ACE inhibitors and angiotensin receptor blockers for hypertension tied to lower death risk with COVID-19
Taking a step toward resolving a prickly clinical conundrum, a retrospective analysis of COVID-19 in patients taking angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) for hypertension found that the treated group had almost a 60% lower risk of all-cause mortality than hypertensive COVID-19 patients not taking ACEIs or ARBs. 
That association held true in diverse models adjusted for variables that may affect death risk.
NEJM Journal Watch analysts Allan Brett and David Rind frame the problem as deciding whether ACEIs and ARBs have potentially harmful – or potentially beneficial – effects on the natural history of COVID-19. [2, 3]
Angiotensin-converting enzyme 2 (ACE2) plays a role in SARS-CoV-2 entry into human cells, and ACEIs and ARBs may boost expression of ACE2 and so worsen the course of COVID-19. On the other hand, experts invoke other mechanisms suggesting that ACEIs and ARBs could benefit people with COVID-19. For example, ACE2 transforms angiotensin II to angiotensin-(1-7), and angiotensin-(1-7) may enhance vasodilation and stifle inflammation.
Researchers working in Wuhan, the initial site of the COVID-19 epidemic, did not address specific ACE2-related mechanisms but instead weighed the impact of ACEIs or ARBs on the ultimate outcome – all-cause mortality after 28 days – in people taking those agents for hypertension while in the hospital for COVID-19. 
All 1128 people in the analysis had hypertension, and 188 of them (17%) took an ACEI or an ARB for their high blood pressure. The comparison group took other antihypertensives (alpha or beta blockers) or no blood pressure medication. Both groups had a median age of 64 years, and about 53% in both groups were men.
A slightly (but significantly) higher proportion of the ACEI/ARB group than the control group received antiviral medication (88.8% versus 81.7%, p=0.02), and a higher proportion received a beta blocker (28.2% versus 17.9%, p=0.002) or lipid-lowering drug (22.9% versus 10.0%, p=1.51(E-6)). But the groups did not differ significantly in use of systemic corticosteroids, antibiotics, vasoactive drugs, or use of invasive or noninvasive ventilation.
Unadjusted 28-day all-cause mortality stood at 3.7% in the ACEI/ARB group, less than half the 9.8% mortality in the comparison group, a significant difference (p=0.01). A Cox model that adjusted for age, gender, comorbidities, and in-hospital medication determined that ACEI/ARB takers had almost a 60% lower risk of death than hypertensive people not taking these drugs (adjusted hazard ratio [aHR] 0.42, 95% confidence interval [CI] 0.19 to 0.92, p=0.03). A propensity score-matched analysis that adjusted for imbalanced variables in a mixed-effect Cox model determined that ACEI/ARB treatment cut the risk of death by almost two thirds (aHR 0.37, 95% CI 0.15 to 0.89, p=0.03). A similar analysis found that, compared with use of other antihypertensives, ACEI/ARB therapy sliced the death risk 70% (aHR 0.30, 95% CI 0.12 to 0.70, p=0.01).
The American College of Cardiology and the American Heart Association recommend continued use of ACEI/ARB agents by people already taking those drugs when diagnosed with COVID-19 . The Wuhan team concludes that their findings support that recommendation.
- Zhang P et al. Association of inpatient use of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.
- Brett AS, Rind DM. ACE inhibitors and ARBs during the COVID-19 pandemic. NEJM Journal Watch. April 9, 2020.
- Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: What is the evidence? JAMA 2020 Mar 24; [e-pub].
- American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. ACC News Story. March 17, 2020.