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CLINICAL RESEARCH

The Effect of Losartan Versus Atenolol on Cardiovascular Morbidity and Mortality in Patients With Hypertension Taking Aspirin

The LIFE Study

Eigil Fossum, MD, PhD^_*,_*, Andreas Moan, MD, PhD, Sverre E. Kjeldsen, MD, PhD^_*,, Richard B. Devereux, MD, FACC, Stevo Julius, MD, ScD, Steven M. Snapinn, PhD^||, Jonathan M. Edelman, MD^||, Ulf de Faire, MD, PhD^¶, Frej Fyhrquist, MD, PhD^#, Hans Ibsen, MD, PhD^**, Krister Kristianson, PhD, Ole Lederballe-Pedersen, MD, PhD, Lars H. Lindholm, MD, PhD, Markku S. Nieminen, MD, FACC^#, Per Omvik, MD, PhD^||||, Suzanne Oparil, MD, FACC^¶¶, Hans Wedel, PhD^##, Björn Dahlöf, MD, PhD^*** for the LIFE Study Group

^_* Department of Cardiology, Ullevaal University Hospital, Oslo, Norway
MSD, Drammen, Norway
Department of Cardiology, University of Michigan, Ann Arbor, Michigan
Division of Cardiology, Cornell Medical Center, New York, New York
^|| Merck and Co., Inc., Whitehouse Station, New Jersey
^¶ Department of Medicine, Karolinska University Hospital, Stockholm, Sweden
^# Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland
^** Department of Internal Medicine, Glostrup University Hospital, Glostrup, Denmark
Merck Research Laboratories Scandinavia, Stockholm, Sweden
Department of Internal Medicine, Viborg Hospital, Viborg, Denmark
Department of Family Medicine, Umeå University, Umeå, Sweden
^|||| Department of Cardiology, Haukeland University Hospital, Bergen, Norway
^¶¶ Department of Medicine, University of Alabama, Birmingham, Alabama
^## The Nordic School of Public Health, Göteborg, Sweden
^*** Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden

Manuscript received February 23, 2005; revised manuscript received May 12, 2005, accepted May 15, 2005.

^_* Reprint requests and correspondence: Dr. Eigil Fossum, Department of Cardiology, Ullevaal University Hospital, N-0407 Oslo, Norway (Email: eigil.fossum{at}medisin.uio.no).

OBJECTIVES: We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study to determine whether aspirin interacted with the properties of losartan, an angiotensin-II receptor antagonist.

BACKGROUND: Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported. There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin.

METHODS: The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan- or atenolol-based therapy for a mean of 4.7 years, with 1,970 (21.4%) taking aspirin at baseline. The primary composite end point (CEP) included cardiovascular death, stroke, and myocardial infarction (MI). The present cohort was stratified by aspirin use at baseline.

RESULTS: Blood pressures were reduced similarly in the losartan with aspirin (n = 1,004) and atenolol with aspirin (n = 966) groups. The CEP was reduced by 32% (95% confidence interval 0.55 to 0.86, p = 0.001) with losartan with aspirin compared to atenolol with aspirin, adjusted for Framingham risk score and LVH. The test for treatment versus aspirin interaction, excluding other covariates, was significant for the CEP (p = 0.016) and MI (p = 0.037).

CONCLUSIONS: There was a statistical interaction between treatment and aspirin in the LIFE study, with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline. Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment.

Abbreviations and Acronyms   BP = blood pressure   CI = confidence interval   ECG = electrocardiogram   LIFE = Losartan Intervention For Endpoint reduction in hypertension   LVH = left ventricular hypertrophy   MI = myocardial infarction   RR = relative risk

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