Maintenance of RAAS Inhibitors with Known or Suspected Covid-19
Despite these theoretical uncertainties regarding whether pharmacologic regulation of ACE2 may influence the infectivity of SARS-CoV-2, there is clear potential for harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable condition. Covid-19 is particularly severe in patients with underlying cardiovascular diseases,9 and in many of these patients, active myocardial injury,14,54,58-60 myocardial stress,59 and cardiomyopathy59 develop during the course of illness. RAAS inhibitors have established benefits in protecting the kidney and myocardium, and their withdrawal may risk clinical decompensation in high-risk patients.
Although rates of heart failure have been infrequently reported in epidemiologic reports from China to date, the prevalence of heart failure among critically ill patients with Covid-19 in the United States may be high (>40%).59 In the Quinapril Heart Failure Trial, among patients with chronic symptomatic heart failure, withdrawal of quinapril resulted in a progressive decline in clinical status.61 In the TRED-HF trial, among asymptomatic patients with heart failure with recovered left ventricular ejection fraction, the phased withdrawal of medical therapy (including RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy.62 In addition, RAAS inhibitors are a cornerstone of therapy after myocardial infarction: maintenance of therapy in the days to weeks after the index event has been shown to reduce early mortality.63 Among patients with unstable clinical status, myocardial injury associated with Covid-19 may pose even higher early risks after withdrawal of RAAS inhibitors.
Withdrawal of RAAS inhibitors that are being administered for the management of hypertension may be less risky than withdrawal of RAAS inhibitors that are being administered for conditions in which they are considered guideline-directed therapy but may be associated with other challenges. Switching from a RAAS inhibitor to another antihypertensive therapy in a stable ambulatory patient may require careful follow-up to avoid rebound increases in blood pressure. In addition, selection of dose-equivalent antihypertensive therapies may be challenging in practice and may be patient-dependent. Even small and short-lived periods of blood pressure instability after a therapeutic change have been associated with excess cardiovascular risk.64-66 This may be an especially important consideration in patients with Covid-19, which appears to result in a state of RAAS activation,44 and in settings (e.g., China) where baseline blood-pressure control is infrequently reached at the population level.11,12
The effects of withdrawing RAAS inhibitors or switching treatments are uncertain among patients with chronic kidney disease. Although reported rates of chronic kidney disease appear to be low among hospitalized patients with Covid-19 in China (1 to 3%) (Table S1), the prevalence may be higher among patients who are critically ill and among those in other geographic regions.59 Many patients have varying degrees of acute kidney injury during illness.14,67,68 For these high-risk patients, individualized treatment decisions regarding the maintenance of RAAS inhibitors that are guided by hemodynamic status, renal function, and clinical stability are recommended.
On the basis of the available evidence, we think that, despite the theoretical concerns and uncertainty regarding the effect of RAAS inhibitors on ACE2 and the way in which these drugs might affect the propensity for or severity of Covid-19, RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, are being evaluated for, or have Covid-19 (see text box), a position now supported by multiple specialty societies (Table S2). Although additional data may further inform the treatment of high-risk patients with Covid-19, clinicians need to be cognizant of the unintended consequences of prematurely discontinuing proven therapies in response to hypothetical concerns that may be based on incomplete experimental evidence.69
Key Points Related to the Interplay between Covid-19 and the Renin–Angiotensin–Aldosterone System
• ACE2, an enzyme that physiologically counters RAAS activation, is the functional receptor to SARS-CoV-2, the virus responsible for the Covid-19 pandemic
• Select preclinical studies have suggested that RAAS inhibitors may increase ACE2 expression, raising concerns regarding their safety in patients with Covid-19
• Insufficient data are available to determine whether these observations readily translate to humans, and no studies have evaluated the effects of RAAS inhibitors in Covid-19
• Clinical trials are under way to test the safety and efficacy of RAAS modulators, including recombinant human ACE2 and the ARB losartan in Covid-19
• Abrupt withdrawal of RAAS inhibitors in high-risk patients, including those who have heart failure or have had myocardial infarction, may result in clinical instability and adverse health outcomes
• Until further data are available, we think that RAAS inhibitors should be continued in patients in otherwise stable condition who are at risk for, being evaluated for, or with Covid-19