Characteristics of 9194 Patients With Left Ventricular Hypertrophy
The LIFE Study
Abstract—Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the β-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and ≈7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.
- antihypertensive agents
- cardiovascular diseases
- hypertrophy, left ventricular
- randomized controlled trials
Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 (AT1) receptor approved for the treatment of essential hypertension.1 2 3 The existence of left ventricular hypertrophy (LVH) identifies patients at particularly high risk for cardiovascular complications in essential hypertension4–6; studies in animals suggest that treatment with losartan may be beneficial for target organ protection and, more importantly, improve survival.7 8 9 10 Promising results have now been seen with losartan for survival in heart failure.11
The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a multicenter, double-blind, double-dummy, randomized, prospective, active-controlled parallel group study designed to compare the effects of losartan with those of the β-blocker atenolol (both in doses of 50 to 100 mg/d) on cardiovascular morbidity and mortality in patients with essential hypertension and ECG-documented LVH. Additional treatment may be given in the form of open-label hydrochlorothiazide (12.5 to 25 mg) and, if needed, any other antihypertensive medication except for other β-blockers, AT1 receptor antagonists, or angiotensin-converting enzyme (ACE) inhibitors to reach a target blood pressure of <140/90 mm Hg. After the 2-week, single-blind placebo run-in period, there will be a period of at least 4 years of randomized, active double-blind treatment until 1040 patients have experienced a primary cardiovascular event defined as cardiovascular death, nonfatal clinically evident acute myocardial infarction, or nonfatal cerebral stroke. This study is end-point driven and has been calculated to have 80% power, with 8300 patients enrolled to detect a 15% further reduction in the primary outcome rate from 15% in the atenolol group to 12.75% in the losartan group. The rationale, objectives, design, and methods of the LIFE Study, including outcome measures and statistical methods, have been published recently.12
Altogether, 9223 eligible patients in Scandinavia, the United Kingdom, and the United States were randomized as of April 30, 1997. The LIFE Study is the largest study ever to be undertaken in patients with LVH and one of the largest intervention studies in essential hypertension. The LIFE Study is also unique in that it used ECG criteria for LVH to recruit a large population of high-risk hypertensives. This report describes the baseline characteristics of the LIFE participants.
Eligible patients were men and women between 55 and 80 years of age with previously untreated or treated essential hypertension and ECG-documented LVH (see below). To be included, they had to have mean trough sitting diastolic blood pressure (BP) readings of 95 to 115 mm Hg and/or mean sitting systolic BP readings of 160 to 200 mm Hg after 1 and 2 weeks of single-blind placebo treatment. BP and heart rate were measured with standardized techniques after subjects had been seated for 5 minutes. Subjects were questioned about alcohol intake, smoking habits, exercise level, and employment status, and weight and height were measured. Information on previous diseases and drug therapies was collected by the investigators before randomization, and a physical examination was performed to detect concomitant diseases. Laboratory tests performed in the central laboratory included determinations of levels of hemoglobin, serum sodium, potassium, creatinine, uric acid, total cholesterol, HDL cholesterol, and glucose. Mean BPs for the randomized patients averaged 169.9/94.8, 172.6/96.6, and 174.4/97.8 mm Hg, respectively, at screening and after 1 and 2 weeks of placebo.
Exclusion criteria included cardiovascular conditions and obvious noncardiac diseases that may limit long-term survival of the patient or increase the likelihood of nonadherence to study medication.12
After a pilot phase at 8 sites in Norway and Sweden in June through August, 1995, 945 centers in Denmark, Finland, Iceland, Norway, Sweden, United Kingdom, and the United States actively participated in the study and included patients during the period of September 1995 through April 1997. The vast majority of the centers are active in primary care; however, in Denmark most LIFE patients were referred from primary-care physicians to hospital-based centers. An average of 9.7 (range, 1 to 148) participants were enrolled in each center.
LVH was diagnosed electrocardiographically from standard 12-lead ECGs in all participants before randomization by the Core Laboratory at Sahlgrenska University Hospital/Östra in Göteborg, Sweden. LVH was identified by the core laboratory using criteria based on the Cornell voltage×QRS duration product13–15: (RaVL+SV3)×QRS duration >2440 mm×ms in men and (RaVL+SV3+8 mm)×QRS duration >2440 mm×ms in women. Beginning on May 1, 1996, at which time 2375 patients had been enrolled, the gender correction of Cornell criteria in women was revised from 8 to 6 mm, both based on data published after the LIFE design had been established16 and because of an initial relative oversampling of women (Table 1⇓). From this date, an additional acceptance criterion was introduced based on the Sokolow-Lyon voltage combination (SV1+RV5 or V6) >38 mm.17 The rationale for adding the Sokolow-Lyon criterion was based on the following assumption: Both Cornell and Sokolow-Lyon criteria (>35 mm) have specificities of ≈95% in normal adults18 but sensitivities of only ≈30% to 40%. In reanalysis of published data sets,13 14 15 18 combining the two (and increasing Sokolow-Lyon voltage to >38 mm) increased the sensitivity by more than 10% without loss of specificity.13 14 15 16 17 The ECG criteria for LIFE participants will be further validated in a large echocardiographic substudy comprising about 12% of the LIFE study population.
