key: cord-0870410-aq2iz9tq
authors: Kaur, Upinder; Chakrabarti, Sankha Shubhra; Patel, Tejas K.
title: Renin–angiotensin–aldosterone system blockers and region-specific variations in COVID-19 outcomes: findings from a systematic review and meta-analysis
date: 2021-05-14
journal: Ther Adv Drug Saf
DOI: 10.1177/20420986211011345
sha: 9a7fdebe6d462c9e054a51fcbdb688f46998c92a
doc_id: 870410
cord_uid: aq2iz9tq

BACKGROUND AND AIMS: : Coronavirus disease 2019 (COVID-19) has been observed to cause a high mortality in people with cardiometabolic diseases. Renin–angiotensin–aldosterone system (RAAS) blockers enhance the expression of ACE2, the binding receptor of SARS-CoV-2, and can enhance viral infectivity. We aim to provide a pooled estimate of the effect of RAAS blockers on COVID-19 outcomes. METHODS: A literature search was performed using MEDLINE/PubMed, Google Scholar and preprint servers. All clinical studies analyzing the effect of RAAS blockers on clinical outcomes in COVID-19 patients were included in this study. Newcastle–Ottawa scale was used for quality assessment of studies. MOOSE checklist was followed. Mortality and severity outcomes were recorded as pooled odds ratio (OR) with 95% Confidence Intervals (CIs) and level of heterogeneity (I(2)). Odds of mortality was the primary outcome. Odds of severity, hospitalization, intensive care unit (ICU) admission, mechanical ventilation (MV), steroid use and acute kidney injury were the secondary outcomes. Severity outcomes were chosen depending upon the definition used by respective authors. Country-specific variations and effects of individual class of RAAS blockers were also explored. RESULTS: In total 47 published studies were included in the final analysis, with a total of 26,432 patients from 31 studies in mortality analysis and 20,127 patients from 23 studies in severity analysis. No increased risk of mortality [Pooled OR 0.91 (0.65–1.26), I(2) = 89%] or severity [Pooled OR 1.08 (0.79–1.46), I(2) = 88%] was seen with RAAS blockers. The drug class was protective in hypertension [pooled OR 0.63 (0.46–0.86), I(2) = 58%]. Severity of COVID-19 outcomes was high for Europeans [Pooled OR 2.08 (1.52–2.85), I(2) = 77%] and US patients [Pooled OR 1.87 (1.62–2.17)]. Nearly 4 times higher risk of hospitalization and 2 times higher risk of ICU admission and MV were observed in US patients. Class-wise, angiotensin receptor blocker use was associated with 1.6 times higher odds of severity, mainly in Europeans. CONCLUSION: RAAS blockers are not associated with increased mortality in COVID-19 patients and should be continued in hypertensives. US and European patients are at higher risk of severe outcomes. Pharmacogenetic differences may explain the ethnicity-related variations. PLAIN LANGUAGE SUMMARY: Effect of RAAS-blocking medicines on COVID-19 Background and aims: Higher deaths have been observed in COVID-19 patients who have other long-term diseases such as heart disease, diabetes, and high blood pressure. Many of these patients are prescribed a class of medicines called RAAS blockers (ramipril, telmisartan, etc). We studied whether the use of these medicines worsens the course of COVID-19 disease in these patients or causes excess deaths. Methods: We conducted a pooled analysis of 47 observational studies on the use of RAAS blocker drugs in COVID-19 patients. Results: We found that RAAS blockers do not cause excess deaths in patients with COVID-19. On the contrary, they have benefits if prescribed to those with high blood pressure. We also found that whereas European and US patients of COVID-19 taking these medicines had higher disease severity, this was not the case for Chinese patients. Conclusion: Theremay be some genetic and other factors responsible for differences by ethnicity.

