From the Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia
Coronary artery disease (CAD) is often thought of as a disease of the middle aged and the elderly. The presentation of myocardial infarction (MI) or other manifestations of CAD in a patient in his or her 30s is often surprising in clinical practice. For many years, there has been a sentiment that such patients were not only rarely seen, but they could be expected to have a relatively benign course. This belief was fostered by reports in the medical literature; however, most of these studies described small series of patients with minimal long-term follow-up.1-4 Furthermore, clinicians often feel as if they are struggling to affect these patients’ clinical courses because the extent to which traditional risk factor modification predicts outcome in these patients is not clear.5
To better describe CAD in young adults, we undertook a study to evaluate long-term outcomes and to analyze traditional coronary risk factors in these patients.6 Subjects were selected from cases in the Emory University cardiac database from 1975 to 1985. Included patients were younger than
40 years and had angiographically documented CAD. Traditional cardiac risk factors were recorded for each patient, and included sex, known previous MI, hypertension, diabetes mellitus, current or past smoking history, and a family history of CAD in a relative younger than 50 years. Further variables included a history of congestive heart failure, angina classification, and details of coronary anatomy. Information was also collected on the initial treatment strategy for each patient: drug therapy alone, percutaneous intervention, or coronary surgery. Fifteen-year survival was analyzed using the Kaplan-Meier method, and a Cox proportional regression hazards model was developed to evaluate the effect of individual covariates on long-term mortality.
A total of 843 patients were identified, and most (n = 729) were men. Traditional cardiac risk factors were present in many of the patients. Most patients (65%) were current or former smokers, and approximately 65% also described a family history of CAD in relatives younger than 50 years. Hypertension was present in 42% of the women and 27% of the men. Diabetes had been diagnosed in 26% of the women; however, only 8% of the men were diabetic (P < .001). Heart failure was present in about 5% of the cohort, but approximately one half had Canadian Cardiovascular Society class III to IV angina. As far as initial treatment, 39% received medical therapy only, 27% percutaneous transluminal coronary angioplasty (PTCA), and 34% underwent coronary artery bypass graft (CABG) surgery.
At 15 years, overall mortality was 31%. This percent is significantly higher than might have been expected on the basis of previous studies. Further stratification demonstrated that the diabetic patients did significantly worse than nondiabetics; the 15-year survival rate for those with diabetes was only 35% (figure 1).
Other groups likewise had poor prognoses. The 451 individuals who had a history of MI had a 15-year survival rate of 55%. Although few patients in the study had an ejection fraction of less than 30%, their survival was abysmal, with an 11-year mortality rate of 72%.
The next component of our analysis considered subjects on the basis of their initial treatment strategy (figure 2). Freedom from new
MI was roughly equal for the three treatment groups (medical treatment, PTCA, and CABG surgery) for the first 8 years of follow-up. At this time, which might be considered to be the average expected life of a saphenous vein bypass graft, more events began to be observed
in the CABG surgery group. At
year 15, 27% of the PTCA patients, 33% of the medical therapy patients, and 40% of the CABG surgery patients had an MI. Eventually, 26% of the medical group, but only 12% of the PTCA group, went on to require bypass surgery.
To identify the risk factors most predictive of adverse outcome in young adults with CAD, a Cox proportional hazard model was developed to identify individual predictors of 15-year mortality. Active tobacco use (hazard ratio [HR], 1.59; 95% confidence interval [CI], 1.14—
2.21), diabetes (HR, 1.41; 95% CI, 1.04—1.90), and a history of heart failure (HR, 1.75; 95% CI, 1.03–2.97) were significant predictors of adverse outcome. Several variables, including age, sex, and number of diseased vessels, did not correlate with poor prognosis.
Finally, the choice of revascularization procedure was entered in-
to the model, and either PTCA or CABG surgery led to significantly decreased mortality rates relative to those treated with medical therapy alone. In a comparison with medical therapy, the hazard ratio for PTCA was 0.51 (95% CI, 0.32—0.81), and
for CABG surgery, the hazard ratio was 0.68 (95% CI, 0.50—0.94).
This set of patients is, to our knowledge, the largest series of CAD patients younger than 40 years ever published. We found surprisingly high long-term mortality rates in this group. Previous studies, such
as the Grupo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardio II (GISSI-2) analysis, demonstrated that patients younger than 50 years had low short-term mortality rates.7 These studies, however, did not provide long-term follow-up. Other series have described
relatively low mortality rates out
to about 7 years.8 In our analysis,
the significant mortality increase
appeared after year 7.
Another way in which our study differs is that the definition for inclusion was based on angiographic CAD, whereas most previous series used MI to define the population. It has been hypothesized that approximately 20% of young adults with MI do not have concomitant CAD and may have a better prognosis than those who do.9,10
Our data emphasize the importance of traditional cardiac risk factors in this group of patients. Correlates of long-term mortality included diabetes, heart failure, and current tobacco abuse. The importance of risk factor modification, particularly smoking cessation, is clear, because former smokers and nonsmokers had similar 15-year mortality rates. Smoking was an important risk factor regardless of the treatment strategy.
Our analysis of outcome by treatment strategy emphasizes the val-
ue of revascularization in young patients. Previous small series have shown short-term benefit for PTCA vessel patency and for short-term survival after CABG surgery.11,12
We showed that PTCA and CABG surgery interventions predicted much better long-term survival than medical treatment.
Subgroup analysis was relatively predictable. The angioplasty patients had more revascularization procedures during the first year after admission, and CABG surgery patients had the highest rate of MI beginning in year 8 after the pro-cedure, perhaps corresponding to graft loss. It is possible that our study had a selection bias that could not be corrected by modeling techniques. Despite this possibility, our data show that revascularization can provide significant potential benefit for young CAD patients.
Clinical recommendations. What are the important clinical recommendations for young adults with CAD? This group of individuals may be more heterogeneous than older patients with the disease. We know young adults with CAD tend to have significant family histories, mixed dyslipidemia (often low levels of high-density lipoproteins, and new markers of inherited risk, including lipoprotein(a). A striking number of patients (65%) in our series had a family history of early CAD. Many of these patients undoubtedly carry genetic risk factors that we are only beginning to fully characterize.
A focus on modifying risk factors is crucial for this population. The importance of smoking cessation cannot be overstated. The full armamentarium of current preventive cardiac medications should be strongly considered. When the individuals in our cohort were first identified in the late 1970s and early 1980s, the importance of cholesterol as a coronary risk factor was only beginning to be understood, and the outcomes of major trials documenting the benefit of HMG Co-A re-
ductase inhibitors did not become available until well into the 1990s. Similarly, angiotensin-converting enzyme inhibitors and beta blocking agents would not have been uniformly given to these patients. In light of the significant mortality shown by our data, it becomes vital to apply all of these tools in an aggressive fashion.
Our ability to identify subclinical manifestations of atherosclerosis in the young continues to improve. A recent report shows that abnormal endothelial function may be detected in apparently healthy young people with a strong family history of CAD.13 A better understanding of endothelial dysfunction, oxidative stress, and various inflammatory markers will help guide our understanding of CAD in the young and potentially support earlier screening of family members. In the meantime, however, we must use every tool at our disposal—perhaps with a bias toward revascularization in appropriate patients—to change the poor outcomes of CAD when it manifests in young adults.