J A C C : H E A R T F A I L U R E V O L . 6 , N O . 8 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

SPECIAL ISSUE: HEART FAILURE WITHPRESERVED EJECTION FRACTION (HFpEF)

JACC: HEART FAILURE EXPERT SCIENTIFIC PANEL

Heart Failure With Preserved EjectionFraction Expert Panel Report

Current Controversies and Implications for Clinical Trials

Kishan S. Parikh, MD,a,b Kavita Sharma, MD,c Mona Fiuzat, PHARMD,a,b Howard K. Surks, MD,d Jyothis T. George, MD,e

Narimon Honarpour, MD, PHD,f Christopher Depre, MD, PHD,f Patrice Desvigne-Nickens, MD,g

Richard Nkulikiyinka, MD,h Gregory D. Lewis, MD,i Mardi Gomberg-Maitland, MD, MSC,j

Christopher M. O’Connor, MD,j Norman Stockbridge, MD,k Robert M. Califf, MD,b,l,m Marvin A. Konstam, MD,n

James L. Januzzi, JR, MD,o Scott D. Solomon, MD,p Barry A. Borlaug, MD,q Sanjiv J. Shah, MD,r

Margaret M. Redfield, MD,q G. Michael Felker, MDa,b

JACC: HEART FAILURE CME/MOC

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ISSN 2213-1779/$36.00

From the aDuke Clinical Research Institute, Durham, North Carolina; bDuke UncJohns Hopkins University, Baltimore, Maryland; dSanofi, Bridgewater, New

Ingelheim, Germany; fAmgen, Inc., Thousand Oaks, California; gNational In

Institute, Bethesda, Maryland; hBayer AG, Wuppertal, Germany; iMassachus

Heart and Vascular Institute, Falls Church, Virginia; kU.S. Food and Drug Ad

versity, Stanford, California; mVerily Life Sciences, San Francisco, CalifornoBrigham andWomen’s Hospital, Boston, Massachusetts; pHarvardMedical Sch

clinicians, investigators, industry, and regulators in the current HFpEF

field; 2) discuss results of prior HFpEF trials and potential pitfalls of trial

design; and 3) select appropriate strategies to diagnose HFpEF and

identify subpopulations that may fit a targeted therapy.

CME/MOC Editor Disclosure: Editor-in-Chief Christopher M. O’Connor,

MD, has received consultant fees/honoraria from AbbVie, Inc., Actelion

Pharmaceuticals Ltd., Bayer, Bristol Myers Squibb, Cardiorentis,

Merco & Co., Inc., ResMed, and Roche Diagnostics; and ownership

interest in Biscardia, LLC. Executive Editor Mona Fiuzat, PharmD, has

received research support from ResMed, Gilead, Critical Diagnostics,

Otsuka, and Roche Diagnostics. Tariq Ahmad, MD, MPH, has received a

travel scholarship from Thoratec. Abhinav Sharma, MD, has received

support from Bayer-Canadian Cardiovascular Society, Alberta Innovates

Health Solution, Roche Diagnostics, and Takeda. Mitchell Psotka, MD,

PhD, and Kishan Parikh, MD, have no relationships relevant to the

contents of this paper to disclose.

Author Disclosures: Dr. Fiuzat has received personal fees from ResMed

outside the submittedwork. Dr. Surks is an employee of Sanofi. Dr. George

is an employee of Boehringer Ingelheim. Dr. Honarpour is an employee of

Amgen and has received stock grants from Amgen, Inc. Dr. Depre is an

employee of Amgen, Inc. Dr. Nkulikiyinka is an employee and shareholder

of Bayer AG. Dr. Lewis has received grants from Abbott Vascular, Iron-

wood, National Institutes of Health, and American Heart Association; and

is a consultant for Amgen, Luitpold, and Cytokinetics. Dr. Gomberg-

Maitland has received grants and other support from Actelion; personal

fees from Bayer, Acceleron, Medronic, Arena, Merck, St. Jude’s/Abbott,

https://doi.org/10.1016/j.jchf.2018.06.008

iversity School of Medicine, Durham, North Carolina;

Jersey; eBoehringer Ingelheim Clinical Development,

stitutes of Health, National Heart, Lung, and Blood

etts General Hospital, Boston, Massachusetts; jInova

ministration, Silver Spring, Maryland; lStanford Uni-

ia; nTufts Medical Center, Boston, Massachusetts;

ool,Wellesley, Massachusetts; qMayo Clinic, Rochester,

Parikh et al. J A C C : H E A R T F A I L U R E V O L . 6 , N O . 8 , 2 0 1 8

Expert Scientific Panel on HFpEF A U G U S T 2 0 1 8 : 6 1 9 – 3 2

620

and Liquidia; other support from Reata and PCORI; grants, personal fees,

and other support from United Therapeutics; grants from AADi; and per-

sonal fees from Janssen during the conduct of the study. Dr. O’Connor has

received personal fees from ResMed, Bayer, Stealth Peptides, Bristol-

Myers Squibb Foundation, Dey, L.P., and Merck outside the submitted

work. Dr. Califf served as Commissioner for Food and Drugs at the U.S.

Food and Drug Administration from 2016 to 2017 and as Deputy Commis-

sioner forMedical Products and Tobacco from 2015 to 2016; is employed as

a scientific advisor by Verily Life Sciences (Alphabet); has received stock

from Verily Life Sciences; is a consultant for Merck, Amgen, and Boeh-

ringer Ingelheim; and receives consulting payments from Merck.