Corona Virus Disease-2019 (COVID- 19) caused by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) has affected 141 million individuals worldwide and claimed 3 million lives as of 20th April 2021. 1 ACE2 is the major binding receptor of SARS-CoV-2 and is located on pulmonary epithelial cells, endothelial cells and in cells of the kidney, among others. Acute respiratory distress syndrome, myocardial injury, multiorgan failure and disseminated intravascular coagulation including diffuse pulmonary intravascular coagulopathy are responsible for the majority of the deaths, and stem from a state of inflammatory cytokine storm and vascular thrombosis. 2, 3 Older individuals and those with co-morbidities such as hypertension, diabetes mellitus and ischemic heart disease are at increased risk of severe disease. The use of renin-angiotensin-aldosterone system (RAAS) blockers such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and mineralocorticoid receptor antagonists in such patients is not uncommon. With experimental evidence of upregulation of ACE2 by RAAS blockers, concerns were raised regarding the increased risk of infection and severity of disease in users of these drugs. 4, 5 Following this, multiple observational studies were conducted to assess the relationship between use of RAAS blockers and COVID-19 severity. This systematic review and meta-analysis aim to compile the information obtained from these studies and elucidate the association between the use of RAAS blockers and clinical outcomes in patients of COVID-19. Few such meta-analyses have been published, but these have shortcomings such as inclusion of only a small number of studies, absence of subgroup analysis, and inclusion of retracted studies. The current meta-analysis of 47 studies provides a comprehensive view of the issue by involving larger number of patients, analyzing for multiple health outcomes, and performing region-specific analyses. We hypothesized that RAAS blockers may not be detrimental to COVID-19 outcomes.

A comprehensive search was conducted in PubMed, Google Scholar, and the preprint servers medRxiv.org and bioRxiv.org using keywords: ACEI OR ACE-I OR Angiotensin converting enzyme inhibitors AND COVID-19/SARS-CoV-2, Angiotensin receptor blocker OR AT-1 receptor blocker OR Ang II blocker OR ARB AND COVID-19/SARS-CoV-2, RAAS blocker AND COVID-19/SARS-CoV-2, Aldosterone antagonist AND COVID-19/SARS-CoV-2, Renin inhibitor AND COVID-19/SARS-CoV-2. The final search was conducted on 9 July 2020. Only articles published in English language were included. MOOSE checklist was followed for the present study.

• All clinical studies (observational studies/ clinical trials) analyzing the effect of RAAS journals.sagepub.com/home/taw 3 blockers on clinical outcomes in laboratory confirmed COVID-19 patients were included in this study. Thus, the review involved inclusion of studies which compared the disease outcomes between users and non-users of RAAS blockers as well as those which assessed the use of RAAS blockers in COVID-19 patients of varying severity. RAAS blockers include ACEIs, ARBs, aldosterone antagonists and renin inhibitors. Studies were considered irrespective of the dose and duration of drug use. • Studies should have provided comparative data of mortality and/or severity between users and non-users of RAAS blockers in COVID-19 patients. • All types of study setting (outpatient, inpatient, nursing homes, home care) were included. • All age groups of study population were included.

Exclusion criteria • Studies focusing on individual RAAS blockers only. • Studies focusing only on outcomes based on laboratory parameters (e.g. serum/urinary ACE2 expression). • Non-comparative studies, review articles, in vitro studies, animal studies, viewpoints.

All relevant abstracts were scrutinized, and full text and bibliography was searched for those found useful. In case of lack of clarity in the abstracts, full text was analyzed. This was done by author UK assisted by author SSC and confirmed by author TKP assisted by author SSC.

Data extraction. From the included studies, data were extracted in a Microsoft Excel sheet. Data included author name, publication year, country, study design, total duration of study, mean/ median follow-up, characteristics of patients or specific population of COVID-19 patients in whom the particular study was conducted, age, gender, sample size, use of RAAS blockers, mortality outcomes, severity outcomes, need of hospitalization, care in intensive care unit (ICU), need of mechanical ventilation, corticosteroid use and occurrence of acute kidney injury (AKI).

assessed the risk of bias in the included studies as per the Newcastle-Ottawa quality assessment scale (NOS) adapted for cross-sectional design. Criteria considered were representativeness of the study sample, sample size, non-respondents, ascertainment of exposure, comparability of study groups for confounders (age and major co-morbidities), assessment of outcome and statistical tests. The maximum possible score was 10. 6

Outcomes with the use of RAAS blockers. The primary outcome was odds of mortality in the users of RAAS blockers with respect to non-users among confirmed cases of COVID-19. The secondary outcomes were odds of severity, hospitalization, ICU admission, mechanical ventilation, steroid use, and AKI in users of RAAS blockers with respect to non-users. A subgroup analysis of all outcomes was performed based on the geographical locations (country or continent of origin) of the included studies. The mortality outcome was further analyzed as per study subpopulations (e.g. patients with hypertension) and severity outcome as per definitions used by the individual study authors.

Outcomes with the use of subclass of RAAS blockers (ACEIs and ARBs). Both the subclasses were explored for the mortality and severity outcomes as per the availability of studies. Both outcomes were analyzed according to the geographical locations (country or continent of origin) of the included studies. In the absence of universally accepted definitions, severity was considered as defined by the authors in the included studies. When outcomes were reported both under "critical" and "severe" headings, we considered the more serious outcome under severity analysis. In case of multiple timepoints for the outcome estimation, we considered data at the end of study period.

