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PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) Trial

2012; Lippincott Williams & Wilkins; Volume: 5; Issue: 5 Linguagem: Inglês

10.1161/circheartfailure.112.969071

1941-3297

Margaret M. Redfield, Barry A. Borlaug, Greg Lewis, Selma F. Mohammed, Marc J. Semigran, Martin M. LeWinter, Anita Deswal, Adrian F. Hernandez, Kerry L. Lee, Eugene Braunwald,

Cardiac pacing and defibrillation studies

HomeCirculation: Heart FailureVol. 5, No. 5PhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) Trial Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBPhosphdiesteRasE-5 Inhibition to Improve CLinical Status and EXercise Capacity in Diastolic Heart Failure (RELAX) TrialRationale and Design Margaret M. Redfield, MD, Barry A. Borlaug, MD, Greg D. Lewis, MD, Selma F. Mohammed, MBBS, Marc J. Semigran, MD, Martin M. LeWinter, MD, Anita Deswal, MD, Adrian F. Hernandez, MD, Kerry L. Lee, MD, Eugene Braunwald, MD and For the Heart Failure Clinical Research Network Margaret M. RedfieldMargaret M. Redfield From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Barry A. BorlaugBarry A. Borlaug From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Greg D. LewisGreg D. Lewis From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Selma F. MohammedSelma F. Mohammed From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Marc J. SemigranMarc J. Semigran From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Martin M. LeWinterMartin M. LeWinter From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Anita DeswalAnita Deswal From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Adrian F. HernandezAdrian F. Hernandez From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Kerry L. LeeKerry L. Lee From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). , Eugene BraunwaldEugene Braunwald From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). and For the Heart Failure Clinical Research Network From the Department of Medicine, Baylor College of Medicine, Houston, TX (A.D.); Duke Clinical Research Institute, Durham, NC (A.F.H., K.L.L.); Harvard Medical School, Boston, MA (E.B.); Department of Medicine, Massachusetts General Hospital, Boston, MA (G.D.L., M.J.S.); Department of Medicine, Mayo Clinic, Rochester, MN (M.M.R., B.A.B., S.F.M.); and University of Vermont, Burlington, VT (M.M.L.). Originally published1 Sep 2012https://doi.org/10.1161/CIRCHEARTFAILURE.112.969071Circulation: Heart Failure. 2012;5:653–659Heart Failure With Preserved Ejection FractionHeart failure with preserved ejection fraction (HFpEF) or diastolic heart failure (HF) accounts for approximately half of HF cases in the community, and the portion of HF with preserved ejection fraction (EF) is increasing.1 Patients with HFpEF have limited functional capacity and poor prognosis. With ongoing shifts in the age distribution of the population, the burden of HFpEF is projected to increase. To date, there is no proven therapy for HFpEF. There is an urgent need for effective therapies for HFpEF.Randomized Clinical Trials in HFpEFTo date, 3 randomized control trials in HFpEF have tested the impact of renin-angiotensin-aldosterone antagonists on clinical outcomes in HFpEF. None of these trials demonstrated benefit individually (Figure 1) or in a pooled analysis (n=8021).2 An aldosterone antagonist trial in HFpEF is ongoing (clinicaltrials.gov NCT00094302). A trial of the β-blocker nebivolol in HF patients with normal or reduced EF was underpowered but suggested a benefit of β-blocker in the relatively small subset of HFpEF patients (Figure 1).3 The digitalis investigation group (DIG) trial showed no reduction in mortality with digoxin in a small ancillary study of HFpEF patients.4Download figureDownload PowerPointFigure 1. Previous randomized clinical trials in heart failure with preserved ejection fraction (HFpEF): Summary of the hazards ratios (95% CI) for the primary outcome measure of the large randomized placebo-controlled clinical trials in HFpEF to date. CHARM-Preserved indicates Candesartan in Patients With Chronic Heart Failure and Preserved Left Ventricular Ejection Fraction; I-PRESERVE, Irbesartan in Patients With Heart Failure and Preserved Ejection Fraction; PEP-CHF, Perindopril in Elderly People With Chronic Heart