Warfarin-Aspirin Recurrent Stroke Study Research Articles

Amino Terminal Pro–B-Type Natriuretic Peptide, Secondary Stroke Prevention, and Choice of Antithrombotic Therapy

Because of its association with atrial fibrillation and heart failure, we hypothesized that amino terminal pro-B-type natriuretic peptide (NT-proBNP) would identify a subgroup of patients from the Warfarin-Aspirin Recurrent Stroke Study, diagnosed with inferred noncardioembolic ischemic strokes, where anticoagulation would be more effective than antiplatelet agents in reducing risk of subsequent events. NT-proBNP was measured in stored serum collected at baseline from participants enrolled in Warfarin-Aspirin Recurrent Stroke Study, a previously reported randomized trial. Relative effectiveness of warfarin and aspirin in preventing recurrent ischemic stroke or death over 2 years was compared based on NT-proBNP concentrations. About 95% of 1028 patients with assays had NT-proBNP below 750 pg/mL, and among them, no evidence for treatment effect modification was evident. For 49 patients with NT-proBNP >750 pg/mL, the 2-year rate of events per 100 person-years was 45.9 for the aspirin group and 16.6 for the warfarin group, whereas for 979 patients with NT-proBNP ≤750 pg/mL, rates were similar for both treatments. For those with NT-proBNP >750 pg/mL, the hazard ratio was 0.30 (95% confidence interval: 0.12-0.84; P=0.021) significantly favoring warfarin over aspirin. A formal test for interaction of NT-proBNP with treatment was significant (P=0.01). For secondary stroke prevention, elevated NT-proBNP concentrations may identify a subgroup of ischemic stroke patients without known atrial fibrillation, about 5% based on the current study, who may benefit more from anticoagulants than antiplatelet agents. Clinical Trial Registration- This trial was not registered because enrollment began before 2005.

Ralph Sacco: putting the heart into neurology

Ralph Sacco: putting the heart into neurology

Aortic Arch Plaques and Risk of Recurrent Stroke and Death

Aortic arch plaques are a risk factor for ischemic stroke. Although the stroke mechanism is conceivably thromboembolic, no randomized studies have evaluated the efficacy of antithrombotic therapies in preventing recurrent events. The relationship between arch plaques and recurrent events was studied in 516 patients with ischemic stroke who were double-blindly randomized to treatment with warfarin or aspirin as part of the Patent Foramen Ovale in Cryptogenic Stroke Study (PICSS), based on the Warfarin-Aspirin Recurrent Stroke Study (WARSS). Plaque thickness and morphology were evaluated by transesophageal echocardiography. End points were recurrent ischemic stroke or death over a 2-year follow-up. Large plaques (> or =4 mm) were present in 19.6% of patients; large complex plaques (those with ulcerations or mobile components) were seen in 8.5%. During follow-up, large plaques were associated with a significantly increased risk of events (adjusted hazard ratio [HR], 2.12; 95% confidence interval [CI], 1.04 to 4.32), especially those with complex morphology (HR, 2.55; 95 CI, 1.10 to 5.89). The risk was highest among cryptogenic stroke patients, both for large plaques (HR, 6.42; 95% CI, 1.62 to 25.46) and large complex plaques (HR, 9.50; 95% CI, 1.92 to 47.10). Event rates were similar in the warfarin and aspirin groups in the overall study population (16.4% versus 15.8%; P=0.43). In patients with stroke, especially cryptogenic stroke, large aortic plaques remain associated with an increased risk of recurrent stroke and death at 2 years despite treatment with warfarin or aspirin. Complex plaque morphology confers a slight additional increase in risk.

