key: cord-0765787-9wssbenf
authors: Barochiner, Jessica; Martínez, Rocío
title: Use of inhibitors of the renin‐angiotensin system in hypertensive patients and COVID‐19 severity: A systematic review and meta‐analysis
date: 2020-08-07
journal: J Clin Pharm Ther
DOI: 10.1111/jcpt.13246
sha: d8eb21deb5640445de706515071084abb6dc136d
doc_id: 765787
cord_uid: 9wssbenf

WHAT IS KNOWN AND OBJECTIVE: Controversy has arisen in the scientific community on whether the use of renin‐angiotensin system (RAS) inhibitors in the context of COVID‐19 would be beneficial or harmful. A meta‐analysis of eligible studies comparing the occurrence of severe and fatal COVID‐19 in infected hypertensive patients who were under treatment with angiotensin‐converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) vs no treatment or other antihypertensives was conducted. METHODS: PubMed, Google Scholar, the Cochrane Library, medRxiv and bioRxiv were searched for relevant studies. Fixed‐effects models or random‐effects models were used depending on the heterogeneity between estimates. RESULTS AND DISCUSSION: A total of eighteen studies with 17 311 patients were included. The use of RAS inhibitors was associated with a significant 16% decreased risk of the composite outcome (death, admission to intensive care unit, mechanical ventilation requirement or progression to severe or critical pneumonia): RR: 0.84 (95% CI: 0.73‐0.95), P = .007, I(2) = 65%. WHAT IS NEW AND CONCLUSION: The results of this pooled analysis suggest that the use of ACEI/ARB does not worsen the prognosis of COVID‐19, and could even be protective in hypertensive subjects. Hypertensive patients should continue these drugs even if they become infected with SARS‐CoV‐2.

mechanisms including direct damage and systemic inflammatory responses. 6 Subjects with preexisting cardiovascular diseases might be more susceptible to COVID-19-induced heart injury.

SARS-CoV-2 gains entrance to cells through the angiotensin-converting enzyme 2 (ACE2), 7 a carboxypeptidase that converts angiotensin II into angiotensin-(1-7) and counterbalances the renin-angiotensin-aldosterone system, exerting protective effects in the cardiovascular system. Given that there are limited reports that ACE inhibitors affect the expression of ACE2 in the heart and the kidney, 8 there has been a growing concern about angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) increasing patient susceptibility to viral host cell entry and propagation. [8] [9] [10] Of note, many patients with cardiovascular comorbidities, particularly hypertension, are treated with these drug classes. On the other hand, it is hypothesized that SARS-CoV-2, like SARS-CoV, not only gains initial entry through ACE2 but also subsequently downregulates ACE2 expression, 11 and deregulated ACE2 may theoretically mediate acute lung injury. 12 In fact, some experts have advocated for the use of ACEI and ARB to prevent organ injury and there are currently several registered clinical trials that will evaluate the potential benefit of ARB or ACEI in either hospitalized or not hospitalized COVID-19-infected patients.

To date, there is insufficient clinical or scientific evidence to recommend the discontinuation or maintenance of ACEI/ARB treatment in hypertensive patients in face of COVID-19. Therefore, in this article, we conducted a systematic literature search to determine a possible association between the use of ACEI/ARB in hypertensives who become infected with COVID-19 and the progression of the disease to severe forms or death.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement 13 was followed for the conduct and reporting of this systematic review (PRISMA checklist provided as Supporting Information).

To identify publications regarding the clinical outcomes of COVID-19 in infected hypertensive patients under treatment or not under treatment with ACEI/ARB, an extensive search of the literature was conducted in MEDLINE (through PubMed interface), Cochrane Library, Google Scholar and the preprint servers for the health sciences medRxiv and bioRxiv, from December 2019 to 5 June 2020.

In addition, we manually searched from the reference lists of all relevant retrieved studies (snowball technique) to identify any other studies that may have been missed by our search strategy.

The following search strategy was implemented: 

Our outcome was a combination of death, admission to intensive care unit (ICU), mechanical ventilation requirement or progression to severe or critical pneumonia. According to the Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19), 14 severe pneumonia was defined as dyspnoea, respiratory frequency ≥ 30/min, blood oxygen saturation ≤ 93%, PaO2/FiO2 ratio < 300 and/or lung infiltrates > 50% of the lung field within 24-48 hours, whereas critical pneumonia was defined as respiratory failure, septic shock and/or multiple organ dysfunction/failure and critical pneumonia as respiratory failure, septic shock and/or multiple organ dysfunction/failure.

Data were collected by two independent reviewers (RM and JB) and entered into a predesigned data extraction form. Differences between the two reviewers regarding study eligibility were resolved by consensus.

Study and population characteristics were extracted from each included study. Regarding study characteristics, the name of the first author, the date of publication, the study type, the number of centres and countries contributing to the research and possible funding were extracted. Also, total population, mean age, percentage of male participants, number of patients taking ACEI and/or ARB, number of patients taking other antihypertensives or no treatment, type and dose of antihypertensive drug, number of patients experiencing the primary outcome in each treatment group and details for possible matched characteristics were recorded.

The Newcastle-Ottawa Scale (NOS) was used to assess the quality of studies. 15 In this scale, a 'star system' is used, in which a study is judged on three aspects: selection of the study groups; comparability of the groups; and ascertainment of either the exposure or outcome of interest for case-control or cohort studies, respectively. A study can be awarded a maximum of one star for each numbered item within the selection and exposure categories.

