Valsartan (Page 6 of 8)

14.2 Heart Failure

The Valsartan Heart Failure Trial (Val-HeFT) was a multinational, double-blind study in which 5,010 patients with NYHA class II (62%) to IV (2%) heart failure and LVEF less than 40%, on baseline therapy chosen by their physicians, were randomized to placebo or valsartan (titrated from 40 mg twice daily to the highest tolerated dose or 160 mg twice daily) and followed for a mean of about 2 years. Although Val-HeFT’s primary goal was to examine the effect of valsartan when added to an ACE inhibitor, about 7% were not receiving an ACE inhibitor. Other background therapy included diuretics (86%), digoxin (67%), and beta-blockers (36%). The population studied was 80% male, 46% 65 years or older and 89% Caucasian. At the end of the trial, patients in the valsartan group had a blood pressure that was 4 mmHg systolic and 2 mmHg diastolic lower than the placebo group. There were two primary end points, both assessed as time to first event: all-cause mortality and heart failure morbidity, the latter defined as all-cause mortality, sudden death with resuscitation, hospitalization for heart failure, and the need for intravenous inotropic or vasodilatory drugs for at least 4 hours. These results are summarized in the following table.

Placebo

(N=2,499)

Valsartan

(N=2,511)

Hazard Ratio

(95% CI*)

Nominal

p-value

All-cause mortality

484 (19.4%)

495 (19.7%)

1.02 (0.90 to 1.15)

0.8

HF morbidity

801 (32.1%)

723 (28.8%)

0.87 (0.79 to 0.97)

0.009

* CI = Confidence Interval

Although the overall morbidity result favored valsartan, this result was largely driven by the 7% of patients not receiving an ACE inhibitor, as shown in the following table.

Without ACE Inhibitor

With ACE Inhibitor

Placebo

(N=181)

Valsartan

(N=185)

Placebo

(N=2,318)

Valsartan

(N=2,326)

Events (%)

77 (42.5%)

46 (24.9%)

724 (31.2%)

677 (29.1%)

Hazard ratio (95% CI)

0.51 (0.35, 0.73)

0.92 (0.82, 1.02)

p-value

0.0002

0.0965

The modest favorable trend in the group receiving an ACE inhibitor was largely driven by the patients receiving less than the recommended dose of ACE inhibitor. Thus, there is little evidence of further clinical benefit when valsartan is added to an adequate dose of ACE inhibitor.

Secondary end points in the subgroup not receiving ACE inhibitors were as follows.

Placebo

(N=181)

Valsartan

(N=185)

Hazard Ratio

(95% CI)

Components of HF morbidity

All-cause mortality

49 (27.1%)

32 (17.3%)

0.59 (0.37, 0.91)

Sudden death with resuscitation

2 (1.1%)

1 (0.5%)

0.47 (0.04, 5.20)

CHF therapy

1 (0.6%)

0 (0.0%)

CHF hospitalization

48 (26.5%)

24 (13.0%)

0.43 (0.27, 0.71)

Cardiovascular mortality

40 (22.1%)

29 (15.7%)

0.65 (0.40, 1.05)

Non-fatal morbidity

49 (27.1%)

24 (13.0%)

0.42 (0.26, 0.69)

In patients not receiving an ACE inhibitor, valsartan-treated patients had an increase in ejection fraction and reduction in left ventricular internal diastolic diameter (LVIDD).

Effects were generally consistent across subgroups defined by age and gender for the population of patients not receiving an ACE inhibitor. The number of black patients was small and does not permit a meaningful assessment in this subset of patients.

14.3 Post-Myocardial Infarction

The VALsartan In Acute myocardial iNfarcTion trial (VALIANT) was a randomized, controlled, multinational, double-blind study in 14,703 patients with acute myocardial infarction and either heart failure (signs, symptoms or radiological evidence) or left ventricular systolic dysfunction (ejection fraction ≤40% by radionuclide ventriculography or ≤35% by echocardiography or ventricular contrast angiography). Patients were randomized within 12 hours to 10 days after the onset of myocardial infarction symptoms to one of three treatment groups: valsartan (titrated from 20 or 40 mg twice daily to the highest tolerated dose up to a maximum of 160 mg twice daily), the ACE inhibitor, captopril (titrated from 6.25 mg three times daily to the highest tolerated dose up to a maximum of 50 mg three times daily), or the combination of valsartan plus captopril. In the combination group, the dose of valsartan was titrated from 20 mg twice daily to the highest tolerated dose up to a maximum of 80 mg twice daily; the dose of captopril was the same as for monotherapy. The population studied was 69% male, 94% Caucasian, and 53% were 65 years of age or older. Baseline therapy included aspirin (91%), beta-blockers (70%), ACE inhibitors (40%), thrombolytics (35%) and statins (34%). The mean treatment duration was 2 years. The mean daily dose of valsartan in the monotherapy group was 217 mg.

The primary endpoint was time to all-cause mortality. Secondary endpoints included (1) time to cardiovascular (CV) mortality, and (2) time to the first event of cardiovascular mortality, reinfarction, or hospitalization for heart failure. The results are summarized in the following table.

Valsartan vs. Captopril (N=4,909) N=4,909)

Valsartan + Captopril vs. Captopril (N=4,885) (N=4,909)

No. of Deaths Valsartan/Captopril

Hazard Ratio CI


p-value

No. of Deaths Comb/Captopril

Hazard Ratio CI


p-value

All-cause mortality

979 (19.9%)
/958 (19.5%)

1.001 (0.902, 1.111)

0.98

941 (19.3%)
/958 (19.5%)

0.984
(0.886, 1.093)

0.73

CV mortality

827 (16.8%)
/830 (16.9%)

0.976 (0.875, 1.090)

CV mortality, hospitalization for HF, and recurrent non-fatal MI


1,529 (31.1%)
/1,567 (31.9%)


0.955 (0.881, 1.035)

There was no difference in overall mortality among the three treatment groups. There was thus no evidence that combining the ACE inhibitor captopril and the angiotensin II blocker valsartan was of value.

The data were assessed to see whether the effectiveness of valsartan could be demonstrated by showing in a non-inferiority analysis that it preserved a fraction of the effect of captopril, a drug with a demonstrated survival effect in this setting. A conservative estimate of the effect of captopril (based on a pooled analysis of 3 post-infarction studies of captopril and 2 other ACE inhibitors) was a 14% to 16% reduction in mortality compared to placebo. Valsartan would be considered effective if it preserved a meaningful fraction of that effect and unequivocally preserved some of that effect. As shown in the table, the upper bound of the CI for the hazard ratio (valsartan/captopril) for overall or CV mortality is 1.09 to 1.11, a difference of about 9% to 11%, thus making it unlikely that valsartan has less than about half of the estimated effect of captopril and clearly demonstrating an effect of valsartan. The other secondary endpoints were consistent with this conclusion.

Effects on Mortality Amongst Subgroups in VALIANT
(click image for full-size original)

There were no clear differences in all-cause mortality based on age, gender, race, or baseline therapies, as shown in the figure above.

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