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Current Concepts in
Editor’s Comments
The Losartan Intervention For Endpoint Reduction
Wading Through the Alphabet Soup
(LIFE) in Hypertension Study
As the century draws to a close, a plethora of outcome stud-ies are in progress to compare the effects of specific The Losartan Intervention For Endpoint Reduction (LIFE) in Hypertension study is a double-blind, prospective, parallel group study designed to com- antihypertensive treatments on cardiovascular disease and pare the effects of losartan with those of the β-blocker atenolol on the reductiona few have recently been completed. No longer is the ques- of cardiovascular morbidity and mortality in hypertension. Approximately 9,000tion whether hypertension should be treated but rather in hypertensive patients (initial sitting diastolic blood pressure 95 to 115 mg Hgwhom, how far and with what. In addition, the ongoing and/or systolic blood pressure 160 to 200 mm Hg) with electrocardiographicallystudies are designed to examine the benefit of blood pres- documented left ventricular hypertrophy (LVH) will be studied in over 800 cen-sure reduction on specific cardiovascular events and to ters in Scandinavia, the United Kingdom and the United States.
determine whether some drugs convey more or less benefitthan others. Each of these studies has been given an acro- LVH is defined by the core laboratory according to criteria based on the productnym, some descriptive, some catchy, leading to confusion of Cornell voltage (RaVL + SV ) x QRS duration product criteria: >2,440 mm x regarding their design and intent. This issue of Current Con- msec in men and the product of QRS duration times Cornell voltage plus 6 mmcepts in Hypertension inaugurates a series of articles designed exceeding the same value in women.1 A Sokolow-Lyon voltage combination (SV1 to provide a brief review of these studies as well as to sum- + RV or V ) >38 mm is accepted as an alternate criterion for LVH in both men marize and provide commentary on recently completed and women.2 Preliminary results from a pilot study in Scandinavia showed thatstudies of interest to those treating hypertensive patients.
the prevalence of electrocardiographic (ECG) LVH in hypertensive patients wasapproximately 22%.
In this issue is a brief summary of a recent nonpharmacologicstudy examining the impact of dietary modification on the The rationale for use of ECG rather than echocardiographic criteria for LVHdevelopment or progression of hypertension in a group of in the LIFE study is that an ECG can detect LVH with a high degree of speci-subjects at risk. The DASH Study has been cited as an impor- ficity and identifies elevated risk as efficiently or better than echocardiographytant new element in preventing hypertension or controlling at a lower cost. The cardiovascular risk (depending on age and sex) of hyper-Stage I levels of blood pressure elevation by the most recentreport of the Joint National Committee on Prevention, Detec-tion, Evaluation, and Treatment of High Blood Pressure (JNC Secondary and Tertiary Objectives of LIFE
VI). While the findings of this study are most impressive, we Editorial Board
Robert A. Kloner, MD, PhD
Myron H. Weinberger, MD
Laurence R. Krakoff, MD
Managing Editor
William E. James, PhD
Franz H. Messerli, MD, FACC, FACP
Stevo Julius, MD, ScD
Michael A. Weber, MD
The University of Michigan Medical Center The opinions or views expressed in the articles are those of the authors and do notnecessarily reflect the opinions or recommendations of the publisher, the sponsor, the American Journal of Hypertension, or the American Society of Hypertension.
Supported by an unrestricted educational grant from Pfizer, Inc.
Titration Schedule for the LIFE in Hypertension Study
Losartan 100 mg
+ HCTZ 12.5 mg
+ other antihypertensive agents (excluding ACEIs, angiotensin II antagosists, and
Losartan 100 mg + HCTZ 12.5 mg*
Losartan 50 mg + HCTZ 12.5 mg*
Losartan 50 mg
Sitting diastolic BP
95 to 115 mm Hg

Atenolol 50 mg
Sitting systolic BP

Atenolol 50 mg + HCTZ 12.5 mg*
160 to 200 mm Hg
Atenolol 100 mg + HCTZ 12.5 mg*
at day -7 and 1
Atenolol 100 mg
and LVH patient
+ HCTZ 12.5 mg
+ other antihypertensive agents (excluding ACEIs, angiotensin II antagosists, and
* Titration upward if sitting diastolic BP 90 mm Hg or sitting systolic BP 140 mm Hg.