Decoding cryptogenic cardioembolism

Decoding cryptogenic cardioembolism

Caring for the Adult with Congenital Heart Disease: Management of Common Defects

Caring for the Adult with Congenital Heart Disease: Management of Common Defects

Comparison of Warfarin versus Aspirin for the Prevention of Recurrent Stroke or Death: Subgroup Analyses from the Warfarin-Aspirin Recurrent Stroke Study

Background and Purpose: We performed a combination of prespecified and exploratory subgroup analyses to detect any treatment differences among various baseline subgroups in the Warfarin-Aspirin Recurrent Stroke Study (WARSS) cohort. Methods: The WARSS compared the efficacy of adjusted-dose warfarin (INR 1.4–2.8) to aspirin (325 mg/day) for recurrent ischemic stroke or death within 2 years. The effect of warfarin and aspirin was compared among prespecified and exploratory subgroups with respect to sociodemographic and vascular risk factors, stroke subtype, arterial territory, and infarct topography. Hazard ratios and 95% confidence intervals comparing warfarin to aspirin were calculated using Cox proportional hazards models. Differences in hazard ratios were tested using interaction terms. Results: No treatment differences between warfarin and aspirin were found across multiple prespecified subgroups. In a multivariate model, warfarin was associated with greater hazard among patients with moderate stroke severity (HR 1.63, 95% CI 1.005–2.64, p = 0.047) and a greater benefit among those with posterior circulation location without brainstem infarction (HR 0.54, 95% CI 0.33–0.88, p = 0.013). In post-hoc analyses of the cryptogenic subgroup, warfarin was associated with worse outcomes among patients with moderate stroke severity and better outcomes among those without baseline hypertension or with posterior circulation infarcts sparing the brainstem. Conclusions: In the WARSS, the majority of subgroup analyses showed no benefit of warfarin over aspirin. Warfarin benefit was limited to brainstem-sparing posterior circulation infarcts and select cryptogenic stroke subgroups. Pending future clinical trial evidence to the contrary, antiplatelets are recommended for survivors of noncardioembolic stroke.

Management of Patients with Symptomatic Intracranial Atherosclerosis

Intracranial atherosclerosis is a common cause of stroke, accounting for about 50% of ischaemic stroke in Asia and 8% in North America. Many prospective studies have confirmed that intracranial stenosis is an independent predictor for poor outcomes such as recurrent vascular event and death, despite the use of antiplatelet agents. The annual event rate is about 15% per year. The dismal outcome prompts the study of more aggressive treatment strategies, including warfarin and endovascular intervention. We have reviewed the published literature for the treatment of symptomatic intracranial stenosis. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial and Warfarin-Aspirin Recurrent Stroke Study (WARSS) studies failed to show that oral anticoagulation was better than aspirin in IAS. Initial encouraging results were found in the use of dual antiplatelet therapy in arresting the progression of stenosis. The results of the endovascular studies are mixed: there are more encouraging results with recent advances of technology in stent design, but a randomized controlled study is still lacking. Although there is still no established therapy for IAS, the results of ongoing randomized clinical trials to study dual antiplatelet agents and the use of endovascular intervention may soon provide clinicians with more evidence to better manage patients with this condition.

Thoughts evoked by MATCH and other trials.

Many different processes are involved in platelet activation. Most drugs affect one of these chemical reactions. Theoretically, platelet functions (secretion, aggregation, and adhesion) can be reduced most effectively by using >1 agent or by inhibiting the final step in the attachment of the platelet to fibrin at the level of the glycoprotein IIb/IIIa (GpIIb/IIIa) receptor. Preliminary experience with oral and intravenous GpIIb/IIIa inhibitors has shown that bleeding is an important problem. In MATCH, 2 platelet function inhibitors, clopidogrel and aspirin, did prevent slightly more strokes (but not with statistical significance) but at the price of significantly more excess bleeding. Killing platelets causes bleeding. Platelets seem to swim happily in the blood until they reach an area of irregular or damaged endothelium, for example, on the surface of an ulcerated atherosclerotic plaque in a large artery. They then stick to that irregular surface and to each other in an attempt to heal the vascular irregularity. The white platelet–fibrin thrombus can break loose and embolize. The platelet plug also activates the coagulation cascade, promoting the formation of a red erythrocyte–fibrin-rich clot. Perhaps rather than killing the platelet, it might be better to inhibit platelet attachment to the endothelium. Antiplatelet drugs might do this but have not been tested thoroughly for their effect on endothelial–platelet interaction. Theoretically, antiplatelet agents should work by inhibiting formation of white clots. These tend to form on irregular …

