Over the past decade, the conceptual understanding of heart failure has changed significantly.Several large clinical trials have demonstrated that non-pharmacological and pharmacological interventions can dramatically reduce the morbidity and mortality associated with heart failure.
Many clinical trials have extended the therapeutic paradigm for treating heart failure beyond the goal of limiting congestive symptoms of volume overload.
General Principles in Treatmemt of Heart Failure
The goals of treating heart failure are relief of symptoms, improvement in exercise tolerance,and reduction in the number of hospitalizations, decreasing morbidity and mortality by various non-pharmacological and pharmacological measures.The treatment of heart failure requires close attention to both the primary aetiology and the stage of the disease. It also varies depending on whether one is treating acute heart failure or chronic stable heart failure, systolic versus diastolic heart failure.
Management of acute heart failure is a medical emergency that includes bed rest, oxygen administration, morphine, intravenous diuretics, ACE inhibitors, digoxin, IABP, ventricular assist devices or even emergency surgery depending on the clinical scenario.
Initial Approach
This includes control of factors that may cause or precipitate heart failure and/or augment its manifestations. Treatment is individualized depending on the severity, acuity, aetiology and precipitating factors.
Non-pharmacological Measures
Restriction of physical activities to reduce myocardial work and oxygen consumption. However,care should be taken to prevent deep vein thrombosis.
— Oxygen administration in dyspnoeic, hypoxic patient.
— Once patient is stabilized, cardiac rehabilitation and appropriate aerobic exercise may improve functional capacity.
— Weight loss in obese patients. This will reduce systemic vascular resistance and myocardial oxygen demand.
— Dietary salt restriction (2-2.5 g sodium or 5-6 g salt per day) should be advised.
— Fluid and water restriction to 1 to 1.5 L/24 h in patients with advanced heart failure is important in the presence of hyponatremia and volume overload. Very severe fluid restriction may lead to pre-renal azotemia.
— Discontinuation of negative inotropic agents, if any (beta blockers, diltiazem, verapamil,disopyramide, flecainide) and agents that cause fluid retention (NSAID).
— Dialysis or ultra-filtration in patients with severe heart failure and renal dysfunction.
Correction of Reversible Causes
In the long term reversible causes of heart failure like valvular lesions, myocardial ischemia,uncontrolled hypertension, arrhythmias, alcohol, negative inotropic agents, intracardiac shunts,and high-output states should be identified and corrected.Some metabolic and infiltrative cardiomyopathies may be partially reversible, or their progression may be slowed; these include hemochromatosis, sarcoidosis, and amyloidosis.
Reversible causes of diastolic dysfunction include pericardial disease and left ventricular hypertrophy due to hypertension.
Pharmacological Treatment
Diuretic Therapy
One of the aims of treatment of congestive heart failure is directed toward controlling salt and water retention (central or peripheral edema). Diuretics provide effective relief of symptoms in patients with moderate to severe congestive heart failure. Though excessive diuresis can lead to electrolyte imbalance and neuro-humoral activation, most of the symptomatic patients require some diuretics for symptom relief. Daily weight measurement is an important guide to the adequacy of this therapy.
Thiazide Diuretics and Similar Agents
When fluid retention is mild, a thiazide diuretics or a similar type of agent may be sufficient (hydrochlorothiazide, 25-100 mg; metolazone, 2.5-5 mg; chlorthalidone, 25-50 mg; etc).Thiazide agents are generally ineffective when the glomerular filtration rate falls below 30-40 mL/min. Metolazone maintains its efficacy down to a glomerular filtration rate of approximately 20-30 mL/min.
Adverse reactions: Hypokalemia, prerenal azotemia, skin rashes, neutropenia and thrombocytopenia, hyperglycemia, hyperuricemia, and hepatic dysfunction.
