The DEFIANT study of left ventricular function and exercise performance after acute myocardial infarction

Summary

The DEFIANT-I study (Doppler Flow andEchocardiography inFunctional cardiacInsufficiency:Assessment ofNisoldipineTherapy) was a multicenter, multinational double-blind randomized study of the effects of the new calcium channel blocking drug nisoldipine on left ventricular (LV) size and function after acute myocardial infarction. Randomization to placebo or to long-acting nisoldipine core coat (20 mg once daily) was performed in 135 eligible patients with mild to moderate systolic LV dysfunction (LV ejection fraction ≤50%) 20 days (range 7–35) after infarction, with serial clinical, echocardiographic, and Doppler cardiographic measurements during a 4 week follow-up period. At the end of the follow-up period, exercise capacity was determined by bicycle ergometry. Nisoldipine improved indices of diastolic LV function. Early diastolic transmitral blood flow velocity increased, with an increase in peak E wave of 0.06 m/sec (95% confidence intervals [CI], 0.01, 0.11) and an increase in time velocity integral of 1.2 cm (95% CI, 0.16, 2.27). Isovolumic relaxation time was reduced by 14.7 msec (95% CI, −22.5, −6.9), a change not explained by the very small (and not significant) changes in systemic arterial pressure, heart rate, or cardiac output. There was no change in systolic and diastolic LV volume, nor in LV ejection fraction. Exercise capacity was greater by 12 watts (95% CI, 0.8, 23.3) in patients receiving nisoldipine, while the incidence of ≥1 mm ST-segment depression (relative occurrence 0.54, 95% CI, 0.30–0.97) and the incidence of angina pectoris (relative occurrence 0.67, 95% CI, 0.42–1.08) during exercise testing tended to be lower in this group. Although the relations were not exact, peak exercise workload 7 weeks after infarction correlated with resting measurements of diastolic LV function. Exercise workload was inversely related to peak late diastolic transmitral blood flow velocity (A wave, slope, −86.6; 95% CI, −120.9, −52.2) and directly to the E/A ratio (slope, 20.5, 95% CI, 6.0, 35.1). The relations between exercise workload and peak late diastolic flow velocity remained significant after correction for age, sex, resting heart rate, and usage of beta-blocking drugs or nisoldipine. Exercise capacity was not related to measurements of systolic LV function (LV end-diastolic and end-systolic volume, LV ejection fraction, stroke volume, cardiac index). In summary, the calcium channel blocker nisoldipine improved measurements of diastolic LV function in patients recovering from acute myocardial infarction. Exercise capacity was higher in patients receiving the drug, and there was less exercise induced ischemia. In both placebo and nisoldipine groups, exercise capacity was related to measurements of resting diastolic LV function. The observed changes in diastolic LV function during nisoldipine therapy may reflect the antiischemic effect of the drug and/or be due to an improvement in myocardial relaxation. The DEFIANT-II study, presently in progress, will examine the effect of higher doses of nisoldipine on LV function and exercise performance after acute myocardial infarction, with a longer (6 month) follow-up period.