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Editor’s Note: These letters were published on October 27, 2020, at NEJM.org.

Correspondence

RAAS Inhibitors and Risk of Covid-19

To the Editor

In a population-based case–control study conducted in Lombardy, Italy, Mancia et al. (June 18 issue)1 found a significant association between the use of oral anticoagulant agents and coronavirus disease 2019 (Covid-19). The odds ratio for Covid-19 associated with use of oral anticoagulant agents was 1.51 (95% confidence interval [CI], 1.37 to 1.66) before adjustment for several potential confounders and 1.16 (95% CI, 1.04 to 1.30) after adjustment.1

It would be important to know whether this association reflects the presence of atrial fibrillation, venous thromboembolism, or other cardiovascular disorders that are treated with oral anticoagulants. Furthermore, hospitalized patients with Covid-19 have a high risk of pulmonary embolism.2

The prothrombotic state in these patients,3 indicated by several procoagulant factors, including fibrin degradation products and d-dimers, has been associated with an increased risk of death.4,5 Thus, it would be of utmost importance to investigate whether patients with Covid-19 with exposure to anticoagulants before hospital admission have a decreased risk of critical or fatal disease.

Fabio Angeli, M.D.
University of Insubria–Maugeri, Tradate, Italy

Paolo Verdecchia, M.D.
Hospital S.M. della Misericordia, Perugia, Italy

Gianpaolo Reboldi, M.D., Ph.D.
University of Perugia, Perugia, Italy

No potential conflict of interest relevant to this letter was reported.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–angiotensin–aldosterone system blockers and the risk of Covid-19. N Engl J Med 2020;382:2431-2440 .

  2. 2. Klok FA, Kruip MJHA, van der Meer NJM, et al. Incidence of thrombotic complications in critically ill ICU patients with COVID-19. Thromb Res 2020;191:145-147.

  3. 3. Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020;18:844-847.

  4. 4. Wang D, Hu B, Hu C, et al. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020;323:1061-1069.

  5. 5. Wu C, Chen X, Cai Y, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med 2020;180:934-943.

To the Editor

In their editorial related to the articles by Mancia et al. and Reynolds et al.,1 Jarcho et al.2 summarize the results of retrospective studies of the use of angiotensin-converting–enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) in patients with Covid-19 and conclude that these studies showed no evidence of an increased risk of disease or worsening outcomes. Other studies,3 most notably that by Zhang et al.,4 reached similar conclusions or showed beneficial effects.

A critical confounder in retrospective studies was revealed in data on patients with Covid-19 in New York.5 Approximately 50% of the patients who had been prescribed ACE inhibitors or ARBs discontinued the medication when they were hospitalized. This discrepancy may explain the differences between studies that show a benefit of the use of ACE inhibitors or ARBs and those that show no effect.

A mechanistic model of the pathobiology of Covid-19 strongly implies that ACE inhibitors or ARBs may be beneficial.6 Accordingly, discontinuation of ACE inhibitors or ARBs may yield worse outcomes than continuation of their use in patients with a diagnosis of Covid-19; this difference may confound retrospective studies that assess the effects of those agents. Studies that separate these two groups of patients may help to clarify the possible benefits or harms associated with continuation or discontinuation of ACE inhibitors or ARBs. Prospective studies — in particular, ongoing randomized, placebo-controlled trials such as the Ramipril for the Treatment of COVID-19 (RAMIC) trial (ClinicalTrials.gov number, NCT04366050) — may provide clearer insight regarding the effect of ACE inhibitors or ARBs in patients with Covid-19.