A maximum of two stars can be given for comparability. In this systematic review, studies with scores above 6 were considered as high quality, 3-6 as moderate and those with scores below than 3 as low quality. 16 The NOS was applied independently by the two reviewers (RM and JB). Differences between them were resolved by consensus.

Pooled analysis was performed to estimate the risk ratio (RR) and 95% confidence interval (95% CI) comparing the occurrence of the composite outcome in COVID-19-infected hypertensive patients under treatment with ACEI/ARB vs no treatment or treatment other than ACEI/ARB. All analyses were conducted using RevMan software version 5.3. Fixed-effect models or random-effect models were used depending on the heterogeneity between estimates. We used the I 2 statistics to assess the magnitude of heterogeneity. The fixed-effects model was used if I 2 < 50%, and the random-effects model was used if I 2 ≥ 50%.

Publication bias was examined by the use of a funnel plot of each study's effect size against the precision (1/SE).

We planned to conduct two subgroup analyses: (a) including only high-quality studies and (b) including only peer-reviewed published studies. All of the selected studies were published in 2020 and were all of observational nature. [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] In seven studies, the outcome that matched our research question was death 17, 20, 21, [26] [27] [28] 31 ; in two studies, severe pneumonia 23, 34 ; in three studies, critical or severe pneumonia 18, 19, 32 ; in one study, death or critical or severe pneumonia 33 ; in one study, severe pneumonia or death 24 ; and in one study, death, admission to ICU or mechanical ventilation requirement. 25 In three of the studies where the outcomes death and severe pneumonia, 22, 30 or critical pneumonia 29 were discriminated, we chose mortality as the worst possible outcome for our analysis since the data necessary to evaluate the outcome as a composite were not available. Table 1 summarizes the study characteristics. Quality assessment through the Newcastle-Ottawa Scale showed scores between 5 and 9 points, indicating high-quality studies, except for three studies that scored 5 or 6 points (moderate quality).

In a qualitative synthesis, seven studies reported a lower risk of the outcome with the use of ACEI/ARB 20,23,27,31-34 and eleven studies found no association. [17] [18] [19] 21, 22, [24] [25] [26] [28] [29] [30] 

The results of our pooled analysis for the 18 identified studies are presented in Figure 2 . In our subgroup analyses, no significant differences were found when excluding studies with a NOS score below 7: RR: 0.83 (95% CI: 0.72-0.96, P = .01, I 2 = 70%). When excluding preprints, the protective association between RAS inhibitors use and the primary outcome remained marginally significant: RR: 0.82 (95% CI: 0.67, 1.00, P = .05, I 2 = 61%) ( Figure 3) .

Finally, the funnel plot indicated some degree of publication bias, with a lack of small studies showing increased risk of ACEI/ARB use ( Figure 4 ).

In this meta-analysis, we found that the use of ACEI/ARB was not show that this association holds even after such adjustments. 46, 47 As many subjects with cardiovascular morbidities, particularly hypertensives, are under treatment with ACEI/ARB, it has been speculated that the use of these drugs could be the underlying cause of the relation between these morbidities and a poorer COVID-19 prognosis.

If this was the case, we would have found a greater risk of severe forms of COVID-19 in subjects under treatment with ACEI/ARB, but we have not. In fact, the evidence presented in this meta-analysis supports the idea that ACEI/ARB should not be discontinued when treating COVID-19 patients with hypertension.

On the other hand, RAS inhibitors have established benefits in protecting the cardiovascular system. 48, 49 Their discontinuation may increase the chance of decompensation in high-risk patients as the benefits that are specific to these drugs may not be offset by other antihypertensive agents. For instance, it has been shown that the withdrawal of ACEI/ARB during heart failure hospitalization is associated with higher rates of post-discharge mortality. 50 Besides, concern. Fourth, residual confounders may be present in these observational studies, and even when measured, many studies did not make adjustments for such potential confounders. It must be noted, however, that not adjusting for age and cardiovascular comorbidities would shift the results towards a higher risk since these variables are positively associated with both the use of ACEI/ARB and COVID-19 poorer outcomes. In the same line, it is possible for some of the included studies to have actually included a few non-hypertensive subjects but instead some patients with cardiovascular comorbidities under treatment with ACEI/ARB, such as heart failure or acute coronary syndrome.

It must be mentioned, however, that these comorbidities would have acted as positive confounders, being positively associated both with ACEI/ARB use and a worse COVID-19 prognosis. In that case, the result would have been an association between ACEI/ARB use and a worse COVID-19 evolution. However, even under the effect of those potential confounders, ACEI/ARB were still found to be protective.

According to our findings, the use of ACEI/ARB is associated with a modest but significant reduction in the risk of death, admission to intensive care unit (ICU), mechanical ventilation requirement or progression to severe or critical pneumonia in COVID-19-infected hypertensive patients. Large prospective studies are required to confirm these results and to explore the mechanisms for a possible protective role of RAS inhibitors in the context of COVID-19. In the meantime, these early results suggest that patients on ACEI/ARB should continue their treatment during COVID-19 illness, supporting current recommendations from multiple scientific societies.

We are grateful to Ms Erika Barochiner for language editing and to

Prof. Javier Medolla for translation of articles in Chinese.

Rocío Martínez and Jessica Barochiner declare that they have no conflict of interest. 

This is a systematic review and meta-analysis of the literature. No human subjects or animals were involved in this research.

Not applicable.

Not applicable.

The data sets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

Jessica Barochiner https://orcid.org/0000-0002-2176-9762

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