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Chronic heart failure: overview of diagnosis and drug treatment in primary care
Chronic heart failure (CHF) occurs when the heart is unable to deliver blood and oxygen at a rate that meets the requirements of the body. It is characterised by symptoms such as breathlessness and fatigue upon exertion (see Table 1), and signs of fluid retention.1,2 Most people with CHF have left ventricular (systolic) dysfunction, with reduced left ventricular ejection fraction (LVEF), typically identified on echocardiography.4 The reduced cardiac output causes activation of the sympathetic nervous system resulting in an increased heart rate, increased myocardial contractility and vasoconstriction. The renin-angiotensin-aldosterone-system (RAAS) is also activated, leading to vasoconstriction (due to angiotensin) and retention of salt and water (due to aldosterone). Together, these effects lead to further stress on the ventricular wall and dilatation, and a worsening of left ventricular systolic function.5 The most common cause of CHF is coronary heart disease (CHD), which accounts for around two-thirds of cases, and there is usually a history of myocardial infarction (MI).4 The remainder of cases have a non-ischaemic cause, for example hypertension, valvular disease, and arrhythmias such as atrial fibrillation. Advancing age, smoking, hyperlipidaemia and diabetes mellitus are among the associated risk factors.6,7 Infections, anaemia, alcohol abuse, side effects of medicines such as non-steroidal anti-inflammatory drugs (NSAIDs), and non-compliance with prescribed drugs can also exacerbate heart failure.4,8 CHF exerts a heavy toll on patients, their carers and the health service.3 Prognosis is poor. Mortality rates as high as 50% within four years have been suggested and about half of deaths from heart failure are sudden.5 CHF has a considerable impact on patient morbidity. Physical and social functioning declines, and hospitalisations increase as severity progresses. It is estimated that heart failure accounts for around 2% of all inpatient bed-days and 5% of all medical emergency admissions.3 Patients frequently suffer from severe and prolonged depression, and have poor quality of life.3,4,9 A UK study of almost 4,000 random patients aged 45 years and older, conducted in general practice between 1995 and 1999, found a prevalence of definite or probable heart failure of 3.1%, based on echocardiographic assessment.10 Prevalence rises sharply with age from about 1 in 35 people aged 65–74 years, to about 1 in 15 of those aged 75–84 years, and to just over 1 in 7 in those aged 85 years and above.4 The prevalence of CHF is increasing owing to higher survival rates from MI and the increasing elderly population.4 This Bulletin discusses the diagnosis and drug treatment of CHF due to left ventricular systolic dysfunction from the primary care perspective. A review of the treatment of acute heart failure, CHF due to other causes, and co-morbidities is beyond its scope.
How should a diagnosis be made? Diagnosing CHF is difficult because individual symptoms and signs are poorly predictive.4 In addition to the patient’s medical history, symptoms and signs, diagnosis requires objective evidence of cardiac dysfunction and demonstration of a response to treatment directed at CHF. Consideration of the causes, exclusion of other aggravating conditions and alternative diagnoses, and estimation of the prognosis are also needed.3,8 Echocardiography is the single most effective tool in the diagnosis of CHF.8 It allows assessment of chamber dimensions, wall thickness and geometry, and valve function, which are important for ruling out other conditions. It also allows assessment of systolic and diastolic ventricular function. The most important measure is left ventricular ejection fraction (LVEF) for distinguishing people with impaired or preserved systolic function.4,8 It may not be feasible, or cost effective, to refer all patients with suspected heart failure for echocardiography. Patients with a normal electrocardiograph (ECG) and/or B-type natriuretic peptide (BNP) levels are unlikely to have CHF. Therefore, these are useful screening tests, which can reduce the number of unnecessary referrals.4 The National Institute for Health and Clinical Excellence (NICE) clinical guideline on CHF recommends that those suspected of having heart failure because of their history, signs and symptoms should have a 12-lead ECG and/or BNP, with echocardiography being performed where the result of either is abnormal.1 Other tests aimed at excluding other conditions should also be performed (see Panel 1).