Loop Diuretics
Patients with more severe heart failure should be treated with one of the loop diuretics. These agents are active even in severe renal insufficiency.E.g. Furosemide (20-320 mg daily),Bumetanide (1-8 mg daily), and Torsemide (20-200 mg daily).They have a rapid onset and a relatively short duration of action. In patients with preserved renal function, two or more doses are preferable to a single larger dose. In acute situations or when gastrointestinal absorption is in doubt, they should be given intravenously.
Continuous intravenous rather than intermittent administration of loop diuretics is an effective method of overcoming diuretic resistance in heart failure. Furosemide loading dose 30 to 40 mg followed by infusion at a rate of 2.5 to 3.3 mg/h for 48 h.
Adverse reactions: Intravascular volume depletion, prerenal azotemia, and hypotension,hypokalemia, skin rashes, gastrointestinal distress, and ototoxicity.
Potassium Sparing Diuretics
The potassium-sparing agents spironolactone, triamterene, and amiloride are often useful in combination with the loop diuretics and thiazides. Triamterene and amiloride act on the distal tubule to reduce potassium secretion. Their diuretic potency is only mild and not adequate for most patients with heart failure, but they may minimize the hypokalemia induced by more potent agents.
Side effects: Hyperkalemia, gastrointestinal symptoms, renal dysfunction and gynecomastia.
Combined Use of Diuretics
Combination of diuretics may be indicated in patients previously resistant to furosemide alone.Profound diuresis and clinical improvement may occur after the addition of metolazone to furosemide in patients with CHF. Metolazone is particularly useful because of its prolonged duration of action, lipophilicity, and effectiveness in renal failure. Extreme caution should be exercised with this approach as massive diuresis and electrolyte disturbances may ensue.
Inhibitors of the Renin-angiotensin-aldosterone System
Angiotensin-converting Enzyme Inhibitors
Angiotensin Converting Enzyme Inhibitors (ACEI) has shown to reduce mortality in heart failure to the tune of 16-30 per cent in various large trials.
The renin-angiotensin-aldosterone system (RAAS) is activated early in the course of heart failure and plays an important role in the progression of heart failure. Hence, modulation of this system with Angiotensin Converting Enzyme (ACE) inhibitors should be the initial mode of therapy.ACE inhibitors modify neurohormonal activation in heart failure by inhibiting conversion of angiotensin I to angiotensin II (AII) through ACE. This results in the favourable hemodynamic effects of peripheral vasodilatation, reduced afterload, and decreased blood pressure. The reduction in AII, a potent myogenic agent, also may attenuate abnormal left ventricular remodeling; the subsequent reduction in aldosterone decreases sodium and fluid retention. ACE inhibitors also cause down-regulation of the sympathetic nervous system and improve baroreceptor function.
Angiotensin-converting enzyme is also involved in the degradation of bradykinin. So ACE inhibition result in higher bradykinin levels, which in turn stimulate synthesis of prostaglandins and nitric oxide, which may be beneficial.
Adverse Effects
Hypotension, hyperkalemia, taste disturbance, angiedema, renal insufficiency. In the absence of any symptoms of hypotension, and normal renal function and K + levels, the dosage should be titrated to the dosages proved effective in clinical trials (captopril 50 mg three times daily, enalapril 10 mg twice daily, lisinopril 10 mg daily, or the equivalent) over a period of 1-3 months.Some patients may exhibit rises in serum creatinine or K + , but they do not require discontinuation if the levels stabilize even at values as high as 3 mg/dl and 5.5 meq/l, respectively.
Angiotensin II Receptor Blockers (ARB)
Angiotensin receptor blockers block the final common pathway and provide a means of complete blockade of the system.One of two subtypes of AII receptors, the AT 1 receptor produces vasoconstriction and induces muscle cell proliferation when activated; the AT 2 receptor produces antiproliferative effects upon activation. Currently available ARBs selectively block the AT 1 receptor, producing vasodilatation and inhibiting muscle cell proliferation.
