Vesnarinone Trial VEST

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Vesnarinone TrialVEST
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Chronic Heart Failure

• 500,000 new cases of heart failure each year
• Patients who survive heart attacks go on to be at
  risk for heart failure
• Patients with heart failure have an inefficient
  heart function (eg ejection fraction)
• A decade ago, few effect treatments beyond
  diuretics

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Vesnarinone Heart Failure

• A new class of drugs called inotropic drugs makes
  the heart beat harder and improves function
• Vesnarinone one of that class
• Previous studies demonstrate that vesnarinone
  does improve heart function
• A clinical trial evaluating effect on mortality
  morbidity designed

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Vesnarinone in Heart Failure Trial (1)

• First Trial (New Engl J of Med 329149-155, 1993)
• Patients with Class II-III heart failure
• Randomized double blind
• Vesnarinone vs. placebo
• Mortality outcome
• Observed a 50 reduction in mortality

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Vesnarinone Trial 93NEJM 329, 1993

• Background Inotropic therapy, other than with
  digitalis glycosides, has had limited success in
  patients with chronic congestive heart failure.
  We investigated whether vesnarinone, a new
  positive inotropic agent, reduces morbidity and
  mortality and improves the quality of life of
  patients with symptomatic heart failure.
• MethodsPatients receiving concomitant therapy
  with digoxin (87 percent) and an
  angiotensin-converting-enzyme inhibitor (90
  percent) who had ejection fractions of 30 percent
  or less were randomly assigned to receive
  double-blinded therapy with 60 mg of vesnarinone
  per day, 120 mg of vesnarinone per day, or
  placebo. After 253 patients had been enrolled,
  randomization to the 120-mg vesnarinone group had
  to be stopped because of a significant increase
  in early mortality in this group. Thereafter,
  patients were randomly assigned only to 60 mg of
  vesnarinone per day (a total of 239 patients) or
  placebo (a total of 238 patients).

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Vesnarinone 93
Table 1. Base-Line Clinical Characteristics of
the Study Patients
NEJM 329, 1993
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VESNARINONE 93(Temple, 1995)

• An inotrope and vasodilator
• A 60 mg dose had no effect on exercise tolerance
  or symptoms
• A 120 mg dose increases exercise tolerance and
  reduces symptoms
• 120 mg arm stopped early with increased mortality
  (6 vs. 16, plt.01
• 60 mg arm continued

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VESNARINONE(Temple, 1995)

• Plbo 60mg P
• Mortality 33/238 13/239 .002
• Mortality and
• Morbidity 50/238 26/239 .003

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Vesnarinone 93
Figure 1. Cumulative Incidence of Cardiovascular
Morbidity or Mortality from Any Cause, According
to Treatment Group. The values below the figure
are the numbers of patients in each group who
were at risk at base line and after each
eight-week period.
NEJM 329, 1993
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Vesnarinone 93
Figure 2. Cumulative Incidence of Mortality from
Any Cause, According to Treatment Group. The
values below the figure are the numbers of
patients in each group who were alive at base
line and after each eight-week period.
NEJM 329, 1993
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Vesnarinone 93
Table 3. Effect of Vesnarinone on the Combined
End Point of Morbidity and Mortality in
Prospectively Defined Subgroups
NEJM 329, 1993
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Vesnarinone 93
Table 4. Changes in Scores on the Sickness Impact
Profile and Other Measures between Base Line and
Week 12
NEJM 329, 1993
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Vesnarinone Trial (VEST)NEJM 329, 1993

• Results Significantly fewer patients in the
  group receiving 60 mg of vesnarinone than in the
  group receiving placebo (26 vs. 50 patients P
  0.003) died or had worsening heart failure during
  the six-month study period. The reduction in risk
  was 50 percent (95 percent confidence interval,
  20 to 69 percent). Similarly, there was a 62
  percent reduction (95 percent confidence
  interval, 28 to 80 percent) in the risk of dying
  from any cause among the patients receiving
  vesnarinone. Furthermore, quality of life
  improved to a greater extent in the vesnarinone
  group than in the placebo group over 12 weeks (P
  0.008). The principal side effect associated
  with vesnarinone was reversible neutropenia,
  which occurred in 2.5 percent of the patients.
• Conclusions Six months of therapy with 60 mg of
  vesnarinone per day resulted in lower morbidity
  and mortality and improved the quality of life of
  patients with congestive heart failure. However,
  a higher dose of vesnarinone (120 mg per day)
  increased mortality, suggesting that this drug
  has a narrow therapeutic range the long-term
  effects of vesnarinone are unknown.

