Hans Ibsen

Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND Blood pressure reduction achieved with beta-blockers and diuretics is the best recorded intervention to date for prevention of cardiovascular morbidity and death in patients with hypertension. Left ventricular hypertrophy (LVH) is a strong independent indicator of risk of cardiovascular morbidity and death. We aimed to establish whether selective blocking of angiotensin II improves LVH beyond reducing blood pressure and, consequently, reduces cardiovascular morbidity and death. METHODS We did a double-masked, randomised, parallel-group trial in 9193 participants aged 55-80 years with essential hypertension (sitting blood pressure 160-200/95-115 mm Hg) and LVH ascertained by electrocardiography (ECG). We assigned participants once daily losartan-based or atenolol-based antihypertensive treatment for at least 4 years and until 1040 patients had a primary cardiovascular event (death, myocardial infarction, or stroke). We used Cox regression analysis to compare regimens. FINDINGS Blood pressure fell by 30.2/16.6 (SD 18.5/10.1) and 29.1/16.8 mm Hg (19.2/10.1) in the losartan and atenolol groups, respectively. The primary composite endpoint occurred in 508 losartan (23.8 per 1000 patient-years) and 588 atenolol patients (27.9 per 1000 patient-years; relative risk 0.87, 95% CI 0.77-0.98, p=0.021). 204 losartan and 234 atenolol patients died from cardiovascular disease (0.89, 0.73-1.07, p=0.206); 232 and 309, respectively, had fatal or non-fatal stroke (0.75, 0.63-0.89, p=0.001); and myocardial infarction (non-fatal and fatal) occurred in 198 and 188, respectively (1.07, 0.88-1.31, p=0.491). New-onset diabetes was less frequent with losartan. Interpretation Losartan prevents more cardiovascular morbidity and death than atenolol for a similar reduction in blood pressure and is better tolerated. Losartan seems to confer benefits beyond reduction in blood pressure.

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol

BACKGROUND The most suitable antihypertensive drug to reduce the risk of cardiovascular disease in patients with hypertension and diabetes is unclear. In prespecified analyses, we compared the effects of losartan and atenolol on cardiovascular morbidity and mortality in diabetic patients. METHODS As part of the LIFE study, in a double-masked, randomised, parallel-group trial, we assigned a group of 1195 patients with diabetes, hypertension, and signs of left-ventricular hypertrophy (LVH) on electrocardiograms losartan-based or atenolol-based treatment. Mean age of patients was 67 years (SD 7) and mean blood pressure 177/96 mm Hg (14/10) after placebo run-in. We followed up patients for at least 4 years (mean 4.7 years [1.1]). We used Cox regression analysis with baseline Framingham risk score and electrocardiogram-LVH as covariates to compare the effects of the drugs on the primary composite endpoint of cardiovascular morbidity and mortality (cardiovascular death, stroke, or myocardial infarction). FINDINGS Mean blood pressure fell to 146/79 mm Hg (17/11) in losartan patients and 148/79 mm Hg (19/11) in atenolol patients. The primary endpoint occurred in 103 patients assigned losartan (n=586) and 139 assigned atenolol (n=609); relative risk 0.76 (95% CI 0.58-.98), p=0.031. 38 and 61 patients in the losartan and atenolol groups, respectively, died from cardiovascular disease; 0.63 (0.42-0.95), p=0.028. Mortality from all causes was 63 and 104 in losartan and atenolol groups, respectively; 0.61 (0.45-0.84), p=0.002. INTERPRETATION Losartan was more effective than atenolol in reducing cardiovascular morbidity and mortality as well as mortality from all causes in patients with hypertension, diabetes, and LVH. Losartan seems to have benefits beyond blood pressure reduction.

