Prevention of heart failure

In light of the increasing prevalence, morbidity, and mortality of heart failure, preventative strategies are urgently needed. Risk factors include coronary artery disease, renal insufficiency, diabetes, and smoking. Essential strategies for prevention of heart failure are modification of risk factors for its development, and detection and treatment of asymptomatic left ventricular dysfunction (ALVD). In patients with ALVD, angiotensin-converting enzyme (ACE) inhibitor and β-blocker therapy can prevent progression to symptomatic heart failure. Additional recently identified preventative strategies include ACE inhibitor therapy for all coronary artery disease and diabetic patients, clopidogrel therapy in acute coronary syndromes, and avoidance of calcium channel blockers and a-blockers as first-line antihypertensive therapy.     

Tissue angiotensin‐converting enzyme inhibitors: Are they more effective than serum angiotensin‐converting enzyme inhibitors?

Since their discovery in the 1980s, angiotensin-converting enzyme (ACE) inhibitors have been shown to decrease angiotensin formation, prevent breakdown of bradykinin, and may also act on peptides of the renin-angiotensin system. They are effective in reducing the risk of heart failure, myocardial infarction, and death from cardiovascular causes in patients with left ventricular systolic dysfunction or heart failure, and have been shown to reduce atherosclerotic complications in patients who have vascular disease without heart failure. They may preserve endothelial function and counteract initiation and progression of atherosclerosis. Broadly, ACE inhibitors can be divided into tissue specific or serum ACE inhibitors. Tissue-specific ACE inhibitors as a group are not superior to serum ACE inhibitors in the treatment of coronary artery disease. Pending direct comparator clinical trials between a tissue ACE inhibitor and a plasma ACE inhibitor, both ramipril and perindopril can be recommended for secondary risk prevention, based on the evidence.     

Trends of congestive heart failure epidemiology: contrast with clinical trial results

Congestive heart failure (CHF) is an important and growing public health problem and the cause of substantial morbidity and mortality. Its increasing incidence and prevalence may be in part explained by the progressive aging of the world population. The improvement in coronary artery disease and hypertension treatment allows the individuals to lie longer and develop CHF. Indeed, the most common etiology of CHF is coronary artery disease, the leading cause of cardiovascular morbidity and mortality worldwide, and the second cause of CHF is hypertension which is still markedly increasing in developing countries. Estimates of prevalence of CHF are 0.4 to 2% of the general population. The number of hospital admissions for CHF has also been steadily increasing. Half of the patients carrying a diagnosis of CHF will die within 4 years and patients with severe CHF will die within 1 year. At present, there is no evidence that the prognosis of heart failure in the community has changed despite the advances in therapy over the past decades, such as the demonstration that angiotensin-converting enzyme inhibitors and other vasodilators improve the clinical signs and symptoms of patients with CHF, reduce mortality and slow the progression of myocardial dysfunction. Nevertheless, the overall mortality from this condition remains very high. It is possible that the results of the trials have not yet been evidenced in the majority of patients with CHF because the ideal conditions, treatment and follow-up in the trials are not yet widely achieved in the population.     

Heart failure--epidemic of the 21st century

Number of patients with chronic heart failure is increasing in all developed countries. The reasons are both, the improving prevention and treatment of deadly cardiovascular diseases, like acute myocardial infarction or stroke, and the increasing life expectancy. The cardiovascular mortality has declined by 30% and the average life expectancy has increased by 4 years also in the Czech Republic during the last 15 years. The prevalence of heart failure is about 1.5% in a general population, which means that there is about 150,000 patients in the Czech Republic. The annual incidence is about 0.4%, which means that there is about 40,000 new patients in the Czech Republic every year. The prevalence is increasing with age significantly. With respect to the ageing of the population it is expected that number of heart failure patients will be increasing. Based on the results of big clinical trials the treatment of heart failure has changed significantly. ACE inhibitors and beta-blockers became the first choice treatment improving not only symptoms but also mortality. In spite of all the progress in pharmacotherapy the prognosis of heart failure is still bad. Over 40% of patients will die within 4 years after making the diagnosis of heart failure and one-year mortality of patients with advanced heart failure (NYHA class IV) is over 50%. Therefore, a research of new therapeutic possibilities is still continuing. At present, a clinical significance of different devices, like biventricular cardiac pacemakers (cardiac resynchronization therapy) or implantable cardioverter/defibrillators in heart failure treatment is studied. A gene and cell therapy represents a great hope for heart failure treatment in future.     

