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European Heart Journal (2014) 35, 2797–2811 New strategies for heart failure with preservedejection fraction: the importance of targetedtherapies for heart failure phenotypes Michele Senni1, Walter J. Paulus2, Antonello Gavazzi1, Alan G. Fraser3, Javier Dı´ez4,Scott D. Solomon5, Otto A. Smiseth6, Marco Guazzi7, Carolyn S. P. Lam8,Aldo P. Maggioni9, Carsten Tscho¨pe10, Marco Metra11, Scott L. Hummel12,13,Frank Edelmann14, Giuseppe Ambrosio15, Andrew J. Stewart Coats16,17,Gerasimos S. Filippatos18, Mihai Gheorghiade19, Stefan D. Anker20,21,Daniel Levy22,23,24, Marc A. Pfeffer5, Wendy Gattis Stough25, and Burkert M. Pieske26* 1Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy; 2Institute for Cardiovascular Research, VU University Medical Center Amsterdam, Amsterdam, TheNetherlands; 3Wales Heart Research Institute, Cardiff University, Cardiff, UK; 4Division of Cardiovascular Sciences Centre for Applied Medical Research and Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, University of Navarra, Pamplona, Spain; 5Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston,MA, USA; 6Institute for Surgical Research, Department of Cardiology, and Center for Cardiological Innovation, University of Oslo, Oslo, Norway; 7Heart Failure Unit, Department ofBiomedical Sciences for Health, IRCCS Policlinico San Donato, University of Milano, Milan, Italy; 8National University Health System, Singapore, Singapore; 9ANMCO Research Center,Florence, Italy; 10Department of Cardiology and Pneumology, Charite´-University Medicine Berlin, Campus Benjamin Franklin, Germany; 11Cardiology, Department of Experimental and by guest on January 13, 2015 Applied Medicine, University of Brescia, Brescia, Italy; 12Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; 13Section ofCardiology, Ann Arbor Veterans Affairs Medical Center, Ann Arbor, MI, USA; 14Department of Cardiology and Pneumology, University of Go¨ttingen, Go¨ttingen, Germany; 15Division ofCardiology, University of Perugia School of Medicine, Perugia, Italy; 16Monash University, Melbourne, Australia; 17University of Warwick, Conventry, UK; 18Athens University HospitalAttikon, Athens, Greece; 19Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 20Department of Innovative Clinical Trials,University Medical Centre Gottingen, Gottingen, Germany; 21Applied Cachexia Research, Department of Cardiology, Charite, Campus CVK, Berlin, Germany; 22Framingham HeartStudy, Framingham, MA, USA; 23Division of Cardiology, Boston University School of Medicine, Boston, MA, USA; 24Center for Population Studies, National Heart, Lung, and BloodInstitute, Bethesda, MD, USA; 25Department of Clinical Research, Campbell University College of Pharmacy and Health Sciences, North Carolina, USA; and 26Department of Cardiology,Medical University Graz, Ludwig-Boltzmann-Institute for Heart Failure Research, Auenbruggerplatz 15, 8010 Graz, Austria Received 22 March 2013; revised 1 April 2014; accepted 29 April 2014; online publish-ahead-of-print 7 August 2014 The management of heart failure with reduced ejection fraction (HF-REF) has improved significantly over the last two decades. In contrast, little orno progress has been made in identifying evidence-based, effective treatments for heart failure with preserved ejection fraction (HF-PEF). Despitethe high prevalence, mortality, and cost of HF-PEF, large phase III international clinical trials investigating interventions to improve outcomes in HF-PEF have yielded disappointing results. Therefore, treatment of HF-PEF remains largely empiric, and almost no acknowledged standards exist.
There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding ofHF-PEF pathophysiology, the heterogeneity of the patient population, inadequate diagnostic criteria, recruitment of patients without trueheart failure or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimalstudy designs, or inadequate statistical power. Many novel agents are in various stages of research and development for potential use in patientswith HF-PEF. To maximize the likelihood of identifying effective therapeutics for HF-PEF, lessons learned from the past decade of research shouldbe applied to the design, conduct, and interpretation of future trials. This paper represents a synthesis of a workshop held in Bergamo, Italy, and itexamines new and emerging therapies in the context of specific, targeted HF-PEF phenotypes where positive clinical benefit may be detected inclinical trials. Specific considerations related to patient and endpoint selection for future clinical trials design are also discussed.
Heart failure, Diastolic † Clinical trial † Diabetes mellitus † Exercise tolerance † Phenotype † Preserved ejectionfraction * Corresponding author. Tel: +43 31638512544, Fax: +43 3168513763, Email: Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2014. For permissions please email: [email protected].
M. Senni et al.
Heart failure with preserved ejection fraction (HF-PEF) is a complex syndrome characterized by heart failure (HF) signs and symptoms and a normal or near-normal left ventricular ejection fraction (LVEF). More specific diagnostic criteria have evolved over time and include signs/symptoms of HF, objective evidence of diastolic dysfunction, disturbed left ventricular (LV) filling, structural heart disease, and elevated brain natriuretic peptides (Table – However, multiple cardiac abnormalities are often present apart from diastolic LV dysfunction, including subtle alterations of systolic function,impaired atrial function,chronotropic incompetence, or haemodynamic alterations, such as elevated pre-load vo Extracardiac abnormalities and comorbidities, such as hypertension, atrial fibrillation, diabetes, renal or pulmonary disease, anaemia, obesity, and deconditioning, may contribute to the HF-PEF syndrome. Low- grade inflammation with endothelial dysfunction, increased reactive oxygen species production, impaired nitric oxide (NO) bioavailability, and the resulting adverse effects on cardiac structure and function are considered a mechanistic link between frequently encountered comorbidities and the evolution and progression of HF-PEFThe complex pathophysiology of the syndrome is also reflected by ongoing discussion on its terminology. Heart failure with a normal ejec- tion fraction (HFNEF) is preferred over HF-PEF by many authors Prevention of HF-PEF through treatment of risk factors (e.g. hyper- tension) is effectivbut once HF-PEF is present, specific treatments are lacking. Drug classes that improve outcomes in heart failure with reduced ejection fraction (HF-REF) have not been similarly beneficial by guest on January 13, 2015 in HF-PEF– There is no single explanation for the negative results of past HF-PEF trials. Potential contributors include an incomplete understanding of HF-PEF pathophysiology, inadequate diagnostic cri- teria, recruitment of patients without true HF or at early stages of the syndrome, poor matching of therapeutic mechanisms and primary pathophysiological processes, suboptimal study designs, inadequate statistical power, or patient heterogeneity; the latter is possibly the Since novel strategies need to be investigated for the treatment of HF-PEF, this manuscript advocates better phenotyping of patients to target therapies, reviews emerging therapies, and examines the cu- mulative experience from previous trials to suggest approaches for the design and conduct of future HF-PEF trials.
