Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Many conditions culminate in heart failure (HF), a multi-organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence-base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite

Controversies in the Use of Beta Blockers in Heart Failure

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94510/1/j.1527-5299.2003.00294.x.pd

Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring

More women are living with and surviving breast cancer, because of improvements in breast cancer care. Trastuzumab (Herceptin®▾) has significantly improved outcomes for women with HER2-positive tumours. Concerns about the cardiac effects of trastuzumab (which fundamentally differ from the permanent myocyte loss associated with anthracyclines) led to the development of cardiac guidelines for adjuvant trials, which are used to monitor patient safety in clinical practice. Clinical experience has shown that the trial protocols are not truly applicable to the breast cancer population as a whole, and exclude some women from receiving trastuzumab, even though they might benefit from treatment without long-term adverse cardiac sequelae. Consequently, five oncologists who recruited patients to trastuzumab trials, some cardiologists with whom they work, and a cardiovascular lead general practitioner reviewed the current cardiac guidelines in the light of recent safety data and their experience with adjuvant trastuzumab. The group devised recommendations that promote proactive pharmacological management of cardiac function in trastuzumab-treated patients, and that apply to all patients who are likely to receive standard cytotoxic chemotherapy. Key recommendations include: a monitoring schedule that assesses baseline and on-treatment cardiac function and potentially reduces the overall number of assessments required; intervention strategies with cardiovascular medication to improve cardiac status before, during, and after treatment; simplified rules for starting, interrupting and discontinuing trastuzumab; and a multidisciplinary approach to breast cancer care

ACE Inhibition and Endothelial Function: Main Findings of PERFECT, a Sub-Study of the EUROPA Trial

Background: ACE inhibition results in secondary prevention of coronary artery disease (CAD) through different mechanisms including improvement of endothelial dysfunction. The Perindopril-Function of the Endothelium in Coronary artery disease Trial (PERFECT) evaluated whether long-term administration of perindopril improves endothelial dysfunction. Methods: PERFECT is a 3-year double blind randomised placebo controlled trial to determine the effect of perindopril 8 mg once daily on brachial artery endothelial function in patients with stable CAD without clinical heart failure. Endothelial function in response to ischaemia was assessed using ultrasound. Primary endpoint was difference in flow-mediated vasodilatation (FMD) assessed at 36 months. Results: In 20 centers, 333 patients randomly received perindopril or matching placebo. Ischemia-induced FMD was 2.7% (SD 2.6). In the perindopril group FMD went from 2.6% at baseline to 3.3% at 36 months and in the placebo group from 2.8 to 3.0%. Change in FMD after 36 month treatment was 0.55% (95% confidence interval −0.36, 1.47; p = 0.23) higher in perindopril than in placebo group. The rate of change in FMD per 6 months was 0.14% (SE 0.05, p = 0.02) in perindopril and 0.02% (SE 0.05, p = 0.74) in placebo group (0.12% difference in rate of change p = 0.07). Conclusion: Perindopril resulted in a modest, albeit not statistically significant, improvement in FMD

Individualised therapy of angiotensin converting enzyme (ACE) inhibitors in stable coronary artery disease: overview of the primary results of the PERindopril GENEtic association (PERGENE) study

In patients with stable coronary artery disease (CAD) without overt heart failure, ACE inhibitors are among the most commonly used drugs as these agents have been proven effective in reducing the risk of cardiovascular events. Considerable individual variations in the blood pressure response to ACE inhibitors are observed and as such heterogeneity in clinical treatment effect would be likely as well. Assessing the consistency of treatment benefit is essential for the rational and cost-effective prescription of ACE inhibitors. Information on heterogeneities in treatment effect between subgroups of patients could be used to develop an evidence-based guidance for the installation of ACE-inhibitor therapy. Obviously, therapy should only be applied in those patients who most likely will benefit. Attempts to develop such treatment guidance by using clinical characteristics have been unsuccessful. No heterogeneity in risk reduction by ACE inhibitors has been observed in relation to relevant clinical characteristics. A new approach to such ‘guided-therapy’ could be to integrate more patient-specific characteristics such as the patients’ genetic information. If proven feasible, pharmacogenetic profiling could optimise patients’ benefit of treatment and reduce unnecessary treatment of patients. Cardiovascular pharmacogenetic research of ACE inhibitors in coronary artery disease patients is in a formative stage and studies are limited. The PERGENE study is a large pharmacogenetic substudy of the EUROPA trial, aimed to assess the achievability of pharmacogenetic profiling. We provide an overview of the main results of the PERGENE study in terms of the genetic determinants of treatment benefit and blood pressure response. The main results of the PERGENE study show a pharmacogenetic profile related to the treatment benefit of perindopril identifying responders and non-responders to treatment

