Abstract
Objective
We assessed national- and state-level geographic variations among patients with a history of ≥1 major atherosclerotic cardiovascular disease (ASCVD) event in: (1) the proportion of patients with retrospectively identified 2018 American College of Cardiology/American Heart Association guideline very high-risk (VHR) ASCVD criteria; (2) utilization of guideline-directed lipid-lowering therapy (LLT); and (3) the proportion of patients with persistent low-density lipoprotein cholesterol (LDL-C) elevations despite statin and/or ezetimibe use.
Methods
A retrospective cohort study using the Prognos LDL-C database linked to IQVIA longitudinal medical and prescription claims databases. The study period was from January 01, 2011, to November 30, 2019 and the index period was from January 01, 2016, to November 30, 2019; the index date was defined as the most recent LDL-C test during the index period. The study included patients aged ≥18 years at index who had a measured LDL-C level during the index period and had ≥1 inpatient/outpatient claim for ASCVD during the 5-year pre-index period.
Results
Of patients with any ASCVD (N=4652,468), 1537,514 (33.1%) patients had ≥1 major ASCVD event. Among patients with ≥1 major ASCVD event, the VHR ASCVD criteria were retrospectively identified in 1139,018 (74.1%) patients; Hawaii had the highest (81.7%) and Colorado the lowest (65.0%) proportion of these patients. Nationally, 48.8% and 50.2% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had current LLT use; Massachusetts and Colorado had the highest and lowest proportions, respectively. After standardizing for age and sex, 57.3% and 58.8% of patients with ≥1 major ASCVD event and retrospectively identified VHR ASCVD criteria, respectively, had LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite statin and/or ezetimibe use, with substantial state-level variations observed.
Conclusions
The study highlights high rates of elevated LDL-C and pervasive underuse of LLT in health-insured patients with a history of major ASCVD events treated in the United States, with state-level geographic variations observed.
1
Introduction
Cardiovascular disease remains the leading cause of death in the United States (US) , with a combined annual direct and indirect cost burden of $555 billion, which is predicted to rise to $1.1 trillion from 2015 to 2035 . Low-density lipoprotein cholesterol (LDL-C) is a well-established, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) [ , ]. Accordingly, lowering of LDL-C with lipid-lowering therapy (LLT) significantly reduces the risk of cardiovascular events . Recent updates in the 2018 American College of Cardiology/American Heart Association (ACC/AHA) Multisociety blood cholesterol guidelines introduced the very high-risk (VHR) ASCVD classification . Patients in this VHR group have multiple major ASCVD events (i.e. recent acute coronary syndrome [ACS], history of myocardial infarction [MI] other than ACS, history of ischemic stroke [IS], or symptomatic peripheral arterial disease [PAD]), or a single major ASCVD event and a history of multiple high-risk conditions . In patients with VHR ASCVD and LDL-C ≥70 mg/dL (≥1.8 mmol/L) despite high-intensity or maximally tolerated statin therapy, the addition of non-statin therapy (ezetimibe and/or a proprotein convertase subtilisin/kexin type 9 inhibitor [PCSK9i]) is recommended .
Previous studies of US clinical practice have reported suboptimal utilization of guideline-directed LLT for patients with hypercholesterolemia, with poor statin adherence, underdosing and/or discontinuation frequently observed . However, the clinical and treatment characteristics of patients at the highest cardiovascular risk (e.g. those with a history of ≥1 major ASCVD event) remain to be fully elucidated in a real-world setting. Additionally, given the recent introduction of the VHR ASCVD risk stratification in the 2018 ACC/AHA blood cholesterol guidelines, the proportion of patients meeting these criteria in real-world, US clinical practice remains largely unknown. Importantly, the provision of guideline-directed LLT to reduce cardiovascular risk in patients with major ASCVD events should be uniform across the US; however, to date, VHR ASCVD status, LLT utilization, and LDL-C levels in patients with major ASCVD events have not been assessed at the state level in the US. This is an important gap in the literature, with assessment at the state level required to identify potential heterogeneity in the treatment patterns, clinical outcomes, and cardiovascular risk status of patients with major ASCVD events. Moreover, state-level analysis allows for the generalizability of national trends to be assessed, and the uncovering of disparities can inform subsequent public health interventions and policies .
