aiming for rapid INR normalization, replacements of deficient factors include fresh frozen plasma (FFP) and a prothrombin complex concentrate [Resolution RDC n. 10, of January 23, 2004, of the Agência de Vigilância Sanitária (ANVISA) determines that "for the correction of hemorrhages caused by the use of coumarin anticoagulants or rapid reversal of the effects of coumarin anticoagulants, the product of choice is the prothrombin complex. Because this type of concentrate is not yet widely available in Brazilian hospitals, FFP is an acceptable alternative."]⁷⁹.

The dosage of the prothrombin complex concentrate has not yet been standardized; however, its administration according to the patient's INR value is suggested (Tables 10 and 11).

9.3.3. Fondaparinux

Fondaparinux is a synthetic pentasaccharide that selectively inhibits factor Xa by binding to antithrombin. Fondaparinux has more affinity to antithrombin than the native pentasaccharide of UH or LMWH. This binding causes a conformational change in antithrombin that enhances (by a factor of 300) the natural inhibitory effect of antithrombin against factor Xa. This is how fondaparinux functions as an anticoagulant^80-85.

Fondaparinux has been studied in coronary disease, including unstable angina and AMI, and in patients subjected to PCI^86,87.

In patients who are using fondaparinux and need elective surgery, the anticoagulant activity persists for approximately 3-5 half-lives after discontinuation of the agent; in patients with normal renal function, the anticoagulant activity persists for 2-4 days. A longer period would be necessary in patients with decreased renal function. There is no available antidote to reduce this waiting period. Some studies revealed that high doses of the recombinant factor VIIa (90 µg/kg) were able to normalize, up to 6 h, partially prolonged aPTT, endogenous thrombin potential, and prothrombin activation in vivo in healthy volunteers who received 10 mg of fondaparinux^85,88. Recently, to make the use of fondaparinux safer, a variant antithrombin was developed as an antidote for heparin derivatives⁸⁹. However, there are no systematic studies that include patients with bleeding (Table 12).

9.3.4. Bivalirudin

The safety and efficacy of bivalirudin have been investigated in a series of clinical trials in patients with ACS. compared with monotherapy with heparins, isolated or in combination with antiplatelet drugs, bivalirudin reduced the combined primary outcomes (death, myocardial infarction, and emergency revascularization). In addition, it significantly reduced hemorrhagic complications^87-96. Based on the results of these studies and its beneficial effects, bivalirudin has been recommended, in the international guidelines, for use in patients with ACS treated in an invasive manner^91,92.

Bivalirudin has a linear anticoagulating dose-response behavior. The prothrombin time, aPTT, thrombin time, and activated clotting time linearly increase with an increase in the bivalirudin dose⁹⁷. A dose of 0.2 mg/kg/h of bivalirudin increased the prothrombin time from 12 to 16 s, aPTT from 27 to 62 s, and thrombin time from 15 to 73 s⁹⁸. The increase in the rate of bivalirudin infusion to 1 mg/kg/h resulted in a mean aPTT of 98 s, which returned to baseline within 4 h of infusion discontinuation⁹⁹ (Table 13).

9.3.5. Dabigatran

Dabigatran is a drug that directly inhibits the thrombin enzyme, responsible for converting fibrinogen into fibrin. Its use was approved by the European Medicines Agency in 2008 and more recently by ANVISA in Brazil and by the American FDA. It is an oral agent that can be used in a single daily dose, and there is no need to monitor its effect. However, dabigatran does not have an antidote⁷⁸.

Dabigatran has a half-life between 11 and 22 h in patients with normal renal function; in patients with renal impairment, the half-life can reach 35 h. Therefore, in procedures with a high bleeding risk, dabigatran should be discontinued between 2 and 6 days before the surgery^100,101.

In the case of acute intervention, dabigatran should be temporarily discontinued and the surgery should be postponed at least 12 h after the last dose. If it is not possible to postpone the surgery, hemorrhagic risk should be considered. This risk should be weighed against the urgency of the intervention (Table 14).

9.3.6. Rivaroxaban

This is an anticoagulant drug that directly inhibits activated factor X¹⁰². It is indicated for preventing VTE, stroke, and systemic embolism in patients with AF^102,103. Rivaroxaban should not be used in patients with renal failure, in patients with liver disease associated with coagulopathy, and in patients using antimycotic drugs and protease inhibitors for HIV. It should not be administered to individuals younger than 18 years, pregnant women (because of the risk of toxicity as it crosses the placenta), and breastfeeding women (because the drug is excreted in the milk)¹⁰⁰. Rivaroxaban has a mean half-life of 12 h and varies according to renal function¹⁰⁰. In situations of emergency, where the anticoagulating effects of rivaroxaban need to be reversed, the 4-factor prothrombin complex concentrate can be used at a dose of 50 IU/kg. Other products such as plasma and cryoprecipitates do not reverse the anticoagulating effect of this agent¹⁰⁰ (Table 15).

9.3.7. Apixaban

Apixaban is one of the newest oral anticoagulant drugs that directly inhibits activated factor X. It has been shown to be effective and safe in the prevention and treatment of thromboembolism^75,81,82,87. Few clinical studies exist, and the current recommendations are similar to those used for other direct inhibitors of activated factor X, such as dabigatran.

