Effects of Losartan or Atenolol in Hypertensive Patients without Clinically Evident Vascular Disease: A Substudy of the LIFE Randomized Trial

5 August 2003 | Volume 139 Issue 3 | Pages 169-177

Background: Cardiovascular morbidity and mortality are reduced by treatment with the angiotensin II AT₁-receptor antagonist losartan compared with conventional treatment with the ß-blocker atenolol in patients with hypertension and electrocardiogram-defined left ventricular hypertrophy, many of whom had known vascular disease.

Objective: To determine whether losartan reduces cardiovascular event rates in lower-risk hypertensive patients without clinically evident vascular disease.

Design: Subgroup analysis of a randomized trial.

Setting: The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study.

Patients: 6886 men and women (57% women) 55 to 80 years of age (average, 66 years) with essential hypertension (sitting blood pressure, 160 to 200/95 to 115 mm Hg [average, 174/98 mm Hg]) and electrocardiogram-defined left ventricular hypertrophy who did not have clinically evident vascular disease.

Intervention: Patients were randomly assigned to once-daily double-blind treatment with losartan or atenolol.

Measurements: An end point committee ascertained end points (cardiovascular death, stroke, or myocardial infarction).

Results: Blood pressure was reduced similarly by losartan and atenolol. The primary composite end point occurred in 282 losartan-treated patients (17.5 per 1000 patient-years) and 355 atenolol-treated patients (21.8 per 1000 patient-years; relative risk, 0.81 [95% CI, 0.69 to 0.95]; P = 0.008). Cardiovascular death occurred in 103 losartan-treated patients and 132 atenolol-treated patients (relative risk, 0.80 [CI, 0.62 to 1.04]; P = 0.092), stroke (nonfatal and fatal) occurred in 125 losartan-treated patients and 193 atenolol-treated patients (relative risk, 0.66 [CI, 0.53 to 0.82]; P < 0.001), and myocardial infarction (nonfatal and fatal) occurred in 110 losartan-treated patients and 100 atenolol-treated patients (relative risk, 1.14 [CI, 0.87 to 1.49]; P > 0.2). New-onset diabetes occurred less often in patients treated with losartan (n = 173) than in patients treated with atenolol (n = 254) (relative risk, 0.69 [CI, 0.57 to 0.84]; P < 0.001). Benefits of losartan treatment were numerically smaller, but not significantly so, in patients with preexisting vascular disease.

Conclusion: In hypertensive patients without clinically evident vascular disease, losartan was more effective than atenolol in preventing cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction.

*For a list of investigators in the LIFE study, see the Appendix.

Editors' Notes Context The Losartan Intervention for Endpoint reduction in hypertension (LIFE) trial showed that losartan-based treatment improved cardiovascular outcomes more than atenolol-based treatment in patients with hypertension and left ventricular hypertrophy. Because the study sample was heterogeneous, clinicians wondered about effects in the lower-risk participants. Contribution This analysis of lower-risk participants without known vascular disease showed that both losartan and atenolol reduced blood pressure similarly. Cardiovascular events, particularly strokes, and new-onset diabetes occurred less frequently with losartan than with atenolol. Implications Patients with hypertension and left ventricular hypertrophy but no known vascular disease benefit more from losartan than atenolol. –The Editors

 

Author and Article Information

From the Weill Medical College of Cornell University, New York, New York; Sahlgrenska–Ostra University Hospital and The Nordic School of Public Health, Göteborg, Sweden; Ullevaal University Hospital, Oslo, Norway; University of Michigan, Ann Arbor, Michigan; Merck and Co, Inc., Whitehouse Station, New Jersey; City Hospital, Birmingham, United Kingdom; Karolinska University Hospital, Stockholm, Sweden; Helsinki University Central Hospital, Helsinki, Finland; Glostrup University Hospital, Glostrup, Denmark; Viborg Hospital, Viborg, Denmark; Umeå University, Umeå, Sweden; Haukeland University Hospital, Bergen, Norway; and the University of Alabama, Birmingham, Alabama.

Grant Support: By grant COZ-368 from Merck & Co., Inc.