Therefore, the objectives of the current study were to describe US national- and state-level geographic variations among patients with a history of ≥1 major ASCVD event with regard to the proportion of patients with retrospectively identified 2018 ACC/AHA guideline VHR ASCVD criteria, utilization of guideline-directed LLT, and the proportion of patients with persistent LDL-C elevations despite statin and/or ezetimibe use.
2
Methods
2.1
Study design and databases
This was a retrospective cohort study using the nationally representative Prognos LDL-C database (Prognos, New York, NY, USA) linked to anonymized longitudinal medical and prescription claims data across IQVIA (Plymouth Meeting, PA, USA) data sources . Prognos data aggregates LDL-C values from large national and regional laboratory providers in the US, and the Prognos Registry is the largest source of clinical diagnostics information in 35 disease areas, with over 8 billion medical records for 150 million patients. The IQVIA Longitudinal Prescription claims (LRx) database captures information on adjudicated dispensed prescriptions sourced from retail, mail, long-term care, and specialty pharmacies, and represents 86% of prescriptions dispensed in retail pharmacies, 55% of prescriptions dispensed by standard mail service, along with 40%–70% of specialty pharmacy volume. Being a pharmacy claims database, the IQVIA LRx database does not contain clinical and diagnostic information. Thus, to capture clinical characteristics, the IQVIA LRx database was linked to the IQVIA PharMetrics® Plus health plan claims database and the IQVIA Professional Fee Claims database (Dx). The aggregated IQVIA PharMetrics Plus database comprises adjudicated claims for more than 130 million unique patients across the US and is sourced directly from insurance companies. IQVIA PharMetrics Plus data have a diverse representation of geography, employers, payers, providers, and therapy areas. The IQVIA Dx database contains unadjudicated medical claims from office-based physicians, ambulatory facilities, and hospital-based physicians, and is sourced from clearing houses (also referred to as switches) involved in claims processing. The study utilized de-identified health claims data and thus was exempt from institutional review board review.
The overall study period was from January 01, 2011, to November 30, 2019. The index period was from January 01, 2016, to November 30, 2019, to allow for at least a 5-year pre-index period, with the index date defined as the most recent LDL-C test during the index period (Supplementary Fig. 1). No minimum post-index follow-up was required. The 5-year pre-index period was used to capture the patient’s ASCVD status, history of risk factors, and major ASCVD events among all patients, to identify those who retrospectively met the VHR ASCVD criteria per the updated ACC/AHA guidelines published in November 2018 during the index period of the current study (Supplementary Fig. 1; Supplementary Table 1).
Patients across the different IQVIA databases and the Prognos LDL-C dataset were linked to create a final cohort using a Health Insurance Portability and Accountability Act (HIPAA)–compliant encrypted ID. The study complied with all applicable laws regarding patient privacy, using HIPAA-compliant de-identified retrospective data sources. No direct patient contact or primary collection of individual patient data occurred. Study results were in tabular form and aggregate analyses that omitted patient identification.
2.2
Patients and outcomes
The study included patients aged ≥18 years at index, who had a measured LDL-C level during the index period and had ≥1 inpatient/outpatient claim for ASCVD during the 5-year pre-index period identified using International Classification of Diseases (ICD)-9, ICD-10, and/or Current Procedural Terminology codes.
From all patients identified with ASCVD, the proportion of patients with a history of ≥1 major ASCVD event(s) and the proportion of patients with retrospectively identified 2018 ACC/AHA criteria for VHR ASCVD in the 5-year pre-index period were estimated at the national and state levels . While state-level data were calculated and reported for all states, while ranking, only states with a sample size in the top 90th percentile were considered (states with a sample size in the bottom 10th percentile were not ranked).
