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Aims It is unknown whether there is an interaction between aspirin and angiotensin receptor blockers on outcomes in patients with heart failure (HF). Methods and results The efficacy and safety of candesartan vs. placebo was assessed in 7599 patients with symptomatic HF and reduced or preserved left ventricular ejection fraction enrolled in the CHARM programme according to baseline aspirin use. Patients were randomized to candesartan or matching placebo and were followed for a median of 38 months. Aspirin was used in 4246 (55.9%) of patients at baseline. When compared with placebo, candesartan use was associated with lower event rates for cardiovascular (CV) death or HF hospitalization (primary outcome) in both the aspirin group (28 vs. 31.9%, HR 0.81, 95% CI 0.72–0.90) and non-aspirin group (33 vs. 38%, HR 0.81, 95% CI 0.72–0.91). Baseline aspirin use did not modify the effectiveness of candesartan in reducing the risk of CV death or HF hospitalization in CHARM overall (P = 0.64) or in the CHARM individual trials. In addition, there was no significant interaction between aspirin therapy and candesartan in terms of discontinuation of study drug due to adverse reactions (P = 0.72). Conclusion There appears to be no significant modification of the benefit of candesartan on CV mortality and morbidity outcomes or safety by concomitant use of aspirin in patients with chronic HF.

Objectives This study sought to investigate the efficacy and tolerability of candesartan, according to baseline blood pressure (BP), in the 4,576 patients with a low ejection fraction (EF) (≤0.40) in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) program. Background Hypotension is a predictor of poor prognosis in heart failure, yet many treatments shown to reduce morbidity and mortality lower blood pressure. This paradox creates a dilemma for physicians and may explain why low BP is reported as a reason for under-use of these agents. Methods The interaction between treatment and baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) was examined with patients divided into 6 SBP categories (≤100, 101 to 110, 111 to 120, 121 to 130, 131 to 140 and ≥141 mm Hg) and 4 DBP categories (≤60, 61 to 70, 71 to 80 and ≥81 mm Hg). Results Low SBP and DBP were associated with worse clinical outcomes. Baseline BP did not modify the effects of candesartan on clinical outcomes: the interaction p value between SBP category and treatment was 0.38 (0.22 for DBP category). For both placebo and candesartan, study drug discontinuation for adverse effects (especially hypotension) was highest in patients in the lowest baseline BP categories. However, the relative risk of discontinuation for hypotension, renal dysfunction, and hyperkalemia in the candesartan compared with placebo group was not increased in patients with a low baseline BP. Conclusions In patients with low EF heart failure, the relative risks and benefits of candesartan treatment were similar in patients with a low BP compared to those with a higher BP.

Objectives We explored the incidence and predictors of hyperkalemia in a broad population of heart failure patients. Background When used in optimal doses to treat patients with heart failure, renin-angiotensin-aldosterone system (RAAS) inhibitors improve clinical outcomes but can cause hyperkalemia. Methods Participants in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) (n = 7,599) Program were randomized to standard heart failure therapy plus candesartan or placebo, titrated as tolerated to a target of 32 mg once daily with recommended monitoring of serum potassium and creatinine. We assessed the incidence and predictors of hyperkalemia associated with dose reduction, study drug discontinuation, hospitalization, or death over the median 3.2 years of follow-up. Results Independent of treatment assignment, the risk of hyperkalemia increased with age > or =75 years, male gender, diabetes, creatinine > or =2.0 mg/dl, K+ > or =5.0 mmol/l, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the rate of aggregate hyperkalemia from 1.8% to 5.2% (difference 3.4%, p Conclusions The risk of hyperkalemia is increased in symptomatic heart failure patients with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, or combined RAAS blockade. Although these groups derive incremental clinical benefit from candesartan, careful surveillance of serum potassium and creatinine is particularly important.

Background Whether an angiotensin receptor blocker is of benefit when added to a full dose of angiotensin-converting enzyme (ACE) inhibitor in heart failure (HF) is uncertain. Methods The effect of candesartan, compared with placebo, in 2548 patients randomized in the CHARM-Added trial was analyzed according to (i) ACE inhibitor dose at baseline, (ii) ACE inhibitor dose during follow-up, and (iii) combination treatment with ACE inhibitor and β-blocker at baseline. The main outcome was the composite of cardiovascular death or HF hospitalization. Results The benefit of candesartan was not modified by the dose of ACE inhibitor. In all patients (n = 2548), the candesartan/placebo hazard ratio (HR) for the primary outcome was 0.85 (95% CI 0.75-0.96). In patients taking a guideline recommended dose of ACE inhibitor at baseline (n = 1291), this HR was 0.79 (95% CI 0.67-0.95; interaction P value .26). In patients taking a Food and Drug Administration–designated maximum dose of ACE inhibitor (n = 529), this HR was 0.75 (95% CI 0.57-0.98; interaction P value .29). The benefit of candesartan was preserved in patients taking β-blockers in addition to a higher dose of ACE inhibitor and in patients maintaining a high dose of ACE inhibitor throughout follow-up. Conclusions These clinical findings support the pharmacologic evidence that ACE inhibitors and angiotensin receptor blockers have distinct mechanisms of action and show that their combined use improves outcomes in patients with HF more than an evidence-based dose of ACE inhibitor alone.

