Candesartan In Heart Failure: Assessment Of Reduction In Mortality Research Articles

Performance of Prognostic Risk Scores in Chronic Heart Failure Patients Enrolled in the European Society of Cardiology Heart Failure Long-Term Registry

ObjectivesThis study compared the performance of major heart failure (HF) risk models in predicting mortality and examined their utilization using data from a contemporary multinational registry. BackgroundSeveral prognostic risk scores have been developed for ambulatory HF patients, but their precision is still inadequate and their use limited. MethodsThis registry enrolled patients with HF seen in participating European centers between May 2011 and April 2013. The following scores designed to estimate 1- to 2-year all-cause mortality were calculated in each participant: CHARM (Candesartan in Heart Failure-Assessment of Reduction in Mortality), GISSI-HF (Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure), MAGGIC (Meta-analysis Global Group in Chronic Heart Failure), and SHFM (Seattle Heart Failure Model). Patients with hospitalized HF (n = 6,920) and ambulatory HF patients missing any variable needed to estimate each score (n = 3,267) were excluded, leaving a final sample of 6,161 patients. ResultsAt 1-year follow-up, 5,653 of 6,161 patients (91.8%) were alive. The observed-to-predicted survival ratios (CHARM: 1.10, GISSI-HF: 1.08, MAGGIC: 1.03, and SHFM: 0.98) suggested some overestimation of mortality by all scores except the SHFM. Overprediction occurred steadily across levels of risk using both the CHARM and the GISSI-HF, whereas the SHFM underpredicted mortality in all risk groups except the highest. The MAGGIC showed the best overall accuracy (area under the curve [AUC] = 0.743), similar to the GISSI-HF (AUC = 0.739; p = 0.419) but better than the CHARM (AUC = 0.729; p = 0.068) and particularly better than the SHFM (AUC = 0.714; p = 0.018). Less than 1% of patients received a prognostic estimate from their enrolling physician. ConclusionsPerformance of prognostic risk scores is still limited and physicians are reluctant to use them in daily practice. The need for contemporary, more precise prognostic tools should be considered.

Behavioral changes after cardiovascular events: A cohort study

J 2012, doi:10.1093/eurheartj/ehs092. [14] Shewan LG, Coats AJ. Ethics in the authorship and publishing of scientific articles. Int J Cardiol 2010;144:1–2. [15] O Hartaigh B, Bosch JA, Pilz S, et al. Influence of resting heart rate on mortality in patients undergoing coronary angiography (from the Ludwigshafen Risk and Cardiovascular Health [LURIC] Study). Am J Cardiol May 12 2012 [Epub ahead of print], http://dx.doi.org/10.1016/j.amjcard.2012.03.050. [16] Julius S, Palatini P, Kjeldsen SE, et al. Usefulness of heart rate to predict cardiac events in treated patients with high-risk systemic hypertension. Am J Cardiol 2012;1:109:685–92. [17] Castagno D, Skali H, Takeuchi M, et al. CHARM investigators Association of Heart Rate and Outcomes in a Broad Spectrum of Patients With Chronic Heart Failure: results from the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) Program. J Am Coll Cardiol 2012;59:1785–95.

Association of Heart Rate and Outcomes in a Broad Spectrum of Patients With Chronic Heart Failure: Results From the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity) Program

The aim of this study was to explore the relationship between baseline resting heart rate and outcomes in patients with chronic heart failure (HF) according to baseline left ventricular ejection fraction (LVEF) and cardiac rhythm. Elevated resting heart rate is associated with worse outcomes in patients with HF and reduced LVEF. Whether this association is also found in patients with HF and preserved LVEF is uncertain, as is the predictive value of heart rate in patients in atrial fibrillation (AF). Patients enrolled in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program were divided into groups by tertiles of baseline heart rate. Cox proportional hazard models were used to investigate the association between heart rate and pre-specified outcomes in the overall population as well as in subgroups defined according to LVEF (≤ 40% vs. >40%) and presence (or absence) of AF at baseline. After adjusting for predictors of poor prognosis, patients in the highest heart rate tertile had worse outcomes when compared with those in the lowest heart rate group (e.g., for the composite of cardiovascular death or HF hospital stay hazard ratio: 1.23, 95% confidence interval: 1.11 to 1.36, p < 0.001). The relationship between heart rate and outcomes was similar across LVEF categories and was not influenced by beta-blocker use (p value for interaction >0.10 for both endpoints). However, amongst patients in AF at baseline, heart rate had no predictive value (p value for interaction <0.001). Resting heart rate is an important predictor of outcome in patients with stable chronic HF without AF, regardless of LVEF or beta-blocker use.

