Rationale for the use of angiotensin II receptor blockers in patients with left ventricular dysfunction (part I of II)

Almost 5 million individuals in the United States are diagnosed with chronic heart failure (HF), and the prevalence is increasing. Angiotensin-converting enzyme (ACE) inhibitors and beta blockers, neurohormonal antagonists that block the renin-angiotensin system (RAS) and the sympathetic nervous system, respectively, have been shown in clinical trials to reduce morbidity and mortality in patients with HF, and these therapies are now integral components of standard HF treatment. Yet, morbidity and mortality rates in HF remain unacceptably high, and the limitations of current standard therapies are becoming increasingly apparent. About 10% of patients with HF are unable to tolerate ACE inhibitors, often because of cough. In addition, ACE inhibition may not completely block the RAS because angiotensin II, the main end product of the RAS, can be generated via non-ACE enzymatic pathways. Angiotensin II receptor blockers (ARBs) may exert more complete RAS blockade than ACE inhibitors by interfering with the binding of angiotensin II at the receptor level, regardless of the enzymatic pathway of production. They are also better tolerated than ACE inhibitors and have been shown to improve symptoms and function in clinical trials in patients with HF. These factors provide a strong rationale for the study of the clinical effects of ARBs in patients with HF.     

Importance of in-hospital initiation of evidence-based medical therapies for heart failure-a review

Patients who have had heart failure (HF) face very high risks of hospitalization and mortality. Despite the compelling scientific evidence that angiotensin-converting enzyme inhibitors, aldosterone antagonists, and beta blockers decrease rates of hospitalization and mortality in patients who have had HF, these life-prolonging therapies continue to be underused. Many studies in a variety of clinical settings have documented that important numbers of patients who have had HF are not receiving treatment with these evidence-based therapies, which are recommended by national guidelines, when guided by conventional care. This HF treatment gap results from a variety of complex issues, including lack of systems and disease management programs. This gap in beta-blocker therapy may be due in part to persisting perceptions, despite recent evidence to the contrary, that it should be delayed until patients who developed HF have been stable for 2 to 4 weeks after hospital discharge and that its initiation results in a substantial risk of worsening HF. Conversely, recent clinical trial evidence has substantiated that beta blockers can be safely initiated for patients with HF in the hospital and that there are early benefits, including decreased risks of mortality and hospitalization for worsening HF. It has become increasingly evident that in-hospital initiation of evidence-based cardiovascular therapies and patient education have a positive effect on long-term patient compliance and clinical outcomes. Adopting in-hospital initiation of these therapies as the standard of care (in the absence of contraindications or intolerance) in patients who have HF and stabilized systolic dysfunction could substantially improve treatment rates, decrease the risk of future hospitalizations, and prolong life in the large number of patients who are hospitalized each year for HF.     

Hand Grip Strength Predicts Mortality and Quality of Life in Heart Failure: Insights From the Singapore Cohort of Patients With Advanced Heart Failure

BackgroundFrailty is prevalent among patients with heart failure (HF) and is associated with increased mortality rates and worse patient-centered outcomes. Hand grip strength (GS) has been proposed as a single-item marker of frailty and a potential screening tool to identify patients most likely to benefit from therapies that target frailty so as to improve quality of life (QoL) and clinical outcomes. We assessed the association of longitudinal decline in GS with all-cause mortality and QoL. Decline in GS is associated with increased risk of all-cause mortality and worse overall and domain-specific (physical, functional, emotional, social) QoL among patients with advanced HF.MethodsWe used data from a prospective, observational cohort of patients with New York Heart Association class III or IV HF in Singapore. Patients’ overall and domain-specific QoL were assessed, and GS was measured every 4 months. We constructed a Kaplan-Meier plot with GS at baseline dichotomized into categories of weak (≤ 5th percentile) and normal (> 5th percentile) based on the GS in a healthy Singapore population of the same sex and age. Missing GS measurements were imputed using chained equations. We jointly modeled longitudinal GS measurements and survival time, adjusting for comorbidities. We used mixed effects models to evaluate the associations between GS and QoL.ResultsAmong 251 patients (mean age 66.5 ± 12.0 years; 28.3% female), all-cause mortality occurred in 58 (23.1%) patients over a mean follow-up duration of 3.0 ± 1.3 years. Patients with weak GS had decreased survival rates compared to those with normal GS (log-rank P = 0.033). In the joint model of longitudinal GS and survival time, a decrease of 1 unit in GS was associated with a 12% increase in rate of mortality (hazard ratio: 1.12; 95% confidence interval: 1.05–1.20; P = < 0.001). Higher GS was associated with higher overall QoL (β (SE) = 0.36 (0.07); P = < 0.001) and higher domain-specific QoL, including physical (β [SE] = 0.13 [0.03]; P = < 0.001), functional (β [SE] = 0.12 [0.03]; P = < 0.001), and emotional QoL (β [SE] = 0.08 [0.02]; P = < 0.001). Higher GS was associated with higher social QoL, but this was not statistically significant (β [SE] = 0.04 [0.03]; P = 0.122).ConclusionsAmong patients with advanced HF, longitudinal decline in GS was associated with worse survival rates and QoL. Further studies are needed to evaluate whether incorporating GS into patient selection for HF therapies leads to improved survival rates and patient-centered outcomes.     

