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Unconventional End Points in Cardiovascular Clinical Trials: Should We Be Moving Away From Morbidity and Mortality?
Journal of Cardiac Failure Vol. 15 No. 3 2009
Perspective
Unconventional End Points in Cardiovascular Clinical Trials: Should We Be Moving Away From Morbidity and Mortality? JAY COHN, MD, FACC,1 JOHN G.F. CLELAND, MD, FACC,2 JACOBUS LUBSEN, MD, PhD,3 JEFFREY S. BORER, MD, FACC,4 PHILIPPE GABRIEL STEG, MD, FACC,5 MICHAEL PERELMAN, MD,6 AND FAIEZ ZANNAD, MD7 Minneapolis, Minnesota; Kingston-upon-Hull, United Kingdom; Rotterdam, The Netherlands; New York, New York; Paris, France; Kenilworth, New Jersey; Nancy, France
ABSTRACT Background: Mortality and irreversible or major morbid events are the end points conventionally chosen for cardiovascular clinical trials because they are considered to reflect the effects of intervention on the natural history of disease. Other end points are now being considered and implemented because of the recognized limitations associated with using mortality and morbidity as the sole measures of therapeutic efficacy. Methods and Results: This article reflects the discussion and recommendations regarding nontraditional end points for cardiovascular trials generated from a meeting of clinical trial experts convened to discuss this issue. Less common end points that have been used in cardiovascular clinical trials include composite clinical scores integrating measures of quality of life with mortality and morbidity or using the function of vital organs as end points. Appropriate measurement and applications of such end points is controversial. Conclusions: More experience is needed in applying and analyzing results with these nontraditional end points to enable their optimal use in clinical trials in cardiology, but such approaches have the potential to redress many of the conceptual and actual deficiencies inherent in conventional measures of outcome. (J Cardiac Fail 2009;15:199e205) Key Words: Clinical trials, morbidity, mortality.
Mortality and morbidity end points as efficacy measures in cardiovascular clinical trials are associated with important limitations, including a relatively low incidence of events,
a limited ability to reflect quality of life, and minimal insight into pathophysiologic processes. In December 2006, a group of cardiovascular clinical trialists, biostatisticians, and scientists from academia, industry, the National Institutes of Health, and regulatory bodies met to discuss current issues related to cardiovascular clinical trials (9th Cardiovascular Clinical Trialists Workshop). The limitations of mortality and morbidity end points and alternate end points that may overcome some of these challenges were topics of discussion during this workshop. This manuscript highlights the key points that were raised by the discussion and presents recommendations for addressing issues related to incorporating unconventional end points in cardiovascular clinical trials.
From the 1University of Minnesota, Minneapolis, Minnesota; 2Department of Cardiology, University of Hull, Kingston-upon-Hull, United Kingdom; 3SOCAR Research, Switzerland and Erasmust Medical Centre, Rotterdam, the Netherlands; 4Weill Medical College of Cornell University, New York, New York; 5INSERM U-698, Paris, France; 6Schering Plough, Kenilworth, New Jersey and 7Hypertension and Preventive Cardiology Division, Department of Cardiovascular Disease, Centre d’Investigations Cliniques INSERM-CHU, Nancy, France. Manuscript received August 5, 2008; revised manuscript received October 22, 2008; revised manuscript accepted October 23, 2008. Reprint requests: Jay Cohn, MD, FACC, Cardiovascular Division, MMC 508, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. Tel: 612-625-5646; E-mail: [email protected] Pfizer Inc. provided an unrestricted educational grant to CIC INSERM-CHU of Nancy, France, to support the workshop from which this manuscript was generated (coordinator: Faiez Zannad). Conflict of interest: None. 1071-9164/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.10.029
Limitations of Conventional Mortality and Morbidity End Points Mortality End Points
End points preferably should be clinically relevant, simple, and inexpensive to measure, unambiguous, and sensitive to the intervention.1 Although all-cause mortality 199
200 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 meets many of these criteria and has been widely used in cardiovascular trials, it has several important limitations. Mortality rates for many populations, particularly those with early stages of cardiovascular disease, are sufficiently low that large, expensive trials with long follow-up are required to provide sufficient power for evaluation. This limitation will likely become more challenging as event rates decline with the development of more effective treatments for cardiovascular disease. Mortality accounts for only a minority of events in many cardiovascular trials in which major morbidity end points (myocardial infarction, stroke, heart failure hospitalization, other nonfatal events) are also being measured. In the African American Heart Failure Trial (A-HeFT), only 15% of patients died during a 2-year interval,2 which is equivalent to 8 deaths per 100 patient-years of follow-up. In trials studying myocardial infarction and secondary prevention of coronary disease, the rate of fatal events usually is even lower, often no more than 1.5 deaths per 100 patient-years.3,4 Evaluating all-cause mortality alone fails to assess the effects of treatment on important morbid events such as myocardial infarction, stroke, or hospitalization for progressive heart failure, which often reflect disease processes that will lead to lower quality of life and eventually to death. Mortality in the early phase of chronic cardiovascular disease often results from noncardiovascular causes, unrelated to disease pathophysiology or the intervention’s suspected mechanism of action. Thus a new therapy could reduce cause-specific cardiovascular mortality but have no influence on noncardiovascular deaths. Importantly, if a treatment reduces cardiovascular mortality, then more patients in the treatment group will be exposed to other risks, including the risk of noncardiovascular death.5 Thus all-cause mortality is a less sensitive measure than cause-specific mortality for treatment effects. Unfortunately, however, efforts to distinguish cardiovascular deaths from other lethal events are not always successful.6 Furthermore, all-cause mortality cannot distinguish outcome benefit related to efficacy from outcome harm related to safety. Understanding safety issues can lead to patient selection or cotherapy that might minimize the adverse effects that otherwise counteract benefit.7 Nonetheless, a robust effect on cause-specific mortality should reduce all-cause mortality provided the treatment has no harmful effects on other systems. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (ie, CHARM) program illustrates this issue. The effect of candesartan on all-cause mortality was not significant (HR 0.91, 95% CI 0.83 to 1.00, P 5 .055), whereas favorable effects on cause specific end points including sudden death, progressive heart failure death, and all cardiovascular death were observed.8 Using cause-specific events as end points requires precise definitions and, often, an adjudication committee blinded to assigned treatment and supplied with adequate documentation of events. It is acknowledged that from the patient’s perspective, cause-specific death may not be as relevant as all-cause mortality. However, from the clinicians’
and researchers’ perspectives, understanding the effects of a therapy on cardiovascular and noncardiovascular causespecific mortality has important implications for determining a new agent’s appropriate place in therapy. It may also confirm or refute the presumed relationship between mechanism of drug effect and clinical outcome. Morbidity End Points
