Jonathan M. Edelman

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.

Regression of Hypertensive Left Ventricular Hypertrophy by Losartan Compared With Atenolol The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) Trial

Background—An echocardiographic substudy of the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) trial was designed to test the ability of losartan to reduce left ventricular (LV) mass more than atenolol. Methods and Results—A total of 960 patients with essential hypertension and LV hypertrophy (LVH) on screening ECG were enrolled at centers in 7 countries and studied by echocardiography at baseline and after 1, 2, 3, 4, and 5 years’ randomized therapy. Clinical examination and blinded readings of echocardiograms in 457 losartan-treated and 459 atenolol-treated participants with ≥1 follow-up measurement of LV mass index (LVMI) were used in an intention-to-treat analysis. Losartan-based therapy induced greater reduction in LVMI from baseline to the last available study than atenolol with adjustment for baseline LVMI and blood pressure and in-treatment pressure (−21.7±21.8 versus −17.7±19.6 g/m2; P=0.021). Greater LVMI reduction with losartan was observed in women and men, participants >65 or <65 years of age, and with mild or more severe baseline hypertrophy. The difference between treatment arms in LVH regression was due mainly to reduced concentricity of LV geometry in both groups and lesser increase in LV internal diameter in losartan-treated patients. Conclusions—Antihypertensive treatment with losartan, plus hydrochlorothiazide and other medications when needed for pressure control, resulted in greater LVH regression in patients with ECG LVH than conventional atenolol-based treatment. Thus, angiotensin receptor antagonism by losartan has superior efficacy for reversing LVH, a cardinal manifestation of hypertensive target organ damage.

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.

Influence of body mass index on the response to asthma controller agents

The incidence of asthma has been positively associated with obesity. Asthma comprises diverse “phenotypes” reflecting heterogeneity in a number of characteristics, including response to therapy. The present authors examined whether body mass index (BMI) influenced the response to placebo, as well as to two asthma controller medications. A post hoc analysis was performed, pooling data from four double-blind, placebo-controlled studies randomising 3,073 moderate asthmatic adults to montelukast (n = 1,439), beclomethasone (n = 894) or placebo (n = 740). The primary end point was asthma control days; other end points were forced expiratory volume in one second, β-agonist use and nocturnal awakening. Analyses were conducted using BMI classification into normal (<25.0 kg·m−2; 52% of patients), overweight (25–29.9 kg·m−2; 32%) and obese (≥30.0 kg·m−2; 16%) categories, as well as BMI as a continuous variable. The treatment groups were balanced for BMI, demographic characteristics and parameters of asthma control. The placebo response for all end points was generally lower with increasing BMI. Similarly, the response to the inhaled corticosteroid decreased, whereas the response to the leukotriene antagonist remained stable. In conclusion, post hoc data from the present study suggested that body mass index may influence the natural history of asthma control (as reflected by response to placebo) and may differentially influence response to the two active agents, warranting explicit testing in future prospective studies.

Regression of Electrocardiographic Left Ventricular Hypertrophy by Losartan Versus Atenolol The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study

Background—Electrocardiographic left ventricular hypertrophy (LVH) predicts cardiovascular morbidity and mortality, and regression of ECG LVH may predict improved prognosis in hypertensive patients. However, uncertainty persists as to how best to regress ECG LVH. Methods and Results—Regression of ECG LVH with losartan versus atenolol therapy was assessed in 9193 hypertensive patients with ECG LVH by Sokolow-Lyon voltage or Cornell voltage-duration product criteria enrolled in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study. Patients had ECGs at study baseline and after 6 months, 1, 2, 3, 4, and 5 years of blinded losartan-based or atenolol-based therapy. After 6 months’ follow-up, adjusting for baseline ECG LVH levels, baseline and in-treatment systolic and diastolic pressures, and for diuretic therapy, losartan-based therapy was associated with greater regression of both Cornell product (adjusted means, −200 versus −69 mm · ms, P <0.001) and Sokolow-Lyon voltage (−2.5 versus −0.7 mm, P <0.001) than was atenolol-based therapy. Greater regression of ECG LVH persisted at each subsequent annual evaluation in the losartan-treated group, with between 140 and 164 mm · ms greater mean reductions in Cornell product and from 1.7 to 2.2 mm greater mean reductions in Sokolow-Lyon voltage (all P <0.001). The effect of losartan was consistent across subgroups defined by gender, age, ethnicity, and diabetes. Conclusions—After adjusting for baseline and in-treatment blood pressure and baseline severity of ECG LVH, losartan-based antihypertensive therapy resulted in greater regression of ECG LVH by Cornell voltage-duration product and Sokolow-Lyon voltage criteria than did atenolol-based therapy. These findings support the value of angiotensin receptor blockade with losartan for reversing ECG LVH.

