ESC: Until new anticoagulants arrive, tight INR control needed to prevent stroke
Dabigatran (Pradaxa, Boehringer Ingelheim) was effective in preventing stroke in patients with atrial fibrillation, and has shown that local standards of care affect the benefits of switching to new treatments, based on a post-hoc analysis of the randomized RE-LY trial presented at this week's European Society of Cardiology conference in Stockholm, Sweden, and simultaneously published in the Lancet.

In the RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial, dabigatran versus warfarin (Coumadin, Bristol-Myers Squibb) reduced both stroke and hemorrhage. In this analysis, Lars Wallentin, MD, PhD, from Uppsala University in Uppsala, Sweden, and colleagues sought to investigate the primary and secondary outcomes of the RE-LY trial in relation to each center’s mean time in therapeutic range (cTTR) in the warfarin population. Therefore, the new analysis examined whether or not the benefits shown by dabigatran in RE-LY were consistent even in centers that had poor international normalized ratio (INR) quality control, as estimated by cTTR.

In the RE-LY trial, the researchers randomly assigned 18,113 patients at 951 sites to 110 mg or 150 mg dabigatran twice daily versus warfarin dose adjusted to INR of 2-3. Median follow-up was two years. For 18,024 patients at 906 sites, they estimated cTTR by averaging TTR for individual warfarin-treated patients calculated by the Rosendaal method.

The investigators compared the outcomes of RE-LY across the three treatment groups within four groups defined by the quartiles of cTTR. The quartiles of cTTR for patients in the warfarin group were: less than 57.1 percent, 57.1–65.5 percent, 65.5–72.6 percent, and greater than 72.6 percent. There were no significant interactions between cTTR and prevention of stroke and systemic embolism with either 110 mg dabigatran (interaction p=0.89) or 150 mg dabigatran (interaction p=0.20) versus warfarin.

Neither were there any significant interactions recorded with cTTR with regards to intracranial bleeding with 110 mg dabigatran (interaction p=0.71) or 150 mg dabigatran (interaction p=0·89) versus warfarin, according to Wallentin and colleagues.

However, they discovered a significant interaction between cTTR and major bleeding when comparing 150 mg dabigatran with warfarin (interaction p=0.03). They found less bleeding events at lower cTTR but similar events at higher cTTR, whereas rates of major bleeding were lower with 110 mg dabigatran than with warfarin irrespective of cTTR.

Also, the authors reported significant interactions between cTTR and effects of both 110 mg and 150 mg dabigatran versus warfarin on the composite of all cardiovascular events (interaction p=0.036 and p=0.0006, respectively) and total mortality (interaction p=0.066 and p=0.052, respectively), with reduced event rates at low cTTR, and similar rates at high cTTR.

Based on these findings, Wallentin and colleagues concluded that the benefits of 150 mg dabigatran at reducing stroke, 110 mg dabigatran at reducing bleeding and both doses at reducing intracranial bleeding versus warfarin were consistent irrespective of centers’ quality of INR control.

The findings support the superiority of 150 mg dabigatran twice daily and the noninferiority of 110 mg dabigatran twice daily versus warfarin for protection against stroke in atrial fibrillation irrespective of the quality of INR control that a center can achieve, the authors wrote. However, 150 mg dabigatran was not superior to warfarin at reducing the risk of nonhemorrhagic stroke at higher cTTR quartiles.

“For all vascular events, non-hemorrhagic events, and mortality, advantages of dabigatran were greater at sites with poor INR control than at those with good INR control,” they wrote. “Overall, these results show that local standards of care affect the benefits of use of new treatment alternatives.”

In an accompanying Lancet editorial, Deirdre A. Lane, PhD, and Gregory YH Lip, MD, from the University of Birmingham Centre for Cardiovascular Sciences, City Hospital in Birmingham, England, wrote that the findings mean oral anticoagulants would probably be advocated for an even greater proportion of patients with atrial fibrillation, in view of the future availability of the new oral anticoagulants, such as dabigatran, that overcome the disadvantages of warfarin.

While they suggested that the use of cTTR is a surrogate for INR control and might not “truly reflect TTRs for individual patients,” Lane and Lip added that these findings may affect clinical practice because new guidelines might indicate “shifts in management based on more comprehensive stroke-risk stratification (e.g., CHA2DS2-VASc) and simplified bleeding risk assessment (e.g., HAS-BLED),” they wrote.

"Until the new oral anticoagulants become widely available (a positive advance), we should advocate tight INR control at conventional levels, for which there is a wealth of evidence for benefit, and promote strategies to improve the management of therapy with vitamin K antagonists [such as warfarin]," they added.

Boehringer Ingelheim, headquartered in Ingelheim am Rhein, Germany, funded the post-hoc analysis.