November 13, 2012

LOS ANGELES — Data from an additional 2.3 years of follow-up from the dabigatran (Pradaxa, Boehringer Ingelheim) group in the RE-LY trial of AF patients suggest that the rates of stroke and major bleeding remain low on dabigatran when used long term and are consistent with those seen during the main RE-LY study period.

A second observational study (GARFIELD) found that the risks of AF are graded with the number of risk factors and are high if effective anticoagulation is not on board, which is the case in the majority of patients.

The two studies were presented at last week's American Heart Association 2012 Scientific Sessions.

RE-LY Extension

The latest dabigatran data come from the RELY-ABLE study, which included patients from certain centers who had been in the dabigatran arm of RE-LY and were still receiving the drug at the end of the randomized study period. In the RELY-ABLE extension study, 5851 patients continued to receive dabigatran at the same dose as in the main trial for another 2.3 years.

Presenting the RELY-ABLE results last week, Dr Stuart Connolly (McMaster University, Hamilton, ON) reported that data from a total follow-up of 4.3 years (including the randomized RE-LY study period) show the two doses--150 and 110 mg--of dabigatran were "very comparable" in terms of mortality and net clinical benefit. Both have very low rates of hemorrhagic stroke, while the 150-mg dose is associated with a lower rate of ischemic stroke and a higher rate of major bleeding compared with 110-mg dose, he added.

RELYABLE: Outcomes for the Two Dabigatran Doses in the 2.3-Year Extension Study

Event Dabigatran 150 mg (%/y) Dabigatran 110 mg (%/y) HR (95%CI)
Stroke/systemic embolism 1.46 1.60 0.91 (0.69–1.20)
Major bleed 3.74 2.99 1.26 (1.04–1.53)
Intracranial bleed 0.33 0.25 1.31 (0.68–2.51)
Death 3.02 3.10 0.97(0.80–1.19)
Stroke, systemic embolism, MI, pulmonary embolism, major bleed, or death 7.36 6.89 1.07 (0.94–1.22)

Designated discussant of the RELY-ABLE results, Dr Robert Giugliano (Brigham and Women's Hospital, Boston, MA), pointed out that the study had several limitations, including the fact that it included only 32% of patients from RE-LY, and 28-month follow-up was available for only 12% of RE-LY patients. "This is not a randomized controlled trial," he reminded the attendees, noting that patients were included only from selected centers and if they wanted to participate; they were excluded if they stopped the drug, and follow-up stopped when the drug was stopped.

"I'd like to see the baseline demographics of patients participating and those not participating in RELY-ABLE. I think they would be very different," Giugliano added. However, with all those caveats, he concluded: "Longer-term outcomes with dabigatran look quite favorable."

GARFIELD Plans to Follow 55,000 Patients

The GARFIELD study, presented by Dr Ajay Kakkar (Thrombosis Research Institute and University College London, UK), is investigating clinical outcomes in newly diagnosed AF patients with one or more additional risk factors for stroke randomly selected from a variety of settings to reflect real-world care.

The researchers plan to include 55 000 patients from 35 countries to be prospectively followed. Results presented last week are from the first 10 000 patients from 19 countries with a mean of 11.9 months of follow-up.

Of these patients, 60% were treated by a cardiologist, 20% by an internal-medicine physician, and 20% in primary care.

In terms of treatment, 57% were receiving a vitamin-K antagonist, only 0.2% were taking one of the new oral anticoagulant drugs, 9% were taking other anticoagulants (not guideline recommended), 38% were on an antiplatelet drug, and 6.5% were not receiving any antithrombotic therapy.

Of patients on a vitamin-K antagonist, 81% had INR values available, which indicated good control in only 43% of patients. In his discussion of this study, Giugliano pointed out that these figures translate into only one in four patients getting adequate anticoagulation.

CHA2DS2-VASc scores were said to be "pretty standard," with the majority of patients scoring between 2 and 4. Use of antithrombotic therapies increased with increasing risk scores.

The greatest burden in these patients is of death.

Outcome results showed a rate of stroke of 1.3%, major bleed of 0.6%, and mortality of 2.2%. "The greatest burden in these patients is of death," Kakkar commented.

Numbers of strokes and deaths increased with the number of risk factors. Patients on well-controlled anticoagulant therapy had better outcomes (in terms of stroke, bleeds, and mortality) than those with poor control. And outcomes with poorly controlled anticoagulation therapy were closer to those on no anticoagulant therapy than those with well-controlled therapy.

GARFIELD: Outcomes in Patients According to Anticoagulation Status

Outcome Well-controlled anticoagulant (%) Poorly controlled anticoagulant (%) None or unknown anticoagulant (%)
Stroke/systemic embolism 0.9 1.3 0.8
Bleed 0.5 1.0 0.5
Death 0.9 1.7 3.4

In time, as the study continues and use of the new anticoagulants increases, it will be possible to compare outcomes with the new drugs vs vitamin-K antagonists, Kakkar said.