Abstract
Background:
Understanding how statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 serine protease inhibitors (PCSK9i) are prescribed after a myocardial infarction (MI) or elective coronary revascularization may improve lipid-lowering therapy (LLT) intensification and reduce recurrent atherosclerotic cardiovascular disease (ASCVD) events. We described the use and intensification of LLT among US veterans who had a MI or elective coronary revascularization between July 24, 2015, and December 9, 2019 within 12 months of hospital discharge.
Methods:
LLT intensification was defined as increasing statin dose, or initiating a statin, ezetimibe, or a PCSK9i, overall and among those with a low-density lipoprotein cholesterol (LDL-C) ≥ 70 or 100 mg/dL. Poisson regression was used to determine patient characteristics associated with a with a greater likelihood of LLT intensification following hospitalization for MI or elective coronary revascularization.
Results:
Among 81,372 index events (mean age 69.0 years, 2.3% female, mean LDL-C 89.6 mg/dL, 33.8% with LDL-C < 70 mg/dL), 39.7% were not taking any LLT and 22.0%, 37.2%, and 0.6% were taking a low-moderate intensity statin, a high-intensity statin, and ezetimibe, respectively, prior to MI/coronary revascularization during the study period. Within 14 days, 3 months, and 12 months post-hospitalization, 33.3%, 41.9% and 47.3%, respectively, of veterans received LLT intensification. LLT intensification was most common among veterans taking no LLT (82.5%, n=26,637) prior to MI/coronary revascularization. Higher baseline LDL-C, having a lipid test, and attending a cardiology visit were each associated with a greater likelihood of LLT intensification, while age ≥ 75 vs. <65 years was associated with a lower likelihood of LLT intensification within 12 months post-hospitalization.
Conclusion:
Less than half of veterans received LLT intensification in the year after MI or coronary revascularization suggesting a missed opportunity to reduce ASCVD risk.
Keywords: statin therapy, low-density lipoprotein cholesterol, atherosclerotic disease, secondary prevention
INTRODUCTION
Cardiovascular disease is a leading cause of death in the United States (US).1,2 The use of lipid-lowering therapy (LLT) is foundational to reducing atherosclerotic cardiovascular disease (ASCVD) risk, especially among patients who have already experienced an ASCVD event.3,4 The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) blood cholesterol guideline recommends LLT for all patients with a history of ASCVD.5 Initial lipid management after an ASCVD event includes a high-intensity, or maximally tolerated, statin with a target reduction in LDL-C by ≥50% and a threshold LDL-C level of ≥ 70 mg/dL to consider initiation of ezetimibe followed by a PCSK9i among those with very high risk for ASCVD.2,6–8
Although statin use among US adults with ASCVD is estimated to range between 60% and 80%, the mean LDL-C in this population has been estimated to be 95 mg/dL, substantially higher than the guideline recommended optimal level of < 70 mg/dL.9–12 Determining patterns of LLT intensification after a myocardial infarction (MI) or coronary revascularization may help identify opportunities to optimize LLT use and thus reduce the risk for recurrent ASCVD events. The goal of the current study was to estimate the distribution of LLT being taken and the proportion of patients intensifying treatment in the 12 months following a hospitalization for MI or elective coronary revascularization among US veterans receiving care between 2015 and 2019 using data from the Veterans Health Administration (VHA).
METHODS
Data availability
Data used in this study are available from the VHA on request through VHA data access procedures.
Design, Setting, and Data Sources
This retrospective cohort study utilized clinical, pharmacy, and administrative data from over 140 VHA hospitals and 1,200 VHA outpatient clinics. All data were obtained from the VHA Corporate Data Warehouse. The University of Utah Institutional Review Board and the Salt Lake City Veterans Affairs Health Care System Research and Development Office approved this study.
Study Population
We identified all veterans with a MI or elective coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) between July 24, 2015, and December 09, 2019, using International Classification of Diseases (ICD), 9th and 10th editions, and current procedure terminology (CPT) codes (Table S1). The index date for each veteran was the discharge date of the hospitalization for the included MI or elective coronary revascularization. We restricted the analysis to veterans who met all the following criteria: (1) had continuous enrollment, defined by at least one inpatient or outpatient encounter, in the 12-month period prior to their index date (the “pre-index period”); (2) did not have a pharmacy fill for a PCSK9i identified using the VHA pharmacy fill data prior to the index date; and (3) were alive 12 months after their index event. A veteran could have contributed more than one unique index dates if they had a second eligible event that was more than 12 months after the previous eligible event.
Baseline characteristics
Characteristics of veterans, including demographics, medical history, medication use, and laboratory measures, were identified using data from the pre-index period using validated algorithms (Figure 1, Table S1).13–16 Comorbidities, non-LLT medication use (e.g., antihypertensives), and non-lipid laboratory values (e.g., serum creatinine) were identified using all available data prior to the index date. As the use of LLT may vary by region, Veterans Integrated Service Networks (VISNs) were identified. Participants were grouped into four regions based on the geographic area in which they received care on the index date (Northeast, Southeast, Continental, Pacific; Table S1). Priority group status, which ranges from 1 (highest financial need) to 8 (lowest financial need) according to the VHA needs and disability assessment, was determined for each Veteran and categorized as 1 (no medication co-pay cost to the Veteran) versus 2–8 (medication co-pay cost capped at $700 annually; Table S1). We also identified whether veterans had supplemental insurance coverage beyond their VHA benefits (e.g., Medicare supplemental or Medicaid insurance). The proportion of variables with missing values can be found in Table S2.
Figure 1. Scheme to construct study cohort and define variables among veterans hospitalized for a myocardial infarction or elective coronary revascularization within the Veterans Health Administration.
