Cozaar

Pharmacotherapeutic group: Angiotensin II receptor antagonists, plain; ATC code: C09CA01 Losartan is a synthetic orally active angiotensin II receptor (type AT1) antagonist. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to the AT1 receptor, which is found in many tissues (e.g., vascular smooth muscle, the adrenal glands, the kidneys, and the heart) and mediates several important biological actions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates smooth muscle cell proliferation. Losartan selectively blocks the AT1 receptor. In vitro and in vivo, losartan and its pharmacologically active carboxylic acid metabolite E-3174 block all physiologically relevant actions of angiotensin II, irrespective of the source or route of its synthesis. Losartan has no agonist effect and does not block other hormone receptors or ion channels important in cardiovascular regulation. Furthermore, losartan does not inhibit ACE (kininase II), the enzyme that degrades bradykinin. Consequently, it does not potentiate bradykinin-mediated adverse effects. During administration of losartan, removal of the angiotensin II-mediated negative feedback on renin secretion leads to an increase in plasma renin activity (PRA). The increase in PRA leads to an increase in plasma angiotensin II. Despite these increases, antihypertensive activity and the suppression of plasma aldosterone concentrations are maintained, indicating effective angiotensin II receptor blockade. Following discontinuation of losartan, PRA and angiotensin II levels returned to baseline within three days. Both losartan and its principal active metabolite have a much higher affinity for the AT1 receptor than for the AT2 receptor. The active metabolite is 10 to 40 times more potent by weight than losartan. Hypertension studies In controlled clinical studies, once-daily administration of losartan to patients with mild to moderate essential hypertension produced statistically significant reductions in systolic and diastolic blood pressure. Measurement of blood pressure at 24 hours post-dose, compared with 5 to 6 hours post-dose, demonstrated reduction of blood pressure over 24 hours; the natural diurnal rhythm was preserved. Reduction in blood pressure at the end of the dosing interval was 70 to 80% of the effect observed 5 to 6 hours post-dose. Discontinuation of losartan in hypertensive patients did not result in an abrupt rebound increase in blood pressure. Despite the marked reduction in blood pressure, losartan had no clinically significant effects on heart rate. Losartan is equally effective in women and men, as well as in younger (under 65 years) and older hypertensive patients. LIFE study The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study was a randomised, triple-blind, active-controlled trial conducted in 9,193 hypertensive patients aged 55 to 80 years with ECG-documented left ventricular hypertrophy. Patients were randomised to once-daily losartan 50 mg or once-daily atenolol 50 mg. If target blood pressure (< 140/90 mmHg) was not achieved, hydrochlorothiazide (12.5 mg) was added first, and the dose of losartan or atenolol was subsequently increased to 100 mg once daily if necessary. Other antihypertensives, with the exception of ACE inhibitors, angiotensin II antagonists, or beta-blockers, were added if required to attain the target blood pressure. Mean follow-up was 4.8 years. The primary efficacy endpoint was a composite of cardiovascular morbidity and mortality, measured by the reduction in the combined incidence of cardiovascular death, stroke, and myocardial infarction. Blood pressure was significantly reduced to similar levels in both groups. Treatment with losartan resulted in a 13% reduction in risk versus atenolol (p = 0.021, 95% confidence interval 0.77–0.98) for patients reaching the primary composite endpoint. This was largely attributable to a reduction in the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% versus atenolol (p = 0.001, 95% confidence interval 0.63–0.89). Rates of cardiovascular death and myocardial infarction did not differ significantly between the treatment groups. Race In the LIFE study, Black patients treated with losartan had a higher risk of experiencing the primary composite endpoint, i.e., a cardiovascular event (e.g., myocardial infarction, cardiovascular death) and particularly stroke, than Black patients treated with atenolol. Therefore, the results observed with losartan compared with atenolol in the LIFE study with regard to cardiovascular morbidity/mortality