Heterogeneity of patients with heart failure and preserved ejection fraction: targeting patient Heart failure with preserved ejection fraction is difficult to define as illustrated by the various classifications proposed by experts (Table ) and by disparate inclusion criteria of clinical trials (Table ); these factors contribute to HF-PEF patient heterogeneity so far recruited into trials and registries. Even for the key diagnostic criterion, LVEF, consensus has not been reached on the optimal cut-off that defines HF-PEF, and different cut-offs have been used across classifications and trials. Debate continues as to whether HF-REF and HF-PEF Heterogeneity in heart failure with preserved ejection fraction in recent registries or trials At least three of nine LVEF .40, NYHA LVEF ≥50%, NYHA ≥50 years of age, have HF clinical criteria class II – IV for a signs and symptoms, ≥grade 1 diastolic history of HF with objective evidence LVEF ≥45% within 6 (adjusted for age pressure,140 mmHg (or ≤160 mmHg and on ≥3 medications), serum potassium ,5 mmol/L, ≥400 pg/mL or if hospitalization within 1 randomization with HF management being a major component (not adjudicated) or BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mLwithin 60 days beforerandomization. Specificcriteria for diastolicdysfunction are notrequired LVEF %, mean (SD) NR 56 (median) 51 – 61 (IQR) 1840 (780 – 4148) NR 453 (206 – 1045) 320 (131 – 946) 828 (460 – 1341) 700 (283 – 1553) 91 spironolactone, 91.9 57.4 spironolactone, 60.1 Atrial fibrillation, % 35.5 spironolactone, 35.1 30 placebo, 27 20 placebo, 21 32.8 spironolactone, 32.2 Renal impairment, % 26 52 placebo, 48 NR Median eGFR 65.3 mL/min/ valsartan (mL/min per 1.73 m2) LCZ696, 45%valsartan Downloaded from by guest on January 13, 2015 Median Hb 13.2 g/dL Clinical outcomes Propensity score- Mean 37 49.5 months: all- Death at 24 weeks, Primary composite of CV assessed clinical (placebo vs.
death, aborted cardiac sildenafil): 0 vs. 3%, spironolactone 18.6% vs.
placebo 20.4%, HR 0.89, 95% CI 0.77 – 1.04, HR 0.91 (95% CI: 23% all-cause Death: 1% LCZ696, Hospitalization for CV 13% vs. 13%,P ¼ 0.89 Hospitalization 24% Heart failure: 3% LCZ696, 4%valsartan CV hosp: 7 vs. 10%Non-CV hosp: 18 vs.
Spironolactone 12% vs.
placebo 14.2%, HR 0.83,95% CI 0.69 – 0.99,P ¼ 0.04 Study Limitations High crossover rate Phase 2, short-term Marked regional variation in Observational, event rates. Primary composite endpoint pulmonary arterial significantly reduced in patients from America.
right ventricular Significant interaction of treatment effect with intervals wide.
intervention; these characteristicswere not highlyprevalent inRELAX; possiblyinadequate dosingor duration oftherapy; greaternumber ofsildenafil patientscould not performexercise testingwhich may havebiased results Downloaded from by guest on January 13, 2015 New strategies for HFPEF: targeted therapies represent distinct disease entities, or similar processes along one developed during systole that produce ventricular suction, and disease continuum.– In fact, recent data suggest that LVEF may thus, reduces early diastolic filling. Left ventricular diastolic dysfunc- decline over time even in patients with HF-PEFThis issue tion may be related to extracellular matrix changes, changes in becomes even more apparent when patients within the ‘grey zone' intrinsic myocyte stiffness, microvascular dysfunction, and metabolic of LVEF (i.e. 40 – 50%) are considered. To avoid mixing overt systolic dysfunction and HF-PEF, a higher threshold (LVEF ≥50%) should beused for future clinical trials. Others have argued that the syndrome Modulation of myocyte passive diastolic stiffness referred to as HF-PEF represents either normal ageing, or vascular Alterations within myocytes increase their intrinsic diastolic stiffness.
and renal dysfunction.
Titin is a giant cytoskeletal structural protein expressed in sarco- Irrespective of specific diagnostic criteria and cut-offs, HF-PEF is a meres that functions as a molecular ‘spring', storing energy during syndromal disease where multiple cardiac and vascular abnormalities, contraction and releasing this energy during relaxation. Stiffer titin cardiovascular risk factors, and overlapping extracardiac comorbid- increases diastolic myocyte stiffness. The expression of titin isoforms ities may be present in various combinations (Figure ).
differs between patients with HF-REF and HF-PEF, with a lower ratio In many disciplines of medicine, targeted therapy is the key to of the compliant (N2BA) isoform to the stiff (N2B) isoform in success. For example, breast cancer or haematological disorders patients with HF-PEF.Phosphorylation of the N2B isoform by use phenotyping strategies that include genetic testing, novel biomar- protein kinase A or protein kinase G (PKG) decreases cardiomyocyte kers, or histology for matching specific therapies to patient sub- resting stiffness.– Protein kinase G is activated by cyclic guanosine groups. Matching treatment strategies to a specific patient's monophosphate (cGMP); therapies that increase cGMP may de- phenotype in HF-PEF is a promising approach that warrants testing crease myocardial diastolic stiffness in HF-PEF. This observation pro- in clinical trials and may increase the likelihood of demonstrating clin- vides a compelling rationale to pharmacologically modulate this ical benefit (Figure Targeting specific phenotypes instead of follow- pathway in HF-PEF patients (Figure Cyclic guanosine monopho- ing the ‘one-size-fits-all' approach becomes increasingly important in sphate levels can be increased by preventing breakdown (PDE5 inhi- light of several failed, non-targeted, large-scale HF-PEF trials.
bitors) or stimulating their production (cGMP stimulators). In fact,orally active soluble guanylate cyclase (sGC) stimulators (e.g. rioci- Targeting the diastolic dysfunction guat) have been developed, and both approaches are under clinicaltesting (Table phenotypeDiastolic dysfunction is a dominant feature in many HF-PEF patients, by guest on January 13, 2015 and many factors contribute to diastolic dysfunction, including Cyclic guanosine monophosphate is catabolized by phosphodies- both vascular and myocardial stiffening. Generalized stiffening terases, and phosphodiesterase-5 (PDE5) inhibitors prevent the hy- that occurs throughout the cardiovascular system due to ageing drolysis of cGMP, thereby indirectly raising cGMP levels. It has been or comorbidities interferes with the forces that are normally hypothesized that PDE5 inhibitors may improve diastolic function Figure 1 Heterogeneity of the heart failure with preserved ejection fraction syndrome. BP, blood pressure; COPD, chronic obstructive pulmon-ary disease; EF, ejection fraction.
M. Senni et al.
by guest on January 13, 2015 Figure 2 Potential approach for matching key heart failure with preserved ejection fraction phenotypes to select therapeutic interventions. ARB,angiotensin receptor blocker; ACEI, angiotensin-converting enzyme inhibitor; MRA, mineralocorticoid receptor antagonist; ARNI, angiotensin re-ceptor and neprilysin inhibitor; HF, heart failure; HTN, hypertension; LVEF, left ventricular ejection fraction; PKG, protein kinase G; AGE, advancedglycation end products; PDE, phosphodiesterase; MRA, mineralocorticoid receptor antagonist.
through PKG-mediated regulation of titin stiffness.Sildenafil levels are intrinsically low due to insufficient generation may result reduced LV wall thickness, LV mass index (LVMI), deceleration in little effectiveness in this hypothetical subset of patients.
time, isovolumic relaxation time, and the E/e′ ratio compared with Although PDE5 inhibition was not effective in RELAX, increasing placebo in a study of 44 patients with pulmonary hypertension, cGMP levels might be of value in treating other features of HF-PEF.
recent new onset dyspnoea, and LVEF ≥50%.
