ACEi, ARB use not tied to increased COVID-19 diagnosis, complication risk

Exposure to angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) does not appear to increase the risk of being diagnosed with COVID-19 or hospitalization for COVID-19–related outcomes, according to a study.

“[W]e observed no clear association of increased risk of COVID-19 diagnosis, hospital admission, or subsequent complications associated with outpatient prevalent ACE inhibitor or ARB use,” remarked the investigators.

Using electronic medical records from Spain and the US, the study investigators identified 1,355,349 adults with hypertension who had at least one outpatient prescription for ACE inhibitors or ARBs (target group), or calcium channel blockers (CCBs) or thiazide or thiazide-like diuretics (THZs; comparator group) between November 2019 and January 2020. Of these, 363,785 were on ACE inhibitor or ARB monotherapy, 248,915 were on CCB or THZ monotherapy, 711,799 were on ACE inhibitor and ARB as monotherapy or combination therapy, and 473,076 were on CCB and THZ as monotherapy or combination therapy.

Overall, incidence of COVID-19 diagnosis was 5.6 and 4.8 per 1,000 person-years in ACE inhibitor or ARB and CCB or THZ monotherapy recipients, respectively.

Exposure to ACE inhibitors or ARBs did not carry an elevated risk of being diagnosed with COVID-19 compared with CCB or THZ (calibrated hazard ratio [HR], 0.98, 95 percent confidence interval [CI], 0.84–1.14; p=0.76 for monotherapy comparisons and HR, 1.01, 95 percent CI, 0.90–1.15; p=0.81 for monotherapy or combination therapy comparisons). [Lancet Digit Health 2021;3:e98-e114]

In individual assessment, there was no apparent risk of COVID-19 diagnosis with ACE inhibitor monotherapy compared with CCB or THZ, be it monotherapy (HR, 0.91, 95 percent CI, 0.68–1.21; p=0.51 [>40 percent heterogeneity]) or combination therapy (HR, 0.95, 95 percent CI, 0.83–1.07; p=0.38). Similarly, there was no increased risk of COVID-19 diagnosis with ARB exposure vs CCB or THZ for monotherapy (HR, 1.10, 95 percent CI, 0.89–1.35; p=0.40) or combination therapy (HR, 1.08, 95 percent CI, 0.89–1.31; p=0.49).

When comparing ACE inhibitors with ARBs, there was a reduced risk of COVID-19 diagnosis with ACE inhibitor combination therapy vs ARB combination therapy (HR, 0.88, 95 percent CI, 0.79–0.99; p=0.03), though the results were not significant with monotherapy (HR, 0.85, 95 percent CI, 0.69–1.05; p=0.14).

However, the investigators suggest that this result might be due to a chance finding or residual bias. “[T]he marginal difference between ACE inhibitors and ARBs does not warrant class switching to reduce COVID-19 susceptibility,” they said.

Exposure to ACE inhibitors or ARBs did not increase the risk of hospitalization with COVID-19 compared with CCB or THZ. The HRs for hospitalization with COVID-19 with ACE inhibitors vs ARBs were 0.88 and 0.93 for monotherapy and combination therapy, respectively.

There was also no increased risk of hospitalization due to pneumonia with any of the drug comparisons, nor with regard to the risk of hospitalization due to pneumonia, acute respiratory distress syndrome (ARDS), acute kidney injury (AKI), or sepsis in two of the studied cohorts*. However, in the US Department of Veterans Affairs Observational Medical Outcomes Partnership cohort, there was a small, albeit significantly, increased risk of hospitalization due to pneumonia, ARDS, AKI, or sepsis with ACE inhibitor vs CCB or THZ exposure (HR, 1.17), potentially driven by an increased AKI incidence, with no elevated risk of pneumonia observed.

Current advice: Continue treatment

“Speculation about the effects of renin-angiotensin system (RAS) therapy on susceptibility to and severity of COVID-19 has generated substantial public health concerns, resulting in the release of statements from health regulatory agencies and clinical societies advocating that, in the absence of direct evidence of harm with COVID-19, these medicines should not be discontinued,” the investigators said.

“However, inconsistencies in recommendations have emerged, with suggestions that users of these medicines should be monitored closely,” they continued.

“Our findings support recent regulatory and clinical society recommendations that patients should not halt their ACE inhibitor or ARB therapy despite previously posited mechanisms of increased COVID-19 risk,” they noted.

“The use of an active control [in this study] deserves a specific comment,” said Professor Francisco J de Abajo from the University Hospital Príncipe de Asturias and University of Alcalá in Madrid, Spain, in a commentary. [Lancet Digit Health 2021;3:e70-e71]

“Users of RAS inhibitors present multiple cardiovascular risk factors and, thus, are very different from non-users,” he noted, highlighting that the benefit of using an active control in the present study may have helped reduce confounding compared with previous studies. An avenue for future research is establishing if in-hospital use of these drugs impacts mortality, he said.