Morbidity is usually considered as part of a composite outcome along with mortality, because death and effective treatment are both potential ways of reducing morbid events. Information on morbid events may be collected because the events provide prognostic information, are distressing to patients, or entail high economic cost. Many major events will encompass all 3 of these aspects, but some minor events may have none of these characteristics. Events such as all-cause hospitalization are usually common, and they are a superficially attractive end point in clinical trials because the event rate will be high. However, many hospitalizations may be unrelated to cardiovascular disease. Most trials are analyzed using a time to first event analysis. Therefore, these more frequent events will be the dominant component of any composite end point, a factor that may mask statistically significant findings pertaining to the more relevant component of the composite (ie, mortality). For instance, the Carvedilol or Metoprolol European Trial (ie, COMET) had 2 primary end points.9 All-cause mortality occurred in about 40% of patients over 5 years and was reduced by 17% (P 5 .004). However, all-cause hospitalization (an outcome that included hospitalization for noncardiovascular causes) or mortality occurred in 75% and was not reduced. It could be argued that an effective treatment might keep people alive and well enough to be hospitalized for elective surgeries or other procedures that would fall under the ‘‘all-cause hospitalization’’ umbrella; thus, a high rate of all-cause hospitalizations could be viewed as a marker of success rather than failure, because patients who survive can be hospitalized for a variety of reasons. Patients who have morbid events such as myocardial infarction, hospitalization for heart failure, or stroke have a high likelihood of recurrent admissions and death. However, the value of using morbidity as a surrogate for death or rehospitalization is questionable, and a more informative approach may be to measure the disability that morbid events cause. For instance, in the Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (ie, OPTIMAAL) study, about 300 patients had an adjudicated stroke. By 30 days, one third had died and one third had no reported disability.10 Therefore, only about one third of strokes had chronic disability, although chronic disability is often assumed to be the consequence of most stroke events. The same probably applies to myocardial infarction. Patients with coronary events that result neither in death or subsequent worsening of symptoms are common. In some trials of b-blockers in heart failure, nonfatal
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vascular events increased, possibly because these agents convert some events that would have been rapidly fatal into nonfatal outcomes.11 If the consequences of an event rather than the event itself could be used as an outcome guide, it might provide a more accurate measure of efficacy. When used as a composite with mortality, nonsubstantive events should be excluded. Although such events might provide useful long-term prognostic information, combining them with mortality may confound the evaluation of efficacy of the investigational therapy. A distinction must also be made between all cause hospitalization and cause-specific hospitalizations. In heart failure trials, heart failure hospitalizations account for a minority of total hospitalizations, but they are more likely to reflect treatment effects.12 The primary end point of AHeFT included heart failure hospitalization as a component of the end point. Heart failure hospitalizations were reduced in patients assigned to the fixed-dose combination hydralazine and isosorbide dinitrate, but all-cause hospitalizations were not reduced.2 Similarly, in the Valsartan Heart Failure Trial (ie, Val-HeFT), all-cause hospitalizations were not different between treatment groups, but valsartan reduced cause-specific heart failure hospitalization.12 Hospitalization as an end point is associated with its own limitations. For example, the threshold for and duration of hospitalization differs among institutions and countries, depending in part on reimbursement or other governmental policies, a factor that confounds the interpretation of hospitalization data. Trials investigating the effects of treatment on mortality and morbidity usually focus on high-risk patients with advanced illness to ensure adequate event numbers are accrued in a reasonable interval. This approach is a result, at least in part, of the current regulatory environment and the relatively short patent life of pharmacologic therapies.13 Only after the drugs are licensed can sales generate the income required to finance large outcome studies in low-risk populations. However, identifying effective therapies for patients at an early stage of disease is critically needed to retard or prevent disease progression, disability, and death. Although a link may be assumed between mortality/morbidity reduction in advanced disease and slowing of disease progression in early disease, there is no assurance that interventions will have a similar efficacy:safety profile at different stages of a chronic disease process. Large trials would be needed to document the effectiveness of such early-stage therapy in delaying morbid events. Unconventional End Points Proposed for Use in Clinical Trials Composite Score End Point (A-HeFT)
The primary efficacy end point employed in the A-HeFT trial was a composite score of weighted values for allcause mortality, first heart failure hospitalization during the 18-month follow-up period, and change in diseasespecific quality of life at 6 months as assessed by a self-administered Minnesota Living with Heart Failure
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Questionnaire (Table 1).2 This composite score has several strengths. First, it allows all patients to contribute to the end point. Second, it may be more clinically relevant than mortality or morbidity alone. Most patients are interested in whether or not a treatment will help them get better and remain well, and most patients do not die during the course of a study, even in high-risk populations. Accordingly, a treatment that makes people feel better even if it has no impact on morbidity or mortality might have a high value for patients,14 and it might be perceived as more important than survival in certain situations. Obvious challenges to this end point exist. The magnitude of difference in composite scores that can be accepted as clinically meaningful must be established for the data to be interpretable by patients, clinicians, and regulators. In addition, the weight assigned to each component is often arbitrary, observer-dependent, and not based on objective criteria. It is difficult to achieve agreement among clinicians or researchers as to the relative importance of the individual score components and how such results should be interpreted. In A-HeFT, the effects of intervention on the individual components of the composite score were consistent.2 However, study results are difficult to interpret when all components of the composite do not track in the same direction. Other variations of a composite score have also been proposed and used in clinical trials of acute myocardial infarction15 and heart failure.16 Packer proposed classifying patients as improved, unchanged, or worse depending on the patient’s response to therapy and their vital status at the end of the trial.16 Patients who died or were hospitalized would be classified as worse; thus, this score weights death and hospitalization equally. Packer’s score also incorporates both a physician assessment of symptoms (New York Heart Association Class) and a patient assessment of symptoms (patient global assessment). A change in either of these measures counts toward the end point.
