Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure: Extent of Renal Damage

The National Heart, Lung, and Blood Institute (NHLBI)-funded parent study (PITCH-HF) is the
first well-controlled, randomized, large-scale trial studying the effect of tadalafil, an
FDA-approved selective phosphodiesterase type 5 inhibitor (PDE5i), on cardiovascular and
heart failure-related deaths and hospitalizations in patients with heart failure and
secondary pulmonary hypertension.

Both chronic kidney disease (CKD), as reflected by albuminuria and reduced estimated
glomerular filtration rate (eGFR) and acute kidney injury (AKI) significantly contribute to
morbidity and mortality in the population of patients who will be enrolled in PITCH-HF.
Therapies that alter the course of renal disease in patients with heart failure are lacking.
The biology of treatment with PDE5i strongly suggests a potential protective effect of these
agents on renal function.

This ancillary PITCH-ER study leverages the PITCH-HF infrastructure and randomization,
adding only longitudinal collection of subjects' urine samples to 5 timepoints throughout
the study. With these urine samples collected, PITCH-ER will address 2 major
patient-oriented questions:

1. Does chronic tadalafil treatment slow the rate of GFR decline and/or modify the
development/progression of albuminuria vs placebo? To answer this question,
longitudinal measures of eGFR utilizing state-of-the-art equations that incorporate
serum creatinine and cystatin C and spot urine albumin-to-creatinine ratios (UACR) will
be measured.

2. Does PDE5i treatment reduce AKI frequency and/or the magnitude of urinary biomarker
changes reflecting subclinical renal injury vs placebo? An AKI adjudication committee
will monitor the incidence of AKI events and their severity using the Kidney Disease
Improving Global Outcomes (KDIGO) consensus criteria. Subclinical renal injury will be
detected using validated urinary biomarkers: neutrophil gelatinase-associated lipocalin
(NGAL) and kidney injury marker 1 (KIM-1).

Since 30% of the overall PITCH-HF population will likely have diabetes (which amplifies the
risk for renal injury in HF patients), PITCH-ER will repeat analyses in the population
stratified by baseline diabetes status as secondary endpoints.

Inclusion Criteria:

- All subjects eligible for enrollment into the PITCH-HF parent trial are eligible to
enroll in this ancillary study (Refer to PITCH-HF NCT01910389 for specific
eligibility criteria)

Exclusion Criteria:

- Subjects who are not eligible for enrollment into the PITCH-HF parent trial may not
enroll in this ancillary study (Refer to PITCH-HF NCT01910389 for specific
eligibility criteria)