Early in the process of preparing the final baseline database, irregularities were discovered at 1 center, and it was decided at a steering committee meeting in New York on Sept 12, 1997, to remove the 29 patients randomized at this center.
Results are presented as mean±SD or as percent of the total number of subjects. The statistical significance of the differences between men and women was assessed using the χ2 test for categorical variables and the rank-sum test for continuous variables. An average 5-year risk of coronary heart disease (CHD) was calculated according to the Framingham risk score.19 This score depicts the probability of developing CHD in a population of normal subjects, based on a number of established cardiovascular risk factors. Because some of the patients in the LIFE Study already have CHD, the score is not entirely appropriate, but it does provide a useful index of the patients’ total risk burden.
More than 33 000 screening ECGs were received, and approximately 19 000 ECGs were approved as meeting the study ECG-LVH criteria. Following these ECG approvals, a total of 9223 patients met BP and other inclusion and no-exclusion criteria and gave signed informed consent. Patients were enrolled from June 1995 through April 1997, when randomization was closed. The number of patients in the 7 participating countries are as follows: Denmark (n=1391, 15%), Finland (n=1485, 16%), Iceland (n=133, 1%), Norway (n=1415, 15%), Sweden (n=2245, 25%), United Kingdom (n=817, 9%), and United States (n=1708, 19%). The great majority of the 945 study sites had relatively small numbers of patients (1 to 10 patients in 669 centers). The 25 larger centers with ≥40 patients enrolled 1621 patients or 17.6% of the total population (Figure 1⇓).
Many more women (61.3%) than men were enrolled through April 1996. After changing the gender correction from +8 to +6 mm on Cornell voltage, proportionately fewer women were randomized (51.5%, Table 1⇑), resulting in a total of 54.1% women in the study. Preliminary analysis shows that the proportion of subjects who qualified based on the Cornell voltage QRS duration product formula was approximately 66%; 21% qualified based on Sokolow-Lyon voltage, and 10% fulfilled both criteria.
The patients were an average of 66.9 years of age at randomization. The women were older, had a higher body mass index (BMI), and were more likely to have isolated systolic hypertension (Table 2⇓). More men were working full-time, and the men had higher Framingham risk scores for CHD than the women. However, the predicted 5-year event rate attributable to factors other than gender was only moderately higher (P<0.001) in men (19.3%) than in women (17.1%).
More than 80% of patients were above the age of 60 years at randomization (Table 3⇓). The majority of patients had moderate hypertension at the randomization visit (55.9% with systolic BP 160 to 180 mm Hg and 53.7% with diastolic BP 95 to 105 mm Hg; Figures 2⇓ and 3⇓). Moreover, 27.4% had isolated systolic hypertension (systolic BP ≥160 mm Hg and diastolic BP <95 mm Hg), and 9.8% were randomized based on diastolic hypertension only. BP levels were similar in all countries (Figure 4⇓).
The overwhelming majority of subjects are white (Table 3⇑). Self-reported alcohol and tobacco use are moderate or low; 32.1% of men and 57.6% of women report that they never use alcohol (Table 3⇑), and 80.3% and 86.5%, respectively, do not smoke. Of the men, 46.7% are previous tobacco smokers. The average total cholesterol level was slightly above 6.0 mmol, somewhat compensated for by high HDL cholesterol and a ratio of total to HDL cholesterol of 4.3 (Table 4⇓). Both total cholesterol and HDL cholesterol were higher in women than in men.
Approximately 15% of LIFE participants had 1 or more manifestations of CHD (Table 5⇓). Previous stroke and/or transient ischemic attack was reported by 7.7%, lipid disorders by 18.0%, and diabetes mellitus by 12.3% of patients. A variety of other disorders were reported less frequently.
Although only 2.7% of patients were reported to be overtly obese, 21.3% had a BMI of 30 to 35 kg/m2, 5.4% of 35 to 40 kg/m2, and 1.9% ≥40 kg/m2. There were weak age-adjusted associations between BMI and BP (r=0.034, P<0.002 for sitting systolic; r=0.078, P<0.001 for standing systolic; r values for diastolic in between). There was a weak but significant correlation between BMI and baseline Cornell voltage using either the preamendment (r=0.135, P<0.001) or postamendment (r=0.131, P<0.001) calculation of Cornell voltage. After adjustment for age, the partial correlation was a little larger than the crude correlation (r=0.155, P<0.001 or r=0.149, P<0.001, respectively).