Dr. Konstam has received other support from Amgen, Bristol-Myers

Squibb, Boehringer Ingelheim, andNovartis; and grants and other support

from Ironwood and Livanova outside the submitted work. Dr. Januzzi has

received grants from Roche Diagnostics, Abbott, Singulex, Prevencio, and

Novartis; grants and personal fees from Janssen; and personal fees from

Critical Diagnostics outside the submitted work. Dr. Solomon has received

grants and personal fees from Novartis, AstraZeneca, Bayer, Bristol-Myers

Squibb, Alnylam, GlaxoSmithKline, Myokardia, and Amgen; grants from

Ionis; and personal fees from Corvia, Roche, and Merck outside the sub-

Minnesota; and rNorthwestern University, Chicago, Illinois. Dr. Fiuzat ha

submitted work. Dr. Surks is an employee of Sanofi. Dr. George is an emp

employee of Amgen and has received stock grants from Amgen, Inc. Dr. Dep

an employee and shareholder of Bayer AG. Dr. Lewis has received grants fro

Health, and American Heart Association; and is a consultant for Amgen, Lu

received grants and other support from Actelion; personal fees from Bayer, A

and Liquidia; other support from Reata and PCORI; grants, personal fees, a

from AADi; and personal fees from Janssen during the conduct of the stu

ResMed, Bayer, Stealth Peptides, Bristol-Myers Squibb Foundation, Dey, L.P

served as Commissioner for Food and Drugs at the U.S. Food and Drug

Commissioner for Medical Products and Tobacco from 2015 to 2016; is emp

(Alphabet); has received stock from Verily Life Sciences; is a consultant for Me

consulting payments from Merck. Dr. Konstam has received other suppo

Ingelheim, and Novartis; and grants and other support from Ironwood and L

received grants from Roche Diagnostics, Abbott, Singulex, Prevencio, and N

personal fees from Critical Diagnostics outside the submitted work. Dr. So

Novartis, AstraZeneca, Bayer, Bristol-Myers Squibb, Alnylam, GlaxoSmithKl

personal fees from Corvia, Roche, and Merck outside the submitted work. Dr

the National Institutes of Health (R01 HL107577, R01 HL127028), the Am

#15CVGPSD27260148), Actelion, AstraZeneca, Corvia, and Novartis; and co

Bayer, Boehringer Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sa

received grant funding from National Heart, Lung, and Blood Institute, Am

netics, Merck, and Roche Diagnostics; and consulting for Novartis, Amgen,

GlaxoSmithKline, Cardionomic, Cytokinetics, Myokardia, Stealth, Innolife, an

they have no relationships relevant to the contents of this paper to disclose

this paper.

Manuscript received April 6, 2018; revised manuscript received June 20, 20

mitted work. Dr. Shah has received receiving research funding from the

National Institutes of Health (R01 HL107577, R01 HL127028), the American

Heart Association (#16SFRN28780016 and #15CVGPSD27260148), Actelion,

AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion,

Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiora, Eisai, Iron-

wood,Merck, Novartis, Sanofi, Tenax, andUnited Therapeutics. Dr. Felker

has received grant funding from the National Heart, Lung, and Blood

Institute, American Heart Association, Novartis, Amgen, Cytokinetics,

Merck, and Roche Diagnostics; and consulting for Novartis, Amgen, Roche

Diagnostics, Medtronic, Bristol-Myers Squibb, GlaxoSmithKline, Car-

dionomic, Cytokinetics,Myokardia, Stealth, Innolife, andEBRSystems.All

other authors have reported that they haveno relationships relevant to the

contents of this paper to disclose.

Medium of Participation: Print (article only); online (article and quiz).

CME/MOC Term of Approval

Issue date: August 2018

Expiration date: July 31, 2019

s received personal fees from ResMed outside the

loyee of Boehringer Ingelheim. Dr. Honarpour is an

re is an employee of Amgen, Inc. Dr. Nkulikiyinka is

m Abbott Vascular, Ironwood, National Institutes of

itpold, and Cytokinetics. Dr. Gomberg-Maitland has

cceleron, Medronic, Arena, Merck, St. Jude’s/Abbott,

nd other support from United Therapeutics; grants

dy. Dr. O’Connor has received personal fees from

., and Merck outside the submitted work. Dr. Califf

Administration from 2016 to 2017 and as Deputy

loyed as a scientific advisor by Verily Life Sciences

rck, Amgen, and Boehringer Ingelheim; and receives

rt from Amgen, Bristol-Myers Squibb, Boehringer

ivanova outside the submitted work. Dr. Januzzi has

ovartis; grants and personal fees from Janssen; and

lomon has received grants and personal fees from

ine, Myokardia, and Amgen; grants from Ionis; and

. Shah has received receiving research funding from

erican Heart Association (#16SFRN28780016 and

nsulting fees from Actelion, Amgen, AstraZeneca,

nofi, Tenax, and United Therapeutics. Dr. Felker has

erican Heart Association, Novartis, Amgen, Cytoki-

Roche Diagnostics, Medtronic, Bristol-Myers Squibb,

d EBR Systems. All other authors have reported that

. Barry H. Greenberg, MD, served as Guest Editor for

18, accepted June 20, 2018.

J A C C : H E A R T F A I L U R E V O L . 6 , N O . 8 , 2 0 1 8 Parikh et al.A U G U S T 2 0 1 8 : 6 1 9 – 3 2 Expert Scientific Panel on HFpEF

621

Heart Failure With Preserved Ejection FractionExpert Panel Report

Current Controversies and Implications for Clinical Trials

Kishan S. Parikh, MD,a,b Kavita Sharma, MD,c Mona Fiuzat, PHARMD,a,b Howard K. Surks, MD,d Jyothis T. George, MD,e

Narimon Honarpour, MD, PHD,f Christopher Depre, MD, PHD,f Patrice Desvigne-Nickens, MD,g

Richard Nkulikiyinka, MD,h Gregory D. Lewis, MD,i Mardi Gomberg-Maitland, MD, MSC,j

Christopher M. O’Connor, MD,j Norman Stockbridge, MD,k Robert M. Califf, MD,b,l,m Marvin A. Konstam, MD,n

James L. Januzzi, JR, MD,o Scott D. Solomon, MD,p Barry A. Borlaug, MD,q Sanjiv J. Shah, MD,r

Margaret M. Redfield, MD,q G. Michael Felker, MDa,b

ABSTRACT

The number of persons with heart failure has continued to rise over the last several years. Approximately one-half of

those living with heart failure have heart failure with preserved ejection fraction, but critical unsolved questions remain

across the spectrum of basic, translational, clinical, and population research in heart failure with preserved ejection

fraction. In this study, the authors summarize existing knowledge, persistent controversies, and gaps in evidence with

regard to the understanding of heart failure with preserved ejection fraction. Our analysis is based on an expert panel

discussion “Think Tank” meeting that included representatives from academia, the National Institutes of Health, the U.S.