Failure; SENIORS, Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors With Heart Failure; DIG, Digitalis Investigation Group Trial.Although inadequate power or crossover may have contributed to negative findings in these trials, unique pathophysiology in HFpEF may mediate the differential response to neurohumoral antagonists and mandate novel therapies for the treatment of HFpEF. The PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX trial; clinicaltrials.gov NCT00763867) trial has been designed by and is being conducted within the National Heart, Lung, and Blood Institute–sponsored HF clinical research network. Herein, we provide the rationale for RELAX by summarizing the unique pathophysiological derangements in HFpEF and the studies suggesting that phosphodiesterase-5 inhibition (PDE5I) may target these derangements. The design of the RELAX trial is described with particular emphasis on the rationale for the primary end point (change in peak oxygen consumption [VO2] with sildenafil versus placebo).HFpEF PathophysiologyLV Diastolic DysfunctionIn HFpEF, abnormalities in left ventricular (LV) stiffness and relaxation impair filling and result in the need for elevated filling pressure to achieve adequate LV preload (end-diastolic volume) at rest or during physiological stress. An early study, including patients with hypertrophic and infiltrative cardiomyopathy, identified the inability to enhance end-diastolic volume as a key mechanism limiting exercise capacity in HFpEF.5 However, studies in more typical HFpEF patients have not corroborated this finding.6–8 However, elevation in LV filling pressure at rest or with exertion with normal LV volume is pathognomonic of HFpEF.9Increases in passive LV diastolic stiffness in HFpEF may be caused by structural abnormalities, including myocyte hypertrophy, matrix deposition, posttranslational oxidative modification of collagen, and altered titin isoform expression. Dynamic perturbations in the phosphorylation of titin or other myofilament proteins, diastolic calcium concentrations, and calcium sensitivity may acutely impair LV stiffness in HFpEF.10,11Impaired relaxation may contribute to elevated filling pressures during exercise-related tachycardia in HFpEF.12,13 Isovolumic relaxation is an energy-requiring process, and abnormalities in myocardial energetics, which have been demonstrated in HFpEF, may contribute to abnormal relaxation reserve.14LV Systolic DysfunctionAlthough EF is by definition preserved (≥50%) in HFpEF, other measures of resting myocardial systolic function are subtly but significantly impaired, and the extent of this impairment is associated with higher mortality.15 Furthermore, HFpEF is characterized by dramatic deficits in systolic reserve capacity during exercise7,14,16 or β-adrenergic stimulation.17 Impaired systolic reserve is associated with reduction in overall exercise capacity, HF symptom severity, and incident pulmonary edema.7,18Vascular DysfunctionHFpEF is characterized by vascular-ventricular stiffening, with deleterious effects on LV ejection capacity, blood pressure regulation, and LV relaxation.19,20 Conversely, vascular-ventricular stiffening also accentuates the hypotensive effects of preload or afterload reduction, potentially limiting the efficacy of vasodilators or diuretics in HFpEF.21 Vasodilation in skeletal muscle beds during exercise is, in part, endothelium dependent and is impaired in HFpEF,6,7,16 limiting delivery and extraction of oxygen at the tissue level.8,22 Accumulation of metabolic byproducts in skeletal muscle during exercise may also contribute to dyspnea via ergoreflex activation,23 which is tightly correlated with impaired endothelium-dependent vasodilation in HF with reduced EF (HFrEF).23PH and RV DysfunctionPulmonary hypertension (PH) is extremely common in HFpEF and associated with increased mortality.24 In HF, PH may be related to both pulmonary venous and reactive pulmonary arterial hypertension, which are both equally severe in HFpEF and HFrEF.21 As the right ventricle (RV) is exquisitely sensitive to afterload, resting and exercise-induced PH may contribute to impaired output limiting exercise capacity and leading to progressive RV dysfunction, as is well described in HFrEF.25–28Neurohormonal and Renal AbnormalitiesChronotropic incompetence is common in HFpEF6,7 and may relate to autonomic