Practical recommendations for the use of ACE inhibitors, beta-blockers, aldosterone antagonists and angiotensin receptor blockers in heart failure: putting guidelines into practice

Surveys of prescribing patterns in both hospitals and primary care have usually shown delays in translating the evidence from clinical trials of pharmacological agents into clinical practice, thereby denying patients with heart failure (HF) the benefits of drug treatments proven to improve well-being and prolong life. This may be due to unfamiliarity with the evidence-base for these therapies, the clinical guidelines recommending the use of these treatments or both, as well as concerns regarding adverse events. ACE inhibitors have long been the cornerstone of therapy for systolic HF irrespective of aetiology. Recent trials have now shown that treatment with beta-blockers, aldosterone antagonists and angiotensin receptor blockers also leads to substantial improvements in outcome. In order to accelerate the safe uptake of these treatments and to ensure that all eligible patients receive the most appropriate medications, a clear and concise set of clinical recommendations has been prepared by a group of clinicians with practical expertise in the management of HF. The objective of these recommendations is to provide practical guidance for non-specialists, in order to increase the use of evidenced based therapy for HF. These practical recommendations are meant to serve as a supplement to, rather than replacement of, existing HF guidelines.     

Growth hormone therapy in heart failure: where are we now?

Despite improvement in survival with angiotensin-converting enzyme inhibitors and beta blockers, clinical events for patients with heart failure remain elevated. New therapies for heart failure are needed to improve functional capacity, quality of life, and prognosis. Growth hormone exerts direct and indirect effects on cardiac structure and function. Experimental models of heart failure and small studies have demonstrated significant improvements in cardiac function, hemodynamic parameters, functional capacity, and quality of life. Despite the lack of benefit demonstrated in small, short-term, randomized clinical trials, further studies are needed to assess the potential role of this adjuvant therapy in heart failure patients.     

Quality of life of patients with ulcerative colitis: past, present, and future

Quality of life (QoL) is vitally important to patients with chronic illnesses such as ulcerative colitis (UC) and has been assessed in observational, cross-sectional, and cohort studies. However, relatively few clinical trials have evaluated the QoL of patients with UC. Recently, greater availability of the necessary tools has facilitated the undertaking of studies showing that QoL of patients with UC is reduced significantly compared with that of the general population. Studies using disease-specific instruments have identified disease severity as the strongest predictor of QoL, with other disease-related predictors including type of medical or surgical treatment and the efficacy, tolerability, and acceptability to patients of particular types of medical or surgical treatments. Other factors, such as comorbid medical or psychosocial problems and adherence to treatment, also affect QoL. Combined use of generic and disease-specific instruments in clinical trials can ensure that all clinically relevant unexpected events (generic instrument) and important improvement or deterioration (disease-specific instrument) are captured. For accurate outcomes assessment, the use of comprehensively validated instruments is critical. The need for the development and evaluation of new instruments will be determined by the mechanisms and targets of novel therapies. Ultimately, QoL assessment of effective therapies will play a strong role in pharmacoeconomic evaluations, providing health policy makers with the evidence to support the treatments that can most effectively normalize QoL through complete symptom resolution, minimal side effects, and convenient administration.     

