Cardiovascular morbidity and mortality in hypertensive patients with lower versus higher risk: a LIFE substudy

We hypothesized that losartan was superior to atenolol in reducing cardiovascular events in a lower-risk group (LRG) versus a higher-risk group (HRG) of patients in a Losartan Intervention For Endpoint reduction (LIFE) substudy, independently of blood pressure (BP) reduction. In a post hoc analysis, we designated 4282 patients as LRG on the basis of: (1) no previous cardiovascular disease (coronary, cerebral, peripheral vascular disease); (2) no diabetes; (3) no isolated systolic hypertension; and (4) inclusion of the lowest 3 quartiles of electrocardiographically documented left ventricular hypertrophy. The HRG consisted of 4911 remaining patients who did not qualify for the LRG. In the LRG, losartan was superior to atenolol in reducing stroke: hazard ratio (HR), 0.72 (95% confidence interval [CI], 0.53 to 0.98); new-onset diabetes (HR, 0.74 [95% CI, 0.58 to 0.93]; and new-onset atrial fibrillation: HR, 0.69 (95% CI, 0.51 to 0.92), all P<0.05 but not composite end points or cardiovascular mortality (both P=NS). In the HRG, losartan was superior to atenolol in reducing composite end points: HR, 0.82 (95% CI, 0.71 to 0.94), P<0.01; cardiovascular mortality: HR, 0.77 (95% CI, 0.62 to 0.95), P<0.05; stroke: HR, 0.75 (95% CI, 0.61 to 0.92), P<0.01; new-onset diabetes: HR, 0.76 (95% CI, 0.60 to 0.96), P<0.05; and new-onset atrial fibrillation: HR, 0.71 (95% CI, 0.58 to 88), P<0.05. Test for interaction of treatment with LRG versus HRG was not significant for composite end point, stroke, or atrial fibrillation, but was for cardiovascular mortality (P=0.018). Achieved systolic BP reduction favored losartan over atenolol by -1.8 mm Hg in LRG (P=NS) and -0.7 mm Hg (P=0.001) in HRG, but no significant differences occurred in diastolic or mean BP in either group. In conclusion, losartan compared with atenolol reduces the risk of stroke, new-onset diabetes, and new-onset atrial fibrillation in the LRG and the HRG.     

Losartan benefits over atenolol in non-smoking hypertensive patients with left ventricular hypertrophy: the LIFE study

We studied the impact of smoking in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which 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 in 4656 never-smokers, and 3033 previous and 1499 current smokers, adjusting for gender, age, alcohol intake, exercise and race. Composite endpoint rate was higher in previous (28/1000 years), as well as current (39/1000 years) smokers than in never-smokers (21/1000 years). Composite (hazard ratio 0.78, 95% CI 0.65-0.94, p < 0.01) and stroke (hazard ratio 0.61, 95% CI 0.47-0.80], p < 0.001) risks were lower with losartan than atenolol in never-smokers, but not significantly in previous smokers. Drug regimens did not differ in current smokers (composite hazard ratio 0.99, stroke hazard ratio 0.94). Smoking-treatment interactions were non-significant, but a borderline significant trend (p = 0.05) suggested decreasing benefit of losartan vs atenolol for stroke prevention from never- to previous to current smoking status. Smoking increased cardiovascular risk markedly in the LIFE study. The benefit of losartan vs atenolol is consistent with the overall conclusion of the LIFE study, although the treatment effect appeared largest in non-smokers.     

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.     

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.     

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.     

Cost effectiveness of losartan in patients with hypertension and LVH: an economic evaluation for Sweden of the LIFE trial

