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Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation

2007; Lippincott Williams & Wilkins; Volume: 116; Issue: 4 Linguagem: Inglês

10.1161/circulationaha.107.695163

1524-4539

Stuart J. Connolly, John W. Eikelboom, Martin O’Donnell, Janice Pogue, Salim Yusuf,

Antiplatelet Therapy and Cardiovascular Diseases

HomeCirculationVol. 116, No. 4Challenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessReview ArticlePDF/EPUBChallenges of Establishing New Antithrombotic Therapies in Atrial Fibrillation Stuart J. Connolly, MD, FRCPC, John Eikelboom, MBBS, MSc, FRACP, FRCPA, Martin O'Donnell, MB, MRCPI, Janice Pogue, MA, MSc and Salim Yusuf, DPhil, FRCPC Stuart J. ConnollyStuart J. Connolly From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. , John EikelboomJohn Eikelboom From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. , Martin O'DonnellMartin O'Donnell From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. , Janice PogueJanice Pogue From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. and Salim YusufSalim Yusuf From the Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada. Originally published24 Jul 2007https://doi.org/10.1161/CIRCULATIONAHA.107.695163Circulation. 2007;116:449–455Warfarin is the single most effective treatment to prevent stroke in patients with atrial fibrillation (AF) in that it reduces the risk by about two thirds compared with placebo.1 Despite its effectiveness, however, warfarin is difficult to use and its uptake into clinical practice has been constrained.2 Warfarin has a slow onset and offset of action, it exhibits considerable variability in dose response among individuals, it is subject to multiple food and drug interactions, it has a narrow therapeutic window, and considerable risk of hemorrhage exists. The slow offset of action of warfarin can be beneficial if a patient misses a dose but complicates temporary discontinuation of warfarin for surgery. Thus, warfarin requires careful laboratory monitoring and dose adjustment to maintain the international normalized ratio (INR) in the target therapeutic range. Even with careful laboratory monitoring, major bleeding occurs in 1% to 3% of AF patients on warfarin per year. Consequently, many clinicians and patients are reluctant to use warfarin. Some patients have contraindications to anticoagulation, but others choose not to use it.2 Such patients typically use aspirin.Educational and support programs have been shown to improve knowledge of disease and treatment, INR control, and physician management of AF.3–5 Nonetheless, there have been intensive efforts to find a replacement for warfarin. Several new drugs with the potential to overcome the limitations of warfarin have been evaluated in randomized trials but appeared to be less effective or less safe than warfarin. The experience from these trials has highlighted the methodological challenges of finding a replacement for warfarin, which include a number of difficulties in design and in interpretation of results from noninferiority trials, the widespread use of warfarin in the community, availability of warfarin-naïve patients, and low event rates on warfarin. The present article will review the results of recent phase III randomized trials that evaluated new antithrombotic agents in AF, and it will focus on the methodological challenges in the evaluation of a new antithrombotic therapy.Underuse of WarfarinAs a consequence of pharmacokinetic and pharmacodynamic limitations, warfarin requires frequent laboratory monitoring and dose adjustment. Concern about the inconvenience of the need to undergo regular laboratory monitoring and the risk of bleeding has contributed to the underuse of warfarin in patients with AF. Immediately after the benefits of warfarin for stroke prevention in AF patients were convincingly demonstrated in 1989, its use steadily increased.2 However, recent surveys6–10 suggest that the use of warfarin has plateaued in the past few years at ≈50% to 60% of eligible patients with AF (Table 1). New anticoagulants that do not share the pharmacological limitations of warfarin have the potential to lead to an increase in the proportion of patients with AF on effective antithrombotic therapy. TABLE 1. Use of Oral Anticoagulant Therapy to Prevent Stroke in AF: Results of Recent SurveysYear PublishedSurveyPopulationTreated With Warfarin, % (Patient Status)ATRIA indicates Anticoagulation and Risk Factors in Atrial Fibrillation; NABOR, National Anticoagulation Benchmark and Outcomes Report.1999ATRIA Study1011 082 US patients large health maintenance organization without contraindications60 (high-risk patients)2005NABOR Study9945 US patients from teaching, community, and VA hospitals55 (high-risk patients)2006Euro Heart Survey62706 outpatients in 35 European countries642006Hylek et al7402 US patients, ≥65 years old, not on warfarin at admission to teaching hospital51 (discharged on warfarin)2006Birman-Deych et al816 007 US Medicare patients49Recent