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ACEI/ARBs linked with survival in
hypertensive, Chinese COVID-19 patients
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Publish date: April 22, 2020
https://www.mdedge.com/cardiology/article/221129/coronavirus-updates/acei/arbs-linked-survival-hypertensive-chinese-covid?channel=63993&ecd=wnl_car_200424_mdedge_6am&uac=27194HK&oc_slh=a981fc6bb36aa3fb80893fb787b8d3c08cc312138f4c0b34a025b40f1418d90f&utm_source=News_CARD_eNL_042420_F&utm_medium=email&utm_content=ACEI/ARBs linked with survival in hypertensive patients
FROM CIRCULATION RESEARCH
Hospitalized COVID-19 patients with hypertension and on treatment with an renin-angiotensin system inhibiting drug had significantly better survival, compared with similar hypertensive patients not on these drugs, in observational, propensity score-matched analyses that drew from a pool of more than 3,430 patients hospitalized at any of nine Chinese hospitals during December 2019-February 2020.
"Among patients with hypertension hospitalized with COVID-19, inpatient treatment with ACEI [ACE inhibitor]/ARB [angiotensin receptor blocker] was associated with lower risk of all-cause mortality, compared with ACEI/ARB nonusers, during 28 days of follow-up. While study interpretation needs to consider the potential for residual confounders, it is unlikely that inpatient ACEI/ARB would be associated with an increased risk of mortality," wrote Peng Zhang, MD, a cardiology researcher at Renmin Hospital of Wuhan University, China, and coauthors in Circulations Research, buttressing recent recommendations from several medical societies to maintain COVID-19 patients on these drugs.
"Our findings in this paper provide evidence supporting continuous use of ACEI/ARB for patients with hypertension infected with SARS-COV-2," wrote the authors, backing up recent recommendations from cardiology societies that called for not stopping ACEI/ARB prescriptions in patients at risk for contracting or already have COVID-19 infection, including a statement from the American College of Cardiology, American Heart Association, and Heart Failure Society of America, and also guidance from the European Society of Cardiology.
The study included 1,128 patients with a history of hypertension, including 188 (17%) who received an ACEI/ARB drug during hospitalization. During 28-day follow-up, 99 died (9%), including 7 deaths among the 188 patients (4%) on an ACEI/ARB drug and 92 deaths among the 940 other hypertensive patients (10%).
The authors ran several analyses to try to adjust for the influence of possible confounders. A mixed-effect Cox model with four adjusted variables showed that treatment with an ACEI/ARB drug was tied to a statistically significant 58% lower death rate, compared with patients not receiving these drugs.
The researchers also ran several propensity score-adjusted analyses. One matched 174 of the patients who received an ACEI/ARB drug with 522 who did not, and comparing these two matched arms showed that ACEI/ARB use was linked with a statistically significant 63% cut in mortality, compared with patients not getting these drugs. A second propensity score-matched analysis first excluded the 383 patients who were hypertensive but received no antihypertensive medication during hospitalization. From the remaining 745 patients who received at least one antihypertensive medication, the authors identified 181 patients who received an ACEI/ARB and propensity-score matched them with 181 hypertensive patients on a different medication class, finding that ACEI/ARB use linked with a statistically significant 71% lower rate of all-cause mortality.
Additional analyses also showed that patients with hypertension had a statistically significant, 41% increased rate of all-cause death, compared with patients without hypertension, and another propensity score-matched analysis showed that among hypertensives treatment with an ACEI/ARB drug was linked with a statistically significant 68% reduced rate of septic shock.
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Although this report was received with caution and some skepticism, it was also acknowledged as a step forward in the creation of an evidence base addressing ACEI/ARB treatment during COVID-19 infection.
"These drugs are lifesaving and should not be discontinued" for patients with hypertension, heart failure, and other cardiovascular disease, commented Gian Paolo Rossi, MD, professor and chair of medicine and director of the high blood pressure unit at the University of Padua (Italy). The analysis by Zhang and associates included the largest number of hospitalized COVID-19 patients with hypertension yet reported to assess the impact of treatment with ACEI/ARB drugs, and adds important evidence in favor of continuing these drugs in patients who develop COVID-19 infection, Dr. Rossi said in an interview. He recently coauthored a review that argued against ACEI/ARB discontinuation in COVID-19 patients based on previously reported evidence (Elife. 2020 Apr 6. doi: 10.7554/eLife.57278).
But other researchers take a wary view of the potential impact of ACEI/ARB agents. "If ACEI/ARB therapy increases ACE2 and the virus down-regulates it, and because ACE2 is the viral entry port into cells, why would ACE2-mediated down-regulation of the renin-angiotensin-aldosterone system lead to amelioration of [COVID-19] disease?" asked Laurence W. Busse, MD, a critical care physician at Emory University, Atlanta. "A number of issues could potentially confound the results, including the definition of COVID-19 and imbalance of antiviral therapy," added Dr. Busse, who recently coauthored an editorial that posited using angiotensin II (Giapreza), an approved vasopressor drug, as an alternative renin-angiotensin system intervention for COVID-19 patients including both those in shock as well as potentially those not in shock (Crit Care. 2020 Apr 7. doi: 10.1186/s13054-020-02862-1). Despite these caveats, the new Chinese findings reported by Dr. Zhang and associates "are hypothesis generating and worth further exploration."
