Impact of diabetes on treatment-induced changes in left ventricular structure and function in hypertensive patients with left ventricular hypertrophy. The LIFE study.

BACKGROUND AND AIM: Diabetes is associated with left ventricular hypertrophy (LVH) and impaired systolic function in hypertensive patients, but less is known about its impact on LVH regression and functional improvement during antihypertensive treatment. METHODS AND RESULTS: We performed annual echocardiography in 730 non-diabetic and 93 diabetic patients (aged 55-80 years) with hypertension and electrocardiographic LVH during 4.8-year losartan- or atenolol-based treatment in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Baseline mean blood pressure (BP) and LV mass did not differ between groups. Diabetic patients had higher body mass index and pulse pressure, and lower LV ejection fraction, midwall shortening, stress-corrected midwall shortening, and estimated glomerular filtration rate (all p<0.05), and were more likely to have albuminuria. Despite comparable BP reduction in diabetic and non-diabetic groups during treatment (33/18 vs. 28/16mmHg (ns)), diabetes was associated with higher prevalence of persistent LVH (47 vs. 39%, p<0.05). In multivariate analyses, diabetes independently predicted less LV mass reduction and less improvement in stress-corrected LV midwall shortening (both p<0.01). CONCLUSION: Among hypertensive patients with LVH, diabetes is associated with more residual LVH and less improvement in systolic LV function by echocardiography over 4.8 years of antihypertensive treatment.

Alcohol consumption and cardiovascular risk in hypertensives with left ventricular hypertrophy: the LIFE study.

The Losartan Intervention For End point reduction in hypertension (LIFE) study showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke, and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios (HR) in 4287 and 685 participants who reported intakes of 1-7 and >8 drinks/week at baseline, respectively, with those in 4216 abstainers, adjusting for gender, age, smoking, exercise, and race. Within categories, clinical baseline characteristics, numbers randomized to losartan and atenolol, and blood pressure (BP) lowering were similar on the drug regimens. Overall BP control (<140/90 mmHg) at end of follow-up was similar in the categories. Composite end point rate was lower with 1-7 (24/1000 years; HR 0.87, P<0.05) and >8 drinks/week (26/1000 years; HR 0.80, NS) than in abstainers (27/1000 years). Myocardial infarction risk was reduced in both drinking categories (HR 0.76, P<0.05 and HR 0.29, P<0.001, respectively), while stroke risk tended to increase with >8 drinks/week (HR 1.21, NS). Composite risk was significantly reduced with losartan compared to atenolol only in abstainers (HR 0.81 95% confidence interval, CI (0.68, 0.96), P<0.05), while benefits for stroke risk reduction were similar among participants consuming 1-7 drinks/week (HR 0.73, P<0.05) and abstainers (HR 0.72, P<0.01). Despite different treatment benefits, alcohol-treatment interactions were nonsignificant. In conclusion, moderate alcohol consumption does not change the marked stroke risk reduction with losartan compared to atenolol in high-risk hypertensives. Alcohol reduces the risk of myocardial infarction, while the risk of stroke tends to increase with high intake.

A retrospective analysis comparing the costs and cost effectiveness of amlodipine and enalapril in the treatment of hypertension.

A comparison of treatment costs and cost effectiveness was performed retrospectively by using patient-level data from a randomized, controlled, one-year clinical trial of amlodipine and enalapril in the treatment of mild-to-moderate hypertension. Unit costs of amlodipine and enalapril were applied to the daily dosages of individual patients to calculate the total costs and average costs per patient in each treatment group in the clinical trial on an intent-to-treat basis. Efficacy rates were used to calculate the average treatment costs per success in blood pressure control. Although not statistically significant, amlodipine treatment resulted in a higher efficacy (89.5%) vs. enalapril (85.2%). The average costs per amlodipine-treated patient were consistently lower (-$112.30) than for the enalapril-treated patient by week 50. Treatment with amlodipine resulted in an average cost per success of $609 per patient compared with $772 per enalapril-treated patient. A sensitivity analysis revealed that, in the treatment of mild-to-moderate hypertension over the 50-week treatment period, amlodipine would remain less costly than enalapril, with a decrease in the cost of enalapril of up to 17%, and would remain more cost effective, with a 21% decrease in the cost of enalapril.

