Class III Marked limitation of physical activity \200\224symptoms with minimal levels of exertion (e. g., dressing) Class IV Symptoms at rest CHAPTER 5 Heart failure 220 Suspected heart failure because of history, symptoms, and signs. Seek to exclude heart failure Other recommended tests: (mostly to exclude other conditions) through: 12 lead ECG \200 and/or natriuretic peptides (BNP or NT proBNP) \200\223where available. chest X-ray \200 blood tests: U&ES, creatinine, FBC, RFTs, LFTs, glucose, and lipids \200 urinalysis, peak flow or spirometry One or more abnormal Both normal Heart failure unlikely, Consider alternative diagnosis, Imaging by echocardiography* Abnormal Assess HF severity, etiology, precipitating and exacerbating factors and type of c ardiac dysfunction. Correctable causes must be identified. Consider referral. No abnormality detected Heart failure unlikely, but if diagnostic doubt persists consider d iastolic dysfunction and consider referral for specialist assessment. Figure 5.3 Algorithm summarizing recommendations for the diagnosis of heart failure. Altern ative methods of imaging the heart should be considered when a poor image is produced by tr ansthoracic Doppler 2D echocardiography. Alternatives include transesophageal echocardi- og raphy (TEE), radionuclide imaging, or cardiac magnetic resonance imaging. BNP, B-type natri - uretic peptide; ECG, electrocardiogram; CBC, complete blood count; LFTs, liver function t ests; NTproBNP, N-terminal pro-B-type natriuretic peptide; TFTs, thyroid function tests; U& Es, urea and electrolytes. (a) (b) Figure 5.4 CXR \201 ndings in heart failure. (a) There is cardiomegaly with prominent upp er lobe vessels and alveolar edema ( \200\234bat \200\231s wing shadowing \200\235). (b) Ma gni \201 cation of right costophrenic angle showing septal lines (Kerley B lines) due to i nterstitial edema. DIAGNOSIS AND INITIAL WORKUP 221 Blood tests These may alert you to possible underlying etiologies for heart failure as well as establishing a baseline prior to initiation of therapy. \200 CBC (anemia), Chem7, glucose, liver function tests (LFTs), thyroid function tests (TFTs) (h ypo- or hyperthyroidism), uric acid BNP has a high negative predictive value if <100 pg/mL. Investigations for selected patients with heart failure \200 \200 \200 \200 Ferritin Immunoglobulins and protein electrophoresis Viral titers BNP: serum levels of natr iuretic peptides are frequently elevated in patients with impaired LV function. They appear to have a useful role in identifying patients who merit more extensive investigation of ca rdiac function. Coronary angiography Holter monitoring ( QT dispersion, heart rate variab ility) Cardiopulmonary exercise testing or 6-minute walk test Pulmonary function tests Radi onuclide ventriculography Stress imaging (for assessment of viable/hibernating myocardium) Cardiac magnetic resonance \200 \200 \200 \200 \200 \200 By using these signs and symptoms as well as initial basic diagnostic tests, one can make t he diagnosis of heart failure with reasonable certainty (see Table 5.3). Table 5.3 Framingham criteria for diagnosis of heart failure* Major criteria \200 \200 \200 \200 \200 \200 \200 Paroxysmal nocturnal dyspnea Raised JVP; distended neck veins Crackles in lung \201 elds Cardiomegaly on CXR Acute pulmonary edema S3 gallop rhythm Hepatojugular re \202 ux Weight loss >4.5 kg in 5 days in response to tre atment of heart failure Minor criteria \200 \200 \200 \200 \200 \200 Bilateral ankle edema Nocturnal cough Dyspnea on ordinary exertion Hepatomegaly Pleural effusion Tachycardia rate >120/min Decrease in vital capacity by one-third This table was published in Ho KL (1993). The epidemiology of heart failure: the Framingham Study. J Am Coll Cardiol, 22(Suppl A):6A. Copyright Elsevier 1993. CHAPTER 5 Heart failure 222 Management Management outline \200 \200 Establish that the patient has heart failure. Ascertain severity of symptoms and presenting features: pulmonary edema, exertional breathlessness, fatigue, peripheral edema. Try to de termine the etiology of heart failure. Identify precipitating and exacerbating factors and any concomitant diseases relevant to heart failure and its management. Estimate prognosis. Anticipate complications. Counsel the patient and relatives. Choose appropriate management (e.g., see Fig. 5.5). Monitor progress and manage accordingly. \200 \200 \200 \200 \200 Aims of treatment 1. Prevention of heart failure \200 Prevention and/or controlling of diseases leading to cardiac dysfunction and heart failure Prevention of progression to heart failure once cardiac dysfunction is established 2. Maintenance or improvement in quality of life 3. Increased duration of life It is always better to try and prevent heart failure than to treat it once it has developed. This includes management of risk factors for ischemic heart disease, treatment