do not apply to Black patients with hypertension and left ventricular hypertrophy. RENAAL study The Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study was a controlled clinical trial conducted worldwide in 1,513 patients with type 2 diabetes and proteinuria, with or without hypertension. A total of 751 patients were treated with losartan. The objective of the study was to demonstrate the nephroprotective effects of losartan potassium beyond the benefits of blood pressure reduction. Patients with proteinuria and a serum creatinine of 1.3–3.0 mg/dL were randomised to losartan 50 mg once daily, titrated as needed to achieve a blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACE inhibitors and angiotensin II antagonists. Investigators were instructed to titrate study medication to 100 mg daily as needed; 72% of patients received the 100 mg daily dose for most of the study period. A range of additional antihypertensives (diuretics, calcium antagonists, alpha- and beta-blockers, as well as centrally acting antihypertensives) was permitted as adjunctive therapy as required in both groups. Patients were followed for up to 4.6 years (mean 3.4 years). The primary efficacy endpoint was a composite of doubling of serum creatinine, end-stage renal disease (need for dialysis or transplantation), or death. The results showed that treatment with losartan (327 events) compared with placebo (359 events) led to a 16.1% risk reduction (p = 0.022) for patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results also showed a significant risk reduction in the losartan group: a 25.3% risk reduction in doubling of serum creatinine (p = 0.006); a 28.6% risk reduction in end-stage renal disease (p = 0.002); a 19.9% risk reduction in end-stage renal disease or death (p = 0.009); and a 21.0% risk reduction in doubling of serum creatinine or end-stage renal disease (p = 0.01). The incidence of all-cause mortality was not statistically different between the two treatment groups. Losartan was generally well tolerated in this study, as evidenced by a similar rate of treatment discontinuation due to adverse events compared with placebo. HEAAL study The Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was a controlled, worldwide clinical trial conducted in 3,834 patients aged 18 to 98 years with heart failure (NYHA class II–IV) who were intolerant of ACE inhibitor therapy. Patients were randomised to losartan 50 mg once daily or losartan 150 mg once daily, on a background of conventional therapy excluding ACE inhibitors. Patients were followed for more than 4 years (median 4.7 years). The primary endpoint of the study was a composite of all-cause mortality or hospitalisation for heart failure. The results showed that treatment with losartan 150 mg (828 events) compared with losartan 50 mg (889 events) led to a 10.1% risk reduction (p = 0.027, 95% confidence interval 0.82–0.99) in the number of patients reaching the primary composite endpoint. This was attributed primarily to a reduction in the incidence of hospitalisations for heart failure. Losartan 150 mg reduced the risk of hospitalisation for heart failure by 13.5% compared with losartan 50 mg (p = 0.025, 95% confidence interval 0.76–0.98). All-cause mortality rates did not differ significantly between the treatment groups. Renal impairment, hypotension, and hyperkalaemia were more frequent in the 150 mg group than in the 50 mg group; however, these adverse events did not result in a significantly higher rate of treatment discontinuation in the 150 mg group. ELITE I and ELITE II studies In the ELITE study, conducted over more than 48 weeks in 722 patients with heart failure (NYHA class II–IV), no difference was observed between patients treated with losartan and those treated with captopril with respect to the primary efficacy endpoint of long-term change in renal function. The finding from ELITE I that losartan reduced the risk of mortality compared with captopril was not confirmed in the subsequent ELITE II study, described below. In ELITE II, losartan 50 mg once daily (starting dose 12.5 mg, increased to 25 mg, then to 50 mg once daily) was compared with captopril 50 mg three times daily (starting dose 12.5 mg, increased to 25 mg, then to 50 mg three times daily). The primary efficacy endpoint of this prospective study was all-cause mortality. In this study, 3,152 patients with heart failure (NYHA class II–IV) were followed for nearly two years (median: 1.5 years) to determine whether losartan was superior to captopril in reducing