dysfunction, because heart rate recovery (a marker of vagal tone), arterial baroreflex sensitivity, and cardiac β-adrenoreceptor sensitivity are all reduced in HFpEF.6,14,17,29Renal dysfunction is as common in HFpEF as HFrEF, and its presence is associated with increased morbidity and mortality.1 Natriuretic peptide (NP) levels are less elevated in HFpEF compared with HFrEF,30 despite similar elevation in filling pressures because of lower wall stress, the stimulus for NP production. This NP deficiency may have adverse effects on renal sodium handling.PDE-5 in Cardiac, Vascular, and Renal PhysiologyBoth the NP (via particulate guanylyl cyclase) and NO (via soluble guanylyl cyclase) stimulate cyclic guanosine monophosphate (cGMP), an intracellular second messenger whose effector proteins include cGMP-dependent protein kinase.31 The bioactivity of cGMP/cGMP-dependent protein kinase is regulated via cGMP catabolism by phosphodiesterase 5 (PDE5). Although PDE5 expression is low in normal myocardium, compartmentalization to subcellular locations regulates key cGMP pools32 and modulates β-adrenergic responsiveness.33 Furthermore, PDE5 is markedly upregulated with oxidative stress and pressure overload hypertrophy,34–38 both common in HFpEF.PDE5 is expressed in vascular smooth muscle cells where cGMP/cGMP-dependent protein kinase causes vasorelaxation. In pulmonary arterial hypertension, PDE5 expression and activity are increased in pulmonary vascular smooth muscles cells, promoting vasoconstriction.39In experimental HF, PDE5 is upregulated in the kidney, where it may contribute to renal NP hyporesponsiveness and impaired sodium excretion.40,41Rational for RELAX: Evidence That PDE5I Targets HFpEF PathophysiologyBased on the complex pathophysiological derangements present in HFpEF, upregulation of PDE5 in stress states typical of HFpEF, and the pleiotropic effects of PDE5 on cardiovascular function, there is abundant evidence to suggest PDE5I will have beneficial effects in HFpEF (Figure 2).Download figureDownload PowerPointFigure 2. Potential beneficial effects of phosphodiesterase-5 inhibition in heart failure with preserved ejection fraction: See text for discussion. CCA indicates catecholamine; F, function; PVR, pulmonary vascular resistance; PVC, pulmonary vascular compliance; Phos, phosphorylation; LV, left ventricular; RV, right ventricular; SVR, systemic vascular resistance; NP, natriuretic peptide; LVH, LV hypertrophy.Cardiac EffectsIn experimental HF, chronic pharmacological PDE5I attenuates and reverses maladaptive hypertrophy, fibrosis, and contractile dysfunction,34,42 mitigates deleterious effects of cardiac sympathoexcitation,6,43 and improves cell survival.44 In failing RV cardiac myocytes, PDE5I has positive inotropic effects, possibly because of cGMP inhibition of PDE3 with increased cAMP/protein kinase A.35,36In HFrEF patients, PDE5l increases RV systolic28 and LV diastolic and systolic functions, coupled with reductions in LV size, LV mass, and left atrial size.45 A recent small, single-center trial in HFpEF (n=44) also reported improvements in lung function, RV systolic function, and LV and RV diastolic functions with PDE5I.46 Although chronic PDE5I may cause reverse remodeling, acute administration may also improve diastolic function via cGMP/cGMP-dependent protein kinase–mediated phosphorylation of titin.47Vascular EffectsPDE5I prevents the development of endothelial dysfunction and pulmonary vascular remodeling, coupled with improvements in alveolar capillary membrane structure and RV geometry in experimental HFpEF.48 In humans, PDE5I reduces pulmonary vascular resistance in non-HF and HF states, both at rest and during stress.27,28,39,46,49,50 Exertional PH in HFrEF is reduced with acute or chronic PDE5I,27,28 in association with improvements in exercise capacity and quality of life. Systemic vascular resistance,27,51 aortic stiffness, and wave reflection,52,53 endothelial function,54 and ergoreflex-related hyperventilation have all been shown to improve with PDE5I in HFrEF.23Neurohormonal and Renal EffectsPDE5I acutely reduces cardiac-specific norepinephrine spillover,43 which may restore normal adrenergic sensitivity and diminish catecholamine-mediated concentric remodeling.55 Postsynaptic attenuation of excessive adrenergic stimulation has been demonstrated