Per the 2018 ACC/AHA guidelines , major ASCVD events were defined as the presence of recent ACS (within the past 12 months), history of MI (other than a recent ACS event), history of IS, or symptomatic PAD, identified using ICD-9/ICD-10 codes. Per these guidelines , VHR ASCVD was retrospectively defined in the current study as a history of multiple major ASCVD events, or 1 major ASCVD event and a history of multiple high-risk conditions during the 5-year pre-index period. The detailed criteria and associated operational definitions, including diagnostic codes, for major ASCVD events and high-risk conditions used in the current study are reported in Supplementary Table 1.
LDL-C distribution of the patients was assessed using the most recent LDL-C value measured on the index date. Current LLT use was estimated at the national and state levels, with patients classed as in receipt of current LLT if they received any statin, ezetimibe, or PCSK9i therapy on the index date or during the 3 months prior to the index date. National-level estimates for LLT use on the index date or during the 12 months prior to the index date were also calculated for all patient groups. The following were the categories of LLT use: “PCSK9i use (monotherapy or in combination with statins)”; “statin only”; “statin plus ezetimibe”; and “ezetimibe only”.
Age- and sex-standardized rates of patients with a history of ≥1 major ASCVD event, patients with retrospectively identified VHR ASCVD criteria per the 2018 ACC/AHA guidelines , current LLT use, and patients with elevated LDL-C (≥70 mg/dL [≥1.8 mmol/L] and ≥100 mg/dL [≥2.6 mmol/L]) despite current statin and/or ezetimibe use in the 2 ASCVD subgroups were reported. These were calculated by using the age and sex distribution of a standard population of patients with ASCVD in the US. A standard population of patients with ASCVD was used for age and sex standardization as opposed to census population estimates because the age distribution of patients with ASCVD is different from the age distribution of the general population in the US; thus, the census population cannot be considered a standard population . Prevalence estimates of the standard ASCVD population by state and across each age group and sex category in the US were computed in a separate sample of patients who were enrolled in the IQVIA PharMetrics Plus database during 2017. These prevalence rates across each age group and sex category were then applied to the most recent census data (2017) available at the time of the analysis to obtain the final standard population to be used for the purpose of this study [ , ]. Directly standardized rates were calculated using the following formula: directly standardized rate = (r 1 N 1 + r 2 N 2 + r 3 N 3 + …+ r n N n ) / (N 1 + N 2 + N 3 +…+ N n ), where r k equals the rate in k-th stratum of study sample (stratum refers to each age group category by sex) and N k equals the number of persons in k-th stratum of the standard population.
2.3
Statistical analysis
Analyses were conducted using SAS version 9.3 (SAS Institute, Cary, NC, USA). The study was descriptive in nature and formal statistical tests were not conducted. Mean, median, and standard deviation (SD) were generated as measures of central tendency and variance for continuous variables. Frequencies and percentages were calculated for categorical variables.
3
Results
3.1
Baseline characteristics
From a total population of 33,910,626 patients with a measured LDL-C level in the linked database during the index period, the study included 4652,468 patients with a history of any ASCVD in the 5-year pre-index period. The mean (SD) age of the ASCVD patients was 70.0 (11.8) years and 52.6% were male; their mean (SD) baseline LDL-C was 90.8 (35.3) mg/dL (2.4 [0.9] mmol/L). The majority of patients (56.5%) were insured by a commercial payer, and the Southern region of the US had the highest proportion (51.5%) of patients with ASCVD ( Table 1 ). Of patients with any ASCVD, 1537,514 (33.1%) patients had a history of ≥1 major ASCVD event in the 5-year pre-index period ( Table 1 ). The mean (SD) LDL-C in patients with a history of ≥1 major ASCVD event was 87.2 (35.6) mg/dL (2.3 [0.9] mmol/L); additional patient clinical characteristics are reported in Table 2 .
