The 2018 American Heart Association/American College of Cardiology/Multisociety Cholesterol Guideline (“2018 Guideline”) and the 2022 Expert Consensus Decision Pathways differentiate between “very high-risk” and “not at very high-risk” patients with atherosclerotic cardiovascular disease (ASCVD), with different treatment algorithm recommendations and low-density lipoprotein cholesterol (LDL-C) goals for each group. Very high-risk ASCVD includes patients with ≥2 major ASCVD events or 1 major ASCVD event and ≥2 high-risk conditions.1,2 However, the prevalence of these 2 risk categories has not been comprehensively explored in recent years. It, therefore, remains uncertain whether this form of risk stratification meaningfully informs LDL-C management. This study estimated the prevalence of these 2 risk categories and the incidence rates (IRs) of future ASCVD events within each category to provide insights into the application of this risk stratification.
What is the clinical question being addressed?
What is the contemporary prevalence of very high-risk vs not very high-risk atherosclerotic cardiovascular disease and corresponding risk for future cardiovascular events?
What is the main finding?
Most participants were at very high-risk. The smaller not very high-risk group still demonstrated clinically relevant risk for future events.
Methods
Adults with an inpatient or outpatient diagnosis for ASCVD between January 1, 2016, and December 31, 2024, were identified using the Optum de-identified Clinformatics Data Mart Database, a large commercial and Medicare Advantage database. Optum data include only deidentified health information, in accordance with the Health Insurance Portability and Accountability Act Privacy Rule. It does not contain any direct identifiers of individuals, employers, households, or health care providers. The use of Optum deidentified data for research does not constitute research with human subjects and does not require an Institutional Review Board review or an ethical waiver.
Patients with at least 12 months of continuous enrollment before their first ASCVD diagnosis (index date) during the study period were included. Due to the lack of complete longitudinal data on ASCVD history, we classified very high-risk patients as those with ASCVD and ≥2 high-risk conditions, and not very high-risk patients as those with ASCVD and <2 high-risk conditions. The high-risk conditions included were based on the 2018 guideline1 (Table 1). Future ASCVD events were defined as any postindex hospitalizations for ASCVD. The prevalence of very high-risk and not very high-risk categories, as well as the IR for future ASCVD events within each category were estimated among all ASCVD patients, and separately for those diagnosed inpatient and outpatient.
Table 1.
Prevalence of Very High-Risk Versus Not Very High-Risk ASCVD, and Incidence Rates for Future ASCVD Events Among Patients Diagnosed With ASCVDa, Optum deidentified Clinformatics Data Mart Database, January 1, 2016, to December 31, 2024
| ASCVD (Inpatient or Outpatient Diagnosis) (n = 4,991,899) | ASCVD (Inpatient Diagnosis) (n = 209,525) |
ASCVD (Outpatient Diagnosis) (n = 4,782,374) |
|||||||
|---|---|---|---|---|---|---|---|---|---|
| Risk stratification group | Prevalence (%) (95% CIb) |
Number of future ASCVD events | Incidence rate for future ASCVD events (per 1,000 person-years) (95% CI) | Prevalence (%) (95% CI) |
Number of future ASCVD events | Incidence rate for future ASCVD events (per 1,000 person-years) (95% CI) | Prevalence (%) (95% CI) |
Number of future ASCVD events | Incidence rate for future ASCVD events (per 1,000 person-years) (95% CI) |
| Very high-risk (≥2 high-risk conditionsc) | 87.12 (87.09-87.15) | 337,534 | 27.30 (27.21-27.39) | 90.44 (90.32-90.57) | 18,487 | 47.44 (46.75, 48.12) | 86.97 (86.94-87.00) | 319,047 | 26.65 (26.55, 26.74) |
| Not very high-risk (<2 high-risk conditionsc) | 12.88 (12.85-12.91) | 26,010 | 14.24 (14.07-14.41) | 9.56 (9.43-9.68) | 1,096 | 26.02 (24.48, 27.56) | 13.03 (13.00-13.06) | 24,914 | 13.96 (13.79, 14.14) |
ASCVD = atherosclerotic cardiovascular disease.
ASCVD diagnosis: coronary artery disease (myocardial infarction, percutaneous coronary intervention procedure, coronary artery bypass graft procedure, historical myocardial infarction, other ischemic heart disease due to ASCVD diagnosis, angina or unstable angina, and chronic ischemic heart disease), atherosclerotic cerebrovascular disease (ischemic stroke, transient-embolic stroke, or transient ischemic attack (excluding hemorrhagic stroke), and cerebrovascular revascularization), and peripheral arterial disease (peripheral arterial disease, limb ischemia, lower extremity arterial revascularization, including endovascular stenting and bypass surgery, lower extremity amputation, and claudication).
Clopper-Pearson formula was used to calculate the 95% CI for risks and the Wald to calculate the 95% CI for incidence rates in SAS.
High-risk conditions: age ≥65 years, familial hypercholesterolemia, history of prior coronary artery bypass surgery or percutaneous coronary intervention, diabetes, hypertension, chronic kidney disease, tobacco use, and congestive heart failure. Elevated LDL-C despite therapy was not included due to substantial missingness of laboratory results.