Almost one third of the patients (28.9%) had been untreated for at least 6 months for their high BP before the placebo period, while 39.6% were receiving treatment with 1 antihypertensive agent, 23.3% with 2, and 8.1% on treatment with 3 or more antihypertensive agents. Diuretics were taken by 27.5% and by more women (31.8%) than men (22.5%); β-blockers were taken by 26.7%, calcium channel blockers by 24.3% (men 26.6%, women 22.3%), and ACE inhibitors by 25.2% (men 28.9%, women 22.1%). One of 5 subjects (21.0%) was taking aspirin; other drug therapies were less frequent. These included anti-inflammatory drugs (7.1%), antidiabetics (6.6%), cholesterol-lowering drugs (7.1%), acid-lowering drugs (5.2%), thyroxine (5.1%), nitrates (5.0%), digoxin (3.0%), and warfarin (1.4%). Of the women, 18% were taking postmenopausal hormone-replacement therapy.
The median number of days of placebo therapy was 14 in all participating countries. A limited number of patients (724 men and 832 women) who entered the single-blind placebo phase of the study were not randomized. These subjects were fairly comparable to those who were randomized with respect to age and gender distribution (Table 6⇓). However, relatively more African Americans were not randomized. BP levels outside the windows that qualified for inclusion (29.9%) and nonapproved ECGs (28.9%) were the most common reasons for not being randomized. Other common reasons for discontinuation during the placebo period were exclusion criteria (14.7%), patient being unwilling (10.8%), and clinical adverse experience (8.9%).
Over a period of less than 2 years, 945 centers in the Nordic countries, the United Kingdom, and the United States have applied some strict but simple 12-lead ECG criteria (Cornell voltage×QRS duration product >2440 mm×ms and Sokolow-Lyon voltage combination >38 mm) to identify hypertensive patients between 55 and 80 years of age with LVH. While the aim was a study population of 8300 patients, a total of 9223 patients were included, and 9194 remain after exclusion of a study site at which irregularities were discovered. This population of hypertensives with LVH comprises mostly retired women and men, on average overweight and with relatively high prevalences of diabetes, lipid disorders, and CHD and relatively low prevalence of active smoking. The population is predominantly white but includes 694 patients from other ethnic groups.
Investigators were able to submit 12-lead ECGs from any hypertensive patient between 55 and 80 years for approval by the ECG Core Laboratory. More than 33 000 ECGs were received, and more than 19 000 (57.6%) were approved. Preliminary results from a pilot study in Scandinavia showed that the prevalence of ECG-documented LVH in nearly 1500 mainly treated patients, who otherwise met eligibility criteria to be used in the LIFE study, was approximately 22%.12 Although many investigators submitted unselected ECGs for scrutiny (S. Jern, personal communication, 1997), an approval rate of 57.6% clearly suggests that most investigators accurately read ECGs according to the study criteria before submitting them. The ability to enroll over 9000 hypertensive patients predominantly drawn from primary healthcare centers by use of this procedure supports the usefulness of using ECG for identification of high-risk hypertensives and demonstrates the feasibility of this approach in general practice.
Furthermore, the patients who were randomized comprise about 28% of all patients screened for the study and 48.5% of all those who were approved on the basis of ECG readings. The question of generalizability is important.20 It is reasonable to consider the randomized patients in the LIFE Study to be representative of hypertensive patients with ECG-documented LVH in the age group under study. Furthermore, the demographic characteristics of those patients who entered the 2-week placebo run-in period were similar for nonrandomized patients and randomized patients except for specific exclusion criteria, ie, either not approved ECG or BP outside the range for inclusion.
Beginning on May 1, 1996, the gender correction of the Cornell voltage criteria in women was revised from 8 to 6 mm based on data published after initiation of LIFE recruitment16 because of a relative oversampling of women. On this date, an additional acceptance criterion was introduced based on the Sokolow-Lyon voltage combination (SV1+RV5 or V6) >38 mm.18 After this change was implemented (ie, subjects could fulfill the revised Cornell voltage criteria, the Sokolow-Lyon voltage, or a combination of both), 51.5% of those randomized were women. Thus, ECG criteria used subsequent to May 1, 1996, are appropriate to achieve a balanced gender recruitment. Inclusion of participants with these ECG criteria has resulted in a high prevalence of LV geometric abnormalities (82%) according to a preliminary analysis of baseline echocardiographic data in a substudy of 625 LIFE patients representative of the whole LIFE cohort.