A sensitivity analysis was performed for each outcome after excluding studies with high risk of bias. The studies with score ⩽7 on the modified NOS scale were considered to have high risk of bias.

All outcomes being dichotomous variables were reported as odds ratio (OR) with 95% confidence intervals (CIs). The meta-analysis was weighted with inverse variance method. An I 2 test was used to assess the heterogeneity between studies.

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Fixed-effect model was used if heterogeneity was <50% and random-effect was applied in case heterogeneity exceeded 50%. The funnel plot method was used for reporting publication bias. The meta-analysis was performed using Review Manager Software version 5.4.

A total of 1348 articles were retrieved ( Figure 1 ). Out of 70 full-text articles assessed, 47 studies satisfying the selection criteria were included for detailed qualitative and quantitative analysis in this review. (Figure 2 ). The results were consistent in the sensitivity analysis (Table 2) .

On indication or disease-wise comparison, use of RAAS blockers was found to reduce the overall risk of mortality when prescribed for hypertension [pooled OR 0.63 (0.46-0.86), I 2 = 58%]. A similar trend was observed in sensitivity analysis [pooled OR 0.48 (0.36-0.63), I 2 = 0%]. Ten out of fifteen studies reporting mortality in hypertensive patients were from China. (Figure 3 ).

A total of 20,127 patients (5460 RAAS blocker users and 14,667 non-users) from 23 studies were included in the severity analysis. The overall pooled summary showed no effect on the severity of disease with the use of RAAS blockers [pooled OR 1.08 (0.79-1.46), I 2 = 88%] ( Figure  4) . A similar result was observed in sensitivity analysis [pooled OR 1.32 (0.93-1.87), I 2 = 91%] ( Table 2) . Funnel plot was asymmetrical on visual inspection (Supplemental Figure 2) .

Comparison of studies with respect to the definition of severity showed a protective effect of RAAS blockers against "critical" disease defined by NHC China [pooled OR 0. Figure 3 and Table 2 ). 11 (Figure 4) . A similar trend was observed in sensitivity analysis (Table 2 ). In contrast, no effect on severity with the use of RAAS blockers was evident in the Chinese population in overall [pooled OR 0.69 (0.45-1.06), I 2 = 51%], and sensitivity analysis [pooled OR 0.68 (0.3-1.53), I 2 = 58%] ( Figure 4 and Table 2 ). Figure 4 and Table 2 ). Figure 5 and Table 2 ). 14 journals.sagepub.com/home/taw Therapeutic Advances in Drug Safety 12 Figure 6 and Table 2 ).

Seven studies (n = 1854), all from China, commented on corticosteroid use in relation to RAAS blocker use. Use of RAAS blockers did not affect the requirement for corticosteroid use in the overall analysis [pooled OR 0.82 (0.65-1.04), I 2 = 38%] and also in sensitivity analysis [pooled OR 1.01 (0.64-1.6), I 2 = 35%] (Supplemental Figure 7 and Table 2 ).

Five studies (n = 2143) reporting on AKI were analyzed. Use of RAAS blockers was not associated with increased or decreased risk of AKI in overall analysis [pooled OR 0.94 (0.76-1.16), I 2 = 0%] and also in sensitivity analysis [pooled OR 1.23 (0.52-2.89), I 2 = 0%]. The latter was based on two studies, both from China (Supplemental Figure 8 and Table 2 ). 25 

A total of eight studies involving n = 9328 patients of COVID-19 analyzed specifically the impact of ARBs on mortality outcome. The use of ARBs was not found to contribute to increased or decreased mortality [pooled OR 0.99 (0.71-1.39), I 2 = 71%; and pooled OR 0.92 (0.46-1.81), I 2 = 76% in sensitivity analysis]. As with ACEIs, no region-specific differences were observed in mortality with the use of ARBs (Supplemental Figure 10 and Supplemental Table 1 ). 

Similarly, definition and region-wise analysis did not show significant effect on COVID severity with ACEI use, in overall and sensitivity analysis (Supplemental Figure 11 and Supplemental Table 1 ). Figure 12 and Supplemental Table 1 ).

Severity analysis of patients on ACEIs with respect to those on ARBs. No significant difference in severity outcomes was seen between ACEIs and ARBs in overall [pooled OR 1.00 (0.87-1.14), I 2 = 0%] as well as in sensitivity analysis [pooled OR 0.99 (0.86-1.15), I 2 = 0%] (Supplemental Table 1 ).

