Antivirals on the Cardiovascular Conditions: History
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Subjects: Cardiac & Cardiovascular Systems
Contributor:
Francesco Nappi

The COVID-19 pandemic has resulted in a complex clinical challenge, caused by a novel coronavirus, partially similar to previously known coronaviruses but with a different pattern of contagiousness, complications, and mortality. Safety profiles of antivirals are largely questioned and addressed by health agencies, in consideration of COVID-19 cardiac and pro-thrombotic complications generally experienced by predisposed subjects.

  • SARS-CoV-2
  • antivirals

1. Remdesivir Cardiac Pro-Arrhythmogenic and Hypotensive Effects

Among the most frequent side effects of remdesivir seem to appear anemia, gastrointestinal symptoms, hypertransaminasemia, cutaneous rashes, and kidney injury, other than constitutional local reactions such as infusion-related ones [1]. Notably, patients may also experience hypotension and cardiac conduction disturbances, as documented by electrocardiographic monitoring. One of the hypothesized explanations is attributed to the structural similarity to adenosine and to the binding of the drug to multiple adenosine receptors.
Not every adenosine analog is capable of interacting with adenosine receptors. Nonetheless, pharmacological studies were performed to assess the potential binding of remdesivir and its metabolites to adenosine A1, A2, and A3 receptors. GS-441524 metabolite has been predicted to bind to adenosine receptors A1, A2, and A3 and to adenosine kinase while GS-443902, i.e., remdesivir triphosphate, was demonstrated to not interact with them. Adenosine is a potent vasodilator and both a pro-arrhythmogenic and anti-arrhythmogenic agent, depending on the structural heart disease, thus there has been a tendency to focus on its analogs’ potential adverse effects [2].
Remdesivir can exert an impact on cardiac tissue by inducing electrocardiographic changes such as bradycardia, T-wave abnormalities, atrial fibrillation, and prolonged QT interval [1]. In addition, a few cases of cardiac arrest were demonstrated following remdesivir infusion.
Two main mechanisms are responsible for these changes: the compensatory catecholamines release after adenosine-induced hypotension, which predisposes to ventricular tachycardia and ventricular fibrillation, and the induction of inhomogeneity in ventricular refractoriness as determined by a case report in which a patient suffering from stable ventricular tachycardia was administered adenosine and subsequently experienced ventricular fibrillation [3]. There also are reports of idiosyncratic reactions to adenosine in the absence of structural heart diseases with induction of ventricular fibrillation [4].
Chow et al. [5] reported the case of a pediatric patient administered with a single therapeutic dose of remdesivir because of severe acute COVID-19. Over the following hours, the patient experienced persistent sinus bradycardia, whereby the following administrations were suspended.
Another possible molecular basis of this explanation is the damage to mitochondrial RNA polymerase. A preclinical study using in vitro human pluripotent stem cell-derived cardiomyocytes employed as substitutes of human cardiomyocytes revealed this electrophysiologic toxicity [6]. Multielectrode array (MEA) method was used to assess the automaticity and electrocardiographic parameters, such as QT interval prolongation on cardiomyocytes. Chloroquine was used as a positive control as it induces cardiotoxicity. Results from this study corroborate the toxicity hypothesis: dose-dependent prolongations of field potential duration (FPD), reduced Na+ peak amplitudes, and spontaneous beating rates, suggesting a pro-arrhythmogenicity in human cardiomyocytes [6]. At higher doses, remdesivir was in fact demonstrated to cause QT prolongation.
From a clinical point of view, several other cases of cardiovascular side effects were registered. Two randomized controlled trials, Mulangu et al. [7] and Wang et al. [8], despite differences in statistical power and bias addressing, each reported a case of severe toxicity after remdesivir administration. In the former study, 681 patients suffering from Ebola viral disease in the Democratic Republic of Congo were enrolled and divided into four groups of treatment. Of 681 patients, 175 received remdesivir and in one patient, cardiac arrest was reported [7].
The latter, a randomized, double-blind, placebo-controlled, multicenter trial involving ten hospitals in Hubei, China compared 237 patients, of which 158 were assigned to remdesivir treatment and 79 to placebo. Adverse events were reported in 102 (66%) of 155 remdesivir recipients and in one of them, hypotension and cardiac arrest was noted [8].
VigiBase is an individual case safety report database of the World Health Organization (WHO) evaluated by a group of scientists from Seoul, Korea [9]. Cardiac arrest (adjusted odds ratio (aOR): 1.88, 95% confidence interval (CI): 1.08–3.29), bradycardia (aOR: 2.09, 95% CI: 1.24–3.53), and hypotension (aOR: 1.67, 95% CI: 1.03–2.73) were associated with remdesivir. In particular, from a total number of 2107 individual case safety reports, 93 out of 2107 patients (i.e., 4.41%) experienced cardiac arrest, 79 (3.75%) experienced bradycardia, 19 patients suffered from cardiogenic shock, 48 patients reported hypotension and about a hundred patients experienced electrophysiological conduction changes, including atrial fibrillation, ventricular tachycardia, and fibrillation, sinus tachycardia, QT prolongation, atrial flutter, torsade de points, and others [9].

