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Background beta-Blockers relieve angina/ischemia in stable coronary artery disease (CAD), and angiotensin-converting enzyme inhibitors prevent CAD outcomes. In EUROPA, the angiotensin-converting enzyme inhibitor perindopril reduced cardiovascular outcomes in low-risk stable CAD patients over 4.2 years. This post hoc analysis examined whether the addition of perindopril to beta-blocker in EUROPA had additional benefits on outcomes compared with standard therapy including beta-blocker. Methods EUROPA was a multicenter, double-blind, placebo-controlled, randomized trial in patients with documented stable CAD. Randomized EUROPA patients who received beta-blocker at baseline were identified, and the effect on cardiovascular outcomes of adding perindopril or placebo was analyzed. Endpoints were the same as those in EUROPA. Results At baseline, 62% (n = 7534 [3789 on perindopril and 3745 on placebo]) received beta-blocker. Treatment with perindopril/beta-blocker reduced the relative risk of the primary end point (cardiovascular death, nonfatal myocardial infarction, and resuscitated cardiac arrest) by 24% compared with placebo/beta-blocker (HR, 0.76; 95% CI, 0.64-0.91; P = .002). Addition of perindopril also reduced fatal or nonfatal myocardial infarction by 28% (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and hospitalization for heart failure by 45% (HR, 0.55; 95% CI, 0.33-0.93; P = .025). Serious adverse drug reactions were rare in both groups, and cardiovascular death and hospitalizations occurred less often with perindopril/beta-blocker. Conclusions The addition of perindopril to beta-blocker in stable CAD patients was safe and resulted in reductions in cardiovascular outcomes and mortality compared with standard therapy including beta-blocker.

Background: Angiotensin-converting-enzyme inhibition reduces the risk of cardiovascular events at a group level. Presumably, the absolute effect of treatment varies between individuals. We sought to develop multivariable prediction scores to estimate individual treatment effect of perindopril in patients with stable coronary artery disease (sCAD). Methods: In EUROPA trial participants, we estimated the individual patient 5-year absolute risk reduction (ARR) of major adverse cardiovascular events(MACE) by perindopril. Predictions were based on a new Coxproportional-hazards model with clinical characteristics and an external risk score in combination with the observed relative risk reduction. Second, a genetic profile modifying the relative efficacy of perindopril was added. The individual patient ARR was defined as the difference in MACE risk with and without treatment. The group level impact of selectively treating patients with the largest predicted treatment effect was evaluated using net benefit analysis. Results: The risk score combining clinical and genetic characteristics estimated the 5-year absolute treatment effect to be absent or adverse in 27% of patients. On the other hand, the risk score estimated a small 5-year ARR of = 50) in 20% of patients, a modest ARR of 2-4% (NNT5 25-50) in 26%, and a large ARR of >= 4% (NNT5

The clinical trials described in this article were presented at the Late Breaking Trials and the Clinical Science: Clinical Reports sessions of the American Heart Association Congress held in November 2010 in Chicago. The sessions and topics chosen for this article reflect the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses may be done, which could alter the final publication of the results of these studies. PROTECT (ProBNP Outpatient Tailored Chronic Heart Failure Therapy) was designed to test the hypothesis that adjustment of intensity of chronic heart failure (HF) therapy on the basis of NT-proBNP plasma level monitoring would improve outcomes. The results provided some support of this concept, but needs further evaluation in larger, blinded trials. REVEAL (Reduction of Infarct Expansion and Ventricular Remodeling with erythropoietin after large myocardial infarctions) evaluated in the clinical setting of ischemia-reperfusion following STEMI that erythropoietin could salvage ischemic myocardium. The results did not show a reduction in infarct size, but, in contrast, an increase in adverse event rates in the erythropoietin group. GRAVITAS (Gauging Responsiveness with a VerifyNow assay-Impact on Thrombosis and Safety trial) investigated the effect of a standard vs. high maintenance clopidogrel dose in patients with stable myocardial ischemia or NSTEMI and drug–eluting stent insertion. Patients with high PRU values as determined by VerfyNow assay were randomized to 75 mg or 150 mg clopidogrel daily. The study did not show a significant difference in primary event rate between both groups. The Cholesterol Treatment Trialists’ Collaboration Studies group evaluated the concept proposed in the JUPITER study that HDL levels on statin treatment may not provide useful prognostic information. The CTTC in a large sample size of statin-treated patients observed, on the contrary, a significantly increased risk of CV events, even in patients with low LDL cholesterol levels. DEFINE (Determining the Efficacy and Tolerability of CETP inhibition with Anacetrapib) evaluated possible safety aspects with the CETP inhibitor anacetrapib (increase in blood pressure). The study did not show adverse safety aspects, but significantly reduced LDL cholesterol and increased HDL cholesterol levels. ASSERT, a phase 2 dose–ranging study, investigated whether RVX-208 would increase Apo-A1 production. Apo-A1 may induce cholesterol efflux from macrophages and facilitate atherosclerosis regression. The study did not meet its primary endpoint, but significant prominent effects on lipids were found. ASCEND-HF was a large trial of nesiritide in >7000 patients with acute heart failure. The study did not show convincing symptom benefit, but on the other hand did not show harmful effects of nesiritide. EMPHASIS-HF evaluated the long term effects of eplerenone in patients with mild (NYHA class II) heart failure and systolic dysfunction. The study was prematurely ended because of highly significant beneficial effects. CUPID (Calcium Up-regulation by Percutaneous administration of gene therapy In cardiac Disease) is the first human study with gene transfer of SERCA2a (AVV1/SERCA2a: Mydicar). In a small placebo-controlled dose-ranging study in advanced heart failure patients a multiple endpoint analysis provided positive effects of the highest dose on symptomatic, functional and structural efficacy endpoints without adverse effects.

Most clinicians monitor blood pressure to estimate a patient's response to blood pressure-lowering therapy. However, the apparent change may not actually reflect the effect of the treatment, because a person's blood pressure varies considerably even without the administration of drug therapy. We estimated random background within-person variation, apparent between-person variation, and true between-person variation in blood pressure response to angiotensin-converting enzyme inhibitors after 3 months. We used meta-analytic mixed models to analyze individual patient data from 28 281 participants in 7 randomized, controlled trials from the Blood Pressure Lowering Trialists Collaboration. The apparent between-person variation in response was large, with SDs for change in systolic blood pressure/diastolic blood pressure of 15.2/8.5 mm Hg. Within-person variation was also large, with SDs for change in systolic blood pressure/diastolic blood pressure of 14.9/8.45 mm Hg. The true between-person variation in response was small, with SDs for change in systolic blood pressure/diastolic blood pressure of 2.6/1.0 mm Hg. The proportion of the apparent between-person variation in response that was attributed to true between-person variation was only 3% for systolic blood pressure and 1% for diastolic blood pressure. In conclusion, most of the apparent variation in response is not because of true variation but is a consequence of background within-person fluctuation in day-to-day blood pressure levels. Instead of monitoring an individual's blood pressure response, a better approach may be to simply assume the mean treatment effect. (Hypertension. 2010; 56: 533-539.)