Oral Montelukast Compared with Inhaled Salmeterol To Prevent Exercise-Induced Bronchoconstriction: A Randomized, Double-Blind Trial

Exercise-induced bronchoconstriction is common in patients with chronic asthma (1). Airway cooling or desiccation during exercise may trigger activation of mast cells and release of such mediators as histamine and cysteinyl leukotrienes, resulting in bronchospasm (1, 2). Cysteinyl leukotrienes (LTC4, LTD4, and LTE4), synthesized from arachidonic acid through the 5-lipoxygenase pathway, are potent bronchoconstrictors, with an effect greater than 1000 times that of histamine (3-5). Several researchers have demonstrated an increase in urinary concentrations of LTE4 after exercise (6, 7). Prophylaxis against exercise-induced bronchoconstriction with inhaled mast cell-stabilizing agents and short-acting -agonists must be administered 15 to 30 minutes before exercise. The long-acting inhaled -agonist salmeterol protects against exercise-induced bronchoconstriction for up to 12 hours, thus providing more flexibility in the dosing schedule for active patients with asthma (8, 9). However, in some patients, tolerance to salmeterol develops with long-term use, and the level of bronchoprotection diminishes by 6 to 9 hours (10-12). Montelukast sodium, a leukotriene receptor antagonist, is a potent oral medication for the treatment of asthma. The leukotriene receptor antagonists have demonstrated a significant bronchoprotective effect with exercise after one or two doses (13, 14). In patients with exercise-induced bronchoconstriction, short-term treatment with montelukast (Singulair, Merck & Co., Inc., Whitehouse Station, New Jersey) given once daily diminished the postexercise response, as described by the area under the FEV1 time curve (AUC0-60 min), by more than 50%, even at the end of the dosing interval (20 to 24 hours after administration) (15, 16). Furthermore, tolerance to the bronchoprotective effects of montelukast did not occur with long-term administration (17). We sought to test the hypothesis that the bronchoprotective effects of montelukast were greater than those of salmeterol in patients with chronic asthma who experienced exercise-induced bronchoconstriction. Methods Design We conducted a randomized, parallel-group study consisting of a 2-week, single-blind placebo baseline period followed by an 8-week, double-blind treatment period with montelukast sodium (10-mg tablet taken orally once in the evening) or inhaled salmeterol (50-g aerosol formulation [2 puffs] taken twice daily). Seventeen clinical study sites participated in the trial. To mask formulation differences, a double-dummy treatment regimen was used. Each patient received one tablet daily (active agent or matching placebo) or one inhaler twice daily (active agent or matching placebo) for both the single-blind and double-blind treatment periods. A computer-generated allocation schedule with a blocking factor of 4 was produced by the statistician. Each center was given a block of allocation numbers that were assigned sequentially to consecutive randomly assigned patients. Spirometric measurements were obtained before and after standardized exercise challenges at the beginning and end of the baseline period, within the first 3 days of the double-blind treatment period, and at weeks 4 and 8 of the treatment period. Additional measurements were physical examination, vital signs, electrocardiography, chest radiography, and laboratory tests (hematology, chemistry profile, and urinalysis). At each visit, all spontaneously reported adverse events were recorded. The protocol was approved by the institutional review board of each site, and written informed consent was obtained from each patient. Inclusion Criteria Male and female patients 15 to 45 years of age with a history of chronic asthma were enrolled. All patients had an FEV1 of at least 65% of the predicted value at rest and a decrease in FEV1 of at least 20% after a standardized exercise challenge on two occasions during the baseline period. All patients had been nonsmokers for at least 1 year and had a smoking history of less than 15 pack-years. Exclusion Criteria Persons who had upper respiratory infection or exacerbation of asthma requiring emergency care within the past month or were hospitalized for asthma in the past 3 months were excluded. Use of oral or inhaled corticosteroids, theophylline, cromolyn sodium, nedocromil, oral -agonist, and long-acting antihistamines was prohibited before and during the study. Use of inhaled albuterol for symptomatic relief of asthma and use of short-acting antihistamines were permitted. Evaluations A standard spirometer (Puritan-Bennett PB100/PB110, Puritan-Bennett, Wilmington, Massachusetts) was used to obtain all spirometric measurements according to American Thoracic Society standard criteria (18). Patients had to have discontinued use of inhaled short-acting -agonists for 6 hours before the visit. Exercise testing was done in the early afternoon near the trough of effect for both drugs