We analyzed the results of the Trial of Invasive Versus Medical Therapy in the Elderly with Chronic Coronary Artery Disease (TIME) in which invasive treatment was compared with optimized medical treatment in patients with chronic angina aged 75 years and older. Patients with diabetes had higher mortality than nondiabetic patients, but revascularization improved overall survival similarly in diabetic and nondiabetic patients.
Revascularization has been shown to be beneficial in a general population of patients with diabetes mellitus and symptomatic coronary artery disease (CAD). In elderly diabetic patients with chronic angina pectoris undergoing revascularization, however, the peri-interventional and postinterventional risk may be increased, and CAD is usually more diffuse. Thus, it is unclear whether these patients receive the same advantages from revascularization compared with optimal medical therapy as do younger patients. In the Trial of Invasive Versus Medical Therapy in the Elderly with Symptomatic CAD (TIME), optimal medical treatment was compared with invasive treatment in elderly patients.1-3 In this article, we discuss the findings recently reported in a published subgroup analysis of TIME patients with diabetes mellitus.
Patients and methods
TIME was a prospective, randomized, multicenter study that included patients aged 75 years and older with chronic angina pectoris (Canadian Cardiovascular Society class 2 and higher), treated with 2 or more medications for angina. Subjects were randomly assigned to receive 1 of 2 treatments: (1) optimal treatment with medication (an increased dosage or number of antianginal medications to achieve the best possible reduction in symptoms), or (2) coronary angiography along with either coronary artery bypass graft (CABG) surgery, if possible, or percutaneous coronary intervention (PCI). Outcome was defined as survival without major adverse clinical events (hospitalization for acute coronary syndromes with or without the need for revascularization, myocardial infarction [MI], or death) and quality of life as determined by the Rose questionnaire for angina,4 the Duke Activity Status Index,5 and a standardized questionnaire containing the Short Form 12 (SF-12).6 Follow-up was performed up to a mean of 4.1 years (range, 0.1—6.9 years). In this prespecified subgroup analysis, baseline characteristics and outcome of patients with diabetes mellitus, that is, treated with antidiabetic drugs or having a history of diabetes mellitus (n = 69, 23%), were compared with nondiabetic pa­tients (n = 232, 77%) by the treatment-received principle. Statistical significance was considered P < .05, and all P values were two-sided.
The mean (± SD) age of diabetic patients was 80 ± 4 years, and 41% were women. Compared with nondiabetic patients, those with diabetes mellitus more often had 2 or more atherosclerotic risk factors (93% of diabetic patients compared with 46% of nondiabetic patients; P < .01), previous MI (59% of diabetic patients compared with 43% of nondiabetic patients; P = .02), previous heart failure (22% of diabetic patients compared with 12% of nondiabetic patients; P = .04), peripheral vascular disease (29% of diabetic patients compared with 14% of nondiabetic pa­tients; P < .01), and a lower mean left ventricular ejection fraction (48% ± 12% for diabetic patients compared with 54% ± 12% for nondiabetic pa­tients; P = .02). In contrast, there was no difference in the number of angiographically diseased vessels, parameters of symptom severity, or quality of life at baseline between the 2 groups. At inclusion, patients with diabetes were treated more often with angiotensin-converting enzyme inhib­itors (43% of diabetic patients compared with 22% of nondiabetic pa­tients; P > .01) and diuretics (52% of diabetic patients compared with 35% of nondiabetic patients; P = .01) but less often with beta blocking agents (64% of diabetic patients compared with 81% of nondiabetic pa­tients; P < .01).
The revascularization rate was similar for both diabetic and nondiabetic patients (67% versus 57%, respectively; P = .21). Most procedures were performed within the first year of follow-up (91% of diabetic patients and 99% of nondiabetic patients). Rates of PCI (65% for diabetic pa­tients compared with 61% for nondiabetic patients) and CABG surgery (35% for diabetic patients compared with 39% for nondiabetic patients) were also similar (Figure 1).
