Guidance on Short‐Term Management of Atrial Fibrillation in Coronavirus Disease 2019

Abstract

Atrial fibrillation is a common clinical manifestation in hospitalized patients with coronavirus disease 2019 (COVID‐19). Medications used to treat atrial fibrillation, such as antiarrhythmic drugs and anticoagulants, may have significant drug interactions with emerging COVID‐19 treatments. Common unintended nontherapeutic target effects of COVID‐19 treatment include potassium channel blockade, cytochrome P 450 isoenzyme inhibition or activation, and P‐glycoprotein inhibition. Drug‐drug interactions with antiarrhythmic drugs and anticoagulants in these patients may lead to significant bradycardia, ventricular arrhythmias, or severe bleeding. It is important for clinicians to be aware of these interactions, drug metabolism changes, and clinical consequences when choosing antiarrhythmic drugs and anticoagulants for COVID‐19 patients with atrial fibrillation. The objective of this review is to provide a practical guide for clinicians who are managing COVID‐19 patients with concomitant atrial fibrillation.

Nonstandard Abbreviations and Acronyms

AAD

antiarrhythmic drug

AF

atrial fibrillation

CHF

congestive heart failure

COVID‐19

coronavirus disease 2019

CYP

cytochrome P

I_K

potassium channel

I_Na

sodium channel

Coronavirus disease 2019 (COVID‐19) is caused by severe acute respiratory syndrome coronavirus 2, which was first reported in 2019 in Wuhan, Hubei, China. ¹ , ² It infects host cells through angiotensin‐converting enzyme 2 membrane receptors, which are highly expressed in heart and lungs, especially in patients with underlying cardiovascular disease. ³ COVID‐19 patients with underlying cardiovascular disease have increased risk of morbidity and mortality from complicated myocardial injury, myocarditis, congestive heart failure (CHF), thromboembolism, and arrhythmias. ⁴ Atrial fibrillation (AF) is the most common arrhythmia seen in critically ill patients. ⁵ Several potential pharmacotherapies are emerging. ⁴ , ⁶ Risks of arrhythmogenic effects of COVID‐19 pharmacotherapies have been noted ⁴ , ⁷ (Table). The overall objective of this review is to provide practical guidance for clinicians who are managing COVID‐19 patients with concomitant AF recommendations (Figure 1) based on the pharmacological characteristics of COVID‐19 pharmacotherapies, anticoagulants, and antiarrhythmic drugs (AADs) in the setting of limited clinical data.

Figure 1.

Management guidance algorithm for atrial fibrillation and concomitant coronavirus disease 2019 (COVID‐19).

ACS indicates acute coronary syndrome; CAD, coronary artery disease; CCB, calcium channel blocker; CHF, congestive heart failure; and DCCV, direct current cardioversion.

Table 1.

Mechanisms, Pharmacokinetics, and Dynamics of the Emerging COVID‐19 Pharmacotherapy