In line with reduced production of cGMP, possibly related to impaired The PDE5 inhibition to Improve Clinical Status and Exercise Cap- NO-dependent guanylate cyclase stimulation, orally active sGC sti- acity in Diastolic Heart Failure (RELAX) study enrolled 216 patients mulators have been developed. The ongoing phase II dose-finding with New York Heart Association (NYHA) class II – IV HF and LVEF study SOCRATES will test the effects of a new once-daily sGC ≥Patients were randomized to matching placebo or silde- stimulator in 478 prospectively randomized HF-PEF patients nafil 20 mg three times daily for 12 weeks followed by 60 mg three (NCT01951638). The RELAX experience adds more evidence to times daily for 12 weeks. The primary endpoint was the change in the hypothesis that specific phenotyping and identification of a peak VO2.Median baseline values of peak VO2 and 6-minute primary pathophysiology that can be pharmacologically targeted walk distance were 11.7 mL/kg/min and 308 m, respectively. The might be key to finding successful treatments for HF-PEF.
patients had evidence of chronically elevated LV filling pressures atbaseline (median E/e′ 16, left atrial volume index 44 mL/m2, and pul-monary artery systolic pressure 41 mmHg). After 24 weeks, no sig- Late sodium current inhibition nificant differences between the sildenafil and placebo group were Increased cytosolic calcium (Ca2+) during diastole is another poten- observed in the median change in peak VO tial mechanism of HF-PEF pathophysiology. In the setting of ischaemia 2, 6-minute walk distance, or the mean clinical rank The reasons for the contradicting or HF, increases in late sodium (Na+) currents occur during the results of PDE5 inhibition in HF-PEF are not fully understood, but myocyte depolarization process. This increase in Na+ influx leads may include differences in patient populations and recruitment of to elevated intracellular Na+, thereby resulting in excess Ca2+ patients with phenotypes not amenable to PDE5 inhibitor therapy.
during diastole via Na+/Ca2+ exchanger, with attendant impaired In addition, preventing breakdown in a situation where cGMP New strategies for HFPEF: targeted therapies Figure 3 Role of the nitric oxide – cyclic guanosine monophosphate– protein kinase G pathway in the cardiomyocyte. Cardiomyocyte signallingpathways involved in regulating cardiac titin stiffness. ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CNP, c-type natriuretic peptide;NO, nitric oxide; PDE5, phosphodiesterase-5; pGC, particulate guanylyl cyclase; sGC, soluble guanylyl cyclase. Adapted with permission from theJournal of Molecular and Cellular Cardiology 2009;46:490 – 498.
by guest on January 13, 2015 Ranolazine inhibits the increased late Na+ current, a mechanism that Collagen synthesis is enhanced in the setting of increased load or ac- may minimize intramyocyte Na+ accumulation and the resultant Ca2+ tivation of the renin – angiotensin – aldosterone system (RAAS).
overload. Reduced diastolic tension was observed in failing human Down-regulation of enzymes that degrade collagen occurs in patients heart ventricular tissue after exposure to ranolazine.Ranolazine with HF-PEF.– It is important to note that elevated myocardial improved diastolic function in non-infarcted ischaemic myocardium collagen is present in many, but not all patients,clinical tools to in isolated myocardium from failing human heartsand in chronic identify it are only evolving in practice settings, and the reliability of stable angina.It is hypothesized that ranolazine may have similar serum markers to reflect cardiac processes is uncertain. Neverthe- effects in HF-PEF, a condition associated with substantial alterations less, recent research has suggested galectin-3 as an emerging bio- of the microcirculation even in the absence of coronary artery stenosis.
marker with potential utility in identifying patient subgroups that The Ranolazine for the Treatment of Diastolic Heart Failure may specifically respond to anti-fibrotic ther (RALI-DHF) study was a proof-of-concept trial that evaluated theeffect of ranolazine vs. placebo on haemodynamics, measures of dia- Mineralocorticoid receptor antagonists stolic dysfunction, and biomarkers in 20 patients with HF-PEF and dia- Aldosterone mediates vascular and cardiac remodelling. It binds to stolic dyAfter 30 min of infusion, significant decreases the mineralocorticoid receptor (MR), stimulates cardiac fibroblasts, from baseline were observed in LV end-diastolic pressure (LVEDP) and increases collagen synthesis and deposition. These events lead to and pulmonary capillary wedge pressure (PCWP) in the ranolazine myocardial fibrosis and increased LV stiff– Inflammation and group, but not in the placebo grAlthough invasively deter- oxidative stress are also involved in aldosterone-mediated fibrosis.
mined relaxation parameters and the non-invasive E/e′ ratio were un- Aldosterone stimulates the expression of several profibrotic mole- altered, these limited data justify additional studies of ranolazine in cules [e.g. transforming growth factor-1 (TGF-1), plasminogen acti- vator inhibitor-1 (PAI-1), and endothelin-1] that contribute to thepathogenesis of fibrosis.Animal studies showed that MR antago- Targeting fibrosis as a phenotype nists (MRA) prevent collagen synthesis and r– Small Left ventricular fibrosis occurs early in the evolution to HF-PEF and studies in HF-PEF patients showed improvement in diastolic dysfunc- represents a worthy therapeutic target in the syndrome. Fibrosis tion parameters after treatment with an MRA.
comprises both the heart and vascular system and impacts on both The Aldo-DHF study was a randomized, double-blind, placebo- diastolic and systolic function. Fibrosis will lead to myocardial stiffen- controlled trial of spironolactone 25 mg/day or placebo in 422 ing, impede both suction and filling, and the loss of early diastolic patients with chronic NYHA class II or III HF, LVEF ≥50%, and suction may have major deleterious effects on impaired exercise cap- grade ≥1 diastolic dysfuThe co-primary endpoint E/e′ acity in HF-PEF.Fibrosis is mediated by alterations in the amount was reduced in the spironolactone group, whereas it increased and composition of collagen within the extracellular matrix.– from baseline in the placebo group. The difference between groups Select planned or ongoing studies in heart failure with preserved ejection fraction Patient characteristics Iron deficiency: ferric carboxymaltose n ¼ 260, phase II, 24 NYHA II – III, LVEF . 45, on diuretic, HF hosp , 12 mo OR Change in 6-minute walk distance (not yet recruiting) E/e′ . 13 OR LAVI . 28 OR NBNP/BNP . 300/100pg/mL Energy deficit: bendavia (mitochondrial n ¼ 42, phase Iia, acute LVEF ≥ 45%; E/e′ . 14 OR E/e′9-14 and NBNP . 220 pg/mL; E/e′ during exercise, dose finding, (not yet recruiting) exercise-induced increase in E/e′ of ≥ 5 Heart rate: ivabradine (sinus node n ¼ 400, phase II, 8 SR, HR . 70, NYHA II – III, LVEF ≥ 45%, E/e′ . 13 OR e′ , 10/8 OR Co-primary: E/e, NTproBNP, 6-minute LAVI . 34, NBNP/BNP ≥ 220/80 pg/mL n ¼ 320, phase Iib, 12 pVO2 , 25, EF ≥ 50 Clinical composite score (Packer E/e' . 15 OR E/e' . 8 , 15 and NBNP . 220 pg/mL or Afib Deconditioning: high-intensity interval n ¼ 180, phase Iib, 3 EF . 50%, NYHA II/III, E/e′ . 15 OR E/e′ 8 – 15 and NBNP/ PeakVO2, E/e′, LAVI, NT-pro-BNP BNP . 220/80 pg/mL cGMP deficiency: vericiguat (soluble n ¼ 470, phase Iib, 12 WCHF/i.v. diuretics, EF ≥ 45; NBNP/BNP . 300/100 (600/200 in Co-primary: NT-pro-BNP and LAV guanlyte cyclase stimulation) Afib); LAVI ≥ 28 cGMP deficiency: LCZ696 (neprilysin n ¼ 4300, phase III, up EF ≥ 45%, NYHA II–IV, LA enl. or LV hypertrophy; HF hosp. , 9 Composite: CV death and total mo. or elevated NBNP (recurrent) HF hospitalizations aEffect of IV iron (ferric carboxymaltose, FCM) on exercise tolerance, symptoms, and quality of life in patients with heart failure and preserved LV ejection fraction (HFpEF) and iron deficiency with and without anaemia.