The LIFE Study population is at high risk for cardiovascular end points, with a 5-year probability of coronary morbid or mortal events of 22.3% according to the Framingham risk score. Although the Framingham composite risk score was not used to support the expected number of events in this study,12 we have preliminarily assessed the usefulness of the score in relation to the first 301 reported primary end points. Men have a higher event rate than women (4.0% versus 2.7%), and the event rate increases with higher age. The Framingham risk score seems to be extremely effective for stratifying patients; patients in the lowest tertile have an event rate of 1.9%, the middle tertile 3.1%, and the highest tertile 4.9%.
Beyond high BP and LVH, the subjects are on average elderly and overweight and have high prevalences of diabetes, lipid disorders, and previously known CHD. More than 27% have isolated systolic hypertension, a condition associated with particularly high cardiovascular risk.20 Despite a surprisingly low ratio of total to HDL cholesterol of 4.3, total cardiovascular risk in the LIFE Study is nearly as high as the risk in the recent successful Swedish Trial in Old Patients with Hypertension.21 The lipid profiles of the LIFE participants and the low prevalence of statin use may have been due to selection bias, ie, those with particularly high cardiovascular risk and/or established cardiovascular disease were not eligible for enrollment.
The characteristics of the LIFE Study population and the frequency of early end points suggest that the time course of the study will probably not deviate much from projections,12 ie, a follow-up time of 4 years from enrollment of the last patient and accumulation of 1040 patients with primary end points. However, the study included 894 more patients than initially planned. The study will thus have more than the planned 80% power after 4 years of follow-up on April 30, 2001, provided the discontinuation rate is kept at an acceptable level.
A surprising finding is that almost one third of the patients were untreated for their high BP for at least 6 months when recruited into the LIFE Study, despite the recommendations in several recently published guidelines for detection, treatment, and follow-up of hypertension.22 23 24 The low treatment rate is, however, consistent with the findings of the Hypertension Optimal Treatment Study,25 in which 48% of participants were untreated at enrollment. Not so surprising are the gender differences in choice of antihypertensive drugs: more women were taking diuretics and fewer were taking calcium channel blockers and ACE inhibitors than were men. Because of the high cardiovascular disease comorbidity, it is not surprising that 20% were taking aspirin, a treatment recently supported.26 The BP target in the LIFE Study is <140/90 mm Hg, which seems appropriate in light of the high risk of the participants and the final results of the Hypertension Optimal Treatment Study.26
Smoking and hypertension may be a deadly combination.27 Cross-sectionally, there is less smoking with higher BP.28 The low prevalence of smoking in the LIFE Study may be explained by selection/exclusion bias of smokers with concomitant diseases such as myocardial infarction within 6 months or need for open-label treatment with β-blockers, ACE inhibitors, or angiotensin receptor antagonists. Another important reason for selection bias for smoking prevalence is that sicker patients are more likely to have stopped smoking following medical advice.
In conclusion, by applying simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula and/or Sokolow-Lyon voltage), it has been feasible to identify a large number of hypertensive patients with LVH. By using additional inclusion and exclusion criteria, it has been possible to select from the population and randomize into the LIFE Study a total of 9194 high-risk patients with an average 5-year likelihood of CHD events of 22.3% as assessed by the Framingham risk score. This population will receive BP-lowering treatment (aim, <140/90 mm Hg) according to the protocol for at least 4 years and until 1040 patients have experienced a primary end point.
International Steering Committee, LIFE Study
Björn Dahlöf (Chairman), Sahlgrenska University Hospital/Östra, Göteborg, Sweden; Richard B. Devereux (Vice Chairman), Cornell Medical Center, New York; Stevo Julius (US Coordinator), University of Michigan, Ann Arbor, Michigan; Sverre E. Kjeldsen (Secretary, Scandinavian Coordinator), Ullevaal University Hospital, Oslo, Norway; Gareth Beevers, City Hospital, Birmingham, UK; Ulf de Faire, Karolinska University Hospital, Stockholm, Sweden; Frej Fyhrquist, Helsinki University Central Hospital, Finland; Thomas Hedner (Associate Member, Chairman of Substudy Committee), Sahlgrenska University Hospital, Göteborg, Sweden; Hans Ibsen, Glostrup University Hospital, Denmark; Ole Lederballe-Pedersen, Viborg Hospital, Denmark; Lars H. Lindholm, Umeå University, Sweden; Markku S. Nieminen, Helsinski University Central Hospital, Finland; Per Omvik, Haukeland University Hospital, Bergen, Norway; Suzanne Oparil, University of Alabama Medical Center, Birmingham, Alabama; Hans Wedel, The Nordic School of Public Health, Göteborg, Sweden; and Krister Kristianson, Merck Research Laboratories, Scandinavia, Stockholm, Sweden. Data and Safety Monitoring Board: John Kjekshus (Chairman, Norway), Lewis Kuller (US), Pierre Larochelle (Canada), Giuseppe Mancia (Italy), Joël Ménard (France), Stuart Pocock (UK), John Reid (UK), and Michael Weber (US). Endpoint Committee: Daniel Levy (US) and Kristian Thygesen (Denmark). ECG Core Center (at Clinical Experimental Research Laboratory, Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg, Sweden): Sverker Jern (Chair), Eva Thydén (Secretary), and technicians Agneta Frazer, Annika Johansson, Hannele Korhonen, Margareta Leijon, and Christina Linnér. Data Analysis: Steven Snapinn (Merck Research Laboratory, West Point, Pa, US). Monitoring Offices, Merck Sharp & Dohme: Sigrid Helle Berg, Gro Renstrøm Moen (Scandinavian Headquarters, Drammen, Norway). National Project Leaders: Michael Busch-Sørensen (Denmark/Iceland), Pekka Koskinen (Finland), Andreas Moan (Norway), Gunbritt Lagerbäck (Sweden), Carol Parish (UK), and Jonathan M. Edelman, Polly Lyle (US).