Background— Diabetes is a risk factor for heart failure, and both conditions are increasing. Identifying treatments that prevent both conditions will be clinically important. We previously reported that candesartan (an angiotensin receptor blocker) reduces cardiovascular mortality and heart failure hospitalizations in heart failure patients (CHARM: C andesartan in H eart Failure— A ssessment of R eduction in M ortality and Morbidity Program). Methods and Results— We assessed the impact of candesartan versus placebo on the development of diabetes, a predefined secondary outcome in a randomized, controlled, double-blind study involving 5436 of the 7601 patients with heart failure, irrespective of ejection fraction, who did not have a diagnosis of diabetes at entry into the trial. Patients received candesartan (target of 32 mg once daily) or matching placebo for 2 to 4 years. One hundred sixty-three (6.0%) individuals in the candesartan group developed diabetes, as compared with 202 (7.4%) in the placebo group (hazard ratio [HR], 0.78 with a 95% confidence interval [CI] of 0.64 to 0.96; P =0.020). The composite end point of death or diabetes occurred in 692 (25.2%) and 779 (28.6%), respectively, in the candesartan and placebo groups (HR, 0.86; 95% CI, 0.78 to 0.95; P =0.004). The results were not statistically heterogeneous in the various subgroups examined, although the apparent magnitude of benefit appeared to be smaller among those treated concomitantly with angiotensin-converting enzyme inhibitors at trial entry (HR, 0.88; 95% CI, 0.65 to 1.20) compared with those not receiving these drugs (HR, 0.71; 95% CI, 0.53 to 0.93; P for heterogeneity, 0.28). Conclusions— The angiotensin receptor blocker candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.

The Study on COgnition and Prognosis in the Elderly (SCOPE) assessed the effect of candesartan on cardiovascular outcomes in elderly patients with mild to moderate hypertension. Patients were randomized to candesartan 8-16 mg daily (n = 2477) or placebo (n =2460). Due to extensive add-on therapy, blood pressure reduction was only about 3/2 mmHg greater in the candesartan group than in the control group. Nevertheless, non-fatal stroke was reduced by 28% (p = 0.04) in the candesartan group compared to the control group, and there was a non-significant 11% reduction in major cardiovascular events (p = 0.19). This report provides results in pre-specified subgroups of patients (age, gender, diabetes, history of stroke, smoking and cardiovascular risk at randomization). Reductions in major cardiovascular events and stroke with candesartan-based therapy were indicated in all subgroups. A significant interaction between treatment and subgroups was found for one pair of subgroups only; the reduction in major cardiovascular events with candesartan was greater in patients with a previous stroke (64% reduction, p = 0.004) than in those without (5% reduction, p > 0.20). In conclusion, this analysis indicated consistent favourable effects of candesartan-based therapy on major cardiovascular events and stroke across the different subgroups of patients. However, the benefit was particularly pronounced in patients who entered the study with a previous stroke.

Aims To evaluate the effect of the angiotensin receptor blocker candesartan on New York Heart Association (NYHA) functional class in a broad spectrum of patients with chronic heart failure (CHF). Methods and results Patients in the CHARM Programme with symptomatic CHF were randomized to placebo ( n =3796) or candesartan ( n =3803) and followed for a median of 38 months. NYHA class was assessed at baseline, at two weekly intervals during dose titration and 4 monthly thereafter. Patients were classified as "better", "unchanged" or "worse" at the end of the study compared to baseline. Both a simple "last visit carried forward" (LVCF) analysis and "worst rank carried forward" (WRCF) analysis (where patients who died were allocated NYHA class V) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (35.4% versus 32.5%) and fewer worsened (9.0% versus 10.3%) in NYHA class ( p =0.003). The WRCF analysis also showed a better overall change in NYHA class with candesartan compared to placebo. There was no heterogeneity in the response to candesartan between the CHARM component trials. Conclusions Candesartan improves NYHA functional class to a similar extent to other proven treatments for CHF when added to these other treatments.

