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

  1. Richard B. Devereux, MD;
  2. Björn Dahlöf, MD;
  3. Sverre E. Kjeldsen, MD;
  4. Stevo Julius, MD;
  5. Peter Aurup, MD;
  6. Gareth Beevers, MD;
  7. Jonathan M. Edelman, MD;
  8. Ulf de Faire, MD;
  9. Frej Fyhrquist, MD;
  10. Sigrid Helle Berg, BA;
  11. Hans Ibsen, MD;
  12. Krister Kristianson, MD;
  13. Ole Lederballe-Pedersen, MD;
  14. Lars H. Lindholm, MD;
  15. Markku S. Nieminen, MD;
  16. Per Omvik, MD;
  17. Suzanne Oparil, MD;
  18. Steven Snapinn, PhD;
  19. Hans Wedel, MD; and
  20. for the LIFE Study Group*
  1. 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.

    Abstract

    Background: Cardiovascular morbidity and mortality are reduced by treatment with the angiotensin II AT1-receptor antagonist losartan compared with conventional treatment with the β-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.

    Article and Author Information

    • 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.

    Summary for Patients

    • Summaries for Patients:Benefits of Losartan in Patients with Hypertension and Left Ventricular Hypertrophy but No Vascular Disease Ann Intern Med August 5, 2003 139:I-28
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    1. Ann Intern Med August 5, 2003 vol. 139 no. 3 169-177
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