Purpose High-intensity statins (HIS) are recommended by current treatment guidelines for patients with clinical atherosclerotic cardiovascular disease and should be administered soon after an acute coronary syndrome (ACS) event and maintained thereafter. However, adherence to guidelines remains adequate. Statin utilization patterns during index hospitalization and the first year after ACS event, and the association between statin utilization and post-discharge clinical and economic outcomes, are described. Methods Retrospective, observational study of US adults from the MarketScan Research Databases (2002–2014) with ≥ 1 inpatient admission for ACS and no evidence of previous ACS event < 12 months prior to index. Results In total, 7802 patients met inclusion criteria. The most common index hospitalization primary diagnosis was myocardial infarction (94.6%). In the 3-month period before ACS admission, 3.4 and 14.9% of patients received HIS or low-to-moderate intensity statin, versus 13.2 and 30.7% during index hospitalization, and 16.4 and 45.1% in the year of follow-up. Of 1336 patients with a statin prescription filled on/after discharge, 53.2% filled prescriptions within 15 days of discharge and 14.9% delayed for > 91 days. The most common post-index hospital admissions for cardiovascular events were due to recurrent ACS (incidence rate = 115.2), heart failure (110.0), and revascularization (76.4). During follow-up, 2355 patients (30.2%) had all- cause inpatient admissions and 1136 (14.6%) had cardiovascular-specific admissions; mean all-cause medical and healthcare costs were $2456 and $2870, respectively, per patient per month. Conclusions Statin dosing and utilization of HIS remains lower than recommended in current treatment guidelines, leaving patients at considerable risk of subsequent cardiovascular events. . . Keywords Acute coronary syndrome Statin Cardiovascular events Introduction infarction (MI) with or without ST elevation [1, 2]. In 2010, the estimated number of unique hospitalizations for ACS in Acute coronary syndrome (ACS) refers to a spectrum of clin- the USAwas 1,141,000 . The estimated annual cost of ACS ical symptoms compatible with acute myocardial ischemia was $150 billion in the USA in 2008 . and includes the diagnosis of unstable angina and myocardial Following an initial ACS event, patients are at high risk of recurrent cardiovascular events [4–6]. Reducing low-density lipoprotein cholesterol (LDL-C) with statin therapy reduces Electronic supplementary material The online version of this article the risk of cardiovascular events in high-risk patients with (https://doi.org/10.1007/s10557-018-6800-3) contains supplementary material, which is available to authorized users. atherosclerotic cardiovascular disease (ASCVD) [7–10]. Prior placebo-controlled studies have shown beneficial ef- * Susan H. Boklage fects of low-to-moderate intensity statins (LMIS) [11, 12]. firstname.lastname@example.org In the PROVE-IT trial of patients with a recent ACS event, an intensive lipid-lowering statin regimen (high-in- Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Rd., tensity statins [HIS]) provided greater protection against Tarrytown, NY 10591, USA death or major cardiovascular events than a standard Truven Health Analytics, Bethesda, MD, USA LMIS regimen . 274 Cardiovasc Drugs Ther (2018) 32:273–280 HIS therapy is recommended by the 2013 American Continuous enrollment with medical and pharmacy benefits College of Cardiology (ACC) and American Heart for ≥ 12 months pre-index ACS admission (baseline) was re- Association (AHA) guidelines, and the 2004 updated Adult quired. Patients with a previous ACS admission in the Treatment Panel (ATP III) guidelines, for patients with clinical 12 months prior to the index date were excluded. ASCVD (including ACS), and should be administered soon The study comprised a 12-month pre-index (baseline) pe- after an ACS event and maintained thereafter [13, 14]. riod, the ACS inpatient stay, and a variable-length follow-up Adherence to recommended treatment guidelines should period (Supplementary Fig. 1). The follow-up period extend- translate to an improvement in the survival and quality of life ed from the discharge date for the index admission until the of ACS patients; however, adherence remains inadequate . earliest of 12 months post-discharge, inpatient death, dis- There is a paucity of real-world data on guideline-directed enrollment from health insurance, or end of study period statin use among ACS patients during hospitalization. The (December 31, 2014). present study sought to describe statin utilization patterns among ACS patients during index hospitalization and in the Data Analysis first year after the ACS event and assess the association be- tween statin utilization and post-discharge clinical and eco- Demographics, clinical and hospitalization characteristics at nomic outcomes. baseline, statin treatment patterns, and outcomes were sum- marized descriptively. It was therefore not necessary to de- scribe statistical analysis methods. Methods Statin Use and Intensity, and Lipid-Lowering Therapy Data Source Treatment Pattern, During the ACS Hospitalization This was a retrospective, observational US study of ACS pa- A binary variable was created to indicate whether patients tients using data from the MarketScan® Inpatient Drug Link received any statins. Based on statin intensity, patients were File, comprising the MarketScan Commercial and Medicare divided into LMIS and HIS categories (Supplementary Table Supplemental databases. ACS index hospitalization was de- 1). Based on the proportion of days covered (PDC), defined as fined as the first ACS hospitalization event occurring between the number of days in the observation period covered by med- January 1, 2002 and December 31, 2014. ication divided by the number of days in the observation pe- The MarketScan Commercial Claims database and riod, patients were categorized into (i) HIS, (ii) LMIS, (iii) MarketScan Medicare Supplemental database both comprised monotherapy non-statin lipid-lowering therapy (LLT) treat- inpatient and outpatient medical information as well as outpa- ment, (vi) mixed treatment (for those with evidence of multi- tient prescription drug claims, covered under various health ple intensities of statins, i.e., no single statin intensity with plans between 1995 and 2014. The MarketScan Hospital Drug PDC ≥ 50%), or (v) no treatment (for those with a PDC ≥ Database comprised hospital billing information from 695 50% for no statin treatment). Duration of statin/non-statin acute care hospitals in the USA and included 65.6 million LLT use (total number of days between the first and last ser- hospital discharges between January 2002 and December vice date for the therapy or the discharge date) was calculated. 2014. The MarketScan Inpatient Drug Link file matched pa- tients from the MarketScan Commercial, Medicare Statin Use and Treatment Pattern During Follow-Up Supplemental, and Medicaid databases to hospital discharge records in the MarketScan Hospital Drug Database, using a Statin medications dispensed within 30 days of the ACS hos- match key comprising hospital identifier, admission and dis- pitalization discharge date were considered continued use of charge date, principal diagnosis, and patient age and sex. Non- statin therapies. Patients met the criteria for statin use during unique key values were excluded. This method has been used follow-up if they had their pre-index statin supply available on in previous studies . the ACS discharge date and into the follow-up period, and/or ≥ 1 outpatient prescription claim for any statin during the Study Population and Design follow-up period. Patients were assigned into a treatment cat- egory if the PDC was ≥ 50%. Patients aged ≥ 18 years with at least one inpatient admission Statin treatment patterns were categorized as persistent if (index) for an ACS (defined as MI or unstable angina patients remained in the same LLT category during follow-up [International Classification of Diseases, Ninth Revision, without exceeding a gap of 15 days following the last supply Clinical Modification (ICD-9-CM) codes 410.xx or 411.1x] date of the last observed claim for statin medication in each requiring hospitalization between January 1, 2002 and intensity category. Discontinuation (during follow-up) was defined as absence of prescription claim for 15 days or more December 31, 2014) were included in the analysis. Cardiovasc Drugs Ther (2018) 32:273–280 275 following the last supply date for the statin intensity adminis- tered during the index admission. Cardiovascular Outcomes, Healthcare Utilization, and Healthcare Costs The incidence rates of recurrent ACS, stroke, heart failure (secondary to MI), revascularization, and cardiovascular- specific deaths (identified from the ICD-9-CM codes; Supplementary Table 2) werereported upto12months post- index. Incidence rates were calculated by dividing the number of patients experiencing at least one occurrence of an event during follow-up by the total number of