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PubMed2000

Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators.

OBJECTIVE: The goal of this multicenter, double-blind, randomized, parallel-group study was to compare the effects of losartan potassium (hereafter referred to as losartan), candesartan cilexitil (hereafter referred to as candesartan), and losartan/hydrochlorothiazide (HCTZ) in patients with mild to moderate hypertension (sitting diastolic blood pressure [SiDBP] 95-115 mm Hg). METHODS: A total of 1161 patients were randomized in a 2:2:1 ratio to 12 weeks of treatment with losartan 50 mg QD, possibly titrated to 100 mg QD (n = 461); candesartan 8 mg QD, possibly titrated to 16 mg QD (n = 468); or losartan 50 mg QD, possibly titrated to losartan 50 mg plus HCTZ 12.5 mg QD (n = 232). At 6 weeks, the regimens of patients not reaching a goal SiDBP <90 mm Hg were titrated as described, whereas patients achieving this goal continued with low-dose monotherapy. The single primary end point at 12 weeks tested the equivalence of the 2 monotherapy regimens, predefined as a maximum between-treatment difference in the mean change from baseline trough SiDBP of 2.5 mm Hg. RESULTS: At 12 weeks, changes in SiDBP/sitting systolic blood pressure (SiSBP) of -12.4/-14.4 mm Hg with losartan 50 mg/100 mg and -13.1/-15.8 mm Hg with candesartan 8 mg/16 mg demonstrated equivalence between the 2 monotherapy regimens (95% CI for difference in SiDBP, -1.6 to 0.2). At 12 weeks, the losartan 50 mg/50 mg plus HCTZ 12.5 mg regimen had reduced SiDBP/SiSBP significantly more (-14.3/-18.0 mm Hg) than either the candesartan 8 mg/16 mg (SiDBP, P = 0.045; SiSBP, P = 0.017) or losartan 50 mg/100 mg regimen (SiDBP and SiSBP, P = 0.001). During the last 6 weeks, patients whose regimen had been titrated to losartan 50 mg plus HCTZ 12.5 mg (n = 114) showed a greater reduction in SiDBP/SiSBP (-14.5/ -18.7 mm Hg) than did those whose regimen had been titrated to either losartan 100 mg (-10.5/-12.3 mm Hg; n = 211) or candesartan 16 mg (-11.5/-13.2 mm Hg; n = 206), representing a clinically meaningful > or = 2.5-mm Hg) difference. All 3 treatments were well tolerated, with few patients experiencing drug-related adverse events (6.9% losartan 50 mg/100 mg, 7.5% candesartan 8 mg/16 mg, 3.0% losartan 50 mg/ 50 mg plus HCTZ 12.5 mg). Candesartan 8 mg/16 mg increased serum uric acid levels (0.13 mg/dL; 95% CI, 0.04 to 0.23), whereas losartan 50 mg/100 mg decreased them (-0.14 mg/dL; 95% CI, -0.24 to -0.04), and losartan 50 mg/50 mg plus HCTZ 12.5 mg left them unchanged (0.06 mg/dL; 95% CI, -0.07 to 0.20). CONCLUSIONS: Losartan 50 mg/100 mg and candesartan 8 mg/16 mg were comparable treatments in terms of blood pressure reduction. After titration, losartan 50 mg plus HCTZ 12.5 mg was superior to either candesartan 16 mg or losartan 100 mg in reducing hypertension. Losartan, but not candesartan, lowered serum uric acid levels and attenuated the expected increase in uric acid levels with HCTZ 12.5 mg.

Adult↗
PubMed2000

Comparison of antihypertensive and metabolic effects of losartan and losartan in combination with hydrochlorothiazide--a randomized controlled trial.

