Abstracts
Neurologists feel uneasy when asked about temporary anticoagulant interruption for surgery in patients with atrial fibrillation (AF). Rational decisions can be made based on current scientific evidence.
Method
Critical review of international guidelines and selected references pertaining to bleeding and thromboembolism during periods of oral anticoagulant interruption.
Results
Withholding oral anticoagulants leads to an increased risk of perioperative thromboembolism, depending on factors such as age, renal and liver function, previous ischemic events, heart failure etc. Surgeries are associated with a variable risk of bleeding - from minimal to very high. Individualized decisions about preoperative drug suspension, bridging therapy with heparin and time to restart oral anticoagulants after hemostasis can significantly reduce these opposing risks.
Conclusion
Rational decisions can be made after discussion with all Health care team professionals involved and consideration of patient fears and expectations. Formal written protocols should help managing antithrombotic treatment during this delicate period.
atrial fibrillation; oral anticoagulants; surgery; hemorrhage; thromboembolism
Preocupação com sangramentos em pacientes anticoagulados por fibrilação atrial (FA) expõe os mesmos a riscos tromboembólicos que aumentam ainda mais quando anticoagulantes são suspensos para operações ou outras intervenções invasivas.
Método
Revisão de Diretrizes internacionais e outras publicações sobre riscos relacionados a cirurgias.
Resultados
A suspensão dos anticoagulantes aumenta o risco de complicações tromboembólicas na FA, em razão de idade, função renal e hepática, eventos isquêmicos prévios, cardiopatias etc. O risco hemorrágico das intervenções varia de mínimo a extremamente elevado. Decisões individualizadas sobre suspensão das drogas, recurso a anticoagulantes parenterais no preparo dos pacientes para cirurgia, tempo para retomada do anticoagulante oral após hemostasia reduzem significativamente estes riscos.
Conclusão
Decisões racionais podem ser tomadas após discussão com os profissionais envolvidos – dentistas, anestesistas, cirurgiões; levando em conta inclusive temores e expectativas dos pacientes. Protocolos institucionais favorecem o manejo perioperatório seguro e devem ser discutidos com os pacientes e seus cuidadores.
anticoagulantes; cirurgia geral; fibrilação atrial; hemorragia; tromboembolia
Individuals with atrial fibrillation (AF) - especially older ones or those with previous thromboembolic episodes (cerebral or systemic) - have a high risk of embolic strokes. Except in the presence of specific contraindications, these patients should receive chronic therapy with oral anticoagulant drugs. However, neurologists frequently feel insecure in prescribing anticoagulants to AF patients, despite the publication of many guidelines reinforcing this need, allegedly because of continuing concerns about the risk of bleeding complications, especially intracranial hemorrhage (ICH).
AF patients nowadays live longer with multiple co-morbidities and over time frequently
demand medical and surgical interventions associated with a variable risk of bleeding.
One quarter of anticoagulated patients need temporary drug suspension in 2 years11 .Healey JS, Eikelboom J, Douketis J et al. Periprocedural bleeding
and thromboembolic events with dabigatran compared to warfarin: results from the
RE-LY Randomized Trial. Circulation. 2012;126:343-8.
http://dx.doi.org/10.1161/CIRCULATIONAHA.111.090464
https://doi.org/10.1161/CIRCULATIONAHA.1...
. Simply withholding anticoagulants
however implies in risk of new embolic events. Balancing the opposing risks of bleeding
and embolism may seem empiric. The attending physicians are frequently asked by other
professionals - surgeons, anesthesiologists, and dentists - authorization to temporarily
withhold Warfarin so patients can be submitted to various procedures. This conduct would
be clearly inadequate in many instances.
The present text reviews the scientific evidences guiding rational antithrombotic
management in FA patients who must be submitted to invasive interventions including
surgery. The recommendations should also be useful to stroke patients with less common
indications for chronic anticoagulation - e.g., atrial flutter or cerebral venous
thrombosis. Patients with stroke caused by other mechanisms who are sometimes
anticoagulated for other reasons, especially venous thromboembolism [(VTE) - including
peripheral vein thrombosis and pulmonary embolism], may also need changes in
anticoagulant strategy. It should be remembered however that typical preventive regimens
for venous thrombosis exhibit minimal or no efficacy against arterial thromboembolism.
The manuscript reviews the vitamin K antagonist Warfarin and the new oral anticoagulants
[(NOACs): direct thrombin and factor Xa inhibitors] and is partially based in a number
of recently published guidelines from American and European medical societies to which
the interested reader is directed for more details22 .Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens T, Turakhia MP
et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular
atrial fibrillation: a science advisory for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke
2012;43(12):3442-53. Erratum in: Stroke. 2013;44:e20;Stroke. 2012;43:e181.
http://dx.doi.org/10.1161/STR.0b013e318266722a
https://doi.org/10.1161/STR.0b013e318266...
,33 .Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke.
2014;45(7):2160-236.
http://dx.doi.org/10.1161/STR.0000000000000024
https://doi.org/10.1161/STR.000000000000...
,44 .Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk
BM et al. Guidelines for the early management of patients with acute ischemic
stroke: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2013;44(3):870-947.
http://dx.doi.org/10.1161/STR.0b013e318284056a
https://doi.org/10.1161/STR.0b013e318284...
,55 .Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM,
Chaturvedi S et al. Guidelines for the primary prevention of stroke: a statement
for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2014;45(12):3754-832.
http://dx.doi.org/10.1161/STR.0000000000000046
https://doi.org/10.1161/STR.000000000000...
,66 .Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et
al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2013;15(5):625-51. http://dx.doi.org/10.1093/europace/eut083
https://doi.org/10.1093/europace/eut083...
,77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,88 .You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for
atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e531S-575s.
http://dx.doi.org/10.1378/chest.11-2304
https://doi.org/10.1378/chest.11-2304...
,99 .Anderson MA, Ben-Menachem T, Gan SI, Appalaneni V, Banerjee S, Cash
BD et al. Management of antithrombotic agents for endoscopic procedures.
Gastrointest Endosc. 2009;70(6):1060-70.
http://dx.doi.org/10.1016/j.gie.2009.09.040
https://doi.org/10.1016/j.gie.2009.09.04...
,1010 .Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL
et al. Guidelines for the prevention of stroke in women: a statement for
healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2014;45(5):1545-88. Erratum in: Stroke. 2014;45:e95.
http://dx.doi.org/10.1161/01.str.0000442009.06663.48
https://doi.org/10.1161/01.str.000044200...
.
ATRIAL FIBRILLATION AND STROKE RISK
Chronic or paroxysmal AF is responsible for a large number of thromboembolic events
every year. The main affected area (up to 80%) is the brain – 10 to 12% of cerebral
infarcts (CI)44 .Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk
BM et al. Guidelines for the early management of patients with acute ischemic
stroke: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke. 2013;44(3):870-947.
http://dx.doi.org/10.1161/STR.0b013e318284056a
https://doi.org/10.1161/STR.0b013e318284...
,1111 .Flint AC, Banki NM, Ren X, Rao VA, Go AS. Detection of paroxysmal
atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke:
the Stroke and Monitoring for PAF in Real Time (SMART) Registry. Stroke.
2012;43(10):2788-90.
http://dx.doi.org/10.1161/STROKEAHA.112.665844
https://doi.org/10.1161/STROKEAHA.112.66...
. The frequency increases as age
advances: the attributed risk in individuals with 80 years or more reaches 25%22 .Furie KL, Goldstein LB, Albers GW, Khatri P, Neyens T, Turakhia MP
et al. Oral antithrombotic agents for the prevention of stroke in nonvalvular
atrial fibrillation: a science advisory for healthcare professionals from the
American Heart Association/American Stroke Association. Stroke
2012;43(12):3442-53. Erratum in: Stroke. 2013;44:e20;Stroke. 2012;43:e181.
http://dx.doi.org/10.1161/STR.0b013e318266722a
https://doi.org/10.1161/STR.0b013e318266...
