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Heart failure (HF) with preserved ejection fraction (HFpEF) or “diastolic HF” accounts for approximately half of HF cases. To date, neurohumoral antagonists have failed to show a significant benefit on clinical outcomes in HFpEF. While our understanding of the pathophysiology of HFpEF continues to develop, multiple therapeutic targets have been identified in HFpEF which may be modifiable by augmentation of the intracellular second messenger cyclic guanosine monophosphate (cGMP) via phosphodiesterase-5 inhibition (PDE5I) in HFpEF. The PhosphodiesteRasE-5 Inhibition to Improve CLinical Status And EXercise Capacity in Diastolic Heart Failure (RELAX trial; clinicaltrials.gov NCT00763867) is being conducted within the NHLBI sponsored HF clinical research network and tests the hypothesis that chronic PDE5I (sildenafil® 20 mg tid for 12 weeks followed by 60 mg tid for 12 weeks) improves exercise capacity and clinical status in patients with HFpEF. Here we provide the rationale for RELAX by summarizing the pathophysiologic derangements in HFpEF and the evidence that PDE5I may ameliorate these derangements. The design of the RELAX trial is described and the rationale for the primary endpoint in RELAX (change in peak oxygen consumption) is provided.
Heart failure (HF) with preserved ejection fraction (HFpEF) or “diastolic HF” accounts for approximately half of HF cases in the community and the portion of HF due to HFpEF is increasing1. 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.
To date, three RCT in HFpEF have tested the impact of renin-angiotensin-aldosterone (RAAS) 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 beta blocker (BB) nebivolol in HF patients with normal or reduced EF was underpowered but suggested a benefit of BB 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 patients4.
While 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) has been designed by and is being conducted within the NHLBI sponsored HF clinical research network (HFCRN). Here in we provide the rational for RELAX by summarizing the unique pathophysiologic 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 rational for the primary endpoint (change in peak oxygen consumption with sildenafil versus placebo).
In HFpEF, abnormalities in left ventricular (LV) stiffness and relaxation impair filling and/or result in the need for elevated filling pressure to achieve adequate LV preload (end diastolic volume, EDV) at rest or during physiologic stress. An early study including patients with hypertrophic and infiltrative cardiomyopathy identified the inability to enhance EDV as a key mechanism limiting exercise capacity in HFpEF5. However, studies in more typical HFpEF patients have not corroborated this finding6–8. However, elevation in LV filling pressure at rest or with exertion with normal LV volume is pathognomonic of HFpEF9.
Increases in passive LV diastolic stiffness in HFpEF may be caused by structural abnormalities including myocyte hypertrophy, matrix deposition and post-translational oxidative modification and altered titin isoform expression. Dynamic perturbations in phosphorylation of titin or other myofilament proteins, diastolic calcium concentrations and calcium sensitivity may acutely impair LV stiffness in HFpEF10,11.
Impaired relaxation may contribute to elevated filling pressures during exercise related tachycardia in HFpEF12, 13. Isovolumic relaxation is an energy-requiring process and abnormalities in myocardial energetics which have been demonstrated in HFpEF may contribute to abnormal relaxation reserve14.
While 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 mortality15. Further, HFpEF is characterized by dramatic deficits in systolic reserve capacity during exercise7, 14, 16 or β-adrenergic stimulation17 and impaired systolic reserve is associated with reduction in overall exercise capacity, HF symptom severity and incident pulmonary edema7, 18.
HFpEF is characterized by vascular-ventricular stiffening with deleterious effects upon LV ejection capacity, blood pressure regulation and LV relaxation19, 20. Conversely, vascular-ventricular stiffening also accentuates the hypotensive effects of preload or afterload-reduction, potentially limiting the efficacy of vasodilators or diuretics in HFpEF21. Vasodilation in skeletal muscle beds during exercise is in part, endothelium-dependent and is impaired in HFpEF6, 7, 16 limiting delivery and extraction of oxygen at the tissue level8, 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 HFrEF23
Pulmonary hypertension (PH) is extremely common in HFpEF and associated with increased mortality24. In HF, PH may be related to both pulmonary venous (PVH) and “reactive” pulmonary arterial (PAH) hypertension which are both equally severe in HFpEF and HFrEF21. As the RV is exquisitely sensitive to afterload, resting and exercise-induced PH may contribute to impaired output limiting exercise capacity and lead to progressive RV dysfunction as is well-described in HFrEF25–28.