INTRODUCTION: Losartan is an angiotensin II receptor blocker indicated for treatment of hypertension. It also inhibits platelet agreggation through blockade of thromboxane A2/ prostaglandin H2 receptors, and has a uricosuric effect We determined the effect on ambulatory blood pressure (ABP) of 100 mg losartan monotherapy (L100) versus 50 mg losartan/12.5 mg hydrochlorothiazide (HCTZ) combination therapy (L50H12.5C), in patients uncontrolled on 50 mg losartan. We also assessed the effects of losartan on platelet aggregation and serum urate at these clinically relevant doses. METHODS: This was a randomized, double-blind trial of L100 versus L50H12.5C, in moderate hypertensives (sitting diastolic blood pressure (DBP) >or = 95 mmHg and < 120 mmHg). After 4 weeks of placebo run-in, patients received 50 mg losartan for 6 weeks; patients uncontrolled (sitting DBP > or = 95 mmHg) were randomized to L100 or L50H12.5C for a further 6 weeks. Platelet function was assessed by measuring percentage inhibition of platelet aggregation, and serum uric acid was also measured. RESULTS: Monotherapy with 50 mg losartan reduced ABP by 16.0/9.9 mmHg during the day and 9.8/5.5 mmHg at night However, 16 out of 24 (66%) patients had uncontrolled blood pressure on this treatment L50H12.5C further reduced daytime ABP by 10.7(10.7)/8.4(6.5) mmHg mean (SEM) compared with L100 (-5.3(9.7)/-2.3(4.8), P = 0.013). 50 mg losartan and L100 did not affect platelet function or uric acid levels beyond placebo values; treatment with L50H12.5C was associated with a significant rise in serum urate above levels obtained on 50 mg losartan (366.9(67.6) versus 331.6(65.0), P=0.006), to levels similar to placebo (358.8(80.9)). CONCLUSION: L50H12.5C is an effective antihypertensive regimen in patients with moderate hypertension that is uncontrolled on 50 mg losartan monotherapy, and is the preferred treatment option in these patients compared with increasing the dose of losartan. The additional benefit of losartan on platelet inhibition was not evident in our population at these doses; however, there was evidence to suggest that the uricosuric effects of losartan might ameliorate the uric acid retention effects of therapy with hydrochlorothiazide.

Antihypertensive Agents↗
PubMed1997

Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE)

BACKGROUND: To determine whether specific angiotensin II receptor blockade with losartan offers safety and efficacy advantages in the treatment of heart failure over angiotensin-converting-enzyme (ACE) inhibition with captopril, the ELITE study compared losartan with captopril in older heart-failure patients. METHODS: We randomly assigned 722 ACE inhibitor naive patients (aged 65 years or more) with New York Heart Association (NYHA) class II-IV heart failure and ejection fractions of 40% or less to double-blind losartan (n = 352) titrated to 50 mg once daily or captopril (n = 370) titrated to 50 mg three times daily, for 48 weeks. The primary endpoint was the tolerability measure of a persisting increase in serum creatinine of 26.5 mumol/L or more (> or = 0.3 mg/dL) on therapy; the secondary endpoint was the composite of death and/or hospital admission for heart failure; and other efficacy measures were total mortality, admission for heart failure, NYHA class, and admission for myocardial infarction or unstable angina. FINDINGS: The frequency of persisting increases in serum creatinine was the same in both groups (10.5%). Fewer losartan patients discontinued therapy for adverse experiences (12.2% vs 20.8% for captopril, p = 0.002). No losartan-treated patients discontinued due to cough compared with 14 in the captopril group. Death and/or hospital admission for heart failure was recorded in 9.4% of the losartan and 13.2% of the captopril patients (risk reduction 32% [95% CI -4% to + 55%], p = 0.075). This risk reduction was primarily due to a decrease in all-cause mortality (4.8% vs 8.7%; risk reduction 46% [95% CI 5-69%], p = 0.035). Admissions with heart failure were the same in both groups (5.7%), as was improvement in NYHA functional class from baseline. Admission to hospital for any reason was less frequent with losartan than with captopril treatment (22.2% vs 29.7%). INTERPRETATION: In this study of elderly heart-failure patients, treatment with losartan was associated with an unexpected lower mortality than that found with captopril. Although there was no difference in renal dysfunction, losartan was generally better tolerated than captopril and fewer patients discontinued losartan therapy. A further trial, evaluating the effects of losartan and captopril on mortality and morbidity in a larger number of patients with heart failure, is in progress.

Aged↗
PubMed1999

EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.

