242 CHAPTER 3.2 patients. Future trials should also assess implementation of pharmacotherapy optimization in outpatient settings, such as by GPs or in pharmacies. Strengths and limitations of this study OPERAM has several strengths. Firstly, it enrolled multimorbid patients with minimal exclusion criteria, heightening the generalizability of the results. Secondly, few patients were lost to follow-up and death was the main reason for study discontinuation. Thirdly, OPERAM’s study design addressed many of the limitations of previous trials: its cluster-randomization design limited allocation contamination, blinding was maximized, hospital admissions were adjudicated by a blinded adjudication committee and statistical power was sufficient with an adequate follow-up length for clinical outcomes. OPERAM has some limitations. Although complete blinding was not possible, we sought to maximize blinding and to lower the risk of related bias – in contrast with previous trials [7] – by recruiting staff and adjudicators/outcome assessors who were fully blinded; patients were partially blinded and received a sham intervention in the control group. In addition, the risk of death from cancer was included as a negative control outcome and did not point to strong selection bias. Clusterrandomization was at the physician-level and not at the hospital-level, and the potential for contamination in control clusters cannot be completely ruled out. However, physicians were independent in the treatment decisions on their units and had signed a discretion contract not to share information with their physician or pharmacist colleagues. STRIP was not applied in the control group and whether medication changes in the control group met STOPP/START criteria was not assessed. Therefore, we cannot rule out the possibility that some medication changes in the control group similar to the intervention recommendations may have been made, which might have led to results closer towards no betweengroup difference. Frailty was not assessed at baseline, and we cannot therefore determine whether the intervention effect depended on frailty status. Relying on retrospective chart review for identifying drug-related hospital admissions is the gold standard [38], but it depends on the quality of documentation in the medical record, particularly for assessment of potential underuse; e.g. adherence and patient preferences are often not documented in the medical charts. Finally, one could argue that the lower limit of the confidence interval does not exclude the effect observed in a previous trial with a different follow-up period [57] However, the lower limit is very close to this effect, which still makes it unlikely that any replication of OPERAMwould find such an effect. Moreover, the rate of the primary outcome in the control group was even higher than expected in the original sample size calculation, resulting in a sufficiently powered trial for the targeted effect.
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