Index date: Eligible MI or elective coronary revascularization hospitalization during the index date identification period
* Statin and ezetimibe fill and availability, lipid panel testing, low-density lipoprotein cholesterol, high-intensity statin use, low-moderate-intensity statin use, mortality status, primary care, and cardiologist outpatient visits
MI: myocardial infarction; PCSK9: proprotein convertase subtilisin-kexin type 9; VHA: Veterans Health Administration
Baseline LLT medication use and lipid test results were identified in the 90 days prior to the index date. The most recent LDL-C prior to the index date was identified for each veteran and categorized as <70, 70 to <100, 100 to <130, 130 to <190, and ≥190 mg/dL. Veterans were categorized into one of five, mutually exclusive, baseline LLT regimens: 1) no LLT, 2) low-moderate intensity statin only, 3) high-intensity statin only, 4) ezetimibe only, or 5) any statin dosage and ezetimibe. Details regarding the definition of statin intensity based on the individual statin and dose is provided in Table S3.
Primary outcome: LLT intensification
For the primary analysis, LLT intensification was defined as an increase from a low-moderate statin to high-intensity statin or the initiation of a statin, ezetimibe, or PCSK9i to a baseline LLT regimen that did not include these medications (Table S4).
Secondary outcomes
Secondary outcomes included the number of lipid tests, outpatient cardiology visits, and primary care visits following hospital discharge for MI/coronary revascularization. LLT regimens based on prescription fills were also evaluated as a secondary outcome. Follow-up LLT regimens were categorized based on number of LLT medication classes being taken (i.e., none, monotherapy, dual-therapy, and triple-therapy), and by each unique LLT regimen (e.g., for monotherapy: low-moderate intensity statin only, high-intensity statin only, ezetimibe only, and PCSK9i only).
Statistical Analysis
All analyses were completed for the overall population and stratified by baseline LLT regimen. The proportion of veterans who received LLT intensification within 14 days, 3 months, and 12 months following hospital discharge was estimated. The proportion of veterans who intensified their LLT within 14 days (as well as 3 months and 12 months) following hospital discharge was estimated to capture LLT intensification during the hospitalization and immediately following the hospitalization. The proportion of veterans who intensified their LLT within 3 months and 12 months following hospital discharge was estimated to reflect the 2018 AHA/ACC recommendation of LDL-C monitoring every 3 to 12 months after statin intensification.5 We also estimated the proportion of veterans who received LLT intensification within 30 days of a lipid test result with LDL-C ≥70 mg/dL or ≥100 mg/dL overall in the 3 months and 12 months, separately, following hospital discharge. If more than one LDL-C value ≥70 mg/dL or ≥100 mg/dL was present in the follow-up period, LLT intensification was determined relative to the first value ≥70 mg/dL or ≥100 mg/dL. Also, among veterans with a lipid test in the 12 months following hospital discharge for their index event, the proportion who received LLT intensification was estimated after stratifying veterans by their LLT regimen at the time of the test.
LLT regimens being taken 3 months and 12 months following hospital discharge were described among: 1) all veterans; 2) veterans who received LLT intensification; 3) veterans who received LLT intensification and had an LDL-C ≥70 mg/dL or ≥ 100 mg/dL, separately, within the first 3 months and the last 3 months of the 12-month period following hospital discharge.
Factors associated with intensifying LLT within 14 days, 3 months, and 12 months following hospital discharge were determined as a complete case analysis using Poisson regression.17 This was performed as a stratified analysis in two groups: 1) veterans not taking LLT or taking a low-moderate intensity statin only at baseline; and 2) veterans on a high-intensity statin only, ezetimibe only, or a statin and ezetimibe at baseline. Factors associated with LLT intensification within 12 months following the index date were also determined among veterans who did not receive LLT intensification within the 3 months of their index date.
In secondary analyses, several stratified and sensitivity analyses were performed. Baseline characteristics of veterans by index event type (MI or elective coronary revascularization) were described, and the proportion of veterans that received LLT intensification within 14 days, 3 months, and 12 months following hospital discharge was calculated by index event type. The proportion of veterans who did not receive LLT intensification within 3 months following hospital discharge, and intensified LLT in months 4 to 12 was calculated. To determine sex-based differences in LLT intensification patterns, stratified analysis was performed for male vs. female veterans. Because it is possible that veterans received maximally-tolerated or maximally-intensified LLT intensification after their first event, and further LLT intensification was not feasible after a second event, we repeated the main analysis restricted to only the first eligible index date. Finally, sensitivity analysis including only veterans with a baseline LDL-C ≥ 70 mg/dL were performed. All analyses were conducted using SAS v.9.4 (SAS Institute, Cary, NC).
RESULTS
Veteran characteristics
There were 81,372 index events (n=77,367 unique veterans) for MI or elective coronary revascularization that met the inclusion criteria (Figure S1). The mean (standard deviation [SD]) age was 69.0 (9.7) years, and 2.3% of veterans were female (Table 1). Most veterans self-identified as non-Hispanic White (71.6%), had supplemental government insurance (72.2%), qualified in priority groups 2 through 8 (66.1%), and had diabetes (55.3%). Prior to hospitalization for MI/elective coronary revascularization, 39.7% of the veterans were not taking LLT, 22.0% were taking a low-moderate intensity statin only, 37.2% were taking a high-intensity statin only, 0.6% were taking ezetimibe-only and 0.6% were taking a statin and ezetimibe. Characteristics are shown separately for veterans who had an MI and coronary revascularization as their index event, separately, in Table S5. At discharge, defined as medication fills within 14 days of hospitalization or available pre-index LLT if no new medication fill occurred, 17.3% (n=14,077) were not taking LLT, 16.2% (n=13,140) were taking a low-moderate intensity statin only, 64.9% (n=52,745) were taking a high-intensity statin only, 0.6% (n=459) were taking ezetimibe only, 1.1% (896) were taking a statin and ezetimibe, and 0.1% (n=55) were taking a PCSK9i alone or in combination with other LLT.
