Clinical outcome endpoints in hf trials

REVIEW

Clinical outcome endpoints in heart failure trials:a European Society of Cardiology Heart FailureAssociation consensus documentFaiez Zannad1*, Angeles Alonso Garcia2, Stefan D. Anker3, Paul W. Armstrong4,Gonzalo Calvo5, John G.F. Cleland6, Jay N. Cohn7, Kenneth Dickstein8,Michael J. Domanski9, Inger Ekman10, Gerasimos S. Filippatos11, Mihai Gheorghiade12,Adrian F. Hernandez13, Tiny Jaarsma14, Joerg Koglin15, Marvin Konstam16,Stuart Kupfer17, Aldo P. Maggioni18, Alexandre Mebazaa19, Marco Metra20,Christina Nowack21, Burkert Pieske22, Ileana L. Pina23, Stuart J. Pocock24,Piotr Ponikowski25, Giuseppe Rosano26, Luis M. Ruilope27, Frank Ruschitzka28,Thomas Severin29, Scott Solomon30, Kenneth Stein31, Norman L. Stockbridge32,Wendy Gattis Stough33, Karl Swedberg34, Luigi Tavazzi35, Adriaan A. Voors36,Scott M. Wasserman37, Holger Woehrle38, Andrew Zalewski39 and John J.V. McMurray40

1INSERM, Centre d’Investigation Clinique 9501 and Unite 961, Centre Hospitalier Universitaire, and the Department of Cardiology, Nancy University, Universite de Lorraine, Nancy,France; 2Scientific Advice Working Party European Medicines Agency, Madrid, Spain; 3Applied Cachexia Research, Department of Cardiology, Charite Medical School, Campus Virchow-Klinikum, Berlin, Germany; 4University of Alberta, Edmonton, Canada; 5Hospital Clinic of Barcelona, Barcelona, Spain; 6Department of Cardiology, Castle Hill Hospital, Kingston-upon-Hull, UK; 7Cardiovascular Division, University of Minnesota, Minneapolis, MN, USA; 8University of Bergen, Stavanger University Hospital, Norway; 9Cardiovascular Institute, Mount SinaiSchool of Medicine, New York, NY, USA; 10Sahlgrenska Academy, Gothenburg University; Centre for Person Centred Care Research (GPCC), Gothenburg, Sweden; 11Athens UniversityHospital Attikon, Athens, Greece; 12Center forCardiovascular Innovation, NorthwesternUniversity Feinberg Schoolof Medicine, Chicago, IL, USA; 13DukeUniversity MedicalCenterandDuke Clinical Research Institute, Durham, NC, USA; 14Department of Social and Welfare Studies, University of Linkoping, Sweden; 15Merck, Sharpe & Dohme Corporation, WhitehouseStation, NJ, USA; 16Department of Cardiology, New England Medical Center, Tufts University, Boston, MA, USA; 17Takeda Pharmaceuticals, Deerfield, IL, USA; 18ANMCO ResearchCenter, Florence, Italy; 19Department of Anesthesia, Hopital Lariboisiere, Paris, France; 20Cardiology, University of Brescia, Brescia, Italy; 21Bayer Pharma AG, Wuppertal, Germany;22Department of Cardiology, Medical University of Graz, Graz, Austria; 23Department of Medicine, Division of Cardiology, Montefiore Medical Center, Bronx, NY, USA; 24Department ofMedical Statistics, London School of Hygiene and Tropical Medicine, London, UK; 25Medical University, Military Hospital, Wroclaw, Poland; 26Department of Medical Sciences, IRCCS SanRaffaele Hospital, Rome, Italy; 27Hypertension Unit, Hospital 12 de Octubre, Madrid, Spain; 28University Hospital Zurich, Zurich, Switzerland; 29Novartis Pharma AG, Basel, Switzerland;30Cardiovascular Division, Brighamand Women’sHospital, Boston,MA, USA; 31BostonScientificCorporation, St. Paul,MN, USA; 32Division of Cardiovascular and Renal Products, Centerfor Drug Evaluation and Research, Food and Drug Administration, Rockville, MD, USA; 33Campbell University College of Pharmacy and Health Sciences, Buies Creek, NC, USA;34Sahlgrenska University, Hospital/Ostra, Goteborg, Sweden; 35GVM Hospitals of Care and Research, Villa Maria Cecilia Hospital, Cotignola, Italy; 36Thoraxcenter, Department ofCardiology, University Medical Center, Groningen, Groningen, The Netherlands; 37Amgen, Inc., Thousand Oaks, CA, USA; 38ResMed, Ulm, Germany; 39Novartis PharmaceuticalsCorporation, East Hanover, NJ, USA and 40Western Infirmary and the British Heart Foundation, Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK

Received 26 December 2012; revised 26 April 2013; accepted 3 May 2013; online publish-ahead-of-print 19 June 2013

Endpoint selection is a critically important step in clinical trial design. It poses major challenges for investigators, regulators, and study sponsors,and it also has important clinical and practical implications for physicians and patients. Clinical outcomes of interest in heart failure trials include all-cause mortality, cause-specific mortality, relevant non-fatal morbidity (e.g. all-cause and cause-specific hospitalization), composites capturingboth morbidity and mortality, safety, symptoms, functional capacity, and patient-reported outcomes. Each of these endpoints has strengthsand weaknesses that create controversies regarding which is most appropriate in terms of clinical importance, sensitivity, reliability, and consist-ency. Not surprisingly, a lack of consensus exists within the scientific community regarding the optimal endpoint(s) for both acute and chronicheart failure trials. In an effort to address these issues, the Heart Failure Association of the European Society of Cardiology (HFA-ESC) conveneda group of expert heart failure clinical investigators, biostatisticians, regulators, and pharmaceutical industry scientists (Nice, France, 12–13February 2012) to evaluate the challenges of defining heart failure endpoints in clinical trials and to develop a consensus framework. Thisreport summarizes the group’s recommendations for achieving common views on heart failure endpoints in clinical trials.- - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -Keywords Heart failure † Morbidity † Mortality † Clinical trials

* Corresponding author. CIC INSERM CHU, Hopital Jeanne d’ Arc, 54200 Toul, France. Tel: +33 383 65 66 25, Fax: +33 383 65 66 19, Email: [email protected]

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected].

