Losartan versus atenolol on 24-hour ambulatory blood pressure. A LIFE substudy

Objective. The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that losartan-based treatment reduced risk of the composite endpoint of cardiovascular death, stroke and myocardial infarction compared with atenolol-based treatment in patients with hypertension and left ventricular hypertrophy with similar office blood pressure (BP) reduction. Our aim was to investigate the effect of losartan- and atenolol-based treatment on 24-h ambulatory BP and heart rate (HR) in LIFE. Methods: In 110 patients, 24-h ambulatory BP and heart rate were recorded at baseline and 1 year after randomization. Results: Ambulatory BP was comparably reduced throughout the 24-h period after 1 year of losartan- vs atenolol-based antihypertensive treatment. Office and ambulatory BP were comparably reduced in the follow-up period. Early morning surge in BP was similar between groups. Non-dipping status was more frequent in the losartan group (p = 0.01). From baseline to Year 1 the 24-h HR profile for the losartan group was unchanged, but, as expected, there was a significant decrease in daytime HR in the atenolol group, which was not as large during early night-time. Conclusion: There were no differences in 24-h BP burden and HR that could explain the difference in outcome in favor of losartan vs atenolol in the LIFE study.     

Population impact of losartan use on stroke in the European Union (EU): projections from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study

The Losartan Intervention for Endpoint reduction in hypertension (LIFE) study was designed to compare losartan- vs atenolol-based antihypertensive treatment on cardiovascular morbidity and mortality in a population of 9193 hypertensive patients with left ventricular hypertrophy (LVH). In LIFE, the losartan-based treatment further reduced the primary composite end point (cardiovascular death, myocardial infarction, or stroke) by 13% (risk reduction (RR) 0.87, 95% confidence interval (CI) 0.77-0.98, P=0.021). The further reduction in stroke with losartan (RR 0.75, 95% CI 0.63-0.89, P=0.001) was the major contributing factor to the reduction in the primary end point. Our objective was to project the reduction in stroke observed with a losartan- vs an atenolol-based antihypertensive treatment regimen in the LIFE study to the European Union (EU) population. The number of stroke events averted was estimated by identifying the number of persons in the EU expected to meet the LIFE inclusion criteria, and multiplying this figure by the cumulative incidence risk difference in stroke from LIFE at 5.5 years. The age- and gender-specific prevalence of hypertension, electrocardiographically (ECG)-diagnosed LVH among those with hypertension (inclusion criteria), and heart failure among those with LVH and hypertension (exclusion criteria) were applied to the EU census estimates. We conservatively projected that an estimated 7.8 million individuals aged 55-80 years in the EU are affected by hypertension and ECG-diagnosed LVH. Use of a losartan-based antihypertensive treatment in this population is projected to prevent approximately 125 000 first strokes over a 5.5-year period. A population-wide prevention strategy of using losartan in patients with LVH and hypertension has the potential to have a major public health impact by reducing the morbidity and mortality of stroke in the EU.     

Effects of losartan in women with hypertension and left ventricular hypertrophy: results from the Losartan Intervention for Endpoint Reduction in Hypertension Study

Hypertension is a risk factor for cardiovascular disease and outcomes in women. These posthoc analyses from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study evaluated losartan- versus atenolol-based therapy on the primary composite end point of cardiovascular death, stroke, and myocardial infarction and other end points in 4963 women. Fewer events occurred in women versus men. Women in the losartan group had significant reductions in the primary end point (215 [18.2 per 1000 patient-years] versus 261 [22.5 per 1000 patient-years]; hazard ratio [HR]: 0.82 [95% CI: 0.68 to 0.98]; P=0.031), stroke (109 versus 154; HR: 0.71 [95% CI: 0.55 to 0.90]; P=0.005), total mortality (HR: 0.77 [95% CI: 0.63 to 0.95]; P=0.014), and new-onset diabetes (HR: 0.75 [95% CI: 0.59 to 0.94]; P=0.015) versus the atenolol group, with no between-treatment difference for myocardial infarction (HR: 1.02 [95% CI: 0.74 to 1.39]; P=0.925), cardiovascular mortality (HR: 0.86 [95% CI: 0.64 to 1.14]; P=0.282), or hospitalization for heart failure (HR: 0.94 [95% CI: 0.68 to 1.28]; P=0.677). More women in the losartan group required hospitalization for angina (HR: 1.70 [95% CI: 1.16 to 2.51]; P=0.007). Risk reductions for the primary composite end point, stroke, total mortality, and new-onset diabetes were significantly greater with losartan- versus atenolol-based treatment in women with hypertension and left ventricular hypertrophy in the LIFE study. The risk reductions for losartan, along with the tests for the interaction of treatment and gender, indicated that the treatment effect was consistent in men and women for all of the end points tested, with the exception of hospitalization for angina.     

