Usefulness of Statins as Secondary Prevention Against Recurrent and Terminal Major Adverse Cardiovascular Events

Abstract

Clinical guidelines recommend statins for patients with atherosclerotic cardiovascular disease (ASCVD), but many remain untreated. The goal of this study was to assess the impact of statin use on recurrent major adverse cardiovascular events (MACE). This study used medical records and insurance claims from 4 health care systems in the United States. Eligible adults who survived an ASCVD hospitalization from September 2013 to September 2014 were followed for 1 year. A multivariable extended Cox model examined the outcome of time-to-first MACE, then a multivariable joint marginal model investigated the association between post-index statin use and nonfatal and fatal MACE. There were 8,168 subjects in this study; 3,866 filled a statin prescription ≤90 days before the index ASCVD event (47.33%) and 4,152 filled a statin prescription after the index ASCVD event (50.83%). These post-index statin users were younger, with more co-morbidities. There were 763 events (315/763, 41.3% terminal) experienced by 686 (8.4%) patients. The adjusted overall MACE risk reduction was 18% (HR 0.82, 95% CI 0.70 to 0.95, p = 0.007) and was more substantial in the first 180 days (HR 0.72, 95% CI 0.60 to 0.86, p <0.001). There was a nonsignificant 19% reduction in the number of nonfatal MACE (rate ratio 0.81, 95% CI 0.49 to 1.32, p = 0.394) and a 65% reduction in the risk of all-cause death (HR 0.35, 95% CI 0.22 to 0.56, p <0.001). In conclusion, we found a modest increase in statin use after an ASCVD event, with nearly half of the patients untreated. The primary benefit of statin use was protection against early death. Statin use had the greatest impact in the first 6 months after an ASCVD event; therefore, it is crucial for patients to quickly adhere to this therapy. Clinical guidelines recommend statins for patients with atherosclerotic cardiovascular disease (ASCVD), but many remain untreated. The goal of this study was to assess the impact of statin use on recurrent major adverse cardiovascular events (MACE). This study used medical records and insurance claims from 4 health care systems in the United States. Eligible adults who survived an ASCVD hospitalization from September 2013 to September 2014 were followed for 1 year. A multivariable extended Cox model examined the outcome of time-to-first MACE, then a multivariable joint marginal model investigated the association between post-index statin use and nonfatal and fatal MACE. There were 8,168 subjects in this study; 3,866 filled a statin prescription ≤90 days before the index ASCVD event (47.33%) and 4,152 filled a statin prescription after the index ASCVD event (50.83%). These post-index statin users were younger, with more co-morbidities. There were 763 events (315/763, 41.3% terminal) experienced by 686 (8.4%) patients. The adjusted overall MACE risk reduction was 18% (HR 0.82, 95% CI 0.70 to 0.95, p = 0.007) and was more substantial in the first 180 days (HR 0.72, 95% CI 0.60 to 0.86, p <0.001). There was a nonsignificant 19% reduction in the number of nonfatal MACE (rate ratio 0.81, 95% CI 0.49 to 1.32, p = 0.394) and a 65% reduction in the risk of all-cause death (HR 0.35, 95% CI 0.22 to 0.56, p <0.001). In conclusion, we found a modest increase in statin use after an ASCVD event, with nearly half of the patients untreated. The primary benefit of statin use was protection against early death. Statin use had the greatest impact in the first 6 months after an ASCVD event; therefore, it is crucial for patients to quickly adhere to this therapy. IntroductionMillions of adults in the United States (US) are affected by cardiovascular events each year, reducing their quality of life and increasing their risk for death.1Pahwa R Jialal I Atherosclerosis.StatPearls. 