Analysis of Variance↗
PubMed2000

The efficacy and tolerability of losartan versus atenolol in patients with isolated systolic hypertension. Losartan ISH Investigators Group.

OBJECTIVE: To compare the efficacy and tolerability of angiotensin II (Ang II) antagonist losartan and the beta-blocker atenolol in the treatment of patients with isolated systolic hypertension (ISH) after 16 weeks of treatment. METHODS: A double-blind, randomized, multi-country study was carried out in 273 patients with ISH. Patients with a sitting systolic blood pressure (SiSBP) of 160-205 mmHg, and a sitting diastolic blood pressure (SiDBP) < 90 mmHg at screening and at placebo baseline were subjected to a 4-week placebo period and then randomly grouped to receive 50 mg losartan or 50 mg atenolol once daily for 16 weeks. At 8 and 12 weeks, patients not controlled (SiDBP > or = 160 mmHg) were given additional treatment of 12.5 mg hydrochlorothiazide (HCTZ) once daily. RESULTS: Similar significant reductions in SiSBPs (mean +/- SD) were obtained with 50 mg losartan and 50 mg atenolol, from 173.7 +/- 10.3 and 173.5 +/- 10.7 mmHg at baseline to 149.0 +/- 15.5 and 148.2 +/- 15.3 mmHg after 16 weeks of losartan or atenolol treatment respectively. Sixty-seven percent of the losartan-treated and 64% of the atenolol-treated patients remained on monotherapy throughout the study. Only 1.5% of the losartan-treated patients withdrew because of a clinical adverse event (CAE) compared with 7.2% in the atenolol-treatment group (P= 0.035). Drug-related CAEs were observed significantly more frequently with atenolol than with losartan treatment (20.3 versus 10.4%; P = 0.029). CONCLUSION: It is concluded that 50 mg losartan and 50 mg atenolol produced comparable reductions in SiSBP in patients with ISH but losartan was better tolerated. This is the first demonstration of the therapeutic value of selective Ang II receptor blockade with losartan in the treatment of ISH.

Adrenergic beta-Antagonists↗
PubMedDate not supplied

Use of ambulatory blood pressure monitoring to compare antihypertensive efficacy and safety of two angiotensin II receptor antagonists, losartan and valsartan. Losartan Trial Investigators.

The efficacy and safety of losartan and valsartan were evaluated in a multicenter, double-blind, randomized trial in patients with mild to moderate essential hypertension. Blood pressure responses to once-daily treatment with either losartan 50 mg (n = 93) or valsartan 80 mg (n = 94) for 6 weeks were assessed through measurements taken in the clinic and by 24-hour ambulatory blood pressure monitoring (ABPM). Both drugs significantly reduced clinic sitting systolic (SiSBP) and diastolic blood pressure (SiDBP) at 2, 4, and 6 weeks. Maximum reductions from baseline in SiSBP and SiDBP on 24-hour ABPM were also significant with the two treatments. The reduction in blood pressure was more consistent across patients in the losartan group, as indicated by a numerically smaller variability in change from baseline on all ABPM measures, which achieved significance at peak (P = .017) and during the day (P = .002). In addition, the numerically larger smoothness index with losartan suggested a more homogeneous antihypertensive effect throughout the 24-hour dosing interval. The antihypertensive response rate was 54% with losartan and 46% with valsartan. Three days after discontinuation of therapy, SiDBP remained below baseline in 73% of losartan and 63% of valsartan patients. Both agents were generally well tolerated. Losartan, but not valsartan, significantly decreased serum uric acid an average 0.4 mg/dL at week 6. In conclusion, once-daily losartan 50 mg and valsartan 80 mg had similar antihypertensive effects in patients with mild to moderate essential hypertension. Losartan produced a more consistent blood pressure-lowering response and significantly lowered uric acid, suggesting potentially meaningful differences between these two A II receptor antagonists.

Analysis of Variance↗
PubMed1997

Comparative antihypertensive effects of losartan 50 mg and losartan 50 mg titrated to 100 mg in patients with essential hypertension.