Opposite effects of losartan and atenolol on natriuretic peptides in patients with hypertension and left ventricular hypertrophy: a LIFE substudy

BACKGROUND: Secretion of natriuretic peptides is related to cardiac wall stress and influenced by the renin-angiotensin system. Therefore, we investigated the influence of blood pressure (BP) reduction with losartan versus atenolol on N-terminal pro-atrial natriuretic peptide (Nt-proANP) and N-terminal pro-brain natriuretic peptide (Nt-proBNP). METHODS: In 183 patients with hypertension and electrocardiographic left ventricular (LV) hypertrophy, enrolled in the LIFE Study, we measured BP and serum Nt-proANP and Nt-proBNP by immunoassay after 2 weeks of placebo treatment and after 1, 2, 4, 6, 12, 24, 36 and 48 months of randomized treatment with losartan- or atenolol-based antihypertensive regimens. RESULTS: There was no significant difference in BP at any time point between the two treatment groups. In patients treated with losartan, median Nt-proANP decreased gradually throughout the study, reaching significance after 6 months of treatment (1125-1060 pmol/l, P < 0.001), and Nt-proBNP decreased within the first month (24.7-18.7 pmol/l, P < 0.01) and stayed reduced throughout the study. During losartan-based antihypertensive treatment, Nt-proANP and Nt-proBNP as a percentage of baseline values were correlated to reductions in systolic BP (r = 0.11, P < 0.01 and r = 0.10, P = 0.01) and diastolic BP (r = 0.17, P < 0.001 and r = 0.07, P = 0.09). In atenolol-treated patients, Nt-proANP (1100-1640 pmol/l, P < 0.001) and Nt-proBNP (20.0-37.7 pmol/l, P < 0.001) increased during the first month, and remained elevated throughout the study. During atenolol-based antihypertensive treatment, changes in Nt-proANP (r = -0.16, P < 0.001) and Nt-proBNP (r = -0.07, P = 0.08) were negatively related to change in heart rate. CONCLUSION: Nt-proANP and Nt-proBNP were reduced in parallel with BP in losartan-treated patients whereas they increased in parallel with decreased heart rate in atenolol-treated patients.     

Does long-term losartan- vs atenolol-based antihypertensive treatment influence collagen markers differently in hypertensive patients? A LIFE substudy

BACKGROUND: The aim of this study was to investigate the effects of losartan- vs atenolol-based antihypertensive treatment on circulating collagen markers beyond the initial blood pressure (BP) reduction. METHODS: In 204 patients with hypertension and left ventricular (LV) hypertrophy we measured serum concentration of carboxy-terminal telopeptide of type I procollagen (ICTP), carboxy-terminal propeptide of type I procollagen (PICP), amino-terminal propeptide of type III procollagen (PIIINP), amino-terminal propeptide of type I procollagen (PINP) and LV mass by echocardiography at baseline and annually during 4 years of losartan- or atenolol-based antihypertensive treatment; 185 patients completed the study. RESULTS: Beyond the first year of treatment systolic and diastolic BP, LV mass index (LVMI) as well as collagen markers did not change significantly and were equal in the two treatment groups. Changes in PICP during first year of treatment were related to subsequent changes in LV mass index after 2 and 3 years of treatment (r=0.28 and r=0.29, both p<0.05) in patients randomized to losartan, but not atenolol. CONCLUSION: Long-term losartan- vs atenolol-based antihypertensive treatment did not influence collagen markers differently, making a BP-independent effect of losartan on collagen markers unlikely. However, initial reduction in circulating PICP may predict later regression of LV hypertrophy during losartan-based antihypertensive treatment.     

Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study

OBJECTIVES: This study was designed to evaluate whether different antihypertensive treatment regimens with similar blood pressure reduction have different effects on new-onset atrial fibrillation (AF). BACKGROUND: It is unknown whether angiotensin II receptor blockade is better than beta-blockade in preventing new-onset AF. METHODS: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study 9,193 hypertensive patients and patients with electrocardiogram-documented left ventricular hypertrophy were randomized to once-daily losartan- or atenolol-based antihypertensive therapy. Electrocardiograms were Minnesota coded centrally, and 8,851 patients without AF by electrocardiogram or history, who were thus at risk of developing AF, were followed for 4.8 +/- 1.0 years. RESULTS: New-onset AF occurred in 150 patients randomized to losartan versus 221 to atenolol (6.8 vs. 10.1 per 1,000 person-years; relative risk 0.67, 95% confidence interval [CI] 0.55 to 0.83, p < 0.001) despite similar blood pressure reduction. Patients receiving losartan tended to stay in sinus rhythm longer (1,809 +/- 225 vs. 1,709 +/- 254 days from baseline, p = 0.057) than those receiving atenolol. Moreover, patients with new-onset AF had two-, three- and fivefold increased rates, respectively, of cardiovascular events, stroke, and hospitalization for heart failure. There were fewer composite end points (n = 31 vs. 51, hazard ratio = 0.60, 95% CI 0.38 to 0.94, p = 0.03) and strokes (n = 19 vs. 38, hazard ratio = 0.49, 95% CI 0.29 to 0.86, p = 0.01) in patients who developed new-onset AF in the losartan compared to the atenolol treatment arm of the study. Furthermore, Cox regression analysis showed that losartan (21% risk reduction) and new-onset AF both independently predicted stroke even when adjusting for traditional risk factors. CONCLUSIONS: Our novel finding is that new-onset AF and associated stroke were significantly reduced by losartan- compared to atenolol-based antihypertensive treatment with similar blood pressure reduction.     

In-treatment resolution or absence of electrocardiographic left ventricular hypertrophy is associated with decreased incidence of new-onset diabetes mellitus in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Study

Treatment of hypertensive patients with electrocardiographic left ventricular hypertrophy with losartan-based therapy is associated with lower incidence of diabetes mellitus and greater regression of hypertrophy than atenolol-based therapy. However, whether in-treatment resolution or continued absence of electrocardiographic hypertrophy is independently associated with decreased incidence of diabetes is unclear. Electrocardiographic hypertrophy was evaluated over time in 7998 hypertensive patients without diabetes at baseline in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study who were treated with losartan- or atenolol-based regimens and followed with serial electrocardiograms and blood pressure determinations. Electrocardiographic hypertrophy was defined using gender-adjusted Cornell voltage-duration product criteria >2440 mm.ms. During mean follow-up of 4.6+/-1.2 years, diabetes developed in 562 patients (7.0%). In a Cox model adjusting for treatment assignment, in-treatment resolution or continued absence of Cornell product hypertrophy was associated with a 38% lower risk of new diabetes (HR 0.62, 95% CI 0.50 to 0.78). After adjusting for the association of new diabetes with prior antihypertensive treatment, baseline glucose, and Framingham risk score, baseline and in-treatment systolic and diastolic pressure, HDL, uric acid, and body mass index, and the decreased incidence associated with losartan-based therapy, in-treatment continued absence, or resolution of Cornell product hypertrophy remained associated with a 26% lower risk of new diabetes (HR 0.74, 95% CI 0.58 to 0.93). Thus, compared with presence of hypertrophy by Cornell product criteria during antihypertensive treatment, resolution or continued absence of Cornell product hypertrophy is associated with a lower incidence of diabetes, even after adjusting for the impact of treatment with losartan and other risk factors for diabetes.     

Progressive hypertrophy regression with sustained pressure reduction in hypertension: the Losartan Intervention For Endpoint Reduction study