Table 1.
Characteristics of US veterans enrolled in the Veterans Health Administration who were hospitalized for MI or coronary revascularization, 2015–2019, overall and by baseline lipid-lowering therapy regimen.
| Baseline Lipid-lowering Therapy regimen | ||||||
|---|---|---|---|---|---|---|
| Characteristics | Overall (N = 81,372) | None (N = 32,302) | Low-moderate intensity statin only (N = 17,864) | High-intensity statin only (N = 30,248) | Ezetimibe only (N = 460) | Statin and ezetimibe* (N = 498) |
| Age, years, mean (SD) | 69.0 (9.7) | 68.5 (10.8) | 70.7 (9.3) | 68.5 (8.5) | 70.0 (7.9) | 67.2 (8.9) |
| Age category, years, n (%) | ||||||
| <65 | 23,288 (28.6) | 10,646 (33.0) | 3,891 (21.8) | 8,506 (28.1) | 94 (20.4) | 151 (30.3) |
| 65–74 | 38,984 (47.9) | 13,729 (42.5) | 8,853 (49.6) | 15,886 (52.5) | 251 (54.6) | 265 (53.2) |
| ≥75 | 19,100 (23.5) | 7,927 (24.5) | 5,120 (28.7) | 5,856 (19.4) | 115 (25.0) | 82 (16.5) |
| Female sex, n (%) | 1,884 (2.3) | 960 (3.0) | 372 (2.1) | 525 (1.7) | 14 (3.0) | 13 (2.6) |
| Race/Ethnicity, n (%) | ||||||
| Non-Hispanic White | 58,245 (71.6) | 22,065 (68.3) | 13,507 (75.6) | 21,955 (72.6) | 369 (80.2) | 349 (70.1) |
| Non-Hispanic Black | 13,746 (16.9) | 6,382 (19.8) | 2,372 (13.3) | 4,843 (16.0) | 56 (12.2) | 93 (18.7) |
| Hispanic | 4,862 (6.0) | 1,890 (5.9) | 1,080 (6.0) | 1,852 (6.1) | 12 (2.6) | 28 (5.6) |
| Non-Hispanic Asian | 460 (0.6) | 187 (0.6) | 81 (0.5) | 181 (0.6) | ≤ 10 | ≤ 10 |
| Other/Missing | 4,059 (5.0) | 1,778 (5.5) | 824 (4.6) | 1,417 (4.7) | 17 (3.7) | 23 (4.6) |
| Area-level median income, n (%) | ||||||
| <$25,000 | 1,579 (1.9) | 678 (2.1) | 346 (1.9) | 545 (1.8) | ≤ 10 | ≤ 10 |
| $25,000-$49,999 | 30,062 (37.0) | 12,338 (38.2) | 6,656 (37.3) | 10,768 (35.6) | 158 (34.3) | 142 (28.5) |
| $50,000-$74,999 | 34,730 (42.7) | 13,487 (41.8) | 7,691 (43.1) | 13,113 (43.4) | 210 (45.7) | 229 (46.0) |
| ≥$75,000 | 14,975 (18.4) | 5,782 (17.9) | 3,169 (17.7) | 5,815 (19.2) | 89 (19.3) | 120 (24.1) |
| VISN region, n (%) | ||||||
| Northeast | 21,933 (27.0) | 8,272 (25.6) | 4,820 (27.0) | 8,616 (28.5) | 113 (24.6) | 112 (22.5) |
| Southeast | 29,280 (36.0) | 11,978 (37.1) | 6,625 (37.1) | 10,292 (34.0) | 172 (37.4) | 213 (42.8) |
| Continental | 16,599 (20.4) | 6,454 (20.0) | 3,726 (20.9) | 6,228 (20.6) | 104 (22.6) | 87 (17.5) |
| Pacific | 13,559 (16.7) | 5,597 (17.3) | 2,693 (15.1) | 5,112 (16.9) | 71 (15.4) | 86 (17.3) |
| Supplemental insurance, n (%) | ||||||
| Yes | 58,719 (72.2) | 22,073 (68.3) | 13,820 (77.4) | 22,077 (73.0) | 381 (82.8) | 368 (73.9) |
| No | 22,653 (27.8) | 10,229 (31.7) | 4,044 (22.6) | 8,171 (27.0) | 79 (17.2) | 130 (26.1) |
| Priority group status†, n (%) | ||||||
| 1 | 27,452 (33.9) | 9,178 (28.5) | 6,402 (35.9) | 11,431 (37.9) | 197 (42.9) | 244 (49.1) |
| 2 to 8 | 53,610 (66.1) | 22,980 (71.5) | 11,411 (64.1) | 18,704 (62.1) | 262 (57.1) | 253 (50.9) |
| Current smoker, n (%) | 35,437 (43.5) | 14,169 (43.9) | 7,282 (40.8) | 13,609 (45.0) | 185 (40.2) | 192 (38.6) |
| Systolic blood pressure, mmHg, mean (SD) | 132.0 (18.8) | 133.3 (19.5) | 132.1 (18.4) | 130.7 (18.4) | 132.0 (18.2) | 129.4 (16.4) |
| Antihypertensive medication use, n (%) | 63,019 (77.4) | 18,347 (56.8) | 15,806 (88.5) | 27,985 (92.5) | 413 (89.8) | 468 (94.0) |
| Comorbidities, n (%) | ||||||
| Diabetes | 45,029 (55.3) | 15,280 (47.3) | 10,354 (58.0) | 18,777 (62.1) | 307 (66.7) | 311 (62.4) |
| History of stroke | 12,148 (14.9) | 4,275 (13.2) | 2,542 (14.2) | 5,143 (17.0) | 90 (19.6) | 98 (19.7) |
| Chronic kidney disease | 37,331 (45.9) | 14,504 (44.9) | 8,230 (46.1) | 14,125 (46.7) | 230 (50.0) | 242 (48.6) |
| History of PAD | 15,984 (19.6) | 5,216 (16.1) | 3,540 (19.8) | 6,967 (23.0) | 133 (28.9) | 128 (25.7) |
| History of heart failure | 13,320 (16.4) | 4,462 (13.8) | 2,851 (16.0) | 5,796 (19.2) | 100 (21.7) | 111 (22.3) |