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to top In patients with a confirmed diagnosis of CHF, the aims of treatment are to relieve symptoms, improve quality of life, and reduce morbidity and mortality, with minimum adverse effects.3,7 In general, treatment in primary care will involve addressing lifestyle issues and the use of pharmacological therapies directed at treating CHF. In addition, associated issues that may arise from and/or further aggravate CHF will need to be addressed, such as depression or other underlying co-morbidities. Patients should be kept as fully informed as possible about their condition and the relevant treatment options, so that their preferences can be considered.1 A multi-disciplinary approach to management involving GPs, heart failure nurses, pharmacists, and other primary care support staff is recommended,2 as this may have advantages in ensuring that patients and their carers receive appropriate support and care throughout their treatment. There is evidence of an unmet need in palliative and end-of-life care, and patients and their informal carers should have access to professionals with palliative care skills within the heart failure team.2 What lifestyle issues should we consider in established CHF? Certain behavioural/lifestyle factors can influence the risk of development and progression of several types of cardiovascular disease. Although evidence specifically in patients with CHF is limited, patients should be strongly advised not to smoke and offered smoking cessation support. In addition, as alcohol is a myocardial depressant, all patients should be advised to refrain from excessive alcohol consumption, and those with alcohol-related cardiomyopathy should be advised to abstain from alcohol.2 The evidence base for recommendations on diet and nutrition in established CHF is also limited. Some patients may benefit from weight loss; however, oedema may also partially mask malnourishment. Assessment of nutritional status is therefore complex.3 Patients are often advised to monitor their weight daily to detect early signs of fluid gain and decompensation. This should be done at a set time each day (upon waking, before dressing, before eating and after voiding) so that any changes in weight can be detected. Patients should be advised to report any weight gain of more than 1.5–2.0kg over two days to their GP or heart failure specialist, as appropriate.2 Restriction of salt and fluid intake is also commonly advised. Patients should be advised to limit their salt intake to <6g/day, but fluid restriction is not routinely recommended.2 Low sodium salt substitutes are not appropriate due to their high potassium content,2 which may increase the risk of hyperkalaemia in those taking drugs that act on the RAAS. The Scottish Intercollegiate Guidelines Network (SIGN) guideline for CHF recommends motivational techniques for promoting low-intensity, unsupervised, physical activity, and there is some evidence that this can improve exercise performance.2 Walking and other forms of exercise are preferable to swimming in patients with New York Heart Association (NYHA) class III or IV CHF, due to concerns over central haemodynamic volume and blood pressure responses during immersion in water.2 Formal, supervised, moderate intensity exercise training (such as offered in cardiac rehabilitation programmes) should also be considered for stable patients in NYHA class II–III CHF2 and those stable patients with left ventricular dysfunction following MI.11 Small RCTs have found exercise training programmes improve exercise tolerance and quality of life. However, studies were of short duration, subjects were not representative of the CHF population at large, and results from meta-analyses of mortality were mixed.2 Which drugs should be used in CHF? The current NICE clinical guideline, issued in 2003, includes an algorithm to guide the treatment of patients with symptomatic heart failure due to left ventricular systolic dysfunction.1 A revised alternative algorithm is presented for consideration in Panel 2; this takes into account more recent evidence and recommendations from the 2007 SIGN guideline,2 notably with regard to the use of an A2RA. It should be noted that the NICE clinical guideline for CHF is due for review this year (2008), and when issued may include updated recommendations for drug treatment that differ from and supersede this algorithm. A summary of the key evidence supporting the use of individual drug classes in CHF is given in the following sections. Panel 3 outlines the recommended starting and target doses of some of the drugs used in the treatment of CHF. The summaries of product characteristics should be consulted for more detailed information on contraindications, cautions, interactions, side effects and monitoring information (www.medicines.org.uk).