with PDE5I in animal models32 and humans,33 and chronically, this effect may help restore normal β-adrenergic responsiveness and improve cardiac reserve function in HFpEF. In the kidney, PDE5I restores NP responsiveness to enhance sodium excretion in HF.40,41RELAX DesignRELAX is a randomized (1:1), double-blind, placebo-controlled treatment study designed to test the hypothesis that chronic PDE5I (sildenafil 20 mg TID for 12 weeks followed by 60mg TID for 12 weeks) improves exercise capacity and clinical status in patients with HFpEF.Study procedures include collection of blood for biomarkers, Minnesota Living with Heart Failure Questionnaire, cardiopulmonary exercise testing (CPXT), and 6-minute walk distance at baseline, 12 weeks, and 24 weeks. Doppler echocardiography and cardiac magnetic resonance imaging (CMR; in CMR-eligible patients) are obtained at baseline and 24 weeks. All study parameters are analyzed by the HF clinical research network CORE laboratories, which include the Biomarker CORE (University of Vermont), CPXT CORE (Massachusetts General Hospital, Harvard University), CMR CORE (Duke University), and Echocardiography CORE (Mayo Clinic, Rochester, MN).The primary end point is the change in VO2 from baseline to 24 weeks. Secondary outcomes include change in peak VO2 at 12 weeks, change in 6-minute walk distance at 12 and 24 weeks, and the change in a composite clinical score at 24 weeks. The composite score is a hierarchical rank score based on time to death (tier 1), time to hospitalization for cardiovascular or cardiorenal causes (tier 2), and change in Minnesota Living with Heart Failure Questionnaire from baseline (tier 3).Prespecified subgroup analysis includes comparison of efficacy in patients according to LV mass index, N-terminal prohormone of brain natriuretic peptide, estimated pulmonary artery systolic pressure, study medication dose tolerated, atrial fibrillation, and HF medication use.Tertiary end points include additional exercise and clinical parameters, change in LV mass (by CMR and echo), serological markers of extracellular matrix metabolism, LV diastolic dysfunction, peripheral vascular function, aortic thickness and distensibility, pulmonary artery systolic pressure, and neuroendocrine and renal function biomarkers.Study PopulationSpecific inclusion criteria are listed in the Table. Evidence of resting or exercise-induced elevation in filling pressures (N-terminal prohormone of brain natriuretic peptide/brain natriuretic peptide or hemodynamic data if N-terminal prohormone of brain natriuretic peptide is 18 yearsPrevious clinical diagnosis of HF with current NYHA Class II–IV symptomsAt least one of the following within 12 months before consent:Hospitalization for decompensated HFAcute treatment for HF with intravenous loop diuretic or hemofiltrationChronic treatment with a loop diuretic for control of HF symptoms+chronic diastolic dysfunction on echocardiography as evidenced by left atrial enlargementMean PCWP >15 mm Hg or LV end-diastolic pressure >18 mm Hg at catheterization for dyspneaEF ≥50% within 12 months with clinical stabilityStable medical therapy for 30 days:No addition or removal or major (>100%) dose change of RAAS antagonists, BB, or calcium channel blockersMeet both screening criteriaPeak VO2 ≤60% age/sex-adjusted normal value+ respiratory exchange ratio ≥1.0One of the following:(i) NT-proBNP ≥400 pg/mL or BNP ≥200 pg/mL(ii) NT-proBNP <400 pg/mL/BNP 20 mm Hg at rest or >25 mm Hg with exerciseHF indicates heart failure; NYHA, New York Heart Association; EF, ejection fraction; BB, β-blocker; VO2, peak oxygen consumption; NT-proBNP, N-terminal prohormone of brain natriuretic peptide; BNP, brain natriuretic peptide; RAAS, renin angiotensin aldosterone system; PCWP, pulmonary capillary wedge pressure.Statistical ConsiderationsPower calculations were based on the SD for change in peak VO2 observed in randomized control trials in HFrEF and on limited randomized control trial data in HFpEF. We estimated a 20% rate of incomplete primary end point data because of death, withdrawal, or incidence of new factors limiting ability to exercise. The expected effect size was extrapolated from studies of chronic PDE5I in HFrEF.23,28 Using a 2-sample t test and a 2-sided α of 0.05, a sample size of 190 patients would have 85% power to detect a