A sub-group analysis from the landmark RE-LY trial with Boehringer Ingelheim’s (BI) oral anticoagulant dabigatran etexilate (Pradaxa) suggests the drug’s advantages over standard warfarin therapy in reducing the risk of stroke extend across the spectrum of low- to high-risk patients.

The results presented at the 59th Annual Scientific Session of the American College of Cardiology in Atlanta, US also highlighted lower rates of bleeding with Pradaxa versus warfarin in patients at low-risk of stroke. There were no data available on respective rates of myocardial infarction (MI) with Pradaxa and warfarin in low-, moderate- or high-risk patients.

A small increase in the risk of heart attack with Pradaxa versus warfarin was about the only cloud over the original RE-LY results presented in Barcelona, Spain last August. The Phase III data overall generated an enthusiastic response from clinicians, with suggestions that Pradaxa could revolutionise anticoagulant therapy, given the complications associated with warfarin use and monitoring.

But there were also warnings that the higher risk of MI with Pradaxa could lead the US Food and Drug Administration to err on the side of caution and restrict the drug to the higher-risk population for stroke prevention.

In the top-line results from the 18,113-patient RE-LY (Randomised Evaluation of Long term anticoagulant therapy) trial delivered at the European Society of Cardiology Congress last year, patients given the higher 150mg dose of Pradaxa had a 34% lower risk of stroke and systemic embolism than those on warfarin, with a better safety profile in terms of life-threatening, intracranial and total bleeding.

Benefits were also shown with Pradaxa in secondary outcomes such as haemorrhagic strokes and vascular mortality. RE-LY was the largest ever outcomes trial conducted in patients with atrial fibrillation (AF). According to BI, up to three million people worldwide have strokes related to AF every year, with half of them dying within one year.

Sub-group analysis

The sub-group analysis presented in Atlanta looked at rates of stroke and systemic embolism with Pradaxa and warfarin respectively in patients defined as being at low (5,775 patients), moderate (6,455) or high (5,882) risk of these events, according to the validated stroke risk stratification score, CHADS2.

As BI pointed out, the use of stratification scores such as CHADS2 means that in patients classified as being at high or moderate risk of stroke, the reduction in stroke risk with vitamin K antagonists (VKAs) like warfarin is likely to outweigh the risk of bleeding.

For patients with a low, CHADS2 risk score, though, “the benefits of VKAs are not as clear”. Many of these patients therefore receive only aspirin, which is less effective than warfarin at reducing the risk of stroke, BI noted. It cited Dr Adrian Brady, consultant cardiologist at Glasgow Royal Infirmary, as suggesting that 50% of people with AF in the UK who should be on an anticoagulant are not given warfarin due to concerns about bleeding.

The RE-LY sub-group analysis found that:

- Dabigatran etexilate 150mg bid reduced the rate of stroke and systemic embolism versus well-controlled warfarin across all stroke risk groups, with relative risk (RR) of 0.62 in low-, 0.61in moderate-, and 0.70 in high-risk patients.

- Dabigatran etexilate 110mg bid showed similar reductions in the rate of stroke and systemic embolism to well-controlled warfarin, with RRs of 1.00, 1.04 and 0.79 in low-, moderate- and high-risk patients respectively.

- Both doses of dabigatran etexilate were associated with lower rates of major bleeding than well-controlled warfarin in low-risk patients (RR for 110mg = 0.67, RR for 150mg = 0.73).

- Consistent with the overall RE-LY results, both doses of dabigatran were associated with substantial reductions in the rates of intracranial hemorrhage across all risk groups.

No MI data

As far as the risks of heart attack go, the new data were part of a pre-specified sub-analysis of the main RE-LY study investigating stroke rate in relation to stroke risk according to CHADS, BI told PharmaTimes. As such, “there is no specific information looking at MI rates within this data”, it added.

In the original RE-LY results, myocardial infarction events occurred in 63 (0.53% per year) patients on warfarin and in 86 (0.72%) and 89 (0.74%) patients on dabigatran etexilate 110mg and 150mg respectively, the company pointed out. Of all the adverse outcomes defined in the net clinical benefit outcome (stroke/systemic embolism, myocardial infarction, pulmonary embolism, death and major bleeding events), MIs represented only around 10% of the total.

The overall incidence of MI events in the trial was relatively low compared with other outcomes, BI added. Moreover, the difference in MI events between warfarin and dabigatran “is small and must be viewed in context of the benefits of dabigatran in ischaemic stroke, haemorrhagic stroke, intracranial haemorrhage and vascular mortality. These are the most important outcomes in atrial fibrillation patients and the overall benefit of treatment is resoundingly in favour of dabigatran”.

The lower rate of MIs in the warfarin group “may simply reflect its very potent effect on coronary events compared to other agents”, the company suggested. For example, in the ACTIVE-W (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) study, “the effect of warfarin on MI compared to dual antiplatelet therapy was even greater than the differences between warfarin and dabigatran in RE-LY”.

Blockbuster potential

Analysts from Decision Resources have predicted that Pradaxa will become one of the leading stroke prevention therapies in the pharmaceutical market for atrial fibrillation, running up blockbuster sales of US$1.3 billion by 2018 in the US, France, Germany, Italy, Spain, the UK and Japan.

This will be part of a wider trend whereby novel oral anticoagulants will account for nearly three quarters of the AF drug market by 2018, driven by their rapid onset of action and the convenience of fixed dosing, the analysts believe.

Pradaxa is currently approved in more than 50 countries for the primary prevention of venous thomboembolic events (blood clots) in adults who have undergone elective total hip or elective total knee replacement surgery.

Boehringer Ingelheim submitted a centralised licence application for dabigatran etexilate for the prevention of stroke in adult patients with atrial fibrillation to the European Medicines Agency in January. The company “is unable to comment on timing of marketing authorisations as it relates to confidential discussions with regulatory agencies”, it said.