Managing Anticoagulant Complications With AF

Atrial fibrillation is an epidemic condition that will only become more prevalent as the population ages. Aside from causing symptoms related to tachycardia, rate irregularity and lack of atrial systolic function, AF predisposes patients to arterial thromboembolism.¹ Anticoagulation diminishes the risk of stroke and other thromboembolic events by about two-thirds,^2,3 but this therapy necessarily increases the risk of bleeding complications. Because those who stand to benefit most from anticoagulation are also at highest risk of complications, prevention of stroke is a particular challenge in older adults.

Assessing Risk of Stroke

Before committing a patient to chronic anticoagulation for AF, the clincian must first ensure that a patient’s stroke risk is indeed high enough to warrant the risk of bleeding inherent in such therapy. The most commonly utilized scheme for determining stroke risk is the CHADS2 score, which separates patients into risk categories for thromboembolism based on a point system, taking into account Congestive heart failure, Hypertension, Age (> 75 years), Diabetes, and prior Stroke or other arterial thromboembolic event.⁴ High-risk patients (score > 2) are advised to use oral anticoagulation, moderate-risk patients (score = 1) are counseled to use aspirin 325 mg daily or oral anticoagulation, and low-risk patients (score = 0) may use aspirin alone.

The CHADS2 system has been recently revised to reflect data that suggest that moderate-risk patients may benefit from anticoagulation and low-risk patients may not benefit from aspirin. The CHA2DS2-VASc schema (Table 1), adds to the CHADS2 elements Vascular disease (prior myocardial infarction, peripheral arterial disease or aortic plaque), Age 65 to 74 years, and Sex category (female).⁵ People at low risk have a score of 0 and may be left untreated; all other patients benefit from anticoagulation.

Table 1. CHA2DS2-VASc Scoring System for Prediction of Stroke in Nonvalvular Atrial Fibrillation.⁵

TIA: transient ischemic attack. Vascular disease is defined as prior myocardial infarction, peripheral arterial disease or aortic plaque.

Click here for a larger view of this image.

Assessing Risk of Bleeding

Regardless of whether anticoagulation is recommended based on stroke risk, the risk of bleeding must also be considered; if this risk is prohibitive, anticoagulation may not be warranted. One recent hemorrhage scoring scheme is summarized by the acronym HAS-BLED (Hypertension, Abnormal renal/hepatic function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol use) (Table 2).⁶ Unfortunately, several of the comorbid conditions that increase the risk of stroke also increase the risk of bleeding, and these conditions are also more prevalent in older adults. Side-by-side comparison of the stroke and hemorrhage risks using the CHA2DS2-VASc and HAS-BLED scores places these risks in perspective. However, individual decisions must be made after discussion with the patient; some may be more concerned with stroke risk, even at the risk of bleeding.

Table 2. HAS-BLED Scoring System for Prediction of Major Bleeding Risk in Patients Treated With Anticoagulation for Atrial Fibrillation.⁶

Click here for a larger view of this image.

Patients deemed at high risk for falls are often not treated with anticoagulation because of the perceived increased risk of intracranial hemorrhage.⁷ In one study, Medicare patients with AF who were considered a high fall risk were found to have twice the risk of intracranial hemorrhage as patients not considered high fall risk, yet high-risk patients were also more likely to have ischemic stroke; however, patients with a CHADS2 score of > 2 experienced a net benefit 25% reduction in the composite endpoint of stroke, myocardial infarction or hemorrhage.⁸

Anticoagulation with warfarin requires careful monitoring of the international normalized ratio (INR). Warfarin dosing depends on patient characteristics, including sex, genetic polymorphisms⁹ and concomitant medication. Trials have definitively established an INR between 2.0 and 3.0 as superior to lower INRs.¹⁰ When initiating warfarin, the INR should be assessed weekly.¹¹

Pharmacologic Alternatives

While CHADS2 recommends aspirin for patients at low risk for stroke, supporting data are not compelling. Compared with placebo, aspirin had a statistically nonsignificant 19% reduction in stroke in a meta-analysis of 7 trials.¹² In the SPAF trial, a significant difference was evident in aspirin’s effect depending on whether a patient was in the warfarin-eligible or warfarin-ineligible arm, calling the results into question.¹³ The BAFTA trial showed that the risk of bleeding is similar with warfarin or aspirin in older patients with AF.¹⁴ Aspirin was more frequently discontinued than warfarin in the WASPO trial, possibly because of more common gastrointestinal side effects.¹⁵ These data call into doubt whether aspirin has a role in stroke prevention in patients with AF.