,55 .Meschia JF, Bushnell C, Boden-Albala B, Braun LT, Bravata DM,
Chaturvedi S et al. Guidelines for the primary prevention of stroke: a statement
for healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2014;45(12):3754-832.
http://dx.doi.org/10.1161/STR.0000000000000046
https://doi.org/10.1161/STR.000000000000...
,1010 .Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL
et al. Guidelines for the prevention of stroke in women: a statement for
healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2014;45(5):1545-88. Erratum in: Stroke. 2014;45:e95.
http://dx.doi.org/10.1161/01.str.0000442009.06663.48
https://doi.org/10.1161/01.str.000044200...
,1212 .Stroke Risk in Atrial Fibrillation Working Group. Comparison of 12
risk stratification schemes to predict stroke in patients with nonvalvular
atrial fibrillation. Stroke. 2008;39(6):1901-10.
http://dx.doi.org/10.1161/STROKEAHA.107.501825
https://doi.org/10.1161/STROKEAHA.107.50...
. Risk is also greater in women (in all age groups: HR
1.14 [95%CI, 1.07–1.22]: 20.4% of CI in women vs. 15.6% in men)1010 .Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL
et al. Guidelines for the prevention of stroke in women: a statement for
healthcare professionals from the American Heart Association/American Stroke
Association. Stroke. 2014;45(5):1545-88. Erratum in: Stroke. 2014;45:e95.
http://dx.doi.org/10.1161/01.str.0000442009.06663.48
https://doi.org/10.1161/01.str.000044200...
,1313 .Avgil Tsadok M, Jackevicius CA, Rahme E, Humphries KH, Behlouli H,
Pilote L. Sex differences in stroke risk among older patients with recently
diagnosed atrial fibrillation. JAMA. 2012;307(18):1952-8.
http://dx.doi.org/10.1001/jama.2012.3490
https://doi.org/10.1001/jama.2012.3490...
,1414 .Fonarow GC, Reeves MJ, Zhao X, Olson DM, Simith EE, Saver JL et al.
Age-related differences in characteristics, performance measures, treatment
trends, and outcomes in patients with ischemic stroke. Circulation.
2010;121(7):879-91.
http://dx.doi.org/10.1161/CIRCULATIONAHA.109.892497
https://doi.org/10.1161/CIRCULATIONAHA.1...
. Women also tend to develop strokes in later ages, and
the risk difference between genders concentrates in older AF patients (≥ 75 years).
These two variables - age and gender - are integrated in current predictive models
such as the CHA2DS2-VASc (Table 1)1515 .Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ.
Validation of clinical classification schemes for predicting stroke: results
from the National Registry of Atrial Fibrillation. JAMA. 2001;285(22):2864-70.
http://dx.doi.org/10.1001/jama.285.22.2864
https://doi.org/10.1001/jama.285.22.2864...
,1616 .Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining
clinical risk stratification for predicting stroke and thromboembolism in atrial
fibrillation using a novel risk factor-based approach: the euro heart survey on
atrial fibrillation. Chest. 2010;137(2):263-72.
http://dx.doi.org/10.1378/chest.09-1584
https://doi.org/10.1378/chest.09-1584...
,1717 . Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen
J et al. Validation of risk stratification schemes for predicting stroke and
thromboembolism in patients with atrial fibrillation: nationwide cohort study.
BMJ. 2011;342:d124. http://dx.doi.org/10.1136/bmj.d124
https://doi.org/10.1136/bmj.d124...
,1818 .Van Staa TP, Setakis E, Di Tanna GL, Lane DA, Lip GYH. A comparison
of risk stratification schemes for stroke in 79 884 atrial fibrillation patients
in general practice. J Thromb Haemost. 2011;9(1):39-48.
http://dx.doi.org/10.1111/j.1538-7836.2010.04085.x
https://doi.org/10.1111/j.1538-7836.2010...
.
Risk scales help define the best antithrombotic strategy in AF patients. The main scales used are presented in Table 1. Using for instance the CHADS2 model:
-
low risk (score 0) - acetylsalicylic acid (ASA) 81-325 mg/day or no treatment (optimizing possible associated risk factors);
-
medium risk (score 1) – ASA or Warfarin (consider patient preferences and hemorrhage risk);
-
greater risk (score ≥ 2) – Warfarin (International Normalized Ratio (INR) 2-3 [goal INR- 2.5]).
Recommendations are similar using the CHAD2DS2-VASc, with some authors suggesting the
use of NOACs from a score of 1 or more1919 .Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldfren J, Parekh
A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2009;361(12):1139-51.
http://dx.doi.org/10.1056/NEJMoa0905561
https://doi.org/10.1056/NEJMoa0905561...
. CHAD2DS2-VASc probably better estimates risk in patients
classified as low-risk using the CHADS2 model1616 .Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining
clinical risk stratification for predicting stroke and thromboembolism in atrial
fibrillation using a novel risk factor-based approach: the euro heart survey on
atrial fibrillation. Chest. 2010;137(2):263-72.
http://dx.doi.org/10.1378/chest.09-1584
https://doi.org/10.1378/chest.09-1584...
,1717 . Olesen JB, Lip GY, Hansen ML, Hansen PR, Tolstrup JS, Lindhardsen
J et al. Validation of risk stratification schemes for predicting stroke and
thromboembolism in patients with atrial fibrillation: nationwide cohort study.
BMJ. 2011;342:d124. http://dx.doi.org/10.1136/bmj.d124
https://doi.org/10.1136/bmj.d124...
,1818 .Van Staa TP, Setakis E, Di Tanna GL, Lane DA, Lip GYH. A comparison
of risk stratification schemes for stroke in 79 884 atrial fibrillation patients
in general practice. J Thromb Haemost. 2011;9(1):39-48.
http://dx.doi.org/10.1111/j.1538-7836.2010.04085.x
https://doi.org/10.1111/j.1538-7836.2010...
.
The instruments used to stratify the annual risk of stroke recurrence in AF probably
underestimate the actual risk, most probably around 7 to 10%2020 .The Stroke Risk in Atrial Fibrillation Working Group. Independent
predictors of stroke in patients with atrial fibrillation: a systematic review.
Neurology. 2007;69(6):546-54.
http://dx.doi.org/10.1212/01.wnl.0000267275.68538.8d
https://doi.org/10.1212/01.wnl.000026727...
. Any history of previous thromboembolic event -
usually cerebral - is therefore a marker of high risk of recurrence. Except in cases
with a strong contraindication such as recent severe hemorrhage or a persistent
bleeding tendency these patients should be adequately anticoagulated. Besides the
factors usually included in prediction scales such as coronary heart disease,
congestive heart failure etc., the risk also increases with rheumatic valve disease;
biological heart valves (any position) or aortic mechanical valves; and even more
with mechanical mitral valves (the risk is particularly high with caged-ball or
tilting disk models).
A difficult area is the diagnosis of paroxysmal AF. Some 10 to 12% of stroke patients
will exhibit AF during the initial hospital stay, but at least 10 to 15% more may
have paroxysmal episodes only evident after long monitoring periods. A series of
methods for paroxysmal AF detection have been prospectively evaluated. Ambulatory
monitoring for 30 days in individuals with cryptogenic CI revealed 11% (7.6-15.7%)
of episodes persisting for at least 5 seconds (6.7% for episodes > 30 seconds),
most frequently asymptomatic1111 .Flint AC, Banki NM, Ren X, Rao VA, Go AS. Detection of paroxysmal
atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke:
the Stroke and Monitoring for PAF in Real Time (SMART) Registry. Stroke.
2012;43(10):2788-90.
http://dx.doi.org/10.1161/STROKEAHA.112.665844
https://doi.org/10.1161/STROKEAHA.112.66...
.
More than half of the episodes were detected only after 10 days of monitoring.