days between the ACS discharge date and the event of interest, or censoring at Fig. 1 Patient flow. ACS acute coronary syndrome. Superscript a the end of follow-up for patients without an event. For patients indicates that the first observed inpatient admission for ACS occurring during this period (between January 1, 2002 and December 31, 2014) was with multiple cardiovascular-specific inpatient admissions recorded as the index date, provided that there was no evidence of a during the follow-up period, the first inpatient date and/or previous ACS event in the 12 months prior to this time. Superscript b emergency room date was selected. Rates were multiplied indicates a hospital transfer. Superscript c indicates that patients were by 1000 to present as 1000 person-years. excluded if statin doses administered during the inpatient stay were below the lowest available or above the highest available doses All-cause and cardiovascular-specific healthcare utilization were reported by type of service (inpatient, outpatient, and pharmacy). The follow-up period was capped at 12 months Clinical Characteristics and LLT Treatment Patterns for patients with more than 12 months of follow-up. To ac- During ACS Index Hospitalization and Follow-Up count for the variable-length follow-up, the counts of admis- Period sions, days, visits, or services and prescriptions were present- ed as per patient per month (PPPM) units. The most common index hospitalization primary diagnosis was Healthcare costs were based on allowed amounts of adju- MI (n = 7377; 94.6%), including non-ST-segment elevation MI dicated claims, including insurer and health plan payments, as (n = 4174; 53.5%), ST-segment elevation MI (n = 2882; well as patient cost-sharing in the form of copayments, de- 36.9%), and other MI (n = 313; 4.0% [Supplementary Fig. 2]). ductibles, and coinsurance. All costs were adjusted for infla- A total of 3905 (50.1%) and 863 patients (11.1%) underwent tion using the healthcare consumer price index and standard- percutaneous coronary intervention and coronary artery bypass ized to the year 2014 US dollars. during index hospitalization, respectively. The use of cardiovas- cular medications during index hospitalization was higher over- all than at baseline, with the most common being anticoagulants Results (93.4%), beta blockers (89.4%), antiplatelet agents (76.7%), and statins (70.9%; Supplementary Fig. 2), compared with Patient Demographic and Clinical Characteristics 4.8, 28.1, 10.1, and 30.5%, respectively, at baseline. at Baseline (Pre-Index ACS Hospitalization) In the 3-month period immediately before ACS admis- sion (based on PDC ≥ 50% categorizations), 267 and 1162 Of the 11,536 patients who had at least one inpatient admission patients (3.4 and 14.9%) received HIS or LMIS, respec- with primary diagnosis of ACS, 7802 (67.6%) met the inclu- tively; however, these increased to 1028 (13.2%) and sion criteria (Fig. 1). The mean age was 66.7 years, 2650 2396 (30.7%) during index ACS hospitalization, and (34.0%) were women, and 4241 (54.4%) had Medicare 1282 (16.4%) and 3519 (45.1%) in the year of follow-up (Table 1). The most common comorbid conditions prior to in- (Fig. 2). In the year of follow-up, 6060 patients (77.7%) dex hospitalization were hypertension (45.3%), diabetes filled ≥ 1 statin prescription. Of the 5528 patients using any (24.9%), and dyslipidemia (22.9%). statin at index hospitalization, 4958 patients (89.7%) filled a Before their index event, 2382 patients (30.5%) had re- prescription for any statin treatment in the outpatient setting ceived a filled claim for statin therapy with 1946 (81.7%) during the year of follow-up or had pre-index carryover statin being dispensed LMIS. Based on fill patterns and correspond- supply available at the time of discharge. ing PDC categorization, in the 3 months prior to index, 267 A total of 4468/4958 patients (90.1%) filled a prescription (3.4%), 1162 (14.9%), and 6141 (78.7%) patients were for any statin within 30 days of index hospitalization dis- assigned to HIS, LMIS, and no statin treatment, respectively. charge or had pre-index carryover statin supply available 276 Cardiovasc Drugs Ther (2018) 32:273–280 Table 1 Patients’ demographic and clinical characteristics at baseline (pre-index ACS hospitalization) Study cohort N =7802 Age, mean years (SD) 66.7 (12.8) Gender, n (%) Male 5152 (66.0) Female 2650 (34.0) Geographic US region, n (%) Northeast 131 (1.7) North central 2251 (28.9) South 5163 (66.2) Fig. 2 Statin treatment patterns in all patients