Dabigatran, bleeding, and the regulators
BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4517 (Published 23 July 2014) Cite this as: BMJ 2014;349:g4517
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I read with great interest your review[1] on the regulatory history of dabigatran in the United States and the European Union. It is important to realize that RE-LY never intended to prove whether monitored dabigatran was more efficacious and safer than unmonitored dabigatran, but whether two fixed doses of the drug were non-inferior to INR-adjusted warfarin. In this regards the study was indeed a “positive” one, and to the extent one views p-values as gauges of the strength of evidence, the “p less than 0.001” in RE-LY demonstrate that both doses were substantially non-inferior to warfarin. As you may be aware such low p-values may be used to “waive” the second study that is usually required for approval , a point was also made during the FDA advisory for dabigatran.
Though some secondary analyses of the exposure-response/exposure-safety relationships suggest a potential benefit for pharmacokinetic or pharmacodynamic monitoring of dabigatran it is important to realize that these analyses by both Boehringer Ingelheim (BI)[2] and the FDA[3] (available in the public domain since September 2010) are inherently limited by a number of technical issues. These include the failure to account for intra-individual pharmacodynamic variability, the competing risks of safety (bleed) and efficacy events, uneven discontinuation rates in the dabigatran arms v.s. the warfarin arm and informative missingness of drug concentrations in patients who have an event or dropped out from the study. Even though analyses that address these shortcomings are non-standard, they could improve on the BI models and the independent, nearly identical, ones developed by the FDA. In fact both these analyses are of low quality to merit anything more than a passing consideration. The quality of the BI modeling can be judged by the value of the c-statistic (0.715) quoted by the authors of the subsequent publication[4]. This value barely makes the cutoff for an acceptable predictive model, while the lack of validation in an independent dataset suggests that it would be even less reliable in other settings. Similarly, the FDA models are unable to match the event rates of the RE-LY dataset they were developed on, missing the mark by 6-87% (page 199[3]) depending on the prevailing level of renal function . Given the poor quality of these models I find it premature to use predictions made by them as a justification for regulatory action. Nevertheless, they may be useful hypothesis-generating instruments for the design of further studies of regulatory relevance.
In your paper you also suggest that the regulatory authorities need to agree with the BI on a therapeutic range for dabigatran. In that regards, note that the 48-200 ng/mL range quoted in your paper largely overlaps with the 10th-90th percentile range in the 150mg arm of RE-LY (40-215 ng/mL). In fact the lower end of this range is essentially BI’s estimate for the concentration below which one may expect a partial loss of efficacy(page 157[2]). On the other hand, the upper limit is the simple average of 215 and 185 ng/mL which is the expected concentration of a 300mg twice daily dose that per the FDA’s pharmacometric analyses would be the optimal one for dabigatran (slide 56[5]). Since this range is largely determined by the RE-LY data and given the substantial overlap in plasma levels in patients who had strokes and bleeding, it is likely that drug monitoring will not helpful for most patients receiving the 110mg or the 150mg dose. Hence it might be reasonable to forego drug level testing altogether and opt for pharmacodynamic monitoring e.g. with the Ecarin clotting time (ECT). Validation of this and similar tests against dabigatran concentrations measured by chromatography has been reported in the literature. Furthermore, such tests appear to be as good (or bad) as the dilute thrombin assay (HEMOCLOT), while being available in the US[6–8]. Finally note, that visual inspection of one of the unpublished, yet publicly available analyses, by the FDA suggest that ECT values in patients receiving dabigatran may less variable than the drug level while exhibiting similar or possibly better relationship to bleeding outcomes (Figure 1 found in page 27[3]).
