Jan E. Carlsen

A Clinical Trial of the Angiotensin-Converting–Enzyme Inhibitor Trandolapril in Patients with Left Ventricular Dysfunction after Myocardial Infarction

BACKGROUND Treatment with angiotensin-converting-enzyme (ACE) inhibitors reduces mortality among survivors of acute myocardial infarction, but whether to use ACE inhibitors in all patients or only in selected patients is uncertain. METHODS We screened 6676 consecutive patients with 7001 myocardial infarctions confirmed by enzyme studies. A total of 2606 patients had echocardiographic evidence of left ventricular systolic dysfunction (ejection fraction, < or = 35 percent). On days 3 to 7 after infarction, 1749 patients were randomly assigned to receive oral trandolapril (876 patients) or placebo (873 patients). The duration of follow-up was 24 to 50 months. RESULTS During the study period, 304 patients (34.7 percent) in the trandolapril group died, as compared with 369 (42.3 percent) in the placebo group (P = 0.001). The relative risk of death in the trandolapril group, as compared with the placebo group, was 0.78 (95 percent confidence interval, 0.67 to 0.91). Trandolapril also reduced the risk of death from cardiovascular causes (relative risk, 0.75; 95 percent confidence interval, 0.63 to 0.89; P = 0.001) and sudden death (relative risk, 0.76; 95 percent confidence interval, 0.59 to 0.98; P = 0.03). Progression to severe heart failure was less frequent in the trandolapril group (relative risk, 0.71; 95 percent confidence interval, 0.56 to 0.89; P = 0.003). In contrast, the risk of recurrent myocardial infarction (fatal or nonfatal) was not significantly reduced (relative risk, 0.86; 95 percent confidence interval, 0.66 to 1.13; P = 0.29). CONCLUSIONS Long-term treatment with trandolapril in patients with reduced left ventricular function soon after myocardial infarction significantly reduced the risk of overall mortality, mortality from cardiovascular causes, sudden death, and the development of severe heart failure. That mortality was reduced in a randomized study enrolling 25 percent of consecutive patients screened should encourage the selective use of ACE inhibition after myocardial infarction.

Dofetilide in patients with congestive heart failure and left ventricular dysfunction

BACKGROUND Atrial fibrillation occurs frequently in patients with congestive heart failure and commonly results in clinical deterioration and hospitalization. Sinus rhythm may be maintained with antiarrhythmic drugs, but some of these drugs increase the risk of death. METHODS We studied 1518 patients with symptomatic congestive heart failure and severe left ventricular dysfunction at 34 Danish hospitals. We randomly assigned 762 patients to receive dofetilide, a novel class III antiarrhythmic agent, and 756 to receive placebo in a double-blind study. Treatment was initiated in the hospital and included three days of cardiac monitoring and dose adjustment. The primary end point was death from any cause. RESULTS During a median follow-up of 18 months, 311 patients in the dofetilide group (41 percent) and 317 patients in the placebo group (42 percent) died (hazard ratio, 0.95; 95 percent confidence interval, 0.81 to 1.11). Treatment with dofetilide significantly reduced the risk of hospitalization for worsening congestive heart failure (risk ratio, 0.75; 95 percent confidence interval, 0.63 to 0.89). Dofetilide was effective in converting atrial fibrillation to sinus rhythm. After one month, 22 of 190 patients with atrial fibrillation at base line (12 percent) had sinus rhythm restored with dofetilide, as compared with only 3 of 201 patients (1 percent) given placebo. Once sinus rhythm was restored, dofetilide was significantly more effective than placebo in maintaining sinus rhythm (hazard ratio for the recurrence of atrial fibrillation, 0.35; 95 percent confidence interval, 0.22 to 0.57; P<0.001). There were 25 cases of torsade de pointes in the dofetilide group (3.3 percent) as compared with none in the placebo group. CONCLUSIONS In patients with congestive heart failure and reduced left ventricular function, dofetilide was effective in converting atrial fibrillation, preventing its recurrence, and reducing the risk of hospitalization for worsening heart failure. Dofetilide had no effect on mortality.