beta-Blocker therapy in heart failure

Heart failure is an important public health problem and one for which morbidity and mortality remain high despite treatment with angiotensin converting enzyme (ACE) inhibitors. A large number of clinical trials examining the effects of beta-blockers in the treatment of heart failure have now been performed. Two large-scale clinical trials have recently confirmed significant survival benefits with these agents, with effects that are additive to those achieved with ACE inhibitor therapy. These trials have now established beta-blocker therapy as an important part of standard heart failure treatment. The clinical use of beta-blockers in patients with heart failure requires careful translation of the randomized controlled trials into everyday clinical practice. Patient selection is key to the safe use of beta-blockers. Patients who may be suitable for beta-blockade therapy include those with mild-moderate heart failure due to left ventricular systolic impairment, those who are receiving adequate dose of diuretics and ACE inhibitors and those whose clinical condition is stable at the time of initiation of the beta-blocker. Survival benefits have been demonstrated with bisoprolol, carvedilol and metoprolol. Whether different beta-blockers have important clinical differences with regard to clinical end-points is as yet uncertain. beta-Blockers should be initiated at low dose, with titration of dose over several weeks and careful clinical monitoring for potential adverse effects, such as hypotension or worsening congestion. This careful application of the clinical trials into clinical practice will allow the safe use of this effective treatment for patients with chronic heart failure.     

Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors: A cohort study of 11,575 patients with coronary artery disease

OBJECTIVES

The purpose of this study was to investigate the significance of the possible negative interaction between aspirin and angiotensin-converting enzyme (ACE) inhibitors.

BACKGROUND

Several provocative reports have recently suggested that aspirin is unsafe in patients with heart failure and has negative interaction with ACE inhibitors that might attenuate their beneficial effects upon survival.

METHODS

We analyzed mortality data of 11,575 patients with coronary artery disease screened for the Bezafibrate Infarction Prevention trial. A total of 1,247 patients (11%) were treated with ACE inhibitors. Of them, 618 patients (50%) used aspirin.

RESULTS

Five-year mortality was lower among patients on ACE inhibitors and aspirin than patients on ACE inhibitors without aspirin (19% vs. 27%; p < 0.001). After adjusting for confounders, treatment with aspirin and ACE inhibitors remained associated with lower mortality risk than using ACE inhibitors only (relative risk [RR] = 0.71; 95% confidence interval [CI] = 0.56 to 0.91). Subgroup analysis of 464 patients with congestive heart failure treated with ACE inhibitors revealed 221 patients (48%) on aspirin and 243 patients not on aspirin. Although clinical characteristics and therapy were similar, patients taking aspirin experienced lower mortality than patients who did not (24% vs. 34%; p = 0.001). After adjustment, treatment with aspirin was still associated with lower mortality (RR = 0.70; 95% CI = 0.49 to 0.99).

CONCLUSIONS

Among coronary artery disease patients with and without heart failure who are treated with ACE inhibitors, the use of aspirin was associated with lower mortality than treatment without aspirin. Our findings contradict the claim that aspirin attenuates the beneficial effect of ACE inhibitors and supports its use in patients with coronary artery disease treated with ACE inhibitors.     

Aging of the United States Population: Impact on Heart Failure

The United States population, particularly among older age groups, continues to expand. Because the incidence of heart failure increases with age, largely due to the development of heart failure risk factors such as hypertension and coronary artery disease, the epidemic of heart failure is likely to grow further in the coming decades. This article will review the epidemiology of heart failure among older adults, the influence of an aging population on heart failure prevalence and phenotype, the complications in management for a larger and older heart failure population, and the potential implications of these changes for health care costs and delivery. Ultimately, these challenges demand research into optimal therapeutic strategies for older heart failure patients, including improved prevention and treatment of the major causes of heart failure, an increasing role forpalliative care, and innovations in patient-centered health care delivery.     

