Diovan

[Valsartan]

The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear.

Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure.

The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive. The 7 studies of valsartan monotherapy included over 2,000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ to valsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone.

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Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups. In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg.

There was essentially no change in heart rate in valsartan-treated patients in controlled trials.

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 Valsartan Hazard Ratio Nominal (N= 2,499) (N= 2,511) (95% CI*) p-value
All-cause mortality 484 495 1.02 0.80 (19.4%) (19.7%) (0.90-1.15)

HF morbidity 801 723 0.87 0.009 (32.1%) (28.8%) (0.79-0.97)
* 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 Valsartan Placebo Valsartan
(N= 181) (N= 185) (N= 2,318) (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 Valsartan Hazard ratio
(N= 181) (N= 185) (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).

Concomitant use of an ACE inhibitor, a beta-blocker, and valsartan was associated with a worse outcome for heart failure morbidity, as shown in the following table.

Placebo Valsartan Hazard ratio
(N= 816) (N= 794) (95% CI)

Heart failure morbidity 179 (21.9%) 202 (25.4%) 1. 18 (0. 97, 1.45)
All-cause mortality 97 (11.9%) 129 (16.2%) 1. 42 (1. 09, 1.85)

It is not known if this is a reproducible effect or a chance occurrence. The use of a beta-blocker did not appear to influence the effect of valsartan in patients not receiving an ACE inhibitor.

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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