| Familial hypercholesterolemia | 16,320 (20.1) | 5,501 (17.0) | 3,877 (21.7) | 6,655 (22.0) | 132 (28.7) | 155 (31.1) |
| History of ASCVD | 55,423 (68.1) | 24,406 (75.6) | 11,340 (63.5) | 19,043 (63.0) | 316 (68.7) | 318 (63.9) |
| LDL-C, mg/dL, mean (SD) | 89.6 (38.2) | 99.9 (39.4) | 84.2 (34.3) | 81.8 (36.4) | 112.2 (38.6) | 100.2 (47.9) |
| LDL-C category, mg/dL, n (%) | ||||||
| <70 | 24,924 (33.8) | 6,566 (23.3) | 6,218 (37.5) | 11,943 (42.6) | 58 (13.2) | 139 (28.8) |
| 70 to <100 | 23,733 (32.2) | 8,492 (30.1) | 5,910 (35.7) | 9,078 (32.4) | 106 (24.2) | 147 (30.5) |
| 100 to <130 | 14,190 (19.3) | 7,160 (25.4) | 2,742 (16.5) | 4,073 (14.5) | 138 (31.5) | 77 (16.0) |
| 130 to <190 | 9,669 (13.1) | 5,342 (18.9) | 1,534 (9.3) | 2,581 (9.2) | 119 (27.2) | 93 (19.3) |
| ≥190 | 1,181 (1.6) | 634 (2.2) | 167 (1.0) | 337 (1.2) | 17 (3.9) | 26 (5.4) |
| High-density lipoprotein cholesterol, mg/dL, mean (SD) | 41.5 (15.3) | 42.4 (16.6) | 41.7 (14.6) | 40.5 (14.1) | 42.0 (20.9) | 42.2 (18.5) |
| Total cholesterol, mg/dL, mean (SD) | 157.8 (47.1) | 168.8 (48.4) | 152.7 (42.5) | 149.2 (45.7) | 184.5 (47.4) | 169.9 (55.5) |
| Triglyceride level, mg/dL, median (25th, 75th percentiles) | 129 (89, 193) | 124 (86, 188) | 132 (91, 196) | 131 (91, 195) | 152 (105, 234) | 145 (103, 207) |
| Estimated glomerular filtration rate, median (25th, 75th percentiles), mL/min/1.73m2 | 71 (53, 88) | 72 (54, 90) | 68 (52, 86) | 70 (54, 88) | 70 (53, 87) | 69 (53, 84) |
| Lipid-lowering therapy, n (%) | ||||||
| None | 32,302 (39.7) | - | - | - | - | - |
| Low-moderate intensity statin only | 17,864 (22.0) | - | - | - | - | - |
| High-intensity statin only | 30,248 (37.2) | - | - | - | - | - |
| Ezetimibe only | 460 (0.6) | - | - | - | - | - |
| Any statin and ezetimibe | 498 (0.6) | - | - | - | - | - |
| Index event type, n (%) | ||||||
| Myocardial infarction | 44,018 (54.1) | 21,560 (66.7) | 9,107 (51.0) | 12,970 (42.9) | 209 (45.4) | 172 (34.5) |
| Elective coronary revascularization | 37,354 (45.9) | 10,742 (33.3) | 8,757 (49.0) | 17,278 (57.1) | 251 (54.6) | 326 (65.5) |
ASCVD: atherosclerotic cardiovascular disease; LDL-C: low-density lipoprotein cholesterol; PAD: peripheral artery disease; SD: standard deviation; VISN: Veterans Integrated Service Network
Continuous variables are mean (standard deviation) unless otherwise noted.
Veterans could be included ≥ 1 if an index event occurred > 12 months after the initial index event
Includes any combination of low, moderate, or high dose statin with ezetimibe.
Categorized as a number between 1 (highest need) and 8 (lowest need) according to military service history, disability rating, income level, and participation in other benefits.
Primary outcome – LLT intensification
At 14 days, 3 months, and 12 months following hospital discharge, 33.3% (n=27,111), 41.9% (n=34,115), and 47.3% (n=38,453) of veterans, respectively, had received LLT intensification (Table 2). Within 12 months following hospital discharge, ezetimibe and a PCSK9i were initiated for 4.8% and 0.8% of veterans, respectively. Among veterans not taking LLT at baseline, 59.4%, 75.0% and 82.5% received LLT intensification within 14 days, 3 months, and 12 months following hospital discharge, respectively, while 42.5%, 52.1% and 60.3% of veterans on a low-moderate intensity statin at baseline received LLT intensification within 14 days, 3 months, and 12 months, respectively. Among veterans taking a high-intensity statin only at baseline, 2.5% (n=758) received LLT intensification at 12 months following hospital discharge. For veterans taking ezetimibe only at baseline, 27.8%, 44.8%, and 57.0% received LLT intensification within 14 days, 3 months, and 12 months, respectively, with a high-intensity statin initiated for most veterans within each period.