of ischemia and revascularization where appro- priate, early reperfusio n therapy for acute MI, aggressive management of hypertension, and management of diabetes a nd valvular heart disease. Stop exacerbating drugs if possible (NSAIDs, steroids, negative inotropes). Education of the patient and relatives is an important aspect of manage- ment of patients w ith heart failure. Many hospitals now employ heart fail- ure specialist nurses who are able to provide excellent service and should be used whenever possible. Formal cardiac rehabili tation classes may be bene \201 cial. It is important to explain the diagnosis and symptom s, how the treatment will help, the role of self-weighing, and the importance of exer- cise . Mild to moderate aerobic exercise can increase functional capacity in these patients. General measures include restriction of dietary salt and water intake, smoking cessation, r educing alcohol intake (stopping completely if alcohol is implicated in the etiology of HF) , addressing obesity with a weight- reducing program, and vaccinations (Pneumovax once and in \202 uenza yearly). Patients should also be counseled about their drug therapy. The desired effects and potenti al side effects need to be explained, as well as the fact that while effects may take some time to become apparent, it is import- ant to stay adherent to the therapy. Self-management of diuretics may be appropriate for some patients. Patients also need to be aware of drug interactions (e.g., with over-the-counter NSAIDs). MANAGEMENT 223 Generalist New diagnosis Add Diuretic Diuretic therapy is likely to be required to control congestive symptoms and f luid retention Add Digoxin If a patient is sinus rhythm remains symptomatic despite therapy with a diuretic, ACE inhibitor (or angiotensin-II receptor antagonist) and B-blocker, OR i f a patient is in atrial fibriallation then use as first line therapy Or if ACE inhibitor not tolerated (e.g., due to severe cough) Consider angiotensin-II recep tor antagonist Start ACE inhibitor and titrate upward t u p n Add B-blocker and titrate upward i t s i l a i c e p S Add spironolactone If patient remains moderately to severely symptomatic despite optimal dr ug therapy listed above Specialist Seek specialist advice for further options Figure 5.5 Seeking a specialist opinion for patients with heart failure. Reproduced with pe rmission from NICE guidelines. www.nice.org.uk CHAPTER 5 Heart failure 224 Diuretics in heart failure Diuretics are used for the symptomatic treatment of \202 uid o verload (either pulmonary congestion or peripheral edema). With the exception of aldos- ter one antagonists, there are no randomized, controlled trials that have shown any prognostic bene \201 t. However, they do improve symptoms and may slow the progression of LV remodeli ng. Loop diuretics (furosemide, bumetanide, and torsemide) are the most effective. Use the lowe st dose that controls symptoms effectively (see Table 5.4). If there is insuf \201 cient response to diuretic, a combination of a loop diu- retic and a thiazide diuretic can be used (see Box 5.4). Thiazides reduce magnesium absorption and hy pomagnesaemia may occur with prolonged use. Potassium-sparing diuretics (amiloride and triamterene) used alone do not achieve a net neg ative Na+ balance, as Na+ retention in HF occurs proximal in the tubule. They should be use d with caution in conjunction with ACE inhibitors and spironolactone (may result in hyperka lemia). In \200\234diuretic resistance, \200\235 the effectiveness of loop diuretics may decrease with worsening HF. This is due to a variety of factors, including reduced bioavailability o f oral drug, excessive dietary salt intake, compensatory hypertrophy of the distal tubule i ncreasing Na+ reabsorption, other drugs (e.g., NSAIDs or COX-2 inhibitors), and reduced ren al perfusion pressure by volume depletion. This can be managed by switching to IV diuretics (perhaps by continuous infusion) and/or ad ding in a thiazide. In hospitalized patients, treatments such as IV dopamine at low dose an d even short-term infusion of nesiritide (human BNP) have been shown to enhance effects of diuretics. Table 5.4 Diuretics dosages for treating heart failure Loop diuretics Initial dose Maximum dose Furosemide 20 \200\22340 mg qd or bid Titrate to achieve dry weight (up to 400 mg daily) Bumetanide 0.5 \200\2231 mg qd or bid Titrate to achieve dry weight (up to 10 mg daily) Torsemide 10 \200\22320 mg qd or bid Titrate to achieve dry weight (up to 200 mg daily) Thiazides Hydrochlorothiazide 25 mg qd 50 \200\22375 mg daily Metolazone 2.5 mg qd 10 mg daily Indapamide 2.5 mg qd 2.5 mg daily DIURETICS IN HEART FAILURE 225 Box 5.4 Diuretic therapy for heart failure Initial diuretic treatment \200 \200 \200 Loop diuretics or thiazides. Always administered in addition to an ACE inhibitor (or ARB) I f GFR <30 mL/min, do not use