according to a method described elsewhere (17). Measurements were obtained 20 and 5 minutes before exercise (prechallenge period). Exercise challenge was performed only if the average FEV1 in the prechallenge period was greater than 65% of predicted; otherwise, the test was rescheduled. Patients exercised on a treadmill while inhaling room temperature, compressed, dry air. During the first test, the speed and gradient of the treadmill were adjusted to achieve 80% to 90% of the patients age-predicted maximum heart rate. The settings were maintained for a total of 6 minutes; the same settings were used for future tests. This level of exercise has been used to quantify the level of bronchoconstriction associated with regular exercise (19). Serial spirometric measurements were obtained at 0, 5, 10, 15, 30, 45, and 60 minutes after exercise (postexercise period). Additional measurements were carried out at 15-minute intervals for up to 90 minutes if the patients FEV1 had not returned to within 5% of the prechallenge value by 60 minutes. If the patients FEV1 did not return to the prechallenge value by 90 minutes after exercise, a rescue dose of inhaled -agonist was administered at the discretion of the study investigator. Statistical Analysis An all-patients-treated analysis, which included patients with a baseline visit and at least one post-randomization visit, was performed. The change from baseline in the maximal percentage decrease in FEV1 after exercise at the end of 8 weeks of treatment was the primary end point. Analysis of variance was used to compare the two treatment groups. The analysis of variance model included terms for treatment, center, and the interaction of treatment and center. Ninety-five percent CIs for within-group means and the difference between groups were constructed to assess the magnitude of the treatment effect. Analysis of variance on the ranked data was used to analyze percentage inhibition for all end points. In the event of early termination of the exercise challenge because of administration of rescue medication, the largest percentage decrease in FEV1 achieved before administration of rescue medication was used in the analysis. Secondary end points were change from baseline for maximal percentage decrease in FEV1 at days 1 to 3 and week 4, the time required after maximal decrease in FEV1 to return within 5% of prechallenge values (time to recovery), and the AUC0-60 min at all visits. The mean of the 20- and 5-minute prechallenge measurements was used as the pre-exercise FEV1 value. If a patient required rescue with inhaled -agonist during the postexercise period, the last recorded FEV1 value was used and carried forward for all subsequent readings and 100 minutes was entered for the end point of time to recovery. The AUC0-60 min was calculated by using the trapezoidal method. If a patients FEV1 did not decrease below 95% of the prechallenge value, the time to recovery was assigned a value of zero. The persistence of effect over time was assessed by using a repeated-measures fixed-effects model with terms for center, treatment group, time, and the interaction of treatment group and time to calculate the rate of change over the treatment period. Persistence of effect was defined as a slope of zero. The magnitude of the slopes for each treatment group was estimated, and 95% CIs were calculated. An overall test of equal slopes between the treatment groups was examined, and a 95% CI on the difference in slopes between treatment groups was provided. The number and percentage of patients requiring rescue medication during or at the end of the exercise test were summarized by treatment group at each time point. In addition, the number and percentage of patients whose decrease in FEV1 from pre-exercise levels was less than 10%, 10% to 20%, 20% to 40%, and greater than 40% were summarized by treatment group for each visit. The overall incidence of adverse events and laboratory abnormalities was assessed by using the Fisher exact test, and within-group changes in the number of laboratory abnormalities were assessed by using the McNemar test. Descriptive statistics were provided by treatment group for patient demographic characteristics, clinical characteristics, and baseline profile. The study was designed with a sample size of 160 patients (80 patients per treatment group) to have 95% power (two-sided test at =0.05) to detect a 7% difference in the mean change in maximal percentage decrease in FEV1 between treatments. All statistical analyses were performed by using SAS software, version 6 (SAS Institute, Inc., Cary, North Carolina). Role of the Funding Source Funding for this trial was provided by Merck & Co., Inc., Whitehouse Station, New Jersey. Personnel from Merck U.S. Human Health, Clinical Development department played a significant role in the design, conduct, and analysis of the trial. The trial was conducted in accordance with guidelines for clinical trials of investigational agents established by U.S. regulatory authorities. Results Pati