Renal hemodynamic effects of captopril and doxazosin during slight physical activity in hypertensive patients with type-1 diabetes mellitus.

Angiotensin-converting enzyme inhibitors are renoprotective in diabetes mellitus through their intrarenal hemodynamic effects. Alpha-1 blockade has variable pre- and postglomerular vasodilatory effects dependent upon the stimulation of the sympathetic nervous system. We tested the hypothesis that the two different classes of drugs have similar renal hemodynamic effects when the patients are examined in an upright position where the sympathetic nervous system is activated. Mean blood pressure (MAP), glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were examined in 28 hypertensive type-1 diabetic patients with variable degree of nephropathy treated for a mean period of 7.6 +/- 0.4 months with captopril (n = 13) or doxazosin (n = 15). Average treatment doses were 112 +/- 7 mg/day in the captopril group and 8 +/- 1 mg/day in the doxazosin group. Sitting MAP decreased from 118 +/- 3 to 106 +/- 4 mm Hg after captopril (p < 0.05), and from 117 +/- 4 to 110 +/- 3 mm Hg after doxazosin (p = 0.07). GFR and ERPF were unchanged in both groups. The filtration fraction (FF) decreased from 0.27 +/- 0.02 to 0.25 +/- 0.02 after captopril (p < 0.05) and from 0.26 +/- 0.01 to 0.25 +/- 0.01 after doxazosin (p = 0.08). Calculation of 95% confidence intervals of the difference between the post-treatment values as well as the difference between pre- and post-treatment values of MAP, GFR, ERPF and FF of the two drugs indicates no difference in renal hemodynamic response between the drugs. In conclusion, captopril and doxazosin have similar renal hemodynamic responses when the patients are examined in a situation where the sympathetic nervous system is stimulated, and this suggests that doxazosin has a renoprotective effect beyond the blood pressure-lowering effect.

Long-term central hemodynamic effects at rest and during exercise of losartan in essential hypertension.

BACKGROUND: Losartan reduces blood pressure in patients with essential hypertension, but the long-term central hemodynamic effects at rest and during exercise are not known. METHODS AND RESULTS: After 8 months of losartan treatment (50 to 100 mg daily, mean 82 mg), intra-arterial pressure was reduced from 165/102 mm Hg to 145/91 mm Hg at rest and from 193/104 mm Hg to 179/96 mm Hg during 100 W exercise in 28 patients with essential hypertension. Cardiac index and heart rate remained unchanged, but total peripheral resistance index was reduced 12% to 15%. Stroke index was unchanged at rest but increased 7% to 9% during exercise. Twenty-four-hour ambulatory blood pressure was reduced 10% to 13%. Left ventricular mass was reduced 27% in patients with left ventricular hypertrophy (n = 18). CONCLUSION: Losartan lowers blood pressure by reducing total peripheral resistance at rest and during exercise but cardiac pump function is unchanged or slightly improved. In patients with left ventricular hypertrophy, losartan induces a sizeable reduction in left ventricular mass.

Cardiac biochemical markers after cardioversion of atrial fibrillation or atrial flutter.

