Risk of Dying Doubled in Wuhan COVID-19 Patients With Hypertension

New observational data from Wuhan, China, suggest that hypertensive patients hospitalized with COVID-19 had a twofold increased risk of dying compared to those without hypertension, and that not being on medication for hypertension at the time of hospitalization worsens outcomes. The study also provides additional reassurance about the use of antihypertensives that target the renin-angiotensin-aldosterone system (RAAS).

“Patients with RAAS inhibitors were not exposed to a higher risk of mortality in our study and, after pooling previously published data in a study-level meta-analysis, the use of RAAS inhibitors was shown to be possibly associated with lower risk of mortality,” write Chao Gao, MD (Xijing Hospital, Xi’an, China), and colleagues. Nevertheless, they urge caution in interpreting the results due to the observational nature of the study.

Several prior papers also have concluded that RAAS inhibitors do not appear to increase the risk of in-hospital mortality in COVID-19 patients. Authors for one of those studies, however, recently retracted their paper from the New England Journal of Medicine when they were unable to verify the data sources supplied by a private company. Even without that study, however, the existing data are consistent and support current guideline recommendations, Ankur Kalra, MD (Cleveland Clinic, OH), commented to TCTMD.

“Unless indicated otherwise, for other clinical reasons, you should not discontinue these agents just because there is now a pandemic,” Kalra said. “There is a reason why these agents are prescribed. They’re lifesaving, they're effective, and they're safe.”

In March, the American Society of Cardiology, American Heart Association, and Heart Failure Society of America issued guidance stating that patients should not stop taking RAAS inhibitors unless directed to do so by their physician. At the time, the societies also said more data were needed quickly to address the issue. Kalra noted that while patients were right to be concerned by some of the early data, the new Wuhan study and others, including a recent one he co-authored in JAMA Cardiology, provide a level of confidence for physicians and patients that didn’t exist a few months ago when patients asked their physicians if they should be worried about being on a RAAS inhibitor.

Signal for Lower Mortality

For the study, published in the June 7, 2020, issue of the European Heart Journal, the investigators examined data on 2,877 consecutive hospitalized patients treated in Wuhan. Of those, approximately 30% had a prior history of hypertension, and compared with nonhypertensive patients were more likely to have diabetes, angina, stroke, renal failure, or prior coronary artery revascularization.

There is a reason why these agents are prescribed. They’re lifesaving, they're effective, and they're safe. Ankur Kalra

During hospitalization, 4.0% of hypertensive patients died versus 1.1% of nonhypertensive patients (P < 0.001). After adjustment for confounders, those with versus without hypertension still had a twofold increased risk of death (adjusted HR 2.12; 95% CI 1.17-3.82). The hypertensive group also was more likely to develop severe/critical COVID-19 disease (P for trend < 0.001) and to need mechanical ventilation (P < 0.001).

Among those with hypertension or hypertension history, mortality was more than twice as high in those who were versus were not on an antihypertensive (7.9% vs 3.2%; P = 0.012).

Additionally, when Gao and colleagues compared patients on RAAS versus non-RAAS inhibitors, the adjusted mortality was numerically but not significantly lower in the former group (2.2% vs 3.6%; HR 0.85; 95% CI 0.28-2.58). However, the researchers performed a meta-analysis that included their study and three others from China, which showed a lower risk of mortality with RAAS versus non-RAAS inhibitors (RR 0.65; 95% CI, 0.45-0.94).

To TCTMD, Kalra cautioned that the confidence intervals across the studies in the meta-analysis are wide and straddle 1.0, the number of patients is small, and it was not a patient-level meta-analysis.

“But I think it does beg the question that if you were to accrue more data on a lot more patients, could there be a signal for these agents actually being protective?” he said.

In an accompanying editorial, Luis M. Ruilope, MD, PhD (Hospital Universitario 12 de Octubre, Madrid, Spain), and colleagues say a current hypothesis is that the heart failure drug sacubitril/valsartan (Entresto; Novartis), a combination of a neprilysin inhibitor and an ARB, may be helpful in COVID-19 patients due to its anti-inflammatory properties. They add that studies “investigating the potential good effects of RAAS blockers, including mineralocorticoid receptor antagonists and sacubitril/valsartan, are required” in the setting of COVID-19.

Kalra agreed that the theory needs to be explored further, as does the question of whether it is safe to start COVID-19 patients on ACE inhibitors or ARBs if they don’t have an approved indication for doing so.

“Quite frankly, I think what you really need is a randomized controlled trial in COVID-19 patients who have no exposure, who are completely naive of RAAS antagonists,” he observed. “And then you have an arm in which you are starting these medications and looking at outcomes. That's the only way to know for sure.”