Hypertension, diabetes mellitus, cerebrovascular disease, and ischemic heart disease are co-morbidities which are commonly prevalent and found to be responsible for adverse prognosis in patients with COVID-19. 56 RAAS blockers are used in majority of these diseases and are known for their disease-modifying roles in ischemic heart disease, congestive heart failure, and diabetic nephropathy. With the observation that SARS-CoV-2 binds preferentially to ACE2, which is prone to upregulation by RAAS blockers, speculations were made that the continuation of RAAS blockers would increase virus binding to host cells and SARS-CoV-2 infectivity. On the contrary, ACE2 is known to be protective against lung injury via the Ang (1-7)-Mas-Mrg D axis. 57, 58 Ang (1-7) exerts cardiopulmonary protection via vasodilatory, anti -inflammatory, anti-thrombotic and anti-hypertrophic roles. 59 Downregulation of ACE2 has been shown to exaggerate lung injury and decrease overall survival of mice subjected to agents with potential pulmonary toxicity. 57, 58 Some clinical studies and pooled analyses have shown a protective role of ACEIs against pneumonia particularly in older people with hypertension and diabetes mellitus. 60, 61 Considering this, some groups have hypothesized that upregulation of ACE2 by RAAS blockers might be protective after viral entry, and therapies causing enhancement of ACE2 might be useful in COVID-19. 62, 63 The confusion surrounding RAAS blockers led to a spurt of observational studies focused on RAAS blockers and COVID-19 outcomes. We have tried to compile information from all such studies and provide insights on association between RAAS blocker use and COVID-19 morbidity and mortality outcomes.

In our meta-analysis, RAAS blocker use was not associated with an increased risk of mortality. A reduced risk of mortality was seen in the Chinese population, but the effect was nullified in sensitivity analysis. RAAS blockers were also found to reduce mortality in hypertensive patients. On the other hand, an increased risk of composite outcome of ICU admission/death was seen with the use of RAAS blockers and this effect persisted in sensitivity analysis.

With respect to severity of COVID-19 disease, although no overall effect of RAAS blockers was evident, a reduced risk of "critical" form of the disease (NHC, China) was observed. This was not validated, however, in sensitivity analysis. Further, while RAAS blockers did not produce any adverse effect on disease severity when analyzed in the entire population, the outcomes differed between countries. RAAS blockers were found not to affect disease severity in Chinese patients but they were associated with nearly a two times higher risk of severe disease in US patients and Europeans. Though class-wise subgroup analysis did not show any effect on mortality by ACEIs and ARBs, the use of ARBs was associated with 1.6 times higher odds of severe disease, particularly as ICU admission. As with the combined RAAS blocker class, ARBs were also linked with region-specific differences, with high risk particularly in Europeans. Further, with respect to requirement of corticosteroids and causation of renal injury, no risk could be attributed to RAAS blockers. This interpretation is primarily based on sensitivity analysis involving Chinese studies.

These country-specific variations could be due to interplay of genetic factors which may include, but are not limited to, polymorphisms involving ACE or ACE2 genes. ACE2 is prone to multiple polymorphisms. Traditionally, these have been associated with hypertension as well as reduced blood pressure-lowering response to ACEIs. 64 Some polymorphisms seen predominantly in Europeans, such as K26R, can enhance interaction between SARS-CoV-2 S protein and ACE2, which might lead to increased severity of disease. 65 A preprint analyzed the relationship between ACE2 polymorphisms and COVID-19 severity in a small cohort of 62 patients. Notably, single nucleotide polymorphisms (SNPs) increasing tissue expression of ACE2 were associated with higher rates of hospitalization while a lower odds of severe disease was seen with SNPs decreasing tissue expression. 66 ACE I/D genotype can also influence the severity of COVID-19 pneumonia. Polymorphisms involving ACE can influence circulating and tissue levels of ACE as well as of cytokines like IL-6 and kallikreins. Higher enzyme and cytokine levels are seen in those with ID and DD genotypes. 67 ACE DD genotype has been shown to be associated with increased cardiovascular morbidity and increased risk of pneumonia in some studies. 68, 69 The pneumonia-protective potential of ACEIs is commonly observed in Asians and is linked with II and ID genotypes prevalent in this population. 70, 71 A recently published study assessed the relationship between allele frequency ratio of ACE I/D genotype and COVID-19 recovery. A trend of lesser severity and early recovery was observed with increasing I/D allele ratio. The study showed that I/D ratio of >1 is seen in China, Japan and East Asia, which are some of the less severely affected countries. On the other hand, I/D ratio of less than 1 (0.4-0.6) has been observed for countries like Italy, the US, Spain, Brazil, and the UK, which are affected the most by COVID-19. 72 The sole contribution of genotypic variations behind severity and mortality is, however, unlikely as some countries like India have an I/D ratio of around 0.11 but have considerably low mortality and severity rates of COVID-19 compared with the West. Environmental, biological and immunological factors can also have additive or decisive roles in modulating COVID-19 severity and mortality. 73, 74 Individually, the association of higher rates of worse clinical outcomes of COVID-19 with ARB use in Europeans lacks a clear understanding and warrants further research. The higher levels of Ang-I and Ang-II generated under the influence of AT1 receptor blockers can be shunted to Ang (1-7) or Ang-III pathways depending on ACE and ACE-2 and aminopeptidase A (APA) activity. SNPs affecting any of these components can therefore decide the net effect of ARB use. Europeans harbor a higher frequency of D allele of ACE to the tune of 82-87%, which in turn is associated with higher ACE activity, cytokine levels and severity of lung injury. 75 The neutral effect of RAAS blockers on mortality and a protective effect in hypertensives are consistent with the results of some of the already published meta-analyses. However, among these, the study by Pranata et al. 76 our knowledge have not been addressed in any pooled analyses so far.