BACKGROUND: Cardioversion or defibrillation of cardiac arrhythmias is often necessary in acutely ill cardiac patients. The electrical current may cause elevation of biochemical markers used to diagnose acute myocardial infarction. Therefore it is important to find cardiac markers with high specificity for myocardial necrosis. The purpose of this study was to assess the effects of elective cardioversion of atrial fibrillation or flutter on troponin T and I among conventional markers in patients with no evidence of acute ischemia. METHODS AND RESULTS: Fifty-seven consecutive patients underwent 1 to 4 direct current shocks (mean cumulative energy 407 J, range 100 to 920 J) under general anesthesia. At baseline, all had normal troponin levels; 50 patients (mean age 68 years, range 33 to 84 years) had normal cardiac enzymes and were included in the final analysis. Blood samples were drawn at baseline, and 1 to 2, 6 to 8, and 20 to 24 hours after cardioversion. The troponin levels were unaffected by cardioversion in all patients, whereas creatine kinase and myoglobin increased more than 10-fold. Creatine kinase MB mass and aspartate aminotransferase were above reference limits in 18% and 24% of patients, respectively, 20 to 24 hours after cardioversion. There was a significant association between elevated creatine kinase, myoglobin, and creatine kinase MB levels with cumulated energy delivered as well as when possible confounders such as age and sex were adjusted for. High international normalized ratio with warfarin use was associated with increased levels of creatine kinase, aspartate aminotransferase, lactate dehydrogenase, and myoglobin. CONCLUSIONS: The increase of conventional biochemical markers after direct current cardioversion is positively associated with cumulative energy delivered and international normalized ratio (INR) values; neither influences levels of the cardiac troponins.

Lowering of blood pressure and predictors of response in patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint.

The Losartan Intervention For Endpoint (LIFE) reduction in hypertension study is a double-blind, prospective, parallel-group study comparing the effects of losartan with those of atenolol on the reduction of cardiovascular complications in patients (n = 9,194) with essential hypertension and with electrocardiographically (ECG) documented left ventricular hypertrophy (LVH). Baseline blood pressure was 174.4/97.8 mm Hg (mean), age 66.9 years, body mass index 28.0 kg/m2; 54.1% were women and 12.5% had diabetes mellitus. This population will be treated until at least 1,040 have a primary endpoint. After five scheduled visits and 12 months of follow-up, blood pressure decreased by 23.9/12.8 mm Hg to 150.5/85.1 mm Hg (target < 140/90 mm Hg). The mandatory titration level of < or = 160/95 mm Hg was reached by 72.1% of the patients. At the 12-month visit, 22.7% of all patients were taking blinded study drug alone, 44.3% were taking blinded drug plus hydrochlorothiazide (HCTZ), and 17.7% were taking blinded drugs plus HCTZ and additional drugs. Controlling for all other variables, patients in the US received more medication and had 2.4 times the odds of achieving blood pressure control than patients in the rest of the study (P < .001). Previously untreated patients (n = 2,530) had a larger initial decrease in blood pressure compared with those previously treated. Diabetics (n = 1,148) needed more medication than nondiabetics to gain blood pressure control. Only 13.9% of the patients had discontinued blinded study drug and 1.4% missed the revisit at 12 months. These data demonstrate both the successful lowering of blood pressure during 12 months of follow-up in a large cohort of patients with hypertension and LVH on ECG, but also emphasize the need for two or more drugs to control high blood pressure in most of these patients. Being previously treated and having diabetes were associated with less blood pressure response, whereas living in the US indicated better blood pressure control. It has been possible to keep most of these patients with complicated hypertension taking blinded study drug for 12 months.

Reproducibility of salt sensitivity testing using a dietary approach in essential hypertension.

