Impact of in-hospital discontinuation with angiotensin receptor blockers or converting enzyme inhibitors on mortality of COVID-19 patients: a retrospective cohort study

In mid-March, at the start of the first wave of COVID-19 pandemic in Europe, the hypothesis that the renin-angiotensin system inhibitors (RASIs), including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), increased the risk, and/or severity of the disease [1‐3], was widely spread. Consequently, many hospitals and clinicians adopted the “precautionary measure” to discontinue these drugs from patients who regularly used them. Promptly, in the first weeks of May, three large epidemiological studies were published supporting the lack of association between the outpatient use of RASIs and risk of COVID-19 [4‐6]. Later on, a plethora of studies and meta-analyses were published [7, 8] reaching the same conclusion, which provides reassurance on the safety of these drugs. Yet, the extent of RASI discontinuation at hospital admission during the first wave of the pandemic and, importantly, its impact on health outcomes have been scarcely studied [9‐12].

The downregulation of angiotensin-converting enzyme type 2 (ACE2), as resulted from the SARS-CoV-2 endocytosis, has been postulated to play a key role in the progression of COVID-19 to severe forms [13]. In physiological conditions, the ACE1-angiotensin II-AT1R axis (the classical RAS) is counter-regulated by the ACE2-Angiotensin (1-7)-MasR axis. Thus, when the latter weakens, angiotensin II is unopposed and its vasoconstrictor, pro-inflammatory, and pro-thrombotic actions may contribute to the pathophysiology of severe COVID-19 [13‐15]. In this context, it is conceivable that treatment with RASIs in COVID-19 inpatients could compensate the ACE1/ACE2 imbalance provoked by the SARS-CoV-2 and produce a net beneficial effect. According to this, several observational studies have reported a protective effect of inpatient use of RASIs on mortality as compared to non-use (or non-RASI use) in COVID-19 patients [9‐12]. However, such studies have been criticized for incurring in several types of bias [16, 17]. Recently, two randomized clinical trials have been published [18, 19] reporting no difference in mortality between discontinuation and continuation arms. However, these trials and most observational studies have pooled ACEIs and ARBs and analyzed in a unique group, overlooking that they have different pharmacological actions [20] that could lead to distinct clinical effects [20], particularly in COVID-19 patients [15]. In this sense, no study has carried out a head-to-head comparison of in-hospital use of these drugs in COVID-19 patients admitted to the hospital.

The present research was aimed (1) to quantify the magnitude of RASI discontinuation at admission in seven hospitals from the Autonomous Community of Madrid, Spain; (2) to compare in real-life conditions the in-hospital mortality in patients in whom ACEIs or ARBs were discontinued with those in whom RASIs were continued; and (3) to perform a head-to-head comparison between in-hospital use of ACEIs and ARBs regarding mortality in admitted patients for COVID-19.

The main findings of the present study are as follows: (1) RASIs were discontinued in around half of the patients admitted to hospital for COVID-19 during March 2020; (2) the discontinuation rate increased over time, being particularly notorious since March 11; (3) the discontinuation of RASIs as a group was not associated with an increased or decreased risk of in-hospital death or ICU admission, but the results disaggregated by ARBs and ACEIs were not homogeneous; and (4) the continuation of treatment with ARBs was associated with a significantly lower all-cause mortality than the continuation of treatment with ACEIs.

The RASI discontinuation rate was strongly influenced by the date of admission (doubling from mid-March), which seems to be a direct consequence of the hypothesis that quickly spread since March 11 on the possibility that these drugs could make COVID-19 more severe [3]. Notwithstanding, the rate varied considerably by the hospital (and possibly by the attending physician within each hospital). In other countries, researchers have reported discontinuation rates ranging from 12.4 to 67.7%, though using different definitions for discontinuation (Additional file 1: Table S5) [9‐12, 17, 27‐34] . Of note, in our study, as much as 46.5% of patients in whom treatment with RASIs were discontinued (25.3% of the total number of patients who used them prior to admission) were left without any antihypertensive drug (excluding furosemide), which suggests that in a relevant part of patients RASIs were discontinued for medical reasons, likely related to an unstable hemodynamic situation.