Pharmacotherapy	Mechanism of Action	Metabolism	Mechanism of Interaction	Clinical Manifestation
				Interaction With AADs	Interaction With Anticoagulants
Chloroquine/hydroxychloroquine	Block viral entry into cells Reduce cytokines and inhibit autophagy and lysosomal activity in host cells	CYP2C8, CYP3A4, CYP2D6, and CYP1A1	Blocks IKr CYP2D inhibitors Long half‐life	QT prolongation (TdP)	None
Azithromycin	Induction of interferon and interferon‐related genes	MRP2 and ABCB (minimally by CYP3A4)	Blocks IKr Weak CYP3A4 inhibitor Moderate P‐glycoprotein inhibitor	QT prolongation (TdP)	Increases serum DOAC
Lopinavir/ritonavir	Protease inhibitor	CYP3A4	Strong CYP3A4 inhibitor Moderate CYP2D6 inhibitor Strong P‐glycoprotein inhibitor	QT prolongation (TdP) Nephrotoxicity (may increase serum sotalol and dofetilide)	Increases serum DOAC Nephrotoxicity (may increase serum apixaban, rivaroxaban, dabigatran, and LMWH)
Remdesivir	Adenosine analog (inhibits RNA‐dependent RNA polymerase)	Mainly by phosphorylation in nonspecific organ and partially by CYP2C8, CYP2D6, and CYP3A4	CYP3A4 inhibitor (in vitro without clinical significance)	None	None
Ribavirin	Guanosine analog (inhibits RNA‐dependent RNA polymerase)	Mainly by hydrolase and partially by CYP2C8, CYP2D6, and CYP3A4	None	None	None
Favipiravir	Purine analog (inhibits RNA‐dependent RNA polymerase)	Oxidase and renally excreted	None	None	None
Umifenovir	Inhibits membrane fusion of viral envelope targeting the S‐protein/ACE2 interaction	CYP3A4	CYP3A4 substrate	Plasma concentration may be increased with amiodarone, diltiazem, and verapamil (no documented evidence)	None
Interferon	Interfering with viral replication and promoting activation of the adaptive immune system	Proteolytic degradation by lysosomal enzymes, which are excreted in urine	None	None	None
Tocilizumab	Interleukin‐6 inhibitors	Unknown (expected to undergo catabolism)	Increases mRNA expression of CYP enzymes	None	May increase warfarin metabolism
Sarilumab	Interleukin‐6 inhibitors	Unknown (expected to undergo catabolism)	Increases mRNA expression of CYP enzymes	None	May increase warfarin metabolism
Pirfenidone	Interleukin‐β1 and interleukin‐4 inhibitors	CYP1A2 and renally excreted	None	Amiodarone, a CYP1A2 inhibitor, may increase pirfenidone plasma concentration	None
Bevacizumab	VEGF inhibitor monoclonal antibody	The reticuloendothelial system	None	None	None
Eculizumab	Compliment inhibitor monoclonal antibody	The reticuloendothelial system	None	None	None
Lenzilumab	GM‐CSF inhibitor monoclonal antibody	The reticuloendothelial system	None	None	None
Methylprednisolone	Anti‐inflammatory agent Alters gene expression	CYP3A4	CYP3A4 substrate	Plasma concentration may increase with amiodarone, diltiazem, and verapamil (no documented evidence) Hypokalemia‐induced digoxin toxicity	May interfere with warfarin metabolism and bioavailability
Fingolimod	Sphingosine 1‐phosphate receptor modulator	CYP4F2	Blocks IKach and ICaL	QT prolongation (TdP) Atrioventricular block	None

AAD indicates antiarrhythmic drug; ABCB, ATP binding cassette subfamily B; ACE2, angiotensin‐converting enzyme 2; COVID‐19, coronavirus disease 2019; CYP, cytochrome P; DOAC, direct oral anticoagulant; GM‐CSF, granulocyte‐macrophage colony‐stimulating factor; I_CaL, L‐type calcium channel; I_Kach, acetylcholine‐dependent potassium channels; I_Kr, potassium channel; LMWH, low‐molecular‐weight heparin; MRP2, multidrug resistance‐associated protein 2; TdP, torsade de pointes; and VEGF, vascular endothelial growth factor.

AF in COVID‐19

The prevalence of cardiac arrhythmias was up to 16.7% in hospitalized patients and as high as 44.4% in the intensive care unit in Wuhan. ⁸ In New York City, arrhythmias were reported in 24 of 130 patients (18.5%) who required invasive mechanical ventilation, of whom 23 of 24 patients (95.8%) had atrial arrhythmias. ⁹ In an Italian cohort of 99 patients hospitalized with COVID‐19, AF was found in 19% of all cases and in 36% of patients with underlying cardiovascular disease, and AF was more common in patients who did not survive (42.1% versus 32.5%). ¹⁰ In a small Italian report, 75% of hospitalized COVID‐19 geriatric patients in Italy had a medical history of AF. ¹¹

Evidence of myocardial injury was noted in 19.7% of 416 hospitalized COVID‐19 patients, leading to a higher mortality rate compared with those without myocardial injury (51.2% versus 4.5%, respectively). ¹² Viral activated cytokine storm syndrome in fulminant myocarditis could play a major role in COVID‐19 mortality. ¹³ CHF was present in up to 23.0% of COVID‐19 patients and was more prevalent in nonsurvivors compared with survivors (52% versus 12%; P<0.0001). ¹⁴ AF is associated with in‐hospital mortality and morbidity in patients with acute myocarditis. ¹⁵ Inflammatory cytokines, including CRP (C‐reactive protein), interleukin‐6, and tumor necrosis factor‐α, may have an important role in AF pathogenesis. ¹⁶ Guidelines for the management of AF in various conditions and populations have been published ¹⁷ , ¹⁸ ; however, guidance for managing AF in COVID‐19 patients is currently not available.