However, these agents do not produce increases in bradykinin, prostaglandins, and nitric oxide in the heart, blood vessels, and other tissues. They should be considered as alternatives to ACE inhibitors in ACE-intolerant patients especially patients with chronic dry irritating cough and angiedema. Another potential use is to counteract ACE escape, the attenuation of the benefits of ACE inhibition that may occur with time.Various agents available are losartan, valsartan, irbesartan, candesartan, telmisartan and eprosartan.
Spironolactone
Aldosterone mediates myocardial remodeling and fibrosis, as well as sodium retention and potassium loss at the distal tubules. The anti-aldosterone agent, spironolactone has been shown in RALES trial as an important neuro-hormonal antagonist in the treatment of heart failure. In this trial spironolactone 25 mg daily was compared with placebo in patients with advanced heart failure already receiving ACE inhibitors and diuretics and showed a 29 per cent reduction in mortality.
Caution: Potassium levels should be monitored. This drug may cause gynaecomastia. A more selective aldosterone inhibitor, eplerenone does not cause gynaecomastia.
Beta-Blockers
Beta-blockers have traditionally been considered contraindicated in patients with heart failure because they may block the compensatory actions of the sympathetic nervous system with potential to worsening of symptoms. However, chronically failing heart is adrenergically activated and persistent elevations of catecholamines and sympathetic nervous system activity cause progressive myocardial damage, leading to worsening left ventricular function and dilation.
Several large clinical trials have demonstrated that beta-blockers decrease mortality in patients who are already receiving standard heart failure therapy (i.e., angiotensin-converting enzyme [ACE] inhibitors and diuretics with or without digoxin). Hence the role of beta blockade in heart failure management.
Beneficial effects of beta-blockers in heart failure include improvement in LV ejection fraction over a period of 3-6 months decrease in LV end-systolic and end-diastolic volumes and mass in 4 to 12 months (‘reversed remodeling’).Large randomized trials have shown mortality reduction to the tune of 35 per cent with beta-blocker therapy.Current guidelines recommend that beta-blockers be used in patients with systolic dysfunction,ejection fraction less than 40 per cent, and mild to moderate heart failure as judged by New York Heart Association (NYHA) (10) class II or III symptoms. Beta-blockers should be started at low doses and gradually increased to the target goals. Effective beta blockade can be reached progressively by increasing doses of beta-blocker agents every 2 to 3 weeks.
Agents found useful in heart failure are second generation selective B 1 agents or third generation agents with vasodilatory action. There is evidence for the usefulness of metoprolol, bisoprolol,and cardvedilol in heart failure.
Contraindications for Beta-Blockers
Reversible airways obstructive disease, advanced heart block, or episodic decompensation.
Vasodilators
Agents that dilate arteriolar smooth muscle and lower peripheral vascular resistance reduce left ventricular afterload and agents that diminish venous tone and increase venous capacitance reduce the preload of both ventricles as their principal effect.
Nitrates
Intravenous vasodilators (sodium nitroprusside or nitroglycerin) are used primarily for acute or severely decompensated chronic heart failure, especially when accompanied by hypertension or myocardial ischemia.
Starting dosages of both agents are 10-20 μg/kg/min with upward titration by increments of 10 μg/kg/min as frequently as every 5-10 minutes. Dosages above 200 μg/kg/min are usually not required.
Isosorbide Dinitrate: 20-80 mg orally three times daily, has proved effective in several small studies.
Side effects: headache, tolerance.
Hydralazine
Hydralazine is a potent arteriolar dilator and markedly increases cardiac output in patients with congestive heart failure. However, as a single agent, it has not been shown to improve symptoms or exercise tolerance during chronic treatment. The combination of hydralazine and isosorbide dinitrate is an alternative therapy when ACE inhibitors are contraindicated or cannot be tolerated.Daily doses of hydralazine up to 300 mg in combination with isosorbide dinitrate 160 mg in the presence of cardiac glycosides and diuretics have some effect in reducing mortality.
