Cardiovascular Medication Considerations

ACE/ARB/ARNI

Angiotensin converting enzyme 2 (ACE2) serves as the entry point for SARS-CoV-2 into human cells
ACE2 is expressed in many tissues, including in the heart and kidneys, and lung alveolar epithelial cells (Hamming, et al., J Pathol, 2004)
- Under normal conditions lung ACE2 expression is low (Serfozo, Hypertension, 2020), but may be upregulated in infection
Pharmacologic modulation of the renin-angiotensin-aldosterone system may alter ACE2 levels
- ACE inhibitors in humans do not appear to affect ACE2 activity. These drugs specifically target ACE, which has a different active site than ACE2 (Rice, et al., Biochem J, 2004)

There is conflicting evidence, but in some animal models, both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown to upregulate ACE2 expression in the heart, raising concern that these medications may increase susceptibility to COVID-19 through increased SARS-CoV-2 viral entry. (Patel et al., JAMA 2020)

Withdrawal of ACE/ARB and other goal-directed medical therapy in patients with heart failure is associated with worsening symptoms (Pflugfelder, et al., JACC, 1993; Halliday, et al., Lancet, 2019)
Early initiation of ACE-inhibitors following myocardial infarction/acute coronary syndrome is associated with improved outcomes (Circulation, 1998)
Currently, there is no clinical evidence that ACE/ARB/ARNI are associated with increased risk of COVID-19.
Preclinical models have suggested ARBs may attenuate SARS-CoV-induced lung injury (Kuba, et al., Nature Medicine, 2005)

NSAIDs suppress prostaglandin synthases 1 and 2 (COX-1 and COX-2), enzymes responsible for producing prostaglandins (lipids which can trigger pain and fever)

SARS-CoV-1 binds to the COX-2 promoter, increasing expression of this enzyme. (Yan, et al., Int. J. Biochem. Cell Biol., 2006). Because PGE2 may inhibit coronavirus replication (Amici et al., Antivir. Ther., 2006), there is theoretical concern that NSAID-mediated decreases in PGE2 may increase risk of COVID-19.
NSAIDs may increase risk of cardiovascular events, gastrointestinal ulcer/bleeding, and acute kidney injury, among others

Indomethacin may block coronavirus RNA synthesis independent of COX inhibition (Sander et al., Front. Physiol, 2017)

There is no strong clinical evidence for or against the use of NSAIDs in individuals with (or at-risk-of) SARS-CoV-2 infection (Fitzgerald, Science, 2020), although other patient-specific factors (risk of cardiovascular events, gastrointestinal ulcers/bleeding, chronic kidney disease) should be considered.

Cardiovascular: Atrioventricular block, bundle branch block, cardiac arrhythmia, cardiomyopathy, ECG changes (including prolonged QRS and QTc intervals, T-wave inversion, or depression), hypotension, torsades de pointes, ventricular fibrillation, ventricular tachycardia (UpToDate)
- Development of acute renal failure (but not baseline QTc) predictive of developing prolonged QTc >500ms among patients being treated for SARS-CoV-2 infection with hydroxychloroquine and azithromycin at New York University (Chorin, et al., medRxiv, 2020)
Ophthalmologic: toxicity is uncommon with short-term use; long-term use associated with retinal toxicity

Altered cardiac conduction: QTc prolongation, ventricular arrhythmias, torsades de pointes; consider avoiding use in patients with prolonged QT interval, congenital long QT syndrome, history of torsades de pointes, bradyarrhythmias, uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, decompensated heart failure, or concurrent use of Class IA (eg, quinidine, procainamide) or Class III (eg, amiodarone, dofetilide, sotalol) antiarrhythmic agents or other drugs known to prolong the QT interval. (UpToDate)
- Development of acute renal failure (but not baseline QTc) predictive of developing prolonged QTc >500ms among patients being treated for SARS-CoV-2 infection with hydroxychloroquine and azithromycin at New York University (Chorin, et al., medRxiv, 2020)

Statins may have an anti-inflammatory effect that blunts the immune response to acute viral infection (Virani, ACC.org, 2020)
In preclinical models, statins upregulate ACE2 (Tikoo, et al., Bichem Pharmacol, 2015) - downregulation of ACE2 has been observed in ARDS, and restoring ACE2 levels may be a novel treatment strategy (Wosten-van Aspersen, et al., Pediatr Crit Care Med, 2013).

Overall, there is insufficient evidence to recommend initiation of statns soley for treatment of COVID-19 and/or ARDS
Statins should be continued in patients previously prescribed statins
Initiation of statins should be considered for patients with other indiciations (eg. known coronary artery disease, stroke, peripheral artery disease, diabetes, elevated 10-year risk of ASCVD)