Other methods are being tested. Some researchers suggest teaching patients and family
caregivers to evaluate the arterial pulse as to its frequency and regularity;
preliminary studies show reasonable sensitivity and specificity in the
identification of tachyarrhythmias and its differentiation from sinus rhythm after a
brief training2121 .Kallmünzer B, Bobinger T, Kahl N, Kopp M, Kurka N, Hilz MJ et al.
Peripheral pulse measurement after ischemic stroke: a feasibility study.
Neurology. 2014;83(7):598-603.
http://dx.doi.org/10.1212/WNL.0000000000000690
https://doi.org/10.1212/WNL.000000000000...
. Detection of the
arrhythmia should be followed by formal Electrocardiogram (EKG) exam that can even
be done by telemetry2222 .Gaillard N, Deltour S, Vilotijevic B, Hornych A, Crozier S, Leger A
et al. Detection of paroxysmal atrial fibrillation with transtelephonic EKG in
TIA or stroke patients. Neurology. 2010;74(21):1666-70.
http://dx.doi.org/10.1212/WNL.0b013e3181e0427e
https://doi.org/10.1212/WNL.0b013e3181e0...
. The
so-called event-Holter can be triggered by patients whenever they suspect the
presence of the arrhythmia. These two techniques however tend to detect only a few
episodes. In the study of Flint and cols referred above only 6% of the episodes
detected by EKG monitoring were perceived by the patients1111 .Flint AC, Banki NM, Ren X, Rao VA, Go AS. Detection of paroxysmal
atrial fibrillation by 30-day event monitoring in cryptogenic ischemic stroke:
the Stroke and Monitoring for PAF in Real Time (SMART) Registry. Stroke.
2012;43(10):2788-90.
http://dx.doi.org/10.1161/STROKEAHA.112.665844
https://doi.org/10.1161/STROKEAHA.112.66...
. Other methods of low availability that are not
dependent on patient awareness have been proposed including subcutaneous cardiac
monitors used for periods of many months. Using one of these systems in patients
with cryptogenic CI, AF episodes of at least 30 seconds were detected 6 times more
frequently than in a control group (8.9% vs. 1.4%) after 6 months (12.4% vs. 2% in
12 months)2323 .Sanna T, Diener HC, Passman RS, Crystal AF. Investigators.
Cryptogenic stroke and underlying atrial fibrillation. N Engl J Med.
2014;370(26):2478-86. http://dx.doi.org/10.1056/NEJMoa1313600
https://doi.org/10.1056/NEJMoa1313600...
.
A table including AF patients and other risk groups for thromboembolic complications
has been developed (Table 2)77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,88 .You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for
atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e531S-575s.
http://dx.doi.org/10.1378/chest.11-2304
https://doi.org/10.1378/chest.11-2304...
. It can be used in surgical patients, although it
is based on annual risk in clinical settings77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
. The risk of hemorrhage in anticoagulated patients can
also be reasonably estimated using scales such as HAS-BLED (Table 3)2424 .Pisters R, Lane DA, Nieuwlaat R, Vos CB, Crijns HJ, Lip GY. A novel
user-friendly score (HAS-BLED) to assess one-year risk of major bleeding in
atrial fibrillation patients: The Euro Heart Survey. Chest.
2010;138(5):1093-100. http://dx.doi.org/10.1378/chest.10-0134
https://doi.org/10.1378/chest.10-0134...
, 2525 .Lip GYH, Frison L, Halperin JL, Lane DA. Comparative validation of
a novel risk score for predicting bleeding risk in anticoagulated patients with
atrial fibrillation: the HAS-BLED (Hypertension, Abnormal Renal/Liver Function,
Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol
Concomitantly) score. J Am Coll Cardiol. 2011;57(2):173-80.
http://dx.doi.org/10.1016/j.jacc.2010.09.024
https://doi.org/10.1016/j.jacc.2010.09.0...
. It should be highlighted that the same factors may
increase the risks of both thromboembolism and hemorrhage2626 .Hohnloser S. Stroke prevention versus bleeding risk in atrial
fibrillation. A clinical dilemma. J Am Coll Cardiol. 2011;57(2):181-3.
http://dx.doi.org/10.1016/j.jacc.2010.09.026
https://doi.org/10.1016/j.jacc.2010.09.0...
. Hence, therapeutic decisions should always be
individualized and patients and relatives or caregivers should receive adequate
instruction on the necessary care to help reduce bleeding risks – diet habits,
scheduled laboratory controls, risks related to drug interactions and falls etc.
EFFICACY AND USE OF ORAL ANTICOAGULANTS
Warfarin
The efficacy of Warfarin in AF as compared to placebo is undisputable. In primary
prevention, the risk reduction (RR) reaches 68% (annual risk 1.4% vs. 4.5%)2727 .Stroke Prevention in Atrial Fibrillation Investigators. Stroke
Prevention in Atrial Fibrillation Study: final results. Circulation.
1991;84(2):527-39. http://dx.doi.org/10.1161/01.CIR.84.2.527
https://doi.org/10.1161/01.CIR.84.2.527...
. ASA is also efficacious but
much less so2828 .Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of
thromboembolic complications in chronic atrial fibrillation: the Copenhagen
AFASAk study. Lancet. 1989;1(8631):175-8.
http://dx.doi.org/10.1016/S0140-6736(89)91200-2
https://doi.org/10.1016/S0140-6736(89)91...
. The
differences between Warfarin and ASA are small only in young patients with
non-rheumatic AF and without other risk factors2929 .Stroke Prevention in Atrial Fibrillation Investigators. Warfarin
versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke
Prevention in Atrial Fibrillation II Study. Lancet. 1994;343(8899):687-91.
http://dx.doi.org/10.1016/S0140-6736(94)91577-6
https://doi.org/10.1016/S0140-6736(94)91...
,3030 .Hellemons BS, Langenberg M, Lodder J, Vermeer F, Schouten HJ,
Lemmens T et al. Primary prevention of arterial thromboembolism in non-rheumatic
atrial fibrillation in primary care: randomised controlled trial comparing two
intensities of coumarin with aspirin. BMJ. 1999;319(7215):958-64.
http://dx.doi.org/10.1136/bmj.319.7215.958
https://doi.org/10.1136/bmj.319.7215.958...
. After a thromboembolic event, the annual stroke
risk falls with Warfarin from 12% to 4% (vs. placebo)3131 .EAFT (European Atrial Fibrillation Study Group). Secondary
prevention in non-rheumatic atrial fibrillation after transient ischaemic attack
or minor stroke. Lancet. 1993;342(8882):1255-62.
http://dx.doi.org/10.1016/0140-6736(93)92358-Z
https://doi.org/10.1016/0140-6736(93)923...
. This same study showed a clear advantage of
Warfarin over ASA in patients eligible for anticoagulation.
The INR-goal for most patients is 2.5 (2.0-3.0). The first main studies accepted
higher levels of anticoagulation2727 .Stroke Prevention in Atrial Fibrillation Investigators. Stroke
Prevention in Atrial Fibrillation Study: final results. Circulation.
1991;84(2):527-39. http://dx.doi.org/10.1161/01.CIR.84.2.527
https://doi.org/10.1161/01.CIR.84.2.527...
,2828 .Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B.
Placebo-controlled, randomised trial of warfarin and aspirin for prevention of
thromboembolic complications in chronic atrial fibrillation: the Copenhagen
AFASAk study. Lancet. 1989;1(8631):175-8.
http://dx.doi.org/10.1016/S0140-6736(89)91200-2
https://doi.org/10.1016/S0140-6736(89)91...
,2929 .Stroke Prevention in Atrial Fibrillation Investigators. Warfarin
versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke
Prevention in Atrial Fibrillation II Study. Lancet. 1994;343(8899):687-91.
http://dx.doi.org/10.1016/S0140-6736(94)91577-6
https://doi.org/10.1016/S0140-6736(94)91...
,3030 .Hellemons BS, Langenberg M, Lodder J, Vermeer F, Schouten HJ,
Lemmens T et al. Primary prevention of arterial thromboembolism in non-rheumatic
atrial fibrillation in primary care: randomised controlled trial comparing two
intensities of coumarin with aspirin. BMJ. 1999;319(7215):958-64.
http://dx.doi.org/10.1136/bmj.319.7215.958
https://doi.org/10.1136/bmj.319.7215.958...