difference of 1.2 mL/kg per min in change in peak VO2, assuming 20% missing data and an SD of change in peak VO2 of 2.5 mL/kg per min. Because an early blinded interim analysis of primary end point completeness indicated that the missingness rate approached 20% (this decreased dramatically as enrollment proceeded), the data and safety monitoring board (DSMB) recommended increasing the sample size to 215 and 216 patients were ultimately enrolled. Although the primary statistical approach to missing primary end point data will be to exclude patients without 24-week primary end point data, a variety of sensitivity analyses are planned, including changes in peak VO2 at 12 weeks and carry forward of 12-week data.Peak VO2 at CPXT as the RELAX Primary End PointExercise intolerance is the cardinal manifestation of HFpEF and can be quantified objectively by measurement of peak VO2.56,57 The multifactorial pathogenesis of exercise intolerance in HFpEF coupled with the numerous mechanisms by which sildenafil may ameliorate HFpEF pathophysiology (as above) strongly argues for assessment of peak VO2 as a global indicator of exercise capacity that integrates the physiological consequences of intervention on multiple mechanisms in HFpEF.CPXT, unlike other measurements of functional status such as 6-minute walk distance, permits assessment of the organ system limiting gas exchange. This is crucial in HFpEF, which tends to occur in older individuals with comorbidities that can result in primary pulmonary, mechanical, or orthopedic limitations to exercise that obscure ascertainment of a treatment effect from a cardiovascular intervention. CPXT also permits precise assessment of volitional effort by determining whether the respiratory exchange ratio (VCO2/VO2) exceeds 1.0 during exercise, indicating that a subject has surpassed their anaerobic threshold.58 Finally, in a study of patients with HFpEF and HFrEF, CPXT variables predicted survival whereas 6-minute walk distance did not.59Another advantage of CPXT is that easily derived variables other than peak VO2 reflect distinct aspects of HFpEF pathophysiology. For example, CPXT includes assessment of heart rate and blood pressure augmentation and recovery patterns that are known to be abnormal in HFpEF.6,60 CPXT also permits measurement of ventilatory efficiency (VE/VCO2 slope), which is closely related to pulmonary vascular function during exercise,26 and exercise oscillatory ventilation (EOV), which has been shown to signal reduced exercise cardiac index in HFrEF.61 Elevated VE/VCO2 slope and EOV are present in a subset of patients with HFpEF and confer a poor prognosis.62,63 Both these CPXT variables have been shown to improve with sildenafil in HFrEF.26,64 Finally, CPXT is conducive to being integrated with other forms of physiological testing during exercise as will be assessed in RELAX ancillary studies (see below).Importantly, unlike changes in alternative trial end points, such as circulating biomarkers or echo parameters, there is significant intrinsic value to patients associated with improving exercise capacity.Although a recent meta-analysis found that therapy-induced changes in peak VO2 in HF clinical trials did not uniformly predict the corresponding intervention's effect on mortality in larger phase 3 trials, the reviewed trials often included 200 subjects), concordant changes in peak VO2 and mortality are apparent for interventions, such as cardiac resynchronization therapy (+/+ for change in VO2 and improvement in mortality, respectively),66,67 isosorbide/hydralazine (+/+),68 prazosin (−/−),68 and calcium channel blockade(−/−).69 A notable exception is that small trials with β-blockers in HFrEF (−/+) showed neutral effects on peak VO2,70,71 yet β-blockers clearly prolong survival in HFrEF.Like any measurement, CPXT necessitates attention to detail with metabolic cart testing uniformity across sites, and willingness of subjects to comply with testing. Compliance with repeated maximum exercise testing is of potential concern in an HFpEF population, because these patients are typically sedentary and sometimes frail and may have an aversion to repeated maximum exercise testing.A detailed description of the RELAX CPXT Protocol Design and the RELAX CPXT Core Laboratory methods is provided in the on-line Data Supplement and details the