226 CHAPTER 3.2 was identified as a drug-related hospital admission. Hospitalizations leading to death were also adjudicated for drug-related hospital admission, but not those for diagnostic/elective procedures for pre-existing conditions, or outpatient or emergency department visits, as the documentation of such visits is often too incomplete for adjudication of drug-relatedness. During trial conduct, but before enrolment ended and without looking at the data, non-substantial clarifications of the primary outcome definition were introduced: 1) clarification that the effect measure was a hazard ratio (HR), and 2) shorter description of what constitutes a “hospitalization” in clinicaltrials.gov. Secondary outcomes within 12 months of enrolment included all-cause mortality, cancer mortality (negative control outcome to assess selection bias and blinding [39], as it was not expected to be influenced by the intervention), incident falls, and quality of life (visual analogue scale of the European Quality of Life 5 Dimensions (EQ-5D) questionnaire [40]). Other outcomes were selected according to a core outcome set for trials of medication review in multimorbid older patients with polypharmacy [41] and included pain/discomfort score (EQ-5D questionnaire), number of long-term prescription drugs, activities of daily living (Barthel Index of Activities of Daily Living [42]) and drug compliance (©MMAS-8 [35]), with month 12 as the main outcome month. Secondary outcomes within 2 months after enrolment included the presence of drug overuse and misuse (based on STOPP criteria [22]), drug underuse (defined by START criteria [22]), and clinically significant drug-drug interactions [43] (see Methods appendix for details). As a process measure for intervention patients, we calculated the number of STOPP/START recommendations made to attending hospital physicians and the number of implemented recommendations at 2 months. We also added two post-hoc outcomes: 1) first confirmed preventable drug-related hospital admission, considering admissions to be preventable when deemed potentially related to inappropriate prescribing (drug overuse, underuse or misuse as evaluated by the adjudication committee); 2) first drug-related hospital admission in a subpopulation restricting the intervention group to patients with ≥1 STOPP recommendation implemented after 2 months. Statistical analysis We based the sample size estimation of 80 clusters with 2,000 patients for the primary outcome on an estimated 1-year event rate of ≥1 drug-related hospital admission in 20% of the control group [17,44], 1-year mortality of 20% [45], assumed 1-year drop-out rate of 6%, 80% power to detect a 30% relative risk reduction in the intervention group at a two-sided type-1 error level of 0.05, an assumed intra-
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