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Feature Anticoagulants

Dabigatran: how the drug company withheld important analyses

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4670 (Published 23 July 2014) Cite this as: BMJ 2014;349:g4670

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The authors accuse Boehringer Ingelheim, the manufacturer of dabigatran, of having failed to share with regulators information on how monitoring plasma levels of the drug and subsequent dose adjustment could reduce the risk of major bleeds. Of the numerous misleading statements made regarding dabigatran etexilate in various articles in the BMJ, (1-5) published on July 23 and subsequently on August 11, 2014, we are compelled to address one that we consider particularly important to correct.

The article by Cohen (1) suggests that Boehringer Ingelheim withheld important information from regulators “about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible.” (1)

We would like to reiterate our conclusions on this subject, which had been provided to the BMJ well ahead of the publication of the manuscripts, and to clarify the misleading remarks made in the BMJ. (1-5)

The RE-LY trial demonstrated that dabigatran etexilate 150 mg bid without monitoring and without dose adjustments was superior to standard of care (monitored and dose-adjusted warfarin) in reducing the risk of ischaemic and haemorrhagic stroke in patients with atrial fibrillation, while having a numerically lower rate of major bleeding, and significantly lower rates of life-threatening, intracranial and any bleeding. (6,7)

Data on plasma levels of dabigatran from the RE-LY study, as well as respective PK modelling, were provided to the US and European regulatory authorities and included in their discussions when reviewing dabigatran in 2010 and 2011. While the benefits of dabigatran compared to warfarin were striking as detailed above, we explored potential opportunities to improve dabigatran’s benefit–risk profile even further. In 2012, our scientists performed preliminary exploratory simulations with PK modelling to understand whether dose adjustments based on plasma concentrations might further improve the efficacy and safety profile of dabigatran etexilate. However, after scientific and mathematical scrutiny was applied, the initial hypothesis from the PK model could not be supported. Rather, the information and conclusions reached using the initial PK model (information submitted to regulatory authorities with the initial application for approval) remained unchanged. Therefore, there were no new data or conclusions to share with regulatory authorities. This is contrary to the author’s suggestion that Boehringer Ingelheim withheld important analyses. (1)

A paper recently published by the RE-LY trial investigators documents the exposure–response relationship of dabigatran. (8) The aim of this analysis was to examine the association between plasma concentrations and efficacy and safety outcomes, and to identify patient factors that influenced this relationship. The results of this pre-specified sub-analysis showed that the risks of major bleeding, but also the risk of ischaemic stroke, correlated with dabigatran plasma concentrations. Whether, however, a single optimal concentration range for all patients could be specified was a subject of extensive discussions among the authors. Finally, they came to the conclusion that there is no single range that fits all patients because individual patient characteristics (e.g. age, renal function, prior stroke), put into perspective through medical judgement, are at least as important as the plasma concentrations in assessing benefit–risk and confound the association between drug levels and outcomes. (8,9)

The article by Cohen (1) suggests that determining dabigatran levels by anticoagulant monitoring may further reduce the risk of bleeding and improve outcomes. However, the issue is not simply about how to reduce major bleeds; it is about achieving a balance that maximizes the reduction of strokes and systemic embolisms while minimizing major bleeds. It may appear logical to monitor concentrations and adjust dosing as known from decades of oral anticoagulation with vitamin-K-antagonists (VKAs). However, in contrast to VKAs, which are affected by metabolism and numerous drug–drug and drug–food interactions, the plasma levels of dabigatran are primarily dependent on renal function.

Dabigatran has a direct mode of action on thrombin with different pharmacokinetics to the VKAs, which act indirectly through the vitamin-K-dependent clotting factors. For the overall benefit–risk assessment of dabigatran, the assessment of the patient’s renal function and consideration of the patient’s age is more relevant than the assessment of plasma concentration which is not considered to contribute clinically relevant added value.

In May 2014, the US Food and Drug Administration (FDA) reaffirmed the positive efficacy–safety profile of dabigatran in one of the largest real-world analyses of its kind comprising 134,000 patients above 65 years. (10)

Klaus Dugi, Chief Medical Officer, Boehringer Ingelheim GmbH, Ingelheim, Germany
Joerg Kreuzer, Therapeutic Area Head Medicine Cardiology, Boehringer Ingelheim GmbH, Ingelheim, Germany

1. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ 2014;349:g4670.
2. Cohen D. Concerns over data in key dabigatran trial. BMJ 2014;349:g4747.
3. Moore TJ, Cohen MR, Mattison DR. Dabigatran, bleeding, and the regulators. BMJ 2014; 349:g4517.
4. Charlton B, Redberg R. The trouble with dabigatran. BMJ 2014;349:g4681.
5. Cohen D. Re: Dabigatran: how the drug company withheld important analyses [Response, 11 August 2014]. BMJ 2014;349:g4670.
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;361(12):1139-51.
7. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L; Randomized Evaluation of Long-Term Anticoagulation Therapy Investigators. Newly identified events in the RE-LY trial. N Engl J Med 2010;363(19):1875-6.
8. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63(4):321-8.
9. Reilly PA, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Wallentin L; RE-LY Investigators. Reply: regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014;63(25 Pt A):2885-6.
10. FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin – 13 May 2014. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm Last accessed 24 July 2014.

Competing interests: Employees of Boehringer Ingelheim

14 August 2014
Klaus A. Dugi
Chief Medical Officer
Joerg Kreuzer
Corporate Division Medicine, Boehringer Ingelheim GmbH, Ingelheim, Germany
Boehringer Ingelheim GmbH, Binger Straße 173, 55218 Ingelheim am Rhein, Germany