Overview of Mechanisms and Pharmacokinetics and Dynamics of the Emerging COVID‐19 Pharmacotherapy

A list of emerging COVID‐19 pharmacotherapies is summarized in Table. Pharmacokinetics and pharmacodynamics of AADs (Figure 2) and anticoagulants (Figure 3), focused on known and plausible drug‐drug interactions with emerging COVID‐19 pharmacotherapies, are discussed. Major interactions are illustrated in Figure 4.

Figure 2.

AADs Used in AF and Their Drug Interaction With COVID‐19 Therapy.

AF indicates atrial fibrillation; and COVID‐19, coronavirus disease 2019.

Figure 3.

Anticoagulation Drugs Used in AF and Potential Drug‐Drug Interactions With COVID‐19 Therapy.

AF indicates atrial fibrillation; and COVID‐19, coronavirus disease 2019.

Figure 4.

Drug‐drug interactions between antiarrhythmic drugs/anticoagulants in atrial fibrillation (AF) and emerging coronavirus disease 2019 (COVID‐19) pharmacotherapies. AAD indicates antiarrhythmic drug; CYP, cytochrome P; DOAC, direct oral anticoagulant; and I_Kr, potassium channel.

Hydroxychloroquine and Chloroquine

Chloroquine and hydroxychloroquine (less toxic metabolite of chloroquine) block viral entry into cells, reduce cytokines, and inhibit autophagy and lysosomal activity in host cells ¹⁹ (Table). They are metabolized by cytochrome P (CYP) 2C8, CYP3A4, CYP2D6, and CYP1A1. They are both CYP2D inhibitors, have a long half‐life, have a large volume of distribution, and are renally excreted (chloroquine, 51%; and hydroxychloroquine, 21%). ²⁰ They also block potassium channel (I_Kr), potentially prolonging QT, leading to drug‐induced torsade de pointes (Figure 4) in those with concomitant use of drugs prolonging QT and drugs with CYP metabolic inhibition, and patients with reduced repolarization reserve (concealed or manifested congenital long‐QT syndrome). ⁴

Macrolide

Azithromycin and hydroxychloroquine in combination increase viral clearance compared with hydroxychloroquine monotherapy. ²¹ The mechanism is likely caused by induction of interferon and interferon‐related genes. ²² Major drug interaction with AADs is QT prolongation from I_Kr blockade effect of azithromycin ²³ (Figure 4). Unlike other macrolides, which are strong CYP3A4 inhibitors, azithromycin minimally inhibits CYP3A4. Azithromycin is a P‐glycoprotein substrate and a weak to moderate P‐glycoprotein inhibitor, which may interact with anticoagulants (Figure 3).

Antiviral Therapy

Lopinavir, a protease inhibitor, is extensively metabolized by CYP3A4 and was therefore combined with ritonavir, a strong CYP3A inhibitor, to enhance its efficacy. Lopinavir/ritonavir has strong drug interactions with AADs (Figure 2). Lopinavir is metabolized by the liver and excreted in the gastrointestinal tract, with minimal renal excretion but significant nephrotoxicity (Table). Ritonavir is also a strong P‐glycoprotein inhibitor and may potentially interact with anticoagulants ²⁴ (Figure 4).

