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SBA Recommendations for regional anesthesia safety in patients taking anticoagulants

Description of evidence collection method

We conducted searches in multiple databases (Medline 1965-2012; Cochrane Library, Lilacs) and cross-references with the collected material to identify studies with better methodological design, followed by a critical evaluation of their contents and classification according to the strength of evidence.

We conducted searches between August and December 2012. The following strategies were used for searches in PubMed:

  1. "regional anaesthesia" OR "anesthesia, conduction" OR "anesthesia" AND "conduction" OR "conduction anesthesia" OR "regional" AND "anesthesia" OR "regional anesthesia" AND "antithrombotic";

  2. "regional anaesthesia" OR "anesthesia, conduction" [MeSH Terms] AND "infection" [MeSH Terms] AND "thromboembolism" [MeSH Terms] OR "thromboembolism" [All Fields];

  3. "thromboembolism" [MeSH Terms] OR "thromboembolism" [All Fields] AND "regional anaesthesia" [All Fields] OR "anesthesia, conduction" [MeSH Terms] OR "anesthesia" [All Fields] AND "conduction" [All Fields]) OR "conduction anesthesia" [All Fields] OR "regional" [All Fields] AND "anesthesia" [All Fields] OR "regional anesthesia" [All Fields].

In the field of regional anesthesia, we selected studies addressing managements of different types of regional anesthesia in individuals taking drugs that modify the blood coagulation status. We focused on risk factors, etiology, prevention, diagnosis, and treatment. We also included studies assessing the risk of complications in patients after regional blockade and studies that clarify the management and safe handling of drugs to be administered.

Level of evidence and strength of recommendation

  1. Experimental or observational studies with better consistency.

  2. Experimental or observational studies with less consistency.

  3. Case reports or case series (non-controlled studies).

  4. Opinion without critical evaluation, based on consensus, expert opinions, physiological studies, or animal models.

Objective

To assess the safety aspects of regional anesthesia and analgesia, such as the possible technique's complications; risk factors associated with spinal hematoma, prevention strategies, diagnosis, and treatment; and safe interval for drug suspension and resumption after regional block in patients taking antithrombotic drugs.

Introduction

The current incidence of neurological dysfunction resulting from bleeding complications associated with neuraxial block is unknown.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106. Its occurrence is estimated to be less than 1:150,000 epidural punctures and 1:220,000 subarachnoid punctures.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106. After neuraxial anesthesia, the use of anticoagulants is the risk factor most often associated with spinal hematoma.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31. Because spinal hematoma is rare, recommendations regarding regional anesthesia and concomitant use of thromboprophylaxis or antithrombotic therapy, which would be of greater predictive value if reported by prospective randomized studies, are based on case reports and expert recommendations33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015., which ethically precludes the study.

The number of patients on anticoagulant therapy has been growing due to the aging process, longer life expectancy, and prevalence of cardiovascular disease. Recommendations on safety in regional anesthesia and antithrombotic therapy should be constantly updated, as the introduction of new antithrombotic drugs to the market is done at regular intervals.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

This guideline aims to review the risks and recommendations for regional anesthesia in subjects taking drugs that interfere with coagulation and present safety regulations and guidelines required for regional procedures.

Spinal/epidural hematoma

Incidence

Although the incidence of spinal-epidural hematoma (SEH) is small, the clinical severity of its consequences, along with litigation costs that follow an adverse event, makes it crucial to develop sound strategies for the management of patients on anticoagulants during neuraxial anesthesia.44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208.

In a literature review55. Tryba M. Epidural regional anesthesia and low molecular heparin: Pro. Anasthesiol Intensivmed Notfallmed Schmerzther. 1993;28:179-81. assessing several case reports, we noted that the incidence of SEH was 1:220,000 after spinal anesthesia and 1:150,000 after epidural puncture. However, recent indications suggest a higher incidence, as the studies used in these calculations were conducted before the perioperative thromboprophylaxis routine.66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

After the introduction of enoxaparin (30 mg, twice daily) for thromboprophylaxis in the United States, an alarming number of cases of epidural hematoma, some with permanent paraplegia, the risk of spinal/epidural hematoma with twice daily administration of enoxaparin was reported and calculated at 1:40,800 after spinal anesthesia, 1:6,600 after simple epidural puncture, and 1:3,100 after epidural puncture with epidural catheter insertion.77. Schroeder DR. Statistics: detecting a rare adverse drug reaction using spontaneous reports. Reg Anesthesia Pain Med. 1998;23:183-9. In Europe, a single dose administration of enoxaparin (40 mg) showed a lower incidence of spinal hematoma. In a retrospective Swedish study,88. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology. 2004;101:950-9. the authors found a risk of 1:156,000 after spinal anesthesia and 1:18,000 in epidural anesthesia. Bleeding was rare in the obstetric population (1:200,000) compared with that of women undergoing knee arthroplasty (1:3,600). Subsequent studies showed incidences as high as 1:2,700 to 1:19,505.9–11 However, Cook et al. presented updated results at the Third National Audit Project of the Royal College of Anaesthetists in which only eight cases of SEH were seen in 707,405 neuraxial blocks. Of these, only five met the inclusion criteria, and the incidence was calculated at 1:88,000 to 1:140,000.1212. Cook TM, Counsell D, Wildsmith JA. Major complications of central neuraxial block: report on the third national audit project of the royal college of anaesthetists. Br J Anaesth. 2009;102:179-90.

Risk Factors22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.,44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208.

The occurrence of SEH is more spontaneous than the result of neuraxial anesthesia. Most spontaneous hematomas are idiopathic; cases related to anticoagulant therapy and vascular malformations are the second and third most common causes, respectively. Concomitant use of anticoagulants is the main risk factor related to SEH, when associated with neuraxial block.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Risk factors for SEH have been described by several authors88. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology. 2004;101:950-9.,1313. Brem SS, Hafler DA, Van Uitert RL, et al. Spinal subarachnoid hematoma: a hazard of lumbar puncture resulting in reversible paraplegia. N Eng J Med. 1981;304:1020-1.1818. Horlocker TT, Wedel DJ. Neuraxial block and low-molecular-weight heparin: balancing perioperative analgesia and thromboprophylaxis. Reg Anesth Pain Med. 1998;23:164-77. and are shown in Table 1. The incidence of SEH varies according to the type of surgery, age and gender of patient. For example, the incidence of SEH in obstetric surgery is estimated at 1:200,000, whereas in geriatric age women undergoing knee arthroplasty it is estimated at 1:3,600.88. Moen V, Dahlgren N, Irestedt L. Severe neurological complications after central neuraxial blockades in Sweden 1990-1999. Anesthesiology. 2004;101:950-9. This may be explained by the higher incidence of spinal abnormalities associated with osteoporosis, use of dual antiplatelet/anticoagulant therapy, and accumulation of anticoagulant due to a decrease in renal excretion not detected in this age group.

Table 1
Risk Factors Associated with Hematoma Spinal/Epidural.

Among the type of neuraxial blocks, the risk of SEH is higher with the use of epidural catheters, followed by simple epidural puncture, and less frequent after single subarachnoid puncture,1717. Wulf H Epidural anaesthesia and spinal haematoma. Can J Anaesth. 1996;43:1260-71.,1919. Tryba M, Wedel DJ. Central neuraxial block and low molecular weight heparin (enoxaparine): lessons learned from different dosage regimes in two continents. Acta Anaesthesiol Scand. 1997;111:100-4.,2020. Lawton MT, Porter RW, Heiserman JE. Surgical management of spinal epidural hematoma: relationship between surgical timing and neuro-logical outcome. J Neurosurg. 1995;83:1-7. the latter likely due to the thinner needles used in the technique. Catheter removal is as critical as insertion; therefore, vascular injury may still occur44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208. at the same incidence; that is, half the cases of SEH occurs during epidural catheter removal.1616. Vandermeulen EP, Van AH, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg. 1994;79:1165-77.

There are indications that epidural hematoma is more common after lumbar puncture compared with thoracic puncture.1111. Popping DM, Zahn PK, Van Aken HK, et al. Effectiveness and safety of postoperative pain management: a survey of 18 925 consecutive patients between 1998 and 2006 (2nd revision): a database analysis of prospectively raised data. Br J Anaesth. 2008;101:832-40.

Clinical condition, treatment, and prevention

Bleeding into the spinal canal, which causes thecal sac compression, may result in irreversible neurological damage with paraplegia and is a major concern of anesthesiologists performing neuraxial block in patients on anticoagulant drugs.44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208.

