Comparative effectiveness and safety of the novel oral anticoagulants: do the pivotal clinical trials point to a new paradigm?



    1. Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, NY
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    1. Division of Hematology, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
    2. All Children’s Research Institute, All Children's Hospital-Johns Hopkins Medicine, St. Petersburg, FL
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  • C. M. KESSLER,

    1. Departments of Medicine and Pathology and the Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC
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    1. Department of Biostatistics, University of Colorado School of Public Health—Anschutz Medical Campus, Aurora, CO, USA
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    1. Division of Hematology and Thromboembolism, and Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada
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  • A. G. G. TURPIE,

    1. Division of Hematology and Thromboembolism, and Thrombosis and Atherosclerosis Research Institute, Department of Medicine, McMaster University, Hamilton, ON, Canada
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  • N. R. CUTLER,

    1. Worldwide Clinical Trials, Beverly Hills, CA
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  • W. R. HIATT,

    1. Division of Cardiology, and CPC Clinical Research, University of Colorado School of Medicine, Aurora, CO
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    1. The Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY, USA
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  • for The Antithrombotic Trials Leadership and Steering Group (ATLAS)

Jonathan L. Halperin, The Cardiovascular Institute, Box 1030, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY 10029, USA.
Tel.: +1 212 241 7243; fax: +1 212 831 2195.


Spyropoulos AC, Goldenberg NA, Kessler CM, Kittelson J, Schulman S, Turpie AGG, Cutler NR, Hiatt WR, Halperin JL. Comparative effectiveness and safety of the novel oral anticoagulants: do the pivotal clinical trials point to a new paradigm? J Thromb Haemost 2012; 10: 2621–4.

Several novel oral anticoagulants have been approved by the U.S. Food and Drug Administration and the European Medicines Agency for the treatment of specific thrombotic conditions. The direct thrombin inhibitor, dabigatran, and the direct factor Xa inhibitor rivaroxaban have certain advantages over warfarin, an oral vitamin K antagonist that has been used for over 50 years. Among these advantages are fewer drug–drug and drug–food interactions, predictable pharmacokinetic profiles allowing fixed dosing once or twice daily and, most importantly, the avoidance of the need for routine coagulation monitoring [1]. Their disadvantages include a lack of safe and efficacious reversal agents and inability to reliably assess drug compliance or anticoagulant intensity using standard laboratory assays. Approval of novel oral anticoagulants by regulatory authorities has been based on their similar or more favorable safety and efficacy profiles compared with warfarin in patients with atrial fibrillation and compared with other standard-care antithrombotic regimens for other indications. Differences among these new compounds can be surmized in a limited way from the primary trial data as they apply to dosing frequency, adjustment for renal impairment and other factors affecting drug exposure and long-term side effects other than bleeding, but important questions remain unanswered. Because of the flaws inherent in cross-study comparisons, paramount among these questions is how one novel oral anticoagulant agent would perform compared with another for patients with specific clinical features [2]. A balanced assessment of the risks and benefits of the novel oral anticoagulants requires appreciation of differences in trial design, characteristics of the patients enrolled, quality of anticoagulation management when warfarin is the active comparator, and definition and ranking of primary endpoints in the various studies.

In patients with atrial fibrillation, the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY), Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), and Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) phase III trials [3–5] of dabigatran, rivaroxaban and apixaban, respectively, differed with respect to key features as shown in the Table 1. Differences included study design (double-blind in ROCKET-AF and ARISTOTLE vs. open-label in RELY), patient populations (average CHADS2 stroke risk scores 3.5 in ROCKET AF vs. 2.1 in RELY and ARISTOTLE), methods of calculating anticoagulation time in the therapeutic range (including or excluding warfarin initiation and interruption periods), endpoint determination during transition to standard warfarin care at the end of the studies and subtle differences in bleeding definitions (strict or modified ISTH [6] or other criteria).

Table 1.   Comparisons of trial design, patient populations and endpoints in phase III randomized-controlled trials of atrial fibrillation with the novel oral anticoagulants dabigatran, rivaroxaban and apixaban
Dabigatran 110 mg b.i.d.
Dabigatran 150mg b.i.d.
Rivaroxaban 20 mg q.d.Apixaban 5 mg b.i.d.
  1. CHADS2 score: one point each for congestive heart failure, hypertension, age over 75 years, diabetes and two points for stroke or transient ischemic attack; TIMI, thrombolysis in myocardial infarction; ISTH, International Society of Thrombosis and Haemostasis; CrCL, creatinine clearance.