, but there is a strong consensus nowadays that the
risk of bleeding complications increases disproportionally in patients with INR
of 4 or more33 .Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke.
2014;45(7):2160-236.
http://dx.doi.org/10.1161/STR.0000000000000024
https://doi.org/10.1161/STR.000000000000...
,77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,88 .You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for
atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e531S-575s.
http://dx.doi.org/10.1378/chest.11-2304
https://doi.org/10.1378/chest.11-2304...
.
NOACs
In the last decade large studies comparing NOACs (inhibitors of thrombin–
dabigatran – and of Factor Xa – apixaban, rivaroxaban, edoxaban) and Warfarin in
non-valvular AF were published. They are briefly summarized here. The comparison
between dabigatran and Warfarin (RELY study: one third of patients with
paroxysmal AF) showed non-inferiority of the new drug (combined outcome
including systemic embolism and stroke: 1.69%/year in the Warfarin group) of
lower doses (110 mg b.i.d.: 1.53%/year) and superiority of the higher doses
tested (150 mg b.i.d.: 1.11%/year), despite a very small increase in myocardial
infarct rates and some increase in the risk of gastrointestinal hemorrhage1919 .Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldfren J, Parekh
A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2009;361(12):1139-51.
http://dx.doi.org/10.1056/NEJMoa0905561
https://doi.org/10.1056/NEJMoa0905561...
. The rates of major bleeding
complications were similar in patients on Warfarin or on the higher doses of
dabigatran but were lower in those on lower doses. Mortality was slightly less
in those using the higher doses (3.64%/year vs. 4.13% for Warfarin – p = 0.051).
Some methodological difficulties of the study should however be mentioned: some
40% of both groups used ASA together with the anticoagulants; there was no
blinding in the adjustment of Warfarin doses; in patients with stroke/transient
ischemic attack (TIA) the risk reduction with dabigatran was not statistically
significant even in higher doses (only non-inferiority was demonstrated).
A study comparing rivaroxaban (20 mg/daily [15 mg if Cr Cl 30-49 mL/min]) and
Warfarin in patients with slightly greater embolic risk (CHADS2 ≥, with previous
embolic events in 55%, congestive heart failure in > 60%) demonstrated
non-inferiority but not superiority (even in patients with a previous stroke) in
reducing the annual thromboembolic risk: 2.1% vs. 2.4% (ROCKET-AF)3232 .Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al.
Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med.
2011;365(10):883-91. http://dx.doi.org/10.1056/NEJMoa1009638
https://doi.org/10.1056/NEJMoa1009638...
. Also, there was no
significant difference in annual global risk of hemorrhage (14.9% vs. 14.5%).
Patients on rivaroxaban had more gastrointestinal hemorrhages (3.2% vs. 2.2%)
and more hemorrhages requiring blood transfusions (1.6% vs. 1.3%/year); and
lower rates of ICH (0.5% vs. 0.7%/year) and fatal hemorrhages (0.2% vs.
0.5%/year). An important critic has been made to this study: time spent with
adequate levels of anticoagulation (55%) in the Warfarin group (INR monitored by
a blinded electronic system) was less than in many other studies.
Apixaban (5 mg b.i.d.; patients with Cr levels > 2.5 mg/dL excluded) has been
compared to ASA (AVERROES – see ahead) and with Warfarin. In this case
(ARISTOTLE), the annual risk of the composite outcome (hemorrhagic or ischemic
stroke and systemic embolism) was significantly lower with apixaban (1.27% vs.
1.60%) even in patients with a previous stroke/TIA3333 .Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M
et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J
Med. 2011;365(11):981-92.
http://dx.doi.org/10.1056/NEJMoa1107039
https://doi.org/10.1056/NEJMoa1107039...
. There were also lower rates of severe
hemorrhages (2.1 vs. 3.1%), CH (0.24% vs. 0.47%) and a slight reduction in
global mortality (3.52% vs. 3.94%), with no differences in rates of
gastrointestinal hemorrhage.
A large trial (ENGAGE-AF) suggests similar results (non-inferiority for cerebral
or systemic embolism and lower rates of major bleeding vs. Warfarin) using a
novel anti-Xa drug, edoxaban, in two regimens (30 or 60 mg once daily)3434 .Giugliano RP, Ruff CT, Braunwald E, Murph SA, Wiviott DS, Halperin
JL et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl
J Med. 2013;369(22):2093-104.
http://dx.doi.org/10.1056/NEJMoa1310907
https://doi.org/10.1056/NEJMoa1310907...
. Whatever the dose used it
was halved if the patient’s weight fell below 60 Kg or if Cr Cl was reduced
(30-50 mL/min). In the intention-to-treat analysis, there was a trend for
superiority using larger doses (HR ratio, 0.87; 97.5%CI: 0.73-1.04; p = 0.08)
and an opposite trend for inferiority with the lower doses (HR 1.13; 97.5%CI:
0.96 to 1.34; p = 0.10). Both regimens were associated however with lower rates
of severe hemorrhages, ICH and slightly lower mortality (significant difference
with the higher dose regimen).
In summary, NOACs should be considered as an option on a par with Warfarin in most recently diagnosed non-valvular AF patients, taking into account clinical particulars (e.g., renal function [should be checked regularly during treatment], previous gastrointestinal hemorrhage) and patient preferences (inconvenience of multiple INR tests, cost etc.). Patients adequately anticoagulated with Warfarin (absence of bleeding or recurrent thromboembolism) should not routinely be switched to NOACs. Those with less than 60% of the time with an INR within therapeutic levels are probably at increased risk of thromboembolic or hemorrhagic events and constitute a group in which opting for a NOAC would probably be advantageous.
Special situations
Contraindication to anticoagulant treatment: there is no
doubt about the efficacy of Warfarin or NOACs and their superiority over ASA
(generally 100 mg/day). Warfarin is also superior (annual rate of composite
outcome - 3.9% vs. 5.6%) to the combination of aspirin and clopidogrel in
primary prevention (ACTIVE W: AF plus at least one risk factor)3535 .Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S
et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial
fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for
prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet.
2006;367(9526):1903-12.
http://dx.doi.org/10.1016/S0140-6736(06)68845-4
https://doi.org/10.1016/S0140-6736(06)68...
.
More recently, two studies evaluated strategies for AF patients with
contraindications to Warfarin. In the first study (ACTIVE-A) double
antiaggregation (ASA + clopidogrel) was compared to ASA only3636 .Connolly SJ, Eikelboom JW, Ng J, Hirsh J, Yusuf S, Pogue J et al.
Net clinical benefit of adding clopidogrel to aspirin therapy in patients with
atrial fibrillation for whom vitamin K antagonists are unsuitable. Ann Intern
Med. 2011;155(9):579-86.
http://dx.doi.org/10.7326/0003-4819-155-9-201111010-00004
https://doi.org/10.7326/0003-4819-155-9-...
: the additional reduction in
ischemic events with double therapy was basically neutralized by an increased
risk of severe hemorrhages (RR 0.97; 95%CI: 0.89–1.06; p = 0.54 for the
composite outcome). It is therefore difficult to accept the IIa level AHA
recommendation for double antiaggregation in patients with a contraindication to
Warfarin treatment. Especially as another study with apixaban (5 mg b.i.d.) vs.
ASA (AVERROES: patients with Cr > 2.5 mg/dL excluded) showed superiority of
apixaban (stroke or systemic embolism: annual rate 1.6% vs. 3.7%) and absence of
significant differences in adverse effects (severe hemorrhages, gastrointestinal
bleedings, mortality)3737 .Connolly SJ, Eikelboom J, Joyner C, Diener HC, Hart R, Golitsyn S
et al. Apixaban in patients with atrial fibrillation. N Engl J Med.
