Authors' reply

摘要

Claudia Stollberger and Josef Finsterer, and Rahman Shah and colleagues raise important comments about how international normalised ratio (INR) management affected our analyses. Stollberger and Finsterer specifically ask about the measures taken by the data safety monitoring committees to improve INR control. It is important to point out that these trials were done in about 50 countries, across six continents. The median combined time in therapeutic range (TTR) for all four trials was a respectable 65% (IQR 51-76), which compares very favourably witb the most recent estimate of the quality of INR management in the USA (average TTR 537%). They also raise the relevant question of whether the benefit of new oral anticoagulants compared with warfarin was dependent on how well warfarin was managed. While acknowledging the limitations of using centre-based TTR (cTTR) pointed out by Shah and colleagues (it is the only INR metric available for the trials), in our meta-analysis we examined a cTTR threshold of 66% and found that the reduction in stroke or systemic embolism compared with warfarin was not dependent on how well warfarin was managed. However, an even more pronounced relative reduction in bleeding with new oral anticoagulants seems to take place in patients who have difficulty maintaining a therapeutic INR. As Shah and colleagues point out, we did not report the effect of cTTR on intracranial haemorrhage and mortality because we only had cTTR and outcome data for the primary efficacy (stroke or systemic embolism) and safety (major bleeding) endpoints.