Management of diastolic heart failure--a practical review of pathophysiology and treatment trial data

The lack of large randomised controlled trials to guide therapy in diastolic heart failure causes some difficulties for evidence-based medicine practising clinicians. Traditionally, treatments for systolic heart failure have been highjacked for diastolic heart failure without much proof of benefit. However, recent studies have began to provide some evidence base for our practice. Betablockers and angiotensin receptor antagonists have recently been shown to reduce hospitalisation in large randomised controlled trials. Diuretic based antihypertensive regimes have been shown to reduce heart failure by 50%. Left ventricular hypertrophy regression is likely to be a good surrogate endpoint for diastolic heart failure, although definitive proof for this is not yet available. Angiotensin receptor antagonists, ACEI, calcium channel blockers, diuretics and aldosterone blockers have all been shown to cause left ventricular hypertrophy regression. We recommend these drugs to achieve strict blood pressure control together with dietary and lifestyle modification for the treatment of diastolic heart failure. We emphasise the importance of rate control, as diastolic heart-failure patients tolerate tachycardia poorly. We further argue that the pathophysiology of diastolic heart failure is part of systolic heart failure and the two should not be thought of as separate entities. Therefore, our traditional practice of using systolic heart failure treatments for diastolic heart failure is theoretically sound and should not cause us undue anxiety.     

The role of aldosterone receptor antagonists in the management of heart failure: An update

The aldosterone receptor antagonists (ARAs) spironolactone (Aldactone) and eplerenone (Inspra) have become part of standard medical therapy for heart failure, having shown clinical efficacy in randomized trials in patients with advanced symptomatic systolic heart failure, postinfarction heart failure with cardiac dysfunction, and systolic heart failure with mild symptoms. The benefits include a lower rate of death. Yet to be answered is whether the two drugs are clinically equivalent; another question is whether they may benefit everyone with symptomatic heart failure, including diastolic heart failure.     

Diastolic dysfunction

Although the annual mortality rate for diastolic heart failure is better than that for systolic heart failure, it is still greater than that for age-matched controls. Five-year mortality rates are about 50% for patients with systolic heart failure and are about 25% for patients with diastolic heart failure. In elderly patients (over 65 years of age), the outcome with systolic and diastolic dysfunction may be more comparable. In contrast to systolic heart failure, the effect of therapy in patients with diastolic heart failure has not been evaluated in large clinical controlled trials. Guidelines for managing heart failure with preserved systolic function broadly suggest the direction for management, but specific treatments are currently based on expert consensus, clinical experience, and scientific elucidation of diastolic mechanics. Although evidence-based guidelines are not available for all aspects of management of diastolic heart failure, future research will increase the knowledge of this disorder and improve treatment strategies.     

Heart failure in hypertension in the elderly

Incidence and prevalence of heart failure, in the form of systolic or diastolic ventricular dysfunction, are particularly common in elderly patients with hypertension. The importance of treating hypertension in the elderly as a means of preventing chronic heart failure was emphasized by recent trials including meta-analysis. Fastidious blood pressure control by angiotensin-converting enzyme inhibitors and angiotensin-II receptor antagonists along with low-doses diuretics as first-line therapy is recommended. However, many elderly patients with hypertension have other risk factors, target organ damages and associated cardiovascular conditions, to which the choice of the first drug should be tailored. In such cases, beta blockers, aldosterone blockers and long-acting Ca antagonists are also recommended.     

Aldosterone as a target in congestive heart failure

Based upon the results of the RALES trial and accumulating evidence about the role of aldosterone and aldosterone receptor antagonism in various disease states, the authors anticipate that aldosterone receptor antagonists will become standard therapy, along with ACE inhibitors and beta-adrenergic receptor blocking agents, in patients with heart failure that is caused by systolic left ventricular dysfunction. Furthermore, the prospect of the use of these agents in other disease states that have implicated an activated rennin-angiotensin-aldosterone cascade, such as diastolic dysfunction, aging, and atherosclerosis, remains to be tested. Until further data from well-designed, prospective, randomized trials are available, the use of aldosterone receptor antagonists should be restricted to patients with severe or progressive heart failure caused by systolic left ventricular dysfunction in whom serum creatinine level is < or = 2.0 mg/dL and serum potassium levels are < 5.0 meq/L at baseline.     

Will endothelin receptor antagonists have a role in heart failure?

Mixed ET(A/B) and selective ET(A) receptor antagonists showed promising hemodynamic and symptomatic improvements in patients with heart failure. Randomized, clinical trials to investigate the effects of ET receptor antagonists on survival in patients with heart failure still need to be conducted. Also, the effects of selective ET(A) and mixed ET(A/B) receptor antagonists on the clinical outcome of patients with CHF will have to be assessed.     