2. Electrocardiographic Changes after Ritonavir Administration

The administration of lopinavir/ritonavir also revealed adverse drug reactions such as ventricular tachycardia, ventricular fibrillation, torsade de points, long Q-T syndromes, and cardiac arrest [10].
Concerning ritonavir administration, it is a well known pro-arrhythmogenic when administered alone or in combination with saquinavir (another anti-HIV medication). In particular, the FDA warned physicians about alterations of QT intervals leading to torsades de points and prolonged PR intervals, leading to heart blocks [11].
Ritonavir-linked cases of bradycardia were demonstrated after combination therapy administration of lopinavir/ritonavir. A French observational prospective study [12] reported 9 cases of bradycardia (22%) among 41 COVID-19 positive patients, admitted to the local hospital intensive care unit and administered lopinavir/ritonavir combination drug for at least 48 h. Of these 9 cases, 8 had sinus bradycardia and 1 had a third-degree atrioventricular block. All the cases were resolved after therapy discontinuation or antiviral dose-reduction [12]. The authors also explained the possibility of inflammatory damage from COVID-19 associated with higher intestinal absorption of the antiviral combination and thus of the possible side effect. Several other studies also confirmed the association of lopinavir/ritonavir administration for COVID-19 and new arrhythmic events, including atrial fibrillation, atrial flutter episodes, and long-QT syndromes [13][14].

