Prevention of Thromboembolic Stroke in Patients with Atrial Fibrillation, Valvular Heart Disease, or Cardiomyopathy

Thomas L. Kawano

Jonathan L. Halperin

Patients with various forms of cardiac disease are at risk of ischemic stroke and systemic embolism due to migration of thrombus that forms on endocardial or prosthetic valve surfaces or in the cardiac chambers. The risk varies with the nature of the underlying heart disease, but clinically these events are typically severe, resulting in substantial disability and mortality. Highly effective prophylactic therapy is available in the form of anticoagulant drugs, but treatment is associated with a risk of bleeding complications. Hence, an understanding of the pertinent pathophysiology, clinical factors responsible for variation in individual risk, and evolving management alternatives is crucial to optimum patient care.

ATRIAL FIBRILLATION

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance and an important independent risk factor for ischemic stroke. AF affects approximately 2.5 million individuals in the United States¹^,² and millions more worldwide. Prevalence is greater in men than in women³^,⁴^,⁵ and increases with age, rising rapidly beyond the 6th decade to approximately 10% among those older than 80 years (see FIGURE 92.1).²^,³^,⁴^,⁵^,⁶ The median age of patients with AF is approximately 72 years. As the population ages, the number of individuals with AF is likely to increase substantially in the coming decades.²

Patterns of AF

AF can be classified according to pattern of occurrence as paroxysmal, persistent, or permanent, based on the duration of the arrhythmia and reversibility.⁷ Paroxysmal AF may occur once or multiple times, but involves self-terminating episodes. Persistent AF does not convert to normal sinus rhythm (NSR) spontaneously but NSR can be restored, at least temporarily, with pharmacologic or electrical cardioversion. Permanent AF is refractory and implies a clinical decision to allow AF to continue. Either paroxysmal or persistent AF may occur as a single or recurrent episode. Risk factors associated with the future development of AF have led to the concept that some patients may have “pre-AF,” and the early success of catheter-based ablation therapy has created a cadre of patients with “post-AF,” who merit special considerations with respect to antithrombotic therapy.

Risk of Stroke Associated with AF

As a result of disorganized and ineffective atrial systole, the fibrillating atria become passive conduits of blood from the systemic and pulmonary venous systems to the ventricles. Impaired atrial emptying leads to stasis and increases the risk of thrombus formation, particularly in the left-atrial appendage (LAA).⁸ The factors that promote embolism of intracardiac thrombus and subsequent ischemic events (including stroke and peripheral arterial occlusion) are incompletely understood.⁹^,¹⁰ In addition to cardiogenic embolism, patients with AF commonly have other cardiovascular disease states, such as hypertension and atherosclerosis, which raise the risk of ischemic events.

Approximately 15% of all strokes are attributed to AF.¹¹ The rate of ischemic stroke among patients with AF not given antithrombotic therapy averages 4.5% per year,¹²^,¹³ approximately fivefold greater than in age- and gender-matched individuals with NSR. In the Framingham Heart Study, the risk of stroke attributable to AF rose from 1.5% in patients aged 50 to 59 years to 23.5% in those aged 80 to 89 years.¹⁴ Because both the prevalence of AF and the risk of stroke increase with patient age, the problem of stroke prevention is amplified among the elderly; AF is the most common cause of stroke in women older than 75 years.¹⁵ When compared to ischemic stroke due to other causes, ischemic stroke due to AF is typically more severe and carries a significantly higher mortality rate.¹⁶ Several hypotheses have been advanced to explain the pathogenesis of stroke in patients with AF and the poor clinical outcomes associated with these events. Embolism of thrombus from the LAA may cause complete occlusion of relatively large cerebral arteries, consistent with the relatively frequent finding of large cortical infarcts on brain imaging and less frequent lacunar infarcts.¹⁷ Chronically reduced cerebral blood flow, due either to the arrhythmia itself or to more extensive cerebrovascular disease associated with AF due to hypertension or atherosclerosis, may compromise collateral perfusion when acute infarction develops and contribute to greater stroke severity.

