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Preadmission Statin Treatment and Outcome in Patients Hospitalized With COVID-19

      Preadmission statin therapy is associated with improved outcome in patients hospitalized with COVID-19. Whether inhibition of inflammation and myocardial injury are in part responsible for this observation has not been studied. The aim of the present study was to relate preadmission statin usage to markers of inflammation, myocardial injury, and clinical outcome among patients with established atherosclerosis who were admitted with COVID-19. Adult patients with a diagnosis of coronary artery disease, peripheral artery disease, and/or atherosclerotic cerebrovascular disease who were hospitalized with COVID-19 between March 1, 2020 and December 31, 2020 were included. Statin use was related to the primary composite clinical outcome, death, intensive care unit admission, or thrombotic complications in sequential multivariable logistic regression models. Of 3,584 adult patients who were hospitalized with COVID-19, 1,360 patients met study inclusion criteria (mean age 73.8 years, 45% women, 68% White). Baseline troponin and C-reactive protein were lower in patients on statins before admission. In an unadjusted model, preadmission statin usage was associated with a significant reduction in the primary composite outcome (42.2% vs 53.7%, odds ratio 0.63 [95% confidence interval 0.50 to 0.80], p <0.001). This association remained significant after age, gender, ethnicity, other patient clinical characteristics, and cardiovascular medications were added to the model but became null when troponin and C-reactive protein were also included (odds ratio 0.83 [95% confidence interval 0.63 to 1.09] p = 0.18). In conclusion, among patients with established cardiovascular disease who were hospitalized with COVID-19, preadmission statin therapy was associated with improved in-hospital outcome, an association that was negated once inflammation and myocardial injury were considered.
      COVID-19, caused by SARS-CoV-2, has been associated with significant morbidity and mortality, mainly mediated through an intense inflammatory host response with resultant respiratory and multiorgan failure.
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      Observational studies of patients hospitalized with COVID-19 have found that preadmission statin use is associated with less inflammation, less severe disease manifestations, and improved outcomes;
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      whether statins reduce myocardial injury in this setting is unknown. The present study examined whether markers of inflammation and myocardial injury modify the relation between preadmission statin use and clinical outcome in patients hospitalized with COVID-19.

      Methods

      Baseline demographic, clinical, medication, laboratory, and outcome data were extracted electronically from the EPIC Systems electronic health record. All consecutive patients aged ≥18 years, with a diagnosis of coronary artery disease, peripheral artery disease, and/or atherosclerotic cerebrovascular disease who were hospitalized with COVID-19 at Rhode Island, the Miriam or Newport Hospitals, between March 1, 2020 and December 31, 2020 were included. Co-morbidities, COVID-19 status, and in-hospital outcomes were ascertained using International Classification of Diseases, Tenth Revision codes (Supplementary Material). Approval and waiver of informed consent were granted by the Miriam Hospital Institutional Review Board.
      Statin use was ascertained from home and inpatient medication lists. Statins were categorized by agent, dose, intensity,
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      • Lichtenstein AH
      • Bairey Merz CN
      • Blum CB
      • Eckel RH
      • Goldberg AC
      • Gordon D
      • Levy D
      • Lloyd-Jones DM
      • McBride P
      • Schwartz JS
      • Shero ST
      • Smith Jr, SC
      • Watson K
      • Wilson PW
      American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      and solubility . If 2 statins were listed, the higher intensity statin took precedence and was included in the descriptive table; patients in whom both a lipophilic and hydrophilic statin were listed were excluded from the descriptive statistics on statin solubility.
      Table 1Baseline characteristics
      VariableTotal (n = 1360)Statin therapyP-value
      Yes

      (n = 978)
      No

      (n = 382)
      Age (years), mean ± SD73.8 ± 13.774.8 ± 11.771.3 ± 17.4< 0.001
      Female614 (45.1%)432 (44.2%)182 (47.6%)0.25
      Hispanic or Latino

      Not Hispanic or Latino

      Unknown
      233 (17.1%)

      1116 (82.1%)

      1 (0.1%)
      170 (17.4%)

      802 (82.0%)

      0 (0.0%)
      63 (16.5%)

      314 (82.2%)

