New therapies for stroke prevention

Atrial fibrillation (AF) is a major risk factor for stroke, accounting for over 30% of stroke cases in Ireland. AF-related strokes are usually especially severe and disabling, and this heart rhythm condition raises the risk of stroke five-fold.

For many years, warfarin therapy has been seen as an effective method for reducing stroke risk by around two-thirds of patients with AF. But warfarin does not come without its problems in administration, monitoring and food and drug interactions. As a result, only around half of the patients who could benefit from it actually receive warfarin.

Clinicians therefore have identified a need for management solutions in AF that are easier to use and monitor, and safer in terms of risks such as bleeding. The role of the new oral anticoagulants was explored in a recent seminar on anticoagulation therapy in stroke prevention (New Perspectives on Anticoagulation Therapy in Stroke Prevention and Atrial Fibrillation, organised by Boehringer Ingelheim) held in Barcelona.

Public health issue

Prof Gregory Lip of City Hospital, Birmingham, UK told the meeting of the extent of the AF problem as a public health issue. He said between 3% and 6% of hospital admissions have AF and, as AF is frequently asymptomatic, often the first time it becomes evident is when someone has a devastating stroke. He pointed out that AF incidence is on the increase.

The extent of the AF problem was reiterated by Prof John Camm, of St George’s University of London, stressing the huge cost to both society and health systems from the devastating effects of stroke. He said a 15% reduction in hospital admissions due to stroke in the UK would lead to a saving of £30 million a year.

Efficacy of the new therapies

The question posed at the conference was how effective are the three new oral anticoagulants and whether they offer a practical and effective alternative to warfarin therapy.

Dabigatran etexilate

Prof Stuart Connolly of McMaster University, Hamilton in Canada, gave an overview of the results of the RE-LY trial into Pradaxa (dabigatran etexilate). This international trial involved 18,113 patients and compared both 110mg and 150mg dabigatran to warfarin. Patients enrolled were mostly elderly (median 72 years), with a variety of stroke risk levels.

Prof Connolly said it was found that 150mg dabigatran twice daily was associated with a lower risk of stroke or stroke embolism than warfarin (1.11% per year versus 1.71%). The study also indicated that the lower dose had similar efficacy to warfarin (1.54% per year versus 1.71%).

Ischaemic or unspecified stroke incidence with 150mg dabigatran was 0.92% per year, whereas it was 1.21% with warfarin. In RE-LY, the haemorrhagic stroke rate with warfarin was 0.38% but 0.10% with the newer anticoagulant. The 110mg dose of dabigatran was superior to warfarin in terms of major bleeding incidents.

Prof Connolly said both dabigatran doses were non-inferior to warfarin with respect to the primary efficacy outcome of stroke or systemic embolism. Overall, Prof Connolly said, RE-LY showed that dabigatran was superior to warfarin, with both doses providing important benefits over it.

Rivaroxaban

Prof Keith Fox of the University of Edinburgh, gave an overview of the ROCKET AF trial into Xarelto (rivaroxaban). This study, involving 14,264 patients, compared rivaroxaban 20mg once-daily with warfarin. The trial focused on higher risk patients, with 55% of them having had a prior stroke. 

Prof Fox said the trial showed that rivaroxaban’s efficacy was on a par with warfarin, and while patients were taking the drug it performed better than warfarin.

For the primary outcome (stroke/systemic embolism) in the ‘as treated’ population the percentage for warfarin was 2.2% per year while it was 1.7% for rivaroxaban. There was less of a difference between the two in the primary outcome ‘intention to treat’ population. Rates of bleeding were broadly similar in both treatment arms. 

Prof Fox said irrespective of the study group, rivaroxaban met most criteria for non-inferiority while on treatment, but while patients were off the drug the results were not significantly better than those taking warfarin.

Apixaban

Prof Elaine Hylek from Boston University School of Medicine presented results from the ARISTOTLE trial into Eliquis (apixaban).⁶ The ARISTOTLE trial involved 18,201 patients, comparing 5mg apixaban twice daily with warfarin. In terms of primary outcome, apixaban recorded 1.27% as having a stroke or systemic embolism per year, compared to 1.60% in the warfarin group. 

For ischaemic or unspecified stroke, the results were 0.97% with apixaban and 1.05% with warfarin. Major bleeding rates with warfarin were 3.09% compared to 2.13% with apixaban.

Consensus

The consensus among the expert panel at the meeting appeared to be that, with the newer anticoagulants coming on stream, the days of warfarin and aspirin having a major role in stroke prevention in AF were numbered.

It was felt, however, that the more traditional anticoagulants may continue to be used in countries where the cost of the newer drugs would be prohibitive. 

Prof Camm pointed out that the cost of the newer drugs might be difficult for health systems to bear in current times. This has certainly been the source of some controversy in Ireland, where there have been issues with reimbursement for new anticoagulants.

However, Prof Connolly pointed out that the ‘bigger picture’ was the fact that more effective management of AF in stroke prevention would lead to major savings on the cost of treatment and rehabilitation post-stroke.

Prof Camm said as yet there were no clear guidelines for GPs on which of the  new anticoagulants suited which patients, so in the shorter term, secondary care would be making most of these decisions.  However, the longer-term goal would be to shift more of the responsibility for anticoagulation to primary care.

“All the new anticoagulants are better than warfarin, but the key issue is that patients are put on some anticoagulant” he said.

Prof Connolly predicted that warfarin’s days were numbered, and in the future medical students may not know what an INR (international normalised ratio) is.

The overall consensus was, therefore, that while there may be issues with the cost of the newer anticoagulants, the longer-term value of getting more patients on easier to use anticoagulation therapy and therefore preventing more strokes, would be priceless.