Robert L. Feldman

The Quinapril Ischemic Event Trial (QUIET): evaluation of chronic ace inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function

Angiotensin-converting enzyme inhibitors improve endothelial function, inhibit experimental atherogenesis, and decrease ischemic events. The Quinapril Ischemic Event Trial was designed to test the hypothesis that quinapril 20 mg/day would reduce ischemic events (the occurrence of cardiac death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary artery bypass grafting, coronary angioplasty, or hospitalization for angina pectoris) and the angiographic progression of coronary artery disease in patients without systolic left ventricular dysfunction. A total of 1,750 patients were randomized to quinapril 20 mg/day or placebo and followed a mean of 27 +/- 0.3 months. The 38% incidence of ischemic events was similar for both groups (RR 1.04; 95% confidence interval 0.89 to 1.22; p = 0.6). There was also no significant difference in the incidence of patients having angiographic progression of coronary disease (p = 0.71). The rate of development of new coronary lesions was also similar in both groups (p = 0.35). However, there was a difference in the incidence of angioplasty for new (previously unintervened) vessels (p = 0.018). Quinapril was well tolerated in patients after angioplasty with normal left ventricular function. Quinapril 20 mg did not significantly affect the overall frequency of clinical outcomes or the progression of coronary atherosclerosis. However, the absence of the demonstrable effect of quinapril may be due to several limitations in study design.

Randomized placebo-controlled trial of amlodipine in vasospastic angina

Abstract Objectives. This study was designed to assess the efficacy and safety of amlodipine, a long-acting calcium channel blocker, in patients with vasospastic angina. Background. Previous studies have established the value of short-acting calcium channel blockers in the treatment of coronary spasm. Methods. Fifty-two patients with well documented vasospastic angina were entered into the present study. After a single-blind placebo run-in period, patients were randomized (in a double-blind protocol) to receive either amlodipine (10 mg) or placebo every morning for 4 weeks. Twenty-four patients received amlodipine and 28 received placebo. All patients were given diaries in which to record both the frequency, severity, duration and circumstances of anginal episodes and their intake of sublingual nitroglycerin tablets. Results. The rate of anginal episodes decreased significantly (p = 0.009) with amlodipine treatment compared with placebo and the intake of nitroglycerin tablets showed a similar trend. Peripheral edema was the only adverse event seen more frequently in amlodipine-treated patients. No patient was withdrawn from the double-blind phase of the study because of an adverse event. Patients who completed the double-blind phase as responders to amlodipine or as nonresponders to placebo were offered the option of receiving amlodipine in a long-term, open label extension phase. During the extension, the daily dose of amlodipine was adjusted to 5 or 15 mg if needed and the rate of both anginal episodes and nitroglycerin tablet consumption showed statistically significant decreases between baseline and final assessment. Conclusion. This study suggests that amlodipine given once daily is efficacious and safe in the treatment of vasospastic angina.

Comparison of diltiazem and nifedipine alone and in combination in patients with coronary artery spasm

Fifteen patients with coronary artery spasm completed a double-blind placebo-controlled trial comparing diltiazem and nifedipine. Increasingly, higher daily doses (diltiazem, 90 to 360 mg; nifedipine, 30 to 120 mg) were administered to achieve optimal clinical effects. Daily diaries and ambulatory electrocardiographic recordings were used to assess efficacy and side effects. Both drugs significantly decreased angina frequency compared with that in the preceding placebo period (diltiazem 1.4 +/- 0.4 [mean +/- SEM] to 0.4 +/- 0.2 episodes per day; nifedipine 1.4 +/- 0.3 to 0.4 +/- 0.1 episodes per day; both p less than 0.05). Ambulatory electrocardiographic recordings showed fewer ST shifts than were expected during all treatment periods (0.02/h recorded during placebo, none during diltiazem and 0.02/h during nifedipine therapy). Although some patients responded better to one drug than the other, neither drug resulted in a clearly superior clinical response. Diltiazem was discontinued in one patient because of urticaria, but the total number of side effects was higher with nifedipine (12 of 15 patients) than with diltiazem (5 of 15, p less than 0.01). Nine patients remained symptomatic on single drug treatment and entered open label treatment with the combination of diltiazem and nifedipine. Three patients did not tolerate the combination because of important side effects; the other six also had side effects, but these were relatively minor. Four patients received no more benefit from the combination than from a single agent; the condition of two patients improved. Both diltiazem and nifedipine provide effective antianginal therapy for coronary spasm, but diltiazem has fewer side effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of nicardipine on left ventricular function and energetics in man