Chemotherapy in the treatment of cancer of the pancreas

Opinions about the value of chemotherapy in pancreatic cancer vary from the idea that its use should be abandoned because of lack of proven efficacy and considerable toxicity to the idea that it may produce clinically meaningful responses correlated with improved survival. A systematic review of the available literature-based evidence was undertaken. The results are discussed in relation to supportive evidence from recent studies focusing on patient benefit. Six randomized trials of chemotherapy in advanced disease and two in the adjuvant setting with a no-active treatment group were identified. All eight trials were small, and the methodology was not always what is currently desirable. One of four palliative trials reported during the early 1980s, and both trials completed during the 1990s showed a slight survival benefit with chemotherapy. In one of the trials, quality of life (QoL) was also more often improved after 5-fluorouracil-based chemotherapy than after best supportive care. Supportive evidence for a slight prolongation of survival and a clinical benefit also comes from trials comparing different drugs. No standard regimen is defined, although one drug, gemcitabine, has been approved in some countries for the treatment of advanced pancreatic cancer. The two randomized adjuvant trials included a very small number of patients, and, although a survival benefit was seen, conclusive evidence supporting the use of adjuvant chemo (radio) therapy is still lacking. Chemotherapy has low activity in advanced pancreatic cancer, but it can improve survival and well-being in some patients.     

Quality of life in atrial fibrillation: measurement tools and impact of interventions

Quality of life (QoL) is of central importance in atrial fibrillation as both a treatment goal and an endpoint in the evaluation of new therapies. QoL appears to be impaired in the majority of patients with AF. A number of interventions for AF have been shown to improve QoL, including pharmacologic and nonpharmacologic rate control, antiarrhythmic drugs, and nonpharmacologic rhythm control strategies. This paper will review the rationale, design, strengths, and limitations of the questionnaires most commonly used to assess QoL in AF studies, and present QoL outcomes from major studies of AF interventions.     

Pathophysiologic bases for adjunctive therapies in the treatment and secondary prevention of acute myocardial infarction

Postmyocardial infarction (MI) survival has been steadily improving. This improvement has been due, in part, to the actions of the adjunctive medical therapies for the treatment of MI. Aspirin, beta blockers, angiotensin-converting enzyme (ACE) inhibitors, and lipid-lowering agents have been shown to improve survival in the treatment and secondary prevention of MI. Nitrates have beneficial effects as well. These medications complement the reperfusion strategies through different mechanisms. Other adjunctive medical therapies, namely magnesium, antiarrhythmic agents, and calcium-channel blockers, have not been shown to improve mortality with routine post-MI use despite their theoretical benefits.     

Clinical update: the role of angiotensin II receptor blockers in patients with left ventricular dysfunction (Part II of II)

Almost 5 million individuals in the United States have chronic heart failure (HF), which is increasing in prevalence. Angiotensin-converting enzyme (ACE) inhibitors are standard therapies for HF, although more than 10% of patients with HF are unable to tolerate these agents. Furthermore, ACE inhibitors may not provide complete blockade of the renin-angiotensin system (RAS) in the long term. Because angiotensin II receptor blockers (ARBs) may block the RAS more completely than ACE inhibitors and are better tolerated, several large-scale ARB trials have been performed exploring their potential role in treating patients with symptomatic HF and left ventricular systolic dysfunction. The Losartan Heart Failure Survival Study (ELITE II) demonstrated no significant differences in morbidity and mortality between the ARB losartan and the ACE inhibitor captopril among elderly patients with HF. The Valsartan Heart Failure Trial (Val-HeFT) demonstrated reductions in hospitalizations for HF with the ARB valsartan when added to standard HF therapy, with no effect on mortality. Both trials suggested a potential negative interaction between ARB and beta-blocker therapy. The Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity (CHARM) program demonstrated significant reductions in morbidity and mortality with the ARB candesartan in patients with HF due to systolic dysfunction, with or without ACE inhibitors and with or without beta blockers. Thus, the addition of ARBs to the treatment regimen of patients with symptomatic HF should be strongly considered.     

