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Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX): A Randomized Clinical Trial. Margaret M Redfield, MD on behalf of the NHLBI Heart Failure Clinical Research Network. Background.

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Margaret m redfield md on behalf of the nhlbi heart failure clinical research network

Effect of Phosphodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX): A Randomized Clinical Trial

Margaret M Redfield, MDon behalf of the NHLBI Heart Failure Clinical Research Network


Background
Background Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

  • Phosphodiesterase type-5 (PDE-5) metabolizes nitric oxide (NO) and natriuretic peptide (NP) generated cGMP

  • If PDE-5 is activated in HF; may limit beneficial NO and NP actions in the heart, vasculature and kidney

  • PDE-5 Inhibitor therapy approved for

    • Erectile dysfunction

    • Group I pulmonary arterial hypertension (PAH)

  • Role in heart failure (HF) with reduced (HFrEF) or preserved (HFpEF) ejection fraction unclear


Background1
Background Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

  • Experimental HF: PDE-5 inhibition

    • Reversed cardiac remodeling and dysfunction

    • Improved vascular and renal function

  • Small Clinical Studies: PDE-5 inhibition (sildenafil)

    • HFrEF

      Improved maximal exercise capacity

    • HFpEF + PAH + RV dysfunction

      Improved hemodynamics, lung function, RV function and LV remodeling


Hypothesis
Hypothesis Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

In comparison to placebo, chronic (24 weeks) therapy with the PDE-5 inhibitor sildenafil will improve exercise capacity (peak VO2) and clinical status in HFpEF.


Study population
Study population Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

  • NYHA class II-IV HF symptoms

  • EF ≥ 50%

  • Objective evidence of HF (at least one)

    • HF hospitalization or ED visit + iv diuretic

    • Elevated PCWP at catheterization for dyspnea

    • Left atrial enlargement + chronic diuretic for HF

  • At study entry (both)

    • Peak VO2 < 60% age/sex nl value + RER ≥ 1.0

    • NT-proBNP

      • ≥ 400 pg/ml or

      • < 400 pg/ml with documented ↑ PCWP ≤ two weeks of NT-proBNP < 400


Study design
Study Design Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

Baseline CPXT, 6MWT, Echo-Doppler, MLHFQ, Biomarkers, and CMR (sinus rhythm)

Double-blind; 1 to 1 randomization stratified by site and rhythm (AF)

Placebo 20 mg TID

Sildenafil 20 mg TID

12 week CPXT, 6MWT, MLHFQ

Placebo 60 mg TID

Sildenafil 60 mg TID

24 week CPXT, 6MWT, Echo-Doppler, MLHFQ, Biomarkers and CMR


Study endpoints
Study Endpoints Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

  • Primary Endpoint

    • Change in peak VO2 after 24 weeks of therapy

  • Secondary Endpoints

    • Change in 6MWD after 24 weeks of therapy

    • Hierarchical composite clinical rank score

  • Other Endpoints

    • Change in CV structure and function (24 weeks)

      Echo-Doppler

      Cardiac magnetic resonance imaging (CMR)

    • Change in biomarkers (24 weeks)


Hierarchical composite clinical rank score
Hierarchical composite clinical rank score Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

At 24 weeks, all patients ranked

1

FIRST Death

X

LAST Death


Hierarchical composite clinical rank score1
Hierarchical composite clinical rank score Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

At 24 weeks, all patients ranked

1

FIRST Death

X

LAST Death

X+1

Alive with FIRST CV or cardiorenalhsp

Y

Alive with LAST CV or cardiorenalhsp


Hierarchical composite clinical rank score2
Hierarchical composite clinical rank score Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

At 24 weeks, all patients ranked

1

FIRST Death

X

LAST Death

X+1

Alive with FIRST CV or renal hospitalization

Y

Alive with LAST CV or renal hospitalization

Y+1

LEAST favorable change in MLHFQ

Z

MOST favorable change in MLHFQ

Mean rank score (lower worse) compared between treatment groups

Anchor value (no treatment effect) = Z / 2


Baseline features
Baseline Features Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

*p-value < 0.05

Median values or % shown


Baseline features1
Baseline Features Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

All p > 0.05

Median values or % shown


Results
Results: Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):


Results primary endpoint
Results: Primary Endpoint Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

Withdrew consent (n=14), death (n=3), unwilling (n=3) or unable (n=9) to complete CPXT, inadequate peak VO2 data (n=2)


Results primary endpoint1
Results: Primary Endpoint Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

Sensitivity analyses for missing data

Multiple imputation: p = 0.98; LOCF: p = 0.98

Data are median and IQR


Results secondary endpoints
Results: Secondary Endpoints Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

Data are median and IQR


Results secondary endpoints1
Results: Secondary Endpoints Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):


Results safety
Results: Safety Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

All p > 0.05


Results other endpoints
Results: Other endpoints Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

*p-value < 0.05

Median values shown


Conclusions
Conclusions Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

  • Chronic therapy with the PDE-5 inhibitor sildenafil was not associated with clinical benefit in HFpEF

  • Continued efforts to identify key pathophysiologic perturbations and novel therapeutic targets in HFpEF are needed


Minnesota Heart Failure Consortium Capacity and Clinical Status in Heart Failure with Preserved Ejection Fraction (RELAX):

Mayo Clinic

Montreal Heart Institute

BIOMARKER CORE

University of Vermont

Harvard University

CPXT CORE

ECHO CORE

University of Utah

NHLBI

CMR CORE

DCRI

Duke University

Morehouse School of Medicine

Baylor College of Medicine


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