Regression of Electrocardiographic Left Ventricular Hypertrophy Is Associated with Less Hospitalization for Heart Failure in Hypertensive Patients

Context Regression of left ventricular hypertrophy (LVH) has been associated with reductions in cardiovascular death, stroke, myocardial infarction, and atrial fibrillation in patients with treated hypertension, but heart failure outcomes have not been carefully studied. Contribution This analysis of data from the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial found an association between reduction of LVH by Cornell product electrocardiographic criteria and hospitalization for new-onset heart failure. This relationship appeared to be unrelated to blood pressure reduction and type of therapy. Caution Without clinical trials that directly address the issue, it remains uncertain whether clinicians should adjust antihypertensive therapy on the basis of electrocardiographic findings of LVH. The Editors Heart failure is an increasing public health problemboth men and women have a 20% lifetime risk for this condition (1). Because of the enormous clinical and societal impact of heart failure, current recommendations emphasize the importance of its prevention (24), which requires a better understanding of risk factors for it. Hypertension doubles the lifetime risk for heart failure in men and triples the risk in women (1, 5), accounting for 39% of new heart failure cases in men and 59% of incident cases in women (5). Although numerous studies have documented the efficacy of antihypertensive therapy in preventing heart failure (612), the mechanisms by which hypertension predisposes to heart failure or by which blood pressure reduction prevents or retards its development require further elucidation (5). Left ventricular hypertrophy (LVH) on electrocardiography predicts incident heart failure in both hypertensive and normotensive individuals (5, 1322), and prevention of electrocardiographic LVH appears to attenuate the risk for new-onset heart failure in high-risk patients (22). In the LIFE (Losartan Intervention For Endpoint reduction in hypertension) study (2327), reduction of blood pressure by using antihypertensive therapy induced reduction of electrocardiographic LVH by both Cornell voltage-duration product and SokolowLyon voltage criteria (23), which, in turn, were associated with statistically significant reductions in the risk for cardiovascular death, myocardial infarction, stroke, and the LIFE composite end point of these 3 outcomes, independent of treatment method and blood pressure reduction (24). These findings suggest that reduction of LVH could play an important mechanistic role in decreasing incident heart failure among treated hypertensive patients (512). However, whether reduction of electrocardiographic LVH itself is associated with a decreased incidence of new-onset heart failure during antihypertensive therapy is unclear (19). Accordingly, we examined whether in-treatment reduction of electrocardiographic LVH, as measured by change in Cornell voltage-duration product criteria, is associated with a reduced incidence of heart failure in the LIFE study sample, independent of the effects of blood pressure, baseline severity of electrocardiographic LVH, and other risk factors for heart failure. Methods Patients The LIFE trial (2327) enrolled 9193 hypertensive patients with electrocardiographic LVH by Cornell voltage-duration product (28, 29) or SokolowLyon voltage criteria (30) on a screening electrocardiogram. The trial was a double-blind, randomized study that compared cardiovascular morbidity and mortality with use of losartan-based as opposed to atenolol-based treatment (25, 27). It was approved by all ethics committees concerned. As described in detail elsewhere (2327), patients eligible for the LIFE study were men and women age 55 to 80 years who 1) had previously untreated or treated essential hypertension with a mean seated blood pressure of 160 to 200 mm Hg/95 to 115 mm Hg after 1 and 2 weeks of receiving placebo; 2) had not had myocardial infarction or stroke within 6 months; and 3) did not require treatment with a -blocker, angiotensin-converting enzyme inhibitor, or angiotensin-1antagonist. All participants gave written informed consent. Patients with a history of heart failure (n= 166), incident heart failure before the 6-month electrocardiogram (n= 58), follow-up less than 6 months (n= 101), or no 6-month electrocardiogram (n= 389) were excluded from analyses, leaving 8479 patients in our study. Treatment Regimens Blinded treatment was begun with losartan, 50 mg/d, or atenolol, 50 mg/d, and matching placebo of the other agent, with a target blood pressure of 140/90 mm Hg or lower. During clinic visits, dose of the study drug could be titrated upward by addition of hydrochlorothiazide, 12.5 mg, followed by an increase in the dose of blinded losartan or atenolol to 100 mg/d. In patients whose blood pressure was still not controlled, additional open-label upward titration of the hydrochlorothiazide dose