Have clinical trials of NOACs been fair tests of treatments for atrial fibrillation patients?

This is a pre-publication version of an editorial appearing in the BMJ by Kamal R. Mahtani and Carl Heneghan

We still need to accept uncertainty with NOAC prescribing despite such potential

Warfarin reduces the risk of strokes in patients with nonvalvular atrial fibrillation (NVAF), but has limitations: a narrow therapeutic window, the need for regular monitoring, and risks of bleeding and drug-drug interactions. Partly because of these limitations, alternative novel oral anticoagulants (NOACs) have emerged, including direct thrombin inhibitors (DTIs), such as dabigatran, and factor Xa inhibitors, such as rivaroxaban. These drugs do not need routine monitoring and are subject to fewer drug-drug interactions. Both have evidence of cost effectiveness in stroke prevention (1) and in 2014, NICE (UK) recommended that dabigatran and rivaroxaban should be considered as an “option for the prevention of stroke and systemic embolism in patients with NVAF”.(2)

Despite this, use of NOACs has proved to be highly variable in patients with NVAF most at risk, ranging from 4% to 70% in different areas in England.(3) This may partly be attributable to higher perceived costs in practice, clinical uncertainty about the benefit to harm balance and the current lack routinely available antidotes in cases of overdose (although this looks likely to change in the future).

Questions, however, remain about the key drivers of this uncertainty. NICE technology appraisals for both dabigatran (4) and rivaroxaban (5) in NVAF were primarily based on two large, multinational, industry-sponsored, pivotal clinical trials, RE-LY (6) and ROCKET-AF (7). RE-LY compared warfarin and dabigatran in 18,113 NVAF participants; rates of stroke, systemic embolism, and major haemorrhage were (depending on the dose of dabigatran) either the same as or lower than in those taking warfarin. ROCKET-AF randomised 14,264 NVAF participants to either rivaroxaban or warfarin; rivaroxaban was non-inferior to warfarin and was associated with fewer fatal bleeding events and fewer cases of intracranial hemorrhages.

However, there were early concerns that the conduct of the RE-LY trial and the quality of the data may be compromised, specifically that the manufacturer had not fully disclosed information about the potential benefits of anticoagulation monitoring in dabigatran users, bearing in mind that one of the key selling points for NOACs is a lack of monitoring.(8) The US Food and Drug Administration (FDA) therefore initially refused to file an application for approval in NVAF patients because of concerns over errors in the data. The FDA requested a review of the data, which revealed inconsistencies for 3,054 participants; in particular identifying previously unreported adverse events (32 myocardial infarctions and 69 cases of major haemorrhage). (9)

The validity of the ROCKET-AF trial of rivaroxaban has also been questioned.(10) It has transpired that participants randomised to warfarin were monitored using a defective point of care device that was subsequently recalled. It is therefore unclear whether participants in the warfarin arm were managed appropriately, giving a possible unfair advantage to those in the rivaroxaban arm not exposed to the faulty device. Cohen’s latest investigation highlights that concerns about the faulty device were raised by some of the ROCKET-AF investigators themselves, and that the data monitoring safety board may not have been fully informed about a safety investigation (the Covance Recheck Program) instigated by Janssen, the pharmaceutical arm of Johnson & Johnson. (11)

Published trials suggest NOACs, such as dabigatran and rivaroxaban, are non-inferior to warfarin (12), a finding replicated in routine data collected from observational cohorts.(13) Yet there is still uncertainty about the reliability of the evidence underpinning pivotal trials for these drugs. Part of this uncertainty could be traced back to the rapid review approval process, which aims to accelerate the approval of drugs with the potential for significant clinical benefit. However, when a trial’s validity is then called into question this may hinder translation, and in some cases, delay wider uptake. (14) Furthermore, oral anticoagulants are one of the highest risk drug therapies used in outpatient settings and there have been valid questions asked about why their perceived ease of use has been a greater focus than the need to improve the safety profile of NOACs.(15)

We therefore need to find ways to reduce this uncertainty and provide greater clarity about the benefit to harm balance. Replication of the results from RE-LY and ROCKET-AF in independent trials would be one approach, but this may take several years. Therefore, in the mean time making the data available for independent scrutiny should be a mandatory regulatory requirement, particularly when there are issues with trial rigour. Finally, a detailed independent analysis of unpublished data from clinical study reports, similar to previous analyses of neuraminidase inhibitors,(16) would also help. We have requested from the European Medicines Agency (EMA) the clinical study reports relating to NOACs in patients with NVAF and it has become clear that there are likely to be challenges for the sponsors of these trials in condensing large reports into digestible publications.