The vanishing story of angiotensin II receptor blockers in the treatment of atrial fibrillation

This editorial refers to ‘Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II Study)’ by T. Yamashita et al. , on page 473. Pharmacological inhibition of the renin–angiotensin system (RAS) is a safe and beneficial intervention in patients with structural heart disease. Furthermore, there is good experimental evidence that AT-1 receptor blocker (ARB) therapy can prevent atrial structural remodelling in atrial fibrillation (AF).1–4 Experiments have proved that by angiotensin-converting enzyme (ACE) inhibitors and ARBs, the degree of atrial fibrosis and thereby the inducibility of AF can be reduced.2–4 In these settings, ACE inhibitors and ARBs were similarly effective. Of note, antiarrhythmic effects of ACE inhibitors and ARBs to prevent AF are supported by retrospective analyses of clinical trials including TRACE (Trandolapril Cardiac Evaluation), ValHeFT (Valsartan Heart Failure Trial), SOLVD (Studies of Left Ventricular Dysfunction), CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity), and LIFE (Losartan Intervention For Endpoint reduction in hypertension).1,5 Given the observation that AF induces atrial fibrosis and contributes to electrophysiological changes, ARBs appear as a reasonable and safe additive antiarrhythmic therapy in AF, which is supported by recent meta-analyses.1,5 Yamashita et al .6 present the important data of J-RHYTHM II (Japanese Rhythm Management Trial II for Atrial …

Clinical Outcomes According to Baseline Blood Pressure in Patients With a Low Ejection Fraction in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) Program

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) (<or=0.40) in the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) program. 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. The interaction between treatment and baseline systolic blood pressure (SBP) and diastolic blood pressure (DBP) was examined with patients divided into 6 SBP categories (<or=100, 101 to 110, 111 to 120, 121 to 130, 131 to 140 and >or=141 mm Hg) and 4 DBP categories (<or=60, 61 to 70, 71 to 80 and >or=81 mm Hg). 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. 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.

Red Cell Distribution Width as a Novel Prognostic Marker in Heart Failure: Data From the CHARM Program and the Duke Databank

The goal of this study was to identify potentially novel laboratory markers of risk in chronic heart failure patients. Although a variety of prognostic markers have been described in heart failure, a systematic assessment of routine laboratory values has not been reported. All 2,679 symptomatic chronic heart failure patients from the North American CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity) program had a wide range of laboratory measures performed at a core facility, enabling us to assess the relationship between routine blood tests and outcomes using a Cox proportional hazards model. We then replicated our findings in a cohort of 2,140 heart failure patients from the Duke Databank. Among 36 laboratory values considered in the CHARM program, higher red cell distribution width (RDW) showed the greatest association with morbidity and mortality (adjusted hazard ratio 1.17 per 1-SD increase, p < 0.001). Higher RDW was among the most powerful overall predictors, with only age and cardiomegaly showing a better independent association with outcome. This finding was replicated in the Duke Databank, in which higher RDW was strongly associated with all-cause mortality (adjusted hazard ratio 1.29 per 1 SD, p < 0.001), second only to age as a predictor of outcome. In 2 large contemporary heart failure populations, RDW was found to be a very strong independent predictor of morbidity and mortality. Understanding how and why this marker is associated with outcome may provide novel insights into heart failure pathophysiology.