To investigate the reproducibility of salt sensitivity testing using a dietary approach, 30 essential hypertensive patients underwent salt sensitivity testing on an outpatient basis twice with a 6 month interval. At both tests casual and 24-h ambulatory blood pressure (24-h BP) was recorded on habitual diet, then after a 6-day period on a low salt diet (aiming at 50 mmol/day), and finally after a 6-day period on a high salt diet (supplementation with sodium chloride tablets aiming at 250 mmol/day). Subjects showing > or =10% increase in mean BP when changing from low to high dietary salt intake were classified as salt sensitive. Dietary salt intake was assessed as 24-h urinary sodium excretion. Based on 24-h BP recordings eight patients were characterised as salt sensitive (SS) and 22 as salt resistant (SR) in the first test, and three of the initial SS and 15 of the initial SR patients maintained their salt sensitivity status at the second test. Based on casual BP recordings 13 patients were characterised as SS and 17 as SR in the first test, and three of the initial SS and 13 of the initial SR patients maintained their salt sensitivity status at the second test. Thus, salt sensitivity status was reproducible in 60% when using 24-h BP, and in 53% when using casual BP measurements. There was no difference in baseline BP in dietary salt intake between the two tests. In the total study population, no significant correlation was found between the change in casual or 24-h BP during salt repletion in the first and second test. In conclusion casual and 24-h BP response to a 200 mmol/24h change in dietary salt intake is highly individual and varies over time. Characterisation of salt sensitivity using a dietary approach in out-patients is reproducible in only 53-60% of the patients.

Similar central hemodynamics in salt-sensitive and salt-resistant hypertensive patients.

Salt may be involved in the pathogenesis of essential hypertension but no agreement has been reached on how salt might exert its blood pressure control. One reason for the conflicting results could be differences in response to changes in salt intake--i.e. between salt-sensitive and salt-resistant subjects. Hypertension reflects a hemodynamic disturbance: mainly an increase in total peripheral resistance. In order to determine whether central hemodynamics is different in salt-sensitive and salt-resistant essential hypertension, a study was carried out on 37 patients aged 31-63 years with mean casual blood pressure 165/104 mmHg. Based on an increase in ambulatory 24-h mean blood pressure of > or = 10% after one week of dietary salt loading (260 mmol NaCl/24 h) following a one-week salt depletion period (60 mmol NaCl/24 h), 7 patients (19%) were classified as salt sensitive and 30 patients (81%) as salt resistant. Before the salt-sensitivity test, while patients were on their habitual salt intake (160 mmol NaCl/24 h), central hemodynamics (intra-arterial pressure, cardiac output by dye dilution, heart rate by electrocardiogram, and total peripheral resistance) was examined at rest and during bicycle exercise. None of the central hemodynamic variables were different between the two groups, despite a marked difference in blood pressure response to one week of salt loading between the salt-sensitive and the salt-resistant groups (27/9 mmHg vs -2/1 mmHg). Furthermore, no statistically significant differences were observed in neurohumoral variables or echocardiographic indices of left ventricular dimensions between the two groups. Owing to the invasive hemodynamic procedure, central hemodynamics was not restudied during high- or low salt intake. It is concluded that there is no difference in central hemodynamics in salt-sensitive and salt-resistant hypertensive patients when they are on their habitual salt diet.

Characteristics of 9194 patients with left ventricular hypertrophy: the LIFE study. Losartan Intervention For Endpoint Reduction in Hypertension.

-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 beta-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 approximately 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.

Factors influencing left ventricular mass in salt sensitive and salt resistant essential hypertensive patients.

UNLABELLED: To investigate whether salt sensitivity is associated with differences in left ventricular mass or geometry, salt sensitivity testing and Doppler echocardiography was performed in 30 essential hypertensive patients (7 women and 23 men) with mean age 43+/-9 years. Salt sensitivity was defined as a 10% increase or more in 24-h blood pressure (24hBP) when going from low to high dietary sodium intake based on a single test. Eight patients were characterized as salt sensitive and 22 as salt resistant. At baseline, there was no difference in casual blood pressure (156/103+/-17/9 vs 158/100+/-18/11 mmHg) or 24hBP (152/ 90+/-25/15 vs 159/89+/-19/8 mmHg), in duration of hypertension (5+/-4 vs 4+/-3 years), daily sodium excretion (144+/-68 vs 171+/-68 mmol), left ventricular mass (LVM) (212+/-45 vs 246+/-52 g) or left ventricular relative wall thickness (RWT) between the salt sensitive and salt resistant groups of patients. In the total study population, increased RWT was found in 17 patients, and increased LVM in 10 patients. In only 10 patients were both these variables normal. Left ventricular geometric pattern did not differ between the salt sensitive and salt resistant groups. LVM and RWT were significantly correlated with 24hBP (r = 0.57 and 0.51, respectively; both p < 0.01). Significant correlation was also found between LVM and casual blood pressure, blood volume, body surface area, serum creatinine and albuminuria (r = 0.53, 0.60, 0.54, 0.54 and 0.43, respectively; all p < 0.01). In multiple regression analysis, 24hBP and blood volume were identified as independent predictors of LVM (R = 0.51, p < 0.001). CONCLUSIONS: increased RWT or LVM is common in both salt sensitive and salt resistant essential hypertensive patients. Salt sensitivity status based on a single test does not influence left ventricular hypertrophy or geometry. Twenty-four-hour blood pressure is related to increased RWT and LVM.

