Standard-dose DOACs beat warfarin by more in Asian patients

Design

Patient-level meta-analysis of four randomised trials (COMBINE AF)

Population

71,683 patients with atrial fibrillation, 10,212 of Asian race

Primary outcome

Stroke or systemic embolism; major bleeding; net clinical outcome

Effect

Standard-dose DOAC vs warfarin, stroke/SEE: HR 0.65 (Asian) vs 0.86 (non-Asian)

COMBINE AF pooled individual patient data from the four pivotal trials comparing DOACs with warfarin in atrial fibrillation (dabigatran, rivaroxaban, apixaban and edoxaban). It identified 10,212 Asian patients and 61,471 others. Asian patients were on average 20 kg lighter, had lower creatinine clearance and more prior stroke, and spent less time in the therapeutic range on warfarin (58% vs 66%).

Compared with warfarin, standard-dose DOACs reduced stroke or systemic embolism more in Asian patients (HR 0.65, 95% CI 0.53–0.80) than in non-Asian patients (HR 0.86). The pattern held for major bleeding (0.62 vs 0.91) and for the net clinical outcome. Gastrointestinal bleeding rose with standard-dose DOACs only in non-Asian patients. The benefit held across body weight and kidney function. In Asian patients, lower doses carried a 57% higher stroke risk than standard doses (HR 1.57, 95% CI 1.15–2.13).

In India, clinicians often reduce DOAC doses for lighter patients out of bleeding concern. These data, from randomised trials, point the other way. This is a subgroup analysis across trials and race is a crude proxy, but the direction is consistent and the interaction tests were significant.

• Use standard DOAC doses in Asian patients unless the label's dose-reduction criteria are met.
• Do not reduce the dose for low body weight alone.
• Where warfarin control is poor, the case for switching to a DOAC is stronger in Asian patients.
• Review existing patients on reduced doses and check whether they meet the criteria.
• Recheck creatinine clearance before and during treatment.

Why it matters

This challenges the widespread habit of under-dosing DOACs in lighter Asian patients.

Don't overread it

Asian patients were analysed as one group; results for South Asian patients are not reported separately.

The statistics, in plain English

A hazard ratio of 0.65 means about 35% fewer strokes than on warfarin in Asian patients, against about 14% in non-Asian patients. The 'interaction' test asks whether that difference between groups is likely to be real; here it was statistically significant. A subgroup analysis is weaker than a trial designed for that group, but this one uses randomised data from more than 10,000 patients.

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