Our main finding is that the discontinuation of RASIs, as a group, did not have an impact on in-hospital mortality or in the composite of in-hospital mortality plus ICU admission. This result seems robust as it hardly varied in different sensitivity analyses in which we modified the definition of (dis)continuation. Contrary to the huge number of studies carried out to assess the impact of outpatient use of RASIs on different outcomes (COVID-19 infection, hospitalization, and mortality, among others) [7, 8]; fewer studies have been performed thus far to examine the association of inpatient use of RASIs with in-hospital mortality. One of the first studies was published by Zhang et al. [11] with data from 9 hospitals in Hubei province (China). They found an all-cause mortality among inpatients treated with RASIs much lower than non-treated patients, with an adjusted HR of 0.42 (95%CI 0.19–0.92). However, this study was criticized because the authors considered exposure to all patients who received RASIs at any time point during hospitalization, which implies that exposed patients had to survive long enough, or be clinically stable enough, to receive the treatment with RASIs [16]. Thus, such definition of the exposure could have introduced an immortal-time bias [16] and a confounding by severity (also graphically called “healthy user-sick stopper” bias” [17], that is, RASIs were more likely to be continued, initiated, or reinstated in less severe cases), both favoring an overestimation of the benefit of RASIs on mortality. Most researchers thereafter used similar definitions incurring in the same types of bias and most coinciding to show an important reduced mortality risk associated with RASIs [9, 10, 12, 27‐34] (see Additional file 1: Table S5 for a detailed description of studies). To overcome these problems, we defined continuation or discontinuation during the first 3 days (or during the first 2 days in a sensitivity analysis) and then followed an ITT analysis (each patient analyzed in his/her assigned closed cohort), as it would have been done in a clinical trial. Also, to avoid a reverse causation, we excluded patients directly admitted to the ICU (from the ED or from another hospital), a situation in which RASIs are usually discontinued as a consequence of the disease severity. Interestingly, if we had defined continuation as “use of RASIs at any time point during hospitalization” and included patients directly admitted to the ICU in the discontinuation cohort, the mortality rates would have been 25.3% and 30.3% in the continuation and discontinuation cohorts, respectively, yielding a HR of 0.83 (95%CI 0.66–1.05) for in-hospital mortality. For the composite outcome (death plus ICU admission), the rates would have been 30.0% for patients in whom RASIs were continued and 43.6% in those who discontinued giving rise to a HR of 0.67 (95%CI 0.57–0.83). Therefore, the results would have been dramatically different than the ones we actually obtained, showing the extent of such biases.

Recently, the results from two randomized clinical trials in which regular users of RASIs who were admitted to hospital for COVID-19 were assigned to discontinuation or continuation arms, have been reported (BRACE-CORONA [18] and REPLACE COVID [19] trials) and both found no difference in the mortality rates, supporting our results. However, it is important to emphasize that in the BRACE-CORONA trial the mortality rates were very low (2.7% among patients assigned to discontinuation and 2.8% in those assigned to continuation), casting doubts on the generalizability of their results (the mean age of the study population was 55 years old, 20 years younger than our population). Also, the measure of association of mortality was too imprecise (odds ratio=0.97; 95% CI 0.38–2.52) to be informative. Interestingly, 80% of patients were prior users of ARBs, and the authors found quasi-significant results favoring continuation in older persons, obese patients, and in those clinically more severe, in line with our findings (see later). The REPLACE COVID trial had a more representative population and consistently found no difference in all-cause mortality (15% and 13% in the continuation and discontinuation arms, respectively). Unfortunately, the sample size was too small to make a meaningful separate analysis by ACEIs and ARBs.

The different mortality rates among patients who continued with ACEIs versus those who continued with ARBs is a novel finding that merits specific comments. Firstly, it is important to emphasize that this comparison is ideal for several reasons: (a) these drugs have overlapping indications, thereby the subjects who use them are highly comparable, seemingly reducing by design the possibility of confounding (due to either known and unknown factors); (b) the possibility of an immortal-time bias is inexistent, as the same definition of continuation was applied to both cohorts; (c) the possibility of a confounding by severity is unlikely, as it is not reasonable to think that physicians used different criteria for the continuation of ARBs or ACEIs, and additionally, we applied an ITT analysis once continuation was defined based on the records of the first 3 days of hospitalization; and, finally, (d) the few differences we found (such as the greater in-hospital use of systemic corticosteroids in the ARB continuation cohort) were controlled for by including this factor in the outcome regression model and by stratification, and none of these strategies changed the results, reinforcing the internal validity of the comparison.