The antihypertensive activity of losartan potassium (losartan, Cozaar), an angiotensin II receptor antagonist, was evaluated in a parallel 12-week, double-blind, placebo-controlled trial in hypertensive patients with mild-to-moderate hypertension. After a 4-week, single-blind, placebo lead-in period, which included monitoring of baseline variables, 366 patients with a group mean sitting diastolic blood pressure of 101 +/- 5 (s.d.) mmHg were assigned randomly to one of three treatment groups: placebo, losartan 50 mg, or losartan 50 mg with the option to titrate to 100 mg after the first 6 weeks if the target sitting diastolic blood pressure (< 90 mmHg) was not reached. To assess the potential blood pressure response associated with the act of titration, patients in the placebo and losartan 50 mg treatment groups with a sitting diastolic blood pressure of > or = 90 mmHg at week 6 were mock titrated (changed to a new tablet containing the same study medication and dose). Sitting diastolic blood pressure was also evaluated at the end of the trial during a 1-week off-drug period to assess for rebound hypertension. At week 6, patients in the active-drug-treatment arms experienced significantly greater peak (6 h post-dose) and trough (24 h post-dose) reduction in systolic and diastolic sitting blood pressures compared with placebo (p < or = 0.01). Based on trough blood pressures at week 12, active drug (both arms) was more effective than placebo in lowering sitting diastolic blood pressure, with a very small additional benefit associated with increasing the dose of losartan to 100 mg in patients who did not reach the target blood pressure after the first 6 weeks on losartan 50 mg. There was no evidence of rebound hypertension during 1 week after withdrawal of losartan. The correlation between baseline plasma renin activity and reduction in peak and trough blood pressure at week 12, although statistically significant, was generally poor in the active treatment groups. In this trial, losartan was efficacious and well tolerated, and was similar to placebo with regard to adverse-experience profile. Adverse experiences that could reasonably be related to excessive lowering of blood pressure were not common and there was no evidence of rebound hypertension.

Antihypertensive Agents↗
PubMed2000

Reduction in left ventricular hypertrophy in hypertensive patients treated with enalapril, losartan or the combination of enalapril and losartan.

OBJECTIVE: To compare the regression of left ventricular hypertrophy in patients with moderate hypertension treated with enalapril, losartan or a combination of the two drugs at lower doses. METHODS: Patients of both sexes with moderate hypertension confirmed by ambulatory monitoring of arterial blood pressure and with left ventricular hypertrophy on echocardiogram were assigned to three groups: enalapril (35 mg/day, n=15), losartan (175 mg/day, n=15) and enalapril losartan (15 mg+100 mg/day, n=16). The patients received the drugs for 10 months. RESULTS: The three therapeutic regimens were equally effective in reducing blood pressure and left ventricular mass index (LVMI, g/m2): 141+/-3.9 to 123+/-3.6 in the enalapril group (p<0.05), from 147+/-3.8 to 133+/-2.8 in the losartan group (p<0.05), and from 146+/-3.0 to 116+/-4.0 in the enalapril+losartan group (p<0.05). However, the percent reduction of LVMI was significantly greater (p<0.01) in the enalapril+losartan group (20.5+/-5.0%) than in enalapril (12.4+/-3.2%) and the losartan (9.1+/-2.1%) groups. Normalization of LVMI was obtained in 10 out of the 16 patients who received enalapril+ losartan, in 6 out of the 15 patients who received only enalapril and in 4 out of the 15 patients treated with losartan. CONCLUSION: The combination of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist (AT1 receptor antagonist) in patients produced an additional effect on the reduction of left ventricular hypertrophy. This finding may depend on a more complete inhibition of the cardiac renin-angiotensin.

Adult↗
PubMed2003

Regression of electrocardiographic left ventricular hypertrophy by losartan versus atenolol: The Losartan Intervention for Endpoint reduction in Hypertension (LIFE) Study.

BACKGROUND: Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. METHODS AND RESULTS: Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months' follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, -200 versus -69 mm. ms, P<0.001) and Sokolow-Lyon voltage (-2.5 versus -0.7 mm, P<0.001) than was atenolol-based therapy. Greater regression of ECG LVH persisted at each subsequent annual evaluation in the losartan-treated group, with between 140 and 164 mm. ms greater mean reductions in Cornell product and from 1.7 to 2.2 mm greater mean reductions in Sokolow-Lyon voltage (all P<0.001). The effect of losartan was consistent across subgroups defined by gender, age, ethnicity, and diabetes. CONCLUSIONS: After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.