Effect of dofetilide in patients with recent myocardial infarction and left-ventricular dysfunction : a randomised trial

BACKGROUND Arrhythmias cause much morbidity and mortality after myocardial infarction, but in previous trials, antiarrhythmic drug therapy has not been convincingly effective. Dofetilide, a new class III agent, was investigated for effects on all-cause mortality and morbidity in patients with left-ventricular dysfunction after myocardial infarction. METHODS In 37 Danish coronary-care units, 1510 patients with severe left-ventricular dysfunction (wall motion index < or = 1.2, corresponding to ejection fraction < or = 0.35) were enrolled in a randomised, double-blind study comparing dofetilide (n=749) with placebo (n=761). The primary endpoint was all-cause mortality. Secondary endpoints included cardiac and arrhythmic mortality and total arrhythmic deaths. Analyses were by intention to treat. FINDINGS No significant differences were found between the dofetilide and placebo groups in all-cause mortality (230 [31%] vs 243 [32%]), cardiac mortality (191 [26%] vs 212 [28%]), or total arrhythmic deaths (129 [17%] vs 140 [18%]). Atrial fibrillation or flutter was present in 8% of the patients at study entry. In these patients, dofetilide was significantly better than placebo at restoring sinus rhythm (25 of 59 vs seven of 56; p=0.002). There were seven cases of torsade de pointes ventricular tachycardia, all in the dofetilide group. INTERPRETATION In patients with severe left-ventricular dysfunction and recent myocardial infarction, treatment with dofetilide did not affect all-cause mortality, cardiac mortality, or total arrhythmic deaths. Dofetilide was effective in treating atrial fibrillation or flutter in this population.

Cardiovascular and adrenergic effects of cigarette smoking during immediate non-selective and selective beta adrenoceptor blockade in humans.

Abstract. The cardiovascular and adrenergic responses to cigarette smoking during acute selective and non‐selective beta adrenoceptor blockade were studied in seven young healthy volunteers in a double blind cross‐over fashion. Heart rate, arterial blood pressure, forearm blood flow and plasma levels of adrenaline and noradrenaline were determined before and during the terminal 5 min period of 15 min smoking test.

A randomised trial of a pre-synaptic stimulator of DA2-dopaminergic and α2-adrenergic receptors on morbidity and mortality in patients with heart failure

By pre‐synaptic stimulation of DA2‐dopaminergic and α2‐adrenergic receptors, nolomirole inhibits norepinephrine secretion from sympathetic nerve endings. We performed a clinical study with nolomirole in patients with heart failure (HF).

Acute hemodynamic effects of pinacidil and hydralazine in essential hypertension

In a double‐blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after β‐adrenoceptor blockade in six subjects with hypertension. Both drugs equally reduced total peripheral resistance by about 40%. Pinacidil reduced mean blood pressure by an average of 30 mm Hg, while the reduction after hydralazine was 10 mm Hg. The difference in antihypertensive effect resulted from greater increases in heart rate, cardiac contractility (systolic time intervals), and cardiac index (thermodilution) after hydralazine. These effects after hydralazine could not be fully abolished by β‐blockade, as could the effects after pinacidil. Pinacidil decreased pulmonary blood pressure, whereas there was a slight rise in pulmonary blood pressure after hydralazine. Forearm blood flow (venous occlusion strain gauge plethysmography) increased equally after both drugs; thus pinacidil decreased forearm vascular resistance more than hydralazine did. Serum concentrations of both drugs were within the therapeutic range and correlated with the fall in mean blood pressure. Five subjects complained of side effects after hydralazine, but none were reported after pinacidil. Hydralazine increased myocardial oxygen consumption (as estimated from the rate‐pressure product) by 35%; there was no change after pinacidil. It is suggested that hydralazine has direct cardiostimulatory effects that limit its antihypertensive effectiveness. These effects increase myocardial oxygen consumption and may be responsible for the common and sometimes severe cardiovascular side effects of hydralazine.

The incomplete Bucindolol Evaluation in Acute myocardial infarction Trial (BEAT)

The aim of this study was to evaluate the efficacy of adding the beta‐blocker bucindolol to standard therapy shortly after a myocardial infarction in a high‐risk population with reduced left ventricular function.