3. Drug–Drug Interactions between Antivirals and Cardioactive Medications

In addition, concerns about concomitant administration of cardiovascular medications with ritonavir in combination with nirmaltrevir arose [15]. Ritonavir-boosted nirmatrelvir (Paxlovid) has significant and complex drug–drug interaction potential, primarily due to the ritonavir component of the combination.
Ritonavir is generally known to induce cytochromes CYP2B6, CYP2C19, CYP2C9, and CYP1A2, and, more relevantly, to strongly inhibit CYP3A4 and CYP2D6, this leading to severe drug–drug interactions. Cardioactive medications, especially certain antiplatelets, statins, anticoagulants, and anti-arrhythmic agents are cytochromes substrates and, in several studies, were demonstrated to be partially modified by ritonavir in their pharmacokinetics [15].
Regarding antiplatelets, there is a tendency to replace prasugrel with clopidogrel, as the former requires metabolic activation by CYP3A4 and CYP2B6. The concomitant administration with ritonavir seems in fact to decrease several pharmacokinetic parameters including AUC0–6h and maximum concentration (Cmax) of prasugrel active metabolites [16][17][18]. Aspirin, cangrelor, and other antiplatelet agents can be instead safely co-administered with ritonavir.
Lipid-lowering drugs also have been demonstrated to interact with ritonavir administration. Statins in particular are metabolic substrates for hepatic cytochrome CYP450. More specifically, lovastatin, simvastatin, and atorvastatin i.e., lipophilic statins, are metabolized by CYP3A4.
One of the examined studies presented a direct correlation between the administration of ritonavir-boosted saquinavir and changes in simvastatin pharmacokinetics. Of note, its AUC and Cmax were shown to be increased by 30-fold [19].
Ezetimibe, hydrophilic statins, and fibrates can be instead administered without particular precautions. The only suggestion is to closely monitor possible side effects [15].
Non-vitamin K oral anticoagulants were also studied for the strong interactions. Rivaroxaban and apixaban are metabolized through a variety of pathways, including CYP3A4 and BCRP. Rivaroxaban is a direct factor Xa inhibitor and a life-saving drug, indicated for atherothrombotic event prevention after an acute coronary syndrome or in patients suffering from coronary artery disease (CAD) or peripheral artery disease (PAD) at high ischemic risk. Pharmacological in-vivo studies have demonstrated that concomitant administration with ritonavir strongly increases rivaroxaban AUC and Cmax. In a study by Mueck et al. [20], a 153% increase (95% CI: 134% to 174%) of rivaroxaban AUC in concomitant administration with ritonavir was noted. Edoxaban, unfractionated heparin, enoxaparin, and fondaparinux do not exhibit significant interactions with ritonavir.
Thus, particular attention on possible alterations of coagulative profile should be paid for patients in anticoagulation therapy and ritonavir.
In healthy subjects, 10 days of lopinavir/ritonavir therapy increased CYP2C9 activity by 29% and CYP1A2 by 43% [21]. The induction of these cytochromes by L/R may result in increased warfarin metabolism and a reduction in the international normalized ratio (INR).
Ritonavir coadministration is also contraindicated with dronedarone, encainide, flecainide, propafenone, and quinidine [22].
No significant interactions were instead generally evaluated for beta-blockers, vasodilators diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs).
Concerning the metabolism of Nirmatrelvir, a general consideration to convey is the paucity of data and clinical or pharmacological studies about antiviral interactions and side effects. It is claimed that the agent’s metabolism can be decreased when combined with certain calcium channel blockers (CCBs) such as verapamil, nilvadipine, and Nicardipine, with lovastatin and amiodarone [23][24].
The most important authorized and approved antivirals interactions and side effects are tabulated below, in Table 1.
Table 1. Therapeutic agents’ profiles of potential cardiovascular toxicities and drug–drug interactions with cardioactive medications. In the last column, metabolic properties of the agent, responsible for interactions, are summarized. Abbreviations. DDIs: drug–drug interactions, CYP: cytochrome P450, VT: ventricular tachycardia, VF: ventricular fibrillation, LQTs: long Q-T syndromes.
Antiviral Agent Cardiac Side Effects Relevant DDIs with Cardioactive Medications Metabolic Properties
remdesivir (Veklury®) Pro-arrhytmogenic: bradycardia, T-wave abnormalities, atrial fibrillation, prolonged QT interval, VT, VF, cardiac arrest. Hypotension. Not relevant. Minor substrate of cytochrome CYP3A4.
molnupinavir® Not relevant; mainly gastrointestinal ones. No substantial risk, lack of clinical interaction studies. /
nirmatrelvir (Paxlovid®) Not relevant, paucity of data. Paucity of data; possible DDIs with amiodarone, verapamil, nilvadipine, nicardipine, lovastatin. Minor substrate of CYP3A4.
ritonavir (Paxlovid®) Pro-arrhythmogenic: LQTs, torsades de points, bradycardia, VT, VF, atrial fibrillation, atrial flutter, cardiac arrest. Ticagrelor, simvastatin, rivaroxaban, lercanidipine, anti-arrhythmics (dronedarone, encainidie, flecainide, propafenone, quinidine), ivabradine. Inducer of CYP2B6, CYP2C19, CYP2C9, and CYP1A2, strong inhibitor of P450 3A4 and CYP2D6.

This entry is adapted from the peer-reviewed paper 10.3390/biomedicines10020437

References

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