Aims The efficacy of angiotensin-converting enzyme (ACE)-inhibitors in stable coronary artery disease (CAD) may be increased by targeting the therapy to those patients most likely to benefit. However, these patients cannot be identified by clinical characteristics. We developed a genetic profile to predict the treatment benefit of ACE-inhibitors exist and to optimize therapy with ACE-inhibitors. Methods and resultsIn 8907 stable CAD patients participating in the randomized placebo-controlled EUROPA-trial, we analysed 12 candidate genes within the pharmacodynamic pathway of ACE-inhibitors, using 52 haplotype-tagging-single nucleotide polymorphisms (SNPs). The primary outcome was the reduction in cardiovascular mortality, non-fatal myocardial infarction, and resuscitated cardiac arrest during 4.2 years of follow-up. Multivariate Cox regression was performed with multiple testing corrections using permutation analysis. Three polymorphisms, located in the angiotensin-II type I receptor and bradykinin type I receptor genes, were significantly associated with the treatment benefit of perindopril after multivariate adjustment for confounders and correction for multiple testing. A pharmacogenetic score, combining these three SNPs, demonstrated a stepwise reduction of risk in the placebo group and a stepwise decrease in treatment benefit of perindopril with an increasing scores (interaction P < 0.0001). A pronounced treatment benefit was observed in a subgroup of 73.5 of the patients [hazard ratio (HR) 0.67; 95 confidence interval (CI) 0.56-0.79], whereas no benefit was apparent in the remaining 26.5 (HR 1.26; 95 CI 0.97-1.67) with a trend towards a harmful effect. In 1051 patients with cerebrovascular disease from the PROGRESS-trial, treated with perindopril or placebo, an interaction effect of similar direction and magnitude, although not statistically significant, was observed. Conclusion The current study is the first to identify genetic determinants of treatment benefit of ACE-inhibitor therapy. We developed a genetic profile which predicts the treatment benefit of ACE-inhibitors and which could be used to optimize therapy.

AimsAngiotensin-converting enzyme (ACE) inhibitors have been shown to reduce cardiovascular risk in different groups of patients. Whether these effects can be generalized to the broad group of patients with vascular disease is unknown. Therefore, we undertook a combined analysis using individual data from ADVANCE, EUROPA, and PROGRESS to determine the consistency of the treatment effect of perindopril-based regimen in patients with vascular disease or at high risk of vascular disease.Methods and resultsWe studied all-cause mortality and major cardiovascular outcomes during a follow-up of about 4 years in the 29 463 patients randomly assigned a perindopril-based treatment regimen or placebo. The perindopril-based regimens were associated with a significant reduction in all-cause mortality [hazard ratio (HR) 0.89; 95 confidence interval (CI) 0.82-0.96; P = 0.006], cardiovascular mortality (HR 0.85; 95 CI 0.76-0.95; P = 0.004), non-fatal myocardial infarction (HR 0.80; 95 CI 0.71-0.90; P < 0.001), stroke (HR 0.82; 95 CI 0.74-0.92; P = 0.002), and heart failure (HR 0.84; 95 CI 0.72-0.96; P = 0.015). Results were consistent in subgroups with different clinical characteristics, concomitant medication use, and across all strata of baseline blood pressure.ConclusionThis study provides strong evidence for a consistent cardiovascular protection with an ACE-inhibitor treatment regimen (perindopril-indapamide) by improving survival and reducing the risk of major cardiovascular events across a broad spectrum of patients with vascular disease.

Background. - The European trial on Reduction Of cardiac events with perindopril. in patients with stable coronary Artery disease (EUROPA) demonstrated the benefits of perindopril with respect to secondary prevention of cardiovascular risk in patients with stable coronary artery disease. Aims. - To describe the clinical effects of perindopril in a subpopulation of patients from EUROPA with a history of myocardial infarction and/or revascularization. Patients and methods. - Of the 12,218 patients in the EUROPA study, 10,962 had a history of myocardial infarction and/or revascularization. In this EUROPA subpopulation, 7910 patients had a history of myocardial infarction and 6709 had a history of revascularization. Patients were randomized to treatment with perindopril 8 mg/day or placebo. The primary endpoint was a composite of cardiovascular mortality, myocardial infarction and resuscitated cardiac arrest. Results. - After a mean follow-up of 4.2 years, treatment with perindopril 8 mg/day was associated with a 22.4% reduction in the primary endpoint compared with placebo (p < 0.001) in patients with a history of myocardial infarction. Patients with a history of myocardial revascularization showed a 17.3% reduction in the primary endpoint with perindopril versus placebo (p < 0.05). In the combined population of patients with a history of myocardial infarction and/or revascularization, treatment with perindopril produced a 22.4% reduction in the primary endpoint compared with placebo (p < 0.001). Conclusions. - This study confirms the benefits of a high dose of angiotensin-converting enzyme inhibitor for the secondary prevention of cardiovascular risk among patients with a history of myocardial infarction and/or revascularization. (c) 2008 Elsevier Masson SAS. All rights reserved.

After a long and tedious start, beta-blockade has undeniably become one of the pillars of heart failure therapy. Based on the positive results of large, controlled studies in patients with stable mild, moderate and advanced chronic heart failure, beta-blocking drugs have been approved for the treatment of this syndrome, and are well positioned in national and international guidelines for the treatment of heart failure [1]. Of importance, their beneficial effects are comparable irrespective whether patients are at low, intermediate or high risk of heart failure. The same is true for different age groups. Indeed, elderly heart failure patients clearly benefit from long term beta-blocker therapy. The latter is important, as the heart failure patient in the community is relatively old, on average 74 years, in contrast to the average age (around 60–62 years) of the typical patient recruited in heart failure drug trials, including most studies with beta-blocking agents [2–5]. In the latter studies, beta-blocking therapy has on average been well tolerated. Although one could argue that this may be related to the relatively young age in these studies, a more recent study in elderly heart failure patients, SENIORS, also indicated that these patients (average age 76 years) tolerated beta-blockade well, comparable to placebo [6]. Of importance, in each of these studies beta-blockade was administered in addition to optimal heart failure therapy, which includes ACE inhibition and /or angiotensin receptor blockade in approximately 90% of patients. It is conceivable that, in this way, patients may have been protected from a potential adverse effect of the betablocker, worsening heart failure, and therewith may have tolerated the beta-blocker so well. This, of course, would be a perfect argument in favour of always first prescribing an ACE inhibitor (or ARB in those patients who do not tolerate ACE inhibition) and then follow up with a beta-blocker; exactly as current guidelines mandate [1]. However, and despite the apparent logic, is it really always necessary to follow this order of treatment? The fact that ACE inhibitors have become first choice in heart failure is purely based on historical grounds, placebocontrolled ACE inhibitor trials being performed a decade before those with beta-blockade. The obvious beneficial effects of ACE inhibition in these early trials (with only digitalis and diuretics as background medication) has made it unethical in many eyes to conduct studies without the ACE inhibitor as concomitant therapy [7] The drawback of this is that it is difficult if not impossible to determine the specific effects of different therapies, such as beta-blockade, in heart failure as well as their usefulness as first-line therapy. With this in mind, are there grounds on which to expect a better (or at least similar) efficacy of beta-blockade than ACE inhibition in mild to moderate heart failure, usually the time when the choice of first-line therapy will be made? Cardiovasc Drugs Ther (2008) 22:347–350 DOI 10.1007/s10557-008-6126-7

AIMS: To assess awareness of heart failure (HF) management recommendations in Europe among cardiologists (C), internists and geriatricians (I/G), and primary care physicians (PCPs). METHODS AND RESULTS: The Study group on HF Awareness and Perception in Europe (SHAPE) surveyed randomly selected C (2041), I/G (1881), and PCP (2965) in France, Germany, Italy, the Netherlands, Poland, Romania, Spain, Sweden, and the UK. Each physician completed a 32-item questionnaire about the diagnosis and treatment of HF (left ventricular ejection fraction 90% of their patients (64 vs. 82% C, P < 0.0001), whereas only 47% PCP would routinely prescribe an ACE-inhibitor. Worsening HF was considered a risk of ACE-inhibitor therapy by 35% PCP. I/G and PCP consistently do not prescribe target ACE-inhibitor doses (P < 0.0001 vs. C). Only 39% I/G would use a beta-blocker in >50% of their patients (vs. 73% C, P < 0.0001). Also, only 5% PCP would always, and 35% often, prescribe a beta-blocker and reach target doses in only 7-29%. Moreover, 34% PCP and 26% I/G vs. 11% C (P < 0.0001) do not start a beta-blocker in patients with mild HF, who are already on an ACE-inhibitor and are on diuretic. In mild, stable HF, 39% PCP and 18% I/G would only prescribe diuretics, vs. 7% C (P < 0.0001). In patients with worsening HF in sinus rhythm and on an optimal ACE-inhibitor, beta-blockade and diuretics, significantly more C would add spironolactone, but I/G would more often add digoxin. CONCLUSION: Although each physician group lacks complete adherence to guideline-recommended management strategies, these are used significantly less well by I, G, and PCPs, indicating the need for education of these essential healthcare providers.