European Journal of Heart Failure (2013) 15, 1082–1094doi:10.1093/eurjhf/hft095

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Introduction

Endpoint selection is one of the most critical components of clinicaltrial design. Large pivotal heart failure trials are designed to providerobust evidence that may support regulatory approval, extensionof indications, consolidation or rejection of therapeutic strategies,and reimbursement claims. Thus, the efficacy endpoints for thesestudies usually reflect total and/or cause-specific mortality, morbidity,or clinician-interpreted (NYHA class) or patient-reported outcomes[Minnesota Living With Heart Failure Questionnaire (MLWHFQ)or dyspnoea], either alone or in combination (Figure 1A and B).1 Mea-sures of functional status may be used as endpoints, and they may beadequate for regulatory authorities to be approved for treatment,provided there are sufficient safety data. More than one trial replicat-ing an effect on functional outcomes may be required for regulatoryapproval. However, endpoints that measure functional status (e.g.exercise tolerance oroxygen consumption) or reflect manifestationsofdiseasepathophysiology (e.g. biomarkersor remodelling variables)are typically applied in earlier phases of drug or device developmentto support proof-of-concept, demonstrate dose responsiveness,and/or provide preliminary evidence of safety and efficacy. Mortalityand morbidity endpoints for pivotal trials are the primary focus of thispaper.

The therapeutic agent under investigation should have a mechan-istically plausible effect on the chosen primary endpoint. The primaryendpoint must be clinically relevant, important to both patients andhealthcare providers, measurable, and responsive to therapeuticinterventions such that it distinguishesbetweeneffectiveand ineffect-ive therapies. It should be robust, with minimal bias or other con-founding factors. The choice of endpoint is further influenced bythe target patient population (e.g. acute vs. chronic heart failure)and treatment objective (e.g. reduction of morbidity and/or mortalityvs. symptomatic improvement) (Figure 1A and B).1 The primary effi-cacy endpoint is a key determinant of sample size estimates, sincethese are determined by the expected event rate of the endpoint,its variability, and the expected effect size over standard care.Consensus has not been reached on the optimal phase III endpointsin acute or chronic heart failure trials, but this topic is a centralpriority as evidenced by the attention it has received in the medicalliterature.2 –7

The Heart Failure Association of the European Society of Cardi-ology (HFA-ESC) convened a group of expert heart failure clinicaltrialists, biostatisticians, regulators, and pharmaceutical industryscientists (Nice, France, 12–13 February 2012) to evaluate the chal-lenges of defining heart failure endpoints in clinical trials and todevelop a consensus framework. This report summarizes thegroup’s recommendations for moving towards consensus (Table 1),and it identifies areas of uncertainty where more research isneeded (Table 2).

Specific endpoints used in phase IIIheart failure clinical trialsHeart failure is a syndromewith awide spectrumranging fromasymp-tomatic LV dysfunction to end-stage heart failure. Within this spec-trum, patients may either have heart failure with reduced ejection

fraction (HF-REF) or heart failure with preserved ejection fraction(HF-PEF). They may also oscillate between periods of stability,where they are generally managed well as outpatients (i.e. chronicheart failure), and periods of decompensation requiring hospitaliza-tion [i.e. hospitalized heart failureoracuteheart failure (AHF)]. Selec-tion of the appropriate endpoint should take into account the uniquedifferences (e.g. expected event rates) within these subsets of heartfailure. For the purposes of this paper, endpoints are discussed withinthe general context of heart failure. Where relevant, considerationsthat are important for trials targeting a specific heart failure subset arealso provided.

Mortality endpointsAll-cause death vs. cause-specific deathNo drug can be expected to affect all causes of death (or hospitaliza-tion); rather, a treatment may reduce all-cause mortality by reducingthe major cause or causes of death. The choice between all-cause

Figure 1 Schematic of potential endpoints for phase III pivotalchronic heart failure trials (A) or acute heart failure trials (B). Thehierarchy (or order ranking) of the endpoint options to measure ef-ficacy is not definitive. Different hierarchies may be appropriate de-pending on the endpoint’s relevance to a specific patientpopulation, the ability to measure the endpoint objectively in agiven study, and the possibility of standardizing the endpoint meas-urement through accurate and reliable instruments. CV, cardiovas-cular; HF, heart failure; HRQOL, health-related quality of life.

Clinical outcome endpoints in heart failure trials 1083

events and cause-specific events depends on whether the objective isonly to reflect the benefit of the drug, in which case the endpointshould be as specific as expectations permit, or if the objective is toreflect net benefit, in which case a non-specific (i.e. all-cause) endpoint

clearly shows that the benefit is not obscured by adverse effects ornoise fromcompletely unrelated events.All-causeendpoints, especial-ly all-cause mortality, should reduce bias in unblinded trials. For otherendpoints, a blinded endpoint adjudication committee is key in all

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Table 1 Areas of consensus among heart failure experts

Endpoint Consensus

Mortality endpoints (1) Overall mortality should be captured, an adverse effect on all-cause mortality reasonably ruled out, and a trend tobenefit in all-cause mortality should be observed.

(2) Cause-specific death should be reported to extend the understanding of pathophysiology and to improve targetedtreatment.

(3) Cardiovascular mortality is preferred.(4) Additional analyses should be performed for situations where cardiovascular mortality is reduced but total mortality is

not, to determine if non-cardiovascular mortality is increased, or if the study was underpowered to detect an effect ontotal mortality, or if the event rate or treatment effect was too low to be clinically meaningful.

Heart failure hospitalization (1) Heart failure hospitalization is not a surrogate for overall mortality.(2) A consistent definition for heart failure hospitalization should be implemented across clinical trials. The definitions

chosen should specifically focus on identifying the clinical presentation of interest while minimizing the impact ofvariations in patient or clinician threshold for admission, length of stay, or other external factors that may influence thedecision to hospitalize a patient.

(3) Accurate adjudication of cause-specific hospitalization is difficult. Hospitalizations in a patient with heart failure can beprecipitated by a variety of factors, and their relative importance as a cause of hospitalization can be hard to detect.

(4) Natriuretic peptide values, where available, may be useful to evaluate the likelihood of heart failure as a cause ofhospitalization. Elevated natriuretic peptide values are inadequate as the sole criterion to define a heart failurehospitalization because of its lack of specificity.

Recurrent morbid eventendpoints

(1) Repeat hospitalizations should be considered in future clinical trial endpoints, as the appropriate methods for analysiscontinues to be developed and refined.

(2) Investigators should consider including the win ratio method as a planned supplementary analysis in conjunction withexisting standard analytical methods so that additional experience with the win ratio method can be accrued.

Endpoints other thanhospitalization

(1) More research is needed to develop robust methods for capturing heart failure events other than hospitalization ordeath.

(2) Careful consideration needs to be given to defining these events to avoid capturing non-heart failure events.

Symptomandpatient-reportedhealth outcomes

(1) Dyspnoea is an important outcome to measure in clinical trials focusing on acute heart failure.(2) Consistent measures (e.g. instruments) and standardized methods (e.g. sitting vs. supine, or specifying degree of head

elevation for orthopnoea evaluation) of dyspnoea assessment need to be developed, adopted, and used consistentlywithin the heart failure research community.

