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Vol. 19 No. 2, June 2004 Tanzania Medical Journal 1 THE CURRENT MANAGEMENT OF CONGESTIVE HEART FAILURE Eden E Maro Introduction Congestive heart failure (CHF) represents a complex clinical syndrome characterized by abnormalities of left ventricular function and neurohormonal regulation; which are accompanied by effort intolerance, fluid retention and reduced longevity. The four major diagnostic criteria for this syndrome are: left ventricular dysfunction, exercise intolerance, pulmonary congestion or oedema and ventricular arrhythmias. In 1990, congestive cardiac failure affected 4.7 million patients in the USA. Annually the condition is newly diagnosed in 400,000 persons and the total cost of care exceeds 10 billion US dollars. In Tanzania heart failure accounted for about 0.3% of all admissions and 2.8% of all hospital deaths among patients older than 5 years, in the year 1995.(1) As the primary and secondary treatment of hypertension, rheumatic heart diseases and myocardial infarction improves, the number of patients with CHF will rise, which will present an increasing medical challenge and an increasing economic impact. Cardiac glycosides and diuretics have been considered standard treatment for patients with CHF for many years. Within the last decade, however, the use of digitalis has been debated. Physicians have achieved improved results by using additional drugs. Vasodilators, including angiotensin converting enxyme inhibitors, have been used with some success, as have B-blockers, phosphodiesterase inhibitors and other inotropic agents. The role of antiarrhythmic agents in treating patients at high risk for sudden death remains unclear. Anticoagulation clearly has a role to play in patients with dilated cardiomyopathy as well as patients with history of thromboembolism. With our new understanding of neurohormonal systems and the vascularendothelum, physicians are now able to derive rational approach to clinical management and to the development of suitable medications to treat this chronic disease. Non-Pharmacologic Therapy The goals of treatment for patients with CHF are to make the patient feels better and live longer. Successful treatment generally requires careful monitoring of salt and fluid intake and output. Patients should be placed on a lowsodium diet, with the degree of salt restriction depending on the severity of heart failure. For the majority of patients, non-added salt diet (2-3g sodium per day) is sufficient. However stricter salt restriction should be instituted in patients with refractory symptoms. Correspondence to: Maro EE, Box 65001, Muhimbili National Hospital , Dar-esSalaam, Tanzania Dept. of Internal Medicine Restriction of fluid intake should be increased in those patients with hyponatraemia or symptoms refractory to diuretic therapy. The fluid restriction may result in an uncomfortable sensation of thirst, thus patients should be advised about measures to quench the thirst such as lozenges or mints. Exercise training may be beneficial in CHF and patients should be encouraged to do regular light aerobic exercise. Patients should be advised to avoid substances which may exacerbate their condition, including alcohol and drugs like non-steroidal anti-inflammatory drugs. Patients as well as family members should be counselled and educated about CHF, the goal of treatment and the importance of compliance with diet, fluid restriction and medications. Pharmacologic Therapy It is now well recognized that 10% to 30% of patients with CHF have normal systolic function, implying that abnormal left ventricular diastolic function is the main mechanism responsible for producing congestive symptoms in these patients. Although heart failure patients with systolic dysfunction and those with primarily diastolic dysfunction may show similar symptoms and signs, the differentiation between the two syndrome has important therapeutic and prognostic implications. Certainly different pathophysiologic processes underlie the two syndromes and compensatory neuroendocrine activation appears to be largely seen in those patients with systolic dysfunction. Because the clinical features may fail to distinguish patients with systolic or diastolic dysfunction, most centres recommend echocardiography in all patients with suspected CHF. Systolic Dysfunction Systolic dysfunction is characterized by reduced left ventricular contractility for the degree of preload and manifest in a reduced left ventricular ejection fraction (LVEF). As systolic dysfunction is usually associated with dilatation of the left ventricle and/or prior myocardial infarction, suggestive clues for the physician include displacement of the apex, a third heart sounds, enlarged cardiac shadow on the chest x-ray and Q waves on the ECG. The agents currently employed in the treatment of systolic heart failure include: diuretics, ACE inhibitors, Bblockers, and digoxin. Diuretics The main action of diuretics is to decrease pre-load. Although this effect does not improve cardiac output or survival, diuretics are essential agents for the management of CHF because they relieve bothersome pulmonary and peripheral congestion and thus prevent costly hospitalisation. They are now rarely used as single