OBJECTIVE : To examine the time course of left ventricular (LV) geometric response to blood pressure (BP) control during 2 years of systematic antihypertensive treatment. DESIGN : A total of 754 hypertensive patients with left ventricular hypertrophy (LVH) by Cornell voltage-duration product or Sokolow-Lyon voltage criteria on a screening electrocardiogram had their LV mass measured by echocardiogram at enrolment in the Losartan Intervention For Endpoint Reduction (LIFE) trial, and after 12 and 24 months of blinded therapy with losartan-based or atenolol-based regimens. SETTING : The LIFE trial, in which hypertensive patients with electrocardiographic LVH (Cornell voltage-duration product > 2440 mm x ms and/or Sokolow-Lyon voltage criteria SV1 + RV5-6 > 38 mm) were randomized to >or= 4 years double-blinded treatment with losartan or atenolol. PARTICIPANTS : A total of 754 LIFE participants with serial echocardiographic measurements of LV geometry. INTERVENTIONS : None. MAIN OUTCOME MEASURES : LV wall thicknesses, diameter and mass, and its indices. RESULTS : Mean systolic/diastolic BP fell from 173/95 to 150/84 mmHg after 1 year (P < 0.001) and to 148/83 mmHg at year 2 (P = not significant). Mean echocardiographic LV mass fell from 233 g at baseline to 206 g after 1 year (P < 0.001, adjusted for change in systolic BP) and to 195 g at year 2 (P < 0.001 versus year 1), with a parallel decrease in indexed LV mass [from 56.1 to 49.7 g/m2.7 (P < 0.001), to 47.1 g/m2.7 (P < 0.001 versus year 1)]. Relative wall thickness decreased from 0.41 at baseline to 0.37 at year 1 (P < 0.001), to 0.36 at year 2 (P < 0.001 versus year 1). As a result, there were serial decreases in prevalences of eccentric LVH [44 to 38%, and to 30% (P < 0.001 versus year 1)] and concentric LVH [24 to 7% (P < 0.001), to 2% (P < 0.05 versus year 1)], and increases in the proportion with normal LV geometry [22 to 50% (P < 0.001), and to 64% (P < 0.01 versus year 1)]. CONCLUSIONS : Sustained BP reduction in hypertensive patients with target organ damage causes continued decrease in echocardiographic LV mass and prevalence of anatomic LVH for at least 2 years despite only small BP decreases after the first year of blinded therapy. These data document cardiac benefit of sustained BP control and suggest that maximum LVH regression with effective antihypertensive treatment requires at least 2 years.     

Blood pressure during sleep: antihypertensive medication

To investigate whether excessive reduction of blood pressure (BP) by antihypertensive medications correlates with myocardial infarction, especially during sleep in elderly patients, we used telemetry and cuvette dye-dilution methods to assess the direct BP and the hemodynamics of 68 inpatients with essential hypertension during wakefulness and sleep. There were 25 patients greater than or equal to 60 years old (OH-group) and 43 were less than or equal to 59 years old (YH-group). Of the OH-group, 36% showed high BP during the day, with marked decreases (minimum BP less than 110/70 mm Hg) during sleep. Average cardiac index (CI) of the OH-group was low during wakefulness and extremely low during slow-wave sleep. Changes of mean BP in the OH-group correlated with changes in total peripheral vascular resistance index (TPRI) during sleep, but this correlation was not observed in the YH-group. The antihypertensive effects on nocturnal BP of the various medications was: central adrenergic inhibitors less than or equal to beta blockers with intrinsic sympathomimetic activity less than or equal to alpha (alpha beta) blockers less than or equal to angiotensin-converting enzyme inhibitors less than or equal to calcium antagonists. Because BP and CI were found to be very low and TPRI seems to play an important role in BP regulation in sleeping elderly patients, excessive antihypertensive medication may be harmful to this subgroup. However, because the effects on nocturnal BP differ among various antihypertensive treatments, further research is required on the relation between antihypertensive medication and the hemodynamics of sleeping elderly hypertensive patients.     

Impact of age on left ventricular hypertrophy regression during antihypertensive treatment with losartan or atenolol (the LIFE study)

To assess the influence of age on changes in left ventricular (LV) mass and geometry during antihypertensive treatment, we related age to clinical and echocardiographic findings before and after 4 years of antihypertensive treatment in a subset of 560 hypertensive patients without known concurrent disease in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which randomized patients to blinded losartan- or atenolol-based treatment. Patients >/=65 years (older group) included more women and patients with isolated systolic hypertension or albuminuria (all P<0.05). Compared to patients <65 years, older patients had higher pulse pressure, LV mass, and prevalence of concentric hypertrophy at baseline (78 vs 69 mmHg, 234 vs 224 g, and 28 vs 16%, respectively, all P<0.01), while the mean blood pressure did not differ. Over 4 years, reductions in LV mass and the mean blood pressure were similar in both groups, but older patients more often had residual hypertrophy (31 vs 15%, P<0.001) with a preponderance of eccentric geometry. In multivariate analysis of 4-year change in LV mass controlling for baseline mass, larger hypertrophy reduction was associated with losartan treatment, while age, gender, body mass index, and 4-year change in pulse pressure and albuminuria did not enter (Multiple R (2)=0.40, P<0.001). Thus, in up-to-80-year-old hypertensive patients with left ventricular hypertrophy, age did not significantly attenuate hypertrophy reduction during antihypertensive treatment, although residual hypertrophy was more prevalent in older patients as a consequence of higher initial LV mass.     

Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study

BACKGROUND: There has been uncertainty about the risk of new-onset diabetes in hypertensive individuals treated with different blood pressure-decreasing drugs. OBJECTIVES: To study this risk in hypertensive individuals who were at risk of developing diabetes mellitus in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. METHODS: In the LIFE study, with a double-masked, randomized, parallel-group design, 9193 patients (46% men) with hypertension (mean age 67 years, average pressure 174/98 mmHg after placebo run-in) and electrocardiogram-documented left ventricular hypertrophy were randomly assigned to once-daily losartan- or atenolol-based antihypertensive treatment and followed for at least 4 years (mean 4.8 years). At baseline, 7998 patients did not have diabetes mellitus and were thus at risk of developing this condition during the study. To demonstrate ability to predict new-onset diabetes, we developed a prediction score using the significant variables from multivariate analyses (serum glucose, body mass index, serum high-density lipoprotein cholesterol, systolic blood pressure and history of prior use of antihypertensive drugs). RESULTS: There was a steadily increasing risk of diabetes with increasing level-of-risk score; patients in the highest quartile were at considerably greater risk than those in the three lower ones. Treatment with losartan was associated with lower risk of development of diabetes within each of the four quartiles of the risk score. As previously reported, new-onset diabetes mellitus occurred in 242 patients receiving losartan (13.0 per 1000 person-years) and 320 receiving atenolol (17.5 per 1000 person-years); relative risk 0.75 (95% confidence interval 0.63 to 0.88; P<0.001). CONCLUSIONS: New-onset diabetes could be strongly predicted by a newly developed risk score using baseline serum glucose concentration (non-fasting), body mass index, serum high-density lipoprotein cholesterol concentration, systolic blood pressure and history of prior use of antihypertensive drugs. Independently of these risk factors, fewer hypertensive patients with left ventricular hypertrophy developed diabetes mellitus if they were treated with losartan than if they were treated with atenolol.     

Utility of the myocardial performance index in a population with high prevalences of obesity, diabetes, and hypertension: the strong heart study

INTRODUCTION: The myocardial performance index (MPI) introduced by Tei, a Doppler-derived echocardiographic measure that reflects both left ventricular (LV) systolic and diastolic function, has been shown to have prognostic value in several clinical settings, including myocardial infarction and congestive heart failure. There are scant data on the correlates and prognostic value of MPI in a population without overt cardiovascular (CV) disease. METHODS: We investigated clinical and physiologic correlates of MPI, as assessed from echocardiographic Doppler recordings in 1,862 American Indian participants free of coronary or valvular disease or LV systolic dysfunction in the population-based strong heart study (SHS). We then assessed the prognostic value of MPI for incident CV events, including nonfatal stroke, coronary heart disease, congestive heart failure, and CV death. RESULTS: The study population was 59 +/- 8 years old (66% women); 48% had diabetes, 44% hypertension, and 54% were obese. In univariable analyses, MPI (mean = 0.24 +/- 0.17) showed significant negative associations with creatinine clearance, C-reactive protein (CRP), LV ejection fraction (EF), mitral valve E- and A-wave velocities, cardiac index (CI), stroke index (SI) and stroke index/pulse pressure (SI/PP), and significant positive associations with serum creatinine and total peripheral resistance index (TPRI) (all P < 0.05). There were no significant associations of MPI with hypertension or diabetes status, systolic or diastolic blood pressure, body mass index, hemoglobin A1C or LV mass. After adjusting for age, sex, diabetes, and hypertension, MPI remained weakly but significantly correlated with CRP, EF, CI, SI, SI/PP, mitral E- and A-wave velocities, and TPRI. MPI did not predict fatal and nonfatal CV events (risk ratio 1.06 per unit MPI, 95% C.I. 0.56-2.04; P = 0.85) at a mean follow-up of 7.1 +/- 2.2 years. CONCLUSIONS: In a population-based sample of adults with high prevalence of diabetes, hypertension, and obesity but without overt CV disease, MPI has weak associations with clinical and physiologic determinants of cardiac function. Moreover, MPI does not provide prognostic information for CV events in this population. Though conceptually attractive as a global measure of cardiac function, MPI has limited utility in a high-risk population without clinical CV disease.     

