Abstract
Background
The 2018 AHA/ACC cholesterol guideline changed statin eligibility criteria for primary prevention to include multiple risk enhancers and novel intensive lipid-lowering therapies for secondary prevention.
Objectives
Determine how guideline changes impacted identification for preventive therapy in young adults with premature myocardial infarction (MI).
Methods
We identified adults presenting with first MI at Duke Hospital; statin therapy eligibility was determined using the 2013 ACC/AHA and 2018 AHA/ACC guidelines criteria. We also determined potential eligibility for intensive lipid-lowering therapies (very high risk) under the 2018 AHA/ACC guidelines, assessing the composite of all-cause death, recurrent MI, or stroke rates in adults considered “very high risk” vs. not.
Results
Among 6,639 MI patients, 41% were <55 years (“younger”), 35% were 55–65 (“middle-aged”), and 24% were 66–75 (“older”). Younger adults were more frequently smokers (52% vs. 38% vs. 22%), obese (42% vs. 34% vs. 31%), with metabolic syndrome (21% vs. 19% vs. 17%), and higher low-density lipoprotein cholesterol (117 vs. 107 vs. 103 mg/dL); p-trend <0.01 for all. Pre-MI, fewer younger adults met guideline indications for statin therapy than middle-aged and older adults. The 2018 guideline identified fewer younger adults eligible for statin therapy at the time of their MI than the 2013 guideline (46.4% vs. 56.7%, p<0.01). Younger patients less frequently met very high-risk criteria for intensive secondary prevention lipid-lowering therapy (28.3% vs. 40.0% vs. 81.4%, p<0.01). Over a median 8 years of follow-up, very high-risk criteria were associated with increased risk of major adverse cardiovascular events in individuals <55 years (HR 2.09, 95% CI 1.82–2.41, p<0.001), as was the case in older age groups (p-interaction=0.54).
Conclusions
Most younger patients with premature MI are not identified as statin candidates prior to their event based on the 2018 guidelines and most with premature MI are not recommended for intensive post-MI lipid management.
Keywords: premature coronary artery disease, guideline, statin therapy, treatment differences
CONDENSED ABSTRACT
The 2018 AHA/ACC cholesterol guideline included “risk enhancers” to guide primary prevention, and novel intensive lipid-lowering therapies for secondary prevention. Among 6,639 patients experiencing their first MI, 41% were <55 years, 35% were 55–65, and 24% were 66–75. Pre-MI, fewer younger adults met guideline indications for statin therapy than middle-aged and older adults. The 2018 guideline identified fewer young adults eligible for statin therapy than the 2013 guideline. Younger patients less frequently met very high-risk criteria for intensive lipid-lowering therapy. Very high-risk criteria were associated with increased risk of major adverse cardiovascular events across all age groups.
Introduction
Lipid-lowering therapies are a cornerstone of primary and secondary prevention of cardiovascular disease (1, 2). Previous guidelines for cholesterol management expanded statin treatment eligibility based on 10-year atherosclerotic cardiovascular disease (ASCVD) risk score (3–7), but because this score is highly age-dependent, guidelines often failed to identify young patients at risk for premature coronary artery disease (CAD) (8–10). The identification of those at risk for premature CAD is of increasing importance since young individuals represent a growing portion of the ischemic heart disease population (11). Adults who develop CAD early in life experience a poor overall long-term prognosis with frequent premature death, multiple ischemic recurrences, and rapid evolution towards multivessel disease, thereby highlighting the importance of early primary detection and aggressive early secondary prevention (12).
The 2018 American Heart Association (AHA)/American College of Cardiology (ACC) Multisociety Guideline on the Management of Blood Cholesterol provided new criteria to enable a more tailored risk assessment to guide statin prescription in primary prevention (2). Multiple risk enhancers were included among the new criteria, including chronic inflammatory disorders, high-risk ethnic groups, and premature menopause (12). The 2018 guideline also updated secondary prevention lipid recommendations, including recommendations for non-statin lipid-lowering therapies such as ezetimibe and PCSK9 inhibitors as part of the treatment strategy among myocardial infarction (MI) patients at the highest risk for recurrent ASCVD events (10).
The objectives of this study were to determine: 1) how often lipid guidelines would have recommended statin therapy among those who develop premature CAD; 2) how often intensive post-MI lipid-lowering management is recommended in younger patients; and 3) whether current criteria used to identify those at highest risk in secondary prevention actually identify higher risk similarly across age groups.
Methods
Study Design And Population
The Duke Databank for Cardiovascular Disease (DDCD) is a prospective registry with a pre-specified data collection of clinical and angiographic baseline characteristics of all patients who underwent cardiac catheterization at Duke University Medical Center. In the DDCD, death and cardiovascular events are followed via annual surveys in all patients with significant CAD (13). When patients are hospitalized at Duke hospital, the events are reported by physicians and ascertained from Duke Health System records. Follow-up calls and mailed surveys are sent at 6 and 12 months after the index catheterization and then annually thereafter to collect events occurring outside of Duke Hospital. Hospitalization events reported on follow-up surveys occurring at outside hospitals were classified by an events committee, who reviewed information reported by the patient and medical records acquired from the admitting hospital (14). For patients lost to follow-up, a query of the National Death Index was obtained to ascertain vital status through 2014.
Using the DDCD, we included patients previously free of cardiovascular disease who were admitted from 1995 to 2012 for a first acute MI with angiographic findings of obstructive ASCVD. MI was ascertained at the time of cardiac catheterization based on the hospitalization record. Clinical variables for the patients were collected at the time of admission including age, race, body mass index, cardiovascular risk factors, and blood pressure. Other historical variables were collected in the DDCD using data from the patient medical record prior to the admission including medication pre-MI, history of chronic obstructive pulmonary disease and dialysis. This time period (1995–2012) was chosen to allow for adequate outcomes assessment post-first MI event. Obstructive CAD was defined as a coronary stenosis ≥50%. Patients with missing blood cholesterol values at the time of or within +/− 1 year of the index catheterization were excluded. In order to identify adults who were previously free of ASCVD, patients with prior documented stroke, MI, peripheral artery disease, or obstructive CAD were excluded.