9.4. Management of antiplatelet agents in noncardiac surgeries

9.4.1. ASA

A large meta-analysis involving patients who underwent noncardiac surgery revealed that those receiving ASA exhibited up to 50% increase in the rate of perioperative bleeding. However, with the exception of neurosurgery and transurethral resection of the prostate, there was no increase in the occurrence of severe bleeding¹⁰⁴.

Till date, only one randomized, double-blind, and placebo-controlled study has been published on the perioperative use of ASA in noncardiac surgery. It included 220 patients with vascular disease who were already on ASA (i.e., patients on secondary prevention) and who were scheduled to have noncardiac surgical interventions. These patients were randomly assigned to stay on ASA or to discontinue this therapy in the perioperative period. The postoperative increase in troponin (primary goal) was lower in the group that stayed on ASA; however, the difference was not statistically significant, probably because of the number of patients in the study. However, there was a significant reduction in major cardiac events in patients who stayed on ASA in the perioperative period in comparison with patients who discontinued ASA (1.8% × 9.0%, p = 0.02). Although this was not one of the aims of the study, it did not demonstrate a difference in the rate of hemorrhagic complications between the groups¹⁰⁵.

In most situations, risk-benefit analysis of antiplatelet therapy in coronary patients who undergo noncardiac intervention favors the maintenance of ASA. Situations of exception include neurological surgery (in which even small bleedings can be catastrophic), transurethral prostatectomy (a procedure without primary hemostasis), and other circumstances wherein the risk of bleeding prohibits its use. In these cases, a minimum period of 7 days should be respected for reversal of the antiplatelet agent effect (Table 16).

9.4.2. Thienopyridines

In a systematic review of 37 studies on the use of thienopyridines in the perioperative period, Au et al.¹⁰⁶ concluded that this practice increased the need for reoperation because of bleeding [4.3% × 1.8% (OR 2.62, 95% CI 1.96-3.46)] and mortality [3.7% × 2.6% (OR 1.38, 95% CI 1.3-1.69)]. However, only six studies evaluated patients who underwent noncardiac surgery and, among these patients, the rate of events was too low to allow drawing definitive conclusions (six cases of bleeding that required reoperation among 230 patients and 14 deaths among 492 patients)¹⁰⁶.

In patients who underwent vascular surgery, although a greater number of studies was available, they included a small number of patients or events or they were observational and retrospective, which also did not allow drawing definitive conclusions. Burdess et al.¹⁰⁷ evaluated 113 patients with critical limb ischemia who underwent lower extremity revascularization, amputation, or femoral endarterectomy and who were randomized to receive clopidogrel 600 mg from 4 to 28 h before the surgery or a placebo at a dose of 75 mg/day after the surgery. All the patients were taking ASA. There was no difference in life-threatening major bleeding events between the groups: seven (14%) in the clopidogrel group and six (10%) in the placebo group (p = 0.56). However, the patients in the clopidogrel group exhibited an increase in the number of nonlife-threatening major bleeding events: 11 (22%) in the clopidogrel group and four (7%) in the placebo group (p = 0.024). Furthermore, 20 patients (40%) who received clopidogrel required transfusion of an erythrocyte concentrate, while only eight patients (14%) required this in the placebo group (p = 0.0019). There was no difference between the groups with regard to minor bleeding events (p = 0.12) or the duration of the surgery (p = 0.6) or hospitalization (p = 0.72)¹⁰⁷. De Borst et al.¹⁰⁸ evaluated three different strategies for antiplatelet therapy in 102 patients before carotid endarterectomy. The patients were divided into three groups: dipyridamole + ASA, dipyridamole + ASA + clopidogrel, and dipyridamole + ASA + dextran 40 mg. There was no difference among the groups with regard to the need for reoperation because of bleeding, which occurred in only five patients, thereby limiting the power of the study considerably¹⁰⁸.

Payne et al.¹⁰⁹ randomly assigned 100 patients, scheduled to undergo carotid endarterectomy, to receive 75 mg of clopidogrel or placebo in addition to ASA. There was no difference between the groups with regard to the need for blood transfusion (p = 1.0) and drainage volume (p = 0.65). However, there was an increase in the time to the closure of the surgical incision (p = 0.004) and a tendency for an increase in the occurrence of cervical hematoma (13% × 6%, p = 0.47) and in the need for revision surgery (11% × 6%) in the clopidogrel group, albeit without statistical significance¹⁰⁹. Other observational studies that evaluated the use of clopidogrel in association with ASA in the perioperative period of carotid endarterectomy also included a small number of patients and events; therefore, no significant differences were observed between the groups¹¹⁰. Stone et al.¹¹¹ performed an observational study of 10,406 patients who underwent carotid endarterectomy, lower extremity revascularization, and conventional and endovascular abdominal aortic aneurysm repair. Among these patients, 2,010 (19.3%) did not receive antiplatelet therapy, 7,132 (68.5%) received ASA, 229 (2.2%) received clopidogrel, and 1,017 (9.7%) received double antiplatelet therapy. There was no difference between the groups with regard to reoperation because of bleeding (without antiplatelet therapy, 1.5%; ASA, 1.3%; clopidogrel, 0.9%; and ASA with clopidogrel, 1.5%; p = 0.74) or the need for transfusion (without antiplatelet therapy, 18%; ASA, 17%; clopidogrel, 0%; and ASA with clopidogrel, 24%; p = 0.1). Meanwhile, the number of patients who received clopidogrel in the groups that underwent aortic aneurysm repair was too small to allow drawing conclusions regarding the use of clopidogrel in this population¹¹¹.

