EVEREST-Outcomes

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Konstam MA, et al. "The Effects of Oral Tolvaptan in Patients Hospitalized for Worsening Heart Failure". The Journal of the American Medical Association. 2007. 297(12):1319-1331.
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Clinical Question

In patients with HFrEF on standard therapy, does 60 days of tolvaptan reduce mortality or rehospitalization rates when compared to placebo?

Bottom Line

In patients with HFrEF on standard therapy, tolvaptan has no effect on either all-cause mortality or a composite of CV mortality or HF rehospitalization when given for 60 days following an acute HF episode.

Major Points

Diuretics are central to the management of hospitalizations for acute decompensated heart failure (ADHF) and are widely used as maintenance medications for outpatients with HFrEF. Hyponatremia is a poor prognosticator in HF, and the V2 receptor has previously been associated with the deleterious neurohormonal pathways in HFrEF; antagonism of these receptors has been hypothesized to prevent progression of the disease.[1] Tolvaptan, a V2 antagonist, has been thought to play a dual role in both loss of free water through aquaresis and in the prevention of HF progression.

The 2007 Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan-Outcomes (EVEREST-Outcomes) trial randomized 4,133 patients admitted with ADHF to tolvaptan or placebo for at least 60 days. With a median follow-up of 9.9 months, there was no difference in all-cause mortality (25.9% vs. 26.3%) or the composite of CV mortality or HF rehospitalizations (42.0% vs. 40.2%). The related EVEREST-Symptoms (2007)[2] demonstrated improvement in short-term HF symptoms without increasing adverse events.

Of note, the FDA has subsequently limited use of tolvaptan to 30 days given the elevated rates of liver dysfunction observed in TEMPO 3:4 (2012).[3][4]

Guidelines

AHA/ACCF Heart Failure (2013, adapted)[5]

  • In hospitalized patients with HF or other causes of volume overload with persistent severe hyponatremia at risk for cognitive symptoms despite water restriction and OMT, a vasopressin antagonist may be considered in the short term to improve serum sodium concentration (class IIb, level B)

Design

  • Multicenter, double-blind, placebo controlled trial
  • N=4,133
    • Tolvaptan (n=2,072)
    • Placebo (n=2,061)
  • Setting: 359 centers in North America, South America, and Europe
  • Enrollment: 2003-2006
  • Median follow-up: 9.9 months
  • Analysis: Intention-to-treat
  • Primary outcomes:
    • All-cause mortality
    • CV death or rehospitalization

Population

Inclusion Criteria

  • Age ≥18 years, with LVEF ≤40% with volume expansion findings
  • NYHA class III or IV symptoms
  • Acute-on-chronic HF admission

Exclusion Criteria

  • Cardiac surgery in prior 60 days
  • Cardiac mechanical support
  • Biventricular PPM in prior 60 days
  • Expected survival <6 months
  • MI at time of hospitalization
  • Uncorrected cardiac valvular disease
  • Refractory end-stage HF
  • Hemofiltration or dialysis
  • Supine SBP <90 mmHg
  • Creatinine >3.5 mg/dL
  • K >5.5 mEq/L
  • Hgb <9 g/dL

Baseline Characteristics

From the tolvaptan group.

  • Demographics: Age 65.9 years, male 73.4%, white race 85.3%, black race 7.8%
  • Health data: SBP 120.8 mmHg, EF 27.5%
  • PMH: Ischemic HF 65.1%, HTN 70.8%, DM 39.8%, a fib 43.6%, CKD 26.5%, mitral valvular disease 31.2%
  • Previous HF hospitalization: 79.2%
  • NYHA class: III 60.1%, IV 39.5%
  • Medications: ACE-inhibitors or ARBs 84.3%, beta-blocker 70.8%, diuretics 97.1%, aldosterone antagonists 53.6%
  • Symptoms/signs: Dyspnea 90.9%, orthopnea 53.5%, rales 81.0%, pedal edema 79.3%, JVD ≥10 cm 27.0%

Interventions

  • Randomization to tolvaptan 30 mg by mouth daily or placebo for at least 60 days
  • Physician-directed "standard" heart failure treatment with medications including diuretics, ACE-inhibitors/ARBs, aldosterone antagonists, hydralazine, and or nitrates

Outcomes

Comparisons are tolvaptan vs. placebo..

Primary Outcomes

All-cause mortality
25.9% vs. 26.3% (HR 0.98; 95% CI 0.87-1.11; superiority P=0.68; non-inferiority P<0.001)
Composite CV mortality or HF hospitalization
42.0% vs. 40.2% (HR 1.04; 95% CI 0.95-1.14; P=0.55)

Secondary Outcomes

Composite CV mortality or CV hospitalization
48.5% vs. 46.4% (P=0.52)
CV mortality
20.3% vs. 19.8% (P=0.67)
Worsening HF
36.5% vs. 35.8% (P=0.62)
Improvement in dyspnea score at one day
74.3% vs. 68.0% (P<0.001)
Weight
-1.76 vs. -0.97 kg (P<0.001)
Edema
73.8% vs. 70.5% (P=0.003)
Change in serum sodium at 7 days or discharge
5.49 mEq/L vs. 1.85 mEq/L (P<0.001)
Change in KCCQ score 1 week after discharge
+19.90 vs. +18.52 (P=0.39)

Subgroup Analysis

There were no differences in the primary outcome when stratified by sex, race, age, region, etiology of HF, dyspnea, severity of congestion, EF, SBP, NYHA class, sodium level, BUN, creatinine, AVP, BNP, beta-blocker use, ACE inhibitor/ARB use, or aldosterone antagonist use.

Adverse Events

Discontinuation
22% vs. 21%
Renal failure
6.4% vs. 6.8% (P=0.66)
Hypotension
11.3% vs. 11.0% (P=0.77)
Hypokalemia
8.0% vs. 9.8% (P=0.05)
Symptomatic
Thirst: 16% vs. 2.1% (P<0.001)
Dry mouth: 8.4% vs. 2.1% (P<0.001)

Criticisms

  • High rate of discontinuation of the study drug
  • Dose of therapy was not titrated

Funding

Otsuka, the maker of Samsca, the brand name of tolvaptan

Further Reading

  1. Yancy CW. "Climbing the mountain of acute decompensated heart failure." JAMA. 2007;297(12):1374-1376.
  2. Gheorghiade M, et al. "Short-term clinical effects of tolvaptan, an oral vasopressin antagonist, in patients hospitalized for heart failure." JAMA. 2007;297(12):1332-1343.
  3. Torres VE, et al. "Tolvaptan in patients with autosomal dominant polycystic kidney disease." N Eng J Med. 2012;367(25):2407-2418.
  4. FDA Safety Announcement. "FDA Drug Safety Communication: FDA limits duration and usage of Samsca (tolvaptan) due to possible liver injury leading to organ transplant or death." Released 2013-04-30. Accessed 2013-06-05.
  5. Yancy CW, et al. "2013 ACCF/AHA guideline for the management of heart failure." Circulation. 2013;128:e240-e327.