Similarly, dual antiplatelet therapy with aspirin and clopidogrel is inferior to warfarin. While the combination has been shown to decrease stroke in patients with prior stroke (not necessarily cardiothromboembolic),¹⁶ this strategy is inferior to warfarin in patients with AF. In the ACTIVE W trial, not only was warfarin superior to clopidogrel plus low-dose aspirin at stroke prevention, but patients who were already on warfarin had a lower risk of bleeding than those who were switched from warfarin to dual antiplatelet therapy for the study.¹⁷ The mean CHADS2 score in this population was 2.

The recent approval in the United States of dabigatran, a direct thrombin inhibitor that does not require dose titration, has changed the oral anticoagulation landscape. The RE-LY trial demonstrated that dabigatran 110 mg twice daily was noninferior to warfarin in stroke prevention and systemic embolism and was associated with lower rates of major hemorrhage.¹⁸ Dabigatran 150 mg twice daily, however, was associated with lower rates of stroke and systemic embolism with a similar risk of major hemorrhage, but a higher rate of GI bleeding. Dabigatran eliminates the risk of bleeding posed by labile INRs and may be used in all patients except those with severe renal impairment. Other direct thrombin inhibitors and factor Xa inhibitors, including apixaban and rivaroxaban, should be joining dabigatran in the near future.¹⁹ Dabigatran does not require dose-titration and has immediate onset of action, obviating the need for frequent INR checks and simplifies treatment when anticoagulation must be interrupted for elective procedures.

Warfarin is easily reversible with either parenteral or oral vitamin K, and plasma may be used in life-threatening situations. No specific agent is available for reversing direct thrombin inhibitors; possible options include infusion of fresh frozen plasma, prothrombin plasma concentrate, or desmopressin (DDAVP).²⁰ The effects of these interventions will be transient, possibly necessitating additional infusions, as the effect of dabigatran wanes. The INR is not useful for monitoring anticoagulant effect, so determining whether reversal has been effective is difficult. Clinical experience with dabigatran in the setting of life-threatening bleeding is limited, and more reliable methods of reversing dabigatran’s effect will hopefully be forthcoming.

Nonpharmacologic Alternatives

Left atrial appendage occlusion devices are under investigation in the United States as an alternative to long-term anticoagulation. These devices will be most useful in patients with prohibitive risk of bleeding yet an elevated risk of stroke. Initial studies have been promising with respect to the feasibility of device implantation, but have been plagued by a steep learning curve for the operator,^21,22 and no large, multicenter comparison has been conducted between occlusion devices and warfarin among patients who are not deemed anticoagulation candidates. These patients are precisely those in whom such a device would find use. A small study in this population has been presented in abstract form only.²³ This device requires an invasive procedure, and patients must take warfarin for at least 45 days afterwards, sometimes longer. Long-term experience is also lacking, and incomplete isolation of the left atrial appendage cavity has been reported.

Additional Considerations

In the future, a lower dose of dabigatran may be approved for use, such that patients at high risk for bleeding and extremely high risk for stroke may use this lower dose, and those with low bleeding risk may use the higher, somewhat more effective dose.²⁴ The 110-mg twice-daily dose evaluated in the RE-LY trial seems ideal for this strategy. Prospective evaluation of such an approach will almost certainly be required, as randomization of patients according to both their bleeding and stroke risks would be neccessary.

The relationship between AF burden and the risk of thromboembolism is not clear, and guidelines do not distinguish among permanent, persistent and paroxysmal AF when considering antithrombotic therapy.¹¹ While there is a sound basis for the theory that a greater burden of AF increases the risk of thrombus formation, no definitive data corroborate this assumption. Studies are underway in patients with implanted devices that allow continuous monitoring of AF burden to answer this important clinical question. Currently, using antiarrhythmic drugs to decrease stroke risk is a reasonable strategy, particularly in patients with symptomatic AF, although whether such therapy does reduce the risk of stroke is not known. In the AFFIRM trial, antiarrhythmic drug therapy did not reduce the risk of stroke,²⁵ although those patients who did maintain sinus rhythm, regardless of therapy, had better long-term outcomes, as did those who were maintained on warfarin.²⁶ A related issue is the anecdotal observation that a greater risk of embolization seems to exist on conversion of AF to sinus rhythm, whether spontaneous or via cardioversion. Patients who have converted to sinus rhythm within the prior 4 weeks should be maintained on continuous anticoagulation in the absence of a significant contraindication. Patients in persistent AF may have a smaller risk of embolization, and therefore, anticoagulation may be interrupted more readily in the event of bleeding or surgical procedures. Bridging with unfractionated heparin or low-molecular weight heparin is the standard of care in the former but not in the latter case. Cardioversion should not be performed in patients who are not considered even short-term candidates for anticoagulation.