(3) Repeated assessments of dyspnoea provide more information and are more relevant to patients than measurement at asingle time point. Trials should integratemeasurements of the severityof dyspnoea over time as an endpoint.10,70,110,111

(4) Patient-reported outcomes are independent endpoints, not surrogates for mortality.(5) Unless the regulatory environment changes and assessment instruments improve, it is unlikely that patient-reported

outcome endpoints (quality of life) will be acceptable as the only basis for approval.(6) Other patient-reported outcomes focusing on symptoms in acute heart failure (e.g. dyspnoea) may be acceptable for

approval, provided safety is adequately demonstrated.(7) Instruments should be self-administered when possible. When patients are unable to self-administer, the instruments

should be administered by personnel not involved with the clinical trial or who are blinded to clinical and trial data tominimize bias.

Clinical composite endpoints (1) Multiple components should not be added to compositesonly for the purpose of enriching the event rate, particularly ifcompelling evidence is lacking to suggest the treatment will influence the components similarly.

(2) Individual components of the composite should be reported separately to allow for observation of divergent effects orsituations where one component drives the overall composite.

(3) Components of a unconventional composite endpoint should have a predictable (reproducible) response to thetreatment.

Safety endpoints (1) When mortality is not the primary or secondary efficacy endpoint, the study must still be powered to provide areasonable estimate of the safety margin.

(2) Renal function as a safety measure is challenging. Increasing serum creatinine is not always negatively predictive ofoutcome, particularly in the setting of ACE inhibitors, ARBs, or mineralocorticoid receptor antagonists.

F. Zanaad et al.1084

unblinded trials. Both total death and cause-specific death areimportant to quantify in chronic and acute heart failure trials toachieve a comprehensive evaluation of safety, efficacy, and healtheconomics.

Recent evidence suggests that non-cardiovascular deaths are in-creasing among patients with heart failure, particularly in somesubsets such as patients with HF-PEF.8 Therefore, cardiovasculardeath is a more efficient endpoint than all-cause mortality if non-cardiovascular death is expected to account for a substantialportion of deaths accrued in a trial, and if the effect of the therapyon non-cardiovascular mortality is expected to be neutral. Other-wise, if all-cause mortality is the primary endpoint, sample sizes willneed to be increasingly large to account for the ‘random noise’added by non-cardiovascular deaths.9 Even when a primary endpointof cause-specific mortality is significantly reduced by an intervention,total mortality and non-cardiovascular deaths should be included askey safety endpoints to capture potential adverse effects. A direc-tionally similar decrease in overall mortality (even if not statisticallysignificant) should be demonstrated without an adverse increase innon-cardiovascular deaths. In acute heart failure trials, althoughlong-term event rates are high, it may be difficult to demonstrate ef-ficacy on a mortality endpoint since acute therapies primarily targetsymptoms and are administered for a short duration. Thus, employ-ing total mortality as a key safety measure may be more appropriatethan as a measure of efficacy in acute heart failure trials. It has beenhypothesized that a short-term therapy could reduce long-termmortality if it ameliorated acute myocardial injury that may occurin the setting of worsening heart failure (similar to thrombolysisin acute coronary syndrome), but such an effect has not beendemonstrated to date. Certainly the results of the RELAXinAcute Heart Failure (RELAX-AHF) trial10 suggest that such apossibility exists, although the mechanisms of intermediate-term(6 months) benefits after a short-term (48 h) serelaxin administra-tion are yet to be understood.10

Adjudication of cause-specific deathAlthough endpoints of cause-specific death or hospitalization areoften evaluated by adjudication of protocol-specified definitions bya committee with the appropriate range of clinical and statisticalexpertise, it has been questioned whether adjudication adds valuein cardiovascular trials.11,12 The site investigator often has access tomore information than is captured on the case report forms. If thestudy is unblinded (by design or treatment effects) or the site inves-tigators (or study personnel) lack expertise to adjudicate outcomes,adjudication may reduce noise by applying event definitions consist-ently and should be performed; otherwise, the benefit of adjudicationis less clear, even when site-reported and adjudicated results differ.Adjudication is also expensive, reducing the resources that otherwisemight contribute to a more robust (larger) study or to exploringmore than one dose. Despite these limitations, data suggest thatclinical event adjudication improves the precision of classifying eventsin a clinical trial.13–18 Hence, the need for adjudication remainsunresolved (Table 2).

The mode of death in patients with heart failure is frequently difficultto determine. It is commonly agreed that heart failure deaths may followprogressive symptomaticworsening (‘pump failuredeath’)oroccur sud-denly (‘sudden cardiac death’). Sudden death is the primary cause ofdeath for the majority of patients with mild to moderate heart failure;pump failure death is more common among patients with advancedsymptoms.9,19–22 The determination of the cause of death in patientsfound dead is problematic, and it is debated whether these should becategorized as ‘unknown’ or ‘presumed cardiovascular’. Attributing‘unknown’ cause of death to a specific cause (e.g. defaulting to suddendeath or presumed cardiovascular death) is problematic when thereare insufficient data and may explain why, in some trials, the numbersof sudden deaths and/or cardiovascular deaths may be overestimated.However, where a patient has had no recent contact with medical ser-vices, hasnoobviouscauseofdeath (e.g.metastatic cancer), and is founddead at home, then this provides strong circumstantial evidence of

Table 2 Areas of need for future research

Recurrent morbid eventendpoints

(1) The best analytic methods to handle multiple events need to be determined.

Non-hospitalization endpoints (1) Strategies to reduce variability in the detection of these events.(2) Assessment as to whether adjudication adds value and precision to the detection of events.(3) Determining whether non-hospitalization endpoints are valid (i.e. predict outcome) and robust.(4) Novel analytic techniques for events of lesser severity or of lower prognostic value.57–59

(5) Evaluation of value and feasibility of adjudicating implantable cardioverter defibrillator firing.

Symptoms and patient-reportedhealth outcomes

(1) Validation of combining subjective dyspnoea assessments with objective measures such as pulmonary function.(2) Development of simpler instruments sensitive to changes in health status over time.(3) Development of validated and individualized patient-reported outcome assessments.

Clinical composite endpoints (1) Improved methods for weighting the relative importance of the individual components of composite endpoints.

