Circadian investigation of interval therapy with isosorbide dinitrate in coronary heart disease

One of the most promising concepts in nitrate therapy is interval therapy, a dosage scheme with marked changes of nitrate concentrations in the 24-h interval. In a single-blind, placebo-controlled study in patients with coronary heart disease we investigated the circadian anti-ischaemia and haemodynamic response to interval therapy with isosorbide dinitrate (120 mg sustained release 1 X 1). 10 male patients (46-75 years, mean 60 years) with chronic stable angina and ST-segment depression during exercise entered the trial. At the end of a 10-day placebo period (medication at 8 am) three exercise tests were performed (10 am, 2 pm, 6 pm), recording ST-segment changes, pulmonary capillary wedge pressure (PCP) and cardiac index (CI). Spontaneous ischaemic events were detected by Holter monitoring until 8 am the next day. After three weeks of therapy with isosorbide dinitrate, the protocol was repeated (statistics: paired t-test, *P less than 0.05). PCP was reduced by 8.3 mmHg* at 10 am, 8.0 mmHg at 2 pm, 2.9 mmHg (NS) at 6 pm with a concomitant increase of cardiac index (+0.8,* +0.7*, +0.3 NS l min-1 m-2). While the haemodynamic improvement was maximal in the morning the anti-ischaemia effect (reduction of ST-depression) was constant during the active day (-0.40*, -0.50*, -0.43* mm). Four transient ischaemia episdodes at night were recorded under placebo, none under isosorbide dinitrate. In conclusion, all parameters studied demonstrate the effectiveness of chronic interval therapy with isosorbide dinitrate.