| Demographics | Patients with a history of ASCVD (N=4652,468) | Patients with a history of ≥1 major ASCVD event (N=1537,514) | Patients with retrospectively identified VHR ASCVD criteria (N=1139,018) |
|---|---|---|---|
| Age, years | |||
| Mean ± SD | 70.0 ± 11.8 | 69.8 ± 12.1 | 71.0 ± 11.3 |
| Median (min, max) | 71 (18, 119) | 71 (18, 119) | 72 (18, 119) |
| Age group, years, N (%) | |||
| 18–34 | 42,481 (0.9) | 14,068 (0.9) | 5513 (0.5) |
| 35–44 | 96,669 (2.1) | 34,453 (2.2) | 18,135 (1.6) |
| 45–54 | 332,144 (7.1) | 119,093 (7.8) | 72,745 (6.4) |
| 55–64 | 890,908 (19.2) | 305,829 (19.9) | 199,896 (17.6) |
| 65+ | 3290,266 (70.7) | 1064,071 (69.2) | 842,729 (74.0) |
| Sex, N (%) | |||
| Male | 2446,291 (52.6) | 846,922 (55.1) | 622,203 (54.6) |
| Geographic region, N (%) | |||
| Northeast | 963,084 (20.7) | 297,772 (19.4) | 215,266 (18.9) |
| Midwest | 489,360 (10.5) | 172,428 (11.2) | 131,773 (11.6) |
| South | 2393,943 (51.5) | 793,764 (51.6) | 590,291 (51.8) |
| West | 806,068 (17.3) | 273,545 (17.8) | 201,685 (17.7) |
| Unknown | 13 (0.0) | 5 (0.0) | 3 (0.0) |
| Payer type, N (%) | |||
| Commercial | 2630,016 (56.5) | 877,517 (57.1) | 618,654 (54.3) |
| Medicare | 1984,505 (42.7) | 644,005 (41.9) | 509,195 (44.7) |
| Other | 37,947 (0.8) | 15,992 (1.0) | 11,169 (1.0) |
| Patients with a history of ASCVD (N=4652,468) | Patients with a history of ≥1 major ASCVD event (N=1537,514) | Patients with retrospectively identified VHR ASCVD criteria (N=1139,018) | |
|---|---|---|---|
| Index LDL-C, mg/dL * | |||
| Mean ± SD | 90.8 ± 35.3 | 87.2 ± 35.6 | 87.3 ± 36.1 |
| Median (min, max) | 85 (10, 495) | 81 (10, 492) | 81 (10, 492) |
| Index LDL-C, mmol/L * | |||
| Mean ± SD | 2.4 ± 0.9 | 2.3 ± 0.9 | 2.3 ± 0.9 |
| Median (min, max) | 2.2 (0.3, 12.8) | 2.1 (0.3, 12.7) | 2.1 (0.3, 12.7) |
| Index LDL-C group, N (%) * | |||
| <70 mg/dL (<1.8 mmol/L) | 1384,265 (29.8) | 536,532 (34.9) | 401,443 (35.2) |
| 70–99 mg/dL (1.8–2.6 mmol/L) | 1652,824 (35.5) | 530,122 (34.5) | 381,044 (33.5) |
| 100–129 mg/dL (2.6–3.3 mmol/L) | 982,622 (21.1) | 284,050 (18.5) | 215,636 (18.9) |
| 130–189 mg/dL (3.4–4.9 mmol/L) | 578,443 (12.4) | 168,924 (11.0) | 126,628 (11.1) |
| >189 mg/dL (>4.9 mmol/L) | 54,314 (1.2) | 17,886 (1.2) | 14,267 (1.3) |
| Major ASCVD events, N (%) | |||
| Any major events | 1537,514 (33.1) | 1537,514 (100.0) | 1139,018 (100.0) |
| Recent ACS | 153,552 (3.3) | 153,552 (10.0) | 126,380 (11.1) |
| History of MI (other than recent ACS) | 785,493 (16.9) | 785,493 (51.1) | 579,807 (50.9) |
| History of IS | 675,284 (14.5) | 675,284 (43.9) | 488,780 (42.9) |
