Rivaroxaban was found to be noninferior to warfarin in routine clinical care: A retrospective noninferiority cohort replication study

Abstract

Purpose: To compare the effectiveness and safety of a drug in daily practice with the outcomes of a target non-inferiority trial by rigorously mimickingin an observational study the trial's design features. Methods: This cohort study was conducted using the British Clinical Practice Research Datalink (CPRD) to emulate the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial. Patients with atrial fibrillation who were newly prescribed (>=12 months of no use) either rivaroxaban or warfarinfrom October 2008 to December 2017 were included. Non-inferiority of rivaroxaban to warfarin in the prevention of stroke or systemic embolism was assessed in different analysis populations (intention-to-treat [ITT], per-protocol [PP], and as-treated populations) using a hazardratio (HR) of 1.46 as the non-inferiority margin. Major bleeding (safety outcome) was also assessed and compared to that of the target trial. All outcomes were analyzed using Cox-proportional hazard analyses. Results: We included 25,473 incident users of rivaroxaban (n=4,008) or warfarin (n=21,465). Similar to the trial, non-inferiority in the primary out come was demonstrated in all three analysis populations: HR=1.04 (95%CI 0.84 to 1.30) (ITT), HR=0.98 (95%CI 0.70 to 1.38) (PP), and HR=1.11 (95%CI 0.86 to 1.42) (as-treated). Risk of major bleeding was also similar to the target trial. Conclusion: The results of this study provide supportive evidence to the effectiveness of rivaroxaban and adds knowledge on the usefulness of emulating a non-inferiority trial to assess drug effectiveness.

Reporting of Observational Studies Explicitly Aiming to Emulate Randomized Trials

“…We retrieved 3133 unique records, of which 200 were included in the review (Figure 1). All reasons for excluding records after full-text review are given in eAppendix 6 in Supplement 1.…”

“…One-hundred and fifteen studies (58%) completely reported how the target trial protocol was emulated. Eighty-seven studies (44%) provided both the protocol of the target trial and described how it was emulated (Table 2). The following items of the emulation were frequently reported: eligibility criteria (193 [97%]), treatment strategies (191 [96%]), assignment procedures (173 [87%]), primary outcome (196 [98%]), the follow-up period (186 [93%]), a causal contrast (146 [73%], and an analysis plan (194 [97%]) (Table 2).…”

“…Twenty studies (10%) reported the study was prospectively registered, 16 of these 20 (80%) also provided information on how to access the registration. One hundred and twenty-six studies (63%) specified whether a randomized clinical trial could be feasibly conducted; 61 (31%) stated that the randomized clinical trial was possible. Of the studies that stated a randomized clinical trial was possible, uncertainty in the generalizability of available trial findings was the most common reason for the target trial emulation (22 of 61 [36%]) .…”

“…One hundred and twenty-six studies (63%) specified whether a randomized clinical trial could be feasibly conducted; 61 (31%) stated that the randomized clinical trial was possible. Of the studies that stated a randomized clinical trial was possible, uncertainty in the generalizability of available trial findings was the most common reason for the target trial emulation (22 of 61 [36%]) . Forty-three studies (22%) reported using a guideline, most commonly (29 of 43 [67%]) the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guideline …”

Rituximab vs Ocrelizumab in Relapsing-Remitting Multiple Sclerosis

“…Data from large observational registries can be used to guide clinical decision-making by emulating a clinical trial. [9][10][11] In this study, we used data from 2 MS registries to evaluate the clinical noninferiority of rituximab compared with ocrelizumab in the treatment of patients with relapsingremitting MS. 12,13…”