EVEREST: "Modest" Gains, No Apparent Harm From Vasopressin Antagonist in Acute Heart Failure

March 26, 2007

March 26, 2007 (New Orleans, LA) - Adding the oral vasopressin antagonist tolvaptan (Otsuka Inc) to standard IV therapy in patients hospitalized with acute decompensated heart failure (ADHF), followed by daily therapy after discharge, led to small but significant improvements in some symptoms and clinical signs without causing any apparent toxicities--but also without having an impact either way on long-term mortality or HF-related hospitalizations--in a study reported here today at the American College of Cardiology (ACC) 2007 Scientific Sessions [1].

The findings, as described by Dr Marvin A Konstam (Tufts–New England Medical Center, Boston, MA) in his formal presentation of the Efficacy of Vasopressin Antagonism in Heart Failure Trial (EVEREST), suggest that tolvaptan and perhaps other drugs in its class could play a distinct though limited role in the management of patients with ADHF and volume overload. Based on the trial, he said, tolvaptan can "facilitate fluid management" and alleviate symptoms in this population "with a well-defined and acceptable long-term safety profile."

EVEREST, actually a composite of three distinct analyses covering short- and long-term symptom-based and clinical outcomes after continuous therapy with tolvaptan starting at ADHF hospitalization and continuing long after discharge, was conducted at more than 300 centers in Europe and North and South America. The results were also published online today in the Journal of the American Medical Association [2,3] and are scheduled for its March 28, 2007 issue.

In their formal publication, Konstam and associates write that tolvaptan "is the first agent ever evaluated in patients hospitalized with worsening HF for which the combination of short-term symptomatic benefit and long-term safety has been established." The EVEREST findings, they write, "define tolvaptan as a potentially useful agent for treating patients with an exacerbation of heart failure."

Primary end points in EVEREST outcomes trial

End point Tolvaptan, n=2072 Placebo, n=2061 HR (95% CI)
All-cause mortality (%) 25.9 26.3 0.98 (0.87–1.11) *
CV death or HF hospitalization (%) 42.0 40.2 1.04 (0.95–1.14)

*p<0.001 for noninferiority. All rate differences between treatment groups NS for superiority.

An accompanying editorial, however, observes the symptom-related benefits of tolvaptan were "modest" and expresses concern that, despite "no demonstrable evidence of harm such as worsening of renal failure," there were no long-term clinical benefits [4]. The drug also failed to demonstrate the "expected long-term benefit of this neurohormonal antagonist--a disappointing observation," writes Dr Clyde W Yancy (Baylor University Medical Center, Dallas, TX). Still, the short-term gains and apparent safety are "noteworthy" in that "no other therapeutic intervention has been demonstrated in large-scale, randomized, placebo-controlled studies to positively influence symptoms in ADHF without generating a question of harm."

At a presentation for the media sponsored by the ACC, Yancy said, "The very clear message is that we have another option for patients with decompensated heart failure admitted to the hospital that will relieve the primary symptom driving their admission. But we don't yet have an agent that will change the true natural history of their disease."

Few options in ADHF, but not for a lack of trying

As Yancy's editorial alludes, the trial appears to break what had become a frustrating pattern of disappointments or outright failures in ADHF trials as agent after agent--added to standard management anchored by IV diuretics and vasodilators--visibly improved patients' symptoms but at the cost of serious side effects, increased mortality, or at least nagging suspicions about safety. The list includes inotropes like milrinone, flosequinan, and vesnarinone as well as the recombinant natriuretic peptide nesiritide, a vasodilator. In general, even the drugs now available for ADHF, including loop diuretics, have major limitations.

As a discussant following Konstam's formal EVEREST presentation, Dr Mariell Jessup (University of Pennsylvania, Philadelphia) said, "It strikes me that we have a whole lot of drugs that we use now [in ADHF], like diuretics, that get people feeling better fast, and yet we have a question mark about their long-term outcomes." Inotropic agents are another example, and amiodarone may relieve symptomatic arrhythmias but doesn't make a long-term impact, she added. Tolvaptan "makes people feel better, maybe, but has no [effect on] outcomes. It strikes me as not a very happy situation that most of what we're doing in the hospital is using a lot of drugs without really any long-term effect."

Selected secondary end points in EVEREST outcomes trial

End point Tolvaptan Placebo p
Mean change in body weight at 1 day (kg) -1.76 -0.97 <0.001
Patients showing improved dyspnea scores at 1 day* (%) 74.3 68.0 <0.001
Mean change in serum sodium at 7 days (mEq/L) 5.59 1.85 <0.001
Patients showing >2-grade improvement in edema* (%) 73.8 70.5 0.003

*Limited to patients with symptom at baseline.
†Limited to patients with baseline levels <134 mEq/L.

The limited benefits observed, Konstam responded, should be taken in context. "This is the first drug that's ever been documented to improve symptoms and be associated with a long-term reasonably favorable safety profile. We don't have another drug like that. We have a lot of drugs, but this is the first that has that constellation of findings."

Studies within a study

EVEREST randomized 4133 patients with NYHA class 3-4 HF and an LVEF <40% who had presented with acute exacerbation of chronic HF within the past 48 hours to receive either tolvaptan orally at 30 mg/day or placebo on top of standard medications given at the physicians' discretion.

Within this overall structure, the trial was organized as one long-term "outcomes" study encompassing all patients and a shorter-term analysis of patient- and physician-assessed "clinical status." After randomization but according to prospective design, the clinical-status portion was further divided by participating centers into a pair of identical studies, observes Yancy's editorial, to meet the US Food and Drug Administration requirement that two randomized trials support a drug's application for approval.

