Pharmacology
FDA Approves Fixed-dose Combination Antihypertensive Drug to Reduce the Risk of Stroke
By Merck & Co. Inc.
Apr 18, 2005, 08:54

Merck & Co., Inc. today announced that the U.S. Food and Drug Administration ( FDA ) has approved another new indication for HYZAAR�, Merck's fixed-dose combination antihypertensive drug ( losartan potassium-hydrochlorothiazide tablets ). HYZAAR is now indicated to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy ( LVH ), but there is evidence that this benefit does not apply to black patients.

The new indication for reduction in stroke is based on the landmark LIFE ( Losartan Intervention for Endpoint Reduction in Hypertension ) study.

In March 2003, the FDA approved the same indication for Merck's antihypertensive drug COZAAR� ( losartan potassium tablets ). HYZAAR and COZAAR are the only angiotensin II receptor blockers ( ARBs ) to be indicated to reduce the risk of stroke in patients with hypertension and LVH. HYZAAR is the fixed dose combination of COZAAR ( losartan potassium ) and hydrochlorothiazide. The FDA approved this indication for HYZAAR based on:

1 ) the utilization of COZAAR and hydrochlorothiazide in the study - the patients in both arms were coadministered hydrochlorothiazide the majority of time they were on study drug ( 73.9% and 72.4% of days in the COZAAR and atenolol arms, respectively ) and;

2 ) demonstration by Merck that the losartan and hydrochlorothiazide tablets used in the LIFE study were bioequivalent to the marketed HYZAAR tablets.

In the 9,193-patient LIFE study, treatment with a regimen based on losartan ( COZAAR ) significantly reduced the risk of stroke ( fatal and nonfatal ) by 25 percent in patients with hypertension and LVH versus treatment with a regimen based on the beta-blocker atenolol ( p=0.001 ).

There were 232 fatal and nonfatal strokes in the group treated with losartan, and 309 in the atenolol group. Other findings from the LIFE study showed no significant difference between the treatment groups in the risk of heart attack or cardiovascular death.

"The LIFE study, for the first time, showed that a losartan-based regimen was more effective than an atenolol-based regimen at reducing the risk of stroke in patients with hypertension and LVH, despite similar blood pressure reductions in the treatment groups," said George L. Bakris, M.D., F.A.C.P., F.C.P., director, Hypertension/Clinical Research Center, Rush University Medical Center in Chicago.

Blood pressure reduction measured at trough was similar for both treatment groups. At the end of the study or at the last visit before a primary endpoint, the mean blood pressures were 144.1/81.3 mmHg for the losartan-based group and 145.4/80.9 mmHg for the atenolol-based group. The difference in systolic blood pressure of 1.3 mmHg was significant ( p less than 0.001 ), while the difference of 0.4 mmHg in diastolic blood pressure was not significant ( p=0.098 ).

The impact of stroke

According to the 2005 update of the American Heart Association's Heart Disease and Stroke Statistics, each year an estimated 700,000 Americans experience a new or recurrent stroke. Stroke is the third leading cause of death and a leading cause of severe, long-term disability in the United States. Left ventricular hypertrophy, a thickening of the heart's main pumping chamber ( the left ventricle ), is the most common cardiac abnormality associated with longstanding hypertension and is an important predictor of the risk of stroke. Not all patients with stroke have both hypertension and LVH.

"High blood pressure is the most important risk factor for stroke," said Dr. Bakris. "Widely used guidelines state that more than two-thirds of patients with hypertension require two or more therapies to reach their blood pressure goal, one of which should usually be a thiazide-type diuretic. HYZAAR, in addition to effective blood pressure lowering, now also offers physicians an effective treatment for reducing the risk of stroke in those appropriate patients with hypertension and LVH."

New indication for HYZAAR based on LIFE trial

In the LIFE trial, 4,605 patients were randomized to receive once daily losartan 50 mg and 4,588 patients to receive once daily atenolol 50 mg. If goal blood pressure ( less than 140/90 mmHg ) was not reached, hydrochlorothiazide ( 12.5 mg ) was added first and, if needed, the dose of losartan or atenolol was then increased to 100 mg once daily. If necessary, other antihypertensive treatments ( e.g., increase in dose of hydrochlorothiazide therapy to 25 mg or addition of other diuretic therapy, calcium channel blockers, alpha-blockers, or centrally acting agents, but not ACE inhibitors, angiotensin II antagonists, or beta-blockers ) were added to the treatment regimen to reach the goal blood pressure. Patients in the LIFE trial were followed for an average of 4.8 years.

The results showed that in patients treated with losartan, the risk of first occurrence of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction ( primary endpoint ) was reduced by a statistically significant 13 percent ( p= 0.021 ) compared to patients treated with atenolol. This difference was primarily the result of an effect on fatal and nonfatal stroke. At least one of the components ofthe primary composite endpoint occurred in 508 patients in the group taking losartan and in 588 patients in the atenolol arm.