and, if necessary, therapy with a calcium-channel blocker or other medications (excluding angiotensin-1blockers, -blockers, or angiotensin-converting enzyme inhibitors) was added to the double-blind treatment regimen (25). Electrocardiography Electrocardiograms were obtained at baseline, at 6 months, and at yearly follow-up intervals until study termination or patient death. Electrocardiograms were interpreted at the Core Laboratory at Sahlgrenska University Hospital/stra in Gteborg, Sweden, as reported elsewhere (2326). The product of QRS duration times the Cornell voltage combination (RaVL + SV3, with 6 mm added in women [28, 29]) greater than 2440 mm msec or SokolowLyon voltage (SV1 + RV5/6) greater than 38 mm (30) was used to identify LVH (23, 24). Because patients were selected for the study on the basis of electrocardiographic LVH above these threshold levels on a screening electrocardiogram obtained before baseline (2327), a proportion of patients at baseline would be expected to no longer meet threshold criteria for LVH as a result of regression to the mean (23, 24). As a consequence, despite this selection process, 1934 patients (22.8%) did not meet threshold criteria for electrocardiographic LVH by either Cornell product or SokolowLyon voltage on their baseline electrocardiogram. End Point Determination Hospitalization for heart failure was a prespecified secondary end point in the LIFE study (25); the diagnosis of heart failure was based on clinical and diagnostic findings. Each case was reviewed and verified by the Endpoint Committee, which was blinded to study electrocardiographic LVH findings when classifying possible morbid events (2527). Statistical Analysis Data were managed and analyzed by using SPSS, version 12.0 (SPSS, Chicago, Illinois). Data are presented as means (SDs) for continuous variables and as proportions for categorical variables. Differences in mean values between patients with and without new-onset heart failure were compared by using unpaired t tests; proportions were compared between groups by using chi-square tests. Differences in mean Cornell product between baseline and subsequent in-treatment electrocardiograms were compared with repeated-measures analysis of variance, and differences in changes in Cornell product between baseline and each in-treatment electrocardiogram were compared between patients with and without heart failure by using analysis of variance. The relation of an in-treatment reduction in Cornell product to the risk for heart failure was assessed by using Cox proportional hazards models (31), with the change in Cornell product between baseline and subsequent in-treatment electrocardiograms entered as a time-varying covariate (24). Baseline risk factors and a treatment group indicator were included as standard covariates; baseline and subsequent systolic and diastolic blood pressure and in-treatment changes in SokolowLyon voltage measurements were entered as time-varying covariates. In addition, we also analyzed the relation of a reduction in Cornell product of 236 mm msec or more versus a reduction less than 236 mm msec (the median decrease between baseline and last in-study measurement) treated as a dichotomous time-varying variable to the development of heart failure. The adjusted hazard ratios for the incidence of heart failure associated with in-treatment reduction of Cornell product treated as a continuous variable were computed per 817mm msec lower Cornell product (1 SD of the mean change in Cornell product between baseline and last in-study measurement) as the anti-log of the estimated coefficient times the SD (32). The 95% CI of each hazard ratio was calculated from the estimated coefficients and their SEs. Analyses were repeated by stratifying the population by sex, age, race, treatment group, whether the patient was 65 years of age or older, history of atrial fibrillation, ischemic heart disease, myocardial infarction, prevalent diabetes, and the presence or absence of LVH by Cornell product or SokolowLyon voltage on the baseline electrocardiogram. Interaction between time-varying change in Cornell product and these variables was formally tested by adding cross-product terms of time-varying reduction of Cornell product with these variables into the models of the total population. The relationship of new-onset heart failure over time to in-treatment reduction of Cornell product LVH was illustrated by plotting heart failure rates according to the presence or absence of reduction in Cornell product of 236 mm msec by using a modified KaplanMeier method (33); assignment to groups was adjusted at the time that each electrocardiogram was obtained, on the basis of the change in Cornell product between baseline and those times. For all tests, a 2-tailed P value less than 0.05 was required for statistical significance. Role of the Funding Source Merck & Co. provided the study authors with free access to all of the data; the authors were free to interpret data and write the paper. The sponsor agreed to support perf