Clinical condition is characterized by slow regression or absent sensory or motor block, back pain, urinary retention or return of motor or sensory deficit after complete regression of the previous block, alone or in combination, suggesting the development of spinal hematoma.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

In the presence of clinical suspicion of spinal hematoma, an aggressive diagnostic and therapeutic approach is mandatory. This includes emergency nuclear magnetic resonance imaging (NMRI) or, if unavailable, computed tomography (CT). Because SEH is a neurosurgical emergency, protocols must be established to avoid any delay in diagnosis. Once diagnosis is confirmed, decompressive laminectomy should be performed within 6-12 hours after the onset of symptoms, enabling chances of neurological recovery.1616. Vandermeulen EP, Van AH, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg. 1994;79:1165-77.,2121. Meikle J, Bird S, Nightingale JJ, et al. Detection and management of epidural haematomas related to anaesthesia in the UK: a national survey of current practice. Br J Anaesth. 2008;101:400-4.

Thus, patients should be carefully evaluated to investigate possible signs indicating SEH, both after neuraxial block and epidural catheter removal. The patient should be monitored at regular intervals until regression of sensory block by at least two dermatomes or motor function recovery22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31. and for at least 24 hours after epidural catheter removal.2121. Meikle J, Bird S, Nightingale JJ, et al. Detection and management of epidural haematomas related to anaesthesia in the UK: a national survey of current practice. Br J Anaesth. 2008;101:400-4.

European and American societies have published guidelines with the goal of increasing security in performing neuraxial block in patients on anticoagulants.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106.,66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.,2222. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Reg Anesth Pain Med. 1998;23:178-82.

23. Gogarten W, Van Aken H, Buttner J, et al. Neuraxial blockade and thromboembolism prophylaxis/antithrombotic therapy: revised recommendations of the German Society of Anaesthesiology and Intensive Care. Anasthesiol Intensivmed Notfallmed Schmerzth. 2003;44:218-30.

24. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003;28:172-97.

25. Llau Pitarch JV, De Andres Ibanez J, Gomar Sancho C. Guidelines of hemostasis inhibiting drugs and neuraxial anaesthesia (Spanish). Rev Esp Anestesiol Reanim. 2005;52:413-20.

26. Vandermeulen E, Singelyn F, Vercauteren M, et al. Belgian guidelines concerning central neural blockade in patients with drug-induced alteration of coagulation: an update. Acta Anaesthesiol Belg. 2005;56:139-46.
-2727. Llau JV, De AJ, Gomar C. Anticlotting drugs and regional anaesthetic and analgesic techniques: comparative update of the safety recommendations. Eur J Anaesthesiol. 2007;24:387-98. However, most of these recommendations are expert opinions based on case series and pharmacological data with anticoagulant drugs involved.2727. Llau JV, De AJ, Gomar C. Anticlotting drugs and regional anaesthetic and analgesic techniques: comparative update of the safety recommendations. Eur J Anaesthesiol. 2007;24:387-98. These recommendations include: (I) minimum time interval required between the last dose of anticoagulant and the insertion of neuraxial needle/catheter or catheter removal; (II) minimum interval required between the insertion of neuraxial needle/catheter or catheter removal and next dose of anticoagulant; (III) minimum coagulation time required for the use of neuraxial technique (if available for the drug being used).

Due to the rapid development of anticoagulant drugs by the pharmaceutical industry and their release and increasing use in clinical practice, experiments are lacking and it becomes difficult to make any statement on the use of neuraxial anesthesia in patients on new anticoagulants.

Recently, Rosencher et al. proposed a new strategy for managing patients on new anticoagulants.2828. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62:1154-60. According to this strategy, the insertion and subsequent withdrawal of neuraxial needle/catheter must be made at a time superior to two half-lives of elimination after the last dose of the used anticoagulant. The basis for this proposal is that 30% to 40% of the function of coagulation factors is required for hemostasis, so that after two half-lives, the drug concentration in bloodstream is near 25% of the initial. The next anticoagulant dose should be administered with a time interval (dT) obtained by subtracting the time needed for the drug to reach the peak plasma level and the time to produce stable blood clot, considered 8 hours (8h-Tpeak = dT).2828. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62:1154-60.

Neuraxial block and use of antiplatelet agents

Antiplatelet drugs consist of non-steroidal anti-inflammatory drugs (NSAIDs), thienopyridines (ticlopidine, clopidogrel, and prasugrel), and glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, and tirofiban).

Acetylsalicylic acid (ASA) and NSAIDs

ASA promotes irreversible blockade of platelet function by inhibiting cyclooxygenase enzyme production of thromboxane A2 (potent platelet activator). This effect lasts the same as the platelets' half-life, usually 7-10 days.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Other NSAIDs also inhibit cyclooxygenase-1 and platelet aggregation, but in a reversible manner and proportional to the agent half-life. This process normalizes from 12 to 24 hours after NSAIDs discontinuation.2929. Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 10 non-steroidal analgesics to humans. Scand J Haematol. 1984;33:155-9. The selective inhibitors of Type 2 cyclooxygenase (COX-2) are anti-inflammatory drugs that do not cause platelet dysfunction, as COX-2 is not expressed in platelets.3030. Leese PT, Hubbard RC, Karim A, et al. Effects of celecoxib, a novel cyclooxygenase-2 inhibitor, on platelet function in healthy adults: a randomized, controlled trial. J Clin Pharmacol. 2000;40:124-32.

The bleeding effect caused by ASA appears to be dose-dependent, with more marked effects in patients receiving doses greater than 100 mg.day-1 3131. Serebruany VL, Steinhubl SR, Berger PB, et al. Analysis of risk of bleeding complications after different doses of aspirin in 192.036 patients enrolled in 31 randomized controlled trials. Am J Cardiol. 2005;95:1218-22. However, prospective studies evaluating the safety of neuraxial block with ASA reported no case of spinal hematoma.3232. Clasp (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group Clasp: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619-29.3434. Horlocker TT, Bajwa ZH, Ashraf Z, et al. Risk assessment of hemorrhagic complications associated with nonsteroidal antiinflammatory medications in ambulatory pain clinic patients undergoing epidural steroid injection. Anesth Analge. 2002;95:1691-7.

Although the isolated use of ASA seems not to increase the probability of spinal hematoma, complications have been observed in both medical and surgical patients, if combined with heparin.1414. Ruff RL, Dougherty Jr JH. Complications of lumbar puncture followed by anticoagulation. Stroke. 1981;12:879-81.,3535. Stafford-Smith M. Impaired haemostasis and regional anaesthesia. Can J Anaesth. 1996;43:129-41. Thus, in individuals using ASA, it seems prudent to administer heparin for postoperative thrombosis prophylaxis, as the research team did not observe superiority of thromboprophylaxis when the heparin dose is given preoperatively (B).3636. Hull R, Pineo G, MacIsaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patient undergoing elective hip surgery. Thromb Res. 2000;101:155-62. However, the administration of a low-dose combination of ASA-dipyridamole seems not to increase the risk of spinal hematoma.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

In patients with a history of acute coronary syndrome (ACS), cerebrovascular accident (CVA) or peripheral arterial occlusive disease, ASA reduces the risk of recurrent cardiovascular events by 30% and mortality by approximately 15%.3737. Patrono C, Baigent C, Hirsh J, et al. Antiplatelet drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133:199-233. Recent studies suggest that morbidity and mortality, particularly in patients with newly implanted coronary stents or unstable coronary syndrome is markedly increased if ASA is suspended before a surgical procedure.38–40 Rebound phenomenon has also been described.4141. Herren T Stricker H, Haeberli A, et al. Fibrin formation and degradation in patients with arteriosclerotic disease. Circulation. 1994;90:2679-86. The risk of late thrombosis is higher in patients with drug-eluting stents.

In summary, the perioperative suspension of ASA is unnecessary in most cases and associated with an increased risk of acute thrombosis. We recommend that patients with ACS or stent should continue taking ASA throughout life.4242. Fleisher LA, Beckman JA, Brown KA, et al. ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: Executive Summary. Circulation. 2007;116:1971-96. The American College of Chest Physicians (ACCP) does not recommend platelet function evaluation prior to invasive procedures because there is no apparent correlation with bleeding (D).4343. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy an prevention of thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:S326-50.