Background: In the COMET study, carvedilol improved survival compared to metoprolol tartrate in 3029 patients with NYHA II-IV heart failure and EF

The multicenter EUROPA trial of 12,218 patients showed that perindopril decreased adverse clinical events in patients with established coronary heart disease. The PERSPECTIVE study, a substudy of the EUROPA trial, evaluated the effect of perindopril on coronary plaque progression as assessed by quantitative coronary angiography and intravascular ultrasound (IVUS). In total 244 patients (mean age 57 years, 81% men) were included. Evaluable paired quantitative coronary angiograms were obtained from 96 patients randomized to perindopril and from 98 patients to placebo. Concomitant treatment at baseline consisted of aspirin (90%), lipid-lowering agents (70%), and beta blockers (60%). The primary and secondary end point was the difference of minimum and mean lumen diameters (quantitative coronary angiography) or mean plaque cross-sectional area (IVUS) measured at baseline and 3-year follow-up between the perindopril and placebo groups. After a median follow-up of 3.0 years (range 1.9 to 4.1), no differences in change in quantitative coronary angiographic or IVUS measurements were detected between the perindopril and placebo groups (minimum and mean luminal diameters -0.07 +/- 0.4 vs -0.02 +/- 0.4 mm, p = 0.34; mean luminal diameter -0.05 +/- 0.2 vs -0.05 +/- 0.3 mm, p = 0.89; mean plaque cross-sectional area -0.18 +/- 1.2 vs -0.02 +/- 1.2 mm(2), p = 0.48). In conclusion, we found no progression in coronary artery disease by quantitative coronary angiography and IVUS with long-term administration of perindopril or placebo, possibly because most patients were on concomitant treatment with a statin.

Objectives We explored whether vascular protection by carvedilol could contribute to its superior effects in the treatment of heart failure (HF) compared with metoprolol tartrate in the COMET (Carvedilol Or Metoprolol European Trial) study. Background Full adrenergic blockade by carvedilol and additional (e.g., antioxidative) properties may lead to vascular protection relative to beta-1 blockade alone, and contribute to its efficacy in HF treatment. Methods Three thousand twenty-nine patients with HF due to ischemic (51%) or idiopathic cardiomyopathy (44%) were randomized double-blind to carvedilol (n = 1,511) or metoprolol (n = 1,518) and followed for 58 months. Vascular end points were cardiovascular death, stroke, stroke death, myocardial infarction (MI), and unstable angina. Results The effect of carvedilol on cardiovascular death improved consistently in subgroups with prespecified baseline variables. Myocardial infarctions were reported in 69 carvedilol and 94 metoprolol patients (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.52 to 0.97, p = 0.03). Cardiovascular death or nonfatal MI combined were reduced by 19% in carvedilol (HR 0.81, 95% CI 0.72 to 0.92, p = 0.0009 vs. metoprolol). Unstable angina was reported as an adverse event in 56 carvedilol and in 77 metoprolol patients (HR 0.71, 95% CI 0.501 to 0.998, p = 0.049). A stroke occurred in 65 carvedilol and 80 metoprolol patients (HR 0.79, 95% CI 0.57 to 1.10). Stroke or MI combined occurred in 130 carvedilol and 168 metoprolol patients (HR 0.75, 95% CI 0.60 to 0.95, p = 0.015), and fatal MI or fatal stroke occurred in 34 carvedilol and in 72 metoprolol patients (HR 0.46, 95% CI 0.31 to 0.69, p = 0.0002). Death after a nonfatal MI or stroke occurred in 61 of 124 carvedilol and in 106 of 160 metoprolol patients (HR 0.66, 95% CI 0.48 to 0.90, p = 0.0086). Conclusions Carvedilol improves vascular outcomes better than metoprolol. These results suggest a ubiquitous protective effect of carvedilol against major vascular events.

Anaemia is a common comorbidity in chronic heart failure (CHF). The predictors of new onset anaemia (NOA) and its long-term prognostic value, particularly in patients treated with beta-blockers, are not known.In COMET, 3029 patients with CHF in NYHA II-IV and EF35% were randomized to carvedilol or metoprolol tartrate and were followed for an average of 58 months. Plasma haemoglobin (Hb) concentrations were measured at a central laboratory at randomization, at four monthly intervals for the first year and annually thereafter. According to WHO criteria, anaemia was defined when Hb measured13 g/dL for men and12 g/dL for women. We considered anaemia to be severe when Hb11.5 g/dL for men and10.5 g/dL for women. The baseline mean Hb was 14.2 +/- 1.5 g/dL (n = 2996) and 15.9% of patients had anaemia (males, 16.0%; females, 15.2%). At baseline, severe anaemia was found in 3.3% of patients (males, 3.6%; females, 2.0%). During the study, all-cause mortality (RR 1.47) death or hospitalization (RR 1.28), and heart failure hospitalization (RR 1.43, all P0.0001) were higher in anaemic when compared with non-anaemic patients. In patients without anaemia at baseline, at the end of the study, the cumulative frequency of NOA was 28.1% in males and 27.0% in females. NOA increased over time from 14.2% at year 1 to 27.5% at year 5. Predictors of NOA were: higher age, diuretic dose, creatinine (all P0.0001), higher serum potassium, lower serum sodium, body mass index, and use of aldosterone antagonists, carvedilol, and digitalis (all P0.03). Treatment with carvedilol (vs. metoprolol tartrate) was associated with a 24% increased risk to develop NOA (P = 0.0047), but not severe anaemia (P = 0.18). Patients with a Hb decrease of3 g/dL (RR 3.37, P0.0001) or of 2.0-3.0 g/dL (RR 1.47, P = 0.011) from baseline had an increased subsequent mortality when compared with patients having Hb increases of 0-1.0 g/dL.In stable ambulatory CHF patients, development of NOA is frequent and can be predicted by a set of clinical variables. Decreases in Hb over time relate to future increased morbidity and mortality.

Objectives This study was designed to investigate the loss of well-being, in terms of life-years, overall and in patients randomized to metoprolol versus carvedilol in the Carvedilol Or Metoprolol European Trial (COMET). Background The ultimate objectives of treating patients with heart failure are to relieve suffering and prolong life. Although the effect of treatment on mortality is usually described in trials, the effects on patient well-being throughout the trials’ courses are rarely reported. Methods A total of 3,029 patients randomized in the COMET study were included in the analysis. “Patient journey” was calculated by adjusting days alive and out of hospital over four years using a five-point score completed by the patient every four months, adjusted according to the need for intensification of diuretic therapy. Scores ranged from 0% (dead or hospitalized) to 100% (feeling very well). Results Over 48 months, 17% of all days were lost through death, 1% through hospitalization, 23% through impaired well-being, and 2% through the need for intensified therapy. Compared with metoprolol, carvedilol was associated with fewer days lost to death, with no increase in days lost due to impaired well-being or days in hospital. The “patient journey” score improved from a mean of 54.8% (SD 26.0) to 57.4% (SD 26.3%) (p Conclusions Despite treatment with beta-blockers, heart failure remains associated with a marked reduction in well-being and survival. Loss of quality-adjusted life-years through death and poor well-being seemed of similar magnitude over four years, and both were much larger than the loss that could be attributed to hospitalization.