OBJECTIVE: Evaluate the cost effectiveness of losartan compared with atenolol from a Swedish national health system perspective. DESIGN: The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) was a double-masked, randomized trial of losartan versus atenolol in 9193 patients with essential hypertension and left ventricular hypertrophy (LVH) ascertained by electrocardiography. Losartan reduced the primary composite end point of cardiovascular death, myocardial infarction (MI), or stroke by 13% (P = 0.021) and reduced the risk of stroke by 25% (P = 0.001), despite a comparable degree of blood pressure control. METHODS: Life years gained was estimated by combining the absolute risk reduction in stroke with the life years gained by preventing stroke. Quality-adjusted life years (QALYs) gained was estimated by combining the absolute risk reduction in stroke with the QALYs gained by preventing stroke. QALYs were estimated by weighting life years by health-related quality of life (QoL), as measured with visual analogue scale (VAS) data collected in the trial. Net costs were defined as the total of study medication cost, stroke-related costs, and costs of increased survival. Costs are in 2003 Swedish prices. All costs and effects were discounted at a 3% annual rate. RESULTS: Prevention of a stroke resulted in a gain of 5.7 life years and 4.3 QALYs. As a consequence, losartan treatment resulted in a per patient increase of 0.092 life years [95% confidence interval (CI): 0.038, 0.146] and 0.069 QALYs (95% CI: 0.028, 0.109) as compared with atenolol treatment. Losartan reduced direct stroke-related cost per patient by 1141 euros due to a lower cumulative incidence of stroke for losartan at 5.5 years (4.9%) as compared with atenolol (6.5%) (95% CI of difference: 0.7, 2.5). The reduction in stroke-related cost offset 80% of the added cost of losartan drug therapy. After inclusion of study medication cost, net cost per patient was 289 euros higher for losartan than atenolol. The net cost per QALY gained for losartan was 4188 euros (37,813 SEK), which is well within common Swedish benchmark upper values (200-500,000 SEK) for accepted cost-effective interventions. CONCLUSION: Based on the results from the LIFE trial, treatment with losartan compared with atenolol, in hypertensive patients with LVH, is a cost-effective intervention.     

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.     

The effect of losartan versus atenolol on cardiovascular morbidity and mortality in patients with hypertension taking aspirin: the Losartan Intervention for Endpoint Reduction in hypertension (LIFE) study

OBJECTIVES: We conducted a subgroup analysis in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study to determine whether aspirin interacted with the properties of losartan, an angiotensin-II receptor antagonist. BACKGROUND: Negative interactions between angiotensin-converting enzyme inhibitors and aspirin have been reported. There are no data reported from clinical trials about possible interactions between angiotensin-II receptor antagonists and aspirin. METHODS: The LIFE study assigned 9,193 patients with hypertension and left ventricular hypertrophy (LVH) to losartan- or atenolol-based therapy for a mean of 4.7 years, with 1,970 (21.4%) taking aspirin at baseline. The primary composite end point (CEP) included cardiovascular death, stroke, and myocardial infarction (MI). The present cohort was stratified by aspirin use at baseline. RESULTS: Blood pressures were reduced similarly in the losartan with aspirin (n = 1,004) and atenolol with aspirin (n = 966) groups. The CEP was reduced by 32% (95% confidence interval 0.55 to 0.86, p = 0.001) with losartan with aspirin compared to atenolol with aspirin, adjusted for Framingham risk score and LVH. The test for treatment versus aspirin interaction, excluding other covariates, was significant for the CEP (p = 0.016) and MI (p = 0.037). CONCLUSIONS: There was a statistical interaction between treatment and aspirin in the LIFE study, with significantly greater reductions for the CEP and MI with losartan in patients using aspirin than in patients not using aspirin at baseline. Further studies are needed to clarify whether this represents a pharmacologic interaction or a selection by aspirin use of patients more likely to respond to losartan treatment.     

The effects of losartan compared to atenolol on stroke in patients with isolated systolic hypertension and left ventricular hypertrophy. The LIFE study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study reported that a losartan-based antihypertensive regimen reduced cardiovascular morbidity and mortality (composite of cardiovascular death, stroke, and myocardial infarction) more than therapy based on atenolol in patients with left ventricular hypertrophy and isolated systolic hypertension (ISH). Patients aged 55-80 years with blood pressures 160-200/<90 mm Hg were followed for a mean of 4.7 years. Blood pressure was similarly reduced in the losartan (n=660) and atenolol (n=666) ISH groups. There were 88 (6.6%) patients who experienced a stroke, 18 of which were fatal. Of patients experiencing strokes, 72.7% had an ischemic stroke. ISH patients in LIFE compared to the non-ISH group had a higher incidence of any stroke and embolic stroke, and similar incidences of fatal, atherosclerotic, and hemorrhagic/other strokes. The incidence of any stroke (40% risk reduction [RR], p=0.02), fatal stroke (70% RR, p=0.035), and atherothrombotic stroke (45% RR, p=0.022) was significantly lower in losartan-treated compared to the atenolol-treated patients. The 36% RR for embolic strokes in the losartan group was not statistically significantly (p=0.33) different from the atenolol group. These data suggest that losartan-based treatment is more effective than an atenolol-based treatment for patients with ISH and a high risk for stroke.     

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.     

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.     