Table 1. Composite End Point in African American Heart Failure Trial End Point Death (at any time during the trial) Survival to end of trial First hospitalization for heart failure (adjudicated) No hospitalization Change in quality of life at 6 months (or at last measurement if earlier than 6 months) Improvement by $10 units Improvement by 5e9 units Change by !5 units Worsening by 5e9 units Worsening by $10 units Possible score
Score 3 0 1 0
þ2 þ1 0 1 2 6 to þ2
Reprinted with permission from Taylor AL et al. N Engl J Med 2004;351:2049-57.2
202 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 This methodology introduces the possibility that the physician and patient assessments could differ substantially from or contradict each other. Days Alive and Out of the Hospital
The days alive and out of the hospital end point integrates death and hospitalization. It offers some unique advantages compared with ‘‘time to event’’ analyses. The days alive and out of the hospital end point captures multiple hospitalization events, rather than only the first event. For example, a patient who has multiple prolonged hospitalizations would have a worse outcome than a patient who was only hospitalized once, or who died at the end of the follow-up period. In contrast, a time to all cause death or hospitalization analysis would treat a patient hospitalized for a noncardiovascular condition at follow-up day 7 as having had a worse outcome than a patient who died at follow-up day 30. The problem with this outcome is that typically, one third of patients neither die nor are hospitalized even during extended follow-up.9 This situation will lead to a highly skewed outcome with many patients achieving a perfect score. Such data are difficult to analyze, and less powerful nonparametric techniques must be used. However, if days alive and out of the hospital are further adjusted for well-being or quality of life measured repeatedly throughout the study, patient outcome scores become more or less normally distributed and parametric statistical analyses that are much more powerful can be applied.17e19 The importance placed on longevity can be adjusted by how much importance is given to quality of life. There need not be 1 fixed view on how to value quality of life.17,18 Most people rate survival with a good quality of life as a highly preferred option. However, 1 person might rate survival as having great value even if quality of life is poor, in the hope that some new intervention might become available. Others may be more fatalistic and rate survival
with low quality of life as having little value, in the belief that they have no future that is worthwhile to them. Interestingly, even when days lost to hospitalization are rated as badly as those lost because of death, hospitalization has little impact on these scores (Fig. 1), because the number of days lost to hospitalization may impact well-being scores but is very small compared with the number of days lost to death. Because this outcome will be strongly affected by duration of follow-up, it is useful to measure outcome over the same period. Failure to ascertain well-being or quality of life at a high proportion of time points will reduce the integrity of the result. Few studies have used this end point, and it is difficult to establish reliable assumptions for sample size calculations at this time. A major advantage is that even if patients initially do badly perhaps because of an unrelated event, but later get benefit from the intervention, they may still have an overall favorable score. In contrast, an early event has an irreversible impact on outcome and great statistical weight in a time to first event analysis using morbidity as part of the composite. This approach does not reflect clinical reality. The days alive and out of the hospital analysis can show that a treatment improves well being despite an increase in mortality.5 How patients, clinicians, and regulators should value such tradeoffs is a valuable and necessary subject of debate that is beyond the scope of this article. Finally, it is not clear that the ‘‘patient journey’’ end point or qualityadjusted life-years should be treated as a composite measure. These outcomes really reflect a single entity or experience curtailed by death. Unbundling them into their different components is not necessarily appropriate. End-Organ Protection End Points
Mortality and major morbidity are the end results of a disease process, but they do not provide insight into the mechanisms of the disease process itself, or methods by which it
Fig. 1. Patient journey analysis from the Carvedilol or Metoprolol European Trial. Cumulative amount of time spent in each health state during different follow-up periods expressed as a proportion of potential days of follow-up, alive or dead. States 1 through 5 represent decreasing ‘‘well-being’’ scores. The paired columns represent observations with 2 different b-blocker regimens that exhibited a significant difference in outcome. Reprinted with permission from Cleland JGF et al. J Am Coll Cardiol 2006;47:1603-11.16
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may be interrupted. End-organ protection end points incorporate both clinical and pathophysiologic measures of the impact of therapy on disease. Such end points may provide evidence of the likelihood of clinical benefit in an individual patient. These nonmortality observations can be relatively sensitive and specific to disease processes. In addition, they can be assessed in all patients, whereas mortality and morbidity apply only to the minority of patients who suffer events in clinical trials. In heart failure, left ventricular remodeling is considered by many investigators to be a reliable structural marker of disease progression.20,21 Remodeling indices can be measured in all patients in a trial, and they can serve as a signal of disease progression, stabilization, or regression. Other nonmortality end points, including specific myocardial remodeling biomarkers (eg, brain natriuretic peptide [BNP], troponin), can be used to supplement the information gained from remodeling end points. The incorporation of end-organ protection end points into clinical trial methodology offers several advantages. First, the use of these end points, if supplemented by but not powered for mortality/morbidity end points, can minimize the size, duration, and cost of clinical trials. Also, they can provide insight into the mechanism of a therapeutic intervention’s effect or disease progression. End-organ protection end points also could be used to study strategies to slow or reverse disease progression in patients with mild disease. Such research would provide opportunities to accelerate the development of primary or secondary prevention strategies that may improve quality of life, health care costs, and ultimately, reduce morbidity and mortality. Of course, reducing the size of therapeutic trials would make it more difficult to document safety, but most lowincidence safety issues unfortunately do not surface until drugs enter wider use in clinical practice. The Detection and Treatment of Early Cardiovascular disease Trial: Intervention with Valsartan (DETECTIV) trial employed an array of end organ protection end points.22 The trial was designed to evaluate the influence of valsartan on cardiovascular disease in patients without symptoms using a scoring system based on 10 markers of functional or structural cardiovascular abnormalities. These include small and large artery elasticity, resting blood pressure, exercise blood pressure, retinal vasculature photography, carotid ultrasonography, microalbuminuria, electrocardiogram, left ventricular ultrasound, and BNP. Each marker is given a score of 0, 1, or 2, according to whether it is normal, borderline, or abnormal, respectively. The total score can range from 0 to 20.22 The DETECTIV study randomized 76 asymptomatic patients with high risk based on this score to valsartan 160 mg/day or placebo. Patients in the placebo group were reassigned to valsartan treatment after 6 months. The primary end point of the study was the trajectory of scores and the individual components at 6 and 12 months. The group randomized to valsartan exhibited a greater improvement in cardiovascular abnormalities.23 This type of study could facilitate