The new label for HYZAAR also states that, in the LIFE trial, black patients with hypertension and LVH taking atenolol had a lower risk of stroke than those taking COZAAR. Given the difficulty in interpreting subset differences in large trials, it cannot be known whether the observed difference is the result of chance. However, the LIFE study does not provide evidence that the benefits of COZAAR on reducing the risk of cardiovascular events in hypertensive patients with left ventricular hypertrophy apply to black patients.

The label indicates that the usual starting dose for hypertensive patients with LVH is 50 mg of losartan once daily. Hydrochlorothiazide 12.5 mg should be added or HYZAAR 50-12.5 substituted if the blood pressure reduction is inadequate. If additional blood pressure reduction is needed, COZAAR 100 mg and hydrochlorothiazide 12.5 mg may be substituted, followed by COZAAR 100 mg and hydrochlorothiazide 25 mg or HYZAAR 100-25. The maximum dose is one tablet of HYZAAR 100-25 once daily.

HYZAAR offered an excellent tolerability profile in the LIFE study

In clinical trials, including the LIFE study, treatment with losartan potassium-hydrochlorothiazide was generally well tolerated. In these trials, adverse experiences have been limited to those that were reported previously with losartan potassium and/or hydrochlorothiazide. Adverse events occurred at about the same rates in men and women. Adverse events were somewhat more frequent in the elderly compared to non-elderly patients and somewhat more frequent in blacks compared to non-blacks for both the losartan-hydrochlorothiazide and the control groups.

HYZAAR for initial use in appropriate patients with severe hypertension

In addition to the new indication for HYZAAR to reduce the risk of stroke in patients with hypertension and LVH, HYZAAR is also the only combination antihypertensive product that is indicated for initial use in appropriate patients with severe hypertension. HYZAAR is not indicated for initial therapy of hypertension, except when the hypertension is severe enough that the value of achieving prompt blood pressure control exceeds the risk of initiating combination therapy in these patients. This unique indication is based on a six week double-blind, randomized study of the efficacy and safety of HYZAAR as initial therapy for severe hypertension ( defined as a mean SiDBP more than 110mmHg confirmed on two separate occasions off all antihypertensive therapy ).

Selected important information about HYZAAR and 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 and HYZAAR should be discontinued as soon as possible.

COZAAR and HYZAAR are contraindicated in patients who are hypersensitive to any component of these products. Because of the hydrochlorothiazide component, HYZAAR is also contraindicated in patients with anuria ( absence of urine formation ) or hypersensitivity to other sulfonamide-derived drugs.

HYZAAR is not recommended for patients with severe renal impairment ( creatinine clearance less than 30mL/min ). HYZAAR is not recommended for titration for patients with hepatic impairment because the appropriate 25 mg starting dose of COZAAR cannot be given. In patients who are volume-depleted ( e.g., those treated with diuretics ), symptomatic hypotension may occur after initiation of therapy with HYZAAR.

This condition should be corrected prior to administration of HYZAAR. 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. In patients with a history of hepatic impairment, a starting dose 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 other clinical trials with losartan 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 losartan vs. 7 percent for placebo ),
-dizziness ( 3 percent for losartan vs. 2 percent for placebo ),
-nasal congestion ( 2 percent for losartan vs. 1 percent for placebo ), and
-back pain ( 2 percent for losartan vs. 1 percent for placebo )

In other clinical trials with losartan potassium-hydrochlorothiazide, the overall incidence of adverse events was comparable to placebo.

The most common adverse events occurring with various doses of losartan potassium-hydrochlorothiazide ( n=858 ) at a rate of one percent or more above placebo ( n=173 ) were:

-upper respiratory infection ( 6.1 percent vs. 4.6 percent ),
-dizziness ( 5.7 percent vs. 2.9 percent ),
-cough ( 2.6 percent vs. 2.3 percent ),
-back pain ( 2.1 percent vs. 0.6 percent ),
-palpitations ( 1.4 percent vs. 0 percent ) and
-rash ( 1.4 percent vs. 0 percent ).

In the clinical study supporting the initial therapy indication, the overall side effect profile for patients with severe hypertension treated with HYZAAR as initial therapy was similar to the side effect profile in patients with severe hypertension treated with COZAAR as initial therapy.

During the study period there were no reported cases of syncope in either treatment group. There were two ( 0.6 percent ) cases and no cases of hypotension reported in the groups treated with HYZAAR and COZAAR, respectively. There were three ( 0.8 percent ) cases and two ( 1.2 percent ) cases of increased serum creatinine ( > 0.5 mg/dL ) in the groups treated with HYZAAR and COZAAR, respectively, during the same time period.

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