Safety endpoints (1) Establishing consensus on the level of excess mortality over time required for concluding drug safety.(2) Development of new biomarkers to detect meaningful acute renal and liver injury.(3) Pre-specified hospitalization for renal failure should be considered for inclusion as part of the assessment of renal

failure.112

(4) Evaluating the relationship between impaired renal function and clinical outcomes.


sudden death. Place of death should be reported more often in trials aswell as the events and patient status in the month prior to death.23

Morbidity and clinical compositeendpointsHeart failure hospitalizationHospitalization for heart failure is clinically meaningful to patients,physicians, and regulators, and it correlates with disease progressionand prognosis. Hospitalizations are relevant to payers because theycreate the majority of the health economic burden of heartfailure.24– 29

Despite the clinical relevance of hospitalizations for heart failure,its use as an endpoint in heart failure trials must take into accountsome limitations. The decision to hospitalize a patient with heartfailure is often based on subjective criteria. The threshold for hospi-talization is highly variable across (and within) regions of the world,which may affect the interpretability and applicability of studyresults in specific regions, particularly in global trials.30 As modelsof healthcare delivery evolve in response to economic pressures,care for many patients may shift from the hospital setting to shortstay or observational unit settings, or patients may be treated withi.v. therapies in outpatient heart failure clinics,31,32 and this is recog-nized as part of the Standardized Data Collection for CardiovascularTrial Initiative definition.33 The decision to hospitalize can also bedriven by external factors unrelated to the patient’s clinical status(e.g. local availability of hospital facilities, day of the week or time ofday the patient presents, or physician and patient local attitudesand traditions).

Local standards of care (such as length of stay or availability ofout-of-hospital treatment resources) may differ in a clinical trial.The mean length of stay ranges from 6 to .10 days in Europe,�21 days in Japan, and 4–6 days in the USA.34– 40 Length of staycan also be influenced by non-clinical factors, such as provider staff-ing.41 For studies where patients are enrolled during a hospitalization,the length of the index admission influences the time available toaccrue subsequent hospitalization events. Patients (or regions) with along index length of stay may have lower rates of re-hospitalizationduring follow-up, thus confounding the interpretation of the hospital-ization endpoint. Showing a consistent effect on the rate of HF hospi-talization across geographical regions strengthens the results of anytrial. Stratifying enrolment by region is one approach that maybalance the standard of care within regions across treatment arms.

Worsening heart failure symptoms and signs during the indexhospitalization (.24 h after study drug initiation through to dis-charge or 7 days) may be used as a component of the primarycomposite endpoint.10,42 In RELAX-AHF, this component was oneof the most favourably affected by serelaxin treatment, comparedwith placebo.10 This approach may capture important non-fatalevents that occur prior to discharge from an index hospitalization.However, adjudication of such events can be difficult, and specificcriteria must be pre-defined to ensure that the events are capturedconsistently across sites.

Defining heart failure hospitalizationsHeart failure hospitalizations have been inconsistently defined acrossclinical trials.43 This practice limits the ability to interpretdata andgain

an in-depth understanding of treatmenteffects across trials. Harmon-izing definitions for heart failure hospitalization endpoints would beuseful to achieve consistency similar to that achieved with myocardialinfarction, and it minimizes the influence of external factors (culturalor societal practices).44 Progression towards adopting specific cri-teria that define a heart failure hospitalization or equivalent event isimperative. Efforts are under way to standardize endpoint events incardiovascular trials, including heart failure hospitalizations.33 Mean-while, this group has reached specific recommendations (Table 3).These criteria may help to differentiate a heart failure hospitalizationfrom a non-heart failure hospitalization (e.g. AF where BNP is oftenelevated).

Recurrent morbid eventsRecurrenthospitalizations are acommon occurrence in patients withheart failure, and they impose a substantial clinical and economicburden on patients, caregivers, physicians, and health systems.Despite their importance, repeat events are ignored in the majorityof clinical trials in favour of ‘time to first event’ analyses.45 Theprimary ‘time to first event’ analysis in the Eplerenone in Mild PatientsHospitalization and Survival Study in Heart Failure (EMPHASIS-HF)did not consider second or subsequent heart failure hospitalizations,but these accounted for 42% of the total admissions for heart failurein the placebo group.46 In CHARM-Preserved, only 53% of heartfailure hospitalizations and 57% of cardiovascular deaths wereincluded in the primary conventional analysis. Methodologiesaccounting for repeat events that are clinically meaningful to patientsand physicians may both achieve practical gains (e.g. increased statis-tical power with smaller sample sizes due to highernumberof events)and better characterize and quantify the patient’s journey throughoutthe follow-up period.47 For instance, analyses using recurrent eventsincrease statistical power substantially, which could potentially halvethe sample size compared with conventional time to first event ana-lyses.48 Several limitations of this approach warrant consideration,including the influence of variations in standard practice patternsacross the world (see above), event clustering in a small proportionof patients, and confounders related to mortality differences in thosepatients who are hospitalized vs. patients who are not.46 Regulatoryauthorities seem to be willing to consider their use as a primaryendpoint in future heart failure trials.

The ‘days alive and out of hospital’ endpoint incorporates the com-ponents of days in hospital (including days of the index hospitalizationand repeat hospitalizations), days alive and not in hospital, and daysdead into a single measure over a defined time frame (e.g. 30 or 60days). This endpoint was developed to address the issue of repeathospitalizations for all causes, but it is limited in its ability to weightthe relative importance of deaths vs. repeat hospitalizations.49

With this approach, early deaths carry much greater weight than mul-tiple recurrent hospitalizations followed by death very late in follow-up. The ‘patient journey’ concept creates a symptom-adjusted(and quality-adjusted if quality of life scores are collected) daysalive and out of the hospital endpoint.50,51 This proposal creates anew space for research and debate, with the potential added valueof information that might be useful to health economic interests.

A novel method has recently been proposed to overcome the lim-itations associated with time to event analyses: the ‘win ratio’.45 –47,52

Patients in the new and control treatment arms are formed into


matched pairs based on their risk profiles. Consider a primary com-posite endpoint, e.g. cardiovascular death and heart failure hospital-ization, in heart failure trials. For each matched pair, the studytreatment patient is labelled a ‘winner’ or a ‘loser’ if it is knownwho had a cardiovascular death first. If that is not known, they are la-belled as a ‘winner’ or ‘loser’ if it is known who had a heart failure hos-pitalization first. Otherwise, they are considered tied. The win ratio isthe total number of winners divided by the total number of losers. A95% confidence interval and P-value for the win ratio are readilyobtained. If formation of matched pairs is impractical, then an alterna-tive win ratio can be obtained by comparing all possible unmatchedpairs. This methodology places a greater emphasis on death, but itis still able to consider time in the analysis. Multiple hospitalizationscan also be considered in this approach. Experience with this ap-proach is still limited, and it will require further validation to gain regu-latory acceptance. Investigators should consider including the win ratiomethod as a planned supplementary analysis in conjunction with exist-ing standard analytic methods so that additional experience with thewin ratio method can be accrued.47 A consistent analytical strategyneeds to be agreed upon among clinical trial experts in the field.