Recommendations

  1. NSAIDs appear to represent no significant additional risk for the onset of spinal hematoma in patients undergoing epidural or spinal anesthesia. NSAIDs (including ASA) have no risk level that interferes with the performance of neuraxial blocks. In patients on these medications, there is no specific concern regarding the interval between spinal/epidural puncture or catheter insertion and the last dose of the given drug, or the need for postoperative monitoring and interval for catheter removal or postoperative drug administration (A).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.,3232. Clasp (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group Clasp: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. Lancet. 1994;343:619-29.3434. Horlocker TT, Bajwa ZH, Ashraf Z, et al. Risk assessment of hemorrhagic complications associated with nonsteroidal antiinflammatory medications in ambulatory pain clinic patients undergoing epidural steroid injection. Anesth Analge. 2002;95:1691-7.

  2. Concomitant use of medications affecting other clotting mechanism components, such as oral anticoagulants, unfractionated or low molecular weight heparin increases the risk of bleeding complications in patients on NSAIDs. In these patients on ASA, the administration of heparin dosage for postoperative thromboprophylaxis is recommended (B).3636. Hull R, Pineo G, MacIsaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patient undergoing elective hip surgery. Thromb Res. 2000;101:155-62. In these patients, if low molecular weight heparin (LMWH) is administered preoperatively, there should be a 24-hour wait period before performing blockade or removing the epidural catheter due to the increased risk of bleeding (C).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  3. Cyclooxygenase Type 2 inhibitors (COX-2) have minimal effect on platelet function and should be preferred in patients who need anti-inflammatory therapy in the presence of anticoagulation (D).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45. There is no evidence supporting the effect on the ability of platelet aggregation or increased tendency to bleeding (D).11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106.

  4. In patients with coronary stent receiving dual platelet therapy (ASA + thienopyridine), needing surgery, and requiring surgical procedure, we recommend postponing surgery for at least 6 weeks in the case of metallic stents and at least 6 months in case of drug-eluting stents (D).4343. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy an prevention of thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:S326-50. If patients need surgery within 6 weeks after metallic stent or 6 months after drug-eluting stent, dual antiplatelet therapy should be maintained, and regional anesthesia is contraindicated via neuraxial route (D).4343. Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative management of antithrombotic therapy an prevention of thrombosis. 9th ed. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:S326-50.

  5. Analgesics, such as paracetamol and dipyrone, are not a contraindication for neuraxial regional anesthesia, insofar there are no cases related to spinal hematoma (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Thienopyridines

Ticlopidine (Ticlid®), clopidogrel (Plavix®), and prasugrel (Efient®) are platelet inhibitors belonging to the class of thienopyridines. They are prodrugs cleaved in vivo in the liver to active metabolites that antagonize the platelet receptor of adenosine dinucleotide phosphate (ADP) (P2Y12) and interfere with platelet activation and aggregation, an effect that can not be antagonized and is irreversible.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106.,22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

There is no prospective study assessing the safety of neuraxial techniques in subjects under treatment with thienopyridines. However, cases of spinal hematoma have been reported after neuraxial anesthesia in patients taking these drugs.4444. Vandermeulen E. Is anticoagulation and central neural blockade a safe combination? Curr Opin Anaesthesiol. 1999;12:539-43.

Ticlopidine (Ticlid®)

Ticlopidine half-life is 30 to 50 hours, which increases up to 96 hours if used routinely for more than 14 days.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31. Platelet dysfunction with the use of ticlopidine remains for 10 to 14 days after drug discontinuation.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106. Unlike clopidogrel, ticlopidine may lead to neutropenia in more than 1% of patients, which is a limiting factor of its use.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Recommendations

Neuraxial block or epidural catheter removal can only be performed after 10-14 days of ticlopidine suspension (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.,66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Clopidogrel (Plavix®)

Clopidogrel half-life is 120 hours. However, its active metabolite half-life is only 8 hours.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31. The platelet function maximum inhibition of oral clopidogrel (75 mg) occurs within 3-7 days or about 12-24 hours after an initial loading dose of 300-600 mg. Recovery of platelet function occurs only 6-7 days after the end of clopidogrel administration.4545. DenningerMH, Necciari J, Serre-Lacroix E, Sissmann J. Clopidogrel antiplatelet activity is independent of age and presence of atherosclerosis. Semin Thromb Hemost. 1999;25(S2):41-5. In patients at high risk for angina, discontinuation for five days has been suggested to prevent cardiovascular morbidity.4646. Fox KA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non ST-elevation acute coronary syndrome: the clopidogrel in unstable angina to prevent recurrent ischemic events (Cure) trial. Circulation. 2004;110:1202-8.

Recommendations

Neuraxial blockade or removal of epidural catheter in patients on clopidogrel should only be performed after at least seven days of drug discontinuation (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015. In the case of patients with high risk of angina recurrence, the interval of five days suspension has been suggested (D).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Prasugrel (Efient®)

A novel thienopyridine that, similar to others, depends on hepatic conversion to active metabolite to bind to platelet P2Y12 receptor (which binds to ADP for platelet activation) and perform its inhibitory activity. This drug has a rapid onset of action (30-60 minutes) and is 10 times more potent than clopidogrel.4747. Angiolillo DJ, Bhatt DL, Gurbel PA, et al. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol. 2009;103:40-51. The antiplatelet effect is equal to the life of platelet, and pretreatment platelet function is restored 7-10 days after drug discontinuation.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

One study comparing prasugrel and clopidogrel in 13,608 patients with acute coronary syndrome undergoing percutaneous coronary intervention showed significant reduction of ischemic events treated with prasugrel, but also a higher and occasionally fatal risk of bleeding.4848. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Eng J Med. 2007;357:2001-15.

Recommendations

There is no available study assessing the combination of prasugrel and neuraxial anesthesia. However, it seems reasonable that treatment with prasugrel be discontinued at least 7-10 days before neuraxial block or removal of epidural catheter (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Glycoprotein IIb/IIIa inhibitors

Glycoprotein IIb/IIIa inhibitors include abciximab (Reopro®), eptifibatide (Integrilin®), and tirofiban (Aggrastat®). Currently, these agents are the most effective drugs available for platelet aggregation inhibition, as they block the platelet glycoprotein IIb/IIIa (the site of fibrinogen binding between platelets), which is the final common pathway of platelet aggregation.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31. These drugs are only available for intravenous use. Antiplatelet effects are reversible and disappear after the discontinuation of eptifibatide, tirofiban, and abciximab within 8, 24, and 48 hours, respectively. The most common side effects are thrombocytopenia and bleeding,5050. Harrington RA, Armstrong PW, Graffagnino C, et al. Dosefinding, safety, and tolerability study of an oral platelet glycoprotein IIb/IIIa inhibitor, lotrafiban, in patients with coronary or cerebral atherosclerotic disease. Circulation. 2000;102:728-35. expressed in 0.3-1% with abciximab.4949. Coller BS. Anti-GPIIb/IIIa drugs: current strategies and future directions. Thromb Haemost. 2001;86:427-43. Abciximab showed better efficacy than tirofiban and eptifibatide.5151. Brown DL, Fann CS, Chang CJ. Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronaryintervention. Am J Cardiol. 2001;87:537-41.

Recommendations

  1. According to the pharmacological properties of these drugs, insertion of epidural/spinal needle/catheter or catheter removal should only be performed after complete recovery of platelet aggregation; that is, with discontinuation of 8-10 hours for tirofiban/eptifibatide and 48 hours for abciximab and exclusion of any thrombocytopenia through a recent platelet count (D);22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

  2. GP IIb/IIIa inhibitors are used in acute coronary syndrome, in combination with anticoagulants and ASA. In this scenario, any neuraxial blockade is contraindicated in emergency procedures that usually involve cardiac surgery with continued anticoagulation (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Other antiplatelet

Ticagrelor (Brilinta®)

Unlike thienopyridines, ticagrelor acts directly on P2Y12 receptor and does not require liver biotransformation into active metabolites by cytochrome P450, although metabolites are also active. Similar to prasugrel, ticagrelor provides a very fast (< 2 h), intense (about 70%), and consistent inhibition of P2Y12 receptor, which is greater than that of clopidogrel (30-40%).4747. Angiolillo DJ, Bhatt DL, Gurbel PA, et al. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol. 2009;103:40-51. It has a rapid onset of action with reversible binding and short duration (48-72 h), and requires oral administration in two doses. The initial effect on platelet aggregation is seen 30 minutes after loading dose. With treatment discontinuation, platelet function is restored within 4-5 days.5252. Gurbel PA, Bliden KP, Butler K, etal. Randomized double-blind assessment of the onset and offset of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease. Circulation. 2009;120:2577-85.

