Finding a Balance in Long-Term Anticoagulation Therapy

The treatment of atrial fibrillation (AF) takes a 2-pronged approach that addresses (1) symptoms caused by the arrhythmia and (2) safety, which is largely focused on reduction of the risk of stroke due to the effects of AF on blood flow. Treatment of AF includes rate-control and rhythm-control strategies. However, achieving control of AF symptoms will generally not protect a patient against the risk of stroke. Currently available antithrombotic agents effectively reduce the risk of stroke in patients with AF, and guidelines have been established for selecting the appropriate agent. Recommendations currently center on a choice between aspirin or warfarin (target international normalized ratio of 2.0-3.0) and are based on an assessment of the level of risk for the individual patient. The choice between aspirin or warfarin comes down to a choice between lower anticoagulant efficacy coupled with a lower bleeding risk versus higher anticoagulant efficacy coupled with a higher bleeding risk. Minimizing the risks of antithrombotic treatment in AF patients involves finding the appropriate balance between the risk for each individual of having a stroke while using less effective anticoagulation versus the risk of having a major bleeding event while using more effective anticoagulation.

(Am J Manag Care. 2010;16:S278-S283)

The 2 main concerns in the treatment of atrial fibrillation (AF) are to achieve control of AF symptoms and lower the risk of stroke with antithrombotic therapy. From a safety standpoint, there is no distinction to be made between paroxysmal AF, persistent AF, and permanent AF; they are all associated with equivalent elevations in the risk of stroke, and appropriate preventative measures should be taken for each.^1,2 Likewise, appropriate stroke prophylaxis should be implemented regardless of whether antiarrhythmic medications are believed to be successfully suppressing AF or not. However, this particular caveat may change as more rigorous methods for detecting silent arrhythmias, such as implantable devices, become more widely available.³

Symptomatic Treatment in AF

Treatment of AF relies on a rate-control strategy or a rhythm-control strategy.⁴ A rate-control strategy does not stop AF, but does act to maintain control of the ventricular rate while the atria are fibrillating. Rate control using pharmacologic agents is recommended for patients with paroxysmal, persistent, or permanent AF. The recommended agents include β-blockers, nondihydropyridine calcium channel antagonists, digitalis, or a combination thereof.⁵ A combination of a β-blocker and digitalis may be beneficial in patients with heart failure; digoxin and digitoxin are effective for rate control at rest, but not during exercise.

Some proven agents recommended for rhythm control in AF include amiodarone, dofetilide, flecainide, propafenone, sotalol, and a newly released medication called dronedarone.⁴ Recommended dosages, routes of administration, and safety considerations are specific to each agent. It is important to be familiar with the specific toxicities of the various rhythm control agents. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study compared rate control against rhythm control in elderly patients with AF and found no difference in outcomes between the 2 strategies.⁶

Catheter ablation of paroxysmal AF achieves effective rhythm control in approximately 75% of patients, but sometimes requires repetition or continued use of an antiarrhythmic agent.⁷ Patients should understand that the goal of ablation is not to gain independence from anticoagulation therapy. Ablation has not yet been shown to prevent stroke and there is a periprocedural stroke risk. There is a large ongoing study sponsored by the National Institutes of Health called the Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial that will evaluate whether percutaneous, left atrial catheter ablation is superior to pharmacologic rate or rhythm control for the reduction of mortality and stroke in AF patients.⁸ CABANA will randomize 3000 patients who have documented AF into 6 months of either catheter ablation or pharmacologic therapy with rate- or rhythm-control drugs. Patients will be at least 65 years of age or less than 65 years of age and with more than 1 risk factor for stroke, and they will be eligible for both catheter ablation and at least 2 rhythm-control agents or at least 3 rate-control drugs. Regardless of whether the rate-control or rhythm-control strategy is used for symptom treatment, antithrombotic therapy should always be used concomitantly.

Improving Safety in Patients Who Are at Elevated Risk of Stroke Due to AF

Table 1

Anticoagulation therapy lowers the elevated risk of clot formation that is associated with AF and reduces the incidence of both mild and severe ischemic strokes and systemic embolism.^2,4 The efficacy of anticoagulation as a stroke prevention measure is shown in . Using pooled data from 5 primary prevention trials in AF, the overall annual rate of stroke was 4.5% in the control group compared with 1.4% in the warfarin group.² As shown in Table 1, the total risk reduction for ischemic stroke attributable to warfarin therapy was 68%. Warfarin efficacy was consistent across all the studies and subgroups of patients. These benefits were balanced against minimal changes in the annual rate of major hemorrhage, which was defined as intracranial bleeding or a bleed requiring hospitalization or 2 units of blood. This pooled analysis reported annual rates of major bleeding of 1.0% in the control group and 1.3% in warfarin-treated patients. These bleeding events included an annual rate of intracranial hemorrhage of 0.1% in the control group versus 0.3% in the warfarin group. In contrast, the efficacy of aspirin for stroke prevention in AF was less consistent. The Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulant Therapy (AFASAK 2) study showed a nonsignificant 18% decrease in risk of stroke with 75-mg aspirin, while the Stroke Prevention in Atrial Fibrillation (SPAF) study found a significant decrease of 44% associated with 325-mg aspirin.² The investigators found identical rates of major bleeding in the control group (1.0%) and in the aspirin group (1.0%). A later meta-analysis of aspirin therapy versus placebo (or no treatment) for both primary and secondary prevention found a 19% reduction in the overall incidence of stroke, with no evidence favoring one dose of aspirin over another.⁹