Background— Patients with symptomatic chronic heart failure (CHF) and reduced left ventricular ejection fraction (LVEF) have a high risk of death and hospitalization for CHF deterioration despite therapies with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and even an aldosterone antagonist. To determine whether the angiotensin-receptor blocker (ARB) candesartan decreases cardiovascular mortality, morbidity, and all-cause mortality in patients with CHF and depressed LVEF, a prespecified analysis of the combined Candesartan in Heart Failure Assessment of Reduction in Mortality and morbidity (CHARM) low LVEF trials was performed. CHARM is a randomized, double-blind, placebo-controlled, multicenter, international trial program. Methods and Results— New York Heart Association (NYHA) class II through IV CHF patients with an LVEF of ≤40% were randomized to candesartan or placebo in 2 complementary parallel trials (CHARM-Alternative, for patients who cannot tolerate ACE inhibitors, and CHARM-Added, for patients who were receiving ACE inhibitors). Mortality and morbidity were determined in 4576 low LVEF patients (2289 candesartan and 2287 placebo), titrated as tolerated to a target dose of 32 mg once daily, and observed for 2 to 4 years (median, 40 months). The primary outcome (time to first event by intention to treat) was cardiovascular death or CHF hospitalization for each trial, with all-cause mortality a secondary end point in the pooled analysis of the low LVEF trials. Of the patients in the candesartan group, 817 (35.7%) experienced cardiovascular death or a CHF hospitalization as compared with 944 (41.3%) in the placebo group (HR 0.82; 95% CI 0.74 to 0.90; P P =0.005) and CHF hospitalizations (516 [22.5%] versus 642 [28.1%]; HR 0.76 [95% CI 0.68 to 0.85]; P P =0.018). No significant heterogeneity for the beneficial effects of candesartan was found across prespecified and subsequently identified subgroups including treatment with ACE inhibitors, β-blockers, an aldosterone antagonist, or their combinations. The study drug was discontinued because of adverse effects by 23.1% of patients in the candesartan group and 18.8% in the placebo group; the reasons included increased creatinine (7.1% versus 3.5%), hypotension (4.2% versus 2.1%), and hyperkalemia (2.8% versus 0.5%), respectivelyt (all P Conclusion— Candesartan significantly reduces all-cause mortality, cardiovascular death, and heart failure hospitalizations in patients with CHF and LVEF ≤40% when added to standard therapies including ACE inhibitors, β-blockers, and an aldosterone antagonist. Routine monitoring of blood pressure, serum creatinine, and serum potassium is warranted.

OBJECTIVES The aim of this study was to test the hypothesis that the angiotensin II type 1 receptor blocker (ARB) candesartan can reduce the risk of stroke in elderly patients with isolated systolic hypertension (ISH). BACKGROUND Isolated systolic hypertension is the predominant form of hypertension in the elderly, and stroke is the most common cardiovascular (CV) complication. METHODS In the Study on Cognition and Prognosis in the Elderly (SCOPE), 4,964 patients age 70 to 89 years were randomly assigned to double-blind candesartan or placebo with open-label antihypertensive therapy (mostly thiazide diuretics) added as needed to control blood pressure. Of the 4,964 patients, 1,518 had ISH (systolic blood pressure >160 mm Hg and diastolic blood pressure

Summary Background Angiotensin II type 1 receptor blockers have favourable effects on haemodynamic measurements, neurohumoral activity, and left-ventricular remodelling when added to angiotensin-converting-enzyme (ACE) inhibitors in patients with chronic heart failure (CHF). We aimed to find out whether these drugs improve clinical outcome. Methods Between March, 1999, and November, 1999, we enrolled 2548 patients with New York Heart Association functional class II–IV CHF and left-ventricular ejection fraction 40% or lower, and who were being treated with ACE inhibitors. We randomly assigned patients candesartan (n=1276, target dose 32 mg once daily) or placebo (n=1272). At baseline, 55% of patients were also treated with β blockers and 17% with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for CHF. Analysis was done by intention to treat. Findings The median follow-up was 41 months. 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0·85 [95% CI 0·75–0·96], p=0·011; covariate adjusted p=0·010). Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for CHF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline β blocker treatment. Interpretation The addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction. Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7417web.pdf

Summary Background Half of patients with chronic heart failure (CHF) have preserved left-ventricular ejection fraction (LVEF), but few treatments have specifically been assessed in such patients. In previous studies of patients with CHF and low LVEF or vascular disease and preserved LVEF, inhibition of the renin-angiotensin system is beneficial. We investigated the effect of addition of an angiotensin-receptor blocker to current treatments. Methods Between March, 1999, and July, 2000, we randomly assigned 3023 patients candesartan (n=1514, target dose 32 mg once daily) or matching placebo (n=1509). Patients had New York Heart Association functional class II–IV CHF and LVEF higher than 40%. The primary outcome was cardiovascular death or admission to hospital for CHF. Anaysis was done by intention to treat. Findings Median follow-up was 36·6 months. 333 (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted hazard ratio 0·89 [95% Cl 0·77–1·03], p=0·118; covariate adjusted 0·86 [0·74–1·0], p=0·051). Cardiovascular death did not differ between groups (170 vs 170), but fewer patients in the candesartan group than in the placebo group were admitted to hospital for CHF once (230 vs 279, p=0·017) or multiple times. Composite outcomes that included non-fatal myocardial infarction and non-fatal stroke showed similar results to the primary composite (388 vs 429; unadjusted 0·88 [0·77–1·01], p=0·078; covariate adjusted 0·86 [0·75–0·99], p=0·037). Interpretation Candesartan has a moderate impact in preventing admissions for CHF among patients who have heart failure and LVEF higher than 40%. Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7419web.pdf