AF in the Setting of Valvular Heart Disease

Patients with AF and rheumatic mitral valve disease or mechanical or biologic prosthetic heart valves have been considered at high risk of stroke¹⁰ and were excluded from most randomized
trials of antithrombotic therapy because of the perceived need for anticoagulation. Hence, available empirical data pertain mainly to patients with nonvalvular AF.

FIGURE 92.1 Prevalence of atrial fibrillation according to sex and age.

Atrial Flutter

Sustained atrial flutter is uncommon because the rhythm typically either degenerates to AF or reverts to NSR. Patients with persistent atrial flutter may have periods of AF and vice versa. There are scant data from longitudinal studies assessing the thromboembolic risk associated with isolated, sustained atrial flutter. Echo-Doppler examinations of patients with atrial flutter demonstrate more organized atrial mechanical function and greater LAA flow velocities than are typical in patients with AF.¹⁸ Despite this functional distinction, intra-atrial thrombus and stroke have been documented in patients with atrial flutter.⁶^,¹⁹ In a transesophageal echocardiographic (TEE) study before cardioversion, 25% of patients with atrial flutter of slightly longer than 6 months mean duration had spontaneous echocardiographic contrast, a marker of stasis thought to represent a prethrombotic state, and 7% had LAA thrombus.²⁰ In patients with prior cerebral ischemic events, the prevalence of intraatrial thrombus associated with atrial flutter was even higher.²¹ A retrospective study of 100 patients with persistent atrial flutter found a higher than anticipated risk of stroke.²² Although the role of anticoagulant therapy for patients with atrial flutter has not been evaluated in clinical trials, current treatment guidelines recommend that antithrombotic therapy follows the same risk-stratification approach applied to patients with AF.

Stroke Risk Stratification in Patients with AF

A combined analysis of untreated control groups in five primary prevention trials found a stroke rate of over 8% per year in patients with AF older than 75 years who had one additional clinical risk factor (hypertension, diabetes mellitus, heart failure (HF), or prior stroke or transient ischemic attack [TIA]). For patients of any age with a history of thromboembolism, the annual risk of stroke was 12%.¹²^,²³ In a study of elderly nursing home patients who were not anticoagulated, the 3-year stroke rate exceeded 50%.²⁴

Risk factors that increase the risk of stroke among patients with AF not treated with anticoagulants have been determined from randomized trials of antithrombotic therapy.²³^,²⁴^,²⁵^,²⁶^,²⁷^,²⁸ The most commonly cited risk-stratification strategies were generated from pooled analyses of five trials by the Atrial Fibrillation Investigators (AFI)¹² and from the Stroke Prevention in Atrial Fibrillation (SPAF) cohorts.²⁵^,²⁸ The AFI group¹² found the following independent risk factors: age (relative risk [RR] 1.4 per decade), prior stroke or TIA (RR 2.5), a history of hypertension (RR 1.6), and diabetes mellitus (RR 1.7). Analysis of 854 patients assigned to aspirin from the first two SPAF trials²⁹ identified three independent risk factors for stroke: women older than 75 years (RR 3.7), systolic hypertension >160 mm Hg (RR 2.2), and impaired left ventricular (LV) function defined as recent (within 3 months) HF, moderate-to-severe systolic dysfunction as assessed by two-dimensional echocardiography, or fractional shortening <0.25 by M-mode echocardiography (RR 1.8). Extending the analysis to 2,012 patients allocated to the aspirin or combination therapy arms of the SPAF-I to SPAF-III studies³⁰ identified five characteristics significantly associated with an increased risk of stroke: prior thromboembolism (RR 2.9), age (RR 1.8 per decade), female gender (RR 1.6), history of hypertension (RR 2.0), and systolic blood pressure >160 mm Hg (RR 2.3).