Change in pulse pressure/stroke index in response to sustained blood pressure reduction and its impact on left ventricular mass and geometry changes: the life study

BACKGROUND: In cross-sectional data in hypertensive subjects, brachial pulse pressure (PP)/Doppler stroke index (SVi), (PP/SVi) correlates weakly but significantly with left ventricular (LV) mass and relative wall thickness (RWT). METHODS: In the Losartan Intervention For End-point reduction in hypertension (LIFE) study, we evaluated the impact of antihypertensive treatment on change of PP/SVi as raw indicator of systemic arterial stiffness, and further explored the impact of the change in PP/SVi on the change in LV mass and RWT. RESULTS: Compared to baseline, mean PP/SVi reduction was -13% at year 1, -15% at year 2, and -16% at year 3 follow-up, and was sustained through year 4 and year 5 follow-ups; change in PP/SVi was related to increased SVi and decreased PP during the annual follow-ups, but not to LV mass change. Restricting analyses to the first two follow-ups to ensure highest statistical power, age >65 and diabetes were associated with higher PP/SVi at baseline and throughout follow-ups; black participants and women had baseline PP/SVi mean values comparable with those of their counterparts, showed blunted PP/SVi reduction after 1 year, but differences became smaller and not statistically significant at year 2 follow-up. Losartan- or atenolol-based treatments were associated with comparable reduction of PP/SVi. At year 2 follow-up, reduced PP/SVi was associated with greater reductions in mean blood pressure (BP) and heart rate and greater increase in SVi, but not with lower LV mass; RWT was lower with lower PP/SVi at year 2 follow-up. CONCLUSIONS: Reduction in PP/SVi by long-term antihypertensive treatment did not have significant impact on change in LV mass index, but correlated with LV remodeling toward eccentric geometry.     

Cardiovascular risk reduction in hypertensive black patients with left ventricular hypertrophy: the LIFE study

OBJECTIVES: We report on a subanalysis of the effects of losartan and atenolol on cardiovascular events in black patients in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. BACKGROUND: The LIFE study compared losartan-based to atenolol-based therapy in 9,193 hypertensive patients with left ventricular hypertrophy (LVH). Overall, the risk of the primary composite end point (cardiovascular death, stroke, myocardial infarction) was reduced by 13% (p = 0.021) with losartan, with similar blood pressure (BP) reduction in both treatment groups. There was a suggestion of interaction between ethnic background and treatment (p = 0.057). METHODS: Exploratory analyses were performed that placed LIFE study patients into black (n = 533) and non-black (n = 8,660) categories, overall, and in the U.S. (African American [n = 523]; non-black [n = 1,184]). RESULTS: A significant interaction existed between the dichotomized groups (black/non-black) and treatment (p = 0.005); a test for qualitative interaction was also significant (p = 0.016). The hazard ratio (losartan relative to atenolol) for the primary end point favored atenolol in black patients (1.666 [95% confidence interval (CI) 1.043 to 2.661]; p = 0.033) and favored losartan in non-blacks (0.829 [95% CI 0.733 to 0.938]; p = 0.003). In black patients, BP reduction was similar in both groups, and regression of electrocardiographic-LVH was greater with losartan. CONCLUSIONS: Results of the subanalysis are sufficient to generate the hypothesis that black patients with hypertension and LVH might not respond as favorably to losartan-based treatment as non-black patients with respect to cardiovascular outcomes, and do not support a recommendation for losartan as a first-line treatment for this purpose. The subanalysis is limited by the relatively small number of events.     

Long-term effects of a losartan- compared with an atenolol-based treatment regimen on carotid artery plaque development in hypertensive patients with left ventricular hypertrophy: ICARUS, a LIFE substudy

In the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, there was a 25% risk reduction for stroke with angiotensin receptor blocker-based therapy (losartan) as compared with beta-blocker-based therapy (atenolol) despite comparable blood pressure reductions. This substudy examines treatment effects on the amount and density of atherosclerotic lesions in the common carotid arteries and the carotid bulb in 81 patients during 3 years of treatment. There were no statistically significant changes in the amount of carotid plaque in patients treated with losartan compared with an atenolol-based treatment program. A statistically nonsignificant increase in plaque density and index (average of plaque amount and density) was seen in the atenolol group compared with those treated with losartan. The small number of patients evaluated may have limited the power to detect a difference in outcome. The difference in carotid plaque index increase between the treatment groups during 3 years of treatment could not be statistically linked to specific treatments in the present substudy.     