Krishna Sriram, Ph.D.
Rohit Loomba, M.D.
Paul A. Insel, M.D.
University of California San Diego, La Jolla, CA

Dr. Loomba reports receiving consulting fees from Alnylam–Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol Myers Squibb, Eli Lilly, Galmed Pharmaceuticals, Intercept Pharmaceuticals, Ionis Pharmaceuticals, Janssen, Merck, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Pfizer, and Theratechnologies, fees for serving as an advisory board member from 89Bio, CohBar, Galmed Pharmaceuticals, Gilead Sciences, Glympse Bio, Inipharm, Intercept Pharmaceuticals, Sagimet Biosciences, and Viking Therapeutics, being an employee of Liponexus, and receiving grant support, paid to his institution, from Allergan, Boehringer Ingelheim, Bristol Myers Squibb, Cirius, Eli Lilly, Galectin Therapeutics, Galmed Pharmaceuticals, General Electric, Genfit, Gilead Sciences, Grail, Intercept Pharmaceuticals, Janssen, Madrigal Pharmaceuticals, Merck, NGM Biopharmaceuticals, NuSirt Sciences, Pfizer, pH Pharma, Prometheus Laboratory, and Siemens; and Dr. Insel, receiving consulting fees from Merck and CuraSen Therapeutics and grant support from Pfizer and Bristol Myers Squibb. No other potential conflict of interest relevant to this letter was reported.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med 2020;382:2441-2448.

  2. 2. Jarcho JA, Ingelfinger JR, Hamel MB, D’Agostino RB Sr, Harrington DP. Inhibitors of the renin–angiotensin–aldosterone system and Covid-19. N Engl J Med 2020;382:2462-2464.

  3. 3. Sparks MA, Hiremath S. The coronavirus conundrum: ACE2 and hypertension edition. NephJC. 2020 (http://www.nephjc.com/news/covidace2).

  4. 4. Zhang P, Zhu L, Cai J, 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;126:1671-1681.

  5. 5. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA 2020;323:2052-2059.

  6. 6. Sriram K, Insel PA. A hypothesis for pathobiology and treatment of COVID-19: the centrality of ACE1/ACE2 imbalance. Br J Pharmacol 2020 April 24 (Epub ahead of print).

To the Editor

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the ACE 2 (ACE2) receptor to enter human cells.1 ACE2 expression may be up-regulated by ACE inhibitors and ARBs. These observations have led to speculation regarding potential harmful effects of ACE inhibitors and ARBs.

Recent observational studies have shown no association between mortality from Covid-19 and ACE inhibitors and ARBs, after adjustment for a range of potential confounders. However, they have not shown an association between the duration of the underlying diseases or the duration of the ACE inhibitor or ARB treatment and mortality from Covid-19. This lack of an association is particularly important for several reasons. First, ACE2 activity is correlated with the duration of diabetes.2 Second, in a recent study,3 the adjusted effects of angiotensin blockade on the incidence of influenza varied nonlinearly, with a higher risk of influenza among patients who received treatment for 0.5 years to less than 1.5 years with ACE inhibitors (adjusted hazard ratio, 1.07; 95% CI, 0.97 to 1.17) and ARBs (adjusted hazard ratio, 1.15; 95% CI, 0.98 to 1.35) than among those who had not received these agents. Third, the spike protein of SARS-CoV-2 is primed by the transmembrane protease, serine 2 (TMPRSS2),1 the expression of which has also been reported to be associated with disease duration.4 Therefore, can the authors report the effects according to the duration of underlying conditions, according to the duration of treatment with ACE inhibitors, ARBs, and other inhibitors of the renin–angiotensin–aldosterone system (RAAS), or according to both durations?

Nazrul Islam, M.B., B.S., Ph.D.
University of Oxford, Oxford, United Kingdom

Kamlesh Khunti, M.D., Ph.D.
University of Leicester, Leicester, United Kingdom

Gerardo Chowell, Ph.D.
Georgia State University, Atlanta, GA

No potential conflict of interest relevant to this letter was reported.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020;181(2):271-280.e8.

  2. 2. Soro-Paavonen A, Gordin D, Forsblom C, et al. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens 2012;30:375-383.

  3. 3. Chung S-C, Providencia R, Sofat R. Association between angiotensin blockade and incidence of influenza in the United Kingdom. N Engl J Med 2020;383:397-400.

  4. 4. Burgueño JF, Reich A, Hazime H, et al. Expression of SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in the gut of patients with IBD. Inflamm Bowel Dis 2020;26:797-808.

