Status: Not yet recruiting
Keywords: Heart Failure , Left Ventricular Dysfunction , Pulmonary Hypertension , Tadalafil , Phosphodiesterase Type 5 Inhibition
IRB Number: 00067706
Specialty: Cardiology, Cardiology, Cardiology
Sub Specialties: General Cardiology, Heart Failure

Brief Summary

Trial Objectives and Purpose
The study hypothesis is that chronic tadalafil therapy will have a beneficial effect on clinical outcomes in HF patients with LVSD and secondary PH.

Primary and Secondary Objectives
The primary objective of this study is to assess the effect of chronic PDE5 inhibitor therapy, compared to placebo, on morbidity and mortality in HF patients with LVSD (LVEF <0.40) and secondary PH.
A secondary objective of this study will be to assess the effect of chronic PDE5 inhibition, compared to placebo, on changes in functional capacity and quality of life in patients with HF.

Additional Objectives
An additional objective of this study is to establish the PITCH-HF Repository of blood specimens. These specimens will be collected at baseline, 3 months, and 18 months and stored at or below -80°C. This will enable future ancillary studies, which will operate under separate protocols.

Principal Investigator: Jose Nativi-Nicolau
Department: Cardiology
Co Investigator: Stavros Drakos
Co Investigator: James Fang
Co Investigator: John Ryan
Co Investigator: Edward Gilbert
Co Investigator: Josef Stehlik

Contact Information

Name:Melissa Whipple
Phone: 801-587-9048
Email: melissa.whipple@hsc.utah.edu

Inclusion Criteria

1. Male or female age 21 years or older. (Note: Women of child bearing potential must have a negative urine pregnancy test at study entry and must use effective contraception during study participation.)

2. NYHA Class II-IV HF with LVSD (most recent LVEF < 0.40). The most recent LVEF must have been measured within the 12 months prior to eligibility assessment, using any of the following techniques: echocardiography (transthoracic preferred, but transesophageal is acceptable); contrast ventriculography; radionuclide ventriculography (either Multi Gated Acquisition Scan (MUGA) or Single-photon emission computed tomography (SPECT); gated cardiac computed axial tomography (CT); or cardiac magnetic resonance imaging

3. At high risk of future clinical instability, indicated by EITHER:
a. A hospitalization for the primary reason of decompensated HF within the 12 months prior to screening;
b. A plasma BNP level ≥ 300 pg/ml or NT-proBNP ≥1800pg/ml measured during a period of clinical stability in the 3 months prior to screening.

4. Documented secondary PH within the last 6 months defined as:
a. RV systolic pressure ≥ 40 mmHg calculated from 4*(peak tricuspid regurgitation Doppler velocity)2 + 5 mmHg at rest;
b. Mean PAP of ≥ 25 mmHg at rest calculated from either
-Doppler measurements of RV outflow tract acceleration time Mean PAP = 79 - (0.45 x RVOT acceleration time); OR
-Pulmonic regurgitation (PR) velocity:
Mean PAP = 4∙(peak velocity of PR jet)2 + 5 mmHg
c. Mean PAP ≥ 25 mmHg at rest or ≥ 35 mmHg with supine or upright exercise measured by right heart catheterization.

5. Medication and device treatment according to current AHA/ACC guidelines. Additional treatments beyond those specified by the guidelines are acceptable.

6. Stable medical therapy for 30 days prior to randomization
a. No addition or discontinuation of ACE-inhibitors, ARBs, beta-blockers, calcium channel blockers (CCBs), or diuretics.
b. No change in dosage of ACE-inhibitors, ARBs, beta-blockers, CCBs, or diuretics of more than 100%.
c. Changes in diuretic dose guided by a patient-directed flexible dosing program are considered as stable medical therapy.

7. African-American patients intolerant of or otherwise unable or unwilling to utilize isosorbide dinitrate/hydralazine therapy will be included.
a. AHA/ACC guidelines recommend treatment of African-American Class III-IV HF patients with isosorbide dinitrate (ISDN) and hydralazine as first line therapy.
b. Tadalafil treatment is contraindicated in subjects receiving ISDN, and these patients cannot be enrolled in PITCH HF. African-American subjects who are not able to tolerate ISDN or other nitrate therapy, or are unwilling to utilize such therapy, are eligible for enrollment. The reason that a Class III-IV African-American subject is not taking ISDN/hydralazine (e.g. allergic reaction, intolerance related to a side effect) will be recorded on the screening case report form.

8. Willingness to comply with protocol, attend follow-up appointments, complete all study assessments and provide written informed consent.

Exclusion Criteria

Contraindications to randomization to PDE5 inhibitor therapy:
1. Concurrent or anticipated nitrate use for any reason, or nitrate use within the 14 days prior to screening through the day of randomization. This includes patients:
a. With a stress test demonstrating significant ischemia within the year prior to screening who have not undergone subsequent successful revascularization as demonstrated by relief of angina or anginal equivalent.
b. With unstable angina or percutaneous coronary intervention (PCI) within 60 days prior to screening, or requiring either PCI or coronary artery bypass grafting (CABG) between the time of screening and consent
2. Known allergy, hypersensitivity (anaphylaxis), or adverse reaction to tadalafil or other PDE5 inhibitor
3. Erectile dysfunction treated with a PDE5 inhibitor. Subjects currently taking sildenafil or vardenafil may be enrolled 24 hours after cessation of these agents, and those already taking tadalafil may be enrolled 72 hours after ceasing its administration.
4. Severe renal dysfunction defined as an estimated glomerular filtration rate (GFR) < 30 ml/min/1.73 m2 or requiring chronic dialysis
5. Current use of alpha antagonists (except carvedilol or tamsulosin) or use of cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, or cimetidine). Patients who have used a protease inhibitor that is a P450 3A4 inhibitor longer than one week can be enrolled in the trial. 18
6. Pulmonary arterial hypertension (WHO Group I, III-V) for which PDE5 inhibitor therapy may be indicated
7. Severe pulmonary disease requiring home oxygen therapy
8. Comorbidities including clinically significant valvular stenosis (aortic valve area < 0.8 cm2 or a mitral valve area <1.0 cm2), uncontrolled hypertension (systolic blood pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg) or hypotension (systolic blood pressure <85 mmHg)
9. Chronic intravenous inotrope therapy
10. Non-arteritic anterior ischemic optic neuropathy (NAION)
Factors that may complicate assessment of study endpoints:
11. ST elevation MI (STEMI) within 90 days prior to screening
12. CABG or mitral valve surgery, initiation of cardiac resynchronization (CRT) or β-blocker therapy within the 6 months prior to screening
a. Patients with CABG, mitral valve surgery, CRT, or initiation of β-blocker therapy should have an assessment of LVEF and pulmonary pressures at least 6 months after these interventions
13. Infiltrative or inflammatory myocardial disease (e.g. amyloid, sarcoid)
14. Heart transplant recipient
15. United Network Organ Sharing (UNOS) status 1A or 1B
16. Mechanical circulatory support (MCS) use or planned MCS use at time of consent
17. Active malignancy (except non-melanoma skin cancer) requiring therapy other than observation.
18. Severe non-cardiac illness resulting in life expectancy judged less than three years
19. Known chronic hepatic disease defined as AST and ALT levels > 3.0 times the upper limit of normal
20. Inability to walk even a few steps due to non-cardiac (e.g. orthopedic) reasons
21. Participation in any clinical trial within the