[show abstract][hide abstract] ABSTRACT: IntroductionWe recently developed and validated in existing trials a novel algorithm (PRE score) to predict long-term drug efficacy based on short-term (month-6) drug-induced changes in multiple risk markers. To show the value of the PRE score for ongoing and planned clinical trials, we here report the predicted long-term cardio-renal efficacy of aliskiren in type 2 diabetes, which was investigated in the ALTITUDE trial, but unknown at the time this study was conducted.Methods
We established the relation between multiple risk markers and cardio-renal endpoints (as defined in ALTITUDE) using a background database from past clinical trials. The short-term effect of aliskiren on multiple risk markers was taken from the AVOID trial. A PRE score was developed by multivariate Cox analysis in the background population and was then applied to the baseline and month-6 measurements of the aliskiren treatment arm of the AVOID trial to predict cardio-renal risk. The net risk difference at these time-points, after correction for placebo effects, was taken to indicate the estimated long-term cardio-renal risk change.ResultsBased on the PRE score, we predicted that aliskiren treatment in ALTITUDE would confer a relative risk change of -7.9% (95% CI -2.5 to -13.4) for the cardio-renal endpoint, a risk change of -5.1% (-1.2 to -9.0) for the CV endpoint and a non-significant risk change of -19.9% (-42.1 to +2.1) for the renal endpoint.ConclusionsPRE score estimations suggested that aliskiren has only a marginal additive protective effect on cardio-renal endpoints. These predictions were validated by the results of the ALTITUDE trial, confirming the potential of the PRE score to prospectively predict drug efficacy on cardio-renal outcomes.
European journal of preventive cardiology. 03/2013;
[show abstract][hide abstract] ABSTRACT: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study has previously demonstrated a beneficial effect of losartan compared to atenolol-based antihypertensive treatment in patients with essential hypertension and left-ventricular hypertrophy (LVH). However, patient age often influences the choice of antihypertensive drugs. Therefore, we investigated the influence of age on the effects of losartan versus atenolol-based antihypertensive treatment.
A total of 9193 hypertensive patients with LVH aged 45-83 years were followed for a mean of 4.8 years. Blood pressure, high-density lipoprotein cholesterol (HDL-C), Sokolow-Lyon voltage, Cornell voltage-duration product and urine albumin-creatinine ratio (UACR) were measured yearly throughout the study. Patients were divided into two age groups according to the median age of 67 years and the effects of losartan versus atenolol-based antihypertensive treatment on the primary composite endpoint (CEP) consisting of cardiovascular death, nonfatal stroke or nonfatal myocardial infarction were investigated.
The beneficial effect of losartan versus atenolol-based treatment was greater in the group of patients older than 67 years [hazard ratio 0.79 (0.69-0.91), P = 0.001] compared to the group of patients younger than 67 years [hazard ratio 1.03 (0.82-1.28), P = 0809], P = 0.045 for interaction. The beneficial effects of losartan versus atenolol-based antihypertensive treatment on pulse pressure, HDL-C, UACR, and Cornell and Sokolow-Lyon voltage were not more pronounced in patients older than 67 years compared to patients younger than 67 years. All five risk factors considered as time-varying covariates predicted CEP independently (P < 0.01) with the exception of pulse pressure (P = 0.37) and the interaction between age and treatment on outcome remained significant (P = 0.042).
We showed a greater beneficial effect of losartan versus atenolol-based antihypertensive treatment in the group of patients older than 67 years compared to the group of patients younger than 67 years. This difference was not explained by a more pronounced effect of losartan-based treatment on any of the cardiovascular risk factors demonstrated to have independent prognostic importance.
Journal of hypertension 04/2012; 30(6):1252-9. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Low serum potassium (K) is associated with increased blood pressure, impaired cardiac function and renal dysfunction. Although lower serum K is associated with cardiac hypertrophy in animal models, the relationship of low serum K to the presence and severity of electrocardiographic left ventricular hypertrophy (LVH) is unclear.
Baseline and yearly Cornell product LVH levels were examined in relation to low serum K (serum K ≤ 3.90 mEq/l, the lowest quartile of baseline K levels) in 8586 patients with baseline K levels. Patients were randomized to losartan-vs atenolol-based treatment and additional hydrochlorothiazide (HCTZ) therapy as needed.
