Valsartan (Page 6 of 9)

Pediatric Hypertension

The antihypertensive effects of Valsartan were evaluated in two randomized, double-blind clinical studies.

In a clinical study involving 261 hypertensive pediatric patients 6 to 16 years of age, patients who weighed < 35 kg received 10, 40 or 80 mg of valsartan daily (low, medium and high doses), and patients who weighed ≥ 35 kg received 20, 80, and 160 mg of valsartan daily (low, medium and high doses). Renal and urinary disorders, and essential hypertension with or without obesity were the most common underlying causes of hypertension in children enrolled in this study. At the end of 2 weeks, valsartan reduced both systolic and diastolic blood pressure in a dose-dependent manner. Overall, the three dose levels of valsartan (low, medium and high) significantly reduced systolic blood pressure by -8, -10, -12 mmHg from the baseline, respectively. Patients were re-randomized to either continue receiving the same dose of valsartan or were switched to placebo. In patients who continued to receive the medium and high doses of valsartan, systolic blood pressure at trough was -4 and -7 mm Hg lower than patients who received the placebo treatment. In patients receiving the low dose of valsartan, systolic blood pressure at trough was similar to that of patients who received the placebo treatment. Overall, the dose-dependent antihypertensive effect of valsartan was consistent across all the demographic subgroups.

In a clinical study involving 90 hypertensive pediatric patients 1 to 5 years of age with a similar study design, there was some evidence of effectiveness, but safety findings for which a relationship to treatment could not be excluded mitigate against recommending use in this age group. [see Adverse Reactions (6.1)].

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 <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 table below.

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 (0.90-1.15) 0.8
HF morbidity 801 (32.1%) 723 (28.8%) 0.87 (0.79-0.97) 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.

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