Valsartan (Page 6 of 8)

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

Valsartan + Captopril vs. Captopril

(N=4,909)

(N=4,909)

(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.

1
(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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Valsartan tablets, USP are available as tablets containing valsartan, USP 40 mg, 80 mg, 160 mg, or 320 mg.

Valsartan tablets USP, 40 mg, are supplied as yellow, oval, film-coated scored tablets debossed with “3” bisect “7” on one side and “AN” on the other side.

They are available as follows:

Bottles of 30: NDC 42291-856-30

Valsartan tablets USP, 80 mg, are supplied as pink, oval, film-coated tablets with beveled edges, debossed with “838” on one side and “AN” on the other side.
They are available as follows:

Bottles of 90: NDC 42291-857-90

Valsartan tablets USP, 160 mg, are supplied as yellow, oval, film-coated tablets with beveled edges, debossed with “839” on one side and “AN” on the other side.
They are available as follows:

Bottles of 90: NDC 42291-858-90

Valsartan tablets USP, 320 mg, are supplied as brown, oval, film-coated tablets with beveled edges, debossed with “840” on one side and “AN” on the other side.
They are available as follows:

Bottles of 90: NDC 42291-859-90

Store at 20º to 25ºC (68º to 77ºF); excursions permitted between 15º to 30ºC (59º to 86ºF) [see USP Controlled Room Temperature].

Protect from moisture.

Dispense in a tight container with a child-resistant closure as defined in the USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Pregnancy: Advise female patients of childbearing age about the consequences of exposure to valsartan tablets during pregnancy. Discuss treatment options with women planning to become pregnant. Ask patients to report pregnancies to their healthcare provider as soon as possible [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)] .

Lactation: Advise women not to breastfeed during treatment with valsartan [see Use in Specific Populations (8.2)].

Symptomatic Hypotension: Advise patients that lightheadedness can occur, especially during the first days of therapy, and that it should be reported to their healthcare provider. Tell patients that if syncope occurs to discontinue valsartan until the physician has been consulted. Caution all patients that inadequate fluid intake, excessive perspiration, diarrhea, or vomiting can lead to an excessive fall in blood pressure, with the same consequences of lightheadedness and possible syncope [see Warnings and Precautions (5.2)] .

Hyperkalemia: Advise patients not to use salt substitutes without consulting their healthcare provider [see Drug Interactions (7.1)] .

Manufactured for:

AvKARE

Pulaski, TN 38478

Manufactured by:
Amneal Pharmaceuticals of New York, LLC
Brookhaven, NY 11719

Rev. 10-2019-03 AV 05/20

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