Age Factors↗
PubMed2004

Effects of losartan and captopril on left ventricular systolic and diastolic function after acute myocardial infarction: results of the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) echocardiographic substudy.

BACKGROUND: Angiotensin-converting enzyme inhibitors have been shown to attenuate adverse remodeling after acute myocardial infarction (AMI), and the same has been suggested for angiotensin II type 1 receptor antagonists in animal models. Therefore the aim of the study was to compare the effects of losartan and captopril on regional systolic, diastolic, and overall left ventricular (LV) function after AMI. METHODS: Two hundred twenty-five patients aged > or =50 years with documented AMI and heart failure and/or LV dysfunction were randomly assigned treatment with either losartan (50 mg/d) or captopril (50 mg 3 times/d). Echocardiography was performed at randomization and after 3 months; echocardiograms were analyzed blinded at the core laboratory. Main outcome measures were changes in wall motion score index (WMSI), E-wave deceleration time (E-DT), and Tei index of overall LV function. RESULTS: WMSI decreased in both groups (losartan 1.58 +/- 0.23 to 1.52 +/- 0.26, P =.009, captopril 1.60 +/- 0.24 to 1.48 +/- 0.22, P <.001), although the decrease was greater in patients allocated to captopril (captopril -0.12 +/- 0.17 vs losartan -0.05 +/- 0.19, P =.007). In both groups E-DT increased, although the increase was significant only in patients treated with captoril (193 +/- 61 ms to 208 +/- 70 ms, P =.05). The change in E-DT was not different between treatment groups (captopril 14 +/- 74 ms vs losartan 7 +/- 80 ms, P =.52). Tei index decreased in both groups (losartan 0.59 +/- 0.13 to 0.55 +/- 0.15, P =.04, captopril 0.62 +/- 0.15 to 0.55 +/- 0.13, P <.001). However, the reduction was significantly greater in patients treated with captopril (captopril -0.08 +/- 0.14 vs losartan -0.03 +/- 0.14, P =.01). CONCLUSION: Losartan and captopril improve systolic and overall LV function after AMI, but the benefit is greater for patients treated with captopril.

Aged↗
PubMed1997

Comparative effects of losartan and enalapril on exercise capacity and clinical status in patients with heart failure. The Losartan Pilot Exercise Study Investigators.

OBJECTIVES: This study was designed to determine 1) whether 12-week oral administration of losartan, an angiotensin II receptor antagonist, in patients with heart failure is well tolerated; and 2) whether functional capacity and clinical status of patients with heart failure in whom treatment with an angiotensin-converting enzyme (ACE) inhibitor is replaced with losartan for 12 weeks will remain similar to that noted in patients in whom treatment with an ACE inhibitor is continued. BACKGROUND: Losartan is a specific, nonpeptide angiotensin II receptor antagonist. Although specific receptor blockade with losartan has certain theoretic advantages over nonspecific ACE inhibition, definitive demonstration of comparable effects in patients with congestive heart failure is lacking. METHODS: A double-blind, multicenter, randomized, parallel, enalapril-controlled study was conducted in 116 patients with congestive heart failure (New York Heart Association functional classes II to IV) and left ventricular ejection fraction < or = 45% previously treated with stable doses of ACE inhibitors and diuretic agents, with or without concurrent digitalis and other vasodilators. After a baseline exercise period, open-label ACE inhibitors were discontinued, and patients were randomly assigned to 12 weeks of therapy with losartan, 25 mg/day (n = 38); losartan, 50 mg/day (n = 40); or enalapril, 20 mg/day (n = 38). Drug efficacy was evaluated by changes in maximal treadmill exercise time (using a modified Naughton protocol), 6-min walk test, left ventricular ejection fraction and dyspnea-fatigue index. Safety was measured by the incidence of clinical and laboratory adverse experiences. RESULTS: The treadmill exercise time and the 6-min walk test did not change significantly after replacement of ACE inhibitor therapy with losartan. Similarly, a significant change was not observed in either the dyspnea-fatigue index or left ventricular ejection fraction at the end of double-blind period relative to baseline. CONCLUSIONS: Losartan was generally well tolerated and comparable to enalapril in terms of exercise tolerance in this short-term (12-week) study of patients with heart failure. The clinical effects of long-term angiotensin II receptor blockade compared with ACE inhibition remain to be studied.