Non-heart failure hospitalizationsDiagnoses other than heart failure (e.g. cardiac dysrhythmia or acutecoronary syndrome) are the primary reason formosthospitalizationsin patients with heart failure.53 Many cardiovascular (and non-cardiovascular) factors can exacerbate heart failure and lead to hos-pital admission.54 Cardiovascular conditions other than heart failurethat necessitate hospitalization may share many features (e.g. similarsymptoms or elevated BNP) with heart failure. It is often difficult toidentify the importance of heart failure as the reason for admissionor prolongation of hospitalization. A well-designed case reportform should record the importance of heart failure (e.g. primary, con-tributory, or non-contributory) both to admission and to length ofstay. When an endpoint of heart failure hospitalization is reducedby an intervention, it is important to document that this was notaccompanied by an increase in other admissions. A reduction in

all-cause hospitalization is even more reassuring. Hospitalizationscontribute to both safety and economic analyses.

Non-hospitalization endpointsWorsening heart failure without hospitalizationPatients are often treated for symptoms of worsening heart failure innon-hospital settings.26 Thus, focusing on heart failure hospitaliza-tions alone may fail to characterize the full spectrum of progressiveheart failure. The outpatient management of worsening heartfailure (in either the emergency department, observation units, orother outpatient settings) is expected to increase as the expectedgrowth in the heart failure population is realized and reimbursementmodels shift to encourage lower rates of hospitalization or penalize re-current admissions. Thus, the development of methods to capturethese ‘hospitalization equivalent’ events is warranted (Table 2).

Similar to the challenges described for hospitalization endpoints,treatment practices for worsening heart failure vary substantiallyamong individual physicians as well as regions of the world.30 Sincemost endpoints that capture worsening heart failure without hospi-talization require a treatment component to define the event, het-erogeneity in treatment practices creates substantial challenges forthe analysis and interpretation of such data. Although standard defi-nitions for heart failure requiring hospitalization33 and also forin-hospital worsening of heart failure55 have been proposed, theissue of worsening heart failure without hospitalization (or hospital-ization equivalent events) has not been addressed.

One concern with considering outpatient heart failure events isthat they may be less meaningful outcomes that increase the eventrate but dilute the treatment effect. However, data suggest that thepresence of non-hospitalization events still indicates a high risk popu-lation.56 If these events are used in a composite endpoint, weightingof the endpoints is key to avoid situations where the least importantelement drives the overall result and conclusion.57– 59

Although these events may be substantially important to the clin-ical course and prognosis of patients with heart failure, their use mayresult in an unacceptable lack of specificity linked to the uncertaindiagnosis, and they may be highly susceptible to observation bias.

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Table 3 Proposed definition for heart failure hospitalization

Category Definition

Heart failurehospitalization

A hospitalization requiring at least an overnight stay in-hospital caused by substantive worsening of heart failure symptoms(although, admittedly, the decision to admit a patient for worsening heart failure may vary subjectively across centres and more soacross various healthcare systems) and/or signs requiring the augmentation (an increase in the dose or frequency ofadministration) of oral medications or new administration of i.v. heart failure therapy, including inotropes, diuretics, orvasodilators, ideally pre-defined in the critical events manual.

aThe Standardized Data Collection for Cardiovascular Trials initiative defines heart failure hospitalization as an admission to aninpatient unit or a visit to an emergency department that results in at least a 24 h stay (or a date change if the time of admission/discharge is not available). The required duration of stay should be flexible depending on the population and drug profile understudy, AND at least one new or worsening clinical symptom of heart failure, AND at least two physical signs of heart failure,AND need for additional/increased therapy, AND no other non-cardiac or cardiac aetiology is identified.33

aThis definition was developed by the Standardized Data Collection for Cardiovascular Trials initiative, a working group of academicians, professional societies, Clinical DataInterchange Standards Consortium (CDISC), Health Level 7, Clinical Trials Transformation Initiative (CTTI), industry, and the Food and Drug Administration (FDA).While experts agree there is value in standardizing definitions, some experts are concerrned that the definition suggested by the Standardized Data Collection for CardiovascularTrials initiative is too restrictive and may result in low sensitivity to detect heart failure events (i.e. lower event rates), and potential loss of safety signals.


Adjudicating non-hospitalization heart failure events is one approachto address these problems, but it has not been widely used for thispurpose in clinical trials to date, and its utility remains uncertain. Itmay be difficult to determine the underlying cause of the event forpatients with a history of heart failure who present with dyspnoeain the setting of a recent respiratory illness (e.g. influenza or upper re-spiratory infection) or other concomitant medical condition. Adjudi-cation committees are limited by the documentation available tothem. If medical records are incomplete or lack sufficient detail,then the ability to determine the cause of the event precisely islimited. The physician caring for the patient may be better suited tomake the judgement of worsening heart failure in suchcircumstances.More experience is needed with non-hospitalized heart failure end-points before a conclusion can be drawn regarding the need, or lackthereof, for event adjudication.

Implantable cardioverter device shocksLife-threatening arrhythmia [ventricular tachycardia (VT) or ven-tricular fibrillation (VF)] is a potential endpoint that has not beenwidely used in clinical heart failure trials to date. Implantable cardio-verter defibrillators (ICDs) are indicated in many patients with heartfailure, and they act to terminate arrhythmias that would otherwisebe fatal. Using VT/VF as an endpoint was challenging prior to thewidespread use of ICDs, since most episodes were undocumented.Recent registry and clinical trial data from the USA suggest that� 40–50% of HF-REF patients have ICDs.60,61 In Europe, the rateof ICD use is widely variable across countries, but it is increasingamong most countries where data have been collected.62 Datafrom the EURObservational Research Program ESC-HF pilotshowed that 32.7% of patients with clinical characteristics suggestingthey had an indication for an ICD received the device.35

The availability of detailed information through device interroga-tion has renewed interest in considering VT/VF as an endpoint inheart failure trials for several reasons. Arrhythmic events competewith pump failure as the primary mode of death in patients withheart failure. ICDs prevent fatal arrhythmic death, which mayimpact the overall magnitudeof effect for anewtherapyon total mor-tality, particularly if the therapy is more likely to reduce arrhythmicevents than pump failure events. Additionally, many drugs havebeen found to be proarrhythmic, particularly in the heart failurepopulation. Such an effect might be missed if arrhythmic events arenot considered. Finally, VT/VF is a marker of worsening heartfailure and may be a useful indicator of heart failure progression.

