Rationale and Design of the Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST)

Journal of Cardiac Failure Vol. 11 No. 4 2005

Clinical Trials Methods and Design

Rationale and Design of the Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) MIHAI GHEORGHIADE, MD,1 CESARE ORLANDI, MD,2 JOHN C. BURNETT Jr, MD,3 DAVID DEMETS, PhD,4 LILIANA GRINFELD, MD,5 ALDO MAGGIONI, MD,6 KARL SWEDBERG, MD,7 JAMES E. UDELSON, MD,8 FAIEZ ZANNAD, MD,9 CHRISTOPHER ZIMMER, MD,2 AND MARVIN A. KONSTAM, MD8 Chicago, Illinois; Rockville, Maryland, Rochester, Minnesota; Madison, Wisconsin; Buenos Aires, Argentina; Florence, Italy; Go¨teburg, Sweden; Boston, Massachusetts; Nancy, France

ABSTRACT Background: Hospitalizations for worsening heart failure due to fluid overload (congestion) are common. Agents that treat congestion without causing electrolyte abnormalities or worsening renal function are needed. Tolvaptan is an oral vasopressin (V2) antagonist that decreases body weight and increases urine volume without inducing renal dysfunction or hypokalemia. The Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial is evaluating mortality, morbidity, and patient-assessed global clinical status in patients treated with tolvaptan compared with standard care. Methods and Results: Patients are eligible for inclusion if they have a reduced left ventricular ejection fraction and are hospitalized for worsening heart failure with evidence of systemic congestion. Patients are randomized 1:1 to tolvaptan 30 mg/day or matching placebo for a minimum of 60 days. Time to allcause mortality and time to cardiovascular mortality or heart failure hospitalization are the coprimary end points. Patient-assessed global clinical status and quality of life are also evaluated. EVEREST will be continued until 1065 deaths occur. As of April 18, 2005, 2260 patients have been enrolled. Conclusion: Tolvaptan has been shown to reduce body weight in patients with worsening heart failure without inducing renal dysfunction or causing hypokalemia. The results of EVEREST will determine whether these effects translate into improved clinical outcomes. Key Words: Heart failure, vasopressin, clinical trials, mortality, morbidity.

Hospitalizations for heart failure are common in the United States. The National Hospital Discharge Survey data report 995,000 discharges for heart failure in 2001, at a rate of 3.5 per 1,000 adults.1 The hospitalization rate is similar in Europe, with 2.5 admissions per 1000 adults and 26.5 admissions per 1000 adults age 80 or older.2 Patients hospitalized for worsening heart failure can be divided into 2 groups. The first group is frequently characterized by progressive fluid retention, often manifested by an increase in body weight over several days or weeks, which leads to congestive symptoms and necessitates hospitalization. These patients have a prior history of heart failure, are normotensive or mildly hypertensive, and predominantly have systolic dysfunction (“cardiac” failure). In contrast, the second group comprises patients who are older, present with hypertension,

From the 1Division of Cardiology, Northwestern Feinberg School of Medicine, Chicago, Illinois; 2Otsuka Maryland Research Institute, Rockville, Maryland; 3Mayo Clinic College of Medicine, Rochester, Minnesota; 4 University of Wisconsin, Madison, Wisconsin; 5Hospital Italiano de Buenos Aires, Buenos Aires, Argentina; 6ANMCO Research Centre, Florence, Italy; 7 ¨ stra, Go¨teDepartment of Medicine, Sahlgrenska University Hospital/O burg, Sweden; 8Division of Cardiology, Tufts-New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts; 9INSERM, Centre d’Investigation Clinique CIC-INSERM CHU, Ho˚pital Jeanne d’Arc, De´partement des Maladies Cardio-Vasculaires, and Universite´ Henri Poincare´, Nancy, France. Manuscript received December 29, 2004; revised manuscript received February 22, 2005; revised manuscript accepted March 16, 2005. Reprint requests: Marvin A. Konstam, MD, Division of Cardiology, Tufts-New England Medical Center, Box 108, 750 Washington St. Boston, MA 02111. Supported by Otsuka Maryland Research Institute, Rockville, MD. 1071-9164/$ - see front matter 쑕 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.cardfail.2005.03.009

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EVEREST: Tolvaptan for Worsening HF

and usually have preserved systolic function and severe radiographic pulmonary congestion that are related to redistribution from the systemic to the pulmonary circulation, rather than total body overload (“vascular” failure). The remainder of this manuscript and the overall Efficacy of Vasopressin antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) study focuses on the population of patients with “cardiac” failure. This group represents approximately half of the patients hospitalized for acute heart failure.3 Standard treatments do not generally result in substantial weight loss or complete resolution of symptoms; persistent congestion is a known significant predictor of mortality.4,5 The ability of diuretics to induce significant weight loss is often limited by adverse effects including hyponatremia and renal insufficiency. The ideal drug to treat congestive symptoms should significantly increase fluid loss and lower filling pressures without negatively affecting blood pressure, heart rate, electrolytes, renal function, neurohormones, or clinical outcomes. These properties are absent from non–potassiumsparing loop diuretics, the mainstay of current treatment for heart failure congestion. Tolvaptan (OPC-41061) is a novel, oral, once-daily, nonpeptide vasopressin V2 receptor antagonist without intrinsic agonist properties.6,7 Several studies, including the Acute and Chronic Therapeutic Impact of a Vasopressin antagonist in Congestive Heart Failure (ie, ACTIV in CHF) trial, demonstrated that tolvaptan, in addition to standard therapy, resulted in a significant increase in urine output and a decrease in body weight without hypokalemia or worsening renal function.8–10 This study generated the hypothesis that tolvaptan might improve survival in patients with chronic heart failure hospitalized from congestion. The EVEREST trial is designed to test this hypothesis. Methods EVEREST is an international, multicenter, randomized, doubleblind, placebo-controlled study designed to evaluate the long-term efficacy and safety of oral once-daily tolvaptan 30 mg in patients hospitalized with worsening heart failure. Patients must have reduced left ventricular ejection fraction (ⱕ40%), signs of volume expansion, and New York Heart Association class III/IV symptoms. The study is approved in each center by the local Institutional Review Board or Independent Ethics Committee. The subject eligibility criteria are provided in Table 1. EVEREST consists of 2 components: the primary outcomes study, and 2 identical embedded studies within the main trial to assess global clinical status according to regulatory requirements (Fig. 1A, 1B). The primary outcomes study has 2 coprimary end points: (1) time to all-cause mortality and (2) time to first occurrence of cardiovascular mortality or heart failure hospitalization. The primary efficacy end point of the embedded studies is the change from baseline in patient-assessed global clinical status using a 100point visual analog scale on the 7th inpatient day or discharge, whichever occurs earlier. Quality of life is a secondary end point, and it will be evaluated by the change from baseline to outpatient week 1 in the Kansas City Clinical Questionnaire overall summary score. The end points for the primary outcomes and embedded studies