Activities of Daily Living↗
PubMed2004

Regression of hypertensive left ventricular hypertrophy by losartan compared with atenolol: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial.

BACKGROUND: An echocardiographic substudy of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial was designed to test the ability of losartan to reduce left ventricular (LV) mass more than atenolol. METHODS AND RESULTS: A total of 960 patients with essential hypertension and LV hypertrophy (LVH) on screening ECG were enrolled at centers in 7 countries and studied by echocardiography at baseline and after 1, 2, 3, 4, and 5 years' randomized therapy. Clinical examination and blinded readings of echocardiograms in 457 losartan-treated and 459 atenolol-treated participants with > or =1 follow-up measurement of LV mass index (LVMI) were used in an intention-to-treat analysis. Losartan-based therapy induced greater reduction in LVMI from baseline to the last available study than atenolol with adjustment for baseline LVMI and blood pressure and in-treatment pressure (-21.7+/-21.8 versus -17.7+/-19.6 g/m2; P=0.021). Greater LVMI reduction with losartan was observed in women and men, participants >65 or <65 years of age, and with mild or more severe baseline hypertrophy. The difference between treatment arms in LVH regression was due mainly to reduced concentricity of LV geometry in both groups and lesser increase in LV internal diameter in losartan-treated patients. CONCLUSIONS: Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for pressure control, resulted in greater LVH regression in patients with ECG LVH than conventional atenolol-based treatment. Thus, angiotensin receptor antagonism by losartan has superior efficacy for reversing LVH, a cardinal manifestation of hypertensive target organ damage.

Adrenergic beta-Antagonists↗
PubMed1998

Pharmacokinetics of losartan and its metabolite, EXP3174, after intravenous and oral administration of losartan to rats with streptozotocin-induced diabetes mellitus.

The pharmacokinetics of losartan and its active metabolite, EXP3174, were investigated after intravenous and oral administration of the drug, 5 mg/kg, to control rats and streptozotocin-induced diabetes mellitus rats (SIDRs). After 1-min intravenous infusion, the mean arterial plasma concentrations and the resultant area under the plasma concentration-time curve from zero to infinity (AUC) of both losartan and EXP3174 were not significantly different between control rats and the SIDRs. However, the renal clearance (CLR) of losartan (0.181 versus 0.0815 ml/min/kg) and EXP3174 (0.0677 versus 0.0277 ml/min/kg) were significantly faster in SIDRs than in control rats due to significant increase in glomerular filtration rate. After oral administration, the mean arterial plasma concentrations and the resultant AUC of losartan (97 versus 166 micrograms min/ml) and EXP3174 (244 versus 423 micrograms min/ml) were significantly lower in SIDRs than in control rats. The absolute extent of oral bioavailability of losartan, F, (32.5 versus 55.1%) decreased considerably in SIDRs and it was possibly due to the reduced gastrointestinal absorption of losartan by gastrointestinal disorders occurring in the diabetic state. The low F in both groups of rats was at least partially due to the increase in first-pass effects. The CLR of losartan (0.207 versus 0.101 ml/min/kg) and EXP3174 (0.0615 versus 0.0196 ml/min/kg) were significantly faster in SIDRs than in control rats after oral administration of losartan.

Administration, Oral↗
PubMed2002

Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy.