Aims We studied the influence of heart rate (HR), systolic blood pressure (SBP), and beta-blocker dose on outcome in the 2599 out of 3029 patients in Carvedilol Or Metoprolol European Trial (COMET) who were alive and on study drug at 4 months after randomization (time of first visit on maintenance therapy). Methods and results By multivariable analysis, baseline HR, baseline SBP, and their change after 4 months were not independently related to subsequent outcome. In a multivariable analysis including clinical variables, HR above and SBP below the median value achieved at 4 months predicted subsequent increased mortality [relative risk (RR) for HR>68 b.p.m. 1.333; 95% confidence intervals (CI) 1.152-1.542; P120 mmHg 0.78; 95% CI 0.671-0.907; P

Background The Carvedilol or Metoprolol European Trial (COMET) reported a significant survival benefit for carvedilol, a β1-, β2- and α1-blocker, vs. metoprolol tartrate, a β1-selective blocker, in patients with mild-to-severe chronic heart failure (CHF). Patients on treatment with metoprolol might benefit from switching to carvedilol. Aim To investigate the safety and tolerability of switching β-blockers in CHF. Methods At the end of COMET, the Steering Committee recommended that study medication was stopped without unblinding, and patients were commenced on open-label β-blockade at a dose equivalent to half the dose of blinded therapy, with subsequent titration to target or maximum tolerated dose. Patients were followed for 30 days. Results 1321 out of 1440 patients were transitioned to open-label treatment (76.8% to carvedilol). Serious adverse and CHF-related events were respectively 9.4% and 4.7% in those switching from carvedilol to metoprolol and 3.1% and 1.5% in patients switching from metoprolol to carvedilol. Patients who switched from carvedilol to metoprolol showed the highest mortality or hospitalisation rate (12.3%) in comparison with those who switched from metoprolol to carvedilol (3.1%, p

Neurohormonal activation contributes greatly to the development and progression of heart failure. Neuroendocrine systems, the most relevant in this respect, include the renin–angiotensin system (RAS), the sympathetic nervous system (SNS), aldosterone, and endothelins. They play a pivotal role in cardiac remodeling, an essential mechanism underlying the development of ventricular dysfunction and heart failure, and contribute to structural and functional changes in the cardiovascular system, such as cellular hypertrophy, apoptosis, and fibrosis. Although some systems become activated later in the development of heart failure, the SNS is an early contributor, reportedly preceding activation of the RAS. In the Studies of Left Ventricular Dysfunction (SOLVD), plasma measurements of neurohormones indicated an earlier activation of the SNS than the RAS [1]. In heart failure, sympathetic overactivation occurs particularly in the heart and the kidney. As a consequence, increased cardiac norepinephrine production stimulates the b1-, b2-, and a1-adrenergic receptors, each of which are linked to pathways leading to cardiac cellular remodeling signals (Fig. 1). Although some pathways also can be modulated by the RAS, other b-adrenergic intracellular signaling pathways are independent. Consequently, full b-adrenergic receptor blockade would modulate the remodeling process more completely than inhibition of the RAS.

OBJECTIVES Whether beta-blockers reduce atrial arrhythmias and, when added to an angiotensin-converting enzyme (ACE) inhibitor, ventricular arrhythmia is unknown. BACKGROUND Ventricular and atrial arrhythmias are common after acute myocardial infarction (AMI) and are associated with a poor prognosis. Angiotensin-converting enzyme inhibitors reduce the incidence of both types of arrhythmia. METHODS The antiarrhythmic effect of carvedilol was examined in a placebo-controlled multicenter trial, the Carvedilol Post-Infarct Survival Control in Left Ventricular Dysfunction (CAPRICORN) study, which enrolled 1,959 patients with reduced left ventricular systolic function after AMI, 98% of whom were treated with an ACE inhibitor. RESULTS The incidence of atrial fibrillation/flutter was 53 to 984 (5.4%) in the placebo group and 22 to 975 (2.3%) in the carvedilol group, giving a carvedilol/placebo hazard ratio (HR) of 0.41 (95% confidence interval [CI] 0.25 to 0.68; p = 0.0003). The corresponding rates of ventricular tachycardia/flutter/fibrillation were 38 to 984 (3.9%) and 9 to 975 (0.9%) (HR 0.24, 95% CI 0.11 to 0.49; p < 0.0001). CONCLUSIONS Carvedilol has a powerful antiarrhythmic effect after AMI, even in patients already treated with an ACE inhibitor. Carvedilol suppresses atrial as well as ventricular arrhythmias in these patients.

Background & Aims: The COMET trial was a prospective, double-blind, randomised trial comparing carvedilol, a comprehensive adrenergic receptor antagonist, with metoprolol, a beta-1-selective agent in patients with heart failure and left ventricular systolic dysfunction. The trial showed a reduction in mortality with carvedilol that was consistent across subgroups. The purpose of this report is to describe in greater detail the heterogeneity of this population at baseline with particular reference to the impact of symptomatic severity, age and gender on patient characteristics. Methods: A descriptive report using data entered in the COMET study data-base. Results: The characteristics of the population studied were similar to those reported in previous trials of beta-blockers. Almost all patients were receiving diuretics and ACE inhibitors with few patients taking angiotensin receptor blockers. As expected, older patients had more co-morbidity. Older patients and women reported worse symptoms and poorer well-being despite similar ventricular dimensions and systolic dysfunction. NT-proBNP was higher in patients with more severe symptoms and older patients but not in women, although differences in NT-proBNP may have been confounded by differences in renal function. Conclusion: Age and gender, as well as the severity of cardiac dysfunction, appear to have an important effect on the severity of heart failure symptoms and patient 'well-being'. This could have important implications for the relationship between symptoms and prognosis and therefore the way in which patients are selected for clinical trials and the goals of treatment. This will be the subject of further analyses.

Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and beta-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of beta-blockade should not be delayed.

Summary Backgroundblockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. Methods In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardio- vascular reason, an ejection fraction of less than 0·35, and to have been treated optimally with diuretics and angiotensin- converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. Findings The mean study duration was 58 months (SD 6). The mean ejection fraction was 0·26 (0·07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0·83 (95% CI 0·74-0·93), p=0·0017). The reduction of all- cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0·94 (0·86-1·02), p=0·122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Interpretation Our results suggest that carvedilol extends survival compared with metoprolol.

In large clinical trials both carvedilol and metoprolol have been shown to reduce mortality and morbidity in patients with chronic heart failure. Carvedilol is an adrenoceptor antagonist, which inhibits beta(1)-, beta(2)-, and alpha(1)-adrenergic receptors. Carvedilol has additional metabolic and antioxidant properties. Metoprolol is a selective antagonist of beta(1)-adrenergic receptors. The carvedilol or metoprolol European trial (COMET) is the first study to investigate whether beta-blocking agents with differing pharmacological profiles exert different effects on morbidity and mortality in patients with chronic heart failure. 3029 patients from 15 different European countries were enrolled into COMET and will be followed until 1020 fatal events have been observed, unless the data and safety monitoring committee (DSMC) recommends early termination. The target dose for carvedilol is 25 mg bid and for metoprolol tartrate 50 mg bid. This manuscript outlines the rationale, design and possible outcomes of COMET.

