Performance of PREVENT equations for cardiovascular risk prediction in young patients with myocardial infarction: From the MGB YOUNG-MI registry

Abstract

Background

Predicting cardiovascular risk in young adults remains challenging. The newly developed PREVENT equations offers several advantages for short and long-term cardiovascular risk prediction.

Objective

To determine how often PREVENT equations identify increased cardiovascular risk among young adults who experience premature myocardial infarction compared with existing risk calculators

Methods

The YOUNG-MI registry is a retrospective cohort from two large academic centers, which included individuals who experienced an MI at age ≤ 50 years. Study physicians adjudicated diagnosis of Type 1 MI. Cardiovascular risk was estimated by pooled cohort equations and PREVENT equations based on data available prior to MI or at the time of presentation.

Results

The study cohort included 1149 individuals with a median age of 45 years and 19 % women. The median 10-year ASCVD risk calculated by pooled cohort equations and 2023 PREVENT equations was 4.6 % and 2.3 %, respectively. Using the 10-year ASCVD risk estimates from the 2023 PREVENT equations, only 33 (3 %) individuals met the 7.5 % threshold while 93 (8 %) met the 5 % threshold and 333 (29 %) met the 3 % threshold. For 30-year ASCVD risk using PREVENT, 827 (72 %) met a threshold of ≥ 10 %.

Conclusion

The PREVENT equations may lead to undertreatment of young adults who experienced an MI. Using the 30-year risk PREVENT equations may improve long-term risk assessment in this population.

Despite advances in cardiovascular risk prediction, accurately identifying risk of cardiovascular events among young adults remains challenging. Several studies have demonstrated that existing risk prediction tools often fail to identify a significant proportion of young adults who ultimately experience a myocardial infarction (MI) [1,2]. We have previously reported [3] that existing atherosclerotic cardiovascular disease (ASCVD) risk calculated from the 2013 Pooled Cohort Equations (PCE) may underestimate risk in young adults. Current guidelines now impart a greater emphasis on risk-enhancing factors and lifetime risk in young adults [4].

Recently, the Predicting Risk of cardiovascular disease EVENTs (PREVENT) equations [5] were developed and validated in a significantly larger, race-agnostic, contemporary cohort, and offer several potential advantages over the PCE, including inclusion of younger individuals, assessment of 30-year risk, improved calibration, and incorporation of metabolic parameters such as A1c and microalbuminuria to predict global cardiometabolic risk.

Our objective was to assess statin eligibility based on current and alternative risk thresholds of the 2023 PREVENT score in the YOUNG-MI Registry which represents a large cohort of individuals who experienced a first-time MI at a young age.

The design of the YOUNG-MI registry has been previously published. In brief, this is a retrospective cohort study from two large academic medical centers (Brigham and Women's Hospital and Massachusetts General Hospital), which included patients who experienced an MI at or before 50 years of age between 2000 and 2016. Individuals with known CAD (defined as prior MI or revascularization) were excluded. All risk scores were calculated based on risk factor data available prior to MI. Lipid data at time of MI was only used if data prior to MI was not available, as previously described [3]. The study was approved by the Mass General Brigham IRB, with a waiver of informed consent.

We applied the PREVENT equations to calculate the 10-year and 30-year risk of ASCVD. The PREVENT score allows calculations of risk for individuals aged 30–79 years. For individuals younger than 30 years in our cohort (n = 27), an age of 30 was assigned to allow for calculation of the PREVENT score. Estimated glomerular filtration rate was calculated using CKD-EPI eGFR equations, as recommended. Patients with missing data (n = 173), and those with diabetes or LDL-cholesterol ≥ 190 mg/dL were excluded, as these individuals would meet criteria for statin initiation independent of their 10-year risk. The 2019 ACC/AHA Prevention guidelines were used to assess statin eligibility with the 2023 PREVENT equations. Additionally, we assessed lower statin thresholds of PREVENT (3 % and 5 %), which experts have suggested as an option that may be used to identify patients who may derive net benefit from statin therapy [6]. Lastly, we used ≥ 10 % as a cutoff for elevated 30-year ASCVD risk using PREVENT in the absence of an established threshold. We also conducted sensitivity analyses using thresholds ranging from 5 % to 30 %. All analyses were performed using STATA version 17 (StataCorp, College Station, TX).