Evidence is even scarcer for patients who underwent nonvascular surgery. A retrospective study compared 28 patients who received clopidogrel up to 6 days before undergoing general surgery with 22 patients in whom the treatment was discontinued 7 or more days prior to surgery. Patients who used clopidogrel exhibited a greater number of bleeding events that required transfusion than those who suspended clopidogrel 7 or more days before the surgery (21.4% × 9.5%); however, this difference was not statistically significant (p = 0.53). Approximately 32% of the patients in the clopidogrel group and 40% of the patients in the clopidogrel discontinuation group were taking ASA. None of the patients presented bleeding that required reoperation, and there was no difference between the groups with regard to mortality or duration of hospitalization¹¹².

Sim et al.¹¹³ retrospectively evaluated 21 patients who were taking clopidogrel and underwent femoral fracture surgical repair and compared them with 114 control patients; those authors showed that there was no difference between the groups with regard to the need for transfusion or the presence of hematoma in the surgical wound¹¹³. Recently, Chechik et al.¹¹⁴ evaluated 60 patients with femoral fracture who were taking clopidogrel; among them, 30 patients underwent surgery during treatment with this agent and 30 patients underwent surgery only 5 days after the treatment was suspended. There was no difference between the groups with regard to the need for transfusion or mortality, although there was a tendency for a greater number of clinical complications related to immobility (PTE, pressure ulcers, pulmonary edema, and sepsis) in the group in which surgery was delayed because of the use of clopidogrel¹¹⁴. These data are important because early surgery in patients with femoral fracture reduces mortality, and delaying the surgery because of the use of clopidogrel may be more damaging than beneficial. Furthermore, the discontinuation of the administration of antiplatelet therapy in patients with coronary disease increases the risk of ACS¹¹⁵.

Another retrospective study compared 142 patients who were taking clopidogrel with 1,243 control patients who underwent colonoscopic polypectomy with regard to the occurrence of immediate and delayed bleeding. Seventy-seven patients (54%) in the clopidogrel group were also taking ASA. Although there was no difference between the groups with regard to immediate bleeding (2.1% × 2.1%), the patients who were taking clopidogrel exhibited a greater number of late bleeding events (3.5% × 1.0%, p = 0.02) and a greater need for hospitalization, transfusion, or additional intervention (2.1% × 0.4%, p = 0.04). We should consider that the eight patients in the clopidogrel group who exhibited bleeding were using ASA. In multivariate analysis, the independent variables that were related to bleeding were the use of double antiplatelet therapy (RR 3.69, 95% CI 1.6-8.52, p = 0.002) and the number of dried polyps (RR 1.28, 95% CI 1.19-138, p < 0.001)¹¹⁶.

It is possible that isolated antiplatelet therapy using clopidogrel does not represent a great risk for bleeding; however, there is no current evidence in support of this contention.

The decision regarding the continuation or discontinuation of antiplatelet therapy should always be reached after a risk-benefit multidisciplinary discussion among the cardiologist/clinician, the anesthesiologist, and the surgeon (Table 17).

9.4.3. Patients with coronary artery stents

Approximately 5% of patients who undergo coronary angioplasty with stent placement require noncardiac surgery within 1 year¹¹⁷. The premature discontinuation of double antiplatelet therapy is the main risk factor for stent thrombosis, with a thrombosis-related mortality that can reach 45%¹¹⁸. Other risk factors for thrombosis of the drug-eluting Stents (DES) are advanced age, stent placement because of acute coronary syndrome (ACS), diabetes mellitus, reduced left ventricular ejection fraction, chronic renal failure, and angiographic characteristics (ostial lesions, long stents, bifurcations, and small vessels)¹¹⁹. Patients who undergo angioplasty with placement of stent must take ASA indefinitely, and thienopyridines should be used for a minimum of 1 month for conventional stents and 12 months for DES¹²⁰. In approximately 30%-40% of patients in whom double antiplatelet therapy was prematurely discontinued, the reason for the discontinuation was surgical intervention¹²¹.

The performance of noncardiac operations less than 2 weeks after angioplasty with conventional stent placement is associated with prohibitive rates of perioperative complications (AMI or hemorrhagic complications)¹²². Nuttall et al.¹²³ retrospectively evaluated 899 patients who underwent noncardiac surgery up to 1 year after angioplasty with conventional stent placement. Forty-seven patients (5.2%) exhibited a cardiovascular event (death, AMI, and need for revascularization). The rate of cardiovascular events was 10.5% when the surgery was performed less than 30 days after angioplasty, 3.8% between 31 and 90 days, and 2.8% after 91 days. Therefore, the risk for cardiovascular complications significantly decreased with every 30 days that passed between the angioplasty and the surgery (p = 0.003)¹²³. In contrast, a study using the same design that evaluated 520 patients who underwent angioplasty with DES placement showed that the rate of cardiovascular events was constant during the first year after the angioplasty. A decrease in the rate of cardiovascular events was observed only after the first year after angioplasty with DES ¹²⁴. Therefore, elective noncardiac surgery should be postponed for at least 1 month after angioplasty with conventional Stent placement and 1 year after angioplasty with DES ^78,121.