Does albuminuria predict cardiovascular outcome on treatment with losartan versus atenolol in hypertension with left ventricular hypertrophy? A LIFE substudy

OBJECTIVES: To examine a possible relationship between baseline albuminuria and effect of losartan versus atenolol on cardiovascular (CV) events in hypertensive patients with left ventricular hypertrophy, the effect of losartan versus atenolol on albuminuria, and whether the benefits of losartan versus atenolol could be explained by influence of losartan on albuminuria. DESIGN: Double-blind, randomized, controlled trial of 4.8 years. SETTING: Out-patient setting. PATIENTS: A total of 8206 with hypertension and left ventricular hypertrophy. INTERVENTIONS: Losartan or atenolol, supplemented with diuretics and/or calcium antagonists to reach blood pressure < 140/90 mmHg MAIN OUTCOME MEASURES: The urine albumin/creatinine ratio, and the primary composite endpoint (CEP) of CV death, myocardial infarction, and stroke. RESULTS: The blood pressure was reduced similarly on losartan (30.2/16.6 mmHg) versus atenolol (29.1/16.8 mmHg). The risk of a primary CEP increased linearly from the lowest to the highest decile of baseline albuminuria. The benefits of losartan versus atenolol for the primary CEP and for stroke tended to be more pronounced among patients above the median value for baseline albuminuria (urine albumin/creatinine ratio, 1.28 mg/mmol). The decrease in albuminuria was significantly greater with losartan versus atenolol throughout the study (a decrease from baseline to year 2 of 33% losartan versus 25% atenolol). One-fifth of the difference in favor of losartan on the primary CEP was explained by the greater reduction in albuminuria on losartan. CONCLUSIONS: Baseline albuminuria is a powerful risk factor for CV events. Baseline albuminuria did not identify the group of patients with greatest benefit on losartan versus atenolol in LIFE. Reduction in albuminuria explained one-fifth of the benefits of losartan versus atenolol.     

Beyond blood pressure reduction in the treatment of arterial hypertension. Clinical implications of the LIFE study

To date, blood-pressure lowering has been the main therapeutic objective in patients with arterial hypertension, regardless of the drug used, except for drugs selected for accompanying conditions. The LIFE study, carried out in 9,193 high-risk hypertensive patients (with ECG criteria of left ventricular hypertrophy), has shown that a therapeutic regimen based on losartan combined with a thiazide was accompanied by a significant reduction in the risk of cardiovascular complications in more than 90% of patients compared with atenolol and a thiazide over a mean follow-up period of 4.8 years. The incidence of the primary endpoints (cardiovascular death, stroke, and myocardial infarction) was 11% in the losartan group and 13% in the atenolol group (13% relative risk reduction, p = 0.021). Losartan therapy was associated with more benefits in stroke risk reduction and in the development of new cases of diabetes. In the analysis of the subgroup of 1,195 patients with hypertension and diabetes included in the LIFE study, losartan had a special prognostic benefit. One of the cardiovascular events included as a primary endpoint was observed in 18% of the losartan-treated patients and in 23% of the atenolol-treated patients (24% relative risk reduction, p = 0.031).The LIFE trial showed that losartan produced better cardiovascular protection than atenolol, a similar blood pressure reduction, and was better tolerated. This drug seems to confer extra cardiovascular protection in addition to reducing blood pressure.     

Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study.

BACKGROUND: Total homocysteine levels are associated with arteriosclerotic outcomes. OBJECTIVE: To determine whether total homocysteine levels predict incident stroke in elderly persons. DESIGN: Prospective population-based cohort study with 9.9 years of follow-up. SETTING: Framingham, Massachusetts. PATIENTS: 1947 Framingham Study participants (1158 women and 789 men; mean age +/- SD, 70 +/- 7 years). MEASUREMENTS: Baseline total homocysteine levels and 9.9-year stroke incidence. RESULTS: The quartiles of nonfasting total homocysteine levels were as follows: quartile 1, 4.13 to 9.25 micromol/L; quartile 2, 9.26 to 11.43 micromol/L; quartile 3, 11.44 to 14.23 micromol/L; quartile 4, 14.24 to 219.84 micromol/L. During follow-up, 165 incident strokes occurred. In proportional hazards models adjusted for age, sex, systolic blood pressure, diabetes, smoking, and history of atrial fibrillation and coronary heart disease, relative risk (RR) estimates comparing quartile 1 with the other three quartiles were as follows: quartile 2 compared with quartile 1--RR, 1.32 (95% CI, 0.81 to 2.14); quartile 3 compared with quartile 1--RR, 1.44 (CI, 0.89 to 2.34); quartile 4 compared with quartile 1--RR, 1.82 (CI, 1.14 to 2.91). The linear trend across the quartiles was significant (P < 0.001). CONCLUSION: Nonfasting total homocysteine levels are an independent risk factor for incident stroke in elderly persons.     