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are summarized in Table 2. Dyspnea will be assessed using a 7point scale. Patients will be asked to rate the degree of breathing difficulty just before the study drug was started compared with the degree of breathing difficulty at inpatient day 1. Edema will be assessed using the standard 1⫹ to 4⫹ scale. Using a blocked randomization within each center, subjects are assigned to receive oral tolvaptan 30 mg once daily or matching placebo within 48 hours of hospitalization. A central interactive voice response system is employed in EVEREST. The study includes an inpatient treatment period and a postdischarge treatment and follow-up period. All patients will receive the study drug for a minimum of 60 days. All patients will continue to receive standard therapy for worsening heart failure, including: diuretics, digoxin, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, hydralazine, nitrates, or β-blockers at the discretion of the treating physician. The first day of inpatient treatment will begin on the calendar day after randomization. The discharge visit will occur the day the subject is discharged from the hospital. The first outpatient visit will occur 7 days after discharge for those subjects discharged from the hospital on or before the 10th day or the 17th day after randomization for those still in the hospital on Day 10. Outpatient assessments will be performed after 1, 4, and 8 weeks and every 8 weeks thereafter. A follow-up visit will occur 7 days after the last dose of the study drug for all subjects to allow for adjustments in concomitant diuretic therapy. Safety information will be collected during a telephone call 14 days after the last dose of study drug for all subjects. Subjects terminating the study drug before the study termination date will be contacted every 3 months until the study termination to collect safety and end point information. Statistical Analysis The EVEREST statistical design allows for the analysis of the acute and chronic effects of tolvaptan using 3 studies in an integrated, but independent manner. The primary outcome study is a single study designed to assess the effect of tolvaptan on clinical outcomes. Embedded within the primary outcome study are 2 distinct but identical studies, study A and study B. These studies are designed and powered to assess the short-term effect of tolvaptan on patient-assessed global clinical status. Studies A and B are designed to be analyzed separately for the global clinical status end points and to be pooled for the analysis of the outcome study. The intent-to-treat dataset including all randomized subjects will be used for the efficacy analysis of the main study and for the global clinical status outcome of the embedded studies. The patient population for the embedded studies will be obtained by randomizing centers to study A or study B at the conclusion of enrollment (Fig. 1B). Center allocation to the 2 studies is based on enrollment size. Centers within each geographic region will be sorted by their enrollment size from largest to smallest. The center with the greatest enrollment in the largest region will be assigned to study A, the second greatest will be assigned to study B, the third greatest will be assigned to study A, and so forth. All-cause mortality, total cardiovascular mortality, and total heart failure hospitalizations occurring from randomization until study termination will be included in the analysis. The study will be terminated after the 1065th death and a minimum of 60 days of therapy for all current subjects. The assessment of global clinical status will be evaluated separately in studies A and B. The primary test for this end point will be based on an analysis of covariance using the baseline value as a covariate and treatment and (pooled) clinical center as factors.

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Journal of Cardiac Failure Vol. 11 No. 4 May 2005 Table 1. Main Patient Eligibility Criteria

Inclusion Criteria A history of chronic heart failure (defined as requiring treatment for a minimum of 30 d before hospitalization) Most recent left ventricular ejection fraction ⱕ40% within 1 y Current hospitalization for chronic heart failure with admission up to 48 h before randomization. Chronic heart failure is defined as requiring treatment for a minimum of 30 d before hospitalization Symptoms classified as New York Heart Association class III or IV at the time of hospitalization Signs of extracellular volume expansion, defined as ⱖ2 of the following: jugular venous distention, pitting edema (⬎1⫹), or dyspnea. Age ⱖ18 y

Exclusion Criteria Cardiac surgery within 60 d of potential study enrollment, excluding percutaneous coronary interventions Planned revascularization procedures, electrophysiologic device implantation, cardiac mechanical support implantation, cardiac transplantation, or other cardiac surgery within 30 days after study enrollment Subjects who are on cardiac mechanical support

History of biventricular pacer placement within the last 60 d Comorbid condition with an expected survival ⬍6 mo Subjects with acute ST segment elevation myocardial infarction at the time of hospitalization History of sustained ventricular tachycardia or ventricular fibrillation within 30 days, unless in the presence of an automatic implantable cardioverter defibrillator History of a cerebrovascular accident within the last 30 d Hemodynamically significant uncorrected primary cardiac valvular disease Hypertrophic cardiomyopathy (obstructive or nonobstructive) Congestive heart failure from uncorrected thyroid disease, active myocarditis, or known amyloid cardiomyopathy Subjects with refractory, end-stage, heart failure defined as subjects who are appropriate candidates for specialized treatment strategies, such as ventricular assist devices, continuous positive intravenous inotropic therapy, or hospice care Progressive or episodic neurologic disease such as multiple sclerosis or history of multiple strokes History of primary significant liver disease or acute hepatic failure Chronic uncontrolled diabetes mellitus as determined by the investigator Subjects currently treated with hemofiltration or dialysis Morbid obesity, defined as ⬎159 kg (or 350 lb) or body mass index ⬎42 Supine systolic arterial blood pressure ⬎90 mm Hg Serum creatinine ⬎3.5 mg/dL or ⬎309.4 µmol/L Serum potassium ⬎5.5 mEq/L or ⬎5.5 mmol/L Hemoglobin ⬍9 g/dL or ⬍90 g/L or 5.586 mmol/L History of hypersensitivity or idiosyncratic reaction to benzazepine derivatives (such as benazepril) Women who will not adhere to the reproductive precautions as outlined in the informed consent form Positive urine pregnancy test Inability to provide written informed consent History of drug or medication abuse within the past year, or current alcohol abuse Previous participation in this or any other tolvaptan clinical trial Inability to take oral medications Participation in another clinical drug or device trial in which the last dose of drug was within the past 30 d or an investigation medical device is implanted