Recommendations

There is no available data regarding the perioperative use of this agent. Theoretically, its short and reversible antiplatelet effect can facilitate perioperative management. However, neuraxial anesthesia should be discouraged during treatment with ticagrelor, unless it is suspended for at least five days before the anesthetic procedure, so that platelet function can return to normal (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Cilostazol (Vasogard®, Cebralat®, Pletal®)

Cilostazol provides selective inhibition of phosphodiesterase IIIa (PDEIIIa); thus, it increases the level of intracellular cyclic adenosine monophosphate (cAMP) and leads to weak platelet aggregation inhibition.53,54 Because vascular smooth muscle contains PDEIIIa, cilostazol also provides direct arterial vasodilation. Nevertheless, cilostazol mechanism of action is not fully understood. Its use is indicated for peripheral arterial disease and intermittent claudication in individuals who do not respond to exercise therapy and those with low possibility of surgical intervention.5555. Sobel M, Verhaeghe R. Antithrombotic therapy for peripheral artery occlusive disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133:S815-43.

The route of administration is orally at a dose of 100 mg twice daily, and peak plasma level is achieved within 2.7 to 3.6 hours. Drug compound is mainly eliminated by hepatic metabolism and subsequent urinary excretion of metabolites. The terminal elimination half-life of cilostazol and its active metabolites is approximately 21 hours, and some of its metabolites inhibit platelet aggregation at a higher intensity than the parent compound.5454. Woo SK, Kang WK, Kwon KI. Pharmacokinetic and pharmacodynamic modeling of the antiplatelet and cardiovascular effects of cilostazol in healthy humans. Clin Pharmacol Therap. 2002;71:246-52.

A recent case report found spinal hematoma after epidural catheter removal during treatment with cilostazol,5656. Kaneda T Urimoto G, Suzuki T. Spinal epidural hematoma following epidural catheter removal during antiplatelet therapy with cilostazol. J Anesth. 2008;22:290-3. but, in general, there is no prospective data on this drug's perioperative use and its effect on bleeding incidence is unknown.

Recommendations

Neuraxial block and catheter removal may be performed considering the minimum clearance interval of two half-lives between blockade and the last dose of cilostazol (i.e., 42 hours), although laboratory recommendation is five days of suspension.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015. The next dose of cilostazol should only be administered 5 hours after catheter removal (D).2828. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62:1154-60.,5757. Llau JV, Ferrandis R. New anticoagulants and regional anesthesia. Curr Opin Anaesthesiol. 2009;22:661-6.

Heparins

Unfractionated heparin (UFH)

The major anticoagulant effect of heparin is due to pentasaccharide present in one third of heparin molecules, which binds to antithrombin III (ATIII).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45. After this binding, UFH catalyses the inactivation of IIa (thrombin), IXa, and Xa, and, to a lesser extent, XIa and XIIa factors.44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208. In the absence of heparin, antithrombin III has low affinity for thrombin. However, when UFH binds to ATIII, the thrombin-binding rate accelerates from 100 to 1,000 times, similarly to other coagulation factors inhibited by it. UFH also binds strongly to several plasma proteins, endothelial cells, macrophages, and platelet factor 4 (PF4), which results in low bioavailability, inaccurate pharmacokinetics, and heparin-induced thrombocytopenia (HIT).5858. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133: 141-59.

The anticoagulant activity of UFH depends on both the number of heparin molecules with the pentasaccharide chain in its composition and the size of molecules containing the pentasaccharide. The high molecular weight heparins will catalyze the inhibition of Xa and IIa factors, while the low molecular weight heparins will only inhibit the Xa factor.5858. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133: 141-59.,5959. Hirsh J, Raschke R, Warkentin TE, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1995;108:S258-75.

Intravenous administration of UFH results in immediate anticoagulation, while subcutaneous administration results in onset of action within 1-2 hours. The anticoagulant effect is both molecular weight and dose dependent, in a nonlinear manner, and increases disproportionately with increased dose.66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45. The biological half-life of heparin increases from 30 minutes with 25 UI.kg-1 IV to 60 minutes with 100 UI.kg-1 and to 150 minutes with 400 UI.kg-1.5959. Hirsh J, Raschke R, Warkentin TE, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1995;108:S258-75.

When given in therapeutic doses, UFH anticoagulation is monitored by the activated partial thromboplastin time (aPTT). During cardiopulmonary bypass, coagulation inhibition by high doses of heparin is monitored by the activated clotting time (ACT). Subcutaneous administration of small doses (5,000 IU) for prophylaxis of deep venous thrombosis (DVT) usually does not change the aPTT. One of the advantages of heparin anticoagulation is the reversal by protamine. Each milligram of protamine can neutralize 100 IU of heparin.5858. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133: 141-59.

A review study of more than 9,000 patients undergoing neuraxial block with prophylactic doses for DVT with heparin showed no cases of spinal hematoma.6060. Liu SS, Mulroy MF. Neuraxial anesthesia and analgesia in the presence of standard heparin. Reg Anesth Pain Med. 1998;23:157-63. However, isolated cases have been reported subsequently to that revision.9,16,10,61–63 In patients receiving two- daily dose regimen of subcutaneous UFH (5,000 IU) there is no contraindication for the use of neuraxial techniques.66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45. However, there are insufficient data to confirm the safety of neuraxial techniques with three daily doses, despite being the most effective dosage for DVT prevention.6464. King CS, Holley AB, Jackson JL, et al. Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: a metaanalysis. Chest. 2007;131:507-16.

In contrast to UFH prophylactic regimen, anticoagulation therapy is definitely associated with increased risk of spinal hematoma44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208.. A prospective study (n = 342) comparing the incidence of spinal hematoma in patients with and without therapeutic doses of UFH and undergoing lumbar puncture showed incidence of 2% in the UFH group. The risk factors were: (i) less than 1 hour interval between the onset of heparin and lumbar puncture; (ii) concomitant use of ASA at the time of lumbar puncture; and (iii) traumatic procedure.1414. Ruff RL, Dougherty Jr JH. Complications of lumbar puncture followed by anticoagulation. Stroke. 1981;12:879-81. Recently, two cases of epidural hematoma were reported associated with UFH therapy and neuraxial block.6565. Rosen DA, Hawkinberry DW, Rosen KR, et al. An epidural hematoma in an adolescent patient after cardiac surgery. Anesth Analg. 2004;98:966-9.,6666. Davignon KR, Maslow A, Chaudrey A, et al. Epidural hematoma: when is it safe to heparinize after the removal of an epidural catheter? J Cardiothor Vasc Anesth. 2008;22:774-8.

Heparinization during surgery involves the use of 5,000 to 10,000 U of heparin intravenously during surgery, particularly in vascular surgery to prevent thrombosis during artery clamping.5959. Hirsh J, Raschke R, Warkentin TE, et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest. 1995;108:S258-75. Most published cases series uses the same guidelines for neuraxial anesthesia management in these patients, based on the exclusion of high-risk patients (preexisting coagulopathy) and performing the neuraxial technique at least one hour before heparin administration.6060. Liu SS, Mulroy MF. Neuraxial anesthesia and analgesia in the presence of standard heparin. Reg Anesth Pain Med. 1998;23:157-63. Stafford-Smith showed increased incidence of bleeding in patients on ASA associated with intraoperative intravenous heparin. SEH risk increased to 1:8,500 after epidural puncture and to 1:12,000 after spinal anesthesia, even when neuraxial anesthesia and subsequent heparinization occurred after one-hour interval.3535. Stafford-Smith M. Impaired haemostasis and regional anaesthesia. Can J Anaesth. 1996;43:129-41.