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documentation of favorable therapeutic effects that would need to be confirmed in larger clinical trials. End-organ protection end points have some limitations. The individual clinical and pathophysiologic measures that comprise end-organ protection end points may not independently predict clinical outcome.24 Ventricular remodeling is a promising surrogate marker in heart failure21 as is BNP or NT-proBNP.25 Vascular structural remodeling may be a surrogate for progression of vascular disease. Other disease markers such as hemodynamics, ventricular arrhythmias, and many neurohormones have failed to correlate with clinical outcomes. Many agents have had positive effects on these latter surrogates, but were associated with increased mortality in Phase 3 trials.26e28 Torcetrapib, a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein cholesterol, is a recent example. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ie, ILLUMINATE) trial of torcetrapib plus atorvastatin versus atorvastatin alone in more than 15,000 patients demonstrated an increased risk of cardiovascular events and all-cause mortality for patients treated with torcetrapib, despite significant increases in high-density lipoprotein cholesterol and decreases in low-density lipoprotein cholesterol.28,29 Another lipid-lowering agent, ezetimibe, was not shown to favorably effect carotid intimal-medial thickness, although lipoprotein parameters were favorably improved.28,30 Drug-eluting stents have consistently reduced the need for target lesion revascularization, but recent evidence suggests that they may be associated with a higher rate of death or myocardial infarction compared with bare metal stents.31 Thus the clinical and pathophysiologic measures selected to represent end-organ protection end points must be carefully chosen. Selecting multiple measures for inclusion in the end point, such as the scoring system used in the DETECTIV trial, may strengthen the end-organ protection end point, because it is not dependent on a single measure that may or may not correlate with clinical outcome. Another challenge to ‘‘mechanistic’’ end points is that some therapeutic interventions may have unanticipated detrimental effects on survival, such as liver toxicity or electrocardiographic QT prolongation, that are unrelated to disease progression. Thus, although end-organ protection end points offer a potential advantage in understanding disease pathophysiology, they should be considered as supplements rather than substitutes for assessments of clinical outcome and safety. Nonetheless, ‘‘mechanistic’’ end points should be incorporated into clinical trial design so that the reasons for the success or failure of an intervention can be better explained, thereby informing future generations of research. Regulatory Perspective The choice of an end point depends largely on the labeling claim that will be sought. Rarely, a therapy may be
204 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 approved on the basis of a surrogate end point putatively related to its mechanistic effectdfor instance, lowering of cholesterol or blood pressure. Licensing agents on the basis of these surrogates is controversial.13 The labeled indication will reflect the mechanistic end point rather than a clinical outcome. Approvals can be granted on the basis of improving symptoms or quality of life, but an estimate of morbidity and mortality must be provided to demonstrate safety or to quantify the change in morbidity or mortality so that an informed decision can be made regarding the relation of benefit and risk. For example, flosequinan was approved on the basis of its ability to increase exercise time, but was subsequently shown to increase mortality.32 The approved labeling indicated the risk of increasing mortality. The regulatory approval of drugs with similar divergent effects depends on the magnitude of improvement in symptoms versus the magnitude of adverse outcomes.
Conclusions and Recommendations for Future End Points Several unresolved issues require attention in order to advance the utility of nontraditional end points in cardiovascular clinical trials. 1. Standards for weighting composite scores are needed. Although the actual weights placed on the individual components of composite scores may differ depending on the disease characteristics of the study population, general guidance would be useful to researchers and regulators. 2. Consensus is needed within the scientific, research, and regulatory communities regarding the criteria to define a clinically meaningful effect on composite scores. 3. It is relatively simple to interpret composite outcomes when all measures are either neutral or move in the same direction.33 However, when some components are positive and others negative, interpretation is complex and the value of the ‘‘tradeoff’’ position needs to be considered with care. 4. The concept of measuring disease progression and using a therapeutic intervention to alter pathophysiology with the goal of improving outcomes is a complex and challenging area of clinical research but necessary for therapeutics targeting early intervention in chronic conditions. A mixture of end points should be employed during a development program. Mechanistic outcomes and end-organ protection end points provide an explanation for the clinical outcomes observed, and they may indicate what might be expected if follow-up were extended. Clinical benefit focusing on well-being, morbidity, and longevity are the ultimate goals of intervention. The construction of a logical framework in which disease concept, disease progression, and clinical outcome are all consistent is the ideal to which clinical trials should strive. Positive clinical trials that are not
readily explained and supported by a mechanism of benefit should be viewed cautiously. Acknowledgment Wendy Gattis Stough, PharmD, provided editorial support and contributed to the development of this manuscript, and receives support from CIC INSERM-CHU. The following individuals participated in the December 2006 9th Cardiovascular Clinical Trialists Workshop: Eric Abadie, MD; Chris Adamopoulos, MD; Kirkwood F. Adams, MD; Ali Ahmed, MD; Franc¸ois Alla, MD; Douglas G. Altman, MD, PhD; Corine Bernaud, MD; Jeffrey Borer, MD; John Cleland, MD; Jay Cohn, MD; Mehul Desai, MD; Stephen Evans, MSc; Renaud Fay, PharmD; Nancy Geller, PhD; Mathieu Ghadanfar, MD; David Gordon, MD, PhD, MPH; David Guez, MD; Etienne Huvelle, MD; Desmond Julian, MD; Francois Lemaire, MD; Raymond Lipicky, MD; Dan Longrois, MD; Jacobus Lubsen, MD, PhD; Steinmar Madsen, MD; Patricia Maillere, MD; Lamia MoundejiBoudiaf, MD; Michael Perelman, MD; Bertram Pitt, MD; Stuart Pocock, BA, MSc, PhD; Hubert Pouleur, MD, PhD; Edmond Roland, MD; Patrick Rossignol, MD, PhD; David Sackett, MD; Susan Shurin, MD; Peter Sleight, MD; George Sopko, MD; Philippe Gabriel Steg, MD; Jeremy Sugarman, MD; John Warren, MD; Hans Wedel, MD; Janet Wittes, PhD; and Faiez Zannad, MD, PhD.