Quality of life in elderly heart failure patients

Quality of life(QOL),as a relevant area of research in the understanding of heart failure(HF)patient outcomes,has been increasingly studied during the last two decades.The purposes of this review article are to (1)describe QOL in older adults with HF,(2) identify and critique research designed to test interventions to improve QOL,(3)identify gaps in the literature,and (4)provide recommendations for future research.Seventeen studies describing QOL in older adults with HF were identified.Elderly HF patient QOL has been reported to be fair to poor and is worse as compared to a healthy control group.Furthermore,there is some evidence that suggests that QOL is better in older adults than younger adults and worse in women(both older and younger)than in men,although these findings are not consistent across studies.Predictors of QOL and its dimensions in older HF patients included demographic,clinical,and psychosocial variables.Sixteen interventional studies were identified that reported QOL as an outcome in older adults.Findings among randomized clinical trials(RCTs)to improve QOL outcomes in elderly HF patients do not allow strong conclusions about the benefits of the interventions.It must be noted,though,that while not all studies reported improvements in QOL(either significant or as a trend), no studies reported deterioration in QOL with randomization to an intervention versus control.These studies were limited by several methodological issues.While there has been some research of QOL in this elderly cohort,it is paramount that we address methodological issues and thereby improve the scientific rigor of our research,continue to explore QOL in elderly HF patients,and design intervention trials for elders at risk for poor QOL.     

Use of beta-blockers in obesity hypertension: potential role of weight gain

Beta‐blockers are the most frequently used drugs for the treatment of hypertension. Apart from concerns regarding potential adverse metabolic effects on lipids or insulin sensitivity, beta‐blockers can also cause weight gain in some patients. This fact appears little known to clinical practitioners and trialists. Thus, only a minority of clinical trials with beta‐blockers report weight changes during treatment. In trials that do report weight changes, beta‐blockers are associated with a weight gain of 1.2 (range ?0.4–3.5) kg. This may be attributable to the fact that beta blockade can decrease metabolic rate by 10%. Beta‐blockers may also have other negative effects on energy metabolism. Obesity management in overweight hypertensive patients may therefore be more difficult in the presence of beta‐blocker treatment. We therefore question the use of beta‐blockers as first‐line therapy for overweight or obese patients with uncomplicated hypertension.     

Heart failure and diabetes: Clinical significance and epidemiology of this two-way association

People with type 2 diabetes (T2DM) and those with prediabetes have an increased risk of heart failure (HF). Longer duration of T2DM correlates with a greater risk of HF, but HF is also seen in patients with recent-onset diabetes. Insulin resistance is more likely to be present in patients with HF. The risk of HF persists even in the face of standard-of-care preventive treatments for atherosclerotic cardiovascular (CV) disease. HF is commonly the presenting symptom of CV disease in people with diabetes and is the most expensive complication of diabetes because of the high cost of hospitalizations. Recently hospitalization for HF has been included in CV outcome trials (CVOTs), including for medications that are used to treat T2DM, which has led to new therapies for all HF patients. In addition, these CVOTs have shown that many drugs used in the therapy of diabetes are either neutral or detrimental in the HF patient and should be used with caution in patients with existing HF or those at high risk of HF. Most recently, sodium-glucose cotransporter-2 receptor blockers have shown efficacy in both HF with reduced ejection fraction (EF) and HF with preserved EF. The only other oral or injectable diabetes agent shown to improve outcomes in both is metformin.     

Role of beta adrenergic receptor polymorphisms in heart failure: systematic review and meta-analysis

Heart Failure (HF) is a common disorder associated with substantial morbidity and mortality. beta adrenergic receptors (betaAR) are the primary pathway through which cardiac function is influenced. Chronic beta(1)AR activation is implicated in the pathogenesis of HF and betaAR blockade improves survival in left ventricular systolic dysfunction. Common functional polymorphisms in beta adrenergic receptor genes (ADRB) have been associated with HF phenotypes, and with pharmacogenetic interaction with beta adrenergic receptor blockers (beta blockers). However, these associations have not been consistently replicated. The evidence for ADRB variant involvement in pathogenesis, progression and response to beta blockers in HF is reviewed. In addition, a meta-analysis of three studies analysing the effect of ADRB1 Arg389Gly polymorphism on left ventricular remodelling with the use of beta blockers, demonstrating a 5% improvement in left ventricular ejection fraction in Arg389 homozygotes, is presented. There is now accumulating molecular evidence for a different functional response to beta blockers associated with this polymorphism. In the future, confirmed genotypic associations may enable patients to be identified who are either at greater risk of developing HF, whose HF may rapidly progress, or who are unlikely to benefit from beta blockers, and such patients may benefit from targeted aggressive therapy.     