Although prior stroke or TIA, older age, and hypertension were identified as risk factors for stroke in patients with AF in both the AFI and SPAF risk-stratification schemes, there was a differential impact of age in these cohorts. The AFI scheme classified all patients with AF 65 years or older as at elevated risk, whereas the SPAF criteria classified women 75 years or younger and men of any age without other risk factors as at low risk. Uncertainty about risk in either gender aged 65 to 75 years and in men of any age without other risk factors applies to approximately 20% of the population with nonvalvular AF.³¹

Current guidelines recommend a risk-based approach to selection of patients with AF for oral anticoagulation to prevent stroke.⁷ The main clinical risk factors are presented
in Table 92.1. A modified scale, CHADS₂ (Cardiac failure, Hypertension history, Age >75 years, Diabetes, and Stroke or TIA [doubled]), integrates elements from the AFI and SPAF schemes in assessing the annual risk of stroke. This index allots two points for a history of stroke or TIA and one point each for age over 75 years, history of hypertension (not further defined), diabetes mellitus, recent clinical HF, or impaired LV systolic function (generally taken as an ejection fraction ≤35%) (Table 92.2). The scheme was initially evaluated in 1,733 Medicare beneficiaries with nonvalvular AF aged 65 to 95 years who were discharged from hospital off warfarin³² and has been validated in several cohorts.

Table 92.1 Principal clinical risk factors associated with stroke and systemic embolism in patients with nonvalvular atrial fibrillation^a

High-Risk Factors

Mitral stenosis

Prosthetic heart valve

History of stroke or TIA

Moderate Risk Factors

Age > 75 y

Hypertension

Diabetes mellitus

HF or ↓ LVEF

Less Validated Risk Factors

Age 65-75 y

Coronary artery disease

Female gender

^aPatients with any of the high-risk factors should be anticoagulated. Those with one moderate risk factor also benefit from anticoagulation, but the number of patients needed-to-treat with an anticoagulant as compared with aspirin is considerably larger, so some patients with one moderate risk factor may choose platelet inhibitor therapy. The moderate risk factors shown here and prior thromboembolism form the basis for the CHADS₂ risk score (see Table 92.2), while the less-validated risk factors have been incorporated into the CHA₂DS₂VASc score (see Table 92.3). LVEF, left ventricular ejection fraction.

Adapted from Singer DE, Albers GW, Dalen JE, et al. Long-term antithrombotic therapy for chronic atrial fibrillation or atrial flutter: anticoagulants and antiplatelet agents. In Seventh ACCP Consensus Conference on Antithrombotic Therapy: Antithrombotic Therapy in Atrial Fibrillation. American College of Chest Physicians. Chest 2004;126(Suppl):429S-456S; Fang MC, Singer DE, Chang Y, et al. Gender differences in the risk of ischemic stroke and peripheral embolism in atrial fibrillation: the AnTicoagulation and Risk factors In Atrial fibrillation (ATRIA) study. Circulation 2005;112:1687-1691.

The CHADS₂ index has the advantage of simplicity, but classifies a relatively large proportion of patients with AF as at intermediate risk and has imperfect predictive capacity overall (c-statistic ˜0.6). Additionally, many of those designated as low risk carry as high as a 1.3% annual risk of stroke. Additional risk factors, albeit less well validated than those that comprise the CHADS₂ index, should be considered in the stratification of stroke risk in patients with AF. Women with AF appear at higher risk than men with otherwise comparable risk profiles.³³^,³⁴^,³⁵ Vascular disease, including peripheral arterial disease, coronary disease (specifically prior myocardial infarction [MI]), and morphologically complex atheromatous plaque involving the thoracic aorta, is also associated with an increased risk of stroke, but its independent predictive value is controversial. An updated risk-stratification scheme, the CHA₂DS₂VASc score (Table 92.3), incorporates vascular disease (V) and female sex (S) into the risk-stratification schematic, assigning each of these factors one point, and distinguishes two age categories to account for the continuous relationship of risk to age, allocating one point to patients with AF beyond age 65 and two points to those over 75 years.³⁶ The CHA₂DS₂VASc score was validated in the Euro Heart Survey cohort, anticoagulated clinical trial cohorts, and a national patient registry of patients with AF who were not anticoagulated.³⁷ When compared with the CHADS₂ risk score, CHA₂DS₂VASc had greater negative predictive value for stroke for patients classified in the low-risk category and classified fewer patients as intermediate risk, but the c-statistics still indicated imperfect capture of all attributable risks.³⁶