Limitations exist to the use of VT/VF episodes as endpoints.Importantly, not all episodes of VT are life threatening. The frequencyof detected episodes depends on device programming, which differsacross patients. Devices can be programmed to terminate fast VT byantitachycardia pacing instead of shocks. This therapy is deliveredfaster than shocks, and it is possible that some episodes of VTtreated by antitachycardia pacing would not have required deliveryof a shock (i.e. they would have been non-sustained even if the deliv-ery of antitachycardia pacing were delayed).63 Inappropriate shocksoccur, and the available evidence suggests that device programmingcan greatly influence shock rates.64 In the Multicenter Automatic De-fibrillator Implantation II Trial (MADIT II), the likelihood of patientsexperiencing ≥1 inappropriate shocks was 13% after 2 years, and in-appropriate shocks accounted for 31.2% of all shock events.65

Inappropriate shocks were associated with increased all-cause mor-tality during follow-up.65 Other observational studies have shownsimilar results.66 Adjudication of shocks is mandatory for any clinicaltrial using such events as surrogates for fatal arrhythmias to minimizethe noise associated with inappropriate shocks. While the process isstrengthened by the availabilityof remote monitoring and stored ICDECGs, the quality of ECG recordings is generally poor and reviewerswould be limited by the lack of clinical documentation surroundingsuch events (e.g. symptoms or vital signs). Discordance amongreviewers may also be problematic in some scenarios.67 Finally, theglobal variation in ICD use limits the use of shocks as an endpointin international trials.68

Symptoms and patient-reportedoutcomesDyspnoeaDyspnoea is the most common symptom reported among patientspresenting with AHF,34,37,38,69– 71 and it has been widely adoptedas an endpoint in the majorityof AHF trials.2,72 Regulatory authoritiesmay approve a drug if it has a favourable impact on symptoms in theabsenceof anyadverse effectonoutcomes. However, dyspnoea as anendpoint is associated with several limitations. Dyspnoea respondswell to standard therapy in most patients. Most patients reportimprovement in dyspnoea by 6 h after initiation of standardtherapy.70,73 Early patient identification and rapid drug administrationmay be required to demonstrate advantages of a new therapy overexisting therapies. Clinical trials that require the presence of dys-pnoea for inclusion, but allow patients to be enrolled 24–48 h afteradmission, may capture patients with refractory dyspnoea who areunlikely to respond to therapy.

Patient presentation for worsening heart failure is often heteroge-neous. Dyspnoea may be due to volume overload, elevated pulmon-ary pressures, low cardiac output, deconditioning, co-morbidconditions, or some combination of these factors. Its baseline sever-ity is also variable among patients. In ASCEND-HF, specific clinicalvariables includingolder age, oedemaon chest radiograph, higher sys-tolic blood pressure, respiratory rate, and natriuretic peptide level,and lower blood urea nitrogen, sodium, and haemoglobin were pre-dictors of early dyspnoea improvement. In addition, substantial geo-graphic variation was noted in dyspnoea relief.74 This heterogeneitymakes it more difficult to demonstrate significant dyspnoea reduc-tions in the majority of patients.

The ability to detect changes in dyspnoea may depend on the scaleused to measure it or the patient’s position when it is assessed (i.e.supine vs. sitting), and an agreed method has not yet been adoptedor used consistently in clinical trials.70 Instruments used to assess dys-pnoea in clinical trials include 5- or 7-point Likert scales and visualanalogue scales (VAS). A Likert scale can be biased by patient recallof symptoms, the level of baseline symptom severity, or patientperception of administered treatments (if a study is unblinded). Inter-mediate levels of change (e.g. mild vs. moderate on a 7-point scale)may be difficult to differentiate given the large spontaneous variabilityin this measurement. On the other hand, some investigators proposethat the Likert scale is more easily understood by patients than theVAS. However, in RELAX-AHF, the VAS did detect treatmenteffect better than the Likert, in agreement with earlier observations


reported by Grant et al.75,76 One analysis showed that the 5-pointLikert scale and the VAS have a high degree of agreement in termsof assessing baseline dyspnoea (correlation coefficient 0.891) orchange in dyspnoea (correlation coefficient 0.8), whereas less agree-ment was observed between these instruments and the 7-pointLikert scale [correlation coefficient 0.512 (with the 5-point Likert)and 0.500 (with the VAS)].70 The VAS has been effective in detectingdyspnoea improvement in two recent trials, RELAXin Acute HeartFailure (RELAX-AHF)10 and Clevidipine in the Treatment of BloodPressure in Patients with Acute Heart Failure (PRONTO).77 Inthese and other studies,76 the VAS improved in the treatment armcompared with standard of care,while other dyspnoea measurementtools remained unchanged. In PRONTO, improvement in the VASwas evident within a few hours after clevidipine administration com-pared with the standard of care arm, although it should be noted thatitwas anopen-label trial anddyspnoea improvementwasa secondaryendpoint. Further studies are needed to confirm that the VAS is sen-sitive to detect small and/or early changes in dyspnoea and that thesechanges are clinically relevant. In the interim, using both scales in clin-ical trials will facilitate more validation research that might lead toevidence-based determination of the best scale for dyspnoea assess-ments. Importantly, symptoms must be measured on an absolutescale at baseline. Whether it is better then to measure change frombaseline by repeated measurement on an absolute scale or askingthe patient to report change is less clear. Analytical approachesalso differ across trials (e.g. change from baseline to a single timepoint, change from baseline to multiple time points, or area underthe curve). Consensus on the optimal analytic approach is desirableto achieve a common and consistent style of reporting across trialswhenever possible.

The clinical communityhasnot reachedagreementon the meaningof changes in dyspnoea scores and what constitutes an importantchange. The meaningful change must first be determined, then the in-cremental level of dyspnoea improvement (both degree of and timeto improvement) that a new therapy must demonstrate over stand-ard therapy to be considered cost-effective needs to be established.

Health status and patient-reported health outcomesQuality of life and patient-reported health outcomes, while tradition-ally viewed as ‘soft’ endpoints, provide insight into treatment effectsfrom the patient’s perspective.78 The therapeutic goal in heart failurepatients is not limited to prolonging survival; improving the quality oflife gained is equally important. The relativeweight given to these out-comes may vary substantially from patient to patient. Thus, patient-reported data from clinical trials are very useful to physicians strivingto inform their patients of the relative benefits and risks of specifictreatments. Patient-reported outcomes can be used to supportclaims;79 however, for new heart failure drugs, they are generallynot acceptable as the sole basis for approval because of the uncertainbenefit to risk ratio (i.e. what level of risk needs to be excluded toachieve net benefit on a symptom-based claim). Patient-reportedoutcomes, health-related quality of life endpoints, and cost-effectiveness endpoints are also relevant endpoints to include intrials because they are important to payers and society, and theycan impact the uptake of a therapy after regulatory approval, evenif regulatory approval was not based on these endpoints.

