|Pharmacotherapeutic group: Angiotensin II Receptor Antagonists, ATC code: C09CA01Losartan is a synthetic oral 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 found in many tissues (e.g. vascular smooth muscle, adrenal gland, kidneys and the heart) and elicits several important biological actions, including vasoconstriction and the release of aldosterone. 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, regardless of the source or route of its synthesis.Losartan does not have an agonist effect nor does it 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, there is no potentiation of undesirable bradykininmediated effects.During administration of Losartan, removal of the angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). Increase in the PRA leads to an increase in angiotensin II in plasma. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration are maintained, indicating effective angiotensin II receptor blockade. After discontinuation of Losartan, PRA and angiotensin II values fell within three days to the baseline values.Both Losartan and its principal active metabolite have a far greater affinity for the AT1-receptor than for the AT2-receptor. The active metabolite is 10- to 40- times more active than Losartan on a weight for weight basis.|
Hypertension StudiesIn 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. Measurements of blood pressure 24 hours post-dose relative to 5 6 hours post-dose demonstrated blood pressure reduction over 24 hours; the natural diurnal rhythm was retained. Blood pressure reduction at the end of the dosing interval was 70 80% of the effect seen 5-6 hours postdose.Discontinuation of Losartan in hypertensive patients did not result in an abrupt rise in blood pressure (rebound). Despite the marked decrease in blood pressure, Losartan had no clinically significant effects on heart rate.Losartan is equally effective in males and females, and in younger (below the age of 65 years) and older hypertensive patients.
LIFE-StudyThe Losartan Intervention For Endpoint Reduction in Hypertension [LIFE] study was a randomised, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECGdocumented left-ventricular hypertrophy. Patients were randomised to once daily Losartan 50mg or once daily atenolol 50mg. If goal blood pressure (< 140/90mmHg) was not reached, hydrochlorothiazide (12.5mg) was added first and, if needed, the dose of Losartan or atenolol was then increased to 100mg once daily. Other antihypertensives, with the exception of ACE-inhibitors, angiotensin II antagonists or beta-blockers were added if necessary to reach the goal blood pressure.The mean length of follow up was 4.8 years.The primary endpoint was the composite of cardiovascular morbidity and mortality as measured by a reduction in the combined incidence of cardiovascular death, stroke and myocardial infarction. Blood pressure was significantly lowered to similar levels in the two groups. Treatment with losartan resulted in a 13.0% risk reduction (p=0.021, 95% confidence interval 0.77-0.98) compared with atenolol for patients reaching the primary composite endpoint. This was mainly attributable to a reduction of the incidence of stroke. Treatment with losartan reduced the risk of stroke by 25% relative to atenolol (p=0.001 95% confidence interval 0.63-0.89). The rates of cardiovascular death and myocardial infarction were not significantly different between the treatment groups.
RaceIn the LIFE-Study black patients treated with Losartan had a higher risk of suffering the primary combined endpoint, i.e. a cardiovascular event (e.g. cardiac infarction, cardiovascular death) and especially stroke, than the black patients treated with atenolol. Therefore the results observed with losartan in comparison with atenolol in the LIFE study with regard to cardiovascular morbidity/mortality do not apply for black patients with hypertension and left ventricular hypertrophy.