2021; Google Scholar Hyperlipidemia is a significant risk factor for the development of atherosclerotic cardiovascular disease (ASCVD), which is present in 47% of young adults with ASCVD.2Virani SS Alonso A Benjamin EJ Bittencourt MS Callaway CW Carson AP Chamberlain AM Chang AR Cheng S Delling FN Djousse L Elkind MSV Ferguson JF Fornage M Khan SS Kissela BM Knutson KL Kwan TW Lackland DT Lewis TT Lichtman JH Longenecker CT Loop MS Lutsey PL Martin SS Matsushita K Moran AE Mussolino ME Perak AM Rosamond WD Roth GA Sampson UKA Satou GM Schroeder EB Shah SH Shay CM Spartano NL Stokes A Tirschwell DL VanWagner LB Tsao CW American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2020 update: a report from the.American Heart Association. Circulation. 2020; 141: e139-e596Google Scholar,3Vikulova DN Grubisic M Zhao Y Lynch K Humphries KH Pimstone SN Brunham LR. Premature atherosclerotic cardiovascular disease: trends in incidence, risk factors, and sex-related differences, 2000 to 2016.J Am Heart Assoc. 2019; 8e012178Crossref PubMed Scopus (43) Google Scholar Lipid-lowering therapy is a cornerstone of secondary ASCVD prevention, but many patients remain untreated. The near-term consequences of medication underutilization after an acute event are not well understood. Although there is a panoply of lipid-lowering therapies, we chose to limit this analysis to the American Heart Association guideline-recommended first-line medication of statins.4Arnett DK Blumenthal RS Albert MA Buroker AB Goldberger ZD Hahn EJ Himmelfarb CD Khera A Lloyd-Jones D McEvoy JW Michos ED Miedema MD Muñoz D Smith SC Virani SS Williams KA Yeboah J Ziaeian B. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 140: e596-e646PubMed Google Scholar Hence, the purpose of this report is to study the association between statin use/nonuse and recurrent major adverse cardiovascular events (MACE) in a cohort of patients across the US who had a recent acute ASCVD event.MethodsThis study is a collaboration between 4 US health care systems (Baylor Scott & White [BSW], Texas; Henry Ford, Michigan; Geisinger, Pennsylvania; and Marshfield Clinic, Wisconsin) participating in the Health Care Systems Research Network (HCSRN). The HCSRN maintains data standards between health care organizations to create a common data model to assemble pooled data sets to answer multicenter research questions.5Health Care Systems Research Network. Mission and vision. Available at: http://www.hcsrn.org/en/About/. Accessed June 29, 2021.Google Scholar For this project, BSW developed and distributed code to collaborators to extract the minimum necessary care, administrative, and claims data to yield a deidentified dataset. This study received approval from the Baylor Scott & White Research Institute's institutional review board through expedited review and a waiver of informed consent. Henry Ford and Marshfield ceded to the Baylor Scott & White Research Institute's institutional review board with a reliance agreement, and Geisinger's institutional review board determined that the study did not involve human subjects and was not subject to their oversight.We used a retrospective cohort design to answer our research question. Eligible adults survived an index ASCVD hospitalization from September 30, 2013 to September 30, 2014 and were followed up to 1 year. We extracted demographics (gender, age, race, Hispanic ethnicity, and insurance type), and used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes and prescription fills during the year prior to the index to identify co-morbidities (type II diabetes mellitus, chronic kidney disease, hyperlipidemia, and hypertension). We recorded statin use 90 days before and after the index. The primary outcome was MACE (acute myocardial infarction, ischemic stroke, revascularization, unstable angina, acute presentation of chronic ASCVD, all-cause death) within 1 year of index.We created a multivariable extended Cox model with robust sandwich estimates to investigate the association between post-index statin use (assessed through prescription fill) and time-to-first recurrent MACE while accounting for clustering (by healthcare system), demographics (gender, age, race), and co-morbidities (type II diabetes mellitus, chronic kidney disease, hyperlipidemia, hypertension, ASCVD history). After analyzing the time-to-first MACE, we considered an alternate analytic framework using the marginal joint model of Huang and Wang6Huang CY Wang MC. Joint modeling and estimation for recurrent event processes and failure time data.J Am Stat Assoc. 