Although results were not published until late 2013, the RE-LY trial had included a large sub-study (n=9183) that raised serious questions about whether patients taking dabigatran needed plasma level testing to reduce the risk of bleeding or clotting and to ensure maximum benefit from the drug.6 The RE-LY sub-study showed a fixed dose of dabigatran had wide variability in plasma levels that were directly related to risk of bleeding. After a month of treatment, the 150 mg twice daily dose could produce peak plasma levels as low as 2.3 ng/mL and as high as 1000 ng/mL. A conservative measure that omitted 20% patients at the extremes and used log transformed data indicated a 5.5 fold variably. Dabigatran’s high variability was not a desirable characteristic for a drug where not enough anticoagulation means loss of benefit in stroke prevention and too much anticoagulation increases the risk of haemorrhage.
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By December of 2011 regulators in the United States, Europe, and Japan were learning about thousands of postmarketing adverse event reports of serious and fatal bleeding, mainly in older patients taking dabigatran in the United States at the 150 mg dose. The FDA published a notice that it was reviewing cases,16 and the EMA asked the manufacturer for a detailed tabulation of all reported deaths from bleeding.17
The EMA assessment,17 a company internal study,18 and an independent outside review19 all told the same story. Serious bleeds and deaths were occurring in older patients, median age of 80. Where details were known, data showed 26.1% of fatal bleeds were occurring within 10 days of starting treatment, and 67.8% within the first 30 days. Spontaneous adverse event reports (MedWatch reports in the US, Yellow Card Scheme in the UK) do not provide reliable estimates of how frequently bleeds were occurring, but they do provide a profile of the affected patients. As of December 2011, the company summary cited 9049 reported bleeding events in its global experience, including 368 deaths.18
Why were so many dabigatran bleeds being reported? Data now publicly available on plasma concentration of dabigatran in RE-LY participants provides one answer.6 At least 10% of patients had peak plasma level concentrations ≥383 ng/mL when taking the 150 mg dose. This is about seven times (48-50 ng/mL) the minimum level needed for stroke prevention, according to the company.20 Other factors could increase bleeding risk further. The EMA concluded that concomitant therapy with antiplatelet agents such as aspirin or clopidogrel roughly doubled bleeding risk with either dabigatran or warfarin.13 And the 12% stronger reformulation that was being prescribed by doctors increased the risk of bleeding beyond the rates reported in the RE-LY sub-study.
