Tailoring therapy in chronic heart failure

The syndrome of chronic heart failure consists of two main components – cardiac dysfunction and its related symptoms. In every patient, the severity of the syndrome reflects the course of these two components. Establish that the patient has heart failure Identify presenting symptom(s) Assess the severity of limitation Determine the etiology Exclude or confirm concomitant disease Predict the prognosis Choose the therapy Monitor progress Choosing and tailoring therapy for the individual patient is based primarily on changes in symptoms. A number of factors may influence symptom response and these form the focus for this review: adherence, comorbidities, and renal function. Key issues in the appropriate tailoring of therapy are also discussed. Adherence to treatment is an important issue in cardiology, and particularly in heart failure, where patients are likely to require a combination of treatments. The importance of adherence to treatment was demonstrated in CHARM, the largest randomized trial of heart failure to be performed to date5. In the placebo arm of CHARM (n = 3774), patients who adhered to therapy at a rate ≤80% were at significantly increased risk of death (P < 0.001) (Figure 1). The explanation of these findings is that patients who adhered poorly to placebo (and, probably to their other, life-saving medications) were at increased risk of death. Comorbidities may have a substantial impact on the prognosis of heart failure. The following discussion focuses on three significant comorbidities: diabetes, depression, and anemia. An analysis of the impact of comorbidities in CHARM identified diabetes as a strong, independent prognostic risk factor for all-cause mortality, which ranked second in impact only to age, and above myocardial systolic function (Figure 2)11. Diabetes clearly requires to be managed carefully following its diagnosis in patients with heart failure. Depression is increasingly recognized as an important comorbidity in heart failure that impacts on prognosis independently of other factors such as the patient's age and the severity or etiology of heart failure. A meta-analysis of seven studies that investigated the impact of depressive symptoms on mortality in heart failure identified a twofold elevated risk of short- to medium-term mortality for patients who had depressive symptoms (odds ratio 2.24; range 1.39–3.60)2. Why depression should increase the risk of mortality in heart failure remains to be elucidated. There may be a number of mechanisms. Depression may, for instance, decrease adherence to changes in lifestyle, increase the number of risk factors for heart failure, increase the risk of arrhythmias/sudden cardiac death, alter inflammatory markers, increase platelet aggregation, and increase coronary blood flow through increased stress4. Depression is a common finding in patients with chronic heart failure, at a frequency of 13.9% for major depressive episodes and 21% for mild or subclinical depression1. Screening for depression is straightforward and can be performed based on two simple questions: “Have you lost interest in pleasurable activities” and “Are you feeling blue or down”? A positive answer to these questions will identify patients in need of further investigation. The impact of depression on heart failure will likely be investigated widely in the next few years. These investigations may extend to include the impact of interventions for depression, for which there is little evidence currently. Anaemia is an independent predictor of increased mortality in chronic heart failure, as shown recently in a meta-analysis of seven studies13. By this analysis, the risk of death increased as the haemoglobin concentration decreased. 13 also observed that an elevated risk of anemia in patients with chronic heart failure is associated with a number of clinical characteristics. These characteristics include advanced age, female gender, chronic renal disease, heart failure severity, acute (as compared to chronic) settings, other comorbidities, decreased body mass index, and the use of ACE inhibitor therapy. The appropriate management of anaemia in chronic heart failure remains unclear. Experience of anaemia in chronic renal disease suggests that to elevate haemoglobin levels too greatly increases the risk of mortality. An ongoing trial – RED-HF – is investigating the management of anemia in chronic heart failure and, it is hoped, will offer guidance on therapy. Renal function and cardiac function are interrelated via the cardiorenal axis, and dysfunction in one system may lead to deterioration in the other. The influence of renal dysfunction on heart function is exemplified by data from CONSENSUS, which was the first trial to show that ACE inhibitors improve survival in heart failure3. An analysis of the effects of enalapril on mortality in CONSENSUS showed that benefits of treatment were predominantly in patients with a baseline creatinine level above 120 µmol/l, i.e. those patients at greatest risk of developing renal dysfunction (Figure 3). The impact of renal dysfunction was also investigated in CHARM, a study in which a large proportion of patients had a baseline glomerular filtration rate (GFR) <60 ml/min/1.73 m2,6. Patient outcome, measured in terms of cardiovascular death or rehospitalization due to heart failure, was significantly related to the degree of baseline renal dysfunction (Figure 4). The influence on outcome of a GFR at 35 ml/min/1.73 m2 was similar in magnitude to that of a left ventricular ejection fraction of 20%. GFR and New York Heart Association (NYHA) class act together to increase risk of mortality, so that patients with a high NYHA class and a low GFR require strenuous efforts to improve their prognosis7. Therapy may need to be adjusted if there is deterioration in cardiac function or in symptoms. Options to adjust therapy to successfully reverse the patient's deterioration include changing the agent administered, amending the dose of the agent given, and introducing a combination of agents. As the ESC guidelines point out, choosing an appropriate combination of agents is the key to successful therapy for many patients. It is recommended that almost all patients, regardless of their NYHA class, should receive a combination of an ACE inhibitor and a beta-blocker. Patients may additionally, according to their individual clinical circumstances, receive an angiotensin receptor blocker or an aldosterone antagonist (Figure 5). Complementing these approaches for improved survival, the components of diuretic therapy may be modified to improve symptom control. The beta-blockers were, until relatively recently, contraindicated for the treatment of chronic heart failure because of their potential for adverse affects. These deleterious effects included hypotension, hypoperfusion, increased fluid retention, atrioventricular block, and (in the longer term) increased symptoms of heart failure. Now it is well established that beta-blockers are among the most effective agents available for the treatment of chronic heart failure9. Beta-blockers, together with ACE inhibitors, are indicated in the first-line treatment of potentially all patients with stable mild or moderate heart failure. Providing appropriate cautions are taken or specialist advice is sought, the use of beta-blockers may be attempted in all patients, with the sole exception of those with bronchial asthma. The beta-blockers recommended in the ESC guidelines are limited to those agents for which well-documented evidence is available, and the guidelines include specifications on the target dose (Figure 6). Clinical trials suggest that the target dose for a beta-blocker may be achieved in as many as two thirds of patients. It is likely that the target dose is reached in a lower proportion of patients in routine care because dose escalation is halted early. Although this is less than optimal, it is better to administer some beta-blocker therapy than none at all. Monitoring during beta-blocker dose escalation must include the patent's heart rate, blood pressure, and clinical status (in particular, for signs of congestion and change in body weight). A specialist heart failure nurse in a nurse-led outpatient clinic can offer valuable assistance in a number of roles including patient education, follow-up, and dose titration. A continued deterioration in the patient's symptoms may require adjustment to therapy. For instance, if congestion is increasing, the diuretic dose may be doubled and, if that measure alone is not successful, the beta-blocker dose may be halved. In a patient with marked fatigue and / or bradycardia, the beta-blocker dose may be halved, followed by review at 1–2 weeks; specialist advice should then be sought, if required. A serious deterioration in symptoms may similarly indicate a halving in the beta-blocker dose and the need for specialist advice. No change in beta-blocker therapy is usually required for patients with asymptomatic low blood pressure. For patients with symptomatic hypotension in the presence of dizziness, light-headedness, and / or confusion, supplemental therapy with nitrates, calcium channel blockers, or other vasodilators may be considered. In the absence of signs or symptoms of congestion, the diuretic dose may also be reduced. Specialist advice is recommended if these measures do not resolve the symptoms. A frequently asked question is how should beta-blockers be combined with ACE inhibitors in patients with low blood pressure, which is a particular problem in advanced heart failure. For these patients, the ACE inhibitor should usually be initiated and optimally titrated before the beta-blocker is added. An earlier initiation of beta-blocker therapy may be considered for some patients, however, including those who remain tachycardic. Patients with dilated cardiomyopathy, in particular, may show a dramatic response to beta-blocker therapy in these circumstances. Beta-blockers should never be stopped suddenly, unless absolutely necessary, because of the risk of a rebound in myocardial ischaemia/infarction and arrhythmias. Ideally, specialist advice should be sought before beta-blocker therapy is discontinued. ACE inhibitors have a well-known mechanism of action (Figure 7) and well-established efficacy in heart failure, and these agents will not be considered in detail here. Despite the benefits of ACE inhibitor therapy in terms of short-term mortality, there remains an enormous unmet need. This is exemplified in the CONSENSUS trial, which found that, by 5 years, almost all the patients in the trial had died12. A practical approach to meeting the unmet needs of a patient who is receiving combined ACE inhibitor and beta-blocker therapy is to consider which additional agent to add. The options include a therapy that targets the ATII receptor or one that targets other effects of angiotensin II, such as production of aldosterone. The effects of adding an angiotensin receptor blocker were investigated in CHARM. In this placebo-controlled trial, candesartan added to beta-blocker therapy (with background ACE inhibitor therapy in 60% of patients) reduced the one-year mortality by 33% (P < 0.001) compared to placebo added to background therapy14. Candesartan additionally reduced morbidity, measured as rehospitalization for worsening heart failure (hazard ratio 0.80, P < 0.001). The second option, of adding an aldosterone antagonist, was investigated in RALES10. This trial demonstrated that spironolactone improved survival over 3 years compared to placebo in symptomatic patients with systolic dysfunction. Of note, only 10% of patients in RALES were receiving background beta-blocker therapy. There are no trials that directly compare the benefits of an angiotensin receptor blocker and an aldosterone antagonist when added to existing therapy. However, analyses of the effects of candesartan and spironolactone in NYHA III/IV patients in CHARM and RALES indicate that these two therapies offer similar benefits on mortality, with hazard ratios of 0.70 and 0.79, respectively, compared to placebo (Figure 8). To summarize this section, patients who remain symptomatic during treatment with an ACE inhibitor and a beta-blocker should additionally receive either an angiotensin receptor blocker or an aldosterone antagonist, followed by close monitoring of the response. A practical approach to combination therapy with these agents, based on the trial evidence available, is provided in Figure 98. Comorbidities have a substantial impact on the prognosis of patients with chronic heart failure and assessments should include indications for diabetes, depression, and anemia. Renal dysfunction is additionally important because of its potential to interact with heart disease. In patients who deteriorate during therapy, a structured approach to optimizing therapy is recommended. This typically comprises tailoring patients' therapy with a combination of additional agents.