I Aagaard-Hansen, JAZ Adriansen, E Agner, JR Andersen, I Andresen, S Beeken, J Bendsen, E Bjerre, J Blaaberg, P Bladt, C Bolsing, N Borrild, M Brahm, O Brassøe, K Brockelmann, F Børsting-Larsen, E Christiansen, J Dahl, N Dall, U Davidsen, U Dixen, B Dorff, P Duedal, M Dupont, J Edlund, K Ege Rasmussen, P Elsborg Nielsen, EW Eriksen, A Evers, K Gedebjerg, N Gerdes, HS Hansen, OB Hansen, V Hansen, M Hecht Olsen, M Heitmann, P Hildebrandt, JA Hejlesen, H Hoby Andersen, J Holm-Pedersen, H Horst, S Husted, JJ Hygum, M Højgaard, J Ingerslev, B Jastrup, B Jensen, F Jensen, N Jensen, A Johannessen, J Johansen, U Jørgensen, P Kaiser-Nielsen, J Kanters, B Kilde, C Kjellerup, E Kjøller, E Klarholt, AK Knudsen, K Kølendorf, K Kristiansen, V Lade, J Larsen, PT Larsen, E Lassen, J Leer-Andersen, A Leth, O Lindegaard, M Lund, M Lytje, J Mertz, JK Magnussen, K Mølenberg, O Møller Andersen, L Møller Sørensen, P Nelby, S Neldam, HV Nielsen, L Nielsen, J Ninn-Hansen, L Nis-Hansen, F Nørgaard, NE Nørmark-Larsen, H Olesen, JF Olsen, H Orsholt, E Oxhøj, S Paulin, F Pedersen, J Petersen, JG Petersen, N Ralfkiær, O Ryom Petersen, T Pindborg, C Pisinger, SE Poulsen, HH Rasmussen, A Rasmussen, K Rasmussen, J Refsgaard, H Rickers, S Roed, M Scheibel, PJ Schultz, P Schultz-Larsen, P Sederberg-Olsen, T Skottun, M Skoven, J Sølling, E Søndergaard, E Sørensen, R Sørensen, T Sørensen, S Strandgaard, H Strøm, P Thoft-Christensen, A Thomassen, N Thøgersen, C Tidemand-Dal, C Tuxen, P Tønnesen, J Vang Andersen, B Varming, S Vejlø, SA Vinter, K Wachtell, N Wickers-Nielsen, P Wiggers, T Yde, M Zarling, H Ærenlund Jensen.
H Airaksinen, J Airas, K Ala-Kaila, M Alaluoto, T Aronkytö, I Castren, T Ebeling, T Espo, R Grönfors, T Grönroos, M Haapio, T Hakamäki, K Halavaara, K Halonen, K Harno, H Hedborg, K Helin, M Helin, P Helo, H Holstila, T Honkanen, M Honkavaara, J Hopsu, T Huopaniemi, L Hänninen, R Ikäheimo, J Isojärvi, B Isomaa, K Jaakkola, M R Jaakkola, T Jääskeläinen, M Jääskivi, PT Jaatinen, V Järveläinen, A Joensuu, J Jouppila, S Junnila, P Kaipiainen, E Kanniainen, I Kantola, A Kärkkäinen, J Karmakoski, H Kauma, R Kauppinen-Mäkelin, A Kesäniemi, S Kekki, M Kekäläinen, T Keski-Opas, E Kettunen, J Kiesilä, M Kiviluoto, J Korhonen, K Korhonen, R Korhonen, H Kortesuo, I Kuisma, K Kuismanen, J Kukkonen, R Kuronen, K Kuusisto, K Laine, J Laurikainen, E Lehmus, M Lilja, C-J Lindström, M Luomala, I Luukkanen, O Luurila, J Määttänen, M Matintalo, M Mattila, P Mattila, PT Mattila, R Mauno, S Mella, M Meriläinen, M Nikkilä, L Niskanen, P Nuorttila, M Oikkonen, J Opas, H Pälvimaa, K Pasula, T Pehkonen, S Pentti, H Penttilä, O Penttilä, J Perttilä, A Pinola, K Pohjola, M Puhakka, H Puolijoki, A Raassina, M Rantala, J Rantonen, M Rasmussen, J Rönkä, M Rönty, H Ruokolainen, J Ruoppa, M Saari, T Saaristo, P Sakaranaho, S Säkö, E Salonen, O Sammalkorpi, C Sarti, H Selin, V Sillanpää, R Siloaho, K Soininen, A Strandberg, M Suhonen, S Sulosaari, M Suokas, J Teittinen, M Their, P Tietäväinen, I Tikkanen, T Tikkanen, E Toivanen, R Tossavainen, J Tuomilehto, T Unkila, J Vaarala, M Vanhala, P Vanhala, E Vanhatalo, J Venäläinen, T Ventilä, P Villa, K Vilppula, A Virtanen, M Virtanen, J Wenning.