To the Editor

In the article by Reynolds et al., the data suggest that in patients with Covid-19 and hypertension, previous treatment with an ACE inhibitor was more likely to be associated with a reduced risk of severe disease than previous treatment with an ARB (propensity-score–matched median difference, −3.3 percentage points [95% credible interval, −8.2 to 1.7] and −0.1 percentage points [95% credible interval, −4.8 to 4.9], respectively). This difference might have been more apparent if mortality alone had been considered, rather than the combined end point of severe disease in 634 patients, which included admission to the intensive care unit (in 422 patients) and mechanical ventilation (in 165) as well as death (in 343).

Placebo-controlled trials before Covid-19 showed that the use of ACE inhibitors reduced mortality by 9 to 11% (P<0.05) among high-risk patients, whereas ARBs resulted in a nonsignificant excess of deaths.1 Similar differences in mortality were noted in a meta-analysis of hypertension trials.2 In these trials, the results of which were published after 2000, the mortality benefits of ACE inhibitors included effects that were independent of blood-pressure lowering.3 Forthcoming clinical trials are unlikely to evaluate mortality among patients who were randomly assigned to receive ACE inhibitors or ARBs during previous infection with SARS-CoV-2, and since neither medication increases the risk of Covid-19,4 the use of an ACE inhibitor is preferred. The mortality data reported by Reynolds et al., however, are relevant to this question and should be shared.

Martin H. Strauss, M.D.
North York General Hospital, Toronto, ON, Canada

Alistair S. Hall, M.B., Ch.B., Ph.D.
National Institute for Health Research, Leeds, United Kingdom

Carl J. Lavie, M.D.
University of Queensland School of Medicine New Orleans, New Orleans, LA

Drs. Strauss and Hall report receiving consulting and speaker’s fees from Servier. No other potential conflict of interest relevant to this letter was reported.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Strauss MH, Hall AS. Angiotensin receptor blockers do not reduce risk of myocardial infarction, cardiovascular death, or total mortality: further evidence for the ARB-MI paradox. Circulation 2017;135:2088-2090.

  2. 2. van Vark LC, Bertrand M, Akkerhuis KM, et al. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J 2012;33:2088-2097.

  3. 3. Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens 2007;25:951-958.

  4. 4. Mackey K, King VJ, Gurley S, et al. Risks and impact of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers on SARS-CoV-2 infection in adults: a living systematic review. Ann Intern Med 2020;173:195-203.

Response

Dr. Mancia and colleagues reply: Angeli et al. focus on the positive association observed in our study between the use of oral anticoagulants and the risk of Covid-19. A superficial reading could suggest that the use of oral anticoagulants per se increases the risk, when in fact, exposure to these drugs is a surrogate for many diseases and conditions (e.g., atrial fibrillation) that in themselves make the patient more susceptible to SARS-CoV-2 infection. An observational study such as ours has a limited ability to discriminate between these possibilities and can at most elucidate signals that could direct us toward understanding a complex phenomenon. We thank Angeli et al. for helping us to clarify that not all associations in our study have direct implications for clinical practice.

Sriram et al. mention a widely debated question — that is, whether outcomes in patients admitted to the hospital for Covid-19 may be affected by the continuation or discontinuation of RAAS blockers. Our study focused on the relationship between pretreatment with RAAS blockers and Covid-19, so it cannot provide an answer to this question. This issue has been addressed by a few observational studies that have shown that the initiation or continuation of RAAS blockers in hospitalized patients with Covid-19 may have a protective effect.1,2 This was not the conclusion of a recent randomized, open-label trial (BRACE-CORONA, the results of which were presented at the 2020 meeting of the European Society of Cardiology) that showed that in 659 hospitalized patients with Covid-19, there was no difference between continuation and discontinuation of ACE inhibitors or ARBs with respect to the number of days the patients were alive and out of the hospital.

Finally, we agree with Islam et al. that the duration of treatment with ACE inhibitors or ARBs and the duration of underlying diseases warrant much more attention. Some evidence on this issue is currently available. For example, de Abajo et al. did not find any difference between patients with short-term use of RAAS blockers and those with long-term use (i.e., ≤1 year or >1 year) with respect to the risk of Covid-19.3 A retrospective historical series that is extensive enough to investigate the function between time to exposure and the risk of Covid-19 is lacking. Moreover, in a retrospective study such as ours, an analysis based on the duration of use of RAAS inhibitors would have an implicit selection bias.