Purpose: To use data from the Randomized Aldactone Evaluation Study (RALES) to compare clinical outcomes and costs as part of the assessment of the economic implications of spironolactone treatment of advanced heart failure.

s of Communications to be Presented at 11th International Congress on Cardiovascular Pharmacotheraphy, Montreal, QC, Canada 18–21 May 2002. In Cardiovascular Drugs and Therapy, 2002, v. 16 n. 1, Suppl., p. 27, abstract no. P206

Background. ACE inhibition reduces morbidity and mortality among a variety of patients. Among mechanisms explaining these beneficial effects are the effects on the sympathetic system and on local vasodilating substances such as nitric oxide and bradykinins at the level of the endothelium. The PERFECT study was designed to verify the above mentioned pathophysiological concepts. Methods. The PERFECT study is a study nested within the EUROPA trial, a three year double-blind, multi-centre, placebo-controlled randomised study that aims at studying the effect of the ACE-inhibitor Perindopril on morbidity and mortality in over 12,000 patients with stable coronary artery disease without clinical heart failure. The PERFECT study is designed as a parallel group randomised placebo controlled trial to determine the effect of Perindopril (8 mg) on brachial artery endothelial function in patients with stable coronary artery disease without clinical heart failure. In the PERFECT study, B-mode ultrasonography of the brachial artery is used as a model for changes in the coronary arteries. Endothelial function in response to ischaemia (reactive hyperaemia) and to vasoconstriction (cold pressor test) is assessed. The ischemia test is used a model to assess the effects of ACE inhibition on nitric oxide/bradykinine mediated vasodilatatory response to ischaemia, whereas the cold pressor test is applied to assess the effect of ACE inhibition on the neurohormonal response. The recruitment for the PERFECT study started in May 1998 en was completed in June 1999. 345 patients were recruited in 20 European centers. The Vascular Imaging Center Utrecht, an ultrasound core laboratory, is performing the endothelial function measurements. The primary study outcomes are (1) percentage change in flow-mediated vasodilatation of the brachial artery between the 36 month measurement and the baseline measurement and (2) percentage change in neurohormonal mediated vasoconstriction of the brachial artery between the 36 month measurement and the baseline measurement. The size of the study allows detection of an absolute difference in FMD of 2.0% with a 90% power and a two-sided alpha of 5%. Conclusion. The findings of the PERFECT study may help to understand and explain the effects of ACE inhibition, in particular Perindopril, on cardiovascular morbidity and mortality.

OBJECTIVESWe sought to define the therapeutic dose range of levosimendan in patients with New York Heart Association class II-IV heart failure of ischemic origin.BACKGROUNDLevosimendan is a calcium sensitizer for treatment of acute decompensated heart failure.METHODSA double-blind, placebo-controlled, randomized, multicenter, parallel-group study included 151 adult patients. Levosimendan was given as a 10-min intravenous bolus of 3, 6, 12, 24 or 36 μg/kg, followed by a 24-h infusion of 0.05, 0.1, 0.2, 0.4 or 0.6 μg/kg/min, respectively. Dobutamine, for comparative purposes, was given as an open-label infusion (6 μg/kg/min). The primary efficacy variable was the proportion of patients achieving in each treatment group at least one of the following: 1) a ≥15% increase in stroke volume (SV) at 23 h to 24 h; 2) a ≥25% decrease in pulmonary capillary wedge pressure (PCWP) (and ≥4 mm Hg) at 23 h to 24 h; 3) a ≥40% increase in cardiac output (CO) (with change in heart rate [HR]

Background and Methods Aldosterone is important in the pathophysiology of heart failure. In a double-blind study, we enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of no more than 35 percent and who were being treated with an angiotensin-converting–enzyme inhibitor, a loop diuretic, and in most cases digoxin. A total of 822 patients were randomly assigned to receive 25 mg of spironolactone daily, and 841 to receive placebo. The primary end point was death from all causes. Results The trial was discontinued early, after a mean follow-up period of 24 months, because an interim analysis determined that spironolactone was efficacious. There were 386 deaths in the placebo group (46 percent) and 284 in the spironolactone group (35 percent; relative risk of death, 0.70; 95 percent confidence interval, 0.60 to 0.82; P

Heart failure is a clinical syndrome that is predominantly caused by cardiovascular disorders such as coronary heart disease and hypertension. However, several classes of drugs may induce heart failure in patients without concurrent cardiovascular disease or may precipitate the occurrence of heart failure in patients with preexisting left ventricular impairment. We reviewed the literature on drug-induced heart failure, using the MEDLINE database and lateral references. Successively, we discuss the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, antidepressants, calcium channel blocking agents, nonsteroidal anti-inflammatory drugs, antiarrhythmics, beta-adrenoceptor blocking agents, anesthetics and some miscellaneous agents. Drug-induced heart failure may play a role in only a minority of the patients presenting with heart failure. Nevertheless, drug-induced heart failure should be regarded as a potentially preventable cause of heart failure, although sometimes other priorities do not offer therapeutic alternatives (e.g., anthracycline-induced cardiomyopathy). The awareness of clinicians of potential adverse effects on cardiac performance by several classes of drugs, particularly in patients with preexisting ventricular dysfunction, may contribute to timely diagnosis and prevention of drug-induced heart failure.

The pharmacological approach to heart failure is an area of universal interest. Nevertheless, the number of different types of drugs available and approved for the therapy of chronic heart failure is limited. ACE inhibitors and, to some extent, diuretics are uniformly accepted as baseline treatment of all phases of heart failure. In selected cases, the combination of the vasodilators hydralazine and nitrates may be considered, whereas there is evidence of a potentially beneficial effect of beta-blockade in subsets of heart failure patients. Finally, the current recommendation is that digitalis glycosides are prescribed to all patients with atrial fibrillation, but in patients in sinus rhythm only to those who have advanced heart failure. Neurohormonal modulation apart, it is of interest to note that at present, emphasis is on unloading of the heart or on agents with negative inotropic effects rather than on positive inotropic support. Although structural changes in the heart, leading to predominantly diastolic dysfunction, are important features of the syndrome, cardiac contractile dysfunction has always been considered the primary disorder in most heart failure patients. Consequently, there have been numerous attempts throughout the last two decades to improve cardiac contractile force with a variety of positive inotropic agents. However, this has been without much success. Of the inotropes developed, only digitalis, a drug that has been with us for over

Experience accumulated from several large trials strongly suggests that beta-blockers should be used for the management of chronic heart failure[87]. It is appropriate to add beta-blockade to conventional therapy such as diuretics, ACE inhibitors and digoxin, as this was the approach used in the major trials. It is appropriate to treat patients with mild, moderate and, when stable, severe chronic heart failure. The benefits obtained include improvements in left ventricular function, reductions in symptoms and morbidity, improvement of quality of life, and delay of clinical progression, reflected in a reduced need for cardiac transplantation and, probably, a reduction in mortality. beta-blockers are much better tolerated, when used appropriately in selected patients, than was previously supposed. To confirm the improvement in survival recently reported with carvedilol, further prospective trials using different beta-blockers are warranted. No major comparative trials have been carried out between beta-blockers in chronic heart failure, therefore it is not known whether the differences between them are clinically significant. The optimal dose of beta-blocker and the effect in patient groups excluded from or poorly represented in the clinical trials (e.g. elderly patients) have yet to be determined. Placebo-controlled mortality trials with bucindolol (BEST) and bisoprolol (CIBIS-II) are under way[89,90]. A large study of carvedilol versus metoprolol (COMET), added to conventional treatment, is planned.

Cardiac L-carnitine content, essential for mitochondrial fatty acid transport and ATP-ADP exchange, decreases during ischemia. In animal models, administration of the natural derivative, L-propionylcarnitine, may reduce ischemia and improve cardiac function. To evaluate possible antiischemic effects of L-propionylcarnitine was compared with placebo in a randomized, double-blind, parallel design, in addition to preexisting therapy. Patients with > or = 2 anginal attacks per week and objective signs of ischemia with angina during bicycle exercise testing were included. After an initial 2-week, single-blind placebo phase, 37 patients received 500 mg L-propionylcarnitine tid, and 37 patients received placebo for 6 weeks. Both groups were comparable at baseline. Three patients discontinued the study while on placebo (two because of noncompliance, one because of palpitations) and one while on L-propionylcarnitine (noncompliance). Although heart rate, blood pressure at rest, and maximal exercise were not affected, L-propionylcarnitine increased the time to 0.1 mV ST-segment depression [44 +/- 3 vs. 8 +/- 2 seconds (mean +/- SEM) in the placebo group; p = 0.05], and exercise duration improved by 5% compared with placebo. Anginal attacks and the consumption of nitroglycerin were not affected in either group. Thus, following a 6 week treatment period, L-propionylcarnitine induced additional, albeit marginal, antiischemic effects in anginal patients who were still symptomatic despite maximal conventional antianginal therapy. It is questionable whether in these patients this form of metabolic treatment will achieve great benefit, although in some improvement can be expected.

