Lesly A. Pearce

Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis.

Nonvalvular atrial fibrillation is an important independent risk factor for stroke. Since 1989, 16 published clinical trials have conducted 36 separate randomized comparisons of antithrombotic agents in approximately 10 000 participants with atrial fibrillation (1-17). Previously published meta-analyses and pooled analyses of individual patient data (18-20) have considered, in various combinations, the first 6 clinical trials to be published. We present a meta-analysis of all currently available trials to further characterize the comparative efficacy and safety of antithrombotic therapy for the prevention of stroke in patients with atrial fibrillation. Methods Randomized trials testing long-term (>3 months) use of antithrombotic agents in patients with atrial fibrillation were sought by a computerized search of the OVID/MEDLINE databases (from 1966 to 1999, not restricted by language) and by inquiries to the Cochrane Collaboration Stroke Review Group and Antithrombotic Trialists Collaboration. Studies of atrial fibrillation associated with prosthetic cardiac valves or mitral stenosis were not considered; trials reporting results for subgroups of participants with atrial fibrillation among other participants without atrial fibrillation were included (14, 16). Double-blind and nonblinded trials were included, and sensitivity analysis was used to compare pooled results, as appropriate. We excluded one randomized trial in which results for participants with atrial fibrillation (approximately half of all participants) were not reported separately (21). We have anecdotal knowledge of two additional trials that are ongoing or have not been published (Table 1). Table 1. Randomized Clinical Trials for Nonvalvular Atrial Fibrillation Two reviewers independently extracted data from published sources on the number of patients treated, total follow-up exposure, and the occurrence of five outcomes by intention-to-treat analysis: all stroke (hemorrhagic and ischemic), ischemic stroke, intracranial hemorrhage, all-cause mortality, and major extracranial bleeding. The criteria for each of these outcomes were those used in each individual trial; major deviations are noted in footnotes to the tables. Intracranial hemorrhage included spontaneous and traumatic subdural hematomas. Transient ischemic attacks (TIAs) were not considered. The percentage of participants who underwent neuroimaging or autopsy to reliably distinguish between ischemic or hemorrhagic stroke varied, and this percentage was not always reported. Therefore, all stroke (hemorrhagic and ischemic) was chosen as the primary outcome. Effects of antithrombotic therapy on combinations of events (for example, stroke, myocardial infarction, or vascular death) and effects of age and sex were not consistently reported and are not considered here. Intention-to-treat results were used for the main analyses, but only results noted during treatment were available for one small trial that tested antiplatelet agents (14). Primary prevention refers to patients without previous stroke or TIA; secondary prevention refers to patients with previous stroke or TIA. Detailed consideration of the design and execution of individual trials can be found in our systematic reviews prepared for the Cochrane Collaboration Stroke Review Group (16, 22). The authors participated in the Stroke Prevention in Atrial Fibrillation (SPAF) I, II, and III clinical trials (1987 to 1999), which were funded by the National Institute of Neurologic Disorders and Stroke. Meta-analyses of the results of the trials are presented as relative risk reductions and absolute risk reductions for treatment groups compared with control groups. To estimate the relative risk reduction, the combined odds ratio was computed by using the modified Mantel-Haenszel (Peto) method (23), and the estimate was then subtracted from 1. For a study in which no events were observed for a specific outcome and treatment, 0.5 was added to the empty cell. The absolute risk reduction is a weighted estimate of the difference in annualized event rates (24). Before we estimated risk reduction, we tested the assumption of the statistical homogeneity of the treatment effect (across trials and within a specific scenario) by using the QL statistic for the relative odds scale (24) or the QW statistic with unequal weights for the absolute risk scale (24). Lack of homogeneity across trials precluded estimation of the treatment effect, as noted. Homogeneity was assessed for all meta-analyses of relative risk reduction and absolute risk reduction; the exact P value was reported for all main analyses and for analyses in which the P value was less than 0.2. Estimates of relative risk reduction in individual trials were computed by subtracting the estimated odds ratio from 1. We estimated absolute risk reductions in individual trials by calculating the absolute difference in annualized event rates (events per person-years