Nucleotide analogs that inhibit RNA‐dependent RNA polymerase, such as remdesivir (adenosine analog), ribavirin (guanosine analog), and favipiravir (purine analog), are being studied in COVID‐19 patients. Remdesivir is mainly metabolized by hydrolase and partially metabolized by CYP2C8, CYP2D6, and CYP3A4. Remdesivir is a CYP3A4 inhibitor in vitro, but no clinically significant drug interaction is documented, likely because of its rapid clearance ²⁵ (Table). Ribavirin is metabolized by non–organ‐specific phosphorylation and renally excreted without CYP metabolism. ⁴ , ²⁶ Ribavirin does not have documented interaction with AAD but elevates international normalized ratio when used with warfarin by unclear mechanisms. ⁴ , ²⁷ Favipiravir was approved for influenza treatment in Japan. It is metabolized by oxidase and excreted in the urine. ²⁸ Cardiovascular adverse effects are not yet established. ⁴

Umifenovir inhibits membrane fusion of viral envelope targeting the S‐protein/angiotensin‐converting enzyme 2 interaction. It is approved in China and Russia. It is mainly metabolized by CYP3A4 and excreted by gastrointestinal tract. ²⁹ There is no documented evidence of drug interaction between AAD and umifenovir. However, given its CYP3A4 substrate, plasma concentration of umifenovir may be increased with amiodarone, diltiazem, and verapamil (Table).

Interferon is a cytokine that has antiviral activity by interfering with viral replication and promoting activation of the adaptive immune system. Interferons undergo proteolytic degradation by lysosomal enzymes and are excreted in urine. ³⁰ The cardiovascular adverse effects include nonspecific arrhythmias, myocardial infarction, cardiomyopathy, and hypotension. Their interaction with AADs is unknown. ⁴

Interleukin Inhibitor

Critically ill COVID‐19 patients have elevated inflammatory cytokines, including interleukin, granulocyte/macrophage colony‐stimulating factor, interferon, and tumor necrosis factor‐α. ¹ Tocilizumab and sarilumab are interleukin‐6 inhibitors. They were found to increase mRNA expression of CYP 450 isoenzymes by reversing the CYP inhibition effect of interleukin‐6. ³¹ Pirfenidone inhibits interleukin‐β1 and interleukin‐4. Its cardiovascular adverse effects and interaction with AADs are unknown. ⁴ It is metabolized by CYP1A2 and renally excreted. ³² Amiodarone, a CYP1A2 inhibitor, may increase pirfenidone plasma concentration (Table).

Monoclonal Antibody

Bevacizumab (vascular endothelial growth factor inhibitor), eculizumab (compliment inhibitor), and lenzilumab (granulocyte/macrophage colony‐stimulating factor inhibitor) are under investigation. ³³ Mechanism of action includes inhibiting inflammatory cytokines. They are metabolized by the reticuloendothelial system, and a common cardiovascular adverse effect is hypertension. However, their interaction with AADs is unknown. Bevacizumab can cause myocardial toxicity and thromboembolic events, and eculizumab may cause tachycardia and peripheral edema. ⁴

Immunosuppression

Methylprednisolone is an anti‐inflammatory agent that alters gene expression. It is metabolized by CYP3A4 and renally excreted but does not affect CYP3A4 activity. ³⁴ No significant drug interaction with AADs is reported.

Fingolimod is an immunosuppressive agent through sphingosine 1‐phosphate receptor modulator, which reduces lymphocyte migration. Fingolimod has L‐type calcium channel blockade effect, causing prolongation of PR, RR, and QT intervals. It also activates acetylcholine‐dependent potassium channels in sinoatrial node, causing dose‐dependent bradycardia. ³⁵ Fingolimod is not recommended in patients with recent myocardial infarction, decompensated CHF, stroke, high‐grade atrioventricular block, corrected QT interval >500 ms, or concomitant use of class IA or class III AADs. ³⁶ It is metabolized by hepatic CYP4F2 and excreted in gastrointestinal tract.

Antiarrhythmic and Rate Control Drugs for AF and Interactions With COVID‐19 Pharmacotherapy

Antiarrhythmic drug‐drug interactions were reported as the most common cause of drug‐related life‐threatening ventricular arrhythmias, and 84% of these cases were associated with CYP inhibition and 74% were QT prolongation related. ³⁷ Most COVID‐19 pharmacotherapies under investigation have unintended nontherapeutic target effects, including I_Kr blockade, CYP inhibition, and P‐glycoprotein inhibition (Figure 4). Lopinavir/ritonavir is the only drug that has nephrotoxicity. A summary of AADs used in AF and their interactions with COVID‐19 pharmacotherapies are shown in Figure 2. Dosages and routes of administration are provided in Table S1. A stepwise approach in managing COVID‐19 patients who present with AF is shown in Figure 1.

