COZAAR Rx

Nephropathy in Type 2 Diabetic Patients

The RENAAL study (n=1513) was a randomized, placebo-controlled, double-blind, multicenter study conducted worldwide in patients with type 2 diabetes with nephropathy (defined as serum creatinine 1.3–3.0 mg/dL in females or males ≤60 kg, and 1.5–3.0 mg/dL in males >60 kg and proteinuria [urinary albumin to creatinine ratio ≥300 mg/g]).

• Patients were randomly assigned to receive Cozaar 50 mg once daily or placebo on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists.
• After 1 month, patients were titrated on the study drug to 100 mg once daily if the trough blood pressure goal (140/90 mmHg) was not achieved.
• Overall, 72% of patients received the 100-mg daily dose more than 50% of the time they were on study drug. The study was designed to achieve equal blood pressure control in both groups, and therefore other antihypertensive agents (diuretics, calcium-channel blockers, alpha- or beta-blockers, and centrally acting agents) could be added as needed in both groups.
• Patients were followed for a mean duration of 3.4 years.
• The primary endpoint of the study was the time to first occurrence of any one of the following events: doubling of serum creatinine, end-stage renal disease (ESRD) (need for dialysis or transplantation), or death.
• Treatment with Cozaar resulted in a 16% risk reduction (P =0.022) in this endpoint.
• Treatment with Cozaar also reduced the occurrence of sustained doubling of serum creatinine by 25% and ESRD by 29% as separate endpoints, but had no effect on overall mortality.
• The secondary endpoints of the study were change in proteinuria, change in the rate of progression of renal disease, and the composite of morbidity and mortality from cardiovascular causes (hospitalization for heart failure, myocardial infarction, revascularization, stroke, hospitalization for unstable angina, or cardiovascular death).
• Compared with placebo, Cozaar significantly reduced proteinuria by an average of 34% within 3 months of treatment initiation, and significantly reduced the rate of decline in glomerular filtration rate during the study by 13% (as measured by the reciprocal of the serum creatinine concentration).
• There was no significant difference in the incidence of the composite endpoint of cardiovascular morbidity and mortality.

For more clinical trial data, see full labeling.

Adult Hypertension

The antihypertensive effects of Cozaar were evaluated in 4 placebo-controlled, 6- to 12-week trials of dosages from 10–150 mg per day in patients with baseline diastolic blood pressures of 95–115. The studies allowed comparisons of two doses (50–100 mg/day) as once-daily or twice-daily regimens, comparisons of peak and trough effects, and comparisons of response by gender, age, and race. Additionally, 3 studies examined the antihypertensive effects of losartan and hydrochlorothiazide in combination.

• In the 4 studies of losartan monotherapy, patients were randomly assigned to several doses of losartan (n=1075) and to placebo (n=334).
• The 10- and 25-mg doses produced some effect at peak (6 hours after dosing) but small and inconsistent trough (24 hour) responses.
• Doses of 50, 100 and 150 mg once daily demonstrated statistically significant systolic/diastolic mean decreases in blood pressure, compared to placebo in the range of 5.5–10.5/3.5–7.5 mmHg, with the 150-mg dose giving no greater effect than 50–100 mg.
• Twice-daily dosing at 50–100 mg/day demonstrated consistently larger trough responses than once-daily dosing at the same total dose. Peak (6 hour) effects were uniformly, but moderately, larger than trough effects, with the trough-to-peak ratio for systolic and diastolic responses 50–95% and 60–90%, respectively.
• Addition of a low dose of hydrochlorothiazide (12.5 mg) to losartan 50 mg once daily resulted in placebo-adjusted blood pressure reductions of 15.5/9.2 mmHg.
• Trial analysis of age, gender, and race subgroups of patients showed that men and women, and those over and under 65, had generally similar responses.
• Cozaar was effective in reducing blood pressure regardless of race, although the effect was somewhat less in Black patients (usually a low-renin population).

Pediatric Hypertension

The efficacy of losartan was studied in one trial (n=177) involving hypertensive pediatric patients aged 6 to 16 years old. Children who weighed <50 kg received 2.5, 25 or 50 mg of losartan daily and patients who weighed ≥50 kg received 5, 50 or 100 mg of losartan daily. Children in the lowest dose group were given losartan in a suspension formulation. The majority of the children had hypertension associated with renal and urogenital disease. 

• The sitting diastolic blood pressure (SiDBP) on entry into the study was higher than the 95th percentile level for the patient's age, gender, and height.
• At the end of 3 weeks, losartan reduced systolic and diastolic blood pressure, measured at trough, in a dose-dependent manner.
• Overall, the two higher doses (25–50 mg in patients <50 kg; 50–100 mg in patients ≥50 kg) reduced diastolic blood pressure by 5–6 mmHg more than the lowest dose used (2.5 mg in patients <50 kg; 5 mg in patients ≥50 kg).
• The lowest dose, corresponding to an average daily dose of 0.07 mg/kg, did not appear to offer consistent antihypertensive efficacy.
• When patients were randomly assigned to continue losartan at the two higher doses or to placebo after 3 weeks of therapy, trough diastolic blood pressure rose in patients on placebo between 5 and 7 mmHg more than those who were randomly assigned to continue losartan.
• When the low dose of losartan was randomly withdrawn, the rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan, again suggesting that the lowest dose did not have significant antihypertensive efficacy.
• Overall, no significant differences in the overall antihypertensive effect of losartan were detected when the patients were analyzed according to age (<, ≥12 years old) or gender. 

Hypertensive Patients with Left Ventricular Hypertrophy

The LIFE study (n=9193) was a multinational, double-blind trial comparing Cozaar vs atenolol in hypertensive patients with ECG-documented left ventricular hypertrophy. Patients with myocardial infarction or stroke within 6 months prior to randomization were excluded.

• Patients were randomly assigned to receive once daily Cozaar 50 mg or atenolol 50 mg. If goal blood pressure (<140/90 mmHg) was not reached, HCTZ (12.5 mg) was added first and, if needed, the dose of Cozaar or atenolol was then increased to 100 mg once daily.
• If necessary, other antihypertensive treatments (eg, increase in dose of HCTZ therapy to 25 mg or addition of other diuretic therapy, calcium-channel blockers, alpha-blockers, or centrally acting agents, except ACE inhibitors, angiotensin II antagonists, or beta-blockers) were added to the treatment regimen to achieve blood pressure goal.
• The mean duration of follow-up was 4.8 years.
• The primary endpoint was the first occurrence of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction.
• Patients with nonfatal events remained in the trial, so that there was also an examination of the first event of each type even if it was not the first event (eg, a stroke following an initial myocardial infarction would be counted in the analysis of stroke).
• Treatment with Cozaar resulted in a 13% reduction (P =0.021) in risk of the primary endpoint vs the atenolol group; this difference was primarily the result of an effect on fatal and nonfatal stroke.
• Treatment with Cozaar reduced the risk of stroke by 25% relative to atenolol (P =0.001).

Although the LIFE study favored Cozaar over atenolol with respect to the primary endpoint (P =0.021), this result is from a single study and, therefore, is less compelling than the difference between Cozaar and placebo. Although not measured directly, the difference between Cozaar and placebo is compelling because there is evidence that atenolol is itself effective (vs placebo) in reducing cardiovascular events, including stroke, in hypertensive patients.

For more clinical trial data, see full labeling.