by PDC ≥ 50% (N =7802). West 240 (3.1) ACS acute coronary syndrome, HIS high-intensity statin, LLT lipid- lowering therapy, LMIS low-to-moderate-intensity statin, PDC Unknown 17 (0.2) proportion of days covered. Superscript a identifies therapies assigned Payer, n (%) according to PDC in the 3-month pre-index hospitalization. Superscript Commercial 3561 (45.6) b indicates that statins were prescribed in the outpatient setting for 64% of all patients Medicare 4241 (54.4) Comorbid conditions, n (%) Hypertension 3531 (45.3) A sub-analysis categorizing statin treatment patterns into Diabetes 1946 (24.9) the periods 2002–2005 (n = 2917) and 2006–2014 (n =4885), Dyslipidemia 1788 (22.9) to examine the potential impact of the PROVE-IT study , Valvular heart disease 740 (9.5) showed that HIS was received by 1017 patients (20.8%) with Heart failure 704 (9.0) an ACS event during 2006–2014 compared with 265 (9.1%) Stroke 575 (7.4) during 2002–2005 (Supplementary Fig. 3). Unstable angina 505 (6.5) Of the 1336 patients with any statin prescription filled on or after ACS discharge (i.e., excluding patients with Atrial fibrillation 493 (6.3) Chronic kidney disease/renal impairment 490 (6.3) pre-index hospitalization carryover statin supply available at the time of discharge), 711 (53.2%) filled prescriptions Revascularization 327 (4.2) within 15 days of being discharged and 199 (14.9%) de- Percutaneous coronary intervention 250 (3.2) layed for > 91 days (Fig. 3). Overall, 1182 patients (26.5%) History of MI 136 (1.7) discontinued statin treatment in the follow-up year. Coronary artery bypass graft 40 (0.5) Cardiovascular medications, n (%) Any statin 2382 (30.5) Clinical and Economic Outcomes Following an ACS Beta-blockers 2190 (28.1) Inpatient Event (Follow-Up Period) Angiotensin-converting enzyme inhibitor 1613 (20.7) Diuretics 1586 (20.3) Following an ACS inpatient event, the most common post- Calcium channel blockers 1555 (19.9) index hospital admissions for cardiovascular events were due Angiotensin receptor blockers 1152 (14.8) to recurrent ACS (incidence rate 115.2/1000 person-years), Antiplatelet agents 791 (10.1) heart failure (110.0), and revascularization (76.4). Incidence Non-statin LLT 648 (8.3) rates of MI and unstable angina-related admissions were 72.5 Anticoagulants 377 (4.8) and 61.7, respectively; the incidence rate for cardiovascular- ACS acute coronary syndrome, LLT lipid-lowering therapy, MI myocar- specific inpatient deaths was 11.4 (Supplementary Table 3). dial infarction, SD standard deviation During the follow-up period, 2355 patients (30.2%) had an Patients could have had more than one statin in the 12-month pre-index all-cause inpatient admission and 1136 (14.6%) had hospitalization period cardiovascular-specific inpatient admissions (Table 2). The mean all-cause PPPM medical and healthcare (medical + out- patient pharmacy) costs were $2456 and $2870, respectively; at the time of discharge. Of these, during the follow-up period, a similar proportion experienced changes in statin the corresponding values for cardiovascular-specific costs were $1111 and $1391, respectively (Supplementary Table treatment regimen (3.8% from LMIS to HIS and 3.9% 4). Inpatient services, and outpatient and pharmacy costs, from HIS to LMIS), whereas 2137 patients (47.8%) had were the key drivers of healthcare costs. no modifications. Cardiovasc Drugs Ther (2018) 32:273–280 277 These patients would have received statin treatment as recom- mended in the 2002 ATP III guidelines, which were developed when there was less evidence of the benefit of HIS therapy , before publication of the PROVE-IT study . There was, however, a growing body of evidence demonstrating a benefit of early initiation of statin therapy in patients with ACS. The MIRACL study, highlighted in the ATP III guide- lines, demonstrated that statin treatment initiated in the hospi- tal in patients with non-Q MI or unstable angina was safe and associated with a 16% relative risk reduction at 16 weeks . The ATP III guidelines update published in 2004  ac- knowledged the PROVE-IT study; nevertheless, 39.3 and 33.6% of patients from the present study did not receive statin Fig. 3 Proportion of patients filling statin prescriptions by time after ACS during the index hospitalization or follow-up, respectively. discharge (N = 1336 ). ACS acute coronary syndrome, SD standard Studies have shown low adherence to, and suboptimal dos- deviation. Superscript a indicates the number of patients with any statin ing of, statins in patients at high