2011;364(9):806-17. http://dx.doi.org/10.1056/NEJMoa1007432
https://doi.org/10.1056/NEJMoa1007432...
. The
best strategy in this important group of patients remains under scrutiny. The
availability of antagonists for both thrombin and Factor Xa inhibitors in the
near future3838 .Costin J, Ansell J, Laulicht B, Bakhru S, Steiner S. Reversal
agents in development for the new oral anticoagulants. Postgrad Med.
2014;126(7):19-24. http://dx.doi.org/10.3810/pgm.2014.11.2829
https://doi.org/10.3810/pgm.2014.11.2829...
,3939 .Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P,
Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants.
Expert Rev Cardiovasc Ther. 2015;13(1):95-103.
http://dx.doi.org/10.1586/14779072.2015.987126
https://doi.org/10.1586/14779072.2015.98...
could possibly make the
decision to start a NOAC the most appropriate in many cases.
Anticoagulants associated with platelet antiaggregants: an
also much discussed question regards patients with coronary heart disease and
stents with indication for anticoagulation because of AF (with or without
previous stroke/TIA). Some 20% of patients with AF and stroke have symptomatic
coronary disease (and many more will develop it in the future). The risks of the
simultaneous use of Warfarin and antiplatelet drugs are well known and generally
contraindicate their routine association. Triple therapy (double antiaggregant
and anticoagulation) is associated with increased mortality and major bleeding
risk and no additional reduction of thromboembolic events when compared to
single antiaggregation with clopidogrel plus Warfarin treatment4040 .Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herman
JP et al. Use of clopidogrel with or without aspirin in patients taking oral
anticoagulant therapy and undergoing percutaneous coronary intervention: an
open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-15.
http://dx.doi.org/10.1016/S0140-6736(12)62177-1
https://doi.org/10.1016/S0140-6736(12)62...
. Some medical societies
suggest, based in somewhat limited evidence, the concomitant use of Warfarin and
ASA or clopidogrel/prasugrel in special situations for 12 months (CHADS2 ≥ 2) or
for an undefined time (acute coronary syndromes); and triple therapy for 12
months after pharmacological stent placement33 .Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke.
2014;45(7):2160-236.
http://dx.doi.org/10.1161/STR.0000000000000024
https://doi.org/10.1161/STR.000000000000...
,77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,88 .You JJ, Singer DE, Howard PA, et al. Antithrombotic therapy for
atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th
ed: American College of Chest Physicians Evidence-Based Clinical Practice
Guidelines. Chest. 2012;141(2 Suppl):e531S-575s.
http://dx.doi.org/10.1378/chest.11-2304
https://doi.org/10.1378/chest.11-2304...
,4040 .Dewilde WJ, Oirbans T, Verheugt FW, Kelder JC, De Smet BJ, Herman
JP et al. Use of clopidogrel with or without aspirin in patients taking oral
anticoagulant therapy and undergoing percutaneous coronary intervention: an
open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-15.
http://dx.doi.org/10.1016/S0140-6736(12)62177-1
https://doi.org/10.1016/S0140-6736(12)62...
,4141 .Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr
et al. 2012 ACCF/AHA focused update of the guideline for the management of
patients with unstable angina/non-ST-elevation myocardial infarction (updating
the 2007 guideline and replacing the 2011 focused update): a report of the
American College of Cardiology Foundation/American Heart Association Task Force
on Practice Guidelines. J Am Coll Cardiol. 2012;60(7):645-81.
http://dx.doi.org/10.1016/j.jacc.2012.06.004
https://doi.org/10.1016/j.jacc.2012.06.0...
. In AF anticoagulated patients undergoing
angioplasty/stent placement, the antiplatelet drugs should be used in low doses;
whenever possible, non-pharmacological stents should be preferred in
anticoagulated patients (minimizing time on triple therapy).
There are fewer data on antiaggregation in patients using NOACs. Concomitant
exposure to antiaggregants and NOACs markedly increases the risk of
bleeding66 .Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et
al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2013;15(5):625-51. http://dx.doi.org/10.1093/europace/eut083
https://doi.org/10.1093/europace/eut083...
. One third of
patients included in large studies comparing Warfarin and theses drugs were
receiving antiplatelet drugs, usually ASA in low doses. Specific trials
comparing different strategies for double or triple therapy following
percutaneous coronary interventions are under way (RE-DUAL-PCI, PIONEER AF-PCI).
Even recognizing the empiric nature of this suggestion, the same strategy
considering coronary risks and the time since the coronary events or stent
implantation (and the differences between pharmacological and
non-pharmacological stents) is recommended (see ref. 6 for further
discussion).
Recurrence while on treatment with Warfarin: The ideal strategy here is still undefined. Increasing the INR (e.g., to 3) or adding antiplatelet drugs are strategies that do not seem to reduce the risk of recurrence but clearly add to the risk of severe hemorrhages. The use of NOACs in this setting has not been studied.
When to start treatment: the golden rule– primum
non nocere – should prevail when deciding when to start the
anticoagulant treatment after a stroke related to AF. The AHA/ASA Guidelines on
secondary stroke prevention suggest that it is safe to postpone treatment up to
two weeks in most patients33 .Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke.
2014;45(7):2160-236.
http://dx.doi.org/10.1161/STR.0000000000000024
https://doi.org/10.1161/STR.000000000000...
.
Data pointing to a high risk of early recurrence of embolism in patients with
AF-related stroke - up to 8.5% in 14 days -would suggest a need to start
anticoagulation in a shorter time4242 .Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight
heparin versus aspirin in patients with acute ischaemic stroke and atrial
fibrillation: a double-blind randomised study. Heparin in acute embolic stroke
trial. Lancet. 2000;355(9211):1205-10.
http://dx.doi.org/10.1016/S0140-6736(00)02085-7
https://doi.org/10.1016/S0140-6736(00)02...
. These data contrast however with a much lower risk
indicated in very large prospective studies (CAST, IST) which found daily rates
not exceeding 0.5%4343 .Chen ZM. CAST: randomized placebo-controlled trial of early aspirin
use in 20,000 patients with acute ischaemic stroke. Lancet.
1997;349(9066):1641-9.
http://dx.doi.org/10.1016/S0140-6736(97)04010-5
https://doi.org/10.1016/S0140-6736(97)04...
,4444 .International Stroke Trial Collaborative Group. The International
Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both,
or neither among 19435 patients with acute ischaemic stroke. Lancet.
1997;349(9065):1569-81.
http://dx.doi.org/10.1016/S0140-6736(97)04011-7
https://doi.org/10.1016/S0140-6736(97)04...
. The recommendation to withhold early
anticoagulation is strongly based on results of a study including 449 patients
with AF treated up to 30 hours after stroke onset4242 .Berge E, Abdelnoor M, Nakstad PH, Sandset PM. Low molecular-weight
heparin versus aspirin in patients with acute ischaemic stroke and atrial
fibrillation: a double-blind randomised study. Heparin in acute embolic stroke
trial. Lancet. 2000;355(9211):1205-10.
http://dx.doi.org/10.1016/S0140-6736(00)02085-7
https://doi.org/10.1016/S0140-6736(00)02...
. Treatment with a LMWH - dalteparin - was not
superior to that with ASA, with a low risk of ICH in both groups. Studies like
the IST also indicate that the reduction in the risk of early recurrence (first
14 days) obtained by treatment with full doses of UFH is counterbalanced by an
increased risk of ICH4444 .International Stroke Trial Collaborative Group. The International
Stroke Trial (IST): a randomised trial of aspirin, subcutaneous heparin, both,
or neither among 19435 patients with acute ischaemic stroke. Lancet.
1997;349(9065):1569-81.
http://dx.doi.org/10.1016/S0140-6736(97)04011-7
https://doi.org/10.1016/S0140-6736(97)04...