† Titration encouraged if sitting diastolic BP
90 mm Hg or sitting systolic BP 140 mm Hg but is mandatory if sitting BP 160/95 mm Hg.

Dahlöf B, Devereaux R, DeFaire U, et al. The Losartan Intervention for Endpoint Reduction (LIFE) in hypertension study: rationale, design, and methods. The LIFE study group. Am J Hypertens 1997:10:705–713.
tensive patients with LVH compared with hypertensives without LVH tality. It is the first prospective study with adequate power to link is 1 to 6 times higher for angina pectoris, 2 to 5 times higher for reversal of LVH to reduction in major cardiovascular events.
myocardial infarction (MI), 6 to 17 times higher for heart failure,and 3 to 10 times higher for stroke. The importance of LVH is con- Suzanne Oparil, MD
firmed by the finding that, within 5 years of its appearance, one-third of men and one-fourth of women with LVH are dead, usually from Director, Vascular Biology & Hypertension Program of the Division of Cardiovascular DiseaseUniversity of Alabama at Birmingham The major hypothesis of the LIFE study is that, in patients with es- sential hypertension and LVH, losartan will reduce the incidence ofcardiovascular morbidity and mortality to a greater extent than the β- Footnotes
1. R-wave amplitude in aVL plus S-wave amplitude in V .
blocker atenolol, possibly through a greater effect on LVH regression.
2. S-wave amplitude in V plus R-wave amplitude in V or V .
This hypothesis is based on the assumption that the renin-angiotensinsystem plays an important role in mediating hypertension-induced Editor’s Comments (continued from page 1) functional and structural cardiovascular abnormalities. Atenolol wasselected as the comparative agent in the LIFE study because β-blockers need to recognize that they are based on short term (eight weeks) obser- reduce cardiovascular morbidity and mortality when used for treat- vations that say nothing about cardiovascular disease outcome.
ment of hypertension and secondary prevention of heart attack, becauseit is the most widely used β-blocker, and because efficacy and toler- In addition to this completed study, this issue of Current Concepts in ability have been compared with those of losartan.
Hypertension features two articles that are devoted to an ongoing inter-vention trial, The LIFE study. The first, by Dr. Suzanne Oparil, outlines the The primary objective of the LIFE study is to evaluate the long-term rationale behind the study design and the second, prepared by Dr. Sveffe effects (≥4 years) of losartan compared to atenolol in hypertensive Kjeldsen, provides information about the population demographics of patients with documented LVH on the combined incidence of car- this multinational study for which enrollment has now been completed.
diovascular mortality (death due to MI, stroke, sudden death, andprogressive heart failure) and morbidity (nonfatal MI and nonfatal Finally, this issue of Current Concepts in Hypertension includes a reply stroke). Secondary and tertiary objectives are shown in table 1. Study card that can provide extremely important information. Your responses design is shown in figure 1. LIFE will continue for at least 4 years and will help us understand how we can best provide future information until 1,040 patients experience one primary endpoint. It has been and will tell us more about the readership of this series. It also is an designed with a statistical power that will detect a difference of at least excellent opportunity for you to dialog with us and share your opinions 15% in the incidence of combined cardiovascular morbidity and mor- Demographics of the LIFE Study
The Losartan Intervention For Endpoint (LIFE) Reduction in Hy- cholesterol ratio of 4.3. Both total cholesterol and HDL cholesterol pertension study is a multicenter, double-blind, randomized, pro- spective, active-controlled parallel group study designed to compare theeffects of losartan with those of the ß-blocker atenolol, both in dosages Almost 15% of LIFE participants had one or more manifestations of of 50 to 100 mg qd, on cardiovascular morbidity and mortality in pa- CHD. Previous strokes and/or transient ischemic attacks were reported tients with essential hypertension and electrocardiographically (ECG) by 7.6%, lipid disorders by 16.7%, and diabetes mellitus by 12.1% of documented left ventricular hypertrophy (LVH). Additional treatment patients. A variety of other disorders were less frequently reported.
may be given as open-label hydrochlorothiazide 12.5 to 25 mg and, if Although only 2.5% were reported to have overt obesity, 21.3% had a needed, any other antihypertensive medication except for other ß- BMI of 30 to 35, 5.4% of 35 to 40 and 1.9% >40 kg/m2.