Factors influencing reduction in blood pressure and left ventricular mass in hypertensive type-1 diabetic patients using captopril or doxazosin for 6 months.

The effect of doxazosin versus captopril on blood pressure, albuminuria, and left ventricular mass was studied in 33 hypertensive type-1 diabetic patients randomized to 6 months treatment with captopril (17 patients, mean daily dose 100 mg) or doxazosin (16 patients, mean daily dose 9 mg). Casual and 24-h ambulatory blood pressure (24hBP) were reduced from 163/95 to 144/83 mm Hg and 152/86 to 145/81 mm Hg, respectively, in the captopril group, and from 160/93 to 145/86 mm Hg and 156/86 to 147/79 mm Hg in the doxazosin group (all P < .05). The achieved 24hBP on treatment was positively associated with pretreatment levels of glycosylated hemoglobin (HbA1c) and plasma atrial natriuretic peptide (r = 0.53 and 0.59, respectively, both P < .01). Albuminuria did not change significantly in either group. Left ventricular hypertrophy was present in 13 patients (7 in the captopril and 6 in the doxazosin group). Left ventricular mass was reduced by an average of 27% and 23%, respectively, in these patients (both P < .01), but did not change significantly in patients without left ventricular hypertrophy. The reduction in left ventricular mass was positively associated with the presence of baseline left ventricular hypertrophy and inversely with dietary sodium intake and achieved casual blood pressure on treatment (R2 = 0.59, P < .001). We conclude that doxazosin and captopril used for 6 months are equally effective in reducing blood pressure and left ventricular hypertrophy in hypertensive type-1 diabetic patients; the antihypertensive effect is closely related to glycemic control; and dietary sodium intake and achieved casual blood pressure after treatment are independent determinants of the reduction in left ventricular mass seen in these patients.

Beta-2 adrenoceptor genetic variation is associated with genetic predisposition to essential hypertension: The Bergen Blood Pressure Study.

We tested the hypothesis that genetic variation in the beta-2 adrenoceptor gene is associated with a genetic predisposition to hypertension. Offspring of two hypertensive parents were compared with offspring of two normotensive parents. The subjects were participants of the Bergen Blood Pressure Study, where couples were recruited in 1963 to 1964 and re-examined in 1990. We studied offspring of those couples in which both partners were either hypertensive or normotensive in both examinations. Twenty-three hypertensive and 22 normotensive families met the inclusion criteria. DNA samples from the first born of hypertensive family-history offspring and normotensive family-history offspring were analyzed. We used multiplex sequencing and specifically examined the promoter and the N-terminal portion of the beta-2 adrenoceptor gene. We found four genetic variants: at position -47, a C-->T substitution in the 5' leader cistron causing an Arg-->Cys exchange, at -20, a T-->C substitution, at +46 an A-->G substitution leading to an Arg16-->Gly exchange, and at +79, a C-->G substitution leading to a Gln27-->Glu exchange. The frequency of the Arg16 allele was significantly higher in the hypertensive family-history offspring compared to normotensive family-history offspring (58% vs. 28% P < 0.011). We constructed haplotypes for the four intragenic variants and found significant linkage dysequilibrium. In particular, the 5' leader cistron mutant with the wild type alleles at the other loci was significantly more frequent in offspring of hypertensive parents, compared to offspring of normotensive parents. We also performed a relative risk analysis comparing the Gly/Gly, Arg/Gly, and Arg/Arg alleles, which implicated the Arg-containing allele. Finally, we analyzed the effect of genotype on blood pressure in the offspring. We found a significant step-wise effect for all four polymorphisms examined. Our data suggest that the Arg variant of the Arg-->Gly exchange is associated with parental hypertension and higher blood pressure values in this northern European population.