. A
meta-analysis of patients with cardioembolic stroke confirmed this idea4545 .Paciaroni M, Agnelli G, Micheli S, Caso V. Efficacy and safety of
anticoagulant treatment in acute cardioembolic stroke: a meta-analysis of
randomized controlled trials. Stroke. 2007;38(2):423-30.
http://dx.doi.org/10.1161/01.STR.0000254600.92975.1f
https://doi.org/10.1161/01.STR.000025460...
. In the IST, UFH treatment
starting in the first 48 hours was also useless in the subgroup of patients with
AF4646 .Saxena R, Lewis S, Berge E, Sandercock PA, Koudstaal PJ. Risk of
early death and recurrent stroke and effect of heparin in 3169 patients with
acute ischemic stroke and atrial fibrillation in the International Stroke Trial.
Stroke. 2001;32(10):2333-7.
http://dx.doi.org/10.1161/hs1001.097093
https://doi.org/10.1161/hs1001.097093...
.
Oral anticoagulation should probably be started earlier (first week) in
individuals without an increased risk of symptomatic hemorrhage - large lesions,
initial hemorrhagic transformation, general bleeding tendency, uncontrolled
hypertension. The risk of early recurrence is greater for instance in patients
with CHF or an acute anterior myocardial infarct, and this should also be
considered in making the best individualized decision. In stroke patients with
AF starting oral anticoagulants, there is a tendency to avoid initial bridging
with UFH or LMWH. The bridging strategy does not confer obvious benefits (or
increased risks) and prolongs hospital stay4747 .Audebert HJ, Schenk B, Tietz V, Schenkel J, Heuschmann PU.
Initiation of oral anticoagulation after acute ischaemic stroke or transient
ischaemic attack: timing and complications of overlapping heparin or
conventional treatment. Cerebrovasc Dis. 2008;26(2):171-7.
http://dx.doi.org/10.1159/000145324
https://doi.org/10.1159/000145324...
.
BLEEDING RISK AND MANAGEMENT OF ANTICOAGULATED PATIENTS UNDERGOING SURGERY
Temporary withholding of anticoagulants is necessary in up to one quarter of
patients in the first two years of use, most frequently because of fear of
hemorrhage during surgery or invasive procedures11 .Healey JS, Eikelboom J, Douketis J et al. Periprocedural bleeding
and thromboembolic events with dabigatran compared to warfarin: results from the
RE-LY Randomized Trial. Circulation. 2012;126:343-8.
http://dx.doi.org/10.1161/CIRCULATIONAHA.111.090464
https://doi.org/10.1161/CIRCULATIONAHA.1...
. Any period without anticoagulant poses an
increased risk of thromboembolic events in AF patients4848 .Broderick JP, Bonomo JB, Kissela BM, Khoury JC, Moomaw CJ, Alwell K
et al. Withdrawal of antithrombotic agents and its impact on ischemic stroke
occurrence. Stroke. 2011;42(9):2509-14.
http://dx.doi.org/10.1161/STROKEAHA.110.611905
https://doi.org/10.1161/STROKEAHA.110.61...
. Opposing risks vary according to age,
associated cardiac disease, bleeding history and other patient factors (cancer,
renal failure etc.). In patients with AF-related strokes the risk of recurrence
is inversely related to the time elapsed since the ischemic event77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,4848 .Broderick JP, Bonomo JB, Kissela BM, Khoury JC, Moomaw CJ, Alwell K
et al. Withdrawal of antithrombotic agents and its impact on ischemic stroke
occurrence. Stroke. 2011;42(9):2509-14.
http://dx.doi.org/10.1161/STROKEAHA.110.611905
https://doi.org/10.1161/STROKEAHA.110.61...
. The intrinsic bleeding risk
of the surgery or endoscopic procedure should also be carefully evaluated (Tables 4 and 5). Major surgeries and endoscopic procedures with mucosal
or submucosal lesion resections are associated with a high bleeding risk77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
,99 .Anderson MA, Ben-Menachem T, Gan SI, Appalaneni V, Banerjee S, Cash
BD et al. Management of antithrombotic agents for endoscopic procedures.
Gastrointest Endosc. 2009;70(6):1060-70.
http://dx.doi.org/10.1016/j.gie.2009.09.040
https://doi.org/10.1016/j.gie.2009.09.04...
. These patients should have
anticoagulants (and clopidogrel) withheld. Superficial interventions (skin,
teeth) or ophthalmological surgeries in sites without vascularization (such as
cataract surgery with or without lens implantation) have a minimal risk and
should be made without changes in the antithrombotic regimen. This last
recommendation is especially relevant in individuals with a recent stroke/TIA
(i.e., in the last 3-6 months).
Some principles should be kept in mind:
•The disappearance of antithrombotic effects (and hence the reversal of bleeding
risk) depends on the time without the drug - this is greater with platelet
antiaggregants (because of the expected platelet turnover) - around 7-10 days;
and lower with NOACs (beware of renal insufficiency - see ahead). Warfarin has a
half-life of 36 to 42 hours, and after 3 half-lives the expected residual
anticoagulant activity is 12.5% (sometimes slower reduction in older patients).
The INR is normal in almost all patients after 5 days without the drug. Some 7%
of patients will have an INR over 1.5 on the day before surgery. In surgeries
associated with a high bleeding risk they should receive oral vitamin K (1-2.5
mg), and have another test confirming INR normalization on the day of
surgery4949 .White RH, McKittrick T, Hutchinson R, Twitchell J. Temporary
discontinuation of warfarin therapy: changes in the international normalized
ratio. Ann Intern Med. 1995;122(1):40-2.
http://dx.doi.org/10.7326/0003-4819-122-1-199501010-00006
https://doi.org/10.7326/0003-4819-122-1-...
,5050 .Kovacs MJ, Kearon C, Rodger M, Anderson DR, Turpie AG, Bates SM et
al. Single-arm study of bridging therapy with low-molecular-weight heparin for
patients at risk of arterial embolism who require temporary interruption of
warfarin. Circulation. 2004;110(12):1658-63.
http://dx.doi.org/10.1161/01.CIR.0000142859.77578.C9
https://doi.org/10.1161/01.CIR.000014285...
. Low risk procedures can be
performed with an INR between 1.5 and 1.8, allowing for a shorter time without
anticoagulation5151 .Marietta M, Bertesi M, Simoni L et al. A simple and safe nomogram
for the management of oral anticoagulation prior to minor surgery. Clin Lab
Haematol. 2003;25(2):127-30.
http://dx.doi.org/10.1046/j.1365-2257.2003.00499.x
https://doi.org/10.1046/j.1365-2257.2003...
.
•Bridging therapy with UFH or LMWH when oral antithrombotic treatment is withheld increase the risk of hemorrhages. This risk varies with the doses used (therapeutic doses > VTE prophylactic doses); and the time since the last preoperative dose or from surgery to treatment return. Postponing this return and reducing the doses used can minimize the bleeding risks but increase the time with a high risk of thromboembolic events. Bridging with heparin is considered in patients with a high risk of arterial thromboembolism (> 10%/year) but not in those with low risk (< 5%). Decisions should be highly individualized in individuals with an intermediate risk (see Table 2).
-
Bridging for the prevention of arterial thromboembolism only makes sense with full doses of heparin (UFH or LWH); studies using intermediate or “subtherapeutic” doses (e.g., enoxaparin 40 mg b.i.d.) are scarce5252 .Malato A, Saccullo G, Lo Coco L, Caramazza D, Abbene I, Pizzo G et al. Patients requiring interruption of long-term oral anticoagulant therapy: the use of fi xed sub-therapeutic doses of low-molecular-weight heparin. J Thromb Haemost. 2010;8(11):107-13. http://dx.doi.org/10.1111/j.1538-7836.2009.03649.x
https://doi.org/10.1111/j.1538-7836.2009... . Table 6 summarizes the suggested conduct. -
Typical therapeutic and prophylactic doses: Unfractionated heparin (UFH) – continuous IV infusion to reach aPTT 1.5-2 times the control values, 5,000 IU SC every 8 or 12 hours; enoxaparin – 1 mg/Kg b.i.d., 40 mg/daily dose.
