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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 PointsO_LIQuestion: How does polypharmacy affect the eligibility of older adults to receive Nirmatrelvir-ritonavir? C_LIO_LIFindings: 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. C_LIO_LIMeaning: Due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI). C_LI
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ImportanceWidely available and affordable options for the outpatient management of COVID-19 are needed, particularly therapies that prevent hospitalization. ObjectivePerform a meta-analysis of the available randomized clinical trial evidence for fluvoxamine in the outpatient management of COVID-19. Data SourcesWorld Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov. Study SelectionCompleted outpatient trials with available results which compared fluvoxamine to placebo. Data Extraction and SynthesisWe followed the PRISMA 2020 guidelines. We extracted study details in terms of inclusion criteria, trial demographics and the pre-specified outcome of all-cause hospitalization. Risk of bias was assessed by the Cochrane Risk of Bias 2 tool. We conducted a frequentist random effects meta-analysis, as well as two sensitivity analyses using a Bayesian random effects meta-analysis with different estimates of prior probability: a weakly neutral prior (50% chance of efficacy with 95% confidence interval for Risk Ratio [RR] between 0.5 and 2) and a moderately optimistic prior (85% chance of efficacy). We contextualized the results by estimating the probability of any effect (RR [≤]1) and moderate effect (RR [≤]0.9) on reducing hospitalization. Main Outcome(s) and Measure(s)All cause hospitalization. Results2196 participants were included from 3 identified trials. The risk ratios for hospitalization were 0.75 (95%CI, 0.57-0.97) for the frequentist analysis, 0.78 (95%CI 0.58-1.08) for the Bayesian weakly neutral prior, and 0.73 (95%CI, 0.53-1.01) for the Bayesian moderately optimistic prior. Depending on the scenario, the probability of any effect on hospitalization ranged from 94.1% to 98.3% and a moderate effect from 81.6% to 91.1%. Conclusions and RelevanceUnder a variety of assumptions, fluvoxamine shows a high probability of preventing hospitalization in outpatients with COVID-19. While ongoing randomized trials are important to evaluate alternative doses, explore the effectiveness in vaccinated patients, and provide further refinement to these estimates, fluvoxamine could be recommended as a treatment option, particularly in resource-limited settings or persons without access to SARS-CoV-2 monoclonal antibody therapy or direct antivirals. Key PointsO_ST_ABSQuestionC_ST_ABSDoes early administration of fluvoxamine prevent hospitalization in symptomatic adult outpatients with confirmed COVID-19? FindingsIn this meta-analysis with Bayesian sensitivity analyses that accounted for varying prior probabilities, there was a high probability (94.1% to 98.3%) that fluvoxamine reduces hospitalization with frequentist risk ratio of 0.75 (95%CI 0.57-0.97). MeaningFluvoxamine is a widely available and inexpensive option that prevents hospitalization in patients with early COVID-19 based on randomized controlled trial evidence to date.
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The role of inhaled corticosteroids for outpatient COVID-19 is evolving. We meta-analyzed reported clinical trials and estimated probability of any effect and number needed to treat of 50 or 20 for symptom resolution by day 14 [100%, 99.8%, 93.1%] and hospitalization [89.3%, 72.9%, 26.7%] respectively.