Background: Chronic heart failure (CHF) is an increasing burden to health care. Pharmacological treatment with angiotensin-converting enzyme (ACE) inhibitors and beta blockers improve survival and reduce hospitalizations in patients with low left ventricular ejection fraction (LVEF). Despite these therapies, morbidity and mortality remains problematic. Furthermore, 30% to 50% of patients with CHF have a preserved LVEF. It is not known if treatments are of benefit in this group. Design: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) is a program designed to investigate the clinical usefulness of the long-acting angiotensin II type 1 receptor blocker, candesartan cilexetil, in a broad spectrum of patients with symptomatic heart failure. Patients with systolic dysfunction, tolerant or intolerant to an ACE-inhibitor, and patients with preserved systolic function are included. Specifically, the CHARM program consists of 3 independent, parallel, placebo-controlled studies in patients with (1) LVEF less than or equal to 40%, ACE-inhibitor treated (n = 2,300); (2) LVEF less than or equal to 40%, ACE-inhibitor intolerant (n = 1,700); (3) LVEF greater than 40%, not treated with ACE inhibitors (n = 2,500). The 3 studies will be combined to evaluate the effect of candesartan cilexetil on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization. Other endpoints include the effects on myocardial infarction, all-cause hospitalization, and resource utilization. CHARM is intended to randomize 6,500 patients with symptomatic heart failure from 26 countries in Europe, the United States, Canada, South Africa, and Australia. The CHARM program started to enroll patients in March 1999. The follow-up period is a minimum of 2 years. The study is expected to end in the third quarter of 2002.

12 healthy male volunteers participated in this open, randomised, crossover study. On 2 study days at least 6 days apart the volunteers were given a single oral dose of lansoprazole 30mg with or without a standardised breakfast. When lansoprazole was concomitantly given with breakfast, the peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) were decreased by approximately 50% for each of the two parameters. The time to reach Cmax (tmax) was doubled when lansoprazole was coadministered with breakfast. In conclusion, lansoprazole should not be taken concomitantly with food.

Central nervous system (CNS)-related symptoms and quality of life during treatment with controlled-release (CR) metoprolol and a standard formulation of atenolol were compared in a double-blind crossover study in 60 patients with mild to moderate hypertension. After a 4-week placebo run-in period, each beta 1-adrenoceptor blocker was administered at a dosage of 100 mg once daily for 6 weeks. Quality of life was assessed regularly during the active treatment phases by use of two standardized self-administered questionnaires, the minor symptom evaluation (MSE) profile, and the psychologic general well-being (PGWB) index. Both questionnaires have previously been shown to be effective in detecting CNS symptoms and changes in well being produced by beta-blockers. Blood pressure and heart rate were monitored to assess the antihypertensive efficacy of the two drugs. Metoprolol CR and atenolol produced equivalent, clinically effective reductions in systolic and diastolic blood pressures measured 24 hours after administration. The drugs were found to exert similar effects on general well being, as assessed by the PGWB index, and there were no significant differences between the two treatments with regard to the three dimensions of the MSE profile, contentment, vitality, and sleep. Thus, at equivalent antihypertensive dosages, metoprolol CR and atenolol are clinically comparable with regard to the degree of CNS-related symptoms produced and effects on general well being. Because these agents differ markedly in lipophilicity, other factors, such as beta 1-selectivity/nonselectivity, may be more important determinants of whether these subjective symptoms occur during therapy with beta-blockers.

Results from three double-blind, randomized, placebo-controlled studies on the treatment of mild-to-moderate hypertension with a low dose (50 mg) of controlled-release metoprolol (CR/ZOK) were pooled and analyzed to increase sample size and thereby improve the reliability and strengthen the statistical analysis of the studies. All three studies had almost identical designs. Systolic and diastolic blood pressures and heart rate were measured in the supine and standing positions 24 hours after dosing during 4 or 6 weeks of treatment with metoprolol CR/ZOK 50 mg or placebo. Analysis of the pooled results showed significant changes between treatment with metoprolol CR/ZOK 50 mg in relation to placebo in supine systolic and diastolic blood pressures (−8.4 mmHg, P P P P P P

Steady-state bioavailability and day-to-day variability of plasma levels were evaluated in 18 healthy male subjects in a crossover study of multiple once-daily administration of two novel oral drug delivery systems of metoprolol and an immediate-release tablet (100 mg metoprolol tartrate). Data were collected over two consecutive 24-hr dosing intervals on treatment days 6 and 7. The two extended-release formulations investigated were metoprolol CR/ZOK (95 mg metoprolol succinate), a multiple-unit system consisting of several hundred membrane-coated delivery units, and metoprolol OROS (95 mg metoprolol fumarate), a single-unit osmotic delivery system. The extended drug release and absorption observed after administration of metoprolol CR/ZOK and metoprolol OROS resulted in similar steady-state plasma concentrations after once-daily dosing. Compared to the immediate-release tablet, they produced considerably lower plasma peaks, three- to fourfold higher trough concentrations, 8–9 hr longer mean residence times, and 20% lower relative bioavailability. Moreover, the two once-daily metoprolol products were found bioequivalent in C max and AUC based on 90% confidence intervals for the mean ratio CR/OROS. Repeated plasma concentration measurements on two consecutive 24-hr periods suggested that all three metoprolol treatments produced reproducible and consistent plasma concentrations from day to day at steady state. Assessment of day-to-day variability, however, resulted in significantly lower variation in AUC for the multiple-unit CR/ZOK formulation compared to the single-unit OROS tablet. These results imply that there may be formulation-related differences in the in vivo behavior of the two products despite their being bioequivalent in extent and rate of absorption.