-
Time to effective antithrombotic action should be remembered when restarting treatment – minutes after UFH or ASA, many hours after Low molecular-weight heparin (LMWH) or NOACs, and many days after clopidogrel maintenance doses or Warfarin.
Warfarin
The scenario is somewhat more complicated for patients on Warfarin than those on
NOACs, as the time to full disappearance of the anticoagulant effects is
significantly longer - usually several days. Patients with a high risk of
recurrent thromboembolism - such as those with a CHADS2 score of 5 or 6,
stroke/TIA in the last 3 months, severe CHF, rheumatic valvular disease or
mechanical valves - usually receive bridging therapy with full doses of LMWH. An
ambulatory strategy can reduce costs5050 .Kovacs MJ, Kearon C, Rodger M, Anderson DR, Turpie AG, Bates SM et
al. Single-arm study of bridging therapy with low-molecular-weight heparin for
patients at risk of arterial embolism who require temporary interruption of
warfarin. Circulation. 2004;110(12):1658-63.
http://dx.doi.org/10.1161/01.CIR.0000142859.77578.C9
https://doi.org/10.1161/01.CIR.000014285...
,5353 .Douketis JD, Johnson JA, Turpie AG. Low-molecular weight heparin as
bridging anticoagulation during interruption of warfarin: assessment of a
standardized periprocedural anticoagulation regimen. Arch Intern Med.
2004;164(12):1319-26.
http://dx.doi.org/10.1001/archinte.164.12.1319
https://doi.org/10.1001/archinte.164.12....
. Heparin bridging is started when the INR is below
2.0, with the last dose given 24 hours before surgery; treatment is again
started after assessment indicates full hemostasis, usually 48 hours after major
interventions (24 hours after low-risk procedures)33 .Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI,
Ezekowitz MD et al. Guidelines for the prevention of stroke in patients with
stroke and transient ischemic attack: a guideline for healthcare professionals
from the American Heart Association/American Stroke Association. Stroke.
2014;45(7):2160-236.
http://dx.doi.org/10.1161/STR.0000000000000024
https://doi.org/10.1161/STR.000000000000...
,77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
. Similar recommendations apply to patients
anticoagulated for recent VTE (i.e., < 3 months) or with severe
thrombophilias (e.g., antiphospholipid syndrome). Patients with an intermediate
CHADS2 score (3 to 4) should have individualized decisions as to the use of LMWH
after careful assessment of the specific surgery-related bleeding risks. The
thromboembolic risk is probably similar in patients with VTE occurring 3 to 12
months before, more benign thrombophilias, or recent oncologic treatment. In
most patients with an even lower risk (CHADS2 = 0 to 2 without stroke/TIA, VTE
> 12 months before, and no other risk factors) it is probably safe to simply
withhold Warfarin for 4 or 5 days. An INR is obtained on the day before planned
surgery to assess the eventual need of oral vitamin K (usually 1-2.5 mg); and in
the next morning just before surgery (fresh plasma given if necessary).
Surgical urgencies with a high bleeding risk should be postponed whenever
possible for one or two days, giving fresh plasma and oral or intravenous
Vitamin K to obtain reversal of anticoagulation. A normal point of care INR test
- as suggested nowadays for the urgent evaluation of possible thrombolysis in
hyperacute CI patients using Warfarin) probably suffices to assure that
coagulation has returned to basal conditions. The point of care test tends to
overestimate the INR when compared to standard INR analysis5454 .Bruch TP, Mendes DC, Pedrozo JC, Figueiredo L, Nóvak EM, Zétola VF
et al. Is point-of-care accurate for indicating thrombolysis in anticoagulated
patients on oral anticoagulation treatments? Arq Neuropsiquiatr.
2014;72(7):487-9. http://dx.doi.org/10.1590/0004-282X20140075
https://doi.org/10.1590/0004-282X2014007...
.
Treatment with Warfarin after surgeries with a high bleeding risk should be
reinitiated in patients with a medium to high risk of recurrent thromboembolic
events as soon as a full hemostasis is secured, usually after 12 to 24 hours
(not later)77 .Douketis JD, Spyropoulos AC, Spencer FA, Mayr M, Jaffer AK, Eckman
MH et al. Perioperative management of antithrombotic therapy: antithrombotic
therapy and prevention of thrombosis, 9th ed.: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2
Suppl):e326S-50S. Erratum in: Chest. 2012;141:1129.
http://dx.doi.org/10.1378/chest.11-2298
https://doi.org/10.1378/chest.11-2298...
. In very high-risk
patients full doses of UFH or LMWH should be given while waiting for the INR to
reach therapeutic levels. The first two weeks following any procedure here
discussed are associated with an increased risk of both thromboembolic and
hemorrhagic events, and frequent contact is always indicated after hospital
discharge.
Minimal risk surgeries: these include a number of dental,
skin and ocular interventions. Dental extraction and root canal treatment should
be done without interruption of the anticoagulant (some patients may be more
fearful of the hemorrhages than the thromboembolic risks and may prefer to
withhold the drug for 2 to 3 days instead [INR around 1.6-1.9]). Suturing and
the use of fibrinolytics (e.g., mouth-washing/oral tranexamic acid
[Transamin®] 5 mL 10 minutes before and 3-4 times a day for 1-2
days) reduce even further the bleeding risk5555 .Borea G, Montebugnoli L, Capuzzi P, Magelli C. Tranexamic acid as a
mouthwash in anticoagulant-treated patients undergoing oral surgery. An
alternative method to discontinuing anticoagulant therapy. Oral Surg Oral Med
Oral Pathol. 1993;75(1):29-31.
http://dx.doi.org/10.1016/0030-4220(93)90401-O
https://doi.org/10.1016/0030-4220(93)904...
,5656 .Ramström G, Sindet-Pedersen S, Hall G, Blombäck M, Alander U.
Prevention of postsurgical bleeding in oral surgery using tranexamic acid
without dose modification of oral anticoagulants. J Oral Maxillofac Surg.
1993;51(11):1211-6.
http://dx.doi.org/10.1016/S0278-2391(10)80291-5
https://doi.org/10.1016/S0278-2391(10)80...
,5757 .Sacco R, Sacco M, Carpenedo M, Moia M. Oral surgery in patients on
oral anticoagulant therapy: a randomized comparison of different INR targets. J
Thromb Haemost; 2006;4(3):688-9.
http://dx.doi.org/10.1111/j.1538-7836.2006.01762.x
https://doi.org/10.1111/j.1538-7836.2006...
. Patients should be warned that some gingival
oozing may persist for a few days, during which local compression and tranexamic
acid should be continued. Simple skin biopsies should be done without any change
in anticoagulant use. Excision of lesions (nevi, keratosis, carcinomas) are
frequently associated with minor bleedings but rarely (< 5%) major ones, and
optimization of local hemostasis should generally suffice5858 .Alcalay J. Cutaneous surgery in patients receiving warfarin
therapy. Dermatol Surg. 2001;27(8):756-8.
http://dx.doi.org/10.1046/j.1524-4725.2001.01056.x
https://doi.org/10.1046/j.1524-4725.2001...
,5959 .Syed S, Adams BB, Liao W, Pipitone M, Gloster H. A prospective
assessment of bleeding and international normalized ratio in
warfarin-anticoagulated patients having cutaneous surgery. J Am Acad Dermatol.
2004;51(6):955-7. http://dx.doi.org/10.1016/j.jaad.2004.07.058
https://doi.org/10.1016/j.jaad.2004.07.0...
. Cataract extraction is an avascular surgery
usually done nowadays with phacoemulsion and topical anesthetics - retrobulbar
anesthesia is rarely associated with significant bleeding in anticoagulated
patients but this could mandate urgent decompression6060 .Kallio H, Paloheimo M, Maunuksela EL. Haemorrhage and risk factors
associated with retrobulbar/peribulbar block: a prospective study in 1383
patients. Br J Anaesth. 2000;85(5):708-11.
http://dx.doi.org/10.1093/bja/85.5.708
https://doi.org/10.1093/bja/85.5.708...