CONTEXT: Drug intervention in placebo-controlled trials has been beneficial in isolated systolic hypertension. OBJECTIVE: To test the hypothesis that losartan improves outcome better than atenolol in patients with isolated systolic hypertension and electrocardiographically documented left ventricular hypertrophy (ECG-LVH). DESIGN: Double-blind, randomized, parallel-group study conducted in 1995-2001. SETTING AND PARTICIPANTS: A total of 1326 men and women aged 55 through 80 years (mean, 70 years) with systolic blood pressure of 160 to 200 mm Hg and diastolic blood pressure of less than 90 mm Hg (mean, 174/83 mm Hg) and ECG-LVH, recruited from 945 outpatient settings in the Nordic countries, the United Kingdom, and the United States. INTERVENTIONS: Patients were randomly assigned to receive once-daily losartan (n = 660) or atenolol (n = 666) with hydrochlorothiazide as the second agent in both arms, for a mean of 4.7 years. MAIN OUTCOME MEASURE: Composite end point of cardiovascular death, stroke, or myocardial infarction. RESULTS: Blood pressure was reduced by 28/9 and 28/9 mm Hg in the losartan and atenolol arms. The main outcome was reduced by 25% with losartan compared with atenolol, 25.1 vs 35.4 events per 1000 patient-years (relative risk [RR], 0.75; 95% confidence interval [CI], 0.56-1.01; P =.06, adjusted for risk and degree of ECG-LVH; unadjusted RR, 0.71; 95% CI, 0.53-0.95; P =.02). Patients receiving losartan had reductions in the following without a difference in the incidence of myocardial infarction: cardiovascular mortality (8.7 vs 16.9 events per 1000 patient-years; RR, 0.54; 95% CI, 0.34-0.87; P =.01), nonfatal and fatal stroke (10.6 vs 18.9 events per 1000 patient-years; RR, 0.60; 95% CI, 0.38-0.92; P =.02), new-onset diabetes (12.6 vs 20.1 events per 1000 patient-years; RR, 0.62; 95% CI, 0.40-0.97; P =.04), and total mortality (21.2 vs 30.2 events per 1000 patient-years; RR, 0.72; 95% CI, 0.53-1.00; P =.046). Losartan decreased ECG-LVH more than atenolol (P<.001) and was better tolerated. CONCLUSION: These data suggest that losartan is superior to atenolol for treatment of patients with isolated systolic hypertension and ECG-LVH.

Aged↗
PubMed2000

Randomised comparison of losartan vs. captopril on quality of life in elderly patients with symptomatic heart failure: the losartan heart failure ELITE quality of life substudy.

OBJECTIVE: To measure health-related quality-of-life (HRQoL) in elderly symptomatic heart failure patients following treatment with an angiotensin II receptor antagonist (losartan) vs. an angiotensin-converting-enzyme (ACE) inhibitor (captopril). METHODS: Patients (age > or = 65 years) were randomised to losartan, titrated to 50 mg once daily, or captopril, titrated to 50 mg three times daily, as tolerated. Sickness Impact Profile (SIP) and Minnesota Living with Heart Failure (LIhFE) questionnaires were administered at baseline, weeks 12 and 48. Composite hypothesis testing of change in HRQoL from baseline for completers, and withdrawal for unfavourable events (death, clinical/laboratory adverse experience) was used to account for differential dropout rates. RESULTS: In 203 patients completing the substudy (week 48), significant and comparable improvements in HRQoL from baseline were observed for both treatment groups (p < or = 0.001). Although there was a trend favouring losartan vs. captopril for the composite HRQoL endpoint (unadjusted p = 0.018, one-sided), this was not considered significant after adjusting for multiple testing. Significantly more captopril patients in the substudy subset withdrew for unfavourable reasons (19.6 vs. 10.9%, p = 0.038). CONCLUSIONS: Significant improvements in HRQoL were observed in elderly patients with symptomatic heart failure treated with losartan and captopril long-term. A trend favouring losartan in the composite measure of drug tolerability/quality of life was not significant, but losartan was generally better tolerated than captopril in that significantly fewer losartan patients discontinued therapy.

Aged↗
PubMed2004

Renoprotective effect of losartan in comparison to amlodipine in patients with chronic kidney disease and hypertension--a report of the Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients (JLIGHT) study.