bAn Exploratory Proof of Concept Clinical Pharmacology Study of the Effects of a Single 4 Hour Intravenous Infusion of BendaviaTM (MTP-131) in patients hospitalized patients with heart failure and preserved left ventricular ejection fraction.
cEffect of ivabradine vs. placebo on cardiac function, exercise capacity, and neuroendocrine activation in patients with chronic heart failure with preserved left ventricular ejection fraction.
dExercise training in diastolic heart failure, a prospective, randomized, controlled study to determine the effects of exercise training in patients with heart failure and preserved ejection fraction.
eOptimizing exercise training in prevention and treatment of diastolic heart failure.
fPhase IIb safety and efficacy study of four dose regimens of BAY1021189 in patients with heart failure and preserved ejection fraction suffering from worsening chronic heart failure.
gEfficacy and safety of LCZ696 compared with valsartan on morbidity and mortality in heart failure patients with preserved ejection fraction.
LAVI, left atrial volume index (mL/m2); NBNP, NT-pro-BNP; SR, sinus rhythm; HR, heart rate; Afib, atrial fibrillation; WCHF, worsening chronic heart failure; LA enl., left atrial enlargement.
Downloaded from by guest on January 13, 2015 New strategies for HFPEF: targeted therapies was statistically significant (21.5, 95% CI: 22 to 20.9, P , 0.001).
elevated filling pressures with exercise, leading to reduced early dia- The co-primary endpoint peak VO2 was not affected by spironolac- stolic filling and producing HF symptoms.Elevated atrial pressures tone. Left ventricular ejection fraction increased, and LV end-diastolic may also lead to atrial remodelling, fibrosis, and the development of dimension (LVEDD), LVMI, and NT-proBNP significantly decreased atrial fibrillation. Atrial fibrillation is common in patients with HF-PEF, from baseline in the spironolactone group, suggesting reverse func- and it is associated with worse outcomes. Therapies that chronically tional and structural remodelling.
reduce atrial pressures and prevent atrial remodelling and fibrosis The findings from pre-clinical studies and intermediate size clinical might reduce the risk of developing atrial fibrillation. Left atrial dys- trials of MRAs in HF-PEF support the hypothesis that MRAs may function is also common in these patients, and the decline in atrial improve outcomes in HF-PEF. The NIH-funded phase III Treatment function in the setting of poor diastolic filling may be a significant con- of Preserved Cardiac Function Heart Failure with an Aldosterone An- tributor to symptoms during exercise. Diuretic therapy is generally tagonist (TOPCAT) trial tested this hypothesis (Table The recommended, but diuretics are often insufficient to control symp- TOPCAT trial found that, compared to placebo, spironolactone toms, have not been shown to improve outcomes, and are associated did not reduce the composite of cardiovascular death, aborted with undesirable side-effects, such as neuroendocrine activation.
cardiac arrest, or heart failure hospitalization in patients with symp- Therefore, new therapies for modulating fluid homoeostasis and tomatic heart failure and a LVEF 45% or greater, although the individ- renal function are under investigation.
ual component of heart failure hospitalization was reduced byspironolactone. However, there was a significant interaction between Natriuretic peptide axis treatment effect and patient recruitment strategy (natriuretic peptides Natriuretic peptides [BNP and atrial natriuretic peptide (ANP)] have vs. hospitalisation with HF management being a major component), antiproliferative and natriuretic properties. Neprilysin (NEP) is the highlighting the importance of patient selection criteria and recruitment primary enzyme that degrades natriuretic peptides. The novel angio- of patients with true heart failure and preserved EF for future trials.
tensin receptor and NEP inhibitor (ARNI) LCZ696 combines angio- Novel, non-steroidal, MRAs with greater selectivity than spironolac- tensin type 1 (valsartan) and NEP receptor (AHU377) antagonism tone and stronger MR binding affinity than eplerenone are currently thereby increasing the bioavailability of natriuretic and vasodilator pep- under clinical development. In the recently presented phase II dose- tideThe phase II Prospective Comparison of ARNI with ARB on finding study ARTS [MinerAlocorticoid Receptor Antagonist Tolerability Examination of Heart Failure with Preserved Ejection Fraction (PARA- Study (ARTS; NCT01345656)] in HF-REF patients with impaired renal MOUNT) trial randomized 301 patients with LVEF ≥45%, HF signs function, BAY 94–8862 had beneficial effects on the cardiovascular and symptoms, and elevated NT-proBNP plasma levels to LCZ696 by guest on January 13, 2015 system comparable with spironolactone with less renal and electrolyte 50 mg twice daily (titrated to 200 mg twice daily) or valsartan 40 mg side-eNew anti-fibrotic therapies with less side-effects may re- twice daily (titrated to 160 mg twice daily) for 12 weekThe present an important step towards better management of suitable sub- primary endpoint was change in NT-proBNP from baseline to 12 groups of HF-PEF patients.
weeks. Over three-fourths of the patients had LVEF ≥50%. Theratio of change in NT-proBNP for LCZ696 vs. valsartan was 0.77 Other renin – angiotensin – aldosteron system inhibitors (95% CI: 0.64– 0.92, P ¼ 0.005) at 12 weeks. Left atrial volumes and Several studies have evaluated the role of angiotensin-converting dimensions were significantly reduced after 36 weeks in the LCZ696 enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) group.These data suggest that LCZ696 may reduce LA volumes for the treatment of HF-PEF, including PEP-CHFCHARM- and wall stress. An outcomes trial, PARAGON-HF, is being planned preserved,or I-Preserv(Table Improvement in clinical to assess the effects of LCZ696 on clinical endpoints.
outcomes was not detected among patients randomized to theACE-inhibitor or ARB in these trials, but the studies were limited Targeting the pulmonary hypertension by high crossover rates and, in part, insufficient power. Renin – angiotensin–aldosterone system blockers are indicated in the HF-PEF Pulmonary hypertension is a haemodynamic consequence of HF-PEF syndrome to control risk factors such as blood pressure and to with a reported prevalence of 53–83% in epidemiological cohorts; prevent progression of end-organ damage such as renal dysfunction.
the prevalence in patients enrolled in clinical trials may be lower.– In this context, RAAS inhibitors are clearly recommended in major Pulmonary hypertension is associated with higher mortality in patients guidelines as baseline therapy for patients with HF-PEF. The recent with HF-PEFleading to the hypothesis that it is an active patho- ACC/AHA 2013 HF guidelines recommend ACE-inhibitors, ARBs, physiological factor in HF-PEF progression, rather than solely second- or beta-blockers in hypertensive patients with HF-PEF with the ary to left heart dysfunction. In fact, both pre-capillary (related to goal of controlling blood pressure (class IIa recommendation, level pulmonary arteriolar remodelling, intimal fibrosis, or reactive increases of evidence but data on beneficial outcome effects beyond in pulmonary arterial tone)and post-capillary (pulmonary venous risk factor control are inadequate to support recommendations for hypertension) components contribute to pulmonary hypertension in the use of these agents specifically for the treatment of HF-PEF.