Efficacy monitoring will be based on the primary end point of all-cause mortality with the treatment comparison performed using the Peto-Peto-Wilcoxon log-rank test.11 A boundary based on the O’Brien-Fleming α-spending function will be used to account for interim analyses of unblinded mortality data. After adjusting for interim analyses, the significance level for the all-cause mortality coprimary end point will be approximately 0.0376, for an overall type I error rate of 0.0402. The significance level for the cardiovascular mortality or heart failure hospitalization coprimary end point will be 0.009.12 The primary end point of time to all-cause mortality will be tested for both superiority (tolvaptan is superior to placebo) and noninferiority (tolvaptan is not inferior to placebo). The null hypothesis for the test of noninferiority is that the hazard for allcause mortality in subjects receiving tolvaptan is at least 1.25 times higher than the hazard for all-cause mortality in subjects receiving

placebo. This null hypothesis will be rejected if a 95.98% confidence interval for the hazard ratio of tolvaptan to placebo exceeds 1.25. Because this testing procedure is closed, no type I error penalty is incurred at a significance of 0.0402.13,14 Statistical Power and Sample Size The sample size for this study was estimated based on the number of death events. An overall 20% reduction in all-cause mortality was originally assumed. In addition, a 15% dropout rate was assumed during the course of the study. These dropouts would have no effect on the mortality rate in placebo group, but were assumed to reduce the magnitude of the effect of tolvaptan in the tolvaptan treatment group because these dropouts would no longer be on active treatment. After all these considerations, 1065 deaths are required to provide 90% power to compare all-cause mortality at

EVEREST: Tolvaptan for Worsening HF

Patients hospitalized with worsening of chronic heart failure

Randomized within 48 hrs of admission

Placebo qd

Follow-up until 1065 deaths and a minimum of 2 months of treatment Primary outcome

• Time to all cause death • Time to first occurrence of cardiovascular mortality or heart failure hospitalization

B Patients hospitalized with worsening of chronic heart failure

Tolvaptan 30 mg

Study B

Placebo

Tolvaptan 30 mg

Placebo

Day 7 or discharge, if earlier Primary outcome

263

The incidence of the cardiovascular mortality or heart failure hospitalization end point was assumed to be 1.4 times the incidence of all-cause mortality. Based on this estimate, 1065 deaths will provide 90% power to test a hazard ratio of 0.8184 with the log-rank test (2-sided α ⫽ 0.009). For the global clinical status end point, the standard deviation for the visual analog scale measure was assumed to be 20 units. Thus 1200 subjects in each study will provide 90% power to detect a mean change of 3.85 units for each study separately or 82% power for observing a statistically significant benefit in both studies simultaneously. EVEREST will have 90% power for detecting a mean change of 4.26 units in both studies simultaneously. These power calculations are based on a 2-sample test (Table 4). Study Organization

Randomized within 48 hrs of admission

Study A

Gheorghiade et al

• A proportional hazards model is assumed such that tolvaptan reduces the 6-month mortality rate by 20% (hazard ratio ⫽ 0.776), which results in mortality rates in the tolvaptan group of 7.8%, 20%, and 28.4% at 2 months, 6 months, and 1 year, respectively. • It is also assumed that the discontinuation rate at 18 months will be 15% with treatment discontinuations uniformly distributed over the follow-up time (Table 3).

A

Tolvaptan 30 mg/qd

•

Improvement in patient-assessed global status

Fig. 1. (A) Schematic of the main study design. (B) Schematic of embedded study design.

a 2-sided alpha of 0.009 (a level that has regulatory significance), assuming a hazard ratio of 0.7865 in all-cause mortality. This hazard ratio would translate to a 17.9% reduction in annual mortality based on an annual mortality rate of 35% in the placebo group. After adjusting for interim analyses, the alpha for final analysis is 0.008. For a less stringent 2-sided alpha of 0.0402 (0.0376 after adjusting for interim analyses), 1065 deaths will provide 90% power to detect a hazard ratio of 0.8132 for all-cause mortality. Based on a projected annual mortality rate of 35% in the placebo group, this hazard ratio would translate to a 15.6% reduction in the annual mortality rate. An estimated 3600 patients will be enrolled to obtain 1065 deaths. The following assumptions were used to generate this estimate: • The placebo rates of all-cause mortality are assumed to be 10%, 25%, and 35% at 2 months, 6 months, and 1 year, respectively. An annual rate of 30.5% is assumed beyond 1 year.

The Steering Executive Committee is composed of 1 chair and 2 cochairs from the United States, 3 members from Europe, and 1 member from South America; 1 sponsor (Otsuka Maryland Research Institute) representative; and a lead statistician. The Clinical Event Committee will adjudicate primary and secondary end points based on investigator reported data collected from source documents, written event narratives, and a specific adjudication form. The committee will be blinded for therapy assignment and will use predefined criteria for adjudication. The Independent Data Monitoring Committee (IDMC) is independent of the sponsor, the study management organizations, and the investigators. It is composed of a statistical coordinating center representative, a chairperson, and independent physicians. The efficacy and safety analyses will be performed semiblinded by the statistical primary investigator at the statistical coordinator center. The IDMC statistician will possess a copy of the treatment codes for unblinding purposes if deemed necessary by the IDMC. The IDMC will meet either in person or by teleconference during the planning phase, in the last half of the first year of enrollment, and at least annually for the duration of the study. The IDMC will convey its recommendation to the Executive Committee after each meeting. To date, the IDMC has identified no safety concerns, and it recommended that the study continue as planned. Current Status The first patient was enrolled October 7, 2003. As of April 18, 2005, 2260 patients have been enrolled. The duration of individual exposure will vary, because the study is event-driven. The end of enrollment will be determined so that the last subject enrolls approximately 2 months before the expected time of the 1065th death event. Patients from Argentina, Belgium, Brazil, Canada, Czech Republic, France, Germany, Italy, Netherlands, Norway, Poland, Romania, Russian Federation, Spain, Sweden, Switzerland, the United Kingdom, and the United States will be enrolled in the study.