After adjusting for age, sex, race, prior antihypertensive treatment, losartan vs atenolol therapy, HCTZ use, baseline diastolic and systolic pressure, body mass index, serum creatinine and urine albumin/creatinine ratio, baseline serum K ≤ 3.90 was associated with significantly higher mean baseline Cornell product LVH (2898 vs 2801 mm•ms, p = 0.001) and a 24% higher risk of Cornell product LVH > 2440 mm•ms at baseline (OR 1.24, 95% CI 1.11-1.38, p < 0.001). After also adjusting for baseline Cornell product and changes in diastolic and systolic pressure between baseline and each year of measurement, in-treatment serum K ≤ 3.90 determined yearly was associated with significantly higher mean Cornell product LVH at years 1-3 and with statistically significant 16-32% increased risks of LVH by Cornell product at years 1-4.
A low serum K is independently associated with a greater likelihood and severity of Cornell product LVH during antihypertensive therapy.
[show abstract][hide abstract] ABSTRACT: To determine the population distribution of cardiovascular risk in eight low- and middle-income countries and compare the cost of drug treatment based on cardiovascular risk (cardiovascular risk thresholds ≥ 30%/≥ 40%) with single risk factor cutoff levels.
Using World Health Organization (WHO) and the International Society of Hypertension risk prediction charts, cardiovascular risk was categorized in a cross-sectional study of 8,625 randomly selected people aged 40-80 years (mean age, 54.6 years) from defined geographic regions of Nigeria, Iran, China, Pakistan, Georgia, Nepal, Cuba, and Sri Lanka. Cost estimates for drug therapy were calculated for three countries.
A large fraction (90.0-98.9%) of the study population has a 10-year cardiovascular risk <20%. Only 0.2-4.8% are in the high-risk categories (≥ 30%). Adopting a total risk approach and WHO guidelines recommendations would restrict unnecessary drug treatment and reduce the drug costs significantly.
Adopting a total cardiovascular risk approach instead of a single risk factor approach reduces health care expenditure by reducing drug costs. Therefore, limited resources can be more efficiently used to target high-risk people who will benefit the most. This strategy needs to be complemented with population-wide measures to shift the cardiovascular risk distribution of the whole population.
Journal of clinical epidemiology 04/2011; 64(12):1451-62. · 2.96 Impact Factor
[show abstract][hide abstract] ABSTRACT: To investigate whether in-treatment measurements of subclinical organ damage (SOD) assessed by elevated urine albumin/creatinine ratio (UACR) or electrocardiographic left ventricular hypertrophy improved the prediction of the composite cardiovascular endpoint of cardiovascular death, nonfatal myocardial infarction and stroke beyond in-treatment Framingham risk score (FRS).
Excluding patients with a composite cardiovascular endpoint within the first year of treatment, 598 endpoints occurred in 6460 patients from the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study with baseline and 1 year values for UACR, left ventricular hypertrophy by electrocardiography and FRS available.
Using Cox-regression analyses, FRS(1year) [hazard ratio=1.006 (0.98-1.04)] did not predict the endpoint independently of history of cardiovascular disease [hazard ratio=1.76 (1.49-2.08)], FRS(baseline) [hazard ratio=1.07 (1.04-1.11)], UACR(baseline) [hazard ratio=1.15 (1.07-1.23), all three P<0.001], Sokolow-Lyon(baseline) [hazard ratio=1.01 (1.006-1.02), P<0.01] and treatment allocation, whereas Cornell product(1year) [hazard ratio=1.01 (1.006-1.02), P<0.001] and to some degree UACR(1year) [hazard ratio=1.05 (0.99-1.10), P=0.09] predicted the endpoint independently of history of cardiovascular disease [hazard ratio=1.71 (1.44-2.02)], FRS(baseline) [hazard ratio=1.08 (1.06-1.10)], Sokolow-Lyon(baseline) [hazard ratio=1.01 (1.007-1.02), both P<0.001], UACR(baseline) [hazard ratio=1.11 (1.03-1.20), P<0.01] and treatment allocation decreasing -2 Log likelihood significantly (P<0.01).Presence of left ventricular hypertrophy by Cornell product(1year) or UACR(1year) at least 1 mmol/l [hazard ratio=1.40 (1.15-1.70), P=0.001] but not FRS(1year) above the median baseline value of 20 [hazard ratio=1.22 (0.94-1.57), not significant] was associated with higher risk of subsequent endpoint after adjustment for history of cardiovascular disease [hazard ratio=1.82 (1.54-2.15)], FRS(baseline) at least 20 [hazard ratio=1.67 (1.30-2.16)], left ventricular hypertrophy by Sokolow-Lyon(baseline) or UACR(baseline) at least 1 mmol/l [hazard ratio=1.61 (1.33-1.94), all P<0.001] and treatment allocation [hazard ratio=0.93 (0.79-1.09), not significant]. In contrast to FRS(1year) at least 20 decreased, SOD(1year) decreased -2Log likelihood significantly (P<0.01).