Class IA

Quinidine is a vagolytic and α‐blocker with use‐dependent sodium channel (I_Na) blockade and I_Kr reverse use‐dependent blockade, ³⁸ therefore prolonging the QT interval. ³⁹ It is primarily metabolized by CYP3A4. Plasma concentration of quinidine can be decreased with CYP3A4 inducers (tocilizumab and sarilumab) and can be increased with CYP3A4 inhibitors (lopinavir/ritonavir) ⁴⁰ (Figure 2).

Disopyramide is also a use‐dependent I_Na blocker and a reverse use‐dependent I_Kr blocker. Disopyramide has potent anticholinergic effects and should be avoided in glaucoma, prostatic hyperplasia, and myasthenia gravis patients. ³⁸ Given its negative inotropic effect, disopyramide is not recommended in patients with CHF. ⁴¹ Plasma concentration of disopyramide can be decreased through CYP3A4 metabolism ⁴⁰ (Figure 2).

Procainamide is an I_Na and I_Kr blocker. It is available in the intravenous form and can be useful in patients with Wolff‐Parkinson‐White syndrome presenting with preexcited AF. ¹⁷ Procainamide is partially metabolized by CYP2D6 ⁴² and mainly (60%) excreted by the kidney. ⁴³ Plasma concentration of procainamide can be decreased with CYP2D6 inducers (tocilizumab and sarilumab) (Figure 2).

Because chloroquine, hydroxychloroquine, azithromycin, and fingolimod have I_Kr blocking effect, concomitant use of a class IA AAD could potentiate QT prolongation. ³⁹ Interactions of class IA AADs with lopinavir/ritonavir, interleukin‐6 inhibitors, and azithromycin are at the CYP metabolic level. Any class IA AAD should be used with caution when combined with hydroxychloroquine, chloroquine, macrolides, or lopinavir/ritonavir (Figures 1 and 2). Documentation of baseline and sequential QT intervals following initiation of an AAD is recommended. Class IA AAD is not recommended in patients who are treated with fingolimod attributable to QT prolongation and risk of torsade de pointes. ³⁵ , ³⁶ Class IA AADs are not used often in the contemporary management of AF because of less than desired efficacy, cardiac and extracardiac adverse effects, and multiple potential drug‐drug interactions.

Class IC

Flecainide is a use‐dependent I_Na blocker with moderate negative inotropic effect. Because of specific blocking effect on I_Na, unlike class IA, flecainide delays depolarization (prolonging QRS duration) with minimal effect on ventricular repolarization (QT interval). ³⁸ However, there are several case reports stating that flecainide can lead to prolonged QT and torsade de pointes. ⁴⁴ Flecainide is predominantly metabolized by CYP2D6. ⁴⁵ Flecainide is reasonable for pharmacological cardioversion in the short‐term setting and can be used to maintain sinus rhythm in patients without coronary artery disease or structural heart disease. ¹⁷ Because of possible increases in plasma concentration of flecainide when administered with hydroxychloroquine/chloroquine and lopinavir/ritonavir (CYP2D6 inhibitors), we recommend sequential electrocardiographic monitoring before and after drug initiation.

Propafenone is an I_Na blocker with mild β‐blocking effect (negative inotropic and chronotropic effect) and predominantly metabolized by CYP2D6. Similar to flecainide, propafenone has minimal effect on repolarization. We recommend monitoring for QRS/QT prolongation when administered with hydroxychloroquine/chloroquine and lopinavir/ritonavir (CYP2D6 inhibitors). Given documented prolonged QT from I_Kr blockade by azithromycin, ²³ we also recommend ECG monitoring when azithromycin is used with class IC AADs.

