key: cord-0763242-ft701xa7 authors: Diaz-Arocutipa, Carlos; Melgar-Talavera, Beatriz; Alvarado-Yarasca, Ángel; Saravia-Bartra, María M.; Cazorla, Pedro; Belzusarri, Iván; Hernandez, Adrian V. title: Statins reduce mortality in patients with COVID-19: an updated meta-analysis of 147,824 patients date: 2021-08-08 journal: Int J Infect Dis DOI: 10.1016/j.ijid.2021.08.004 sha: cd0510ee85001d04b74c2f951b648723c2728207 doc_id: 763242 cord_uid: ft701xa7 OBJECTIVES: There is conflicting evidence about the utility of statins use on clinical outcomes in patients with coronavirus disease 2019 (COVID-19). We performed a systematic review and meta-analysis to examine the effect of statins use on mortality in COVID-19 patients. METHODS: We searched electronic databases from inception to March 3, 2021. We pooled unadjusted and adjusted effect estimates with their 95% confidence intervals (95% CI) using random-effects models. RESULTS: Twenty-five cohort studies involving 147824 patients were included. The mean age ranged from 44.9 to 70.9 years and 57% of patients were men. The use of statins was not associated with mortality using unadjusted risk ratio (uRR, 1.16; 95% CI, 0.86-1.57, 19 studies). In contrast, meta-analyses of adjusted odds ratio (aOR, 0.67; 95% CI, 0.52-0.86, 11 studies) and adjusted hazard ratio (aHR, 0.73; 95% CI, 0.58-0.91, 10 studies) showed that statins were independently associated with a significant reduction of mortality. Subgroup analyses showed that only chronic use of statins significantly reduced mortality according to the adjusted models. CONCLUSIONS: The use of statins was associated with a lower risk of mortality in COVID-19 patients based on adjusted effects of cohort studies. However, randomized controlled trials are still needed to confirm these findings. The current coronavirus disease 2019 pandemic, which is caused by severe acute respiratory coronavirus-2 (SARS-CoV-2), remains a major public health problem across the globe, despite the availability of vaccines (Hamed et al., 2021) . In the meantime, we continue to need effective pharmacological therapies that reduce the morbidity and mortality of patients with COVID-19. Statins are widely used drugs in the current medical practice. Given its lipidlowering effect, it is a mainstay in the treatment of patients with dyslipidemia and atherosclerosis-related diseases (Adhyaru and Jacobson, 2018) . Recently, statins have emerged as a potential new therapy for patients with COVID-19 due to their pleiotropic effects (Oesterle et al., 2017) . However, there are conflicting data about the utility of statins in COVID-19 patients (Masana et al., 2020 , Saeed et al., 2020 . Therefore, we performed a systematic review and meta-analysis to examine the effect of statins use on mortality in COVID-19 patients. This review was reported according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) statement (Moher et al., 2009) . We searched in the following six electronic databases: Embase, PubMed, Web of Science, Scopus, CENTRAL, and Cochrane COVID-19 register. The search was conducted from inception to November 25, 2020, and updated on March 3, 2021. We used the following key words with their combinations, but not limited to: hydroxymethylglutaryl-CoA reductase inhibitors, statin, COVID-19, and SARS-CoV-2. The complete search strategy is shown in Supplementary Table 1. There were no restrictions on language or publication year. In addition, we also performed a handsearch of reference lists of included articles to identify further eligible studies. We included cohort studies and randomized controlled trials that evaluated the effect of statins on mortality in COVID-19 patients diagnosed by reverse transcriptionpolymerase chain reaction. Case reports, case series, reviews, abstracts, and editorials were excluded. All articles from the electronic search were downloaded to EndNote X8 and duplicates were eliminated. Title and abstract were independently assessed by three review authors (MSB, PC, and AAY) to identify potentially eligible studies. Two review authors (BMT and AAY) independently screed the full-text and registered reasons for the exclusion. Any disagreement of title/abstract and full-text selection was resolved by a third review author (CDA). We defined the use of statins as chronic (i.e. before hospital admission) or inhospital administration (i.e. during hospitalization) of any type and dose of statins. The outcome of interest was mortality. We used all author-reported definitions for mortality. Data from each included study was independently extracted by two review authors (BMT and IB) using a standardized data extraction form that was previously piloted. Any disagreement was resolved by a third review author (CDA). If additional data was required, we contacted the corresponding author through email to request this information. We extracted the following information: name of the first author, publication year, country, sample size, population, age, sex, comorbidities, use of statins, and mortality. If available, unadjusted and adjusted effect estimates were extracted. The risk of bias of cohort studies