Food and Drug Administration, the Centers for Medicare & Medicaid Services, and industry. (J Am Coll Cardiol HF

2018;6:619–32) © 2018 by the American College of Cardiology Foundation.

A pproximately 6.5 million American adults areestimated to have heart failure (HF), and thenumber of persons is projected to increase

46% by 2030 (1); approximately one-half of these pa-tients have heart failure with preserved ejection frac-tion (HFpEF) (2). Perhaps the most agreed-uponcharacteristic of HFpEF is that a better understandingis needed. Critical unsolved questions remain acrossthe spectrum of basic, translational, clinical, and pop-ulation research in HFpEF. In particular, it remainsunknown whether the term HFpEF applies to a singledisease state or multiple diseases that are character-ized by unique underlying pathophysiologic mecha-nisms. In this expert panel report, we identify gapsin evidence with regard to the understanding ofHFpEF in 3 pivotal areas: 1) definition of thedisease; 2) subtypes of HFpEF; and 3) endpoints inHFpEF clinical trials. Our analysis is based on anexpert panel discussion “Think Tank” meeting thatwas hosted by the Duke Clinical Research Institutein Washington, DC, in June 2017, which includedrepresentatives from academia, the NationalInstitutes of Health, the U.S. Food and DrugAdministration, the Centers for Medicare &Medicaid Services, and industry. In the followingdiscussion, we approach critical HFpEF issues froma variety of perspectives in hopes of elucidatingcommon themes and offering a potential future

roadmap for improved HFpEF care (CentralIllustration). To focus our discussion and avoidoverlap with different disease processes, we do notaddress the HF patient populations with mid-rangeejection fraction (EF) (i.e., 40% to 49%) orrecovered EF while considering these issues.

IS HFpEF A SINGLE ENTITY?

Challenges associated with HFpEF begin with itsdefinition. HFpEF is usually diagnosed afterexcluding noncardiac causes of dyspnea that canmimic HF, and alternate established diseases with leftventricular EF >50% causing HF symptoms (e.g.,constrictive pericarditis, infiltrative cardiomyopa-thies, isolated right-sided HF, valvular heart disease,non–group 2 pulmonary hypertension [PH]) (3). Earlystudies of HFpEF focused on 1 or 2 predominantmechanistic pathways, such as diastolic dysfunction(4,5); however, subsequent key studies demonstratedthat not only was diastolic dysfunction not ubiqui-tously present on resting echocardiography in HFpEF,but several other mechanisms were likely implicated,including atrial dysfunction, systolic impairment,ventricular-vascular stiffening, and chronotropicincompetence (6–8). As a result, the definition ofHFpEF has evolved over the last 2 decades, movingaway from a primary focus on echocardiographic

ABBR EV I A T I ON S

AND ACRONYMS

BNP = B-type natriuretic

peptide

EF = ejection fraction

HF = heart failure

HFpEF = heart failure with

preserved ejection fraction

HFrEF = heart failure with

reduced ejection fraction

PAH = pulmonary arterial

hypertension

PH = pulmonary hypertension

QOL = quality of life

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evidence of diastolic dysfunction in thesetting of an EF $50%, and moving toward adefinition inclusive of (but not restricted to)cardiac structural abnormalities resultingfrom high filling pressures, diastolic abnor-malities, elevated biomarkers, and elevatedleft heart filling pressures by invasive he-modynamic assessment (4,9). Despite het-erogeneous contribution of putativepathomechanisms, HFpEF patients do havecommon patterns of clinical presentation,such as impaired exercise tolerance orphysical limitations in activities of dailyliving. Furthermore, EF $50% remains adefining feature in HFpEF, as illustrated by

variability in patient characteristics and outcomes byEF observed in the TOPCAT (Treatment of PreservedCardiac Function Heart Failure with an AldosteroneAntagonist) trial of spironolactone (10) and similardifferential beta-blocker effects in subjects withEF <40%, 40% to 49%, and $50% (11).

Consequently, there is controversy about whetherHFpEF patients respond similarly to interventions ornot. How HFpEF should be categorized has over-arching implications for future treatment goals andapproaches to drug development, and both perspec-tives are discussed next.

YES, HFpEF IS A SINGLE-DISEASE ENTITY. A singledisease can be defined by a phenotype or constella-tion of signs, biomarkers, and symptoms that sharea common denominator (12). Left ventricular diastolicdysfunction is a common denominator among HFpEFpatients, but varying degrees of other pathophysio-logic components are observed, including abnormal-ities in left ventricular systolic function, conduitvessel stiffening, pulmonary vascular disease, rightventricular function, microvascular function, skeletalmuscle function, and changes in body composition.A key unanswered question is whether these differ-ential expressions arise from a common mechanism,or whether they are caused by different discreteprocesses. Paulus and Tschöpe (13) proposed a uni-fying hypothesis that is consistent with the formerscheme: an underlying proinflammatory state (causedby 1 or more of the commonly associated comorbidconditions in HFpEF, including obesity, diabetes,and hypertension) triggers a cascade of events thatleads to decreased nitric oxide bioavailability,cyclic guanosine monophosphate, and protein kinaseG activity, thereby causing increased cardiomyo-cyte stiffness (due to titin hypophosphorylation)and/or interstitial myocardial fibrosis, and increased

ventricular wall stiffness. In this model, HFpEF ismediated by endothelial dysfunction involvingboth arterial and venous systems, in contrast toprimary myocardial injury caused by cardiomyocyteloss as in HF with reduced EF (HFrEF). This patho-physiology provides a distinct potential therapeutictarget for new drug candidates that can be developedto modify disease course.