Table 92.2 CHADS₂ score^a

	Score (Points)	Prevalence (%)
Congestive HF	1	32
Hypertension	1	65
Age > 75 y	1	28
Diabetes mellitus	1	18
Stroke or TIA	2	10
Moderate-high risk	≥2	50-80
Low risk	0-1	40-50
^aFor estimation of thromboembolic risk in patients with nonvalvular atrial fibrillation. One point each is assigned for a history of clinical HF or impaired left-ventricular systolic function (corresponding roughly to ejection fraction ≤35%), hypertension (not further defined), and diabetes mellitus and two points for prior ischemic stroke, TIA, or systemic arterial embolism. The approximate prevalence in the Euro Heart survey cohort is shown in the right-hand column, and proportion of patients falling into low-, intermediate-, and high-risk strata is given at the bottom.
Adapted from van Walraven C, Hart RG, Wells GA, et al. A clinical prediction rule to identify patients with atrial fibrillation and a low risk for stroke while taking aspirin. Arch Intern Med 2003;163:936-943; Nieuwlaat R, Capucci A, Lip GY, et al. Antithrombotic treatment in real-life atrial fibrillation patients: a report from the Euro Heart Survey on atrial fibrillation. Eur Heart J 2006;27:3018-3026.

Table 92.3 CHA₂DS₂VASc risk-stratification scheme^a

	Weight (Points)
Congestive HF or LVEF ≤ 35%	1
Hypertension	1
Age >75 y	2
Diabetes mellitus	1
Stroke/TIA/systemic embolism	2
Vascular disease/peripheral arterial disease/aortic plaque	1
Age 65-74 y	1
Sex: category (female)	1
High risk	>2
Low risk	0-1
^aThis scheme has the advantage of assigning fewer patients than the CHADS₂ score to the intermediate-risk category. This score was adopted in the European clinical practice guidelines for management of patients with AF in 2010 but is not universally accepted as superior to the CHADS₂ score. LVEF, left ventricular ejection fraction.
Adapted from Lip GYH, Halperin JL. Improving stroke risk stratification in atrial fibrillation. Am J Med 2010;123:484.

The controlled clinical trials of warfarin included mainly patients with chronic, persistent, and permanent AF and smaller proportions of patients with paroxysmal AF.⁷ For the purpose of determining stroke risk, the distinction between paroxysmal, persistent, and permanent AF proved immaterial. Patients with paroxysmal AF typically have a lower risk of stroke than those with persistent or permanent AF, as they are often younger and have fewer associated risk factors,³⁸^,³⁹ but multivariate analyses of prospectively followed cohorts found that the pattern of AF was not a significant predictor of stroke risk.¹²^,⁴⁰ Current recommendations for anticoagulation, therefore, do not distinguish patients on the basis of the pattern of AF, though the available evidence does not address transient self-limited AF caused by acute medical illness or recent cardiac or noncardiac surgery.⁷

Postoperative Atrial Fibrillation

Patients who develop AF after undergoing cardiothoracic surgery are also at an increased risk of thromboembolic stroke. While there is a small but significant increased risk of in-hospital stroke in patients who develop AF after surgery involving cardiopulmonary bypass, the risk of stroke seems related to underlying comorbidities rather than to AF itself. This was demonstrated in a series of close to 4,000 patients who had cardiac surgery on cardiopulmonary bypass. The rate of AF after surgery was reduced with prophylactic therapy, but the incidence of stroke was not reduced.⁴¹

The decision to anticoagulate patients with AF in the postoperative period is confounded by the risk of bleeding and its associated sequelae (cardiac tamponade, hematoma, hemothorax, etc.). Additionally, a significant percentage of patients who develop AF postoperatively convert back to sinus rhythm. The duration of AF postoperatively, the associated risk of thromboembolic stroke, and the decision of when to anticoagulate are unclear. Practice guidelines differ on when to start anticoagulation for postoperative AF. At the time of this writing, the American College of Chest Physicians (ACCP) guidelines recommend initiating anticoagulation with vitamin K antagonist (VKA) 48 hours after a patient has developed AF. The American Heart Association/American College of Cardiology (AHA/ACC) guidelines recommend starting a VKA after 24 hours of developing AF. Both guidelines agree that anticoagulation should continue for 4 weeks following reversion to and maintenance of sinus rhythm, but the level of evidence supporting this duration of therapy is low.