tailoring of the CPXT protocol to the HFpEF population, harmonization of bike and treadmill protocols to allow paired use of either exercise mode, the rigorous site certification process, secure electronic breath-by-breath data transmission, standardized encouragement scripts, pre-CPXT spirometry and hemoglobin data collection, and rigorous end point measurement methodologies.Ancillary StudiesSeveral ancillary studies have been approved before completion of enrollment in RELAX.Mechanisms Mediating the Effects of PDE5I on Exercise Capacity in HFpEF: Ventricular-Vascular Reserve and Ergoreflex ControlThis prospective, 2-center study seeks to define the effect of PDE-5 inhibition on LV and RV contractile reserve, pulmonary and systemic arterial vasodilator reserve, vascular stiffening, endothelial function, and ergoreflex function in RELAX.Effect of PDE5I on VE/CO2 and EOV in HF With Preserved EF.Breath-by-breath gas exchange data collected during CPET testing in all subjects will establish the incidence, severity, reproducibility, and phenotypic correlates of heightened VE/VCO2 slope and EOV in HFpEF. The effect of PDE5I on VE/VCO2 slope and EOV will also be assessed.Oxygen Kinetics Characterization in RELAXThis study tests the hypotheses that HFpEF patients display delayed O2 kinetics and reduced aerobic efficiency, that impaired O2 kinetics are related to perceived dyspnea during exercise and quality of life measures, and that O2 kinetics and the VO2/work rate relationship will improve with chronic PDE5I.Resting Ventricular-Vascular Function and Exercise Capacity in HFpEF.This study will test the hypothesis that resting aortic stiffness and LV systolic and diastolic dysfunctions predict exercise capacity in HFpEF.Impact of Atrial Fibrillation on Exercise Capacity in HF With Preserved EFThis study will characterize the clinical, echocardiographic, and neurohumoral phenotype associated with AF in the setting of HFpEF and will determine whether AF influences exercise capacity compared with sinus rhythm.DiscussionThe RELAX trial design has many strengths, including the multicenter design, rigorous entry criteria, novel therapeutic intervention, and extensive phenotyping, which will provide insight into mechanisms responsible for the outcome of the study and through ancillary analyses, the pathophysiology of HFpEF. The primary end point is well suited to the enrollment capacity of the HF clinical research network, the pathophysiology of HFpEF, and the biological actions of PDE5I, but its utilization precludes enrollment of frailer patients and may limit generalization of study results to all HFpEF patients.Although the RELAX trial will determine whether chronic PDE5I improves exercise capacity in HFpEF patients, it is not considered a pivotal trial, and thus the RELAX trial will not result in labeling of sildenafil for the treatment of HFpEF. However, the results from RELAX could lead to guideline recommendations for use of PDE5I to improve symptoms in HFpEF and to an outcome-based study of PDE5I in HFpEF.Sources of FundingThe Heart Failure Clinical Research Network is supported by grants HL084861, HL084875, HL084877, HL084889, HL084890, HL084891, HL084899, HL084904, HL084907, and HL084931. S.F.M. is supported by HL07111-83, whereas support for mentoring S.F.M. as an HF Clinical Research Network Clinical Research Skills Development fellow is provided by HL084907 and UL1 RR024150.DisclosuresDr Redfield receives educational grants from Medtronic and Thoratec, as well as royalties from Anexon. Dr Semigran receives research support from Bayer Inc. Dr LeWinter receives research support from Gilead and Medtronic, as well as consultant fees from Gilead Pharma and Merck. Dr Lewis receives research support from Pfizer via the ASPIRE Award. Dr Braunwald is the Founding Chairman of the TIMI Study Group at the Brigham and Women's Hospital. The Brigham and Women's Hospital receives grant support for the TIMI Study Group from Merck & Co, Inc. Dr Borlaug receives research support from Gilead and Atcor Medical. The other authors have no conflicts to report.FootnotesThe online-only Data Supplement is available at http://circheartfailure.ahajournals.org/lookup/suppl/doi:10.1161/CIRCHEARTFAILURE.112.969071/-/DC1.Correspondence to Margaret M. Redfield, MD, Guggenheim 9, Mayo Clinic, 200 First St, Sout