The initial cohort consisted of 1512 patients, of whom 210 were on statin therapy prior to their MI. Of the remaining 1302 individuals, 33 had LDL levels ≥ 190 mg/dL, and 120 had diabetes, qualifying them for statin therapy. For the final cohort (N = 1149), the median age was 45 years (interquartile range 41–48 years) and 219 (19 %) were women. The median 10-year ASCVD risk calculated by 2013 PCE and 2023 PREVENT equations was 4.6 % and 2.3 %, respectively.

Using the 10-year ASCVD risk estimates based on the PCE, 250 (21.8 %) individuals met the ≥ 7.5 % threshold, and 508 (44.2 %) individuals met the ≥ 5 % threshold. Using the 10-year ASCVD risk estimates from the 2023 PREVENT equations, only 33 (2.9 %) individuals met the ≥ 7.5 % threshold, and only 93 (8.1 %) individuals met the ≥ 5 % threshold. A lower threshold of 3 % for 10-year ASCVD risk using PREVENT was also evaluated, and 333 (28.9 %) individuals met this threshold.

We also assessed the Framingham Heart Study lifetime risk estimated from traditional risk factors using a threshold of 39 % and 30-year ASCVD risk estimates from PREVENT using a threshold of 10 %, respectively, and 776 (67.5 %) and 827 (71.9 %) of individuals met these criteria. The results stratified by sex are displayed in the Fig. 1. We conducted sensitivity analyses at different thresholds of the 30-year PREVENT ASCVD risk and the following proportion of patients met the specified thresholds: 5 % threshold – 1092 (95 %), 15 % threshold – 425 (36.9 %), 20 % threshold – 177 (15.4 %) and 30 % threshold – 33 (2.9 %).

Fig. 1.

Bar graph illustrating the percentage of young adults eligible for statin therapy based on 10-year ASCVD-PCE, 10-year ASCVD-PREVENT, Lifetime risk and 30-year ASCVD-PREVENT thresholds.

Caption: Y-axis represents % of individuals eligible for statin therapy. Men are represented in blue, women in orange. The far-left panel shows the results for 10-year ASCVD risk calculated from the Pooled Cohort Equations (PCE). The middle panel shows the results for 10-year ASCVD risk calculated from the PREVENT equations. The far-right panel shows the results for 30-year ASCVD risk calculated from PREVENT and lifetime risk from Framingham Heart Study.

This study applied the 2023 PREVENT equations to a cohort who experienced an MI at a young age. Our findings show that compared with the PCE, use of the new 2023 PREVENT equations would lead to a substantially lower number of individuals eligible for statin therapy, if evaluated prior to their MI. Even at a threshold of 5 % for 10-year ASCVD risk, less than 10 % of young adults who had an MI would have been eligible for primary prevention statin therapy, if the PREVENT equations were utilized prior to their event. These differences are even more apparent for young women. These data are in line with other recent studies suggesting adoption of PREVENT equations could considerably decrease statin eligibility among US adults [7]. The implications of these findings are profound, considering the increasing rate of cardiovascular comorbidities, financial toxicity of cardiovascular disease, and the loss of personal and societal productivity from cardiovascular morbidity and mortality affecting young adults. Given the underestimation of risk by PREVENT, a reduced threshold of 3 % has been suggested. However, even this liberal threshold would identify the majority of our population as low-risk and ineligible for statin therapy.

It is important to acknowledge that accurately identifying young adults at risk for premature cardiovascular events remains challenging with other risk prediction tools, and not just PREVENT [1–3]. Prior studies and our findings highlight the ongoing challenges for risk prediction in young adults and emphasize the need for novel personalized approaches for cardiovascular risk prediction in younger populations, as highlighted by our findings in the YOUNG-MI cohort.

Despite the above limitations of PREVENT, one of the advantages is its ability to predict 30-year ASCVD risk. Even at a conservative cutoff of 10 % for 30-year risk, most of our population would qualify for statin therapy. When directly compared with the lifetime risk calculator, a significantly higher proportion of women are identified as statin-eligible by the PREVENT 30-year ASCVD equation.