Factors influencing LVM in hypertensive type-1 diabetic patients.

Diabetes mellitus is associated with a high prevalence of hypertension and left ventricular hypertrophy (LVH), and a causative relationship with abnormal sodium metabolism in diabetic patients has been suggested. Factors influencing left ventricular mass (LVM) were assessed in 30 hypertensive type-1 diabetic patients, mean age 46 +/- 9 (range 24-67) years, with a mean duration of diabetes and hypertension of 19 +/- 10 and 6 +/- 5 years, respectively. In the total study population, casual blood pressure was 163/94 +/- 24/10 mmHg and 24 h blood pressure was 155/87 +/- 17/8 mmHg. Twenty-four-hour urine samples were obtained to measure daily albumin excretion (0.77 +/- 1.06 g) and dietary sodium intake was assessed as 24 h sodium excretion (173 +/- 77 mmol). Creatinine clearance averaged 1.41 +/- 0.53 ml/s. LVM determined by echocardiography was 221 +/- 74 g (range 104-408 g) and 33% of the patients had LVH. Multiple regression analysis identified dietary sodium intake and plasma atrial natriuretic peptide as independent predictors of LVM (R2 = 0.52, p < 0.001). No significant association was found between LVM and blood pressure or albuminuria. The results propose dietary sodium intake as an important factor in the development of LVH in hypertensive type-1 diabetic patients.

The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study: rationale, design, and methods. The LIFE Study Group.

The treatment of hypertension mainly with diuretics and beta blockers reduces cardiovascular mortality and morbidity, largely due to a decreased incidence of stroke, whereas the beneficial effects of antihypertensive therapy on the occurrence of coronary events have been less than expected from epidemiological studies. Furthermore, treated hypertensive patients still have a higher cardiovascular complication rate, compared with matched normotensives. This is particularly evident in patients with left ventricular hypertrophy (LVH), a major independent risk indicator for cardiovascular disease. In addition to elevating blood pressure, angiotensin II (A-II) exerts an important influence on cardiac structure and function, stimulating cell proliferation and growth. Thus, to further reduce morbidity and mortality when treating hypertensive patients, it may be important to effectively block the effects of A-II. This can be achieved directly at the A-II receptor level by losartan, the first of a new class of antihypertensive agents. It therefore seems pertinent to investigate whether selective A-II receptor blockade with losartan not only lowers blood pressure but also reduces LVH more effectively than current therapy, and thus improves prognosis. The Losartan Intervention For Endpoint reduction (LIFE) in Hypertension study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality in approximately 8,300 hypertensive patients (initial sitting diastolic blood pressure 95 to 115 mm Hg or systolic blood pressure 160 to 200 mm Hg) with electrocardiographically documented LVH. The study, which will continue for at least 4 years and until 1,040 patients experience one primary endpoint, has been designed with a statistical power that will detect a difference of at least 15% between groups in the incidence of combined cardiovascular morbidity and mortality. It is also the first prospective study with adequate power to link reversal of LVH to reduction in major cardiovascular events. The rationale of the study, which will involve more than 800 clinical centers in Scandinavia, the United Kingdom, and the United States, is discussed, and the major features of its design and general organization are described. On April 30, 1997, when inclusion was stopped, 9,218 patients had been randomized.