Though important for clinical care, these technicalities should not obscure the major point about “dabigatran and the regulators”, namely the decision of the FDA NOT to approve the 110 mg dose despite BI’s proposal (and subsequent efforts) to do so. In my opinion this is not due to a myopic view exhibited by the FDA but rather a paternalistic attitude towards both patients and practicing physicians. Reading the transcript of the discussions between regulatory officials and external advisors regarding dabigatran one gets the impression that reaching this decision was like a pendulum swinging between the positions of “first do no harm” and “do more good than harm” (page 281[9]). In the end, the principle that “medical practice and medical research are designed to keep things getting better” dictated the decision to approve only the larger dose since it was superior to warfarin but only marginally so compared to the lower and apparently safer 110mg dose. In reaching this decision the FDA explicitly expressed a preference for fewer strokes over an excess of bleeding events. Note that this ranking of outcomes is not shared by many patients who opt not to be treated with warfarin and their physicians, or even the only patient in that advisory (himself on warfarin for atrial fibrillation).
The bigger question that merits an immediate answer is whose preferences about the trade-off between efficacy and safety should regulatory authorities take into account when evaluating novel drugs and devices? In this exceedingly multistakeholder environment for the provision of healthcare and drug development is it acceptable to “keep things getting better” based on the opinions of just regulatory officials and medical authorities without considering the values ofthe medical community at large and their patients? For dabigatran in particular, isn’t it time for the FDA to revisit their decision and approve the 110 mg in accordance with their own pharmacometric and BI analyses for our elderly patients?
Competing interests: No competing interests
Efficacy, safety and optimal dosing of dabigatran – a commentary on the BMJ articles on dabigatran
In some recent articles, the British Medical Journal (BMJ) raised questions about the reliability of the RE-LY study, and whether plasma concentration monitoring should be recommended for dabigatran therapy. We, the leaders of RE-LY-trial, would like to restate the strong evidence for the currently recommended use of dabigatran provided by the trial; but also emphasize that the available data are inadequate for recommending dose adjustments based on monitoring of dabigatran plasma levels.
Efficacy and Safety of Dabigatran
The RE-LY study was a collaboration between three academic institutions and the sponsor, enrolling more than 18,000 patients from more than 900 hospitals/clinics in over 40 countries around the world. Patients were randomized to unblinded warfarin or to one of two blinded doses of dabigatran. The design was extensively discussed with the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in advance, and numerous safeguards were incorporated to minimize potential biases related the open comparison of dabigatran vs warfarin. The results showed that the higher dose of dabigatran (150 mg BID) was superior to warfarin (P less than 0.0001) and the lower dose was non-inferior in reducing stroke or systemic embolism. There was a highly significant reduction in intracranial hemorrhage (the most feared complication of any anti-thrombotic therapy) with both doses of dabigatran compared to warfarin (P less than 0.0001) (1).
The recent BMJ articles argued that there are reasons to doubt the evidence regarding the efficacy and safety of dabigatran. One argument was that unblinded warfarin might bias the results? There is however a rationale for open trials using warfarin as this design better reflects the real world situation allowing optimized warfarin dosing and INR control and more adequate management of bleeding, especially concerning antidotes. In order to avoid bias in the open trial we used central blinded event adjudication and review of all hospitalizations, deaths and adverse event reports for potential missed events. We also checked whether there was any evidence of bias in reporting of bleeding by reviewing hemoglobin changes to detect unreported bleeds. These extensive efforts did not identify any events that would alter the conclusions of RE-LY either on efficacy or safety.
After initial filing of the RE-LY database, the FDA raised questions about data inaccuracies, related mainly to INR reporting and major bleeds. As reported previously a subsequent double entry of all INR values changed the mean study time in therapeutic range from 64.2 to 64.4 (2,3). An exhaustive additional review of data was also undertaken at that time to assure regulatory agencies that there was no bias in the reporting of events. The findings before and after extensive checks indicated little change in the differences in the primary outcome and bleeding between the 3 randomized groups. Recently the fatal events were again reevaluated because of a litigation process in the USA. This second review also turned up a few previously unreported events in all 3 groups, which did not affect the differences in outcome between the treatment groups. The results of the two repeated reviews have been fully published (2, 3). The fact that the results of RE-LY do not change despite multiple and repeated checks of the data, attest to the robustness of the RE-LY findings. Table 1 in the attached document shows the first published results of RE-LY (1) and the results with the additional events included (2,3).