In cardiac surgery, the benefits of thoracic epidural anesthesia on pulmonary function and analgesia are evident, with lower intensity for arrhythmia management and no effect on hospital and ICU length of stay and mortality.6767. Liu SS, Block BM, Wu CL. Effects of perioperative central neuraxial analgesia on outcome after coronary artery bypass surgery: a meta-analysis. Anesthesiology. 2004;101:153-61.,6868. Roediger L, Larbuisson R, Lamy M. New approaches and old controversies to postoperative pain control following cardiac surgery. Eur J Anaesthesiol. 2006;23:539-50. However, the benefits must be evaluated concerning the high risk of SEH. The probability of spinal hematoma in patients undergoing cardiac surgery with full heparinization is 1:1,528 with epidural and 1:3,610 with spinal techniques.6969. Ho AM, Chung DC, Joynt GM. Neuraxial blockade and hematoma in cardiac surgery: estimating the risk of a rare adverse event that has not (yet) occurred. Chest. 2000;117:551-5.,7070. Chaney MA. Intrathecal and epidural anesthesia and analgesia for cardiac surgery. Anesth Analg. 1997;84:1211-21. Experts recommend that neuraxial block be performed the day before surgery due to complete surgical heparinization.2222. Tryba M. European practice guidelines: thromboembolism prophylaxis and regional anesthesia. Reg Anesth Pain Med. 1998;23:178-82.,7171. Gogarten W, Van Aken H, Buttner J, et al. Regional anaesthesia and thromboembolism prophylaxis/anticoagulation. Revised recommendations of the German Society of Anaesthe-siology and Intensive Care Medicine. Anaesth Intensivmed. 2007;48:S109-24.,7272. Chaney MA. Cardiac surgery and intrathecal/epidural techniques: at the crossroads? Can J Anaesth. 2005;52:783-8. Because neuraxial blockade in cardiac surgery carries significant risks without improving morbidity and mortality, there is discussion whether epidural or spinal anesthesia is justified, probably with the contraindication of the technique in this group.7272. Chaney MA. Cardiac surgery and intrathecal/epidural techniques: at the crossroads? Can J Anaesth. 2005;52:783-8.

Recommendations

  1. In patients on two daily prophylactic doses of UFH (5,000 IU) there are no contraindications to neuraxial block (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  2. The safety of neuraxial block in patients receiving prophylactic doses of UFH above 10,000 IU or above two daily doses is not established. Although dosage of three daily doses may lead to increased surgical bleeding, it is unclear whether there is an increased risk for spinal hematoma development (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  3. Because heparin-induced thrombocytopenia (HIT) may occur during UFH administration, platelet count should be done before neuraxial technique or catheter removal, if the patient is on HNF for five or more days (B);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  4. Wait a minimum interval of 4 hours between the last prophylactic dose of UFH and spinal/epidural puncture or epidural catheter removal. The next dose of prophylactic UFH should be administered at least one hour after neuraxial anesthesia or epidural catheter removal (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  5. If UFH is used in therapeutic doses to perform neuraxial anesthesia, administration of continuous intravenous heparin therapy should be discontinued for at least 4 hours before puncture or catheter removal, and it is necessary to check the return of normal coagulation by determining aPTT or ACT (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  6. In situations of intraoperative heparinization, the following recommendations should be considered: 1) minimum interval of one-hour between puncture or catheter placement and heparinization; 2) do not perform neuraxial block in patients with coagulopathy or on anticoagulants; 3) wait 4 hours between the last dose and epidural catheter removal, preferably with laboratory coagulation tests; 4) after catheter removal, wait one hour for UFH dose application; 5) although the occurrence of difficult puncture or blood output from puncture needle may increase the risk of spinal hematoma, there are no data to justify surgery cancellation (A).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Low molecular weight heparin (LMWH)

LMWH has become the treatment of choice for both prevention and treatment of DVT, due to the greater bioavailability (almost 100%) after subcutaneous administration, which results in higher anticoagulant effect without increasing bleeding tendency and ease of use without the need for blood coagulation monitoring.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Pharmacology of LMWH differs from UFH. The main differences are the highest inhibitory activity against the Xa factor compared with thrombin (IIa), anticoagulant effect difficult monitoring (factor Xa levels), prolonged half-life, and lack of complete reversibility with protamine.5858. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 8th ed. Chest. 2008;133: 141-59. With subcutaneous administration, peak plasma levels are reached in approximately 3-4 hours, and the half-life of elimination, with normal renal function, is within 4-6 hours.7373. Weitz JI. Low-molecular-weight heparins. N Eng J Med. 1997;337:688-98.,7474. Sanderink G-JCM, Guimart CG, Ozoux ML, et al. Pharmacokinetic and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impair-ment. Thromb Res. 2002;105:225-31. However, the anti-factor Xa activity remains considerable (50%) after 10-12 hours of administration. If creatinine clearance falls below 30 mL.min-1, the half-life doubles.7474. Sanderink G-JCM, Guimart CG, Ozoux ML, et al. Pharmacokinetic and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impair-ment. Thromb Res. 2002;105:225-31. Compared to UFH, the risk of thrombocytopenia (HIT) is 10 times lower. However, they are contraindicated in HIT due to the high risk of cross-reaction, approximately 90%.7575. Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Eng J Med. 1995;332:1330-5.

If thromboprophylaxis with LMWH is prescribed in two daily doses (30 mg), compared to a daily dose regimen, the risk of spinal hematoma may be increased, as the minimum levels of anti-Xa activity are higher.7676. Douketis JD, Kinnon K, Crowther MA. Anticoagulant effect at the time of epidural catheter removal in patients receiving twice-daily or once-daily low-molecular-weight heparin and continuous epidural analgesia after orthopedic surgery. Thromb Haemost. 2002;88:37-40.

The use of LMWH in patients undergoing neuraxial block was adopted in Europe in 1987. Dosages used were 20-40 mg in a single dose 12 hours before surgery. To prevent the occurrence of spinal hematoma, guidelines recommended insertion/removal of epidural catheter at a minimum interval of 10-12 hours after the last dose of LMWH. The subsequent dose was restarted after 8-12 hours.55. Tryba M. Epidural regional anesthesia and low molecular heparin: Pro. Anasthesiol Intensivmed Notfallmed Schmerzther. 1993;28:179-81.,1616. Vandermeulen EP, Van AH, Vermylen J. Anticoagulants and spinal-epidural anesthesia. Anesth Analg. 1994;79:1165-77. Thus, reviews involving data from millions of patients showed that the use of neuraxial block in subjects on LMWH under the European regime was safe, with report of only one case of spinal hematoma.7777. Bergqvist D, Lindblad B, Matzsch T. Low molecular weight heparin for thromboprophylaxis and epidural/spinal anaesthesia - is there a risk? Acta Anaesthesiol Scand. 1992;36: 605-9.,7878. Bergqvist D, Lindblad B, Matzsch T. Risk of combining low molecular weight heparin for thromboprophylaxis and epidural or spinal anesthesia. Seminars in Thromb Hemost. 1993;19:147-51.

On the other hand, in the United States, enoxaparin introduced in 1993 had no recommendation regarding time between drug administration and neuraxial block or catheter removal. Enoxaparin was routinely administered in the immediate postoperative period at a dose of 30 mg twice daily. After five years of use, the Food and Drug Administration (FDA) accumulated reports of 43 patients undergoing neuraxial blocks who developed spinal hematoma.7979. Wysowski DK, Talarico L, Bacsanyi J, et al. Spinal and epidural hematoma and low-molecular-weight heparin. N Eng J Med. 1998;338:1774-5. In 1998, 13 cases of spinal hematoma associated with LMWH had been reported in Europe, while in United States, it reached 60 cases.2424. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003;28:172-97. Reasons for the high rates were attributed to: (i) higher daily dose prescription of LMWH; (ii) more frequent doses, possibly leading to higher minimum blood level during catheter insertion/removal; (iii) lack of practical guidelines for neuraxial block and LMWH administration; (iv) lack of larger series.1919. Tryba M, Wedel DJ. Central neuraxial block and low molecular weight heparin (enoxaparine): lessons learned from different dosage regimes in two continents. Acta Anaesthesiol Scand. 1997;111:100-4.,2424. Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med. 2003;28:172-97.

After the Second American Society of Regional Anesthesia (ASRA) resolution in 2003, studies in the English literature reported 10 cases related to the combination of LMWH and spinal hematoma. Five additional cases were reported by the Royal College of Anesthetists Consensus in the UK in 97,925 epidural blocks, but without proven evidence of association with anticoagulant drugs.1212. Cook TM, Counsell D, Wildsmith JA. Major complications of central neuraxial block: report on the third national audit project of the royal college of anaesthetists. Br J Anaesth. 2009;102:179-90.