Potential Financial Conflicts of Interest:Employment: P. Aurup (Merck & Co., Inc.), J.M. Edelman (Merck & Co., Inc.), S.H. Berg (Merck & Co., Inc.), K. Kristianson (Merck & Co., Inc.), S. Snapinn (Merck & Co., Inc.); Consultancies: R.B. Devereux (Merck & Co., Inc.), B. Dahlöf, G. Beevers, H. Ibsen, S. Oparil (Bristol Myers Squibb, Merck & Co., Inc., Pfizer, Sanofi, Novartis, The Salt Institute, Wyeth-Ayerst); Honoraria: R.B. Devereux (Merck & Co, Inc.), B. Dahlöf, S.E. Kjeldsen (Merck & Co., Inc.), S. Julius, G. Beevers, F. Fyhrquist (Merck, Sharpe & Dohme), H. Ibsen, L.H. Lindholm, M.S. Nieminen, P. Omvik, S. Oparil; Stock ownership or options (other than mutual funds): P. Aurup (Merck & Co., Inc.), J.M. Edelman (Merck & Co., Inc.), S.H. Berg (Merck & Co., Inc.), K. Kristianson (Merck & Co., Inc.), S. Snapinn (Merck & Co., Inc.); Expert testimony: S. Julius (Food and Drug Adminstration), G. Beevers; Grants received: R.B. Devereux (Cornell University), S. Julius, G. Beevers, H. Ibsen, S. Oparil (Abbott Laboratories, Astra Zeneca, Aventis, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Monarch, Novartis, Merck & Co., Inc., Pfizer, Sankyo, Sanofi/BioClin, Schering Plough, Schwarz Pharma, Scios, Inc., G.D. Searle, Solvay, Texas Biotechnology Corp., Wyeth-Ayerst); Grants pending: G. Beevers.

Requests for Single Reprints: Richard B. Devereux, MD, Division of Cardiology, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021; e-mail, rbdevere{at}med.cornell.edu.

Current Author Addresses: Dr. Devereux: Division of Cardiology, New York Presbyterian Hospital, 525 East 68th Street, New York, NY 10021.

Dr. Dahlöf: University of Göteborg, Ostra University Hospital, 416 85 Göteborg, Sweden.

Dr. Kjeldsen: Division of Cardiology, Ulleval Hospital, N-0407 Oslo, Norway.

Dr. Julius: University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109.

Dr. Aurup: 1 Merck Drive, Whitehouse Station 52 (WS 3C-60), NJ 08889.

Dr. Beevers: Dudley Road Hospital, Dudley Road, Birmingham B18 7QH, United Kingdom.

Dr. de Faire: Karolinska University Hospital, Department of Cardiology, S-171 76 Stockholm, Sweden.

Drs. Fyhrquist and Nieminen: Division of Cardiology, Helsinki University Central Hospital, Haartmaninkatu 4, SF-00290 Helsinki, Finland.

Dr. Berg: Merck, Sharp & Dohme Scandinavia, PO Box 458 Brakeroya, N-3001 Drammen, Norway.

Dr. Ibsen: Department of Medicine, Copenhagen University Hospital Glostrup, DK-2600 Glostrup, Denmark.

Dr. Kristianson: Merck, Sharp & Dohme AB, Rotebergsuägen 3, 192 07 Sollentuna, Sweden.

Dr. Lederballe-Pedersen: Viborg Hospital, Medicinsk AFd, 8800 Viborg, Denmark.

Dr. Lindholm: Haukeland Hospital, Department of Public Health and Clinical Medicine, Umeå University Hospital, S-90 185 Umeå, Sweden.

Dr. Omvik: Haukeland Hospital, Department of Medicine, N-5021 Bergen, Norway.

Dr. Oparil: University of Alabama at Birmingham, 703 19th Street South, ZRB 1034, Birmingham, AL 35294.

Dr. Snapinn: Merck Research Labs, 518 Township Line Road, Blue Bell, PA 19422.

Dr. Wedel: The Nordic School of Public Health, PO Box 12133, Göteborg, Sweden 40242.

Author Contributions: Conception and design: R.B. Devereux, B. Dahlöf, S.E. Kjeldsen, P. Aurup, J.M. Edelman, K. Kristianson, P. Omvik, S. Oparil, S. Snapinn.

Analysis and interpretation of the data: R.B. Devereux, B. Dahlöf, S.E. Kjeldsen, P. Aurup, J.M. Edelman, F. Fyhrquist, K. Kristianson, S. Oparil, S. Snapinn.

Drafting of the article: R.B. Devereux, B. Dahlöf, S.E. Kjeldsen, F. Fyhrquist, S. Snapinn.

Critical revision of the article for important intellectual content: R.B. Devereux, B. Dahlöf, S.E. Kjeldsen, P. Aurup, J.M. Edelman, F. Fyhrquist, S.H. Berg, P. Omvik, S. Snapinn.

Final approval of the article: R.B. Devereux, B. Dahlöf, S.E. Kjeldsen, J.M. Edelman, P. Omvik, S. Oparil, S. Snapinn.

Provision of study materials or patients: B. Dahlöf, S.E. Kjeldsen, P. Aurup, S.H. Berg, P. Omvik.

Statistical expertise: S. Snapinn.

Obtaining of funding: S.E. Kjeldsen, J.M. Edelman.

Administrative, technical, or logistic support: B. Dahlöf, S.E. Kjeldsen, P. Aurup, J.M. Edelman, S.H. Berg, K. Kristianson.

Collection and assembly of data: R.B. Devereux, S.E. Kjeldsen, J.M. Edelman, S.H. Berg, K. Kristianson.