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Journal of Cardiac Failure Vol. 11 No. 4 May 2005 Table 2. Clinical End Points

End Point Primary Secondary

Incidence of:

Change from baseline in:

Safety

Main Study

Embedded Study

Time to: All-cause mortality First occurrence of CV mortality or HF hospitalization Time to first occurrence of CV mortality/morbidity (morbidity includes HF hospitalization, acute MI, stroke, arrhythmia, and other CV morbidity such as unstable angina, pulmonary embolism) CV mortality, including: sudden cardiac death, HF, acute MI, stroke, other CV mortality (eg, ruptured aortic aneurysm, cardiac tamponade) Clinically worsening HF: HF hospitalization; unscheduled visit for HF to an emergency department, outpatient clinic, or observation unit associated with IV therapy for HF; or death from HF Body weight on first day of inpatient treatment Edema score after 7 d of treatment or at discharge, if earlier, for those with edema at baseline Serum sodium after 7 d of treatment or at discharge, if earlier, in subjects with a serum sodium ⬍134 mEq/L at baseline Dyspnea on first day of inpatient treatment for those with dyspnea at baseline Kansas City Clinical Questionnaire overall summary score at outpatient week 1 Adverse events, vital signs, clinical laboratory tests, 12-lead electrocardiograms

Change from baseline in patient-assessed global clinical status on the 7th inpatient day or discharge, if earlier

Body weight on first day of inpatient treatment Edema score on the 7th day of inpatient treatment or at discharge, if earlier, for those with edema at baseline Dyspnea on the first day of inpatient treatment for those with dyspnea at baseline

CV, cardiovascular; HF, heart failure; MI, myocardial infarction.

Discussion Importance of Congestion in Heart Failure

In patients hospitalized with heart failure, congestion is an important therapeutic target not only for symptomatic improvement, but also for prevention of rehospitalization and mortality.15,16 Congestion is usually related to increased intravascular volume associated with elevated left ventricular diastolic pressure.16 This increase in pressure may cause subendocardial ischemia or necrosis. Congestion is a driving force for adverse ventricular remodeling, which may result in secondary mitral insufficiency and arrhythmia.17,18 Despite relatively low in-hospital mortality, patients admitted with heart failure have 10% mortality and 25% readmission rates within 60 days after discharge.1,3 These high event rates are observed even among patients who appear to be stable at discharge and who are without adverse prognostic factors such as hypotension or renal insufficiency.19,20 It has been documented that patients with persistent congestive symptoms at the time of discharge are at higher risk of readmission.3,21 If these symptoms can be treated more effectively during the hospitalization, it is possible that subsequent morbidity and mortality can also be reduced.3 Volume status assessment is recognized by the American College of Cardiology/American Heart Association and the European Society of Cardiology Guidelines as a crucial component of the management of heart failure.22,23 However, the clinical and radiographic presence and severity of fluid overload remain challenging to assess.21,24–26 Change in body weight appears to be the most reliable measurement of shortterm shifts in fluid status or congestion in the absence of hemodynamic measurements.22

Role of Vasopressin Antagonism in Heart Failure

Vasopressin antagonism is a rational approach to the treatment of heart failure related congestion. Arginine vasopressin (AVP) is elevated in patients with reduced left ventricular ejection fraction, even in the absence of symptoms, and its level is proportional to the severity of heart failure.27–30 It may lead to myocardial fibrosis/hypertrophy and vasoconstriction through V1a receptor activation. Water retention and hyponatremia are mediated through V2 receptor activation.27–31 In heart failure, vasopressin antagonists not only may prevent progression of left ventricular dysfunction, but in contrast with other neurohormonal modulators such as ACE inhibitors or β-blockers, they may also produce an acute and sustained reduction in congestive symptoms and correction of hyponatremia.31 Until recently, the potential benefits of AVP receptor blockade in heart failure have not been well explored because of the lack of orally active, effective, and well-tolerated nonpeptide agents. Newly developed compounds targeting the V1a (vascular) and V2 (renal) vasopressin receptors may represent the next generation of neurohormonal modulators that have a beneficial effect in heart failure.31 Tolvaptan (OPC-41061) is a novel vasopressin receptor blocker. The compound binds predominantly to the V2 receptor in the kidney, resulting in significantly increased production of dilute urine. Tolvaptan reduces body weight and appears to improve signs of heart failure in outpatients with mild chronic disease.8 Unlike furosemide, tolvaptan has been shown to increase renal blood flow, decrease renal vascular resistance, and improve glomerular filtration rate in patients with heart failure.32 The improvement in glomerular filtration

EVEREST: Tolvaptan for Worsening HF

rate in this study was not statistically significant because of the small study population. However, the observed trend is an important finding, and it suggests that tolvaptan may not be associated with adverse renal effects. In patients with heart failure and signs of volume overload, tolvaptan without concomitant loop diuretic therapy reduced body weight and edema when compared to placebo, without adverse changes in serum electrolytes.33 Normalization of serum sodium has also been observed after tolvaptan treatment in patients with hyponatremia from heart failure, liver cirrhosis, or the syndrome of inappropriate antidiuretic hormone production.34 Neurohormonal abnormalities of the renin-angiotensinaldosterone system (RAAS), sympathetic nervous system, and AVP system are contributors to the pathophysiology of heart failure.19,20,35 ACE inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists (spironolactone, eplerenone), and β-blockers are known to improve the neurohormonal profile and have been shown to significantly reduce mortality and morbidity in heart failure.36 Although these life-saving therapies may prevent congestion by decreasing the progression of heart failure, they may not be effective in rapidly reducing congestion after it develops. The frequency with which patients develop congestive symptoms is likely to increase because of the currently effective therapies for sudden death prevention. Vasopressin antagonists may provide a dual role of reducing heart failure progression by neurohormonal modulation and reducing congestive symptoms after they occur. Tolvaptan Clinical Trials

