A key advertising argument for the new oral anticoagulants put forth by the manufacturers is that this therapy does not need to be monitored unlike with coumarines. A prespecified subanalysis for the marketing authorisation study for dabigatran (PRADAXA) in atrial fibrillation (RE-LY; cf. a-t 2011; 42: 74-7) published only now raises considerable doubts about the correctness of this claim (1). In the RE-LY study (2), the dabigatran plasma concentrations were measured in 9,183 patients and correlated with ischaemic strokes and systemic embolisms, as well as with cases of severe bleeding. As expected, the plasma concentrations were dependent on age, weight, sex and renal function, among other factors. Despite an adjustment of the dosage to account for age and renal function, as is recommended in the summary of product characteristics, the plasma concentrations deviated by a factor of five upon examination of the 10th and 90th percentiles. The concentrations correlate directly and highly significantly with the rate of severe bleeding (p < 0.0001) and inversely with the rate of strokes and embolisms (p = 0.045) (1).

In the publication the authors come to the somewhat tentative-seeming conclusion that adjusting the dosage to the dabigatran plasma concentrations could improve the benefit-to-risk ratio for certain patients (1). The analysis has apparently been cause for considerable alarm within Boehringer Ingelheim, the supplier of dabigatran. Multiple internal Boehringer Ingelheim emails, which became public as part of thousands of lawsuits for damages in the United States (3, 4), indicate that the authors had to revise and considerably tone down their original conclusions. They would have be counter to marketing interests and would have been detrimental for competing with the other new oral anticoagulants. There was even discussion of not publishing at all. As can be further inferred from the correspondence, the development of a laboratory test for monitoring the anticoagulant effect was considered several years ago, but then rejected. Likewise, the reason for this was that laboratory testing would not have fit in with the marketing profile of the thrombin inhibitor (4).

Until there is evidence to the contrary, the dabigatran findings similarly would be allowed to apply also to the other new oral anticoagulants. In contrast with coumarines, for which the use of laboratory tests for monitoring has been established for many years and the optimal therapeutic range is evidence-based, there are no established monitoring options for the new oral anticoagulants.

We think it is scandalous how pure corporate interests were put before the entitlement to and the rights of patients to the safest drug treatment possible. For the new oral anticoagulants we still see only an indication when good INR management is demonstrably not possible with coumarin or if there are specific contraindications (a-t 2014; 45: 13-4).

(R = randomized trial)

1

REILLY, P.A. et al.: J. Am. Coll. Cardiol. 2014; 63: 321-8

R

2

CONNOLLY, S.J. et al.: N. Engl. J. Med. 2009; 361: 1139-51

3

McCARTHY, M.: Brit. J. Med. 2014; 348: g1505 (2 pages)

4

New York Times: Unsealed Court Documents in Pradaxa Case, 5 Febr. 2014; http://www.a-turl.de/?k=amwe