Trial designOpen-labelDouble-blindDouble-blind
Trial size18 11314 26418 201
Patient populationAtrial fibrillation (mean CHADS2 Score* 2.1)Atrial fibrillation (mean CHADS2 Score 3.5)Atrial fibrillation (mean CHADS2 Score 2.1)
Percentage of warfarin-naïve patients50%37.6%43%
Non-inferiority margin1.461.461.38
Primary efficacy endpointStroke (ischemic, hemorrhagic, or unspecified) or systemic embolismComposite of stroke (ischemic and hemorrhagic) and systemic embolismStroke (ischemic, hemorrhagic, or unspecified) or systemic embolism
Primary safety endpointMajor bleeding (ISTH criteria: life threatening bleeding using TIMI definitions as subcategory of major bleeding)Major bleeding (ISTH criteria)Major bleeding (ISTH criteria)
Time-in-therapeutic range of comparator drug warfarin (mean)64% (excluding initiation and interruption periods)55% (including all periods)62.2% (excluding transition, initiation, and interruption periods)
Endpoint determination during transition to standard warfarinUnclearYesYes
Renal insufficiencyCrCl < 30 mL min−1 excludedCrCl 30–49 mL min−1 with rivaroxaban 15 mg q.d.CrCl < 25 mL min−1 excluded

For these reasons it is difficult to determine whether one oral anticoagulant is superior to another without trials designed to directly compare their effectiveness and safety. Depending on the disease setting and indication, each registration trial is likely to require slightly different treatment strategies (including ancillary and transition treatments) and definitions for safety and efficacy endpoints. This is particularly true in this field where standard care is constantly evolving, and where indications are extended to new populations. For example, trials of anticoagulation treatment in children are unlikely to provide adequate sample sizes to allow comparisons based on hard clinical endpoints that might be considered essential in adult trials with higher event rates. Thus, even although the harmonization and use of hard clinical endpoints are important objectives, they may not be feasible across the spectrum of antithrombotic trials in typical populations.

Several approaches have been suggested to estimate a net clinical benefit in antithrombotic trials from a balance of safety and efficacy assessments. A common approach is to present separate comparisons of treatment effects on many different endpoints. A global synthesis is then based on a qualitative weighing of risks and benefits that considers the type and severity of all adverse events observed in the trial. For example, in non-valvular atrial fibrillation, separate comparisons can be presented for death, stroke and bleeding over 1 year for no treatment, warfarin and each novel oral anticoagulant in a hypothetical population of patients, extrapolating from trial data. Another method is to assign relative weights that reflect the clinical importance of key outcome events such as ischemic stroke and intracranial hemorrhage and calculate the net clinical benefit as the weighted average of these events [7]. Whatever the approach, the assessment and comparison of a net clinical benefit is challenging and may not allow comparisons across disparate trials with heterogeneous compliance and differences in the definition of outcome measures. In this setting, an unbiased comparison of different novel agents is nearly impossible without trials specifically designed to make such comparisons. This raises the worrisome possibility that estimates of relative efficacy and safety across agents within an indication, such as non-valvular atrial fibrillation or venous thromboembolism prevention, will be based on marketing claims rather than reliable evidence.

Current regulations governing new drug approval provides lengthy periods of proprietary protection for registered compounds once stringent criteria for demonstrating safety and efficacy have been met. Public policy is founded on assuring sufficient financial protection to support the costly research and development process that in the case of novel oral anticoagulant drugs has taken decades and billions of dollars. As unmet medical needs typically attract the focus of multiple investigators and investors and engender parallel development efforts, it is not surprising that similar or alternative approaches bear fruit in relatively short succession. Such is the case with the novel oral anticoagulants for stroke prevention in patients with atrial fibrillation, with two novel agents approved within a 2-year period, a third under review and a fourth in an advanced stage of development [8]. The pricing of these compounds is determined by competitive market forces, but the cost is ultimately born by patients, either individually or through health systems, and as the target population is generally elderly, the burden is born principally by taxpayers. Even in a crowded field of approved and forthcoming agents, the rate of return on investment in indications such as stroke prevention in atrial fibrillation and venous thromboembolism prevention in joint replacement surgery is so great as to turn a drug development effort profitable early in the period of proprietary protection. This leaves prescribers, patients and payers challenged for a considerable time to develop a basis to select one product over another.

The advent of novel oral anticoagulants represents a milestone in thromboembolism prevention, but also an opportunity for the revision of regulatory policy in the pharmaceutical arena to better fulfill a mandate for comparative effectiveness trials. We propose a new concept in pharmaceutical development that would require each manufacturer of new drugs for the same clinical indication to commit a small portion of net profits from the approved compound to a managed fund specifically to support the design and conduct of such trials. This regulatory requirement would reflect the real expense of determining which treatments serve the greater public interest. The practicalities of implementing such a system could consider mechanisms such as granting a longer period of proprietary protection for the first approved compound for a given indication and progressively shorter ones for products approved subsequently unless substantial advantages are demonstrated in comparative studies of one new agent against another.