of observation). A P value less than 0.05 was considered statistically significant; all tests and CIs are two-sided. Calculations were done by using SPSS software (SPSS, Inc., Chicago, Illinois) and EGRET software (Cytel Software Corp., Cambridge, Massachusetts). Results Sixteen randomized trials published between 1989 and 1999 included 9874 participants with nonvalvular atrial fibrillation, with 2239 participants assigned to placebo (Table 1) (1-16). Total reported exposure was about 16 400 person-years (mean follow-up, 1.7 years). Fourteen trials included only participants with atrial fibrillation (1-13, 15); 2 trials included participants with atrial fibrillation in larger trials of secondary stroke prevention (14, 16). Warfarin was used exclusively in 10 trials testing oral anticoagulant agents; other derivatives of coumarin were also used in 2 additional trials (9, 15). Adjusted-Dose Warfarin Compared with Placebo In six trials involving 2900 patients with a total of 186 strokes, anticoagulation with oral vitamin K antagonists was compared with placebo (in five trials [1, 3, 7-9]) or control (in one trial [6]) (Table 2). The mean age of participants at study entry was 69 years (approximately 20% of participants were>75 years of age). Twenty-nine percent of participants were women, 45% had hypertension, and 20% had previous stroke or TIA. The target range for the international normalized ratio (INR) varied (Table 2); the mean achieved INR ranged from 2.0 to 2.6 in the five primary prevention trials and was 2.9 in the single secondary prevention trial. Mean duration of follow-up ranged from 1.2 to 2.3 years (overall average, 1.6 years per participant). The rate of stroke among participants who were not assigned to receive anticoagulation averaged 4.6% per year for primary prevention and 12.3% per year for secondary prevention. Four of these six trials were stopped at an interim analysis because of treatment efficacy (1, 3, 6, 8). Table 2. Adjusted-Dose Warfarin Compared with Placebo Meta-analysis showed that therapy with adjusted-dose warfarin reduced the relative risk for stroke by 62% (95% CI, 48% to 72%). This effect was statistically significant in four individual trials (3, 6, 8, 9) (Figure). The pooled result of primary prevention trials (59% reduction) was similar to that from the secondary prevention trial (68% reduction); results from the two double-blind trials (58% reduction) (7, 8) and the four open-label trials (63% reduction) (1, 3, 6, 9) were also similar. Warfarin was associated with similar relative risk reductions in disabling stroke (59%) and nondisabling stroke (61%). The absolute risk reduction for all stroke was 2.7% per year (number needed to treat [NNT] for 1 year to prevent one stroke, 37) for primary prevention and 8.4% per year (NNT, 12) for secondary prevention. Figure. Effects on all stroke (ischemic and hemorrhagic) of therapies for patients with atrial fibrillation. Top. Middle. Bottom. When only ischemic strokes were considered, treatment with adjusted-dose warfarin was associated with a 65% (CI, 52% to 74%) relative risk reduction. Twice as many intracranial hemorrhages were identified in participants who were assigned to receive warfarin (six compared with three), but the difference was not statistically significant. The rate of intracranial hemorrhage averaged 0.3% per year during anticoagulation and was 0.1% per year with placebo. The rate of major extracranial hemorrhage averaged 0.6% per year in patients who received placebo. The relative risk for major extracranial hemorrhage was 2.4 (CI, 1.2 to 4.6; absolute risk increase, 0.3% per year) for participants who received warfarin (excluding one trial in which almost half of the control group took aspirin [6]). All-cause mortality decreased in participants who received warfarin (relative risk reduction, 26% [CI, 4% to 43%]; P>0.2 for homogeneity; absolute risk reduction, 1.6% per year). Antiplatelet Therapy Compared with Placebo Six trials compared antiplatelet therapy with placebo (1, 3, 9, 13, 14, 16). In these trials, 3337 participants experienced a total of 376 strokes while being randomly assigned to receive antiplatelet therapy or placebo (Table 3). In five trials (1, 3, 9, 14, 16), assignment was double-blind. Approximately 90% of total follow-up exposure during antiplatelet therapy was with aspirin alone. Aspirin dosage ranged from 25 mg twice daily to 1300 mg/d. On the basis of available data from the three largest trials (1, 3, 9), the mean age of participants was 70 years (about 33% of participants were>age 75 years). Thirty-eight percent of participants were women, 46% had hypertension, and 40% had previous stroke or TIA. Mean duration of follow-up in these trials ranged from 1.2 to 4 years (overall average, 1.5 years per participant). The average rate of stroke among participants assigned to placebo was 5.2% per year for primary prevention and 12.9% per year for secondary prevention. Table 3. Antiplatelet Agents Compared with Placebo Meta-

Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin

Background—The rate of stroke in atrial fibrillation (AF) depends on the presence of comorbid conditions and the use of antithrombotic therapy. Although adjusted-dose warfarin is superior to aspirin for reducing stroke in AF, the absolute risk reduction of warfarin depends on the stroke rate with aspirin. This prospective cohort study tested the predictive accuracy of 5 stroke risk stratification schemes. Methods and Results—The study pooled individual data from 2580 participants with nonvalvular AF who were prescribed aspirin in a multicenter trial (Atrial Fibrillation, Aspirin, Anticoagulation I study [AFASAK-1], AFASAK-2, European Atrial Fibrillation Trial, Primary Prevention of Arterial Thromboembolism in patients with nonrheumatic Atrial Fibrillation in primary care study, and Stroke Prevention and Atrial Fibrillation [SPAF]-III high risk or SPAF-III low risk). There were 207 ischemic strokes during 4887 patient-years of aspirin therapy. All schemes predicted stroke better than chance, but the number of patients categorized as low and high risk varied substantially. AF patients with prior cerebral ischemia were classified as high risk by all 5 schemes and had 10.8 strokes per 100 patient-years. The CHADS2 scheme (an acronym for Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack) successfully identified primary prevention patients who were at high risk of stroke (5.3 strokes per 100 patient-years). In contrast, patients identified as high risk by other schemes had 3.0 to 4.2 strokes per 100 patient-years. Low-risk patients identified by all schemes had 0.5 to 1.4 strokes per 100 patient-years of therapy. Conclusions—Patients with AF who have high and low rates of stroke when given aspirin can be reliably identified, allowing selection of antithrombotic prophylaxis to be individualized.

Stroke with intermittent atrial fibrillation: incidence and predictors during aspirin therapy

OBJECTIVE This study was performed to characterize the risk of stroke in elderly patients with recurrent intermittent atrial fibrillation (AF). BACKGROUND Although intermittent AF is common, relatively little is known about the attendant risk of stroke. METHODS A longitudinal cohort study was performed comparing 460 participants with intermittent AF with 1,552 with sustained AF treated with aspirin in the Stroke Prevention in Atrial Fibrillation studies and followed for a mean of two years. Independent risk factors for ischemic stroke were identified by multivariate analysis. RESULTS Patients with intermittent AF were, on average, younger (66 vs. 70 years, p < 0.001), were more often women (37% vs. 26% p < 0.001) and less often had heart failure (11% vs. 21%, p < 0.001) than those with sustained AF. The annualized rate of ischemic stroke was similar for those with intermittent (3.2%) and sustained AF (3.3%). In patients with intermittent AF, independent predictors of ischemic stroke were advancing age (relative risk [RR] = 2.1 per decade, p < 0.001), hypertension (RR = 3.4, p = 0.003) and prior stroke (RR = 4.1, p = 0.01). Of those with intermittent AF predicted to be high risk (24%), the observed stroke rate was 7.8% per year (95% confidence interval 4.5 to 14). CONCLUSIONS In this large cohort of AF patients given aspirin, those with intermittent AF had stroke rates similar to patients with sustained AF and similar stroke risk factors. Many elderly patients with recurrent intermittent AF have substantial rates of stroke and likely benefit from anticoagulation. High-risk patients with intermittent AF can be identified using the same clinical criteria that apply to patients with sustained AF.