To describe the antihypertensive dose-response of combination therapy with candesartan and hydrochlorothiazide (HCT).Data from 4632 men and women (sex ratio 1:1, mean age 54 years) with mild to moderate hypertension, who participated in one of seven randomized, double-blind, placebo-controlled studies with candesartan-HCT for 8-12 weeks, were entered in a common database. The daily dose of candesartan ranged from 2 to 32 mg, and that of HCT from 6.25 to 25mg. An E(max) model was used to describe the placebo-adjusted dose-response surface for systolic and diastolic blood pressure (BP) reductions.The BP reduction increased with increasing doses of candesartan and HCT, ranging from 5.9 to 17.4 mmHg systolic, and from 2.8 to 10.2 mmHg diastolic with combination therapy. As these figures represent pure drug effects, the effect observed in placebo treated patients (mean reduction 6.0/5.6 mmHg) should be added to estimate the average BP reduction in the usual clinical setting. The reduction with candesartan-HCT represented fully additive contributions of the components.The effect of candesartan-HCT is dose-related over a wide range of doses, and the effects of the components are fully additive. This analysis provides guidance for dosing.

Four studies using different daily doses (100 mg, 200 mg, 300 mg and 400 mg) have examined the bioequivalence of the once daily formulation metoprolol CR/ZOK and conventional metoprolol tablets (CT). These studies showed metoprolol CR/ZOK to have a similar beta 1-blocking activity to metoprolol CT but that the bioavailability of the new formulation was lower. This paper presents the analysis of data from all four studies, looking at the relationship between plasma concentrations and beta 1-blockade measured as reduction of exercise induced tachycardia. The log linear pharmacodynamic model was used for each of the four doses to compare the two formulations. Mean slopes and intercepts in the linear regression analysis of log plasma concentration of metoprolol versus beta 1-blockade did not differ significantly between CR/ZOK and CT in any of the four studies. After having shown lack of influence of the absorption rate of the plasma concentration-effect relationship, data for CR/ZOK and CT formulations from the 200 mg study were pooled for each individual subject and fitted to an Emax model. The maximal beta 1-blocking effect (Emax) was 28% (95% confidence interval: 25-31%) and the plasma concentration for obtaining 50% of Emax (C50) was 105 nmol/L (95% confidence interval: 74-135 nmol/L). The plasma concentration-effect data from the 100 mg, 300 mg and 400 mg studies were reasonably well within the 95% prediction interval based on the 200 mg study, which showed the validity of the obtained relationship.(ABSTRACT TRUNCATED AT 250 WORDS)

Four studies of identical design, each on 18 young healthy subjects, were undertaken to study the pharmacokinetics and beta 1-receptor blockade at steady state after a once daily dose (od) of 100, 200, 300 and 400 mg of metoprolol CR/ZOK (a new controlled release preparation) in comparison with 100 mg dosages (od, bid, tid and qid, respectively) of conventional metoprolol tablets (CT). All studies were of randomized three-way crossover design with 7-day double-blind treatment periods separated by 7-day single-blind washout periods. A number of predose plasma concentrations and assessments of beta 1-blockade were made during the study and a full pharmacokinetic and pharmacodynamic study was performed on day 7. The maximal plasma concentration, Cmax, was significantly lower after metoprolol CR/ZOK compared to CT after all doses--the most pronounced difference being observed after the 100 mg dose when both preparations were given once daily (145 nmol/L vs 606 nmol/L) and the least difference after the 400 mg dose when metoprolol CT was given every 6 hours (837 nmol/L vs 1111 nmol/L). The maximal plasma concentration occurred later after metoprolol CR/ZOK than CT in all studies (median 2.5-4.1 hours vs 1.0-1.2 hours). The trough plasma concentration, Cmin, was significantly higher after 100 mg metoprolol CR/ZOK compared to CT dosed once daily; CminS were comparable between the two preparations in the 200 mg and 300 mg studies and lower after metoprolol CR/ZOK in the 400 mg study (278 nmol/L vs 469 nmol/L). In all four studies the AUCs were significantly lower after metoprolol CR/ZOK compared to CT with the mean relative bioavailability being approximately similar (73-84%). All metoprolol treatments produced a statistically significant beta 1-blockade (measured as percent reduction of exercise induced tachycardia) throughout the whole day compared to placebo except in the 100 mg study where the effect of once daily CT did not differ from placebo during the last 6 hours. Consequently, a significantly higher beta 1-blockade was observed after metoprolol CR/ZOK compared to CT in this latter period. The maximum beta 1-blockade (Emax) after CR/ZOK 100 mg was significantly lower than after CT 100 mg once daily (12.6% vs 23.3%) but when CT was given in divided doses from 200 to 400 mg daily, Emax did not differ between the two formulations. Once daily administration of 100 mg of both products resulted in a significantly higher beta 1-blockade 24 hours after dosing with CR/ZOK compared to CT, but when CT was taken in divided doses this difference between the treatments was less pronounced.(ABSTRACT TRUNCATED AT 400 WORDS)