Cornell product(1year) and UACR(1year) improved in contrast to FRS(1year) risk prediction based on FRS(baseline), Sokolow-Lyon(baseline) and UACR(baseline) significantly in LIFE patients during antihypertensive treatment.
Journal of hypertension 02/2011; 29(5):997-1004. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Patients with resistant hypertension are at increased risk for cardiovascular events. The addition of new treatments to existing therapies will help achieve blood pressure (BP) goals in more resistant hypertension patients. In the current trial, 849 patients with resistant hypertension receiving ≥3 antihypertensive drugs, including a diuretic, at optimized doses were randomized to the selective endothelin A receptor antagonist darusentan, placebo, or the central α-2 agonist guanfacine. The coprimary end points of the study were changes from baseline to week 14 in trough, sitting systolic BP, and diastolic BP measured in the clinic. Decreases from baseline to week 14 in systolic BP for darusentan (-15±14 mm Hg) were greater than for guanfacine (-12±13 mm Hg; P<0.05) but not greater than placebo (-14±14 mm Hg). Darusentan, however, reduced mean 24-hour systolic BP (-9±12 mm Hg) more than placebo (-2±12 mm Hg) or guanfacine (-4±12 mm Hg) after 14 weeks of treatment (P<0.001 for each comparison). The most frequent adverse event associated with darusentan was fluid retention/edema at 28% versus 12% in each of the other groups. More patients withdrew because of adverse events on darusentan as compared with placebo or guanfacine. We conclude that darusentan provided greater reduction in systolic BP in resistant hypertension patients as assessed by ambulatory BP monitoring, in spite of not meeting its coprimary end points. The results of this trial highlight the importance of ambulatory BP monitoring in the design of hypertension clinical studies.
[show abstract][hide abstract] ABSTRACT: It is unclear whether serum uric acid (SUA) is associated with development of new-onset diabetes (NOD) in patients with hypertension and left ventricular hypertrophy (LVH). The aim of the present investigation was to test the hypothesis that SUA predicts development of NOD in these patients.
In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, a double-masked, parallel-group design, 9,193 patients with hypertension and electrocardiographic LVH were randomized to losartan- or atenolol-based antihypertensive treatment and followed for a mean of 4.9 years. At baseline, 7,489 patients with available SUA measurements did not have diabetes mellitus and were thus at risk of its development during the study. We used Cox regression analyses to investigate whether SUA predicted development of NOD.
NOD developed in 522 of 7,489 patients. The association between baseline SUA and development of NOD was significant (hazard ratio (HR) 1.29 per s.d. (1.3 mg/dl), 95% confidence interval (CI) 1.18-1.42, P < 0.001) after adjustment for treatment with losartan vs. atenolol, baseline serum glucose, urinary albumin/creatinine ratio, estimated glomerular filtration rate and Framingham risk score, time-varying systolic and diastolic blood pressure, and time-varying LVH by Cornell voltage-duration product and Sokolow-Lyon voltage. In parallel analyses, baseline quartiles of SUA were significantly associated with increasing NOD (HR 1.28, 95% CI 1.18-1.40, P < 0.001). Time-varying SUA was also associated with NOD (HR 1.10 per s.d. [1.3 mg/dl], 95% CI 1.02-1.19, P = 0.015).