Secondly, most previous studies have pooled ACEIs and ARBs (see Additional file 1: Table S5), as if they were the same type of drugs. However, our results show that this approach may be wrong; also, there are profound pharmacological reasons that make this grouping invalid, in particular for COVID-19 patients. ARBs block selectively the action of angiotensin II on AT1 receptor (AT1R), and free angiotensin II is then converted by the ACE2 into angiotensin (1–7) which acts on Mas1 receptor (Mas1R) to induce opposite actions to angiotensin II (anti-inflammatory, anti-oxidant, anti-fibrotic, anti-thrombotic, anti-hypertrophic, vasodilatation, and natriuresis) [13‐15]. Also, angiotensin II not used in activating AT1R acts on AT2 receptor (AT2R) (for which ARBs have no affinity), whose activation is known to produce opposite actions to the ones derived from the activation of AT1R [15], thereby collaborating with the protective effect of angiotensin (1–7). Instead, ACEIs inhibit the formation of angiotensin II, which pre-empts the generation of angiotensin (1–7) from both angiotensin II via ACE2, but also from angiotensin (1–9) via ACE1 [13‐15]; additionally, the beneficial actions derived from activation of AT2R do not take place. In sum, both ARBs and ACEIs effectively block RAS, whereas only ARBs appear to reinforce its counterregulatory system, via ACE2-angiotensin (1–7)-Mas1R axis and AT2R activation, a difference that could be critical in COVID-19 patients. Additionally, ACE1 is well-known to be the major vascular peptidase of bradykinin, an abundant peptide which promotes vasodilatation, vascular permeability, and liberation of inflammatory cytokines (IL-1, IL-2, IL-6, IL-8, and TNF-alpha) implicated in the cytokine storm associated with the severe forms of COVID-19 [15]. Therefore, ACEIs will reduce bradykinin degradation, thereby potentiating its effects, which ultimately could be detrimental for COVID-19 patients [15, 35, 36]. These negative collateral actions of ACEIs may offset the benefits derived from the inhibition of angiotensin II formation and, we postulate, that these could account for the important difference we found in the mortality rates among inpatients treated with ARBs and those treated with ACEIs (an absolute difference of 12.3%, corresponding to a number needed to treat as low as 8). Importantly, the benefit of ARBs seems to be particularly evident in high-risk subgroups: males, the very old, obese, diabetics, and patients with antecedents of heart failure (as the BRACE-CORONA trial [18] also has shown, as commented before). Nevertheless, our results need confirmation, in particular through randomized clinical trials, and until then, we should take these findings with caution. Some are in progress aiming to assess the benefits of using ARBs in COVID-19 patients with the acute respiratory syndrome as compared to placebo or standard care [NCT04394117, NCT04312009, and NTC04355936], but, as far as we know, no study has been designed to compare ARBs with ACEIs in this context. Rodilla et al. [30] compared survival of COVID-19 patients according to the use of ARBs and ACEIs prior to admission and found a significantly reduced mortality risk with the former (25.6% vs. 30.4%, respectively, p=0.0001); but, unfortunately, a head-to-head comparison of in-hospital use of ARBs vs. ACEIs was not reported. Finally, it is of interest to note that in the study by Zhang et al. [11], 83.5% of patients reported to be on RASIs were actually treated with ARBs.

Our study has some limitations that must be discussed: (1) as in all observational studies, the possibility exists that there is some residual confounding due to unknown or unmeasured factors; also, a residual confounding by indication cannot be ruled out. Notwithstanding, it is important to remark that all our patients were users of RASIs prior to admission and were highly comparable at baseline, as shown by the good balance of covariates and the fact that the mean and median of the propensity scores for RASI discontinuation was close to 0.5 (Additional file 1: Figure S8); indirectly, it is likely that unmeasured confounding variables are evenly distributed too, albeit this cannot be assured; as previously commented, this is specially applicable to the comparison of ACEI and ARB continuation cohorts; (2) the information on some severity biomarkers (i.e., interleukins 6 or 1β) were not routinely performed at that time and were not considered in the severity score built for this study; on this regard, we would like to emphasize that such score was created to reduce the number of covariates included in the PS models, and it is not proposed as a prognostic index (as we are quite aware that a specific and independent validation study would be necessary for that); (3) the study period selected (March, 2020) was the most critical of the first wave in Spain and, at that time, health professionals worked under an extraordinary pressure, which may have led to under-recording of some relevant clinical information; this limitation, however, does not apply to drugs as they were prescribed through an electronical tool, making unlikely the misclassification of drug exposure; and (4) the mortality rates recorded in our study were extraordinary high (partly accounted for the lack of preparedness of the health system to address this disease at the very beginning of the pandemic) and remarkably different from figures corresponding to other periods during the first and successive waves in Spain or in other countries, so the generalizability of our data on this regard cannot be assured; however, we do not think that this affects the internal validity of our results.

The discontinuation of RASIs at hospital admission was common place in the first wave of COVID-19 pandemic in Spain, influenced by the widely spread hypothesis that postulated a more severe disease in patients treated with these drugs. Our results show that the discontinuation of these drugs at admission did not improve the in-hospital survival. On the contrary, we found that the discontinuation of treatment with ARBs was associated with a trend to an increased mortality risk as compared to their continuation. Moreover, the continuation with ARBs was associated to a significantly lower mortality risk as compared to the continuation with ACEIs, particularly evident in high-risk subgroups.