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Perspective
Unconventional End Points in Cardiovascular Clinical Trials: Should We Be Moving Away From Morbidity and Mortality? JAY COHN, MD, FACC,1 JOHN G.F. CLELAND, MD, FACC,2 JACOBUS LUBSEN, MD, PhD,3 JEFFREY S. BORER, MD, FACC,4 PHILIPPE GABRIEL STEG, MD, FACC,5 MICHAEL PERELMAN, MD,6 AND FAIEZ ZANNAD, MD7 Minneapolis, Minnesota; Kingston-upon-Hull, United Kingdom; Rotterdam, The Netherlands; New York, New York; Paris, France; Kenilworth, New Jersey; Nancy, France
ABSTRACT Background: Mortality and irreversible or major morbid events are the end points conventionally chosen for cardiovascular clinical trials because they are considered to reflect the effects of intervention on the natural history of disease. Other end points are now being considered and implemented because of the recognized limitations associated with using mortality and morbidity as the sole measures of therapeutic efficacy. Methods and Results: This article reflects the discussion and recommendations regarding nontraditional end points for cardiovascular trials generated from a meeting of clinical trial experts convened to discuss this issue. Less common end points that have been used in cardiovascular clinical trials include composite clinical scores integrating measures of quality of life with mortality and morbidity or using the function of vital organs as end points. Appropriate measurement and applications of such end points is controversial. Conclusions: More experience is needed in applying and analyzing results with these nontraditional end points to enable their optimal use in clinical trials in cardiology, but such approaches have the potential to redress many of the conceptual and actual deficiencies inherent in conventional measures of outcome. (J Cardiac Fail 2009;15:199e205) Key Words: Clinical trials, morbidity, mortality.
Mortality and morbidity end points as efficacy measures in cardiovascular clinical trials are associated with important limitations, including a relatively low incidence of events,
a limited ability to reflect quality of life, and minimal insight into pathophysiologic processes. In December 2006, a group of cardiovascular clinical trialists, biostatisticians, and scientists from academia, industry, the National Institutes of Health, and regulatory bodies met to discuss current issues related to cardiovascular clinical trials (9th Cardiovascular Clinical Trialists Workshop). The limitations of mortality and morbidity end points and alternate end points that may overcome some of these challenges were topics of discussion during this workshop. This manuscript highlights the key points that were raised by the discussion and presents recommendations for addressing issues related to incorporating unconventional end points in cardiovascular clinical trials.
From the 1University of Minnesota, Minneapolis, Minnesota; 2Department of Cardiology, University of Hull, Kingston-upon-Hull, United Kingdom; 3SOCAR Research, Switzerland and Erasmust Medical Centre, Rotterdam, the Netherlands; 4Weill Medical College of Cornell University, New York, New York; 5INSERM U-698, Paris, France; 6Schering Plough, Kenilworth, New Jersey and 7Hypertension and Preventive Cardiology Division, Department of Cardiovascular Disease, Centre d’Investigations Cliniques INSERM-CHU, Nancy, France. Manuscript received August 5, 2008; revised manuscript received October 22, 2008; revised manuscript accepted October 23, 2008. Reprint requests: Jay Cohn, MD, FACC, Cardiovascular Division, MMC 508, University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55455. Tel: 612-625-5646; E-mail: [email protected] Pfizer Inc. provided an unrestricted educational grant to CIC INSERM-CHU of Nancy, France, to support the workshop from which this manuscript was generated (coordinator: Faiez Zannad). Conflict of interest: None. 1071-9164/$ - see front matter Ó 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2008.10.029
Limitations of Conventional Mortality and Morbidity End Points Mortality End Points
End points preferably should be clinically relevant, simple, and inexpensive to measure, unambiguous, and sensitive to the intervention.1 Although all-cause mortality 199
200 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 meets many of these criteria and has been widely used in cardiovascular trials, it has several important limitations. Mortality rates for many populations, particularly those with early stages of cardiovascular disease, are sufficiently low that large, expensive trials with long follow-up are required to provide sufficient power for evaluation. This limitation will likely become more challenging as event rates decline with the development of more effective treatments for cardiovascular disease. Mortality accounts for only a minority of events in many cardiovascular trials in which major morbidity end points (myocardial infarction, stroke, heart failure hospitalization, other nonfatal events) are also being measured. In the African American Heart Failure Trial (A-HeFT), only 15% of patients died during a 2-year interval,2 which is equivalent to 8 deaths per 100 patient-years of follow-up. In trials studying myocardial infarction and secondary prevention of coronary disease, the rate of fatal events usually is even lower, often no more than 1.5 deaths per 100 patient-years.3,4 Evaluating all-cause mortality alone fails to assess the effects of treatment on important morbid events such as myocardial infarction, stroke, or hospitalization for progressive heart failure, which often reflect disease processes that will lead to lower quality of life and eventually to death. Mortality in the early phase of chronic cardiovascular disease often results from noncardiovascular causes, unrelated to disease pathophysiology or the intervention’s suspected mechanism of action. Thus a new therapy could reduce cause-specific cardiovascular mortality but have no influence on noncardiovascular deaths. Importantly, if a treatment reduces cardiovascular mortality, then more patients in the treatment group will be exposed to other risks, including the risk of noncardiovascular death.5 Thus all-cause mortality is a less sensitive measure than cause-specific mortality for treatment effects. Unfortunately, however, efforts to distinguish cardiovascular deaths from other lethal events are not always successful.6 Furthermore, all-cause mortality cannot distinguish outcome benefit related to efficacy from outcome harm related to safety. Understanding safety issues can lead to patient selection or cotherapy that might minimize the adverse effects that otherwise counteract benefit.7 Nonetheless, a robust effect on cause-specific mortality should reduce all-cause mortality provided the treatment has no harmful effects on other systems. The Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity (ie, CHARM) program illustrates this issue. The effect of candesartan on all-cause mortality was not significant (HR 0.91, 95% CI 0.83 to 1.00, P 5 .055), whereas favorable effects on cause specific end points including sudden death, progressive heart failure death, and all cardiovascular death were observed.8 Using cause-specific events as end points requires precise definitions and, often, an adjudication committee blinded to assigned treatment and supplied with adequate documentation of events. It is acknowledged that from the patient’s perspective, cause-specific death may not be as relevant as all-cause mortality. However, from the clinicians’
and researchers’ perspectives, understanding the effects of a therapy on cardiovascular and noncardiovascular causespecific mortality has important implications for determining a new agent’s appropriate place in therapy. It may also confirm or refute the presumed relationship between mechanism of drug effect and clinical outcome. Morbidity End Points
