Cardiovascular Drug Interactions With Nirmatrelvir/Ritonavir in Patients With COVID-19

JACC Review Topic of the Week

Sonu Abraham, MD; Anju Nohria, MD; Tomas G. Neilan, MD; Aarti Asnani, MD; Anu Mariam Saji, MD; Jui Shah, MBBS; Tara Lech, PHARMD, BCPS; Jason Grossman, MD; George M. Abraham, MD, MPH; Daniel P. McQuillen, MD; David T. Martin, MD; Paul E. Sax, MD; Sourbha S. Dani, MD, MSC; Sarju Ganatra, MD


J Am Coll Cardiol 

In This Article

Abstract and Introduction


Nirmatrelvir-ritonavir (NMVr) is used to treat symptomatic, nonhospitalized patients with coronavirus disease-2019 (COVID-19) who are at high risk of progression to severe disease. Patients with cardiovascular risk factors and cardiovascular disease are at a high risk of developing adverse events from COVID-19 and as a result have a higher likelihood of receiving NMVr. Ritonavir, the pharmaceutical enhancer used in NMVr, is an inhibitor of the enzymes of CYP450 pathway, particularly CYP3A4 and to a lesser degree CYP2D6, and affects the P-glycoprotein pump. Co-administration of NMVr with medications commonly used to manage cardiovascular conditions can potentially cause significant drug-drug interactions and may lead to severe adverse effects. It is crucial to be aware of such interactions and take appropriate measures to avoid them. In this review, we discuss potential drug-drug interactions between NMVr and commonly used cardiovascular medications based on their pharmacokinetics and pharmacodynamic properties.


A 57-year-old man with ischemic cardiomyopathy and a history of percutaneous coronary intervention (PCI) a month before, presents with symptomatic coronavirus disease-2019 (COVID-19) despite being vaccinated with 3 doses of an mRNA COVID-19 vaccine. His home medications include aspirin, clopidogrel, high-dose atorvastatin, metoprolol succinate, sacubitril/valsartan, spironolactone, and dapagliflozin. He is prescribed nirmatrelvir-ritonavir (Paxlovid [Pfizer]). At the recommendation of his primary care physician, he calls his cardiologist to inquire about potential interactions with his medications. He is advised to continue aspirin, spironolactone, dapagliflozin, and metoprolol succinate. Clopidogrel is switched to prasugrel. Atorvastatin and sacubitril/valsartan are temporarily withheld. All cardiovascular medications are resumed after completion of a 5-day course of NMVr except atorvastatin, which is restarted 3 days after completion of treatment with NMVr.

Nirmatrelvir-ritonavir (NMVr) received emergency use authorization from the U.S. Food and Drug Administration in December 2021 as one of the first oral antiviral agents for the treatment of symptomatic nonhospitalized adults with mild to moderate SARS-CoV-2 infection who are at high risk for progression to severe disease.[1] Compared with placebo, NMVr reduces progression to severe COVID-19 by 89% in nonvaccinated high-risk symptomatic patients.[2] Patients with cardiovascular disease (CVD) and risk factors such as diabetes, hypertension, chronic kidney disease, and smoking constitute a large proportion of the high-risk population among whom NMVr is beneficial.[2] In the EPIC-HR trial, patients with CVD benefitted the most from NMVr therapy (a difference of 24% in COVID-19–related hospitalizations or death from any cause when compared to placebo).[2] In the trial, NMVr was tested exclusively in nonvaccinated patients; but real-world data suggest that it may be equally effective in those who have been vaccinated against COVID-19.[3–5] Najjar-Debbiny et al[3] retrospectively analyzed outcomes in unvaccinated and vaccinated patients who were prescribed NMVr, 32% of whom had CVD, and demonstrated a combined risk reduction of 46%, with subgroup analysis showing a similar magnitude of effectiveness in both populations. The use of NMVr reduces disease progression, time to achieve a lower viral load, emergency room visits, hospitalizations, and all-cause mortality.[4,5] More than a million courses of NMVr have been prescribed thus far, and its use is predicted to increase with emerging variants of SARS-CoV-2 resistant to monoclonal antibody therapies. While NMVr has been shown to be very effective in patients with pre-existing CVD, it has significant drug-drug interactions (DDIs) with commonly used cardiovascular medications and therefore it is important that all clinicians are familiar with those DDIs.


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