Rationale and study design of a cross sectional study documenting the prevalence of Heart Failure amongst the minority ethnic communities in the UK: the E-ECHOES Study (Ethnic - Echocardiographic Heart of England Screening Study)

Background: Heart failure is an important cause of cardiovascular morbidity and mortality. Studies to date have not established the prevalence heart failure amongst the minority ethnic community in the UK. The aim of the E-ECHOES (Ethnic - Echocardiographic Heart of England Screening Study) is to establish, for the first time, the community prevalence and severity of left ventricular systolic dysfunction (LVSD) and heart failure amongst the South Asian and Black African-Caribbean ethnic groups in the UK.Methods/Design: This is a community based cross-sectional population survey of a sample of South Asian (i.e. those originating from India, Pakistan, Bangladesh) and Black African-Caribbean male and female subjects aged 45 years and over. Data collection undertaken using a standardised protocol comprising a questionnaire incorporating targeted clinical history taking, physical examination, and investigations with resting electrocardiography and echocardiography; and blood sampling with consent. This is the largest study on heart failure amongst these ethnic groups. Full data collection started in September 2006 and will be completed by August 2009.Discussion: The E-ECHOES study will enable the planning and delivery of clinically and cost-effective treatment of this common and debilitating condition within these communities. In addition it will increase knowledge of the aetiology and management of heart failure within minority ethnic communities

“Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: Implications for therapy

Despite the findings in randomized trials of a significant effect of angiotensin-converting enzyme (ACE) inhibitors in reducing morbidity and mortality of patients with symptomatic left ventricular dysfunction, the morbidity and mortality of these patients remains relatively high. One potential strategy to further improve morbidity and mortality in these patients is blockade of aldosterone. Many clinicians have assumed that ACE inhibitors would block both angiotensin II and aldosterone. However, there are data to suggest that aldosterone production may “escape” despite the use of an ACE inhibitor. An escape of aldosterone production has several important consequences, including: sodium retention, potassium and magnesium loss, myocardial collagen production, ventricular hypertrophy, myocardial norepinephrine release, endothelial dysfunction, and a decrease in serum high density lipoprotein cholesterol. Due to the potential importance of these mechanisms, the finding that there is a significant correlation between aldosterone production and mortality in patients with heart failure, as well as evidence that an aldosterone antagonist, spironolactone, when administered to patients with heart failure treated with conventional therapy including an ACE inhibitor results in increased diuresis and symptomatic improvement, an international prospective multicenter study has been organized, the Randomized Aldactone Evaluation Study (RALES Pilot Study), to evaluate the safety of blocking the effects of aldosterone in patients with heart failure treated with an ACE inhibitor.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/44631/1/10557_2004_Article_BF00877755.pd

Diabetic cardiomyopathy

Diabetic cardiomyopathy is a distinct primary disease process, independent of coronary artery disease, which leads to heart failure in diabetic patients. Epidemiological and clinical trial data have confirmed the greater incidence and prevalence of heart failure in diabetes. Novel echocardiographic and MR (magnetic resonance) techniques have enabled a more accurate means of phenotyping diabetic cardiomyopathy. Experimental models of diabetes have provided a range of novel molecular targets for this condition, but none have been substantiated in humans. Similarly, although ultrastructural pathology of the microvessels and cardiomyocytes is well described in animal models, studies in humans are small and limited to light microscopy. With regard to treatment, recent data with thiazoledinediones has generated much controversy in terms of the cardiac safety of both these and other drugs currently in use and under development. Clinical trials are urgently required to establish the efficacy of currently available agents for heart failure, as well as novel therapies in patients specifically with diabetic cardiomyopathy