The main findings of the RE-LY trial have recently been supported by an FDA sponsored analysis of clinical outcomes in greater than 134,000 Medicare patients aged 65 years and older, receiving dabigatran or warfarin (4). This analysis shows that the results in clinical practice mirror the results of the RE-LY trial (Table 2 in the attached document).
Plasma Concentration Monitoring
We recently published the results of retrospective measurements of dabigatran plasma concentration from samples obtained during RE-LY. Blood samples at trough and peak of dabigatran plasma concentration were obtained after a few weeks of therapy in more than 9,000 dabigatran patients to enable population pharmacokinetic analysis (5). As with most pharmacologic agents there were substantial variations in plasma concentration in patients receiving dabigatran, which were primarily due to differences between patients in kidney function, age, weight and gender – which together explained much of the variation in plasma concentration of dabigatran. There was a strongly significant association between dabigatran plasma concentration and major bleeding and a weaker relationship between plasma concentration and stroke. A multi-variate analysis indicated that the factors associated with increased major bleeding included dabigatran plasma concentration (p less than 0.001), age (p less than 0.001) and aspirin use (p less than 0.003). This relationship between plasma concentration and bleeding raises the possibility that adjusting dabigatran dose according to plasma concentration could be useful in clinical practice to reduce the risk of bleeding. It is worth noting however that dabigatran dose adjustment for increased age, reduced renal function, or for co-administration of platelet inhibitors is clinically sensible, and stated in labelling in several countries where dabigatran 110 mg is available. Additional dose adjustments based on measurement of dabigatran concentration, might theoretically provide incremental clinical utility. However prospective studies would be needed to properly assess the utility of monitoring of dabigatran plasma concentration. Until these studies are done it would not be appropriate to recommend routine plasma concentration measurement.
Looking Forward
All the new oral anticoagulants, developed as alternatives to warfarin, have used fixed doses (with or without dose reduction in selected cases based on clinical features). In clinical practice both dabigatran doses are widely used with dose reductions in older patients, at lower renal function, lower body weight, and at factors associated with both higher bleeding risk and/or higher dabigatran plasma concentrations. Can we improve the individualization of therapy of the novel oral anticoagulants with monitoring of the concentration in plasma? While data from dabigatran population pharmacokinetic studies raise this possibility, stroke and major bleeding in atrial fibrillation have complex etiology and correlate with multiple clinical factors (e.g. age, renal dysfunction, myocardial dysfunction, coagulation activity) as well as with plasma concentration. Several of these factors interact and also change over time. Before recommending plasma concentration measurements we need to better understand how this information would add to readily available clinical information for dose selection; and what would be the effects on clinical outcomes. We also need to know when, or how often to measure plasma levels; and how exactly to react to the information. The cost benefit and other impacts of such measurements also should be evaluated. At present, we should not lose sight of the advances already made. The currently recommended use of the novel agents, while not perfect, provides substantial advances in both efficacy and safety compared to warfarin. Thus, the pursuit of the perfect must not be an impediment to implementing the advances already made.
Stuart J. Connolly (1), Salim Yusuf (1), Lars Wallentin (2)
1. Population Health Research Institute, Hamilton Health Sciences, McMaster University, Hamilton Ontario, Canada
2. Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden.
References
1. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L; the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009; 361(12):1139-51
2. 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 Nov 4;363: 1875-6.
3. Connolly SJ, Yusuf S, Wallentin L; Letter to New England Journal of Medicine (in press) 2014.
4. 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 http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm
5. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Nehmiz G, Wang S, Wallentin L; RE-LY Investigators. 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 Feb 4;63(4):321-8.
Competing interests: Dr Wallentin has received grant support/honoraria/consulting fees from Boehringer Ingelheim, Regado Biosciences, Athera Biosciences, Astra-Zeneca,GlaxoSmithKline, Eli Lilly, Schering-Plough, and Bristol-Myers Squibb. Drs. Connolly and Yusuf have received grant support/honoraria/consulting fees from Boehringer-Ingelheim, Bristol-Myers Squibb, Bayer, Pfizer, Sanofi-Aventis, and Portola.