Defining Exposure in Observational Studies Comparing Outcomes of Treatment Discontinuation

BACKGROUND: Continuation of antiplatelet therapy beyond 12 months after a drug-eluting stent procedure reduced the risk of a major adverse cardiovascular and cerebrovascular event (MACCE) in the DAPT trial (Dual Antiplatelet Therapy). Observational studies have evaluated outcomes related to different durations of therapy but are susceptible to bias. METHODS AND RESULTS: Using deidentified claims from commercially insured and Medicare populations in the United States, we compared how increasingly stringent definitions of exposure affect associations between antiplatelet continuation versus discontinuation and MACCE, myocardial infarction, and intracerebral hemorrhage or gastrointestinal bleeding in patients meeting DAPT trial inclusion criteria between 2004 and 2013. Therapy continuation at 12 months was defined as (1) having antiplatelet supply on hand versus not (landmark time); (2) refilling within 30 days versus not among individuals with antiplatelet supply; (3) criteria 2 plus continuous prior antiplatelet use; and (4) criteria 2 and 3 plus a cardiologist visit in months 10 to 12. Propensity score-adjusted hazard ratios were compared. Cohort sizes were 53 679, 27 524, 16 971, and 7948, respectively, of which 20% were discontinuers on average. Increasing restriction led to progressively larger associations with continued treatment: cohort 1 MACCE hazard ratio, 0.79 (0.73, 0.87); myocardial infarction, 0.74 (0.65, 0.83); bleed, 1.03 (0.96, 1.11) versus cohort 4 MACCE hazard ratio, 0.66 (0.48, 0.91); myocardial infarction, 0.56 (0.37, 0.86); bleed, 1.24 (0.95, 1.61). Estimates trended toward DAPT trial estimates and were associated with reduced levels of exposure misclassification. CONCLUSIONS: In an example of long-term antiplatelet use, increasing restrictions on the definition of therapy continuation yielded results consistent with trial estimates by reducing exposure misclassification.