thiazides, except as therapy prescribed synergistically with a loop diuretics (see below). Inadequate response \200 \200 \200 Increase dose of diuretic. Combine loop diuretics and thiazides. With persistent \202 uid retention: administer loop diuretics twice daily and consider changing from furosemide to alternatives that are better absorbed (e.g., bumetanide or torsemide). In severe chronic he art failure add a thiazide (e.g., metolazone) with frequent measurement of creatinine and e lectrolytes. Potassium-sparing diuretics: triamterene, amiloride, spironolactone \200 Use only if hypokalemia persists after initiation of therapy with ACE inhibitors and diuret ics. Start 1-week low-dose administration, check serum potassium and creatinine after 5 \200\2237 days, and titrate accordingly. Recheck every 5 \200\2237 days until potassium val ues are stable. ACE, angiotensin-converting enzyme; CHF, chronic heart failure; GFR, glomerular \201 ltra tion rate. Adapted with permission from Swedberg K, et al. (2005). Eur Heart J 26(11):1115 \200\223114 0. CHAPTER 5 Heart failure 226 ACE inhibitors for heart failure Angiotensin-converting enzyme (ACE) inhibitors signi \201 cantly improve the survival and symptoms and reduce hospitalization of patients with mod- erate and severe HF and LV systolic dysfunction. ACE inhibitors should be used as \201 rs t-line therapy for patients with a reduced LV systolic func- tion (ejection fraction [EF] < 40% \200\22345%). The absolute bene \201 t is greatest in patients with most severe heart failure. In the absence of \202 uid retention, ACE inhibitors should be given \201 rst. In patients with \202 uid retention, diuretics may be added. Furthermore, the dosage of ACE inhibitors should be up-titrated to the dosages shown to be effective in large, controlled trials in heart failure, and not titrated on the basis of sy mptomatic improvement alone (see Table 5.5). Asymptomatic patients with a documented LV systolic dysfunction ben- e \201 t from long-te rm ACE inhibitor therapy. Large trials (SOLVD Prevention Study, SAVE, and TRACE) have shown that asymptomatic patients, but with left ventricular dysfunction, will have less developm ent of sympto- matic heart failure and hospitalizations for heart failure. ACE inhibitors may prevent further deterioration of LV function and attenuate further cardi ac dilatation. However, they do not consistently reduce cardiac size. Starting an ACE inhibitor \200 \200 \200 \200 Review diuretic dose and avoid excessive diuresis before treatment. Consider giving \201 rst dose at night to minimize the hypotensive effect. Start with a low dose and build up to target levels. Stop treatment if there is a substantial deterioration in renal function (s ee Table 5.6). Avoid NSAIDs and potassium-sparing diuretics. Check BP and Chem7 1 \200\2232 weeks after each dose increment and at 6-month intervals. Low BP (systolic <90 mmHg) is ac ceptable if patient is asymptomatic. \200 ACE INHIBITORS FOR HEART FAILURE 227 Table 5.5 Which ACE inhibitor and at what dose? Licensed ACE-I Starting dose (mg) Target dose (mg)* Captopril 6.25 three times daily 50 \200\223100 three times daily Enalapril 2.5 twice daily 10 \200\22320 twice daily Fosinopril 10 once daily 40 once daily Lisinopril 2.5 \200\2235.0 once daily 30 \200\22335 once daily Quinapril 2.5 \200\2235.0 once daily 10 \200\22320 once daily Target dose is based on manufacturer \200\231s recommendation rather than large outcome stu dy. How to use? \200 \200 Start with a low dose (see above). Seek specialist advice when the patient is on a high dos e (e.g., furosemide 80 mg) of a loop diuretic. Double dose at not less than 2-week interval s. Aim for target dose (see above) or, failing that, the highest tolerated dose. Remember, some ACE inhibitor is better than no ACE inhibitor. Monitor blood electrolytes (in particul ar potassium), urea, creatinine, and blood pressure. When to stop up-titration/down-titrati on \200\224see Table 5.6. \200 \200 \200 Advice to patient? \200 \200 Explain expected bene \201 ts. Treatment is given to improve symptoms, prevent worsening o f heart failure, and increase survival. Symptoms improve within a few weeks to a few months . Advise patients to report principal adverse effects, symptomatic hypotension, cough. \200 i.e., dizziness/ CHAPTER 5 Heart failure 228 Table 5.6 Problem solving with ACE inhibitors Asymptomatic low blood pressure usually does not require any change in therapy. Symptomatic hypotension \200 If there is dizziness, light-headedness, and/or confusion and a low blood pressure, conside r discontinuing nitrates, calcium channel blockers,* and other vasodilators. If no signs or symptoms of congestion consider reducing diuretic dose. If these measures do not solve the problem seek specialist advice. \200 Cough \200 Cough is common in patients with chronic heart failure, some of whom may also