      1 (0.3%)
      0.34
      White

      Asian

      Black

      Native Hawaiian/other Pacific Islander

      Other

      Unknown
      919 (67.6%)

      19 (1.4%)

      173 (12.7%)

      3 (0.2%)

      236 (17.4%)

      10 (0.7%)
      665 (68.0%)

      15 (1.5%)

      119 (12.2%)

      3 (0.3%)

      170 (17.4%)

      6 (0.6%)
      254 (66.5%)

      4 (1.0%)

      54 (14.1%)

      0 (0.0%)

      66 (17.3%)

      4 (1.0%)
      0.66
      Hypertension1193 (87.7%)901 (92.1%)292 (76.4%)< 0.001
      Obesity375 (27.6%)289 (29.6%)86 (22.5%)0.009
      Smoker< 0.001
       Current109 (8.0%)73 (7.5%)36 (9.4%)
       Former562 (41.3%)454 (46.4%)108 (28.3%)
       Never528 (38.8%)365 (37.3%)163 (42.7%)
       Unknown161 (11.8%)86 (8.8%)75 (19.6%)
      Diabetes mellitus662 (48.7%)533 (54.5%)129 (33.8%)< 0.001
      Previous coronary artery disease1088 (80.0%)800 (81.8%)288 (75.4%)0.007
      Previous cerebrovascular disease253 (20.8%)177 (20.0%)76 (22.7%)0.31
      Previous peripheral artery disease26 (2.1%)18 (2.0%)8 (2.4%)0.70
      Previous percutaneous coronary intervention222 (16.3%)197 (20.1%)25 (6.5%)< 0.001
      Previous coronary artery bypass grafting96 (7.1%)85 (8.7%)11 (2.9%)< 0.001
      Previous myocardial infarction312 (22.9%)268 (27.4%)44 (11.5%)< 0.001
      Previous transient ischemic attack/stroke312 (22.9%)242 (24.7%)70 (18.3%)0.011
      Heart failure499 (36.7%)376 (38.4%)123 (32.2%)0.031
      Valvular heart disease122 (9.0%)94 (9.6%)28 (7.3%)0.18
      Cardiac dysrhythmias626 (46.0%)458 (46.8%)168 (44.0%)0.34
      Chronic kidney disease355 (26.1%)275 (28.1%)80 (20.9%)0.006
      Chronic obstructive pulmonary disorder175 (12.9%)128 (13.1%)47 (12.3%)0.70
      Obstructive sleep apnea155 (11.4%)124 (12.7%)31 (8.1%)0.017
      Liver disease128 (9.4%)79 (8.1%)43 (11.3%)0.06
      Dementia402 (29.6%)275 (28.1%)127 (33.2%)0.06
      Cancer151 (11.1%)108 (11.0%)43 (11.3%)0.91
      Inflammatory rheumatic disease200 (14.7%)145 (14.8%)55 (14.4%)0.84
      Cardiac troponin, ng/ml, median (IQR)0.065 (0.02, 0.25)0.055 (0.02, 0.23)0.090 (0.02, 0.37)0.001
      C-reactive protein, mg/L, median (IQR)68.6 (27.0, 139.5)64.9 (27.0, 134.3)76.1 (27.0, 156.0)0.008
      Preadmission medications, n (%)
       Nonstatin anticholesterol agent104 (7.6%)78 (8.0%)26 (6.8%)0.46
       Renin-angiotensin-aldosterone system inhibitors684 (50.3%)537 (54.9%)147 (38.5%)< 0.001
       Beta blocker687 (50.5%)546 (55.8%)141 (36.9%)< 0.001
       Antiplatelet agent812 (59.7%)682 (69.7%)130 (34.0%)< 0.001
      The primary composite outcome included in-hospital death, intensive care unit (ICU) admission, or composite thrombotic complications. Secondary clinical outcomes included individual components of the primary composite outcome, composite death or ICU admission, individual thrombotic complications, and length of stay. Baseline levels of inflammation and myocardial injury were gauged by C-reactive protein (CRP) and cardiac troponin I levels on admission, respectively (Supplementary Material).
      Table 2Statin usage
      Statin intensity
      Classification of statin intensity by agent and dose is presented in Supplemental Material.
       Low91 (6.7%)
       Intermediate409 (30.1%)
       High506 (37.2%)
      Statin solubility
      Classification of statin lipophilicity by agent is presented in Supplemental Material.
       Lipophilic824 (84.3%)
       Hydrophilic172 (17.6%)
      Statin agent
       Atorvastatin675 (69.0 %)
       Simvastatin108 (11.0 %)
       Pravastatin87 (8.9 %)
       Rosuvastatin68 (7.0 %)
       Lovastatin39 (4 %)
       Pitavastatin1 (0.1 %)
      low asterisk Classification of statin intensity by agent and dose is presented in Supplemental Material.
      Classification of statin lipophilicity by agent is presented in Supplemental Material.
      Continuous variables are presented as means ± SD or medians with interquartile range (IQR) and were compared using the Student t test or Wilcoxon rank-sum test, as appropriate. Categoric variables are presented as frequencies and percentages and were compared using the chi-square test.
      Preadmission statin use was related to the primary composite clinical outcome in unadjusted and adjusted analyses. Plausible demographic, clinical characteristics, and cardiovascular medications that were related to the primary outcome (p ≤0.15) were eligible for inclusion in multivariable models and are detailed in Supplementary Material. Analyses were performed using sequential multivariable logistic regression models, as follows: (1) unadjusted; (2) model 1 + age, gender, and ethnicity; (3) model 2 + other patient characteristics; (4) model 3 + other cardiovascular medications, and (5) model 4 + CRP and troponin. Patients with missing information regarding preadmission medication use were excluded (n = 17). Missing troponin (10%) and CRP (19%) values were imputed using simple imputation techniques (IVEware, Ann Arbor, Michigan). All analyses were performed with SAS 9.4 (SAS Institute, Cary, North Carolina).