A Árnason, EP Haraldsson, B Jónasson, Á Kristinsson, H Magnússon, O Mixa, JÁ Sigurosson, P Porgeirsson.
KB Andersen, TP Andersen, R Apelseth, S Bakken, LI Balle, S Barbo, F Berset, A Bjørge, L Bjørndal, T Bøe, B Bratland, J Brodwall, JE Brovold, O-P Brunstad, R Byre, K Dickstein, Ø Digranes, T Eikeland, BI Embrå, T Enersen, N Espeland, JK Fagernæs, J Fauske, S Fosse, OG Gabrielsen, G Gerhardsen, RE Gilhuus, K Gisholt, M Glasø, C Groth, Ro Gundersen, Ru Gundersen, AG Haanshuus, L Hæstad, CH Hagelund, A Hagen, A Hallaråker, OP Halvorsen, TY Halvorsen, T Hansen, T Hatlebrekke, S Haugsbø, O Hegelstad, SM Helgeland, O Helgesen, H Helvig, A Hestnes, T Hillestad, K Hjelle, I Hjermann, OJ Hjort, G Hjorth, S Holm-Johnsen, J Johansen, R Johansen, T Johnsen, GE Johnson, O Jordal, R Karlsen, S Karper, T Karsrud, JF Kayser, G Kittang, SE Kjeldsen, V Koefoed, KE Langaker, OF Lehn, JO Lindebø, Ø Line, A Lislerud, T Lømsland, K Mariadasan, BO Markussen, T Meling, K Michelsen, IK Modalsli, V Moldegård, H Myrland, T Næss, S Nasrala, O Nestegard, JF Nilsen, P Norheim, OG Nygaard, K Olafsson, P Omvik, F Oppøyen, JS Pettersen, O Petterson, JO Prytz, H Rafat, S Reimer, S Reiten, R Retzius, T Risanger, O Rivelsrud, S Rognstad, B Rogstad, S Rønbeck, S Røsnes, L Røssås, I Rypdal, E Saltvedt, P Sandbakken, L Sandsdalen, E Sandvik, R Sannes, JB Simonsen, G Skjelvan, R Skjesol, P Skuseth, JC Slørdahl, T Smedsrud, P Smith, BH Sørensen, R Stene, H Steenfeldt-Foss, OG Stokke, T Sund, H Sunde, K Sveen, A Svilaas, JO Syvertsen, S Thomassen, T Thomassen, L Tjeldflaat, S Toft, T Tomala, F Tysland-Johnsen, Eg, Vaage, Ei Vaage, S Vabo, K Valnes, S Vatle, T Vattekar, A Vedvik, Y Vestjord, B Vig, I Vika, A Visted, P Walvik, T Winsnes, A Aarflot, E Åserud.