Phase III Trials of Novel Antithrombotic Therapies to Prevent Stroke in AFXimelagatranThe oral direct thrombin inhibitor Ximelagatran is a prodrug of melagatran, a small molecule that targets the active site of thrombin and blocks the enzyme's catalytic activity. Ximelagatran produces a predictable anticoagulant response with no known drug or food interactions, which thereby reduces the need for laboratory monitoring. Two phase III noninferiority trials compared unmonitored Ximelagatran (36 mg twice daily) with dose-adjusted warfarin (target INR, 2.5; range, 2.0 to 3.0) in patients with nonvalvular AF and at least 1 additional risk factor for stroke. The Stroke Prevention Using the Oral Thrombin Inhibitor in Patients with Nonvalvular Atrial Fibrillation III (SPORTIF III)11 trial used an open-label design with blinded adjudication, whereas SPORTIF V12 was a double-blind trial that used a sham INR scheme to maintain blinding. The primary outcome measure in both trials was a combination of all strokes and systemic thromboembolism.SPORTIF III (open-label n=3407) showed a trend to fewer strokes in favor of Ximelagatran. The annual rates of stroke and systemic embolism were 1.6% on Ximelagatran and 2.3% on warfarin. SPORTIF V (double-blind n=3922), on the other hand, showed results that tended to favor warfarin. The annual rates of stroke and systemic embolism were 1.6% on Ximelagatran and 1.2% on warfarin. In both trials, rates of major bleeding were somewhat lower on Ximelagatran compared with warfarin. Although some heterogeneity between the results of the 2 SPORTIF trials was observed for the impact on stroke, a prespecified analysis of the data pooled from SPORTIF III and SPORTIF V was reported. The rates of stroke and systemic embolic events were almost identical with Ximelagatran and warfarin (1.6% per year and 1.6% per ear; risk ratio 0.98; 95% confidence interval [CI], 0.73 to 1.30; P=0.98). The rate of major bleeding (on treatment) in the pooled analysis tended to be lower with Ximelagatran (1.9% per year versus 2.5% per year; risk ratio 0.76; 95% CI, 0.56 to 1.03; P=0.07).13Ximelagatran failed to receive approval from the US Food and Drug Administration. The main reason was concern about safety; Ximelagatran was associated with raised transaminase levels in 4% to 6% of patients and with a few cases of fulminant hepatic failure.14 However, regulatory authorities and other commentators14 also concluded that noninferiority had not been established, even though both trials satisfied their prespecified noninferiority hypotheses. This conclusion was based on re-analysis of the noninferiority margin with more conservative estimates of efficacy of warfarin based on a somewhat different meta-analysis of previous warfarin trials, which applied a more conservative rule for determination of noninferiority margin and focused on the double-blind SPORTIF 5 results in preference to the open-label SPORTIF 3 results because of the heterogeneity between SPORTIF III and V results.IdraparinuxIdraparinux is a synthetic analog of the active pentasaccharide sequence contained in unfractionated heparin and low molecular weight heparin that selectively inhibits activated coagulation factor X. It has a plasma half-life of 80 hours, which allows it to be administered subcutaneously once weekly.15 The Atrial Fibrillation Trial of Monitored, Adjusted Dose Vitamin K Antagonist, Comparing Efficacy and Safety With UnadjustedSanOrg 34006/Idraparinux (AMADEUS) Study was an open-label phase III trial that aimed to recruit >7000 patients to compare subcutaneous idraparinux (given subcutaneously once weekly without coagulation monitoring) with dose-adjusted warfarin (target INR, 2.5; range, 2.0 to 3.0) in patients with AF and at least 1 additional risk factor for stroke. Designed as a noninferiority trial, the primary efficacy outcome measure was a composite of all strokes (ischemic and hemorrhagic) and systemic embolic events. The trial was terminated early because of safety concerns with regard to bleeding.Aspirin and ClopidogrelThe Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE)-W trial, an open-label randomized controlled trial (n=6706 patients), compared combination aspirin (75 to 100 mg recommended) and clopidogrel (75 mg) therapy to oral anticoagulation (INR 2 to 3) in patients with AF and at least 1 risk factor for stroke.16 Designed as a noninferiority trial, ACTIVE-W was terminated early when oral anticoagulation was found to be superior to combination antiplatelet therapy for prevention of stroke. After a median follow-up of 1.28 years, the annual rate of the primary outcome (a composite of stroke, systemic thromboembolism, myocardial infarction, and vascular death) was 3.9% in the oral anticoagulation group and 5.6% in the combination antiplatelet therapy group (P=0.0003).New Agents in Phase III TrialsDabigatranDabigatran is a novel oral direct thrombin inhibitor and a prodrug of dabigatran etexilate. Like Ximelagatran, dabigatran produces a predictable anticoagulant response