Transesophageal Echocardiographic Correlates of Clinical Risk of Thromboembolism in Nonvalvular Atrial Fibrillation

OBJECTIVES This study explored the mechanisms linking clinical and precordial echocardiographic predictors to thromboembolism in atrial fibrillation (AF) by assessing transesophageal echocardiographic (TEE) correlations. BACKGROUND Clinical predictors of thromboembolism in patients with nonvalvular AF have been identified, but their mechanistic links remain unclear. TEE provides imaging of the left atrium, its appendage and the proximal thoracic aorta, potentially clarifying stroke mechanisms in patients with AF. METHODS Cross-sectional analysis of TEE features correlated with low, moderate and high thromboembolic risk during aspirin therapy among 786 participants undergoing TEE on entry into the Stroke Prevention in Atrial Fibrillation III trial. RESULTS TEE features independently associated with increased thromboembolic risk were appendage thrombi (relative risk [RR] 2.5, p = 0.04), dense spontaneous echo contrast (RR 3.7, p < 0.001), left atrial appendage peak flow velocities < or = 20 cm/s (RR 1.7, p = 0.008) and complex aortic plaque (RR 2.1, p < 0.001). Patients with AF with a history of hypertension (conferring moderate risk) more frequently had atrial appendage thrombi (RR 2.6, p < 0.001) and reduced flow velocity (RR 1.8, p = 0.003) than low risk patients. Among low risk patients, those with intermittent AF had similar TEE features to those with constant AF. CONCLUSIONS TEE findings indicative of atrial stasis or thrombosis and of aortic atheroma were independently associated with high thromboembolic risk in patients with AF. The increased stroke risk associated with a history of hypertension in AF appears to be mediated primarily through left atrial stasis and thrombi. The presence of complex aortic plaque distinguished patients with AF at high risk from those at moderate risk of thromboembolism.

Factors Associated With Ischemic Stroke During Aspirin Therapy in Atrial Fibrillation Analysis of 2012 Participants in the SPAF I–III Clinical Trials

BACKGROUND AND PURPOSE Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, but the absolute rate of stroke varies widely among AF patients, importantly influencing the potential benefit of antithrombotic prophylaxis. We explore factors associated with ischemic stroke in AF patients taking aspirin. METHODS We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I-III trials followed for a mean of 2.0 years, during which 130 ischemic strokes were observed. RESULTS Age (relative risk [RR]=1.8 per decade, P<0.001), female sex (RR=1.6, P=0.01), history of hypertension (RR=2.0, P<0.001), systolic blood pressure >160 mm Hg (RR=2.3, P<0.001), and prior stroke or transient ischemic attack (RR=2.9, P<0.001) were independently associated with increased stroke risk. Regular consumption of >/=14 alcohol-containing drinks per week was associated with reduced stroke risk (adjusted RR=0.4, P=0.04). Among SPAF III participants, estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke (adjusted RR=3.2, P=0.007). With the use of these variables, a risk stratification scheme for primary prevention separated participants into those with high (7.1%/y, 22% of the cohort), moderate (2.6%/y, 37% of the cohort), and low (0.9%/y, 41% of the cohort) rates of stroke. Ischemic strokes in low-risk participants were less often disabling (P<0.001). CONCLUSIONS Patients with AF who have high and low rates of stroke during treatment with aspirin can be identified. However, validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management. Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF, but these findings require confirmation.

Effects of clopidogrel added to aspirin in patients with recent lacunar stroke.