Protective Effects of Angiotensin-Converting Enzyme Inhibitors in High-Risk African American Men With Coronary Heart Disease

Angiotensin-converting enzyme (ACE) inhibitors have been extensively used for the treatment of patients with cardiovascular disease, but several concerns have been raised about their efficacy in African American (AA) patients with heart failure, hypertension, and left ventricular hypertrophy. In this study the authors assessed the effect of ACE inhibitors on total and cardiovascular mortality in high-risk AA patients with angiographically proven coronary artery disease (CAD). This was a retrospective analysis of 810 AA men who underwent diagnostic coronary angiography between 1995 and 2003. All patients had demonstrable CAD and had undergone a complete ischemic workup. Follow-up was from 3 to 10 years. ACE inhibitors were administered to 237 patients, while the remaining 537 patients were not taking ACE inhibitors. Patients taking ACE inhibitors had significantly more comorbidities (hypertension, diabetes, left ventricular hypertrophy, heart failure, severe CAD) at baseline, compared with patients not taking ACE inhibitors (P<.05 for all comorbidities). Despite the unfavorable baseline profile, patients taking ACE inhibitors had significantly lower mortality from CAD during follow-up than patients who were not taking ACE inhibitors (P=.006). Stroke mortality rates were similar in both groups. Cox regression analysis showed an 80% higher relative risk in patients not receiving ACE inhibitors. These data indicate a substantial benefit from ACE inhibitor therapy in high-risk AA patients with CAD.     

Surgery in advanced heart failure

BACKGROUND: ACE inhibitors and beta blockers have reduced morbidity and mortality from chronic heart failure significantly during the last years. Apart from medical therapy several surgical strategies for the treatment of heart failure are available. PREREQUISITES OF SURGICAL TREATMENT: Surgical treatment should be directed towards the underlying etiology and mechanisms. To decide for a special surgical therapy indications and contraindications must be considered. SURGICAL PROCEDURES: The surgical therapy of heart failure can be performed with or without replacement of the heart. Especially concerning the organ-conserving techniques there has been significant progress during the last years: left ventricular aneurysmectomy, mitral valve surgery as well as high-risk coronary artery bypass surgery and electrostimulating procedures. Concerning heart replacement therapy, cardiac transplantation with a 10-year survival of 50% still remains superior to all available mechanical devices at the moment.     

Epidemiology of heart failure

Of all persons aged over 40 years, approximately 1% have heart failure. The prevalence of heart failure doubles with each decade of life, and is around 10% in persons over 70 years of age. In Spain, heart failure causes nearly 80,000 hospital admissions every year. As in other developed countries, heart failure is the most frequent cause of hospitalization among persons 65 years of age and over, and is responsible for 5% of all hospitalizations. The incidence of heart failure increases with age, and reaches 1% per year in those over 65. Heart failure is a progressive, lethal disorder, even with adequate treatment. Five-year survival is around 50%, which is no better than that for many cancers. In Spain, heart failure is the third leading cause of cardiovascular mortality, after coronary disease and stroke. In 2000, heart failure caused 4% of all deaths and 10% of cardiovascular deaths in men; the corresponding figures for women were 8% and 18%. In recent decades the prevalence and number of hospitalizations due to heart failure have increased steadily in developed countries. Heart failure will probably continue to increase in coming years: although its incidence has not materially decreased, survival is increasing due to better treatment. The control of risk factors for hypertension and ischemic heart disease, the main causes of heart failure in Spain, is the only method to halt the foreseeable increase in heart failure in the near future.     