Side effect: Gastrointestinal distress, headaches, tachycardia, and hypotension.
Many clinical trials have extended the therapeutic paradigm for treating heart failure beyond the goal of limiting congestive symptoms of volume overload.
General Principles in Treatmemt of Heart Failure
The goals of treating heart failure are relief of symptoms, improvement in exercise tolerance,and reduction in the number of hospitalizations, decreasing morbidity and mortality by various non-pharmacological and pharmacological measures.The treatment of heart failure requires close attention to both the primary aetiology and the stage of the disease. It also varies depending on whether one is treating acute heart failure or chronic stable heart failure, systolic versus diastolic heart failure.
Management of acute heart failure is a medical emergency that includes bed rest, oxygen administration, morphine, intravenous diuretics, ACE inhibitors, digoxin, IABP, ventricular assist devices or even emergency surgery depending on the clinical scenario.
Initial Approach
This includes control of factors that may cause or precipitate heart failure and/or augment its manifestations. Treatment is individualized depending on the severity, acuity, aetiology and precipitating factors.
Non-pharmacological Measures
Restriction of physical activities to reduce myocardial work and oxygen consumption. However,care should be taken to prevent deep vein thrombosis.
— Oxygen administration in dyspnoeic, hypoxic patient.
— Once patient is stabilized, cardiac rehabilitation and appropriate aerobic exercise may improve functional capacity.
— Weight loss in obese patients. This will reduce systemic vascular resistance and myocardial oxygen demand.
— Dietary salt restriction (2-2.5 g sodium or 5-6 g salt per day) should be advised.
— Fluid and water restriction to 1 to 1.5 L/24 h in patients with advanced heart failure is important in the presence of hyponatremia and volume overload. Very severe fluid restriction may lead to pre-renal azotemia.
— Discontinuation of negative inotropic agents, if any (beta blockers, diltiazem, verapamil,disopyramide, flecainide) and agents that cause fluid retention (NSAID).
— Dialysis or ultra-filtration in patients with severe heart failure and renal dysfunction.
Correction of Reversible Causes
In the long term reversible causes of heart failure like valvular lesions, myocardial ischemia,uncontrolled hypertension, arrhythmias, alcohol, negative inotropic agents, intracardiac shunts,and high-output states should be identified and corrected.Some metabolic and infiltrative cardiomyopathies may be partially reversible, or their progression may be slowed; these include hemochromatosis, sarcoidosis, and amyloidosis.
Reversible causes of diastolic dysfunction include pericardial disease and left ventricular hypertrophy due to hypertension.
Pharmacological Treatment
Diuretic Therapy
One of the aims of treatment of congestive heart failure is directed toward controlling salt and water retention (central or peripheral edema). Diuretics provide effective relief of symptoms in patients with moderate to severe congestive heart failure. Though excessive diuresis can lead to electrolyte imbalance and neuro-humoral activation, most of the symptomatic patients require some diuretics for symptom relief. Daily weight measurement is an important guide to the adequacy of this therapy.
Thiazide Diuretics and Similar Agents
When fluid retention is mild, a thiazide diuretics or a similar type of agent may be sufficient (hydrochlorothiazide, 25-100 mg; metolazone, 2.5-5 mg; chlorthalidone, 25-50 mg; etc).Thiazide agents are generally ineffective when the glomerular filtration rate falls below 30-40 mL/min. Metolazone maintains its efficacy down to a glomerular filtration rate of approximately 20-30 mL/min.
Adverse reactions: Hypokalemia, prerenal azotemia, skin rashes, neutropenia and thrombocytopenia, hyperglycemia, hyperuricemia, and hepatic dysfunction.
Loop Diuretics
Patients with more severe heart failure should be treated with one of the loop diuretics. These agents are active even in severe renal insufficiency.E.g. Furosemide (20-320 mg daily),Bumetanide (1-8 mg daily), and Torsemide (20-200 mg daily).They have a rapid onset and a relatively short duration of action. In patients with preserved renal function, two or more doses are preferable to a single larger dose. In acute situations or when gastrointestinal absorption is in doubt, they should be given intravenously.