agents. Vol. 19 No. 2, June 2004 Tanzania Medical Journal 2 The choice between a loop diuretic or a thiazide depends on the degree of fluid overload and the patients renal function (thiazides have greatly reduced efficacy in the setting of renal failure). Patients with refractory fluid overload despite massive doses of loop diuretics should be given in addition agents which act on different segments of the rephron such as thiazides or metolazone which may help induce a brisk diuresis. Potassium sparing diuretics should be used cautiously in patients on ACE inhibitors because ACE inhibitors are known to counteract the depletion of potassium and magnesium caused by diuretics similar actions to ACE inhibitors captopril (as measured by symptoms scores and functional class) but was better tolerated. Other short term studies have shown survival benefit with losartan and Irbersatan 3. The valsartan heart failure trial (val-HeFT) showed that valsartan significantly reduced the combined end-point of mortality and morbidity by 13.2% when added to the prescribed therapy of patients with heart failure. The discussion of whether ACE inhibitors, angiotensin II antagonists or the combination of both are superior in the pharmacotherapy of congestive heart failure is still being investigated. Ace Inhibitors Other Vasodilators ACE inhibitors have become a cornerstone in the treatment of chronic congestive heart failure as they reduce morbidity and mortality of these patients. They are the agents of first choice in the treatment of systolic congestive heart failure for both symptomatic and asymptomatic patients. They have been shown to reduce morbidity and cardiac mortality, decreased hospitalisations and improved exercise tolerance(2) while in asymptomatic patients with reduced left ventricular systolic function, hospitalisations and the progression to overt congestive heart failure were reduced. Also ACE inhibitors have been shown to reduce cardiovascular mortality and hospitalisations for congestive heart failure and acute coronary events (fatal and non-fatal) in patients with reduced left ventricular function and NYHA Class II-IV failure or recent myocardial infarction as well as in post-infarction patients.(2) The beneficial effects of ACE inhibitors are thought to be secondary to after-load reduction and amelioration of neurohormonal activation.(3) These benefits of ACE inhibitors appear to be a consistent class effect, thus the choice of specific agent should be based on the duration of action and cost. Although the dose required for maximal therapeutic efficacy is not known, however some studies support the contention that ACE inhibitor dosage should be maximised in patients with congestive heart failure (20mg of enalapril, 150mg of captopril and 10mg of ramipril). High doses of ACE inhibitors are superior to low doses with respect to prognosis and symptoms.(3) Euvolaemic or fluid overloaded patients tend to tolerate ACE inhibitors well, however those who develop hypotension should have the dose of their diuretic reduced.. The combination therapy with hydralazine and isosorbide dinitrate has been shown to improve exercise tolerance and reduced mortality in patients with moderate to severe systolic dysfunction (NYHA II-III). The Veteran Administration Cooperative Study on vasodilator therapy of heart failure VHeFT-1)(5) studied men with moderately severe heart failure who were receiving standard therapy. When hydralazine and isosorbide dinitrate were added to the therapy, the cumulative mortality at 2 years fell from 34% in the placebo group to 26% in the treated group, a “mortality risk reduction” of 25%. To sum up, the combination of hydralazine with nitrates seems to improve survival. However, the survival benefits are usually greater with ACE inhibitors than hydralazine/isosorbide dinitrate combination. Thus hydralazine/isosorbide dinitrate is now recommended only for those patients unable to tolerate ACE inhibitors (due to renal dysfunction, hyperkalaemia, hypersensitivity, or persistent cough). No evidence that the other direct vasodilators such as minoxidil and prazosin are of any benefits in congestive heart failure. Angiotensin II (A-II) Receptor Antagonists ACE inhibitors remain first line therapy in patients with CHF due to systolic dysfunction. However, in patients not able to tolerate ACE inhibitors induced side effects in particular cough, angiotensin II antagonists are an acceptable alternatives. Angiotensin receptor blockers produce a more complete blockade of the effects of angiotensin II by a combination of both ACE dependent and non-ACE dependent pathways but they lack some of the effects thought to be important to the benefits of ACE inhibitors such as inhibition of bradykinin degradation(4) The study of Losartan in the elderly (ELITE) study(4) confirmed that the angiotensin II antagonist losartan had Calcium Channel Blockers The first generation calcium channel blockers (nifedipine, diltiazem and verapamil) have negative inotropic effects and they may increase mortality in cardiac patients. The Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial(6) reported that amlodipine (a second generation calcium channel blocker) significantly reduced mortality when added to usual therapy (including ACE inhibitors) in patients with non-ischaemic dilated cardiomyopathy and exhibited a neutral effect in patients with ischaemic disease. Further studies are required before routine use is recommended. Beta Blockers Beta adrenergic receptor blockers have become established therapy for a broad spectrum of patients with heart failure due to left ventricular systolic dysfunction, as a result of the experience from the US Carvedilol Program and two dedicated survival trials, the Cardiac Insufficiency Bisoprolol Study II (CIBIS II) and the Metoprolol CR/XL (controlled release/extended release) Randomized Intervention Trial on Chronic Heart Failure (MERIT-HF).