Efficacy of Anticoagulation for Stroke Prevention and Risk Stratification in Atrial Fibrillation: Translating Trials into Clinical Practice

As one of the most powerful independent risk factors for ischemic stroke and the most clinically relevant arrhythmia, atrial fibrillation (AF) poses a serious clinical and public health threat as the global population ages. AF increases the risk of ischemic stroke 4- to 5- fold¹ although this statistic varies with age of the patient. Indeed, the prevalence rises to 1 in 25 people aged ≥60 years and 1 in 10 people aged ≥80 years.² More than 2.3 million Americans have diagnosed AF, and that number is expected to increase dramatically over the coming decades.² Ischemic stroke causes the most major disability and remains the third leading cause of death in the United States. Therapeutic strategies and optimal risk stratification offer the best hope for decreasing the burden of AF-related thromboembolism.

This article focuses on the randomized trial evidence for the efficacy and safety of oral vitamin K antagonists (eg, warfarin) for stroke prevention in AF. In particular, this article explores how well these findings translate into clinical practice, especially among patients with AF treated outside of clinical trials. Discussion centers on using evidence-based data to guide treatment for patients who are at increased risk for stroke. Such strategies would enhance the net benefit of oral anticoagulation. Concluding points provide information on improving risk stratification for stroke in patients with AF.

(Am J Manag Care. 2004;10:S58-S65)

Randomized Trial Evidence for Efficacy of Oral Vitamin K Antagonists

Multiple randomized trials completed during the late 1980s and through the 1990s investigated the efficacy of oral vitamin K antagonists for the prevention of thromboembolism (primarily ischemic stroke) in patients with nonvalvular atrial fibrillation (AF). Six randomized trials involving more than 4600 patients with AF compared oral anticoagulation with a control group.^3-8The 5 studies of primary prevention in patients with AF and no prior transient ischemic attack, ischemic stroke, or other systemic embolism include:

• Atrial Fibrillation, Aspirin, and Anticoagulation (AFASAK);
• Boston Area Anticoagulation Trial for Atrial Fibrillation (BAATAF);
• Stroke Prevention in Atrial Fibrillation (SPAF-I);
• Canadian Atrial Fibrillation Anticoagulation (CAFA); and
• Stroke Prevention In Nonrheumatic Atrial Fibrillation (SPINAF).

A single secondary prevention study, the European Atrial Fibrillation Trial (EAFT), studied subjects with AF and a recent transient ischemic attack or minor stroke. Together these 6 studies are outlined in Table 1. These studies primarily included patients with persistent, permanent, and to a lesser degree, paroxysmal or intermittent AF. Patients with valvular causes of AF were excluded from these trials. Except for EAFT, which used phenprocoumon or acenocomarol, these trials used warfarin as the oral anticoagulant. Notably, the control group in the BAATAF trial took aspirin. The primary prevention trials showed a consistent benefit of oral vitamin K antagonist therapy for stroke prevention, with relative risk reductions ranging from 52% to 82%. In EAFT, the benefit of oral anticoagulation in secondary prevention was similar, with a relative risk reduction of 66%. The absolute decrease in stroke was greater because of the higher baseline risk in these patients.

Several primary prevention trials (AFASAK-1, SPAF-II, SPAF-III, AFASAK-2, and Hellemons and colleagues)^3,9-12 and the secondary prevention trial, EAFT,⁸ also evaluated the potential utility of the antiplatelet agent, aspirin, at various doses (50-325 mg daily) compared with oral vitamin K antagonist therapy (Table 2). Overall, warfarin caused a greater reduction in the risk of ischemic stroke compared with aspirin, especially in patients considered at higher risk for stroke (eg, SPAF-III). Furthermore, the combination of aspirin with low-dose warfarin does not appear to convey any greater benefit than aspirin alone for preventing thromboembolism in AF. Statistically significant results were found in 3 of 7 individual trials. This may be related to a variety of factors, including different inclusion criteria between trials, sample size issues, and/or varying target anticoagulation intensity in warfarin-treated patients.