Morbidity is usually considered as part of a composite outcome along with mortality, because death and effective treatment are both potential ways of reducing morbid events. Information on morbid events may be collected because the events provide prognostic information, are distressing to patients, or entail high economic cost. Many major events will encompass all 3 of these aspects, but some minor events may have none of these characteristics. Events such as all-cause hospitalization are usually common, and they are a superficially attractive end point in clinical trials because the event rate will be high. However, many hospitalizations may be unrelated to cardiovascular disease. Most trials are analyzed using a time to first event analysis. Therefore, these more frequent events will be the dominant component of any composite end point, a factor that may mask statistically significant findings pertaining to the more relevant component of the composite (ie, mortality). For instance, the Carvedilol or Metoprolol European Trial (ie, COMET) had 2 primary end points.9 All-cause mortality occurred in about 40% of patients over 5 years and was reduced by 17% (P 5 .004). However, all-cause hospitalization (an outcome that included hospitalization for noncardiovascular causes) or mortality occurred in 75% and was not reduced. It could be argued that an effective treatment might keep people alive and well enough to be hospitalized for elective surgeries or other procedures that would fall under the ‘‘all-cause hospitalization’’ umbrella; thus, a high rate of all-cause hospitalizations could be viewed as a marker of success rather than failure, because patients who survive can be hospitalized for a variety of reasons. Patients who have morbid events such as myocardial infarction, hospitalization for heart failure, or stroke have a high likelihood of recurrent admissions and death. However, the value of using morbidity as a surrogate for death or rehospitalization is questionable, and a more informative approach may be to measure the disability that morbid events cause. For instance, in the Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan (ie, OPTIMAAL) study, about 300 patients had an adjudicated stroke. By 30 days, one third had died and one third had no reported disability.10 Therefore, only about one third of strokes had chronic disability, although chronic disability is often assumed to be the consequence of most stroke events. The same probably applies to myocardial infarction. Patients with coronary events that result neither in death or subsequent worsening of symptoms are common. In some trials of b-blockers in heart failure, nonfatal
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vascular events increased, possibly because these agents convert some events that would have been rapidly fatal into nonfatal outcomes.11 If the consequences of an event rather than the event itself could be used as an outcome guide, it might provide a more accurate measure of efficacy. When used as a composite with mortality, nonsubstantive events should be excluded. Although such events might provide useful long-term prognostic information, combining them with mortality may confound the evaluation of efficacy of the investigational therapy. A distinction must also be made between all cause hospitalization and cause-specific hospitalizations. In heart failure trials, heart failure hospitalizations account for a minority of total hospitalizations, but they are more likely to reflect treatment effects.12 The primary end point of AHeFT included heart failure hospitalization as a component of the end point. Heart failure hospitalizations were reduced in patients assigned to the fixed-dose combination hydralazine and isosorbide dinitrate, but all-cause hospitalizations were not reduced.2 Similarly, in the Valsartan Heart Failure Trial (ie, Val-HeFT), all-cause hospitalizations were not different between treatment groups, but valsartan reduced cause-specific heart failure hospitalization.12 Hospitalization as an end point is associated with its own limitations. For example, the threshold for and duration of hospitalization differs among institutions and countries, depending in part on reimbursement or other governmental policies, a factor that confounds the interpretation of hospitalization data. Trials investigating the effects of treatment on mortality and morbidity usually focus on high-risk patients with advanced illness to ensure adequate event numbers are accrued in a reasonable interval. This approach is a result, at least in part, of the current regulatory environment and the relatively short patent life of pharmacologic therapies.13 Only after the drugs are licensed can sales generate the income required to finance large outcome studies in low-risk populations. However, identifying effective therapies for patients at an early stage of disease is critically needed to retard or prevent disease progression, disability, and death. Although a link may be assumed between mortality/morbidity reduction in advanced disease and slowing of disease progression in early disease, there is no assurance that interventions will have a similar efficacy:safety profile at different stages of a chronic disease process. Large trials would be needed to document the effectiveness of such early-stage therapy in delaying morbid events. Unconventional End Points Proposed for Use in Clinical Trials Composite Score End Point (A-HeFT)
The primary efficacy end point employed in the A-HeFT trial was a composite score of weighted values for allcause mortality, first heart failure hospitalization during the 18-month follow-up period, and change in diseasespecific quality of life at 6 months as assessed by a self-administered Minnesota Living with Heart Failure
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Questionnaire (Table 1).2 This composite score has several strengths. First, it allows all patients to contribute to the end point. Second, it may be more clinically relevant than mortality or morbidity alone. Most patients are interested in whether or not a treatment will help them get better and remain well, and most patients do not die during the course of a study, even in high-risk populations. Accordingly, a treatment that makes people feel better even if it has no impact on morbidity or mortality might have a high value for patients,14 and it might be perceived as more important than survival in certain situations. Obvious challenges to this end point exist. The magnitude of difference in composite scores that can be accepted as clinically meaningful must be established for the data to be interpretable by patients, clinicians, and regulators. In addition, the weight assigned to each component is often arbitrary, observer-dependent, and not based on objective criteria. It is difficult to achieve agreement among clinicians or researchers as to the relative importance of the individual score components and how such results should be interpreted. In A-HeFT, the effects of intervention on the individual components of the composite score were consistent.2 However, study results are difficult to interpret when all components of the composite do not track in the same direction. Other variations of a composite score have also been proposed and used in clinical trials of acute myocardial infarction15 and heart failure.16 Packer proposed classifying patients as improved, unchanged, or worse depending on the patient’s response to therapy and their vital status at the end of the trial.16 Patients who died or were hospitalized would be classified as worse; thus, this score weights death and hospitalization equally. Packer’s score also incorporates both a physician assessment of symptoms (New York Heart Association Class) and a patient assessment of symptoms (patient global assessment). A change in either of these measures counts toward the end point.