risk of cardiovascular events prescription filled on or after ACS discharge, excludes patients with pre- index carryover statin at the time of discharge. Mean (SD) time to first in the USA [20–22]. For example, in a study of 273,308 statin prescription fill was 42.1 (71.3) days ASCVD patients, only 8.8% had received HIS, 29.5% had received LMIS, and 61.7% were non-statin users . Discussion Similarly, of 23,040 recent ACS patients with a filled stat- in prescription, only 27% received HIS . The propor- Despite evidence that treatment with statins, especially HIS, tion of patients prescribed HIS in a study of 117,989 pa- reduces the risk of cardiovascular events in high-risk patients tients hospitalized for an MI was higher than that observed with ASCVD , results from the present study showed that a in our study (in 2014, the first filled prescription after considerable proportion of patients did not receive any statin discharge was HIS in 71.7% of those aged 19–64 years during index hospitalization. HIS was underutilized during, and 57.5% of those aged 66–75 years ). However, and in the year following, the index ACS event. HIS was adherence to treatment post-discharge in a similar cohort received by a greater proportion of patients with an index of MI patients was low, with only 41.6% remaining highly ACS event in 2006–2014 (21%) than 2002–2005 (9%), po- adherent to HIS after 2 years . Suboptimal statin ther- tentially due to the impact of results from the PROVE-ITstudy apy is a frequent factor limiting LDL-C goal attainment [5, 7]; however, utilization remained lower than is recom- among high-risk patients in the USA. Suggested reasons mended in current treatment guidelines [13, 16, 17]. Of note, for suboptimal statin dosing include statin intolerance, the 2013 ACC/AHA guideline  did not apply at the time lack of acceptance of guideline recommendations, and that many of the patients in this study were being treated. contraindications [20, 21, 23]. Table 2 All-cause and All discharges, N = 7802 cardiovascular-specific healthcare utilization outcomes during the All-cause Cardiovascular-specific follow-up period Any inpatient admissions, n (%) 2355 (30.2) 1136 (14.6) Duration to first inpatient admissions 262 (130.3) 290 (119.4) or censoring, mean days (SD) Outpatient services, n (%) Emergency room 3266 (41.9) 1297 (16.6) Physician office 7131 (91.4) 6411 (82.2) Laboratory 5740 (73.6) 2619 (33.6) Radiology 5934 (76.1) 2969 (38.1) Other 7505 (96.2) 6420 (82.3) Outpatient pharmacy 7393 (94.8) 7231 (92.7) ICD-9-CM International Classification of Diseases, Ninth Revision, Clinical Modification, SD standard deviation Cardiovascular-specific healthcare utilization and costs were defined by pulling medical claims with ICD-9-CM diagnosis codes for a cardiovascular condition and pharmacy claims for cardiovascular medications. For inpatient admissions, the diagnosis code must be in the primary diagnosis position on the claim 278 Cardiovasc Drugs Ther (2018) 32:273–280 Our findings, along with published data [20, 21, 23], un- with this linkage that negatively impact the ability to general- derscore a major issue with both underutilization and non- ize these results to all regions and practices. However, the use adherence to HIS, and the potential health consequences of linked data could be considered a strength as it allows caused. Data have shown that, in patients with recent ACS, individuals to be followed from inpatient to outpatient set- HIS provided greater protection against death or major cardio- tings. These findings are also strengthened by the consistency vascular events than LMIS , emphasizing the need for ad- of this sample with other published studies, with a similar herence to guideline-directed statin use in ACS . In a proportion of patients with non-ST-segment elevation MI recent study, older age, female sex, renal dysfunction, and compared with ST-segment elevation MI to that reported in heart failure during hospital admission were the most common the literature [32–34]. baseline characteristics of non-use of Bhigh-potency statins^ Results from the present study do not provide information . Factors that have been linked with an increased likeli- on the rationale for prescribing statin therapy at different hood of being prescribed a HIS in high CV risk patients in- doses, or for not prescribing statin therapy. While pharmacy clude male sex , no previous statin use [26, 27], younger claims show the amount of medication a patient was dis- age , presence of hypertension , and