(7) In the two survival trials, the beta-blockers, bisoprolol and Vol. 19 No. 2, June 2004 metoprolol CR/XL, have been shown significantly decrease mortality by 34%. Speculation about the benefit of betablockers in heart failure has been ongoing for more than two decades. The results from these recent trials however, have clearly established their beneficial effects on total mortality, death due to progressive heart failure and sudden death, when added to standard therapy with diuretics and ACE inhibitors. In addition to their effect on mortality, they also reduce the need for hospitalisation for worsening heart failure and they are well tolerated.(7) The results of these trials have changed the attitude about the use of these drugs. Nevertheless resistance to their incorporation into clinical care continues largely due to concerns about their benefit in patients with severe heart failure. The recent Carvedilol Prospective Randomized Cumulative Suvival (COPERNICUS) trial showed a 35% decrease in mortality (95% confidence interval (CI), 19% to 48%, p=0.00014) in a patient population with a mean baseline ejection fraction of 0.20 i.e. severe heart failure.(8) On the basis of several trials, beta-blocker treatment has been included in the current guidelines for CHF therapy and is now strongly recommended as standard therapy for all patients with CHF and systolic dysfunction. Beta-blocker treatment should be initiated in stabilized patients with no pulmonary oedema, hypoperfusion, hypotension or the other contraindications of B-Blockers. The doses should be carefully uptitrated to the target dose or the highest tolerated dose. Digoxin Digoxin is a positive inotrope which reduces neurohormonal activation and inhibits AV nodal conduction. It is strongly recommended in patients with systolic dysfunction and atrial fibrillation, however its role in heart failure with sinus rhythm was once debatable. Studies have shown addition of digoxin to the treatment regiment of patients with systolic dysfunction significantly reduced deaths and hospsitalisations due to worsening heart failure, however there was no change in overall mortality. Patients with lower ejection fractions, dilated hearts, severe symptoms (NYHA II-IV) and non-ischaemic aetiologies benefited most from digoxin. Based on the available evidence digoxin has a role as a fourth line agent for symptom relief in those patients with sinus rhythm and systolic heart failure refractory to ACE inhibitors Bblockers and diuretics. Other Inotropes Studies on inotropic agents other than digoxin have not been encouraging. Intravenous dobutamine and dopamine do improve the short-term hemodynamic profile in patients with systolic congestive heart failure but do not improve long-term survival. Thus they have a role in the critical care areas only. Natriuretic Peptides Tanzania Medical Journal 3 Despite the first line use of ACE inhibitors, and more recently beta-adrenergic blocking agents, the prognosis of CHF remains poor. The Natriuretic peptides are counter regulatory to the rennin angiotension system, causing vasodilatation; diuresis and natriuresis. Augmention of their levels with exogenously administered atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) resulted in a reduction in filling pressures, natriuresis and deuresis in acute studies on CHF. However, their therapeutic usefulness is limited by a short half-life, due to rapid degradation by neutral endopeptidase (NEP). Omapatrilat is the first of a new class of drugs known as vasopeptidase inhibitors which simultaneously inhibit both neutral endopeptidase (NEP) and angiotension converting emyme, resulting in increased levels of natriuretic peptides and bradykinin with a reduction in angiotension II. In patients with heart failure, omapatrilat therapy for 24 weeks showed a similar increase in week 12, exercise tolerance but conferred more benefit than lisinopril in the composite of death, hospital admission or discontinuation of study treatment for worsening heart failure.