Is it TIME For a Change of Heart?

Abstract & Commentary

Synopsis: The TIME trial found that invasive vs. medical therapy in elderly patients with symptomatic coronary disease resulted in a higher quality of life in patients older than 75.

Source: The TIME Investigators. Lancet. 2001;358:951-957.

The TIME trial randomized 305 elderly patients (age > 75) with angina refractory to medical management to receive either aggressive medical management or invasive management. Patients who had experienced a myocardial infarction or predominant congestive heart failure in the past 10 days were excluded, as were patients who had life-limiting diagnoses. All patients had experienced angina despite at least 2 anti-anginal drugs. The primary end point was a quality-of- life survey that was completed before randomization and 6 months later. Secondary end points included an index of major adverse cardiac events.

Twenty-six percent of the patients assigned to the invasive strategy were not candidates for angioplasty or surgery and were treated with medical management. Thirty-six percent of the medical management group required invasive therapy within 6 months. Data were interpreted with an intention-to-treat analysis. Nineteen percent of patients did not complete the quality-of-life questionnaire at the study’s conclusion.

Quality of life was higher in the invasive group. The mean improvement on the SF36 general health survey was 7 points (95% CI, 2-13; P = 0.001); the mean improvement on the SF36 vitality index was 5 points (95% CI, -2-11; P = 0.001).

Forty-nine percent of patients assigned to the medical management group had a major adverse cardiac event; 19% of the invasive management group had an event. This was predominantly due to a reduction in readmissions to the hospital (10% in the invasive group vs 50% in the medial management group). The mortality rate was higher in the subjects assigned to the invasive group (8% vs 4%; P = 0.15).

Comment by Jeff Wiese, MD

Two previous trials have established that invasive management of refractory angina is superior to medical management in improving quality of life.1,2 This trial asks the important question of whether this finding applies to patients older than 75 years of age.

The validity of this trial was compromised by the small number of subjects and ineffective randomization. More patients in the invasive management group were receiving beta blockers (82% vs 72%); more patients in the medical management group were receiving ACE inhibitors (35% vs 23%). Validity was further compromised by the high degree of crossover between the 2 groups, and the number of patients (19%) who did not complete the quality-of-life questionnaire.

Generalizing this study to clinical practice may be limited. Forty percent of the medical management group were already receiving 3 or more antianginal drugs. The expected benefit of aggressive medical management may have been limited; many patients appear to have been maximally medically managed at the onset of the trial. Fifty-five percent of patients had the dose of their current medications increased; the average increase in medications was 0.8. In this way, the medical management group served more as a control than as an alternative treatment strategy.

The trial nonetheless provides insight into the potential costs and benefits of invasive management in the elderly. Invasive management improved quality of life and readmission rate. Three patients would have to be treated with invasive therapy to prevent 1 readmission to the hospital. This benefit came at a cost, however, there was a nonstatistically significant increase in mortality in the invasive group. The number needed to harm was 25.

The TIME investigators note that a larger clinical trial is ongoing. This will be required to provide reliable insight into the potential costs and benefits of invasive vs. medical management. For now, this trial suggests that both aggressive medical management and invasive therapy can improve quality of life in patients older than 75. Invasive medical management should be considered for patients who value an improved quality of life over the potential risk of mortality from the procedure.


1. Strauss WE, et al. Circulation. 1995;92:1710-1719.

2. Pocock SJ, et al. J Am Coll Cardiol. 2000;35:907-914.

Dr. Wiese, Chief of Medicine, Charity, and University Hospitals, Associate Chairman of Medicine, Tulane Health Sciences Center, is Associate Editor of Internal Medicine Alert.