Article ID: CJ-21-0087
Background: Cardiovascular diseases and/or risk factors (CVDRF) have been reported as risk factors for severe coronavirus disease 2019 (COVID-19).
Methods and Results: In total, we selected 693 patients with CVDRF from the CLAVIS-COVID database of 1,518 cases in Japan. The mean age was 68 years (35% females). Statin use was reported by 31% patients at admission. Statin users exhibited lower incidence of extracorporeal membrane oxygenation (ECMO) insertion (1.4% vs. 4.6%, odds ratio [OR]: 0.295, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, P=0.004) despite having more comorbidities such as diabetes mellitus.
Conclusions: This study suggests the potential benefits of statins use against COVID-19.
The current pandemic of coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Patients with chronic cardiovascular disease and cardiovascular risk factors are more likely to be critical if infected with COVID-19. There is ample evidence of the use of statins for secondary prevention of atherosclerotic disease and many guidelines recommend their use. Despite the evidence of the beneficial effects of statins in the prevention of atherosclerosis, complications such as rhabdomyolysis, renal injury, and hepatic injury are of concern, especially in the elderly population. Some authors believe that statins should be discontinued after the diagnosis of COVID-19 in these high-risk patients.
Patients affected by COVID-19 who experience serious and fatal outcomes are characterized as having pneumonia-associated acute respiratory distress syndrome (ARDS) and sepsis-associated multi-organ failure. The underlying mechanisms are linked to endothelial dysfunction.1 Statins not only lower cholesterol but also increase the number of endothelial progenitor cells.2 Moreover, a recent in silico docking study suggested the possibility of direct binding and inhibition of the main protease of SARS-CoV-2 by statins. It also suggested that the binding energy of some statins might be greater than that of protease or polymerase inhibitors.3 Recent clinical data reported that statins are beneficial in reducing mortality of COVID-19.4–12
In the present study, we retrospectively investigated the association between statin use prior to the diagnosis of COVID-19 and the severity of COVID-19 in a high-risk Japanese study population with cardiovascular diseases and/or risk factors (CVDRF).
The clinical outcomes of COVID-19 infection in hospitalized patients with CVDRF (CLAVIS-COVID) was a Japanese nationwide multicenter retrospective study sponsored by the Japanese Circulation Society. This study aimed to investigate the characteristics and outcomes of patients hospitalized with COVID-19 between 1 January 2020 and 31 May 2020. Presence of COVID-19 was defined as a positive polymerase chain reaction test on nasal or pharyngeal swab specimens in all patients. All patients enrolled in this study were discharged by 8 November 2020, the deadline of data transfer.
The CLAVIS-COVID registry enrolled 1,518 patients with COVID-19. We selected 693 patients with underlying CVDRF, including 213 with cardiovascular disease and 480 with risk factors. In the present study, we analyzed 693 patients with COVID-19 and CVDRF and divided them into 2 groups based on the use of statins prior to admission. Associations among prior statin use, patient characteristics, and in-hospital outcomes were evaluated. Underlying cardiovascular diseases included heart failure, coronary artery disease, myocardial infarction, peripheral artery disease, valvular heart disease, cardiac arrhythmia, pericarditis, myocarditis, congenital heart disease, pulmonary hypertension, deep vein thrombosis, pulmonary embolism, aortic dissection, aortic aneurysm, cerebral infarction/transient ischemic attack, the use of cardiac devices (pacemaker, implantable cardioverter defibrillator, cardiac resynchronization therapy, and left ventricular assist device), heart transplantation, and cardiac arrest. Cardiovascular risk factors included hypertension, diabetes mellitus, and dyslipidemia.
The investigation followed the principles outlined in the Declaration of Helsinki. The study protocol, including the opt-out consent, was approved by the ethics committee of Toho University Omori Medical Center (no. M20253) and the local ethics committees of all participating institutions. Furthermore, in accordance with the International Committee of Medical Journal Editors, this clinical study was registered with the University Hospital Medical Information Network Clinical Trial Registry before the first patient was enrolled (UMIN-ID: UMIN000040598).