Background: The efficacy and safety of adding an angiotensin receptor blocker (ARB) in heart failure (HF) patients already taking an angiotensin-converting enzyme-inhibitor (ACE-I) plus an aldosterone antagonist is uncertain (especially if taking a beta blocker as well). The CHARM-Added trial describes the largest experience of using multiple inhibitors of the renin–angiotensin–aldosterone system (RAAS) together. Methods and results: 2548 HF patients, taking an ACE-I (936 no spironolactone/no beta blocker; 1175 no spironolactone/beta blocker; 199 spironolactone/no beta blocker; 238 sprionolactone/beta blocker), were randomized to placebo or candesartan and followed for 41 months (median). The primary outcome was cardiovascular death or HF hospitalization. In patients taking both a beta blocker and spironolactone (in addition to an ACE-I) at baseline, the candesartan:placebo hazard ratio was 0.85(95% CI 0.56, 1.29), compared to 0.85(95% CI 0.75, 0.96) in all randomized patients (interaction p value 0.49). The relative risk of discontinuation of candesartan (compared to placebo) because of hypotension, increased serum creatinine or hyperkalemia was not increased in patients taking spironolactone at baseline. Conclusions: An ARB may provide added benefit, at acceptable risk, in HF patients already taking spironolactone as well as an ACE-I and beta blocker. These findings must be confirmed in a prospective randomized trial before this approach can be recommended, routinely.

Chronic heart failure (CHF) is an important cause of hospital admission and death. Poor adherence to medication is common in some chronic illnesses and might reduce the population effectiveness of proven treatments. Because little is known about adherence in patients with CHF and about the consequences of non-adherence, we assessed the association between adherence and clinical outcome in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme.CHARM was a double-blind, randomised, controlled clinical trial, comparing the effects of the angiotensin receptor blocker candesartan with placebo in 7599 patients with CHF. Median follow-up was 38 months. The proportion of time patients took more than 80% of their study medication was defined as good adherence and 80% or less as poor adherence. We used a Cox proportional hazards regression model, with adherence as a time-dependent covariate in the model, to examine the association between adherence and mortality in the candesartan and placebo groups.We excluded 187 patients because of missing information on adherence. In the time-dependent Cox regression model, after adjustment for predictive factors (demographics, physiological and severity-of-illness variables, smoking history, and number of concomitant medications), good adherence was associated with lower all-cause mortality in all patients (hazard ratio [HR] 0.65, 95% CI 0.57-0.75, p0.0001). The adjusted HR for good adherence was similar in the candesartan (0.66, 0.55-0.81, p0.0001) and placebo (0.64, 0.53-0.78, p0.0001) groups.Good adherence to medication is associated with a lower risk of death than poor adherence in patients with CHF, irrespective of assigned treatment. This finding suggests that adherence is a marker for adherence to effective treatments other than study medications, or to other adherence behaviours that affect outcome. Understanding these factors could provide an opportunity for new interventions, including those aimed at improving adherence.

Aims To evaluate the effect of the angiotensin receptor blocker candesartan on patients' perception of symptoms, using the McMaster Overall treatment evaluation (OTE), in a broad spectrum of patients with chronic heart failure (CHF). Methods and results Patients with symptomatic CHF, randomised in the CHARM Programme in North America (n=2498), were studied. OTE was assessed at baseline, at 6, 14 and 26 months and the patient's final or closing visit. Patient's status was classified as “improved (score +1 to +7)”, “unchanged (score 0)” or “deteriorated (score–1 to –7)” at the end of the study compared to baseline. Both a simple “last visit carried forward” (LVCF) analysis and “worst rank carried forward” (WRCF) analysis (where patients who died were allocated the worst OTE score) were used. In the LVCF analysis, compared to placebo, more candesartan patients improved (37.7% versus 33.5%) and fewer worsened (10.8% versus 12.0%) in OTE (p=0.017). The WRCF analysis also showed better overall OTE scores with candesartan compared to placebo (p=0.029). There was no heterogeneity in the response to candesartan between the CHARM component trials or across four exploratory sub-groups (age, sex, NYHA class and beta-blocker). Conclusions Candesartan was shown to be better than placebo, when using the McMaster OTE to measure patient perception of treatment. More patients treated with candesartan reported improvement and fewer reported deterioration. This benefit was obtained when candesartan was added to extensive background therapy and is consistent with the benefits of candesartan on NYHA class, hospital admission for worsening heart failure and mortality.

The Study on COgnition and Prognosis in the Elderly (SCOPE) was a multinational, randomised, double-blind study to assess the effects of candesartan 8-16 mg daily on cardiovascular events and cognitive function in elderly patients (aged 70-89 years) with mild to moderate hypertension. A total of 4937 patients were randomised to candesartan or placebo with other antihypertensive drugs (mostly diuretics, beta-blockers, and calcium antagonists) added as needed to control blood pressure. Only 16% of the patients in the control group received placebo alone. The mean follow-up was 3.7 years. The aim of this health-related quality of life (HRQL) substudy analysis was to investigate changes in HRQL during antihypertensive treatment, and possible differences in patients receiving candesartan-based or other antihypertensive treatment. Three validated HRQL instruments were used: the Psychological General Well-being (PGWB) Index, the Subjective Symptoms Assessment Profile (SSA-P), and the EuroQoL Health Utility Index (EuroQoL). The HRQL was generally good at baseline and well preserved during follow-up in the presence of substantial blood pressure reductions in both treatment groups. Several of the observed changes in score from baseline to last visit favoured candesartan-based compared to control treatment, particularly the changes in PGWB Anxiety (-0.5 vs -1.0, P=0.01), PGWB Positive well-being (-0.8 vs -1.1, P=0.04), SSA-P Cardiac symptoms (0.03 vs 0.10, P=0.03), and EuroQoL Current health (-3.1 vs -5.3, P=0.008). This favourable result may be related to the somewhat lower blood pressure associated with candesartan-based treatment. In conclusion, there should be no reason to withhold modern antihypertensive therapy in elderly patients due to concerns for a negative effect on HRQL.