Table 1. Composite End Point in African American Heart Failure Trial End Point Death (at any time during the trial) Survival to end of trial First hospitalization for heart failure (adjudicated) No hospitalization Change in quality of life at 6 months (or at last measurement if earlier than 6 months) Improvement by $10 units Improvement by 5e9 units Change by !5 units Worsening by 5e9 units Worsening by $10 units Possible score
Score 3 0 1 0
þ2 þ1 0 1 2 6 to þ2
Reprinted with permission from Taylor AL et al. N Engl J Med 2004;351:2049-57.2
202 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 This methodology introduces the possibility that the physician and patient assessments could differ substantially from or contradict each other. Days Alive and Out of the Hospital
The days alive and out of the hospital end point integrates death and hospitalization. It offers some unique advantages compared with ‘‘time to event’’ analyses. The days alive and out of the hospital end point captures multiple hospitalization events, rather than only the first event. For example, a patient who has multiple prolonged hospitalizations would have a worse outcome than a patient who was only hospitalized once, or who died at the end of the follow-up period. In contrast, a time to all cause death or hospitalization analysis would treat a patient hospitalized for a noncardiovascular condition at follow-up day 7 as having had a worse outcome than a patient who died at follow-up day 30. The problem with this outcome is that typically, one third of patients neither die nor are hospitalized even during extended follow-up.9 This situation will lead to a highly skewed outcome with many patients achieving a perfect score. Such data are difficult to analyze, and less powerful nonparametric techniques must be used. However, if days alive and out of the hospital are further adjusted for well-being or quality of life measured repeatedly throughout the study, patient outcome scores become more or less normally distributed and parametric statistical analyses that are much more powerful can be applied.17e19 The importance placed on longevity can be adjusted by how much importance is given to quality of life. There need not be 1 fixed view on how to value quality of life.17,18 Most people rate survival with a good quality of life as a highly preferred option. However, 1 person might rate survival as having great value even if quality of life is poor, in the hope that some new intervention might become available. Others may be more fatalistic and rate survival
with low quality of life as having little value, in the belief that they have no future that is worthwhile to them. Interestingly, even when days lost to hospitalization are rated as badly as those lost because of death, hospitalization has little impact on these scores (Fig. 1), because the number of days lost to hospitalization may impact well-being scores but is very small compared with the number of days lost to death. Because this outcome will be strongly affected by duration of follow-up, it is useful to measure outcome over the same period. Failure to ascertain well-being or quality of life at a high proportion of time points will reduce the integrity of the result. Few studies have used this end point, and it is difficult to establish reliable assumptions for sample size calculations at this time. A major advantage is that even if patients initially do badly perhaps because of an unrelated event, but later get benefit from the intervention, they may still have an overall favorable score. In contrast, an early event has an irreversible impact on outcome and great statistical weight in a time to first event analysis using morbidity as part of the composite. This approach does not reflect clinical reality. The days alive and out of the hospital analysis can show that a treatment improves well being despite an increase in mortality.5 How patients, clinicians, and regulators should value such tradeoffs is a valuable and necessary subject of debate that is beyond the scope of this article. Finally, it is not clear that the ‘‘patient journey’’ end point or qualityadjusted life-years should be treated as a composite measure. These outcomes really reflect a single entity or experience curtailed by death. Unbundling them into their different components is not necessarily appropriate. End-Organ Protection End Points
Mortality and major morbidity are the end results of a disease process, but they do not provide insight into the mechanisms of the disease process itself, or methods by which it
Fig. 1. Patient journey analysis from the Carvedilol or Metoprolol European Trial. Cumulative amount of time spent in each health state during different follow-up periods expressed as a proportion of potential days of follow-up, alive or dead. States 1 through 5 represent decreasing ‘‘well-being’’ scores. The paired columns represent observations with 2 different b-blocker regimens that exhibited a significant difference in outcome. Reprinted with permission from Cleland JGF et al. J Am Coll Cardiol 2006;47:1603-11.16
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may be interrupted. End-organ protection end points incorporate both clinical and pathophysiologic measures of the impact of therapy on disease. Such end points may provide evidence of the likelihood of clinical benefit in an individual patient. These nonmortality observations can be relatively sensitive and specific to disease processes. In addition, they can be assessed in all patients, whereas mortality and morbidity apply only to the minority of patients who suffer events in clinical trials. In heart failure, left ventricular remodeling is considered by many investigators to be a reliable structural marker of disease progression.20,21 Remodeling indices can be measured in all patients in a trial, and they can serve as a signal of disease progression, stabilization, or regression. Other nonmortality end points, including specific myocardial remodeling biomarkers (eg, brain natriuretic peptide [BNP], troponin), can be used to supplement the information gained from remodeling end points. The incorporation of end-organ protection end points into clinical trial methodology offers several advantages. First, the use of these end points, if supplemented by but not powered for mortality/morbidity end points, can minimize the size, duration, and cost of clinical trials. Also, they can provide insight into the mechanism of a therapeutic intervention’s effect or disease progression. End-organ protection end points also could be used to study strategies to slow or reverse disease progression in patients with mild disease. Such research would provide opportunities to accelerate the development of primary or secondary prevention strategies that may improve quality of life, health care costs, and ultimately, reduce morbidity and mortality. Of course, reducing the size of therapeutic trials would make it more difficult to document safety, but most lowincidence safety issues unfortunately do not surface until drugs enter wider use in clinical practice. The Detection and Treatment of Early Cardiovascular disease Trial: Intervention with Valsartan (DETECTIV) trial employed an array of end organ protection end points.22 The trial was designed to evaluate the influence of valsartan on cardiovascular disease in patients without symptoms using a scoring system based on 10 markers of functional or structural cardiovascular abnormalities. These include small and large artery elasticity, resting blood pressure, exercise blood pressure, retinal vasculature photography, carotid ultrasonography, microalbuminuria, electrocardiogram, left ventricular ultrasound, and BNP. Each marker is given a score of 0, 1, or 2, according to whether it is normal, borderline, or abnormal, respectively. The total score can range from 0 to 20.22 The DETECTIV study randomized 76 asymptomatic patients with high risk based on this score to valsartan 160 mg/day or placebo. Patients in the placebo group were reassigned to valsartan treatment after 6 months. The primary end point of the study was the trajectory of scores and the individual components at 6 and 12 months. The group randomized to valsartan exhibited a greater improvement in cardiovascular abnormalities.23 This type of study could facilitate