Echocardiographic Markers of Stroke Risk

Although left-atrial size and LV systolic function can be assessed by transthoracic (precordial) echocardiography, TEE is necessary to consistently visualize abnormalities of the LAA and aortic arch linked with thromboembolism. This approach is used not only as an adjunct to elective cardioversion (see below) but sometimes in patients with persistent AF to assist in thromboembolic risk assessment.⁴²^,⁴³ Visible thrombus or dense spontaneous echo-contrast in the left atrium (LA), and particularly in the LAA, is associated with a two- to fourfold increased risk of stroke.⁷^,⁸ In the SPAF-III study, patients with atheromatous plaque in the thoracic segments of the aorta that had complex morphology (mobility, pedunculation, ulceration, or thickness >4 mm) had high stroke rates. Because many of these abnormalities were observed in the descending aorta beyond the origins of the cerebral vessels, the association with stroke may reflect either associated cerebrovascular disease or the pathogenic role of risk factors such as hypertension that are common both to atherosclerosis and to conditions of atrial stasis in patients with AF.⁴³

Other Potential Stroke Risk Factors in AF

Other characteristics that may augment stroke risk include genetic polymorphisms, abnormalities of hemostatic and thrombotic function, increased platelet activation and aggregation, endothelial dysfunction,⁴⁴^,⁴⁵ and serum levels of troponin and B-type natriuretic protein, but none have yet proven sufficiently robust for routine clinical use. Thyrotoxicosis is a poorly understood risk factor for stroke among patients with AF, because patients with thyrotoxicosis were excluded from the randomized trials of antithrombotic therapy. AF develops in 10% to 15% of patients with hyperthyroidism, and thyrotoxicosis is evident in 2% to 5% of patients with AF.⁴⁶ A high frequency of stroke and systemic embolism has been reported in some⁴⁷^,⁴⁸^,⁴⁹^,⁵⁰^,⁵¹ but not all studies.⁵² The association, if real, may be mediated partly by concomitant HF.

Antithrombotic Drug Therapy for Prevention of Thromboembolism in Patients with AF

Oral Anticoagulant Therapy with a Vitamin K Antagonist

Several randomized trials demonstrated the efficacy of adjusted-dose warfarin for prevention of first or recurrent ischemic stroke in patients with AF with relative risk reductions (RRR) of 47% to 86% versus placebo or no therapy. Results from these trials are summarized in FIGURE 92.2. In a pooled analysis, adjusted-dose warfarin reduced the risk of stroke by about two-thirds.²⁷^,⁴⁶ The magnitude of benefit was fairly consistent among trials despite variations in design and in the intensity of anticoagulation. Compared with aspirin, adjusted-dose warfarin reduced the overall risk of stroke by 36% (95% CI 14% to 52%) and ischemic stroke by 46% (95% CI 27% to 60%).³⁰ The discrepancy is driven largely by the results of the SPAF-II trial (mean international normalized ratio [INR] 2.6), which involved an older patient cohort than enrolled in most other studies,⁵³ and the risk of intracranial bleeding among patients receiving adjusted-dose warfarin was substantially increased among patients more than 75 years old. Exclusion of SPAF-II data from the meta-analysis revealed a 49% reduction in the risk of all stroke for adjusted-dose warfarin compared with aspirin (95% CI 26% to 65%).³⁰ Anticoagulation lowered all-cause mortality by 33% (95% CI 9% to 51%) and the combined outcome of stroke, systemic
embolism, and death by 48% (95% CI 34% to 60%).¹² Due to concern about bleeding, particularly intracranial hemorrhage, when warfarin is given to elderly patients, the BAFTA trial compared open-label warfarin and aspirin in patients 75 years of age and older during treatment by primary doctors in the UK.⁵⁴ The annual risk of the primary outcome of (ischemic or hemorrhagic) stroke, other intracranial hemorrhage, or systemic embolism was significantly lower in the warfarin group than in patients randomized to aspirin (yearly risk 1.8% vs. 3.8%, RR 0.48, 95% CI 0.28 to 0.80, P = 0.003).⁵⁴ These data support the advantage of treating older patients who have AF with warfarin, unless there are other contraindications.