Table 2.
Lipid-lowering therapy intensification within 14 days, 3 months, and 12 months after an MI or elective coronary revascularization overall and by baseline lipid-lowering therapy, 2015–2019.
| Baseline Lipid-lowering Therapy |
||||||
|---|---|---|---|---|---|---|
| Intensification and added medications | Overall (N = 81,372) | None (N = 32,302) | Low-moderate intensity statin only (N = 17,864) | High-intensity statin only (N = 30,248) | Ezetimibe only (N = 460) | Statin and ezetimibe* (N = 498) |
| Within 14 days following hospital discharge | ||||||
|
| ||||||
| Intensified, N (% [95% CI]) | 27,111 (33.3 [33.0, 33.6]) | 19,197 (59.4 [58.9, 60.0]) | 7,591 (42.5 [41.8, 43.2]) | 187 (0.6 [0.5, 0.7]) | 128 (27.8 [23.7, 31.9]) | ≤10 |
|
| ||||||
| New medication, N (% [95% CI]) | ||||||
|
| ||||||
| Low-moderate intensity statin | 3,361 (12.4 [12.0, 12.8]) | 3,315 (17.3 [16.7, 17.8]) | ≤10 | ≤10 | 46 (35.9 [27.5, 44.4]) | ≤10 |
|
| ||||||
| High-intensity statin | 23,562 (86.9 [86.5, 87.3]) | 15,934 (83.0 [82.5, 83.5]) | 7,546 (99.4 [99.2, 99.6]) | ≤10 | 82 (64.1 [55.6, 72.5]) | ≤10 |
|
| ||||||
| Ezetimibe | 492 (1.8 [1.7, 2.0]) | 255 (1.3 [1.2, 1.5]) | 54 (0.7 [0.5, 0.9]) | 183 (97.9 [95.8, 100.0]) | ≤10 | ≤10 |
|
| ||||||
| PCSK9i | 55 (0.2 [0.1, 0.3]) | 27 (0.1 [0.1, 0.2]) | ≤10 | ≤10 | ≤10 | ≤10 |
|
| ||||||
| Within 3 months following hospital discharge | ||||||
|
| ||||||
| Intensified, N (% [95% CI]) | 34,115 (41.9 [41.6, 42.3]) | 24,237 (75.0 [74.6, 75.5]) | 9,310 (52.1 [51.4, 52.8]) | 345 (1.1 [1.0, 1.3]) | 206 (44.8 [40.2, 49.3]) | 17 (3.4 [1.8, 5.0]) |
|
| ||||||
| New medication, N (% [95% CI]) | ||||||
|
| ||||||
| Low-moderate intensity statin | 5,497 (16.1 [15.7, 16.5]) | 5,414 (22.3 [21.8, 22.9]) | ≤10 | ≤10 | 83 (40.3 [33.5, 47.0]) | ≤10 |
|
| ||||||
| High-intensity statin | 29,145 (85.4 [85.1, 85.8]) | 19,791 (81.7 [81.2, 82.1]) | 9,235 (99.2 [99.0, 99.4]) | ≤10 | 119 (57.8 [51.0, 64.6]) | ≤10 |
|
| ||||||
| Ezetimibe | 898 (2.6 [2.5, 2.8]) | 454 (1.9 [1.7, 2.0]) | 106 (1.1 [0.9, 1.4]) | 338 (98.0 [96.5, 99.5]) | ≤10 | ≤10 |
|
| ||||||
| PCSK9i | 136 (0.4 [0.3, 0.5]) | 76 (0.3 [0.2, 0.4]) | 11 (0.1 [0.0, 0.2]) | 14 (4.1 [2.0, 6.2]) | 18 (8.7 [4.8, 12.6]) | 17 (100.0 [.,.]) |
|
| ||||||
| Within 12 months following hospital discharge | ||||||
|
| ||||||
| Intensified, N (% [95% CI]) | 38,453 (47.3 [46.9, 47.6]) | 26,637 (82.5 [82.0, 82.9]) | 10,765 (60.3 [59.5, 61.0]) | 758 (2.5 [2.3, 2.7]) | 262 (57.0 [52.4, 61.5]) | 31 (6.2 [4.1, 8.4]) |
|
| ||||||
| New medication, N (% [95% CI]) | ||||||
|
| ||||||
| Low-moderate intensity statin | 7,278 (18.9 [18.5, 19.3]) | 7,162 (26.9 [26.4, 27.4]) | ≤10 | ≤10 | 116 (44.3 [38.2, 50.3]) | ≤10 |
|
| ||||||
| High-intensity statin | 32,736 (85.1 [84.8, 85.5]) | 21,975 (82.5 [82.0, 83.0]) | 10,621 (98.7 [98.4, 98.9]) | ≤10 | 140 (53.4 [47.4, 59.5]) | ≤10 |
|
| ||||||
| Ezetimibe | 1,835 (4.8 [4.6, 5.0]) | 842 (3.2 [3.0, 3.4]) | 255 (2.4 [2.1, 2.7]) | 738 (97.4 [96.2, 98.5]) | ≤10 | ≤10 |
|
| ||||||
| PCSK9i | 320 (0.8 [0.7, 0.9]) | 165 (0.6 [0.5, 0.7]) | 35 (0.3 [0.2, 0.4]) | 46 (6.1 [4.4, 7.8]) | 43 (16.4 [11.9, 20.9]) | 31 (100.0 [.,.]) |
Includes any combination of low, moderate, or high dose statin with ezetimibe.
Percentage represents veterans who intensified treatment.