Statistical AnalysisContinuous variables with normal distribution are expressed as mean±standard deviation and analyzed using the Student’s t-test. Categorical variables are expressed as percentages and analyzed using the chi-squared test. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
A total of 693 patients with COVID-19 having CVDRF were analyzed. The average age was 68 years and the proportion of females was 35% (Table 1). Statin users accounted for 31% (n=214) of the patients. All baseline characteristics except diabetes mellitus, coronary artery disease, old myocardial infarction, and malignancy were similar between the groups. Baseline blood urea nitrogen was lower and oxygen saturation was higher in statin users, but the 4C mortality score13 was similar between the groups.
| Total | Statin (+) | Statin (−) | P value | |
|---|---|---|---|---|
| No. of patients | 693 | 214 | 479 | |
| Age (years) | 68.3±14.9 | 67.8±12.9 | 68.5±15.6 | 0.55 |
| Female gender (%) | 35 | 35 | 35 | 0.94 |
| Nationality, Japanese (%) | 96 | 95 | 97 | 0.26 |
| Height (cm) | 162.9±10.6 | 162.6±9.8 | 163.1±10.9 | 0.53 |
| Weight (kg) | 64.8±17.6 | 64.8±16.5 | 64.8±18.2 | 0.99 |
| Body mass index | 24.3±5.1 | 24.4±5.0 | 24.2±5.1 | 0.66 |
| Systolic blood pressure (mmHg) | 133.0±21.8 | 132.8±21.7 | 133.2±21.8 | 0.82 |
| Diastolic blood pressure (mmHg) | 78.5±15.4 | 77.3±15.5 | 79.0±15.3 | 0.19 |
| Smoking (no/current/former) (%) | 59/13/28 | 56/13/31 | 60/13/27 | 0.58 |
| Hypertension (%) | 73 | 69 | 75 | 0.12 |
| Diabetes mellitus (%) | 38 | 49 | 34 | 0.0001 |
| Heart rate (beats/min) | 86.4±17.8 | 86.3±16.9 | 86.4±18.2 | 0.93 |
| Respiratory rate (breaths/min) | 20.9±6.1 | 20.3±5.3 | 21.1±6.4 | 0.16 |
| Heart failure symptoms on admission (%) | 7.4 | 8.4 | 6.9 | 0.48 |
| Peripheral edema (%) | 2.5 | 2.8 | 2.3 | 0.69 |
| Pulmonary congestion (%) | 5.6 | 7.0 | 5.0 | 0.29 |
| Chronic heart failure (%) | 8.7 | 9.8 | 8.1 | 0.47 |
| Coronary artery disease (%) | 10 | 19 | 6 | <0.0001 |
| Old myocardial infarction (%) | 4.3 | 10 | 1.7 | <0.0001 |
| Valvular heart disease (%) | 2.7 | 4.2 | 2.1 | 0.11 |
| Obesity (%) | 6.8 | 8.9 | 5.9 | 0.14 |
| Bronchial asthma (%) | 4.9 | 7.0 | 4.0 | 0.09 |
| COPD (%) | 5.1 | 6.1 | 4.6 | 0.41 |
| Chronic kidney disease (%) | 6.9 | 6.6 | 7.1 | 0.79 |
| Liver cirrhosis (%) | 0.1 | 0 | 0.1 | 0.50 |
| Chronic neurologic condition (%) | 0.9 | 0.5 | 1.0 | 0.45 |
| Autoimmune disease (%) | 2.2 | 2.8 | 1.9 | 0.43 |
| Malignancy (%) | 2.2 | 4.2 | 1.3 | 0.01 |
| History of malignancy (%) | 7.9 | 6.5 | 8.6 | 0.36 |
| Baseline BUN (mg/dL) | 21.4±15.3 | 19.5±14.1 | 22.2±15.8 | 0.02 |
| Baseline CRP | 7.8±7.6 | 7.2±6.9 | 8.1±7.9 | 0.14 |
| Oxygen saturation (%) | 95.0±4.7 | 95.6±3.4 | 94.7±5.2 | 0.01 |
| 4C mortality score | 8.7±3.8 | 8.6±3.4 | 8.8±3.9 | 0.49 |
Data are presented as mean±standard deviation or percentage. 4C, Coronavirus Clinical Characterisation Consortium; BUN, blood urea nitrogen; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein.
