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Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug–drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. Objectives We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking which would interact with hydroxychloroquine. Methods We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug–drug interactions with hydroxychloroquine that might exclude them from participation in a typical coronavirus disease 2019 (COVID‐19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as being potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine. Results The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and anti‐diabetic agents. Conclusion The COVID‐19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID‐19. This article is protected by copyright. All rights reserved.

ImportanceOlder adults, at high-risk of developing complications from COVID-19, could benefit from nirmatrelvir-ritonavir, an oral antiviral treatment for outpatients at high risk of complications from COVID-19; however, due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).ObjectivesIdentify how common DDIs are between nirmatrelvir-ritonavir, common medications, and PIMs in older adults with polypharmacy. Craft anticipatory deprescribing guidance for PIMs that interact with nirmatrelvir-ritonavir to help prioritize deprescribing resources, and increase the proportion of older adults potentially benefitting from treatment.DesignIn this secondary analysis, we retrospectively analyzed all patients in the MedSafer cluster randomized deprescribing trial (N=5698 participants) to investigate the proportion of older adults (age >65) with polypharmacy (≥5 usual home medications) who would be ineligible for treatment with nirmatrelvir-ritonavir due to pre-existing DDIs.SettingThe setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals.ParticipantsHospitalized persons, age 65 years and older, on 5 or more daily home medications, with an expected survival of 3 months or longer were included in this secondary analysis.Main outcomes and measuresWe identified the prevalence of (PIMs), as defined by the MedSafer software. We then developed deprescribing guidance, so clinicians could proactively deprescribe in an effort to increase the proportion of older adults eligible for safe treatment with nirmatrelvir-ritonavir in the event of a SARS-CoV-2 infection.ResultsOf 5698 participants, a total of 3869 (68%) were taking a medication with a known nirmatrelvir-ritonavir DDI, and of these 823 (21%) had at least one PIM. Of 823 PIMs, 627 (76%) were medications with a known high risk DDI and 213 (26%) were considered moderate risk DDIs with nirmatrelvir-ritonavir. Many of the PIMs required “advanced deprescribing” and could not simply be stopped, held, or adjusted at the time of nirmatrelvir-ritonavir receipt.Conclusions and relevanceOlder adults are at high risk of developing severe complications from COVID-19. Deprescribing PIMs in advance of a COVID-19 infection could increase the proportion of older adults who can safely receive nirmatrelvir-ritonavir, in addition to the usual benefits observed with medication management.Impact StatementWe certify that this work is novel. This timely clinical investigation explores the unforeseen consequences of polypharmacy and the use of potentially inappropriate medication in older adults during the COVID-19 pandemic. This manuscript addresses the many drug-drug interactions between nirmatrelvir-ritonavir, an antiviral treatment for COVID-19, and potentially inappropriate medications in older adults with polypharmacy from the MedSafer cluster randomized trial. Our work highlights that the pandemic has created an even greater urgency to examine the medication lists of older adults and proactively deprescribe to improve the safety and tolerability of different COVID-19 treatments.Key PointsQuestion: How does polypharmacy affect the eligibility of older adults to receive Nirmatrelvir-ritonavir?Findings: 68% of older adults in the MedSafer cluster randomized trial had a DDI with nirmatrelvir-ritonavir, and 21% were taking at least 1 potentially inappropriate medication.Meaning: Due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).

Objectives Polypharmacy is common in older adults and associated with adverse drug events (ADEs). Several methods have been described in studies to help correlate ADE causation. We performed a narrative review to identify methods for ADE adjudication. We compared their strengths and limitations to assess their applicability to deprescribing studies (of which clinical trials are a subset) and to encourage the use of a standardized method in future studies. Design We performed a review of original articles (1946-2019) using the Medline (Ovid) and Cochrane databases. We also conducted a manual reference search of review articles. Abstracts were screened for relevance. Measurements Adjudication methods were compared for advantages and limitations including validity, ease of use, and applicability to clinical trials with deprescribing as the primary intervention. Results The search yielded 1881 articles of which 175 articles were included for full-text review. Following in-depth review, 135 were excluded: 79 had no ADE outcome data, 35 were not specific to older adults, 9 were not relevant, 6 were review articles, 5 contained duplicate data, and 1 was not written in French or English. Forty articles remained for analysis, from which we identified 10 unique ADE adjudication methods. No method was developed originally for use in a deprescribing setting. Conclusion A standard method to identify ADEs is important to capture the outcome reliably in deprescribing studies. All methods we identified had limitations in terms of capturing adverse events from the withdrawal of medications. Future work should focus on refining adjudication methods for capturing ADEs related not only to medication continuation and new drug starts but also to deprescribing and drug discontinuation. J Am Geriatr Soc 68:1594-1602, 2020.