September 14 Highlights

Furie et al. measured serial levels of prothrombin fragment F1.2, a marker of thrombin generation, in 320 patients enrolled in the Warfarin Aspirin Recurrent Stroke Study (WARSS). Mean F1.2 levels did not differ by stroke subtype at baseline, but changes in F1.2 over time did vary by stroke mechanism. F1.2 levels were associated with vascular risk factors and were suppressed by warfarin in a dose-dependent fashion. There was a trend toward a higher risk of recurrent stroke or death as F1.2 levels increased. see page 777 The accompanying editorial by Gregory del Zoppo reviews the activation of the coagulation cascade to ask, “Can a marker of thrombin generation be used as an indicator of stroke etiology?”—and can strokes with unassigned etiology be identified by evidence of thrombosis? He further notes that while a causal relationship between cryptogenic stroke and increased PF1.2 levels was not revealed by this study, thrombin may still be important. see page 768 Ohtake et al. screened sporadic and familial …

“Lacunarization” of Stroke Prevention Studies

HomeStrokeVol. 35, No. 10“Lacunarization” of Stroke Prevention Studies Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUB“Lacunarization” of Stroke Prevention Studies Seemant Chaturvedi Seemant ChaturvediSeemant Chaturvedi Department of Neurology and Stroke Program, Wayne State University, Detroit, Mich Search for more papers by this author Originally published12 Aug 2004https://doi.org/10.1161/01.STR.0000140889.23517.d8Stroke. 2004;35:2238–2239Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: August 12, 2004: Previous Version 1 To the Editor:Recent stroke prevention studies that have compared differing antithrombotic regimens have been somewhat disappointing in that the more intense antithrombotic regimen has failed to demonstrate superiority over the more conservative regimen. Although this may reflect the fact that established therapy is difficult to improve on,1 I am concerned that the stroke subtype composition in these trials may be distorting the outcome and that they are not reflective of the larger community of patients with ischemic stroke.As examples, in the Warfarin Aspirin Recurrent Stroke Study, the lacunar infarct patients represented 56.1% of the study cohort.2 In the African-American Antiplatelet Stroke Prevention Study, the small vessel infarct subtype accounted for 67.5% of patients.3 Finally, in the recently reported Management of Atherothrombosis With Clopidogrel in High-Risk Patients Study, 52.5% of patients had lacunar infarcts as the qualifying subtype.4Thus, to some extent, each of these studies could be viewed as a referendum on lacunar infarction treatment. In a study that excluded cardioembolic strokes, one would expect that ≈40% of patients would have cryptogenic infarcts, and ≈30% should have large vessel atherosclerotic and lacunar infarcts. The fact that recent studies are enrolling >50% of the study population as lacunar infarction patients does not seem representative of the larger spectrum of ischemic stroke patients. It also impairssubgroup comparison and hypothesis generation for future studies of large vessel atherosclerotic and cryptogenic infarction.Clinical trialists who design future studies of “noncardioembolic stroke” should consider limiting lacunar infarct enrollment to ≤30% of the study cohort and should try to avoid making the entry criteria overly restrictive so that only patients with minimal disability (who tend to be those with lacunar stroke) are allowed in the trial.1 Anderson DC, Goldstein LB. Aspirin: it’s hard to beat. Neurology. 2004; 62: 1036–1037.CrossrefMedlineGoogle Scholar2 Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HP Jr, Jackson CM, Pullicino P; Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001; 345: 1444–1451.CrossrefMedlineGoogle Scholar3 Gorelick PB, Richardson D, Kelly M, Ruland S, Hung E, Harris Y, Kittner S, Leurgans S; African-American Antiplatelet Stroke Prevention Study Investigators. Aspirin and ticlopidine for prevention of recurrent stroke in black patients: a randomized trial. J Am Med Assoc. 2003; 289: 2947–2957.CrossrefMedlineGoogle Scholar4 Brass, LM. Management of ATherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke. Paper presented at: the European Stroke Conference; May 12–15, 2004; Mannheim-Heidelberg, Germany.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ioli P (2010) Estudios de no-inferioridad en Neurología: tratamientos nuevos, ¿eficacia demostrada?, Neurología Argentina, 10.1016/S0325-0938(10)70008-8, 2:1, (42-49), Online publication date: 1-Jan-2010. Estol C (2016) About PRoFESS, International Journal of Stroke, 10.1111/j.1747-4949.2005.00010.x, 1:1, (49-50), Online publication date: 1-Feb-2006. October 2004Vol 35, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/01.STR.0000140889.23517.d8PMID: 15308786 Originally publishedAugust 12, 2004 Keywordsanticoagulantsplatelet aggregationPDF download Advertisement

The role of warfarin and aspirin in secondary prevention of stroke.