Baseline medications are listed in Table 2. The use of angiotensin receptor antagonists, aspirin, and non-steroidal anti-inflammatory drugs was higher in the statin group.
| Total | Statin (+) | Statin (−) | P value | |
|---|---|---|---|---|
| No. of patients | 693 | 214 | 479 | |
| Statins (%) | 31 | 100 | 0 | |
| ACE inhibitors (%) | 5 | 7 | 4 | 0.11 |
| ARBs (%) | 33 | 44 | 29 | <0.0001 |
| β-receptor blockers (%) | 16 | 24 | 13 | 0.0002 |
| Calcium channel blockers (%) | 38 | 39 | 38 | 0.76 |
| Loop diuretics (%) | 8 | 6 | 9 | 0.19 |
| MRAs (%) | 4 | 5 | 3 | 0.31 |
| Aspirin (%) | 11 | 21 | 6 | <0.0001 |
| Clopidogrel (%) | 3 | 4 | 3 | 0.23 |
| Warfarin (%) | 2 | 3 | 2 | 0.32 |
| DOACs (%) | 5 | 7 | 5 | 0.24 |
| NSAIDs (%) | 4 | 8 | 3 | 0.001 |
| Steroids (%) | 5 | 7 | 4 | 0.09 |
| Immunosuppressive drugs (%) | 1 | 2 | 1 | 0.13 |
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; DOAC, direct oral anticoagulant; MRA, mineralocorticoid receptor antagonist; NSAIDs, non-steroidal anti-inflammatory drugs.
The clinical outcomes are presented in Table 3. The incidence of extracorporeal membrane oxygenation (ECMO) use (1.4% vs. 4.6%, odds ratio [OR]: 0.295, 95% confidence interval [CI]: 0.087–0.998, P=0.037) and septic shock (1.4% vs. 6.5%, OR: 0.205, 95% CI: 0.062–0.680, P=0.004) was significantly lower in the statin group. The statin use group had a higher rate of angiotensin receptor blocker (ARB), β-blockers, and aspirin use, which could be potential confounding factors. However, multivariate analysis showed that only statins had the effect to reduce ECMO induction and septic shock (Supplementary Tables 1–3). Other endpoints such as admission to the intensive care unit (ICU), ARDS, mechanical ventilation, multi-organ failure, pulmonary embolism, cardiopulmonary arrest, or in-hospital death did not exhibit significant differences between the groups.
| Total (%) | Statin (+) (%) | Statin (−) (%) | OR | 95% CI | P value | |
|---|---|---|---|---|---|---|
| No. of patients | 693 | 214 | 479 | |||
| ICU admission (%) | 29 | 27 | 30 | 0.862 | (0.601–1.236) | 0.42 |
| ARDS (%) | 14 | 14 | 13 | 1.060 | (0.669–1.681) | 0.80 |
| Mechanical ventilation (%) | 22 | 21 | 22 | 0.926 | (0.625–1.371) | 0.70 |
| ECMO (%) | 3.6 | 1.4 | 4.6 | 0.295 | (0.087–0.998) | 0.037 |
| Septic shock (%) | 4.9 | 1.4 | 6.5 | 0.205 | (0.062–0.680) | 0.0043 |
| Multi-organ failure (%) | 6.1 | 4.7 | 6.7 | 0.685 | (0.330–1.420) | 0.24 |
| Pulmonary embolism | 1.7 | 0.9 | 2.1 | 0.442 | (0.096–2.037) | 0.28 |
| Cardiopulmonary arrest | 13.4 | 11.7 | 14.2 | 0.799 | (0.490–1.305) | 0.37 |
| In-hospital death | 16 | 14 | 16 | 0.838 | (0.531–1.322) | 0.44 |
ARDS, acute respiratory distress syndrome; CI, confidence interval; ECMO, extracorporeal membrane oxygenation; ICU, intensive care unit; OR, odds ratio.
The present study showed that statin use prior to hospital admission reduced the incidence of ECMO induction and septic shock in COVID-19 patients with CVDRF. We did not observe statistically significant differences in outcomes such as ICU admission, ARDS, mechanical ventilation, or in-hospital mortality. However, these outcomes showed a downward trend, which was believed to be due to the lack of statistical power. Importantly, there was no trend of worsening of COVID-19 severity due to the use of statins in high-risk patients.
Comorbidities such as diabetes mellitus, malignancy or coronary artery disease have been reported to caused poor prognosis in patients with COVID-19. The 4C mortality score has been reported as a stratification score to predict mortality of COVID-19 based on the scores with age, sex, number of comorbidities, respiratory rate, peripheral oxygen saturation on room air, Glasgow coma scale, blood urea nitrogen and C-reactive protein. In this study, no difference was observed in the 4C mortality score between statin users and non-users.