with no known drug or food interactions, which thereby reduces the need for coagulation monitoring. The half-life of dabigatran is ≈8 hours after single-dose administration and up to 14 to 17 hours after multiple doses. It is usually given twice daily.17 Dabigatran is compared with warfarin (INR 2 to 3) in a very large, ongoing, phase III, noninferiority, randomized controlled trial, Randomized Evaluation of Long-Term Anticoagulant Therapy (RELY). This trial will enroll 15 000 patients randomized to warfarin, or to 1 of 2 doses of dabigatran (110 mg or 150 mg, twice daily). The trial will balance enrollment between warfarin-experienced patients and those who have received it for 15 years ago and now include better control of blood pressure and increased use of drugs such as statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers.11,12,16 Evidence also exists, based on lower stroke rates in recent trials,12,16 that warfarin may be used more effectively today than in the previous generation of trials (see first paragraph of Improved INR Control and the Challenge for Modern Trials and Table 3). Such a change might justify a more liberal noninferiority margin, as the standard therapy may have become harder to match. Most researchers and regulators feel uncomfortable with this approach, but the margins chosen for noninferiority trials should be based on all available evidence. In summary, important regulatory concerns about noninferiority trial design and its long-term implications for the drug approval process have led to a conservative approach to setting the noninferiority margin. This sets a high standard for new agents to achieve, compared with the original standards where trials have evaluated the superiority of agents versus placebo therapy. Table 2 summarizes key features of noninferiority trial design. TABLE 3. Stroke Rates on Oral Anticoagulation in Large AF Trials in High-Risk PatientsTrialYear PublishedBaseline Systolic BPINR in Therapeutic Range, %Warfarin-Naïve, %Annual Event Rates in Warfarin GroupIschemic Stroke, %Total Stroke, %Hemorrhagic Stroke, %BP indicates blood pressure.SPAF III199614061441.92.40.5SPORTIF III200313966271.92.30.4SPORTIF V200513268161.11.20.1ACTIVE W200613364231.01.40.4Superiority Trials Against AspirinA superiority trial of a new agent against aspirin is ethical and feasible in high-risk patients with AF. As shown in Table 1, many patients exist who cannot or will not take warfarin. Some of these have increased risk of bleeding and are not suitable for a trial of antithrombotic therapy. However, others have compliance issues specifically related to vitamin K antagonists, and these patients may be able to safely use an antithrombotic agent that does not require monitoring. Recent guideline changes25 indicate that AF patients with a single risk factor may receive either warfarin or aspirin. These patients are at lower risk of events, and this would mean that, if they were the only patients enrolled, the study size could be very large. This is offset in part by the fact that superiority trials designed to detect fairly large treatment effects (35% to 45% relative risk reduction) require far fewer patients and events than noninferiority trials in AF.An important synergy exists in the performance of a superiority trial against aspirin in support of a noninferiority trial against warfarin, with the same therapeutic agent, in the 2 populations of AF patients at high risk for stroke. Trials that demonstrate superiority of a new agent over an existing agent or placebo provide the most direct way to establish the efficacy of the new agent. Unlike noninferiority trials, superiority trials do not require interpretation of a meta-analysis of previous trials, do not require agreement on a noninferiority margin, and do not make assumptions about historical constancy of treatment effects. Also unlike noninferiority trials, superiority trials do not raise concerns about the balance of the potential loss of efficacy and also face less serious problems when noncompliance with the study drug is prominent. Although most investigators would be hesitant to accept a superiority trail against aspirin as pivotal for development of a new antithrombotic agent, few would disagree that clear evidence of substantial efficacy of a new agent against aspirin would provide support to an application for approval based on a noninferiority trial against warfarin.Evaluation of the feasibility of a superiority trial against aspirin in AF patients at moderate to high risk is a goal of the ongoing Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events (ACTIVE A) trial, which compares clopidogrel plus aspirin to aspirin therapy alone. It has completed enrollment of 7645 high-risk AF patients in >30 countries and 500 centers worldwide and will report results in 2008.26Declining Event RatesRates of strokes in AF trials appear to be declining over time (Table 3). The primary prevention randomized controlled trials before 1995 did not select high-risk AF patients.27 In