Although independent replication of trials, data transparency and detailed analysis of clinical study reports will be arduous and costly, the concerns highlighted by recent investigations have demonstrated how essential these approaches are to increase our confidence in these drugs. In the meantime patients and clinicians considering using them must, for now, live with the uncertainty that the current evidence underpinning them brings.

 

References

  1. Harrington AR, Armstrong EP, Nolan PE, Malone DC. Cost-Effectiveness of Apixaban, Dabigatran, Rivaroxaban, and Warfarin for Stroke Prevention in Atrial Fibrillation. Stroke. 2013 Jun 1;44(6):1676–81.
  2. Atrial fibrillation: management | Guidance and guidelines | NICE [Internet]. [cited 2016 Apr 20]. Available from: https://www.nice.org.uk/guidance/cg180
  3. NOAC prescribing varies 16-fold between CCG areas | GPonline [Internet]. [cited 2016 May 29]. Available from: http://www.gponline.com/noac-prescribing-varies-16-fold-ccg-areas/cv-blood-pressure/article/1394082
  4. Dabigatran etexilate for the prevention of stroke and systemic embolism in atrial fibrillation | 4-Consideration-of-the-evidence | Guidance and guidelines | NICE [Internet]. [cited 2016 Feb 8]. Available from: https://www.nice.org.uk/guidance/ta249/chapter/4-Consideration-of-the-evidence
  5. Rivaroxaban for the prevention of stroke and systemic embolism in people with atrial fibrillation | 4-Consideration-of-the-evidence | Guidance and guidelines | NICE [Internet]. [cited 2016 Feb 8]. Available from: https://www.nice.org.uk/guidance/ta256/chapter/4-consideration-of-the-evidence
  6. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus Warfarin in Patients with Atrial Fibrillation. N Engl J Med. 2009 Sep 17;361(12):1139–51.
  7. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus Warfarin in Nonvalvular Atrial Fibrillation. N Engl J Med. 2011 Sep 8;365(10):883–91.
  8. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ. 2014 Jul 23;349(jul23 12):g4670–g4670.
  9. Cohen D. Concerns over data in key dabigatran trial. BMJ. 2014 Jul 23;349:g4747.
  10. Cohen D. Rivaroxaban: can we trust the evidence? BMJ. 2016 Feb 3;i575.
  11. Cohen D. Manufacturer failed to disclose faulty device in rivaroxaban trial. BMJ. 2016;354:i5131 doi: 10.1136/bmj.i5131
  12. Mahtani KR, Spencer EA, Onakpoya I, Roberts N, Nunan D, Hobbs FDR, et al. Direct thrombin inhibitors and factor Xa inhibitors for atrial fibrillation. Cochrane Database Syst Rev Online [Internet]. 2016 [submitted]
  13. Larsen TB, Skjøth F, Nielsen PB, Kjældgaard JN, Lip GYH. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2016 Jun 16;i3189.
  14. Martin J, Shenfield G. The hazards of rapid approval of new drugs. Aust Prescr. 2015 Feb 1;39(1):2–3.
  15. QuarterWatch – Institute for Safe Medication Practices (ISMP) [Internet]. ANNUAL REPORT ISSUE – Data from 2015 Q4. 2016 [cited 2016 Sep 8]. Available from: https://www.ismp.org/quarterwatch/pdfs/2015Q4.pdf
  16. Jefferson T, Jones MA, Doshi P, Del Mar CB, Hama R, Thompson MJ, et al. Neuraminidase inhibitors for preventing and treating influenza in adults and children. In: The Cochrane Library [Internet]. John Wiley & Sons, Ltd; 2014 [cited 2016 Jan 31]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD008965.pub4/abstract

 

Competing interests: We have read and understood the BMJ policy on declaration of interests. Both KRM and CH have received funding from the National Institute for Health Research (NIHR) to support some of their work on anticoagulation.

Disclaimer: The views expressed are those of the authors and not necessarily those of the host institution, the NHS, the NIHR or the Department of Health.

Acknowledgements: KRM is supported by an NIHR Clinical Lecturer award.

We thank Jeffery Aronson and Deborah Cohen for comments on an earlier draft

Kamal Mahtani

About Kamal Mahtani

Kamal R. Mahtani is a GP and and Clinical Lecturer at the University of Oxford

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2 comments on “Have clinical trials of NOACs been fair tests of treatments for atrial fibrillation patients?

  1. Pingback: Novel oral anticoagulants for atrial fibrillation. - Carl Heneghan's BlogCarl Heneghan's Blog

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