Higher Dose of Merck's COZAAR (Losartan Potassium Tablets) Significantly Reduced Deaths and Hospitalizations Due to Heart Failure In Investigational Study

In an investigational study, Merck's medicine COZAAR (losartan potassium tablets) 150 mg, administered once daily, significantly reduced the risk of all-cause death or hospitalization due to heart failure compared to a lower 50 mg once daily dose of COZAAR. The Merck-sponsored study compared the safety and efficacy of two doses of COZAAR in patients with chronic heart failure and reduced cardiac function (left ventricular ejection fraction) who were intolerant of angiotensin-converting enzyme (ACE) inhibitors. The results of the study, called HEAAL -- Heart failure Endpoint evaluation of the A-II-Antagonist Losartan -- were presented by researchers during a late breaking clinical trial session at the American Heart Association (AHA) Scientific Sessions 2009.

COZAAR is not indicated in the U.S. for the treatment of patients with chronic heart failure and is not approved for use, for any indication, at the 150 mg dose used in the HEAAL study. COZAAR is an angiotensin II antagonist (AIIA), cardiovascular medicine approved for three indications:

• for the treatment of hypertension and may be used alone or in combination with other antihypertensive agents, including diruetics.
• to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, although there is evidence that this benefit does not apply to black patients.
• for the treatment of diabetic nephropathy with an elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio =300 mg/g) in patients with type 2 diabetes and a history of hypertension. In this population, COZAAR reduces the rate of progression of nephropathy as measured by the occurrence of doubling of serum creatinine or end stage renal disease (need for dialysis or renal transplantation).

"HEAAL is the first study to examine and document the incremental benefit on clinical outcomes of prescribing a higher dose of an angiotensin II antagonist in patients with heart failure," said lead study investigator Marvin A. Konstam, M.D., Chief Physician Executive, the Cardiovascular Center, Tufts Medical Center, and Professor of Medicine, Tufts University School of Medicine.

"HEAAL is another important study in a long-line of large outcomes studies that Merck has sponsored and conducted to help the medical community to better understand the role of our cardiovascular medicines in improving cardiovascular outcomes," said Francis Plat, M.D., Vice President and clinical therapeutic area head for Atherosclerosis and Cardiovascular, Merck Research Laboratories. "Like SOLV-D, 4S, LIFE and RENAAL, this study, too, advances our understanding of the role that pharmaceutical innovations can have and answers an important outstanding question as only a clinical outcomes trial can."

About the HEAAL Study
Study results demonstrated COZAAR administered in a 150 mg once daily dose, when compared with COZAAR 50 mg per day, significantly reduced the risk of the primary composite endpoint (all cause death or hospitalization for heart failure) in patients with reduced left ventricular ejection fraction (LVEF); and reduced ACE inhibitor intolerance (p=0.027).

The multicenter, prospective, randomized, double-blind, event-driven clinical trial enrolled 3,834 patients with symptomatic congestive heart failure intolerant of ACE inhibitor treatment at 255 sites in 30 countries. Patients were randomized to two treatment arms: COZAAR 150 mg once daily (n=1,921) and COZAAR 50 mg once daily (n=1,913). Among these patients, 3,723 completed endpoint follow-up with a median follow-up time of 4.7 years. Prior to randomization, patients not already receiving an AIIA were titrated onto losartan from 12.5 mg daily to 25 mg daily over two weeks. For patients already receiving an AIIA, their prescription was discontinued, and investigators had the option of initiating open-label losartan 25 mg daily for one week or directly randomizing the patient.

The primary composite endpoint of the HEAAL study was all cause death or hospitalization for heart failure and the secondary composite endpoint was all cause death or cardiovascular hospitalization. Secondary symptom assessments, including an increase in LVEF and changes in New York Heart Association (NYHA) classification, were also completed.

Patients in the COZAAR 150 mg treatment group had a significantly lower risk of hospitalization due to heart failure or cardiovascular hospitalization compared to patients in the 50 mg treatment group. 450 patients in the COZAAR 150 mg treatment group (6.0 per 100 patient-years of follow-up) were hospitalized for heart failure during the course of the study compared to 503 patients in the 50 mg treatment group (7.0 per 100 patient-years of follow-up) (p=0.025).

Renal impairment, hyperkalameia (p<0.001), hypotension (p=0.002) and angioedema (p=0.03) as defined by the investigator were more common in the COZAAR 150 mg group than in the 50 mg treatment arm. Renal impairment was the adverse event which most commonly lead to drug discontinuation in the two groups (0.65 and 0.49 per 100 patient years respectively) but the number (and rate) of individual or total discontinuations were similar for the two treatment groups.

Additional important information about COZAAR
When used in pregnancy during the second or third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, COZAAR should be discontinued as soon as possible.

COZAAR is contraindicated in patients who are hypersensitive to any component of these products. All patients receiving thiazides should be observed for clinical signs of fluid or electrolyte imbalance, including hypokalemia.

In patients who are volume-depleted, symptomatic hypotension may occur after initiation of therapy with COZAAR. This condition should be corrected prior to administration of COZAAR, or a dosage of COZAAR 25 mg should be used. As with other drugs that block angiotensin II or its effects, concomitant use of potassium-sparing diuretics, potassium supplements, or salt substitutes containing potassium may lead to increases in serum potassium.

In clinical trials with COZAAR for hypertension, the most common adverse events with an incidence greater or equal to two percent of patients treated with COZAAR (n=1,075) and occurring more commonly than placebo (n=334) included upper respiratory infection (8 percent for COZAAR vs. 7 percent for placebo), dizziness (3 percent for COZAAR vs. 2 percent for placebo), nasal congestion (2 percent for COZAAR vs. 1 percent for placebo), and back pain (2 percent for COZAAR vs. 1 percent for placebo).

Dosing and administration
In patients with hypertension, the usual starting dose is COZAAR 50 mg once daily. The maximum daily dose is 100 mg. If the antihypertensive effect measured at trough using once-a-day dosing is inadequate, a twice-a-day regimen at the same total daily dose or an increase in dose may give a more satisfactory response. In patients who are volume-depleted, symptomatic hypotension may occur after initiation of therapy with COZAAR. This condition should be corrected prior to administration of COZAAR, or a dosage of COZAAR 25 mg should be used. In patients with a history of hepatic impairment, a starting dose of COZAAR 25 mg should be used. In hypertensive patients with left ventricular hypertrophy, treatment should be initiated with COZAAR 50 mg once daily.

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SOURCE: Merck