Summary Background Increased excretion of albumin in urine might be a marker of the various pathophysiological changes that arise in patients with heart failure. Therefore our aim was to assess the ...prevalence and prognostic value of a spot urinary albumin to creatinine ratio (UACR) in patients with heart failure. Methods UACR was measured at baseline and during follow-up of 2310 patients in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) Programme. The prevalence of microalbuminuria and macroalbuminuria, and the predictive value of UACR for the primary composite outcome of each CHARM study—ie, death from cardiovascular causes or admission to hospital with worsening heart failure—and death from any cause were assessed. Findings 1349 (58%) patients had a normal UACR, 704 (30%) had microalbuminuria, and 257 (11%) had macroalbuminuria. The prevalence of increased UACR was similar in patients with reduced and preserved left ventricular ejection fractions. Patients with an increased UACR were older, had more cardiovascular comorbidity, worse renal function, and a higher prevalence of diabetes mellitus than did those with normoalbuminuria. However, a high prevalence of increased UACR was still noted among patients without diabetes, hypertension, or renal dysfunction. Elevated UACR was associated with increased risk of the composite outcome and death even after adjustment for other prognostic variables including renal function, diabetes, and haemoglobin A1c . The adjusted hazard ratio (HR) for the composite outcome in patients with microalbuminuria versus normoalbuminuria was 1·43 (95% CI 1·21–1·69; p<0·0001) and for macroalbuminuria versus normoalbuminuria was 1·75 (1·39–2·20; p<0·0001). The adjusted values for death were 1·62 (1·32–1·99; p<0·0001) for microalbuminuria versus normoalbuminuria, and 1·76 (1·32–2·35; p=0·0001) for macroalbuminuria versus normoalbuminuria. Treatment with candesartan did not reduce or prevent the development of excessive excretion of urinary albumin. Interpretation Increased UACR is a powerful and independent predictor of prognosis in heart failure. Funding AstraZeneca.
Incidence and Predictors of Hyperkalemia in Patients With Heart Failure: An Analysis of the CHARM Program Akshay S. Desai, Karl Swedberg, John J. V. McMurray, Christopher B. Granger, Salim Yusuf, ...James B. Young, Mark E. Dunlap, Scott D. Solomon, James W. Hainer, Bertil Olofsson, Eric L. Michelson, Marc A. Pfeffer We examined the incidence and predictors of hyperkalemia in a broad population of patients with symptomatic heart failure enrolled in the CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity) Program. Independent of assignment to candesartan or placebo, the risk of hyperkalemia increased with advanced age, male gender, baseline hyperkalemia, renal failure, diabetes, and background use of angiotensin-converting enzyme inhibitors or spironolactone. Candesartan increased the observed rate of hyperkalemia in these subgroups but was associated with a consistent reduction in the risk of cardiovascular death or heart failure hospitalization. Although renin-angiotensin-aldosterone antagonists improve clinical outcomes in heart failure patients, careful surveillance of serum potassium and creatinine is essential.
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.
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.
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.
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.
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.
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.
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 indicates 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.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
BACKGROUNDThe prognostic benefits of blood pressure lowering treatment in elderly hypertensive patients were established more than a decade ago, but are less clear in those with mildly to moderately ...elevated blood pressure.
OBJECTIVETo assess whether candesartan-based antihypertensive treatment in elderly patients with mildly to moderately elevated blood pressure confers a reduction in cardiovascular events, cognitive decline and dementia.
DESIGNProspective, double-blind, randomized, parallel-group study conducted in 1997–2002.
SETTING AND PARTICIPANTSThe study was of 4964 patients aged 70–89 years, with systolic blood pressure 160–179 mmHg, and/or diastolic blood pressure 90–99 mmHg, and a Mini Mental State Examination (MMSE) test score ≥ 24. A total of 527 centres in 15 countries participated in the study.
INTERVENTIONPatients were assigned randomly to receive the angiotensin receptor blocker candesartan or placebo, with open-label active antihypertensive therapy added as needed. As a consequence, active antihypertensive therapy was extensively used in the control group (84% of patients). Mean follow-up was 3.7 years.
MAIN OUTCOME MEASURESThe primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction. Secondary outcome measures included cardiovascular death, non-fatal and fatal stroke and myocardial infarction, cognitive function measured by the MMSE and dementia.
RESULTSBlood pressure fell by 21.7/10.8 mmHg in the candesartan group and by 18.5/9.2 mmHg in the control group. A first major cardiovascular event occurred in 242 candesartan patients and in 268 control patients; risk reduction with candesartan was 10.9% 95% confidence interval (CI), −6.0 to 25.1, P = 0.19. Candesartan-based treatment reduced non-fatal stroke by 27.8% (95% CI, 1.3 to 47.2, P = 0.04), and all stroke by 23.6% (95% CI, −0.7 to 42.1, P = 0.056). There were no significant differences in myocardial infarction and cardiovascular mortality. Mean MMSE score fell from 28.5 to 28.0 in the candesartan group and from 28.5 to 27.9 in the control group (P = 0.20). The proportions of patients who had a significant cognitive decline or developed dementia were not different in the two treatment groups.
CONCLUSIONSIn elderly hypertensive patients, a slightly more effective blood pressure reduction during candesartan-based therapy, compared with control therapy, was associated with a modest, statistically non-significant, reduction in major cardiovascular events and with a marked reduction in non-fatal stroke. Cognitive function was well maintained in both treatment groups in the presence of substantial blood pressure reductions. Both treatment regimens were generally well tolerated.
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.
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.
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.
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
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.
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.
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).
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
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% Cl 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%, p<0·0001) 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.
Published online Sept 1, 2003 http://image.thelancet.com/extras/03art7416web.pdf
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