New medication groups are not mutually exclusive; for example, a veteran could start a high-intensity statin and ezetimibe and be represented in both rows.MI: myocardial infarction; PCSK9i: proprotein subtilisin convertase kexin type-9 inhibitor
Secondary outcomes
Among veterans with at least one lipid test within 3 months following hospital discharge (n=30,083, 37.0% of the overall cohort), 49.8% had an LDL-C ≥70 mg/dL and 19.2% had LDL-C ≥100 mg/dL (Table S6 and Table S7). Within 12 months following hospital discharge, 81.7% (n=66,476) of veterans had at least one lipid test, and of these veterans, 58.4% (n=38,828) had an LDL-C ≥70 mg/dL and 26.3% (n=17,504) had LDL-C ≥100 mg/dL. Among veterans with LDL-C ≥70 mg/dL, 40.2% received LLT intensification, compared to 39.8% of veterans with an LDL-C ≥ 100 mg/dL (Figure 2 and Table S6). LLT intensification among veterans with an LDL-C ≥ 70 mg/dL and ≥ 100 mg/dL by baseline LLT regimen is shown in Table S4. LLT intensification among veterans with LDL-C ≥ 70 mg/dL and ≥ 100 mg/dL by LLT regimen at the time of lipid testing is shown in Figure 2 and Table S8. Overall, 83.4% and 94.5% of veterans had at least one outpatient cardiology and primary care follow-up visit within 12 months following their MI/coronary revascularization, respectively (Table S9). Overall, the most common LLT regimen at any follow-up time point was monotherapy with a high-intensity statin (Tables S10-S13).
Figure 2. Lipid-lowering therapy intensification within 30-days of lipid testing by LDL-C test result overall and by lipid-lowering therapy at the time of the lipid test.
* Includes any combination of low, moderate, or high dose statin with ezetimibe.
LDL-C: low-density lipoprotein cholesterol
Factors associated with LLT intensification
Among veterans not taking LLT or taking a low-moderate intensity statin only at baseline, intensification within 14 days, 3 months and 12 months following hospital discharge was more likely among veterans of Non-Hispanic Black or Hispanic vs. Non-Hispanic White race/ethnicity, without supplemental insurance, priority groups 2 through 8 vs. group 1, Continental or Pacific vs. Northeast VISN region, current vs. never/former smoking, with higher systolic blood pressure (SBP) and LDL-C, and attending at least one cardiology visit (Figure 3, Figure 4, Figure S2, Table S14). Intensification within 14 days, 3 months, and 12 months following hospital discharge was less likely among females, veterans residing in the Southeast vs. Northeast VISN region, taking antihypertensive medication, and with a history of chronic kidney disease, and heart failure (Figure S3).
Figure 3. Factors associated with lipid-lowering therapy intensification within 3 months of hospital discharge among veterans hospitalized for an MI or elective coronary revascularization, 2015–2019.
Two columns (left-to-right): 1) veterans taking no LLT or a low-moderate intensity statin only prior to hospitalization for MI or elective coronary revascularization who were intensified within 3 months following hospital discharge, 2) veterans taking a high-intensity statin only, ezetimibe only, or any statin and ezetimibe prior to hospitalization for MI or elective coronary revascularization who were intensified within 3 months following hospital discharge. PR obtained from modified Poisson regression with robust error variance. Adjusted for age, sex, race/ethnicity, area-level median income, VISN region, supplemental insurance type, priority group status, smoking status, diabetes, chronic kidney disease, heart failure, familial hypercholesterolemia, history of ASCVD, history of stroke, peripheral artery disease, systolic blood pressure, diastolic blood pressure, antihypertensive medication use, LDL-C lipid test in the previous 3 months, cardiology visit in the previous 3 months, primary care visit in the previous 3 months, index year, and indication for index.
ASCVD: atherosclerotic cardiovascular disease; CI: confidence interval; LDL-C: low-density lipoprotein cholesterol; LLT: lipid lowering therapy; MI: myocardial infarction; PR: prevalence ratio; VISN: Veterans Integrated Service Network
Figure 4. Factors associated with lipid-lowering therapy intensification within 12 months of hospital discharge among veterans hospitalized for an MI or elective coronary revascularization, 2015–2019.
Two columns (left-to-right): 1) veterans taking no LLT or a low-moderate intensity statin only prior to hospitalization for MI or elective coronary revascularization who were intensified within 12 months following hospital discharge, 2) veterans taking a high-intensity statin only, ezetimibe only, or any statin and ezetimibe prior to hospitalization for MI or elective coronary revascularization who were intensified within 12 months following hospital discharge. PR obtained from modified Poisson regression with robust error variance. Adjusted for age, sex, race/ethnicity, area-level median income, VISN region, supplemental insurance type, priority group status, smoking status, diabetes, chronic kidney disease, heart failure, familial hypercholesterolemia, history of ASCVD, history of stroke, peripheral artery disease, systolic blood pressure, diastolic blood pressure, antihypertensive medication use, LDL-C lipid test in the previous 12 months, cardiology visit in the previous 12 months, primary care visit in the previous 12 months, index year, and indication for index.
ASCVD: atherosclerotic cardiovascular disease; CI: confidence interval; LDL-C: low-density lipoprotein cholesterol; LLT: lipid lowering therapy; MI: myocardial infarction; PR: prevalence ratio; VISN: Veterans Integrated Service Network
Among veterans taking a high-intensity statin only, ezetimibe only, or any statin and ezetimibe at baseline, intensification within 14 days, 3 months, and 12 months following hospital discharge was more likely for those with a history of familial hypercholesterolemia, each 10 mg/dL increase in LDL-C, having at least one follow-up lipid test, and attending at least one cardiology visit. (Figure 3, Figure 4, Figure S2, Table S14). Intensification was also more likely with each calendar year following 2015 (Figure S3). No factors were consistently associated with a lower likelihood of intensification across every time period following hospital discharge (14 days, 3 months, and 12 months). Factors associated with LLT intensification during months 4 through 12 among veterans who did not intensify within 3 months following hospital discharge are shown in Table S15.