These primary prevention trials included patients with persistent or permanent AF, as well as paroxysmal or intermittent AF.^10-14 It was common for AF to have been present for many months or years. Anticoagulation was found to reduce all-cause mortality by 33% (95% confidence interval [CI], 9%-51%) and a combined outcome of stroke, systemic embolism, and death by 48% (95% CI, 34%-60%).¹⁵ Overall, evidence for the efficacy of anticoagulation in AF is strong, consistent, and based on high-quality studies.

Anticoagulation Guidelines for Stroke Prophylaxis in Patients With AF

Table 2

Because the purpose of anticoagulation therapy is to inhibit clot formation, it can have both beneficial and adverse effects. Anticoagulation therapy blocks thromboembolism leading to stroke, but it also blocks appropriate clot formation, which could lead to a major bleeding event.¹⁶ Thus, the clinician must find a balance between the benefits and inherent risks of the therapy. The American College of Cardiology (ACC)/American Heart Association (AHA)/European Society of Cardiology (ESC) 2006 guidelines for antithrombotic therapy are shown in .⁴ The guidelines represent a systematic approach to finding a balance between the risk of thromboembolism and the risk of major bleeding events. Aspirin is recommended for patients with a lower risk of stroke (ie, those with no risk factors other than AF). Warfarin (target international normalized ratio [INR] of 2.5) is recommended for patients with a high risk of stroke (ie, those with a high risk factor or >1 moderate risk factor). For patients with 1 moderate risk factor, clinicians must decide between aspirin or warfarin.

These guidelines stand in contrast to the recently revised guidelines of the ESC, especially with respect to patients whose stroke risk is at the lower end of the spectrum.⁵ The ESC has recently implemented a revised, 9-point scoring system, called CHA₂DS₂VASc, for estimating the risk of stroke in patients with AF.¹⁷ This scoring system stratifies the contribution of age to stroke risk by assigning 2 points (A2) to patients who are aged at least 75 years, and 1 point (A) to patients aged 65 to 74 years. The new system also takes into account the contributions of vascular disease (V) and sex category (Sc), assigning 1 point for each. Based on the risk of stroke determined by this method, the ESC now recommends choosing between aspirin or no treatment for patients with a CHA₂DS₂VASc score of 0, noting that the preferred choice is no treatment.⁵ The recommendation for a CHA₂DS₂VASc score of 1 is now a choice between warfarin or aspirin, where warfarin is designated as the preferred choice.

Antithrombotic Therapy Is Underused in Patients With AF

Figure

A commonly used, validated method of quantitating the risk of stroke is to score a patient's risk factor using 1 point each for congestive heart failure, hypertension, age greater than 75 years, and diabetes.¹⁸ Finally, 2 points are added for a history of prior stroke. The scoring system is abbreviated using the acronym, CHADS₂. A recent study from the Atrial Fibrillation: Focus on Effective Clinical Treatment Strategies (AFFECTS) Registry provides an example of using the CHADS₂ score to gauge stroke risk in patients with AF.¹⁹ This study found that appropriate antithrombotic therapy is not being implemented in many patients with AF who are at elevated risk of stroke. The results are shown in the . Anticoagulant use was high among participating cardiologists, but still did not match guidelines and evidence-based recommendations for patients with AF. Among patients with AF and a CHADS2 score of at least 2, 73% were receiving warfarin concomitantly with rate-control treatment, and 66% were receiving both warfarin and rhythm-control treatment. The AFFECTS Registry did not report the reasons why physicians did not use anticoagulation therapy.

An elevated risk of bleeding events is sometimes the underlying reason for underuse of anticoagulation therapy in patients who would otherwise benefit. Despite the availability of relevant and validated tools, as well as regularly updated guidelines, anticoagulants continue to be underused in clinical practice.²⁰ Table 3 shows recent data from the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE-W) study that further illustrates the relative hazards of bleeding risk compared with stroke risk.²¹ In this analysis, the risk of death attributable to thromboembolic events was greater than the risk of death due to major bleeding events, which suggests that although the bleeding risk is a valid concern, avoiding the risk of death due to stroke is the greater concern in treating many patients with AF. Furthermore, only the major bleeding events that were considered severe were associated with increased mortality, further supporting the priority of stroke prevention.