was evaluated using the Newcastle-Ottawa Scale (NOS). Each article was classified as follows: high risk of bias (0-4 points), moderate risk of bias (5-7 points), and low risk of bias (8-9 points). Two review authors (MSB, PC, and BMT) independently assessed the risk of bias and any disagreement was resolved by a third review author (CDA). We performed all meta-analyses using a random-effects model with an inversevariance method. Between-study variance (tau 2 ) was estimated using the Paule-Mandel method. We pooled unadjusted risk ratios (uRR), adjusted odds ratios (aOR), and adjusted hazard ratios (aHR) with their 95% CI for the assessment of the effect of statins on mortality. Heterogeneity among studies was evaluated using the chi-squared test (threshold p<0.10) and the I 2 statistic. Heterogeneity was defined as low if I 2 <30%, moderate if I 2 =30-60%, and high if I 2 >60%. Subgroup analyses were conducted according to the timing of statins use (chronic versus in-hospital). Funnel plots were used to assess publication bias and the Egger's test was performed to measure asymmetry of funnel plots only if 10 or more studies were included. All meta-analyses were conducted using the meta package from R 3.6.3. A two-tailed p<0.05 was considered statistically significant. Our electronic search strategy identified initially 857 articles. After the removal of duplicates, 409 articles remained. After the screening of studies by title/abstract, 359 articles were excluded. After the full-text assessment of 50 articles, 25 articles were excluded. A total of 25 studies (Ahlström et al., 2021 , Alamdari et al., 2020 , Aparisi et al., 2021 , Bifulco et al., 2020 , Butt et al., 2020 , Cariou et al., 2020 , Daniels et al., 2020 , Mallow et al., 2020 , Masana et al., 2020 , Mitacchione et al., 2021 , Nicholson et al., 2021 , Oh et al., 2021 , Peymani et al., 2021 , Rodriguez-Nava et al., 2020 , Rosenthal et al., 2020 , Rossi et al., 2020 , Saeed et al., 2020 , Selçuk et al., 2020 , Song et al., 2020 ) (all cohorts) were finally selected (Figure 1 ). The main characteristics of the 25 included studies (n=147824) were summarized in Table 1 . The mean age ranged from 44.9 to 70.9 years and 57% of patients were men. In general, 32% of patients received statins. Twenty studies reported a chronic use of statins and five studies an in-hospital use. The type of statin was reported in only 8 studies. The most common types were atorvastatin (71%), rosuvastatin (13%), and simvastatin (13%). Most studies were from the United States of America (n=9) and Italy (n=4). The most frequent comorbidities were hypertension (51%), dyslipidemia (41%), and diabetes (33%). The majority of studies (n=17) only included hospitalized patients. Besides, four studies included outpatients and hospitalized patients and four studies only included patients admitted to the intensive care unit (ICU). The adjusted effect estimates and adjusted variables for each individual study are shown in Supplementary Table 2 . The NOS evaluation showed that 18 studies were scored as low risk of bias, six studies as moderate risk of bias, and one study as high risk of bias (Supplementary Table 3) . In 19 studies (n=114881), the use of statins was not significantly associated with mortality in COVID-19 patients (uRR, 1.16; 95% CI, 0.86-1.57; I 2 =99%) ( In 10 studies (n=44033), the use of statins was significantly associated with lower mortality in COVID-19 patients (aHR, 0.73; 95% CI, 0.58-0.91; I 2 =64%) ( Figure 4) . The funnel plot showed asymmetry (Supplementary Figure 3) , suggesting publication bias that was confirmed by the Egger's test (p=0.03). Subgroup analysis by the timing (chronic versus in-hospital) of statins use revealed that only chronic use of statins was significantly reduced mortality in COVID-19 patients according to adjusted models (Figure 2, Figure 3 , and Figure 4) . Moreover, no significant differences were found between the subgroups. We found that the use of statins was significantly associated with a lower risk of mortality compared to non-statins users based on adjusted estimates. In addition, our subgroup analyses showed that only chronic use of statins was associated with a significant risk reduction in mortality. The risk of bias was low to moderate in almost all studies. Several pathways are involved in the pathogenesis of COVID-19. SARS-CoV-2 enters into cells using the angiotensin-converting enzyme 2 (ACE2), which is ubiquitously expressed with predominance in the lungs, heart, kidneys, and vascular system (Hossain et al., 2020) . ACE2 plays a key role in the renin-angiotensin system (RAS) by negatively regulating the RAS activation and attenuating the harmful effects of angiotensin II (Samavati and Uhal, 2020) . After viral entry, a robust local and systemic inflammatory response is elicited leading, in some cases, to an overproduction of proinflammatory cytokines (Hossain et al., 2020) . Furthermore, compelling data are supporting that COVID-19 patients exhibit a hypercoagulable state as evidenced by a high incidence of thrombotic complications in these patients (Abou-Ismail et al., 2020) . Statins are