Eisenberg et al.¹²⁵ conducted retrospective analysis of 161 cases of DES thrombosis to determine the average time between the discontinuation of double antiplatelet therapy and thrombosis. The average time for the occurrence of stent thrombosis was 7 days after the simultaneous or sequential discontinuation of ASA and clopidogrel, whereas it was 122 days for patients who discontinued only clopidogrel therapy and continued taking ASA. Moreover, among the 94 patients who continued ASA therapy and discontinued clopidogrel therapy, Stent thrombosis occurred within the first 10 days only in six cases¹²⁵. Therefore, in patients with an indication for the discontinuation of clopidogrel before a surgical procedure, this drug should be reintroduced as quickly as possible, preferably before 10 days after its discontinuation, to avoid stent thrombosis⁷⁸ (Table 18).

9.4.4. Glycoprotein (GP) IIb/IIIa inhibitors

A preliminary study evaluated the efficacy and safety of tirofiban as a bridging therapy in the perioperative period in patients with DES who underwent surgery within 1 year and thus required discontinuation of clopidogrel. The study included 30 patients who required emergency surgery with DES placement less than 6 months or less than 1 year prior to the surgery but who had risk factors for stent thrombosis. Clopidogrel was discontinued 5 days before the procedure and tirofiban was started 4 days before the surgery. The infusion of tirofiban was stopped 4 h before the procedure (8 h if CrCl was less than 30 ml/min), restarted 3 h after the procedure, and discontinued 4 h after the administration of a dose of clopidogrel. Clopidogrel was restarted using a loading dose of 300 mg right after the patient was allowed oral ingestion. There were no cardiovascular events during hospitalization. One patient exhibited major bleeding (proctorrhagia on the 7th postoperative day) and required transfusion; this symptom was reversed after colonoscopic clipping. Two patients exhibited minor bleeding and required transfusion¹²⁶. This was a pilot study that included few patients and no ischemic events, which does not allow recommending bridging therapy with tirofiban as a routine procedure; however, it can be used in patients at a very high risk of stent thrombosis.

It should be stressed that the use of UH or LMWH as bridging therapy for preventing stent thrombosis is not indicated because these agents not only protect against stent thrombosis but also yield a rebound prothrombotic effect after their discontinuation.

Abciximab is a universal platelet inhibitor with an action that lasts for 7 days; therefore, there is no indication for its use in the perioperative period in noncardiac surgeries, given its high risk of hemorrhage¹¹⁸ (Table 19).

9.4.5. Cilostazol

Cilostazol has a half-life of approximately 10 h. In general, its administration is discontinued because of a high level of occurrence of side effects, such as headache and gastrointestinal disturbances. In addition, it is contraindicated in patients with heart failure because of its potential to induce ventricular arrhythmias¹²⁷.

No studies have evaluated the benefits or potential damaging effects of the use of cilostazol in the perioperative period of noncardiac surgeries. Based on the potential increase in bleeding and absence of evidence that corroborate the benefits of its continuation in this context, it is recommended that cilostazol be discontinued on the day before the planned noncardiac surgery (Table 20).

9.4.6. Dipyridamole

Similar to cilostazol, dipyridamole has a half-life of approximately 10 h. Although it exerts reversible effects on platelet function, dipyridamole is associated with an increase in the risk of bleeding, particularly when co-administered with ASA^128-130.

A study analyzed the rate of postoperative cerebral embolism detected by transcranian Doppler in 120 patients who underwent carotid endarterectomy and were on three different antiplatelet regimens, all of which included a combination of ASA and dipyridamole. There was no difference in embolic events between the groups (despite the low number of patients analyzed); however, a higher rate of bleeding than that usually detected in this type of procedure was observed in all the groups^128-130. Because of a potential increase in risk for bleeding, it seems prudent to discontinue dipyridamole on the day before noncardiac surgery. Risk-benefit evaluation for the continuation of ASA must be performed at the individual level (Table 21).

9.5. Management of anticoagulants in noncardiac surgeries

9.5.1. Heparin

9.5.1.1. Anticoagulation bridging therapy during the perioperative period

In the absence of randomized studies evaluating the risks and benefits of anticoagulation bridging therapy, the transition regimens of oral anticoagulation during the perioperative period considerably vary among different departments. Therefore, there is no established regimen for the management of anticoagulation during the perioperative period. The main goal of this bridging therapy is the maximal minimization of the risk for arterial thromboembolic events in patients with metallic prosthetic valves and risk for AF and to avoid the recurrence of previous thromboembolic events. Therefore, the indication for the transition from oral anticoagulation to parenteral or subcutaneous anticoagulation is based on two main factors: risk for thromboembolic events after the discontinuation of anticoagulation and risks for bleeding and the proposed surgery⁷⁸.

The existing directives recommend the estimation of the risk for thromboembolism and the evaluation of the risk for perioperative bleeding for managing perioperative anticoagulation^78,131. The appraisal of the risk for perioperative thromboembolic events is mainly based on the three clinical conditions that result in the indication of oral anticoagulation: the presence of a mechanical prosthetic valve, presence of atrial fibrillation (AF), and previous history of ventous thromboembolism (VTE). Both the perioperative guideline of the Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia) and the latest update of the American College of Chest Physicians similarly classify the estimation of the risk of thromboembolic events during the perioperative period (Table 8)^78,131.