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documentation of favorable therapeutic effects that would need to be confirmed in larger clinical trials. End-organ protection end points have some limitations. The individual clinical and pathophysiologic measures that comprise end-organ protection end points may not independently predict clinical outcome.24 Ventricular remodeling is a promising surrogate marker in heart failure21 as is BNP or NT-proBNP.25 Vascular structural remodeling may be a surrogate for progression of vascular disease. Other disease markers such as hemodynamics, ventricular arrhythmias, and many neurohormones have failed to correlate with clinical outcomes. Many agents have had positive effects on these latter surrogates, but were associated with increased mortality in Phase 3 trials.26e28 Torcetrapib, a cholesteryl ester transfer protein inhibitor that raises high-density lipoprotein cholesterol, is a recent example. The Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ie, ILLUMINATE) trial of torcetrapib plus atorvastatin versus atorvastatin alone in more than 15,000 patients demonstrated an increased risk of cardiovascular events and all-cause mortality for patients treated with torcetrapib, despite significant increases in high-density lipoprotein cholesterol and decreases in low-density lipoprotein cholesterol.28,29 Another lipid-lowering agent, ezetimibe, was not shown to favorably effect carotid intimal-medial thickness, although lipoprotein parameters were favorably improved.28,30 Drug-eluting stents have consistently reduced the need for target lesion revascularization, but recent evidence suggests that they may be associated with a higher rate of death or myocardial infarction compared with bare metal stents.31 Thus the clinical and pathophysiologic measures selected to represent end-organ protection end points must be carefully chosen. Selecting multiple measures for inclusion in the end point, such as the scoring system used in the DETECTIV trial, may strengthen the end-organ protection end point, because it is not dependent on a single measure that may or may not correlate with clinical outcome. Another challenge to ‘‘mechanistic’’ end points is that some therapeutic interventions may have unanticipated detrimental effects on survival, such as liver toxicity or electrocardiographic QT prolongation, that are unrelated to disease progression. Thus, although end-organ protection end points offer a potential advantage in understanding disease pathophysiology, they should be considered as supplements rather than substitutes for assessments of clinical outcome and safety. Nonetheless, ‘‘mechanistic’’ end points should be incorporated into clinical trial design so that the reasons for the success or failure of an intervention can be better explained, thereby informing future generations of research. Regulatory Perspective The choice of an end point depends largely on the labeling claim that will be sought. Rarely, a therapy may be
204 Journal of Cardiac Failure Vol. 15 No. 3 April 2009 approved on the basis of a surrogate end point putatively related to its mechanistic effectdfor instance, lowering of cholesterol or blood pressure. Licensing agents on the basis of these surrogates is controversial.13 The labeled indication will reflect the mechanistic end point rather than a clinical outcome. Approvals can be granted on the basis of improving symptoms or quality of life, but an estimate of morbidity and mortality must be provided to demonstrate safety or to quantify the change in morbidity or mortality so that an informed decision can be made regarding the relation of benefit and risk. For example, flosequinan was approved on the basis of its ability to increase exercise time, but was subsequently shown to increase mortality.32 The approved labeling indicated the risk of increasing mortality. The regulatory approval of drugs with similar divergent effects depends on the magnitude of improvement in symptoms versus the magnitude of adverse outcomes.
Conclusions and Recommendations for Future End Points Several unresolved issues require attention in order to advance the utility of nontraditional end points in cardiovascular clinical trials. 1. Standards for weighting composite scores are needed. Although the actual weights placed on the individual components of composite scores may differ depending on the disease characteristics of the study population, general guidance would be useful to researchers and regulators. 2. Consensus is needed within the scientific, research, and regulatory communities regarding the criteria to define a clinically meaningful effect on composite scores. 3. It is relatively simple to interpret composite outcomes when all measures are either neutral or move in the same direction.33 However, when some components are positive and others negative, interpretation is complex and the value of the ‘‘tradeoff’’ position needs to be considered with care. 4. The concept of measuring disease progression and using a therapeutic intervention to alter pathophysiology with the goal of improving outcomes is a complex and challenging area of clinical research but necessary for therapeutics targeting early intervention in chronic conditions. A mixture of end points should be employed during a development program. Mechanistic outcomes and end-organ protection end points provide an explanation for the clinical outcomes observed, and they may indicate what might be expected if follow-up were extended. Clinical benefit focusing on well-being, morbidity, and longevity are the ultimate goals of intervention. The construction of a logical framework in which disease concept, disease progression, and clinical outcome are all consistent is the ideal to which clinical trials should strive. Positive clinical trials that are not
readily explained and supported by a mechanism of benefit should be viewed cautiously. Acknowledgment Wendy Gattis Stough, PharmD, provided editorial support and contributed to the development of this manuscript, and receives support from CIC INSERM-CHU. The following individuals participated in the December 2006 9th Cardiovascular Clinical Trialists Workshop: Eric Abadie, MD; Chris Adamopoulos, MD; Kirkwood F. Adams, MD; Ali Ahmed, MD; Franc¸ois Alla, MD; Douglas G. Altman, MD, PhD; Corine Bernaud, MD; Jeffrey Borer, MD; John Cleland, MD; Jay Cohn, MD; Mehul Desai, MD; Stephen Evans, MSc; Renaud Fay, PharmD; Nancy Geller, PhD; Mathieu Ghadanfar, MD; David Gordon, MD, PhD, MPH; David Guez, MD; Etienne Huvelle, MD; Desmond Julian, MD; Francois Lemaire, MD; Raymond Lipicky, MD; Dan Longrois, MD; Jacobus Lubsen, MD, PhD; Steinmar Madsen, MD; Patricia Maillere, MD; Lamia MoundejiBoudiaf, MD; Michael Perelman, MD; Bertram Pitt, MD; Stuart Pocock, BA, MSc, PhD; Hubert Pouleur, MD, PhD; Edmond Roland, MD; Patrick Rossignol, MD, PhD; David Sackett, MD; Susan Shurin, MD; Peter Sleight, MD; George Sopko, MD; Philippe Gabriel Steg, MD; Jeremy Sugarman, MD; John Warren, MD; Hans Wedel, MD; Janet Wittes, PhD; and Faiez Zannad, MD, PhD.
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