Losartan

Dahlof B, Devereaux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality, in the losartan intervention for end-point reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 2002; 359:995-1003.

* BACKGROUND Left ventricular hypertrophy may be responsible for the higher risk of cardiovascular events that hypertensive patients suffer even after blood pressure reduction. Because angiotensin 11 is associated with the development of left ventricular hypertrophy, selective blockade of angiotensin II may reverse the hypertrophy and lead to decreased cardiovascular morbidity beyond just lowering blood pressure.

* POPULATION STUDIED A total of 9193 adults, aged 55 to 80 years, with hypertension (previously treated or untreated) and electrocardiographic (ECG) evidence of left ventricular hypertrophy were enrolled in the trial. Study participants were from Northern Europe and the United States; 54% were female and 92% were white. Patients with secondary hypertension, heart failure or left ventricular ejection fraction of 40% or less, history of myocardial infarction (MI) or stroke within the last 6 months, or angina pectoris requiring beta-blockers or calcium channel blockers were excluded. Also excluded were patients with disorders that required treatment with losartan or other angiotensin II type 1-receptor blockers, atenolol or other beta-blockers, hydrochlorothiazide, or angiotensin-converting enzyme (ACE) inhibitors.

* STUDY DESIGN AND VALIDITY Alter a run-in period with placebo, 9222 patients were randomized in a double-blind fashion to receive either losartan (50 mg daily) or atenolol (50 mg daily). Of these, 29 patients were excluded prior to group assignment and the remaining 9193 were included in an intention-to -reat analysis. The authors did not specifically state whether the treatment allocation process was concealed. In addition to either losartan or atenolol, patients were treated with hydrochlorothiazide and other antihypertensive medications as needed to obtain a blood pressure goal of less than 140/90 mm Hg. An independent clinical committee blinded to treatment group assignment determined the validity of all cardiovascular end points.

Two percent (n = 197) of patients dropped out of the study, in roughly equal numbers from each treatment group. Patients were followed for at least 4 years (average 4.8 years). A monitoring committee terminated the study when an adequate number of cardiovascular events had occurred.

* OUTCOMES MEASURED The primary end point was cardiovascular morbidity and death, a composite end point consisting of stroke, MI, or cardiovascular death. The authors also measured individual cardiovascular events (stroke, MI, death) separately. Extensive data on blood pressure, use of additional medications, changes in ECG evidence of left ventricular hypertrophy, and adverse events were also compared.

* RESULTS Treatment groups had similar demographics, including baseline vital signs, ECG findings, cardiovascular risk scores, and mean arterial blood pressure on treatment. Patients in the losartan group had a significantly lower relative risk (RR) of the composite end point (stroke, MI, or cardiovascular death; RR = 0.87; 95% confidence interval [CI], 0.77-0.98; numbers needed to treat [NNT] = 244 patients per year). On individual outcomes, patients in the losartan group had a reduced risk of stroke (RR = 0.75; 95% CI, 0.63-0.89), but no statistically significant reduction in cardiovascular mortality (RR = 0.89; 95% CI, 0.73-.07), MI (RR = 1.07; 95% CI, 0.88-1.31) or all-cause mortality (RR = 0.90; 95% CI, 0.78-1,03).

RECOMMENDATIONS FOR CLINICAL PRACTICE

Losartan may reduce cardiovascular morbidity and related deaths in hypertensive patients with documented left ventricular hypertrophy beyond that expected from only lowering blood pressure, especially through a reduction in stroke risk. However, this benefit was small in a select group of patients and no additional reduction was demonstrated in all-cause mortality compared with less expensive atenolol. The benefit of losartan over atenolol was more pronounced in a separate trial of hypertensive diabetic patients with left ventricular hypertrophy (NNT = 122 patients per year). (1) Losartan was previously shown to be inferior to an ACE inhibitor agent (captopril) in the treatment of heart failure. (2) Thus, there is no reason to believe that the benefit of losartan shown in this study is superior to (and may actually be less than) that of less expensive ACE inhibitors.

REFERENCES

(1.) Lindhom LH, Ibsen H, Dahlof B, et al. Cardiovascular morbidity and mortality in patients with diabetes in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet 2002; 359:1004-10

(2.) Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial the losartan heart failure survival study ELITE II. Lancet 2000; 355:1582-7

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