NO, HFpEF COMPRISES MANY DIFFERENT DISEASES.

However, the Paulus and Tschöpe (13) hypothesisis weakened by prior negative trials of statins,renin-angiotensin-aldosterone system inhibition,and phosphodiesterase-5 inhibitors—therapies thatshould stabilize vascular inflammation and promoteendothelial function. Contrasting to the theorythat HFpEF may result from a single underlyingcause is the possibility that HFpEF is a multiorgandisease resulting from not only primary cardiacabnormalities, but also noncardiac comorbiditiesimplicated in the development of clinical HF.These noncardiac conditions may have independentmechanistic implications that do not all result in acommon pathway of inflammation and subsequentmyocardial damage. Limitations in systolic reserve,vascular function, nitric oxide bioavailability, leftatrial function, chronotropic incompetence, changesin body composition, skeletal muscle function, andother mechanisms (all of which have been assessedby hemodynamic, imaging, and biomarker studies)have been associated with HFpEF (6). Many of theseperturbations occur with aging and, therefore, age-associated changes in cardiovascular structure andfunction become “partners” with pathophysiologicaldisease mechanisms to determine the threshold,severity, and prognosis of HFpEF (14). Additionalinfluential factors have been explored. For example,obesity (84% prevalence in a U.S. HFpEF population)has a U-shaped relationship with survival, as it doesin HFrEF patients (15), and displays unique patho-physiological features compared with those foundin nonobese HFpEF patients (16); furthermore, weightloss in obese patients with HFpEF improves peakoxygen consumption (17). Other factors influencingHFpEF severity include hypertension ($80%), dia-betes mellitus (20% to 45%), chronic lung disease,atrial fibrillation, and chronic kidney disease.The complexity of interactions between HFpEF andcomorbid conditions complicates development ofa universal HFpEF animal model. Instead, currentHFpEF animal models recapitulate isolated featuresof HFpEF. The ability of an animal model toprovide pathophysiological insights and predict

CENTRAL ILLUSTRATION Key Questions With Critical Gaps Identified in HFpEF

Parikh, K.S. et al. J Am Coll Cardiol HF. 2018;6(8):619–32.

HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction.

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TABLE 1 Summary of Major Published HFpEF Randomized Clinical Trials (Phase 2–3)

Drug/Intervention(Ref. #) Phase Study Size Primary Endpoint Result

Candesartan (31) 3 3,023 Composite of cardiovascular mortality or HF hospitalization Neutral

Irbesartan (30) 3 4,128 Composite of all-cause mortality or cardiovascular hospitalization Neutral

Perindopril (29) 3 850 Composite of all-cause mortality and HF hospitalization Neutral

Nebivolol (60) 3 752 Composite of all-cause mortality or cardiovascular hospitalization Neutral

Carvedilol (61) 2 245 Composite of cardiovascular mortality or HF hospitalization Neutral

Digoxin (62) 3 988 Composite of HF mortality or HF hospitalization Neutral

Spironolactone (63) 2 422 E/e’ on echocardiography; peak oxygen consumption Positive; neutral

Spironolactone (64) 3 3,445 Composite of death from cardiovascular cause, aborted cardiac arrest,or HF hospitalization

Neutral

Eplerenone (65) 2 44 6-min-walk distance Neutral

Sildenafil (66) 2 216 Peak oxygen consumption Neutral

Ivabradine (67) 2 61 Exercise capacity/peak oxygen consumption Positive

Ivabradine (68) 2 44 Peak oxygen consumption Negative

Ivabradine (69) 2 179 E/e’ on echocardiography; 6-min-walk distance; NT-proBNP Neutral; neutral;neutral

Exercise training (70) N/A 64 Peak oxygen consumption Positive

Sacubitril/valsartan (71) 2 301 NT-proBNP Positive

Vericiguat (72) 2 477 NT-proBNP; left atrial volume Neutral; neutral

Isosorbide mononitrate (57) 2 110 Daily activity level Negative

HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide.

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human HFpEF therapeutic response to preclinicalintervention testing is uncertain (18).

Therefore, evidence exists on both sides, but it isincreasingly accepted that the clinical presentationof HFpEF is influenced to varying degrees by morethan 1 physiological perturbation or risk factor.Relative influences of contributing etiologies andpossible links between them must be better under-stood at both individual and population levels. Theapplicability of animal models to human HFpEF re-mains a matter of controversy and requires furtherstudy.

IS A CLINICALLY BASED SCHEME THE RIGHT

APPROACH TO HFpEF CLASSIFICATION?

Regardless of whether HFpEF is a single disease or acommon presentation of multiple pathophysiologicalprocesses, the condition encompasses a broad spec-trum of clinical phenotypes. The need to categorizepatients is increasingly evident as the disease burdengrows, with more therapeutic interventions beingstudied and failing. Merits of various methods ofclassification, including pathophysiologic, etiologic,clinical presentation, and phenomapping, have beenpreviously explored (19) and reveal several possiblefuture directions. We believe whatever scheme isdeveloped should be flexible (i.e., have the capacityto adapt to new findings) and practical (i.e., can be

classified in a variety of settings), with the goalof driving specific therapies in distinct subgroups.With this in mind, we must consider the initialbroad distinction of a clinically versus mechanisti-cally based classification scheme in HFpEF.

YES, HFpEF CLASSIFICATION SHOULD BE CLINICALLY

ORIENTED. There are basically 2 approaches that canbe used together. One is hypothesis-driven based onclinical observations. HFpEF patients are divided intophenotypes, such as obese HFpEF/HFpEF with pul-monary vascular disease/HFpEF with arterial stiff-ening/HFpEF with endothelial dysfunction. Anotheris an agnostic, machine-learning approach where thecomputer identifies groups that differ to create clin-ical groups. Integration of both approaches and useof both inductive- and reductionist-type approachesis needed. Relative contributions of cardiac andvascular etiologies could be quantified in thismanner.