Our analysis suggests that SUA is an independent risk marker for NOD in hypertensive patients with LVH.
American Journal of Hypertension 08/2010; 23(8):845-51. · 3.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Treatment of hypertensive patients with a losartan-based regimen was associated with greater regression of electrocardiographic (ECG) left ventricular hypertrophy (LVH) than atenolol-based therapy in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study, independent of blood pressure (BP) changes. However, whether concomitant hydrochlorothiazide (HCTZ) therapy in >70% of LIFE patients was associated with greater regression of LVH independent of BP changes and whether this effect differed between treatment arms has not been examined.
Changes in Cornell product and Sokolow-Lyon voltage LVH were assessed in 9,193 hypertensive patients randomly assigned to treatment with losartan or atenolol, with additional HCTZ therapy added as necessary to achieve target BP goal per study protocol.
After controlling for baseline and change in systolic and diastolic pressure, age, sex, race, prior antihypertensive treatment, baseline and year-4 body mass index and baseline LVH by either Cornell product or Sokolow-Lyon voltage, at year-4 follow-up HCTZ therapy was associated with greater regression of Cornell product LVH (-244 +/- 788 vs. -172 +/- 771 mm.msec, P < 0.05) and Sokolow-Lyon voltage (-4.2 +/- 6.7 vs. -3.0 +/- 7.0 mm, P < 0.001) and this effect was significantly greater in patients on losartan (-341 +/- 743 vs. -189 +/- 775 mm.msec and -5.2 +/- 6.6 vs. -3.3 +/- 6.6 mm) than in patients on atenolol (-142 +/- 822 vs. -158 +/- 765 mm.msec and -3.1 +/- 6.6 vs. -2.7 +/- 7.4 mm; both P < 0.001 for interaction of HCTZ with losartan vs. atenolol therapy). CONCLUSIONs: HCTZ use was associated with greater regression of ECG LVH and this effect was greater in patients on losartan- than atenolol-based therapy, independent of baseline severity of ECG LVH and hypertension and changes in BP.
American Journal of Hypertension 07/2010; 23(7):786-93. · 3.67 Impact Factor
[show abstract][hide abstract] ABSTRACT: Construction of prognostically relevant endpoints for clinical trials in hypertension has increasingly included coronary revascularization with myocardial infarction (MI) as manifestations of coronary artery disease. However, whether coronary revascularization and MI predict other cardiovascular events similarly is unknown.
We examined risks of cardiovascular death, all-cause death, and stroke following MI or coronary revascularization in hypertensive patients with left ventricular hypertrophy (LVH) enrolled in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). We studied 9113 patients after excluding those who died within 7 days after MI or underwent coronary revascularization within 24 h after MI.
In multivariate Cox regression adjusting for participating countries, time-varying systolic blood pressure, and Framingham risk score, hazard ratios for cardiovascular death, all-cause death, and stroke were, respectively, 4.5 (P<0.0001), 2.9 (P<0.0001), and 1.9 (P=0.003) in 321 patients with MI as first event. In similar models, coronary revascularization as first event (n=202) was not associated with increased risks of cardiovascular death, all-cause death, and stroke (P=0.06-0.86).
During follow-up of hypertensive patients with LVH, occurrence of MI but not coronary revascularization as first cardiovascular event significantly increased risk of subsequent cardiovascular death, all-cause death, and stroke. In view of differences in prognostic implications, when the goal is to have a prognostically relevant composite endpoint for trials in hypertensive patients, caution should be used in combining coronary revascularization with MI.
Journal of hypertension 06/2010; 28(6):1134-40. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: Hypertension cannot always be adequately controlled with available drugs. We investigated the blood-pressure-lowering effects of the new vasodilatory, selective endothelin type A antagonist, darusentan, in patients with treatment-resistant hypertension.
