By Michael H. Crawford, MD, Editor

SYNOPSIS: An analysis of the PROMISE trial by age showed that cardiovascular death or myocardial infarction was predicted by a positive stress test in patients with symptoms suggesting myocardial ischemia who were >age 65 years, but only CT angiography or a calcium score was predictive in symptomatic patients < age 65 years.

SOURCE: Lowenstern A, Alexander KP, Hill CL, et al. Age-related differences in the noninvasive evaluation for possible coronary artery disease: Insights from the prospective multicenter imaging study for evaluation of chest pain (PROMISE) trial. JAMA 2020;5:193-201.

The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) showed that patient outcomes were no different overall with an initial functional stress test compared to coronary CT angiography (CTA). While digging deeper into PROMISE, Lowenstern et al hypothesized that patient age may alter this finding.

In this analysis, 8,966 patients were included, of whom 71% were < age 65 years, 23% were between age 65 and 74 years, and 6% were > age 75 years. Patients were randomized to a strategy of an initial functional test (exercise ECG, stress echo, or stress nuclear perfusion) or coronary CTA and coronary artery calcium (CAC) score. The primary endpoint was a composite of cardiovascular (CV) death or myocardial infarction (MI) over a median follow-up of 25 months.

Older patients produced more positive tests of either type. A positive functional test was associated with CV death and MI in older patients: age 65-74 years (hazard ratio [HR], 3.2; 95% confidence interval [CI], 1.4-7.0) and ≥ age 75 years (HR, 6.6; 95% CI, 1.5-29.4), but not in patients < age 65 years (HR, 1.1; 95% CI, 0.4-2.8).

On the other hand, a positive CTA was associated with CV death or MI in patients < age 65 years (HR, 3.0; 95% CI, 1.5-6.3), but not in older patients: age 65-74 years (HR, 0.7; 95% CI, 0.2-2.9) and ≥ age 75 years (HR, 1.1; 95% CI, 0.2-5.3). A CAC > 100 (Agatston score) was associated with CV death or MI in those < age 65 years (HR, 2.7; 95% CI, 1.3-5.7), but not in older patients: age 65-74 (HR, 0.4; 95% CI, 0.1-1.4) and > age 75 years (HR, 1.3; 95% CI, 0.3-6.9).

The authors concluded older patients with stable symptoms suggestive of episodic myocardial ischemia are more likely to produce a positive stress test and more CAC, but only a positive functional stress test was associated with an increased risk for CV death or MI. Conversely, in younger patients, only a positive CTA or CAC was predictive of the primary endpoint. The authors suggested age should be considered in choosing the initial diagnostic evaluation of patients with stable symptoms suggestive of myocardial ischemia.

COMMENTARY

The PROMISE authors reported no difference in patient outcomes with either testing strategy, and positive tests of both types were more common in older patients: < age 65 years (10%), age 65-74 years (15%), and ≥ age 75 years (20%). However, when the results were stratified for age, there was a difference between the two types of tests. Lowenstern et al noted the extent of CAC increases with age, but is not related to outcome. Since all the patients studied exhibited symptoms suggestive of myocardial ischemia, presumably the majority of them had coronary artery disease (CAD). Others have shown with serial CT imaging that increasing calcium over the years in those with baseline CAC detected is the norm despite risk factor control. Lowenstern et al suggested this may be part of the plaque stabilization process and not necessarily a bad thing. For this reason, serial CT scans in those positive for calcium are not recommended. Thus, the results of the Lowenstern et al study, which showed the lack of predictive value of CT scans for CAD events in older individuals, is not surprising. Also, CTA is limited by dense calcium and atrial fibrillation, which are more common in older patients.

On the other hand, a positive functional stress test did predict events in older patients, but not younger patients; this dichotomy is unclear. Perhaps younger symptomatic patients have a lower prevalence of CAD, which could lead to more false-positive functional tests. That CTA and CAC were predictive of events in younger patients may be related to the higher certainty of the diagnosis of coronary artery atherosclerosis. These results are important because the next step in the evaluation of the symptomatic patient with a positive test usually is invasive coronary angiography and possibly a percutaneous coronary intervention or bypass surgery. Thus, it is important to pick the most accurate test for each patient.

This analysis of PROMISE by age suggests that in those < age 65 years, a coronary CT may be a good test if the resting heart rhythm is sinus with a rate < 70 beats per minute. In those > age 65 years, a functional test would be better. Since the type of functional test was selected by each physician and not randomized, no recommendation on the type of test can be made based on this study.

There were limitations. Although this analysis by age was a prespecified subgroup, age was not included in the randomization scheme; technically, these results are hypothesis-generating. Also, the group of patients > age 75 years was small. The follow-up was short and there were few events: 1% in the < age 65 years patients, 2% in age 65-74 years patients, and 3% in the ≥ age 75 years group. The distribution of stress test type by age was not uniform, since nuclear perfusion studies, especially with pharmacologic stress, were deployed more commonly in the elderly. The guidelines recommend CT studies in intermediate risk patients, but this study suggests stratification by age is important with functional stress tests preferred in those > age 65 years.