Tezosentan in the Treatment of Acute Heart Failure

Inclusion Criteria:

• 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 reliablemethod of contraception).

3.Acute heart failure (ischemic or non-ischemic). 4.Randomization within 24 hours ofhospitalization (including emergency room stay) for acute heart failure.

5.Dyspnea at rest as assessed by the patient and breathing rate ³ 24/min (measuredduring 60 seconds).

6.At least two out of the following four criteria: · elevated BNP or N terminalpro-BNP (more than three times the upper limit of normal for the site) in patients nottreated with nesiritide,· clinical evidence of pulmonary congestion/edema (e.g., ralesor crackles more than a third above bases),· evidence of pulmonary congestion on chestX-ray, · left ventricular systolic dysfunction (EF < 40% or wall motion index £ 1.2within 12 months prior to randomization).

7.Patients in need of i.v. therapy for acute heart failure and who have received atleast one dose of i.v. diuretic within 24 hours prior to study drug initiation (lastbolus dose must have been more than 2 hours prior to study drug initiation).

8.Written informed consent.

Exclusion Criteria:

• Criteria only for patients hemodynamically monitored:

1. Baseline cardiac index > 2.5 l/min/m2 and/or PCWP < 20 mmHg within 6 hours priorto 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. Patientsreceiving i.v. vasodilators (e.g., nitrates, nitroprusside, nesiritide) atbaseline: 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 thrombolytictherapy.

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 constrictivepericarditis. Heart failure caused by valvular disease.

10. Acute heart failure associated with uncontrolled hemodynamically relevant atrialfibrillation/flutter or ventricular rhythm disturbances.

11. Acute heart failure secondary to clinical evidence of digoxin toxicity or anyother drug-related toxicity.

12. Significant chronic and/or acute lung disease that might interfere with theability 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, ifdiscontinued 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-cardiacsurgery within the last 30 days.

16. Patients who received another investigational drug within 30 days prior torandomization.

17. Re-randomization in the current study.

18. Any factors that might interfere with the study conduct or interpretation of theresults such as known drug or alcohol dependence.

19. Concomitant treatment with cyclosporin A or tacrolimus.