Relationship between time in therapeutic range and comparative treatment effect of rivaroxaban and warfarin: results from the ROCKET AF trial

Abstract

Background: Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.

Methods and results: TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger-stick point-of-care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non-central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower-risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non-major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.

Conclusions: The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.

Keywords: rivaroxaban; time in therapeutic range; warfarin.

Figure 1.

Distribution of cTTR across all sites. This histogram illustrates the distribution of the sites according to cTTR. cTTR indicates center time in therapeutic range; INR, international normalized ratio.

Figure 2.

Probability of stroke or non‐CNS embolism in rivaroxaban and warfarin treated patients according to cTTR. cTTR is shown on the x‐axis. Probability of stroke or non‐CNS embolism by 1‐year of follow‐up is shown on the y‐axis. This plot shows the probability of having a stroke or non‐CNS embolism according to cTTR for rivaroxaban‐ and warfarin‐treated patients (solid lines) with corresponding 95% CIs (dashed lines). Centers with higher cTTR values had a lower risk of stroke and systemic embolus in both the rivaroxaban‐ and warfarin‐treated arms. CNS indicates central nervous system; cTTR, center time in therapeutic range; INR, international normalized ratio.

Figure 3.

Treatment effect for the reduction of stroke or non‐CNS embolism in rivaroxaban and warfarin treated patients at a given cTTR threshold. The x‐axis shows the threshold value for cTTR and the y‐axis shows the HR for the time to stroke or non‐CNS embolism for rivaroxaban vs warfarin given a certain threshold cTTR. The y‐axis also shows the mean individual TTR in those centers that meet the threshold cTTR. There is instability in the estimate of the treatment effect at high cTTR thresholds due to smaller sample size, but no evidence that warfarin is superior to rivaroxaban in the prevention of stroke and systemic embolus at any cTTR threshold. CNS indicates central nervous system; cTTR, center time in therapeutic range; INR, international normalized ratio.

Figure 4.

Risk of intracranial hemorrhage in rivaroxaban‐ vs warfarin‐treated patients according to cTTR at a given threshold. The x‐axis shows the threshold value for cTTR and the y‐axis shows the HR for the time to stroke or non‐CNS embolism for rivaroxaban vs warfarin given a certain threshold cTTR. The y‐axis also shows the mean individual TTR in those centers that meet the threshold cTTR. There is instability in the estimate of the treatment effect at high cTTR thresholds due to smaller sample size, but no evidence that warfarin is superior to rivaroxaban in the prevention of stroke and systemic embolus at any cTTR threshold. CNS indicates central nervous system; cTTR, center time in therapeutic range; INR, international normalized ratio.