The outpatient bleeding risk index (OBRI) is used to evaluate bleeding risk in a patient prior to initiating long-term oral anticoagulation therapy.¹⁶ The OBRI is scored on the basis of (1) history of stroke; (2) age older than 65 years; (3) history of gastrointestinal bleeding; and (4) presence of at least 1 comorbid condition, including recent myocardial infarction, renal insufficiency, severe anemia, or diabetes. On the OBRI scale, a score of 0 is a low risk, while scores of 1 to 2 reflect a moderate risk of bleeding, and scores of 3 to 4 indicate a high bleeding risk. In the original report, cumulative rates at 2 years for major bleeding according to the OBRI risk score ranged from 3% to 53%.²²

The persistent disparity between real-world stroke prevention practices and published stroke prevention guidelines was examined recently in studies involving patients with AF.²³ Undertreatment was defined as treatment of less than 70% of high-risk patients. In this analysis, of 54 studies examined, the majority demonstrated underuse of oral anticoagulants in high-risk patients. Furthermore, 25 of 29 studies examining patients with prior stroke or transient ischemic attack (TIA) reported undertreatment, with 21 of 29 studies reporting oral anticoagulation treatment levels below 60% (range 19%-81.3%). The case study below provides an example of a patient who has both high stroke risk and high bleeding risk for whom there is no clear-cut "right" answer.

Case Study Discussion: William H.

The patient is a 91-year-old man who was diagnosed 1 year ago with persistent AF. Because he has not shown clear improvement, a rate-control strategy was chosen to address the symptoms of AF. His clinician must now choose an appropriate treatment to address the safety aspect of his treatment plan. An examination of his medical history shows some risk factors that will help estimate his level of stroke risk. Regarding his CHADS2 score, he is well over 75 years of age and has borderline hypertension (ie, blood pressure is typically 152/82 mm Hg), but does not have diabetes, or any history of congestive heart failure, stroke, or TIA. The fact that he has AF raises his risk of stroke considerably; furthermore, a transthoracic echocardiogram showed mild left ventricular hypertrophy and moderate left atrial enlargement, but a normal ejection fraction. A subsequent transesophageal echocardiogram (TEE) in AF revealed that he may have a thrombus in the left atrial appendage.

Another important consideration is the fact that William uses a walker and had a traumatic fall within the past year. It is likely that he has had a few less serious falls or close calls that he is reluctant to tell you about. Given his high risk of stroke, aspirin alone may not provide adequate protection. Given his instability, however, a fall while using anticoagulation could result in a serious hematoma. William represents the typical patient in whom the risk of stroke (due to inadequate anticoagulation) must be balanced against the risk of bleeding with anticoagulation therapy. Because the imaging data indicate that he has a likely left atrial thrombus that could potentially reach the brain, causing a catastrophic stroke or death, the recommended treatment for William is warfarin therapy with the goal of maintaining an INR between 2.0 and 3.0. Even without the possible clot on the TEE, warfarin is likely the safest overall approach at this time, despite the bleeding risk associated with warfarin.

Conclusion

Anticoagulation therapy has been shown to effectively lower the incidence of stroke in high-risk populations, including patients who are at risk of stroke due to AF. Unfortunately, anticoagulation therapy in AF is underused. Underuse is more prevalent in cases of paroxysmal AF than in cases of permanent AF, despite the fact that the risk of stroke is essentially the same for both. When considering the choices for anticoagulation therapy, treatment decisions made by clinicians often lean toward taking the risk of inadequate anticoagulation versus the risk of major bleeding. As a consequence, many studies now demonstrate underuse of anticoagulation in populations who are at risk of stroke, including patients with AF. However, it can be argued that a shift in opinion would only result in more studies that show increased incidence of major bleeding events. The underuse of anticoagulants may simply translate to fewer deaths due to intracranial hemorrhage. Thus, clinicians now anxiously await a new generation of anticoagulant agents that promise to offer more protection against thromboembolism with lower bleeding risk and simpler dosing and monitoring. These emerging agents, direct thrombin inhibitors and factor Xa inhibitors, promise to diminish the risks that currently must be considered with anticoagulation therapy.^24,25

Author Affiliation: Oregon Health & Science University, Portland, OR.

Funding Source: Financial support for this work was provided by an educational grant from Boehringer Ingelheim Corporation.

Author Disclosure: Dr Stecker reported that he is a consultant to AstraZeneca. He also reported that he received a one-time patent royalty from Medtronic, Inc.

Authorship Information: Concept and design; drafting of the manuscript; critical revision of the manuscript for important intellectual content; administrative, technical, or logistical support; and supervision.

Address correspondence to: TCL Institute, LLC, 104 Towerview Court, Cary, NC 27513. E-mail: cme@tclinstitute.com.

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