Recommendations

  1. Antiplatelet drugs and oral anticoagulants concomitantly administered with LMWH increase the risk of spinal hematoma, and in such conditions blockade is contraindicated. In patients on ASA, it seems prudent to administer the thromboprophylatic dose of heparin postoperatively (B).3636. Hull R, Pineo G, MacIsaac S. Low-molecular-weight heparin prophylaxis: preoperative versus postoperative initiation in patient undergoing elective hip surgery. Thromb Res. 2000;101:155-62. In these patients, if LMWH is administered preoperatively, wait 24 hours to perform blockade or catheter removal due to increased risk of bleeding (C);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  2. Bleeding during needle or catheter insertion does not justify surgery cancellation. The beginning of therapy with LMWH in this circumstance should occur 24 hours after the end of surgery (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  3. In preoperative patients receiving LMWH thromboprophylaxis, neuraxial block is recommended 10-12 hours after the last dose of LMWH (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  4. In patients on therapeutic doses of LMWH, such as enoxaparin 1 mg.kg-1 every 12 hours, enoxaparin 1.5 mg.kg-1 per day, dalteparin 120 IU.kg-1 every 12 hours, dalteparin 200 IU.kg-1 per day or tinzaparin 175 IU.kg-1 per day, an interval of at least 24 hours is recommended between the last dose and neuraxial block to ensure normal hemostasis (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  5. Patients under prophylactic regimen of LMWH every 12 hours (enoxaparin 30 mg twice daily), one dose should be omitted to enable a 24 hours interval before neuraxial block or catheter removal (A);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  6. Regarding LMWH postoperative use, the first dose should be administered 6-8 hours after surgery. A second dose of LMWH should not be administered before 24 hours of the first dose. Thus, epidural catheter may be safely maintained. However, epidural catheter removal should only be done after 10-12 hours of the last dose. The subsequent dose of LMWH after catheter removal should be administered after 2 hours. No drugs that alter hemostasis should be given due to the risk of additive effects (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  7. In patients under twice daily dosage regimen, there is greater risk of spinal hematoma, and continued monitoring is recommended. The first dose of LMWH should be administered 24 hours after the end of surgery, regardless of the anesthetic technique, and only in the presence of adequate surgical hemostasis. Epidural catheter should be removed before restarting LMWH regimen. If the technique of continuous analgesia is chosen, catheter may be maintained until the morning of the day following surgery, provided that removed before the first dose of LMWH, which may be administered 2 hours after catheter removal (D).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Vitamin K antagonists (coumarins)

Vitamin K antagonists include acenocoumarol, phenprocoumon, and warfarinas. These drugs inhibit the gamma-carboxylation synthesis of vitamin K-dependent factors (II, VII, IX, X) and C and S proteins, which makes them unable to bind phospholipid in platelet membranes during coagulation. Prothrombin time (PT) and international normalized ratio (INR) are tests commonly used to monitor these drugs and reflect the plasma activity of three (II, VII, and X) of the four clotting factors. Clinical experiences suggest that the 40% activity level of each factor is adequate for normal hemostasis, or near normal.8080. Xi M, Beguin S, Hemker HC. The relative importance of the factors II, VII, IX and X for the prothrombinase activity in plasma of orally anticoagulated patients. Thromb Haemos. 1989;62:788-91. INR of 1.5 is associated with the 40% activity of factor VII.8181. Enneking FK, Benzon H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med. 1998;23:140-5. Because factor VII has a shorter half-life (about 6 hours), the initial increase of INR when coumarin anticoagulants are used reflects the loss of factor VII activity. However, these drugs therapeutic effect is more dependent on the reduction of factors II and X, which have half-lives relatively longer, 60 to 72 hours and 24 to 36 hours, respectively. After warfarin discontinuation, factor II is the latest to normalize.8282. Ansell J, Hirsh J, Hylek E, et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based v Clinical Practice Guidelines. 8th ed. Chest. 2008;133:S160-98. Thus, after drug discontinuation, INR may return to near normal values due to the activity restoration of factor VII. However, factors II and X may not have been restored to normal hemostatic levels.8181. Enneking FK, Benzon H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med. 1998;23:140-5. Its anticoagulant effect can be effectively prevented by vitamin K, fresh frozen plasma or prothrombin complex concentrate (II, VII, IX, and X factors) administration.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Although the ASRA has recommended epidural catheter removal with INR less than 1.5, this value has been considered as conservative. Reports show epidural catheter removal with INR higher and uneventful.8383. Buvanendran A, Lubenow T, Majewski M, et al. The INR values at removal of epidural catheter in 4013 patients receiving warfarin. ASA Annual Meeting, Available at: http://www.asaabstracts.com/strands/asaabstracts/searchArticle.htm, 2008. Acesso: dez. 2012.
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,8484. Parvizi J, Viscusi ER, Frank HG, et al. Can epidural anesthesia and warfarin be coadministered? Clin Orthop Relat Res. 2007;456:133-7. If it occurs in the first 48 hours of medication use, it is likely that there are adequate levels of clotting factors activity, particularly II and X factors. Beyond this period, all vitamin K-dependent clotting factors will be affected. There was no reported case of spinal hematoma in 11,235 patients receiving epidural analgesia after total knee arthroplasty, and treated with warfarin (5-10 mg) started the night before the procedure. Epidural catheters were removed 48 hours postoperatively. Mean INR at recession time of was 1.5 (0.9-4.3). INR was less than 1.5 in approximately 40% of cases. These series suggest that not only the INR value should be considered during epidural catheter management, but also the duration of therapy with warfarin, and that a prolonged time for more than 48 hours may represent significant increased risk of hematoma.8484. Parvizi J, Viscusi ER, Frank HG, et al. Can epidural anesthesia and warfarin be coadministered? Clin Orthop Relat Res. 2007;456:133-7.

Perioperative management of patients on warfarin remains controversial. Recommendations are based on drug pharmacology, clinically relevant levels, and deficiency of vitamin K-dependent clotting factors, case series, and spinal hematoma reports.66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Recommendations

  1. Neuraxial blockade should only be performed 4-5 days after drug discontinuation, confirmed by normal INR. Consider that in the first three days after drug discontinuation, coagulation (reflected primarily by levels of factors II and X) may not be adequate for hemostasis, despite a decrease in INR (indicating a return of factor VII activity). Appropriate levels of factors II, VII, IX, and X may not be present until INR is within the reference range (B);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  2. If warfarin thromboprophylaxis was initiated postoperatively, remove neuraxial catheter with an INR less than 1.5. This value was obtained from studies that correlated hemostasis with clotting factor activity levels greater than 40%. In these, neurological monitoring must be kept for least 24 hours after catheter removal (D);66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

  3. When replacing coumarin by LMWH or UFH preoperatively, consider the UFH and LMWH recommendations for neuraxial block (D);22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

  4. If patient is on low doses of warfarin during epidural analgesia, INR monitoring should be done daily (D).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Factor Xa inhibitors

Fondaparinux (Arixtra®)

Fondaparinux is a synthetic selective pentasaccharide that indirectly inhibits factor Xa. Unlike the LMWH, it has no effect on factor IIa (thrombin). Platelet aggregation is unaffected.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015. This compound has approximately 100% bioavailability after subcutaneous administration and half-life of elimination of 18-21 hours, primarily by the kidneys. Half-life is prolonged to 36-42 hours when creatinine clearance is less than 50 mL.min-1, and is contraindicated in patients with clearance less than 30 mL.min-1.8585. Sanofi-Synthelabo & Organon NV. Clinical Investigator Brochure Org31540/SR 90107A. 10ª ed. Apr. 2001. Prophylactic dose is 2.5 mg via subcutaneous rout once daily.

Fondaparinux is usually administered 6-12 hours after surgery, as its preoperative use may increase the risk of surgical bleeding without improving antithrombotic efficacy.8686. Kwong LM, Muntz JE. Thromboprophylaxis dosing: the relationship between timing of first administration, efficacy, and safety. Am J Orthop. 2002;31:16-20. Because it is used postoperatively, there are no problems with single puncture neuraxial anesthesia. However, if the catheter is inserted, it should be removed only in the absence of fondaparinux plasma levels. The recommendations for epidural catheter management in patients on fondaparinux are based on the conditions used in the study by Singelyn et al.8787. Singelyn FJ, Verheyen CCPM, Piovella F et al. The safety and efficacy of extended thromboprophylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a neuraxial or deep peripheral nerve catheter. Anesth Analg. 2007;105:1540-7. This study evaluated 5,387 patients, of whom 1,428 underwent regional anesthesia, and the single dose of fondaparinux the night before catheter removal was omitted. Thus, the research team ensured an interval of 36 hours between the last dose and catheter removal and 12 hours between catheter removal and the subsequent dose of fondaparinux. There was no case of spinal hematoma and no increased risk of DVT.8787. Singelyn FJ, Verheyen CCPM, Piovella F et al. The safety and efficacy of extended thromboprophylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a neuraxial or deep peripheral nerve catheter. Anesth Analg. 2007;105:1540-7.