NO, HFpEF CLASSIFICATION SHOULD BE BASED ON

MECHANISTIC PATHWAYS. Using identified mecha-nistic processes to categorize HFpEF patients mayprovide opportunities to study targeted therapeutics(20). In contrast to focusing on clinical presentation,a system detailing specific, underlying biologicprocesses can assess the specific pathophysiologicalfactors contributing to a patient’s HFpEF diseaseburden. Lewis et al. (20) have recently proposedinclusion of dysfunction in vascular beds, kidneys,

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mitochondrial function, calcium handling, and car-diac diastole, among others. However, many of theseHFpEF variables are dynamic, so routine measure-ment followed by synthesis seems to be a formidabletask. Even in the case of HFrEF, these underlyingmechanisms may or may not be accurate or sufficientto pinpoint a specific disease entity.

The previous discussion suggests that furthercomparisons of clinically and biologically based clas-sifications are needed. An alternative way to viewHFpEF clinical/biologic phenotypes is to look throughdifferent lenses into this complex syndrome. Forexample, we are just beginning to examine variationin presentation and outcomes by sex, race, ethnicity,socioeconomic factors, hemodynamics, biomarkers,imaging, or responses to physiologic perturbations,such as exercise (21,22). Techniques, such as machinelearning, that can integrate data from various sourcesmay lead to discovery of biologically distinct pheno-types and potentially differentiate responsiveness totherapy. However, ultimately machine learning isonly as good as the input variables, and if the criticalpathophysiologic features that drive HFpEF are notdirectly or indirectly represented within the inputvariables, the analysis can be unhelpful or evenmisleading.

SHOULD CLINICAL TRIALS CONTINUE TO

ADDRESS ALL HFpEF SIMILARLY?

To date, randomized trials of a variety of potentiallypromising interventions have been unable todemonstrate a definitive benefit in HFpEF patients(Table 1). What is unclear is whether this lack ofdemonstrative benefit was caused by failed trialdesigns or inefficacious study interventions. A clin-ical trial that results in negative findings is certainlynot a failure because knowledge is obtained fromthese results, but negative findings resulting from apotential therapy compel us to reconsider clinicaltrial design in the context of prior efforts in HFpEF. Inthe following 2 sections, we consider 2 divergent ap-proaches to identifying appropriate HFpEF clinicaltrial populations to maximize the chances of finding atherapeutic intervention: 1) trials that would includea broad group of subjects; and 2) trials that wouldbe smaller, focusing on individual subpopulations.

YES, HFpEF CLINICAL TRIALS SHOULD INCLUDE A

BROAD GROUP OF SUBJECTS. When compared withobservational registries and epidemiological studies,patients included in HFrEF clinical trials are often atlower risk for adverse outcomes, largely because theeligibility criteria for HFrEF trials in general exclude

the sickest patients (e.g., the very elderly and thosewith advanced chronic kidney disease, frailty,high-risk comorbidities). The standard therapeuticHFrEF treatment regimen (including newer agents)has been built on large randomized controlled trials,and consequently, many HFrEF patients have seensignificant improvements in survival and other HFoutcomes including hospitalizations. In HFrEF,diverse etiologic categories (i.e., ischemic and non-ischemic dilated cardiomyopathies) have showngenerally similar therapeutic responses to neurohu-moral antagonists.

To date, HFpEF clinical trials have also adoptedbroad inclusion criteria. Ensuring adequate statisticalpower to detect signals may be especially important inHFpEF trials, given the many comorbid conditions inHFpEF, which may influence clinical endpointsbeyond HF severity and therapeutic effect. Targetingtrials to specific phenotypes posited to respond tothe tested intervention may increase the ability toidentify efficacy, but this approach may also limitability to enroll enough patients for a sufficientlypowered trial.

Enrichment strategies must be assessed carefully.Many HFrEF outcome trials have enriched a broadHFrEF population for event rates by requiringelevated natriuretic peptide assays for enrollment toenhance power with a smaller study size. Similarly,HFpEF studies have commonly required elevatedBNP levels to ensure participants have HF andto enrich event rates. Although B-type natriureticpeptide (BNP) levels are prognostic in HFpEF (23),numerous studies have shown that BNP levels inHFpEF are lower than in HFrEF for any given HFseverity and that a significant proportion of HFpeFpatients do not have elevated BNP assay levels(24,25). Further, post hoc analyses from 2 clinicaltrials, I-PRESERVE (Irbesartan in Heart Failure WithPreserved Systolic Function) and TOPCAT, showedactive therapy (irbesartan or spironolactone) wasassociated with treatment benefit in subjects withlower natriuretic peptide levels, but not in subjectswith higher levels (26,27). These observations maychallenge the common practice of using natriureticpeptide assays to enrich HFpEF trials for event rates.

NO, HFpEF CLINICAL TRIALS NEED TO BE NARROWER

AND FOCUSED ON INDIVIDUAL SUBPOPULATIONS. For aHFpEF trial to be successful, the right patientsneed to be matched to the therapies from whichthey are most likely to benefit. Even in HFrEF,certain therapies (cardiac resynchronization therapyand defibrillators) are helpful only in specific HFrEFphenotypes. A large number of ongoing HFpEF

TABLE 2 Representative Summary of Registered Current and Upcoming Clinical Trials for HFpEF at Time of Publication

Study (Intervention) Phase Target HFpEF Population Primary Outcomes

CAPACITY-HFpEF (IW-1973, solubleguanylate cyclase stimulator)

2 EF $45%Peak VO2 <80% predicted

Peak VO2

6-min-walk

SPIRRIT (spironolactone) 4 EF $40% MortalityHF hospitalization

SERENADE (macitentan) 2 EF $40%Pulmonary vascular disease or right

heart failure

Natriuretic peptides

PARAGON-HF (sacubitril/valsartan) 3 EF $45% Cumulative events of CV death and total HFhospitalizations