The Acute and Chronic Therapeutic Impact of a Vasopressin antagonist in Congestive Heart Failure (ACTIV in CHF) trial was conducted to evaluate the short- (in-hospital) and intermediate-term (outpatient, after hospital discharge) effects of tolvaptan in patients with reduced left ventricular ejection fraction hospitalized for worsening heart failure.9 The study included 320 patients and evaluated 3 tolvaptan doses. Compared with placebo, tolvaptan significantly reduced body weight at 24 hours (a primary end point), hospital discharge, and 60 days. Tolvaptan was not associated with changes in heart rate, blood pressure, or renal function.10 Rapid and sustained normalization of serum sodium was observed in patients who were hyponatremic at baseline. Tolvaptan treatment did not significantly affect the other primary end point of worsening heart failure, defined as death, rehospitalization, or unscheduled visits for heart failure within 60 days. However, the study was underpowered with only 320 patients to detect significant differences in these end points. In a retrospective analysis, a trend toward lower total mortality was observed in the combined tolvaptan groups compared with placebo, particularly in patients with hyponatremia, renal dysfunction, or severe congestion at baseline.17 Potential Therapeutic Applications

Tolvaptan has the potential to substantially advance the current management of congestion in heart failure. Non–

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Table 3. Power (%) for the End Point of Time to All-Cause Mortality for Analysis at Study Termination* % Change in 6-Mo Rate (observed) ⫺20 ⫺10 0 ⫹4

Superiority Noninferiority Hazard Ratio α ⫽ 0.008 α ⫽ 0.0376 α ⫽ 0.0402 0.776 0.886 1.000 1.048

93 25 — —

98 46 — —

99 99 94 80

*Power under proportional hazard model for superiority or noninferiority as a function of the 6- mo placebo mortality rate and the given reduction in this rate when 1065 total deaths are observed. Noninferiority is defined as a 95.98% (1–0.0402) confidence interval for the hazard-ratio excluding 1.25 or greater (ie, a 25% increase in the hazard of death due to tolvaptan). Based on an assumed event rate of 25% in the placebo group.

potassium-sparing loop diuretics are the mainstay of therapy for heart failure congestion, but their use is associated with frequent and significant adverse effects including hypotension, hyponatremia, hypokalemia, hypomagnesemia, renal insufficiency, hyperglycemia, hyperuricemia, and increased sensitivity to digoxin.20,35,37–39 The potential benefits of tolvaptan may be mediated by several mechanisms: its neurohormonal effects, its ability to reduce congestion without adversely altering electrolytes, or by decreasing the need for high doses of diuretics.10 The reduced need for non-potassium sparing diuretics may have a positive effect on clinical outcomes. Tolvaptan is not devoid of side effects. More patients randomized to tolvaptan reported thirst or dry mouth in the ACTIV in CHF trial. These side effects, although important for tolerability, are less concerning than the primary adverse effects of loop diuretics, namely hyponatremia, electrolyte disturbances, and renal insufficiency. Tolvaptan may treat congestion more effectively than loop diuretics. Non–potassium-sparing loop diuretics do not completely reduce systemic congestion or decrease edema in all patients. These diuretics are known to decrease plasma osmolality and renal blood flow, resulting in prerenal azotemia even in patients who continue to be fluid overloaded.40 Hospitalized patients with worsening heart failure and congestion often have hyponatremia, elevated blood urea nitrogen, and low systolic blood pressure, all of which are major predictors of poor prognosis.41 Non–potassium-sparing loop diuretics can further worsen these conditions.

Table 4. Critical Values for Interim Analysis of All-Cause Mortality Nominal 1-Sided P Values* Death (%) 25 50 75 100

Critical Values

Safety Boundaries

Efficacy Boundaries

⫺2.5, 3.50 ⫺2.5, 3.50 ⫺2.5, 3.09 ⫺2.14, 2.65 ⫺2.14, 2.08

.0062 .0062 .0062 .0162 .0162

.000235 .000235 .00095 .004 for α/2 ⫽ .0045 .0188 for α/2 ⫽ .0201

*P value derived from Peto-Peto-Wilcoxon log-rank test.

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Trial Design Issues in Patients Hospitalized for Worsening Heart Failure

Studies evaluating new agents for heart failure have traditionally been conducted examining acute effects in hospitalized patients or chronic effects in outpatients.19,36,42 This approach was related to the Food and Drug Administration’s approach to approving new heart failure drugs and to the difficulties in conducting clinical trials in patients hospitalized for worsening heart failure. As evidence, the first randomized trials in patients hospitalized for decompensated heart failure were published only in 2002.19,42 These trials were critical in establishing the feasibility of placebo-controlled studies in patients hospitalized with worsening heart failure, but they had important limitations. Both studies focused on acute interventions with treatment duration of 48 hours. The Outcomes of a Prospective Trial of Intravenous Milrinone for Exacerbations of Chronic Heart Failure (OPTIME-CHF) studied the intermediate-term effects (60 days) of the marketed drug milrinone on clinical outcomes. The Vasodilatation in the Management of Acute CHF (VMAC) trial studied the short-term (3-hour) symptomatic effect of the experimental drug nesiritide. The design of EVEREST is unique in that it is the first trial to examine an oral therapy for both its acute effect during hospitalizations for worsening heart failure and for its chronic outpatient effects after discharge. Most treatments for decompensated heart failure are short-term, intravenous therapies with minimal potential for chronic maintenance therapy.19,42

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Summary

The design of EVEREST will test both the acute and chronic effects of tolvaptan in patients hospitalized for worsening heart failure and reduced systolic function. The results of the study will define the role of tolvaptan in the management of both acute and chronic heart failure.