Comparative effectiveness of beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure

Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood. We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002. Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases. Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders. During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other). Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years). After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14). In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol.     

New paradigm shift in the pharmacotherapy for heart failure-where are we now and where are we heading?

Over the past 30 years, accumulating evidence has shown that three main therapies including angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, ß-blockers, and mineralocorticoid receptor antagonists are the standard treatment for patients with heart failure (HF) who exhibit reduced ejection fraction (EF). However, lessons learned from recent large-scale clinical trials have added a paradigm shift including angiotensin receptor-neprilysin inhibitor, sodium glucose co-transporter 2 inhibitor, and ivabradine. In addition, soluble guanyl cyclase stimulator and omecamtiv mecarbil are also suggested as next generation therapeutic measures for these patients. From these clinical trials, we learned some patients with preserved EF will benefit from certain agents, which has been one of the largest unmet needs over these decades. This article will review these paradigm shifts over the past 10 years and address a new therapeutic algorithm for patients with HF.     

Quality of life with an LVAD: A misunderstood concept

The present study aims to synthesize current evidence on the impact of LVAD implantation on quality of life. Current evidence was systematically reviewed to obtain relevant quantitative and qualitative articles published after 2007. Sandelowski's recommended steps for meta-summary were used to analyze the 19 studies that met the inclusion criteria. LVADs can improve HF symptoms and some aspects of QoL. Emotional and physical adaptation involves many changes and learning to manage the device takes time. Functional limitations still exist and patients still lack independence. LVAD-related complications significantly impact QoL. Psychological distress remains high after implantation. LVADs significantly impact the caregiver as well and their perspective is not well heard in the existing evidence. It is important for providers to have ongoing, in-depth discussions with patients and their caregivers regarding treatment options, goals of care, anticipated end-of-life trajectories with an LVAD, possible LVAD-complications, and the caregiver burden associated with an LVAD.     

Heart Failure and its Treatment in Women

Large differences exist between women and men in the syndrome of heart failure (HF).In contrast to men, hypertension and diabetes represent the major risk factors for development of HF in women and hypertension is also the major cause of left ventricular hypertrophy and stroke. Left ventricular hypertrophy in women increases the risk for mortality to a higher degree than it does in men. The clinical course of HF is generally more benign and more frequently characterized by HF with preserved systolic function.Estrogen receptors are present in the human heart. Based on data from rodent models, they are believed to modulate hypertrophy and the progression of HF. Some of the signaling pathways have been described and involve phosphorylation of intracellular kinases and production of nitric oxide. Interestingly, estrogen receptors are upregulated in human hypertrophy and HF.The clinical course of HF in women is characterized by the more frequent occurrence of diastolic HF. Myocardial remodeling with age and, as a consequence, of mechanical load is different in both genders.Adherence to guidelines in the diagnosis and treatment of HF is less strict in women than in men, leading to undertreatment with inhibitors of the renin-angiotensin system. Women are generally underrepresented in clinical trials in HF and gender-specific analyses have been neglected in most older large survival trials. In some of the large survival studies angiotensin-converting enzyme inhibitors or beta-receptor blockers did not reach significant endpoints in women. However, meta-analyses show overall positive effects for these groups of substances. Angiotensin receptor blockers were effective in large studies including high percentages of women.     

Effect of drug therapy for heart failure on quality of life

Symptomatic heart failure interferes with a patient's quality of life (QOL) by limiting his or her ability to perform physical tasks and daily activities and by lowering his or her sense of psychological well-being. Therefore, in addition to decreasing mortality and morbidity, improving QOL should be an important goal when selecting pharmacotherapy. QOL questionnaires, both generic and disease specific, are used widely, but in randomized controlled trials of heart failure treatments, QOL has not been a routine study end point. Beta blockers and angiotensin-converting enzyme inhibitors, medications widely used in the management of heart failure and hypertension--one of the most common causes of heart failure--have been associated with negative, neutral, and modestly positive QOL effects. Angiotensin receptor blockers, combined with other therapy, including angiotensin-converting enzyme inhibitors (usually with a diuretic) and/or b blockers in heart failure, have produced improvements in QOL. Patients with hypertension whose blood pressure has been lowered have also experienced an improvement in QOL scores. With current heart failure regimens prolonging life, improving QOL becomes an even more essential end point in assessing the effectiveness of new medications, whether used alone or in combination with standard therapy.