At long-term follow-up, both diabetic and nondiabetic patients were similar with regard to the number of antianginal drugs being taken, quality of life as measured by SF-12, and severity of angina as measured by the Rose score and Canadian Cardio­vas­cular Society class. Patients with diabetes, however, scored markedly lower on the Duke Activity Status Index score, which measures the ability to perform daily activities.
Long-term all-cause mortality rates were higher for diabetic patients than for nondiabetic patients (41% compared with 25%, respectively, P = .01; adjusted hazard ratio [HR], 1.86, P = .01), as were cardiac mortality rates (33% compared with 18%, respectively, P = .01; adjusted HR, 1.98, P = .02) (Figure 2). A lower percentage of diabetic patients than nondiabetic pa­tients, however, had survival without major adverse clinical events (16% versus 34%, respectively, P = .01; adjusted HR, 1.33).
Within the first year of follow-up, revascularization procedures resulted in improved long-term survival in the total study population (79% with revascularization compared with 61% without revascularization, P = .01; adjusted HR, 1.68, P = .03), an effect seen in both diabetic (74% with revascularization compared with 52% without revascularization) and nondiabetic patients (90% with re­vascularization compared with 72% without revascularization, P < .01) (Figure 3). Nondiabetic patients who underwent revascularization procedures had the highest rate of freedom from major adverse clinical events (53%), followed by diabetic patients who underwent re­vascularization procedures (41%), non­­diabetic pa­tients who did not undergo revascularization (40%), and diabetic patients who did not undergo revascularization (11%; P = .01 for overall comparison). The mode of revascularization did not result in outcome differences, al­though mortality rates were numerically decreased for patients undergoing PCIs compared with CABG surgery in diabetic (25% compared with 43%, respectively) and nondiabetic (10% compared with 19%, re­spectively) patients. Compared with PCI, however, after CABG sur­gery diabetic patients had less drug use (1.1 ± 0.3 versus 1.9 ± 1.1 drugs, re­spectively; P < .01) and less severe angina (Rose score, 0.9 ± 1.6 versus 2.6 ± 1.9, respectively; P = .04).
Conservative and invasive strategies were compared in younger pa­tients with diabetes mellitus, and results indicate that the beneficial effect of revascularization on outcome is similar in diabetic and nondiabetic patients, although improvement in symptoms may be more pronounced in patients with diabetes mellitus.7,8 There appeared to be no difference in long-term outcomes and symptom relief between elderly diabetic and nondiabetic patients who underwent revascularization in our study. Com­pared with younger patients, however, the overall rate of major adverse clinical events and mortality were significantly higher.9,10 After 4 years of follow-up, 4 of 10 diabetic 80-year-old patients who underwent revascularization were free of major adverse clinical events; only 1 of 10 diabetic 80-year-old patients who did not undergo revascularization, however, were free of any major adverse clinical events. These results show the importance of treating elderly diabetic pa­tients invasively if they have chronic angina pectoris because they appear to benefit as much as patients without diabetes mellitus.
Compared with nondiabetic pa­tients, those with diabetes had more physical limitations with reference to daily activities. In elderly patients, this finding may be of great significance because these patients may need additional help to preserve their independence. Compared with nondiabetic patients, however, the cognitive abilities of elderly patients do not seem to be affected.
Among patients who underwent CABG surgery, the severity of symptoms and the need for additional an­tianginal medications were less than for patients who underwent PCI, as has been shown before in younger patients,11 although at the cost of a somewhat higher postoperative mortality rate.
These results provide support for the use of invasive treatment for CAD in elderly patients with diabetes. Additional, larger, prospective studies concentrating on elderly patients, however, need to be performed. As shown by the results of this study, to improve symptoms, quality of life, and outcomes in elderly diabetic pa­tients, they should be given the opportunity to undergo assessment for invasive procedures and to undergo revascularization.