Effects of omapatrilat on hemodynamics and safety in patients with heart failure.

Omapatrilat, a novel vasopeptidase inhibitor, is a highly potent and selective inhibitor of neutral endopeptidase and angiotensin-converting enzyme; its therapeutic potential is being investigated for treatment of hypertension and heart failure. In the present study, the safety, tolerability, and hemodynamic effects of single oral doses of omapatrilat (1 to 50 mg) are compared with placebo in patients with heart failure. Patients with heart failure (New York Heart Association functional class II to IV) and a resting left ventricular ejection fraction < or = 40% were enrolled in a double-blind, placebo-controlled, sequential-panel study of single doses of omapatrilat of 1, 2.5, 5, 10, 25, or 50 mg, followed by hemodynamic assessment for 24 hours. At 4 to 6 hours after dosing, the 25- and 50-mg doses of omapatrilat, compared with placebo, reduced mean pulmonary capillary wedge pressure by approximately 6 mm Hg from 20 and 23 mm Hg at baseline to 14 and 16 mm Hg. The 50-mg omapatrilat dose maintained this effect compared with placebo with an approximately 2.5-mm Hg reduction in mean pulmonary capillary wedge pressure at 24 hours. Omapatrilat improved additional hemodynamic parameters, including cardiac index, systemic vascular resistance, stroke volume index, and mean arterial pressure. Additionally, by 2 hours after dosing with omapatrilat 25 and 50 mg, a trend in peak increases from baseline in plasma atrial natriuretic peptide (twofold) and cyclic guanosine monophosphate (nearly twofold) was observed. Moreover, omapatrilat was well tolerated. Thus, omapatrilat administered orally to patients with heart failure was safe and well tolerated and resulted in improved hemodynamic performance.

Evaluation of enalapril combined with diltiazem ER in patients with stage 3-4 essential hypertension.

Enalapril combined with an extended-release formulation of diltiazem was evaluated in a 12-week multicenter trial of 112 patients with Stages 3-4 essential hypertension. Patients were randomized to once daily therapy with enalapril 5 mg plus diltiazem ER 120 mg or 180 mg. Dosages could be titrated and other antihypertensive agents added for blood pressure control. Efficacy was assessed with sitting blood pressures at trough (24 hours postdose). Overall, there was a decrease of -21.7/-18.4 mmHg. Patients responding to enalapril/diltiazem ER alone had a reduction of -15.0/-16.3 mmHg. Of all patients, 70% achieved a trough sitting diastolic blood pressure of < 95 mmHg. Common drug-related adverse experiences were headache, dizziness, rash, and asthenia/fatigue. This once daily fixed-combination of enalapril/diltiazem ER was generally well tolerated and effective when given alone or with other antihypertensives in Stage 3-4 hypertension.

Evaluation of indapamide 1.25 mg once daily in elderly patients with mild to moderate hypertension.

The objective of this study was to evaluate the safety and efficacy of indapamide 1.25 mg once daily as monotherapy in elderly patients (65 years and older) with mild to moderate essential hypertension. Two hundred and seventy-nine (279) elderly patients were enrolled in a washout period, during which patients received single-blind placebo for 4 weeks. Patients demonstrating supine diastolic pressures between 95 mm Hg and 114 mm Hg at the end of the 4-week placebo washout period were entered into the 8-week double-blind treatment period. Two hundred and four (204) patients qualified for the study and were randomized to the double-blind treatment; 103 patients received indapamide 1.25 mg and 101 patients received placebo for 8 weeks. Overall, 177 patients (92 indapamide and 85 placebo) completed the study. The primary efficacy criterion was the mean change in supine diastolic blood pressure (DBP) from double-blind baseline to the end of 8 weeks of therapy. By week 8 of the double-blind treatment period, indapamide 1.25 mg produced a statistically significant (P = 0.0037) decrease in supine DBP of 8.2 mm Hg compared to a decrease of 5.3 mm Hg produced in the placebo group. Additionally, indapamide 1.25 mg was statistically (P = 0.0028) more effective than placebo in reducing supine systolic BP (SBP) (-10.1 vs -4.2 mm Hg). The incidence of drug-related adverse events during the double-blind treatment period was similar between the two treatment groups. A low dose of indapamide, 1.25 mg, given once daily for 8 weeks was effective as monotherapy with respect to BP reduction in an elderly population with mild to moderate hypertension. Indapamide 1.25 mg was safe and generally well tolerated in this elderly patient population.

Clinical utility of long-term enalapril/diltiazem ER in stage 3-4 essential hypertension. Long-term Use of Enalapril/Diltiazem ER in Stage 3-4 Hypertension Group.