blockers, angiotensin I receptor antagonists or angiotensin-convertingenzyme (ACE) inhibitors to reach a target blood pressure (BP) of <140/ Almost one third of the patients (29.5%) had been untreated for at 90 mm Hg. After the 2-week single-blind placebo run-in period, there least 6 months for their high BP prior to the placebo period (fewer in will be at least 4 years of randomized active double-blind treatment the US [Fig. 2]), while 39.3% were on treatment with 1 antihyperten- until 1040 patients have experienced a primary cardiovascular eventdefined as cardiovascular death, nonfatal clinically-evident acute myo-cardial infarction, or nonfatal cerebral stroke. This study is Number of Prior Antihypertensives
endpoint-driven and has been calculated to have 80% power with 8300patients enrolled to detect a 15% further reduction in the primary out- 39.3 38.7
come rate from 15% in the atenolol group to 12.75% in the losartan group. The rationale, objectives, and design of the LIFE study, includ- ing outcome measures and statistical methods, have been published.1 23.2 20.4
Altogether 9194 eligible patients in Scandinavia, the United King- dom (UK), and United States (US) were enrolled at 945 study sites: Denmark (n=1391, 15%); Finland (n=1485, 16%); Iceland (n=133, Three or More
1%); Norway (n=1415, 15%); Sweden (n=2245, 25%); UK (n=817,9%); and US (n=1708, 19%). Preliminary analysis showed the pro- Scandinavia
portion of subjects who qualified, based on the Cornell voltage QRSduration product formula, was approximately 67% and 22% quali- fied, based on Sokolow-Lyon voltage; 11% fulfilled both criteria.
sive agent, 23.2% with 2, and 8.0% on treatment with 3 or more This population of hypertensives (mean BP 174.4/97.8 mm Hg) antihypertensive agents. Diuretics were taken by 27.2%, more women with LVH averaged 66.9 years of age at randomization. The women (31.4%) than men (22.3%), ß-blockers by 26.5%, calcium-channel (54.1% of total) were older, had a higher body mass index (BMI), blockers by 24.1% (men 26.3%, women 22.3%), and ACE inhibitors and were more likely to have isolated systolic hypertension. More by 21.3% (men 24.9%, women 18.0%). One of 5 (20.8%) was on men were working full-time and the men had higher Framingham aspirin. Other drug therapies were less frequent.
Risk Scores for coronary heart disease (CHD) than the women. How-ever, the predicted 5-year event rate attributable to factors other than Thus, by applying simple 12-lead ECG criteria for LVH (Cornell volt- gender was only moderately higher (P<0.001) in men (19.2%) than age QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH, with an aver-age 5-year CHD risk of 22.3% according to the Framingham Score More than 80% of patients were above the age of 60 years at random- were identified. This population is now treated (goal <140/90 mm ization. The majority of patients had moderate hypertension at the Hg) in adherence with the protocol for at least 4 years after final en- randomization visit (55.8% with systolic BP 160 to 180 mm Hg and rollment (i.e. through April 2001) and until at least 1040 patients 53.7% with diastolic BP 95 to 105 mm Hg). Moreover, 27.4% had suffer myocardial infarction, stroke, or cardiovascular death.
isolated systolic hypertension (systolic BP >160 mm Hg and diastolicBP <95 mm Hg) and 10.5% were randomized based on diastolic hy- Björn Dahlöf, Richard B. Deveraux, Stevo Julius, *Sverre E. Kjeldsen, Gareth
pertension only. BP levels were similar in all countries.
Beevers, Ulf de Faire, Frej Fyhrquist, Thomas Hedner, Hans Ibsen, Krister
Kristianson, Ole Lederballe-Pedersen, Lars H. Lindholm, Markku S. Niominen,

The overwhelming majority of subjects were Caucasian. Self-reported Per Omvik, Suzanne Oparil, and Hans Wedel for the LIFE Study Group.
alcohol and tobacco use were moderate or low; 32.0% of men and Division of Cardiology, Department of Internal Medicine, Ullevaal Hospital, 57.6% of women reported they never used alcohol whereas 80.3% and 86.5%, respectively, did not smoke. 46.7% of men were previoustobacco smokers. The average total cholesterol level (slightly above Reference
6.0 mmol) was somewhat compensated for by high-density lipopro- 1. Dahlöf B, Devereaux R, DeFaire U, et al. The Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension study: rationale, design, and methods. The LIFE study group. Am J Hypertens tein (HDL) cholesterol of about 1.50 mmol and a total-to-HDL The Effect of Dietary Patterns On Blood Pressure: Results From the Dietary Approaches to
Stop Hypertension (DASH) Clinical Trial
provided 8 to 10 servings of fruits and vegetables and 2 to 3 servings In addition to weight, salt, and alcohol, other diet-related factors may influence blood pressure (BP). In observational studies, sig- of low-fat dairy products each day. Stable body weight was maintained nificant inverse associations of BP with magnesium, potassium, and sodium was held constant in each diet at approximately 3 g/d.
