From Weill Medical College, Cornell University, New York, New York, and Merck Research Laboratories, Whitehouse Station, New Jersey
Hypertension and its consequences continue to be significant burdens to patients and health care systems worldwide. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, therapy with the angiotensin II receptor (type AT1) antagonist losartan was compared with the beta blocking agent atenolol. Losartan was shown to be superior to atenolol for the primary prevention of cardiovascular mortality and morbidity, especially stroke, in a large subgroup of patients with hypertension and left ventricular hypertrophy (LVH) who were without clinically evident vascular disease at the time of enrollment in the study.
Substantial reductions in hypertension-related cardiovascular events have been achieved by treating hypertension to a goal blood pressure with a well-tolerated treatment regimen. Increasing evidence from experiments and small clinical studies, however, suggests that the agents used to treat hypertension, particularly those that interfere with the renin-angiotensin system, can make a difference in the outcomes of patients with hypertension. Therefore, hypertension outcomes clinical trials are now designed to achieve similar blood pressure control between treatment groups so that outcome differences may be related to specific antihypertensive agents. The LIFE study was such a trial. It assessed cardiovascular morbidity and mortality in patients with hypertension and LVH. It also provided the opportunity to examine the effects of antihypertensive treatments on the primary prevention of cardiovascular events in a large subgroup of patients who did not have clinically evident coronary, cerebral, or peripheral arterial disease at the time of enrollment in the study.
Patients and methods
The LIFE study design, statistical methods, and primary results have been published elsewhere.1-3 All patients provided informed consent, and the protocol was approved by the ethics committees associated with each clinical center. The study was designed and directed by independent steering, data and safety monitoring, and end point committees.
The LIFE study was a randomized, double-blind investigation of the effects of treatment with losartan compared with atenolol in 9,193 patients with hypertension and LVH. Patients were 55 to 80 years old and were eligible for enrollment if blood pressure was 160 to 200 mm Hg systolic and 95 to 115 mm Hg diastolic after 1 or 2 weeks of placebo treatment. Patients were excluded if they had secondary hypertension, myocardial infarction (MI), or stroke within the previous 6 months; angina pectoris requiring treatment with a beta blocking agent or calcium antagonist; heart failure or a left ventricular ejection fraction of 40% or less; or need for treatment with the study medication or related drugs.
Patients were treated with 50 mg of losartan or atenolol once daily. The dosage could be titrated to 100 mg, with or without hydrochloro-thiazide and/or another antihyper-tensive therapy (excluding angiotensin-converting enzyme [ACE] inhibitors, beta blocking agents, or angiotensin II receptor antagonists), to reach the target blood pressure of below 140/90 mm Hg.
The primary outcome measure of the LIFE study was a composite end point of the first occurrence of cardiovascular death, stroke, or MI. In this post hoc analysis for the subgroup without clinically evident vascular disease, we report the results for the composite end point, components of the composite end point, total mortality, and new-onset diabetes.
Perhaps as a consequence of the placebo run-in phase of the study and the requirement that no beta blocking agents other than atenolol or its placebo be used during the treatment phase, the study included a large number (6,886; 74.9%) of patients without a history of coronary, cerebral, or peripheral arterial disease at the time of enrollment in the study. The two treatment groups were similar regarding baseline age (overall mean ± SD, 66.6 ± 7.0 years), ethnic distribution (93% white), blood pressure (174.3/98.3 ± 14.3/8.6 mm Hg), heart rate (73.8 ± 11.2 beats/
minute), body mass index (28.1 kg/m2), history of diabetes (11%), isolated systolic hypertension (13%), and atrial fibrillation (3%). They were also similar with regard to severity of LVH (electrocardiographic Cornell voltage duration product and Sokolow-Lyon voltage data not shown).
Patients were followed for a mean of 4.8 years. Mean doses of losartan and atenolol at the time of end point or end of study drug treatment were 82 mg and 79 mg, respectively. Approximately 50% of patients in both treatment groups were also treated with hydrochlorothiazide. The use of other allowed concomitant antihypertensive therapies was comparable in the two groups.
Blood pressure was reduced significantly in both treatment groups. Systolic blood pressure was reduced by 30.2 mm Hg in the losartan group and by 29.3 mm Hg in the atenolol group. Diastolic blood pressure was reduced by 16.7 mm Hg in the losartan group and by 16.8 mm Hg in the atenolol group. Mean blood pressures at the last study visit were 144.0/81.7 mm Hg in the losartan group and 145.1/81.4 mm Hg in the atenolol group. The reduction in heart rate was greater in the atenolol group than in the losartan group (a reduction of 7.6 versus 1.9 beats/
minute, respectively; P < .001).