In general, in surgical procedures with a low risk for bleeding, it is not necessary to discontinue oral anticoagulation. The procedures can be performed at therapeutic INR^78,131. In patients classified as being at low risk for thromboembolic events, there is no need to maintain full anticoagulation during the whole perioperative period because of the low incidence of arterial thromboembolic events in this population. The temporary discontinuation of oral anticoagulant therapy and the use of a prophylactic dose of heparin to prevent thromboembolic events during the perioperative period are indicated. In patients who are considered as being at high risk for thromboembolic events who are scheduled to undergo surgical procedures with moderate to high risk of bleeding, oral anticoagulation bridging therapy is recommended in the perioperative period. In patients at moderate risk, the two approaches mentioned above are used and well accepted. Usually, the indication for a transition from oral anticoagulant therapy is decided by medical evaluation.

9.5.1.2. Mechanical prosthetic valve

Patients with a mechanical prosthetic valve are considered as a group at high risk for thromboembolic events because the rate of events reaches approximately 8% in patients without anticoagulation therapy. The discontinuation of oral anticoagulant drugs in the perioperative period can lead to thromboembolic events such as stroke, systemic embolism, and/or prosthesis thrombosis.

There are no randomized clinical studies with adequate methods that have assessed strategies for anticoagulation bridging therapy in patients with a mechanical prosthetic valve. The existing studies that have evaluated perioperative anticoagulation in patients with mechanical prostheses are scarce and limited. The first studies comprised retrospective series and a single prospective study with a small number of patients who discontinued perioperative anticoagulation or were on unfractionated heparin (UH)^132-134. Thus, perioperative anticoagulation was interrupted (patients with a mechanical prosthetic valve in the aortic position) or performed using UH (patients with a mechanical prosthetic valve in the mitral position). The results of these studies were very limited because there was no established system for anticoagulation management and the follow-up results were not adequately recorded^132-134.

In the absence of scientific evidence regarding the best strategy for perioperative anticoagulation management in patients with indication for bridging therapy, the adopted standard was patient hospitalization and transition to UH in the perioperative period. This choice of anticoagulation approach was confirmed by a Canadian study that assessed the preference for this type of heparin as anticoagulation bridging therapy in patients with a mechanical prosthetic valve, wherein the physicians preferred to use UH for its safety and effectiveness¹³⁵.

In recent years, this practice has been replaced by the use of low-molecular weight heparin (LMWH) because this form of treatment can be administered out of the hospital. Few studies have assessed the use of LMWH as perioperative anticoagulation bridging therapy in patients with a mechanical prosthetic valve. A review study by Spyropoulos et al.¹³⁶ included five studies assessing the efficacy and safety of changing anticoagulation therapy to LMWH in 749 patients with a mechanical prosthetic valve. The rate of cardioembolic complications was 0.4% and the bleeding rate was 2.8%, which showed that it was safe to use LMWH in patients with a mechanical prosthetic valve ¹³⁶.

In patients for whom maintenance of perioperative anticoagulation is indicated, oral anticoagulation therapy with warfarin is usually discontinued 5 days before the surgical procedure and short-term heparin bridging therapy is initiated. This transition can be performed both with intravenous UH and with subcutaneous LMWH, at the therapeutic dose, and the last doses of heparin before the surgery should be in accordance with the half-life of the drug used. The use of UH as an oral anticoagulation bridging requires the patient to be hospitalized before the surgical procedure. In addition, the use of intravenous heparin requires monitoring of aPTT to adjust the therapeutic dose (with target aPTT between 1.5 and 2.5). Its use is usually reserved for patients for whom the use of LMWH is contraindicated, such as patients with severe renal failure or those undergoing dialysis. Anticoagulation transition to LMWH appears to be a good alternative because it can be administered out of the hospital and there is no need to perform laboratory monitoring of the therapeutic level. However, its use should be avoided in some situations, particularly in patients with renal failure (CrCl < 30 ml/min).

There are no randomized studies in the literature comparing different perioperative anticoagulation management strategies and analyzing the best procedure for anticoagulation transition. Most existing studies are prospective and retrospective observational studies that evaluated different forms of anticoagulation transition.

The aim of the REGIME study was to assess perioperative anticoagulation management using two forms of heparin. This was a multicenter, prospective, and observational study involving 14 American and Canadian centers where information on perioperative anticoagulation was collected. The physician in-charge was responsible for deciding what type of bridging therapy would be used for the transition. The 901 patients were divided into two groups: one group received UH as an anticoagulation bridging (180 patients) and another group received LMWH administered twice daily (721 patients). The percentage of patients who received the dose of postoperative heparin was similar in both the groups (91.1% UH × 92.6% LMWH, p = 0.49). The rate of thromboembolic events was low in both the groups (2.4% in the UH group × 0.9% in the LMWH group). There was no statistically significant difference in the rate of major bleeding between the two groups (5.5% UH × 3.3% LMWH, p = 0.25). The group of patients who received anticoagulation bridging therapy with LMWH underwent more procedures as outpatients or was hospitalized for less than 24 h (63.6% × 6.1%, p < 0.001). Among the patients hospitalized for surgeries, the LMWH group was also hospitalized for a shorter time than the UH group (4.6 × 10.3 days, p < 0.001). Although this was the first study to compare anticoagulation transition therapies, it presented important limitations such as not being randomized and not having a control group. The results revealed that the two strategies were as effective and safe as the oral anticoagulation bridging therapy; however, LMWH had the advantage of being administered outside the hospital¹³⁷.