Conclusions

AF is not itself a life-threatening condition, yet it increases the risk of thromboembolic events, including stroke. The ramifications of such an event can be immense. Stroke risk must be weighed against the risk of bleeding and patient preferences taken into account in a discussion of long-term anticoagulation. The vitamin K antagonist warfarin is the most commonly used anticoagulant, but its use is complicated by the need for frequent dose titration and resultant labile anticoagulant effect. Dabigatran is a new anticoagulant in the direct thrombin inhibitor class that, at the 150-mg dose, demonstrated fewer strokes and systemic embolization. Additional options for prevention of stroke include occlusion or ligation of the left atrial appendage and decreasing AF burden with rhythm control therapy.

References

Stoddard MF, Dawkins PR, Prince CR, Ammash NM. Left atrial appendage thrombus is not uncommon in patients with acute atrial fibrillation and a recent embolic event: a transesophageal echocardiographic study. J Am Coll Cardiol. 1995;25(2):452-459.
Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med.1994;154(13):1449-1457.
Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501.
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;285:2864-2870.
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;263-272.
Pisters R, Lane DA, Niewlaat R, de Vos CB, Crijns HJ, Yip 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;1093-1100.
Hylek EM, D’Antonio J, Evans-Molina C, Shea C, Henault LE, Regan S. Translating the results of randomized trials into clinical practice: The challenge of warfarin candidacy among hospitalized elderly patients with atrial fibrillation. Stroke. 2006;37:1075-1080.
Gage BF, Birman-Deych E, Kerzner R, Radford M, Nilasena DS, Rich MW. Incidence of intracranial hemorrhage in patient with atrial fibrillation who are prone to fall. Am J Med. 2005;118:612-617.
Reider MJ, Reiner AP, Gage BF, Nickerson DA, Eby CS, McLeod HL, et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med. 2005;352(22):2285-2293.
Stroke Prevention In Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomized clinical trial. Lancet. 1996;348:633-638.
Fuster V, Rydén LE, Cannom DS, Crijns HJ, Curtis AB, Ellenbogen KA, et al. ACC/AHA/ESC 2006 Guidelines for the Management of Patients With Atrial Fibrillation-Executive Summary. Circulation. 2006;114:700-752.
Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):857-867.
Stroke Prevention in Atrial Fibrillation investigators. A differential effect of aspirin in prevention of stroke on atrial fibrillation. J Stroke Cerebrovasc Dis. 1993;3:181-188.
Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, et al. Warfarin versus aspirin for stroke prevention in an elderly population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomized controlled trial. Lancet. 2007;370(9586):493-503.
Rash A, Downes T, Pritner R, Yeo WW, Morgan N, Channer KS. A randomized controlled trial of warfarin versus aspirin for stroke prevention in octogenarians with atrial fibrillation (WASPO). Age and Ageing. 2007;36(2):151-156.
Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European stroke prevention study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143(1-2):1-13.
Connolly SJ, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S, et al. ACTIVE Writing Group of the ACTIVE Investigators. 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 randomized controlled trial. Lancet. 2006;367(9526):1903-1912.
Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139-1151.
Bauer KA. New anticoagulants. Hematology Am Soc Hematol Educ Program. 2006;450-456.
Crother MA, Warkentin TE. Managing bleeding in anticoagulated patients with a focus on novel therapeutic agents. J Thromb Haemost. 2009;7 (suppl 1):107-110.
Ostermayer SH, Reisman M, Kramer PH, Matthews RV, Gray WA, Block PC, et al. Percutaneous left atrial appendage transcatheter occlusion (PLAATO System) to prevent stroke in high-risk patients with nonrheumatic atrial fibrillation: results from the international multi-center feasibility trials. J Am Coll Cardiol. 2005;46(1):9-14.
Sick PB, Schuler G, Hauptmann KE, Grube E, Yakubov S, Turi ZG, et al. Initial worldwide experience with the WATCHMAN left atrial appendage system for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2007;49(13):1490-1495.
Sievert H, Reddy VY, Neuzil P. LAA closure using the WATCHMAN device in patients with contraindications to warfarin: preliminary results from the “ASA Plavix Registry” (ASAP). J Am Coll Cardiol. 2010;56:b109.
Lip GY. Implications of the CHA2DS2-VASc and HAS-BLED Scores for Thrombophrophylaxis in Atrial Fibrillation. Am J Med. 2011;124(2):111-114.
Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al; The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med. 2002;347(23):1825-1833.
The Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Investigators. Relationships between sinus rhythm, treatment, and survival in the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) Study. Circulation. 2004;109:2509-2513.