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References 1. Hall MJ, DeFrances CJ. 2001 National Hospital Discharge Survey. Advance data from vital and health statistics. Hyattsville (MD): National Center for Health Statistics; 2003. Publication No. 332. 2. Martinez-Selles M, Garcia Robles JA, Prieto L, Serrano JA, Munoz R, Frades E, et al. Annual rates of admission and seasonal variations in hospitalizations for heart failure. Eur J Heart Fail 2002;4:779–86. 3. Fonarow GC. ADHERE Scientific Advisory Committee. The Acute Decompensated Heart Failure National Registry (ADHERE): opportunities to improve care of patients hospitalized with acute decompensated heart failure. Rev Cardiovasc Med 2003;4(Suppl 7):S21–30. 4. Lucas C, Johnson W, Hamilton MA, Fonarow GC, Woo MA, Flavell CM, et al. Freedom from congestion predicts good survival despite previous class IV symptoms of heart failure. Am Heart J 2000;140:840–7. 5. Gattis WA, O’Connor CM, Gallup DS, Hasselblad V, Gheorghiade M. Predischarge initiation of carvedilol in patients hospitalized for decompensated heart failure: results of the Initiation Management Predischarge: Process for Assessment of Carvedilol Therapy in Heart Failure (IMPACT-HF) trial. J Am Coll Cardiol 2004;43:1534–41. 6. Yamamura Y, Nakamura S, Itoh S, Hirano T, Onogawa T, Yamashita T, et al. OPC-41061, a highly potent human vasopressin V2-receptor

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Appendix Executive (Oversight) Steering Committee: M. A. Konstam (chair), M. Gheorghiade (cochair), J.C. Burnett (cochair), L. Grinfeld, A. Maggioni, C. Orlandi, K. Swedberg, F. Zannad, C. Zimmer. Clinical Event Committee: M.C. Bahit, M. Haass, P.E. Carson, P.J. Hauptman, M. Metra, A. Miller (cochair), C. O’Connor (cochair), R.M. Oren, R. Patten, I. Pina, S. Roth, J. Sackner-Bernstein. Main Writing Committee: M. Gheorghiade, M.A. Konstam, K. Swedberg, F. Zannad. Data Safety Monitoring Board: H. Dargie (Glasgow, United Kingdom), D. L. DeMets (Madison, WI), K. Dickstein (Stavanger, Norway), B. Greenberg (San Diego, CA), S. Goldstein (Detroit, MI) Chair, J. Lerman (Buenos Aires, Argentina), B. Massie (San Francisco, CA), B. Pitt (Ann Arbor, MI). Otsuka Maryland Research Institute Representative: C. Orlandi, C. Zimmer. Statistical Analysis: J. Ouyang. Chief Medical Monitor: J. Udelson. Regional Medical Monitors: H.A. Dieterich, Z. Capkova, F. Gadaleta, M. Mule, and M.B. Pricipato.

Clinical Sites and Investigators United States

Martin Bilsker, University of Miami/Jackson Memorial Hospital; Timothy Bishop, Empire Health Services; Dennis Bresnahan, Mid America Cardiology; David Caskey, LSU Health Sciences Center; Andrew Chai, Idaho Cardiology Associates; Eugene Chung, The Lindner Clinical Trial Center; Robert Mel Clark, Integris Baptist Medical Center; William Dec, Mass General Hospital-Bigelow 645; Gary Fishbein, The Dayton Heart Center; Scott Friedman, Shore Health System; Jalal Ghali, ARK-LA-TEX Cardiology; Alan Gradman, The Western Pennsylvania Hospital; David Richards, Midwest Cardiology Research Foundation; Connor Haugh, New England Heart Institute; David Hinchman, Idaho Cardiology Associates; Hassan Ibrahim, North Ohio Research Limited; Michael Imburgia, Louisville Cardiology Medical Group; Eli Roth, Sterling Research Group; Rafael Sequeira, University of Miami/Jackson Memorial Hospital; Robert Siegel, Phoenix Memorial Hospital; Phil Stockwell, Rhode Island Hospital; Kris Vijay, Arizona Heart Institute; Tania Nanevicz, Cardiovascular Association of the Peninsula; Robert Weiss, Androscoggin Cardiology Associates; Richard Wright, Pacific Heart Institute; Jay Alexander, North Shore Cardiologists; Larry Altschul, South Bay Cardiovascular Associates; Mohammad Ashraf, Sierra Medical Research; James Bergin, University of Virginia Medical Center; Chris Brown, The Heart Group; Robert Capodilupo, Northeast Cardiology Associates; Robert Carhart, SUNY; James Carley, Cardiology Research Associates; Barry Clemson, Heart Care Midwest; Terence Connelly, Charlotte Heart Group Research Center; John Corbelli, Buffalo Cardiology and Pulmonary Associates; Robert Doroghazi, Missouri Cardiovascular Specialists; Eric Eichhorn, Cardiopulmonary