Current treatment guidelines for heart failure state that chronic heart failure therapy should always be initiated with an ACE inhibitor and up-titrated until dosages are reached that have been shown effective in terms of mortality and morbidity reduction in large, controlled trials [1,2]. Whether diuretics are to be coadministered depends on the presence of fluid retention and is obviously of less concern in the early, milder forms of heart failure. The prominent place of the ACE inhibitor in heart failure therapy is based on the unequivocal beneficial effects observed in in large randomized, placebocontrolled clinical trials in patients with various grades of heart failure severity. Taken together, ACE inhibition leads to a 14%–31% reduction in annual mortality rate in moderate to severe heart failure [3,4] in patients otherwise treated with diuretics and, to some extent, digitalis glycosides and vasodilators. Besides this significant improvement in survival, ACE inhibitors consistently reduce hospitalizations for heart failure and lead to increased clinical well-being. Thus, in the combined SOLVD studies, enalapril led to a 37% decrease in readmissions for heart failure compared to placebo [4,5]. In a recent meta-analysis a 26% reduction in mortality and a 27% decrease in readmission for heart failure was found in patients with asymptomatic left ventricular dysfunction or heart failure following a myocardial infarction [6]. Benefits were observed early after study start and persisted long-term. Obviously, these consistent beneficial effects, found in a wide range of symptomatic and asymptomatic heart failure patients, warrant a prominent place for the ACE inhibitor in heart failure therapy, indeed as first-line treatment, before other medications are considered. And thus, a paradigm is created. The paradigm that ACE inhibition is the mandatory first step in each patient and that other treatment modalities are only to be considered subsequently if patients remain symptomatic. This rigid approach, supported as it may be by the evidence of large controlled trials, has disadvantages, however. First, it precludes a more individualized approach. Second, the mandatory order in which treatment has to be given may quickly lead to polypharmacy. One has to realize that the prominent place of the ACE inhibitor in heart failure therapy is based on historical evidence, as it was the first drug to be evaluated in this area, against placebo. It may well be that under similar conditions another form of treatment would have led to similar improvements and be made the agent of choice to initiate heart failure treatment. Indeed, the choice of the ACE inhibitor may not be justifiable when such studies had been carried out or when the ACE inhibitor had been compared to such agents, and proven to be less or equally effective. In order to prove or disprove this hypothesis, studies comparing ACE inhibition with other promising therapies, in a head-to-head fashion, are clearly needed. However, is such a comparison ethically acceptable now that ACE inhibitors have proven themselves so well that they have become first-line therapy in heart failure treatment guidelines worldwide? The danger of guidelines is that doctors are treating patients “by the book” without considering specific features of potential importance in the individual. Who is to say that, for instance, a patient with a high heart rate is not better off with beta-blockade rather than ACE inhibition as first-line therapy. It may be more unethical not to explore that possibility, if there is good reason to assume a similar or, possibly, better effect of the beta-blocker than the ACE inhibitor. And there may be good reasons to assume this. As regards clinical endpoints, it is clear that beta-blockade in addition to an ACE inhibitor markedly improves both survival and clinical well-being, in all phases of heart failure. Also, in terms of cardiac remodeling beta-blockade leads to a better effect in combination with ACE inhibition than ACE inhibition alone. In several studies carvedilol has been shown to reduce cardiac volumes in heart failure patients when co-administered with an ACE inihibitor, whereas the ACE inhibitor alone did not lead to reversed remodeling, i.e. a decrease in left ventricular volumes in heart failure [7–9]. This is important in the context of heart failure treatment, as cardiac remodeling and the inherent change in shape and size of the ventricle is pivotal to initiation and progression of heart failure. In all of these studies, the beta-blocker was administered on top of ACE inhibition. The question is: Can we expect a similar effect when the beta-blocker is given singly? In terms of anti-remodeling effects, when one compares the pharmacological profile of carvedilol

Appropriate risk stratification of patients with established, stable coronary artery disease could contribute to the prevention of recurrent cardiovascular events. The purpose of the present study was to develop and validate risk prediction models for various cardiovascular end points in the EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) database, consisting of 12,218 patients with established coronary artery disease, with a median follow-up of 4.1 years. Cox proportional hazards models were used for model development. The end points examined were cardiovascular mortality, noncardiovascular mortality, nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, resuscitated cardiac arrest, and combinations of these end points. The performance measures included Nagelkerke's R 2 , time-dependent area under the receiver operating characteristic curves, and calibration plots. Backward selection resulted in a prediction model for cardiovascular mortality (464 events) containing age, current smoking, diabetes mellitus, total cholesterol, body mass index, previous myocardial infarction, history of congestive heart failure, peripheral vessel disease, previous revascularization, and previous stroke. The model performance was adequate for this end point, with a Nagelkerke R 2 of 12%, and an area under the receiver operating characteristic curve of 0.73. However, the performance of models constructed for nonfatal and combined end points was considerably worse, with an area under the receiver operating characteristic curve of about 0.6. In conclusion, in patients with established coronary artery disease, the risk of cardiovascular mortality during longer term follow-up can be adequately predicted using the clinical characteristics available at baseline. However, the prediction of nonfatal outcomes, both separately and combined with fatal outcomes, poses major challenges for clinicians and model developers.

We evaluated a generic quality of life (QoL) Functional Status Questionnaire (FSQ), in patients with chronic heart failure (CHF). The FSQ assesses the 3 main dimensions of QoL: physical functioning, mental health and social role. It also includes 6 single item questions about: work status, frequency of social interactions, satisfaction with sexual relationships, days in bed, days with restricted activity and overall satisfaction with health status. The FSQ was compared to the Minnesota Living with Heart Failure questionnaire (MLwHF). The FSQ was evaluated in a substudy (n = 340) of the second Cardiac Insufficiency Bisoprolol Survival study (CIBIS-II), a placebo-controlled mortality trial. 265 patients (75%) patients completed both questionnaires at 6 months of follow-up. Both questionnaires indicated substantially impaired QoL. The FSQ demonstrated high internal consistency (Cronbach’s α > 0.7 for all items except “social activity” = 0.66) and construct and concurrent validity. After 6 months, the only item on either questionnaire to show a difference between the placebo- and bisoprolol-treatment groups was the single item FSQ question about “days in bed” (p = 0.018 in favour of bisoprolol). The FSQ performed well in this study, provided additional information to the MLwHF questionnaire and allowed interesting comparisons with other chronic medical conditions. The FSQ may be a useful general QoL instrument for studies in CHF.

Aims To investigate whether genetic variation in the renin-angiotensin-aldosterone system (RAAS) and kallikrein-bradykinin pathways is related to hypertension and blood pressure (BP) response to angiotensin-converting enzyme (ACE) inhibitor therapy in stable coronary artery disease (CAD) patients. Methods and results In 8907 stable CAD patients from the EUROPA trial, 52 haplotype-tagging single-nucleotide polymorphisms (SNPs) in 12 candidate genes within the RAAS and kallikrein-bradykinin pathways were investigated for association with hypertension (defined as BP >= 160/95 mmHg or use of antihypertensives) and BP response to ACE inhibitors, during a 4-week run-in period. All analyses were adjusted for age, sex, body mass index and creatinine clearance and corrected for multiple testing. Results Hypertension was present in 28.3% of the patients (n = 2526); median BP reduction after perindopril was 10/4mmHg. Four polymorphisms, located in the ACE (rs4291), angiotensinogen (rs5049) and (pro) renin receptor (rs2968915; rs5981008) genes were significantly associated with hypertension in two vascular disease populations of CAD (EUROPA) and cerebrovascular disease (PROGRESS; n = 3571). A cumulative profile demonstrated a stepwise increase in the prevalence of hypertension, mounting to a 2-3-fold increase (P for trend < 0.001). Similar associations on hypertension were observed for angiotensinogen in a healthy population (n = 2197). In addition, genetic polymorphisms were identified that significantly modified the BP reduction by ACE inhibitor therapy; however, the observed BP differences were small and did not remain significant after permutation analysis. Conclusion This large genetic association study identified genetic determinants of hypertension in three cohorts of patients with vascular disease and healthy individuals. J Hypertens 29:509-519 (C) 2011 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.

