— The Skeptical Cardiologist asks clinicians and patients to take note
by Anthony Pearson, MD
After looking closely at the drug-drug interactions listed for Pfizer’s new oral COVID-19 drug ritonavir-nirmatrelvir (Paxlovid), I realized that a large percentage of my patients are taking medications on the list.
The antiviral was granted FDA emergency use authorization in late December for the treatment of mild-to-moderate COVID-19 in patients at high risk of severe illness.
Patients with hypertension, coronary artery disease, atrial fibrillation (Afib), and hyperlipidemia should pay close attention to what follows if they are considering starting the drug, as they likely will need to stop or modify their cardiac medications and monitor their blood pressure and heart rates closely while taking it.
Ritonavir has long been used to increase the levels of anti-HIV medications by strongly inhibiting the CYP3A system, which metabolizes many cardiac (and non-cardiac) drugs including nirmatrelvir, the active anti-SARS-CoV-2 antiviral.
Cardiac Rhythm Drug Interactions With Ritonavir-Nirmatrelvir
Cardiac patients taking antiarrhythmics are highly likely to experience significant drug-drug interactions if they take ritonavir-nirmatrelvir, and should consult with their cardiologist about the best approach.
The FDA’s Health Information for Providers document on ritonavir-nirmatrelvir lists several drugs that are highly dependent on CYP3A for clearance and elevated concentrations are associated with serious and/or life-threatening reactions: ranolazine, amiodarone, dronedarone, flecainide, propafenone, quinidine, bepridil, and systemic lidocaine.
Note that ritonavir coadministration is contraindicated with dronedarone, encainide, flecainide, propafenone, and quinidine. The first four are used for the maintenance of sinus rhythm in patients with Afib. If a patient is on one of these, the choices would be:
Stop them if the increased risk of the development of Afib is acceptable, or
Use an alternative to ritonavir-nirmatrelvir
I don’t use quinidine and haven’t seen a patient on it for 15 years.
Amiodarone has unique pharmacokinetics and even if stopped for several days, would still be in the cardiac tissue and have effects for weeks to months. Whether any patient on amiodarone could safely take ritonavir-nirmatrelvir is debatable. Input from cardiology, pharmacy, and infectious disease would be warranted before giving ritonavir-boosted nirmatrelvir to a patient on amiodarone.
Many of my Afib patients take flecainide for the maintenance of sinus rhythm. Some of them will definitely go into fibrillation if they miss one or two dosages, so we will have to carefully weigh options and individualize the approach for each patient should they reach criteria for taking ritonavir-nirmatrelvir. Flecainide can be started and stopped safely as an outpatient and often restarting it converts patients safely back to normal rhythm.
The NIH COVID-19 Treatment Panel’s statement on ritonavir-boosted nirmatrelvir lists disopyramide, dofetilide, and mexiletine as other antiarrhythmics warranting alternative COVID-19 therapy.
Statin Drug Interactions
FDA also lists lovastatin, simvastatin, atorvastatin, and rosuvastatin as also being influenced by ritonavir-nirmatrelvir.
Fortunately, there is no short-term risk to stopping these drugs, so my advice to patients will be to stop taking the four statins as soon as COVID-19 is diagnosed and resume them 7 days after stopping ritonavir-nirmatrelvir.
Calcium Channel Blockers
Calcium channel blockers are also included among ritonavir-nirmatrelvir’s drug-drug interactions.
These drugs are predominantly utilized for hypertension, thus if levels increase then blood pressure can drop too low. We sometimes utilize diltiazem also for Afib or premature beats; higher levels of diltiazem could result in both lower blood pressure and heart rate.
If ritonavir-nirmatrelvir is started in a patient on a calcium channel blocker, the most reasonable approach (supervised by a physician) would be to cut the dose in half and have the patient monitor the BP at home during the 5 days of ritonavir-nirmatrelvir and for 3-5 days after.
Most patients with Afib are taking either warfarin or one of the newer direct oral anticoagulants (DOACs).
FDA flagged two anticoagulants for ritonavir-nirmatrelvir users. Those on warfarin have to be wary of any new medication and should have their INR checked to monitor levels. Of the multiple DOACs, rivaroxaban (Xarelto) is the only one that should be stopped, according to the FDA.
Apixaban (Eliquis) is the blood thinner I most often use in my patients with Afib. While it is not mentioned by the FDA document, the manufacturer has recommended when co-administering with another preparation containing ritonavir a dose reduction to 2.5 mg twice a day. If the patient is already on a 2.5 mg dose, concurrent use should be avoided.
Much of what was reviewed in a detailed article from June of 2021 is relevant to ritonavir-nirmatrelvir and cardioactive medications.
The drug interactions with ritonavir range from insignificant to mild to strong. There are some differences from the NIH recommendations in this chart.
Note that caution is recommended if a patient is on the antiplatelet drug clopidogrel (Plavix) and ticagrelor (Brilinta) is contraindicated. These drugs (plus aspirin) are essential in the early months after placement of a drug-eluting coronary stent. Consultation with a cardiologist is mandatory before stopping them.
Some beta-blockers, commonly used for a variety of indications by cardiologists, are on the caution/monitor category as are two angiotensin receptor blockers widely used for hypertension.
Based on this information, I think it makes sense to monitor heart rate and blood pressure twice daily on any cardiac patient taking ritonavir-nirmatrelvir and adjust medications accordingly.
Ranolazine, an antianginal drug I almost never prescribe but frequently stop, is contraindicated with ritonavir-nirmatrelvir. Similarly, ivabradine, a drug I’ve never prescribed is contraindicated.
We still have some patients with permanent Afib on digoxin and I would advise halving the dosage for 10 days and monitoring heart rate for them if ritonavir-nirmatrelvir started.
These substantial and highly significant drug interactions mean that cardiac patients and their physicians must review medications carefully before beginning a course of ritonavir-nirmatrelvir.
Anthony C. Pearson, MD, is a noninvasive cardiologist and professor of medicine at St. Louis University School of Medicine. He blogs on nutrition, cardiac testing, quackery, and other things worthy of skepticism at The Skeptical Cardiologist, where a version of this post first appeared.