The role of ACE inhibitors in the treatment of hypertensive elderly patients

Hypertension has a high prevalence among elderly patients. Randomised trials have already demonstrated that treating healthy older persons with hypertension is highly efficacious. Nevertheless some questions have arisen. On the one hand the generalizability of these trial results, particularly for older persons with serious medical comorbidities and poor functional status, is not clear. On the other hand different antihypertensive drugs have shown to be effective. Which drug for which patient? Even data from randomised intervention trials showing that the treatment affects cardiovascular morbidity and mortality, were missing, ACE inhibitors have been used for more than a decade to treat high blood pressure. For a younger population the captopril prevention project showed no differences between ACE inhibitors and conventional antihypertensive treatment (diuretics, beta-blocker) concerning the primary endpoints (myocardial infarction, stroke and other cardiovascular death). The STOP-2 study also confirmed these results for elderly patients. When treating elderly patients one must be aware of physiological changes with age and the comorbidities. Of significance among this patient group is declining renal function. Admissions for uraemia that are related to the use of ACE inhibitors are still commonplace, although many cases are preventable by monitoring renal function, but guidelines are still missing. Concerning the comorbidities ACE inhibitors have benefits compared to other antihypertensive drugs, especially in cases of heart failure, diabetes and coronary heart disease.     

The management of heart failure in Sweden

Heart failure is a major concern to health care providers in Sweden due to its increasing prevalence and the rising health care costs. Heart failure affects more than 160000 Swedes, approximately 2% of the population. The costs for the management of heart failure have been calculated to be approximately SEK 2.500 million (Euro 275 million) which is 2% of the total health care budget. Most heart failure patients are managed by primary care physicians but hospitalisation is common and heart failure is the most common cause for hospitalisation in patients over 65 years of age. National diagnostic and treatment guidelines are not completely adhered to. Echocardiography is performed in a little more than 30% of patients in primary care probably due to poor access. In hospitals echocardiography is more easily available and routinely used for diagnosis. Angiotensin-converting enzyme (ACE) inhibitors and beta-blockers appear to be under prescribed. Nurse-led heart failure clinics are being widely established in an attempt to curtail costs and improve management.     

Current perspectives for AT(1)-receptor blockers in the management of heart failure

Despite improvements in therapy, long-term mortality remains high in patients with heart failure and thus there remains a need for new treatment strategies to reduce the burden of mortality and morbidity associated with this condition. AT(1)-receptor blockers represent a rational approach to the management of heart failure, and have been shown to have beneficial effects on heart failure symptoms and exercise tolerance. However, the two outcome trials reported to date have not shown conclusive evidence of improvements in mortality. The potential benefits of AT(1)-receptor blockers in heart failure are currently being investigated in several trials. The CHARM programme (Candesartan in Heart failure - Assessment of Reduction in Mortality and morbidity) is the largest heart failure trial so far. This comprises three trials: CHARM Alternative, in patients with left ventricular dysfunction who are intolerant to ACE inhibitors; CHARM Added, in patients with left ventricular dysfunction who are also receiving ACE inhibitors; CHARM Preserved, in patients with preserved left ventricular systolic function (ejection fraction >40%). The primary end point will be a composite of cardiovascular mortality and hospitalisation for the treatment of heart failure. Other trials are currently investigating the effects of AT(1)-receptor blockers when used as an alternative or in addition to ACE inhibitors. The CHARM programme, together with other studies, should clarify the role of these agents in the management of heart failure.     

Possible interaction between aspirin and ACE inhibitors: update on unresolved controversy

The widespread use of aspirin and angiotensin converting enzyme (ACE) inhibitors in patients with coronary artery disease contributes significantly to the reduction in morbidity and mortality from this common health problem. These agents are widely and concomitantly used, and they share mechanisms that may interact in negative or positive pathways. Data derived from in vitro preparations, animal studies, human studies, and case-control studies are inconsistent. No study has established firm evidence regarding the safety or adverse effect of aspirin on patients who are on ACE inhibitors. The efficacy and safety of aspirin in combination with ACE inhibitors has been questioned and debated. If a negative interaction does exist, it will affect daily practice in treating patients with coronary artery disease and heart failure. This article reviews the available data regarding the safety of combined aspirin and ACE-inhibitor treatment among patients with ischemic heart disease, to assess the possible interaction between the two drugs and to discuss the significance and implications of the data. (c)2000 by CHF, Inc.     

Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers for prevention of type 2 diabetes: a meta-analysis of randomized clinical trials

OBJECTIVES: We sought to investigate the role of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in preventing the new onset of type 2 diabetes mellitus. BACKGROUND: Diabetes is a public health problem of epidemic proportions and its prevalence is on the rise. The typical American born today has a one in three chance of developing type 2 diabetes. This diagnosis is associated with an adverse cardiovascular prognosis and is considered the risk equivalent of established coronary disease. Even in high-risk individuals, diabetes is a preventable disease. Several studies have shown that ACE inhibitors and ARBs decrease the incidence of new-onset type 2 diabetes. However, the exact role of these agents in diabetes prevention has not yet been fully elucidated. METHODS: We conducted a meta-analysis of 12 randomized controlled clinical trials of ACE inhibitors or ARBs, identified through a MEDLINE search and a review of reports from scientific meetings, to study the efficacy of these medications in diabetes prevention. RESULTS: This showed that ACE inhibitors and ARBs were associated with reductions in the incidence of newly diagnosed diabetes by 27% and 23%, respectively, and by 25% in the pooled analysis. CONCLUSIONS: The use of an ACE inhibitor or ARB should be considered in patients with pre-diabetic conditions such as metabolic syndrome, hypertension, impaired fasting glucose, family history of diabetes, obesity, congestive heart failure, or coronary heart disease.     

Comparison of various blood pressure lowering treatments on the primary prevention of cardiovascular outcomes in recent randomised clinical trials

Randomised clinical trials completed over the past 8 to 10 years have provided much new evidence regarding the cardiovascular risks and benefits of treatment with newer blood pressure lowering drugs, particularly ACE inhibitors and calcium channel blockers (CCB). Trials of active treatment against placebo have now established that ACE inhibitors and CCBs reduce the risk of coronary heat disease and stroke in subjects with elevated blood pressure and that ACE inhibitors reduce the risk of heart failure but calcium antagonists do not. Clinical trials comparing active treatment regimens based on different blood pressure lowering drug classes, have provided convincing evidence that ACE inhibitors, CCBs, and "conventional treatment" with diuretics/beta-blockers are equally effective in the primary prevention of coronary heart disease, but that minor differences of the order of 5-12% favouring calcium antagonists may exist. The one area with a major difference is again for the primary prevention of heart failure where calcium antagonists are clearly inferior to diuretics/ beta-blockers and to ACE inhibitors. There is now convincing evidence that blood pressure lowering is effective in the secondary prevention of cardiovascular outcomes in subjects with established coronary heart disease, cerebrovascular disease, diabetes and chronic kidney disease, especially diabetic nephropathy. Clinical trial evidence comprising regimens based on different drug classes for the secondary prevention of cardiovascular outcomes is still very limited. It is possible that longer differences will be found between the efficacy and safety of drugs in secondary prevention than have been reported so far in primary prevention.     

Angiotensin II receptor blockers in the treatment of heart failure

Heart failure treatment centers on antagonism of the renin-angiotensin-aldosterone system and adrenergic nervous system. Angiotensin-converting enzyme (ACE) inhibitors have been shown to benefit patients with left ventricular systolic dysfunction irrespective of symptoms. Despite ACE inhibitor use, left ventricular dysfunction continues to progress in most patients. In addition, ACE inhibitors are substantially underused in patients who would benefit, in large part due to physician concern over potential adverse effects. Angiotensin receptor blockers (ARBs) have been proposed as either potential substitutes for ACE inhibitors or as additive therapy for heart failure patients. The authors will review the importance of the renin-angiotensin-aldosterone system in the progression of heart failure, as well as the mechanisms by which ACE inhibitors and ARBs counteract this effect. The clinical evidence to date supporting the use of ARBs in heart failure also will be reviewed. Based on current trials, ARBs are suitable substitutes for ACE inhibitors in patients who have true ACE inhibitor intolerance, but ACE inhibitors should still be considered first-line therapy in the treatment of left ventricular systolic dysfunction and heart failure. ARBs are a reasonable additive therapy in patients on maximal ACE inhibitor therapy who remain symptomatic, especially in patients unable to tolerate beta blockade.     