Prognostic Value of Aortic Pulse Wave Velocity as Index of Arterial Stiffness in the General Population

Background— Few population studies addressed the prognostic significance of aortic pulse wave velocity (APWV) above and beyond other cardiovascular risk factors. Methods and Results— We studied a sex- and age-stratified random sample of 1678 Danes aged 40 to 70 years. We used Cox regression to investigate the prognostic value of APWV, office pulse pressure (PP), and 24-hour ambulatory PP while adjusting for mean arterial pressure (MAP) and other covariates. Over a median follow-up of 9.4 years, the incidence of fatal and nonfatal cardiovascular end points, cardiovascular mortality, and fatal and nonfatal coronary heart disease amounted to 154, 62, and 101 cases, respectively. We adjusted for sex, age, body mass index, MAP measured in the office (conventional PP and APWV) or by ambulatory monitoring (24-hour PP), smoking, and alcohol intake. With these adjustments, APWV maintained its prognostic significance in relation to each end point (P<0.05), whereas office and 24-hour PP lost their predictive value (P>0.19), except for office PP in relation to coronary heart disease (P=0.02). For each 1-SD increment in APWV (3.4 m/s), the risk of an event increased by 16% to 20%. In sensitivity analyses, APWV still predicted all cardiovascular events after standardization to a heart rate of 60 beats per minute, after adjustment for 24-hour MAP instead of office MAP, and/or after additional adjustment for the ratio of total to HDL serum cholesterol and diabetes mellitus at baseline. Conclusions— In a general Danish population, APWV predicted a composite of cardiovascular outcomes above and beyond traditional cardiovascular risk factors, including 24-hour MAP.

Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'Establishing normal and reference values'

Aims Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.

Prognostic accuracy of day versus night ambulatory blood pressure: a cohort study.

BACKGROUND Few studies have formally compared the predictive value of the blood pressure at night over and beyond the daytime value. We investigated the prognostic significance of the ambulatory blood pressure during night and day and of the night-to-day blood pressure ratio. METHODS We did 24-h blood pressure monitoring in 7458 people (mean age 56.8 years [SD 13.9]) enrolled in prospective population studies in Denmark, Belgium, Japan, Sweden, Uruguay, and China. We calculated multivariate-adjusted hazard ratios for daytime and night-time blood pressure and the systolic night-to-day ratio, while adjusting for cohort and cardiovascular risk factors. FINDINGS Median follow-up was 9.6 years (5th to 95th percentile 2.5-13.7). Adjusted for daytime blood pressure, night-time blood pressure predicted total (n=983; p<0.0001), cardiovascular (n=387; p<0.01), and non-cardiovascular (n=560; p<0.001) mortality. Conversely, adjusted for night-time blood pressure, daytime blood pressure predicted only non-cardiovascular mortality (p<0.05), with lower blood pressure levels being associated with increased risk. Both daytime and night-time blood pressure consistently predicted all cardiovascular events (n=943; p<0.05) and stroke (n=420; p<0.01). Adjusted for night-time blood pressure, daytime blood pressure lost prognostic significance only for cardiac events (n=525; p> or =0.07). Adjusted for the 24-h blood pressure, night-to-day ratio predicted mortality, but not fatal combined with non-fatal events. Antihypertensive drug treatment removed the significant association between cardiovascular events and the daytime blood pressure. Participants with systolic night-to-day ratio value of 1 or more were older, at higher risk of death, and died at an older age than those whose night-to-day ratio was normal (> or =0.80 to <0.90). INTERPRETATION In contrast to commonly held views, daytime blood pressure adjusted for night-time blood pressure predicts fatal combined with non-fatal cardiovascular events, except in treated patients, in whom antihypertensive drugs might reduce blood pressure during the day, but not at night. The increased mortality in patients with higher night-time than daytime blood pressure probably indicates reverse causality. Our findings support recording the ambulatory blood pressure during the whole day.

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study.

Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient’s current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.