Immediate central hemodynamic effects of five different beta-adrenoceptor-blocking agents, acebutolol, atenolol, pindolol, practolol, and propranolol, in patients with ischemic heart disease

The hemodynamic effects of acebutolol were studied in six patients with ischemic heart disease. The changes in heart rate, cardiac output, and arterial blood pressure were determined after intravenous administration of six increasing doses of acebutolol to a cumulative dose of 0.64 mg/kg. After the sixth dose of acebutolol, cardiac output and heart rate were reduced 15% and 8%, respectively. Pulmonary artery pressure was increased by 4 mm Hg. Arterial blood pressure was not changed significantly. The effects of graded doses of acebutolol on heart rate and cardiac output were compared with earlier obtained results after atenolol (0.19 mg/kg), pindolol (0.025 mg/kg), practolol (0.64 mg/kg), and propranolol (0.19 mg/kg). The effects of increasing doses of acebutolol and practolol were very similar and significantly different from the effects of the other three drugs in spite having been administered at equipotent doses. The hemodynamic effects of acebutolol support the hypothesis that the hemodynamic response to beta-adrenoceptor antagonist drugs at rest is determined primarily by the degree of intrinsic sympathomimetic activity, whereas beta-1 selectivity does not modify the central hemodynamic response.

Immediate central and regional haemodynamic effects of a new beta1-adrenergic stimulating drug, xamoterol (Corwin) in healthy volunteers

SummaryDose-response curves for heart rate, arterial blood pressure, cardiac output, total peripheral resistance, systolic time intervals, forearm blood flow and forearm vascular resistance were obtained after i.v. administration of seven logarithmically increasing doses of xamoterol to 8 healthy volunteers. The total cumulative dose was 0.2 mg/kg b.w. At rest after the seventh dose of xamoterol heart rate, systolic blood, pressure, cardiac output and forearm blood flow were increased by 10%, 20%, 23% and 41%, respectively. Diastolic blood pressure was unchanged. Forearm vascular resistance was reduced by 21% and total peripheral resistance by 10%. Systolic time intervals were reduced: total electromechanical systole index (QS2I), left ventricular ejection time index (LVETI), pre ejection period index (PEPI) and PEP/LVET ratio by 4%, 2%, 12% and 14%, respectively. No side-effects were observed. During upright exercise after the seventh dose of xamoterol heart rate was reduced by 11% and systolic BP by 6%. Diastolic blood pressure was unchanged. Thus xamoterol increased the contractility of the heart with only a small increase in heart rate, increased systolic blood pressure and caused vasodilatation in resting skeletal muscle. During exercise the reduction in heart rate and blood pressure suggests beta-adrenoceptor blocking activity of the drug.

Comparison of Efficacy and Tolerability of Spirapril and Nitrendipine in Arterial Hypertension

SummaryIn a double-blind randomised parallel group trial a new angiotensin-converting enzyme (ACE) inhibitor, Spirapril, was compared to nitrendipine in 266 patients with hypertension (diastolic blood pressure 95 to 119mm Hg). Blood pressure was measured 24 hours after administration, and dose titration was performed every fourth week to achieve a diastolic blood pressure ⩽ 90mm Hg. After 4 weeks’ monotherapy with either nitrendipine 20mg once daily or Spirapril 12mg once daily, the dose was increased to 40mg once daily and 24mg once daily, respectively, if goal blood pressure had not been achieved. After 8 weeks of monotherapy hydrochlorothiazide 12.5mg once daily could be added.Both treatments had a low response rate and the reduction in blood pressure was lower than expected. No significant difference was found in the reductions in blood pressures between the 2 treatment regimens. The effect of adding hydrochlorothiazide to Spirapril was as expected, while the combination with nitrendipine only had a marginal extra effect on blood pressure. Significantly more patients in the nitrendipine group were withdrawn due to adverse events (27%) than in the Spirapril group (7%).In conclusion, at the dosages used, nitrendipine and Spirapril lower blood pressure to the same degree, but nitrendipine produces more adverse events. The addition of hydrochlorothiazide to nitrendipine cannot be recommended.