With the aim of assessing the efficacy and safety of LMWH as anticoagulation bridging therapy, Douketis et al.¹³⁸ conducted a study involving 650 patients with a mechanical prosthetic valve, AF, and history of stroke. Warfarin was discontinued 5 days before the surgical procedure, and the patients received anticoagulation transition therapy with dalteparin 100 IU/kg twice daily, which was started on average 3 days before the surgery. The last dose of preoperative dalteparin was administered at least 12 h before the surgery to avoid bleeding. In patients subjected to procedures classified as having high risk for bleeding, the postoperative dalteparin dose was not administered. The main outcomes analyzed were thromboembolism, major bleeding, and mortality. Oral anticoagulation was restarted the day after the surgery. In a mean follow-up period of 13.8 days, there was a low incidence of thromboembolic events (0.4%) and bleeding (0.7% and 1.8%) in this group¹³⁸.

Another multicenter prospective cohort study published in the same year also aimed to assess the safety and efficacy of bridging therapy with LMWH. The study included patients at high risk for arterial thromboembolism (patients with a mechanical prosthetic valve and AF). The study included 224 patients, 112 of which had a mechanical prosthetic valve and 112 had AF. The oral anticoagulant drug was discontinued 5 days before the surgery, and anticoagulation therapy transition was performed with LMWH, which was started 3 days before the surgery and was maintained for 4 days postoperatively. The preoperative dose of dalteparin administered was 200 IU/kg daily. On the day before the surgery, the patients received a dose of 100 IU/kg. In the postoperative period, warfarin was restarted on the first day after the surgery together with a dose of 200 IU/kg of dalteparin; patients at high risk for bleeding were administered a fixed dose of 5000 IU. The rate of thromboembolic events was 3.6% and that of bleeding was 6.7%. The authors concluded that the transition to LMWH was possible but that randomized and controlled studies were required to better define the strategy¹³⁹.

Further assessing the use of LMWH as anticoagulation bridging therapy, the PROSPECT study aimed to evaluate the safety of oral anticoagulation transition with a dose of 1.5 mg/kg of enoxaparin administered daily at home. This was a multicenter prospective cohort study with 260 patients with AF or VTE, and the primary outcome of the study was bleeding incidence. The rate of major bleeding observed in the study was 3.5%; however, analysis of bleeding risk according to the type of surgical procedure revealed that the bleeding rate was higher in the group of patients subjected to major surgeries (orthopedic, cardiovascular, and general surgeries) than in the group of patients subjected to minor procedures (20% vs. 0.7%)¹⁴⁰.

In 2009, a prospective cohort study analyzed patients who were on chronic oral anticoagulation therapy and were subjected to different regimens of anticoagulation bridging therapy in surgical procedures. Warfarin was discontinued 5 days before the surgery and LMWH was initiated (nadroparin or enoxaparin) 4 days before the surgery. The last dose of LMWH was administered at least 12 h before the surgery. Two strategies were adopted for anticoagulation therapy transition. The patients classified as being at high risk for thromboembolic events received bridging therapy with a full dose of LMWH twice daily. All the remaining patients classified as being at moderate or low risk received only a prophylactic dose of LMWH once daily. Of the 1,262 patients included in the study, 23.4% were considered as being at high risk for thromboembolic events and received transition therapy with a full dose of heparin, whereas 76.6% of patients received only a prophylactic dose of heparin. In terms of efficacy, only five cases of thromboembolic events occurred in the high-risk group, with an incidence of 0.4% (95% CI 0.1-0.9). The incidence of major bleeding, in this study was 1.2%, and it was higher in the high-risk group than in the moderate/low risk group (2.7% vs. 0.7%, p = 0.011). The rate of minor bleeding was 4.2% and more significant in the group of patients who received transition therapy with full dose heparin¹⁴¹.

A pharmacoeconomics study that compared the cost of both regimens of perioperative anticoagulation transition therapy revealed that the use of LMWH was the best choice because its cost was lower than that of intravenous heparin, given the possibility of administering the drug outside the hospital, with a reduction in hospitalization costs⁷⁷.

In conclusion, the studies showed a preference for anticoagulation bridging therapy with LMWH because of its ease of administration, without the need for patient hospitalization and therefore lower cost. On the other hand, when the use of LMWH is contraindicated, UH remains the indicated therapy.

9.5.1.3. Timing of heparin discontinuation before surgery

There are no studies assessing the heparin discontinuation time in the preoperative period. The indication is mainly based on the half-life of heparin. Because of its short half-life, with elimination between 30 and 120 min, it is safe to discontinue UH between 4 and 6 h before the surgery¹³¹.

With regard to LMWH, observational clinical studies revealed that discontinuation of LMWH 12 h before the surgery did not increase bleeding during surgery. However, studies that assessed the substitute outcomes such as anti-Xa level dosage revealed that > 90% of patients who received the last dose of heparin 12 h before the surgery still exhibited the anticoagulating effect and > 34% of patients maintained a therapeutic level of anticoagulation. These findings are the basis for the current indication for LMWH to be discontinued at least 24 h before the surgery¹³¹.