Albuminuria and Cardiovascular Risk in Hypertensive Patients with Left Ventricular Hypertrophy: The LIFE Study

Context Microalbuminuria is a known risk factor for cardiovascular disease. Contribution In this large prospective study of hypertensive patients with left ventricular hypertrophy, increasing microalbuminuria was associated with increasing risks for cardiovascular disease. Risks continuously increased without evidence of a threshold or plateau level. Implications Microalbuminuria assessment in hypertensive patients may improve cardiovascular risk stratification. Cautions The study was based on data collected during a randomized, controlled trial of antihypertensive therapy. Albuminuria was measured as the albumincreatinine ratio in a single spot urine collection. Other than for the study drug received, the authors did not adjust for treatments received during the trial. The Editors Microalbuminuria was first associated with essential hypertension in nondiabetic individuals by Parving and colleagues (1), and subsequent studies (2, 3) confirmed the association. Albuminuria is an independent risk factor for cardiovascular disease and increased all-cause mortality in relatively unselected (4, 5) or general (6-8) populations, postmenopausal women (9), older people (10, 11), diabetic patients (12, 13), hypertensive patients with or without concomitant diabetes (8, 14, 15), and people with known high risk for cardiovascular disease (16). Left ventricular hypertrophy is an independent predictor of adverse prognosis (17-19) and is related to albumin excretion independent of age, blood pressure, diabetes, race, serum creatinine level, or smoking; these associations suggest parallel cardiac damage and increased renal albumin excretion rate (20). Other studies suggest that albuminuria at levels well below traditional partition values is a risk factor for coronary vascular disease in patients with and without diabetes (16, 21), indicating that the relation between albuminuria and cardiovascular risk from other populations cannot be directly applied to nondiabetic hypertensive patients. More precise information about the relation between albuminuria and cardiovascular risk would not only help clinicians better estimate the patients absolute risk but also strengthen the decision to initiate antihypertensive treatment, since current guidelines consider not only blood pressure but also target organ damage (for example, albuminuria) (22). We conducted a prospective study to determine the albuminuria level at which cardiovascular morbidity and mortality are increased in a large group of hypertensive patients with left ventricular hypertrophy. In a predefined protocol, we hypothesized that no unique albuminuria threshold predicts increased cardiovascular risk but rather that increasing albuminuria is associated with a graded increase in risk. We anticipated that in hypertensive patients with left ventricular hypertrophy, any threshold identified would be much lower than the threshold traditionally defined in diabetic populations. Methods Patients Participants in our study were outpatients between 55 and 80 years of age. They were recruited from a mix of general and hospital practices and had previously untreated or treated stage II or III hypertension with electrocardiographically confirmed left ventricular hypertrophy (measured according to the product of QRS duration multiplied by Cornell voltage or according to SokolowLyon voltage). The patients were randomly assigned to receive double-blind therapy with losartan or atenolol in the Losartan Intervention For Endpoint reduction (LIFE) study (23, 24). Study Design The hypotheses of the current study were prespecified as part of the LIFE protocol. Inclusion criteria were a mean trough sitting systolic blood pressure of 160 to 200 mm Hg or a diastolic blood pressure of 95 to 115 mm Hg after 1 and 2 weeks of single-blind placebo treatment and no other antihypertensive medication at the time of randomization. Exclusion criteria were myocardial infarction or stroke within 6 months, current congestive heart failure or previously known left ventricular ejection fraction less than 0.40, and renal insufficiency (serum creatinine level >160 mmol/L [>1.8 mg/dL]). We excluded patients who had a condition that the treating physician believed required treatment with losartan or another angiotensin II-receptor blocker, atenolol or another -blocker, hydrochlorothiazide, or angiotensin-converting enzyme inhibitors. Patients gave informed consent under protocols approved by the ethics committees of the participating institutions. End Points and Adjudication This study of the 8206 LIFE participants who had baseline albuminuria determinations (>90% of the entire sample) is based on analysis of a primary composite end point (n = 971): the first occurrence of cardiovascular death, fatal or nonfatal stroke, and fatal or nonfatal myocardial infarction. Additional end points were all-cause mortality (n = 703) and the first occurrence of each component of the composite end