| Symptomatic PAD | 132,921 (2.9) | 132,921 (8.7) | 104,190 (9.2) |
| High-risk conditions, N (%) | |||
| Age ≥65 years | 675,136 (14.5) | 215,016 (14.0) | 179,253 (15.7) |
| HeFH | 132,820 (2.9) | 45,629 (3.0) | 38,554 (3.4) |
| History of prior CABG or PCI outside of major ASCVD event(s) | 446,361 (9.6) | 249,269 (16.2) | 222,732 (19.6) |
| Diabetes mellitus | 658,357 (14.2) | 235,760 (15.3) | 209,093 (18.4) |
| Hypertension | 1856,315 (39.9) | 671,120 (43.7) | 612,348 (53.8) |
| Chronic kidney disease (eGFR 15–59 mL/min/1.73 m 2 ) | 479,358 (10.3) | 195,907 (12.7) | 160,364 (14.1) |
| Current smoking | 435,124 (9.4) | 184,794 (12.0) | 162,936 (14.3) |
| Persistently elevated LDL-C ≥100 mg/dL despite maximally tolerated statin and ezetimibe | 993,948 (21.4) | 305,957 (19.9) | 254,908 (22.4) |
| History of CHF | 644,261 (13.9) | 313,218 (20.4) | 267,979 (23.5) |
| LLT use, N (%) | |||
| Any LLT (12-month pre-index) | 2712,632 (58.3) | 991,624 (64.5) | 758,625 (66.6) |
| Statin only | 2524,665 (93.1) | 924,992 (93.3) | 708,742 (93.4) |
| High-intensity statin | 941,126 (34.7) | 424,052 (42.8) | 323,448 (42.6) |
| Medium-intensity statin | 1368,336 (50.4) | 437,124 (44.1) | 334,918 (44.2) |
| Low-intensity statin | 215,203 (7.9) | 63,816 (6.4) | 50,376 (6.6) |
| Statin + ezetimibe | 127,076 (4.7) | 45,475 (4.6) | 33,830 (4.5) |
| High-intensity statin | 67,383 (2.5) | 26,699 (2.7) | 19,508 (2.6) |
| Medium-intensity statin | 52,580 (1.9) | 16,563 (1.7) | 12,599 (1.7) |
| Low-intensity statin | 7113 (0.3) | 2213 (0.2) | 1723 (0.2) |
| Ezetimibe only | 38,898 (1.4) | 12,034 (1.2) | 9487 (1.3) |
| PCSK9i (monotherapy or in combination with statin) | 21,993 (0.8) | 9123 (0.9) | 6566 (0.9) |
| Current LLT (3-month pre-index) | 2044,686 (43.9) | 749,902 (48.8) | 571,972 (50.2) |
| Statin only | 1903,687 (93.1) | 700,059 (93.4) | 534,965 (93.5) |
| High-intensity statin | 694,927 (34.0) | 316,748 (42.2) | 241,383 (42.2) |
| Medium-intensity statin | 1037,293 (50.7) | 332,718 (44.4) | 253,897 (44.4) |
| Low-intensity statin | 171,467 (8.4) | 50,593 (6.7) | 39,685 (6.9) |
| Statin + ezetimibe | 74,430 (3.6) | 26,421 (3.5) | 19,453 (3.4) |
| High-intensity statin | 39,645 (1.9) | 15,561 (2.1) | 11,215 (2.0) |
| Medium-intensity statin | 30,938 (1.5) | 9695 (1.3) | 7344 (1.3) |
| Low-intensity statin | 3847 (0.2) | 1165 (0.2) | 894 (0.2) |
| Ezetimibe only | 49,837 (2.4) | 16,552 (2.2) | 12,599 (2.2) |
| PCSK9i (monotherapy or in combination with statin) | 16,732 (0.8) | 6870 (0.9) | 4955 (0.9) |
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