As with dyspnoea assessment, patient-reported health outcomeassessments are limited by adherence to instrument completionand patient recall, if the data are collected retrospectively. Real-timemeasurements may overcome these limitations, and employingmodern technology, such as smart phones, may be one way toachieve real-time data collection. Many instruments are available tocollect patient-reported outcome and health-related quality of lifedata. The instrument should demonstrate content validity, i.e. itshould measure the specific concept or construct of interest that itis intended to assess.80 The MLWHFQ and the Kansas City Cardio-myopathy Questionnaire (KCCQ) have shown validity and respon-siveness to change, but this may reflect the fact that thesequestionnaires measure the severity of symptoms rather thanactual quality of life. The Chronic Heart Failure Questionnaire(CHFQ) has also been shown to be responsive to change and to dif-ferentiate between interventions, but it is not self-administeredwhich may limit its usefulness in some trials.81 These instrumentsare heart failure specific, and they are preferred over generic instru-ments, at least when used as endpoints in heart failure clinical trials.However, generic instruments such as EQ5D or SF36 are neededfor economic analyses and to provide a measure of general qualityof life, which also provides insight into the impact of adverse effectsor the burden of taking treatment. Individualization of quality of lifeassessment is important. Dynamic tools to measure health statusfrom a patient’s perspective are available for a variety of conditions.This approach is actively being investigated in the heart failure com-munity (http://www.nihpromis.org).82 Regulatory agencies shouldbe consulted before a patient-reported outcome instrument ischosen for a trial seeking to achieve a label claim on a patient-reported outcome endpoint, to ensure the instrument has beensufficiently validated in the context of its planned use.83,84

Although patient assessment of symptoms has been associatedwith subsequent mortality and hospitalization, patient-reportedhealth outcomes are not reliable surrogates for mortality.85,86

Rather, they are important outcomes independent of mortality.Regulatory agencies recognize scientifically robust assessments ofpatient-reported health outcomes as sufficient to meet labellingrequirements.83 However, the proper validation to develop an in-strument is time consuming and detailed. The instruments must spe-cifically measure the expected effect, and improvement must beevident in all domains. Concordance with other clinical measure-ments (e.g. 6 min walk test or symptoms) strengthens the confidencethat the instrument is accurately measuring the outcomes.

Evaluation of patient-reported outcomes can reasonably beaccomplished with substantially fewer patients than those neededfor outcome studies. Indeed, an additional advantage of these evalua-tions is that they may capture the net effect of interventions, sinceboth efficacy and safety aspects affect quality of life. However,these endpoints do introduce analytical challenges. The clinically im-portant magnitude of change in the commonly used instruments isnot known and often arbitrarily chosen. More research is neededto determine the threshold that constitutes a clinically meaningfulchange. Additionally, new methodologies to minimize bias areneeded for trials that cannot be blinded. Missing data are problematic.Missing data may reflect a greater burden of disease (e.g. patients maybe too sick to complete or they may have died). Thus, the result maybe biased if the data only reflect patients who were well enough to


complete the instrument. Several methods exist to deal with missingdata (e.g. imputation), but all have limitations. Finally, assessingpatient-reported outcomes as an endpoint is only possible in surviv-ing patients, which also introduces bias. New methods should bedeveloped to account for these important confounders when usingpatient-reported outcomes as an endpoint.

Clinical composite endpointsSeveral types of clinical composite endpoints have been proposedthat incorporate aspects of mortality, morbidity, and patient-reported outcomes. These endpoints address the limitations asso-ciated with traditional morbidity and mortality endpoints, and theymay reduce the resources required to conduct clinical trials.87

However, these endpoints have their own challenges, as describedin the following paragraphs, which limit their usefulness as pivotalendpoints for phase III trials.

Composite scores consider physician assessment of symptoms(NYHA class), patient global symptom assessment, and morbidityand mortality. Such scores classify patients as improved, unchanged,or worsened.88 Variations of this score approach have been adaptedin a number of studies.89–92 One challenge with composite scores isthe proper weighting of different outcomes. In A-HeFT, death, hos-pitalization for heart failure, and change in quality of life wereweighted differently in calculating an outcome score for eachpatient. The appropriateness of the arbitrary values assigned toeach of these endpoints could be debated, but the methodologycan reduce the sample size needed to document efficacy as com-pared with using a mortality plus morbidity endpoint. More researchis needed on methods to weight the components of composite end-points appropriately and to quantify clinically relevant changes.

Composite scores should ideally consist of objective clinicalevents, and the components should demonstrate directional con-cordance. The primary endpoint of the Calcium Upregulation by Per-cutaneous Administration of Gene Therapy in Cardiac Disease(CUPID) trial was a composite of seven efficacy variables in fourdomains.90,93 Concordant improvement in the seven efficacy vari-ables was required without clinically significant worsening in anyvariable.

Incorporating mechanistic endpoints (changes in biomarkers orchanges in LV volume) into composites that also reflect clinical out-comes is a concept that merits consideration, at least in phase II trials.However, the optimal assessment variables for mechanistic end-points need to be established (e.g, size/volumes vs. sphericity orlevel of change in a biomarker that is clinically important). Imagingis expensive, impractical for large trials, and may be strongly operatordependent. It is also important to note that complex compositescombining objective measures of mortality/morbidity with subjectivemeasures of symptoms, quality of life, biochemical, functional mea-sures, or changes in concomitant therapy are often difficult to inter-pret and are generally discouraged as primary endpoints by someregulatory bodies.

Data interpretation from clinical composite endpoints can be chal-lenging, since theycanhavemanycomponents thatmaydiverge indir-ection and/or magnitude, and the details are often difficult toascertain. Because of concerns that combining efficacy and safety ina single ‘net clinical benefit’ composite may obscure safety signals,the two components should usually be examined separately.94,95

It is unlikely that a single drug or device will positively influence allcomponents of a clinical composite, particularly as more compo-nents are added. A single endpoint has advantages over clinical com-posite endpoints, because the intent of therapy is clear and the resultscannot be confounded by divergent effects. As multiple differentcomposites are used, evaluating data across trials will be difficultsince the endpoints are likely to differ in perhaps subtle, but import-ant, ways.

Safety endpointsMortalitySeveral examples can be offered where drugs with positive phase IIdata and a solid scientific rationale increased mortality when theywere studied in large, adequately powered, randomized trials.For this reason, if all-cause mortality is not assessed as an efficacyend-point, then the study should still be reasonably powered to rule outexcess mortality. It is less appropriate for early phase trials that areunderpowered to make any reasonable evaluation of mortality risk.