receiving pre- pensed, it is not known whether patients filling their prescrip- scription from a cardiologist . However, the main drivers tions take medications as directed. The data from this study of statin underutilization and non-adherence post-ACS events are subject to data coding limitations and data entry error. need further examination. The present study showed that rec- ommendations for a rapid and maintained treatment of high- risk patients with HIS were generally not followed, with 47% of patients delaying filling their prescription for > 15 days Conclusions following discharge from an ACS event, despite accommoda- tions for those on statins before the event. Utilization of HIS remains lower than is recommended in In this study, following an ACS inpatient event, the highest current treatment guidelines , with poor rates of adher- hospital admission incidence rates were recurrent ACS, heart ence in patients with recent ACS, consequently leaving failure, and revascularization. The cardiovascular event rates patients at considerable risk of subsequent cardiovascular observed during the follow-up period were in keeping with a events. The data from this study show that there is oppor- previous report showing high 1-year cardiovascular risk of tunity to improve statin utilization during and following an 15.1% in recent ACS patients . The overall ACS event. Further investigation to determine drivers of cardiovascular-specific healthcare costs in the present study statin therapy underutilization during index ACS event and contributed to 48% of the overall PPPM total healthcare ex- thereafter is warranted. penditure. Underutilization of statins in this study lends fur- ther support to previously published data that adherence to Acknowledgements We acknowledge Rishi Wadhera, MD, for clinical statins is inadequate . Better use of statins as per recom- consultation on the study design and interpretation of study results. Medical writing support under the direction of the authors was provided mendations may improve clinical outcomes and reduce eco- by Emmanuel Ogunnowo, PhD, of Prime (Knutsford, UK), supported by nomic burdens from patients with ACS. Considering the high Sanofi and Regeneron Pharmaceuticals, Inc., according to Good incidence of recurrent events observed on a background of Publication Practice guidelines (Link). The sponsors were involved in statin therapy in this study, add-on treatment with other the study design, collection, analysis, and interpretation of data, as well as data checking of information provided in the manuscript. The authors lipid-lowering therapies such as ezetimibe or proprotein were responsible for all content and editorial decisions and received no convertase subtilisin/kexin 9 (PCSK9) inhibitors may also honoraria related to the development of this publication. be necessary in this patient population, particularly in those failing to reach LDL-C treatment targets with statins, in accor- Funding/Support This study was funded by Regeneron Pharmaceuticals, Inc. and Sanofi (there is no grant number). dance with recent guidelines [29, 30]. Recent results from a large outcomes study have demonstrated significant reduc- Compliance with Ethical Standards tions in major adverse cardiovascular events with the PCSK9 inhibitor alirocumab in a population of patients who Conflict of Interest Ms. Boklage is an employee of and stockholder in had experienced an ACS event 1–12 months prior to initiation Regeneron Pharmaceuticals, Inc. Dr. Elassal was an employee of and of treatment . stockholder in Regeneron Pharmaceuticals, Inc. at the time the study was conducted. Dr. Ding, Ms. Malangone-Monaco, Ms. Lopez- Gonzalez, and Ms. Henriques are employees of Truven Health Limitations Analytics, an IBM company, which was provided funding to conduct this study on behalf of Regeneron Pharmaceuticals, Inc. and Sanofi. While the evidence to support representation of the adminis- trative claims data has been well established, as this is linked Ethical Approval This article does not contain any studies with human participants or animals performed by any of the authors. with inpatient drug utilization, there may be inherent biases Cardiovasc Drugs Ther (2018) 32:273–280 279 Open Access This article is distributed under the terms of the Creative Heart Association Task Force on Practice Guidelines. 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Cardiovascular Drugs and Therapy – Springer Journals
Published: May 31, 2018
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