FIGURE 92.2 Stroke risk reductions with warfarin compared to control (placebo or no treatment) in patients with nonvalvular atrial fibrillation. The first five trials listed mainly involved primary prevention, whereas the last was confined to patients with prior nondisabling stroke or TIA. Values shown were obtained according to intention-to-treat analysis. AFASAK, Atrial Fibrillation, Aspirin and Anticoagulation trial; SPAF, the Stroke Prevention in Atrial Fibrillation trial; BAATAF, the Boston Area Anticoagulation Trial for Atrial Fibrillation; CAFA, the Canadian Atrial Fibrillation Anticoagulation trial; SPINAF, the Veterans Administration Stroke Prevention in Atrial Fibrillation trial; EAFT, the European Atrial Fibrillation Trial. (Adapted from Hart RG, Halperin JL. Atrial fibrillation and stroke: concepts and controversies. Stroke 2001;32:803.)

AF had been present for months or years in most of the patients enrolled in these studies, yet each was terminated earlier than planned because of the large benefit of antithrombotic therapy (most often warfarin) for prevention of ischemic stroke and systemic embolism. In aggregate, by intention-to-treat analysis, the annual stroke rate was reduced from 4.5% in the control arms to 1.4% with adjusted-dose warfarin. The effect was consistent across studies with an overall RRR of 68% (95% CI 50% to 79%).¹² The absolute risk reduction implies prevention of 31 ischemic strokes each year for every 1,000 patients treated (or 32 patients needed-to-treat [number needed to treat for 1 year] to prevent a single stroke).¹²

The efficacy of anticoagulation with warfarin was consistent across all patient subgroups and for preventing strokes of all degrees of severity. Most strokes occurring in the warfarin arms involved patients who had stopped warfarin or in whom the INR or prothrombin time ratio fell below the therapeutic range. In summary, evidence for the efficacy of anticoagulation with warfarin in patients with AF is strong and consistent, based on several adequately powered, randomized trials, though an important caveat is that these were mostly open-label studies. The one trial that involved double-blind treatment included no women.⁵⁵

In these trials, anticoagulation proved relatively safe when the upper limit of the therapeutic range was less than INR 3.0, but whether comparable safety can be reliably achieved in less carefully selected patients outside the rubric of clinical research protocols is a persistent controversy. Pooled analysis of the first five primary prevention trials reported a 1.0% per year rate of major bleeding in control patients versus 1.3% in those treated with warfarin. Several schemes have been developed to predict the risk of bleeding in patients with AF during anticoagulant therapy, and though several have been validated in various cohorts none has been uniformly accepted (Table 92.4).

Intracranial hemorrhage is the only complication of anticoagulation that regularly produces deficits more severe than the ischemic strokes the therapy is intended to prevent, and in these trials the rate of intracranial hemorrhage was 0.3% per year in anticoagulated patients compared with 0.1% in the control groups.¹² Intracranial hemorrhage is more common in patients with prior ischemic stroke, hypertension, and advanced age.⁵⁶ One reason intracranial hemorrhages occurred at a low rate in these trials may have been the exclusion of patients considered at high risk of bleeding. Even when aggregated, these trials contribute less to understanding the determinants of intracranial hemorrhage than do large observational studies, which show a correlation with the intensity of warfarin anticoagulation (INR > 4.0),⁵⁶^,⁵⁷ although even with INR values in the therapeutic range of 2.0 to 3.0 warfarin doubles the risk.⁵⁸ Even more important is that intracerebral hemorrhage in anticoagulated patients is usually catastrophic and often fatal.