      Results

      A study flow diagram appears in Figure 1. Of 3,584 adult patients hospitalized with COVID-19, 1,377 had established atherosclerotic cardiovascular disease. The final study cohort comprised 1,360 patients; of these, 1,090 patients (80%) had coronary artery disease, 545 patients (40%) had cerebrovascular disease, and 31 patients (2%) had peripheral artery disease. Patient characteristics according to preadmission statin use appear in Table 1. Overall mean age was 73.8 ± 13.7 years, 45% were women, and 67.6% were White. Cardiovascular risk factors and risk markers were common. Half of the patients were taking β blockers and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, and nearly 2/3 were taking antiplatelet agents before admission.
      Figure 1
      Figure 1Study flowchart. CAD = coronary artery disease; CVD = cerebrovascular disease; PAD = peripheral artery disease.
      Table 3Secondary outcomes
      OutcomeTotal (n = 1360)Statin therapyP-value
      Yes (n = 978)No (n = 382)
      Death265 (19.5%)183 (18.7%)82 (21.5%)0.25
      Death or admission to intensive care unit411 (30.2%)281 (28.7%)130 (34.0%)0.06
      Composite thrombotic complications
      Composite thrombotic complications: myocardial infarction, ischemic cerebrovascular accident, venous thromboembolism, acute limb ischemia, and acute mesenteric ischemia. ACS = acute coronary syndrome; MI = myocardial infarction; TIA = transient ischemic attack, DVT = deep venous thrombosis, PE = pulmonary embolism.
      363 (26.7%)235 (24.0%)128 (33.5%)<0.001
       Stroke/TIA137 (10.1%)83 (8.5%)54 (14.1%)0.001
       ACS156 (11.5%)101 (10.3%)55 (14.4%)0.034
       Acute DVT/PE98 (7.2%)67 (6.9%)31 (8.1%)0.42
       Acute mesenteric ischemia2 (0.1%)2 (0.2%)0 (0.0%)0.38
       Acute limb ischemia19 (1.4%)12 (1.2%)7 (1.8%)0.39
      Length of stay, median (IQR)6.0 (4.0, 13.0)6.0 (4.0, 12.0)7.0 (4.0, 14.0)0.002
      low asterisk Composite thrombotic complications: myocardial infarction, ischemic cerebrovascular accident, venous thromboembolism, acute limb ischemia, and acute mesenteric ischemia.ACS = acute coronary syndrome; MI = myocardial infarction; TIA = transient ischemic attack, DVT = deep venous thrombosis, PE = pulmonary embolism.
      In the overall cohort, 978 patients (72%) were taking statins before admission (2 statins were listed for 28 of these). Statin use was significantly more common among those with hypertension, diabetes, obesity, previous myocardial infarction (MI) or percutaneous coronary intervention, and among nonsmokers. Atorvastatin was the most commonly used (n = 675, 69%). Statin use details appear in Table 2 and in Supplementary Material. Of those on preadmission statins, these agents were discontinued during hospitalization in 153 patients (16%); in contrast, of those not on preadmission statins, these agents were initiated in 57 (15.5%) during hospitalization. Patients who were taking statins before admission had lower median (IQR) troponin (0.055 [0.018 to 0.23] vs 0.090 [0.02 to 0.37] ng/ml, p = 0.001) and CRP (64.9 [27.0 to 134.3] vs 76.1 [27.0 to 156.0] mg/L, p = 0.008) at baseline compared with those not on statins. Patients who were taking high/intermediate-intensity statins before admission had lower median (IQR) troponin (0.051 [0.017 to 0.22] vs 0.086 [0.026 to 0.27] ng/ml, p = 0.035) but similar median (IQR) CRP (72.8 [30.7 to 136.7] vs 102.2 [36.0 to 169.9] mg/L, p = 0.14) at baseline compared with those not on low-intensity statins.