New Onset of Type 2 Diabetes Mellitus during Antihypertensive Therapy

Hypertension is a widely diffused clinical condition in the general population and it is often associated with people who are overweight (i.e. have abdominal adiposity) or obese and with metabolic syndrome. Evidence shows that hypertensive patients are at increased risk of developing type 2 diabetes mellitus (T2DM) since angiotensin II is involved in the pathogenesis of hypertension and insulin resistance, which are both the key components of metabolic syndrome. The preventive effect of renin-angiotensin system (RAS) inhibition on the development of T2DM could reflect the closely linked mechanisms of blood pressure and blood glucose homeostasis. Since hyperglycaemia is a consequence of insulin resistance and β-cell dysfunction, preventing T2DM by RAS inhibition may result from an improvement of β-cell function and/or an enhancement of insulin sensitivity, which are secondary to modifications in microcirculation and changes in ionic status. On the basis of this hypothesis, several trials in treating hypertensive patients have shown a positive effect of drugs inhibiting RAS in reducing the number of hypertensive patients that develop T2DM. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. We analysed the results of the following clinical studies that found a reduction in the incidence of new-onset T2DM in hypertensive patients using angiotensin II type 1 receptor blockers (ARBs): LIFE (Losartan Intervention For Endpoint reduction in hypertension) [losartan]; SCOPE (Study on COgnition and Prognosis in the Elderly) [candesartan]; ALPINE (Antihypertensive treatment and Lipid Profile In a North of Sweden Efficacy evaluation) [candesartan]; CHARM (Candesartan in Heart failure Assessment of Reduction in Mortality and morbidity) [candesartan]; and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) [valsartan]. Evidence shows that blood pressure reduction, when associated with lifestyle modifications (especially in high-risk patients), is more important than the mechanism of action of the antihypertensive drugs, which is to normalise blood pressure and thus reduce the incidence of cardiovascular events. In this regard, the identification of the potential influence of RAS inhibition in preventing new-onset T2DM in hypertensive subjects is a promising topic for the healthcare system. In the future, data from the ongoing trials, where prevention of diabetes is the primary endpoint, may prove to what extent this class of drugs is actually effective. However, in the previously mentioned clinical trials, the superior effectiveness of ARBs in preventing T2DM is associated with a lower efficacy in preventing cardiovascular events, because of their lesser capacity in lowering blood pressure. Evidence so far suggests the use of ARBs preferably in association with other classes of antihypertensive drugs and under a constant control of blood pressure. In this latter regard, in the recently published ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm) study, a combination therapy based on a drug inhibiting RAS (perindopril) and a calcium-channel blocker (amlodipine) significantly reduced the incidence of major cardiovascular events and new onset of diabetes in high-risk hypertensive patients, compared with a combination therapy based on thiazide diuretic and a β-blocker.

Adherence to candesartan and placebo and outcomes in chronic heart failure in the CHARM programme: double-blind, randomised, controlled clinical trial

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, p<0.0001). The adjusted HR for good adherence was similar in the candesartan (0.66, 0.55-0.81, p<0.0001) and placebo (0.64, 0.53-0.78, p<0.0001) 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.

Effects of Candesartan on the Development of a New Diagnosis of Diabetes Mellitus in Patients With Heart Failure

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: Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity Program). 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). The angiotensin receptor blocker candesartan appears to prevent diabetes in heart failure patients, suggesting that the renin-angiotensin axis is implicated in glucose regulation.

ACE Inhibitors in Heart Failure

ACE inhibitors have significantly decreased cardiovascular mortality, myocardial infarction (MI), and hospitalizations for heart failure (HF) in patients with asymptomatic or symptomatic left ventricular (LV) systolic dysfunction. Furthermore, the extended 12-year study of the SOLVD (Studies Of Left Ventricular Dysfunction) Prevention and Treatment trials (X-SOLVD) demonstrated a significant benefit with a reduction of cumulative all-cause death compared with placebo (50.9% vs 56.4%) [hazard ratio (HR) 0.86; 95% CI 0.79, 0.93; p < 0.001]. The survival benefits and significant reductions in cardiovascular morbidity related to treatment with ACE inhibitors are likely achieved by titrating the dose of ACE inhibitors to the target dose achieved in clinical trials. Although the ATLAS (Assessment of Treatment with Lisinopril And Survival) study, which randomly allocated HF patients to low- or high-dose lisinopril, showed no significant difference between groups for the primary outcome of all-cause mortality (HR 0.92; 95% CI 0.82, 1.03), the predetermined secondary combined outcome of all-cause mortality and HF hospitalization was reduced by 15% for the patients receiving high-dose lisinopril compared with low-dose (p < 0.001) with a 24% reduction in HF hospitalization (p = 0.002). Despite the use of ACE inhibitors, blockade of the renin angiotensin aldosterone system (RAAS) remains incomplete, with evidence of continued production of angiotensin II by non-ACE-dependent pathways. The safety and potential benefits of angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) in patients with impaired systolic function have been assessed in moderate to large clinical trials. In patients with impaired LV systolic function and HF, combination therapy with ARBs with recommended HF therapy including ACE inhibitors in patients who remain symptomatic may be considered for its morbidity benefit. Based on the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity)-Added data, candesartan cilexetil in addition to standard HF therapy results in a further reduction of cardiovascular mortality. Close monitoring of renal function and serum potassium levels is needed in this setting. The VALIANT (VALsartan In Acute myocardial iNfarction Trial) results suggest that valsartan is as effective as captopril in patients following an acute MI with HF and/or LV systolic dysfunction and may be used as an alternative treatment in ACE inhibitor-intolerant patients. There was no survival benefit with valsartan-captopril combination compared with captopril alone in this trial. Despite these results, ACE inhibitors remain the first-choice therapeutic agent in post-MI patients, and ARBs can be used in patients with clear intolerance. Although the use of ACE inhibitors may be appealing in patients with HF and preserved LV systolic function, there is currently no evidence from large clinical trials to support this.