calcium, fiber, and protein intake have been reported. However, in Trained and certified observers, who were blinded to diet assignment, trials that tested these nutrients, often as dietary supplements, BP re- measured blood pressure with a random zero sphygmomanometer on duction has typically been small and inconsistent.
7 occasions at baseline and again at the end of intervention feeding.
More than 95% of participants completed the 8-week intervention Mean (95 Percent CI) Changes in Systolic
phase. Figure 3 displays within-diet change in BP from baseline to the Blood Pressure From Baseline to End of
end of the intervention period for each diet group. For systolic anddiastolic BPs, a gradient across diets was evident. Compared to the Intervention, by Diet
control diet, the fruits and vegetables’ diet reduced systolic and dias-tolic BPs by 2.8 mm Hg (P<0.001) and 1.1 mm Hg (P=0.07), P<0.001
respectively. Corresponding reductions from the combination diet were P<0.001
5.5 mm Hg and 3.0 mm Hg (each P<0.001). Compared to the fruits and vegetables diet, the combination diet reduced systolic BP by 2.7 mm Hg (P=0.001) and diastolic BP by 1.9 mm Hg (P=0.002). TheBP reductions from the fruits and vegetables diet and combination diet were sustained for the duration of the 8-week intervention as seen in 83% of study participants with complete sets of weekly BP mea- surements (Fig 4). In the subgroup of 133 participants with hypertension, the combination diet reduced systolic BP by 11.4 mm Hg and diastolic BP by 5.5 mm Hg, in comparison to the control diet Change in Systolic BP (mm Hg)
In DASH, the diet rich in fruits, vegetables, and low-fat dairy prod- ucts; reduced in saturated fat, total fat, and dietary cholesterol; and Fruits & Vegetables
moderately increased in protein significantly reduced BP. A diet rich in just fruits and vegetables also reduced BP but to a lesser extent. The Mean (95 Percent CI) Changes in Diastolic
Blood Pressure From Baseline to End of
Because of these observations, DASH, a multicenter, randomized feed- Intervention, by Diet
ing study tested the effects on BP of whole dietary patterns ratherthan individual nutrients.1 Trial participants (n=459, 49% women, P<0.001
60% African American) had diastolic BPs between 80 and 95 mm Hg P=0.07
at entry and were provided all of their food for 11 weeks.2 Participants were fed the control diet for 3 weeks and then randomly assigned toeat, for an additional 8 weeks, (a) the control diet; (b) a diet rich in fruits and vegetables but otherwise similar to the control diet or; (c) a combination diet rich in fruits, vegetables, and low-fat dairy prod- ucts; reduced in saturated, total fat, and dietary cholesterol; and moderately increased in protein. The control diet was typical of what many Americans eat (35.7% of calories from fat, 13.8% of calories from protein, 233 mg/d of cholesterol, 1752 mg/d of potassium, 176 mg/d of magnesium, and 443 mg/d of calcium).
Change in Diastolic BP (mm Hg)
The diet with fruits and vegetables (b above) was designed to increase potassium, magnesium, and fiber by approximately 2.5 times the cor- Fruits & Vegetables
responding values in the control diet. In the combination diet, the percentages of calories from fat and protein were 25.6% and 17.9%, respectively. In addition, its potassium, magnesium, calcium, and fi-ber were approximately 2.5 times the corresponding values in the control diet. To achieve this nutrient profile, the combination diet trial was not designed, however, to identify effective and ineffective DASH Collaborative Research Group members: George A. Bray, MD; Marlene M. Windhauser, PhD; David W. Harsha, PhD
The results of the DASH trial should be broadly applicable to the Pennington Biomedical Research Center United States (US) population. By using commonly available foods, including meats, the trial tested dietary patterns that the general US Larry J. Appel, MD, MPH; Priscilla Steele, MS, RD; Pete Miller, MD
population could potentially adopt. Furthermore, the study sample was broadly representative, covering a wide age range which included equal numbers of men and women, consisted of 60% African Ameri- William M. Vollmer, PhD; Thomas M. Vogt, MD, MPH;
cans, and included persons with high normal BP and individuals with Njeri M. Karanja, PhD, RD;
stage 1 hypertension. Application of the BP reductions observed in DASH to the US population could theoretically reduce incidence of coronary heart disease by 15% and stroke by 27%.