Acute systemic and, possibly, coronary vasoconstriction may limit the usefulness of i.v. beta-blockade for the management of hypertension in ischemic patients. The acute hemodynamic and neurohumoral profile of i.v. dilevalol (50 mg/5 min), a nonselective beta-antagonist and selective partial beta 2-agonist, was evaluated for 1 h in nine patients with stable angina, significant (> 50%) coronary artery disease, and mild hypertension. Immediately after administration, arterial pressures fell significantly by 13% and remained lowered for the entire study period. Concomitantly, heart rate slowed from 76 +/- 2 (mean +/- SEM; control) to 67 +/- 2 beats/min (60 min postadministration, p < 0.05), and cardiac index and stroke work decreased significantly by 15 and 21%, respectively. Isovolumetric contractility indices (measured at fixed heart rates) fell progressively by 9-12%, whereas relaxation (Tau1 and Tau2) slowed by 10% (all p < 0.05 vs. control). Consequently, left ventricular end-diastolic and right atrial pressures increased significantly from 17 +/- 3 and 9 +/- 1.2 mm Hg at baseline to 21 +/- 2.5 and 12 +/- 2.1 mm Hg, respectively. Dilevalol did not affect systemic or coronary resistance. However, coronary flow decreased by 24% (p < 0.05 vs. control), accompanied by significant reductions in myocardial oxygen demand and consumption of 23 and 14%, respectively. Levels of circulating norepinephrine and dopamine increased by 35 and 71%, whereas those of renin and angiotensin II decreased by 26 and 33%, respectively (all p < 0.05 vs. control). Adverse side effects did not occur. None of the patients became ischemic. Thus, at the dose level used, dilevalol has predominant beta-blocking effects.(ABSTRACT TRUNCATED AT 250 WORDS)

Heart failure therapy has dramatically changed in the last two decades. Whereas before, the focus was on symptomatic treatment of heart failure with diuretics and digitalis glycosides, the advent of ACE inhibitors, beta-blocking drugs and aldosterone receptor antagonists has drastically changed our insight in how to approach the heart failure patient. A number of large, controlled clinical trials have clearly indicated that these agents may impact on the natural history of the syndrome and not only improve symptoms, but, in addition, reduce morbidity and mortality. The first drug developed in this context, the ACE inhibitor, has been evaluated against placebo in patients with mild, moderate and severe heart failure, improving survival in each category; its reductions in mortality ranging from 16% in mild to moderate heart failure to 31% in patients with severe heart failure [1,2]. Furthermore, ACE inhibitors decrease hospitalisations for heart failure by approximately 15%. Importantly, in patients who have a reduced systolic left ventricular function, but are still asymptomatic, ACE inhibition prevents or retards the development of heart failure in 37% [3]. When then a beta-blocker is added to the ACE inhibitor, a further 30–35% reduction in mortality is achieved as well as an additional 30% reduction in hospitalisations in both mild, moderate as well as severe heart failure [4–7]. Similar figures are obtained when in advanced heart failure an aldosterone antagonist is added. In the only study investigating this, the RALES study, a 30% reduction in mortality and in cardiovascular hospitalisations was observed over and above those achieved by ACE inhibitors alone [8]. Thus, accumulating evidence from various controlled studies disprove the old notion of heart failure being a terminal disorder requiring symptomatic rather than preventive treatment. As a consequence the focus has shifted towards treatment in the early stages of the disease and to prevention. One might expect that, against this background of a sizeable improvement of survival and significant reductions in both heart failure and all-cause hospitalisations, patient management would have changed significantly over the past years. Indeed, patient management guidelines specify the need for early treatment with ACE inhibitors and beta-blockers, in the later stages followed by aldosterone antagonist being mandatory in the treatment of heart failure [9]. Nevertheless, despite the available evidence-based treatment strategies and clear and precise patient management guidelines, few patients actually receive optimal medical treatment. Somehow evidence-based medicine and strategies have not translated to clinical practice. Patients either do not receive the therapy they need or receive it in insufficient dosages. In the case of ACE inhibition this is particularly true. Nearly 15 years after the first large study demonstrating a beneficial effect of ACE inhibition on mortality in severe heart failure [1], later followed by other studies providing the same evidence in different degrees of heart failure [2,10], at present only 20–40% of patients with heart failure receive an ACE inhibitor, usually in dosages that do not conform to those used in the large studies, which, at least in that context, had shown their beneficial effect. Why is this? Quite a few possibilities may apply. Heart failure patients or patients at risk of heart failure are often not detected, as the required diagnostic tools are not or insufficiently available for the health care provider, who, in most instances, is the general practitioner. The patient or his relatives may to some extent be unknowingly at fault and be unaware of the disease, not perceiving its seriousness, and also be unaware of the therapeutic possibilities and not demand them. It is also likely that the health care provider may be at fault, again without realizing this. Health care providers of different backgrounds, e.g. general practitioners, internists or geriatricians, may not be aware of the results of the large, controlled studies showing the benefits of the ACE inhibitor. Doctors, including specialists, may not be convinced that the results of large, controlled studies on the effect of these medications

Parenterally active dopaminergic compounds such as dopamine are widely used in low output syndromes and acute episodes or exacerbations of heart failure. In this setting, dopamine is normally administered in low dosages to improve renal blood flow and function, in addition to beta-adrenergic agonists such as dobutamine. Temporary support of the failing heart can be successfully achieved under these conditions. In contrast, the experience with orally active dopaminergic agents such as levodopa and ibopamine has not been very positive. Both activate dopamine (DA1 and DA2 receptors and β1 adrenoceptors, and at the higher dose level α1 and α2 adrenoceptors. In addition, ibopamine stimulates β2 adrenoceptors. Activation of DA1 receptors located post-synaptically induces vasodilatation in renal, mesenteric, cerebral and coronary vascular beds. Natriuresis is enhanced through increased renal flow or stimulation of tubular DA1 receptors. Activation of DA2 receptors located prejunctionnally on sympathetic nerve terminals, inhibits norepinephrine release and reduces sympathetic tone. In heart failure patients both levodopa and ibopamine improve cardiac output and reduce systemic vascular resistance [1,2] Ibopamine also reduces left ventricular filling pressure, at least at the higher dose level [2]. The development of levodopa was relatively shortlived, particularly as a result of its central actions leading to nausea and vomiting [3]. Moreover, the effect on DA2 receptors and subsequent reduction in norepinephrine, most likely the more important pharmacological effect of these agents in heart failure, were not sustained [4]. In contrast, a reduction in plasma norepinephrine persisted during long-term treatment with ibopamine, although this did not prevent late tolerance to ibopamine’s initial hemodynamic effects [2]. Also, ibopamine has been reported to reduce circulating plasma renin and, when significantly elevated, aldosterone levels [5]. In contrast, long-term (6-month) treatment with the drug in moderate heart failure had no effect on plasma aldosterone, although small decreases in plasma norepinephrine and renin levels were observed [6]. Thus, ibopamine had some neurohormonal effect and was shown in some, but not all studies to improve exercise capacity over time. The expectations in the first and only large controlled survival study with ibopamine PRIME II, was therefore that the drug would improve the outcome of heart failure patients [7]. In fact, PRIME II was stopped prematurely because of an excess mortality in patients receiving ibopamine. This untoward effect was predominantly observed in patients with severe heart failure, NYHA III/IV and IV, and in patients receiving antiarhythmic drugs at baseline, both ad-hoc analyses in subgroups which were not prespecified. As such, one has to be cautious in speculating the reason of this negative effect of ibopamine on survival. Nevertheless, the result reminds us of the controlled trials with cAMP-dependent positive inotropes; i.e., of predominant phosphodiesterase (PDE) inhibitors, such as milrinone, amrinone and enoximone, and of partial PDE—inhibitors like vesnarinone and pimobendan. These agents are invariably arrhtyhmogenic and increase mortality, particularly in advanced heart failure patients, comparable to those studied in PRIME II [8]. Ibopamine stimulates β1 receptors and therefore may be considered at least a partial cAMP dependent positive inotropic agent. This mechanism may not be apparent during acute administration when dopaminergic effects may predominate, however may become relevant during long-term administration. Although speculative, the message from PRIME II could be that whenever dopaminergic compounds are developed they should preferably be devoid of β adrenergic and, possibly also α1 adrenergic stimulating effects. In this issue, two articles are devoted to such a compound, CHF 1035. CHF 1035 is an orally active prodrug, which after ingestion is rapidly hydrolysed to its active metabolite CHF 1024. CHF 1024 is a predominant DA2and α2-receptor agonist with, in vitro, negligible binding to DA1, β1 and α1 receptors, and significantly less affinity for β2 receptors. Stimulation of prejunctional DA2 and α2 receptors leads to diminished norepinephrine release from sympathetic nerve endings, whereas DA2 stimulation induces a reduction of angiotensin-induced aldosterone secretion from the adrenal cortex.