(9) Although promising, more trials are required. Anti-Arrhythmic Therapy In patients with symptomatic or life threatening arrhythmias (sustained ventricular tachycardia or ventricular fibrillation), the type III anti-arrhythmic drugs amiodarone and perhaps sotalol, are the agents of first choice. In the GESICA trial addition of amiodarone to standard therapy in patients with systolic congestive heart failure was associated with a statistically significant reduction in mortality. Currently amiodarone is recommended for routine use in congestive heart failure patients with symptomatic arrthymias. On the other hand sotalol was shown to cause excess mortality and thus it has no place in patients with compromised left ventricular function. Despite the progress in therapy for congestive heart failure at least 40% of patients die suddenly, mainly as a result of ventricular tachyarrhythmias. Anticoagulation Warfarin prophylaxis is recommended for most patients with coexistent congestive heart failure and atrial fibrillation. Also in the absence of clear contraindications, Warfarin anticonagulation (with a goal PT.INR of 2-3) is recommended for patients who have a history of thromboembolism, episodes of atrial fibrillation, dilated poorly functioning left ventricle (ejection fraction < 25%) with evidence of intracardiac thrombus on echocardiography. Diastolic Dysfunction The main defect in patients with diastolic dysfunction is impaired ventricular relaxation and decreased compliance in diastole. Thus, these patients with diastolic dysfunction, usually have normal left ventricular ejection fraction, but increased left atrial pressures and chamber pressures Vol. 19 No. 2, June 2004 increases markedly in response to increases in left ventricular volume. The common causes of left ventricular diastolic dysfuntion are: hypertension, mitral stenosis, aortic stenosis, hypertrophic obstructive cardiomyopathy, restrictive cardiomyopathy and myocardial ischaemia and/or infarction. These conditions which are associated with diastolic dysfunction, usually do not lead to significant cardiac enlargement and the only clues may be a normal heart size on chest x-ray and the presence of left ventricular hypertrophy on physical examination (sustained apex heave, fourth heart sound) or ECG. The central goals to the treatment of diastolic dysfunction is to improve the compliance of the left ventricle and increase diastolic filling. Slowing of the heart rate (and therefore increasing diastolic filling time) and treating myocardial ischaemia with beta-blockers or calcium channel antagonists is indicated where appropriate. Studies have shown that the non-dihydtropyridine calcium channel blockers (verapamil and diltiazem) given to patients with congestive heart failure with diastolic dysfunction, improved clinical status, exercise capacity and diastolic filling by altering the calcium flux in the myocardium. Reduction of mortality or hospitalisation was not reported. Diuretics are recommended for symptomatic treatment, however with caution so as not to excessively reduce preload. In patients with constrictive pericarditis, cardiac tamponade, mitral stenosis and restrictive cardiomyopathy, ACE inhibitors are contraindicated.(10) The notion that ACE inhibitors are useful in patients with mainly diastolic dysfunction requires proof in well executed studies. Conclusion In patients with congestive heart failure, the distinct syndrome of systolic dysfunction and diastolic dysfunction do determine the therapy. Results from previous studies supported the concept that triple therapy with diuretic, ACE inhibitors and digoxin was the most effective treatment strategy in symptomatic heart failure due to systolic dysfunction. However recent trials showed that adding beta-blockers (carvedilol, metoprolol and bisoprolol) to ACE inhibitors do significantly reduce the morbidity, mortality, progression of heart failure and the recurrent hospitalisation risk (and accompanying costs). Angiotension II antagonists are acceptable alternatives in those patients unable to tolerate ACE inhibitor side effects. Amiodarone appears to be safe for symptomatic arrhythmias in heart failure. References 1. 2. 3. 4. Ministry of Health: National Annual Health Statistics Past Reports 1998. ISIS-4 (fourth International Study of Infarct Survival). Collaborative group, ISIS-4. A randomised factorial trial assessing early oral captopril, oral mononitrate and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction LANCET 1995; 345: 669-85. Brunnerla Rocca HP, Vaddadi G, Esler MD. Recent insight into therapy of congestive heart failure: Focus on ACE inhibitor and angiostension II antagonism. J. Am. Coll. Cardiol. 1999; 33: 1163-73. Maggioni AP, Anand I, Gottlieb SO. et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving, angiotensin – converting enzyme inhibitors. J. Am. Coll, Cardio. 2002; 40: 1414-21. Tanzania Medical Journal 5. 6. 7. 8. 9. 10. 4 Cohn JN, Archbald DG, Ziesche S. et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a veterans administration cooperative study. No. Engl. J. Med. 1986 314; 1547-52 Packer M, O’Connor CM, Ghali K. et al. Effect of amlodipine on morbidity and mortality in severe congestive heart failure N. Engl. J. Med. 1996; 335:1107-14. MERIT-HF study group. Effect of metoprolol CR/XL in chronic heart failure. Metoprolol CR/XL. Randomized Intervention Trial in Congestive Heart Failure (MERT-HF). LANCET 1999; 353:2001-7. Packer M, Coats AJS, Fowler MB et al. Effect of carvedilol on survival in severe chronic heart failure. N. Engl. Med. 2001; 344: 1651-8. Rouleau JL, Pfeffer MA, Stewart DJ, et al. Comparison of vasopeptidase inhibitor, omapatrilat and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. LANCET 2000; 356: 615-20. Leier C.V.,Dismantling Mandates in the treatment of heart failure J. Am. Coll. Cardio.2004;4:1831-3.