The retrospective observational study was approved by the Duke Institutional Review Board (IRB) under a waiver of informed consent and Health Insurance Portability and Accountability Act of 1996 approval. This analysis was approved by the Duke University Health System IRB (PRO 00102546).
Clinical Characteristics of Adults with Obstructive CAD
Baseline clinical and catheterization variables for each patient are collected and registered prospectively at the time of catheterization using pre-specified methods in the DDCD (13, 15). These baseline variables included cardiovascular risk factors, medical and cardiovascular history prior to the index catheterization, and angiographic results. Baseline laboratory measures were ascertained from the DDCD intake form supplemented by a search of the patient’s electronic medical record and were based on the value recorded at catheterization intake or the most recent value within 365 days prior. If no prior measure was available, then the earliest value within the subsequent 365 days was used. Baseline medication use was ascertained from the DDCD intake form, as well as a search of the patient’s medical record. Medication use was defined as any prescription record prior to the current hospital admission and within 365 days prior to catheterization.
Among these variables, active smoking, diabetes, hypertension, dyslipidemia, and familial history of CAD, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels were used to evaluate participants’ 10-year ASCVD risk score and lifetime risk prior to their index MI. The 10-year ASCVD score was calculated using the pooled cohort equations in those 40 to 79 years old, and lifetime risk was assessed per Berry et al. in those older than 20 years (16). The following risk enhancers included in the 2018 AHA/ACC Guidelines for Blood Cholesterol were collected using the DDCD history and physical intake examination forms: connective tissue disease, premature menopause (before 40 years old), family history of CAD, ethnicity, human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), estimated glomerular filtration rate <60 ml/min, and metabolic syndrome. At least 3 of the following criteria needed to be present to meet the definition of metabolic syndrome: body mass index ≥30 kg/m2, baseline triglycerides ≥175 mg/dL, baseline HDL-C <40 mg/dL for men and <50 mg/dL for women, hypertension or on an anti-hypertensive drug, and diabetes. HIV status was not collected at the time of catheterization and, therefore, was derived using a search of the patient’s electronic medical record prior to catheterization. Asian ethnicity was used as a surrogate for South Asian ethnicity.
Continuous variables are presented as median and interquartile ranges, and compared across age categories using p-values for trend: Cochrane-Armitage Trend test for binary variables, Cochran-Mantel Haenszel test for categorical variables, and Spearman Correlation test for continuous variables. P-values and 95% confidence intervals presented in this report have not been adjusted for multiplicity; therefore, inferences drawn from these statistics may not be reproducible. Descriptive summaries of the cohort and risk factors are based on available data with missing values excluded from calculations (Supplemental Figure 1).
Primary Prevention Statin Eligibility
The objective of this analysis was to identify the proportion of adults who would have qualified for a statin prior to their first MI according to each age category: <55 years, 55–65 years, and 66–75 years. Using individuals’ risk profile at the time of their first MI, we identified those eligible for statin therapy in primary prevention based on a class I or a class IIa recommendation in the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults and the 2018 AHA/ACC Multi-society Guideline on the Management of Blood Cholesterol, respectively.
Eligibility for statins in primary prevention was defined as having a class I or IIa recommendation. The criteria for eligibility for statins according to 2013 and 2018 guidelines are listed in Supplemental Table 1. For both the 2013 and 2018 guidelines, individuals with LDL-C ≥190 mg/dL have a class I recommendation for statins, as well as diabetics with an LDL-C higher than 70 mg/dL. The 2013 guideline provided a class I recommendation for statins for non-diabetic individuals with a 10-year ASCVD score ≥7.5%. This recommendation was modified by the 2018 guideline, raising the ASCVD risk to 20% or more to be class I eligible, or higher than 7.5% combined with a risk enhancer. Patients with an ASCVD score higher than 7.5% without a risk enhancer became eligible for statins (class IIa recommendation). Previous class IIa recommendation for statins in individuals with a 5–7.5% 10-year ASCVD score in the 2013 ACC/AHA guideline was downgraded to a class IIb in the 2018 guideline and, therefore, considered as non-eligible in the following analysis. Eventually, the 2018 guideline established an additional class IIa recommendation for statins in young adults 20–39 years with a combination of LDL-C ≥160 mg/dL and a risk enhancer. Patients already treated with statins prior to MI (2.7%) were considered as eligible according to both guidelines. The list of risk enhancers considered in the 2018 AHA/ACC guideline and available in the DDCD is displayed in Supplemental Table 2
Individuals with a weak recommendation (class IIb) were not considered as eligible for statins in the primary analysis; however, the proportion of adults meeting IIb recommendations were evaluated, including those with 10-year risk between 5–7.5% and one risk enhancer, as well as those with LDL-C ≥160 mg/dL and <190 mg/dL without a risk enhancer (Supplemental Table 1).
We compared the sensitivity of the 2013 ACC/AHA vs. 2018 AHA/ACC guideline based on their ability to identify patients for statin therapy prior to their event using the homogeneity test. In order to evaluate the performance of the 2013 and 2018 guidelines, we excluded 252 patients (3.8%), due to missing data for systolic BP. To allow for inferences of results to the entire cohort, inverse probability weighting was used to adjust summary statistics and p-values.
Guideline Recommendations for Secondary Prevention: Assessment of “Very High Risk.”