Aldosteron und Aldosteronrezeptorantagonisten in der Herzinsuffizienztherapie

In addition to the classical effects exerted by aldosterone on water and electrolyte haemostasis, recent data suggest additional roles in the pathophysiology of cardiovascular diseases. Examples are the regulation of blood pressure (by direct aldosterone effects on vessels and the CNS), myocardial hypertrophy and remodelling. Two aldosterone receptor antagonists, spironolactone and eplerenone, are currently available for the long-term therapy of chronic heart failure. Both compounds have clearly demonstrated their efficacy in heart failure treatment in end-point based clinical trials. Spironolactone, in addition to its antagonistic effects on the mineralocorticoid receptor, has anti-androgenic and gestagenic actions which can lead to endocrine side effects. Eplerenone selectively blocks aldosterone receptors and thus lacks adverse effects caused by non-specific steroid receptor blockade. The elimination half-life of eplerenone is shorter than the half-life of the active metabolites of spironolactone. Eplerenone is metabolised by CYP3A4, and pharmacokinetic interactions with inhibitors and inducers of this enzyme have to be considered. Essential for the clinical use of aldosterone antagonists in heart failure is the careful monitoring of potassium levels and renal function. The recommended doses should be followed precisely. Higher doses increase the risk of developing life-threatening hyperkalemia. Particular attention has to be paid to patients with impaired renal function. Aldosterone receptor antagonists should not be used when the glomerular filtration rate is below 50 ml/min.     

Heart failure and sudden death

Sudden death in patients with heart failure (HF) is a topic of great complexity. Neurohumoral activation including adrenergic and renin-angiotensin-aldosterone system has been a suspected trigger for lethal ventricular arrhythmias and sudden deaths. Randomized clinical trials have demonstrated that angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists and beta-adrenergic blockers improve survivals in patients with HF. Although prophylactic implantable cardioverter defibrillator (ICD) therapy is effective reducing mortality in patients with left ventricular (LV) systolic dysfunction, the ICD is unlikely to be appropriate for all patients with LV systolic dysfunction. In addition, the effect of routine prophylactic use of ICDs on health care costs must be carefully considered. The care of patients with LV systolic dysfunction should be individualized for each patient.     

Neurohormones and heart failure: the importance of aldosterone

Heart failure is a major cause of cardiovascular morbidity and mortality and its incidence is on the increase. The pathophysiology of heart failure is multi-factorial but recent studies suggest that aldosterone plays an important and independent role in its progression. Emerging evidence now suggests that aldosterone exerts renal-independent effects. It binds to its mineralocorticoid receptor to produce direct effects on the myocardium and vasculature, leading to damaging processes such as hypertrophy, necrosis, fibrosis and endothelial dysfunction, factors known to contribute to the pathophysiology of heart failure. Mineralocorticoid receptor antagonists have thus emerged as a new paradigm for the treatment of heart failure. The benefits of these agents on both morbidity and mortality when used in patients with chronic symptomatic heart failure have been demonstrated by recent trials.     

Drug and drug-device therapy in heart failure patients in the post-COMET and SCD-HeFT era

Reduced left ventricular ejection fraction and heart failure are the most important risk factors for sudden cardiac death. Recent trials have contributed to the knowledge base of critical therapies for the treatment of left ventricular systolic dysfunction and heart failure as it relates to arrhythmic and sudden cardiac death. Both pharmacologic and device therapies can reduce sudden cardiac death. The trials discussed in this paper have identified the pharmacologic and device interventions that are likely to improve the length and quality of life of the patient with left ventricular dysfunction and reduce the risk of sudden cardiac death. The mortality and anti-arrhythmic effects of angiotensin-converting enzyme inhibitors and beta-blockers have been confirmed in large-scale controlled clinical heart failure trials. Recent trials have evaluated which agents are most effective and which patients will derive the most benefit from device therapy in terms of the reduction in the risk of sudden cardiac death and in the amelioration of heart failure. The recent data from the Carvedilol or Metoprolol European Trial (COMET) and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) are discussed as the latest in the series of landmark studies that have shaped the current approaches to treating patients with heart failure and that have altered the heart failure treatment paradigm.     