The use of angiotensin converting enzyme inhibitors and calcium channel blockers, as monotherapies and in combination, is common in the management of hypertension. Clinical studies have documented the augmentation of blood pressure reduction when these agents are combined compared with the individual agents, in short-term studies. In the present investigation, 93 patients with stage 3-4 essential hypertension, who successfully completed a short-term double-blind study, participated in a 40-week open-label treatment phase. The patients were maintained on their previous doses of enalapril/diltiazem ER (E/D) with or without additional antihypertensive medications. Doses of medication could be adjusted as necessary for blood pressure control. Of the 93 patients, 68% were male and 82% were white; they averaged 52.7 years of age and had a baseline mean sitting blood pressure (SiBP) of 167/111 mmHg. The use of E/D alone (n = 14) reduced mean SiBP by 14.5/14.4 mmHg from baseline, whereas the use of E/ D with other agents (n = 79) decreased it by 27/20.5 mmHg from baseline. E/D alone or in combination with other drugs was well-tolerated, and no serious adverse events were noted. This long-term open-label study demonstrated that the E/D combination alone or with the addition of other antihypertensive drugs was effective, safe, and well-tolerated after prolonged administration.

A randomized comparison of the effects of gradual prolonged versus standard primary balloon inflation on early and late outcome. Results of a multicenter clinical trial. Perfusion Balloon Catheter Study Group.

BACKGROUND: Observational studies have suggested that prolonged balloon inflation during coronary angioplasty is associated with a high clinical success rate. This randomized clinical trial sought to evaluate the impact of primary gradual and prolonged inflations versus standard short dilatations in patients undergoing elective angioplasty. METHODS AND RESULTS: In phase 1 of the study, patients were randomized to receive two to four standard (1 minute) dilatations or one or two prolonged (15 minutes) dilatations after a perfusion balloon had been placed across a single target lesion. Patients with unsuccessful angiographic appearance after phase 1 dilatations had further dilatations in phase 2. Patients were followed for 6 to 12 months after the procedure. Of 478 patients, 242 received a median of one prolonged dilatation of 15 minutes' duration, and 236 received three dilatations for a median of 1 minute. Patients assigned to prolonged dilatations had a higher success rate (< or = 50% residual visual stenosis) (95% versus 89%; P = .016), less severe residual stenosis by quantitative angiography (median [25th and 75th percentiles], 35% [26%, 42%] versus 38% [30%, 46%]; P = .001), and a lower rate of major dissections (3% versus 9%; P = .003) at the end of phase 1. A total of 114 patients had further dilatations in phase 2-43 in the prolonged arm and 71 in the standard arm. The final procedural success rate was 98% with both primary dilatation strategies, which included additional maneuvers such as prolonged dilatations in the patients randomized to the primary standard dilatation. Overall, 320 of 416 patients (77%) who were discharged after a successful procedure without any in-hospital event (death, myocardial infarction, coronary artery bypass graft surgery, abrupt closure, or repeat angioplasty in target vessel) returned for follow-up angiography. The restenosis rate (> 50% residual visual stenosis) was 44% (95% confidence interval, 37% to 52%) in the prolonged dilatation group and 44% (36% to 52%) in the standard dilatation group. The primary angiographic end point of failure at the end of phase 1, abrupt closure, or restenosis throughout the study period was similar in both groups (prolonged, 51%; standard, 49%; P = .62). The secondary end point of absence of clinical events (death, nonfatal myocardial infarction, coronary artery bypass graft surgery, or repeat angioplasty in target vessel) also was similar (prolonged, 66%; standard, 74%; P = .15). CONCLUSIONS: Primary gradual and prolonged dilatations caused less arterial trauma with a modestly larger arterial lumen compared with standard dilatations. This initial improvement in angiographic appearance did not lead to a significant reduction in restenosis or clinical adverse events during follow-up.

Tear or dissection after coronary angioplasty. Morphologic correlates of an ischemic complication.

Intimal tear or dissection is an important descriptor of ischemic complications after coronary angioplasty, but only the minority of patients will develop an acute ischemic event. To identify additional factors that may predict the development of an ischemic event when arterial disruption occurs during otherwise uncomplicated angioplasty, the records of 1,346 patients prospectively identified as having tear or dissection without immediate vessel closure were examined. Ischemic complications, defined as ischemic chest pain, myocardial infarction, the need for coronary bypass surgery, or death, occurred in 120 patients (9%). Significant multivariate correlates of an ischemic complication were the presence of unstable angina or a totally occluded vessel before angioplasty and diameter stenosis of greater than 30% after angioplasty. Detailed geometric and videodensitometric analysis of the postdilatation angiograms of a subset of 96 consecutive patients was carried out. Ischemic complications occurred in 11 patients (11%). Multivariate analysis revealed that the independent correlates of complications, in decreasing order of importance, were the length of the tear or dissection (p = 0.001), diameter stenosis after angioplasty (p = 0.001), cross-sectional area after dilatation measured by videodensitometric methods (p = 0.013), and the presence of extraluminal contrast (p = 0.044). When tear or dissection occurs during otherwise uncomplicated coronary angioplasty, patients at risk of developing delayed ischemic complications can be identified and may benefit from measures designed to minimize this risk. By controlling for the geometric or mechanical factors that result in tear or dissection, it has been possible to identify factors not previously thought associated with ischemic complications.(ABSTRACT TRUNCATED AT 250 WORDS)