have smoking- related lung disease. Cough is also a symptom of pulmonary edema, which should be excluded when a new or worsening cough develops. ACE inhibitor \200\223induced cough rarely requires treatment discontinuation. If the patient develops a troublesome dry cough that interferes with sleep and is likely to be caused by an ACE inhibitor, consider substituting an angiot ensin-II receptor antagonist for the ACE inhibitor. \200 Worsening renal function \200 + is expected after initiation of an ACE Some rise in urea, creatinine, and K inhibitor; if the increase is small and asymptomatic n o action is necessary. An increase in creatinine of up to 50% above baseline, or to 200 m ol, whichever is smaller, is acceptable. An increase in K + rise excessively, consider stop ping concomitant If urea, creatinine, or K nephrotoxic drugs (e.g., NSAIDs), nonessential v asodilators (e.g., calcium antagonists, nitrates), and K+ supplements/retaining agents (tri amterene, amiloride), and if there are no signs of congestion, reduce dose of diuretic. + t han those outlined above persist despite If greater rises in creatinine of K adjustment of concomitant medications, the dose of ACE inhibitor should be halved and blood chemistry rec hecked; if there is still an unsatisfactory response, specialist advice should be sought. + rises to (cid:116)6.0 mmol/L or creatinine increases by >100% or to above If K 4 mg/dL, th e dose of ACE inhibitor should be stopped and specialist advice sought. Blood electrolytes should be monitored closely until K concentrations are stable. \200 + to(cid:3)(cid:100)5.9 mmol/L is acceptable. + and creatinine Note: it is very rarely necessary to stop an ACE inhibitor, and clinical deterioration is l ikely if treatment is withdrawn. Ideally, specialist advice should be sought before treatme nt discontinuation. *Calcium channel blockers should be discontinued unless absolutely esse ntial, e.g., for angina or hypertension. Adapted with permission from McMurray et al. (2001 ). Practical recommendations for the use of ACE Inhibitors, beta-blockers and spironolacton e in heart failure: putting guidelines in to practice. Eur J Heart Failure 3(4):495 \200 \223502. B-BLOCKERS FOR HEART FAILURE 229 B-Blockers for heart failure B-Blockers were once contraindicated in patients with heart fa ilure. However, several studies (Carvedilol studies, Merit-HF, COPERNICUS; see Chapter 15) have shown that they are effective in reducing the risk of sudden cardiac death (of the ord er of 30%). B-Blockers are recommended for all patients with HF, whether due to ischemic heart disease or not and irrespective of the severity of LV dys- function (NYHA classes II to IV). The effect does not appear to be a class effect, and only metoprolol, carvedilol, and bisoprolol can be recommended in HF. B-Blockers should be initiated under careful physician monitoring, as there may be an initi al deterioration in heart failure symptoms. The drugs are started at a low dose and up-titr ated to target over a period of weeks or months (see Table 5.7). Starting a B-blocker (see Table 5.8) \200 \200 \200 Patients should be on an ACE inhibitor if possible. Heart failure symptoms should be relati vely stable before initiation. Start with a low dose and titrate up to target every 1 \200 \2232 weeks if the preceding dose was tolerated. Monitor patient for symptoms and signs of HF, bradycardia, and hypotension. If symptoms worsen, increase dose of diuretics or ACE inh ibitor initially. The B-blocker dose may need to be decreased transiently. If patient is hy potensive, reduce dose of vasodilators and reduce dose of B-blockers if necessary. Table 5.7 Titration scheme for B-blockers Drug First dose Increments Target dose Carvedilol 3.125 mg bid 6.25, 12.5, 25, 50 50 mg daily Bisoprolol 1.25 mg daily 2.5, 3.75, 5, 7.5, 10 10 mg daily Metoprolol succinate 12.5 mg daily 25, 50, 100, 200 200 mg daily NB: Carvedilol maximum dosage is 25 mg bid if there is severe heart failure. For patients w ith mild \200\223moderate heart failure, maximum dosage is 50 mg bid if weight is above 85 kg; otherwise maximum dosage is 25 mg bid. CHAPTER 5 Heart failure 230 Table 5.8 B-Blockers How to use? \200 \200 \200 \200 \200 Start with a low dose (see above). Double dose at not less than 2-week intervals. Aim for t arget dose (see above) or, failing that, the highest tolerated dose. B-blocker is better th an no B-blocker. Remember some Monitor heart rate, blood pressure, and clinical status (sym ptoms, signs, especially signs of congestion, body weight). Check blood electrolytes, urea, and creatinine 1 \200\2232 weeks after initiation and 1 \200\2232 weeks after \201 nal d ose titration. When to down-titrate or stop up-titration \200\224see Table 5.9. Advice to patient \200 \200 Explain expected bene \201 ts. Emphasize that treatment is given as much to prevent worsen ing of heart failure