. Minor bleeding (subconjuntival hemorrhage or
dot hyphemas) without any vision loss may occur in up to 10 percent of patients
but is not a reason for changing the anticoagulant regimen6161 .Jamula E, Anderson J, Douketis JD. Safety of continuing warfarin
therapy during cataract surgery: a systematic review and meta-analysis. Thromb
Res. 2009;124(3): 292-9.
http://dx.doi.org/10.1016/j.thromres.2009.01.007
https://doi.org/10.1016/j.thromres.2009....
.
NOACs indication
NOACs have the general advantage over Warfarin of a shorter effect. A typical difficulty with these drugs however is knowing whether or not there is residual anticoagulant activity. Metabolism is slowed in the elderly and with renal insufficiency. Contrary to widespread view, a large number of drugs interact and either increase or reduce the activity or the half-life for elimination of NOACs including:
-
antiarrhythmic drugs (quinidine, amiodarone, verapamil);
-
calcium channel blockers (diltiazem, verapamil);
-
antibiotics, antifungal and antiretroviral drugs (erythromycin and clarithromycin, all iazolics, rifampicin, protease inhibitors [ritonavir etc.]);
-
antiepileptics (phenobarbital, carbamazepin, phenytoin);
-
antineoplastics (cyclosporin, tacrolimus);
-
antacids and proton or hydrogen pump inhibitors.
The first step is trying to know exactly when the last dose was given. Some tests indicate the persistence of anticoagulant effects including increased activated thromboplastin time (aTPT) for dabigatran; or the prothrombin time/INR (point of care tests not recommended) for Xa factor inhibitors. Direct measurements of thrombin time (dabigatran) and of Xa activity (other drugs) can help but are far less available or fast and have ill-defined cut-off values to ensure a safe surgery.
The hemorrhagic risk of the proposed intervention should be evaluated. Urgent
operations should if at all possible be postponed for 12 or ideally 24 hours.
Hopefully specific antagonists/antibodies against thrombin and Xa factor
inhibitors will be available in the near future3838 .Costin J, Ansell J, Laulicht B, Bakhru S, Steiner S. Reversal
agents in development for the new oral anticoagulants. Postgrad Med.
2014;126(7):19-24. http://dx.doi.org/10.3810/pgm.2014.11.2829
https://doi.org/10.3810/pgm.2014.11.2829...
,3939 .Vanden Daelen S, Peetermans M, Vanassche T, Verhamme P,
Vandermeulen E. Monitoring and reversal strategies for new oral anticoagulants.
Expert Rev Cardiovasc Ther. 2015;13(1):95-103.
http://dx.doi.org/10.1586/14779072.2015.987126
https://doi.org/10.1586/14779072.2015.98...
. In contrast to Warfarin, preoperative bridging
with heparins is not indicated in NOAC treated patients11 .Healey JS, Eikelboom J, Douketis J et al. Periprocedural bleeding
and thromboembolic events with dabigatran compared to warfarin: results from the
RE-LY Randomized Trial. Circulation. 2012;126:343-8.
http://dx.doi.org/10.1161/CIRCULATIONAHA.111.090464
https://doi.org/10.1161/CIRCULATIONAHA.1...
,6262 .Sie P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV et al.
Surgery and invasive procedures in patients on long-term treatment with direct
oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the
Working Group on Perioperative Haemostasis and the French Study Group on
Thrombosis and Haemostasis. Arch Cardiovasc Dis. 2011;104(12):669-76.
http://dx.doi.org/10.1016/j.acvd.2011.09.001
https://doi.org/10.1016/j.acvd.2011.09.0...
.
Any intervention should be made off the last dose peak anticoagulant effect66 .Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et
al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2013;15(5):625-51. http://dx.doi.org/10.1093/europace/eut083
https://doi.org/10.1093/europace/eut083...
. In minimal risk interventions
- dental extractions, cataracts upper or lower endoscopy without biopsies etc. -
an interval of 18 to 24 hours after the last dose is suggested, treatment being
reinitiated after 6 hours (this corresponds to skipping one dose of NOACs that
are given twice daily). Oral tranexamic acid is suggested in dental
surgeries.
In low-risk procedures, withholding NOACs for 24 hours in patients with normal renal function is adequate; 48 hours are suggested for higher-risk surgeries. The degree of renal insufficiency should be carefully assessed. In dabigatran treated patients, even small decreases in renal function (Cr Cl 50-80 mL/min) mandate suspension for 36 hours (low-risk surgeries) or 72 hours (high-risk surgeries); for patients with Cr Cl 30-50 mL/min the corresponding time is 48 hours (low-risk) and up to 96 hours (high-risk). For both rivaroxaban and apixaban, the only suggested change is increasing the interval without the drug in patients with Cr Cl 15-30 mL/min undergoing low risk surgeries to 36 hours. Current data do not allow a precise recommendation for edoxaban treated patients. NOACs should not be used in individuals with Cr Cl below 15 mL/min (including those on hemodialysis).
Of special interest to neurologists is the question of surgeries involving the
neuraxis - NOACs are not recommended in these patients66 .Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et
al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2013;15(5):625-51. http://dx.doi.org/10.1093/europace/eut083
https://doi.org/10.1093/europace/eut083...
. Diagnostic lumbar puncture and spinal or
peridural anesthesia should only be done after hemostasis has been fully secured
(high-risk surgery protocol).
Time to resume drug after surgery should also consider the risks associated with
the specific procedure: 6 to 8 hours in low-risk interventions (also for lumbar
puncture and spinal and peridural anesthesia), but 48-72 hours in high-risk
surgeries. In patients with a high risk of developing VTE, prophylactic or
intermediate doses of LMWH after 6 to 8 hours should be given if hemostasis has
been adequately obtained (there are no dependable data evaluating the use of
small postoperative doses of NOACs in AF patients with this goal)66 .Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J et
al. European Heart Rhythm Association Practical Guide on the use of new oral
anticoagulants in patients with non-valvular atrial fibrillation. Europace.
2013;15(5):625-51. http://dx.doi.org/10.1093/europace/eut083
https://doi.org/10.1093/europace/eut083...
,6262 .Sie P, Samama CM, Godier A, Rosencher N, Steib A, Llau JV et al.
Surgery and invasive procedures in patients on long-term treatment with direct
oral anticoagulants: thrombin or factor-Xa inhibitors. Recommendations of the
Working Group on Perioperative Haemostasis and the French Study Group on
Thrombosis and Haemostasis. Arch Cardiovasc Dis. 2011;104(12):669-76.
http://dx.doi.org/10.1016/j.acvd.2011.09.001
https://doi.org/10.1016/j.acvd.2011.09.0...
. LMWH should be withheld soon
after restarting NOACs, which exhibit full effect after 2 hours.
Final remarks
Neurologists should play an active role in the discussion with cardiologists, surgeons, anesthesiologists, and dentists to reach the best individualized decision regarding antithrombotic perioperative management in AF patients. Decisions should be made considering the objective evaluation of the contrasting risks of thromboembolic recurrence and surgery-related bleeding when withholding anticoagulants or antiplatelet drugs. Uniform care should be pursued and greatly depends on the development of formal institutional protocols. Patients should be evaluated one week before the planned intervention; receive written instructions about anticoagulant suspension, INR testing the day before surgery, the use of parenteral drugs as bridging therapy should follow individualized regimens according to age, renal function and other variables; careful evaluation of hemostasis on days 0 and 1 after surgery; and orientations and regular contact with the Health care team in the following two weeks. In the next few years, further clarification of a number of topics is expected from many studies concerning general surgery (PERIOP-2, BRIDGE) or pacemaker and defibrillation implantation (PACEBRIDGE, BRUISECONTROL) in anticoagulated patients.
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Publication Dates
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Publication in this collection
Aug 2015
History
-
Received
06 Jan 2015 -
Reviewed
06 Mar 2015 -
Accepted
26 Mar 2015