This randomised, double-blind study was undertaken in 117 sites in North and South America, Europe, New Zealand, and Australia. 379 patients with systolic blood pressure of 140 mm Hg or more (>/=130 mm Hg if patient had diabetes or chronic kidney disease) who were receiving at least three blood-pressure-lowering drugs, including a diuretic, at full or maximum tolerated doses were randomly assigned to 14 weeks' treatment with placebo (n=132) or darusentan 50 mg (n=81), 100 mg (n=81), or 300 mg (n=85) taken once daily. Randomisation was made centrally via an automated telephone system, and patients and all investigators were masked to treatment assignments. The primary endpoints were changes in sitting systolic and diastolic blood pressures. Analysis was by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00330369.
All randomly assigned participants were analysed. The mean reductions in clinic systolic and diastolic blood pressures were 9/5 mm Hg (SD 14/8) with placebo, 17/10 mm Hg (15/9) with darusentan 50 mg, 18/10 mm Hg (16/9) with darusentan 100 mg, and 18/11 mm Hg (18/10) with darusentan 300 mg (p<0.0001 for all effects). The main adverse effects were related to fluid accumulation. Oedema or fluid retention occurred in 67 (27%) patients given darusentan compared with 19 (14%) given placebo. One patient in the placebo group died (sudden cardiac death), and five patients in the three darusentan dose groups combined had cardiac-related serious adverse events.
Darusentan provides additional reduction in blood pressure in patients who have not attained their treatment goals with three or more antihypertensive drugs. As with other vasodilatory drugs, fluid management with effective diuretic therapy might be needed.
The Lancet 09/2009; 374(9699):1423-31. · 39.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective: To explore the usefulness of ambulatory blood pressure monitoring when diagnosing hypertension. Design: Comparison between office and ambulatory blood pressure. Setting: Primary Health Care Centre in southern Sweden. Subjects: Previously untreated hypertensives found in a blood pressure screening project concerning middleaged men and women and normotensive controls chosen from the same population. Methods: Comparison between repeated office blood pressures and a single-day ambulatory blood pressure recording in untreated hypertensives and normotensives. Data were compared individually for each patient. Results: The percentage of hypertensives and normotensives ‘correctly’ diagnosed by office-BP depends on where the dividing line between normal and increased ambulatory blood pressure is drawn. No established cut-off point exists, but 85–90 mmHg for diastolic blood pressure has been proposed. When 85 mmHg was used, 94% of the hypertensives and 84% of the normotensives were correctly diagnosed. When instead 90 mmHg was used, the figures were 72% and 97%, respectively. Conclusions: Although hypertensives and normotensives were well separated by office blood pressure, an overlap in day mean ambulatory blood pressure was found between the hypertensives and the normotensives. This overlap varied considerably within the small range of 5 mmHg for diastolic day mean blood pressure. How to interpret and use this information is not obvious, since we do not know if a single day or 24 hour ambulatory blood pressure recording better predicts the risks of cardiovascular disease than do repeated office blood pressure measurements. It therefore seems reasonable that office blood pressure remains the standard for diagnosing hypertension in clinical practice until we have enough data on ambulatory monitoring from prospective studies.
[show abstract][hide abstract] ABSTRACT: It is well established that hypertensive patients benefit from drug treatment of their disorder. In recent years three major out-come studies of antihypertensive treatment in elderly hypertensives have shown substantial benefits, i.e. a reduction in the risk of stroke and other cardiovascular mortality and morbidity. In all these studies β-blockers and/or diuretics were used in comparison with placebo. Newer therapeutic alternatives have, however, at least theoretically, many advantages which could result in further improvements in prognosis. The initial Swedish Trial in Old Patients with Hypertension (STOP-Hypertension 1) was conducted in men and women aged 70–84 years. STOP-Hypertension 2 will evaluate the therapy used in STOP-Hypertension 1 against therapy based on either ACE-inhibitors (enalapril and lisinopril) or on calcium antagonists (isradipine and felodipine), using the PROBE design (Prospective, Randomised, Open, Blinded Endpoint evaluation). The primary aim will be to assess the effect on cardiovascular mortality. Statistical calculations indicate that 6,600 patients, followed for four years will be needed (2p < 0.05, power 90%) to obtain significance if there is a 25% difference between the new and the established therapy. Patients in primary health care (300 centres) will be included if their supine blood pressure is ≥ 180/105 mmHg (and/or). Recruitment of patients started in September 1992 and so far more than 100 patients/week have been included.