as to improve symptoms. B-Blockers also increase survival rates. If sy mptomatic improvement occurs, this may develop slowly \200\224over 3 to 6 months or longer. Temporary symptomatic deterioration may occur (estimated 20% \200\22330% of cases) during initiation/up-titration phase. Advise patient to report deterioration (see Table 5.9) and t hat deterioration (tiredness, fatigue, breathlessness) can usually be easily managed by adj ustment of their medication. Patients should be advised not to stop B-blocker therapy witho ut consulting their physician. Patients should be encouraged to weigh themselves daily (aft er waking, before dressing, after voiding, and before eating) and to consult their doctor i f they have persistent weight gain. B-BLOCKERS FOR HEART FAILURE 231 Table 5.9 Problem solving with B-blockers Worsening symptoms or signs (e.g., increasing dyspnea, fatigue, edema, weight gain) \200 B-blocker If marked fatigue (and/or bradycardia, see below), halve dose of (if increasing diuretic do es not work). If increasing congestion, double dose of diuretic and/or halve dose of B-bloc ker (if increasing diuretic does not work). Reassess patient in 1 \200\2232 weeks; if not i mproved seek specialist advice. If serious deterioration, halve dose of (see note below) (r arely necessary); seek specialist advice. \200 B-blocker or stop this treatment Low heart rate \200 B-blocker or, if If <50 beats/min and worsening symptoms, halve dose of severe deterioration, stop B-blocker (rarely necessary). Consider need to continue treatment with other drugs (if any) that slo w the heart (e.g., digoxin, amiodarone, diltiazem) and discontinue if possible. Arrange ECG to exclude heart block. Seek specialist advice. \200 Asymptomatic low blood pressure \200 This does not usually require any change in therapy. Symptomatic hypotension \200 If low blood pressure causes dizziness, light-headedness, or confusion, consider discontinu ing drugs such as nitrates, calcium channel blockers, and other vasodilators. If no signs o r symptoms of congestion, consider reducing diuretic dose. If these measures do not solve t he problem seek specialist advice. \200 Note: B-Blockers should not be stopped suddenly unless absolutely necessary (there is a ris k of a \200\234rebound \200\235 increase in myocardial ischemia/infarction and arrhythmias ). Ideally, specialist advice should be sought before treatment discontinuation. Adapted wi th permission from McMurry et al. (2001). Practical recommendations for the use of ACE Inhi bitors, beta-blockers and spironolactone in heart failure: putting guidelines in to practic e. Eur J Heart Failure 3:495 \200\223502. CHAPTER 5 Heart failure 232 Angiotensin II receptor antagonists for heart failure Angiotensin II receptor blockers (ARB s) are often used in those patients who do not tolerate an ACE inhibitor because of cough. In patients with heart failure, ARBs are as effective as ACE inhibitors in reducing mortali ty and morbidity. One study (ValHeft II) showed that the combination of an ACE inhibitor and valsartan was be tter than either drug alone. However, this bene \201 t was reversed in patients also takin g a B-blocker. This adverse effect was not seen in the CHARM-Added Trial, which used the AR B candesartan. When combined with ACE inhibitors, ARBs reduce HF hospitalizations. In patients with heart failure and preserved LV systolic function (i.e., patients with diastolic dysfunction), the ARB candesartan reduces hospi- talization for HF. ALDOSTERONE RECEPTOR ANTAGONISTS IN HEART FAILURE 233 Aldosterone receptor antagonists in heart failure Aldosterone levels are not reduced by ACE inhibitors, and these raised levels produce myocardial \201 brosis and predispose to arr hythmias. In the RALES study, spironolactone (an aldosterone receptor antagon- ist) produced a 30% re duction in total mortality of patients with severe CHF (NYHA classes III and IV) compared w ith placebo. Long-term usage of spironolactone is associated with gynecomastia, impotence, and menstrual irregularities. Newer agents have less of these antiandrogenic and progesterone-like effec ts. Eplerenone was evaluated in EPHESUS (Eplerenone Post Acute Myocardial Infarction Heart Fail ure Ef \201 cacy and survival Study). Patients with LVEF <40% were randomized to eplerenon e or placebo 3 \200\22314 days after acute MI. Eplerenone produced a signi \201 cant (15%) reduction in mor- tality. Gynecomastia, breast tenderness, and impotence were no different in the two groups. Starting spironolactone \200 Consider whether a patient is in severe heart failure (NYHA III \200\223IV) despite ACE inh ibition and diuretics. Check serum K Start 25 mg spironolactone daily (see Table 5.10). Che ck serum K If at any time serum K if serum K+ >5.5 mmol/L. If after 1 month symptoms persis t and K 50 mg daily. Check serum potassium/creatinine after 1 week. If endocrine-related si de effects of spironolactone are observed, change to eplerenone. \200 \200 \200 + (<5 0 mmol/L) and creatinine (<2.8 mg/dL). + and creatinine after 4 \200\2236 days. + >5 \200\2235.5< mmol/L, reduce dose by 50%. Stop it +<5.5 mmol/L, increase to CHAPTER 5 Heart failure 234 Table 5.10 Which dose of spironolactone? 