DYNAMIC (riociguat) 2 EF $50%Pulmonary hypertension

HemodynamicsMRI parameters

PARALLAX (sacubitril/valsartan) 3 EF $45%KCCQ summary score <75

Natriuretic peptidesQuality of life

VITALITY-HFpEF (vericiguat) 2 EF $45% Quality of life

SOUTHPAW (oral treprostinil) 3 EF $45%Pulmonary hypertension

6-min-walk

KNO3CK OUT HFpEF (potassium nitrate) 2 EF >50% Peak VO2

EMPEROR-PRESERVED (empagliflozin) 3 EF >40% Time to CV death or HF hospitalization

OPTIMIZE-HFPEF(screening/treatment of comorbidities)

3 EF $50%Age >60 yrs

Composite including quality of life

FAIR-HFpEF (ferric carboxymaltose) 2 EF $45%Diastolic dysfunctionIron deficiency

Exercise capacity6-min-walk

CELLpEF (cell therapy) 2 EF >50%Diastolic dysfunction

Diastolic function by MRIExercise capacity

PH-HFpEF (sodium nitrite) 2 EF $40%Pulmonary hypertension

Exercise hemodynamics6-min-walk

Neladenoson bialanate 2 EF $45% 6-min-walk

CoQ10 and D-ribose 2 EF $50% Quality of life

Nebivolol 4 Pulmonary hypertension Hemodynamics6-min-walk

ONOH (sodium nitrite) 2 EF $40%Age $70 yrs

Peak VO2

INABLE (inhaled sodium nitrite) 2 EF $50% Peak VO2

PRESERVED-HF (dapagliflozin) 4 EF $45%Diabetes mellitus type 2

Natriuretic peptides

Levosimendan 2 Pulmonary hypertension Exercise hemodynamics

CRpEF (cardiac rehabilitation) 3 EF $50%Moderate/severe diastolic dysfunctionAge $50 yrs

Peak VO2

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studies are testing interventions that target uniquemechanistic hypotheses (Table 2) but are not neces-sarily targeting specific subphenotypes selected to beuniquely responsive to the tested therapeutic. Po-tential HFpEF subpopulations that may have uniquepathophysiology and potential response to targetedtherapies are described next, and include: 1) at-risk/metabolic disorders; 2) pulmonary vascular disease;and 3) elevated left atrial pressure.Subpopulat ion : at - r i sk/metabol i c d i sorders . It ispossible that prevention, or delay in progression,of HFpEF may be effective in high-risk populations.Prior studies of neurohormonal modulators in overtHFpEF populations have demonstrated overall neutralfindings for beta-blockers (11,28) and angiotensin-converting enzyme inhibitor-I/angiotensin receptor

blocker therapy (29–31). Yet findings from theRENAAL (Reduction of Endpoints in Non–Insulin-Dependent Diabetes Mellitus with the Angiotensin IIAntagonist Losartan) and HOPE (Heart OutcomesPrevention Evaluation) trials showed that renin-angiotensin-aldosterone system inhibition reducedincident HF in patients with risk factors for cardio-vascular events (32,33). However, the type of HFprevented was not assessed in these studies. InALLHAT (Antihypertensive and Lipid-LoweringTreatment to Prevent Heart Attack Trial), which diddefine the type of HF participants developed, chlor-thalidone was superior to lisinopril in reducing inci-dent HFpEF (34). More recently, 2 studies of differentsodium-glucose cotransporter-2 inhibitors showedreduced HF (type unknown) incidence in patients

TABLE 2 Continued

Study (Intervention) Phase Target HFpEF Population Primary Outcomes

PERSPECTIVE (sacubitril/valsartan) 3 EF $40% Cognitive score

PIROUETTE (pirfenidone) 2 EF $45%Myocardial fibrosis

MRI myocardial extracellular volume fraction

ERADICATE-HF (ertugliflozin) 2 EF $20% (HFrEF and HFpEF)Diabetes mellitus type 2

Proximal tubule sodium reabsorption

REDUCE LAP-HF II (interatrial shuntdevice)

N/A EF $40%Age >40 yrsElevated left atrial pressure

CV mortality or strokeQuality of life

Regress-HFpEF (allogeneic-derivedcells)

2 EF $50%Age $50 yrs

Quality of lifeExercise hemodynamics

PERFECTUS (biventricular pacemaker) N/A EF $50%Chronotropic incompetence

Diastolic function

WTLSSCHF (weight loss) N/A EF $45%BMI >30 kg/m2

6-min-walkQuality of life

RAPID-HF (atrial pacing) N/A EF $50%Chronotropic incompetence

Peak VO2

BEAT-HFpEF (albuterol) 2 EF $50%Elevated LV filling pressures

Exercise hemodynamics

INDIE-HFpEF (inorganic nitrite) 2 EF $50%Age $40 yrsPeak VO2 #75% predicted

Peak VO2

ROPA-DOP (diuretics strategy anddopamine)

4 EF >50%Acute HF

Renal function

Levosimendan, calcium sensitizer/K-ATPactivator

2 EF $40%Pulmonary hypertension

Exercise hemodynamics

TROPHY 2 (pulmonary arterydenervation)

2 EF $40%Pulmonary hypertension

Exercise hemodynamics

This list is not intended to be comprehensive.

BMI¼ body mass index; CV ¼ cardiovascular; EF ¼ ejection fraction; HFrEF ¼ heart failure with reduced ejection fraction; KCCQ ¼ Kansas City Cardiomyopathy Questionnaire;LV ¼ left ventricular; MRI ¼ magnetic resonance imaging; N/A ¼ not applicable; VO2 ¼ oxygen consumption; other abbreviations as in Table 1.