The 2018 AHA/ACC guidelines recommend consideration of PCSK9 inhibitor therapy for those at “very high risk” of events who have uncontrolled LDL-C, despite statin and ezetimibe therapy (Class IIa). We assessed the proportion of patients who would be considered “very high risk” after their first event and, consequently, potentially eligible for PCSK9 inhibitor therapy if LDL-C levels remained elevated. Very high-risk status for future ASCVD was defined as two or more of the following criteria: age ≥65 years, diabetes, hypertension, glomerular filtration rate of 15–59 mL/min/1.73m2, current smoking, or history of heart failure. We evaluated the association between presence or absence of very high-risk criteria and the time from catheterization to the composite of all-cause death, non-fatal recurrent MI, or stroke across age. Patients were followed until 8 years after the index MI, or through the end of DDCD follow-up in December 2014.
We evaluated the cumulative incidence of the composite of stroke, MI, or all-cause mortality stratified by age group in adults considered at “very high risk” and “not at very high risk” using Kaplan-Meier analyses, with cumulative incidence curves through 8 years of follow-up compared using the log-rank test. Heterogeneity in the association between very high-risk criteria and subsequent events across age groups was evaluated by testing for a significant interaction between these factors in a Cox regression model for time-to-first event. All statistical analyses were performed using SAS software, version 9.4, SAS Institute, Inc. (Cary, NC, USA).
Results
Baseline Characteristics
Among 6,639 patients receiving cardiac catheterization who were admitted for a first MI with obstructive CAD, 41% were aged <55 years (n=2733), 35% were 55–65 years (n=2324), and 24% were 66–75 (n=1582). The selection of patients for this study is displayed in Supplemental Figure 1 and Supplemental Table 3. Baseline characteristics are displayed in Table 1. Compared with older and middle-aged adults, younger adults with MI were more frequently male (75.8% vs. 70.8% vs. 58.1%, p <0.001), African-American (25.2% vs. 21.2% vs. 21.1%, p<0.001), smokers (51.8% vs. 38.3% vs. 21.6%, p<0.001), and had higher levels of LDL-C and triglycerides. Conversely, individuals <55 years old less frequently had hypertension (46.5% vs. 56.6% vs. 63.9%, p<0.001) and diabetes (18.9% vs. 24.2% vs. 28.6%, p<0.001).
Table 1.
Baseline Characteristics at Admission for a First MI According to Age Category
| 18 ≤ Age <55 (N=2733) | 55 ≤ Age ≤65 (N=2324) | 65< Age ≤75 (N=1582) | All (N=6639) | P-value for trend | |
|---|---|---|---|---|---|
| Demographics and risk factors | |||||
| Age at catheterization, years | 48 (43 – 51) | 60 (57 – 63) | 70 (68 – 73) | 57 (50 – 65) | |
| Female | 661 (24.2%) | 676 (29.1%) | 663 (41.9%) | 2000 (30.1%) | <.001 |
| Race | <.001 | ||||
| White | 1780 (65.8%) | 1645 (71.6%) | 1133 (72.8%) | 4558 (69.5%) | |
| Black African | 681 (25.2%) | 488 (21.2%) | 329 (21.1%) | 1498 (22.8%) | |
| Asian | 22 (0.8%) | 26 (1.1%) | 9 (0.6%) | 57 (0.9%) | |
| American Indian | 165 (6.1%) | 98 (4.3%) | 62 (4.0%) | 325 (5.0%) | |
| Native Hawaiian | 2 (0.1%) | 1 (0.0%) | 1 (0.1%) | 4 (0.1%) | |
| Other | 56 (2.1%) | 40 (1.7%) | 23 (1.5%) | 119 (1.8%) | |
| BMI (kg/m^2) | 29 (26 – 33) | 28 (25 – 32) | 27 (24 – 31) | 28 (25 – 32) | <.001 |
| BMI categories | <.001 | ||||
| BMI <25 | 520 (19.2%) | 561 (24.3%) | 479 (30.4%) | 1560 (23.6%) | |
| 25 ≤ BMI <30 | 1066 (39.3%) | 971 (42.0%) | 609 (38.7%) | 2646 (40.1%) | |
| 30 ≤ BMI ≤35 | 694 (25.6%) | 467 (20.2%) | 295 (18.7%) | 1456 (22.1%) | |
| BMI >35 | 434 (16.0%) | 311 (13.5%) | 191 (12.1%) | 936 (14.2%) | |
| History of smoking | <.001 | ||||
| Never | 1080 (39.5%) | 1112 (47.8%) | 978 (61.8%) | 3170 (47.7%) | |
| Former | 236 (8.6%) | 321 (13.8%) | 262 (16.6%) | 819 (12.3%) | |
| Current | 1417 (51.8%) | 891 (38.3%) | 342 (21.6%) | 2650 (39.9%) | |
| History of hypertension | 1271 (46.5%) | 1316 (56.6%) | 1011 (63.9%) | 3598 (54.2%) | <.001 |