A 12-month, multicenter (57 clinical institutions), randomized, open-labeled trial was undertaken to compare the efficacy of the angiotensin II receptor antagonist losartan and the calcium channel blocker amlodipine in patients with proteinuric chronic kidney disease (CKD) and hypertension. A total of 117 patients (79, chronic glomerulonephritis; 14, diabetic nephropathy; 24, other CKD) were randomly allocated into two treatment groups. Losartan and amlodipine exerted the same efficacy for blood pressure (BP) control; however, losartan significantly reduced the 24-h urinary protein excretion at months 3, 6, and 12, with the reduction of 20.7%, 35.2%, 35.8%, whereas amlodipine did not change the amount of proteinuria over the 12-month study period. When patients were stratified into groups according to the level of BP control at 3 months, the reduction in urinary protein excretion by losartan was evident in the group for which a BP of <140/90 mmHg was achieved, as well as in the group for which the goal BP (<130/85 mmHg) for treatment of CKD was not achieved. When patients were stratified according to baseline urinary protein excretion, those with > or = 2 g/day showed a reduction in proteinuria by losartan of 23.3%, 39.4%, and 47.9% at months 3, 6, and 12, and those with <2 g/day showed a reduction of 18.5% and 31.2% at months 3 and 6, respectively. No fatal adverse events were experienced in either drug group. We conclude that losartan reduced proteinuria in patients with CKD and hypertension. This positive effect may contribute to the renal protective benefit of losartan, and is beyond the magnitude of BP control.

Aged↗
PubMed2005

The effect of losartan versus atenolol on cardiovascular morbidity and mortality in patients with hypertension taking aspirin: the Losartan Intervention for Endpoint Reduction in hypertension (LIFE) study.

OBJECTIVES: We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study to determine whether aspirin interacted with the properties of losartan, an angiotensin-II receptor antagonist. BACKGROUND: Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported. There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin. METHODS: The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan- or atenolol-based therapy for a mean of 4.7 years, with 1,970 (21.4%) taking aspirin at baseline. The primary composite end point (CEP) included cardiovascular death, stroke, and myocardial infarction (MI). The present cohort was stratified by aspirin use at baseline. RESULTS: Blood pressures were reduced similarly in the losartan with aspirin (n = 1,004) and atenolol with aspirin (n = 966) groups. The CEP was reduced by 32% (95% confidence interval 0.55 to 0.86, p = 0.001) with losartan with aspirin compared to atenolol with aspirin, adjusted for Framingham risk score and LVH. The test for treatment versus aspirin interaction, excluding other covariates, was significant for the CEP (p = 0.016) and MI (p = 0.037). CONCLUSIONS: There was a statistical interaction between treatment and aspirin in the LIFE study, with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline. Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment.

Adrenergic beta-Antagonists↗
PubMed2000

Meta-analysis of observed mortality data from all-controlled, double-blind, multiple-dose studies of losartan in heart failure. Losartan Heart Failure Mortality Meta-analysis Study Group.

Clinical studies of heart failure utilizing losartan, an angiotensin-II receptor antagonist, found that this drug is well tolerated and demonstrates hemodynamic, neurohormonal, and symptomatic improvement. To assess all-cause mortality in heart failure patients treated with losartan, a meta-analysis including 1,896 patients was performed on 6 controlled, double-blind, multiple-dose studies, regardless of sample size or duration of follow-up. A combination of logarithmic (log) odds ratios with a continuity correction was utilized for the meta-analysis. Treatment groups were comparable with regard to demographic characteristics, heart failure characteristics, and concomitant cardiovascular therapies. Concomitant use of open-label angiotensin-converting enzyme (ACE) inhibitors was not allowed in any study. The mean left ventricular ejection fraction obtained in individual studies ranged from 23% to 31%. Seven hundred forty patients were randomized to control therapy and 1,154 patients were randomized to losartan therapy. There were 36 deaths (3.12%) in the losartan groups compared with 47 in the control groups (6.35%) during the double-blind periods. The odds of dying in the losartan groups were 0.51 times (0.31 to 0.81) that of dying in the control groups (p = 0.004). In this analysis, treatment with losartan provided a beneficial effect upon survival. However, because the number of deaths in these studies is relatively small and the follow-up relatively short, a large confirmatory study is needed to assess the mortality benefit of losartan compared with an ACE inhibitor.

Adult↗