The effects of nicardipine, a new dihydropyridine calcium antagonist, on left ventricular function and energetics were studied in 13 patients. Nicardipine was administered as a 2 mg bolus (i.v.) followed by an infusion titrated to maintain a 10-20 mm Hg decrease in systolic pressure. Nicardipine increased heart rate 19% (P less than 0.001) while left ventricular end-diastolic pressure was not significantly changed and stroke volume (ml) increased 13% (P less than 0.01). Peak values for the first and second time derivatives of left ventricular pressure were increased by 26% (P less than 0.01) and 50% (P less than 0.02) respectively. Peak aortic blood flow, peak aortic blood acceleration, and the peak rate of change of ejection power were increased 86% (P less than 0.001), 123% (P less than 0.01), and 113% (P less than 0.001), respectively. Stroke work was not changed during nicardipine infusion. External power increased by 40% (P less than 0.01); however, the ratio of oscillatory to total power was not significantly different. Although the product of heart rate and systolic aortic pressure was not significantly altered with nicardipine, myocardial oxygen consumption increased 18% (P less than 0.02) with a disproportionate increase in coronary blood flow of 41% (P less than 0.001) and decrease in coronary resistance of 39% (P less than 0.001). The time constant for left ventricular isovolumic relaxation decreased 22% (P less than 0.001) during nicardipine infusion while the minimum value of dP/dt was unchanged. Thus, when administered intravenously in man, nicardipine is a potent coronary and systemic vasodilator producing reflex tachycardia, increased indices of myocardial contractile state, and improved isovolumic relaxation with an associated increase in myocardial oxygen consumption.

Effect of glyceryl trinitrate on coronary and systemic hemodynamics in man

The effects of sublingual and intracoronary nitrates on coronary artery diameter were evaluated in five separate experiments in man. The first three are concerned with sublingual nitrates and the last two with intracoronary nitrates. The data obtained indicate that (1) administration of a fixed dose sublingual nitrate results in an increase in percent coronary artery stenosis compared with control measurements; (2) small doses of sublingual nitrates can dilate coronary arteries without a significant reduction in systemic arterial pressure or increase in heart rate; (3) the magnitude of percent coronary artery dilation after a fixed dose of sublingual nitrate is inversely related to the size of the coronary artery, that is, the smaller the coronary artery diameter the greater the relative dilation after administration of sublingual nitrate; (4) fixed dose sublingual nitrate often dilated coronary stenoses, but the more narrow stenoses were less likely to dilate; (5) the optimal dose of intracoronary nitrate required to produce maximal or near maximal coronary dilation without clinically important systemic hemodynamic effects is in the range of 200 micrograms; (6) intracoronary nitrate is a more potent coronary artery dilator than sublingual nifedipine, when administered as a 10 mg dose.

Immunologic studies in a diabetic subject resistant to bovine insulin but sensitive to porcine insulin

Abstract In a diabetic subject shown repeatedly to be resistant to bovine insulin but sensitive to porcine insulin, serum titers of antibody to bovine insulin-I 131 were more than twenty-five times higher than those to porcine insulin-I 131 . Porcine insulin displaced bovine insulin-I 131 from antibody at specific binding sites but was less effective than bovine insulin in this respect. Human insulin was ineffective in the concentration ranges studied. The antiserum neutralized the hypoglycemic effect of bovine insulin in mice but at the same concentration only partially neutralized the effect of porcine insulin. It was concluded that in this human subject, whose peripheral tissue was still sensitive to porcine insulin, insulin resistance was primarily based on immunologic factors. In comparative studies with guinea pig antiserum, bovine, porcine and human insulin were equally effective in displacing bovine insulin-I 131 from most but not all anti bovine insulin serum. Quantitative cross reactions of human and porcine insulin were most consistent. All three species of insulin were equally effective in displacing bovine insulin-I 131 from anti porcine insulin guinea pig serum.