BACKGROUND Lacunar infarcts are a frequent type of stroke caused mainly by cerebral small-vessel disease. The effectiveness of antiplatelet therapy for secondary prevention has not been defined. METHODS We conducted a double-blind, multicenter trial involving 3020 patients with recent symptomatic lacunar infarcts identified by magnetic resonance imaging. Patients were randomly assigned to receive 75 mg of clopidogrel or placebo daily; patients in both groups received 325 mg of aspirin daily. The primary outcome was any recurrent stroke, including ischemic stroke and intracranial hemorrhage. RESULTS The participants had a mean age of 63 years, and 63% were men. After a mean follow-up of 3.4 years, the risk of recurrent stroke was not significantly reduced with aspirin and clopidogrel (dual antiplatelet therapy) (125 strokes; rate, 2.5% per year) as compared with aspirin alone (138 strokes, 2.7% per year) (hazard ratio, 0.92; 95% confidence interval [CI], 0.72 to 1.16), nor was the risk of recurrent ischemic stroke (hazard ratio, 0.82; 95% CI, 0.63 to 1.09) or disabling or fatal stroke (hazard ratio, 1.06; 95% CI, 0.69 to 1.64). The risk of major hemorrhage was almost doubled with dual antiplatelet therapy (105 hemorrhages, 2.1% per year) as compared with aspirin alone (56, 1.1% per year) (hazard ratio, 1.97; 95% CI, 1.41 to 2.71; P<0.001). Among classifiable recurrent ischemic strokes, 71% (133 of 187) were lacunar strokes. All-cause mortality was increased among patients assigned to receive dual antiplatelet therapy (77 deaths in the group receiving aspirin alone vs. 113 in the group receiving dual antiplatelet therapy) (hazard ratio, 1.52; 95% CI, 1.14 to 2.04; P=0.004); this difference was not accounted for by fatal hemorrhages (9 in the group receiving dual antiplatelet therapy vs. 4 in the group receiving aspirin alone). CONCLUSIONS Among patients with recent lacunar strokes, the addition of clopidogrel to aspirin did not significantly reduce the risk of recurrent stroke and did significantly increase the risk of bleeding and death. (Funded by the National Institute of Neurological Disorders and Stroke and others; SPS3 ClinicalTrials.gov number, NCT00059306.).

Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial

BACKGROUND Lowering of blood pressure prevents stroke but optimum target levels to prevent recurrent stroke are unknown. We investigated the effects of different blood-pressure targets on the rate of recurrent stroke in patients with recent lacunar stroke. METHODS In this randomised open-label trial, eligible patients lived in North America, Latin America, and Spain and had recent, MRI-defined symptomatic lacunar infarctions. Patients were recruited between March, 2003, and April, 2011, and randomly assigned, according to a two-by-two multifactorial design, to a systolic-blood-pressure target of 130-149 mm Hg or less than 130 mm Hg. The primary endpoint was reduction in all stroke (including ischaemic strokes and intracranial haemorrhages). Analysis was done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT 00059306. FINDINGS 3020 enrolled patients, 1519 in the higher-target group and 1501 in the lower-target group, were followed up for a mean of 3·7 (SD 2·0) years. Mean age was 63 (SD 11) years. After 1 year, mean systolic blood pressure was 138 mm Hg (95% CI 137-139) in the higher-target group and 127 mm Hg (95% CI 126-128) in the lower-target group. Non-significant rate reductions were seen for all stroke (hazard ratio 0·81, 95% CI 0·64-1·03, p=0·08), disabling or fatal stroke (0·81, 0·53-1·23, p=0·32), and the composite outcome of myocardial infarction or vascular death (0·84, 0·68-1·04, p=0·32) with the lower target. The rate of intracerebral haemorrhage was reduced significantly (0·37, 0·15-0·95, p=0·03). Treatment-related serious adverse events were infrequent. INTERPRETATION Although the reduction in stroke was not significant, our results support that in patients with recent lacunar stroke, the use of a systolic-blood-pressure target of less than 130 mm Hg is likely to be beneficial. FUNDING National Institutes of Health-National Institute of Neurological Disorders and Stroke (NIH-NINDS).

Avoiding Central Nervous System Bleeding During Antithrombotic Therapy Recent Data and Ideas

Background— Approximately 7000 intracerebral hemorrhages (ICHs) annually in the US are caused by use of antithrombotic therapies. We review the incidence, risk factors, and predictors of ICH in patients receiving long-term anticoagulation or antiplatelet therapy. Summary of Review— ICH rates range from 0.3% to 0.6% per year during oral anticoagulation in recent reports. Major risk factors are advanced patient age, elevated blood pressure, intensity of anticoagulation, and previous cerebral ischemia. Combining antiplatelet agents with anticoagulation and the combined use of aspirin plus clopidogrel appear to increase ICH risk. Modest blood pressure-lowering halves the frequency of ICH during antiplatelet therapy. Conclusion— ICH is an uncommon, but often fatal, complication of antithrombotic therapy that particularly afflicts patients with previous stroke. Recent data support that keeping international normalized ratio ≤3.0, control of hypertension, and avoiding the combination of aspirin with warfarin reduce its frequency.

