Randomized Intravenous Tezosentan for the Treatment of Acute Heart Failure - RITZ 2
The goal of the trial was evaluate the hemodynamic effects of 2 doses of tezosentan in a large patient population with acute decompensated heart failure (ADHF) and to confirm positive results observed in phase II trials.
Patients Enrolled: 285
Mean Patient Age: 62
285 patients well matched at baseline in terms of gender (≥72% male), age (average 62 years), and race (≥78% Caucasian) as well as ejection fraction ~23%. Previous myocardial infarction and hypertension occurred in more than half of patients, and diabetes in about one-third. Renal insufficiency was high for this patient population—about one-third of the patients in the placebo and T-50 groups, but only 22.8% in the T-100 cohort. To be included in the trial, patients had to require hospitalization for ADHF as well as hemodynamic monitoring, and have a cardiac index <2.5L/min/m2 and a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg. Hypotensive patients, or those with acute coronary syndromes, acute myocarditis, obstructive hypertrophic or restrictive cardiomyopathy, or severe obstructive lung disease were excluded.
Change in cardiac index from baseline to 6 hours after treatment initiation
Hemodynamic: Change from baseline in cardiac index at 24 hours; other hemodynamic parameters at 24 hours.
Clinical: Dyspnea score assessed by patient at 6 and 24 hours; time to worsening HF or death (over 24 hours).
Intravenous (IV) tezosentan 25 mg/hr for 1st hour up-titrated to 50 mg/hr for next 23 hours (T-50) (Group 1), or up-titrated to 50 mg/hr for 2nd hour then up-titrated to 100 mg/hr for 22 hours (T-100) (Group 2), or placebo (Group 3).
Concomitant medications included IV vasodilator, inotropic, or sympathomimetic drugs (stable for at least 2 hours if initiated before study start); initiation or increase of IV treatment for congestive HF permitted after start of trial drug in case of deterioration or treatment failure; no restriction on oral treatment; IV diuretics not allowed for 2 hours before start of trial drug.
Baseline cardiac index was 1.9 L/min/m2 across all 3 groups. At 6 hours, the index for the T-50 group was increased by 0.42 L/min/m2 and for the T-100 arm there was an increase of 0.41 L/min/m2. This demonstrated a highly significant treatment effect of 38% and 37% respectively versus placebo (p<0.0001). 75% of the drug effect was achieved in the first hour of treatment at the 25 mg dosage. This effect in cardiac index was sustained over the 24-hour treatment period and maintained for at least 6 hours after termination of the drug. Another significant change was seen in PCWP, which was ~25 mm Hg across all groups at baseline. At 6 hours, treatment reduced PCWP by 4.5 and 4.6 in the T-50 and T-100 arms respectively, with virtually no change for the placebo group (p<0.0001). Both tezosentan groups showed decreased systolic, diastolic, and mean pulmonary pressures. On a 7-point dyspnea scale, a significant number of patients on the study drug improved dyspnea scores and fewer patients worsened on tezosentan (p=0.048). Additionally, tezosentan patients were free of more events in terms of death or time to worsening HF, although the results were not significant. (Because the study was not powered to detect these endpoints, investigators combined the 2 active arms to obtain these measurements.) In reviewing safety data, researchers found a dose-dependent reduction in systolic and diastolic blood pressures at 24 hours, which was expected given that tezosentan is a vasodilator. However, this reduction in blood pressure did not translate into an increased heart rate. Headache occurred more frequently in the treatment arms, and overall there were more adverse events (symptomatic hypotension, renal impairment, nausea, vomiting) in the T-100 cohort than the T-50 group. Adverse events in the T-50 group were similar to those in the placebo arm. At 28 days of follow-up, the number of patients with renal impairment was similar across all arms (placebo, 8; T-50, 7; T-100, 9). The need for hemodialysis was present in 3, 4, and 5 patients respectively. Analysis of time to death, cardiac failure, pulmonary edema, or cardiogenic shock at 28 days from treatment start showed virtually identical curves between placebo and the T-100 group, indicating that T-100 was a safe dose at 28 days. However, there were even fewer events in the T-50 group. No changes were detected suggesting a pro-arrhythmic effect or change in electrocardiographic parameters associated with active therapy.
Among patients with acute decompensated heart failure, treatment with tezosentan at both 50 mg and 100 mg was associated with a significantly increased cardiac index and decreased PCWP as well as improved dyspnea scores. While the treatment effects were similar for both arms, the 50 mg dose was associated with fewer adverse events. Thus, investigators concluded that tezosentan offers a new therapeutic strategy to treat ADHF and that the optimal dosing regimen appears to be 25 mg→50 mg. Increased levels of endothelin-1 (ET-1) are deleterious in the cardiovascular system. ET-1 is likely the most potent vasoconstrictor. Also, it potentiates neurohormonal activity as well as facilitates cardiac hypertrophy and fibrosis. ET-1 binds to the ETA and ETB receptors and its effects are mediated by its interaction with both receptors. Thus, researchers believe ET-1 is a potential target for inhibition in ADHF patients (Duchman SM et al. Curr Opin Cardiol 2000;15:136-140).
Tezosentan is a dual ETA/ETB receptor antagonist designed specifically for parenteral use with a short half-life and no renal elimination, which may protect renal function (Clozel M et al. J Pharmacol Exp Ther 1999;290:840-846. Wilhelm SM et al. Transplantation 2001;71:211-216). Safety in normal volunteers was established in a phase I trial, and a more recent phase II study showed improvement in hemodynamics (Torre-Amione G et al. Circulation 2001;103:973-980). The full benefit of tezosentan on clinical outcomes is being further evaluated in the ongoing RITZ 1 trial.
ACC '01, Late Breaking Clinical Trials, presented by Guillermo Torre-Amione, MD, Baylor College of Medicine, Houston, TX
Keywords: Healthy Volunteers, Nausea, Pulmonary Edema, Vomiting, Follow-Up Studies, Vasoconstrictor Agents, Endothelin-1, Hypotension, Blood Pressure, Pyridines, Dyspnea, Tetrazoles, Heart Rate, Headache, Vasodilator Agents, Cardiomegaly, Shock, Cardiogenic, Renal Dialysis, Half-Life, Research Personnel, Heart Failure
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