For restarting LMWH in the postoperative period, the effectiveness of hemostasis and risk for bleeding should be taken into account. In surgeries with high risk for bleeding, the reintroduction of LMWH should be performed at least 24 h after the end of the surgery, ideally 48-72 h. In procedures with low or moderate risk for bleeding, reintroduction can be performed within 24 h after the surgery¹³¹ (Table 22).

9.5.2. Warfarin

The use of anticoagulant agents in the perioperative period depends on the patient's risk for developing thromboembolic events when the agent is discontinued and on the bleeding risk if anticoagulation therapy is not interrupted. Discontinuation of the anticoagulant drug increases the risk for embolic phenomena, such as stroke and mechanical prosthesis thrombosis, and this risk varies according to the presence of other comorbidities and risk factors^77,78,81,142. These events can lead to devastating clinical consequences: stroke leads to significant incapacity or death in 70% of patients; mechanical prosthesis thrombosis is fatal in 15% of patients⁷⁷.

Similar to cardiac surgery, according to risks for embolic events in the perioperative period and comorbidities, risk should be stratified into high, moderate, and low risk, according to the recommendations of the Brazilian Society of Cardiology in the II Perioperative Guideline (Table 8)⁷⁸.

The recommendations for discontinuation of warfarin in the perioperative period are shown in the tables below. In the case of surgery with reintroduction of the drug, urgency/emergency, or need for rapid reversal of the effect of warfarin, the recommendations mentioned for cardiac surgery should be followed (Table 23).

9.5.2.1. Procedures with low risk of bleeding

The following procedures are considered as exhibiting low risk for bleeding: cataract surgery, minor dermatological procedures, and dental procedures (e.g., hygiene, simple extraction, restoration, endodontic, and prosthetic procedures). In these cases, the recommendations in Table 24 should be followed.

9.5.3. Fondaparinux

There are two double-blind randomized studies that assessed the efficacy of fondaparinux as preventive therapy in the perioperative period of general surgery. In the first study, fondaparinux was compared with dalteparin in patients at high risk for VTE undergoing abdominal surgery. In total, 2,927 randomized patients were selected from 131 centers in 22 countries. Fondaparinux was administered 6 h after the end of the surgery. The first dose of dalteparin (2,500 IU) was administered 2 h before the surgery and the second dose was administered 12 h after the end of the surgery. On subsequent days, the administered dose of dalteparin was 5,000 IU per day. The primary outcome of efficacy was the occurrence of VTE (symptomatic or symptomatic). The safety outcome adopted in the study was major bleeding. The rate of VTE was 4.6% in the fondaparinux group and 6.1% in the dalteparin group, with a 24.6% reduction in relative risk (95% CI 9.0-47.9); however, the difference was not statistically significant (p = 0.14). There was no statistically significant difference in bleeding between the two groups (3.4% in the fondaparinux group vs. 2.4% in the dalteparin group, p = 0.12). The results revealed that fondaparinux was not superior to dalteparin as prevention therapy in general surgery; however, analysis of noninferiority revealed that it was at least as effective as LMWH¹⁴³.

In another double-blind, randomized, and placebo-controlled study on intra-abdominal general surgery, patients were randomly assigned to receive prevention therapy with fondaparinux at a dose of 2.5 mg started between 6 and 8 h postoperatively in combination with intermittent pneumatic compression or intermittent pneumatic compression alone. The primary outcome was the occurrence of venous thromboembolic events at the 10th day after the surgery. In total, 1,309 patients were selected from 50 centers. The group of patients that received fondaparinux exhibited a lower rate of VTE (1.7% vs. 5.3%, RR 69.8%, 95% CI 27.9-87.3, p = 0.004). Moreover, fondaparinux reduced the rate of proximal PVT by 86.2% (p = 0.037); however, there was no difference in the rate of symptomatic VTE or mortality between the two groups. Major bleeding was 1.6% in the fondaparinux group and 0.2% in the control group (p = 0.006). Among the cases of bleeding, there was no fatal bleeding or critical organ. Most bleeding resulted from surgical wounds¹⁴⁴.

These studies revealed that fondaparinux is effective in perioperative thromboprophylaxis, both in general and orthopedic surgeries. However, its use is associated with higher risk for bleeding.

In previous meta-analyses, thromboprophylaxis with UH was shown to be effective in the reduction of mortality¹⁴⁵, whereas the use of LMWH did not produce the same results¹⁴⁶. For analyzing the effect of fondaparinux on mortality in studies on VTE prevention, the following meta-analysis was performed. Eight randomized, double-blind, phase III studies were included, with a total of 13,085 patients. The studies focused on the prevention of TEV using fondaparinux at a dose of 2.5 mg daily compared with that using LMWH (in five studies) or a placebo (in three studies). The main objective of the study was to analyze the effect of fondaparinux on mortality at 30 days; day 1 was the day of randomization. Of the eight studies included in meta-analysis, seven were performed in a perioperative context (abdominal or orthopedic surgeries), with a total of 12,236 patients, and one was performed with medical patients. The first dose of fondaparinux in the surgical studies was administered 6 ± 2 h after the surgery and the second dose was administered at least 12 h after the first dose and 24 h before the end of the surgery. The results of meta-analysis revealed a 21% reduction in the risk for mortality in the group that received fondaparinux in comparison with the control group; however, the reduction was not statistically significant (1.6% vs. 2.1%, RR 0.79, 95% CI 0.6-1.01, p = 0.058). This result was consistent both when fondaparinux was compared with LMWH (fondaparinux 1.5% × LMWH 1.9%, OR 0.78, 95% CI 0.58-1.06, p = 0.11) and with a placebo (2.0% vs. 2.6%, RR 0.77, 95% CI 0.46-1.26, p = 0.3). Thus, in the analyzed studies, fondaparinux did not have an effect on perioperative mortality¹⁴⁷.

