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Randomized controlled trials remain a gold standard in evaluating the efficacy and safety of a new treatment. Ideally, patients adhere to their treatments for the duration of the study, and the resulting data can be analyzed unambiguously for efficacy and safety outcomes. However, some patients may discontinue the study treatment due to intercurrent events, which leaves missing observations or observations that do not reflect the randomly assigned treatment. Frequently, an intent-to-treat analysis (or a modification thereof) is done to estimate the treatment effect for all randomized patients regardless of the occurrence of intercurrent events. Alternatively, clinicians may be more interested in understanding the efficacy and safety for those who can adhere to the study treatment. The naive per-protocol analysis may provide a biased estimate for the treatment difference because the observed adherence populations may not be comparable between two treatments. In this article, we propose two methods for estimation of the treatment difference for those who can adhere to one or both treatments based on the counterfactual framework. Theoretical derivations and a simulation study show the proposed methods provide consistent estimators for the treatment difference for the adherent population of interest. A real data example comparing two basal insulins for patients with type-1 diabetes is provided using the proposed methods. for this article are available online. [ABSTRACT FROM AUTHOR]

Background: Oral anticoagulation (OAC) in atrial fibrillation (AF) reduces the risk of stroke/systemic embolism (SE). The impact of OAC discontinuation is less well documented., Objective: Investigate outcomes of patients prospectively enrolled in the Global Anticoagulant Registry in the Field-Atrial Fibrillation study who discontinued OAC., Methods: Oral anticoagulation discontinuation was defined as cessation of treatment for ≥7 consecutive days. Adjusted outcome risks were assessed in 23 882 patients with 511 days of median follow-up after discontinuation., Results: Patients who discontinued (n = 3114, 13.0%) had a higher risk (hazard ratio [95% CI]) of all-cause death (1.62 [1.25-2.09]), stroke/systemic embolism (SE) (2.21 [1.42-3.44]) and myocardial infarction (MI) (1.85 [1.09-3.13]) than patients who did not, whether OAC was restarted or not. This higher risk of outcomes after discontinuation was similar for patients treated with vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) (p for interactions range = 0.145-0.778). Bleeding history (1.43 [1.14-1.80]), paroxysmal vs. persistent AF (1.15 [1.02-1.29]), emergency room care setting vs. office (1.37 [1.18-1.59]), major, clinically relevant nonmajor, and minor bleeding (10.02 [7.19-13.98], 2.70 [2.24-3.25] and 1.90 [1.61-2.23]), stroke/SE (4.09 [2.55-6.56]), MI (2.74 [1.69-4.43]), and left atrial appendage procedures (4.99 [1.82-13.70]) were predictors of discontinuation. Age (0.84 [0.81-0.88], per 10-year increase), history of stroke/transient ischemic attack (0.81 [0.71-0.93]), diabetes (0.88 [0.80-0.97]), weeks from AF onset to treatment (0.96 [0.93-0.99] per week), and permanent vs. persistent AF (0.73 [0.63-0.86]) were predictors of lower discontinuation rates., Conclusions: In GARFIELD-AF, the rate of discontinuation was 13.0%. Discontinuation for ≥7 consecutive days was associated with significantly higher all-cause mortality, stroke/SE, and MI risk. Caution should be exerted when considering any OAC discontinuation beyond 7 days., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)