Continuous intravenous rather than intermittent administration of loop diuretics is an effective method of overcoming diuretic resistance in heart failure. Furosemide loading dose 30 to 40 mg followed by infusion at a rate of 2.5 to 3.3 mg/h for 48 h.
Adverse reactions: Intravascular volume depletion, prerenal azotemia, and hypotension,hypokalemia, skin rashes, gastrointestinal distress, and ototoxicity.
Potassium Sparing Diuretics
The potassium-sparing agents spironolactone, triamterene, and amiloride are often useful in combination with the loop diuretics and thiazides. Triamterene and amiloride act on the distal tubule to reduce potassium secretion. Their diuretic potency is only mild and not adequate for most patients with heart failure, but they may minimize the hypokalemia induced by more potent agents.
Side effects: Hyperkalemia, gastrointestinal symptoms, renal dysfunction and gynecomastia.
Combined Use of Diuretics
Combination of diuretics may be indicated in patients previously resistant to furosemide alone.Profound diuresis and clinical improvement may occur after the addition of metolazone to furosemide in patients with CHF. Metolazone is particularly useful because of its prolonged duration of action, lipophilicity, and effectiveness in renal failure. Extreme caution should be exercised with this approach as massive diuresis and electrolyte disturbances may ensue.
Inhibitors of the Renin-angiotensin-aldosterone System
Angiotensin-converting Enzyme Inhibitors
Angiotensin Converting Enzyme Inhibitors (ACEI) has shown to reduce mortality in heart failure to the tune of 16-30 per cent in various large trials.
The renin-angiotensin-aldosterone system (RAAS) is activated early in the course of heart failure and plays an important role in the progression of heart failure. Hence, modulation of this system with Angiotensin Converting Enzyme (ACE) inhibitors should be the initial mode of therapy.ACE inhibitors modify neurohormonal activation in heart failure by inhibiting conversion of angiotensin I to angiotensin II (AII) through ACE. This results in the favourable hemodynamic effects of peripheral vasodilatation, reduced afterload, and decreased blood pressure. The reduction in AII, a potent myogenic agent, also may attenuate abnormal left ventricular remodeling; the subsequent reduction in aldosterone decreases sodium and fluid retention. ACE inhibitors also cause down-regulation of the sympathetic nervous system and improve baroreceptor function.
Angiotensin-converting enzyme is also involved in the degradation of bradykinin. So ACE inhibition result in higher bradykinin levels, which in turn stimulate synthesis of prostaglandins and nitric oxide, which may be beneficial.
Adverse Effects
Hypotension, hyperkalemia, taste disturbance, angiedema, renal insufficiency. In the absence of any symptoms of hypotension, and normal renal function and K + levels, the dosage should be titrated to the dosages proved effective in clinical trials (captopril 50 mg three times daily, enalapril 10 mg twice daily, lisinopril 10 mg daily, or the equivalent) over a period of 1-3 months.Some patients may exhibit rises in serum creatinine or K + , but they do not require discontinuation if the levels stabilize even at values as high as 3 mg/dl and 5.5 meq/l, respectively.
Angiotensin II Receptor Blockers (ARB)
Angiotensin receptor blockers block the final common pathway and provide a means of complete blockade of the system.One of two subtypes of AII receptors, the AT 1 receptor produces vasoconstriction and induces muscle cell proliferation when activated; the AT 2 receptor produces antiproliferative effects upon activation. Currently available ARBs selectively block the AT 1 receptor, producing vasodilatation and inhibiting muscle cell proliferation.
