Losartan is used alone or in combination with other classes of antihypertensive agents, including diuretics, in the management of hypertension. Angiotensin II receptor antagonists, such as losartan, are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, calcium-channel blockers, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes. Angiotensin II receptor antagonists or ACE inhibitors may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as diabetes mellitus or chronic kidney disease; angiotensin II receptor antagonists also may be preferred, generally as an alternative to ACE inhibitors, in hypertensive patients with heart failure or ischemic heart disease and/or postmyocardial infarction.
Efficacy of losartan in the treatment of hypertension was established in placebo-controlled studies of 6-12 weeks' duration in patients with hypertension (baseline diastolic blood pressure: 95-115 mm Hg). In these patients, losartan potassium dosages of 50-150 mg once daily were associated with mean decreases in systolic blood pressure of 5.5-10.5 mm Hg and diastolic blood pressure of 3.5-7.5 mm Hg. Daily dosages of 150 mg did not result in greater decreases in blood pressure compared with daily dosages of 50-100 mg. Larger decreases in trough blood pressures were observed with twice-daily dosing compared with once daily dosing in patients receiving daily dosages of 50-100 mg. Rebound hypertension following abrupt withdrawal of the drug has not been reported.
Like ACE inhibitors, angiotensin II receptor antagonists such as losartan may produce a smaller blood pressure response in hypertensive black patients compared with nonblack patients.
For additional information on the management of hypertension, For information on overall principles and expert recommendations for treatment of hypertension,
Prevention of Cardiovascular Morbidity and Mortality
Losartan is used alone or in combination with other antihypertensive agents (e.g., hydrochlorothiazide) to reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy; however, there is evidence that the benefit associated with such losartan-based antihypertensive therapy does not apply to black patients. In a randomized, double-blind, comparative study (Losartan Intervention for Endpoint [LIFE] reduction in hypertension) of approximately 4 years' duration in more than 9000 patients, losartan-based antihypertensive therapy (e.g., losartan 50-100 mg with hydrochlorothiazide 12.5-25 mg daily) reduced the risk of the primary outcome of combined cardiovascular death, stroke, and myocardial infarction (relative risk reduction of about 13%, adjusted for Framingham risk score and baseline left ventricular hypertrophy) compared with atenolol-containing therapy (e.g., atenolol 50-100 mg with hydrochlorothiazide 12.5-25 mg daily) despite similar control of blood pressure with each regimen. In addition, the rate of drug-related adverse events and the incidence of new-onset diabetes mellitus was less in patients receiving losartan-based therapy. The study population consisted primarily of white patients 55-80 years of age with ECG evidence of left ventricular hypertrophy but who did not have low left-ventricular ejection fraction (40% or less) or heart failure. The results of the study provided no evidence that the benefits of losartan in reducing the risk of cardiovascular events in patients with hypertension and left ventricular hypertrophy apply to black patients. Among black patients in the study, the risk of experiencing the primary outcome of combined cardiovascular death, stroke, and myocardial infarction was lower in patients receiving atenolol (11%) than in patients receiving losartan (17%).
Subgroup analysis of the LIFE study (mean follow-up 4.7 years) suggests that aspirin therapy at baseline in patients receiving losartan reduced the risk of the primary outcome of combined cardiovascular death, stroke, and myocardial infarction (relative risk reduction of about 32%, adjusted for Framingham risk score and baseline left ventricular hypertrophy) compared with aspirin therapy at baseline in patients receiving atenolol, despite similar control of blood pressure with each regimen. Further studies are needed to determine whether these differences are associated with a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan therapy.
Losartan is used in the management of diabetic nephropathy manifested by elevated serum creatinine and proteinuria (urinary albumin to creatinine ratio of 300 mg/g or greater) in patients with type 2 diabetes mellitus and hypertension.
Both angiotensin II receptor antagonists and ACE inhibitors have been shown to slow the rate of progression of renal disease in patients with diabetes mellitus and persistent albuminuria, and use of a drug from either class is recommended in such patients with modestly elevated (30-300 mg/24 hours) or higher (exceeding 300 mg/24 hours) levels of urinary albumin excretion. Some evidence suggests that these drugs may slow the progression of nephropathy by a mechanism independent of their antihypertensive effects.
Comparative trials evaluating the efficacy of angiotensin II receptor antagonists and ACE inhibitors for improving renal outcomes in diabetic patients are lacking. Evidence supporting use of ACE inhibitors generally is based on studies in patients with type 1 diabetes mellitus, while evidence supporting use of angiotensin II receptor antagonists generally is based on studies in patients with type 2 diabetes mellitus. Findings from these studies indicate that both drug classes delay progression of increased urinary albumin excretion in patients with diabetes mellitus and also may slow the decline in renal function. Because the available data are consistent, some experts suggest that the effects of both drug classes in improving renal outcomes in patients with diabetes mellitus and proteinuria are likely to be similar.
Drugs that inhibit the renin-angiotensin system (i.e., ACE inhibitors, angiotensin II receptor antagonists) also have been shown to delay the onset of albuminuria in patients with type 2 diabetes mellitus and hypertension who have normal levels of urinary albumin excretion.
Although combined therapy with ACE inhibitors and angiotensin II receptor antagonists appears to have additive effects in reducing albuminuria, such combinations provide no additional cardiovascular benefit and increase the risk of adverse effects (e.g., impaired renal function, hyperkalemia). The usual precautions of angiotensin II receptor antagonist therapy in patients with substantial renal impairment should be observed.