HF-PEFTherefore, the pulmonary vascular bed, including endothelialdysfunction, may represent a novel therapeutic target in HF-PEF Targeting fluid retention as a phenotypeElevated filling pressures are the primary haemodynamic abnormality in HF-PEF patients.Volume overload or congestion may be Inhibition of PDE5 leads to accumulation of intracellular cGMP- and present, but visible evidence of fluid retention is absent in many NO-induced pulmonary vasodilation in patients with pulmonary arter- patients. Some patients have normal haemodynamics at rest, but ial hypertensioPhosphodiesterase-5 inhibitors demonstrated M. Senni et al.
Considerations for future clinical trials Eligibility criteria Inclusion criteria should reflect pathophysiologically distinct patient populations, for example Require echocardiographic evidence of diastolic dysfunction for therapies expected to impact cardiac structure orfunctionRequire reduced VO2 max or moderate limitation in 6 minute walk distance for therapies expected to improveexercise tolerance or patient-reported outcomesUse biomarker criteria to identify high-risk patients, or patients with evidence of a pathophysiological process (e.g.
galectin-3 and cardiac fibrosis)Use the diagnostic potential of an (echo) stress testRequire a higher LVEF threshhold (e.g. LVEF ≥50%) to avoid the confounding effects of HF-REF Primary pathophysiological target should be defined The investigational intervention should be selected to specifically target the primary pathophysiology Targeted therapy may Result in a greater treatment effect, orReduce ‘noise' of no effect, orResult in less variation on the treatment effect These factors may decrease the required sample size, but little experience has accumulated regarding event rate oranticipated treatment effects in pathophysiologically distinct subgroupsPhase II proof-of-concept studies will inform assumptions needed to determine sample sizeProof-of-concept studies to identify the pathophysiological target other than clinical endpoints (e.g. resolving thethrombus in acute myocardial infarction)Adaptive designs that prospectively plan interim analyses with the purpose of determining whether aspects of studydesign require modification (e.g. sample may also be considered Endpoint selection Consider cardiovascular-specific endpoints as primary (e.g. cardiovascular mortality) Consider repeat (HF) hospitalizationsConsider all-cause endpoints for safetySymptom relief, quality of life, and other patient-reported outcomes should be a key primary or secondary endpoint inHF-PEF trials by guest on January 13, 2015 Improvement in measures of exercise capacityConsider changes in biomarkers with known information on severity of disease and outcome antiproliferative effects in the pulmonary vasculaturGuazzi et al that was evaluated in the Acute Hemodynamic Effects of Riociguat in randomized 44 patients with HF-PEF, LVEF ≥50%, sinus rhythm, and Patients with Pulmonary Hypertension Associated with Diastolic PASP .40 mmHg (estimated by echocardiography) to placebo or sil- Heart Failure (DILATE-1) study of patients with pulmonary hyper- denafil 50 mg three times daily for 12 months. At 6 and 12 months, tension associated with LV diastolic dysfunction (clinicaltrials.gov patients randomized to sildenafil had significantly lower right atrial pres- NCT01172756). Preliminary results were presented in the abstract sure, pulmonary artery pressures, wedge pressure, transpulmonary gra- form at ESC 2013 and demonstrated improved haemodynamics dient, pulmonary vascular resistance and elastance, and increased with riociguat.
quality of life scores, compared with the placebo group. Pulmonaryfunction also improved in the sildenafil group compared with Targeting diabetes and obesity as a placebo, and sildenafil induced structural and functional reverse remod- ellinThese findings support the hypothesis that treating pulmonary hypertension may be effective in patients with this phenotype.
Diabetes mellitus is a major risk factor for diastolic dysfunction and However, PDE5 inhibition was not effective in the RELAX study the development of HF-PEF. Diabetes directly affects myocardial (see above) but patients with the pulmonary hypertension phenotype structure and functionthrough a variety of mechanismsinde- were not specifically targeted. Small randomized clinical trials with sil- pendent from other cardiovascular risk factors. Lipotoxicity, lipoa- denafil are ongoing in patients with HFPEF and evidence of pulmonary poptosis, free fatty acid oxidation, advanced glycation end products hypertension (clinicaltrials.gov NCT01726049). Further analysis of the (AGE), oxidative stress, impaired NO bioavailability, mitochondrial RELAX data and evidence from ongoing studies in patients with pul- dysfunction, and myocardial fibrosis have all been implicated.– monary hypertension will determine the potential utility of PDE5 inhi- Other signalling pathways are the subject of ongoing research.
bitors in HFPEF patients with this specific phenotype.
Diastolic dysfunction has been detected in patients classified as pre-diabetand in up to 74% of asymptomatic, normotensive Orally active soluble guanylate cyclase stimulators patients with type 2 diabetes mellitus.– The risk of hospitaliza- Other agents are also being tested in HF-PEF patients with the pul- tions or death related to HF increased with increasing HbA1c in a monary hypertension phenotype. Riociguat is an oral sGC stimulator large registry of patients with diabetes and no documented HF New strategies for HFPEF: targeted therapies (n ¼ 74,993).In the Candesartan in Heart Failure Assessment of diastolic function after weight loss among obese patients with atrial fib- Reduction in Mortality and Morbidity (CHARM) study, diabetes was an independent predictor of cardiovascular death or cardiovas-cular hospitalization in patients with either HF-PEF or HF-REF Targeting anaemia or iron deficiency as a Targeting the diabetes phenotype may be one treatment strategy for HF-PEF, but the optimal treatment approach has not been deter- mined. Tight glycaemic control (insulin vs. metformin plus repagli- Anaemia is a known prognostic factor in patients with HF-REF,– nide) did not reverse mild diastolic dysfunction in patients with but its role in patients with HF-PEF is less well established. Potential type 2 diabetes, but this study was small with short-term follow- contributors to anaemia in HF-PEF include renal impairment, cyto- In another small study, improved glycaemic control over kine activation, volume overload (dilutional anaemia), malabsorption, 5 years did not improve subclinical dysfunction in patients who malnutrition, or bone marrow suppression.– An analysis from remained hypertensive and overweight.
the Study of the Effects of Nebivolol Intervention on Outcomes and Some oral hypoglycaemic agents (e.g. metformin) may have Rehospitalization in Seniors with Heart Failure (SENIORS) revealed pleiotropic effects that extend beyond their ability to reduce that the prevalence of anaemia was similar in patients with HF-REF HbA1c or improve insulin sensitivity [e.g. 5′ adenosine monopho- and HF-PEF (including mildly reduced LVEF .Patients sphate (AMP)-activated protein kinase activation, attenuation of with anaemia had a higher risk of all-cause mortality or cardiovascular TNF-a expression, increased myocardial vascular endothelial hospitalization during the follow-up, regardless of ejection frac- growth factor (VEGF) signalling, and/or stimulation of NO produc- tion.In the 3C-HF score, a haemoglobin level ,11 g/dL was a non- tion]Metformin was associated with a lower risk of all-cause cardiac independent predictor of 1-year mortality among patients mortality in a propensity score-matched analysis of 6185 patients with HF-PEF (LVEF ≥50%).However, in a recent small trial, with HF (45% of patients with LVEF ≥40%) and diabetes (HR: epoetin alfa increased haemoglobin, but it did not change end- 0.76, 95% CI: 0.63 – 0.92, P , 0.01).Novel drugs that break diastolic volume, stroke volume, or 6-minute walk distance com- glucose crosslinks (alagebrium chloride) promoted regression of pared with placebo in a prospective, randomized, single-blind LV hypertrophy and improved diastolic function and quality of life 24-week study in 56 patients with HF-PEF and mild in HF-PEF patientsbut data from larger controlled trials arelacking. Prospective, randomized trials are warranted to assess Functional iron deficiency the safety and efficacy of treatments targeting the diabetes Functional iron deficiency (FID) is an independent risk factor for poor by guest on January 13, 2015 phenotype in HF-PEF (Table ).
outcome in advanced HF-REF, but its role in HF with HF-PEF remainsIn an initial small study, FID was present in almost 50% Obesity and metabolic syndrome of HF-PEF patients, but it did not correlate with diastolic function Obesity, atherogenic dyslipidaemia, hypertension, insulin resistance, parameters or exercise capacityMore research is needed into glucose intolerance, and inflammation are components of the meta- the therapeutic options of FID and anaemia in HF-PEF.
bolic syndrome.Obesity may lead to HF-PEF through severalhypothesized mechanisms including inflammation of adipose tissue,endocrine effects of or increased loading conditions.