Based on the previous meta-analysis, the authors analyzed of the association between the occurrence of bleeding and mortality at 30 days and identified the risk factors associated with the risk for bleeding. The risk factors identified as predictors of higher risk for bleeding were age, male gender, low weight, low CrCl, hip surgery or any type of surgery, absence of history of VTE, and treatment with fondaparinux. The mortality rate in the group with some type of bleeding was almost sevenfold higher than that in the group without bleeding (RR 6.83, 95% CI 4.57-10.22, p < 0.001), regardless of the prevention therapy administered. This was the first study to establish a relationship between bleeding and increased mortality in studies on the prevention of VTE¹⁴⁸.

The results of these studies showed that fondaparinux is effective as a thromboprophylactic strategy in the perioperative period in noncardiac surgery. In these studies, fondaparinux was as effective as or more effective than LMWH. However, the use of fondaparinux is associated with a higher rate of nonfatal bleeding and therefore with the need for more blood transfusions in the perioperative period.

No studies have assessed the use of fondaparinux as anticoagulation bridging therapy, probably because of its long half-life and risk for perioperative bleeding (Table 25).

9.5.4. Dabigatran

In patients with normal renal function, dabigatran can be discontinued 48 h before to ensure adequate hemostasis. In procedures with low risk for bleeding, dabigatran can be discontinued 24 h before the surgery. These procedures include catheterism, ablation, endoscopy, colonoscopy without polyp removal, simple laparoscopy, and small orthopedic surgical procedures¹⁰⁰. In major elective surgical procedures in patients with normal renal function, it is recommended to discontinue the agent for 1-2 days¹⁰⁰. In patients with compromised renal function, the discontinuation period should be longer¹⁰¹.

In patients with moderate renal impairment, patients aged > 75 years, and those receiving amiodarone, it is recommended to reduce the standard dose to 150 mg/day (initial dose of 75 mg, followed by a standard dose of 150 mg, once daily)⁷⁸.

Precaution should be taken when the treatment is temporarily discontinued owing to interventions, and coagulation monitoring should be ensured. This should be taken into account in any procedure. A coagulation test can help determine whether hemostasis is still altered.

In the case of an acute intervention, dabigatran should be temporarily discontinued and the surgery should be postponed until at least 12 h after the last dose¹⁰⁰. If it is not possible to postpone the surgery, risks for hemorrhage should be weighed against the urgency of the surgery¹⁰⁰.

Reintroduction of medication exclusively depends on risks for postoperative bleeding¹⁰⁰. In the case of abdominal urological surgery with incomplete hemostasis, the agent should only be reintroduced when there are no signs of active bleeding. In the case of small procedures with good hemostasis, the agent can be started between 4 and 6 h after the procedure and the use of a half dose (75 mg), followed by maintenance of the usual dose, is suggested¹⁰⁰ (Table 26).

9.5.5. Rivaroxaban

Discontinuation of the agent should follow the same recommendations indicated for dabigatran. However, the adequate discontinuation time is shown in Table 27.

In emergency situations where reversal of the anticoagulation effect of rivaroxaban is required, 4-factor prothrombin complex concentrates can be used at a dose of 50 UI/kg¹⁰⁰. Other products such as plasma and cryoprecipitates do not reverse the anticoagulating effect of this agent¹⁰⁰.

With regard to reintroduction of the agent in the postoperative period, a strategy similar to that used for dabigatran can be used for rivaroxaban. The drug should be started at a dose of 10 mg (first dose), and following this, the usual dose should be maintained¹⁰⁰.

9.5.6. Apixaban

Apixaban is one of the newest oral anticoagulant agents, and it has been shown to be effective and safe in the treatment of thromboembolism¹⁴⁹. After an extensive literature review, most questions regarding the perioperative period could not be answered according to the class of recommendation and level of evidence because this agent has not yet been tested in clinical trials.

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10. Specificities of antiplatelet and anticoagulant agents

10.1. Introduction

In recent years, advances have been made with regard to the treatment of heart diseases, particularly acute coronary syndromes (ACS,) and more recently, in the prevention of thromboembolic phenomena in atrial fibrillation (AF). Recent studies and new evidence have shown that cardiologists are increasingly familiarized with the new drugs.

The introduction of new antiplatelet and anticoagulant drugs makes it appropriate to study all the specificities of these agents and to review and update the older agents that are still in use in our daily practice.

In this chapter, we aim to review the mechanism of action, pharmacokinetics, therapeutic indications, precautions, contraindications, drug interactions, bleeding risk, and particularities of special groups to allow the reader to use these drugs with maximum efficacy and safety.

10.2. Specificities of antiplatelet agents

Table 1

Table 2

Table 3

Table 4a

Table 4b

Table 5

Table 6

Table 7

Table 8

10.3. Specificities of anticoagulant agents

Table 1

Table 2

Table 3

Table 4

Table 5

Table 6

Table 7

Publication Dates

• Publication in this collection
  05 Nov 2013
• Date of issue
  Sept 2013