Combined captopril and hydrochlorothiazide therapy in severe hypertension: long-term haemodynamic changes at rest and during exercise

Captopril is an orally active converting enzyme inhibitor lowering blood pressure (BP) in different types of hypertension. A combination of captopril and a diuretic is often used in the treatment of severe hypertension. We have examined the chronic haemodynamic effect of combined captopril and hydrochlorothiazide treatment at rest and during 50 and 100 W dynamic exercise in 12 patients with severe therapy resistant essential hypertension. Blood pressure was measured intra-arterially before and after a mean treatment period of 8.7 months. Cardiac index (CI) was measured by dye dilution (Cardiogreen) and body fluid volumes by radioisotope dilution techniques. During rest sitting BP was reduced by 31/17 mmHg (15%) from a pretreatment value of 205/119 mmHg. Total peripheral resistance index (TPRI) fell 17% whereas CI, heart rate (HR) and stroke index (SI) did not show any significant changes. The fall in mean arterial pressure (MAP) was slightly less during exercise (12%) and the BP reduction was associated with a fall in CI and SI of 15 and 17%, respectively and no fall in TPRI. No significant changes were observed in body fluid volumes.     

Characteristics of response to isometric exercise in women with stable arterial hypertension

In 50 females with Stage II persistent hypertension, tetrapolar thoracic rheography was employed to measure cardiac index (CI), stroke index (SI), specific peripheral resistance (SPR), blood pressure (BP), heart rate (HR) before and during isometric exercise when antihypertensive drugs were withdrawn. The patients with a family history of hypertension were found to have impaired homeostatic mechanisms preventing an excess elevation in BP during isometric exercise. The females of reproductive age showed a greater increase in BP, HR, SI, CI and a lower decrease in SPR in response to the exercise than did menopausal females. Left ventricular hypertrophy contributes to a positive inotropic action shown by sympathetic cardiac stimulation during isometric exercise, as evidenced by a lower reduction or elevation in SI. The detected responses to isometric exercise may serve as criteria for differential approach to the choice of adequate antihypertensive therapy.     

Effects of losartan and atenolol on left ventricular mass and neurohormonal profile in patients with essential hypertension and left ventricular hypertrophy

OBJECTIVE: To compare the effects of the angiotensin II antagonist, losartan, with those of atenolol on left ventricular hypertrophy (LVH), blood pressure and neurohormone concentrations in hypertensive patients with LVH. DESIGN: A multinational, randomized, double-blind trial. SETTING: Hospital. PATIENTS: Hypertensive patients with an echocardiographically documented left ventricular mass index (LVMI) 120 g/m(2) (men) or 105 g/m(2) (women). INTERVENTIONS: Patients allocated randomly to groups received either losartan or atenolol 50 mg/day for 36 weeks, with possible titration to 100 mg/day, and addition of hydrochlorothiazide 12.5 or 25 mg/day. MAIN OUTCOME MEASURES: Changes in LVMI and sitting systolic (SBP) and diastolic (DBP) blood pressures after 36 weeks of treatment (study powered for non-inferiority hypothesis). All echocardiographic data were read in a central laboratory by staff blinded to the treatments and sequence of echocardiographic tapes. RESULTS: The estimated treatment difference between the losartan and atenolol regimens (mean change from baseline at week 36) in LVMI was -2.5 g/m(2) [95% confidence interval (CI) -7.36 to 2.37 g/m(2) ] in favor of losartan, indicating that losartan was significantly non-inferior ( 0.001, non-inferiority limit 8 g/m(2) ) and numerically superior to atenolol in reducing LVMI. The losartan-based regimen significantly reduced LVMI after 36 weeks compared with baseline (-6.56 g/m(2) , 95% CI -10.24 to -2.88 g/m(2) , P<0.001), whereas the atenolol-based regimen had no significant effect (-3.71 g/m, 95% CI -7.75 to 0.32 g/m(2) , P= NS). In a subset of 82 patients, significant changes in serum concentrations of atrial natriuretic peptide, brain natriuretic peptide and immunoreactive amino-terminal pro-brain natriuretic peptide were recorded in losartan-treated ( 0.01) but not atenolol-treated patients. Losartan and atenolol significantly decreased SBP and DBP from baseline after 6, 12, 24 and 36 weeks. The changes from baseline in DBP were greater in the atenolol group at weeks 6 and 36 [difference -2.6 mmHg ( P= 0.016) at week 36]. However, both treatment regimens achieved similar SBP/DBP values at week 36 (141.1 +/- 12.8/86.8 +/- 8.2 mmHg for losartan and 141.4 +/- 17.2/85.0 +/- 10.1 mmHg for atenolol, respectively). Overall, losartan treatment was associated with significantly fewer drug-related clinical adverse events, compared with atenolol (10 and 22%, respectively, P= 0.028). CONCLUSIONS: Both losartan- and atenolol-based regimens effectively decreased blood pressure. Losartan was non-inferior and numerically superior to atenolol in regression of LVH. The reduction in hypertrophy with losartan treatment was accompanied by reductions in circulating concentrations of cardiac natriuretic peptides. Losartan, by specifically blocking angiotensin II, may therefore have effects on the heart beyond those expected from the decrease in blood pressure alone. Losartan was better tolerated than atenolol.     