Results
A total of 4,991,899 eligible patients were included, with 95.8% diagnosed outpatient (Table 1). Overall, among adult patients diagnosed with ASCVD, 87.12% (95% CI: 87.09% to 87.15%) were very high-risk, and 12.88% (95% CI: 12.85% to 12.91%) were not very high-risk. The IRs for future ASCVD events were 27.30 (95% CI: 27.21-27.39) per 1,000 person-years for very high-risk and 14.24 (95% CI: 14.07-14.41) per 1,000 person-years for not very high-risk, with a median follow-up of 2.15 and 2.18 years, respectively. In the subgroup analysis, both prevalence of very-high risk and IR for future ASCVD events in the very high-risk category were higher in ASCVD patients diagnosed inpatient (90.44%, 47.44 per 1,000 person-years) compared to those diagnosed outpatient (86.97%, 26.65 per 1,000 person-years).
Discussion
The 2022 American College of Cardiology Expert Consensus Decision Pathways outline different LDL-C treatment thresholds according to ASCVD risk categories, with a goal of achieving a ≥50% reduction in LDL-C and achievement of an LDL-C threshold of <55 mg/dL for those at very high-risk and <70 mg/dL for those not at very high-risk for future ASCVD events.2 However, our findings based on a large commercial and Medicare Advantage database that included ASCVD patients diagnosed in both inpatient and outpatient settings suggest that the vast majority met the criteria for very high-risk. Although the not very high-risk group constituted a small proportion of the overall population, they still demonstrated clinically relevant risk for future events. Subcategorization of patients with clinical ASCVD to guide LDL-C management goals may not meaningfully differentiate patient risk. Future research is needed to understand how this differentiation impacts access to nonstatin lipid-lowering therapies in the 2 groups.
The prevalence estimates in this study were consistent with a prior study using nationally representative samples from the National Health and Nutrition Examination Survey and MarketScan claims data, which reported that 81.6% (95% CI: 76.7% to 86.4%) of adults with a history of ASCVD had a very high-risk of future ASCVD events.3 The IR for future events in the very high-risk group in this study was lower compared with previously published results by Colantonio et al.4 (53.1 per 1,000 person-years), which may be attributable to the possibly lower proportion of patients with a history of 2 or more major ASCVD events (who are more likely to have recurrent events).5 In the subgroup analyses, ASCVD patients diagnosed inpatient had a higher prevalence of very high-risk ASCVD and a higher future event risk than patients diagnosed outpatient. This may reflect overall more severe disease conditions in patients diagnosed inpatient.
Limitations of this study should be noted. First, generalization is limited to commercially insured and Medicare Advantage populations. Second, there may be underascertainment of certain high-risk conditions due to incomplete information on behavior, laboratory results, and family history. Third, due to the incomplete longitudinal data on ASCVD history, we were unable to differentiate between patients with 1 or multiple major ASCVD events. Claims-based algorithms used to define a history of ASCVD and future events have modest sensitivity,4 which leads to underestimation of prevalence. Future studies using EHR data with more complete ASCVD histories may mitigate this limitation.
These findings suggest that the current ASCVD risk stratification framework, as operationalized in clinical practice, identifies the vast majority of patients as very high-risk, thereby limiting its ability to meaningfully differentiate risk or guide LDL-C treatment decisions.
Funding support and author disclosures
Dr Shapiro has received grant/research support (through his institution) from Amgen, Boehringer Ingelheim, Novartis, Ionis, Merck, New Amsterdam, Eli Lilly, and Cleerly; he has participated in Scientific Advisory Boards with Amgen, Novartis, Eli Lilly, Tourmaline, Merck, Astra Zeneca, and Esperion; and he has served as a consultant for Novartis, Esperion, Merck, Novo Nordisk, Astra Zeneca, Alnylam, and Tourmaline. Dr Michos reports consulting/advisory boards (through her institution) for Arrowhead, Bayer, Boehringer Ingelheim, Edwards Life Science, Ionis, Eli Lilly, Merck, New Amsterdam, Novartis, Novo Nordisk, and Pfizer. Dr Ballantyne receives grant/research support (through his institution) from Abbott Diagnostic, Akcea, Amgen, Arrowhead, Eli Lilly, Ionis, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic; and reports consulting for 89Bio, Abbott Diagnostics, Amgen, Arrowhead, Astra Zeneca, Denka Seiken, Esperion, Genentech, HeartFlow, Ionis, Eli Lilly, Merck, New Amsterdam, Novartis, Novo Nordisk, Roche Diagnostic. Drs Xi, Jiang, Zhang, Bash, Rajpathak, Gellis, and Hilkert are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA, and may own stock and/or hold stock options in Merck & Co, Inc, Rahway, NJ, USA.
Acknowledgments
The authors gratefully acknowledge Drs Tongtong Wang, Julia R. DiBello, and Isil Ulger Isci for their valuable contributions to the study design and for their critical review and interpretation of the results.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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