| History of diabetes | 517 (18.9%) | 562 (24.2%) | 452 (28.6%) | 1531 (23.1%) | <.001 |
| History of hyperlipidemia | 1093 (40.0%) | 1020 (43.9%) | 715 (45.2%) | 2828 (42.6%) | <.001 |
| History of COPD | 60 (2.2%) | 70 (3.0%) | 72 (4.6%) | 202 (3.0%) | <.001 |
| Patient currently on dialysis | 22 (0.8%) | 27 (1.2%) | 22 (1.4%) | 71 (1.1%) | 0.062 |
| History of liver disease | 8 (0.3%) | 8 (0.3%) | 3 (0.2%) | 19 (0.3%) | 0.619 |
| Reason for admission | <0.001 | ||||
| STEMI | 1980 (72.4%) | 1480 (63.7%) | 926 (58.5%) | 4356 (66.1%) | |
| NSTEMI | 698 (25.5%) | 785 (33.8%) | 582 (36.8%) | 2065 (31.1%) | |
| MI unspecified | 55 (2.0%) | 59 (2.5%) | 74 (4.7%) | 188 (2.8%) | |
| Number of significantly diseased vessels | <.001 | ||||
| One | 1512 (55.3%) | 1038 (44.7%) | 587 (37.1%) | 3137 (47.3%) | |
| Two | 738 (27.0%) | 676 (29.1%) | 476 (30.1%) | 1890 (28.5%) | |
| Three | 483 (17.7%) | 610 (26.2%) | 519 (32.8%) | 1612 (24.3%) | |
| Laboratory values* | |||||
| Triglycerides baseline value | 123 (82 – 181) | 112 (75 – 169) | 101 (66 – 149) | 114 (75 – 170) | <.001 |
| Total cholesterol baseline value | 183 (157 – 215) | 175 (148 – 203) | 167 (142 – 197) | 177 (150 – 207) | <.001 |
| HDL baseline value | 37 (31 – 44) | 39 (33 – 47) | 41 (34 – 49) | 39 (32 – 47) | <.001 |
| HDL<40 mg/dL for men,<50 for women | 1808 (66.2%) | 1437 (61.8%) | 945 (59.7%) | 4190 (63.1%) | <.001 |
| LDL baseline value | 117 (91 – 143) | 107 (84 – 133) | 103 (79 – 128) | 110 (85 – 136) | <.001 |
| LDL category | <.001 | ||||
| LDL <70 | 259 (9.5%) | 312 (13.4%) | 254 (16.1%) | 825 (12.4%) | |
| 70 ≤ LDL <100 | 624 (22.8%) | 646 (27.8%) | 492 (31.1%) | 1762 (26.5%) | |
| 100 ≤ LDL <130 | 816 (29.9%) | 718 (30.9%) | 463 (29.3%) | 1997 (30.1%) | |
| 130 ≤ LDL <190 | 897 (32.8%) | 584 (25.1%) | 325 (20.5%) | 1806 (27.2%) | |
| LDL ≥190 | 137 (5.0%) | 64 (2.8%) | 48 (3.0%) | 249 (3.8%) | |
| LDL ≥160 | 422 (15.4%) | 238 (10.2%) | 132 (8.3%) | 792 (11.9%) | <0.001 |
| Systolic BP (mmHg) | 129 (115 – 144) | 132 (117 – 149) | 136 (118 – 154) | 131 (117 – 148) | <.001 |
| Diastolic BP (mmHg) | 79 (70 – 90) | 78 (68 – 88) | 75 (66 – 84) | 78 (68 – 88) | <.001 |
| Heart rate (bpm) | 74 (64 – 85) | 74 (63 – 85) | 73 (64 – 86) | 73 (64 – 85) | 0.583 |
| Medications prior to MI† | |||||
| Hypertension treatment | 190 (7.0%) | 228 (9.8%) | 174 (11.0%) | 592 (8.9%) | <.001 |
| Aspirin | 132 (4.8%) | 154 (6.6%) | 107 (6.8%) | 393 (5.9%) | 0.004 |
| Statin | 74 (2.7%) | 87 (3.7%) | 74 (4.7%) | 235 (3.5%) | <.001 |
Baseline laboratory measures are based on the value recorded at catheterization intake or the most recent value within 365 days prior. If no prior measure was available, then the earliest value within the next 365 days was used.
Baseline medication use was determined by any prescription record prior to the current hospital admission and within 365 days prior to catheterization.
BMI = body mass index; BP = blood pressure; bpm = beats per minute; COPD = chronic obstructive pulmonary disease; HDL = high-density lipoprotein; LDL = low-density lipoprotein; MI = myocardial infarction; NSTEMI = non–ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction
Atherosclerotic Cardiovascular Disease Score and Risk Enhancers
Among younger patients (<55 years), 431 (15.8%) individuals were younger than 40 years old and, therefore, did not have a 10-year ASCVD score. Among younger patients (<55 years), the 10-year ASCVD score could only be evaluated in those 40–54 years of age (84.3%). Younger individuals had a lower 10-year ASCVD risk score (median risk of 6.4% vs. 11.6% vs. 19.6%, p<0.001) calculated prior to their index MI compared with older and middle-aged patients, but a greater lifetime risk (median risk of 33.9% vs. 32.2% vs. 31.9%, p<0.001) (Table 2). Obesity, metabolic syndrome, high triglycerides, and familial history of CAD were more frequent among young patients admitted with premature MI than the other age categories. Conversely, chronic kidney disease was more frequent among older categories of patients (Table 2).
Table 2.
