Gridelli C

Effects of iloprost, a stable prostacyclin analog, on exercise capacity and platelet aggregation in stable angina pectoris

The effects of iloprost, a chemically stable compound with prostacyclin mimetic activity, on exercise capacity and platelet aggregation were assessed in 24 patients with effort angina and proved critical (at least 70% diameter narrowing) coronary artery disease. Upright bicycle ergometer testing (25-W increments every 2 minutes) was performed during drug and placebo infusions using a crossover, randomized, single-blind protocol. Samples for measurements of adenosine diphosphate-induced platelet aggregation in platelet-rich plasma were obtained in all patients before and during the study. Compared with placebo, intravenous iloprost consistently (p less than 0.001) prolonged exercise duration and time to onset of significant (0.1 mV) ST depression. Angina and ST depression occurred at a greater heart rate and rate-pressure product. Benefits were remarkable in some patients (67%) and not in others. Iloprost administration resulted in reduced platelet aggregation at peak exercise in all patients, whether they had consistent or little response to the drug. Thus, iloprost administration may improve exercise capacity in patients with stable exertional angina pectoris. Improvements are independent of changes in the major determinants of myocardial oxygen demand and associated with markedly reduced platelet aggregation, which may account for increased myocardial perfusion in patients with high sensitivity to coronary constriction.

Myocardial ischemia induced by prostacyclin and iloprost

Vasodilators of resistive vessels may induce ischemia in patients with coronary artery disease. To evaluate this possibility during prostacyclin (PGI2; scalar doses up to 10 ng/kg/min) and prostacyclin analog (iloprost; scalar doses up to 6 ng/kg/min) infusions, we studied 33 patients with angina pectoris and proved coronary artery disease. Patients were also submitted to dipyridamole (0.15 mg/kg/min for 4 minutes) and exercise stress testing (starting at 25 W and increasing 25 W every 2 minutes). In a preliminary study the hemodynamic and side effects of iloprost were studied in seven healthy subjects. At an iloprost dose of 4 to 6 ng/kg/min, these subjects had a significant decrease in mean arterial pressure and total peripheral and pulmonary vascular resistances. Side effects were limited to facial flushing and slight headache and were readily reversible. PGI2 induced typical chest pain and significant ST segment depression in six patients with severe coronary artery disease (three with left main and three with triple vessel disease) and poor exercise tolerance (X̄ ± SD = 362 ± 99 seconds). All six patients had had angina during the dipyridamole infusion. Similar findings were observed after iloprost infusion in four of these. Aminophylline (125 mg iv) completely relieved chest pain. Although the rate‐pressure products occasionally rose during PGI2 and iloprost infusions, there were no significant changes between ischemic (11.3 ± 2.3 and 10.6 ± 1.4 × 10−3 U) and preischemic (10.8 ±1.5 and 10.7 ± 1.4 × 10−3 U) rates of infusion. Our data indicate that PGI2 and iloprost may induce ischemia independently of changes in oxygen demand, and suggest that these drugs dilate small coronary vessels. This may result in decreased subendocardial perfusion pressure and/or “coronary steal.”

Myocardial ischemia during intravenous prostacyclin administration: Hemodynamic findings and precautionary measures

This study reports coronary and systemic hemodynamics, and metabolic responses to atrial pacing, prostacyclin (PGI2), and iloprost, its stable analogue, in 16 patients with severe coronary obstruction as well as predominant narrowing in the left anterior descending artery. PGI2 caused ischemia in six patients with low anginal threshold during pacing. In three of them ischemia was also precipitated by iloprost. Drugs were infused at therapeutic doses and were discontinued when pain occurred. Angina disappeared promptly (less than or equal to 3 minutes) and spontaneously after the infusion of PGI2, whereas after the analogue it was long lasting (greater than or equal to 5 minutes) and was relieved by 125 mg intravenous aminophylline, an antagonist of dipyridamole-induced coronary dilation. Ischemia was associated with a drug-induced decrease in arterial blood pressure and reflex tachycardia, and occurred despite increased great cardiac vein (GCV) blood flow and decreased resistance, which is consistent with either a failure of regional flow to increase proportionally to the metabolic demand or a subendocardial-subepicardial steal. However, the following findings favor the latter hypothesis: heart rate and rate-pressure product at the onset of pain were lower with drugs than with pacing, and GCV blood flow, measured at a comparable heart rate, was less with pacing than with drugs. In conclusion, PGI2 and analogues may induce ischemia in patients with advanced coronary artery disease. The mechanism appears to be related to a dipyridamole-like maldistribution of flow. Counteraction of ischemia can be achieved by aminophylline.

Side effects of prostacyclin in patients with angina pectoris and coronary artery disease

SummaryAlthough the exposure of human subjects to prostacyclin (PGI2) infusion has been broad, no systematic approaches have been made in order to investigate the dose-related side effects in patients with angina pectoris and coronary artery disease (CAD). We studied 25 patients with typical chest pain and overt CAD. All patients underwent a cycloergometer stress testing (25 W increments at 2-min intervals). PGI2 was infused in scalar doses up to 10 ng/kg/min. During the infusion 25 patients (100%) had facial flushing, 7 (28%) moderate headache and one (4%) had nausea. In addition, 4 patients experienced the typical chest pain and had significant (≥0.1 mV) ST segment depression at 8·10 ng/kg/min infusion rates. These patients had lower tolerance to exercise (67.7±1.7vs. 8.8±1.9 min; p<0.05) and coronary artery lesions more severe than those observed in patients without drug-induced angina pectoris. Our data therefore indicate that PGI2 at therapeutic doses may induce myocardial ischemia in patients with angina pectoris, low tolerance to exercise and severe CAD. In patients with mild to moderate degree of CAD, PGI2 was found to be well tolerated. These findings suggest that patients with angina pectoris and low tolerance to exercise should be excluded from clinical studies directed at elucidating the effectiveness of PGI2 in cardiovascular disorders.