Table 92.4 HAS-BLED score^a

	Weight (Points)
Hypertension (>160 mm Hg systolic)	1
Abnormal renal or hepatic function	1-2
Stroke	1
Bleeding history or anemia	1
Labile INR (TTR< 80%)	1
Elderly (age > 75 y)	1
Drugs (antiplatelet, NSAID) or alcohol	1-2
High risk (>4% per y)	≥4
Moderate risk (2%-4% per y)	2-3
Low risk (<2% per y)	0-1
^aOne of several risk scores for predicting bleeding in anticoagulated patients with atrial fibrillation. Although adopted in some clinical practice guidelines, no single scheme has yet been widely accepted to guide selection of patients for anticoagulant therapy for prevention of thromboembolism, and bleeding risk must be considered in the context of the patient’s inherent risk of thromboembolism.
INR, International Normalized Ratio of prothrombin suppression; TTR, percent time in therapeutic range; NSAID, nonsteroidal antiinflammatory drug. Adapted from Pisters R, Lane DA, Nieuwlatt R, et al. 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):1093-1100; Lip GYH, Frison L, Halperin JL, et al. Comparative validation of a novel risk score [HAS-BLED] for predicting bleeding risk in anticoagulated patients with AF. J Am Coll Cardiol 2010;57:173-180.

Efficacy of Aspirin

Evidence that aspirin is effective for prevention of thromboembolism in patients with nonvalvular AF is considerably weaker than that supporting warfarin. Meta-analysis of five controlled studies²³^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴ found a 22% (95% CI 2% to 38%) reduction in stroke rates.²⁷ Four of these were placebo-controlled trials,⁶⁴ with aspirin doses ranging from 50 to 325 mg daily. A patient-level meta-analysis of data from the placebo-controlled AFASAK-1, SPAF-I, and EAFT trials estimated that the RRR was a marginally significant 21% (95% CI 0% to 38%).⁶⁷ The SPAF-I trial, in which the RRR was significant at 42%, had two randomized cohorts, one of patients eligible for randomization to warfarin and the other deemed ineligible on the basis of age, physician judgment, or patient refusal. In warfarin-eligible cases, the RRR afforded by aspirin was striking (94%), whereas that in the ineligible cohort was minimal (8%, not significant [NS]), similar to findings in the AFASAK-1 and EAFT studies. In other studies involving patients with AF, the efficacy of aspirin for prevention of thromboembolism was negligible or inconsistent.⁶¹^,⁶²^,⁶⁴^,⁶⁶ Aspirin may be more efficacious for patients with AF and hypertension and diabetes⁶⁵ and for preventing noncardioembolic rather than cardioembolic ischemic strokes.⁶⁷ Cardioembolic strokes are, on average, more disabling than noncardioembolic strokes,⁶⁸ and aspirin appears to prevent nondisabling more than disabling strokes²⁷; therefore, the greater the risk of disabling cardioembolic stroke in patients with AF, the less protection afforded by aspirin.⁶⁸

In trials that compared the two therapies, oral VKA therapy was considerably more effective than aspirin.²⁰^,²³^,⁴⁹^,⁵³^,⁵⁴^,⁵⁹^,⁶²^,⁶³^,⁶⁸^,⁶⁹ Meta-analysis of six studies found an RRR of 46% (95% CI 27% to 60%) with oral anticoagulation compared with aspirin for ischemic stroke and 36% (95% CI 14% to 52%) for all (ischemic or hemorrhagic) strokes related to AF.²⁷ The hazard ratio (HR) for major bleeding associated with anticoagulation was 1.7 (95% CI 1.2 to 2.4).⁷⁰ Hence, treatment of 1,000 patients with AF with adjusted-dose oral anticoagulation instead of aspirin for 1 year would avoid 23 ischemic strokes but cause nine additional major bleeds.