The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)--rationale and design

Inhibition or reversal of ventricular remodelling in heart failure patients is regarded as of prime importance in the treatment of heart failure and in determining long term outcome. Recent studies have demonstrated that the addition of carvedilol to Angiotensin Converting Enzyme (ACE) inhibitors and other routine heart failure therapy results in a valuable improvement in the clinical status and life expectancy of mild, moderate and severe heart failure patients. ACE inhibitors have become the cornerstone of heart failure therapy. Also, carvedilol in combination with standard therapy (including ACE inhibitors) has demonstrable beneficial effects on left ventricular remodelling. Each new treatment has to be added, this quickly leads to polypharmacy, which may not be necessary and even unwanted in the individual patient, as the pharmacological profile of carvedilol compares favourably to ACE inhibitors, this suggests that it could challenge ACE inhibitors as first-line treatment for heart failure.The CARMEN trial (Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN) was designed to compare the effects of carvedilol alone and of carvedilol plus an ACE inhibitor (enalapril) with the effect of an ACE inhibitor alone on different parameters of left ventricular remodelling as well as morbidity and mortality in patients with chronic mild heart failure, thereby allowing conclusions on whether combination therapy may be replaced by the multiple action adrenergic inhibitor carvedilol in the future.     

Tissue angiotensin-converting enzyme inhibitors for the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure: a pooled meta-analysis of randomized placebo-controlled clinical trials

Aim:  The aim of this study was to determine the role of tissue angiotensin-converting enzyme (ACE) inhibitors in the prevention of cardiovascular disease in patients with diabetes mellitus without left ventricular systolic dysfunction or clinical evidence of heart failure in randomized placebo-controlled clinical trials using pooled meta-analysis techniques.
Methods:  Randomized placebo-controlled clinical trials of at least 12 months duration in patients with diabetes mellitus without left ventricular systolic dysfunction or heart failure who had experienced a prior cardiovascular event or were at high cardiovascular risk were selected. A total of 10 328 patients (43 517 patient-years) from four selected trials were used for meta-analysis. Relative risk estimations were made using data pooled from the selected trials and statistical significance was determined using the Chi-squared test (two-sided alpha error <0.05). The number of patients needed to treat was also calculated.
Results:  Tissue ACE inhibitors significantly reduced the risk of cardiovascular mortality by 14.9% (p = 0.022), myocardial infarction by 20.8% (p = 0.002) and the need for invasive coronary revascularization by 14% (p = 0.015) when compared to placebo. The risk of all-cause mortality also tended to be lower among patients randomized to tissue ACE inhibitors, whereas the risks of stroke and hospitalization for heart failure were not significantly affected. Treating about 65 patients with tissue ACE inhibitors for about 4.2 years would prevent one myocardial infarction, whereas treating about 85 patients would prevent one cardiovascular death.
Conclusion:  Pooled meta-analysis of randomized placebo-controlled trials suggests that tissue ACE inhibitors modestly reduce the risk of myocardial infarction and cardiovascular death and tend to reduce overall mortality in diabetic patients without left ventricular systolic dysfunction or heart failure.     

Role of the renin-angiotensin-aldosterone system in atrial fibrillation and cardiac remodeling

PURPOSE OF REVIEW: This review summarizes recent clinical trial evidence showing a reduction in the development and recurrence of atrial fibrillation with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor-blocking agents (ARBs). It then explores the possible mechanisms for this effect based on current animal models and limited human study. RECENT FINDINGS: Post hoc analyses of trials in patients with heart failure, hypertension, or myocardial infarction have observed reductions in atrial fibrillation among patients treated with ACE inhibitors or ARBs. Recent studies of these agents in animal models of atrial fibrillation suggest that they may prevent atrial fibrillation by reversing the cardiac structural and electrical changes, known as cardiac remodeling, that lead to the development of atrial fibrillation. This concept is also supported by two prospective studies showing that ACE inhibitors and ARBs prevent the recurrence of atrial fibrillation after electrical cardioversion. SUMMARY: Inhibition of the renin-angiotensin-aldosterone system is a novel concept for the treatment of atrial fibrillation that may target the underlying substrate of atrial fibrillation. Further human research is required to determine whether ACE inhibitors and ARBs prevent atrial fibrillation, and if so, whether this is a result of blood pressure lowering alone or a specific effect of these agents. Ongoing research will establish whether ACE inhibitors or ARBs have specific benefits in patients with atrial fibrillation.