A Comparative Effectiveness Trial Warfarin versus Direct Oral Anti- Coagulants. Thomas L. Ortel, M.D., Ph.D. 2 December 2016

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1 A Comparative Effectiveness Trial Warfarin versus Direct Oral Anti- Coagulants Thomas L. Ortel, M.D., Ph.D. 2 December 2016

2 Comparative Effectiveness Research The IOM Definition of CER: Comparative effectiveness research is the generation and synthesis of evidence that compares the benefits and harms of alternative methods to prevent, diagnose, treat, and monitor the or improve the delivery of care. The purpose of CER is to assist consumers, clinicians, purchasers, and policy makers to make informed decisions that will improve health care at both the individual and population levels. Sox, HC. Med Care, 2010; 48: S7-S8

3 The Patient-Centered Outcomes Research Institute (PCORI), an independent nonprofit, nongovernmental organization located in Washington, DC, was authorized by Congress in The goal of our work is to determine which of the many healthcare options available to patients and those who care for them work best in particular circumstances. We do this by taking a particular approach to CER called Patient-Centered Outcomes Research, or PCOR, research that addresses the questions and concerns most relevant to patients, and we involve patients, caregivers, clinicians, and other healthcare stakeholders, along with researchers, throughout the process.

4 PCORI is funded through the Patient-Centered Outcomes Research Trust Fund (PCOR Trust Fund), which was established by Congress through the Patient Protection and Affordable Care Act of The PCOR Trust Fund receives income from three funding streams: appropriations from the general fund of the Treasury, transfers from the Centers for Medicare and Medicaid trust funds, and a fee assessed on private insurance and self-insured health plans (the PCOR fee).

5 The PFA

6 PCORI Anticoagulation PFA PCORI seeks to fund randomized clinical trials or observational studies that compare two or more alternatives for addressing management of DVT or PE with extended anticoagulation treatment. The research is expected to examine how different strategies for extended anticoagulation treatment compare for patients who have completed a course of anticoagulation treatment for an initial episode of DVT or PE.

7 PFA: Letter of Intent LOI for NIH submissions LOI for PCORI submissions Detailed, 4 page-document with multiple questions to be addressed Preliminary budget to be proposed, including justification LOI is used by PCORI for screening submissions and inviting full submissions based on review of LOI

8 PFA: Budgetary Instructions Maximum Project Budget (Total Direct Costs): $10 million Funds Available up to: $30 million Note that PCORI will not cover costs for interventions that are being compared in the proposed study. For those rare circumstances in which the estimated total direct costs exceed $10 million, provide detailed justification that ties the extra expense to the success of the project.

9 Letter of Intent Study: Prospective, randomized, controlled trial to compare three anticoagulants (warfarin, rivaroxaban, and apixaban) for the long-term prevention of recurrent VTE Design: PROBE (Prospective, randomized, open-label, blinded end-point) Primary outcome: recurrent VTE Study Leadership: Thomas L. Ortel, MD, PhD, PI Lana Castellucci, MD, MSc, co-pi David Garcia, MD, co-pi Randy Fenninger

10 Letter of Intent: Sample size Primary hypothesis: Rivaroxaban 20 mg/d and apixaban 2.5 mg twice a day will be non-inferior to warfarin, target INR of 2-3, in the prevention of recurrent VTE Estimated risk of recurrent VTE in warfarin arm: 0.87%/yr Estimated risk of recurrent VTE in DOAC arms: 1.5%/yr To exclude a 2% absolute increase in recurrent VTE, proposed sample size of 950 per arm, with 80% power and 2.5% one-sided alpha. Total sample size: 3,000 (includes 5% loss-to-follow-up)

11 Letter of Intent: Draft budget Assumption: sites will follow patient for study duration (one year) Number of sites needed: 60+ sites in US and Canada to enroll 2 patients/site per month Site payments to include start-up costs and per-patient payments for 1-year follow-up and data collection and entry. Also need coordinating center budget. Estimated site budget (total) per patient: $5,000 Total for per-patient site costs: $15,000,000 Total proposed budget (direct costs): $22,000,000

12 PCORI response to LOI Like your proposal Don t like your budget Submission of full application approved and fix your budget

13 PCORI Application: Modifications to the Budget Sites would enroll the patient and then turn data collection at all follow-up time points over to a centralized outcomes group (through DCRI) but Given concern about cost of DOAC s for patients with no, or limited, insurance, included in the budget cost for copays for rivaroxaban and apixaban Final submitted budget: $14.8 million

14 Outcome Summary statement received Average overall score: 49 Invitation to call-in to the Board of Governor s Meeting via teleconference Awardees to be voted on at the conference

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17 Conclusions Not awarded but Not declined either

18 Major criticism The study only seems to be powered to look at differences in efficacy; no power calculations are provided for differences in major bleeding between warfarin and the NOACs. For the various indications for which the NOACs have been approved (atrial fibrillation, initial treatment of VTE), they have at least met non-inferiority with respect to efficacy as compared to warfarin. Some of the agents, particularly apixaban, stand out from warfarin with respect to safety. Given that the major morbidity of the three anticoagulants is bleeding safety, the feasibility of powering the study with respect to this endpoint should have been included. Furthermore no discussion is provided of net clinical benefit as an endpoint (counterbalancing recurrent VTE vs major bleeding).

19 Study Redesign Primary outcome switched from efficacy (prevention of recurrent VTE) to safety (major bleeding + clinicallyrelevant non-major bleeding) with a superiority design Estimated clinically-relevant bleeding rate of 6.0% per year for patients receiving VKA. Targeting a 50% reduction, with 80% power, need 790 patients/arm (including 5% loss-to-follow-up) To make all three comparisons (VKA vs. rivaroxaban; VKA vs. apixaban; rivaroxaban vs. apixaban), used a Bonferroni adjustment to preserve type I error 1,055 patients/arm, or 3,165 patients total

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21 Additional concerns Identifying and recruiting high-enrolling sites CanVECTOR US sites (partially from BRIDGE; also from VENUS) PCORnet

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24 Additional concerns Participating sites and patient enrollment CanVECTOR US sites (partially from BRIDGE; also from VENUS) PCORnet DOAC arm What about the uninsured patient population? Reaching out to industry for assistance in this subgroup Warfarin arm Will patients currently taking DOAC s accept warfarin as an option?

25 Proposed Timeline Contract executed: 1 Jan 2017 Protocol complete: 1 April 2017 First patient enrolled: 15 August 2017

26 Acknowledgements Lana Castellucci, MD, MSc David Garcia, MD Randy Fenninger Kevin Anstrom, PhD Multiple colleagues in the US and Canada Duke Clinical Research Institute Ottawa Hospital Research Institute PCORI