Note upfront:

On June 4, NEJM corresponded that the publication by Mehra et al. had been retracted .

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Entry of the SARS-CoV-2, the causative agent of COVID-19, into human cells is facilitated by interaction with the angiotensin-converting enzyme 2 (ACE2) receptor. ACE2 catalyzes the conversion of angiotensin II to angiotensin-(1-7), which has vasodilatory, anti-inflammatory, antifibrotic and antigrowth effects. ACE2 is thereby protective against detrimental activation of the renin-angiotensin-aldosterone system (RAAS). It has been suggested that ACE inhibitors and ARBs increase the expression of ACE2, leading to more severe infection and adverse outcomes in patients with COVID-19. It has also been hypothesized that ACE inhibitors may counter anti-inflammatory effects of ACE2, but this has not been demonstrated in in vitro studies.

Some patients have stopped treatment with ACE inhibitors and ARBs during the COVID-19 pandemic, but important scientific societies, such as ESC and HFSA/ACC/AHA have strongly recommended that these medications should not be discontinued due to lack of evidence. Studies were therefore performed to investigate the association between use of RAS inhibitors and mortality in COVID-19 patients.

Recently, on May 1 2020, three papers were published in the N Engl J Med on the effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) in CVD patients with COVID-19.

The study by Mehra et al. used data from the Surgical Outcomes Collaborative (Surgisphere), an international registry (data from 169 hospitals in 11 countries in Asia, Europe and North America). Data from patients with PCR-proven COVID-19 admitted between December 20, 2019 and March 15, 2020 were collected. Patient’s hospitalization had to be complete as of March 28, 2020 – thus, patients had died in the hospital or were discharged. 8910 Patients were included in the study, of whom 515 died (5.8%) and 8395 survived. 8.6% Of patients used ACE inhibitors and 6.2% ARBs. Use of ACE inhibitors was associated with increased risk of survival (OD 0.33, 95%CI: 0.22-0.54), while no association was observed for use of ARBs and mortality (OD 1.23, 95%CI: 0.87-1.74). These results did not confirm concerns about potential harmful effects of RAS inhibitors on mortality in patients with COVID-19.

Mancia et al performed a population case-control study in the Lombardy region of Italy, using a promptly established registry of patients with diagnosis of infection of SARS-CoV-2. 6272 cases with confirmed COVID-19 diagnosis between February 21 and March 11, 2020 were matched to 30,759 controls (beneficiaries of the Regional Health Service) based on sex, age, and municipality of residency. 23.9% Of cases used ACE inhibitors vs. 21.4% of controls and 22.2% of cases took ARBs vs. 19.2% of controls. Use of ACE inhibitors or ARBs was not associated with COVID-19 (OR 0.96, 95%CI: 0.87-1.07 and OR 0.95, 95%CI: 0.86-1.05, respectively). These was also no association observed in those with a severe or fatal course of the disease (OR 0.91, 95%CI: 0.69-1.21 for ACE inhibitors and OR 0.83, 95%CI: 0.63-1.10 for ARBs). Therefore, this study showed no evidence of that ACE inhibitors or ARBs affect the risk of COVID-19.

In a third study by Reynolds et al the association between use of antihypertensive medications and likelihood of a positive COVID-19 test was investigated in a cohort of patients in a large health care network in New York City (all patients New York University Langone electronic health record with COVID-19 test results (either positive or negative), recorded from March 1 to April 15, 2020). A total of 12,594 patients had a COVID-19 test result, of whom 46.8% had a positive result and 53.2% a negative result. Patients who had been treated with each medication class were matched to those not treated with that medication class, according to propensity scores. A total of 4357 (34.6%) patients had a history of hypertension; 59.1% were COVID-19-positive and 40.9% were COVID-19-negative. An absolute difference of at least 10 percentage points in the likelihood of a positive COVID-19 test for ACE inhibitors and ARBs was ruled out in these patients. In addition, a substantial difference in likelihood of severe COVID-19 for ACE inhibitors and ARBs was ruled out in hypertensive patients. Similar results were observed when all patients were included in the analyses. This observational study demonstrated that use of ACE inhibitors or ARBs was not associated with an increased risk of testing positive for COVID-19.