Risk Enhancers According to Age Groups
| 18 ≤ Age <55 (N=2733) | 55 ≤ Age ≤65 (N=2324) | 65 < Age ≤75 (N=1582) | All (N=6639) | P-value for trend | |
|---|---|---|---|---|---|
| Risk enhancers | |||||
| Family history of CAD | 919 (33.6%) | 622 (26.8%) | 344 (21.7%) | 1885 (28.4%) | <.001 |
| Metabolic syndrome | 573 (21.0%) | 432 (18.6%) | 273 (17.3%) | 1278 (19.2%) | 0.002 |
| eGFR mL/min <60% | 199 (7.4%) | 409 (17.8%) | 569 (36.3%) | 1177 (17.9%) | <.001 |
| Menopause <40 years old | 24 (3.6%) | 34 (5.0%) | 28 (4.2%) | 86 (4.3%) | 0.596 |
| Body mass index ≥30 | 1128 (41.6%) | 778 (33.7%) | 486 (30.9%) | 2392 (36.3%) | <.001 |
| HIV/AIDS | 16 (0.6%) | 5 (0.2%) | 0 (0.0%) | 21 (0.3%) | <.001 |
| History of connective tissue disease | 10 (0.4%) | 3 (0.1%) | 1 (0.1%) | 14 (0.2%) | 0.026 |
| Asian ethnicity | 22 (0.8%) | 26 (1.1%) | 9 (0.6%) | 57 (0.9%) | 0.598 |
| Triglycerides ≥175 mg/dL | 754 (27.6%) | 537 (23.1%) | 258 (16.3%) | 1549 (23.3%) | <.001 |
| Number of risk enhancers | 0.026 | ||||
| 0 risk enhancer | 725 (26.5%) | 750 (32.3%) | 462 (29.2%) | 1937 (29.2%) | |
| 1 risk enhancer | 1024(37.5%) | 805 (34.6%) | 584 (36.9%) | 2413 (36.3%) | |
| 2 risk enhancers | 511 (18.7%) | 407 (17.5%) | 303 (19.2%) | 1221 (18.4%) | |
| ≥3 risk enhancers | 473 (17.3%) | 362 (15.6%) | 233 (14.7%) | 1068 (16.1%) | |
| Risk scores | |||||
| 10-year ASCVD risk, % | <.001 | ||||
| N* | 2302 | 2230 | 1526 | 6058 | |
| Median (25 th, 75th) | 6.4 (3.7, 10.4) | 11.6 (7.3, 17.2) | 19.6 (13.4, 28.4) | 10.9 (6.0, 18.2) | |
| Lifetime risk, % | <.001 | ||||
| N | 2717 | 2312 | 1566 | 6595 | |
| Median (25th, 75th) | 33.9 (29.2, 39.6) | 32.2 (29.4, 38.2) | 31.9 (29.3, 37.2) | 32.2 (29.3, 38.7) |
10-year ASCVD risk score only calculated among patients ≥40 years old
ASCVD = atherosclerotic cardiovascular disease; CAD = coronary artery disease; eGRF = estimated glomerular filtration rate; HIV/AIDS = human immunodeficiency virus/acquired immune deficiency syndrome
Eligibility For Primary Prevention Statin
Prior to their first MI, younger adults were less likely to meet a class I recommendation for statins under the 2013 guideline (42.9 % vs. 70.0% vs. 82.5%, p<0.001) and the 2018 guideline (39.4% vs. 59.5% vs. 77.4%, p<0.001). When taking into account both class I and class IIa recommendations, individuals aged <55 years were less likely to be eligible for statins prior to their index MI under both the 2013 (56.7% vs. 79.5%, 85.2%, p<0.01) and 2018 guidelines (46.4% vs. 73.5% vs. 88.2%, p<0.01) (Central Illustration). Compared with 2013, the 2018 guideline would have identified fewer young adults for statin therapy prior to their first MI (46.4% vs. 56.7%, p<0.01). Supplemental Table 4 shows the proportion of adults by age group who met a class IIb recommendation for statins. Of those in the younger age group, 6.2% had a 10-year ASCVD risk score between 5–7.5% with a risk enhancer (class IIb recommendation for primary prevention statins), which was higher than the proportion in older age categories (p<0.001). A smaller number (1.3%) had an LDL-C between 160 mg/dL and 190 mg/dL without a risk enhancer, which was also higher than the proportion of older adults who met these criteria (p<0.001).
Central illustration. Performance of the 2013 ACC/AHA and 2018 AHA/ACC Cholesterol Guidelines.
Performance of the 2013 ACC/AHA and 2018 AHA/ACC Cholesterol Guidelines to assign primary prevention statin treatment to individuals with incident MI according to age groups. ACC = American College of Cardiology; AHA = American Heart Association; MI = myocardial infarction
Performance Of “Very High Risk” Criteria Across Age Groups
Subsequent to their first MI, only one in four young patients (28.3%) met the very high-risk criteria compared with 40.0% of middle-aged and 81.4% of older patients (p-trend<0.001) (Figure 1). During 8 years of follow-up, patients with very high risk criteria according to the 2018 guideline had a twice higher rate of death, non-fatal MI, or stroke compared with other patients (hazard ratio [HR] 2.15, 95% confidence interval [CI] 1.98–2.33, p<0.001); this finding was driven by the event of all-cause death (36.1% vs. 14.1%, p<0.01). The association between very high-risk criteria and time to subsequent major adverse cardiovascular events was consistent across age groups (p-interaction=0.54, Supplemental Figure 2). Younger patients with very high-risk criteria were at higher risk of all-cause death, MI, or stroke compared with those without these criteria (44.6% vs. 25.9%, HR 2.09, 95% CI 1.82–2.41, p<0.001). These observations were consistent (p=0.53) among patients aged 55–65 years old (48.1% vs. 28.5%, HR 1.97, 95% CI 1.72–2.27, p<0.001) and 66–75 years (53.6% vs. 40.8%, HR 1.51, 95% CI 1.23–1.84, p<0.001) (Figure 2).
Figure 1. Eligibility for Non-statin Lipid-lowering Therapies.
Eligibility for non-statin lipid-lowering therapies according to the 2018 AHA/ACC guidelines by age groups. ACC = American College of Cardiology; AHA = American Heart Association
Figure 2. Association Between Non-statin Lipid-lowering Therapies and Death, MI, or Stroke.
Association between eligibility for non-statin lipid-lowering therapies for secondary prevention and death, MI, or stroke across age groups. MI = myocardial infarction
DISCUSSION
The 2018 AHA/ACC guideline incorporated a number of updates relative to prior guidelines, including more personalized criteria to identify candidates for statins for primary prevention, as well as a new risk stratification concept to guide the intensity of lipid-lowering in secondary prevention. We sought to determine how these guideline changes affected potential therapy recommendations for adults who develop premature ischemic heart disease. We found that approximately half of adults who developed premature CAD would have failed to meet a statin recommendation prior to their first event, and with fewer adults identified using the 2018 guideline criteria compared with 2013. As age increased, the proportion of adults with incident ischemic heart disease that would have been eligible for statin therapy prior to the onset of their event increased. Additionally, we note that after their first MI, far fewer younger individuals would be eligible for the most intensive lipid-lowering therapies for secondary prevention compared with older adults.