RENAAL-StudyThe Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan RENAAL study was a controlled clinical study conducted worldwide in 1513 Type 2 diabetic patients with proteinuria, with or without hypertension. 751 Patients were treated with LosartanThe objective of the study was to demonstrate a nephroprotective effect of Losartan potassium over and above the benefit of lowering blood pressure.Patients with proteinuria and a serum creatinine of 1.3 3.0mg/dl were randomised to receive Losartan 50mg once a day, titrated if necessary, to achieve blood pressure response, or to placebo, on a background of conventional antihypertensive therapy excluding ACE-inhibitors and angiotension II antagonists.Investigators were instructed to titrate the study medication to 100mg daily as appropriate; 72 % of patients were taking the 100mg daily dose for the majority of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha- and beta-receptor blockers and also centrally acting antihypertensives) were permitted as supplementary treatment depending on the requirement in both groups. Patients were followed up for up to 4.6 years (3.4 years on average).The primary endpoint of the study was a composite endpoint of doubling of the serum creatinine endstage renal failure (need for dialysis or transplantation) or death.The results showed that the treatment with Losartan (327 events) as compared with placebo (359 events) resulted in a 16.1 % risk reduction (p = 0.022) in the number of patients reaching the primary composite endpoint. For the following individual and combined components of the primary endpoint, the results showed a significant risk reduction in the group treated with Losartan: 25.3% risk reduction for doubling of the serum creatinine (p = 0.006); 28.6 % risk reduction for end-stage renal failure (p = 0.002); 19.9% risk reduction for end-stage renal failure or death (p = 0.009); 21.0% risk reduction for doubling of serum creatinine or end-stage renal failure (p = 0.01).All-cause mortality rate was not significantly different between the two treatment groups.In this study losartan was generally well tolerated, as shown by a therapy discontinuation rate on account of adverse events that was comparable to the placebo group.
HEAAL StudyThe Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan (HEAAL) study was a controlled clinical study conducted worldwide in 3834 patients aged 18 to 98 years with heart failure (NYHA Class II-IV) who were intolerant of ACE inhibitor treatment. Patients were randomised to receive losartan 50 mg once a day or losartan 150 mg, on a background of conventional therapy excluding ACE-inhibitors.Patients were followed for over 4 years (median 4.7 years). The primary endpoint of the study was a composite endpoint of all cause death or hospitalization for heart failure.The results showed that treatment with 150 mg losartan (828 events) as compared with 50 mg losartan (889 events) resulted in 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 mainly attributable to a reduction of the incidence of hospitalization for heart failure. Treatment with 150 mg losartan reduced the risk of hospitalization for heart failure by 13.5% relative to 50 mg losartan (p=0.025, 95% confidence interval 0.76-0.98). The rate of all cause death was not significantly different between the treatment groups. Renal impairment, hypotension, and hyperkalaemia were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.
ELITE I and ELITE II StudyIn the ELITE Study carried out over 48 weeks in 722 patients with heart failure (NYHA Class II-IV), no difference was observed between the patients treated with Losartan and those treated with captopril was observed with regard to the primary endpoint of a long-term change in renal function. The observation of the ELITE I Study, that, compared with captopril, Losartan reduced the mortality risk, was not confirmed in the subsequent ELITE II Study, which is described in the following.In the ELITE II Study Losartan 50mg once daily (starting dose 12.5mg, increased to 25mg, then 50mg once daily) was compared with captopril 50mg three times daily (starting dose 12.5mg, increased to 25mg and then to 50mg three times daily). The primary endpoint of this prospective study was the all-cause mortality.In this study 3152 patients with heart failure (NYHA Class II-IV) were followed for almost two years (median: 1.5 years) in order to determine whether Losartan is superior to captopril in reducing all cause mortality. The primary endpoint did not show any statistically significant difference between Losartan and captopril in reducing all-cause mortality.In both comparator-controlled (not placebo-controlled) clinical studies on patients with heart failure the tolerability of Losartan was superior to that of captopril, measured on the basis of a significantly lower rate of discontinuations of therapy on account of adverse events and a significantly lower frequency of cough.An increased mortality was observed in ELITE II in the small subgroup (22% of all HF patients) taking beta-blockers at baseline.