Because myocarditis and CHF are common clinical manifestations in critically ill COVID‐19 patients, the use of class IC AADs in this population needs to be exercised with caution. Their interactions with CYP2D6 inducers (tocilizumab and sarilumab) and CYP2D6 inhibitors (litonavir/ritonavir) need to be recognized by closely monitoring any ECG changes. Fingolimod increases the risk of bradycardia and heart block through L‐type calcium channel and acetylcholine‐dependent potassium channel blockade. ECG before starting AADs, ECG at 6 hours after first dose, and continuous telemetry monitoring are recommended. ³⁶

Class II

β Blockers are recommended as a first‐line therapy for rate control in AF with COVID‐19 infection. ⁴⁶ All β blockers may have drug interactions with lopinavir/ritonavir, including PR prolongation, second‐degree heart block, and third‐degree heart block. ²⁴ , ⁴⁷ Lopinavir/ritonavir may increase carvedilol and metoprolol serum concentration through CYP2D6 inhibition, ⁴⁷ and telemetry should be monitored closely (Figure 1).

Hydroxychloroquine and chloroquine inhibit CYP2D6 and may increase plasma concentration of metoprolol ⁴⁸ ; a similar effect may be observed in carvedilol but has never been studied.

Carvedilol is a nonselective β blocker. Only immediate release is recommended in AF guidelines and only oral form is available, which limits its utility in acute AF with rapid ventricular response. ¹⁷ , ⁴⁹ Metoprolol and esmolol are cardioselective β blockers. ⁵⁰ Metoprolol comes in both intravenous and oral forms, ¹⁷ whereas esmolol only has intravenous preparation. Both are effective when administered in AF, with rapid ventricular response. ¹⁷ β Blockers should also be avoided in acute decompensated CHF and bronchospasm. ⁴⁹

Class III

Amiodarone blocks multiple ion channels, including I_Na, I_Kr, calcium channel, and acetylcholine‐dependent potassium channel, as well as α and β receptors. ³⁸ It prolongs QT but is rarely associated with torsade de pointes (<0.5%). ⁵¹ Amiodarone is the most effective and most common AAD used in AF. ⁵² It is preferred for AF rate and rhythm control in critically ill COVID‐19 patients with significant CHF or borderline blood pressure. ⁴⁶ However, information on amiodarone and COVID‐19 pharmacotherapy interactions is limited. Surveillance for liver, lung, and thyroid toxicity is recommended for long‐term amiodarone therapy and for short‐term use if clinically indicated. Long‐ and short‐term presentations of amiodarone toxicity have been reported. ⁵³ , ⁵⁴ Pulmonary toxicity may be a concern for COVID‐19 patients with severe pneumonia who require prolonged mechanical ventilation. Amiodarone should be used with extreme caution when coadministered with lopinavir/ritonavir (QT prolongation).

Dronedarone shares similar pharmacokinetics with amiodarone ³⁸ ; however, its use is contraindicated in patients with CHF or left ventricular dysfunction. ⁵⁵ Dronedarone is contraindicated with lopinavir/ritonavir because of dependence on CYP3A4 for clearance and risk of life‐threatening arrhythmia. ⁴⁷ Therefore, the utility of dronedarone may be limited for AF in COVID‐19 patients.

Amiodarone and dronedarone may cause QT prolongation, particularly when used with hydroxychloroquine, chloroquine, or macrolides. Plasma concentration of amiodarone and dronedarone can be decreased when administered with tocilizumab or sarilumab (CYP3A4 inducers) (Figure 4).

Dofetilide is an I_Kr blocker and predominantly excreted by the kidney (Figure 2). Hospitalization for ECG monitoring is required for the 3‐day loading period. ³⁸ Dofetilide is more effective than cardioversion in maintaining sinus rhythm ⁵⁶ and proved to be safe in patients with underlying CHF and myocardial infarction. ⁵⁷ Information is not available on any long‐term use of dofetilide in patients on COVID‐19 pharmacotherapy.

Ibutilide is an I_Kr blocker and late inward I_Na agonist. Ibutilide is used for pharmacological cardioversion (Figure 1) of AF or atrial flutter. QT interval must be monitored for 2 to 6 hours after the infusion. ⁵⁸ Ibutilide is metabolized by CYP3A4 and CYP2D6.

Dofetilide and ibutilide use may be limited in COVID‐19 patients already receiving hydroxychloroquine, chloroquine, macrolides, or lopinavir/ritonavir because of their intrinsic dose‐dependent QT prolongation. However, the use of ibutilide may be a good option for conversion of acute symptomatic AF (Figure 1).