However, these agents do not produce increases in bradykinin, prostaglandins, and nitric oxide in the heart, blood vessels, and other tissues. They should be considered as alternatives to ACE inhibitors in ACE-intolerant patients especially patients with chronic dry irritating cough and angiedema. Another potential use is to counteract ACE escape, the attenuation of the benefits of ACE inhibition that may occur with time.Various agents available are losartan, valsartan, irbesartan, candesartan, telmisartan and eprosartan.
Spironolactone
Aldosterone mediates myocardial remodeling and fibrosis, as well as sodium retention and potassium loss at the distal tubules. The anti-aldosterone agent, spironolactone has been shown in RALES trial as an important neuro-hormonal antagonist in the treatment of heart failure. In this trial spironolactone 25 mg daily was compared with placebo in patients with advanced heart failure already receiving ACE inhibitors and diuretics and showed a 29 per cent reduction in mortality.
Caution: Potassium levels should be monitored. This drug may cause gynaecomastia. A more selective aldosterone inhibitor, eplerenone does not cause gynaecomastia.
Beta-Blockers
Beta-blockers have traditionally been considered contraindicated in patients with heart failure because they may block the compensatory actions of the sympathetic nervous system with potential to worsening of symptoms. However, chronically failing heart is adrenergically activated and persistent elevations of catecholamines and sympathetic nervous system activity cause progressive myocardial damage, leading to worsening left ventricular function and dilation.
Several large clinical trials have demonstrated that beta-blockers decrease mortality in patients who are already receiving standard heart failure therapy (i.e., angiotensin-converting enzyme [ACE] inhibitors and diuretics with or without digoxin). Hence the role of beta blockade in heart failure management.
Beneficial effects of beta-blockers in heart failure include improvement in LV ejection fraction over a period of 3-6 months decrease in LV end-systolic and end-diastolic volumes and mass in 4 to 12 months (‘reversed remodeling’).Large randomized trials have shown mortality reduction to the tune of 35 per cent with beta-blocker therapy.Current guidelines recommend that beta-blockers be used in patients with systolic dysfunction,ejection fraction less than 40 per cent, and mild to moderate heart failure as judged by New York Heart Association (NYHA) (10) class II or III symptoms. Beta-blockers should be started at low doses and gradually increased to the target goals. Effective beta blockade can be reached progressively by increasing doses of beta-blocker agents every 2 to 3 weeks.
Agents found useful in heart failure are second generation selective B 1 agents or third generation agents with vasodilatory action. There is evidence for the usefulness of metoprolol, bisoprolol,and cardvedilol in heart failure.
Contraindications for Beta-Blockers
Reversible airways obstructive disease, advanced heart block, or episodic decompensation.
Vasodilators
Agents that dilate arteriolar smooth muscle and lower peripheral vascular resistance reduce left ventricular afterload and agents that diminish venous tone and increase venous capacitance reduce the preload of both ventricles as their principal effect.
Nitrates
Intravenous vasodilators (sodium nitroprusside or nitroglycerin) are used primarily for acute or severely decompensated chronic heart failure, especially when accompanied by hypertension or myocardial ischemia.
Starting dosages of both agents are 10-20 μg/kg/min with upward titration by increments of 10 μg/kg/min as frequently as every 5-10 minutes. Dosages above 200 μg/kg/min are usually not required.
Isosorbide Dinitrate: 20-80 mg orally three times daily, has proved effective in several small studies.
Side effects: headache, tolerance.
Hydralazine
Hydralazine is a potent arteriolar dilator and markedly increases cardiac output in patients with congestive heart failure. However, as a single agent, it has not been shown to improve symptoms or exercise tolerance during chronic treatment. The combination of hydralazine and isosorbide dinitrate is an alternative therapy when ACE inhibitors are contraindicated or cannot be tolerated.Daily doses of hydralazine up to 300 mg in combination with isosorbide dinitrate 160 mg in the presence of cardiac glycosides and diuretics have some effect in reducing mortality.
Side effect: Gastrointestinal distress, headaches, tachycardia, and hypotension.
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