point, regardless of whether it was preceded by another component of the primary end point: 383 cardiovascular deaths, 479 strokes, and 344 myocardial infarctions. In the nondiabetic subgroup there were 755 composite end points, including 292 cardiovascular deaths, 379 fatal and nonfatal strokes, 261 fatal and nonfatal myocardial infarctions, and 554 all-cause deaths. Investigators reported all end points; source data were verified by independent monitors and were adjudicated by an independent committee on the basis of definitions provided in a predefined end point manual (24). Patients and the investigators reported the prevalences of coronary, cerebral, or peripheral vascular disease and smoking habits. Diabetes was defined according to investigator report and plasma glucose level. The Framingham risk score (25) was estimated from baseline blood pressure, total cholesterol level, high-density lipoprotein cholesterol level, smoking status, glucose level, and level of left ventricular hypertrophy on electrocardiography (ECG). Renal Evaluation On the same day, a spot urine sample was collected as the first morning voiding and the serum creatinine level was measured. Urine albumin concentration was determined by standard methods (26) using a turbidometric method (Hitachi 717 analyzer, Hoffmann-La Roche Ltd., Basel, Switzerland) (27) on a single urine specimen. Both serum and urine levels of creatinine were analyzed by using the Jaff reaction without deproteinizing and then quantified by a photometric method using the same analyzer. The ratio of urine albumin (in mg/L) to creatinine concentration (UACR) (in mmol/L) provided a composite measure (in mg/mmol) of renal glomerular capillary permeability that adjusted for urine dilution (28). To derive U.S. measures of UACR (mg/g), UACR in mg/mmoL is multiplied by 8.84. Statistical Analysis We used SPSS software, version 11.0.1 (SPSS, Inc., Chicago, Illinois), for statistical analyses. The study sample as a whole and the nondiabetic patients were divided into UACR deciles; diabetic patients were divided into UACR quintiles. We used Cox proportional-hazards models to compare hazard ratios among groups and to evaluate the contributions of differences in the degree of left ventricular hypertrophy (both Cornell voltage duration product and SokolowLyon voltage as continuous variables), the Framingham risk score (25), and treatment allocation (losartan or atenolol) as covariates. To express the increase in risk per increase in UACR as a continuous variable, we log-transformed UACR. We used a Cox model in the test for trend and used the decile group as a continuous variable. Hazard ratios from the decile groups were then used to estimate the best-fitting curve (SPSS curve estimation function). Two-tailed P values less than 0.05 were considered statistically significant. Role of the Funding Source The funding source had no role in the design, analysis, and reporting of the study or in the decision to submit the manuscript for publication. Results Patient Characteristics Descriptive data for the LIFE study sample (23) and relations of microalbuminuria and macroalbuminuria to cardiovascular risk factors have been reported elsewhere (20). Of the 9193 patients participating in the LIFE study, 8206 had the baseline UACR measurements necessary for inclusion in the present study. The mean age (SD) was 66 7 years; 54% of patients were women, and 92% were white. Thirteen percent had diabetes, 13.5% had coronary heart disease, and 7.7% had had a stroke. The mean arterial blood pressure (SD) was 174 14/98 9 mm Hg, the mean serum creatinine level (SD) was 87 20 mmol/L, and the median UACR was 1.28 mg/mmol. Additional baseline characteristics of patients with albuminuria are described elsewhere (20). To stratify risk in hypertensive patients with albuminuria and left ventricular hypertrophy, patients were divided into UACR deciles, with 814 to 821 patients in each group. Patients were followed for a median of 4.8 years and a total of 39 122 patient-years. End point rates were 24.8 per 1000 patient-years of follow-up for the composite endpoint, 9.4 for cardiovascular mortality, 17.6 for all-cause mortality, 11.9 for stroke, and 8.5 for myocardial infarction. Age; sex; race; body mass index; blood pressure; level of left ventricular hypertrophy on ECG; Framingham risk score; prevalence of known diabetes, coronary heart disease, or peripheral vascular disease; and smoking habits did not differ between the patients who provided a urine sample and the 987 patients who did not. The prevalence of history of cerebral vascular disease (13.2% vs. 10.5%; P = 0.029) and mean serum creatinine level (90.0 vs. 86.7 mmol/L; P = 0.001) were higher in patients who did not provide a urine sample than in those who did. When we considered differences in left ventricular mass on ECG, Framingham risk score, and study treatment, patients without a urine sample had a 52% higher all-cause mortality rate (95% CI, 23% to 87%); the rates of t

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.