Secondary Analyses
When stratified by index event type, 38.4%, 46.6%, and 51.8% of veterans with an index MI, compared to 27.3%, 36.4%, and 41.8% of veterans with an index elective coronary revascularization, received LLT intensification within 14 days, 3 months, and 12 months following hospital discharge, respectively (Tables S16-S17). Among veterans who did not intensify LLT within 3 months following hospital discharge (n=47,257), 9.2% received LLT intensification between 4 and 12 months following hospital discharge (Table S18). Stratified analysis by sex did not reveal qualitatively different patterns in LLT intensification within 12 months of hospitalization and across all baseline LLT-regimens (Table S19 and S20). Factors associated with LLT intensification by sex were largely consistent, though a higher likelihood of LLT intensification with having at least one follow-up lipid test and attending at least one cardiology visit and a lower likelihood among participants > 75 years old, taking antihypertensive medication, and a history of chronic kidney disease were unique to male participants. No factors associated with LLT intensification were found to be unique to all female participants, though an increased baseline LDL-C was associated with increased LLT intensification among both male and female participants (Table S21). Sensitivity analysis restricted to the first index date were similar findings to the primary analysis including all eligible index dates (Tables S22 and S23). Sensitivity analysis of LLT intensification among only veterans with a baseline LDL-C ≥ 70 mg/dL demonstrated comparable results (Tables S24 and S25).
DISCUSSION
In the current analysis of US veterans, 47.3% received LLT intensification within 12 months following hospital discharge for MI or elective coronary revascularization. The majority of veterans on no LLT or a low-moderate intensity statin (74.6%) and ezetimibe only (57.0%) at baseline received LLT intensification, compared to only 2.5% taking a high-intensity statin at baseline. Notably, only 37.0% of veterans received a lipid test within 3 months following hospital discharge. Among veterans with an LDL-C result ≥ 70 mg/dL during the 12 months following hospital discharge for MI or elective coronary revascularization, only 40.2% received LLT intensification within 30 days of the test result. A high proportion with an LDL-C ≥ 70 mg/dL, or even ≥ 100 mg/dL, were not taking LLT after a MI/elective coronary revascularization. LLT intensification among veterans taking a high-intensity statin at baseline with a follow-up LDL-C ≥ 70 mg/dL rarely occurred, as only 2.8% added ezetimibe or a PCSK9i to their LLT regimen. The current analysis highlights the underutilization of LLT for secondary prevention of ASCVD and the need for better implementation of guideline-directed medical therapy.
Intensification of LLT is often helpful to reduce the risk of recurrent ASCVD events.18 However, many patients are under-treated following an ASCVD event despite the high risk of a recurrent events. In an analysis of 15,366 patients with very high ASCVD risk, the ASCVD event rate was 53.1 per 1,000 patient-years.19 Additionally, in the Getting to an Improved Understanding of Low-Density Lipoprotein Cholesterol and Dyslipidemia Management (GOULD) cohort, among 4,452 participants with ASCVD and an LDL-C ≥70 mg/dL not on a PCSK9i, LLT intensification occurred in only 17.7% of participants after 2-years follow-up.20 In contrast, in the current analysis, 40.2% of veterans with an LDL-C ≥ 70mg/dL received LLT intensification, most of which involved the initiation of a high-intensity statin or switching from a low-moderate to high intensity statin. There remains a substantial gap between guideline indicated LLT intensification and the actual LLT regimens patients are prescribed.
Lipid testing may prompt appropriate LLT prescription and intensification.21 In Alberta, Canada, where 86.6% of patients post-acute coronary syndrome had a lipid test within 90 days of discharge, high-intensity statin prescribing was greater among patients who underwent versus did not undergo lipid-testing (85.1% vs. 71.4%).21 Among adults receiving care at Kaiser Permanente Northern California for MI or stroke, lipid testing within 12 months of hospitalization was associated with a 4.3% and 5.4% increase in LLT adherence and intensification after follow-up lipid testing.22 Prior analysis of the VHA demonstrated a 3.9% increase in intensification and 12.8% increase in initiation of LLT among veterans with a lipid test within 12 months before, and 3 months after, a clinic visit.23 Further, the likelihood of LLT intensification among veterans with ASCVD increased with additional lipid testing and monitoring.23 In the current analysis, only 37.0% of veterans underwent lipid-testing in the 3 months following hospitalization. Having a lipid test following hospital discharge was associated with a greater likelihood of LLT intensification at both 3 month and 12 months regardless of baseline LLT regimen. However, the 40.2% of veterans with a lipid test who had an LDL-C ≥ 70mg/dL received LLT intensification. Increasing post-event lipid testing may help to provide guidance for intensification to optimize LLT regimens, achieve guideline-recommended LDL-C goals, and reduce ASCVD risk.