Following the completion of these studies, meta-analyses using pooled patient data from available randomized trials summarized the effects of various antithrombotic therapies for stroke prevention (Table 3).^13-15In these pooled analyses, adjusted-dose warfarin therapy had an overall relative risk reduction of 68% for ischemic stroke compared with no antithrombotic treatment. In comparison, aspirin was less effective and of borderline statistical significance. Compared with aspirin, adjusted-dose warfarin therapy was associated with a 52% relative risk reduction for stroke. In addition, these trials revealed the bleeding risks of anticoagulant therapy. Use of oral vitamin K antagonists is associated with a modest risk of major hemorrhage (typically defined as fatal or permanent disability, leading to hospitalization, requiring blood transfusions, or occurring at a critical anatomic site, such as intracranial bleeding) and minor bleeding. This was particularly true if international normalized ratio (INR) levels were >3.0. In these trials, there was no significant major bleeding risk associated with adjusted-dose anticoagulation. The annual rate of major hemorrhage was 1.3% in anticoagulated patients compared with 1.0% in control subjects.¹³ The observed annual rate of intracranial hemorrhage was approximately 0.3% in anticoagulated subjects compared with 0.1% among control subjects. In clinical context, these findings suggest that treating 1000 patients with AF for 1 year would prevent 23 ischemic strokes and cause an excess of 9 major bleeding events. As expected, as the baseline risk of stroke increases, a greater net benefit exists for using oral vitamin K antagonists.

Can Results from Trials Be Implemented into Practice?

Evidence from existing randomized trials suggests that oral vitamin K antagonists may have advantages compared with aspirin or placebo for stroke prevention. However, some residual concerns still exist among many clinicians. For instance, can these results be duplicated in clinical practice where sicker patients with AF are managed with less intensive anticoagulation monitoring? Several observational studies have been performed to evaluate the effectiveness and safety of antithrombotic therapy for prevention of thromboembolism in AF outside of randomized trials. Unfortunately, many of these studies have been limited by including patients from selected clinical settings (eg, long-term care institutions), modest sample sizes, and few thromboembolic and bleeding events to generate accurate and precise event rates (Table 4).^16-23In 2 studies of high-risk patients with AF who suffered an ischemic stroke, warfarin was found to be significantly more effective than either aspirin or no antithrombotic therapy for secondary prevention.^16,17 Among a sample of patients hospitalized with AF, prescription of warfarin therapy at discharge was associated with lower risks of stroke and transient ischemic attack compared with aspirin or no antithrombotic therapy.^19,20Furthermore, the reported risk of ischemic stroke was 1.3%²³ to 2.0 per 100 person-years ¹⁸ in 2 studies involving selected patients treated with warfarin.

Recently, 2 larger studies of the effectiveness of warfarin therapy have been reported. In Denmark, a sample of 5124 people with diagnosed AF had a stroke rate of 3 per 100 person-years. Warfarin therapy was associated with lower risk of stroke in men (adjusted relative risk 0.6, 0.4-1.0) but not in women.²⁴ The AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) study,²⁵ a contemporary population-based cohort of 13 559 ambulatory adults with diagnosed nonvalvular AF in northern California, collected longitudinal information on warfarin use along with associated clinical outcomes. In this study, the rate of thromboembolism was significantly reduced in subjects taking warfarin (1.33 vs 2.53 per 100 person-years, respectively), with an adjusted 49% (95% confidence interval, 39%-57%) decreased risk.²⁶

In addition, the ATRIA study has shown that anticoagulation to a therapeutic INR level of 2.0 to 3.0 can reduce both the incidence of ischemic stroke as well as reduce the severity and short-term risk of death in patients with AF.²⁷

Some physicians are concerned about the risk of major hemorrhage when anticoagulation is used outside of clinical trials in older patients with AF. Reassuringly, intracranial hemorrhage and its associated high mortality and morbidity rates occurred at relatively low rates on anticoagulation (range, 0%-0.8%) in most observational studies. These rates are similar to those reported in randomized trials, although the absolute number of events were low (Table 4).^16-18,21 In the ATRIA study, anticoagulation with warfarin was independently associated with a small but increased risk of intracranial hemorrhagic events (adjusted relative risk 1.57, 1.09-2.26).²⁶ The absolute risk of intracranial hemorrhage with warfarin treatment was relatively close to the rate in the control patients who were not receiving warfarin (0.51 vs 0.33 per 100 person-years, respectively). Notably, approximately 80% of patients in the ATRIA study cohort were managed by specialized pharmacists or nurses in anticoagulation clinics, so these results may not be applicable to other care settings.