Antithrombotic therapy plays a central role in secondary prevention after ischemic stroke and transient ischemic attack. The choice among warfarin, aspirin, and other antiplatelet agents, however, depends on the cause of stroke and other individual patient characteristics. The use of warfarin anticoagulation in patients with atrial fibrillation and ischemic stroke has demonstrated robust reductions in risk of recurrent events, comparable with those achieved in primary prevention. Warfarin may also be recommended for patients with other high-risk cardioembolic sources of stroke. The role of warfarin in noncardioembolic ischemic stroke is more controversial. The Warfarin Aspirin Recurrent Stroke Study found no evidence of superiority of warfarin over aspirin in stroke patients overall, nor in any major stroke subtype, including those patients with patent foramen ovale. In post-hoc analyses, there was some evidence of benefit with warfarin in patients with cryptogenic stroke without hypertension. Risks of major bleeding did not differ significantly between warfarin and aspirin groups. For most patients with noncardioembolic strokes, therefore, antiplatelet therapy is the preferred option, although clinician experience still dictates practice in individual situations. Newer antiplatelet agents, and the combination of novel agents with aspirin, are also finding a role in stroke prevention as clinical trial data become available.

Atrial anatomy in non-cardioembolic stroke patients: Effect of medical therapy

ObjectivesThe purpose of the study was to assess the mechanism responsible for increased stroke risk in patients with atrial septal aneurysm (SA) and patent foramen ovale (PFO), and to determine the efficacy of medical therapy for preventing stroke recurrence or death. BackgroundAtrial septal aneurysm and PFO are associated with stroke. However, the mechanism for this association is undefined, and the efficacy of medical therapy has not been investigated in a randomized fashion. MethodsThe Patent foramen ovale In Cryptogenic Stroke Study (PICSS) evaluated transesophageal echocardiography findings in patients enrolled in the Warfarin-Aspirin Recurrent Stroke Study, a randomized double-blind trial to evaluate the efficacy of warfarin compared with aspirin. ResultsLarge PFO and prominent eustachian valve (EV) or right atrial (RA) filamentous strands were found more frequently in patients with SA compared with those without SA (37.7% vs. 10.9%, p < 0.001 and 59.4% vs. 43.1%, p = 0.02). Patients with SA and PFO had no significant difference in time to recurrent stroke or death compared with those having neither (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.49 to 2.38, p = 0.84; two-year event rates 15.9% vs. 14.5%). Patients with SA, PFO, and RA anatomy predisposing to paradoxical embolization also had no difference compared with those without these findings (HR 1.22, 95% CI 0.43 to 3.47, p = 0.71; two-year event rates 18.2% vs. 14.2%). There was no significant difference in time to recurrent stroke or death between the patients treated with warfarin or aspirin (HR 1.00, 95% CI 0.22 to 4.47, p = 1.0; two-year event rates 16.0% vs. 15.8%). ConclusionsAtrial septal aneurysm is associated with the presence of large PFO and prominent EV or RA filamentous strands. On medical therapy, patients with SA and PFO did not experience increased risk of adverse events, and there was no difference between treatment results for warfarin and for aspirin.

Editorial Comment: Low-Dose or Moderate-Dose Anticoagulation: Dream or Hope for Stroke Prevention?

The preliminary contribution by the European/Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) Study Group1 supports the idea that ESPRIT might settle the issue after Stroke Prevention in Reversible Ischemia Trial (SPIRIT)2 and Warfarin Aspirin Recurrent Stroke Study (WARSS)3 as to whether or not patients with noncardioembolic ischemic stroke benefit from oral anticoagulation versus platelet inhibition in secondary prevention of stroke. Ale Algra, on behalf of the ESPRIT Study Group, argues in favor of this hypothesis and claims that their study continues after WARSS …

Warfarin versus aspirin in the secondary prevention of stroke: the WARSS study.