      The primary composite outcome occurred in 618 patients (45%). In an unadjusted analysis, preadmission statin usage was associated with a significantly lower incidence of the primary composite outcome (413 [42.2%] vs 205 [53.7%], odds ratio [OR] 0.63 [95% confidence interval (CI) 0.50 to 0.80], p <0.001). This association remained significant after sequential adjustment (model 2 OR 0.65 [95% CI 0.51 to 0.83], p <0.001; model 3 OR 0.75 [95% CI 0.58 to 0.99], p = 0.039; and model 4 OR 0.75 [95% CI 0.57 to 0.99], p = 0.04). However, in model 4, when troponin and CRP were also included, the association between preadmission statin ue and the primary outcome was further attenuated and no longer significant (OR 0.83 [95% CI 0.63 to 1.09] p = 0.18) (Figure 2). Unadjusted secondary outcomes appear in Table 3. Compared with those who were not taking statins before admission, preadmission statin use was associated with significant reduction in thrombotic complications and lengths of stay. In-hospital all-cause mortality and composite death or ICU admission occurred less frequently in those on preadmission statins, but these differences were not statistically significant.
      Figure 2
      Figure 2Forrest plot summarizing unadjusted and sequential multivariable logistic regression models. Demographic and clinical characteristics considered for inclusion in multivariable models were demographics (age, gender, ethnicity), clinical characteristics (smoking, obesity, hypertension, previous myocardial infarction, previous cerebrovascular disease, previous cardiac arrhythmias, pulmonary circulatory disorders, liver disease), cardiovascular medications (β blockers, renin-angiotensin-aldosterone system inhibitors, antiplatelets).

      Discussion

      In a retrospective analysis of patients with established atherosclerotic cardiovascular disease who were hospitalized with COVID-19, preadmission statin usage was associated with a lower incidence of composite in-hospital death, ICU admission, or thrombotic complications. This association persisted despite sequentially adjusting for demographics, clinical characteristics, and other cardiovascular medications but became null after including baseline CRP and troponin levels, suggesting that the observed association between preadmission statin use and clinical outcome may have been mediated, in part, by reductions in inflammation and/or myocardial injury.
      Elevated troponin, even at low levels, portends a poorer outcome in patients with COVID-19. Even minor myocardial injury is associated with significant increase in mortality,
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      • Dabbagh A
      • Beigmohammadi MT
      • Payandemehr P
      • Yadollahzadeh M
      • Riahi T
      • Khalili H
      • Jamalkhani S
      • Rezaeifar P
      • Abedini A
      • Lookzadeh S
      • Shahmirzaei S
      • Tahamtan O
      • Matin S
      • Amin A
      • Parhizgar SE
      • Jimenez D
      • Gupta A
      • Madhavan MV
      • Parikh SA
      • Monreal M
      • Hadavand N
      • Hajighasemi A
      • Maleki M
      • Sadeghian S
      • Mohebbi B
      • Piazza G
      • Kirtane AJ
      • Lip GYH
      • Krumholz HM
      • Goldhaber SZ
      • Sadeghipour P.
      Intermediate versus standard-dose prophylactic anticoagulation and statin therapy versus placebo in critically-ill patients with COVID-19: rationale and design of the INSPIRATION/INSPIRATION-S studies.
      ,

      American College of Cardiology. ACC.21 presentation slides | INSPIRATION-S. Available at:https://www.acc.org/education-and-meetings/image-and-slide-gallery/media-detail?id=9DF17809F35C4CA6B149C64C9D700AC6. Accessed on May 22, 2021.

