The angiotensin-converting enzyme 2 (ACE2) plays a key role in the renin-angiotensin-aldosterone system (RAAS) which regulates blood pressure, volume status and vascular tone.1 Concerns were raised during the early COVID-19 pandemic about the entry of SARS-CoV-2 into the host cells mediated by the ACE2 membrane-bound form.2 This led to the indiscriminate discontinuation of RAAS inhibitors in a large number of patients with cardiovascular disease. However, RAAS inhibitors are critical in the management of hypertension and other cardiovascular diseases, such as heart failure (HF). As a consequence, many cardiovascular scientific societies released statements calling for caution and recommending continuing chronic treatment with angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB) in COVID-19 patients.3 Indeed, recent research has confirmed that the chronic use of ACEi and ARB is not associated with a higher likelihood of COVID-19 infection or poorer outcomes in this disease.4–7 However, the specific impact of withdrawing ACE inhibitors, ARB or mineralocorticoid receptor antagonists (MRA) during hospital admission for COVID-19 is unknown, and published results from ongoing randomized controlled trials are pending8.

During the study period, 5556 patients with clinical suspicion of COVID-19 attended the emergency department of our tertiary care center. Of these, 3416 had confirmed SARS-CoV-2 infection and were screened for participation in the present study. Finally, 2042 patients (mean age 68.4±17.6 years, 57.1% male) were admitted to hospital and entered the present analysis (Figure 1). A total of 583 died during the study period, and the median length of follow-up was 57 (21-55) days. One thousand and eighty patients (53.0%) had a history of hypertension. Before hospital admission, 847 were receiving chronic treatment with RAAS inhibitors: 468 (22.9%) with ACE inhibitors, 343 (16.8%) with ARB and 83 (4.1%) with MRA.

Figure 1.

Study flow. Of the 3416 screened patients with confirmed SARS-CoV-2 infection, 2042 were admitted to hospital and included in the analysis.

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Full baseline characteristics and comparisons depending on whether or not patients were receiving chronic treatment with RAAS inhibitors are shown in Supplementary Table 1. Patients in the RAASi group were older, more frequently male and had a significantly worse baseline clinical profile. Regarding laboratory data, RAASi patients showed more profound abnormalities of C-reactive protein, fibrinogen and prothrombin activity, without differences in cardiac biomarkers such as NT-proBNP and hs-troponin I. Except for steroids, both groups received similar dedicated COVID-19 treatment during hospital admission. RAASi patients presented higher mortality (36.7% vs 22.8%, p<0.001). However, no differences were observed using the log-rank test after stratifying for baseline hypertension (p=0.828). Similarly, different Cox-proportional hazards models with sequential adjustment for age, sex, baseline cardiovascular risk factors and baseline cardiovascular comorbidities showed no independent relationship between chronic treatment with RAAS inhibitors and mortality (HR 1.01 [95% CI 0.83-1.26], Supplementary Table 2).

Of 847 patients on RAAS inhibitors, a total of 436 (51%) underwent RAASi withdrawal at hospital admission. There were no significant differences in baseline characteristics between those with and without RAASi withdrawal (Table 1). At presentation, the former had lower blood pressure and received less hydroxychloroquine and azithromycin. Patients discontinuing RAASi were more frequently admitted to an intensive care unit and had higher mortality. Log-rank test analysis with hypertension stratification showed significantly worse survival in patients who had RAAS inhibitors withdrawn (p<0.001, Figure 2). Multivariable analysis using a Cox-proportional hazards model adjusting for a large number of relevant covariates (Table 2) confirmed that RAASi withdrawal was independently associated with mortality during follow-up (HR 1.47 [95% CI 1.15-1.89]).

Figure 2.

Kaplan-Meier survival analysis stratified based on prior history of hypertension. Statistically significant differences were observed in both groups of patients: with (left panel) and without (right panel) history of hypertension.

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Regarding the impact of each different RAASi therapeutic group, 216 (46.2%), 193 (56.3%) and 41 (49.4%) patients discontinued ACEi, ARB and MRA respectively during hospital stay. Survival analysis using the log-rank test stratified by hypertension (Figure 3) showed that ACEi withdrawal (p<0.001) and MRA withdrawal (p=0.007) were associated with higher mortality. Among patients discontinuing ARB, there was a trend for lower mortality (p=0.056), but the association did not reach statistical significance. A multivariable analysis adjusted for multiple confounders confirmed that ACEi withdrawal (HR 1.62 [95% CI 1.23-2.14]) and MRA withdrawal (HR 2.10 [95% CI 1.32-3.34]) were independent predictors of mortality while ARB withdrawal (1.25 [95% CI 0.93-1.68]) did not reach statistical significance (Table 3). Patients discontinuing ACEi or ARB plus MRA had the worst prognosis (p<0.001 by the log-rank test, Figure 4).

Figure 3.

Kaplan-Meier survival analysis among strata of patients with different groups of chronic renin-angiotensin-aldosterone system inhibitors: Angiotensin converting enzyme inhibitors (upper panel), angiotensin receptor blockers (middle panel) and mineralocorticoid receptor antagonists (lower panel).