According to the American College of Chest Physicians (ACCP), even with two reported cases of HIT with fondaparinux, its use in patients with a history of HIT is suggested as an option to UFH or LMWH.8888. Linkins L, Dans AL, Moores LK, et al. Treatment and prevention of heparin-induced thrombocytopenia antithrombotic therapy and prevention of Ttrombosis. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. 9th ed. Chest. 2012;141(2):495-530.

Recommendations

  1. At prophylactic dose (2.5 mg) fondaparinux may be used in postoperative with atraumatic neuraxial anesthesia. If used, epidural catheter should be removed only after 36 hours of the last dose and the subsequent dose administered only after 12 hours of removal (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  2. Neuraxial aneshesia is contraindicated when fondaparinux (5-10 mg.day-1) is used in therapeutic doses due to the risk of unpredictable residual effect in the body (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Rivaroxaban (Xarelto®)

Rivaroxaban is a selective inhibitor of factor Xa. It is orally administered and approved for DVT prevention after total knee and hip replacement surgery. Treatment is initiated 6-8 hours after surgery; with a single dose of 10 mg, peak plasma levels are achieved in 2-4 hours. Studies show better efficacy compared to enoxaparin for thromboprophylaxis,8989. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Eng J Med. 2008;358:2765-75. as well as compared to heparins and vitamin K antagonists for treating DVT.9090. Buller H, Lensing A, Prins M, et al. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EinsteinI-DVT Dose-Ranging Study. Blood. 2008;112:2242-7.

Rivaroxaban has a half-life of 5-9 hours, is poorly influenced by renal function (33% clearance occurs via kidneys), as it also has hepatic clearance. However, in the elderly, the half-life may be prolonged to 11-13 hours.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Rivaroxaban prolongs aPTT and HepTest, but these tests are not recommended to evaluate the drug anticoagulant effect.9191. Bayer Xarelto. Summary of Product Characteristics. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdf; 2009.
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Prothrombin time (PT) is influenced by rivaroxaban in a dose dependent manner, with close correlation with plasma concentrations,9292. Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939 - An oral, direct factor Xa inhibitor after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61:873-80. and should be measured in seconds and not by IRN. However, routine monitoring is not considered necessary. Similar to most new anticoagulants, rivaroxaban cannot be antagonized.22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Recommendations

  1. Due to the lack of prospective studies, an interval greater than two half-lives of elimination is recommended (24 hours) to perform neuraxial block or epidural catheter removal;2828. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62:1154-60.

  2. Because peak plasma level occurs within 2-4 hours, the subsequent dose should be given 4-6 hours after catheter removal (D);2828. Rosencher N, Bonnet MP, Sessler DI. Selected new antithrombotic agents and neuraxial anaesthesia for major orthopaedic surgery: management strategies. Anaesthesia. 2007;62:1154-60.

  3. If there is traumatic puncture with bleeding, rivaroxaban should be delayed for 24 hours (D).9191. Bayer Xarelto. Summary of Product Characteristics. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/xarelto/H-944-PI-en.pdf; 2009.
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Apixaban (Eliquis®)

Apixaban is a direct factor Xa inhibitor, administered orally. It has 60% bioavailability and does not require biotransformation for activation.9393. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523-32. In contrast with vitamin K antagonists, apixaban does not interact with food. Peak plasma levels are reached in 3 hours, half-life is about 12 hours (10-15 hours), and two daily doses are required.9393. Eikelboom JW, Weitz JI. New anticoagulants. Circulation. 2010;121:1523-32.,9494. Garcia D, Libby E, Crowther MA. The new oral anticoagulants. Blood. 2010;115:15-20. There is no need for routine coagulation monitoring. Kidneys eliminate only 25% and the hepatic and biliary metabolisms eliminate 75%, excreted via the bowel.

Randomized studies have shown the efficacy and safety of apixaban after knee and hip replacement surgeries.9595. Lassen MR, Raskob GE, Gallus A, et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Eng J Med. 2009;361:594-604.9797. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Eng J Med. 2010;363:2487-98. Evaluation of 18,201 individuals with atrial fibrillation, which compared apixaban with warfarin, showed that apixaban was superior in thromboprophylaxis, with low risk of bleeding and lower mortality rate.9898. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Eng J Med. 2011;365:981-92. Based on these studies, apixaban is likely to be approved for anticoagulation in non-valvular atrial fibrillation and thromboprophylaxis in hip and knee surgeries.

Recommendations

  1. Use the same rules for new anticoagulants; i.e., interval of two half-lives of elimination (20-30 hours) to perform neuraxial block or remove epidural catheter (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  2. After catheter removal, restart apixaban within 4-6 hours (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Thrombin inhibitors

Dabigatran (Pradaxa®)

Dabigatran is a new thrombin reversible inhibitor orally administered and recently approved for DVT prophylaxis in patients undergoing hip or knee replacement surgery.9999. Weitz JI, Eikelboom JW, Samama MM. New antithrombotic drugs antithrombotic therapy and prevention of thrombosis. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines 9th ed. Chest. 2012;141:120-51. Dabigatran is administered as the prodrug (dabigatran etexilate), which is converted to dabigatran by plasma esterases. This compound has a half-life of 12-17 hours, eliminated mainly by the kidney, and cannot be antagonized. After administration, peak plasma levels are reached in 2-4 hours. Effects of continuous use may persist for 5-7 days, depending on renal function.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106.

Treatment is initiated 1-4 hours after surgery at doses ranging from 75 mg (creatinine clearance 30-50 mL.min-1) to 110 mg (normal renal function). Dosage is escalated to 150 mg to 220 mg on subsequent days. Dabigatran prolongs aPTT without linear effect. Thrombin time (TT) is particularly sensitive and reference for anticoagulation management, with linearity between dose-response in therapeutic concentrations.11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106. Anticoagulation reversal is theoretically possible by administration of recombinant factor VIIa, although not clinically tested.100100. Eriksson BI, Quinlan DJ, Weitz JI. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin Pharmacokinet. 2009;48:1-22.

The effectiveness of dabigatran (220 mg) for DVT prevention is compared to that of enoxaparin (40 mg.day-1) and without increased bleeding.101101. Eriksson B, Dahl O, Rosencher N, et al. Oral dabigatran Etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the remodel randomized trial. J Thromb Haemost. 2007;5:2178-85. Preliminary studies of dabigatran and neuraxial block were conducted with epidural catheter removal 4-6 hours before the first dose. There is no study of patients on dabigatran and use of epidural catheters.

Recommendations

  1. Because DVT prophylaxis with dabigatran is initiated postoperatively, there is no limitation to simple neuraxial block (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  2. Dabigatran discontinuation should be at least seven days before neuraxial block to allow return to normal coagulation (D);11. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107:96-106.

  3. The half-live of 12-17 hours suggests a 34 hours interval between the last dose and catheter management or removal. However, the manufacturer's102102. Boehringer-Ingelheim Pradaxa. Summary of Product Characteristics. Available from: http://www.emea.europa.eu/humandocs/PDFs/EPAR/pradaxa/H-829-PI-en.pdf, 2009.
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    recommendation is to avoid epidural catheter in patients on this drug and that the first dose should be administered at least 2 hours after catheter removal (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  4. However, because plasma level can be reached in 2 hours, it is prudent to observe a minimum interval of 6 hours after catheter removal to start drug administration (D).22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Argatroban (Argatra®)

Argatroban is a direct thrombin reversible inhibitor that binds to the different forms of thrombin.103,104 It is indicated for patients with thrombosis associated with heparin-induced thrombocytopenia (HIT) by the lack of interaction with platelet factor 4 (PF4).22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Argatroban is administered by continuous IV infusion and eliminated exclusively by the liver, and may be used in renal failure. The dose of 0.5-2 μg.kg.min-1 is adjusted to maintain aPTT within 1.5 to 3 of the normal value. In patients with good liver function, aPTT normalization occurs 2-4 hours from the end of infusion due to the short half-life of 35-45 minutes.105105. Yeh RW, Jang I-K. Argatroban: update. Am Heart J. 2006;151:1131-8.

Recommendations

  1. The insertion of spinal/epidural needle/catheter should be made at least 4 hours after drug discontinuation. The drug reintroduction time after the blockade or catheter removal is 2 hours and always excluded residual coagulant effect by aPTT and ACT measurements (D);22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

  2. If the patient is under argatroban therapy due to diagnosis of acute HIT, treatment should not be discontinued because of the risk of thromboembolism and, therefore, blockade is contraindicated (D).22. Vandermeulen E. Regional anaesthesia and anticoagulation. Best Pract Res Clin Anaesthesiol. 2010;24:121-31.