Targeting deconditioning and the Subclinical diastolic dysfunction was detected in 48 obese, other- periphery as a phenotype wise healthy women compared with 25 normal weight women.In Peripheral muscle exercise training a study of 109 overweight or obese subjects, increasing body mass Vascular stiffness increases and diastolic function declines with age, as index (BMI) was associated with a reduced mitral annular velocity, a consequence of ageing, a culmination of risk factors, or both.
myocardial early diastolic velocity, and elevated filling pressure.
These processes may lead to inadequate LV filling during exercise, Insulin levels were inversely associated with measures of diastolic resulting in symptoms of HF. Decreased LV compliance has been function, but on multivariate analysis, BMI remained a significant pre- demonstrated in healthy, but untrained elderly subjects, but trained dictor after adjustment for age, mean arterial pressure, LVMI, and elderly had diastolic pressure volume relations similar to young sed- entary In a recent analysis from the Framingham data set, Left ventricular mass index, LVEDD, and left atrial volume were the level of physical activity at a study entry was associated with the higher in obese subjects compared with lean controls in a study of risk for long-term incident HF-PEF, and even moderate physical activ- 612 adolescents who were either (i) obese and had type 2 diabetes; ity prevented HF-PEF.
(ii) obese without type 2 diabetes; or (iii) non-obese without type 2 The multicentre Exercise Training in Diastolic Heart Failure Pilot diabetes. An average E/e′ ratio was significantly different across the study (Ex-DHF-P) randomized patients with NYHA class II – III symp- three groups, with the highest value in the obese diabetic group.
toms, LVEF ≥50%, echocardiographic evidence of diastolic dysfunc- These data show that obesity contributes to diastolic dysfunction tion (grade ≥1), sinus rhythm, and ≥1 additional cardiovascular risk and suggest that type 2 diabetes mellitus may confer additional risk.
factor to 32 sessions of combined endurance/resistance exercise A recent post hoc analysis of I-Preserve demonstrated that obesity training (n ¼ 46) or usual care (n ¼ Peak VO2 after 3 was common in HF-PEF patients and was associated with a U-shaped months (the primary endpoint) increased in the training group, relationship for outcome. The greatest rate of adverse outcomes was resulting in a between-group difference of 3.3 mL/min/kg (P , confined to the lowest and highest BMI catA recent study 0.001). Several measures of diastolic function and quality of life also demonstrated improvement in some echocardiographic measures of improved at 3 months.
M. Senni et al.
A systematic review of five exercise training studies (228 patients) ambulatory blood pressure; while improving diastolic function and in patients with HF-PEF or diastolic HF with follow-up ranging from ventricular-arterial couThe DASH-DHF 2 study (Table ) 12 to 24 weeks showed an overall between-group difference in will provide mechanistic data needed to determine whether large, peak VO2 of 2.9 mL/kg/min (95% CI: 2.36 –3.56) in favour of exercise randomized clinical trials of dietary modification in patients with Overall improvements in Minnesota Living With Heart HF-PEF are warranted.
Failure total scores were also noted for exercise training comparedwith Electrical and mechanical dyssynchrony Additional studies are needed to confirm the safety of exercise Both systolic and diastolic mechanical dyssynchrony have been training, determine the effect on clinical outcomes, define the reported in patients with HF-PEF.In one study of 138 patients, optimal exercise modalities (intensity, frequency, duration, and the prevalence of inter- and intraventricular dyssynchrony was com- type of exercise), address adherence issues, and establish cost- parable for patients with HF-PEF and HF-REF, if the QRS duration was effectiveness. The ongoing phase II Ex-DHF study (ISRCTN ≥120 ms (42 vs. 55%).In other small studies of HF-PEF, the preva- 86879094, ) will further evaluate the lence of electrical and/or mechanical dyssynchrony varies between role of exercise training in this population (Table 10 and 60%; its association with clinical outcomes is uncertain.In an analysis of 25 171 patients from the Swedish Heart Failure Developing concepts in Registry, a QRS ≥120 ms was an independent predictor of mortality pathophysiology and treatment of even after adjustment for LVEFIn patients with left bundle branchblock, there is usually marked shortening of the LV diastolic filling heart failure with preserved time due to prolongation of isovolumic contraction and relax- ejection fraction ation.The Karolinska – Rennes (KaRen) study is an ongoingprospective, multicentre, observational study designed to evaluate Renal function and fluid homoeostasis the prevalence and prognostic importance of electrical and mechan-ical dyssynchrony in patients with HF-PEF.Even in the absence of The cardiorenal interactions potentially contributing to HF-PEF are electrical dyssynchrony, exercise-induced torsional dyssynchrony complex and include volume overload (due to inadequate renal has been reported in patients with HF-PEF, but validation of the handling of salt or fluid), renal hypertension, or oxidative stress and techniques used to detect torsional dyssynchrony and determination inflammatory processes.The Cardiovascular Health Study of threshold values is The potential effect of cardiac by guest on January 13, 2015 showed that development of HF-PEF was associated with mild resynchronization therapy on electrical, mechanical, and torsional renal dysfunction, and subtle chronic volume overload was proposed dyssynchrony in HF-PEF patients remains to be determined.
to underlie structural and functional cardiac remodelling.In Recently, the concept of atrial dyssynchrony and left atrial pacing as patients hospitalized for HF-PEF, an estimated glomerular filtration a potential therapeutic approach was intrThis concept rate (eGFR) ,60 mL/min/1.73 m2 on admission independently pre- clearly needs further research before more definite answers can be dicted total and cardiovascular mortality over 7 years of follow-up.