Giuseppe Mancia, M.D.
Federico Rea, Ph.D.
Giovanni Corrao, Ph.D.
University of Milano–Bicocca, Milan, Italy

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Zhang P, Zhu L, Cai J, 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;126:1671-1681.

  2. 2. Cannata F, Chiarito M, Reimers B, et al. Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality. Eur Heart J Cardiovasc Pharmacother 2020 June 5 (Epub ahead of print).

  3. 3. de Abajo FJ, Rodríguez-Martín S, Lerma V, et al. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet 2020;395:1705-1714.

Response

Dr. Reynolds and colleagues reply: Sriram and colleagues raise the concern that prehospital use of antihypertensive therapy is not relevant to the outcome in patients with Covid-19 because physicians may have discontinued specific antihypertensive therapies in patients after hospital admission, particularly during the period of our study when there were concerns among the medical community about the safety of ACE inhibitors and ARBs. We agree this is a potential confounder. However, ACE inhibitors and ARBs do not act on ACE2, the protein that acts as a SARS-CoV-2 receptor, and treatment with ACE inhibitors or ARBs does not appear to result in increased ACE2 expression.1-3 In a recently completed trial involving 659 hospitalized patients with Covid-19 who had received ACE inhibitors or ARBs on a long-term basis, the patients were randomly assigned to either suspend use of these medication classes during the following 30 days or to continue use. There was no significant effect on the number of days the patients were alive and out of the hospital over the 30-day follow-up period (mean [±SD], 21.9±8.0 days in the continuing ACE inhibitor–ARB group and 22.9±7.1 days in the suspended ACE inhibitor–ARB group).4

Islam and colleagues request additional data on the durations of disease and treatment in our study. We regret that we are not able to provide these data because we cannot be certain that the duration of hypertension or other conditions and the duration of treatment with specific agents would be accurately reflected in our electronic health records. We capture the date when patients start and stop medications while they are patients at New York University (NYU) Langone Health. We do not reliably capture how long they may have taken a medication before establishing care with NYU Langone Health.

Likelihood of Death after Positive Test for Covid-19, According to Treatment with Various Antihypertensive Agents, among Propensity-Score–Matched Patients, with Hypertension and Overall.

The mortality data requested by Strauss and colleagues are provided in Table 1. We report the likelihood of death by April 15, 2020, among patients who tested positive for Covid-19 at our center between March 1 and April 15, 2020, within the cohorts matched according to propensity score for the use of each class of antihypertensive medication, as we reported in our article. In both sets (i.e., matched patients with hypertension and all matched patients), the risk of death was no more than 4 percentage points higher among treated patients than among untreated patients for each medication class tested.

Harmony R. Reynolds, M.D.
Samrachana Adhikari, Ph.D.
Eduardo Iturrate, M.D., M.S.W.
New York University Grossman School of Medicine, New York, NY

Since publication of their article, the authors report no further potential conflict of interest.

This letter was published on October 27, 2020, at NEJM.org.

  1. 1. Tucker NR, Chaffin M, Bedi KC Jr, et al. Myocyte-specific upregulation of ACE2 in cardiovascular disease: implications for SARS-CoV-2-mediated myocarditis. Circulation 2020;142:708-710.

  2. 2. Milne S, Yang CX, Timens W, Bossé Y, Sin DD. SARS-CoV-2 receptor ACE2 gene expression and RAAS inhibitors. Lancet Respir Med 2020;8(6):e50-e51.

  3. 3. Lubel J, Garg M. Renin–angiotensin–aldosterone system inhibitors in Covid-19. N Engl J Med 2020;382(24):e92-e92.

  4. 4. Jia X, Al Rifai M, Hussain A, Martin S, Agarwala A, Virani SS. Highlights from studies in cardiovascular disease prevention presented at the Digital 2020 European Society of Cardiology Congress: prevention is alive and well. Curr Atheroscler Rep 2020;22:72-72.

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