Candesartan Cilexetil

Candesartan cilexetil is the orally administered pro-drug of candesartan, a highly selective antagonist of the angiotensin II subtype 1 receptor that mediates the pressor activities of angiotensin II. Candesartan cilexetil is widely used for the treatment of hypertension and has recently been approved in Europe for the treatment of chronic heart failure (CHF) in patients with impaired left ventricular (LV) systolic function. Results of the CHARM (Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity) programme suggest that oral candesartan cilexetil reduces morbidity and mortality in patients with CHF and LV ejection fraction (LVEF) < or =40%. There are cardiovascular benefits when candesartan cilexetil is administered as an alternative to an ACE inhibitor, or as an add-on to current treatment regimens that include an ACE inhibitor, in symptomatic CHF. While tolerability is generally good, renal monitoring is required. The recent approval of candesartan cilexetil as both add-on and alternative therapy to ACE inhibitors in patients with CHF and impaired LV systolic function recognises the cardiovascular benefits of candesartan cilexetil in both types of treatment regimens.

Cardiovascular News

Cardiovascular News

Exploring New Treatment Strategies in Heart Failure

Heart failure remains a major and increasing cause of mortality and morbidity, even when the best available treatments are used. One of its key causes is neuroendocrine activation via the sympathetic nervous system and the renin-angiotensin system (RAS). Neuroendocrine blockers of the sympathetic nervous system (beta-blockers) and of the RAS (angiotensin-converting enzyme [ACE] inhibitors and angiotensin II type 1 [AT 1 ] receptor blockers) therefore have an important potential therapeutic role in heart failure. The promising results from clinical trials with beta-blockers suggest that these drugs will become an established part of the future management of patients with mild to moderate symptomatic heart failure. Blockade of the RAS with ACE inhibitors has also been shown to be effective in reducing the risk of morbidity and mortality in patients with heart failure. Blockade of the AT1-receptor, with agents such as candesartan, produces more specific and, theoretically, more complete blockade of the major negative cardiovascular effects of angiotensin II than is possible using ACE inhibitors, whilst maintaining placebo-like tolerability. Furthermore, AT 1 -receptor blockade leads to increased stimulation of the angiotensin II type 2 (AT 2 ) receptor, which, according to experimental data, may have favourable cardiovascular effects. Following encouraging results from two pilot studies, a major new international study programme - CHARM (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) - has been initiated to define the clinical benefits of candesartan cilexetil in a wide variety of patients with symptomatic heart failure. CHARM is the first study to accept all relevant heart failure patients who may benefit from RAS blockade, irrespective of their left ventricular function or tolerance of ACE inhibitors. The 6500 patients to be recruited will be divided among three integrated outcome studies. Two of these studies will examine the effect of candesartan cilexetil versus placebo in patients with an ejection fraction of 40% or less who are tolerant or intolerant of ACE inhibitors. The third study arm will examine the benefits of candesartan cilexetil in a previously seldom studied group: those with symptomatic heart failure, but with preserved left-ventricular systolic function. Recruitment of patients into the study has started.