12.5 \200\22325 mg daily, although 50 mg may be advised by a specialist if heart failure de teriorates and there is no problem with hyperkalemia. How to use? \200 \200 Start at 25 mg once daily. Check blood chemistry at 1, 4, 8, and 12 weeks; 6, 9, and 12 mon ths, and every 6 months thereafter. If K 2.3 mg/dL, reduce dose to 25 mg on alternate days and monitor blood chemistry closely. If K and seek specialist advice. + rises to between 5.5. and 5.9 mmol/L or creatinine rises to + rises to (cid:116)6.0 mmol/L or creatinine to >2.3 mg/dL stop spironolactone Advice to patient? \200 \200 Explain expected bene \201 ts Treatment is given to improve symptoms, prevent worsening of heart failure, and increase survival rate. Symptom improvement occurs within a few weeks t o a few months of starting treatment. Avoid NSAIDs not prescribed by a physician (self-purc hased over-the- counter treatment, e.g., ibuprofen). Temporarily stop sprionolactone if the re is diarrhea and/or vomiting and contact physician. Problem solving \200\224worsening renal function/hyperkalemia \200 \200 See How to Use? section, above. A major concern is hyperkalemia ( uncommon in the RALES cli nical trial. A potassium level at the higher end of normal range may be desirable in patien ts with heart failure, particularly if taking digoxin. Some low-salt substitutes have a hig h K Male patients may develop breast discomfort and/or gynecomastia. (cid:116)6.0 mmol/L), although this was \200 + content. Adapted with permission from McMurray et al. (2001). Practical recommendations for the use of ACE inhibitors, beta-blockers and spironolactone in heart failure; putting guidelines in to practice. Eur J Heart Failure 3:495 \200\223502. VASODILATORS IN HEART FAILURE 235 Digoxin in heart failure Digoxin is very useful controlling heart rates in supraventricular arrhyth- mias, including AF, in patients with chronic HF. Its role in patients with sinus rhythm, however, is less clear. Two large digoxin withdrawal trials (RADIANCE and PROVED) dem- onstrated that patients from whom digoxin was withdrawn were more likely to be admitted with worsening HF. The DIG trial enrolled 6800 patients with classes I to III HF with a mean EF of 28%. This s howed that there was no decrease in overall mortality in the group given digoxin. There was a trend to a decrease in mortality due to pump-failure, balanced by a slight increase in n on-pump failure related cardiac deaths. Digoxin reduced the number of hospitalizations for HF signi \201 cantly. Overall the clinical trials support the use of digoxin in patients in sinus rhythm with mil d to moderate HF for symptomatic control. Trough levels should be maintained between 0.5 \200\2231.0 ng/mL. Contraindications are signi \201 cant bradycardia; heart block, WPW. Vasodilators in heart failure Vasodilators are not a particularly effective method to impro ve the natural history of chronic HF, but are useful for dealing with acute decompensa- tio n. They are also useful in patients intolerant of both ACE-I and ARBs. Nitrates are primarily venodilators, but are potent coronary vasodila- tors making them use ful in ischemic HF. Isosorbide dinitrate is the only nitrate formulation that has been show n to increase exercise tolerance, and in combination with hydralazine, prolongs survival in patients with HF. The addition of hydralazine appears to attenuate nitrate tolerance by ac ting as a reducing agent. In V-HeFT-II, enalapril was shown to be superior to hydralazine and isosorbide dinitrate ex cept in African Americans, where the opposite was found: this is still under investigation. Nesiritide (human brain natriuretic peptide, hBNP) infusion has been shown to improve hemod ynamics and clinical status in patients with decompensated HF, and is less arrhythmogenic t han dobutamine. It is in trial as a subcutaneous injection for chronic HF. Neutral endopeptidase inhibitors with or without intrinsic ACE-inhibitor activity are being explored for the treatment of chronic HF as they pre- vent the inactivation of ANP and BNP ; promising small trials have been followed by disappointing results in larger scale studie s. Although all three classes of calcium antagonists are effective arteriolar vasodilators, no ne produces a sustained improvement in HF. All except amlodipine appear to worsen symptoms. CHAPTER 5 Heart failure 236 Phosphodiesterase inhibitors in heart failure In large-scale placebo-controlled trials, sel ective type III phosphodieste- rase inhibitors (PDEI) are associated with an increase in mo rtality. Individual agents