In the 6,886 patients without clinically evident vascular disease at baseline, the primary composite end point (cardiovascular death, stroke, or MI) occurred in 282 patients (17.5 per 1,000 patient-years) in the losartan group and in 355 patients (21.8 per 1,000 patient-years) in the atenolol group (risk reduction, —19%;
P = .008; table). Cardiovascular death occurred in 103 patients in the losartan group and 132 patients in the atenolol group (risk reduction, —20%). Nonfatal and fatal stroke occurred in 125 patients in the losartan group and 193 patients in the atenolol group (risk reduction, –34%; P < .001). Nonfatal and fatal MI occurred in 110 patients in the losartan group and 100 patients in the atenolol group (risk reduction, 14%).
The incidence of new-onset diabetes was 31% lower in the losartan group: 173 versus 254 patients (risk reduction, —31%; P < .001). There was a trend toward lower total mortality in the losartan group: 223 versus
268 deaths (risk reduction, —15%). The incidence of noncardiovascular death was also lower in the losartan group (120 deaths) compared with the atenolol group (136 deaths).
In the 2,307 patients with clin-ically evident vascular disease at baseline, the primary composite
end point occurred in 226 patients (18.8%) in the losartan group (43.0 per 1,000 patient-years) and in 233 patients (21.1%) in the atenolol group (48.6 per 1,000 patient-years; risk reduction, —7%; table). Cardiovascular death occurred in 101 patients in the losartan group and 102 patients in the atenolol group (risk reduction, –5%). Stroke occurred in 107 patients in the losartan group and 116 patients in the atenolol group (risk reduction, –13%). MI occurred in 88 patients in each treatment group (risk reduction, –3%). Death from any cause occurred in 160 patients in the losartan group and 163 patients in the atenolol group (risk reduction, – 6%).
Almost 75% of the LIFE study patients did not have clinically evident vascular disease at baseline. In these patients, blood pressure was reduced to similar levels in the losartan and atenolol treatment groups; therefore, differences in results between the treatment groups are attributable to effects of treatment other than those on blood pressure. The results in the subgroup of patients without clinically evident vascular disease are similar to those in the overall study and did not differ statistically from those in patients with a history of vascular disease.
In the subgroup of patients without clinically evident vascular disease, losartan significantly reduced the predefined primary composite end point (cardiovascular death, stroke, and MI) rate by 19% versus that for the atenolol group (P = .006). In this subgroup, losartan reduced the rate of fatal and nonfatal stroke, the most common component of the primary composite end point, by 34%. Some4 but not all5 other trials
of drugs that affect renin-angiotensin system activity have influenced the stroke outcome beyond an effect on blood pressure. Stroke was 44% more common than MI in the LIFE study, which is consistent with other recent hypertension trials.6 It is important to identify new ways to prevent stroke, especially in light of the fact that the stroke rate in industrialized countries, after a decades-long decline, has reached a plateau or even begun to increase in recent years.
The similar rates of MI in the losartan and atenolol groups suggest that protection of coronary ar-teries from the direct toxic effects of angiotensin II by losartan might have offset a reduction in myocardial oxygen demand achieved by treatment with atenolol.7 The 31% difference in new-onset diabetes was expected from findings in trials that studied ACE inhibitors.8 The LIFE study was not designed to investigate the mechanism of the new-onset diabetes finding; therefore, we cannot conclude whether this finding was the result of a beneficial effect of losartan, a detrimental effect of atenolol, or some combination of both.
The beta blocking agent atenolol was the comparator in the LIFE study. Treatment with beta blockade has reduced cardiovascular complications in placebo-controlled studies in both patients with hypertension and those with a history of MI or other manifestations of vascular disease.9-12 Studies that have compared newer therapies with beta blocker or diuretic therapy did not report outcomes separately for patients without vascular disease at baseline; however, the lack of difference in primary outcome between treatment groups in those studies makes it unlikely that beta blockade reduced cardiovascular events in the subset of patients without vascular disease.9,13
Statistical independence from blood pressure lowering suggests that the incremental benefits shown with losartan in the LIFE trial are a result of tissue-level inhibition of angiotensin II with losartan. In the present analysis of patients without clinically diagnosed arterial disease, the important benefits suggest that the protection of arteries from adverse effects of angiotensin II in the entire LIFE sample also apply to patients who have not yet developed clinically evident atherosclerosis..
The clinical benefits shown with losartan therapy in the primary prevention of cardiovascular morbidity and mortality in hypertensive patients without clinically evident vascular disease suggest that antihypertensive therapy regimens that include losartan may improve outcome, especially by preventing stroke.