To our knowledge, this is among the first studies to comprehensively evaluate statin guideline eligibility with a focus on premature heart disease since the release of the most recent cholesterol guideline and implementation of risk enhancers. Previous studies have demonstrated that older cholesterol guidelines frequently failed to assign primary prevention statins to young individuals at risk of acute MI (8, 17). Our results demonstrate that the situation has not improved under the 2018 guideline, with more than 50% of young patients not eligible for statins prior to their acute MI. In contrast, more than 90% of older adults presenting with their first MI would have been recommended for statin therapy prior to their event. This failure to detect young patients at risk occurs despite these young patients having a higher prevalence of cardiovascular risk factors compared with their older counterparts, including higher rates of smoking, obesity, high LDL-C, and low HDL-C.
By providing risk enhancers specific to young patients at risk of premature CAD, the 2018 AHA/ACC guideline had the potential to improve risk identification. Many of these risk enhancers, such as obesity and metabolic syndrome, are described as strong correlates of poor cardiovascular outcomes and premature cardiovascular death among middle-aged American adults (18–20). Nevertheless, the 2018 guideline identified fewer younger patients for statin therapy than the 2013 guideline. There are several potential explanations for the ongoing missed opportunity to improve the detection of young patients at risk for premature ischemic heart disease. First, the risk factors that are more common in young adults, such as smoking and low HDL-C, are not independently considered risk enhancers. Young adults with an estimated 5–20% predicted 10-year risk can only receive a class I indication if a risk enhancer is present. Second, neither the 2013 nor 2018 guideline provides comprehensive recommendations for adults younger than 40, who can only become eligible for statin therapy in primary prevention with a class I indication if they have an LDL-C level higher than 190 mg/dl, regardless of their smoking status, body mass index, or other risk factors. The 2018 guideline provides a class IIa recommendation for statins for those aged 20–39 with an LDL-C higher than 160 mg/dL and a risk enhancer, but this recommendation was not enough to target individuals at risk for premature CAD. Finally, while relatively few adults had events before age 40, the development of atherosclerosis precedes clinical events by many years. Adults with a predicted 10-year risk of 20% or more are considered high risk, but very few younger individuals can reach this risk threshold because of the significance of older age in the risk model.
The implementation of risk enhancers on top of the 10-year ASCVD risk score to better identify high-risk young individuals requiring statins is an important step taken by the AHA/ACC 2018 Cholesterol Guideline. Nonetheless, our analysis suggests that the guidelines’ ability to identify young adults for statin therapy prior to their first MI remains suboptimal. Several proposed solutions may improve detection of at-risk young adults. First, broader utilization of coronary artery calcium (CAC) screening, which is emphasized in the latest guidelines, particularly in younger adults, may lead to detection of those with subclinical atherosclerosis who are at risk for events. Data from longitudinal cohort studies have shown that CAC can be used to improve risk stratification in young adults (21). Unfortunately, limited uptake of CAC scoring remains a barrier since CAC scoring is not universally reimbursed, and many are unable to pay the out-of-pocket cost. Second, improvements in screening for risk enhancers is needed to maximize the capture of these risk enhancers. In our study, we did not have access to information on maternal pregnancy complications since they were not collected. Efforts to improve routine capture of these data may improve risk prediction in young women. Third, the guidelines may consider upgrading the class IIb recommendation to a IIa recommendation to emphasize the importance of recognizing low or borderline-risk young adults, including treatment of younger adults with 5–7.5% 10-year risk and a risk enhancer, as well as adults with LDL-C 160–190 mg/dL. These two criteria alone would have identified an additional 7.5% of patients for therapy prior to their event, increasing the number of adults identified from 46.4% to 53.9%. Finally, another risk-based method to identify young adults at risk for MI include recommending statins for those at high lifetime risk (22) or those at high risk compared to age- and sex-matched peers (10). In our cohort, young individuals admitted for a first MI had a higher lifetime ASCVD risk score than the older age categories.
Adults who present with CAD earlier in life are at extremely high risk of recurrent events, highlighting the importance of aggressive secondary prevention (12, 23). In a prospective cohort study of patients with obstructive CAD before age 45, one-third of patients presented with a recurrent cardiovascular or cerebrovascular event within a median time of 5 years (12). Within a maximum follow-up of 20 years, multiple ischemic recurrences were frequent, despite guideline-based secondary prevention and premature death occurring in 10% of these young individuals. A similarly high rate of recurrent MI, stroke, or death was observed in the younger individuals in the present study. Nonetheless, in our cohort, fewer than 30% of patients with premature CAD would have been considered very high risk and met criteria for more intensive non-statin lipid-lowering therapy had they failed to achieve an LDL-C level <70 mg/dL on statins alone. While ezetimibe and PCSK9 inhibitors are associated with a significant reduction in major adverse cardiovascular events, including mortality, young individuals are rarely considered eligible, and less frequently deemed eligible than older adults (24–26). Current criteria to be considered very high risk requires the presence of two additional risk factors, which is rare in younger adults. By comparison, being ≥65 years of age is considered a high-risk criterion in and of itself, so the bar for very high risk is essentially lower in older vs. younger adults. In secondary prevention, our data suggest that relatively few younger adults are meeting guideline-based criteria for the most aggressive lipid-lowering therapy after their event, despite having a long potential treatment time. Given evidence that the benefit of these therapies increases with time on treatment and provides an absolute reduction in LDL-level, younger adults may be a group that has the most potential benefit on therapy (27). In contrast with the AHA/ACC guideline, the 2019 European Society of Cardiology/European Atherosclerosis Society Task Force for management of dyslipidaemias consider all patients with MI as very high risk and eligible for additional non-statin lipid-lowering therapies in case of persistently high LDL-C with statins (3). Such an approach would increase the overall number eligible for therapy, thereby increasing the cost to the system. As costs have been lowered for PCSK9 inhibitors, and new therapies are made available in the future, cost-related barriers should continue to drop. This approach would also lead to treatment of a population at overall lower risk of recurrent events than just those with risk enhancers, increasing the overall number needed to treat, but would ensure that the benefit of these therapies to the overall burden of disease is maximized.