G Alm, G Almkvist, M Alvin, L Andersen, E Andersson, F Andersson, JE Andersson, PO Andersson, M Appert, J Arlestig, B Atmer, L Belfrage, PO Bengtsson, C Berg, B Björkman, A Björndahl, H Blom, J Boberg, R Borelius, G Borglund, PÅ Boström, H Brandström, I Bruce, P Carlsson, O Christoffersson, B Cöster, G Dahlén, P E:son Jennersjö, E Edvinsson, A Egilsson, A Ehnberg, E Eizyk, K Ekenbratt, L Ekholm, V Ekstedt, B Eliasson, J Ellström, C Elofsson, M Enander, M Engberg, J Engborg, L Engquist, UB Ericsson, K Eriksson, LT Eriksson, S Eriksson, H Fermhede, E Folin-Nilsson, PG Franke, JE Frisell, C Frisenette-Fich, O Garmén, M Grubb, K Gunnarsson, J Gustafsson, SR Gyhrs, R Hagman, B Hallmans, B Hamborg, E Hammarström, B Hanson, E Haugnes, T Hedner, S Hellerstedt, NC Henningsen, A Henriksson, K Henriksson, S Hjalmers, C Högberg, C Höglund, J Holm, AM Hörnqvist Budell, A Hult, BM Iacobaeus, B Jacobson, B Jansson, A Jayawardena, SA Jensen, B Johansson, G Johansson, G Johansson, S Johansson, S Johansson-Fredin, K Johnson, H Jones, R Jönsson, A Kadesjö, EL Kekki, J Kjellberg, S Kullman, A Kulneff-Herlin, H Kvande, H Larnefeldt, I Larsbrink, B Larsson, H Larsson, R Larsson, J Leffler, B Leijd, A Lerner, A Lindberg, M Lindbergh, A Lindborg, B Lindwall, P Löfdahl, E Löfsjögård-Nilsson, L Lönneborg, P Lorenzon, E Löwenhoff, R Lundgren, L Lundin, G Lyngstam, E Mägi, P Malm, L Malmberg, K Malmqvist, P Möller, CM Mölstad, M Montell, P Montnemery, R Muammar, G Nabseth, P Nicol, H Nilsson, H Nilsson, K Nilsson, T Nilsson, T Nilsson, A Norberg, C Norberg, M Norberg, V Norlund-Elmroth, L Nygaard Pedersen, R Ödegården, P Öhman, P Olsson, S Olsson, T Olsson, AM Ottosson, M Oweling, K Pedersen, R Peste, C Petersson, U Petersson, B Pettersson, B Pettersson, B Pettersson, M Rautureau, N Regnström, G Rose, U Rosenquist, S Röstlund, F Rucker, B Samuelsson, A Shah, L Sjöberg, C Sjödin, P Sjöström, E Skarfors, N Skönland, P Skoog, A Spjuth, I Stålberg, J Stålhammar, G Steinertz, B Sträng-Olander, B Sundqvist, S Sunnerö, CA Svanberg, P Tenbrock, P Thambert, Å Theander, T Thulin, C Tillberg, K Tolagen, T Ulvatne, G Ulvenstam, G Umefjord, E van Mansvelt, K Vetterskog, R Viberg, K Viidas, L Viktorsson, P Vinnal, M Vlastos, N Voergaard, R Wahlström, G Wåström, AC Weibull, P Weng, B Westerdahl, K Westergren, T Widelius, G Widerström, J Zettergren, V Åhgren, L Åkerman, B Åkerström.
RM Adams, A Amadi, N Amin, J Anderson, D Baird, H Ball, P Batin, P Bennett, M Blagden, R Boyle, M Brown, C Cackette, T Cahill, I Cathcart, J Cecil, A Chadha, K Channer, J Chapman, G Charlwood, R Clark, A Coats, R Cook, P Corrie, A Cowie, B Dass, SM Davis, J Dhawan, I Dickie, M Duckworth, F Dunn, B Fehilly, D Fernell, A Fuat, K Gillespie, A Golding-Cook, N Gough, BA Gould, N Gray, T Greenwood, J Hampton, P Harvey, A Hetherington, E Higgs, N Higson, JG Hole, W Jago, SK Jain, C Jarvis, M Johnson, D Johnston, I Jones, D King, B Kuenssberg, M Kumwenda, C Kyle, M Laws, P Lee, C Lennon, P Lewis, S Lightfoot, B Lightstone, J Litchfield, J Lovejoy, GD Martin, T Maxwell, G McInnes, J McLay, F McNaughton, P Megarity, P Mennim, A Michie, A Middleton, A Millar, MW Millar-Craig, J Miller, E Minhas, T Moody, V Nathoo, R Newland, RJ Northcote, M Parashchak, S Patel, R Paton, M Percy, M Peverley, P Peverley, J Pittard, R Pool, K Premawardhana, L Ramsay, S Rao, J Reckless, J Repper, S Riley, M Rogerson, R Ross, A Rotheray, S Rowlands, P Rubin, D Russell, P Rutherford, J Ryan, P Rylance, M Sidhom, J Silas, V Sim, D Sprigings, G Tanner, C Temple, GD Walker, T Wall, M Wilkins, P Wilkinson, A Williams, N Willmott, B Young.