all-cause mortality. The primary efficacy endpoint showed no statistically significant difference between losartan and captopril in reducing all-cause mortality. In both active comparator-controlled (non-placebo-controlled) clinical studies in patients with heart failure, the tolerability of losartan was better than that of captopril, as measured by a significantly lower rate of treatment discontinuation due to adverse events and a significantly lower frequency of cough. In a small subgroup (22% of all patients with heart failure) receiving beta-blockers at baseline, an increase in mortality was observed with losartan in the ELITE II study. Dual blockade of the renin-angiotensin-aldosterone system (RAAS) Two large randomised, controlled trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affairs Nephropathy in Diabetes)) evaluated the use of the combination of an ACE inhibitor with an angiotensin II receptor blocker. ONTARGET was a study conducted in patients with a history of cardiovascular or cerebrovascular disease, or in patients with type 2 diabetes mellitus accompanied by evidence of end-organ damage. VA NEPHRON-D was a study in patients with type 2 diabetes mellitus and diabetic nephropathy. These studies showed no significant beneficial effect on renal and/or cardiovascular outcomes or mortality, while an increased risk of hyperkalaemia, acute kidney injury, and/or hypotension was observed compared with monotherapy. Given the similar pharmacodynamic properties, these results are also relevant for other ACE inhibitors and angiotensin II receptor blockers. ACE inhibitors and angiotensin II receptor blockers should therefore not be used concomitantly in patients with diabetic nephropathy. ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was designed to evaluate the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus and chronic kidney disease, cardiovascular disease, or both. The study was terminated early because of an increased risk of adverse outcomes. Cardiovascular death and stroke were numerically more frequent in the aliskiren group than in the placebo group, and adverse events and serious adverse events of interest (hyperkalaemia, hypotension, and renal dysfunction) were reported more frequently in the aliskiren group than in the placebo group. Paediatric population Paediatric hypertension The antihypertensive effect of losartan was established in a clinical trial enrolling 177 hypertensive paediatric patients aged 6 to 16 years, with body weight > 20 kg and glomerular filtration rate > 30 mL/min/1.73 m². Patients weighing > 20 kg to < 50 kg received either 2.5, 25, or 50 mg of losartan daily, and patients weighing > 50 kg received either 5, 50, or 100 mg of losartan daily. At the end of three weeks of once-daily administration, losartan reduced trough blood pressure in a dose-dependent manner. Overall, a dose-response relationship was observed. The dose-response relationship was very evident when comparing the low-dose group with the medium-dose group (period I: -6.2 mmHg vs. -11.65 mmHg); however, it was attenuated when comparing the medium-dose group with the high-dose group (period I: -11.65 mmHg vs. -12.21 mmHg). The lowest doses studied, 2.5 mg and 5 mg, corresponding to a mean daily dose of 0.07 mg/kg, did not appear to provide a consistent antihypertensive effect. These results were confirmed during period II of the study, in which patients were randomised after three weeks of treatment to continue losartan or to receive placebo. The difference in the increase in blood pressure compared with placebo was greatest in the medium-dose group (6.70 mmHg in the medium-dose group vs. 5.38 mmHg in the high-dose group). The increase in trough diastolic blood pressure was, however, the same in patients receiving placebo and in patients continuing on the lowest dose of losartan in each group, again suggesting that the lowest dose in each group does not have a meaningful antihypertensive effect. The long-term effects of losartan on growth, puberty, and overall development have not been studied. The long-term efficacy of antihypertensive treatment with losartan in childhood in reducing cardiovascular morbidity and mortality has also not been established. The effect of losartan on proteinuria was evaluated in hypertensive (n = 60) and normotensive (n = 246) children with proteinuria in a 12-week placebo- and active-controlled (amlodipine) clinical trial. Proteinuria was defined as a urinary protein/creatinine ratio ≥ 0.3. Hypertensive patients (aged 6–18 