Effect of losartan on sudden cardiac death in people with diabetes: data from the LIFE study.

In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, a major reduction of all-cause mortality--especially cardiovascular mortality--in patients with diabetes with left ventricular hypertrophy was reported for treatment with losartan. We postulated post hoc that losartan might have a better effect on sudden cardiac death than atenolol, and we aimed to test this hypothesis. 44 patients with diabetes died of sudden cardiac death; significantly fewer deaths arose in the losartan group (14) than in the atenolol group (30; p=0.027). In the losartan group, five (6%) of 86 patients with diabetes and atrial fibrillation during the trial died of sudden cardiac death compared with nine (2%) of 500 in those without atrial fibrillation. The respective figures for the atenolol group were 14 (13%) of 105 and 16 (3%) of 504. Our results suggest losartan affords better protection against cardiac death from arrhythmias for patients with diabetes mellitus than does atenolol. Importantly, our analyses were exploratory and require confirmation.

Efficacy, tolerability, and effects on quality of life of losartan, alone or with hydrochlorothiazide, versus amlodipine, alone or with hydrochlorothiazide, in patients with essential hypertension

A randomized, double-masked, parallel-group, multicenter clinical trial was conducted to compare the efficacy, tolerability, and effects on quality of life associated with treatment regimens including the angiotensin II receptor antagonist losartan, with hydrochlorothiazide (HCTZ) added as needed, with regimens including the dihydropyridine calcium channel blocker amlodipine with HCTZ added as needed. The trial included patients whose sitting diastolic blood pressure (SiDBP) measurements were between 95 and 114 mm Hg, inclusive, at placebo baseline. Patients were randomized to receive either losartan or amlodipine in a double-masked, double-dummy fashion. A 4-week placebo washout period was followed by a 12-week active treatment period. Patients in the losartan arm (n = 97) were initially given 50 mg of oral (PO) losartan once a day (QD); the medication could be titrated to 50-mg losartan/ 12.5-mg HCTZ PO QD after 4 weeks, followed by 50-mg losartan plus 25-mg HCTZ PO QD after 8 weeks as necessary. Patients in the amlodipine group (n = 93) received 5-mg amlodipine PO QD, which could be titrated to 10 mg PO QD after 4 weeks, followed by 10 mg plus 25-mg HCTZ PO QD after 8 weeks. Medication was titrated upward as necessary to achieve trough SiDBP < 90 mm Hg. Efficacy, tolerability, and quality-of-life scores were assessed after 12 weeks of therapy with each regimen. Trough SiDBP reductions after 4, 8, and 12 weeks of therapy were clinically comparable (losartan group: 7.3, 10.4, and 11.1 mm Hg, respectively; amlodipine group: 7.9, 11.2, and 11.8 mm Hg, respectively). Similar reductions in systolic blood pressure were also seen for both treatment groups. The percentage of patients reaching goal SiDBP (defined as trough SiDBP < 90 mm Hg or SiDBP > or = 90 mm Hg with a > or = 10 mm Hg drop from placebo baseline) was comparable for