Association of Statins for Primary Prevention of Cardiovascular Diseases With Hospitalization for COVID‐19: A Nationwide Matched Population‐Based Cohort Study

Abstract

Background There is little evidence on the relationship between statin use and the risk of hospitalization attributable to COVID‐19. Methods and Results The French National Healthcare Data System database was used to conduct a matched‐cohort study. For each adult aged ≥40 years receiving statins for the primary prevention of cardiovascular diseases, one nonuser was randomly selected and matched for year of birth, sex, residence area, and comorbidities. The association between statin use and hospitalization for COVID‐19 was examined using conditional Cox proportional hazards models, adjusted for baseline characteristics, comorbidities, and long‐term medications. Its association with in‐hospital death from COVID‐19 was also explored. All participants were followed up from February 15, 2020, to June 15, 2020. The matching procedure generated 2 058 249 adults in the statin group and 2 058 249 in the control group, composed of 46.6% of men with a mean age of 68.7 years. Statin users had a 16% lower risk of hospitalization for COVID‐19 than nonusers (adjusted hazard ratio [HR], 0.84; 95% CI, 0.81–0.88). All types of statins were significantly associated with a lower risk of hospitalization, with the adjusted HR ranging from 0.75 for fluvastatin to 0.89 for atorvastatin. Low‐ and moderate‐intensity statins also showed a lower risk compared with nonusers (HR, 0.78 [95% CI, 0.71–0.86] and HR, 0.84 [95% CI, 0.80–0.89], respectively), whereas high‐intensity statins did not (HR, 1.01; 95% CI, 0.86–1.18). We found similar results with in‐hospital death from COVID‐19. Conclusions Our findings support that the use of statins for primary prevention is associated with lower risks of hospitalization for COVID‐19 and of in‐hospital death from COVID‐19.

In Vitro Evidence of Statins’ Protective Role against COVID-19 Hallmarks

“…In conclusion, the in vitro data emerging from our study provide useful additional information to dissect the mechanism underlying the potential protective effects of statin use in COVID-19. The results are coherent with the clinical reports published in the last two years that highlighted how statins, usually prescribed in patients with pre-existing cardiovascular disease and then frail patients with high risk of severe disease, protect patients from worse prognoses, ICU admissions, and death [ 41 , 42 , 43 , 44 ]. The understandings of statins’ molecular mechanisms in COVID-19 could have a relevant translational impact on disease management.…”

“…Despite this, the overall conclusion emerging so far from several meta-analyses is that statins used in COVID-19 patients is associated with improved clinical outcomes and reduced Intensive Care Unit (ICU) admission, mechanical intubation, ARDS, and in-hospital death [ 20 , 40 , 41 , 42 ]. The studies included in these meta-analyses and emerging observational studies [ 43 , 44 ] strongly suggest that statin therapy exerts a protective effect against complications from COVID-19, preventing the worst prognosis. These effects are probably related to the immunomodulatory and anti-inflammatory properties of statins, but it has been also proposed that there is a possible direct inhibitory effect on the key steps of the virus life cycle, including internalization, replication, and virion release [ 13 , 39 ].…”

“…In agreement with our findings, Arefieva and colleagues demonstrated that increasing concentrations of ATS induce the activation of NfKB, and this increase was inversely correlated with the reduction in FPP (farnesyl pyrophosphate) and GPP (geranyl pyrophosphate) mediated by the mevalonate pathway inhibitor, suggesting that isoprenoids may exert an inhibitory effect on NfKB activity [ 46 ]. Coherent with these observations, in a recent population-based cohort study including two million adult statin users, it has been highlighted that low-and moderate-intensity statins showed a lower risk of hospitalization and in-hospital mortality from COVID-19, whereas high-intensity statins did not [ 44 ].…”

Statin Therapy to Improve Outcome of COVID-19 Patients: Useful or Not Useful?

“…Pre-hospitalization statin use was shown not detrimental and not associated with an increased risk of all-cause death, ICU admission, need for invasive mechanical ventilation, and onset of myocardial infarction, transient cerebral ischemic attack, or stroke (adjusted OR, 0.82; 95% CI, 0.60–1.11; p = 0.82) [ 21 ]). Furthermore, accumulating retrospective findings suggested interesting benefits of pre-COVID-19 use or post-COVID-19 diagnosis administration of statins on the outcome, including large cohort studies from China [ 22 ], the US [ 23 ], the UK [ 24 ], Canada [ 25 ], and France [ 26 ], confirming the results of the South Korean registry study [ 1 ]. Reduction in the risk of death (up to 28% as evaluated in 2.9 million patients [ 24 ]) was found.…”

“…Additionally, in some studies, benefits on the different outcomes were dissociated, such as in the nationwide Swedish cohort study including 572,695 individuals, which showed a decreased risk of death (HR, 0.86; 95% CI, 0.79–0.95; p < 0.001) but not of ICU admission [ 33 ]. Use of low- and moderate-intensity statins was associated with lowered risk compared with non-statin users (HR, 0.78; 95% CI, 0.71–0.86 and HR, 0.84; 95% CI, 0.80–0.89, respectively) in contrast to high-intensity statins (HR, 1.01; 95% CI, 0.86–1.18) [ 26 ]. All statin molecules reduced the risk of hospitalization, whereas pravastatin, rosuvastatin, and simvastatin, but not atorvastatin and fluvastatin, reduced the risk of death.…”