Elsevier

The Lancet

Volume 359, Issue 9311, 23 March 2002, Pages 995-1003
The Lancet

Articles
Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

https://doi.org/10.1016/S0140-6736(02)08089-3Get rights and content

Summary

Background

Blood pressure reduction achieved with β-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension. Left ventricular hypertrophy (LVH) is a strong independent indicator of risk of cardiovascular morbidity and death. We aimed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death.

Methods

We did a double-masked, randomised, parallel-group trial in 9193 participants aged 55–80 years with essential hypertension (sitting blood pressure 160–200/95–115 mm Hg) and LVH ascertained by electrocardiography (ECG). We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event (death, myocardial infarction, or stroke). We used Cox regression analysis to compare regimens.

Findings

Blood pressure fell by 30·2/16·6 (SD 18·5/10·1) and 29·1/16·8 mm Hg (19·2/10·1) in the losartan and atenolol groups, respectively. The primary composite endpoint occurred in 508 losartan (23·8 per 1000 patient-years) and 588 atenolol patients (27·9 per 1000 patient-years; relative risk 0·87, 95% Cl 0·77–0·98, p=0·021). 204 losartan and 234 atenolol patients died from cardiovascular disease (0·89, 0·73–1·07, p=0·206); 232 and 309, respectively, had fatal or non-fatal stroke (0·75, 0·63–0·89, p=0·001); and myocardial infarction (non-fatal and fatal) occurred in 198 and 188, respectively (1·07, 0·88–1·31, p=0·491). New-onset diabetes was less frequent with losartan.

Interpretation

Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure.

Introduction

The benefits of drug intervention in hypertension to reduce blood pressure are well established, especially in high-risk individuals.1 However, treated patients with hypertension still have significantly higher rates of hypertension-related cardiovascular complications than matched people without hypertension. This anomaly might result from failure to achieve normal blood pressure, residual target organ damage such as left ventricular hypertrophy (LVH), or both.

The Losartan Intervention For Endpoint reduction (LIFE)2 study was designed in the early 1990s with consideration of several factors: β-blocker and diuretic antihypertensive drugs do not return rates of cardiovascular morbidity and death to normal in patients with hypertension, LVH is a cardinal manifestation of preclinical cardiovascular disease and an independent risk factor for all cardiovascular complications in hypertension, reversal of LVH has possible prognostic benefits that are independent of blood pressure,3 angiotensin II is associated with development of LVH,4 and blocking angiotensin II could be especially effective in reversing LVH.5, 6 Experimental4 and clinical7 evidence suggests that blocking the actions of angiotensin II might confer protective benefits beyond lowering blood pressure. To date, no drug for the treatment of essential hypertension has prevented cardiovascular morbidity and death beyond the reductions in blood pressure achieved with β-blockers and diuretics.1, 8

Losartan was the first available selective angiotensin-II type 1-receptor antagonist9 and atenolol was chosen as a suitable drug for comparison with losartan because it was recognised worldwide as a first-line treatment for hypertension with similar antihypertensive efficacy to losartan10 and benefits for hypertension treatment and secondary cardiovascular protection.8, 11, 13 Hydrochlorothiazide can be added to both drugs in case of insufficient reduction in blood pressure. The primary hypothesis of the LIFE study was that selective angiotensin-II type 1-receptor antagonism with losartan would be more effective than β-blockade with atenolol in reducing cardiovascular morbidity and death in patients with essential hypertension and signs of LVH. LIFE is an investigator-initiated, double-masked, double-dummy, randomised comparison of the long-term effects of losartan with atenolol in patients with hypertension and LVH. The primary endpoint was cardiovascular morbidity and death, a composite endpoint of cardiovascular death, myocardial infarction, and stroke. Other outcome measures were total mortality, angina pectoris or heart failure requiring admission to hospital, coronary or peripheral revascularisation procedures, resuscitated cardiac arrest, and new-onset diabetes mellitus.

Section snippets

Participants

The complete study protocol with design, organisation, clinical measures, endpoint definitions, basis for choice of comparative agent, statistical power calculations, recruitment details, baseline characteristics, and 1-year follow-up results for the LIFE population have been published.2, 14, 15

We included patients aged 55–80 years, with previously treated or untreated hypertension and ECG signs of LVH. We excluded patients with secondary hypertension; myocardial infarction or stroke within the

Results

9222 participants were assigned to treatment groups. 9193 were available for final analyses (figure 2)—this figure is given as 9194 in reference 15, however, one patient had wrongly been identified as randomised despite not receiving study drugs. We enrolled patients from June, 1995, to May 2, 1997, from 945 centres in Denmark (1391), Finland (1485), Iceland (133), Norway (1415), Sweden (2245), UK (817), and the USA (1707). Primary endpoints occurred in 1096 patients in 44 119 patient-years of

Discussion

Our results show that losartan, an angiotensin II type 1-receptor antagonist, was better than atenolol in reducing the frequency of the primary composite endpoint of cardiovascular death, stroke, and myocardial infarction. The reduction of the primary composite end-point of cardiovascular morbidity and mortality was significant both before (14·6%, p=0·009) and after (13·0%, p=0·021) adjustment for Framingham risk score and ECG-LVH degree at baseline. There was substantial blood-pressure

References (30)

  • B Neal et al.

    Effects of ACE inhibitors, calcium antagonists, and other blood-pressure-lowering drugs: results of prospectively designed overviews of randomised trials. Blood Pressure Lowering Treatment Trialists' Collaboration

    Lancet

    (2000)
  • B Dhlöf et al.

    The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension Study: rationale, design, and methods

    Am J Hypertens

    (1997)
  • J Mathew et al.

    Reduction of cardiovascular risk by regression of ectrocardiographic markers of left ventricular hypertrophy by the angiotensin-converting enzyme inhibitor ramipril

    Circulation

    (2001)
  • HR Brunner

    Experimental and clinical evidence that angiotensin II is an independent risk factor for cardiovascular disease

    Am J Cardiol

    (2001)
  • B Dahlöf et al.

    Reversal of left ventricular hypertrophy in hypertensive patients – a meta-analysis of 109 treatment studies

    Am J Hypertens

    (1992)
  • Cited by (0)

    Members listed at end of article

    View full text