The authors of an editorial that accompanied the Zhang study in Circulation Research made similar points. "While the investigators used standard techniques to attempt to reduce bias in this observational study via propensity matching, it is not a randomized study and the residual confounding inherent to this approach renders the conclusions hypothesis generating at best," wrote Ravi V. Shah, MD, and two coauthors in the editorial (Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317174). They also agreed with the several society statements that have supported continued use of ACEI/ARB drugs in COVID-19 patients. "Withdrawal of these medications in the context of those conditions in which they have proven benefit (e.g., heart failure with reduced left ventricular ejection fraction) may actually inflict more harm than good," they warned. "In the end we must rely on randomized clinical science," and while this level of evidence is currently lacking, "the study by Zhang and colleagues is a direct step toward that goal."
Dr. Zhang and coauthors had no commercial disclosures. Dr. Rossi and Dr. Busse had no disclosures. The authors of the Circulation Research editorial reported several disclosures.
SOURCE: Zhang P et al. Circ Res. 2020 Apr 17. doi: 10.1161/CIRCRESAHA.120.317134.
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ACEing COVID-19: A Role For Angiotensin Axis Inhibition in SARS-CoV-2 infection?
Venkatesh L. Murthy, Mika Koupenova, Ravi Shah
1Department of Medicine and Radiology, University of Michigan, Ann Arbor, MI; 2Department of
Medicine, University of Massachusetts Medical School, Worcester, MA; 3Cardiology Division,
Department of Medicine, Massachusetts General Hospital, Boston, MA
While these investigators are to be congratulated for this study and the care of COVID-19 patients,
their conclusions have to be viewed in the context of a retrospective observational design. Statistical
considerations include the use of a single method for propensity matching, residual confounding by
unknown confounders or mediators (e.g., circulating ACE2 levels) or by features still different between
ACE-I/ARB and non-ACEI/ARB groups (e.g., D-dimer, lipid lowering therapies, other anti-hypertensives),
selection biases in terms of region and penetrance of different types of anti-hypertensive therapy, and
difficulties in handling individuals who ceased therapy in hospital for worsening illness. Duration of
antecedent ACE-I/ARB therapy may impact degree of ACE2 induction. Moreover, the time on ACE-I/ARB
therapy during hospitalization (and better characterization of those individuals forced toward
discontinuation for worsening disease severity) are likely critical factors. It is important to note that, while
the investigators used standard techniques to attempt to reduce bias in this observational study via
propensity matching, it is not a randomized study and the residual confounding inherent to this approach
renders the conclusions hypothesis-generating at best.
With these caveats in mind, why might angiotensin system blockade with ACE-I/ARB be "protective"
(or at least not necessarily harmful)? Certainly, for both SARS-CoV-1 and SARS-CoV-2, ACE2—
potentially upregulated in target organs by ACE-I/ARB—is requisite for viral entry. Strikingly, after SARSCoV-
1 viral entry, the virus reduces cellular ACE2 expression, with subsequent lung injury dependent on
the presence of ACE211. Reduced ACE2 expression has been associated with increased pulmonary
inflammation12, with complete abrogation of ACE2 (and subsequent higher circulating angiotensin-II)
associated with lung injury in an avian influenza model13. This physiology is mirrored in myocardial tissue:
infection with SARS-CoV-1 in mice reduces myocardial ACE2 expression, and patients with SARS-CoV-
1 in the heart exhibit increased myocardial inflammation in conjunction with lower ACE2 expression14.
These observations have been clear since the first SARS crisis and have renewed interest in clinical studies
of angiotensin system modulation in COVID-19 via recombinant ACE2 administration (clinicaltrials.gov
identifier NCT04287686) and randomized studies examining the role of losartan in COVID-19
(NCT04312009, NCT04311177).
Needless to say, these studies (and others with appropriate randomization and controls) are sorely
needed to offer our patients relief from COVID-19. The current pandemic, however, has forced a nimble
response to guide therapeutic decisions in the immediate term. How do we interpret the findings of Zhang
et al. in this context? The conclusions of this study should not be taken as a surrogate for appropriate
randomized data guiding the clinical management of individuals on ACE-I/ARB with COVID-19. While
we cannot conclude from this data anything on the pathophysiologic/mechanistic role of ACE-I/ARB
during COVID-19, it offers retrospective, observational support to ongoing randomized controlled studies
of these medications in the fight against COVID-19. Currently, outside of clear clinical indications to stop
these medications that have existed long before the current pandemic (e.g., expected or concurrent
worsening renal failure, hyperkalemia, hypotension, etc.), the withdrawal of these medications in the
context of those conditions in which they have a proven benefit (e.g., heart failure with reduced left
ventricular ejection fraction) may actually inflict more harm than good. In the end, we must rely on
randomized clinical science for the benefit of our patients, and the study of Zhang and colleagues is a
directed step toward that goal.
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