Patients with chronic heart failure (CHF) are at high risk of cardiovascular death and recurrent hospital admissions. We aimed to find out whether the use of an angiotensin-receptor blocker could reduce mortality and morbidity.In parallel, randomised, double-blind, controlled, clinical trials we compared candesartan with placebo in three distinct populations. We studied patients with left-ventricular ejection fraction (LVEF) 40% or less who were not receiving angiotensin-converting-enzyme inhibitors because of previous intolerance or who were currently receiving angiotensin-converting-enzyme inhibitors, and patients with LVEF higher than 40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg once daily) or matching placebo (n=3796), and followed up for at least 2 years. The primary outcome of the overall programme was all-cause mortality, and for all the component trials was cardiovascular death or hospital admission for CHF. Analysis was by intention to treat.Median follow-up was 37.7 months. 886 (23%) patients in the candesartan and 945 (25%) in the placebo group died (unadjusted hazard ratio 0.91 [95% CI 0.83-1.00], p=0.055; covariate adjusted 0.90 [0.82-0.99], p=0.032), with fewer cardiovascular deaths (691 [18%] vs 769 [20%], unadjusted 0.88 [0.79-0.97], p=0.012; covariate adjusted 0.87 [0.78-0.96], p=0.006) and hospital admissions for CHF (757 [20%] vs 918 [24%], p0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalaemia.Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for heart failure. Ejection fraction or treatment at baseline did not alter these effects.

Aims: To describe the clinical characteristics and contemporary treatment of a broad spectrum of patients with chronic heart failure (CHF) randomised in the Candesartan in Heart failure—Assessment of Reduction in Mortality and morbidity (CHARM) programme, consisting of three component studies comparing placebo to candesartan. Methods and results: CHARM Alternative, CHARM Added and CHARM Preserved enrolled 2028 low left ventricular ejection fraction (LVEF) ACE inhibitor intolerant patients, 2548 low LVEF ACE inhibitor treated patients and 3025 preserved LVEF patients, respectively. Patients in CHARM Preserved were more often female. The proportion of women in CHARM Preserved was 40% compared to 32% in CHARM Alternative and 21% in CHARM Added. Patients in CHARM Preserved were also more often hypertensive than in the other two trials (64% vs. 50% and 48%, respectively). Symptoms and signs (with the exception of a third heart sound) were similar in all three patient groups. Beta-blockers were used in over half of patients in all three groups. Digoxin and spironolactone were used less frequently and calcium antagonists more frequently in CHARM Preserved. Spironolactone was used most frequently in CHARM Alternative, i.e. in ACE inhibitor intolerant patients. Conclusions: The CHARM Programme provides the largest and most detailed comparison to date of patients low- and preserved-LVEF CHF. It also describes the causes of ACE-inhibitor intolerance in a large cohort of patients and the other treatment which these patients receive.

The relationships between dose and antihypertensive effect of the first four available AT1-receptor blockers. i.e. losartan, valsartan, irbesartan and candesartan, were assessed based on data obtained from the FDA's evaluation reports of the respective New Drug Application files. All available randomized, double-blind, placebo-controlled, parallel-group studies in adult men and women with mild to moderate primary diastolic hypertension were included, provided that the reduction in trough (24 h post-dose) supine or sitting diastolic blood pressure (DBP) had been assessed using the intention-to-treat approach. All studies had an initial single-blind placebo run-in period followed by at least 4 weeks double-blind treatment. The selected studies were included in a meta-analysis of the dose-response relationship for each drug. The dose-response relationship was estimated by fitting the placebo-adjusted, weighted mean reductions in DBP for each dose of the drug to an Emax model. The Emax (maximal effect at an infinitely large dose) for the reduction in DBP, with corresponding 95% confidence intervals in brackets, were found to be 5.6 (3.6-7.5) mmHg for losartan, 5.8 (5.0-6.6) mmHg for valsartan, 6.9 (5.9-7.9) mmHg for irbesartan and 7.5 (6.1-8.9) mmHg for candesartan (p = 0.014, candesartan vs valsartan). In conclusion, this investigation demonstrates that candesartan can reduce DBP significantly more than valsartan, and is supportive of previous head-to-head comparisons, which have proven candesartan to have a greater antihypertensive effect than losartan at recommended doses. Thus, differences in efficacy between different AT1-receptor blockers do exist, and should have implications for the choice of AT1-receptor blocker when treating patients with hypertension, considering the importance of good blood pressure control.