Pediatric HypertensionThe antihypertensive effect of Losartan potassium film-coated Tablets was established in a clinical study involving 177 hypertensive pediatric patients 6 to 16 years of age with a body weight > 20kg and a glomerular filration rate >30ml/min/1.73m2. Patients who weighted >20kg to <50kg received either 2.5, 25 or 50mg of losartan daily and patients who weighted >50kg received either 5, 50 or 100mg of losartan daily. At the end of three weeks, losartan administration once daily lowered trough blood pressure in a dose-dependent manner.Overall, there was a dose-response. The dose-response relationship became very obvious in the low dose group compared to the middle dose group (period I: -6.2 mmHg vs. -11.65mmHg), but was attenuated when comparing the middle dose group with the high dose group (period I: -11.65mmHg vs. -12.21mmHg). The lowest doses studied, 2.5mg and 5mg, corresponding to an average daily dose of 0.07mg/ kg, did not appear to offer consistent antihypertensive efficacy.These results were confirmed during period II of the study where patients were randomized to continue losartan or placebo, after three weeks of treatment. The difference in blood pressure increase as compared to placebo was largest in the middle dose group (6.70mm Hg middle dose vs. 5.38mmHg high dose). The rise in trough diastolic blood pressure was the same in patients receiving placebo and in those continuing losartan at the lowest dose in each group, again suggesting that the lowest dose in each group did not have significant antihypertensive effect.Long-term effects of losartan on growth, puberty and general development have not been studied. The long-term efficacy of antihypertensive therapy with losartan in childhood to reduce cardiovascular morbidity and mortality has also not been established.In hypertensive (N=60) and normotensive (N=246) children with proteinuria, the effect of losartan on proteinuria was evaluated in a 12-week placebo- and active-controlled (amlodipine) clinical study. Proteinuria was defined as urinary protein/creatinine ratio of ≥0.3. The hypertensive patients (ages 6 through 18 years) were randomized to receive either losartan (n=30) or amlodipine (n=30). The normotensive patients (ages 1 through 18 years) were randomized to receive either losartan (n=122) or placebo (n=124). Losartan was given at doses of 0.7 mg/kg to 1.4 mg/kg (up to maximum dose of 100 mg per day). Amlodipine was given at doses of 0.05 mg/kg to 0.2 mg/kg (up to a maximum dose of 5 mg per day).Overall, after 12 weeks of treatment, patients receiving losartan experienced a statistically significant reduction from baseline in proteinuria of 36% versus 1% increase in placebo/amlodipine group (p≤0.001). Hypertensive patients receiving losartan experienced a reduction from baseline proteinuria of -41.5% (95% CI -29.9;-51.1) versus +2.4% (95% CI -22.2; 14.1) in the amlodipine group. The decline in both systolic blood pressure and diastolic blood pressure was greater in the losartan group (-5.5/-3.8 mmHg) versus the amlodipine group (-0.1/+0.8 mmHg). In normotensive children a small decrease in blood pressure was observed in the losartan group (-3.7/-3.4 mmHg) compared to placebo. No significant correlation between the decline in proteinuria and blood pressure was noted, however it is possible that the decline in blood pressure was responsible, in part, for the decline in proteinuria in the losartan treated group. Long-term effects of losartan in children with proteinuria were studied for up to 3 years in the open-label safety extension phase of the same study, in which all patients completing the 12-week base study were invited to participate. A total of 268 patients entered the open-label extension phase and were re-randomized to losartan (N=134) or enalapril (N=134) and 109 patients had ≥3 years of follow-up (pre-specified termination point of ≥100 patients completing 3 years of follow-up in the extension period). The dose ranges of losartan and enalapril, given according to investigator discretion, were 0.30 to 4.42 mg/kg/day and 0.02 to 1.13 mg/kg/day, respectively. The maximum daily doses of 50 mg for <50 kg body weight and 100 mg>50 kg were not exceeded for most patients during the extension phase of the study.In summary, the results of the safety extension show that losartan was well-tolerated and led to sustained decreases in proteinuria with no appreciable change in glomerular filtration rate (GFR) over 3 years. For normotensive patients (n=205), enalapril had a numerically greater effect compared to 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/1.73m2)). For 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 GFR (18.9(95%CI 5.2; 32.5) vs -13.4(95%CI -27.3; 0.6)) ml/min/1.73m2.