COVID-SAFER: Deprescribing Guidance for Nirmatrelvir-ritonavir Drug Interactions in Older Adults

Importance Older 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). Objectives Identify 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. Design In 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. Setting The setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals. Participants Hospitalized 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 measures We 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. Results Of 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 relevance Older 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 Statement We 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 Points ### Competing Interest Statement Todd Lee and Emily McDonald have received research funding from the Canadian Frailty Network, the Canadian Institutes for Health Research, and the Centre for Aging and Brain Health Innovation for the development of MedSafer. Drs Lee and McDonald, along with McGill University, own the intellectual property to MedSafer and are executives of MedSafer CORP, a for-profit company. Drs. Lee and McDonald receive research salary support from the Fonds de recherche du Québec - Santé. ### Clinical Protocols [https://cdn.jamanetwork.com/ama/content\_public/journal/intemed/0/ioi210080supp1\_prod\_1642198696.39131.pdf?Expires=1649169920&Signature=K6WZSgGHyo~r2cGwewqSrg5DIMoFzLp0FwPk0zfr4dpHX9i-PlVRbXA0Nuk8ImICsFbNHJEYy1KjsnGV4379-cPr0MaJE775EzI4XK7SM0OLugMEf-VPseYsUXhms154K5icDbcUXKIYsNIP~0hNbIeklGM1bjhaRWUv-Sfqs2jUqb5ZFnGA4xZ7eDogNGE0TbmG39kvGtCjZGYhKBIJKhYCNtIl9QTrlcczm~X0gzpuNw43wmarAFlezBEVtSb9vDB-F4GxlgcSAbqEEk5Kd1tNl1JYpIqMNSE5yHRBqWosiXck~XwloTYCWLGvgE4VIYbio1IpIxmuM1Ldo1LZ1g\__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA][1] ### Funding Statement This study did not receive funding. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: IRB of Foothills Medical Centre, Calgary, Alberta, Canada gave ethical approval for this work IRB of University of Alberta, Edmonton, Alberta, Canada gave ethical approval for this work IRB of St-Paul's Hospital (University of British Columbia), Vancouver, British Columbia, Canada gave approval for this work IRB of Kingston General Hospital, Kingston, Ontario, Canada gave approval for this work IRB of The Ottawa Hospital, Ottawa, Ontario, Canada gave approval for this work IRB of the University Health Network, Toronto, Ontario, Canada gave approval for this work IRB of McGill University Health Centre, Montreal, Quebec, Canada gave approval for this work Potentially eligible patients were approached for consent for a 30‐day post-discharge telephone interview. For patients lacking capacity, family or proxy provided consent as per Canadian ethics guidelines. Patients consented to have their data anonymized and used in secondary analyses from the initial MedSafer Study. Additional information on consent provision can be found here: I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors. [1]: https://cdn.jamanetwork.com/ama/content_public/journal/intemed/0/ioi210080supp1_prod_1642198696.39131.pdf?Expires=1649169920&Signature=K6WZSgGHyo~r2cGwewqSrg5DIMoFzLp0FwPk0zfr4dpHX9i-PlVRbXA0Nuk8ImICsFbNHJEYy1KjsnGV4379-cPr0MaJE775EzI4XK7SM0OLugMEf-VPseYsUXhms154K5icDbcUXKIYsNIP~0hNbIeklGM1bjhaRWUv-Sfqs2jUqb5ZFnGA4xZ7eDogNGE0TbmG39kvGtCjZGYhKBIJKhYCNtIl9QTrlcczm~X0gzpuNw43wmarAFlezBEVtSb9vDB-F4GxlgcSAbqEEk5Kd1tNl1JYpIqMNSE5yHRBqWosiXck~XwloTYCWLGvgE4VIYbio1IpIxmuM1Ldo1LZ1g__&Key-Pair-Id=APKAIE5G5CRDK6RD3PGA