What is the role of ACE inhibitors? One systematic review that included five RCTs (n=12,763) found that, compared with placebo over a median follow up of 35 months, ACE inhibitors were associated with lower rates of death (23.0% vs. 26.8%; odds ratio [OR] 0.80, 95%CI 0.74 to 0.87; number needed to treat [NNT] 26; P<0.001) and readmission for heart failure (13.7% vs. 18.9%; OR 0.67, 95%CI 0.61 to 0.74; NNT 19; P<0.001).13 The benefits were observed early after the start of therapy and persisted long term, and were independent of age, sex, and baseline use of diuretics, aspirin and beta-blockers. Benefits occurred over a range of ventricular function. Similar benefits were found in the three trials conducted only in patients who had experienced a MI; rates of reinfarction were also reduced (10.8% vs.13.2%; OR 0.80, 95%CI 0.69 to 0.94; NNT 42; P=0.006).13 The ATLAS study compared low-dose (2.5 to 5mg/day) and high-dose (32.5 to 35mg/day) lisinopril in 3,164 patients with mild-to-severe heart failure (NYHA class II–IV, LVEF< 30%) over a period of 39 to 58 months.14 Although there was no significant difference in the primary endpoint of all-cause mortality, high-dose lisinopril was associated with a statistically significant reduction in the risk of the combined endpoint of all-cause mortality or hospitalisation for any reason (79.7% vs. 83.8%; hazard ratio [HR] 0.88, 95%CI 0.82 to 0.96; NNT 24; P=0.002). The high-dose regimen was also associated with 24% fewer hospitalisations for heart failure during the study (1199 vs. 1576; P=0.002). Side effects (e.g. dizziness, hypotension, worsening renal function) were more common in the high-dose group, but there was no difference in the number of patients who stopped treatment because of them (high dose 17% vs. low dose 18%). Cough was responsible for less than 1% of discontinuations.14 ACE inhibitor doses should be increased upwards from their starting dose (see Panel 3) at short intervals (e.g. every two weeks) until the target dose or highest tolerated dose is reached.3 The NICE guideline takes the view that some dose of ACE inhibitor is better than no ACE inhibitor at all in those patients who cannot tolerate the target dose.3 What is the role of beta-blockers? Several systematic reviews provide consistent evidence of the benefits of beta-blockers compared with placebo.7 One such review of 22 RCTs (n=10,135), conducted in patients with any grade of heart failure, found that beta-blockers significantly reduced the risk of death (8.4% vs. 12.8%; OR 0.65, 95% credible intervalÞ [CrI] 0.53 to 0.80; NNT 23) and hospital admissions for heart failure (10.3% vs. 15.6%; OR 0.64, 95% CrI 0.53 to 0.79; NNT 19). The results were consistent for both selective and non-selective beta-blockers.16 Whether or not a class effect exists for beta-blockers in heart failure is uncertain. In the COMET study 3,029 patients were randomised to carvedilol or normal-release metoprolol tartrate, in addition to their standard treatments of ACE inhibitors and diuretics.17 Over a mean follow-up of 58 months, all-cause mortality was significantly reduced with carvedilol compared with metoprolol (34% vs. 40%; HR 0.83, 95% CI 0.74 to 0.93; NNT=17; P=0.0017), although the composite endpoint of mortality or all-cause admission was not significantly different (74% vs. 76%; HR 0.94, 95% CI 0.86 to 1.02; P=0.122).17 Given this result, it is possible that different beta-blockers have different effects in heart failure. NICE and SIGN guidelines therefore recommend that licensed beta-blockers should be used when initiating therapy in heart failure.2,3 Only bisoprolol, carvedilol and nebivolol (in patients aged over 70 years) currently have heart failure as a licensed indication in the UK. In patients who are already taking beta-blocker therapy (e.g. atenolol) when they develop heart failure, the existing NICE guidance states (based on expert opinion) that they could either continue with their current beta-blocker or switch to an alternative licensed for heart failure.3 Clinical Knowledge Summaries (CKS, formerly PRODIGY) guidance suggests that switching to a licensed beta-blocker may be a better option as the evidence suggests the benefits of beta-blockers may not be a class effect.4 Beta-blockers should be started at low doses and gradually increased up to the target, or highest tolerated, dose (see Panel 3). In the short term, they can cause decompensation and worsening of heart failure symptoms. If this occurs, it can often be managed with additional diuretic doses and/or beta-blocker dose reduction until stable.4 Beta-blockers are contraindicated in patients with co-existing asthma, second or third degree atrioventricular heart block or symptomatic hypotension,12 and should be used with caution in those with low initial blood pressure. What is the role of diuretics? A Cochrane systematic review of small RCTs identified that diuretics reduced the risk of death (three trials, n=202; OR 0.24, 95%CI 0.07 to 0.83; P=0.02) and hospitalisation for worsening heart failure (two trials, n=169; OR 0.07, 95%CI 0.01 to 0.52; P=0.01) in comparison with placebo.18 However, a recent retrospective analysis of patient data (n=2,782) from the DIG study,19 provides apparently conflicting data. Over a median of 40 months, patients with CHF who received potassium-sparing diuretics were apparently at a significantly greater risk of death from any cause (29% vs. 21%; HR 1.31, 95%CI 1.11 to 1.55; P=0.002) and hospitalisation due to heart failure (23% vs. 18%; HR 1.37, 95%CI 1.13 to 1.65; P=0.001) compared with matched patients who did not receive diuretics.19 The study raises concerns about the long-term use of diuretics in patients who are asymptomatic or mildly symptomatic. However, findings from this retrospective, observation study should only be regarded as hypothesis generating and require confirmation in RCTs. Loop diuretics tend to be preferred over thiazide diuretics