There have been concerns that statins should be used with caution in patients with COVID-19, as they might cause myalgia, myopathies, or rhabdomyolysis; thereby exacerbating the disease.14 It is difficult to differentiate the appearance of myalgia, rhabdomyolysis, increased creatine phosphokinase, and acute kidney injury in COVID-19 patients from the side-effects of statins. Furthermore, other studies have reported that patients with COVID-19 did not benefit from the administration of statins.4,15
In contrast, the effects of statins have been proposed based on the intracellular pathways.7,16 In silico molecular docking studies have shown that pitavastatin, rosuvastatin, lovastatin, and fluvastatin could efficiently inhibit the main protease of SARS-CoV-2.3 An increase in the endothelial progenitor cells by statins2 could improve endothelial dysfunction, which is believed to be the underlying mechanism of worsening COVID-19.
Clinical data have shown the beneficial effects of statins. Statin use was associated with the absence of symptoms.11,17 Statin use within 30 days prior to admission for COVID-19 was associated with a lower risk of developing severe COVID-19 and a faster recovery among patients without severe disease.10,18 A slower progression to death was associated with atorvastatin use in patients with COVID-19 admitted to the ICU.8 The use of statins was associated with lower mortality, lower incidence of ARDS development, and lower incidence of ICU admission in 2,147 COVID-19 patients.5 A meta-analysis reported a reduction in fatal or severe disease by 30% and discredited the suggestion of harmful effects of statins in COVID-19 patients.6 Use of statins (OR: 0.60, 95% CI: 0.56–0.65, P<0.001) was associated with decreased odds of death in an analysis of 64,781 patients with COVID-19.9 Based on a mixed-effect Cox model after propensity score matching in 13,981 patients with COVID-19, the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively (adjusted hazard ratio: 0.58).12
It is important to note that beneficial effects of statins regarding protection against severe COVID-19 were shown in Japanese patients. The guidelines for lipid management are different from those in other countries, and statin doses are clearly lower in Japan. It was questionable whether the overseas data on statins for COVID-19 would be directly applicable. However, our findings also support benefits of statins against severe COVID-19 in a Japanese population.
The present study has several limitations. It was a retrospective analysis including high-risk patients with chronic cardiovascular disease or cardiovascular risk factors. Thus, biases in the study cannot be ignored. The database did not include the names or the types of statins; hence, it was impossible to analyze which types of statins were more effective. The present study analyzed statin use on admission. It is unknown whether the use of statins was continued or discontinued after hospital admission.
The authors would like to acknowledge all the investigators participating in the CLAVIS-COVID and the Japanese Circulation Society.
Y. Ikari received lecture fees from Asteras, Amgen Biopharma, AstraZeneca, Sanofi, Daiichi Sankyo, Bayer, and Bristol Myers Squib and research grants from Boston Scientific, Daiichi Sankyo, and Japan Mediphysics, and royalty from Terumo.
T. Yonetsu belongs to endowed departments of Abbott Vascular Japan, Boston Scientific Japan, Japan Lifeline, WIN International, and Takeyama KK.
S. Kohsaka received unrestricted research grants from the Department of Cardiology, Keio University School of Medicine provided by Daiichi Sankyo Co., Ltd. And Bristol-Meyers Squibb, and lecture fees from AstraZeneka and Bristol-Meyers Squibb.
I. Komuro received unrestricted research grants from Daiichi Sankyo Company, Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Ltd., Mitsubishi Tanabe Pharma Corporation, Teijin Pharma Ltd., Idorsia Pharmaceuticals Ltd., Otsuka Pharmaceutical Co., Ltd., Bayer Yakuhin, Ltd., Ono Pharmaceutical Co., Ltd., and Toa Eiyo Ltd. and lecture fees from AstraZeneka, Daiichi Sankyo Company, Ltd., Takeda Pharmaceutical Company Ltd., Bayer Yakuhin, Ltd., Pfizer Japan Inc., and Ono Pharmaceutical Co., Ltd.
Y. Matsue is affiliated with a department endowed by Philips Respironics, ResMed, Teijin Home Healthcare, and Fukuda Denshi, received an honorarium from Otsuka Pharmaceutical Co. and Novartis Japan, received a consultant fee from Otsuka Pharmaceutical Co., and joint research funds from Otsuka Pharmaceutical Co. and Pfizer Inc.
K. Hirata, I. Komuro, Y. Ikari, and K. Node are members of Circulation Journal’s Editorial Team.
The present study was approved by the ethics committee of Toho University Omori Medical Center (Reference number: M20253).
Due to the nature of this research, participants of this study did not agree for their data to be shared publicly or upon request; hence, the data are not available.
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-21-0087