Heart failure with preserved ejection fraction was observed in 21% of The timing of ventricular – arterial coupling may also be important patients undergoing peritoneal dialysis in a university teaching dialysis in HF-PEF patients. Lower amplitude of mid-systolic wave reflections centre, and it was associated with an increased risk of fatal or non-fatal predicted better clinical outcomes in a substudy of the ASCOT cardiovascular events in this population.
trial.Women demonstrate less efficient ventricular – arterial Animal models suggest that high dietary sodium intake in the coupling than men (higher wall stress development for any given setting of abnormal renal sodium handling may be a stimulus for LV geometry, arterial properties, and flow which may the development and progression of HF-PEF through increased oxi- be a factor in HF-PEF development. Modulation of the timing and dative stress, perivascular inflammation, and increased ‘local' renal amplitude of wave reflections merits further pathophysiological and cardiac angiotensin II and aldosterone (despite suppression of circulating levelThe demographics and comorbiditiesfound in human salt-sensitive hypertension are nearly identical to Autonomic modulation and chronotropic those of HF-PEF. Salt-sensitive subjects develop cardiovascular struc-tural and functional abnormalities associated with HF-PEF,– leading to the hypothesis that high sodium intake contributes to Autonomic dysfunction is a potential pathophysiological factor in HF-PEF, contributing to exertional dyspnoea and fatigue.– Observational evidence suggests that dietary sodium restriction Modulation of autonomic function is being investigated as a strategy may reduce morbid events in patients with HF-PEF. In a propensity for treating patients with HF-PEF, for example, by baroreceptor acti- score, adjusted multivariable analysis of 1700 patients discharged vation, vagal nerve stimulation, and renal artery denervaIm- from a HF hospitalization (n ¼ 724 with HF-PEF), documentation portantly, a significant subgroup of HF-PEF patients suffers from that a sodium-restricted diet was associated with a lower risk of chronotropic – Chronotropic incompetence 30-day death or rehospitalization (OR: 0.43, 95% CI: 0.24 – 0.79, can be readily detected by an exercise stress test, and it largely P ¼ The Dietary Approaches to Stop Hypertension in impairs cardiac output in patients with a small stiff ventricle.
Diastolic Heart Failure (DASH-DHF) pilot study showed that a Without a clear indication, beta-blockers (often prescribed for arter- sodium-restricted DASH diet significantly reduced clinic and 24-h ial hypertension) should be avoided. Rate-responsive pacing may be New strategies for HFPEF: targeted therapies an option in selected patients, but data from clinical trials in HF-PEF Also, trials have used different LVEF thresholds to define HF-PEF.
are lacking.
Requiring a higher LVEF threshold (e.g. LVEF ≥50%) should beconsidered in future HF-PEF trials to avoid the confounding effects Heart rate as a therapeutic target of HF-REF. However, in addition to HF-PEF (LVEF ≥50%), a substantialnumber of patients are in a ‘grey zone' of global LV function with Elevated heart rate is a risk factor for cardiovascular events, both in an LVEF between 40 and 50%. Similar to HF-PEF, almost no the general population, and in patients with HF-REF. In a diabetes guideline-recommended proven HF therapies exist for this substantial mouse model of HF-PEF, selective heart rate reduction by If- subgroup of patients, since few studies have enrolled these patients.
inhibition improved vascular stiffness, LV contractility, and diastolic Renin– angiotensin– aldosterone system antagonist therapies might function.Short-term treatment with the If channel inhibitor ivab- be particularly beneficial in this group, and further investigation in radine increased exercise capacity, with a contribution from the subgroup of patients with LVEF 40 – 50% is urgently needed.
improved LV filling pressure response to exercise, in a small, placebo- Some trials require evidence of diastolic dysfunction, whereas controlled trial.Therefore, If-inhibition might be a therapeutic others do not. The ideal balance between sensitivity and specificity concept for HF-PEF. Currently, a phase II trial with ivabradine in of the HF-PEF diagnosis is hard to achieve, particularly since HF-PEF has started.
HF-PEF is a disease of the elderly in whom age-associated comorbid-ities are common with multiple reasons for breathlessness. The def- Considerations for future clinical inition of HF-PEF used in future trials may largely depend on thetherapeutic intervention being studied. It may be necessary to require evidence of diastolic dysfunction for therapies expected toimpact cardiac structure and function. Evidence of exercise intoler- As new clinical trials are planned, it is important to apply the lessons ance or a greater symptomatic burden may be necessary for therapies learned from previous – Clinical trials to date have not expected to improve peak VO produced therapies that improve clinical outcomes, but the knowl- 2, submaximal exercise capacity, or patient-reported outcomes. Experts have not reached consensus edge gained can guide the development of future studies (Table ).
on the optimal methods to define HF-PEF patients for clinical trials, although most agree that assessments at rest are not sufficient. In Patient selection the future, objective evidence of exercise intolerance (e.g. low or Heart failure with preserved ejection fraction is a heterogeneous syn- reduced VO2 max, or limited distance on the 6 min walk) will by guest on January 13, 2015 drome, and a ‘one-size-fits-all' approach may not be effective. This become important for a firm diagnosis. The diastolic stress test concept is the critical element that has ‘doomed' many past clinical (echocardiography during exercise) is being validated, and HF-PEF trials. Heart failure with preserved ejection fraction encompasses a patients with a history of recent HF hospitalization are a subgroup broad patient population, reflecting many comorbidities and patho- at particular high risk for future adverse cardiovascular events. Emer- physiological prComorbidities influence ventricular- ging biomarkers are on the horizon, such as galectin-3, that are not vascular properties and outcomes in HF-PEF, but fundamental only elevated but may also point to a specific pathology for the disease-specific changes in cardiovascular structure and function disease, thereby allowing patient selection for targeted therapies.
underlie this supporting the search for mechanistically Additional work is needed to refine principles of patient selection targeted therapies in this disease. It is unlikely that patients with dif- for clinical trials. Future trials should strive to phenotype patients ferent phenotypes will respond uniformly to a single drug or into relevant pre-specified categories so that adequately powered device. Future clinical trials should identify pathophysiologically dis- subgroups of responders and non-responders can be identified.
tinct groups and target the key pathophysiological mechanism with Such subgroup data, although insufficient to guide clinical practice, a specific therapeutic strategy (Figures and It may be appropriate could help generate specific hypotheses for prospective testing.
to enrol patients at an earlier stage of the natural history of HF-PEF,for example, before myocardial interstitial fibrosis becomes promin- Endpoint selection ent and possibly irreversible. Although this targeted approach may Although combined all-cause mortality and HF hospitalization is a result in a smaller pool of eligible patients for a specific trial or in clin- widely accepted primary endpoint for HF-REF trials, it may be sub- ical practice, the probability of observing a significant and meaningful optimal for phase III HF-PEF trials. Large community-based cohort benefit may be greater. It is important to note that results generated data suggest that HF-PEF is associated with high mortality similar to from trials with specific patient subpopulations will not be broadly HF-REF.However, a recent meta-analysis using individual generalizable but will only apply to patients similar to those enrolled data from 41 972 patients contributing 10 774 deaths showed that in such trials.
patients with HF-PEF (LVEF ≥50%) had a lower risk of total mortality Importantly, elderly, deconditioned patients without true HF need (HR: 0.68, 95% CI: 0.64 – 0.71) and cardiovascular mortality (HR: to be excluded from targeted HF trials in HF-PEF. Hence, confirming 0.55, 95% CI: 0.49 – 0.61) than patients with HF-REFWhen the the HF diagnosis is key in patient selection. Some trials have enrolled analysis was performed by LVEF subgroups, an increased risk of patients with only mild elevations in NT-proBNP, which may have either total or cardiovascular mortality was only observed when contributed to the neutral findings of prospective, randomized the LVEF was ,40% (when compared with LVEF ≥60).Similar trials to date (Table On the other hand, in the observational findings were reported in an analysis of the CHARM programme.
Swedish study, the positive result was likely in part related to Another complicating factor is that non-cardiovascular death higher levels of NT-proBNP (Table accounts for a greater proportion of deaths in HF-PEF than in M. Senni et al.