A randomized non-pharmacological intervention study for prevention of ischaemic heart disease: baseline results Inter99 (1):

Background Various strategies have been used to induce lifestyle changes to reduce ischaemic heart disease (IHD) with various successes. The aim of Inter99 is to assess the effect on IHD incidence of individually tailored non-pharmacological intervention on lifestyle using a newly developed computer-based health educational tool. The article describes the study and baseline results. Methods From a population of 61,301 individuals two random samples (high intensity intervention group (A), n = 11,708; low intensity intervention group (B), n = 1308) are screened to assess their absolute risk of IHD. Those at high risk receive individual lifestyle counselling. Individuals in group A are furthermore offered lifestyle counselling in groups on smoking cessation or physical activity/diet over a 6-month period. Individuals in group B are referred to their GP. High-risk persons are re-counselled after 1 and 3 years and the whole group is re-invited after 5 years. The remaining 48,285 (group C) are followed by questionnaire. The total population is followed through central registers. Intermediate end-points are changes in lifestyle, cholesterol, blood pressure and body mass index. Final end-point is reduction in incidence of IHD. Results The randomization leads to comparable groups. Participation rate was 52.5%. A total of 60% fulfilled the predetermined criteria for being at high risk for developing IHD. After an individual lifestyle counselling 41% accepted group-based counselling. Conclusion This large randomized population based trial discloses a noticeable need for and acceptance of lifestyle intervention in the general population. Eur J Cardiovasc Prevention Rehab 10:377-386

Characteristics of 9194 Patients With Left Ventricular Hypertrophy: The LIFE Study

-Losartan was the first available orally administered selective antagonist of the angiotensin II type 1 receptor developed for the treatment of hypertension. The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study is a double-blind, prospective, parallel group study designed to compare the effects of losartan with those of the beta-blocker atenolol on the reduction of cardiovascular morbidity and mortality. Patients with essential hypertension, aged between 55 and 80 years, and ECG-documented left ventricular hypertrophy (LVH) were included. Altogether, 9223 patients in Scandinavia, the United Kingdom, and the United States were randomized from June 1995 through April 1997, and 9194 remain after exclusion of a study center at which irregularities were discovered. This population of hypertensives (mean systolic/diastolic blood pressure, 174.4/97.8 mm Hg) with LVH comprises women (54.1%) and men, mostly retired from active work (mean age, 66.9 years), with a high prevalence of overweight (mean body mass index, 28.0 kg/m2), diabetes mellitus (12.3%), lipid disorders (18.0%), and symptoms or signs of coronary heart disease (15.1%). There were fewer current smokers (<17%) than in the general population, and approximately 7% were nonwhite. Almost 30% of participants had been untreated for at least 6 months when screened for the study. Only 1557 persons who entered the placebo run-in period of 14 days were excluded, predominantly because of sitting blood pressures above or below the predetermined range of 160-200/95-115 mm Hg and ECG-LVH criteria not met. By application of simple 12-lead ECG criteria for LVH (Cornell voltage QRS duration product formula plus Sokolow-Lyon voltage read by a core laboratory), hypertensive patients with LVH with an average 5-year coronary heart disease risk of 22.3% according to the Framingham score were identified. This population is now being treated (goal, <140/90 mm Hg) in adherence with the protocol for at least 4 years after final enrollment (ie, through April 2001) and until at least 1040 patients suffer myocardial infarction, stroke, or cardiovascular death.