[show abstract][hide abstract] ABSTRACT: Beta-blockers and angiotensin II receptor blockers have different effects on lipids.
We examined lipid levels in the Losartan Intervention For Endpoint reduction in hypertension study and their impact on the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke. We measured total and high-density lipoprotein cholesterol at baseline and annually during 4.8 years of losartan-based compared with atenolol-based treatment in 8611 patients with hypertension and left ventricular hypertrophy.
Patients randomized to losartan-based or atenolol-based treatment had similar baseline total (6.04 +/- 1.12 vs. 6.05 +/- 1.13 mmol/l, NS) and high-density lipoprotein (HDL) cholesterol (1.50 +/- 0.44 vs. 1.49 +/- 0.44 mmol/l, NS). Total cholesterol decreased significantly but equally (-0.37 +/- 1.05 vs. -0.34 +/- 1.09 mmol/l, NS), whereas HDL cholesterol decreased less during the first 2 years in patients randomized to losartan compared with atenolol (-0.13 +/- 0.24 vs. -0.19 +/- 0.25 mmol/l) and remained higher each year (1.38, 1.37, 1.42, 1.47, and 1.48 mmol/l vs. 1.32, 1.30, 1.36, 1.40, and 1.42 mmol/l, all P < 0.001) independent of hydrochlorothiazide or statin treatment. In Cox regression analysis, baseline total cholesterol [hazard ratio (HR) = 1.08 (1.02-1.14) per mmol/l, P < 0.01], HDL cholesterol [HR = 0.56 (0.48-0.66) per mmol/l, P < 0.001], and treatment allocation [HR = 0.86 (0.76-0.98), P < 0.05] predicted composite endpoint independently. Using time-varying analyses, the predictive strength of HDL cholesterol was increased [HR = 0.36 (0.30-0.44) per mmol/l, P < 0.001], whereas that of total cholesterol [HR = 1.03 (0.97-1.09) per mmol/l, NS] and treatment allocation [HR = 0.91 (0.80-1.03), NS] were reduced.
Losartan blunted the decrease in HDL cholesterol during antihypertensive treatment in the LIFE study. Higher intreatment HDL cholesterol was associated with fewer composite endpoints and may partly explain the better outcome of losartan-based treatment.
Journal of hypertension 03/2009; 27(3):567-74. · 4.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: The prognostic importance of hemoglobin is controversial. We investigated the prognostic importance of baseline and in-treatment hemoglobin in the LIFE study.
Eight thousand one hundred ninety-four LIFE patients with hypertension and left ventricular hypertrophy with available baseline hemoglobin measurements were randomized to losartan- or atenolol-based treatment and followed for 4.8 years for end points of all-cause mortality and composite of cardiovascular death, nonfatal stroke, or nonfatal myocardial infarction.
U-shaped relations were observed between deciles of baseline hemoglobin and all-cause mortality and the composite end point. In univariate Cox models, baseline hemoglobin in the lowest gender-specific decile (women/men: <12.5/13.4 g/dL) was associated with all-cause mortality (hazard ratio [HR] 2.01, 95% CI 1.64-2.64) and the composite end point (HR 1.53, 95% CI 1.27-1.85, both P < .001), whereas hemoglobin in the highest gender-specific decile (women/men: > or =15.0/16.2 g/dL) was not. The decrease in hemoglobin was higher (P < .001) in patients allocated to losartan- (14.3-13.8 g/dL) versus atenolol-based treatment (14.3-14.0 g/dL). In Cox models with the same gender-specific definitions for high and low hemoglobin as time-varying covariates with adjustment for treatment allocation and established risk factors and diseases, hemoglobin in the lowest decile was associated with higher rates of all-cause mortality (HR 3.03, 95% CI 1.89-4.85, P < .001) and the composite end point (HR 1.36, 95% CI 1.08-1.71, P < .01), whereas hemoglobin in the highest decile was not.
After adjusting for other risk factors, relatively low, but not high, hemoglobin during antihypertensive treatment was associated with higher incidence of all-cause mortality and the composite end point.
American heart journal 01/2009; 157(1):177-84. · 4.65 Impact Factor