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Dabigatran trial halted early due to excess of bleeding events

A major anticoagulant trial has had to be halted early due to an excess of thromboembolic and bleeding complications in the dabigatran group, compared with those taking warfarin.

The study in patients recently fitted with mechanical heart valves, adds to the debate surrounding the safety of the new oral anticoagulants.

But it also comes as separate analysis suggests the drugs are the ‘most promising treatments’ to reduce cardiovascular events and all-cause mortality in patients with atrial fibrillation.

The RE-ALIGN study looked at 252 patients who had undergone aortic or mitral valve replacement within the past seven days and those who had undergone such replacement at least three months earlier. Patients were randomly assigned to receive either dabigatran or warfarin.

Dose adjustment or discontinuation of dabigatran was required in 52 of 162 patients (32%). Ischaemic or unspecified stroke occurred in nine patients (5%) in the dabigatran group and in no patients in the warfarin group.

Major bleeding occurred in seven patients - 4% - and two patients - 2% - respectively. All patients with major bleeding had pericardial bleeding.

Study leader Professor John Eikleboom, associate professor at McMaster University in Ontario, Canada said: ‘The results of our study indicate that dabigatran is not appropriate as an alternative to warfarin for the prevention of thromboembolic complications in patients who require anticoagulation after the implantation of a prosthetic heart valve.

‘The results may also be relevant to studies of other new oral anticoagulants in patients with mechanical heart valves.’

The findings follow mixed evidence for dabigatran. A Danish study last year suggested dabigatran had a significantly higher rate of complications than warfarin, and that it was associated with a higher risk of coronary events than other newer anticoagulants. But a recent meta-analysis - carried out by a team at Harvard Medical School found that compared with placebo/control, dabigatran 150 mg was associated with the lowest risk of stroke, the composite of ischaemic stroke or systemic embolism and mortality.

The analysis looked at 20 studies with 79,808 patients with atrial fibrillation allocated to eight treatments: aspirin, aspirin plus clopidogrel, vitamin K antagonists, dabigatran 110 mg, dabigatran 150 mg, rivaroxaban, apixaban or placebo/control.

They concluded: ‘The novel oral anticoagulants were the most promising treatments to reduce stroke, stroke or systemic embolism, and all-cause mortality in patients with atrial fibrillation.’

Commenting on the NEJM findings, Dr Matthew Fay, a cardiology GPSI in Shipley in West Yorkshire, said: ‘The current published evidence is again re-enforcing that the new oral anticoagulants cannot be used in those where a higher range international normalized ratio is required. This study shows an increased stroke rate in the novel agent limb of the study, confirming that this is not a role for these agents.’

He added that despite the current debate surrounding them, GPs were likely to use the newer oral anticoagulants more in the future for atrial fibrillation.

He said: ‘I think it will be a slow-burn. There is a slow adoption of these new medications as both clinicians and patients seem wary of the lack of experience in the British clinical community regarding their use, this will slowly change.’

A spokesperson from the manufacturer of dabigatran, Boehringer Ingelheim said they had halted the trial on the basis of interim results showing an ‘imbalance in results between the treatments investigated’.

He said: ‘Based on the results seen in the interim analysis, the company core data sheet and the pertaining product labels for dabigatran etexilate were updated worldwide from “not recommended” to “contra-indicated in patients with a prosthetic (EU) heart valve requiring anticoagulation/ mechanical (US) heart valve”.

‘These label updates were communicated directly to healthcare professionals in agreement with the respective regulatory authorities.’

Readers' comments (1)

  • Vinci Ho

    It is a phase 2 trial i.e. an optimal dose was to be identified to serve the purpose. Doses chosen were higher 150 / 220/300mg bd as desired INR was higher 2.5-3.5 for mechanical heart valves. Looks like a balanced dose could not be found.

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