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Figure 4.

Kaplan-Meier survival analysis among all patients with RAASi treatment. Patients discontinuing both an angiotensin converting enzyme inhibitors/angiotensin receptor blockers plus a mineralocorticoid receptor antagonists showed the worst prognosis.

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Alternatively, in order to test the hypothesis that discontinuation of oral medications may be a surrogate for the severity of COVID-19, we studied the association of withdrawing beta-blockers and statins (two drugs commonly included in the chronic treatment of patients being admitted for COVID-19) and mortality. Among the study participants, 337 patients were receiving beta-blockers and 827 were receiving statins before hospital admission. Respectively, 78 (23.2%) and 456 (55.1%) discontinued that medication after being diagnosed with SARS-CoV-2 infection. Neither of these situations were associated with higher mortality during follow-up (p=0.821 and p=0.247 according to the log-rank test).

Concerns regarding a possible association between ACEi/ARB treatment and poor outcomes in SARS-CoV-2 infection9 were raised early in the COVID-19 pandemic. They were based on the potential interaction between SARS-CoV spike protein and its host receptor ACE2.2 However, recent research suggests that their use is not linked to more severe disease4–7 and there is a clear potential for harm related to RAAS inhibitor withdrawal in patients with established indications.10 A multicenter retrospective study11 suggested that in-patient use of ACEi/ARB may actually result in better outcomes. However, only 188 patients with ACEi/ARB were included in the analysis and prior use of these medications before hospital admission was not reported.

Our group recently demonstrated that withdrawal of guideline-directed medical therapy in patients with history of chronic HF was associated with higher COVID-19-related mortality.12,13 However, data on the whole population of COVID-19 patients are scarce. We report here data from a large cohort of real-life consecutive patients with a significant length of follow-up, for whom in-hospital prescriptions were carefully reviewed and confirmed. Overall, these data convincingly illustrate that, after adjustment for a large number of relevant potential confounders, withdrawal of ACEi during hospital admission for COVID-19 was associated with higher mortality. Moreover, the association with higher mortality was not confirmed for the withdrawal of other therapeutic groups, such as beta-blockers or statins. This disputes the hypothesis that withdrawal of any oral medications may act as a surrogate for the severity of COVID-19. It is in agreement with previous data from patients with viral pneumonia of other etiologies.14 The different effects of ACEi and ARB in COVID-19 patients have not been reported before. However, there is conflicting evidence regarding their effects on angiotensin II, the substrate of ACE2, and uniform responses should not be expected for both groups of drugs.10 Therefore, ACEi and ARB may result in differential effects on bradykinin levels via their interaction with the prekallikrein/kallikrein system.15 Bradykinin interacts with nitric oxide and prostaglandins, therefore influencing platelet activation and release of von Willebrand factor,16 which may play a role in COVID-19 coagulopathy.17 However, there is the alternative possibility that our study did not have enough statistic power to detect harm from ARB withdrawal.

In addition, we report for the first time that the withdrawal of mineralocorticoid receptor antagonists is independently associated with mortality in COVID-19 patients after adjusting for multiple relevant confounders, and in our series, patients who stopped both types of medications (an ACEi/ARB plus a MRA) had a significantly worse prognosis than those who only discontinued ACEi/ARB.

Even though the underlying link between ACEi withdrawal and higher mortality is unknown, there is the possibility that it may be related to a stronger inflammatory state in the patients discontinuing these drugs.18 In addition, elevated levels of plasma angiotensin II have been reported in COVID-19 patients, which correlates with viral load and lung injury.19 ACE2 is the most potent enzyme that converts the vasoconstrictor angiotensin II to angiotensin (1–7). Angiotensin (1–7) has organ-protective properties that oppose and counterbalance those of angiotensin II.20 Mineralocorticoid receptor antagonists increase ACE2 activity in patients with HF,21 and this effect theoretically may act against angiotensin II accumulation and local RAAS activation.22 However, a recent study also including non-COVID-19 HF patients showed that neither ACEi, nor ARB were associated with higher plasma ACE2 concentrations.23 Effects reported from MRA were small and inconsistent. Thereby, further studies are needed to understand the physiopathological pathways underlying RAAS inhibitors and COVID-19.

In our large cohort of hospitalized patients with COVID-19, withdrawal of ACE inhibitors and mineralocorticoid receptor antagonists is independently associated with higher mortality. Strong consideration should be given to not discontinuing this medication during hospital admission. These decisions should be individualized based on the whole clinical picture.

This work has received no funding.

J.L.M. reports grants and personal fees from Bayer, grants and personal fees from Correvio, grants from Daiichi-Sankyo, personal fees from Sanofi, outside the submitted work; E.L.S reports grants from Zoll Medical Corporation, Boehringer Ingelheim and Servier; personal fees from Daiichi Sankyo, Rovi, Servier, BARD and Astra Zeneca, all outside the submitted work. All other authors had no conflict of interest.