HF-REFThus, all-cause mortality or hospitalization may be insensi- trials to date. Adaptations to current clinical trial methodology may tive to detect disease-specific therapeutic effects. Clinical trialists be needed to accommodate this paradigm shift. The forthcoming are often tempted to add components to composite endpoints to results of several clinical trials are eagerly awaited, and they will increase event rates and achieve adequate study power with small provide direction for future research and guide the clinical manage- sample sizes. However, statistical noise is introduced, rather than ment of these patients.
power, when endpoints are used that a therapeutic agent is unlikelyto influence (e.g. all-cause mortality includes non-cardiovascular death, which most cardiovascular drugs do not impact). Consideration This manuscript was generated from discussions held during an should be given to assessing all-cause mortality as a safety endpoint and international workshop (Bergamo, Italy, 14 – 16 June 2012) organized choosing cardiovascular-specific endpoints to assess drug efficacy.
by Hospital Papa Giovanni XXIII Bergamo, Cardiovascular Depart- Heart failure is a chronic disease characterized by frequent exacerba- ment and from Research Foundation, and the Medical University of tions necessitating hospitalization. Traditional time-to-first-event end- Graz, Department of Cardiology and Ludwig-Boltzmann Institute points do not reflect the full burden of disease. Efforts to develop for Translational Heart Failure Research. The authors acknowledge methods that robustly evaluate recurrent events are ongoingThe the workshop participants as the discussions held during the work- Food and Drug Administration has now accepted study designs in shop framed the content of this paper: Hans P. Brunner La Rocca, HF-PEF that use recurrent HF hospitalizations as a component of Dirk L. Brutsaert, Gianni Cioffi, Gaetano De Ferrari, Renata De the primary endpoint.
Maria, Andrea Di Lenarda, Pierre Vladimir Ennezat, Erwan Donal, A cardinal feature of HF-PEF is reduced exercise tolerance, which James Fang, Michael Frenneaux, Michael Fu, Mauro Gori, Ewa Karwa- reflects symptoms as well as quality of life. Many patients with HF-PEF towska-Prokopczuk, William Little, Selma Mohammed, Massimo are elderly and often frail, and for them, the therapy that quickly Piepoli, Pietro Ruggenenti, Roberto Trevisan, Theresa McDonagh.
improves symptoms or exercise capacity may be more importantthan an uncertain possibility of a brief prolongation of survival.
Symptom relief is, therefore, an important target of therapy, but it The workshop was supported by an unrestricted grant from Fondazione is a subjective endpoint and difficult to evaluate. The 6-minute walk Internazionale Menarini, Milan, Italy. Dr Scott Hummel's contributions to test is a simple stress test that can be used in clinical trials. In addition, the article were supported by a K23 grant from NIH/NHLBI several instruments have evolved to assess the impact of disease and the effect of treatment on health-related quality of life and other by guest on January 13, 2015 Conflict of interest: M.S.: Novartis, Abbott Vascular, A.G., W.J.P., J.D.,O.A.S., C.T., S.L.H., D.L.: None declared. A.G.F.: Travel expenses for It may also be important in future clinical trials to avoid relying on meeting, Menarini Foundation. S.D.S.: Research support from Amgen, simple, single surrogate echocardiographic endpoints. Particular Boston Scientific, Novartis, Alnylam, ISIS, and have consulted for Bayer, indices can be selected that reflect the expected mechanism of Amgen, Novartis, Takeda, and Pfizer, M.G.: Merck Sharpe, Pfizer, Acte- action of a drug. Recent studies have used E/e′ as a correlate of the lion, Bayer, Novartis, Takeda, Otsuka, J & J, Cardiocell, C.S.P.L.: Clinician mean LV filling pressure, but the utility of this variable in HF-PEF Scientist Award from the National Medical Research Council of Singa- has been seriously quesAlternative indices include pore; advisory board consultant for heart failure research Bayer, Inc.; un- the propagation velocity of mitral inflow (an excellent correlate of restricted educational grant from Vifor Pharma, A.P.M.: Advisory board early diastolic LV and the difference in duration member for Novartis, Amgen, Bayer, Cardiorentis, Sanofi, F.E.: Investiga- between antegrade flow into the LV and retrograde flow into the tor, consultant, or speaker for Berlin Chemie, Novartis, Pfizer, Servier, pulmonary veins during atrial contraction (an indicator of LV Bayer, Gilead, CVRx, Relypsa, BG Medicine, Sanofi, Astra-Zeneca, and end-diastolic pressure in patients with HF-REF and HF-PEF).Left Abbott Laboratories, G.A.: Consultant to Menarini International,Servier International, Merck, Angelini, Boheringer; grant support Menar- atrial volume is increasingly recognized as an integrated parameter ini International; lectures for Menarini International, Merck, and Boherin- for elevated LV filling pressures and the duration of the disease ger, A.J.C.: Consultant to DCD devices; speaker for Menarini, G.S.F.: (similar to HbA1c in diabetes), and it is currently used as an inclusion Member of the Executive or Steering Committee of trials sponsored criterion and as a secondary endpoint in several Phase II HF-PEF trials.
by Bayer, Corthera, Cardiorentis; speaker/lectures for Menarini, M.G.: Finally, HF is pathophysiologically defined as impaired pump function, Abbott Laboratories, Astellas, Astra-Zeneca, Bayer Schering Pharma and the non-invasive estimation of filling pressures and stroke volume AG, Cardiorentis Ltd, CorThera, Cytokinetics, CytoPherx, Inc, Debio- (e.g. by 3D echocardiography) during rest and stress may improve Pharm S.A., Errekappa Terapeutici, GlaxoSmithKline, Ikaria, Intersection diagnostic accuracy and assessment of an eventual treatment effect.
Medical, INC, Johnson & Johnson, Medtronic, Merck, Novartis PharmaAG, Ono Parmaceuticals USA, Otsuka Pharmaceuticals, Palatin Tech-nologies, Sanofi-Aventis, Sigma Tau, Solvay Pharmaceuticals, Sticares InterACT,-Takeda Pharmaceuticals North America, Inc., and Trevena Therapeutics; Significant progress has been made in understanding HF-PEF patho- and has received signficant (.$10 000) support from Bayer Schering physiology, recognizing the importance of disease heterogeneity, Pharma AG, DebioPharm S.A., Medtronic,Novartis Pharma AG, and identifying novel therapies that may reduce symptoms and Otsuka Pharmaceuticals, Sigma Tau, Solvay Pharmaceuticals, Sticares improve clinical outcomes. Designing therapies to match specific InterACT and Takeda Pharmaceuticals North America, Inc., S.D.A.: patient phenotypes may prove to be a more effective approach Vifor, BG Medicine, Vifor, Brahms GmbH, Marc Pfeffer: Consultant/ than the traditional model of applying a given treatment uniformly advisor to Aastrom, Amgen, Anthera, Bayer, Bristol Myers Squibb, to all patients, which has not been successful in clinical HF-PEF Cerenis, Concert, Genzyme, Hamilton Health Sciences, Karo Bio, New strategies for HFPEF: targeted therapies Keryx, Merck, Novartis, Roche, Sanofi-Aventis, Servier, Teva, University 14. Fonarow GC, Stough WG, Abraham WT, Albert NM, Gheorghiade M, of Oxford, Xoma; Research grants from Amgen, Celladon, Novartis, Greenberg BH, O'Connor CM, Sun JL, Yancy CW, Young JB. Characteristics, treat-ments, and outcomes of patients with preserved systolic function hospitalized for Sanofi-Aventis; Co-inventor of patents for the use of inhibitors of the heart failure: a report from the OPTIMIZE-HF Registry. J Am Coll Cardiol 2007;50: renin – angiotensin system in selected survivors of MI with Novartis Phar- 768 – 777.
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