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Research Science & Technology Institute; Mahfouz El-Shahawy, Cardiovascular Center of Sarasota; Enrique Flores Georgia Heart Specialists; John Foley, Backus Hospital, Clinical Research Department; Mihai Gheorghiade, Northwestern University; Mark Goldberg, Saguaro Clinical Research; David Goldscher, MidAtlantic Cardiovascular Associates; Steven Goldsmith, Hennepin County Medical Center; Terrence Hack, Primary Care Cardiology Research; Ethan Haskel, MidAtlantic Cardiovascular Associates; David Hassel, Jacksonville Heart Center; Paul Hauptman, St Louis University; Pamela Rama, Jacksonville Heart Center; Philip Houck, Scott & White Clinic Division of Cardiology; Donald Jansen, Atlanta Heart and Vascular Research Group; Scott Jerome, MidAtlantic Cardiovascular Associates; Yamil Aude, University of Arkansas for Medical Science; David Joyce, North Ohio Research Limited; Richard Kachel, Florida Cardiovascular Research; Shaival Kapadia, Cardiovascular Associates of Virginia; Robert Kipperman, Oklahoma Foundation for Cardiology Research; Richard Krasuski, Wilford Hall Medical Center; Marvin Kronenberg, Vanderbilt Clinical Trials Center; Farhad Aduli, Northshore Medical Research, LLC; Michael Liston, VA Medical Center-Kansas City; James Hodsen, Akron General Medical Center; James McCriskin, Illinois Heart &Lung Associates; Frank McGrew, Stern Cardiovascular Center; Robert Shor, The Cardiovascular Group PC; Karan Munuswamy, Cardiology Associates of Fort Lauderdale; Puneet Narayan, VA Medical Center; Imran Niazi, Wisconsin Center For Clinical Research; E. Dean Nukta, Cleveland Cardiovascular Research; John O’Brien, Inova Institute of Research; Joseph O’Bryan, Southwest Florida Heart Group; Maria-Teresa Olivari, Minneapolis Heart Institute; Mary Ann Peberdy, Medical College of Virginia; Mark Jeffrey Pirwitz, Austin Cardiovascular Associates; Rakesh Prashad, Ocala Research Institute; David Rubin, Midatlantic Cardiovascular Associates; Jonathan Safren, Midatlantic Cardiovascular Associates; Mitchell Saltzberg, Midwest Heart Research Foundation; Gregg Schuyler, The Heart and Vascular Institute of Florida; Jonathan Roberts, Miami Cardiology Group; Bramah Singh, VA Medical Center-W. Los Angeles; Rodolfo Sotolongo, Southeast Texas Cardiology Associates; David Stagaman, Rockwood Clinic; Dwight Stapleton, Guthrie Clinic, Ltd; William Van Decker, Medical College of Pennsylvania; Charles Wilkins, Covenant Medical Center; Mohamad El-Zaru, Albany Associates in Cardiology; Brian Kahn, MidAtlantic Cardiovascular Associates; Yamil Aude, University of Arkansas for Medical Sciences; Joseph Lash, Cardiovascular Associates; John Banas, Morristown Memorial Hospital; Supratim Banerjee, Bakersfield Memorial Hospital; Marlo Leonen, Michigan Heart; Raymond Benza, University of Alabama at Birmingham; Harry Colfer, Nisus Research; Edouard Daher, John Dingell VA Medical Center; Peter Fattal, Covenant Medical Center; Jack Foster, Cardiology Associates of North Mississippi; Peter Goodfield, Hendersonville Cardiology; Dinesh Gupta, Tennessee Center for Clinical Trials; William Hathaway, Asheville Cardiology Associates; Herbert Haught, The Heart Center; Tetsuo Ishimori, Central Cardiology Medical Center; Bruce Iteld, The Louisiana Heart Center; Michael Kesselbrenner, The Valley Hospital; Marc Klapholz, St Vincents Hospital and Medical Center; Peter

McCullough, William Beaumont Hospital; John Cieszkowski, Beaumont Hospital; Edward McMillan, Mid Carolina Cardiology; Andrew Boyle, University of Minnesota; Mark Nathan, Cardiovascular Consultants Medical Group, Inc.; Terrence O’Brien, Ralph H. Johnson VAMC; Gary Felker, Duke Cardiology Research; William Oellerich, The Chattanooga Heart Institute; Naveen Pereira, Medical University of South Carolina; James Sandberg, The Heart Care Group; Ernst Schwarz, University of Texas Medical Branch; Ralph Vicari, Melbourne Internal Medicine Associates; Frederick Whittier, Clinical Research Limited; Rene Alvarez, Cardiology Associates of West Reading; Alan Bank, St Paul Heart Clinic; Fred Cobb, Durham VA Medical Center; David Cullinane, Heart and Vascular Clinic of Northern Corolado; Himadri Dasgupta, South Carolina Heart Center; J.T. Heywood, Loma Linda University Medical Center; Steve Krueger, Bryan LGH Heart Institute; Brian Lowes, University of Colorado; Jack Rose, Pitt County Memorial Hospital Heart Center; Joel Sklar, Cardiology Associates; J. Thomas Suh, Park Nicollet Heart Center; Nampalli Vijay, Aurora Denver Cardiology Associates; Mary Walsh, The Care Group; Doug Chapman, Heart Consultants, PC; Justine Lachmann, St Francis Hospital; John Gordon, San Diego Cardiac Center; David Kraus, Baptist Clinical Research Center; Brent DeVries, Northwest Ohio Cardiology Consultants; Kirk Adams, University of North Carolina; Rachel Bijou, New York Presbyterian Hospital; Uri Elkayam, LAC/ USC Medical Center; Kenneth Fath, Alamance Regional Medical Center; Hillel Ribner, The Center for Advanced Heart Failure, PC Furrukh Malik Cardiovascular Associates; John Schmedtje, Roanoke Heart Institute; Bruce Jackson, ARI Clinical Trials; Joseph Wight, Maine Medical Center; Michael Miyamoto, Mission Internal Medical Group; Hal Skopicki, North Shore University Hospital; Robert Frantz, Mayo Clinic, Division of Cardiology; Marrick Kukin, St. Lukes- Roosevelt Hospital Centers; John McBride, Regions Hospital; Lana Tsao, Beth Israel Medical Center; Richard Ryder, Cardiology Associates P.C.; Michael Koren, Jacksonville Center For Clinical Research; Kenneth Taylor, Cardiac Disease Specialists PC; Kathy Hebert, Leonard J. Chabert Medical Center; Mara Slawsky, Baystate Hospital; Narendra Singh, Northside Hospital; Christopher Brian, Birmingham Heart Clinic, P.C.; Syed Jafri, Henry Ford Medical Center; David Smith, Tallahassee Research Institute; Van Stephen Monroe, Jr, The Chattanooga Heart Institute; Mitchell Greenspan, Buxmont Cardiology Associates, PC; Marc Silver, Advocate Christ Medical Center; Lynne Wagoner, University Of Cincinnati; Ricky Schneider, The Broward Heart Group, P.A.; Robert Moskowitz, Cardiac Specialists; Muhammad Yasin, Southwest Cardiology; Douglas Waldo, Heart & Vascular Clinic; Tali Arik. Canada

Anique Ducharme, Montreal Heart Institute; Bruce Sussex, Health Sciences Center; Asaad Bakbak, Lakeridge Health Oshawa; David Borts, Brampton Research Associates; Y.K. Chan, Greater Niagara General Hospital; L. John Charles, Cardiology Research Associates; Sherryn Roth, Scarborough Hospital; Nadia Giannetti, Royal Victoria Hospital; J.E. Goode, Scarborough Cardiology Research; W. Peter

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Klinke, Victoria Heart Institute Foundation; Jan Kornder, Cardiology Clinical Trials; Peter Giannoccaro, Peter Lougheed Centre; Simon Kouz, CHRDL; Jacques Lenis, Invascor Clinical Research; Serge LePage, Centre Hospitalier de l’Universite de Sherbrooke; Gordon Moe, St. Michael’s Hospital; Andrew Morris, St. Boniface General Hospital; Yves Pesant, Hotel-Dieu de Saint-Jerome; Diego Delgado, University Health Network, Toronto Western Hospital; Thao Huynh, Montreal General Hospital; Patrick Ma, Heart Health Institute; Frank Halperin, Kelowna General Hospital; Thomas Rebane, Mississauga Clinic Research Center; A.S. Pandey, Cambridge Cardiac Care.