The current labeled indication for losartan in hypertensive patients with type 2 diabetes mellitus and nephropathy (indicated by an elevated serum creatinine and urinary albumin to creatinine ratio of 300 mg/g or greater) is based principally on the results of a long-term (mean duration of follow-up: 3.4 years), multicenter, placebo-controlled trial, the Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan (RENAAL) study. In the RENAAL trial, therapy with losartan potassium (50 mg daily initially and titrated to 100 mg daily) reduced the risk of the primary composite clinical end point, which was defined as a doubling of the baseline serum creatinine concentration, end-stage renal disease (i.e., need for dialysis or renal transplantation), or death, by 16% compared with placebo. Additional antihypertensive agents (diuretics, calcium-channel blocking agents, α- or β-adrenergic blocking agents (β-blockers), and/or centrally acting agents) were used as needed in all treatment groups to achieve a trough blood pressure of less than 140/90 mm Hg in the sitting position; ACE inhibitors and other angiotensin II receptor antagonists could not be used. Most of the delay in time to occurrence of composite clinical events seen with losartan-containing therapy was the result of a reduction in the risk of doubling serum creatinine concentration and end-stage renal disease (25 and 28% reductions, respectively); losartan-containing therapy had no appreciable effect on overall mortality. Similar mean blood pressures were achieved with losartan or placebo plus conventional antihypertensive therapy.
Angiotensin II receptor antagonists have been used in the management of heart failure.
Current guidelines for the management of heart failure in adults generally recommend a combination of drug therapies to reduce morbidity and mortality, including neurohormonal antagonists (e.g., ACE inhibitors, angiotensin II receptor antagonists, angiotensin receptor-neprilysin inhibitors [ARNIs], β-blockers, aldosterone receptor antagonists) that inhibit the detrimental compensatory mechanisms in heart failure. Additional agents (e.g., cardiac glycosides, diuretics, sinoatrial modulators [i.e., ivabradine]) added to a heart failure treatment regimen in selected patients have been associated with symptomatic improvement and/or reduction in heart failure-related hospitalizations. Experts recommend that all asymptomatic patients with reduced left ventricular ejection fraction (LVEF) (American College of Cardiology Foundation [ACCF]/American Heart Association [AHA] stage B heart failure) receive therapy with an ACE inhibitor and β-blocker to prevent symptomatic heart failure and reduce morbidity and mortality. In patients with prior or current symptoms of chronic heart failure with reduced LVEF (ACCF/AHA stage C heart failure), ACCF, AHA, and the Heart Failure Society of America (HFSA) recommend inhibition of the renin-angiotensin-aldosterone (RAA) system with an ACE inhibitor, angiotensin II receptor antagonist, or ARNI in conjunction with a β-blocker, and an aldosterone antagonist in selected patients, to reduce morbidity and mortality. While ACE inhibitors have been the preferred drugs for inhibition of the RAA system because of their established benefits in patients with heart failure and reduced ejection fraction, some evidence indicates that therapy with sacubitril/valsartan, an ARNI, may be more effective than ACE inhibitor therapy (enalapril) in reducing cardiovascular death and heart failure-related hospitalization. ACCF, AHA, and HFSA recommend that patients with chronic symptomatic heart failure and reduced LVEF (New York Heart Association [NYHA] functional class II or III) who are able to tolerate an ACE inhibitor or angiotensin II receptor antagonist be switched to therapy containing an ARNI to further reduce morbidity and mortality. However, in patients in whom an ARNI is not appropriate, continued use of an ACE inhibitor for all classes of heart failure with reduced ejection fraction remains strongly advised. In patients in whom an ARNI or ACE inhibitor is not appropriate, an angiotensin II receptor antagonist may be used. For additional information on the use of angiotensin II receptor antagonists in the management of heart failure, and .
Several clinical trials have evaluated the use of angiotensin II receptor antagonists as add-on therapy to conventional regimens including an ACE inhibitor, as add-on therapy to conventional regimens compared with an ACE inhibitor, as combination therapy with an ACE inhibitor compared with therapy with either type of agent alone, or as an alternative therapy in patients intolerant of ACE inhibitors. Data from these and other long-term placebo-controlled clinical trials indicate that angiotensin II receptor antagonists produce hemodynamic and neurohormonal effects associated with their suppression of the renin-angiotensin system; reduced hospitalizations and mortality also have been demonstrated. However, in some studies, these drugs did not show consistent effects on cardiac symptoms or exercise tolerance.
In one comparative study (Evaluation of Losartan in the Elderly [ELITE]) in geriatric patients 65 years of age and older who received losartan (up to 50 mg daily) or captopril (up to 150 mg daily) in addition to conventional therapy for 48 weeks, patients receiving losartan had a 46% lower risk of death and also experienced a lower incidence of adverse effects than those receiving captopril. However, after interim analysis of data, the difference in survival was no longer significant and no difference in morbidity and mortality or frequency in hospitalizations for heart failure was found between the 2 therapies. Results of a follow-up study (ELITE II), failed to confirm a survival benefit for losartan therapy compared with captopril. In this study, losartan did not provide a statistically significant difference in reduction of overall death, sudden cardiac death, and/or resuscitated cardiac arrest compared with captopril, although ELITE II was not designed to demonstrate equivalence between the 2 therapies. For additional details on the use of angiotensin II receptor antagonists in the management of heart failure,
While angiotensin II receptor antagonists are considered reasonable alternatives in patients who are unable to tolerate ACE inhibitors (e.g., because of cough or angioedema), angioedema, including swelling of the larynx and glottis (causing airway obstruction) and/or swelling of the face, lips, pharynx, and/or tongue, has been reported rarely during postmarketing experience in patients receiving losartan. The manufacturer states that some of these patients had a history of angioedema associated with other drugs (e.g., ACE inhibitors).
(See Sensitivity Reactions under Cautions: Warnings/Precautions.)