Chronotropic incompetence is common in HFpEF6, 7 and may relate to autonomic dysfunction, as heart rate recovery (a marker of vagal tone), arterial baroreflex sensitivity and cardiac β-adrenoreceptor sensitivity are all reduced in HFpEF6, 14, 17, 29.
Renal dysfunction is as common in HFpEF as HFrEF, and its presence is associated with increased morbidity and mortality1. Natriuretic peptide (NP) levels are less elevated in HFpEF compared with HFrEF30 despite similar elevation in filling pressures due to lower wall stress, the stimulus for NP production. This “NP deficiency” may have adverse effects on renal sodium handling.
Both the NP (via particulate guanylyl cyclase) and nitric oxide (NO, via soluble guanylyl cyclase) stimulate cyclic guanosine monophosphate (cGMP), an intracellular second messenger whose effector proteins include cGMP-dependent protein kinase (PKG)31. Bioactivity of cGMP/PKG is regulated via cGMP catabolism by phosphodiesterase 5 (PDE5). While PDE5 expression is low in normal myocardium, compartmentalization to subcellular locations regulates key cGMP pools32 and modulates β-adrenergic responsiveness33. Further, PDE5 is markedly up-regulated with oxidative stress and pressure-overload hypertrophy34–38 both common in HFpEF.
PDE5 is expressed in vascular smooth muscle cells where cGMP/PKG causes vasorelaxation. In PAH, PDE5 expression and activity are increased in pulmonary vascular smooth muscles cells, promoting vasoconstriction39.
Based upon the complex pathophysiologic 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).
In experimental HF, chronic pharmacologic PDE5I attenuates and reverses maladaptive hypertrophy, fibrosis and contractile dysfunction34, 42, mitigates deleterious effects of cardiac sympathoexcitation6, 43, and improves cell survival44. In failing RV cardiac myocytes, PDE5I has positive inotropic effects, possibly due to cGMP inhibition of PDE3 with increased cAMP/PKA35, 36.
In HFrEF patients, PDE5l increases RV systolic28 and LV diastolic and systolic function, coupled with reductions in LV size, LV mass and left atrial size45. A recent small, single-center trial in HFpEF (n=44) also reported improvements in lung function, RV systolic function and LV and RV diastolic function with PDE5I46. While chronic PDE5I may cause reverse remodeling, acute administration may also improve diastolic function via cGMP/PKG-mediated phosphorylation of titin47.
PDE5I prevents the development of endothelial dysfunction and pulmonary vascular remodeling coupled with improvements in alveolar-capillary membrane structure and RV geometry in experimental HFpEF48. In humans, PDE5I reduces pulmonary vascular resistance in non-HF and HF states, both at rest and during stress27, 28, 39, 46, 49, 50. Exertional PH in HFrEF is reduced with acute or chronic PDE5I27, 28, in association with improvements in exercise capacity and quality of life. Systemic vascular resistance27, 51, aortic stiffness and wave reflection52, 53, endothelial function54 and ergoreflex-related hyperventilation have all been shown to improve with PDE5I in HFrEF23.
PDE5I acutely reduces cardiac specific norepinephrine spillover43 which may restore normal adrenergic sensitivity and diminish catecholamine-mediated concentric remodeling55. Post-synaptic attenuation of excessive adrenergic stimulation has been demonstrated with PDE5I in animal models32 and humans33, 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 HF40, 41.
RELAX 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 60 mg 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 (MLHFQ), cardiopulmonary exercise testing (CPXT) and six minute walk distance (6MWD) at baseline, 12 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 HFCRN 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 endpoint is the change in peak oxygen consumption (VO2) from baseline to 24 weeks. Secondary outcomes include change in peak VO2 at 12 weeks, change in 6MWD 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 MLHFQ from baseline (tier 3).
Pre-specified subgroup analysis include comparison of efficacy in patients according to left ventricular (LV) mass index, NT-proBNP, estimated pulmonary artery systolic pressure (PASP), study medication dose tolerated, atrial fibrillation and HF medication use.
