Table compares the clinical characteristics of the exercise and adenosine SPECT groups. The adenosine patients were older, had fewer males, greater BMI, a greater mean pre-test likelihood of CAD, and they contained more patients with chest pain symptom. The adenosine patients also had a greater frequency of diabetes and hypertension, lower frequency of smokers, higher resting mean heart rate and systolic blood pressure, and more frequent LBBB, LVH, and atrial fibrillation, and less frequent left ventricular enlargement. During a mean follow-up of 10.2 ± 1.7 years (range 7.5-14 years), 978 patients (16.1%) died, including 466 (10%) of the exercise patients, and 512 (34%) of the adenosine patients. The annualized mortality event rate was markedly higher in the adenosine patients compared to the exercising patients (4.3% [95% CI: 4.0%-4.7%] vs 1.1% [95% CI: 1.0%-1.1%], P < .0001). This difference in mortality rates was present both for adenosine vs exercise patients tested without influence of beta-blocking medications (4.5% vs 1.0%, P < .0001) and those tested under the influence of beta-blocking medication (3.1% vs 1.2%, P < .0001). Likewise the annual mortality rate was 4.2% vs 1.0% (P < .0001) and 5.3% vs 1.5% (P < .0001) for adenosine vs exercise patients, for those not under the influence and those under the influence of calcium channel blockers, respectively.
Comparison of exercise and adenosine patients
The presence of TID was noted among 7 (0.2%) of the exercise patients and 7 (0.5%) of the adenosine patients (P = .03), and in both groups, the annualized mortality rate (presented with confidence intervals) was higher for those with TID than those without: 4.8% (1.5%-14.9%) vs 1.0% (1.0%-1.1%), P = .003, for the exercise patients, and 7.9% (3.0%-21.2%) vs 4.3% (3.9%-4.7%), P = .23, for the adenosine patients.
Among the exercise patients, 839 (18%) had ST depression during testing, whereas only 61 (4%) had ST depression during adenosine infusion. The annualized mortality in the exercise and adenosine patients with ST segment depression was (0.8% and 2.6%/year, respectively, P < .0001). In the exercise patients, 424 (9%) had chest pain with exercise, compared to only 25 (2%) adenosine patients, with annualized mortality rates of 1.1 and 1.9%/year in these two groups, respectively, P = .26.
We next used propensity analysis to match exercise and adenosine patients who did not have TID, LBBB, paced, afib, or were taking digoxin, or had left ventricular enlargement or shortness of breath. Matching was done on the basis of age (grouped for the purpose of matching by half-decade), gender, asymptomatic or non-anginal chest pain symptom, diabetes, hypercholesterolemia, smoking, family history of CAD, hypertension, body mass index, influence of beta-blockers or calcium-blockers, resting heart rate, resting systolic and diastolic blood pressure, and left ventricular hypertrophy. The propensity model is presented in the Appendix
. The propensity scores were matched to an average difference of 0.05 (median matching precision = 0.03) and the largest difference was <0.15 between individual adenosine and matched exercise patients. The resultant clinical characteristics of the two propensity-matched subgroups are listed in Table . A small but statistically significant difference persisted in the average diastolic blood pressure between the two groups, but the groups were otherwise comparably matched in terms of clinical presentation, risk factor profiles, and Bayesian likelihood of CAD. Yet within these propensity-matched subgroups, the annualized mortality event rate remained substantially higher within the adenosine cohort (3.9% [95% CI: 3.5%-4.3%] vs 1.6% [95% CI: 1.4%-1.9%], P
< .0001). A comparison of adjusted Kaplan–Meier estimates for mortality in the exercise and adenosine patients before and after propensity matching indicated an approximately fourfold higher rate of mortality prior to propensity-matching (Figure A), and twofold higher rate following propensity matching (Figure B).
Comparison of exercise and adenosine patients following propensity matching
Figure 1 Comparison of probability of survival from death (y-axis) during 10-year follow-up from all causes in patients undergoing exercise vs adenosine SPECT. (A) Comparison of all exercise and adenosine patients in our study prior to propensity matching. (B (more ...)
To assess if these differences varied in younger vs older patients, we divided our matched patients into those who were ≤55, 55-65, and >65 years. Analysis of the Kaplan–Meir curves revealed that the difference in mortality rates among the normal SPECT exercise vs adenosine patients persisted in each age group (Figure ).
Comparative survival of the propensity-matched exercise and adenosine patients following division of these patients by age
Among the propensity-matched patients, comparison was also made between the adenosine and exercise groups after dividing the latter group according to exercise duration (Figure ). As exercise duration diminished, mortality rate increased progressively. The annualized mortality rates for those exercising ≥9, 6-8.9, 3-5.9, and <3 min were 0.8%, 1.3%, 2.0%, and 3.4%, respectively (trend P < .0001). The mortality rate for patients unable to exercise for more than 3 min was similar to that observed among patients undergoing adenosine SPECT (P = .65).
Figure 3 Comparison of survival in the propensity-matched exercise and adenosine patients, with the exercise patients divided according to exercise duration. Mortality rate increased progressively as exercise duration diminished. There was no statistical difference (more ...)
We also assessed outcomes among the 349 (8%) of our exercising patients who underwent a modified Bruce protocol compared to the 4,208 (92%) patients who underwent standard Bruce protocol exercise. The subgroup undergoing modified Bruce protocol exercise were older (66.0 ± 12.1 vs 59.4 ± 12.3 years, P < .0001), had a lower mean exercise duration (7.0 ± 3.2 vs 7.5 ± 2.7 min, P = .003), and a substantially higher annualized mortality event rate: 2.4% (1.9%-3.0%) vs 0.9% (0.8%-1.0%), P < .0001. Comparable differences in event rates persisted for the exercise versus adenosine patient subgroups that did and did not have resting ECG abnormalities at rest (P < .003 for both pairwise comparisons).
We further assessed the comparative event rate in the propensity-matched groups, after excluding the patients with the following co-morbidities in addition to the ones that were excluded before:current smoking, diabetes, BMI ≥ 30, presence of LVH, or peripheral vascular disease. Among the 606 exercise patients and 535 adenosine patients without any of these co-morbidities, the annual mortality rate remained significantly greater among the adenosine patients: 3.6% vs 1.5% (P < .0001).
Comparison of Short-Term Cardiac Outcomes
Short-term cardiac events occurred among 44 of our adenosine patients, including 31 (with one censored) cardiac deaths and 13 non-fatal myocardial infarctions, as well as among 27 of our exercise patients, including 12 cardiac deaths and 15 non-fatal myocardial infarctions. The annualized cardiac event rate in the adenosine vs exercise groups was 1.2% vs 0.2% (P < .0001). Within the propensity-matched cohorts, the annualized cardiac event rate in the adenosine vs exercise patients also remained twofold higher: 1.1% vs 0.2%, P < .0001.