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with diabetes with known cardiovascular disease(35,36). Two HF prevention trials using natriureticpeptide screening of patients with clinical cardiovas-cular risk factors to target cardiovascular specialistevaluation and management showed reduction innew systolic or diastolic dysfunction and HF (37)and HF (type unknown) incidence (38). HF guidelinesnow endorse use of natriuretic peptide assays totarget patients for HF prevention interventions (39).Assessing the impact of these types of preventiveinterventions on HFpEF versus HFrEF will be animportant endeavor moving forward.

Obesity, an important risk factor for HFpEF, mayrepresent another target for prevention and/or treat-ment. In 1 center’s experience, several novel mecha-nistic differences in obese versus nonobese HFpEFpatients were demonstrated, suggesting the potentialfor obesity-specific therapies in this large HFpEFsubgroup (16).Subpopulat ion : pu lmonary vascu lar d isease .Many HFpEF patients have PH (40,41), which isassociated with increased symptom burden, hospi-talizations, and mortality (42,43) and unique histo-pathology (44). A subgroup analysis of an implantablepulmonary artery pressure monitor for patients with

HF demonstrated that pulmonary artery pressure–guided HF therapy was associated with improve-ments in hemodynamics and the composite endpointof HF hospitalization/death in HFpEF (45). Thesmaller cohort of patients with HFpEF and combinedpre- and post-capillary PH (Table 3) is receivingincreasing attention as a possible population tobenefit from pulmonary vasodilator therapy (43,46).Nonetheless, this enthusiasm is tempered by cautionrelated to inducing pulmonary edema in patients withsignificant pulmonary venous hypertension, andprior negative trial results of pulmonary vasodilatorsin HF populations (47). However, the RELAX (Phos-phodiesterase-5 Inhibition to Improve Clinical Statusand Exercise Capacity in Diastolic Heart Failure)study did not specifically target HFpEF PH, and pul-monary pressures were not invasively measured. Asmaller randomized trial of sildenafil in patients withHFpEF PH reported improvements in right heartfunction (48), which is the central determinant of PHoutcomes, but, these right heart function improve-ments could not be confirmed in subsequenttrials (49,50).

Although routine use of pulmonary arterial hy-pertension (PAH) therapies is not recommended, the

TABLE 3 Hemodynamic Distinction Within Pulmonary Hypertension as Pre-Capillary, Isolated Post-Capillary, or Combined Pre- and Post-Capillary Has

Important Implications for Management

PH Subgroup mPAP PCWP PVR Other Therapeutic Targets Clinical Trial Implications

Pre-capillary PH

Typical PAH $25 mm Hg #15 mm Hg >3 Wood units PH; right ventricle

Atypical PAH $25 mm Hg #15 mm Hg >3 Wood units With multiple risk factorsfor left heart disease*or elevation in PCWPexclusively duringstress

PH; right ventricle;consider HFpEF

Growing population; morediscriminatory tools/phenotyping neededbecause PAH and HFpEFsymptoms overlap

Isolated post-capillary PH

$25 mm Hg >15 mm Hg #3 Wood units Some may have PCWPelevation duringstress

HFpEF

Combined pre- andpost-capillary PH

$25 mm Hg >15 mm Hg >3 Wood units HFpEF; right ventricle;consider PH

Ongoing studies to evaluatePH treatment; may havea differentpathophysiology frompre-capillary; carefulphenotyping needed

*Risk factors include coronary artery disease, hypertension, diabetes/metabolic syndrome, obesity, and atrial fibrillation.mPAP ¼ mean pulmonary artery pressure; PAH ¼ pulmonary arterial hypertension; PCWP ¼ pulmonary capillary wedge pressure; PH ¼ pulmonary hypertension; PVR ¼ pulmonary vascular

resistance; other abbreviations as in Table 1.

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question of pulmonary vasodilator use in a subsetof the HFpEF PH population remains open(42,47,51). Furthermore, registry data and clinicaltrial demographics over the last several years sug-gest that the overall PAH population is getting olderwith more comorbidities (52–54). Sometimesreferred to as having “atypical PAH,” a subgroup ofpatients meeting hemodynamic criteria for PAH(including a low pulmonary capillary wedge pres-sure) with $3 cardiovascular risk factors were foundto resemble HFpEF PH patients phenotypically, butexhibited response to PAH therapies, which sug-gests that treatment response may not beadequately defined by traditional categorical di-visions (31). Methods for provocative testing to riskstratify and identify responders, including volumechallenge and exercise testing in the catheterizationlaboratory, may help delineate patients in this grayarea (42). Additionally, clinical trials are ongoing,testing inhaled b-adrenergic agonists (Inhaled Beta-adrenergic Agonists to Treat Pulmonary VascularDisease in Heart Failure With Preserved EF [BEATHFpEF]; NCT02885636), oral endothelin antagonists(A Study to Evaluate Whether Macitentan is anEffective and Safe Treatment for PatientsWith Heart Failure With Preserved Ejection Fractionand Pulmonary Vascular Disease [SERENADE];NCT03153111), and oral prostanoids (Study of OralTreprostinil in Subjects With Pulmonary Hyperten-sion Associated With Heart Failure With PreservedEjection Fraction [SOUTHPAW]; NCT03043651) inpatients with HFpEF and pulmonary vasculardisease.

Subpopulat ion: e levated lef t at r ia l pressure . Amechanical intervention to unload the left atrium viacreation of an interatrial shunt with a device tostandardize the shunt size has been shown to reduceexercise pulmonary capillary wedge pressure at 1month in a phase 2 trial, and further testing isongoing (55). Treatment with intravenous, inhaled, ororal inorganic nitrite or nitrate has also been shown toimprove exercise capacity and/or reduce pulmonarycapillary wedge pressure in early single-centerstudies, but the recent INDIE-HFpEF (Inorganic Ni-trite Delivery to Improve Exercise Capacity in HFpEF;NCT02742129) trial did not show benefit of inhaledinorganic nitrite on peak oxygen consumption. Morestudies using a variety of inorganic nitrite/nitrateformulations are ongoing.