Tertiary endpoints 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 (PASP), and neuroendocrine and renal function biomarkers.
Specific inclusion criteria are listed in Table 1. Evidence of resting or exercise induced elevation in filling pressures (NT-proBNP/BNP or hemodynamic data if NT-proBNP is < 400 pg/ml) is required for study entry. Randomization is stratified by site and by the presence of atrial fibrillation (to insure equal treatment assignment in the CMR cohort). Exclusion criteria (supplemental Table 1) and safety considerations are detailed in supplemental material.
Power calculations were based on the standard deviation for change in peak VO2 observed in RCT in HFrEF and on limited RCT data in HFpEF. We estimated a 20% rate of incomplete primary endpoint (PEP) data due to death, withdrawal or incidence of new factors limiting ability to exercise. The expected effect size was extrapolated from studies of chronic PDE5I in HFrEF23, 28. Using a two sample t-test and a two-sided alpha of 0.05, a sample size of 190 patients would have 85% power to detect a difference of 1.2 ml/kg/min in change in peak VO2 assuming 20% missing data and a SD of change in peak VO2 of 2.5 ml/kg/min. As an early blinded interim analysis of primary endpoint completeness indicated that the missingness rate approached 20% (this decreased dramatically as enrollment proceeded), the DSMB recommended increasing the sample size to 215 and 216 patients were ultimately enrolled. While the primary statistical approach to missing PEP data will be to exclude patients without 24 week PEP data, a variety of sensitivity analyses are planned, including changes in peak VO2 at 12 weeks and “carry-forward” of 12 week data.
Exercise intolerance is the cardinal manifestation of HFpEF and can be quantified objectively by measurement of peak VO256, 57. The multifactorial etiology 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 physiologic consequences of intervention on multiple mechanisms in HFpEF.
CPXT, unlike other measurements of functional status such as 6MWD, permits assessment of the organ system limiting gas exchange. This is crucial in HFpEF, which tends to occur in older individuals with co-morbidities 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 (VAT)58. Finally, in a study of patients with HFpEF and HFrEF, CPXT variables predicted survival while 6MWD did not59..
Another 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 HFpEF6, 60. CPXT also permits measurement of ventilatory efficiency (VE/VCO2 slope) which is closely related to pulmonary vascular function during exercise26; and exercise oscillatory ventilation (EOV) which has been shown to signal reduced exercise cardiac index in HFrEF61. Elevated VE/VCO2 slope and EOV are present in a subset of patients with HFpEF and confer a poor prognosis62, 63. Both of these CPXT variables have been shown to improve with sildenafil in HFrEF26, 64. Finally, CPXT is conducive to being integrated with other forms of physiologic testing during exercise as will be assessed in RELAX ancillary studies (see below).
Importantly, unlike changes in alternative trial endpoints such as circulating biomarkers or echo parameters, there is significant intrinsic value to patients associated with improving exercise capacity.
While 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 fewer than 50 individuals65. In adequately powered studies of peak VO2 of similar size to RELAX (i.e. >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 beta-blockers in HFrEF (−/+) showed neutral effects on peak VO270, 71 yet beta-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 a 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 are provided in the on-line supplement and detail 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 endpoint measurement methodologies.
A number of ancillary studies have been approved prior to completion of enrollment in RELAX.
This prospective, two-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.
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.
This 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.
This study will test the hypothesis that resting aortic stiffness and LV systolic and diastolic dysfunction predict exercise capacity in HFpEF.
This study will characterize the clinical, echocardiographic, and neurohumoral phenotype associated with AF in the setting of HFpEF and determine if AF influences exercise capacity when compared to sinus rhythm.
The 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 endpoint is well suited to the enrollment capacity of the HFCRN, 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.
While the RELAX trial will determine whether chronic PDE5l 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/or to an outcome based study of PDE5I in HFpEF.
Funding sources The Heart Failure Clinical Research Network is supported by grants HL084861, HL084875, HL084877, HL084889, HL084890, HL084891, HL084899, HL084904, HL084907, and HL084931. SFM is supported by HL07111–83 while support for mentoring SFM as a HF Clinical Research Network Clinical Research Skills Development fellow is provided by HL084907 and UL1 RR024150.
Disclosures Dr. 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 received 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.
All other authors have no disclosures.
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