Hemodynamic effects of nitroglycerin combined with diltiazem in patients with coronary artery disease

Resting coronary and left ventricular hemodynamic effects of diltiazem and nitroglycerin, given intravenously in combination, were studied in 12 patients with coronary heart disease. Results observed with this combination were compared with those in seven patients given diltiazem initially (group I) and five patients given nitroglycerin initially (group II). The diltiazem-nitroglycerin combination reduced systolic blood pressure 27 percent (p less than or equal to 0.05) with no significant change in heart rate to affect a 22 percent (p less than or equal to 0.05) decrease in the rate-pressure product. Left ventricular end-diastolic pressure (-36 percent) and dp/dt (-6.4 percent) both declined (p less than or equal to 0.05). Coronary flow and cardiac output were both maintained. Diltiazem alone and nitroglycerin alone also reduced systolic pressure and the rate-pressure product but to a lesser degree than the combination. Diltiazem did not significantly affect left ventricular end-diastolic pressure and dp/dt. Nitroglycerin reduced left ventricular end-diastolic pressure to an extent similar to the reduction produced by the combination but increased heart rate whereas this determinant of myocardial oxygen demand did not increase significantly with the combination. These findings suggest that the combination of diltiazem and nitroglycerin produces a greater reduction in myocardial oxygen demand than either drug alone. In addition, the combination maintains coronary blood flow without increases in determinants of myocardial oxygen demand. This potentially beneficial drug combination warrants further trial in patients with myocardial ischemia.

Systemic, pulmonary, and coronary hemodynamic effects of labetalol in hypertensive subjects

Long-term therapy with oral labetalol, an alpha- and beta-blocking agent, has been shown to effectively lower blood pressure and heart rate without decreasing cardiac output. We examined the hemodynamic effects of the acute intravenous administration of labetalol in nine hypertensive patients. Labetalol (0.6 +/- 0.1 mg/kg) promptly reduced arterial pressure, heart rate, and systemic vascular resistance without change in stroke volume. Heart rate responses to passive tilt and the Valsalva maneuver were significantly blunted. With isometric exercise, heart rate and mean arterial pressure increased significantly during labetalol therapy but less than in the pre-labetalol phase. In eight patients oral labetalol therapy was continued for six weeks (mean dose 1,050 +/- 105 mg/day), and hemodynamic evaluation was repeated. During oral labetalol therapy, decreases in arterial pressure and heart rate were sustained. Systemic vascular resistance was reduced in five of the eight patients. Hemodynamic responses to tilt, Valsalva maneuver, and handgrip were similar to those during intravenous administration. Coronary blood flow decreased, but coronary as well as pulmonary vascular resistances were unchanged. These data show the efficacy of intravenously administered labetalol in lowering blood pressure and systemic vascular resistance promptly. With long-term oral therapy, decreases in blood pressure are sustained. Labetalol does not appear to have significant effects on pulmonary or coronary vascular resistances.

Nitrates for treatment of unstable angina pectoris and coronary vasospasm

The treatment of a patient with unstable angina at the time of the initial presentation of the physician can begin with nitrates. The beneficial action of nitrates are several. Nitrates dilate epicardial coronary arteries as well as many coronary artery stenoses. They may be effective because of this action plus a marked effect on decreasing ventricular volume and ventricular end diastolic pressure. Perhaps the best way to manage patients with severe angina that may be in part related to coronary artery vasoconstriction is to combine a long-acting nitrate with a calcium antagonist. The combined use of nitrates and calcium antagonists will (1) dilate the coronary arteries to maintain coronary blood flow, (2) decrease systemic arterial pressure and thus decrease peripheral vascular resistance, and (3) dilate peripheral veins and thus decrease ventricular volume and pressure. When proper doses are used, the combination may be more effective than either drug alone. Of course, proper dosing must be determined for the individual patient by the physician. Initial treatment with the nitrates should begin with small doses and gradually build up. Similar dosing schedules should be used for the calcium antagonists. Both doses can be increased to high levels is the clinical situation warrants it.

Regional coronary hemodynamic responses during the cold pressor test: Lack of effect of nitroglycerin

The effects of large coronary vessel dilation on responses to immersion of a hand and forearm in ice water for 1 minute (that is, the cold pressor test) were calculated for 17 patients. Regional coronary blood flow and aortic and left ventricular pressures were continuously measured before and during two cold pressor tests, each performed before and after administration of sublingual (0.4 mg) or low dose intracoronary (0.01 mg) nitroglycerin. During the initial cold pressor test, heart rate and coronary pressures increased in all patients; total and regional coronary resistance usually increased in patients with severe coronary artery disease and usually decreased in patients with a normal coronary angiogram. Sublingual nitroglycerin induced important systemic effects, but intracoronary nitroglycerin did not; both induced dilation of coronary arteries viewed angiographically. Regardless of the route of nitroglycerin administration, coronary hemodynamic responses were directionally similar during the repeat cold pressor test compared with the initial one. These data support the concept that changes in tone of the large coronary arteries are not important in producing the cardiac responses observed during the cold pressor test.