One meta-analysis published while the present study was in peer review included 49 observational studies for main analysis and has also found no effect of RAAS blocker use on severity or mortality outcomes. Similar findings were seen in geographical location-dependent subgroup analysis. 79 The definition of severity used in the study, however, differed from ours. The authors considered the composite of severe COVID-19 as defined in individual studies, ICU admission and mechanical ventilation. Further, individual outcomes were not explored for geographical differences. In contrast, our study assessed severity under specific headings and explored all outcomes for geographical variations. This may explain the ethnicityrelated differences in severity outcomes by RAAS blockers observed in our study.

While the present study was in peer review process, numerous other observational studies addressing the association between RAAS blocker use and COVID-19 outcomes were published; their inclusion is, however, beyond the scope of the present study. One such study based on a retrospective cohort of around 43,000 COVID-19 patients is probably the largest observational study to date. No effect of RAAS blockers on overall mortality was seen, in concordance with the highlights of our present study. 80 Similar findings were observed in a phase IV open-label, but observer-blinded, randomized trial (BRACE CORONA) that investigated the effect of continuing versus suspending RAAS blockers in more than 650 hospitalized COVID-19 patients. No difference was seen in the number of days alive and in all-cause mortality at 30 days between the two groups. 81 Whether dose or duration of treatment of RAAS blockers can influence the COVID-19 outcomes is another potential area to be explored. So far, the few studies addressing this issue have ruled out the possibility of dose or duration effect relationship between RAAS blockers and COVID-19 mortality and severity outcomes. 17, 21, 80 However, for some outcomes such as AKI, 25-31% increase in renal dysfunction has been observed with every 10 mg increase of lisinopril or equivalent RAAS blocker. 37 This systematic review has some limitations. The pooled analysis is mainly based on observational studies, which are more likely to have study populations with difference in baseline characteristics and co-interventions than randomized controlled trials. Being observational, the elements of confounding, residual confounding and observer bias also cannot be ruled out. The country-specific subgroup analysis was based on only a small number of studies. Further, the current metaanalysis aimed to generate data related to RAAS blockers and therefore excluded those studies (n = 11) which focused on ACEI and ARB class in isolation and did not provide information about the outcomes in combined RAAS blocker class. However, from the included studies, subgroup analysis was performed to explore the effect of ACEIs and ARBs on mortality and severity outcomes.

There is a need to investigate racial or region/ country-specific differences in the clinical outcomes of COVID-19. Genetic polymorphisms may govern the pharmacodynamic response to RAAS blockers in different population groups, as seen in our meta-analysis, and should be explored actively in future. There is a need to explore excess risk of ICU admission and mechanical ventilation in the US and increased severity of COVID-19 disease in Europeans, both of which were found to be associated with RAAS blocker usage. Increased risk of severe disease was replicated especially with ARBs. Overall, the use of RAAS blockers does not seem to have any impact on COVID-19 mortality and severity. In the presence of a protective effect in patients with hypertension, it may be advisable to continue these drugs in those patients with pre-COVID indication for the same. Randomized controlled trials and pharmacogenetic studies are required to generate clear and concise evidence on ethnicity and outcomes in the presence of RAAS blocker use. 22 journals.sagepub.com/home/taw Therapeutic Advances in Drug Safety 12

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Dr Patel and Dr Kaur wish to thank the administration of the All India Institute of Medical Sciences, Gorakhpur for providing research support.