Multicenter, Double-blind, Randomized, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of Tezosentan in Patients With Acute Heart Failure.
- 1.Patients 18 years of age or older. 2.Male or non-breast-feeding, non-pregnant
female (only females who are post menopausal, surgically sterile or practicing a
reliable method of contraception).
3.Acute heart failure (ischemic or non-ischemic). 4.Randomization within 24 hours of
hospitalization (including emergency room stay) for acute heart failure.
5.Dyspnea at rest as assessed by the patient and breathing rate ³ 24/min (measured
during 60 seconds).
6.At least two out of the following four criteria: · elevated BNP or N terminal
pro-BNP (more than three times the upper limit of normal for the site) in patients
not treated with nesiritide,· clinical evidence of pulmonary congestion/edema (e.g.,
rales or crackles more than a third above bases),· evidence of pulmonary congestion
on chest X-ray, · left ventricular systolic dysfunction (EF < 40% or wall motion
index £ 1.2 within 12 months prior to randomization).
7.Patients in need of i.v. therapy for acute heart failure and who have received at
least one dose of i.v. diuretic within 24 hours prior to study drug initiation (last
bolus dose must have been more than 2 hours prior to study drug initiation).
8.Written informed consent.
- Criteria only for patients hemodynamically monitored:
1. Baseline cardiac index > 2.5 l/min/m2 and/or PCWP < 20 mmHg within 6 hours prior
to study drug initiation.
Criteria for all patients:
2. Patients not receiving i.v. vasodilators (e.g., nitrates, nitroprusside,
nesiritide) at baseline: supine systolic blood pressure < 100 mmHg. Patients
receiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) at
baseline: supine systolic blood pressure < 120 mmHg.
3. Cardiogenic shock within the last 48 hours or evidence of volume depletion.
4. Ongoing myocardial ischaemia, coronary revascularisation procedure (PCI or CABG)
during current admission or planned revascularisation.
5. ST-segment elevation myocardial infarction or administration of thrombolytic
6. Baseline creatinine ≥ 2.5 mg/dl (221 mmol/l).
7. Baseline hemoglobin < 10 g/dl or a hematocrit < 30%.
8. Hemodialysis, ultrafiltration or peritoneal dialysis within the last 7 days.
9. Heart failure due to active myocarditis, obstructive hypertrophic
cardiomyopathy, congenital heart disease, restrictive cardiomyopathy or
constrictive pericarditis. Heart failure caused by valvular disease.
10. Acute heart failure associated with uncontrolled hemodynamically relevant atrial
fibrillation/flutter or ventricular rhythm disturbances.
11. Acute heart failure secondary to clinical evidence of digoxin toxicity or any
other drug-related toxicity.
12. Significant chronic and/or acute lung disease that might interfere with the
ability to interpret the dyspnea assessments or hemodynamic measurements (e.g.,
severe chronic obstructive pulmonary disease or acute pneumonia).
13. Mechanical circulatory or ventilatory support. Prior CPAP use is allowed, if
discontinued at least 2 hours prior to study drug initiation.
14. Acute systemic infection/sepsis or other illness with a life expectancy less
than 30 days.
15. Coronary artery bypass graft, or other cardiac surgery, or major non-cardiac
surgery within the last 30 days.
16. Patients who received another investigational drug within 30 days prior to
17. Re-randomization in the current study.
18. Any factors that might interfere with the study conduct or interpretation of the
results such as known drug or alcohol dependence.
19. Concomitant treatment with cyclosporin A or tacrolimus.