Other Platelet-Inhibitor Agents and Lower-Intensity Anticoagulation

A randomized trial comparing adjusted-dose warfarin with the platelet inhibitor indobufen found no significant difference in rates of the combined endpoint of stroke, MI, pulmonary embolism, or vascular death (12% with indobufen vs. 10% with warfarin over an average follow-up of 12 months; P = 0.47).⁷¹ None of the patients treated with indobufen developed major bleeding, which occurred in 0.9% of those treated with warfarin. Trials of very low-intensity anticoagulation with or without aspirin have generally not identified a suitable alternative to adjusted-dose warfarin at INR 2.0 to 3.0 for prevention of thromboembolism in patients with AF. Meta-analysis of three studies⁶⁴^,⁶⁹^,⁷² comparing fixed, low-dose warfarin (1.25 mg daily) with adjusted-dose warfarin (INR 2.0 to 3.0) found a mean RRR of 38% (95% CI 20% to 68%) favoring more intensive dosing.²⁷ Aspirin may augment protection against ischemic coronary events but raises the risk of hemorrhage in anticoagulated patients, and the incremental coronary benefit of adding aspirin to oral anticoagulation seems modest.⁷³ The SPAF-III trial compared a combination of warfarin (targeting INR initially to 1.2 to 1.5 with a maximum daily dose of 3 mg) plus aspirin (325 mg daily, enteric coated) with adjusted-dose warfarin (target INR 2.0 to 3.0). The trial was terminated early because of a higher rate of ischemic stroke and systemic embolism in patients taking the combination therapy (7.9% per year) than in those assigned to conventional warfarin (1.9% per year). There was no significant difference in rates of major hemorrhage between the two groups, and no significant advantage in terms of coronary outcomes because of the relatively low frequency of such events.

Two small-scale studies have addressed the use of lowerintensity warfarin. In one, targeting a lower INR value (1.9) was comparable to more conventional warfarin therapy (target INR 2.5) for secondary stroke prevention in patients with nonvalvular AF and was associated with a lower frequency of severe bleeding (P = 0.0103).⁷⁴ Patients in the conventional therapy group who developed bleeding complications were older (mean age 73.7 years), but the results must be interpreted cautiously because the study was terminated prematurely while the sample size was small (n = 115). The other trial compared low-intensity (target INR 1.8) and standard (target INR = 2.5) warfarin therapy for primary stroke prevention in patients over 75 years old.⁷⁵ There was no significant difference in the combined rate of thromboembolism or major bleeding with the two regimens (HR 0.7, 95% CI 0.4 to 1.1, P = 0.1). Despite a combined endpoint constellation, the event rate was lower than expected, and the results raise the possibility that less intensive anticoagulation may be adequate for primary stroke prevention in low-risk patients with AF.

Dual Antiplatelet Therapy

Although monotherapy with aspirin offers marginal benefit for thromboembolism prevention in patients with AF, the combination of aspirin plus clopidogrel, which blocks platelet aggregation through inhibition of adenosine diphosphate-dependent pathways,⁷⁶ reduces the incidence of ischemic events compared to aspirin alone. Early studies of clopidogrel showed a reduction of ischemic events with clopidogrel when added to aspirin therapy⁷⁷ or in place of aspirin⁷⁸ in patients with AF and atherosclerosis. The ACTIVE (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) studies compared dual antiplatelet therapy with aspirin and clopidogrel to adjusted-dose warfarin (ACTIVE-W) and to aspirin alone (ACTIVE-A) in patients with AF and a high risk of stroke (CHADS₂ score > 1).⁷⁹^,⁸⁰ The ACTIVE-W study was terminated early because of the overwhelming superiority of warfarin (RR with aspirin plus clopidogrel = 1.44, 95% CI 1.18 to 1.76, P = 0.0003) without any increase of the risk for major hemorrhage. ACTIVE-A was a randomized, double-blind study of 7,554 patients with AF who were not considered candidates for VKA therapy. Reasons for enrollment in ACTIVE-A included specific risk of bleeding (22.9% of patients), physician’s judgment that the patient was a poor candidate for anticoagulation (49.7%), or the patients’ preferences (26%). The primary endpoint included major vascular events (strokes, noncentral nervous system systemic embolic events, MIs, and deaths from vascular causes). The main secondary outcome was stroke. In ACTIVE-A, the combination of aspirin plus clopidogrel was
superior to aspirin alone for prevention of the primary outcome (RR 0.89, 95% CI 0.81 to 0.98, P = 0.01) and stroke alone (RR 0.72, 95% CI 0.62 to 0.83, P < 0.001). There was, however, a significantly higher risk for major bleeding with dual antiplatelet therapy (RR 1.57, 95% CI 1.29 to 1.92).

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