__________________________

The Cardio-Renal Advisory Committee is asked to give counsel regarding the use of valsartan for the treatment of chronic congestive heart failure. Pre-clinical pharmacology, biopharmaceutics, and chemistry present no barriers to its approval.

The development program randomized a total of 6,120 patients in 5 clinical trials. There were 2 studies of acute hemodynamics and 3 studies of clinical benefit. An effect on acute hemodynamics is not an appropriate basis for approval of a treatment for chronic heart failure. In ascending order of size, the studies of clinical benefit were:

  1. Consider the exercise tolerance studies 110 and 106.
    1. In study 110, all subjects were on ACE inhibitor for at least 3 months prior to enrollment. Thus, subjects randomized to valsartan were withdrawn from ACE inhibitor. What is known about the time course for the loss of effects of an ACE inhibitor on exercise tolerance?
    2. In study 110, subjects walked 420 meters in 6 minutes at baseline. What degree of impairment does this represent?
    3. What is known about effects of valsartan and enalapril on exercise can be summarized as follows:

     

    Treadmill

    6-minute

    Enalapril vs. placebo

    Improved

    No data

    Valsartan vs placebo

    Unaffected

    No data

    Valsartan vs enalapril

    No data

    Similar

    What is the effect of valsartan on exercise tolerance?

     

     

     

     

  2. Ignoring Val-HeFT, …
    1. …what role do the 2 studies of hemodynamics and 2 studies of exercise ability and quality of life have in the case for approval?
    1. …how important are these 4 studies in the case for approval?
  1. Consider the components of the morbidity and mortality end point of Val-HeFT.
  2.  

    Events

    Hazarda

    P

    All-cause mortality

    979

    1.02

    0.80

    CHF hospitalizations

    812

    0.73

    <0.0001

    Resuscitations

    50

    0.66

    0.15

    CHF therapy

    15

    0.87

    0.79

    aValsartan:placebo

    1. What role do each of the components have in the case for approval?
    1. How do you reconcile large effects on CHF hospitalization with post-hoc analyses that show little or no effect on…
  1. If more Val-HeFT patients on valsartan had had events, the hazard ratio and the p-value would both have been larger. If fewer patients on valsartan had had events the hazard ratio and p-value would both have been smaller. The actual study result is in the middle of the scale below. If Val-HeFT had had no secondary end points other than components of its primary end point, but all other aspects of this development program were unchanged, what value for the hazard ratio would be necessary to conclude the development program was successful? Why do you pick the value you do?
  2. Hazard 0.82 0.85 0.87 0.90 0.92

    ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½

    P-value 0.0001 0.00125 0.009 0.05 0.1

     

     

     

     

     

     

     

  3. Consider other end points that were not individual components of the morbidity-mortality primary end point of Val-HeFT.
 

Favors

P

 

Favors

P

Cardiovascular mortality

Placebo

0.86

Signs & symptoms

Paroxysmal nocturnal dyspnea

Fatigue

Edema

Dyspnea at rest

Dyspnea on effort

Orthopnea

Jugular venous distension

Rales

Third heart sound

Valsart

Valsart

Valsart

Valsart

Valsart

Valsart

Valsart

Valsart

Valsart

0.001

0.010

0.003

0.037

0.003

0.2

0.001

0.001

0.22

NYHA class

Valsart

0.001

Ejection fraction

Valsart

0.001

Left ventricular diastolic diameter

Valsart

0.0001

Quality of life questionnaire

Overall

Physical

Emotional

Valsart

Valsart

Valsart

0.004

0.009

0.029

What role do each of these secondary end points have in the case for approval?

  1. If all other aspects of this development program were unchanged, including what you know about all of Val-HeFT's secondary end points, what value for the hazard ratio would be necessary to conclude the development program was successful? Why do you pick the value you do?
  2. Hazard 0.82 0.85 0.87 0.90 0.92

    ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½ ¾ ¾ ¾ ¾ ¾ ¾ ¾ ½

    P-value 0.0001 0.00125 0.009 0.05 0.1

  3. Consider the effects on mortality and morbidity end points by (non-randomized) use of ACE inhibitors and beta-blockers:
 

Mortalitya

Morbiditya

Beta-blocker

Beta-blocker

Yes

No

All

Yes

No

All

ACEI

Yes

1.09, 1.85

0.81, 1.11

0.93, 1.21

0.97, 1.45

0.73, 0.93

0.82, 1.03

No

0.37, 1.74

0.28, 0.86

0.37, 0.91

0.26, 0.97

0.34, 0.81

0.35, 0.73

All

1.05, 1.73

0.79, 1.06

 

0.91, 1.33

0.71, 0.90

 

a95% confidence limits for hazard ratio (valsartan : placebo)

With which of the following hypotheses are these data most consistent?

  1. Evaluate the following findings with respect to whether they are considerations related to approval, or to labeling:
  1. Has adequate information been obtained to describe instructions for the use of valsartan in heart failure?
  2. Should valsartan be approved for use in the treatment of patients with chronic congestive heart failure? If so, what should labeling say about …
    1. … patients also receiving ACE inhibitors?
    1. … patients also receiving beta-blockers?
    1. … use in Blacks?
    2. … any other issues?