Effect of hemoglobin levels on cardiovascular outcomes in patients with isolated systolic hypertension and left ventricular hypertrophy (from the LIFE study)

The optimal hemoglobin level in patients with hypertension or heart failure is not yet defined. The aim of the present investigation was to examine the relation of hemoglobin with cardiovascular outcomes in high-risk patients with isolated systolic hypertension (ISH) and left ventricular hypertrophy (LVH). In 1,326 patients with ISH in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, hemoglobin and cardiovascular outcomes were examined using Cox proportional hazard models. Baseline hemoglobin was negatively related to rate of cardiovascular death (hazard ratio 0.81 per 1 g/dl, 95% confidence interval [CI] 0.67 to 0.98, p = 0.032) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. Hemoglobin decreased slightly during the study and the decrease was more pronounced in the losartan group (13.9 +/- 1.3 to 13.6 +/- 1.4 g/dl) than in the atenolol group (13.9 +/- 1.2 to 13.8 +/- 1.4 g/dl). Hemoglobin as a time-varying covariate was negatively associated with rate of cardiovascular death (hazard ratio 0.75, 95% CI 0.63 to 0.90, p <0.001) and stroke (hazard ratio 0.84, 95% CI 0.72 to 0.99, p = 0.040) after adjusting for baseline Framingham risk score, LVH, treatment, and estimated glomerular filtration rate. In conclusion, in this high-risk population with ISH and LVH, lower hemoglobin at baseline was associated with higher probability of cardiovascular death, and decrease in hemoglobin over time was associated with higher probability of cardiovascular death or stroke; this effect was attenuated by treatment with losartan.     

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.     

Regression of electrocardiographic left ventricular hypertrophy or strain is associated with lower incidence of cardiovascular morbidity and mortality in hypertensive patients independent of blood pressure reduction – A LIFE review

Cornell product criteria, Sokolow–Lyon voltage criteria and electrocardiographic (ECG) strain (secondary ST-T abnormalities) are markers for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, the relationship of regression of ECG LVH and strain during antihypertensive therapy to cardiovascular (CV) risk was unclear before the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. We reviewed findings on ECG LVH regression and strain over time in 9193 hypertensive patients with ECG LVH at baseline enrolled in the LIFE study.The composite endpoint of CV death, nonfatal MI, or stroke occurred in 1096 patients during 4.8 ± 0.9 years follow-up. In Cox multivariable models adjusting for randomized treatment, known risk factors including in-treatment blood pressure, and for severity ECG LVH by Cornell product and Sokolow–Lyon voltage, baseline ECG strain was associated with a 33% higher risk of the LIFE composite endpoint (HR. 1.33, 95% CI [1.11–1.59]). Development of new ECG strain between baseline and year-1 was associated with a 2-fold increased risk of the composite endpoint (HR. 2.05, 95% CI [1.51–2.78]), whereas the risk associated with regression or persistence of ECG strain was attenuated and no longer statistically significant (both p > 0.05). After controlling for treatment with losartan or atenolol, for baseline Framingham risk score, Cornell product, and Sokolow–Lyon voltage, and for baseline and in-treatment systolic and diastolic blood pressure, 1 standard deviation (SD) lower in-treatment Cornell product was associated with a 14.5% decrease in the composite endpoint (HR. 0.86, 95% CI [0.82–0.90]). In a parallel analysis, 1 SD lower in-treatment Sokolow–Lyon voltage was associated with a 16.6% decrease in the composite endpoint (HR. 0.83, 95% CI [0.78–0.88]).The LIFE study shows that evaluation of both baseline and in-study ECG LVH defined by Cornell product criteria, Sokolow–Lyon voltage criteria or ECG strain improves prediction of CV events and that regression of ECG LVH during antihypertensive treatment is associated with better outcome, independent of blood pressure reduction.     

Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study

The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study showed that treatment with the angiotensin II type-1 receptor antagonist losartan reduces overall stroke risk compared with conventional therapy with the beta-blocker atenolol. We conducted secondary analyses in LIFE to determine the extent to which the cerebrovascular benefits of losartan apply to different clinical subgroups and stroke subtypes and to assess the dependence of these benefits on baseline and time-varying covariates. Among 9193 hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy, random allocation to losartan-based treatment lowered the risk of fatal (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.43 to 0.96; P=0.032) and atherothrombotic stroke (HR, 0.72; 95% CI, 0.59 to 0.88; P=0.001) compared with atenolol-based therapy. Although comparable risk reductions occurred for hemorrhagic and embolic stroke, these were not statistically significant. The number of neurological deficits per stroke was similar, but there were fewer strokes in the losartan group for nearly every level of stroke severity. Effects were consistent in all clinical subgroups except for those defined by age and ethnicity. The benefits of losartan on all strokes were independent of baseline and time-varying risk factors, including blood pressure. The number needed to treat for 5 years to prevent 1 stroke was 54 for the average participant, declining to 25, 24, and 9 for patients with cerebrovascular disease, isolated systolic hypertension, and atrial fibrillation, respectively. In conclusion, substantial cerebrovascular benefit could be realized with the institution of losartan-based therapy over conventional therapy among hypertensive patients with left ventricular hypertrophy across the spectrum of cardiovascular risk.     

Contrasting Hemodynamic Mechanisms of Losartan- vs. Atenolol-Based Antihypertensive Treatment: A LIFE Study

BackgroundPharmaceutical differences in central hemodynamics might influence cardiac response to antihypertensive treatment despite similar lowering of brachial blood pressure (BP).MethodsData from all patients with at least two echocardiographic examinations in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) echocardiographic substudy (n = 801); high-risk patients on losartan- vs. atenolol-based antihypertensive therapy. Echocardiography was performed annually for 4 years to measure stroke index (SI), heart rate, cardiac index (CI), conduit artery stiffness assessed as pulse pressure/stroke index (PP/SI) and total peripheral resistance index (TPRI).ResultsAtenolol- and losartan-based therapy reduced BP similarly (cumulative difference in mean brachial blood pressure 0.3 mm Hg, P = 0.65). After 4 years the cumulative means of SI and heart rate were 1.8 ml/m(2) higher and 5.7 beats/min lower on atenolol-based treatment, respectively (both P < 0.001). This kept CI below baseline in atenolol-treated patients, whereas in the losartan group CI was unchanged from baseline throughout the study. TPRI was decreased more and remained lower in the losartan group (cumulative difference in mean TPRI 287 dynes/sec(-5)/cm/m(2), P < 0.001). These findings partly explained univariate differences in systolic- and diastolic function indices between the two treatments; fully adjusted losartan was only associated with a smaller left atrial diameter (cumulative mean difference 0.07 cm; 95% confidence intervals, -0.13 to -0.01, P = 0.03).ConclusionsContrasting hemodynamics impacted cardiac response to similar reductions in brachial BP on losartan- vs. atenolol-based therapy. The similar reduction of PP/SI suggests that the antihypertensive regimens used in the LIFE study had comparable effects on arterial stiffness (LIFE study; NCT00338260)American Journal of Hypertension, (2012); doi:10.1038/ajh.2012.81.     

Electrocardiographic strain pattern and prediction of cardiovascular morbidity and mortality in hypertensive patients

The ECG strain pattern of lateral ST depression and T-wave inversion is a marker for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, whether ECG strain is an independent predictor of cardiovascular (CV) morbidity and mortality in the setting of aggressive antihypertensive therapy is unclear. ECGs were examined at study baseline in 8854 hypertensive patients with ECG LVH who were treated in a blinded manner with atenolol- or losartan-based regimens. Strain was defined by the presence of a downsloping convex ST segment with an inverted asymmetrical T wave opposite to the QRS axis in leads V5 and/or V6 and was present in 971 patients (11.0%). The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study composite end point of CV death or nonfatal myocardial infarction or stroke occurred in 1035 patients (11.7%). In Cox analyses adjusting only for treatment effect, ECG strain was a significant predictor of CV death (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.78 to 2.86), fatal/nonfatal myocardial infarction (HR 2.16, 95% CI 1.67 to 2.80), fatal/nonfatal stroke (HR 1.76, 95% CI 1.39 to 2.21), and the composite CV end point (HR 1.99, 95% CI 1.70 to 2.33). After further adjusting for standard CV risk factors, baseline blood pressure, and severity of ECG LVH, ECG strain remained a significant predictor of CV mortality (HR 1.53, 95% CI 1.18 to 2.00), myocardial infarction (HR 1.55, 95% CI 1.16 to 2.06), and the composite CV end point (HR 1.33, 95% CI 1.11 to 1.59). Thus, ECG strain is a marker of increased CV risk in hypertensive patients in the setting of aggressive blood pressure lowering, independent of baseline severity of ECG LVH.