Therapeutic inertia, the act of not intensifying a medication regimen despite having a medical indication, has been identified as a barrier to statin and PCSK9i use.24–26 Lipid testing and outpatient follow-up visits after an MI or coronary revascularization are important in reducing therapeutic inertia and maintaining medication adherence. A structured care pathway, an organized and well-defined approach to disease management, may reduce therapeutic inertia in LLT. For example, an analysis of Medicare beneficiaries found that post-MI follow-up occurs most frequently in the 2 to 6-week window after an event, and statin adherence was 10% lower if the first follow-up occurred more than 6 weeks following hospital discharge for MI.27 Further, follow-up by both cardiology and primary care providers, as opposed to only one provider is associated with increased statin use (risk ratio 1.11; 95% CI, 1.01–1.22).28 Among veterans in the current analysis, 94.5% of veterans had a follow-up visit with a primary care provider and 83.4% had follow up with a cardiologist in the 12 months following their index MI or coronary revascularization event, which was associated with a higher likelihood of LLT intensification. However, appropriate inaction, the act of not intensifying a medication regimen despite not meeting guideline-recommendations is, at times, warranted and may contribute to sub-optimal a LLT regimen. Some providers may not intensify due to patient non-acceptance of taking additional medication, drug-drug interactions, or clinical uncertainty around the true etiology of event (e.g., plaque rupture vs. sepsis-induced MI). Pragmatic and implementation studies are needed to address therapeutic inertia in LLT.
This study has several limitations. The sample was predominantly male and of non-Hispanic White race/ethnicity, which may limit generalizability. Data on barriers to LLT, such as statin intolerance or patient-preference were not captured. Further, veterans who were hospitalized for a scheduled elective revascularization procedure may have received LLT intensification following a diagnostic coronary angiogram prior to the index event. This LLT intensification would not be captured in the current analysis of LLT intensification pre- and post-hospitalization. Additionally, because medication use was only identified from VHA pharmacies, we could not determine the overall proportion of veterans or LLT regimens for veterans who received medication directly from the clinic, manufacturer, or a non-VHA pharmacy. While clinicians in the VHA are required to make a nonformulary requests for specific prescriptions (e.g., PCSK9i), this process ranges from an additional check box within the electronic health record to a formal pharmacy consult. The process for requesting a nonformulary prescription varies by VHA location but is often less burdensome than the process of going through a prior authorization.29,30 Veterans receiving care within the VHA receive medication at a range of $5 (e.g., atorvastatin) to $11 (e.g., evolocumab) per prescription per month with an annual cap at $700. The VHA also employs strategies to improve preventive services, such as team-based care. This cost structure and clinical support does not apply to many adults receiving non-VHA care in the US and may limit generalizability. Additionally, it is possible that veterans were hospitalized and experienced a Type II MI (e.g., acute blood loss anemia, sepsis, acute hypoxia) as an MI in any coded position were included. Though the VHA is an integrated healthcare system, there may be regional differences in clinician availability and LLT prescribing and monitoring patterns which may influence post-hospitalization LLT management and aggressiveness in intensifying LLT. The current analysis relies on administrative codes for MI/elective coronary revascularization, which are subject to miscoding. However, prior studies have demonstrated strong reliability of administrative codes for these discrete cardiac events.31–33 Finally, we only assessed veterans following an MI or elective revascularization instead of any qualifying ASCVD event (e.g., stroke, peripheral revascularization), and findings may differ between these populations.
Conclusion
In the current study, LLT intensification among veterans hospitalized for an MI or undergoing elective coronary revascularization was low. Despite many veterans having a follow-up LDL-C ≥ 70 mg/dL, less than half of veterans received LLT intensification, either with low use of dual- or triple- LLT regimens. The current analysis supports the need for interventions following an MI or coronary revascularization that can optimize LLT use to reduce risk of recurrent ASCVD events.
Supplementary Material
What is Known
For adults with atherosclerotic cardiovascular disease, clinicians are recommended to consider additional lipid-lowering therapy (LLT) if low-density lipoprotein cholesterol (LDL-C) is ≥ 70 mg/dL.
Clinical follow-up and lipid testing are associated with improved LLT intensification and adherence among adults with ASCVD on LLT.
What the Study Adds
In this sample of 81,372 veterans receiving care at the Veterans Health Administration (VHA), less than half of veterans received LLT intensification in the 12 months after hospitalization for myocardial infarction or elective coronary revascularization.
More than 80% of included veterans received a lipid test in the 12 months following hospitalization, with 58.4% and 26.2% having an LDL-C ≥ 70 mg/dL and 100 mg/dL, respectively.
Despite a measured LDL-C ≥ 70 mg/dL after hospitalization for MI or elective coronary revascularization, only 40.2% of veterans received LLT intensification within 30 days of the lipid test.
Acknowledgements:
Sources of Funding:
This work was supported by an industry-academic partnership with Amgen, Inc. The academic authors conducted all analyses and maintained the rights to publish this article.
Disclosures:
Drs. Bress, Muntner, and Derington receive research support to their institution from Amgen related to the current manuscript. Drs. Bress and Derington receive research support to their institution from Amarin Corporation for research unrelated to the current manuscript. Dr. Virani receives research support from the Department of Veterans Affairs, World Heart Federation, and Tahir and Jooma family, as well as honorarium from the American College of Cardiology (Associate Editor for Innovations, ACC.org). Dr. Woodward is a consultant to Amgen, Freeline and Kyowa Kirin. Dr. Rosenson receives research support from his institution from Amgen, Arrowhead, Novartis and Regeneron; consulting fees from Amgen, CVS Caremark, Lilly, Novartis and Regeneron; non-promotional speaking fees from Kowa; royalties from Wolters Kluwer (UpToDate) and stock holdings in MediMergent LLC. Dr. Orroth is employed by and owns stock in Amgen. All other authors: no disclosures.
Non-standard Abbreviations and Acronyms:
- LLT
lipid-lowering therapy
- ASCVD
atherosclerotic cardiovascular disease
- MI
myocardial infarction
- VHA
Veterans health administration
- ICD
International Classification of Disease
- CPT
current procedure terminology
- VISN
Veteran integrated service network
- PCSK9i
proprotein convertase subtilisin/kexin type 9 serine protease inhibitors
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Data used in this study are available from the VHA on request through VHA data access procedures.