Sotalol is an I_Kr blocker (dose dependent) with moderate β‐blockade effect. ³⁸ Sotalol is renally excreted (Figure 2). ³⁸ If sotalol is used in the presence of lopinavir/ritonavir, which is nephrotoxic, QT interval should be followed closely. Sotalol may be used with lopinavir/ritonavir, tocilizumab, or sarilumab, given lack of interaction on CYP3A4 or CYP2D6. However, there are dose‐dependent QT prolongation drug interactions with hydroxychloroquine, chloroquine, and macrolides, so monitoring should be implemented. Class III AADs are generally contraindicated in patients who are treated with fingolimod because of QT prolongation and risk of torsade de pointes. ³⁶

Class IV

Nonhydropyridine calcium channel blockers are used as first‐line rate‐control agents in AF. ¹⁷ Diltiazem and verapamil block L‐type calcium channels and are contraindicated in patients with decompensated CHF or significantly reduced ejection fraction because of negative inotropic effect ¹⁷ , ⁴⁹ (Figure 1).

Diltiazem is metabolized by CYP2C19 and CYP3A4. The use of diltiazem (P‐glycoprotein inhibitor) with azithromycin (P‐glycoprotein substrate) has been reported to prolong QT interval, leading to torsade de pointes. ⁵⁹ Lopinavir/ritonavir may cause prolonged PR and second‐ or third‐degree heart block when used with calcium channel blockers. ²⁴ Lopinavir/ritonavir can increase calcium channel blocker plasma concentration through CYP3A4 inhibition and should be closely monitored ⁴⁷ , ⁶⁰ (Figure 1).

Digoxin

Digoxin is a sodium/potassium ATPase pump inhibitor. It could be considered in CHF patients given lack of negative inotropic effect ¹⁷ and in patients with marginal blood pressure who do not tolerate calcium channel blockers or β blocker.

Lopinavir/ritonavir increases serum digoxin concentration and toxicity through inhibition of P‐glycoprotein. ⁶¹ Lopinavir/ritonavir may cause prolonged PR and second‐ or third‐degree heart block when used with digoxin. ²⁴ Routine monitoring of digoxin levels should be considered.

COVID‐19 patients treated with both fingolimod and digoxin should receive ECG before medication initiation, sequential ECG, and telemetry monitoring for bradycardia and QT prolongation. ³⁶

Concomitant Use of Anticoagulation Therapy and COVID‐19 Drug Therapy

Coagulopathy has been reported in critically ill COVID‐19 patients, and anticoagulation with heparin has shown some mortality benefit. ⁶² The prevalence of drug‐drug interactions from anticoagulation was reported as up to 26.3% in the AF population. ⁶³ The interaction increased risk of bleeding up to 7‐fold ⁶³ and is expected to be higher in COVID‐19 patients. The guiding principles for anticoagulation in COVID‐19 patients with AF are the same as in patients without COVID‐19, although little is known about potential drug‐drug interactions with COVID‐19 pharmacotherapy. We aim to review the choice of anticoagulation on the basis of possible drug interactions with COVID‐19 pharmacotherapy, as summarized in Figure 3.

Direct Oral Anticoagulation

Direct Factor Xa Inhibitor

Apixaban is predominantly metabolized by CYP3A4 with a minor (27%) component of renal elimination. Lopinavir/ritonavir is a strong CYP3A4 and P‐glycoprotein inhibitor. Coadministration is generally not recommended, but if necessary, the dose can be reduced by 50% (discontinue if on 2.5 mg twice a day) (Table S1). ⁴

Rivaroxaban is metabolized in the liver by CYP3A4, with 30% excreted in the urine. It also has a drug interaction with lopinavir/ritonavir (strong CYP3A4 and P‐glycoprotein inhibitor), and coadministration is not recommended. ⁴ However, rivaroxaban can be used in patients who receive azithromycin (weak CYP3A4 inhibitor) with caution (Figure 3). ⁶⁴

Edoxaban is mainly excreted in the urine, with <4% metabolized by liver CYP3A4. The dose should be reduced with concomitant use of azithromycin (P‐glycoprotein inhibitor) (Table S1). ⁶⁵ Concurrent treatment with ritonavir/lopinavir (strong P‐glycoprotein) and edoxaban is not recommended, given lack of adequate data on interaction. ⁶⁶