Stroke Risk Stratification in Atrial Fibrillation

Both randomized trial evidence and findings from large observational studies show that oral vitamin K antagonist therapy effectively reduces the risk of ischemic stroke in patients with nonvalvular AF and is substantially more effective than treatment with aspirin. Oral vitamin K antagonist therapy leads to a higher risk of major bleeding and is associated with greater lifestyle inconveniences (eg, dietary restrictions and frequent INR testing) compared with aspirin. Therefore, anticoagulation therapy needs to be limited to patients who are at higher intrinsic risk of stroke or are at an acceptable risk of hemorrhage. Because of the relatively low rates of bleeding observed in trials and clinical populations with well-managed anticoagulation services, and the lack of definitive data on predictors of major bleeding with anticoagulation, physicians have focused on improving risk stratification for ischemic stroke.^28,29

The most rigorous data on risk factors for stroke in patients with AF have come primarily from subjects enrolled in trials of antithrombotic therapy who were randomized not to receive oral vitamin K antagonists. ^8,30-32 Risk stratification schemes have been derived from pooled analyses from the Atrial Fibrillation Investigators (AFI),³³ 2 analyses from the SPAF investigators,^31,34 and the recently published Framingham score ³⁵ (Table 5). Additional derived schemes include the Congestive Heart Failure, Hypertension, Age, Diabetes, and Stroke (CHADS₂) score ³⁶ and the American College of Chest Physicians (ACCP) Consensus Guidelines on Antithrombotic Therapy.³⁷

As shown in Table 5, the identified clinical predictors of stroke are largely overlapping across the various risk stratification schemes, with commonly identified factors including older age, prior systemic thromboembolism, and a history of hypertension. Other factors identified less consistently by these schemes were female sex, diagnosed heart failure (significant left ventricular systolic function), diabetes mellitus, and systolic blood pressure level. In the AFI and SPAF trials, patients who had 1 or more of the proposed risk factors suffered higher annual rates of stroke, depending on the number and type of risk factor (eg, AFI, 4.3%- 8.1%; SPAF, 2.6%-7.1%).^31,32 A recent study from the Framingham Heart Study, which enrolled 705 patients with new-onset AF, used a scoring system that assigned points according to age, gender, systolic blood pressure, diabetes status, and prior stroke or transient ischemic attack. Using a threshold annual predicted rate of stroke of ≤1.5 per 100 person-years, the proportion of patients who were considered at "low risk" and less likely to benefit from anticoagulation was 14.3%.³⁵

The CHADS₂ risk index combined variables from the AFI and SPAF-I—II schemes to create a point system using administrative claims data in which 2 points were given for a previous diagnosis of stroke or transient ischemic attack, and 1 point each for age &#8805;75 years, a history of hypertension, diabetes, or congestive heart failure (scoring range, 0-6).³⁶Among 1733 hospitalized Medicare beneficiaries aged 65 to 95 years with nonvalvular AF not discharged on warfarin, a greater CHADS₂ score was associated with a progressively higher risk of stroke. Few patients had a very high score of &#8805;5, and <7% of patients had a score of zero (ie, low risk).

Guidelines from the ACCP also have been developed based on existing studies, and the most recently published version stratifies patients into high-, moderate-, and low-risk groups for stroke.³⁷ High-risk patients either have &#8805;1 high risk factor (ie, prior transient ischemic attack, systemic embolus, or stroke; history of hypertension; poor left ventricular systolic function; age >75 years; rheumatic mitral valve disease; prosthetic heart valve) or >1 moderate risk factor (ie, age 65-75 years, diabetes mellitus, coronary artery disease with preserved left ventricular systolic function). Moderate-risk patients have only 1 moderate risk factor, and low risk patients have no risk factors. An upcoming substantive revision to these guidelines is expected in mid-2004.

Finally, several transthoracic echocardiographic studies have identified moderate-to-severe left ventricular dysfunction by itself was a significant incremental risk factor. Left atrial diameter has not been found to add independent prognostic information after accounting for other known risk factors.³⁰ Transesophageal echocardiographic (TEE) studies have demonstrated that the presence of thrombus or a dense and spontaneous echo-contrast in the left atrium or a complex plaque in the aortic arch as high risk factors for stroke. However, there is no clear evidence that TEE findings contribute significant independent prognostic information for the majority of patients with chronic atrial AF. These findings do not appear to merit the added financial expense and periprocedural risks of the procedure.

Conclusion

The clinical and public health impact of AF will continue to expand with the growing elderly population worldwide. The consistent evidence from many randomized trials and large "real-world" studies demonstrate the advantage of oral vitamin K antagonist (warfarin) therapy for stroke prevention. With careful anticoagulation monitoring, this therapy has generally acceptable levels of bleeding. Complete consensus does not yet exist on the optimal risk stratification scheme to identify which individual patients are at a high enough risk for stroke to justify the use of oral anticoagulants. Present evidence suggests that the presence of 1 or more risk factors for stroke warrants an evaluation for eligibility to receive anticoagulation therapy. Despite the available data, warfarin appears to be underused. Novel methods are needed to improve evidence-based use of this therapy to prevent thromboembolism in patients with AF.

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