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Drug-drug interaction with oral antivirals for the early treatment of COVID-19

Open AccessPublished:December 01, 2022DOI:https://doi.org/10.1016/j.ijid.2022.11.039

      Highlights

      • Statins need to be continued during nirmatrelvir/ritonavir therapy in COVID-19.
      • Simvastatin use is contraindicated during nirmatrelvir/ritonavir therapy.
      • Pravastatin and fluvastatin can be safely used as a substitute for simvastatin.
      • Statin treatment is associated with an improved prognosis for COVID-19.
      • Withdrawal from statin therapy may also acutely worsen cardiovascular prognosis.

      Keywords

      We read with interest the Danish population-based study estimating the risk of significant drug-drug interactions (DDIs) with the antiviral component, nirmatrelvir, of the drug combination nirmatrelvir/ritonavir (NMV/r) in the age groups ≥65 years and ≥80 years [
      • Larsen CS.
      Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.
      ]. The study highlights the potentially detrimental effects of DDIs if this antiviral treatment is used as part of polypharmacy in this elderly population at a high risk for the progression of SARS-CoV-2 infection to severe COVID-19.
      Regarding statin treatment and NMV/r DDIs, it was found that 15.45% of the study population in the age group ≥65 years used simvastatin or lovastatin and that the respective percentage among those aged ≥80 years was 17.70%. The percentages for atorvastatin in the age groups ≥65 and ≥80 years were 19.91% and 15.85%, respectively. Because simvastatin and lovastatin are contraindicated during NMV/r treatment, Larsen [
      • Larsen CS.
      Assessing the proportion of the Danish population at risk of clinically significant drug-drug interactions with new oral antivirals for early treatment of COVID-19.
      ] recommends that “patients at low risk of atherosclerotic events could potentially pause the statin treatment during NMV/r administration”.
      For several reasons, we are concerned about the potential danger associated with the recommendation to discontinue statin treatment in the age group ≥65 years. First, according to the current guidelines, statins are not routinely prescribed to patients having a low risk for atherosclerotic cardiovascular disease (ASCVD) [
      • Mach F
      • Baigent C
      • Catapano AL
      • Koskinas KC
      • Casula M
      • Badimon L
      • et al.
      2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
      ]. Moreover, the decision to use statin in older individuals is not evidence-based and, therefore, must be made individually [
      • Strandberg TE
      • Kolehmainen L
      • Vuorio A.
      Evaluation and treatment of older patients with hypercholesterolemia: a clinical review.
      ]. Second, it is challenging to estimate the actual ASCVD risk in older patients, especially those aged ≥75 years and who are free of clinically overt ASCVD [
      • Saeed A
      • Mehta LS.
      Statin therapy in older adults for primary prevention of atherosclerotic cardiovascular disease: the balancing act.
      ]. Among patients aged <75 years, the efficacy of statins used for primary prevention is well proven, and the relative risk reduction of major vascular events is about 20-30% for every 1 mmol/l reduction in low-density lipoprotein cholesterol [
      • Mihaylova B
      • Emberson J
      • Blackwell L
      • Keech A
      • Simes J
      • Barnes EH
      • Voysey M
      • Gray A
      • Collins R
      • Baigent C.
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      ]. Third, in patients with COVID-19, several studies have shown that the use of statins is associated with an improved prognosis [
      • Wu KS
      • Lin PC
      • Chen YS
      • Pan TC
      • Tang PL.
      The use of statins was associated with reduced COVID-19 mortality: a systematic review and meta-analysis.
      ]. In addition, the main protease (Mpro) of the SARS-CoV-2 virus adversely affects the microvascular endothelial cells in the brain, and statins may directly inhibit Mpro activity [
      • Vuorio A
      • Kovanen PT
      • Raal F.
      Statin needs to be continued during Paxlovid therapy in COVID-19.
      ]. Fourth, withdrawal from statin therapy may acutely worsen the prognosis of patients with non-ST-segment elevation myocardial infarction, even in patients without the additional cardiovascular burden caused by a viral infection [
      • Spencer FA
      • Fonarow GC
      • Frederick PD
      • Wright RS
      • Every N
      • Goldberg RJ
      • et al.
      Early withdrawal of statin therapy in patients with non-ST-segment elevation myocardial infarction: national registry of myocardial infarction.
      ]. Finally, the option that statin withdrawal remains permanent is a major concern.
      Based on the previously mentioned considerations, we recommend that rather than discontinuing simvastatin treatment, simvastatin should be substituted by either pravastatin or fluvastatin [
      • Vuorio A
      • Kovanen PT
      • Raal F.
      Cholesterol-lowering drugs for high-risk hypercholesterolemia patients with COVID-19 while on Paxlovid™ therapy.
      ]. By taking into account the prognosis of both COVID-19 and ASCVD, the patient would then be at low risk of side effects from statin therapy and will be guaranteed the best possible benefits from the statin treatment.

      Funding

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      Not applicable.
      Author contributions
      AV writing the first draft. AV, FR, PTK reviewing and editing to produce the final draft.

      Declaration of competing interest

      AV has received consultancy fees from Amgen and Novartis. PTK has received consultancy fees, lecture honoraria, and/or travel fees from Amgen, Novartis, Raisio Group, and Sanofi. FR has received research grants, honoraria, or consulting fees for professional input and/or lectures from Sanofi, Regeneron, Amgen, and Novartis.

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