Desirudin (Iprivask®) e lepirudin (Refludan®)

Recombinant hirudins (lepirudin and desirudin) are from the first generation of direct thrombin inhibitors and are parenterally administered. They have no interaction with platelet factor 4 (PF4) and, therefore, do not trigger heparin-induced thrombocytopenia (HIT). Desirudin is indicated for DVT prophylaxis and lepirudin for DVT treatment of patients with history of HIT.33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Both lepirudin and desirudin have half-lives of 1.3-2 hours, but it increases significantly in renal failure. Due to the potential risk of bleeding, the anticoagulant effect of hirudin should be routinely monitored with aPTT or ecarin clotting time (ECT).106106. Greinacher A. Lepirudin: a bivalent direct thrombin inhibitor for anticoagulation therapy. Expert Rev Cardiovasc Ther. 2004;2:339-57.

Recommendations

  1. In patients with normal renal function, wait 8-10 hours from last dose to perform neuraxial block with or without epidural catheter installation (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  2. In patients with normal renal function, wait 8-10 hours from last dose to remove catheter (A);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  3. Wait 2-4 hours to restart these drugs after puncture or epidural catheter removal (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  4. Absence of residual anticoagulant effect should always be confirmed by determining aPTT and ECT (D).33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

Neuraxial block and laboratory tests

Current guidelines and consensus state that neuraxial block should not be performed in patients with thrombocytopenia; however, none of them determine the minimum limit of platelets number to perform neuraxial block.44. Green L, Machin SJ. Managing anticoagulated patients during neuraxial anaesthesia. Br J Haematol. 2010;149:195-208.

Platelet function appears to be more important than the isolated number of, platelet.107107. Abramovitz S, Beilin Y. Thrombocytopenia, low molecular weight heparin, and obstetric anesthesia. Anesthesiol Clin N Am. 2003;21:99-109. Researchers suggest a platelet count greater than 50,000.mm-3 with preserved function as acceptable, while a platelet count greater than 100,000.mm-3 is acceptable without considering evaluation test of platelet function.108108. Douglas MJ. Coagulation abnormalities and obstetric anaesthesia. Can J Anaesth. 1991;38:17-25.,109109. Schindler M, Gatt S, Isert P et al. Thrombocytopenia and platelet functional defects in pre-eclampsia: implications for regional anaesthesia. Anaesth Intens Care. 1990;18:169-74.

A recent study reported that in the absence of risk factors, platelet count > 80,000.mm-3 is considered safe to perform spinal/epidural blocks and platelet count > 40,000.mm-3 to perform simple lumbar puncture.110110. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol. 2010;148:15-25.

Regarding secondary hemostasis, the 40% activity level of each factor is adequate or near normal for normal hemostasis.8080. Xi M, Beguin S, Hemker HC. The relative importance of the factors II, VII, IX and X for the prothrombinase activity in plasma of orally anticoagulated patients. Thromb Haemos. 1989;62:788-91. INR of 1.5 is associated with the 40% activity of factor VII. Bleeding may occur if the level of any coagulation factor is reduced to 20-40% of its normal value.8181. Enneking FK, Benzon H. Oral anticoagulants and regional anesthesia: a perspective. Reg Anesth Pain Med. 1998;23:140-5.

Recommendations

  1. Epidural or spinal blocks, in the absence of risk factors for bleeding, may be performed with platelet count above 80,000.mm-3 (D);110110. Van Veen JJ, Nokes TJ, Makris M. The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. Br J Haematol. 2010;148:15-25.

  2. INR <1.5 is considered safe to perform neuraxial blocks (D).66. Horlocker TT, Birnbach DJ, Connis RT, et al. Practice advisory for the prevention, diagnosis, and management of infectious complications associated with neuraxial techniques: a report by the American Society of Anesthesiologists Task Force on infectious complications associated with neuraxial techniques. Anesthesiology. 2010;112:530-45.

Peripheral nerve blocks and anticoagulants

Although spinal hematoma is the most important hemorrhagic complication of regional anesthesia because of the catastrophic nature of bleeding into a restricted and non-compressible space, the associated risk after plexus and peripheral nerve blocks remains undefined.

The presence of hematoma may increase morbidity and mortality, and there are reported cases involving retroperitoneal hematoma after lumbar plexus block with the use of enoxaparin or clopidogrel. In one of these reports, the catheter inserted into the lumbar plexus was removed 1.5 hours after the last dose of heparin.111111. Aveline C, Bonnet F. Delayed retroperitoneal haematoma after failed lumbar plexus block. Br J Anaesthesia. 2004;93:589-91.,112112. MaierC, GleimM, WeissT, et al. Severe bleeding following lumbar sympathetic blockade in two patients under medication with irreversible platelet aggregation inhibitors. Anesthesiology. 2002;97:740-3.

Although most of the cases have evolved without neurological damage, there was extension of the hospital stay, with injury and patient dissatisfaction, as well as need for transfusion of packed red blood cells. Some showed deficits engines and sensitives, renal failure and death by bleeding.111111. Aveline C, Bonnet F. Delayed retroperitoneal haematoma after failed lumbar plexus block. Br J Anaesthesia. 2004;93:589-91.113113. Weller RS, Gerancher JC, Crews JC, et al. Extensive retroperitoneal hematoma without neurologic deficit in two patients who underwent lumbar plexus block and were later anticoagulated. Anesthesiology. 2003;98:581-5.

The German Society of Anesthesiology and Intensive Care Medicine adopts the same recommendations for neuraxial, peripheral nerve, and plexus blocks in patients on antithrombotic drugs.114114. Buttner J, Burkle H, Gogarten W, et al. Thromboembolism prophylaxis and peripheral nerve blocks for regional anaesthesia. Guideline of the German Society of Anaesthesiology and Intensive Care Medicine. Anaesth Intensiv Med. 2005;46:319-22. The Austrian Society differentiates neuraxial blocks from deep or superficial peripheral blocks.115115. Kozek-Langenecker SA, Fries D, Gu M, et al. Locoregional anesthesia and coagulation inhibitors. Recommendations of the Task Force on Perioperative Coagulation of the Austrian Society for Anesthesiology and Intensive Care Medicine. Anaesthesist. 2005;54:476-84. These latter, similar to axillary brachial plexus, femoral nerve, and distal sciatic blocks, may be performed with the use of ASA and anticoagulants.115115. Kozek-Langenecker SA, Fries D, Gu M, et al. Locoregional anesthesia and coagulation inhibitors. Recommendations of the Task Force on Perioperative Coagulation of the Austrian Society for Anesthesiology and Intensive Care Medicine. Anaesthesist. 2005;54:476-84.

With the increasing use of ultrasound to aid peripheral nerve and plexus blocks, the number of complications, such as vascular puncture, decreased because of the dynamic visualization of structures adjacent to the nerve to be blocked.116116. Marhofer P, Chan VWS. Ultrasound-guided regional anesthesia: current concepts and future trends. Anesth Analg. 2007;104:1265-9. Thus, evidence probably will demonstrate the actual decrease in complication rates with this technique and, therefore, recommend the relatively safe use of peripheral nerve blocks guided by ultrasound in anticoagulated patients.

Recommendations

  1. Respect the interval between LMWH administration and insertion/removal of catheters similar to those used for neuraxial blocks (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  2. Do not remove any catheter in the period of anticoagulant greatest activity (D);33. Gogarten W, Vandermeulen E, Van Aken H, et al. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015.

  3. Because morbidity is associated with retroperitoneal hematoma, paravertebral or lumbar plexus blocks have the same recommendations used in neuraxial blocks (D).111111. Aveline C, Bonnet F. Delayed retroperitoneal haematoma after failed lumbar plexus block. Br J Anaesthesia. 2004;93:589-91.

  4. Superficial blocks, such as axillary, femoral or distal sciatic, may be performed with the use of anticoagulation or antiplatelet therapy (D).111111. Aveline C, Bonnet F. Delayed retroperitoneal haematoma after failed lumbar plexus block. Br J Anaesthesia. 2004;93:589-91.

Referências

  • 1
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Publication Dates

  • Publication in this collection
    Jan-Feb 2014

History

  • Received
    23 Apr 2013
  • Accepted
    28 Apr 2013
Sociedade Brasileira de Anestesiologia R. Professor Alfredo Gomes, 36, 22251-080 Botafogo RJ Brasil, Tel: +55 21 2537-8100, Fax: +55 21 2537-8188 - Campinas - SP - Brazil
E-mail: bjan@sbahq.org