the pooled analysis of these trials, 35% of patients were <65 years of age and had no risk factors for stroke. With the publication in 1996 of Stroke Prevention in Atrial Fibrillation (SPAF) 3, AF trials have only included patients with risk factors for stroke.28 SPAF 3 reported an ischemic stroke risk on warfarin of 1.9% per year. Trials published recently generally report much lower rates of ischemic stroke on warfarin or vitamin K antagonists: 1.9% per year in SPORTIF 3 (2003), 1.1% per year in SPORTIF 5 (2005), and 1.0% per year in ACTIVE W (2006) (Table 3). The lower risk of ischemic stroke on warfarin, despite selection of high-risk patients in recent trials, may be related to more effective concomitant therapies, more aggressive control of systemic hypertension, and improved control of oral anticoagulant therapy. The last decade has seen an increased use of statin therapy and more aggressive treatment of blood pressure with increased use of angiotensin-converting enzyme inhibitors and angiotensin receptor blocking drugs. The mean systolic blood pressure at baseline in the pooled analysis of the controlled trials of warfarin in AF27 was 141 mm Hg and in SPAF 3 was 140 mm Hg.28 The corresponding baseline mean systolic blood pressures in SPORTIF 3, SPORTIF 5, and ACTIVE W were 139 mm Hg, 132 mm Hg, and 133 mm Hg, respectively. Very low event rates on warfarin create a challenge for study design. If the total rate of ischemic hemorrhagic stroke and systemic embolism is only 1.5% per year, 30 000 patient years of follow-up are needed to have the 450 events required in a typical noninferiority trial in AF. By contrast, a total of only 108 ischemic strokes (from 3706 patients) are reported in the pooled data from the first 5 trials of warfarin against placebo or control in AF.1Improved INR Control and the Challenge for Modern TrialsINR control of warfarin therapy has improved since the first trials with warfarin were performed. At the time of the first 5 placebo-controlled trials, use of the INR to control warfarin was just being introduced clinically in North America, and 3 of the 5 studies controlled warfarin by means of the prothrombin time ratio.29–31 This method is inferior to the use of the INR because it does not correct for the variable characteristics of different thromboplastin reagents and is likely to lead to less optimal INR control. INR was used to monitor anticoagulation in 2 of the original placebo-controlled trials (Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation [AFASAK] study32 and Canadian Atrial Fibrillation Anticoagulation [CAFA] study33), in which the percentages of INR values in the target range were 42% and 44%, respectively. In the recent SPORTIF 3, SPORTIF 5, and ACTIVE W trials, the time in therapeutic range of the INR was 66%, 68%, and 64%, respectively.The relationship between INR control and both embolic and hemorrhagic outcomes is well established, and improved INR control will result in lower event rates on warfarin.34,35 This makes modern warfarin therapy a formidable comparator therapy and creates a dilemma for noninferiority trial design and conduct. In a noninferiority trial, should one target the rates of INR control observed in the original placebo-controlled trials, or a level typically achieved in clinical practice, or the best possible level of INR control? Insistence on the latter may demand a level of rigor that is artificial and inconsistent with the constancy principle of noninferiority trials. If one uses the former approach, the investigators may run the risk of not using best possible therapies.Potential for Different Treatment Effects in Warfarin-Naïve and Warfarin-Experienced PatientsAnother challenge for the design of antithrombotic trials in AF is the widespread use of warfarin therapy in specialists' practices in Western countries. Because patients are most easily recruited into clinical trials from such practices (especially from anticoagulant clinics), a tendency exists to enroll patients already on successful warfarin treatment for years. Such patients are thus likely to be self-selected "responders" to warfarin because patients with a tendency to hemorrhage on warfarin, or in whom INR control is difficult, will self-identify during prestudy exposure to warfarin. In recent studies such as SPORTIF 3, SPORTIF 5, and ACTIVE W, ≈80% of patients were warfarin experienced (Table 3). In ACTIVE W, considerable evidence was produced that previous warfarin experience predicted a better response to warfarin with lower risk of hemorrhage.16 The upper 2 panels of the Figure show the cumulative risk of a primary event for patients on and not on oral anticoagulant therapy at entry to ACTIVE W, and the lower 2 panels show the same data from the outcome of major bleeding. For the primary outcome, a trend exists toward a greater benefit with oral anticoagulant therapy (compared with clopidogrel plus aspirin) in patients on oral anticoagulant at entry. The interaction is more impressive for major bleeding where patie