2004; 99: 1153-1165Crossref PubMed Scopus (154) Google Scholar to make inferences using the comprehensive profile of recurrent and terminal events.7Charles-Nelson A Katsahian S Schramm C. How to analyze and interpret recurrent events data in the presence of a terminal event: an application on readmission after colorectal cancer surgery.Stat Med. 2019; 38: 3476-3502PubMed Google Scholar This model implies that the subject-specific event rate is positively correlated with the risk of terminal event (i.e., subjects who survive longer tend to have lower event rates); although, this model has also been shown to yield unbiased estimates for independent processes.7Charles-Nelson A Katsahian S Schramm C. How to analyze and interpret recurrent events data in the presence of a terminal event: an application on readmission after colorectal cancer surgery.Stat Med. 2019; 38: 3476-3502PubMed Google Scholar Herein, we distinguished MACE as being nonfatal (recurrent) or fatal (terminal). Because the model could not provide stable estimates for the third or fourth events owing to the small event counts, we included information only through the second MACE. We used the same covariates as the first model but dichotomized age and race to improve computational efficiency. We used a nonparametric bootstrap method for clustered data by repeatedly sampling the subjects with replacement to estimate standard errors and obtain 95% confidence intervals (CIs) and p-values. Analyses were performed in SAS version 9.4 (Cary, North Carolina) and the ‘reReg’ R package.8Chiou SH, Huang CY. Recurrent event regression. CRAN. Available at: https://cran.r-project.org/web/packages/reReg/reReg.pdf. Accessed March 8, 2021.Google ScholarResultsThere were 8,168 patients in this study, with the 3 leading causes of entry being acute presentation of chronic ASCVD (2,337, 28.6%), acute myocardial infarction (2,156, 25.4%), and ischemic stroke (1,458, 17.9%). There were 3,866 patients (47.33%) who filled a statin prescription in the 90 days before the index event; statin users increased to 4,152 within 90 days after index (50.83%). These post-index statin users were younger with more co-morbidities than nonusers (Table 1). Of the pre-index statin users, 3,274 continued treatment after the index event (84.69%); 878 of pre-index nonusers (20.41%) were initiated on statins after index. There were 763 events experienced by 686 patients (8.4%) within 1 year (Table 2). Of all events, 315 were terminal (41.3%); most deaths (284, 90.2%) occurred as the first MACE in follow-up.Table 1Patient characteristics of statin users and non-usersStatin use after index eventCharacteristicYes (n = 4,152)No (n = 4,016)P-valueMale2,346 (56.5%)2,176 (54.18%)0.0350Age (years)72.3 [62.2, 81.0]75.2 [65.9, 83.5]<0.0001Age category (years)<0.0001 18–348 (0.19%)62 (1.54%) 35–4485 (2.05%)72 (1.79%) 45–54334 (8.04%)250 (6.23%) 55–64835 (20.11%)555 (13.82%) 65–741,115 (26.85%)1,015 (25.27%) 75+1,775 (42.75%)2,062 (51.34%)Race0.0032 Black378 (9.1%)406 (10.11%) White3,287 (79.17%)3,056 (76.1%) Other/unknown487 (11.73%)554 (13.79%)Hispanic0.0003 Yes80 (1.93%)52 (1.29%) No3,619 (87.16%)3,425 (85.28%) Unknown453 (10.91%)539 (13.42%)Insurance<0.0001 Commercial1,644 (39.60%)1,295 (32.25%) Medicaid213 (5.13%)181 (4.51%) Medicare2,241 (53.97%)2,383 (59.34%) Other payors†Includes health maintenance organizations, indemnity plans, patient-funded, and unknown/missing insurance data. ASCVD = atherosclerotic cardiovascular disease.54 (1.30%)157 (3.91%)Current smoker645 (15.53%)604 (15.04%)0.5345Type I diabetes mellitus424 (10.21%)336 (8.37%)0.0041Type II diabetes mellitus1,902 (45.81%)1,615 (40.21%)<0.0001Chronic kidney disease1,108 (26.69%)1,142 (28.44%)0.0767Hyperlipidemia3,496 (84.2%)3,020 (75.2%)<0.0001Hypertension3,624 (87.28%)3,402 (84.71%)0.0008Index event<0.0001 Acute myocardial infarction1,143 (27.53%)1,013 (25.22%) Angina pectoris60 (1.45%)93 (2.32%) Ischemic stroke or transient ischemic attack736 (17.73%)859 (21.39%) Peripheral arterial disease445 (10.72%)592 (14.74%) Revascularization547 (13.17%)343 (8.54%) Other1,221 (29.41%)1,116 (27.79%)History of ASCVD (in year prior to index)602 (14.5%)563 (14.02%)0.5350† Includes health maintenance organizations, indemnity plans, patient-funded, and unknown/missing insurance data.ASCVD = atherosclerotic cardiovascular disease. Open table in a new tab Table 2Description of all major adverse cardiac eventsMajor Adverse Cardiac Event Within 1 y of IndexEvent TypeFirstSecondThirdFourthTotalAcute myocardial infarction141 (20.6%)12 (16.7%)1 (25.0%)0154 (20.2%)Angina pectoris63 (9.2%)9 (12.5%)1 (25.0%)073 (9.6%)Ischemic stroke66 (9.6%)7 (9.7%)0073 (9.6%)Revascularization132 (19.2%)15 (20.8%)01 (100%)148 (19.4%)Death284 Open table in a new tab The of post-index statin use was with a reduction in the risk of MACE 95% to p = and was after for demographics and co-morbidities 0.82, 95% 0.70 to 0.95, p = We a of statin use between time and statin p and the by the time as and This model a risk reduction 95% to p = in the 180 days after the index for who used a statin who did it was not with the MACE outcome after 180 days 95% to p = the adjusted model a risk reduction 0.72, 95% 0.60 to 0.86, p = in the 180 days after the index event for who used a statin with who did not 1). death was a substantial of the MACE risk with post-index statin users nonusers the alternate analytic which distinguished MACE as nonfatal (recurrent) and we found that a statin after index was with a reduction in the number of nonfatal MACE (rate ratio = 95% CI to p = and a reduction in the risk of all-cause death (HR 95% CI to p <0.001). The of a statin was after for demographics and co-morbidities (Table this multivariable joint we found that a statin was with a 19% reduction in the number of nonfatal MACE (rate ratio = 0.81, 95% CI 0.49 to 1.32, p = 0.394) as well as a 65% reduction in the risk of all-cause death (HR 0.35, 95% CI 0.22 to 0.56, p <0.001). than the age of this cohort (i.e., more than the risk of all-cause death and being White was with more than a increase in risk of recurrent MACE. the patients and their MACE to statin from the joint marginal model for recurrent and terminal major adverse cardiovascular Event Event use post-index II of ASCVD Open table in a new tab and the of their recurrent and terminal events to post-index statin this multicenter study of 8,168 we found that half of the cohort did not a statin prescription within 90 days after an ASCVD had MACE within 1 year after their index ASCVD event, but post-index statin users had 19% risk of MACE. 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Heart disease and stroke statistics-2020 update: a report from the.American Heart Association. Circulation. 2020; 141: e139-e596Google Scholar,3Vikulova DN Grubisic M Zhao Y Lynch K Humphries KH Pimstone SN Brunham LR. Premature atherosclerotic cardiovascular disease: trends in incidence, risk factors, and sex-related differences, 2000 to 2016.J Am Heart Assoc. 2019; 8e012178Crossref PubMed Scopus (43) Google Scholar Lipid-lowering therapy is a cornerstone of secondary ASCVD prevention, but many patients remain untreated. The near-term consequences of medication underutilization after an acute event are not well understood. Although there is a panoply of lipid-lowering therapies, we chose to limit this analysis to the American Heart Association guideline-recommended first-line medication of statins.4Arnett DK Blumenthal RS Albert MA Buroker AB Goldberger ZD Hahn EJ Himmelfarb CD Khera A Lloyd-Jones D McEvoy JW Michos ED Miedema MD Muñoz D Smith SC Virani SS Williams KA Yeboah J Ziaeian B. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 140: e596-e646PubMed Google Scholar Hence, the purpose of this report is to study the association between statin use/nonuse and recurrent major adverse cardiovascular events (MACE) in a cohort of patients across the US who had a recent acute ASCVD

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