We demonstrated that very high-risk criteria as presented in the current guidelines do successfully identify individuals at higher risk of fatal events or ischemic recurrences, with a consistent effect across age groups. Despite the fact that young adults who were not at very high risk had lower event rates than those considered very high risk, 25% still had major adverse ischemic events, suggesting that they could benefit from more aggressive therapy. Statins remain the cornerstone of lipid-lowering in secondary prevention, as supported by the recommendation for high-intensity statins for all patients <75 years of age with ASCVD in the current and prior guidelines. Nonetheless, who to treat with additional lipid-lowering therapy remains uncertain. Our analysis suggests that the current paradigm of treating only those at highest risk of recurrent events in the short-term may lead to large numbers of younger adults failing to meet guideline recommendations for treatment. Analyses from the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY) Outcomes trials show no interaction on the relative scale by age (28–29), and data from long-term follow-up of lipid-lowering therapy trials shows that the benefit of therapy improves with time on treatment (30). Therefore, those with early onset disease have the highest potential treatment time, due to higher overall life expectancy. Given that the recommendation for limiting PCSK9 inhibitors for those at higher risk was largely driven by the cost of therapy, the requirement for additional risk factors beyond a single event may be reconsidered when the price is lowered.
Study limitations
We acknowledge our study had some limitations. First, patients treated with statins prior to the index event were considered to have class I eligibility for both guidelines. As previously mentioned, not all risk enhancers listed in the 2018 guideline were present in the DDCD (Supplemental Table 2). Furthermore, not all risk enhancers are captured in routine clinical practice and, consequently, were not part of the DDCD dataset, including biomarkers and CAC scoring and history. Familial history of CAD was used as a surrogate for familial history of premature CAD; similarly, Asian ethnic background was used as a surrogate for South Asian population because these were not split in the DDCD data collection form. By considering any family history of CAD as “premature” and all Asian ethnicity as “South Asian” we may have overestimated the prevalence of this risk enhancer, and potentially over-estimated the number of adults considered at higher risk due to family history. Second, the event rates in our data are likely higher than a contemporary cohort given advances in the treatment of CAD patients. Contemporary cohorts likely have lower absolute event rates; however, this change should not have affected estimates for statin eligibility or the relative difference in event rates by risk status. Since patients may have had MI due to non-atherosclerotic disease (dissection, vasospasm, or type 2 MI), we required both the presence of an MI and obstructive CAD as an inclusion criterion in the cohort. Therefore, our findings should only be extrapolated to adults with angiographically-proven obstructive CAD. Finally, we attempted to identify a cohort of patients with newly-diagnosed ASCVD who presented with MI and obstructive CAD, but we were unable to determine whether these patients had been previously diagnosed with non-obstructive CAD, since this was not captured in the DDCD. As a result, our sample may have included some patients with previously diagnosed disease; patients taking statins for that indication would have been considered “eligible” in our analysis.
Conclusions
The majority of adults with premature CAD would not have been recommended for statin therapy prior to their first MI according to criteria from both the 2013 ACC/AHA and 2018 AHA/ACC guidelines. Younger individuals are also less frequently eligible for secondary prevention with intensive non-statin lipid-lowering therapies compared with older adults, despite having a much longer potential lifespan for recurrent events. Younger individuals with very high-risk criteria are at higher risk of major adverse cardiovascular events, supporting the appropriate implementation of intensive lipid-lowering therapies in these patients.
Supplementary Material
Perspectives.
Competency in Patient Care
Half the patients with premature myocardial infarction did not meet the criteria in current clinical practice guidelines for antecedent treatment with statin medication for primary prevention. Younger patients, in particular, are less likely than older individuals to exhibit high features for which intensive lipid-lowering therapy is generally recommended, despite their high rate of ischemic events.
Translational Outlook
Better strategies for risk assessment are needed to improve primary prevention of myocardial infarction in young adults.
Acknowledgments
We thank Erin Campbell, MS, for her editorial contributions to this manuscript.
Sources of funding: Dr. Navar is supported by NIH K01HL133416. Dr. Nanna is supported by NIH training grant 5T32-HL069749–15.
Conflict of interest disclosures
Michel Zeitouni has received research grants from Federation Française de Cardiologie and Institut Servier, lecture fees from BMS/Pfizer.
Michael G. Nanna is supported by NIH training grant 5T32-HL069749–15.
Eric D. Peterson has received the following research support: Research Grant: Amgen, Sanofi, AstraZeneca, Merck. Consultant/Advisory Board; Amgen. Consultant/Advisory Board: Significant; AstraZeneca, Merck, and Sanofi Aventis.
Ann Marie Navar is funded by NIH K01HL133416. In addition: Research Grant: Amarin, Janssen, Amgen, Sanofi, and Regeneron Pharmaceuticals. Consultant/Advisory Board: Amgen, Astra Zeneca, Janssen, Esperion, Amarin, Sanofi, Regeneron, NovoNordisk, Novartis, The Medicines Company, New Amsterdam, Cerner, and Pfizer
Jie-Lena Sun and Karen Chiswell have no conflicts of interest.