Gathering the means to conduct comparative effectiveness research would represent only the first step in a series of challenges. The design of comparative effectiveness trials needed to clearly establish the relative advantages and disadvantages of one new antithrombotic agent over another or a particular antithrombotic strategy using a new agent over another presents substantial methodological hurdles, in part because of the low rates of major ischemic/thromboembolic and hemorrhagic events observed in typical patients. Such trials must target well-defined delineated populations based on specific clinical attributes that reflect the full range of use in clinical practice. In addition to clinical outcomes, comparative effectiveness trials should address pharmaco-economic outcomes. The recruitment of subjects would be facilitated by funding the cost of the new drugs evaluated during the trials and by the clinical equipoise arising as a result of the current lack of comparative evidence favoring one agent over another.

To serve the public interest, comparative effective trials must be free of commercial bias. This points squarely in the direction of independent academic research organizations that are uniquely qualified and equipped to provide the expert oversight necessary to bring these trials efficiently and objectively to meaningful conclusions. The model we recently proposed involves an academic research consortium that specializes in antithrombotic trials [9] that utilizes the operational resources of a global contract research organization but places responsibility for trial design, oversight, analysis and reporting on the shoulders of the non-profit academic research organization, led by academic trialists positioned beyond the reach of shareholders, insurance payers and other parties with vested financial interests in the outcomes. While at first sight this proposal for funding and execution of comparative effectiveness trials may seem a radical departure from the conventional business of new drug development, it comes at a time when the quest to identify new treatments requires a new paradigm, and there is no better test than one that involves promising treatments already in hand.


A.C. Spyropoulos, N.A. Goldenberg, C.M. Kessler, J. Kittelson, S. Schulman, A.G.G. Turpie, N.R. Cutler, W.R. Hiatt, and J.L. Halperin conceptualized the work, drafted and revised the manuscript, were fully responsible and autonomous in writing the manuscript, approved its submission for publication, and confirm that no pharmaceutical industry writers were involved in any phase of its development; A.C. Spyropoulos and J.L. Halperin co-drafted the initial manuscript.

Disclosure of Conflict of Interest

A.C.S. receives fees from sanofi-aventis, Boehringer Ingelheim, Bristol Myers-Squibb, Johnson & Johnson and Bayer Healthcare for consulting activities, from Astellas Pharma for data and safety monitoring committee activities, from Eisai and Bayer for data and safety monitoring Committee and steering committee activities and receives honoraria from CPC Clinical Research, a non-profit ARO affiliated with the University of Colorado.

N.A.G. receives salary and research support in the form of a Career Development Award from the National Institutes of Health, National Heart, Lung and Blood Institute, and salary support through pharmaceutical industry sponsored research from CPC Clinical Research.

C.M.K. received consulting fees for advisory, data and safety monitoring board and/or steering committee activities from Baxter Immuno, Bayer Healthcare, CSL Behring, Eisai, NovoNordisk, Octapharma, Pfizer and sanofi-aventis, and honoraria from CPC Clinical Research. Georgetown University receives research support on his behalf from the National Institutes of Health, the Maternal and Child Health Bureau and the Centers for Disease Control and Prevention, as well as from Amgen, Baxter Immuno, Eisai, Genentec, GlaxoSmithKline, Griffols, NovoNordisk, Octapharma and sanofi-aventis.

S.S. receives fees from Merck, Bayer Healthcare and Boehringer Ingelheim for adjudication committee, data and safety monitoring committee and steering committee activities and honoraria from CPC Clinical Research.

A.G.G.T. receives fees from Bayer Healthcare, Schering Pharma, Astellas Pharma, Portola, Takeda, Eisai and Pfizer for consulting activities, CSL Behring for data and safety monitoring committee, from Bayer Healthcare, Schering Pharma, Takeda, and Astellas Pharma for steering committee activities, and honoraria from CPC Clinical Research.

N.R.C. is President and CEO of Worldwide Clinical Trials, Inc., a contract research organization.

W.R.H. is President of CPC Clinical Research. He receives support from grants provided by the National Institutes of Health and from the pharmaceutical industry for sponsored research initiatives, partial salary support through research grants provided to CPC Clinical Research and the University of Colorado, as well as fees from the U.S. Food and Drug Administration as a Special Government Employee for several advisory committees. He provides consulting services to the pharmaceutical industry though CPC Clinical Research. Current relationships include GlaxoSmithKline, sanofi-aventis, Kowa, Portola, TheraVasc, AstraZeneca, Pluristem and Zona.

J.L.H. receives consulting fees for advisory and/or steering committee activities from Bayer Healthcare, Biotronik, Boehringer Ingelheim, Bristol Myers-Squibb, Daiichi Sankyo, Johnson & Johnson, Pfizer and sanofi-aventis, honoraria from AstraZeneca for data and safety monitoring board activities, research support from the National Institutes of Health, National Heart, Lung, and Blood Institute, and honoraria from CPC Clinical Research. He is a member of the Cardiovascular and Renal Drugs Advisory Committee of the U.S. Food and Drug Administration.