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The largest dataset of randomized trials examining the safety of ACE inhibitors and angiotensin receptor blockers in patients with COVID-19 has shown overall reassuring results, albeit with the new observation of a link to acute kidney injury in hospitalized patients.

The new meta-analysis, led by the International Society of Hypertension, was presented at the recent American Heart Association (AHA) Scientific Sessions.

“In patients with COVID-19 who were randomized to renin-angiotensin system inhibitors vs controls, we found no effect on short-term all-cause deaths, a trend toward decreased myocardial infarction, are zyrtec and benadryl the same thing and increased risk of acute kidney injury,” lead author Alta Schutte, PhD, told | Medscape Cardiology.

“The totality of data from this international collaboration provides strong evidence to suggest that inhibitors of the renin-angiotensin system can be safely used in patients with COVID-19 while being aware of a potential increased risk of acute kidney injury,” she added.

Schutte, who is professor and principal theme lead of cardiac, vascular, and metabolic medicine at the School of Population Health, University of New South Wales, Sydney, Australia, and the immediate past president of the International Society of Hypertension, explained that this meta-analysis is the largest pooled analysis of randomized controlled trials investigating inhibitors of the renin-angiotensin system in COVID-19 patients.

“Although the overall size of participant data (over 1800) is modest, this is the most highly powered randomized analysis to assess binary clinical endpoints, and the first to directly compare ACE inhibitors vs angiotensin receptor blockers,” she said.  

Noting that the meta-analysis demonstrated no statistically significant differences between ACE inhibitors vs angiotensin receptor blockers. Schutte commented: “This suggests that neither the upstream renin angiotensin inhibition by ACE inhibitors nor the downstream inhibition at receptor level by angiotensin receptor blockers influence mortality outcomes in COVID-19.”

However, the analysis found an almost twofold increased risk of acute kidney injury in hospitalized patients associated with ACE inhibitors and angiotensin receptor blockers in acute COVID-19 (7% vs 3.6%).

“The overall event rate was low, but effects were consistent across trials that initiated and those that continued renin-angiotensin system inhibitors, but was not associated with increased need for dialysis or mortality at short-term follow-up,” Schutte reported.

The meta-analysis combined data from 14 randomized clinical trials including 838 patients (mean age 59 years, 58% male, mean 26 days post-COVID-19 diagnosis).

Results showed no effect of renin-angiotensin system blockers vs control on all-cause mortality (7.2% vs 7.5%, relative risk 0.95; 95% CI, 0.69 – 1.30), either overall or in subgroups defined by severity or trial type (RASi initiation or continuation).

Users of ACE inhibitors or angiotensin receptor blockers had a nonsignificant reduction in acute myocardial infraction (MI, 2.1% vs 3.6%; RR 0.59; 95% CI 0.33 – 1.06), but a statistically significant increased risk of acute kidney injury (7% vs 3.6%, RR, 1.82; 95% CI, 1.05 – 3.16).

Other results showed there was:

  • no increase in need for dialysis (RR, 1.15; 95% CI, 0.60 – 2.21)

or differences in:

  • congestive cardiac failure (RR, 0.86; 95% CI, 0.47 – 1.54)

  • cerebrovascular events (RR, 1.62; 95% CI, 0.43 – 6.15)

  • venous thromboembolism (RR, 1.18; 95% CI, 0.45 – 3.05)

  • hospitalization (RR, 1.92; 95% CI, 0.50 – 7.35)

  • admission to intensive care (RR, 1.00; 95% CI, 0.77 – 1.30)

  • inotropes (RR, 1.01; 95% CI, 0.73 – 1.41)

  • mechanical ventilation (RR, 1.00; 95% CI, 0.76 – 1.31) 

Increased Risk of Acute Kidney Injury

On the observation of an increased risk of acute kidney injury, Schutte pointed out that acute kidney injury is common in COVID-19, as SARS-CoV-2 can directly infect the kidneys, and it is well recognized that renin-angiotensin system inhibitors produce nonpathological reduction in intraglomerular pressure and glomerular filtration rate.

“Analyses in patients without COVID-19 have demonstrated that a decline in glomerular filtration rate associated with intensive blood pressure reduction actually preserves blood flow to the renal tubules, a region highly sensitive to hypoxia and susceptible to acute tubular necrosis with sustained hypoperfusion,” Schutte noted. “It is unclear whether the increased risk of acute kidney injury in COVID-19 patients using renin-angiotensin system inhibitor therapy will produce long-term repercussions.

“Longer term follow-up is needed to investigate renal outcomes and whether there may even be benefits of these drugs to slow progression of proteinuric chronic kidney disease in such patients,” she said.   

Still, Schutte added that there does not appear to be an increased risk of acute kidney injury in outpatients, “which is where the vast majority of COVID-19 is managed.”

Schutte stressed that patients who are using ACE inhibitors or angiotensin receptor blockers should continue taking their medication as prescribed. “The overall cardiovascular benefits of these drugs are overwhelming and early alerts of potential increased risk in COVID-19 patients have been silenced.”

She stated that clinicians should also not be hesitant to initiate treatment with these agents in patients with COVID-19. “Several trials included COVID-19 patients newly initiated on renin-angiotensin system inhibitors and no increased risk was observed. Overall, and as one would expect from these drugs with important cardiovascular protective effects, COVID-19 patients using these agents had a statistically borderline lower risk for myocardial infarction.”

But Schutte added that if patients become severely ill with COVID-19 and are treated with renin-angiotensin system inhibitors, there is a potential risk for acute kidney injury. “This increased risk is similar as seen with severely ill patients without COVID-19 using renin-angiotensin system inhibitors, and hence clinicians should carefully evaluate kidney function.”

Overall, she concluded, “these findings provide strong evidence that renin-angiotensin system inhibitors can be used safely in COVID-19 patients, balancing both the benefits and risks on cardiovascular and renal outcomes respectively.”

Commenting on this new analysis for | Medscape Cardiology, Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, said: “An increased risk of acute kidney injury is not quite unexpected since COVID-19, like many infectious diseases, can give rise to dehydration and hypotension, which make the kidney more vulnerable to the adverse effect of renin-angiotensin system inhibitors. The good news is that there was no increase in need for dialysis, indicating the observed acute kidney injury was mostly transient and resolved with therapy.”

He added: “Like quite a few previous studies, the meta-analysis concludes that these drugs can safely be used in COVID-19 patients, and thus corroborates and extends previous data.”

The current meta-analysis was funded by the International Society of Hypertension. Schutte reports speaker fee/honoraria from Novartis South Africa, Servier South Africa, Abbott, Omron Healthcare, and Takeda.

American Heart Association (AHA) Scientific Sessions 2021. Presented November 14, 2021. FS04. Abstract   

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