Since the mid-late nineties beta-blockade has become one of the pillars of chronic heart failure treatment. Based on a significant and consistent beneficial effect on survival and a reduction of worsening heart failure (HF) in large, placebocontrolled studies performed at that time, beta-blockade has been accepted as mandatory therapy in patients with stable mild, moderate and severe HF. These pivotal studies were, in order of sequence: the US carvedilol programme (carvedilol), CIBIS II (bisoprolol), MERIT-HF (metoprolol), and COPERNICUS (carvedilol) performed in patients with chronic HF and left ventricular (LV) dysfunction [1–4]. Whereas the focus in the first 3 studies was in mild/ moderate HF, COPERNICUS was exclusively carried out in patients with severe, albeit stable. HF. In addition, in patients with LV dysfunction and/or HF directly after an acute myocardial infarction, carvedilol also significantly improved survival compared to placebo treatment [5]. A later study, SENIORS, performed in an elderly population irrespective of cardiac function with nebivolol, showed a significant reduction in the primary outcome, a composite of all-cause mortality and hospital admission for HF, but for all-cause mortality alone [6]. In all of these studies background therapy included ACE inhibitors. As a consequence of these results, carvedilol, bisoprolol, metoprolol succinate and nebivolol have been accepted for the treatment of chronic, stable HF (NYHA II-IV) of ischemic or non-ischemic origin in international guidelines for the treatment of HF [7, 8]. Such guidelines however do not address an important question for the clinician: “which beta-blocker to use”? Are they all similarly effective and equally tolerated, or may there be a preferred beta-blocker for the treatment of chronic heart failure?

Aims Information on the effectiveness of beta-blockade in patients with heart failure (HF) and concomitant renal impairment is scarce and beta-blockers are underutilized in these patients. Methods and results The Cockcroft–Gault formula normalized for body surface-area was used to estimate renal function (eGFRBSA) in 2622 patients with HF, left ventricular ejection fraction ≤35%, New York Heart Association class III/IV and serum creatinine

We determined whether blood pressure (BP) lowering by perindopril was related to its benefit in the EUROPA study. Twelve thousand two hundred eighteen patients with documented coronary artery disease received perindopril 8 mg once daily or matching placebo after a 4-week run-in period in which all patients received perindopril. Patients were excluded if systolic (S) BP was > 180 or < 100 mmHg. Mean age was 60 years (range 26-89). 27% had a history of hypertension. After 4.2 years of follow-up, the primary endpoint (cardiovascular death, nonfatal myocardial infarction, or resuscitated cardiac arrest) was observed in 603 (9.9%) placebo versus 488 (8.0%) perindopril patients [20% relative risk reduction (RRR), CI 9-29%, P = 0.003]. There was no interaction between baseline SBP levels (using JNC-7 cutoff values) and treatment effect. If anything, the greatest RRR of the primary endpoint (32%) occurred in patients with the lowest SBP (< 120 mmHg) in whom perindopril did not reduce SBP. Also, RRR during blinded treatment was comparable, irrespective of whether BP decreased or not or of the extent of BP reduction during perindopril treatment. The treatment benefit in EUROPA cannot be fully explained by baseline BP or BP reduction with perindopril. Other mechanisms including direct anti-atherosclerotic effects of ACE inhibition may play a role.

The historical choice of angiotensin-converting enzyme (ACE) inhibition as first-line therapy in heart failure is challenged by early activation of the sympathetic system and multiple ways beta blockade (in particular, unselective agents such as carvedilol) may affect cardiac remodeling, its underlying mechanisms, and, hence, progression of heart failure, compared with ACE inhibition. Existing comparisons indicate similar or possible greater efficacy of beta blockade than ACE inhibition. As beta blockade is well tolerated, it could be considered in individual stable patients. However, early combined treatment with both neurohormonal antagonists remains preferable to either neurohormonal antagonist alone and should not be delayed.

The European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) investigated the effect of angiotensin-converting enzyme inhibition on the prevention of cardiac events in patients with stable coronary artery disease (CAD) without apparent heart failure. Perindopril 8 mg/day significantly reduced a composite outcome of cardiovascular death, nonfatal myocardial infarction or resuscitated cardiac arrest by 20% compared with placebo, in addition to standard preventive therapies. This review describes the substudies and subpopulation analyses carried out within the EUROPA population, concluding that the benefits of perindopril extend to all stable CAD patients, even revascularized patients or those with preserved left ventricular function. Data on the pathophysiological mechanisms underlying CAD indicate direct vascular protection with perindopril. This helps explain why perindopril is beneficial in preventing cardiac events in stable CAD patients.

The Clinical Trials described in this article were presented at the Hotline and Clinical Trial Update Sessions of the European Society of Cardiology Congress held in September 2007 in Vienna, Austria. The sessions chosen for this article represent the scope of interest of Cardiovascular Drugs and Therapy. The presentations should be considered preliminary, as further analyses could alter the final publication of the results of these studies. PROSPECT evaluated echocardiographic criteria for optimal selection of patients with moderate to severe heart failure who may benefit from cardiac resynchronisation therapy, however concluded that no single echocardiographic measure can be recommended. EVEREST found that tolvaptan, a vasopressin V-2 antagonist, resulted in early weight reduction and improvement of dyspnoea in patients with acute heart failure, but lacked long term improvement. In ARISE, the anti-oxidant succinobucal did not affect the primary outcome in high risk cardiovascular patients, but improved the combination of cardiovascular death, myocardial infarction and stroke, and diabetic control in diabetics. ALOFT showed that the addition of the renin inhibitor aliskiren to an ACE inhibitor or ARB and a beta-blocker leads to favourable effects on neurohormonal actions in heart failure. FINESSE markedly improved coronary patency before PCI with half-dose reteplase/abciximab in STEMI patients, however without significantly improving short-term outcome. The Prague-8 Study evaluated whether routine clopidogrel administered > 6 h pre-angiography would be a safe way to achieve therapeutic drug levels in case a follow-up intervention would be considered immediately, but appeared not justified because of bleeding complications. CARESS in MI showed that high risk patients with evolving STEMI who undergo thrombolytic therapy should undergo PCI early after the thrombolysis. Finally, the ACUITY trial found that in moderate or high risk Non ST elevation ACS patients triaged to PCI, coronary artery bypass graft (CABG) surgery, or medical management, bivalirudin, with or without associated GPIIb/IIIa inhibitor therapy, resulted in a marked reduction of bleeding at 30 days whilst preserving the ischemic and mortality benefit at 1 year follow up.