the two groups, with 68% of patients in the losartan group and 71% of patients in the amlodipine group reaching goal. Significantly more patients in the amlodipine group had drug-related adverse experiences (27% vs 13%). In particular, drug-related edema was more common in patients receiving the amlodipine regimen than in those receiving the losartan regimen (11% vs 1%). Patients in the amlodipine arm reported significantly more bother due to edema, regardless of whether edema was present at baseline, than did patients in the losartan arm (12% vs 2%), although overall quality of life was not different in the two treatment groups. This study demonstrates that a regimen of losartan with HCTZ added as needed, when compared with a regimen of amlodipine with HCTZ added as needed, provides comparable efficacy and superior tolerability and less bother to patients with respect to edema.

Impact of Diabetes Mellitus on Regression of Electrocardiographic Left Ventricular Hypertrophy and the Prediction of Outcome During Antihypertensive Therapy The Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study

Background— Diabetes mellitus is associated with increased cardiovascular (CV) morbidity and mortality and with greater ECG left ventricular hypertrophy (LVH); however, it is unclear whether diabetes attenuates regression of hypertensive LVH and whether regression of ECG LVH has similar prognostic value in diabetic and nondiabetic hypertensive individuals. Methods and Results— A total of 9193 hypertensive patients (1195 with diabetes) in the Losartan Intervention For Endpoint (LIFE) Reduction in Hypertension Study were treated with losartan- or atenolol-based regimens and followed up with serial ECG and blood pressure determinations at baseline and 6 months and then yearly until death or study end. ECG LVH was defined with gender-adjusted Cornell voltage-duration product (CP) criteria >2440 mm · ms. After a mean follow-up of 4.8±0.9 years, patients with diabetes had less regression of CP LVH (−138±866 versus −204±854 mm · ms, P<0.001), remained more likely to have LVH by CP (56.0% versus 48.1%, P<0.001), and had higher rates of CV death, myocardial infarction, stroke, and all-cause mortality and of the LIFE composite end point of CV death, myocardial infarction, or stroke. In multivariable Cox proportional hazards models, in-treatment regression or absence of ECG LVH by CP was associated with between 17% and 35% reductions in event rates in patients without diabetes but did not significantly predict outcome in patients with diabetes. Conclusions— Hypertensive patients with diabetes have less regression of CP LVH in response to antihypertensive therapy than patients without diabetes, and regression of ECG LVH is less useful as a surrogate marker of outcomes in hypertensive patients with diabetes. These findings may in part explain the higher CV morbidity and mortality in hypertensive patients with diabetes, and the absence of a demonstrable improvement in prognosis in diabetic patients in response to regression of ECG LVH suggests a more complex interrelation between underlying LV structural and functional abnormalities and outcome in these patients.