Letter Regarding Article by Connolly et al, “Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation”

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HomeCirculationVol. 117, No. 5Letter Regarding Article by Connolly et al, “Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter Regarding Article by Connolly et al, “Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation” Michael D. Ezekowitz and Rangadham Nagarakanti Michael D. EzekowitzMichael D. Ezekowitz Lankenau Institute for Medical Research, Main Line Health Heart Center, Wynnewood, Pa Search for more papers by this author and Rangadham NagarakantiRangadham Nagarakanti Lankenau Institute for Medical Research, Main Line Health Heart Center, Wynnewood, Pa Search for more papers by this author Originally published5 Feb 2008https://doi.org/10.1161/CIRCULATIONAHA.107.736082Circulation. 2008;117:e149To the Editor:Dr Connolly and colleagues in the July 24, 2007, issue of Circulation1 have clearly defined the important challenges we face in evaluating antithrombotic drugs for stroke prevention in atrial fibrillation (AF). We are in general agreement with the authors. However, we differ on the advisability of conducting a superiority trial of a new, presumably effective antithrombotic agent against aspirin in patients at high risk for stroke.The only evidence supporting the benefit of aspirin against the placebo for stroke prevention in AF is from the Stroke Prevention in Atrial Fibrillation (SPAF) I trial.2 The relative risk reduction of stroke and systemic embolism was 42%. The confidence interval was wide (95% confidence interval, 9% to 63%). Other trials, such as the Copenhagen AF, Aspirin, and Anticoagulation Study (AFASAK) and European AF Trial (EAFT), showed a nonsignificant risk reduction of 17% and 11%, respectively. The EAFT included high-risk patients and had an annual stroke rate of 12%, 10%, and 4% in patients assigned to placebo, aspirin, and anticoagulation, respectively.3The SPAF III trial reported an annual stroke rate of 7.9% and 1.9% in high-risk patients randomized to aspirin plus low-dose warfarin (international normalized ratio, 1.2 to 1.5) and adjusted-dose warfarin (international normalized ratio, 2 to 3), respectively.4 The Birmingham AF Treatment of the Aged (BAFTA) study of high-risk patients reported annual stroke rates of 3.8% and 1.8% in patients assigned to aspirin and warfarin, respectively.5 Thus, with the exception of the SPAF I study, the evidence is overwhelming that stroke rates on aspirin approximate placebo rates in high-risk patients.A second consideration is the definition of warfarin ineligibility. Definition of warfarin ineligibility in the SPAF I study included patients aged >75 years, now considered a risk factor for stroke prevention and an inclusion factor for current trials. Patients with uncontrolled hypertension or at high risk for bleeds were also excluded. These represent exclusions for any anticoagulant. In the Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE) A trial, warfarin ineligibility is defined as contraindication to or unwillingness (subjective) to take “oral anticoagulation therapy.” ACTIVE A compares reduction in stroke risk between 2 antiplatelet treatment arms. It is difficult to conceive how a patient who is deemed warfarin ineligible can be randomized to another effective anticoagulant unless obvious differences exist such as route of administration or elimination or proven advantages of the drug to be tested. We therefore believe that the known lack of efficacy of aspirin in high-risk patients and the subjectivity of the definition of warfarin ineligibility raise concerns about the trial that Connolly and colleagues propose.DisclosuresDr Ezekowitz reports receiving consulting fees from Sanofi-Aventis, Pfizer, Wyeth, Johnson & Johnson, Boehringer Ingelheim, Schering-Plough, and ARYx Therapeutics; lecture fees from Pfizer and Boehringer Ingelheim; and grant support from Boehringer Ingelheim and ARYx Therapeutics. No other potential conflict of interest relevant to this article was reported. Dr Nagarakanti reports no conflicts. References 1 Connolly SJ, Eikelboom J, O’Donnell M, Pogue J, Yusuf S. Challenges of establishing new antithrombotic therapies in atrial fibrillation. Circulation. 2007; 116: 449–455.LinkGoogle Scholar2 Stroke Prevention in Atrial Fibrillation Investigators. Stroke Prevention in Atrial Fibrillation Study. Circulation. 1991; 84: 527–539.CrossrefMedlineGoogle Scholar3 EAFT (European Atrial Fibrillation Trial) Study Group. Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke. Lancet. 1993; 342: 1255–1262.CrossrefMedlineGoogle Scholar4 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high-risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet. 1996; 348: 633–638.CrossrefMedlineGoogle Scholar5 Mant J, Hobbs FDR, Fletcher K, Roalfe A, Fitzmaurice D, Lip GYH, Murray E, on behalf of the BAFTA Investigators. Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet. 2007; 370: 493–503.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 5, 2008Vol 117, Issue 5 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.107.736082PMID: 18250275 Originally publishedFebruary 5, 2008 PDF download Advertisement SubjectsArrhythmias