SHOULD HFpEF TRIALS USE

QUALITY-OF-LIFE METRICS AS

MAIN ENDPOINTS?

Changes in quality of life (QOL) and functional ca-pacity in patients living with chronic diseases areoften overlooked or underemphasized as importantendpoints (56). These measures, although not neces-sarily correlated with morbidity and mortality, maybe particularly relevant for HFpEF, which oftenmanifests in advanced age, reducing exercise toler-ance and causing dyspnea, thereby pervading all as-pects of daily life by impairing function andindependence, 2 things that are commonly importantto older adults. Given that HFpEF studies have notachieved morbidity/mortality endpoints in any trial

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to date, we must consider whether focusing on end-points related to functional or symptom improve-ment may improve QOL outcomes; this wouldrepresent a paradigm shift. Both perspectives areexplored next.

NO, MORBIDITY AND MORTALITY SHOULD REMAIN

PRIMARY TARGETS OF HFpEF TRIALS. Survival andhospitalizations are the key endpoints that havedriven drug development in HFrEF and offer directrelevance to patients, health systems, and payers.They currently represent the standard in assess-ment of HFrEF interventions. For these reasons, thevalue placed on improvements in exercise toleranceand QOL, unaccompanied by morbidity/mortalitybenefits, can seem less significant when contrastedwith established benefits of standard HFrEFtherapies.

YES, HFpEF STUDIES SHOULD FOCUS ON QOL AND

EXERCISE ENDPOINTS. Preventing morbidity andmortality is the most critical goal for providerswhen considering the best HFpEF treatment for anindividual patient; however, HFpEF patients’ pri-mary focus is often finding ways to be less limitedby increasing their own functional capacity. TheNEAT-HFpEF (Nitrate’s Effect on Activity Tolerancein Heart Failure with Preserved Ejection Fraction)study of isosorbide mononitrate demonstrated thatemployment of novel methods to measure dailyactivity is not only feasible but is correlated withother measures of HF severity (57). Changes in ac-tivity measures were not associated with changes in6-min-walk distance or Kansas City CardiomyopathyQuestionnaire results (57,58), perhaps because ofdecreased sensitivity of the changes in standardassessments to deterioration or improvement.Nevertheless, patient-centric endpoints are beingused in increasing numbers of HFpEF trials. From astudy design perspective, QOL/exercise primaryendpoints may be helpful, as the increased non-cardiovascular comorbid burden and older age ofHFpEF patients compared with the HFrEF popula-tion presents greater challenges in showing thera-peutic efficacy and assessing cardiovascularmortality (59).

However, payers may not be willing to coverexpensive drugs and devices for QOL indications.This represents a challenge to both industry and in-vestigators and may be a limiting influence on clinicaltrial design considerations.

Beyond the previously mentioned subphenotypes,given the heterogeneity of HFpEF presentations andlikely biologic pathways, the interventions that may

benefit this growing patient population may vary indelivery (e.g., mechanical devices, inhaled therapy,lifestyle modification, activity tracking) and desiredeffect. Investigators could ideally select differentcategories of endpoints targeting different patientpresentations and goals. For example, exercise-limited and primarily dyspneic HFpEF patients maynot decompensate in a way that would require hos-pitalization, but they may benefit from an increase inwalking distance and functional capacity. Other pa-tients may have more difficulty with volume status/redistribution and benefit from interventions to pre-vent or address volume overload and frequent hos-pitalizations. To refine endpoints and increase therelevancy of findings, we believe it is necessary todevelop more sophisticated clinical phenotyping andtarget testing of interventions to the goals of patientsin subphenotypes.

CONCLUSIONS

In this summary of current controversies in HFpEF,we outline the findings from our Think Tank meeting,which was an expert panel discussion on existingevidence, persistent controversies, and gaps inHFpEF care. We approach critical HFpEF issues froma variety of perspectives. The HFpEF controversiesexplored throughout this paper are interrelated andcodependent and but serve to highlight gaps andopportunities in the field. The design of meaningfulHFpEF research should involve the full scope ofstakeholders, including investigators, regulators, in-dustry, and payers, and must consider the lessonslearned thus far to understand how future trials andobservational studies will close critical knowledgegaps and lead to optimal care for the patient withHFpEF.

ACKNOWLEDGMENTS The authors thank all ThinkTank participants for their ideas and unique per-spectives shared at the Think Tank meeting.Furthermore, the authors specifically acknowledgeBishow Adhikari, Javed Butler, Julie Catini, MathewMaurer, Gail Pearson, Matthew Roe, Lothar Roessig,Leo Seman, and Robert Temple for their contributionsat the meeting, and for providing feedback andeditorial recommendations for this manuscript. Theauthors also acknowledge Erin Campbell and MorganDeblecourt for their editorial contributions.

ADDRESS FOR CORRESPONDENCE: Dr. Kishan S.Parikh, Duke Clinical Research Institute, PO Box17969, Durham, North Carolina 27715. E-mail: kishan.parikh@duke.edu.

PERSPECTIVES

COMPETENCY IN MEDICAL KNOWLEDGE: The

number of persons with HF in the United States has

continued to rise; approximately one-half of these

patients have HFpEF, which is not well understood.

Central to developing an improved understanding of

HFpEF is the determination as to whether this condition is

caused by a single disease state or multiple diseases

characterized by unique underlying pathophysiological

mechanisms.

TRANSLATIONAL OUTLOOK: The design of mean-

ingful HFpEF research should involve the full scope of

stakeholders, including investigators, regulators, indus-

try, and payers, and must consider the lessons learned

thus far to understand how future trials and observational

studies will close critical knowledge gaps and lead to

optimal care for the patient with HFpEF.

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KEY WORDS classification scheme,diagnosis, diastolic, ejection fraction,endpoints, heart failure, pathophysiology,preserved ejection fraction, pulmonaryhypertension, subject eligibility, treatment

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