      However, an interaction between treatment assignment and duration of symptoms was of marginal statistical significance, raising the possibility that treatment initiation closer to symptom onset (i.e., before admission) when inflammation is less pronounced might have conferred benefit. Given that the mean time from symptoms to hospitalization with COVID-19 is approximately 6 days,
      • Quaresima V
      • Scarpazza C
      • Sottini A
      • Fiorini C
      • Signorini S
      • Delmonte OM
      • Signorini L
      • Quiros-Roldan E
      • Imberti L.
      Sex differences in a cohort of COVID-19 Italian patients hospitalized during the first and second pandemic waves.
      and that statin-induced reductions in CRP and troponin are evident in 1 and 7 days,
      • Pasceri V
      • Patti G
      • Nusca A
      • Pristipino C
      • Richichi G
      • Di Sciascio G
      ARMYDA Investigators
      Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) study.
      respectively, initiation of statin therapy among naïve patients with COVID-19 could potentially translate into lower levels of inflammation and myocardial injury and reduce the likelihood of clinical deterioration. Although randomized trials are examining the role of statin therapy in patients with COVID-19, most have included patients only after they are hospitalized.
      • Talasaz AH
      • Sadeghipour P
      • Aghakouchakzadeh M
      • Dreyfus I
      • Kakavand H
      • Ariannejad H
      • Gupta A
      • Madhavan MV
      • Van Tassell BW
      • Jimenez D
      • Monreal M
      • Vaduganathan M
      • Fanikos J
      • Dixon DL
      • Piazza G
      • Parikh SA
      • Bhatt DL
      • Lip GYH
      • Stone GW
      • Krumholz HM
      • Libby P
      • Goldhaber SZ
      • Bikdeli B.
      Investigating lipid-modulating agents for prevention or treatment of COVID-19: JACC state-of-the-art review.
      Only 1 small ongoing trial is evaluating upstream statin therapy in ambulatory patients with COVID-19, but that trial is designed to assess changes in viral load and CRP and is likely underpowered to identify statin-mediated differences in secondary clinical outcomes.

      ClinicalTrials.gov. Combination therapies to reduce carriage of SARS-Cov-2 and improve outcome of COVID-19 in Ivory Coast: a phase randomized IIb trial (INTENSE-COV]. Available at: https://clinicaltrials.gov/ct2/show/NCT04466241. Accessed on November 13, 2021.

      There are noteworthy limitations to our study. First, by restricting our cohort to those with clinically manifest atherosclerotic vascular disease, we attempted to minimize the likelihood of confounding by indication; however, we cannot exclude potential sources of residual confounding, despite multivariable modeling of the primary composite outcome. Second, we used International Classification of Diseases, Tenth Revision codes to define clinical outcomes; resultant, under-, or miscoding may have introduced inaccuracies in our data; although, if that were the case, it would likely have biased our results toward the null. Third, preadmission statin use was confirmed through medication reconciliation by patient report at the time of admission; pharmacy data, which indicated whether prescribed statins were dispensed or refilled, were not available. Fourth, our results may not be generalizable to the primary prevention setting. Finally, only in-hospital clinical outcomes were ascertained; whether preadmission statin use is associated with more favorable long-term outcomes after COVID-19 is unknown.
      In conclusion, among patients with established atherosclerotic cardiovascular disease hospitalized with COVID-19, preadmission statin therapy was associated with improved in-hospital outcome; this association was no longer significant after markers of inflammation and myocardial injury were considered, suggesting that the observed association may be mediated through upstream suppression of these phenomena.

      Disclosures

      The authors have no conflicts of interest to declare.

      Appendix. Supplementary materials

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