Our study has limitations. We only included young individuals who experienced a cardiovascular event, and thus, we are unable to estimate the performance characteristics of the PREVENT score among individuals who did not have an event. Our study did not identify an optimal threshold for treatment, as any algorithm that identifies more at-risk young individuals would also result in a higher number needed to treat to prevent an event (i.e. lower specificity). We did not evaluate the optional variables available in PREVENT, including HbA1c, urine microalbumin to creatinine ratio, and zip code, which may have further refined the risk prediction. For patients between 30 and 39 years of age, an age of 40 was assigned for the PCE, whereas PREVENT includes individuals above 30 years of age, so their actual age was assigned. This may have biased the results in favor of PCE. We excluded patients who were already on statin therapy or qualified for statin therapy prior to their MI, which may have biased towards selecting a lower risk population. Lastly, while we adopted a threshold of ≥ 10 % for 30-year ASCVD, this cutoff is not yet formally established. Future studies should validate optimal thresholds for long-term risk assessment using PREVENT in young adult populations.

In conclusion, current treatment thresholds based on the 2023 PREVENT equations may lead to undertreatment of young adults who eventually experienced an MI. Lowering the threshold for treatment or using the 30-year risk PREVENT equations may improve long-term risk assessment in this population. Because most young adults who ultimately experience an MI at a young age have underlying risk factors, in addition to evaluating risk scores, prevention strategies should focus on identifying and treating underlying risk factors [8]. Further studies are necessary to refine the most appropriate thresholds for the PREVENT risk score, while also considering how to integrate information on the presence and severity of various risk factors in young adults.

Fig. 1

Singh, DiCarli, Bhatt and Blankstein designed the study. Singh and Blankstein conducted the analysis and wrote the initial draft. All authors made critical contributions in reviewing and revising the manuscript.

Funding

This study did not receive funding. The authors received funding unrelated to the study and is listed under the author disclosures.

CRediT authorship contribution statement

Avinainder Singh: Writing – review & editing, Writing – original draft, Formal analysis, Conceptualization. Arthur Shiyovich: Writing – review & editing. Camila Veronica Freire: Writing – review & editing. Gary Peng: Writing – review & editing. Stephanie A. Besser: Writing – review & editing, Formal analysis. Adam N. Berman: Writing – review & editing. Brittany N. Weber: Writing – review & editing. Daniel M. Huck: Writing – review & editing. Rhanderson Cardoso: Writing – review & editing. Cian P. McCarthy: Writing – review & editing. Khurram Nasir: Writing – review & editing. Marcelo F. DiCarli: Writing – review & editing, Conceptualization. Deepak L. Bhatt: Writing – review & editing, Conceptualization. Ron Blankstein: Writing – review & editing, Writing – original draft, Conceptualization.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:

Dr. Singh is supported by NIH grant 5T32HL007604–39. Dr. Huck is supported by AHA Career Development Award (23CDA1037589). Dr. Weber is supported by NIH/NHLBI K23HL159276, AHA 21CDA851511 and reports consulting/advisory board fees from Novo Nordisk, Kiniksa, and Oruka. Dr. McCarthy is supported by a National Heart, Lung, And Blood Institute Career Development Award (K23HL167659) and has received consulting fees/honorarium from Roche Diagnostic, Abbott Laboratories, New Amsterdam Pharma, and HeartFlow, Inc. Dr. Weber is supp Dr. Bhatt discloses the following relationships - Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, E-Star Biotech, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, NirvaMed, Novo Nordisk, Stasys; Tourmaline Bio; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock); Consultant: Broadview Ventures, Corcept Therapeutics, GlaxoSmithKline, Hims, SFJ, Summa Therapeutics, Youngene; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, 89Bio; Royalties: Elsevier (Editor, Braunwald’s Heart Disease); Site Co-Investigator: Cleerly. Dr. Blankstein has received research support from Amgen Inc, Novartis Inc, Heartflow Inc, and Nanox AI, and has served as a consultant for Caristo Inc, Hearflow Inc, Novartis Inc, and Nanox AI.

If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.