Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19

Muthiah Vaduganathan, M.D., M.P.H., Orly Vardeny, Pharm.D., Thomas Michel, M.D., Ph.D., John J.V. McMurray, M.D., Marc A. Pfeffer, M.D., Ph.D., and Scott D. Solomon, M.D. DOI: 10.1056/NEJMsr2005760 Disclaimer: This is a summary of the highlights of this article, I do not own any or endorse any of the findings within this article. This is for educational purposes only and a link for further review is included.

Key Points:

1. Highlight that the data in humans is too limited to support or refute these hypotheses and concern.

2. Specifically, discussed the uncertain effects of RAAS blockers on ACE2 levels and activity in humans.

3. They proposed an alternative hypothesis that ACE2 may be beneficial rather than harmful in patients with lung injury.

4. They explicitly raise the concern that withdrawal of RAAS inhibitors may be harmful in certain high-risk patients with known or suspected Covid-19.

5. Switching from RAAS inhibitor to another antihypertensive therapy in stable ambulatory patient may require careful follow-up to avoid rebound increases in BP.

   • Selection of dose-equivalent antihypertensive therapies might be challenging and patient-dependent.

   • Even small and short-lived periods of BP instability after therapeutic change have been associated with excess cardiovascular risk.

   • Important consideration in COVID19 patients (which appears to be a state of RAAS activation) and in settings where baseline BP control is infrequently reached at population level.

COVID-19 and Older Adults with Coexisting Conditions

1. Coexisting conditions (including HTN) have consistently been reported to be more common among patients with Covid-19 who have had severe illness, been admitted to the intensive care unit, received mechanical ventilation, or died than among patients who have had mild illness.

2. Conditions track closely with advancing age is the strongest predictor of COVID-19 related death.

3. Details are lacking in studies since population-based studies estimate only 30-40% of patients in China are treated with hypertensive medication (and of these, only 25-30% are on RAAS inhibitors).

Uncertain Effects of RAAS Inhibitors on ACE2 in Humans

1. Generally, circulating levels of soluble ACE2 are low and there is a minimal role of ACE-2 in lungs in normal conditions but in certain clinical situations, they may be up-regulated.

2. ACE and ACE2 have distinctly different exam sites and so ACE-inhibitors in clinical use do not directly affect ACE2 activity.

3. There are mixed findings with regard to the effects of ACE-inhibitors on ACE2 levels or activity in tissue and in animal models. Some studies show that ARBS might increase mRNA expression or protein levels of ACE2 in tissue but some have no effect. 

4. Contrastingly, there are very few studies in humans regarding effects of ACE-inhibitors on ACE2 expression. The few studies that are done in humans have conflicting data. Data suggests effects on ACE2 should not be assumed to be uniform across RAAS-inhibitors or even in response to therapies within a drug class.

5. Plasma ACE2 levels might not be a reliable indicator of the activity of the full-length membrane bound form since the ACE2 is shed from membrane (regulated by an endogenous inhibitor)

6. Not enough data in experimental animal and human models regarding the effect of ACE-inhib/ARBS and other RAAS inhibitors on lung-specific expression of ACE2. 

Potential for Benefit Rather Than Harm of RAAS Blockers in COVID19

1. SARS-COV2 appears to gain initial entry through ACE2 and then down-regulate ACE2 expression so that the enzyme can’t exert protective effects in organs. 

   • Its been speculated but unproved that unopposed angiotensin II might be partially responsible for organ injury in COVID2.

1. There is initial attachment of SARS-COV2 spike protein —> down regulation of ACE2 on cell surfaces —> in-vitro cultured cells have continued viral infection and replication —> down-regulation of ACE2 in lungs —> initial neutrophil infiltration in response to bacterial endotoxin —> unopposed angiotensin II accumulation + local RAAS activation. 

2. A small study showed COVID (+) patients had elevated levels of plasma angiotensin II which correlated with total viral load and degree of lung injury.

   • Giving recombinant ACE2 and restoring ACE2 appeared to reverse lung-injury process in preclinical models of other viral infections and reduced angiotensin II in a phase 2 trial of ARDS in humans.

1. Theoretically dysregulated ACE2 can decrease cardioprotection. Markers of myocardial injury have been shown to be elevated during COVID19 disease and increase rapidly with clinical deterioration and preceding death.

2. ACE2 has well recognized role in myocardial recovery and injury response.

   • One study: ACE2 knockout in animals contributed to LV remodeling in response to angiotensin II related acute injury.

   • 2nd study: in autopsies of SARS patients, 35% of heart samples were (+) for viral RNA, which was associated with reduced ACE2 protein expression

   • Giving recombinant ACE2 normalized angiotensin II levels in human explanted hearts with dilated cardiomyopathy

   • These hypotheses have prompted trials to test if provision of recombinant ACE2 protein might be beneficial in restoring balance to RAAS network and possibly preventing lung injury.

   • Another paired trial is being conducted to use losartan as a treatment for COVID19 among pts that have not previously been treated with RAAS inhibitor and are either hospitalized or not hospitalized.

Maintenance of RAAS Inhibitors with Known or Suspected COVID19

1. There is a clear potential for harm related to the withdrawal of RAAS inhibitors in patients in otherwise stable condition.

2. COVID19 is particularly severe in pts with underlying cardiovascular disease —> during course of illness, patients may develop active myocardial injury, myocardial stress and cardiomyopathy.

3. Withdrawal may risk clinical decompensation in high-risk patients.

   • Quinapril Heart Failure Trial: in pts w/ chronic symptomatic heart failure, the withdrawal of quinapril resulted in progressive decline in clinical status.

   • TRED-HR trial: in asymptomatic pts with heart failure with recovered LVEF, the phased withdrawal of medical therapy (including RAAS inhibitors) resulted in rapid relapse of dilated cardiomyopathy.

4. RAAS inhibitors are cornerstone of therapy after myocardial infarction. Maintenance of

therapy in the days – weeks after the index event has been shown to reduce early mortality.

5. Among patients with unstable clinical status, myocardial injury associated with COVID19 may

have higher early risks after withdrawal of RAAS-inhibitors.

6. Withdrawal of RAAS inhibitors that are being administered for HTN might be less risky but

has other challenges.

7. Switching from RAAS inhibitor to another antihypertensive therapy in stable ambulatory patient

may require careful follow-up to avoid rebound increases in BP.

• Selection of dose-equivalent antihypertensive therapies might be challenging and patient-dependent.

• Even small and short-lived periods of BP instability after therapeutic change have been associated with excess cardiovascular risk.

• Important consideration in COVID19 patients (which appears to be a state of RAAS activation) and in settings where baseline BP control is infrequently reached at population level.

8. Effects of withdrawing RAAS inhibitors or switching treatments are uncertain among patients

with CKD.

• In high risk patients, individualized decisions about RAAS-inhibitor maintenance are guided by hemodynamic status, renal function, and clinical stability.