ABBREVIATIONS
- ACC
American College of Cardiology
- AHA
American Heart Association
- ASCVD
atherosclerotic cardiovascular disease
- CAC
coronary artery calcium
- DDCD
Duke Databank for Cardiovascular Disease
- HDL-C
high-density lipoprotein cholesterol
- LDL-C
low-density lipoprotein cholesterol
- MI
myocardial infarction
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References
- 1.Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014. July 1;63(25 Pt B):2889–934.doi: 10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12. [DOI] [PubMed] [Google Scholar]
- 2.Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2018;73:e285–e350. [DOI] [PubMed] [Google Scholar]
- 3.Mach F, Baigent C, Catapano AL, et al. 2019. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular riskThe Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J 2020;41:111–188. [DOI] [PubMed] [Google Scholar]
- 4.Pencina MJ, Navar-Boggan AM, D’Agostino RB Sr, et al. Application of new cholesterol guidelines to a population-based sample. N Engl J Med 2014;370:1422–31. [DOI] [PubMed] [Google Scholar]
- 5.Pagidipati NJ, Navar AM, Mulder H, Sniderman AD, Peterson ED, Pencina MJ. Comparison of recommended eligibility for primary prevention statin therapy based on the US Preventive Services Task Force Recommendations vs the ACC/AHA Guidelines. JAMA 2017;317:1563–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889–934. [DOI] [PubMed] [Google Scholar]
- 7.Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001;285:2486–97. [DOI] [PubMed] [Google Scholar]
- 8.Singh A, Collins BL, Gupta A, et al. Cardiovascular risk and statin eligibility of young adults after an MI: Partners YOUNG-MI Registry. J Am Coll Cardiol 2018;71:292–302. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41:1475–9. [DOI] [PubMed] [Google Scholar]
- 10.Navar-Boggan AM, Peterson ED, D’Agostino RB Sr., Pencina MJ, Sniderman AD. Using age- and sex-specific risk thresholds to guide statin therapy: one size may not fit all. J Am Coll Cardiol 2015;65:1633–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Arora S, Stouffer GA, Kucharska-Newton AM, et al. Twenty year trends and sex differences in young adults hospitalized with acute myocardial infarction: the ARIC Community Surveillance Study. Circulation 2019;139:1047–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Collet JP, Zeitouni M, Procopi N, et al. Long-term evolution of premature coronary artery disease. J Am Coll Cardiol 2019;74:1868–78. [DOI] [PubMed] [Google Scholar]
- 13.Harris PJ, Harrell FE, Lee KL, Behar VS, Rosati RA. Survival in medically treated coronary artery disease. Circulation 1979;60:1259–69. [DOI] [PubMed] [Google Scholar]
- 14.Eisenstein EL, Shaw LK, Anstrom KJ, et al. Assessing the clinical and economic burden of coronary artery disease: 1986–1998. Med Care 2001;39:824–35. [DOI] [PubMed] [Google Scholar]
- 15.Rosati RA, McNeer JF, Starmer CF, Mittler BS, Morris JJ, Wallace AG. A new information system for medical practice. Arch Intern Med 1975;135:1017–24. [PubMed] [Google Scholar]
- 16.Berry JD, Dyer A, Cai X, et al. Lifetime risks of cardiovascular disease. N Engl J Med 2012;366:321–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Akosah KO, Schaper A, Cogbill C, Schoenfeld P. Preventing myocardial infarction in the young adult in the first place: how do the National Cholesterol Education Panel III guidelines perform? J Am Coll Cardiol 2003;41:1475–9. [DOI] [PubMed] [Google Scholar]
- 18.Lakka H-M, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 2002;288:2709–16. [DOI] [PubMed] [Google Scholar]
- 19.Mottillo S, Filion KB, Genest J, et al. The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 2010;56:1113–32. [DOI] [PubMed] [Google Scholar]
- 20.Shin D, Kongpakpaisarn K, Bohra C. Trends in the prevalence of metabolic syndrome and its components in the United States 2007–2014. Int J Cardiol 2018;259:216–9. [DOI] [PubMed] [Google Scholar]
- 21.Carr JJ, Jacobs DR, Terry JG, et al. Association of Coronary Artery Calcium in Adults Aged 32 to 46 Years With Incident Coronary Heart Disease and Death. JAMA Cardiol. 2017;2:391–399. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Berry JD, Dyer A, Cai X, et al. Lifetime Risks of Cardiovascular Disease. N. Engl. J. Med. 2012;366:321–329. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Maglietta G, Ardissino M, Tagliazucchi GM, et al. Long-term outcomes after early-onset myocardial infarction. J Am Coll Cardiol 2019;74:2113–5. [DOI] [PubMed] [Google Scholar]
- 24.Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387–97. [DOI] [PubMed] [Google Scholar]
- 25.Morrone D, Weintraub WS, Toth PP, et al. Lipid-altering efficacy of ezetimibe plus statin and statin monotherapy and identification of factors associated with treatment response: a pooled analysis of over 21,000 subjects from 27 clinical trials. Atherosclerosis 2012;223:251–61. [DOI] [PubMed] [Google Scholar]
- 26.Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713–22. [DOI] [PubMed] [Google Scholar]
- 27.Cholesterol Treatment Trialists’ (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–590. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sever P, Gouni-Berthold I, Keech A, et al. LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial. Eur J Prev Cardiol 2020:2047487320902750. doi: 10.1177/2047487320902750. [Online ahead of print]. [DOI] [PubMed] [Google Scholar]
- 29.Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J 2019;ehz809. doi: 10.1093/eurheartj/ehz809. [Online ahead of print]. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol 2019;74:2132–46. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.