Direct Thrombin Inhibitor

Dabigatran is hydrolyzed and 80% renally excreted. However, there are no data on any interaction with azithromycin or ritonavir. ⁶⁷

Vitamin K Antagonist

Azithromycin increases the effect of warfarin, ⁶⁸ whereas ribavirin and lopinavir/ritonavir diminish warfarin's effect by unclear mechanisms. In several case reports, the dose of warfarin needed to be increased up to 40% with ribavirin and 125% with ritonavir to maintain international normalized ratio goal. ²⁷ , ⁶⁹ Tocilizumab and sarilumab can potentially increase warfarin metabolism through induced CYPs. Steroids may increase the bioavailability of warfarin, ⁷⁰ affecting international normalized ratio. We recommend regular international normalized ratio monitoring in patients who are treated with COVID‐19 pharmacotherapy.

Heparin

Unfractionated heparin and enoxaparin potentiate antithrombin III activity. They have no documented drug interaction with COVID‐19 pharmacotherapy. Unfractionated heparin is metabolized by the reticuloendothelial system and endothelial cells, and enoxaparin metabolites are renally excreted. ⁷¹

Therefore, we recommend heparin as an anticoagulant of choice in COVID‐19 patients with AF in the short‐term setting. Direct oral anticoagulants can be used in AF patients with COVID‐19 after hospital discharge without lopinavir/ritonavir.

Clinical Approach

Stepwise approach in COVID‐19 patients with AF is summarized in Figure 1.

General Considerations

1. QT interval should be monitored closely when class IA, IC, and III AADs are administered with hydroxychloroquine/chloroquine, macrolide, or lopinavir/ritonavir.

2. Classes IA and IC are contraindicated in COVID‐19 patients on fingolimod.

3. For patients on fingolimod, we recommend obtaining an ECG before AAD initiation, ECG at 6 hours after first dose, periodic ECG, and continuous telemetry monitoring.

4. β Blockers are recommended as a first‐line therapy for rate control strategy.

5. Calcium channel blockers are not recommended in myocarditis patients with acute decompensated CHF.

6. Digoxin can be used in CHF or in combination with β blockers or calcium channel blockers to achieve rate control.

7. Heparin is the anticoagulant of choice in hospitalized COVID‐19 patients with AF, especially if patients are being treated with lopinavir/ritonavir.

8. Direct oral anticoagulants can be used in AF patients with COVID‐19 after discharge without lopinavir/ritonavir.

Rhythm Control

1. Amiodarone can be useful for rhythm and rate control in critically ill COVID‐19 patients with CHF. Close monitoring with caution is recommended with concurrent lopinavir/ritonavir use. It is not recommended in patients undergoing treatment with fingolimod.

2. Flecainide is a preferred option for pharmacological cardioversion in patients with no structural heart disease or coronary artery disease who are on fingolimod.

3. Ibutilide can be used for cardioversion in the patient is not on fingolimod.

Conclusions

The use of AADs or anticoagulants in AF may have significant adverse effects because of drug‐drug interactions with emerging COVID‐19 pharmacotherapy, including I_Kr blockade, CYP inhibition or enhanced activity, and P‐glycoprotein inhibition. Drug‐drug interactions may lead to increased propensity for bradycardia, tachyarrhythmias, or severe bleeding. The choice of AADs and anticoagulants for COVID‐19 patients with AF should be individualized on the basis of drug interactions, mechanisms of drug metabolism, and potential consequences. A baseline ECG before the initiation of AAD in addition to continuous rhythm monitoring after AAD initiation are recommended. If anticoagulation is started, extra caution should be exercised when used in combination with azithromycin or lopinavir/ritonavir. It is crucial for clinicians to be aware of the indications, contraindications, and key drug‐drug interactions between AADs, anticoagulants, and emerging COVID‐19 pharmacotherapies in this challenging cohort of patients to achieve optimal clinical outcomes.

Sources of Funding

This research is partially supported by Mayo Clinic Cardiovascular Research Publishing Grant.

Disclosures

None.

Supporting information

Table S1

(J Am Heart Assoc. 2020;9:e017529 DOI: 10.1161/JAHA.120.017529.)