like milrinone and enoximone produce sustained ino- tropic and vasodilato r effects when administered intravenously and are useful in the short term in decompensated HF. Positive inotropic support Inotropes (e.g., dobutamine) can be used to limit very severe ep isodes of heart failure or as a bridge to transplantation in end-stage heart failure. While longer term inotropic therapy may improve a patient \200\231s quality of life, they also i ncrease mortality and are therefore not recommended. Antiplatelet agents and anticoagulants There has been much controversy regarding the use of aspirin in patients with CHF. As a general rule, NSAIDs are avoided because of their \202 uid- retaining and renotoxic properties. It is also thought that the bene \201 cial e ffect of ACE inhibitors is reduced by these drugs. Generally, patients with ischemic heart disease as their underlying etiol- ogy should be treated with aspirin. Formal anticoagulation with warfarin is indicated for patients with heart failure and atria l \201 brillation (paroxysmal or persistent). It is also often used in those with demonst rated LV thrombus or patients with very large LV cavities where it is thought that the risk of LV thrombus formation is high. There are, however, no randomized data to support this u se. Miscellaneous drugs for heart failure Patients with CHF may require drug treatment for syst ems other than the heart: \200 Gout is a common problem. Acute \202 are-ups should be treated with colchicine followed b y allopurinol once the acute event has settled. While most calcium channel antagonists are avoided in patients with CHF, amlodipine has a neutral effect on prognosis and can be used for the treatment of hypertension or angina. Anemia is frequently seen in CHF patients. Cor rection of this with IV iron and erythropoietin has been shown to improve symptoms. DEVICE THERAPY FOR HEART FAILURE 237 Device therapy for heart failure Clearly, patients ful \201 lling the standard indications for permanent pace- maker implantation should undergo this procedure. Wherever possible, d ual-chamber systems should be implanted to maintain atrioventricular synchrony. Implantable cardiac de \201 brillators (ICD) ICDs are devices capable of recognizing ventr icular arrhythmias (VT or VF) and delivering a DC shock to terminate them. They are implant ed in the same way as pacemakers. Several studies have shown that patients with impaired LV function ben- e \201 t from thei r implantation. The MADIT II trial showed a 30% improve- ment in survival in patients with ischemic heart disease and an ejection fraction of <30%. The SCD-HeFT trial enrolled patients with ischemic and with nonischemic cardiomyopathies wi th an LVEF <35%. There was a simi- lar reduction in mortality in ischemic and nonischemic c ardiomyopathy patients who received an AICD compared with those patients receiving amiodaro ne. Cardiac resynchronization (CRT) Many patients with CHF have bundle branch block (BBB) patte rns on their ECG, in particular LBBB. A wide QRS duration is associated with a worse outcom e in patients with CHF. LBBB results in delayed depolarization and contraction of the later al LV free wall, which is thought to contribute to disease progression. Biventricular pacem akers are able to reduce this ven- tricular dysynchrony by pacing the LV via a cardiac vein . Current indications for implantation include severe symptoms (NYHA III or IV), a broad QRS complex (>130 ms), and impaired LV function (LVEF <35%). These indications alone, however, do not necessarily pre- dict patients who will bene \201 t from resynchronization. Current research is assessing the value of using noninvasive imaging techniques (tissue Doppler an d MRI) to identify true inter- and intraventricular dysynchrony. Studies in patients with HF undergoing cardiac resynchronization (CRT) have shown an improv ement in quality of life, improved exercise capacity (6-minute walk test), and, in one stud y, improved survival. Biventricular devices can now be combined with ICDs to further improve the outlook of these patients. The devices can be dif \201 cult to implant, require close and careful fol- low-up, and are expensive, which has reduced their widespread use. CHAPTER 5 Heart failure 238 Surgery for heart failure Valve surgery Patients with valve disease as the source of their heart failure should be co nsidered for valve replacement surgery. This is discussed more fully in Chapter 4 on valve disease. Coronary artery bypass grafting (CABG) Ischemic heart disease is the most common cause of h eart failure in devel- oped countries. In some cases, these patients will have evidence of either stress-induced ischemia or hibernation (muscle that has reduced function due to redu ced blood supply but is still viable). Revascularizing these patients can lead to an improvement in cardiac function. Transplantation Cardiac