in CHF. The dose should be individualised to reduce fluid retention without producing dehydration, which may place them at risk of hypotension and renal dysfunction.2 What about angiotensin–2 receptor antagonists? A2RAs have not, however, been found to be superior to ACE inhibitors. The large ELITE II trial (n=3,152) of losartan vs. captopril in patients with mainly NYHA class II–III CHF21 found no statistically significant difference in all-cause mortality (losartan 17.7% vs. captopril 15.9%; HR 1.13, 95.7%Cl 0.95 to 1.35; P=0.16). However, significantly fewer patients in the losartan group (excluding those who died) discontinued treatment because of adverse effects (9.7% vs. 14.7%; number needed to harm [NNH]=20; P<0.001), including cough (0.3% vs. 2.7%). A meta-analysis of eight RCTs involving a total of 5,201 patients followed up from four weeks to 2.7 years also found no significant difference in all cause mortality (OR 1.06, 95%CI 0.90 to 1.26) or heart failure hospitalisations (three RCTs; n=4,310; OR 0.95, 95%CI 0.80 to 1.13).22 At present, the evidence supports the use of an ACE inhibitor in preference to an A2RA.4 Current guidelines recommend A2RAs as alternatives in those patients who are truly intolerant of ACE inhibitors.1,2 There is conflicting evidence regarding the value of using an ACE inhibitor and an A2RA together for the treatment of CHF, and this combination is not recommended in current NICE guidelines.1,3 However, the more recent SIGN guideline considers the addition of candesartan an option, following specialist advice, in patients who are still symptomatic despite (optimised) treatment with an ACE inhibitor and a beta-blocker.2 This advice is based mainly on the CHARM-Added trial, in which the addition of candesartan to patients already receiving ACE inhibitor treatment (55.5% were also receiving beta-blocker treatment, 17% spironolactone) reduced the composite primary endpoint of cardiovascular death or hospital admission for CHF compared with placebo (37.9% vs. 42.3%; adjusted HR 0.85, 95%CI 0.75 to 0.96; P=0.01; NNT 23). All-cause mortality was not significantly reduced. Significantly more patients in the candesartan group permanently discontinued study medication because of an adverse event or an abnormal laboratory value (24% vs. 18%; NNH 16; P=0.0003).23 Similarly, the Val-HEFT trial of the addition of valsartan to the current therapy of 5,010 patients (93% were receiving ACE inhibitors) over a mean duration of 23 months identified a significant reduction in the proportion of patients who suffered a composite mortality and morbidity endpoint (28.8% vs. 32.1%; RR 0.87, 95%CI 0.77 to 0.97; NNT=30; P=0.009).24 However, although there was no difference in mortality between groups overall, in the subgroup of patients (36%) who were taking both an ACE inhibitor and a beta-blocker at baseline, valsartan had an adverse effect on mortality (P=0.009).24 Discontinuations due to adverse effects were significantly higher in the valsartan group than in the placebo group (9.9% vs. 7.2%; NNH=37; P<0.001). Therefore, if an A2RA is added to an ACEi in people with heart failure it is likely there is some reduction in hospitalisations and cardiovascular events and deaths - particularly if usage and doses of ACEis, beta blockers and (where indicated) spironolactone are not optimised. However, there is no evidence that adding an A2RA to previously optimised therapy will improve survival, and combination therapy confers an increased risk of adverse effects and drug discontinuations. What about aldosterone antagonists? Eplerenone is a more selective aldosterone antagonist and is less likely to cause sexual side effects than spironolactone.2 In the EPHESIS study, eplerenone was shown to improve survival compared with placebo when added to existing medical therapy within 3–14 days following acute MI. Patients (n=6,632) were required to have reduced LVEF (<40%) and diabetes or clinical signs of heart failure.26 During a mean follow up of 16 months, 14.4% of patients receiving eplerenone and 16.7% of patients receiving placebo died (RR 0.85; 95%CI 0.75 to0.96; NNT=43; P=0.008). Rates of severe hyperkalaemia were significantly higher with eplerenone than with placebo (5.5% vs. 3.9%; NNT=63; P=0.002).26 There is no evidence for eplerenone in other CHF settings, but the SIGN guideline considers eplerenone as an alternative in patients who experience the side effect of gynaecomastia with spironolactone.2 Both spironolactone and eplerenone are potassium-sparing diuretics and are contraindicated in patients with renal impairment or hyperkalaemia. Careful monitoring of blood urea, creatinine and potassium is required with both agents.2 The efficacy and safety of combining aldosterone antagonists with both an ACE inhibitor and an A2RA is uncertain and is not recommended.2 If patients are still symptomatic following treatment with both an A2RA and an ACE inhibitor, the A2RA should be stopped before addition of spironolactone (Panel 2). What is the role of digoxin? Digoxin is also recommended as a treatment for patients with atrial fibrillation and any degree of heart failure in the current NICE guideline.5 The SIGN guideline states that beta-blocker therapy is preferred for control of ventricular rate, but digoxin may be used while beta-blocker therapy is being initiated.2
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