Pre-specifying non-inferiority boundaries for mortality (i.e. thenew therapy does not increase mortality compared with thecontrol by a pre-specified margin) may be considered. Oneproblem is the arbitrary selection of the non-inferiority margin; themargin may have to be inappropriately liberal to achieve feasiblesample size estimates.96 Specifically for AHF trials, the optimal timeperiod to record mortality remains an unresolved issue. It is reportedat 30 days in some studies and up to 180 days in others. An examin-ation of reported event rates seems to indicate that mortalitybecomes linear after �60–90 days;42,97 thus, 60–90 days may bethe optimal time point to assess death post-discharge for AHF trials.

Renal functionBoth baseline renal function and change in renal function are inde-pendent predictors of outcome in patients with heart failure.98–103

Substantial attention has been paid to cardiorenal interactions andthe importance of renal function in patients with heart failure.However, many uncertainties exist with regard to renal function asan endpoint in heart failure trials. It is unknown if a transient changein renal function is more or less important than a persistentchange. Whether renal function performs best as a clinical or safetyendpoint is debated. The ideal predictor for assessment of renalsafety has also not been determined. Is it discharge serum creatinine(SCr)? Change in SCr by some threshold level? Decrease in estimatedglomerular filtration rate (eGFR)? Should the endpoint be a compos-ite of glomerular and tubular markers of renal damage?

Although renal function does predict outcome, it is a poor surro-gate for clinical outcomes in patients with heart failure. It is documen-ted that several life-saving therapies [ACE inhibitors, ARBs, andmineralocorticoid receptor antagonists (MRAs)] may increase SCr,but these therapies still improve outcomes despite the change inrenal function.104 An analysis from Eplerenone Post-Acute Myocar-dial Infarction Heart Failure Efficacy and Survival Study (EPHESUS)showed that eplerenone was associated with a lower risk of cardio-vascular death or hospitalization compared with placebo despite agreater proportion of eplerenone-treated patients experiencing adecline in eGFR.105 Similar results from a post-hoc analysis of theRandomized Aldactone Evaluation Study (RALES) have been recent-ly published.106 This example illustrates the caution that must be


exercised when using change in renal function as either a safety or anefficacy endpoint, since worsening renal function does not alwayscorrelatewith worse clinical outcomes, depending on the therapeut-ic intervention.

BiomarkersBiomarkers are not acceptable surrogates of clinical outcome, butsome may be useful indicators of safety.107 Increased troponin,serum creatinine, cystatin-C, or hepatic transaminases108 were asso-ciated with a higher risk of 6-month mortality, and larger decreases inNT-proBNP were associated with a lower risk of 6-month mortalityin the phase III RELAX-AHF study.109 Patients randomized to sere-laxin had significantly lower levels of serum creatinine, blood urea ni-trogen, and uric acid within the first 5 days after randomization, and alower level of hepatic transaminases within the first 3 days after ran-domization compared with patients randomized to placebo. Thesedata are hypothesis generating but suggest that favourable effectson laboratory variables might be an indicator of better long-termoutcome.109 Further research and validation of this approach,along with input from regulatory authorities, will be required to de-termine whether a single or composite biomarker endpoint couldbe used as a safety endpoint for phase III trials.

ConclusionThe selection of primary efficacy and safety endpoints in heart failuretrials continues to challenge clinical trialists, regulators, and sponsors.As event rates decline in response to greater adoption of evidence-based, guideline-recommended therapies, the resources needed toconduct trials with traditional endpoints of mortality and morbiditymay be prohibitive. In many circumstances, it will be necessary totailor the endpoint to meet the needs of the population understudy, since therapeutic goals and underlying event rates differacross the spectrum of patients with AHF, chronic heart failure, orHF-PEF. The endpoint chosen for a single pivotal trial is unlikely toaddress the needs of all relevant parties. This Working Group ofthe HFA-ESC identified several important areas of consensusrelated to endpoints in heart failure trials, as well as areas of uncer-tainty where more research and analysis is needed to progress thefield. The points summarized in Table 1 should serve as a resourcefor investigators and sponsors who are actively planning clinicaltrials. Several of these points represent a ‘call to action’ for stake-holders to cooperate and jointly develop strategies or research initia-tives to address the unmet needs of clinical trials in this therapeuticspace (Table 2). Future collaborative and timely efforts are requiredin order to influence favourably the direction of heart failure researchgoing forward, and, ultimately, patient outcomes.

FundingThe Heart Failure Association of the European Society of Cardiology(HFA-ESC)

Conflictsof interest:P.W.A. received research grants fromBoehringerIngelheim, Hoffman LaRoche, SanofiAventis Canada, Inc., Merck Sharp& Dohme, GlaxoSmithKline, Amylin Pharmaceuticals, and Merck &Company, Inc., and consulting fees from AstraZeneca, Eli Lilly, Merck &Company, Inc., F. Hoffman-La Roche Ltd, Axio/Orexigen, and GlaxoS-mithKline. A.F.H. received research funding from Johnson & Johnson,

Amylin, and Portola, and a honorarium from Corthera. J.K. is an employeeof Merck Research Laboratories. S.K. is an employee of Takeda Pharma-ceuticals. A.P.M. received consultancy fees for participation in SteeringCommittees or DSMB of studies sponsored by Novartis, Bayer,Abbott Vascular, Amgen, and Cardiorentis. M.M. received honorariafor consultancy and speaking from Abbott Vascular, Bayer, Corthera,Novartis, and Servier. C.N. is an employee of Bayer Pharma AG. T.S. isan employee and shareholder of Novartis Pharma AG. K.S. is an employ-ee of Boston Scientific Corporation. W.G.S. received support from theHeart Failure Association of the European Society of Cardiology. L.T. isa consultant or committee member for LoneStar Heart, Servier, SaintJude Medical, and Vifor Pharma. A.A.V. received consultancy fees andor research grants from Alere, Bayer, Cardio3Biosciences, Celladon,Ceva, Novartis, Servier, Torrent, and Vifor, grant support from the Euro-pean Commission (FP7-242209-BIOSTAT-CHF), and is a Clinical Estab-lished Investigator of the Dutch Heart Foundation (2006T37). S.M.W. isan employee of Amgen, Inc., and has received Amgen stock/stockoptions. H.W. is an employee of ResMed, Martinsried, Germany. A.Z.is an employee of Novartis Pharmaceuticals Corporation. All otherauthors have no conflicts of interest to declare.

AcknowledgementsWe acknowledge Roger Mills, MD, who participated in and contrib-uted to discussions that took place during the Third Heart FailureClinical Trialists Workshop of the Heart Failure Association of theEuropean Societyof Cardiology, Nice, France, 12–13 February 2012.

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Clinical outcome endpoints in hf trials