a class of lipid-lowering agents that act primarily by inhibiting 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (Adhyaru and Jacobson, 2018) . Statins can also have other effects known as "pleiotropic" that act through many mechanisms independent of low-density lipoprotein-cholesterol reduction, including antiinflammatory, antioxidative, anti-thrombotic, and immunomodulatory functions (Oesterle et al., 2017) . In addition, statins significantly increased the ACE2 expression in the heart and kidney in an animal model of atherosclerosis, suggesting a positive effect on the RAS balance (Tikoo et al., 2015) . Although the clinical significance of the pleiotropic effects of statins remains controversial, there is evidence of clinical benefit in a diversity of diseases such as respiratory viral infections, bacterial pneumonia, venous thromboembolism, among others (Oesterle et al., 2017) . Furthermore, statins, especially pitavastatin, could exert a direct antiviral effect by interacting with the main protease enzyme of SARS-CoV-2 (Reiner et al., 2020) . Overall, these mechanisms are the different targets where statins could act directly or indirectly during SARS-CoV-2 infection explaining their beneficial effect. The distinction between the chronic and in-hospital use of statins is an important issue to highlight. In our subgroup analyses, we found that only patients with chronic use had independently lower mortality. This suggests that prolonged exposure to statins would be required to manifest their beneficial effects in patients with COVID-19. However, these results should be considered only hypothesis-generating since there was a lack of detailed description about the timing of statins use in almost all studies. It is not known whether patients who reported pre-admission use of statins continued to receive it during hospitalization. Moreover, in the cases that reported in-hospital use, it is not clear whether it was initiated de novo or was a continuation of previous use. In the only 2 studies (Fan et al., 2020 , Oh et al., 2021 that reported continued use of statins during hospitalization, only one (Fan et al., 2020) reported a significant reduction in mortality in COVID-19 patients. Therefore, randomized controlled trials are needed to clarify whether the de novo or continued administration of statins has a favorable impact in these patients. There are few previously published systematic reviews examining the effect of statins use in COVID-19 patients (Hariyanto and Kurniawan, 2020 , Pal et al., 2021 , Permana et al., 2021 . Two reviews (Pal et al., 2021 , Permana et al., 2021 concluded that statins use was associated with a significant reduction of mortality or intensive care unit admission. In contrast, one review concluded that statins did not improve in-hospital outcomes. The largest review was performed by Permana et al. (Permana et al., 2021) , which only included 13 studies involving 52122 patients. In addition, it was the only review that evaluated chronic and in-hospital use of statins; however, it only combined unadjusted estimates. Compared to these reviews, our study included substantially more studies and patients. Furthermore, we pooled a significant number of adjusted estimates. Our study has some limitations. First, given that only observational studies were evaluated, there is still a risk of residual confounding that could alter our results. Second, heterogeneity was high in all estimates. Possible reasons for heterogeneity include sample size, types and timing of statins, heterogeneous population, among others. FinallyThird, there is a risk of misclassification about the timing of statins use (chronic versus in-hospital) due to a lack of detailed information. Finally, some studies included outpatients and others included only ICU patients. This difference in disease severity could be a potential source of selection bias, affecting the pooled effect estimates. Our review shows that statins significantly reduce mortality in COVID-19 patients based on adjusted estimates of cohort studies. Subgroup analysis revealed that only patients who were chronically treated with statins had a significant benefit. However, large randomized controlled trials are still needed to confirm these findings. Informed consent: Not applicable. Disclosure: The authors declares that there is no conflict of interest. Data availability: Data are available from the corresponding author on reasonable request. Carlos Diaz-Arocutipa: participated in database search, study review, data analysis and manuscript preparation. Ángel Alvarado-Yarasca: participated in database search, study review, and manuscript preparation. María M. Saravia-Bartra: participated in database search, study review, and manuscript preparation. Pedro Cazorla: participated in database search, study review, and manuscript preparation. Iván Belzusarri: participated in database search, study review, and manuscript preparation. Adrian V. Hernandez: participated in study review and manuscript preparation. The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. 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