Factors associated with ischemic stroke during aspirin therapy in atrial fibrillation: analysis of 2012 participants in the SPAF I-III clinical trials. The Stroke Prevention in Atrial Fibrillation (SPAF) Investigators.

BACKGROUND AND PURPOSE Nonvalvular atrial fibrillation (AF) is a strong, independent risk factor for stroke, but the absolute rate of stroke varies widely among AF patients, importantly influencing the potential benefit of antithrombotic prophylaxis. We explore factors associated with ischemic stroke in AF patients taking aspirin. METHODS We performed multivariate logistic regression analysis of 2012 participants given aspirin alone or in combination with low, inefficacious doses of warfarin in the Stroke Prevention in Atrial Fibrillation I-III trials followed for a mean of 2.0 years, during which 130 ischemic strokes were observed. RESULTS Age (relative risk [RR]=1.8 per decade, P<0.001), female sex (RR=1.6, P=0.01), history of hypertension (RR=2.0, P<0.001), systolic blood pressure >160 mm Hg (RR=2.3, P<0.001), and prior stroke or transient ischemic attack (RR=2.9, P<0.001) were independently associated with increased stroke risk. Regular consumption of >/=14 alcohol-containing drinks per week was associated with reduced stroke risk (adjusted RR=0.4, P=0.04). Among SPAF III participants, estrogen hormone replacement therapy was associated with a higher risk of ischemic stroke (adjusted RR=3.2, P=0.007). With the use of these variables, a risk stratification scheme for primary prevention separated participants into those with high (7.1%/y, 22% of the cohort), moderate (2.6%/y, 37% of the cohort), and low (0.9%/y, 41% of the cohort) rates of stroke. Ischemic strokes in low-risk participants were less often disabling (P<0.001). CONCLUSIONS Patients with AF who have high and low rates of stroke during treatment with aspirin can be identified. However, validation of our risk stratification scheme is necessary before it can be applied with confidence to clinical management. Postmenopausal estrogen replacement therapy and moderate alcohol consumption may additionally modify the risk of stroke in AF, but these findings require confirmation.

Prognostic Value of Plasma von Willebrand Factor and Soluble P-Selectin as Indices of Endothelial Damage and Platelet Activation in 994 Patients With Nonvalvular Atrial Fibrillation

Background—Abnormal plasma markers of a prothrombotic state have been described in atrial fibrillation (AF), but no such marker has yet been shown to reliably predict future stroke or cardiovascular outcome in AF. We hypothesized that raised plasma levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) and/or soluble P-selectin (sP-sel, an index of platelet activation) might predict vascular events in AF. Methods and Results—We measured vWf and sP-sel levels by ELISA in 994 participants receiving aspirin in the Stroke Prevention in Atrial Fibrillation III trial, at study entry or after 3 months, and related these indices to the subsequent incidence of stroke and vascular events. Plasma vWf levels were a significant predictor of both stroke (P =0.03) and vascular events (P <0.001), with the greatest risk for those with the highest levels of vWf. After adjustment for other clinical predictors, the relationship between vWf and stroke became nonsignificant, but vWf remained an independent predictor of vascular events (relative risk, 1.2 [95% CI, 1.0–1.4] per 20 IU/dL increase in vWf; P =0.02). No significant relationships were found between sP-sel levels and outcome. Conclusion—Among patients with AF who received aspirin, raised levels of vWf (endothelial damage/dysfunction) were predictive of stroke and vascular events, but raised sP-sel levels (platelet activation) were not associated with increased cardiovascular risk. Endothelial damage/dysfunction (or vWf itself) may play an important role in the mechanisms behind stroke and cardiovascular outcome among aspirin-treated AF patients and might represent a target for novel therapies or an adjunctive aid to risk stratification in AF.