years) were randomised to receive either losartan (n = 30) or amlodipine (n = 30). Normotensive patients (aged 1 to 18 years) were randomised to receive either losartan (n = 122) or placebo (n = 124). Losartan was administered at doses of 0.7 mg/kg to 1.4 mg/kg (up to a maximum daily dose of 100 mg). Amlodipine was administered at doses of 0.05 mg/kg to 0.2 mg/kg (up to a maximum daily dose of 5 mg). At the end of the 12-week treatment period, patients receiving losartan showed a statistically significant 36% reduction in proteinuria from baseline compared with a 1% increase in the placebo/amlodipine group (p ≤ 0.001). Hypertensive patients receiving losartan showed a -41.5% reduction in proteinuria (95% CI -29.9; -51.1) from baseline, compared with +2.4% (95% CI -22.2; 14.1) in the amlodipine group. Reductions in both systolic and diastolic blood pressure were greater in the losartan group (-5.5/-3.8 mmHg) than in the amlodipine group (-0.1/+0.8 mmHg). In normotensive children, a small reduction in blood pressure was observed in the losartan group (-3.7/-3.4 mmHg) compared with placebo. No significant correlation was recorded between the reduction in proteinuria and the reduction in blood pressure, although it is possible that the reduction in blood pressure was partly responsible for the reduction in proteinuria in the losartan-treated group. The long-term effects of losartan in children with proteinuria were evaluated for up to 3 years in an open-label, extended safety phase of the same study, in which all patients who completed the core 12-week study were invited to participate. A total of 268 patients entered the open-label extension and were randomised to losartan (n = 134) or enalapril (n = 134), with 109 patients followed for more than 3 years (the prespecified time of completion was reached when ≥ 100 patients in the extension phase had completed 3 years of follow-up). The dose ranges of losartan and enalapril, administered at the investigator's discretion, were 0.30 to 4.42 mg/kg/day and 0.02 to 1.13 mg/kg/day, respectively. Maximum daily doses of 50 mg in patients < 50 kg and 100 mg in patients > 50 kg were not exceeded for most patients during the extension phase. Overall, the results of the extended safety phase demonstrated that losartan was well tolerated over 3 years and produced a sustained reduction in proteinuria with no detectable changes in glomerular filtration rate (GFR). In normotensive patients (n = 205), enalapril had a numerically greater effect than losartan on proteinuria (-33.0% (95% CI -47.2; -15.0) vs. -16.6% (95% CI -34.9; 6.8)) and on GFR (9.4 (95% CI 0.4; 18.4) vs. -4.0 (95% CI -13.1; 5.0) mL/min/1.73 m²). In hypertensive patients (n = 49), losartan had a numerically greater effect on proteinuria (-44.5% (95% CI -64.8; -12.4) vs. -39.5% (95% CI -62.5; -2.2)) and on GFR (18.9 (95% CI 5.2; 32.5) vs. -13.4 (95% CI -27.3; 0.6) mL/min/1.73 m²). An open-label, dose-ranging clinical study was conducted to evaluate the safety and efficacy of losartan in paediatric patients with hypertension aged 6 months to 6 years. A total of 101 patients were randomised to one of three open-label initial-dose groups of losartan: low dose 0.1 mg/kg/day (n = 33), medium dose 0.3 mg/kg/day (n = 34), or high dose 0.7 mg/kg/day (n = 34). Among these patients, 27 children aged 6 to 23 months were identified. The study medication was up-titrated at weeks 3, 6, and 9 in patients who had not reached the target blood pressure and who were not yet receiving the maximum dose of losartan (1.4 mg/kg/day, not to exceed 100 mg/day). Of the 99 patients who received study medication, 90 (90.9%) continued in the extension phase with follow-up visits every 3 months. The mean duration of treatment was 264 days. Overall, the mean reduction in blood pressure from baseline was similar across all treatment groups (the change from baseline in systolic blood pressure at week 3 was -7.3 mmHg in the low-dose group and -7.6 and -6.7 mmHg in the medium- and high-dose groups, respectively; the reduction from baseline in diastolic blood pressure at week 3 was -8.2 mmHg in the low-dose group and -5.1 and -6.7 mmHg in the medium- and high-dose groups, respectively); however, no statistically significant dose-dependent response in systolic and diastolic blood pressure was observed. Losartan, including at high doses such as 1.4 mg/kg, was generally well tolerated after 12 weeks of treatment in hypertensive children aged 6 months to 6 years. The overall safety profile was comparable across treatment groups.