The role of anticoagulation in the secondary prevention of noncardioembolic stroke has long been an area of debate. Previous evidence has shown that anticoagulation is unsafe at an International Normalized Ratio between 3.0 and 4.5. Results of the recently published Warfarin-Aspirin Recurrent Stroke Study (WARSS) suggest that there is no difference between warfarin and aspirin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Differences in the therapeutic interventions used may have had an effect on the differences in endpoints achieved as compared with previous studies. Results of ongoing trials are anticipated to further clarify the role of anticoagulation in the secondary prevention of stroke.

Patent Foramen Ovale and Recurrent Stroke

Clinical management of patients with acute stroke and the approach used for secondary prevention depends upon clarification of pathogenesis. Although most strokes are a consequence of cerebrovascular disease, ≈15% to 20% of ischemic (nonhemorrhagic) strokes have been attributed to cardiogenic embolism.1 In practice, determination of the stroke mechanism is fraught with uncertainty, particularly when the possibility of thromboembolism emanating from atherosclerotic lesions in the aorta or cervical arteries is considered. When cardiogenic embolism is suspected, cardiac ultrasound is the principal method used to identify the potential source. The finding of left atrial enlargement has been shown to bear a significant relationship to the risk of stroke in a multivariate analysis of population-based data from the Framingham Heart Study2. The most frequent confounding variable is atrial fibrillation, occurring in >2 million patients in North America and in over half of all patients with cardiogenic embolism. Criteria for selection of patients with acute ischemic stroke for transesophageal echocardiography (TEE) to search for a potential cardiac source of embolism are controversial, particularly because cardiogenic embolism is often an uncertain diagnosis that is inferred merely on the basis of the finding of potential cardiac source. Even after extensive investigation, ≈40% of ischemic stroke patients have no clearly identifiable pathogenesis (cryptogenic stroke).3 In one study, 62% of patients younger than 60 years of age without an obvious source of cerebral infarction and 23% of those with arterial lesions had potential sources of cardiogenic embolism identified by TEE ( P =0.0007 for the difference).4 See p 2625 Among the cardiac anomalies detected by TEE that have been implicated as risk factors for stroke are patent foramen ovale (PFO) and atrial septal aneurysm (ASA).5,6⇓ The foramen ovale, a remnant of the fetal circulation, remains patent through adulthood in ≈1 in 4 …

The 27th International Stroke Conference San Antonio, Texas, February 7-9, 2002.

The 27th International Stroke Conference San Antonio, Texas, February 7-9, 2002.

The Warfarin-Aspirin Recurrent Stroke Study (WARSS): Initial Results

72 The Warfarin-Aspirin Recurrent Stroke Study (WARSS) enrolled 2206 patients from 47 US centers with acute ischemic stroke within 30 days of onset and randomized them to a double-blinded two-year treatment program of aspirin 325 mg per day or warfarin doses of 2 mg tablets sufficient to maintain a target INR of 1.4–2.8 determined monthly or more often. The INR studies were performed in one central laboratory. The Columbia University Data Management Center blinded the INR values to ensure patients and local invesigators could not determine which of the two active treatments was applicable to any patient. Endpoints of death recurrent stroke, together with complications, were adjudicated by committees whose members were also blinded as to therapy. The trial ended 31-Jul-2000 with final data planned for analysis beginning 30-Oct-2000. Initial results are expected to be completed for presentation at the 26th Conference. Data may also be available for outcomes from four parallel studies of the same patient cohort concerning antiphospholipid status (APASS), patent cardiac foramen ovale (PICSS), hemostatic coagulation factors (HAS), and genetics (GENESIS).

The Feasibility of a Collaborative Double-Blind Study Using an Anticoagulant

We present the methodology and data indicating the feasibility of a five-study collaborative stroke trial. The core study, the Warfarin-Aspirin Recurrent Stroke Study (WARSS), is a prospective, random