The Study on COgnition and Prognosis in the Elderly (SCOPE) is a multicentre, prospective, randomized, double-blind, parallel-group study designed to compare the effects of candesartan cilexetil and placebo in elderly patients with mild hypertension. The primary objective of the study is to assess the effect of candesartan cilexetil on major cardiovascular events. The secondary objectives of the study are to assess the effect of candesartan cilexetil on cognitive function and on total mortality, cardiovascular mortality, myocardial infarction, stroke, renal function, hospitalization, quality of life and health economics. Male and female patients aged between 70 and 89 years, with a sitting systolic blood pressure (SBP) of 160-179 mmHg and/or diastolic blood pressure (DBP) of 90-99 mmHg, and a Mini-Mental State Examination (MMSE) score of 24 or above, are eligible for the study. The overall target study population is 4000 patients, at least 1000 of whom are also to be assessed for quality of life and health economics data. After an open run-in period lasting 1-3 months, during which patients are assessed for eligibility and those who are already on antihypertensive therapy at enrolment are switched to hydrochlorothiazide 12.5 mg o.d., patients are randomized to receive either candesartan cilexetil 8 mg once daily (o.d.) or matching placebo o.d. At subsequent study visits, if SBP remains160 mmHg, or has decreased by10 mmHg since the randomization visit, or DBP is85 mmHg, study treatment is doubled to candesartan cilexetil 16 mg o.d. or two placebo tablets o.d. Recruitment was completed in January 1999. At that time 4964 patients had been randomized. All randomized patients will be followed for an additional 2 years. If the event rate is lower than anticipated, the follow-up will be prolonged.

In this steady state, cross-over study, the bioavailability and beta 1-blocking effects of metoprolol CR/ZOK 50 mg, conventional metoprolol 50 mg tablets and placebo were evaluated in 12 healthy male subjects (mean age 25 years) after once daily treatment in 5 days. The drugs were administered in a randomized order. The beta 1-blocking effect was defined as percent reduction from baseline in exercise heart rate. The plasma concentration-time profile following metoprolol CR/ZOK 50 mg administration was more even compared to conventional metoprolol tablets, with significantly lower Cmax (mean: 71 vs 221 nmol/L) and significantly higher Cmin (mean: 39 vs 6 nmol/L) for the CR/ZOK formulation. This difference in plasma concentrations was also well reflected by a significantly lower fluctuation index for metoprolol CR/ZOK 50 mg compared with the conventional 50 mg tablet (mean: 69 vs 529%). There was, however, no difference in systemic bioavailability between the two metoprolol formulations (90% confidence limits: 86-106%). The beta 1-blockade was also more even after metoprolol CR/ZOK 50 mg compared to conventional tablets with a significantly lower Emax (mean: 14 vs 19%) and higher Emin (mean: 9 vs 0%) for CR/ZOK. The total effect over a dosage interval, defined as area under the effect curve, was significantly higher for metoprolol CR/ZOK compared to conventional tablets (90% confidence limits: 123-213%). In conclusion, once daily administration of metoprolol CR/ZOK 50 mg to young healthy subjects resulted in smooth plasma concentration and produced a significant beta 1-blocking effect for 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term ambulatory Holter-monitoring was used to evaluate the arrhythmogenic effects of beta 2 -agonist therapy, alone and in combination with a xanthine derivative, theophylline or enprofylline. Twenty patients (mean age 51 years) with mild-to-moderate obstructive lung disease (bronchial asthma or chronic bronchitis), but without concomitant ischemic heart disease were studied. Compared with beta 2 -agonist therapy alone, both combined regimens were associated with a small but significant increase in the frequency of ventricular arrhythmias. Few serious arrhythmias were observed, however, and the clinical significance of these findings is thought to be minor. Although adenosine has been suggested to have an antiarrhythmic effect, a difference between theophylline and enprofylline in the effect on adenosine (theophylline but not enprofylline being an adenosine antagonist) would appear to be of less cardiac relevance in patients without ischemic heart disease.

Twenty-four patients (five women) aged 53-72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline (600 mg daily), enprofylline (600 mg daily) or placebo. The study was double-blind, randomized, triple-crossover with each regimen given for two weeks. Holter monitoring was used during 48 consecutive hours in each period. Compared with placebo, addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm (p less than 0.001). A small, but statistically significant (p less than 0.05) increase in mean hourly frequency of premature ventricular beats (PVBs) occurred with enprofylline as compared with placebo. However, in only two patients with enprofylline (and one patient with theophylline) the increase in PVBs was such that a clinically relevant proarrhythmic effect seems possible. Furthermore, ventricular tachycardia was not more frequently observed with any xanthine than with placebo. Thus, combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease. Holter monitoring is recommended to assess the individual patient's response to such therapy.

1. Titrations of wool with hydrochloric acid in the presence of sodium chloride, sodium sulphate, potassium chloride, potassium sulphate, and barium chloride, and with sulphuric acid in the presence of sodium chloride and sodium sulphate, have been performed, the absorption of hydrogen, chloride, and sulphate ions being determined. 2. The presence of sulphate ions always gives greater absorption of hydrogen ions than does that of chloride ions. 3. A critical review of absorption theories is given, as regards their value for interpreting the experimental results. 4. Both the Gilbert-Rideal and the theories are used for accurate comparison with the experiments; the former gives quite satisfactory results, but the latter gives only qualitative agreement. 5. It is concluded that chloride and sulphate ions are not dispersed at random in the fibre phase, but are to some extent localized at positive sites, the former having greater affinity for the wool fibre than the latter ions.