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Vesnarinone (VEST)in Heart Failure (2)

• Second Trial (New Engl J of Med 3391810-16,
  1998)
• Two doses vs. placebo
• Randomize double blind
• Mortality outcome
• Observed significant increase in mortality
  (higher dose)

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Vesnarinone Trial (VEST)NEJM 339, 1998

• Background Vesnarinone, an inotropic drug was
  shown in a short-term placebo-controlled trial to
  improve survival markedly in patients with severe
  heart failure when given at a dose of 60mg/day,
  but there was a trend toward an adverse effect on
  survival when the dose was 120 mg/day. In a
  longer-term study, we evaluated the effects of
  daily doses of 60 mg or 30 mg of vesnarinone, as
  compared with placebo, on mortality and
  morbidity.
• Methods We enrolled 3833 patients who had
  symptoms of NYHA class III or IV heart failure
  and a left ventricular ejection fraction of 30
  or less despite optimal treatment. The mean
  follow-up was 286 days.

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VEST(NEJM, 1998)

• Vesnarinone vs. Placebo
• 60mg vs. 30 mg vs. placebo
• NYHA Class III/IV CHF patients
• LVEF less than 30
• 3833 patients randomized
• Primary Outcome All cause mortality
• Secondary Outcome
• Mortality plus CHF hospitalization
• Quality of Life

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Vesnarinone Trial (VEST)NEJM 339, 1998

• Results There were significantly fewer deaths
  in the placebo group (242 deaths, or 18.9) than
  in the 60-mg vesnarinone group (292 deaths, or
  22.9) and longer survival (P0.02). The increase
  in mortality with vesnarinone was attributed to
  an increase in sudden death, presumed to be due
  to arrhythmia. The quality of life had improved
  significantly more in the 60-mg vesnarinone group
  than in the placebo group at 8 weeks (Plt0.001)
  and 16 weeks (P0.003) after randomization.
  Trends in mortality and in measures of the
  quality of life in the 30-mg vesnarinone group
  were similar to those in the 60-mg group but not
  significantly different from those in the placebo
  group. Agranulocytosis occurred in 1.2 of the
  patients given 60 mg of vesnarinone/day and 0.2
  of those given 30 mg of vesnarinone.

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Vesnarinone Trial (VEST)
NEJM 339, 1998
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VESTSurvival in the Three Groups
NEJM 339, 1998
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Vesnarinone Trial (VEST)
NEJM 339, 1998
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Vesnarinone Trial (VEST)
TABLE 3. MAJOR MORBIDITY IN THE THREE
GROUPS 30 mg of 60 mg
of PLACEBO VESNARINONE VESNARINONE EVENT
(N1283) (N1275) (N1275) Any
hospitalization 635 (49.5) 602 (47.2) 617 (48.
4) For cardiac disease 509 (39.7) 488 (38.3)
487 (38.2) For worsening heart
failure 360 (28.1) 342 (26.8) 335 (26.3) Emerg
ency room visit 226 (17.6) 210 (16.5) 214 (16.8
) For cardiac disease 49 (3.8) 58 (4.5) 50 (3.
9)
NEJM 339, 1998
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Vesnarinone Trial (VEST)
TABLE 4. QUALITY OF LIFE SCORES IN THE THREE
GROUPS VARIABLE PLACEBO
30 mg of VESNARINONE 60 mg of
VESNARINONE MEDIAN MEAN SD MEDIAN MEAN SD P
VALUE MEDIAN MEAN SD P VALUE Base-line
score 55 53.323.6 -56 53.424.5 56 53.324.4
Change at 8 wk -5 -5.918.0 -5 -6.918.5 0.34
-7 -8.818.2 0.001 Change at 16
wk -6 -7.320.1 -5 -7.420.3 0.74 -8 -10.119.7
0.003 Change at 26 wk -7 -8.621.4 -7 -8.421.7
0.83 -7 -10.020.9 0.41 Lower scores
indicate better quality of life. P values are for
the comparison of the medians with those in the
placebo group.
NEJM 339, 1998
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VEST
NEJM 339, 1998
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Vesnarinone Trial (VEST)NEJM 339, 1998

• Conclusions Vesnarione is associated with a
  dose-dependent increase in mortality among
  patients with severe heart failure, an incrase
  that is probably related to an increase in deaths
  due to arrhythmia. A short-term benefit in terms
  of the quality of life raises issues about the
  appropriate therapeutic goal in treating heart
  failure.

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Vesnarinone Lesson

• Replication is the key to the scientific method
• Small trials with impressive results need to be
  replicated
• No explanation based on patient characteristics,
  compliance to treatment