Thomas J. Moore, MD; Frank M. Sacks, MD; Marjorie McCullough, MS, RD;
Janis Swain, MS, RD

In conclusion, a diet rich in fruit, vegetables, and low-fat dairy prod- ucts; and reduced in saturated fat, total fat and dietary cholesterol; and moderately increased in protein can substantially lower BP. Thisdiet offers an additional nutritional approach to preventing and treat- Laura P. Svetkey, MD; Pao-Hwa Lin, PhD
Duke University Medical CenterDurham, North Carolina References
Eva Obarzanek, PhD, MPH, RD; Jeffrey A. Cutler, MD;
1. Sacks FM, Obarzanek E, Windhauser MM, and others, for the DASH investigators. Rationale and design of the dietary approaches to stop hypertension trial (DASH): A multicenter controlled-feeding Denise Simons-Morton, MD, MPH; Marguerite A. Evans, MS, RD
study of dietary patterns to lower blood pressure. Ann Epidem 1995;5:108-118.
National Heart, Lung, and Blood Institute Project Office 2. Appel LJ, Moore TJ, Obarzanek E, and others. A clinical trial of the effects of dietary patterns on blood pressure. New Engl J Med 1997;338:1117-1124.
American Society of Hypertension
The American Society of Hypertension (ASH) is the largest US orga- hypertension and/or related cardiovascular disease, those involved in the nization dedicated exclusively to hypertension and related diagnosis and treatment of hypertension and related cardiovascular dis- cardiovascu-lar disease. ASH was founded in 1985 by Dr. John Laragh ease, and those with a demonstrated serious interest in the field. Among and 16 other world-famous clinicians and scientists in an effort to evalu- the benefits of ASH membership are association and interaction with ate the vast accumulation of data on hypertension and to provide a separate clinicians and scientists who are world leaders in the field, a subscription forum for those involved in the study or management of high blood pres- to the American Journal of Hypertension and all its supplements, a listing in sure. The mission of the Society became “to organize and conduct the ASH Member Directory used for patient referral, and a savings of educational activities designed to promote and encourage the develop- 50% or more on registration fees for the annual scientific meeting.
ment, advancement, and exchange of scientific information in all aspectsof research, diagnosis, and treatment of hypertension, and related cardio- The American Society of Hypertension sponsors three award programs annually. The first award program focuses on the area of ongoing researchtraining in the field of hypertension for young clinicians planning a career Today, the Society boasts a membership of over 3,000 strong with 95% of in academic medicine. Another recognizes and rewards three scientists its members holding an MD, PhD, or other advanced degree. The Soci- who have carried out a significant body of work in the field of hyperten- ety continues to fulfill its mission by annual meetings that provide sion or related cardiovascular diseases. The last award program recognizes registrants with the rare opportunity to exchange information and ideas and rewards five young physicians, currently residents or fellows, who with more than 2,500 fellow scientists from around the world. Highlights have a demonstrated interest in the study of hypertension or who plan a of the meeting include state-of-the-art lectures by renowned faculty, ple- nary sessions, original communications, poster presentations, technicaland scientific exhibits, and provocative special symposia.
For further information on ASH membership, awards programs, futuremeeting dates or to add your name to the ASH mailing list, contact: In addition, the Society publishes the prestigious American Journal of Hy-pertension, a monthly publication containing the latest information in The American Society of Hypertension
both basic science and clinical research.
515 Madison Avenue, Suite 1212New York, NY 10022 Membership in ASH is open to all those who have undertaken and ac- complished meritorious original scientific investigation in the field of American
Society of

Current Concepts in
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The Effect of Dietary Patterns On Blood Pressure: The Losartan Intervention For Endpoint Reduction Results From the Dietary Approaches to Stop Published by Postgraduate Institute for Medicine Englewood, CO 800-423-3576 Copyright 1998 All rights reserved
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