transplantation is reserved for those patients with end-stage heart failure (see Table 5.11). It is a major undertaking for the patient, who must be willing t o undergo intensive treatment and be emotion- ally capable of withstanding the uncertaintie s that occur before and after transplantation. There are a number of contraindications, listed below. Contraindications for heart transplantation \200 \200 \200 \200 \200 Persistent alcohol or drug abuse Treated cancer with remission and <5 years follow-up Syste mic disease with multiorgan involvement Infection Fixed high pulmonary vascular resistance Despite problems with rejection and complications of immunosuppressive therapy (infection, hypertension, renal failure, malignancy) the 5-year sur- vival is of the order of 70% \200 \22380% with many patients returning to work. Assist devices Because of the lack of organ donors for cardiac transplantation, much intere st has been shown in the development of left ventricular assist devices (LVAD) and mechanic al hearts. LVADs are automatic pumps that take over the work of the heart. They have been u sed as a bridge to trans- plantation and as a bridge to recovery in those with potentially reversible causes for their heart failure (e.g., post-viral). The next stage up from these large devices is the implantation of a permanent arti \201 ci al heart. An example is the Jarvik 2000, which has been successfully been implanted in a re latively small number of patients. SURGERY FOR HEART FAILURE 239 Table 5.11 Heart transplantation guidelines adapted from ESC/AHA guidelines Indications \200 Contraindications and cautions \200 \200 Present alcohol and/or drug abuse Chronic mental illness that cannot be adequately controll ed Treated cancer with remission and <5 years follow-up Systemic disease with multiorgan in volvement Uncontrolled infection Severe renal failure (creatinine clearance <50 mL/min) or creatinine >2.3 mg/dL, although some centers accept patients on hemodialysis Fixed high pul monary vascular resistance (6 \200\2238 Wood units and mean transpulmonary gradient >15 mmH g and pulmonary artery systolic pressure >60 mmHg) Recent thromboembolic complication Unhea led peptic ulcer Evidence of signi \201 cant liver impairment Other coexisting disease wit h a poor prognosis Patients must be willing and able to withstand the physical and emotional demands of the pr ocedure and its postoperative sequelae. Objective evidence of limitation, e.g., peak oxygen consumption <10 mL/min/kg on cardiopulmonary exercise test with evidence for anaerobic met abolism* Patients dependent on intravenous inotropes and mechanical circulatory support \200 \200 Patients with signi \201 cant exercise limitation that have a peak oxygen consumption <55% predicted or between 11 and 15 mL/min/kg also warrant consideration for cardiac transplant ation if they have recurrent unstable myocardial ischemia untreatable by other means, or re current episodes of congestive heart failure in spite of adherence to optimum medical thera py. CHAPTER 5 Heart failure 240 Palliative care for heart failure The demographic spread of most patients with heart failur e means that the hi-tech and expensive therapies outlined earlier are not available and con sideration must be made about end-of-life issues. Increased input from specialist palliativ e care teams will help to allow patients and their rela- tives live with a chronic and term inal disease and help the patient die with dignity. WORSENING HEART FAILURE 241 Worsening heart failure When a patient is seen with worsening heart failure, it is importan t to try and ascertain the cause. The most frequent reasons for symptom deteri- oration are shown below. Causes of worsening heart failure Noncardiac \200 \200 \200 \200 \200 \200 Noncompliance Newly prescribed drugs (see Table 5.12) Renal dysfunction Infection Pulmonary embolus Anemia (lifestyle changes, medication) Cardiac \200 \200 \200 \200 \200 Atrial \201 brillation Other tachyarryhthmias Bradycardia/heart block Worsening valve dis ease Myocardial ischemia (including infarction) Table 5.12 Side effects of drugs for heart failure Drugs Complications Diuretics Common: postural hypotension, gout, urinary urgency Serious: electrolyte imbalance (hypokal emia, hypomagnesemia, hyponatremia), arrhythmia ACE inhibitors Common: cough, hypotension including postural Serious: worsening renal function, renal infa rction in renal artery stenosis, angioedema B-Blockers Common: tiredness, bradycardia, coldness Serious: asthmatic attack, exacerbation of heart f ailure, heart block Spironolactone Common: gynecomastia, tiredness, rashes Serious: hyperkalemia, hyponatremia Digoxin Common: nausea Serious: life-threatening arrhythmias Angiotensin-II receptor antagonists Common: hypotension including postural Serious: worsening renal function, renal infarction in renal artery stenosis Amiodarone