Italy

Argentina

Norway

Jorge Tronge; Norberto Vulcano; Julio Jorge Bluguermann; Miguel Angel Riccitelli; Sergio Martin Chekherdemian; Roberto Colque; Marcos Amuchastegui; Eduardo Roque Perna; Aristo´bulo Enrique Ballestrini; Dr. Alejandro Posadas; Ana Maria Salvatti; Luis Girotti; Susana Llois; Monica Sultan; Oscar Grosso; Carlos Estrada; Simo´n Mario Salzberg; Daniel Nul; Luis Guzma´n; Marcelo Halac; Sergio Perrone; Alvaro Sosa Liprandi.

Torbjorn Omland; Christian Ostvold; Vernon Bonarjee; Anne Semb.

Luigi Tavazzi; Claudio Marabotti; Maurizio Porcu; Silvio Ricci; Tiziano Moccetti; Giovanni Ruggeri; Cristina Opasich; Franco Cosmi; Franco Masini; Pierfranco Terrosu; Vincenzo Cirrincione; Franco Cobelli; Ernesto Murena; Piergiuseppe Agostoni; Pantaleo Giannuzzi. The Netherlands

Don Hertzberger; AnHo Liem; Walther Jap; Eugene Buys; Frank den Hartog; Pieter van der Burgh; Gerard Louis Bartels; Jan Wesdorp; Dirk Lok; Angela Maas; Rolf Veldkamp; Paul A. R. de Milliano.

Poland

Jacek Grzybowski; Wladyslav Sinkiewicz; Jerzy Kopaczewski; Malgorzata Krzciuk; Janusz Maciejewicz; Andrzej Malinski; Michal Ogorek; Wladyslaw Pluta; Ryszard Sciborski; Tomasz Waszyrowski; Grzegorz Opolski; Krystyna Jaworska; Piotr Ruszkowski; Fryderyk Prochaczek.

Brazil

Antonio Carlos Pereira Barreto; Celso Blacher; Euler Roberto Fernandes; Gilson Soares Feitosa; Gilmar Valdir Greque; Gilmar Reis; Jose´ Marcio Ribeiro; Lilia Nigro Maia; Pedro Pimentel Filho; Salvador Rassi; Paulo Rossi; Alvaro Rabelo Junior; Nadine Clausell; Jose´ Francisco Kerr Saraiva; Lilian Soares da Costa; Maria Sanali Moura de Oliveira Paiva; Denilson Albuquerque; Humberto Villacorta Junior; Joa˜o Carlos Rocha; Jean-Paul Salembier. Belgium

Filip Charlier; Laurence Gabriel; Gilles De Keulenaer; Jean-Paul Salembier.

Romania

Radu Capalneanu; Mircea Cinteza; Mihail Dan Datcu; Carmen Georgeta Fierbinteanu Braticevici; Dorel NastaseMelicovici; Dan Ionescu; Cezar Eugen Macarie; Ioan Tiberiu Nanea; Mariana Radoi; Gabriel Petrisor Tatu-Chitoiu; Stefan Dragulescu; Carmen Ginghina. Spain

Fe´lix Pe`rez-Villa; Jose` Maria Arizo´n; Jordi Merce´; Juan Delgado; Angel Grande; Pedro Montes; Francisco Ridocci; Manuel Vida Sweden

Czech Republic

Thomas Kahan; Ulf Dahlstro¨m; Karl Swedberg; Cecilia Linde; Gerhard Wikstro¨m; Bengt Johansson; Inger Hagerman; Ronnie Willenheimer; Bengt Widgren.

Josef Jandik; Eva Mandysova; Frantisek Padour; Petr Vojtisek; Jiri Vitovec; Lubor Golan II; Lenka Hoskova; Dag Tichy; Josef Drazka; David Alan; Ivo Oral; Jiri Janousek; Bohuslav Cernosek.

United Kingdom

France

John Cleland; Mirza Baig; Steven Lindsay; Jatinder Dhawan; Iain Square; Robert Bain.

Francois Delahaye; Marc Ferriere; Michel Galinier; JeanNoe¨l Trochu; Thierry Laperche; Zukai Chati; Pierre Gibelin; Nadir Benazza; Faiez Zannad; Michel Martelet. Germany

Hermann Ochs; Harald Darius; Thomas Dengler; Raimund Erbel; Hans Figulla; Rainer Hambrecht; Gerd Hasenfuss; Michael Buerke; Robert Schwinger; Stephan Felix; Wolfgang von Scheidt; Stephan Holmer; Juergen Kolditz; Thomas Wichter; Dieter Horstkotte; Hans Neuser; Gerhard Hauf; Holger Vogelshberg.

Russian Federation

Anatoly Baranov; Nikolai Gratsiansky; Maria Sitnikova; Konstantin Zrazhevsky; Victor Kostenko; Vladimir Simanenkov; Olga Berkovich; Vagan Mkrtchuan; Mikhail Boyarkin; Raisa Stryuk; Vecheslav Mareev; Vladislav Novozhenov; Sergey Shustov; Lev Sorokin; Vladimir Zadionchenko; Nikita B. Perepech; Boris M. Tankhileitch; Gennady I. Storozhakov; Igor Bokarev; Natalia Sanina; A. Martynov; Sergey Chernov; Sidorienko; Marina Ballyusek.