Responses in renal functional parameters at day 7 or discharge in the EVEREST outcomes trial

End point Tolvaptan Placebo p
Change inserum urea nitrogen (mg/dL) +1.94 +3.30 <0.001
Change in serum creatinine (mg/dL) +0.08 0.03 <0.001

Konstam et al wrote the long-term analysis, and the report for the clinical status trials, from Dr Mihai Gheorghiade (Northwestern University, Chicago, IL) and colleagues, was published at the same time.

The outcomes study showed no significant differences between the tolvaptan-treated and control groups with respect to all-cause mortality or a composite of cardiovascular death or HF hospitalization, both primary end points, over a median follow-up of about 10 months. Nor were there differences in the secondary end points of CV mortality, CV death or hospitalization, or worsening HF.

There were no significant differences between treatment groups for more than a dozen prespecified subgroups defined by sex, geography, frequency of dyspnea, LVEF, NYHA functional class, measures of renal function, and use of standard HF medications.

Changes in patient-assessed global clinical status and body weight composite by day 7 in the two EVEREST clinical status trials

End point Tolvaptan Placebo p
Global clinical status and body weight, 1st trial 1.06 0.99 <0.001
Global clinical status and body weight, 2nd trial 1.07 0.97 <0.001

On the other hand, compared with the controls, tolvaptan-treated patients lost significantly more weight--a gauge of fluid loss--and were more likely to show improvement in dyspnea during the first day of therapy. Tolvaptan was also associated with improved serum sodium levels among those who had presented with hyponatremia, the difference reaching significance on day 1 and continuing throughout the follow-up. Improvements in edema scores followed a similar pattern.

Clinical status trials

The short-term portion of EVEREST looked at changes in a composite of patient-assessed global clinical status and body weight at day 7 or discharge as the primary end point. The tolvaptan group showed greater improvement in the composite end point compared with the controls in both prespecified substudies.

However, there were no significant differences between the two groups in the patient-assessed global status component of the primary end point, suggesting, Yancy observed, that the significant differences in the primary composite end point were driven predominantly by weight loss.

No differences were seen in blood pressure or heart rate; however, significantly more tolvaptan-treated patients than those on placebo showed improvements in physician-assessed dyspnea, orthopnea, jugular venous distension, rales, and edema over the first several days after presentation.

Improvements* in physician-assessed signs and symptoms on day 1 in the EVEREST clinical status trial

End point Tolvaptan (%) Placebo (%) p
Dyspnea 51.6 47.1 0.006
Orthopnea 63.1 59.2 0.01
Jugular venous distension 48.6 43.8 0.03
Rales 45.8 43.7 0.03
Edema 57.6 52.6 <0.001

*Improvement defined as response by two points on assessment scale for edema and by one point for all other signs.

In a post hoc analysis of the two clinical status trials, the authors write, patients on tolvaptan showed a greater reduction in the daily use of furosemide from baseline to discharge (p=0.002).

"Tolvaptan had little or no effect on renal function, with measurements of blood urea nitrogen and serum creatinine changing very little in either patient group during the entire period of the study," said Konstam in his formal report. Actively treated patients experienced significantly more "dry mouth" (8.4% vs 2.1%, p<0.001) and thirst (16.0% vs 2.1%, p<0.001).

Although the drug's failure to influence hospitalizations or mortality was "disappointing," Konstam told reporters at the media briefing, "I can say that as a clinician who cares for these patients every single day, I'm excited that I have another drug that will help them. I would probably use it every now and then in that population." Although the trial doesn't support long-term therapy with tolvaptan, he said, in a patient who stops taking it and then has recurrent fluid overload and congestion, "I would probably consider reimplementing the drug. If that happened a few times, I might very well consider keeping the patient on it long term--not driven by the results of the trial except to say that the strategy is safe."

Also at the press conference, Jessup said she was a bit more "skeptical" about what the EVEREST trial shows. It and other studies suggest that the acute symptomatic response to some ADHF therapies don't necessarily correspond to long-term clinical outcomes. "We're beginning to understand that losing weight is not the real answer," she said. Agreeing that the observed benefits with respect to symptoms were small, "if it fact they didn't translate into long-term benefit, then maybe they were clinically not very meaningful."

"Otsuka Inc funded the EVEREST trial under the guidance of the EVEREST steering committee," according to the reports. Konstam reported receiving research grants and contracts from, consulting for, and receiving honoraria from Otsuka. Other disclosures of potential financial conflict of interest from EVEREST coauthors appear in the papers. Yancy's editorial states that he has served as a consultant for GlaxoSmithKline, Scios Inc, NitroMed, Medtronic, and AstraZeneca; has received grants or research support from GlaxoSmithKline, Scios Inc, NitroMed, and Medtronic; has received CHF Fellowship salary support from Medtronic and Scios Inc; and has served on the speakers’ bureaus for GlaxoSmithKline and Novartis.

  1. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of vasopressin receptor antagonism with tolvaptan on clinical status, morbidity and mortality in patients hospitalized with acute decompensated heart failure: Results of the EVEREST Trial. American College of Cardiology 2007 Scientific Sessions; March 25, 2007; New Orleans, LA. Special Session 402-7. Late-Breaking Clinical Trials I.

  2. Konstam MA, Gheorghiade M, Burnett JC, et al. Effects of oral tolvaptan in patients hospitalized for worsening heart failure: The EVEREST outcome trial. JAMA 2007; 297:1319-1331.

  3. Gheorghiade M, Konstam MA, Burnett, JC, et al. Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure: The EVEREST clinical status trials. JAMA 2007; 297:1332-1343.

  4. Yancy CW. Climbing the mountain of acute decompensated heart failure: the EVEREST trials. JAMA 2007; 297:1374-1376.

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