D Abu-Hamdan, O Ahmed, MH Alderman, HL Alpern, L Alwine, LB Amacker, T Amidon, J Anderson, J Aragam, S Arnold, S Atlas, G Aurigemma, J Babb, M Ball, MA Bartz, VE Battles, J Benabe, JL Benedum, M Berk, RJ Berkowitz, G Bialy, G Bidwell, JE Blanchard, K Blaze, SB Bleifer, D Bloomfield, ED Blumberg, SA Bowser, MT Brown, PE Brown Jr, K Browne, J Buckley, L Byrd, DA Calhoun, J Camp, VM Campese, M Canossa-Terris, AA Carr, LB Chaykin, SG Chrysant, A Chu, C Clinkingbeard, JA Cobler, IS Cohen, JD Cohen, P Coleman, HT Colfer, GV Collins, H Collins, C Corder, DL Courtney, F Crisafulli, WC Cushman, J Cyrus, SJ D’Amico, K Danisa, R Davidson, A Davis, KC Dellsperger, DM Denny, V DeQuattro, R Devereux, J Diamond, SB Dianzumba, P Diller, M Doyle, J Durden, L Dworkin, DA Eisenberg, S El Hafi, F Elijovich, VA Elinoff, SH Ellahham, WJ Elliott, WT Ellison, JG Evans, TC Fagan, P Fanti, J Farahi, HM Faris Jr, JT Farrell, R Feldman, T Feldman, J Felicetta, P Fenster, VA Fonseca, F Fouad-Tarazi, RE Fowles, CK Francis, SS Franklin, RG Free, R Freireich, W Frishman, K Fujioka, C Gaboury, T Gardner, M Gedeon, VR Geer, BG Gegas, MJ Geller, DB George, T Giles, SP Glasser, MC Goldberg, DA Goldscher, F Goldstein, R Goldstein, J Gorkin, JI Gorwit, RC Gove, AH Gradman, W Graettinger, RM Graham, CE Grim, RH Grimm, G Habib, TA Haffey, C Hamburg, RC Hamdy, J Hamilton, P Hammond, JA Herd, S Heatley, JA Heinsimer, B Hettleman, T Hilton, JL Holtzman, SD Hsi, J Izzo, WC Jacobs, EJ Jacobson, DW Johns, JC Jones, WH Kaesemeyer, B Kansupada, R Kaplan, RE Katholi, CJ Kaupke, J Kirstein, TR Klein, MS Kochar, L Kohler, MJ Koren, G Koshkarian, JB Kostis, L Krakoff, SP Kutalek, K LaBresh, JA Lash, B Lazar, S Lerman, FM Lester, B Levine, R Lloret, IK Loh, J Lohr, AP Lovell, DT Lowenthal, GJ MacDonald, PF A Magee, FP Maggiacomo, C Manion, C Margolis, DG Marsh, T Martin, MA Masroor, B Massie, DB Mattingly, M McCartney, D McCarty, J McCue, M McIvor, D Mee-Lee, H Meilman, J Mersey, F Messerli, C Mild, AB Miller, M Mirro, MA Moore, AW Morgan, ME Motta, WJ Mroczek, PJ Mulrow, PD Mumma, V Murthy, W Myalls, D Nash, J Neifing, S Nesbitt, J Neutel, C O’Connor, EO Ofili, RA Oliveros, V Papademetriou, J Pappas, C Paraboschi, T Parker, RZ Paster, R Pasternak, R Patel, GJ Perry, J Perry, S Pershing, RA Phillips, D Pitts, MA Pohl, TL Poling, S Popli, EB Portnoy, S Radwany, A Rahimi, R Ramos-Gonzalez, OS Randall, R Reeves, MS Rendell, LD Rink, VL Roberts, E Roccario, H Rose, J Rosenstock, HM Rosner, E Roth, J Rubino, DA Ruff, S Sabatini, JP Salberg, L Salciccioli, FF Samaha, D Sant Ram, FA Schaller, MJ Schear, RC Schlant, PG Schmitz, EN Schwartz, K Scully, MA Sekkarie, K Shah, L Shane, JG Shanes, NJ Shikuma, D Smith, JW Smith, LK Smith, MC Smith, M Sorrentino, CT Spalding, S Steigerwalt, RG Stefanacci, DE Stone, JC Stringer, DH Sugimoto, JT Suh, W Suki, JE Sutherland, Y Szlachcic, RJ Tatelbaum, AA Taylor, R Thomas, CR Thompson, R Thompson, R Tidman, R Tieszen, MD Tischler, MJ Tonkon, KK Tucker, A Walston, F Ward, F Wei, D Weidler, M Weinberger, M Weir, RJ Weiss, W White, CS Wilcox, G Wilner, N Winer, DG Wombolt, J Wright, S Yarows, D Young, M Zabalgoitia, M Zakrzewski, JH Zavoral, GM Ziady.
This investigation is sponsored by Merck Sharp & Dohme.
- Received March 5, 1998.
- Revision received April 2, 1998.
- Accepted June 26, 1998.
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