Aldosterone receptor antagonism and heart failure: insights from an outpatient clinic

Objective:  In randomized clinical trials, aldosterone antagonists have been shown to reduce mortality and morbidity in heart failure (HF). The aim of the present study was to examine the risk-benefit profile of aldosterone antagonists in routine clinical practice.
Methods:  A retrospective analysis, extending over a 1-year period, of the clinical, instrumental and laboratory data of 264 HF outpatients was performed. All patients were on a β-blocker and an ACE-inhibitor (or angiotensin-II receptor-blocker) and 151 were taking an aldosterone antagonist.
Results:  At baseline, subjects treated with aldosterone antagonists had a higher NYHA class, a larger left-ventricular end-diastolic volume, a worse ejection fraction and a higher systolic pulmonary arterial pressure (sPAP). During follow-up, a greater reduction in sPAP and a tendency towards improved systolic and diastolic function were observed in subjects treated with aldosterone antagonists. Moreover, clinical and laboratory parameters did not deteriorate in patients taking aldosterone antagonists. Mortality rates were similar in the two groups (8·6% vs. 8·8%, P  = NS).
Conclusions:  The use of aldosterone antagonists in HF is associated with an improvement in cardiac function and is well tolerated. In the present study, patients administered these agents had a comparable clinical outcome to that of the control group, despite important differences in baseline risk.     

Influence of beta-blockers on mortality in chronic heart failure

OBJECTIVE: To briefly discuss the pathophysiology of heart failure and the rationale for the use of beta-blockers in the treatment of chronic heart failure. Key morbidity reduction trials are briefly mentioned, and recent mortality reduction trials are reviewed. General recommendations regarding the use of beta-blockers in heart failure are also included to guide clinical practice. STUDY SELECTION/DATA EXTRACTION: Randomized, placebo-controlled clinical trials and meta-analyses evaluating mortality reduction with beta-blockers in the treatment of heart failure were identified using a MEDLINE search from January 1993 to March 2000. Abstracts and presented results from recent scientific meetings were also considered. DATA SYNTHESIS: Beta-blockers have been shown to decrease hospitalization for worsening heart failure, decrease the need for heart transplant, improve New York Heart Association (NYHA) functional class, and increase left-ventricular ejection fraction. A mortality benefit has recently been demonstrated for patients with chronic heart failure. Carvedilol, bisoprolol, and controlled-release/extended-release metoprolol decreased the risk of dying by 65%, 34%, and 34%, respectively, in patients with primarily NYHA functional class II or III and systolic dysfunction. The benefit of these agents in patients with class IV heart failure or determining whether one agent has an advantage over another is being investigated in ongoing clinical trials. CONCLUSIONS: Several beta-blockers have demonstrated mortality reduction in the treatment of patients with NYHA functional class II or III heart failure and systolic dysfunction. Beta-blockers should be considered in these patients when they are clinically stable and taking the current standard therapy of a diuretic plus an angiotensin-converting enzyme inhibitor or other vasodilator agent.     

A review of the current evidence for the use of angiotensin-receptor blockers in chronic heart failure

Angiotensin-converting enzyme (ACE) inhibitors have a central role in the management of heart failure, reflecting the contribution of the renin-angiotensin-aldosterone system to the pathophysiology of the condition. Angiotensin-receptor blockers (ARBs) bind specifically to the angiotensin type 1 receptor and may offer further benefits compared with ACE inhibitors. Candesartan, losartan and valsartan have all been evaluated in large clinical outcome trials in heart failure. They display marked differences in pharmacokinetics and receptor-binding properties that may contribute to observed differences in outcome. ELITE II found no significant difference in outcome with losartan as compared with captopril. In the Val-Heft trial, valsartan reduced heart failure hospitalisations when added to conventional therapy including an ACE inhibitor in most patients, but had no effect on mortality. The CHARM programme showed that candesartan reduced morbidity and mortality in heart failure with reduced systolic function, both when added to ACE inhibitor therapy or when used as an alternative in patients who are intolerant to ACE inhibitors. Moreover, the CHARM-preserved study suggested that candesartan is beneficial in patients with heart failure and preserved left-ventricular systolic function. A growing body of evidence show that ARBs are an important contribution to the pharmaceutical management of patients with heart failure.     

Conivaptan: a selective vasopressin antagonist for the treatment of heart failure

Heart failure commonly manifests as a syndrome of salt and water retention. Arginine vasopressin plays an important role in volume homeostasis and may contribute to this syndrome seen in heart failure patients. Recently, a number of agents have been developed that antagonize the effects of vasopressin. Conivaptan, which is a dual antagonist of the V1a and V2 receptor, has shown promise in animal studies and in small scale human trials as a potential therapeutic option for the treatment of acute and chronic heart failure. Further large studies are being conducted, which may confirm the benefits of conivaptan and other vasopressin antagonists in heart failure patients.     

