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High bleeding risk with dabigatran flagged by ‘real-world’ data

GPs have been urged to prescribe oral anticoagulant dabigatran with caution, after it appeared to be linked to a higher risk of major bleeding than previously thought, according to a US study of ‘real-world’ patients.

Researchers found a third more major bleeding events among patients who were given dabigatran after being diagnosed with atrial fibrillation, compared with patients who were prescribed warfarin.

The team, led by University of Pittsburgh epidemiologists, urged GPs to prescribe dabigatran – brand name Pradaxa – with caution in high-risk patients, until more evidence is available.

The researchers used Medicare medical insurance records to identify a random sample of patients who were newly diagnosed with atrial fibrillation and prescribed warfarin or dabigatran between 2010 and 2011.

Major bleeding events were seen in 9% of the 1,302 patients prescribed dabigatran, compared with 5.9% of the 8,102 patients in the warfarin group.

This translated into a 58% increased relative risk of major bleeding with the newer anticoagulant, after adjusting for potential confounders.

The study also confirmed dabigatran was linked to more gastrointestinal bleeding events, relative to warfarin, but fewer intracranial bleeds.

The increased risk of major bleeding was particularly high for black patients, and those with chronic kidney disease; in both cases, dabigatran was associated with more than twice the risk of major bleeding relative to warfarin use.

The team concluded: ‘To the best of our knowledge, our study is the first to compare the safety profile of dabigatran and warfarin using a nationally representative sample of Medicare beneficiaries.

‘We found that in real-world clinical practice, after adjusting for patient clinical and demographic characteristics, dabigatran was associated with a higher incidence of major bleeding regardless of the anatomical site’

They added: ‘Until more evidence is available, dabigatran should be prescribed with caution in high-risk patients.’

Dabigatran was the first of the non-vitamin K antagonist oral anticoagulants (NOACs) to be introduced as an alternative to warfarin for the prevention of stroke in patients with non-valvular atrial fibrillation. Updated guidance on the management of atrial fibrillation released earlier this year by NICE recommends it alongside the other approved NOACs – rivaroxaban and apixaban – as an option for patients who cannot tolerate warfarin.

The latest conclusions differ from those drawn by an investigation conducted by the Food and Drug Administration (FDA), which was prompted by a higher than expected incidence of serious and fatal bleeding events with dabigatran, reported through the Government’s adverse event reporting system after the drug was approved.

The authors of the current study argue that the FDA study failed to adjust for differences in patient characteristics between dabigatran and warfarin users.

Dr Chris Arden, a GP in Southampton and cardiology lead at West Hampshire CCG said the study underscored the importance of selecting patients carefully for anticoagulation – and of post-marketing surveillance.

Dr Arden said: ‘This reiterates the importance of careful patient selection in order to ensure we achieve an acceptable balance of risks and benefits when it comes to prescribing anticoagulants, as well as demonstrating the importance and value of post-licencing surveillance.’

However, Dr Matthew Fay, a GP in West Yorkshire who helped develop NICE guidelines on anticoagulation, said the latest information should not deter GPs from prescribing dabigatran.

He said: ‘I feel you have to see this in [context of] Veterans data that the FDA collected, which shows increased gastrointestinal bleeding with warfarin but beyond that all other parameters are equal, if not better, for the direct thrombin inhibitor (such as less intracerebral haemorrhage).’

He added: ‘If the patient wishes to use a non-vitamin K antagonist the advice from the clinician should be to suggest that they consider the one used most by the clinician or the local health economy, while we all gain experience and ensure that there is a robust process in practice to keep these drugs under review.

‘I worry that this on going, slightly distorted view, of this particular NOAC is reducing the effectiveness of the message to get aspirin out of the system and to stop the strokes.’

A spokeperson for Pradaxa’s manufacturer Boehringer Ingelheim said the study was ‘based on a much smaller dataset’ than the FDA’s, which included over 67,000 patients.

The spokesperson said: ‘The purpose of the FDA study was to examine the safety profile of dabigatran  in general practice versus the controlled trial settings, and this large real world data set demonstrated that Pradaxa was associated with a reduced risk of ischaemic stroke, intracranial hemorrhage, and death, and increased risk of major gastrointestinal hemorrhage compared with warfarin in elderly patients with non-valvular atrial fibrillation just as was observed in the RE-LY study.

‘We are confident of the positive efficacy and safety profile of our medicine and are supported in this view not only by the FDA, but by regulatory authorities worldwide.’

JAMA Internal Medicine 2014; available online 4 November

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