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November 1, 2014

Doctors can RE-LY on new therapy

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Rory Hafford finds out from the RE-LY trial that dabigatran is the new therapeutic advance in stroke prevention that patients and treating physicians have been waiting on for decades


Barcelona. A city in perpetual motion; constantly reinventing itself; always looking to remodel its traditional confines with a brighter future. With this in mind, it was perhaps appropriate that the Catalonian capital was chosen as the launch pad for a better future for people with atrial fibrillation (AF) and concomitant stroke risk.
Up to now, the gold standard for the management of this increasingly common condition has been warfarin. Today, there’s a new kid on the block; and it goes by the name of dabigatran.
The great and the good
Numerous key opinion leaders in the specialty area had gathered in the city last year to hear the eagerly-awaited results of the Randomised Evaluation of Long-Term anticoagulant therapy in patients with AF – shortened to the RE-LY trial. Eagerly awaited because as the most common cardiac arrhythmia, AF affects 1 per cent of people in the developed world population and its prevalence is projected to increase at least three-fold by the year 2050.
Patients with atrial fibrillation run a greatly increased risk of stroke and other embolic events; for this alone, stroke prevention in atrial fibrillation represents an extremely important clinical priority. Throw in the economic ramifications and you can see why an effective substitute for warfarin is sorely needed.
When Boehringer Ingelheim announced the data for the RE-LY trial, the expectation was already high.
The trial – the largest AF outcomes trial ever conducted (18,113 patients in 44 countries) – uncovered some significant results: dabigatran etexilate 150mg BID significantly reduces the risk of stroke and systemic embolism by 34 per cent (p<0.001) in patients with atrial fibrillation compared to well-controlled warfarin without increasing the risk of major bleeding.
Dabigatran etexilate 110mg BID clearly demonstrated similar reductions in stroke and systemic embolism compared to well controlled warfarin while delivering an impressive 20 per cent reduction in major bleeding rates compared to warfarin.
Key secondary and other outcomes were also a cause for celebration. Both the 150mg and 110mg doses showed a reduction in life-threatening, intracranial and total bleeding. Importantly, these benefits occurred without hepatoxicity.
Long-awaited advance
Out of the number of speakers addressing delegates in the Fira Gran Via Congress Centre, I was particularly looking forward to the contribution of Dr Sarah Jarvis, a part-time GP based in London. I have been to several international conferences at which Dr Jarvis has spoken, and have always found her take on things incredibly insightful. There is a real credibility about her and a penchant for cutting to the chase.
“Patients and treating physicians have waited for an advance in this area for decades,” said Dr Jarvis.
“We have been after a new therapy that can reduce the risk of stroke without imposing restrictions on lives. The need for lifelong blood tests and dose adjustments and the numerous food and drug interactions with warfarin have had a significant adverse impact on patients’ quality of life while placing many of them at continued risk of stroke and major bleeding.
“This could soon be a thing of the past,” she added.
Translating the RE-LY results into what counts – clinical practice – dabigatran 150mg could prevent in the region of 3,000 strokes every day worldwide, compared to well controlled warfarin.
There was a time when warfarin was hailed from on-high. Indeed, the ‘w’ in the name could well have stood for wonder! But most physicians at the Barcelona gathering were united on one thing: the limitations and narrow therapeutic range of the drug.
Intracranial hemorrhage
The most devastating complication of warfarin therapy is intracranial hemorrhage, especially hemorrhagic stroke. As compared with aspirin, warfarin doubles the risk of intracranial bleed. This led to one of the most important advantages of dabigatran, according to researchers: with both doses of dabigatran the risk of intra-cranial hemorrhage was less than one-third with warfarin.
Putting a finer point on it, Dr Jonathan Halperin of the Mount Sinai School of Medicine in New York said the narrow therapeutic index of warfarin requires that the intensity of anticoagulation be maintained within a narrow therapeutic range. Not always easy, or the most desirable situation.
“Since the pharmacokinetics of warfarin vary as a consequence of genetic factors and interactions within multiple drugs and foods, maintenance of the International Normalised Ratio within this range is difficult to achieve in clinical practice without close coagulation monitoring and frequent dose adjustment,” said Dr Halperin.
In effect, it means that the inherent limitations (with vitamin K antagonists) leads to substantial under-use, particularly among elderly people who, on average, take nearly a dozen concomitantly prescribed medications, many of which interact with warfarin.
Mode of action
Okay. Nuts and bolts. What exactly are we talking about here? Basically speaking, the mode of action of dabigatran is, some would argue, elegant. Potent antithrombotic effects are achieved with direct thrombin inhibitors by specifically blocking the activity of thrombin (both free and clot-bound), the central enzyme in the process responsible for clot formation.
In contrast to vitamin-K antagonists, which variably act via different coagulation factors, dabigatran provides effective, predictable and consistent anticoagulation with a low potential for drug-drug interactions and no food-drug interactions, without the need for routine coagulation monitoring or dose adjustment.
The results were obtained using a randomised trial design, comparing two fixed doses of dabigatran, each administered in a blinded manner, with open-label use of warfarin in patients who had AF and were at increased risk of stroke. The only adverse effect that was significantly more common with dabigatran than with warfarin was dyspepsia. However, both dabigatran doses were non-inferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism.
In short, the take-home message, despite the international gathering, was hugely impressive in any man’s language: compared to well controlled warfarin, dabigatran showed:
l Significant reduction in the risk of stroke and systemic embolism – including hemorrhagic strokes;
l Significantly lower bleeding – including life-threatening and intracranial bleeding;
l Significant reduction in vascular mortality.
Needless to say, Boehringer Ingelheim is extremely satisfied with the RE-LY results. “With the robust results from RE-LY, dabigatran etexilate, a compound from our own research and development, can revolutionise anticoagulant treatment for physicians and patients,” said Dr Andreas Barner, the Chairman of the Board of Managing Directors of Boehringer Ingelheim.
“We look forward to expeditiously submitting these results to regulatory authorities around the world so that new options can be made available for millions of patients with atrial fibrillation at risk of stroke.”
Superior protection
From a clinical point of view, the parting comments from Prof Stuart Connolly, co-principal investigator of RE-LY, rang true: “The results exceeded all our expectations. We now have an oral treatment that offers superior protection from stroke with less bleeding and without the need for routine monitoring.
“In addition to protecting patients from strokes, we as physicians are especially concerned about life-threatening or disabling bleeding with warfarin due to its narrow therapeutic window. On top of the efficacy, dabigatran has shown equally impressive safety results, offering a wider safety margin,” concluded Prof Connolly.