Atenolol as a comparator in outcome trials in hypertension: a correct choice in the past, but not for the future?

OBJECTIVE: Twelve years after the design of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan- vs atenolol-based therapy for cardiovascular outcomes, we reviewed the literature for the effect of beta-blockers compared with initial placebo or no treatment on reduction of cardiovascular events to re-evaluate atenolol as the comparator in the LIFE study. METHODS: A literature search was conducted in September 2006 for randomized, controlled trials comparing beta-blockers with/without diuretics with placebo or no treatment in patients with hypertension and without recent cardiovascular morbidity. We calculated risk reductions for combined cardiovascular events, cardiovascular death, stroke, and coronary heart disease from groups of trials using atenolol first-line and all beta-blockers first-line. RESULTS: Five studies met the criteria. Significant risk reductions for cardiovascular events and stroke occurred in groups receiving treatment with atenolol or all beta-blockers, and for cardiovascular death in the all beta-blocker analysis. In meta-analysis of beta-blocker vs placebo or no treatment trials, risk reductions were 19% for combined cardiovascular events (95% CI 0.73-0.91, p<0.001), 15% for cardiovascular death (0.73-0.99, p = 0.037), 32% for stroke (0.57-0.82, p<0.001), and 10% for coronary heart disease (0.78-1.04, p = 0.146). CONCLUSIONS: Beta-blocker-based antihypertensive therapy significantly reduces cardiovascular risk in hypertension compared with placebo or no treatment. Atenolol was an appropriate comparator in the LIFE study. As the results of the LIFE study and other recent trials demonstrate superiority of newer agents over atenolol, this agent is not an appropriate reference drug for future trials of cardiovascular risk in hypertension.     

Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study

OBJECTIVES: We assessed the impact of antihypertensive treatment in hypertensive patients with electrocardiographic (ECG) left ventricular (LV) hypertrophy and a history of atrial fibrillation (AF). BACKGROUND: Optimal treatment of hypertensive patients with AF to reduce the risk of cardiovascular morbidity and mortality remains unclear. METHODS: As part of the Losartan Intervention For End point reduction in hypertension (LIFE) study, 342 hypertensive patients with AF and LV hypertrophy were assigned to losartan- or atenolol-based therapy for 1,471 patient-years of follow-up. RESULTS: The primary composite end point (cardiovascular mortality, stroke, and myocardial infarction) occurred in 36 patients in the losartan group versus 67 in the atenolol group (hazard ratio [HR] = 0.58, 95% confidence interval [CI] 0.39 to 0.88, p = 0.009). Cardiovascular deaths occurred in 20 versus 38 patients in the losartan and atenolol groups, respectively (HR = 0.58, 95% CI 0.33 to 0.99, p = 0.048). Stroke occurred in 18 versus 38 patients (HR = 0.55, 95% CI 0.31 to 0.97, p = 0.039), and myocardial infarction in 11 versus 8 patients (p = NS). Losartan-based treatment led to trends toward lower all-cause mortality (30 vs. 49, HR = 0.67, 95% CI 0.42 to 1.06, p = 0.090) and fewer pacemaker implantations (5 vs. 15, p = 0.065), whereas hospitalization for heart failure took place in 15 versus 26 patients and sudden cardiac death in 9 versus 17, respectively (both p = NS). The benefit of losartan was greater in patients with AF than those with sinus rhythm for the primary composite end point (p = 0.019) and cardiovascular mortality (p = 0.039). CONCLUSIONS: Losartan is more effective than atenolol-based therapy in reducing the risk of the primary composite end point of cardiovascular morbidity and mortality as well as stroke and cardiovascular death in hypertensive patients with ECG LV hypertrophy and AF.