Heart failure with preserved systolic function: giving well-deserved attention to the "other" heart failure

Heart failure with preserved systolic function is common in patients hospitalized with decompensated heart failure and is associated with postdischarge morbidity and costs similar to patients with heart failure and systolic dysfunction. It is common in the older people, and hypertension and cardiac ischemia are often etiological factors. Nurses must be able to recognize left ventricular diastolic abnormalities and understand treatment priorities and treatment options on the basis of structural cardiovascular disease; etiology and risk factors; and signs, symptoms, and hemodynamic parameters. Currently, clinical treatments are on the basis of individual randomized clinical trials; however, there are general principles that should be followed during hospitalization and as part of general practice. As in the treatment of systolic heart failure, nurses have active roles in ensuring accurate assessment; optimal care planning; implementation of clinical, psychosocial; and education interventions; and timely and accurate evaluation so that patients have the best chance for successful hospital and postdischarge outcomes.     

AT1 receptor blockade for the prevention of cardiovascular events after myocardial infarction

Myocardial infarction is associated with high morbidity and mortality. Multiple therapeutic modalities have been shown to be effective in reducing adverse postmyocardial infarction outcomes. The most prominent drugs that have been used in this group of patients are those that oppose the effects of the renin-angiotensin-aldosterone system. These drugs include beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and aldosterone blockers. Following initial success with angiotensin-converting enzyme inhibitors in reducing mortality and cardiac remodeling in postmyocardial infarction patients, recent focus has been on adjunctive or alternative use of angiotensin II-receptor antagonists. Multiple large-scale, randomized trials have been conducted in order to compare angiotensin II-receptor antagonists with a combination of angiotensin II-receptor antagonists and angiotensin-converting enzyme inhibitors, and with angiotensin-converting enzyme inhibitors alone in postmyocardial infarction patients and also in heart failure. Although some results are conflicting, the weight of evidence is towards equivalency of these two groups of medicines, provided that the maximum effective dose of the angiotensin II-receptor antagonists is used. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin II-receptor antagonist may have additional benefits for some, but not all, patients; for example, reducing morbidity and mortality in patients with chronic heart failure but not in postmyocardial infarction patients. Indeed, in the postmyocardial infarction setting, the combination appears simply to increase the side effects, without conferring additional benefits. Use of aldosterone antagonists as adjunctive therapy in postmyocardial infarction patients is associated with added benefits in terms of mortality reduction and will become the standard of care in this group of patients.     

Vasopressin antagonists in the management of heart failure

Vasopressin antagonists have been studied in a variety of clinical settings, including patients with acute and chronic heart failure. The clinical trials published to date have sought to describe the clinical and physiologic effects of these agents in an effort to prove clinical efficacy and safety. A variety of agents with varying effects on V2 and V1a vasopressin receptor subtype have been studied. They have been shown to reduce bodyweight and improve serum sodium without worsening renal function. They may also decrease the need for loop diuretic use and may be particularly useful in patients with hyponatremia in the setting of volume overload. Further studies are underway that are powered to assess for morbidity and mortality benefits. The beneficial effects have been well documented but, until outcomes are understood more fully, the use of these agents should be limited to currently approved indications. In the USA, this includes only the treatment of euvolemic hyponatremia.     

Vasopressin antagonists in the management of heart failure

Vasopressin antagonists have been studied in a variety of clinical settings, including patients with acute and chronic heart failure. The clinical trials published to date have sought to describe the clinical and physiologic effects of these agents in an effort to prove clinical efficacy and safety. A variety of agents with varying effects on V2 and V1a vasopressin receptor subtype have been studied. They have been shown to reduce bodyweight and improve serum sodium without worsening renal function. They may also decrease the need for loop diuretic use and may be particularly useful in patients with hyponatremia in the setting of volume overload. Further studies are underway that are powered to assess for morbidity and mortality benefits. The beneficial effects have been well documented but, until outcomes are understood more fully, the use of these agents should be limited to currently approved indications. In the USA, this includes only the treatment of euvolemic hyponatremia.     

Diastolic heart failure in older people--myth or lost tribe?

Left ventricular diastolic dysfunction occurs due to a variable combination of abnormal myocardial relaxation and reduced ventricular compliance. The diagnosis of diastolic congestive heart failure is controversial. Some studies suggest that up to one-third of older people with symptomatic congestive heart failure (CHF) have echocardiograph evidence of diastolic dysfunction. Other authors have suggested the comorbid diseases often found in persons with suspected diastolic CHF explain the patient's symptoms and hence diastolic CHF is a misdiagnosis in many cases. Many of the characteristic echo features of diastolic dysfunction occur in normal ageing hearts. Unlike in systolic CHF, evidence for disease modifying treatment is lacking. Clinical trials currently in progress to determine the effectiveness of ACE inhibitors and angiotensin II receptor antagonists in the management of diastolic CHF may clarify the prognosis and management of this condition.