Treatment of CHF

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Chapter: Essential pharmacology : Cardiac Glycosides and Drugs for Heart Failure

Inotropic drugs—digoxin, dobutamine/ dopamine, amrinone/milrinone Diuretics—furosemide, thiazides



There are two distinct goals of drug therapy in CHF:


a) Relief of congestive/low output symptoms and restoration of cardiac performance:


Inotropic drugs—digoxin, dobutamine/ dopamine, amrinone/milrinone Diuretics—furosemide, thiazides

Vasodilators—ACE inhibitors/AT1 antagonists, hydralazine, nitrate, nitroprusside

β blocker—Metoprolol, bisoprolol, carvedilol


b) Arrest/reversal of disease progression and prolongation of survival:


ACE inhibitors/AT1 antagonists (ARBs)

β blockers

Aldosterone antagonist—Spironolactone


Important nonpharmacological measures are rest and salt restriction.


Rest reduces peripheral needs, but should be advised only till compensation is restored, beyond that it may lower myocardial reserve and be counterproductive. Salt restriction limits edema formation and is advised in all grades of CHF. The underlying cause of CHF, if treatable like hypertension, myocardial ischaemia, valvular defects, AV shunts, arrhythmias, thyrotoxicosis, anaemia, should be corrected.


The pathophysiological mechanisms that perpetuate heart failure and contribute to disease progression, along with site of drug action are depicted in Fig. 37.5. The current pattern of use of drugs in various stages of heart failure is summarized in Fig. 37.6.




Almost all cases of symptomatic CHF are treated with a diuretic. High ceiling diuretics (furosemide, bumetanide) are the diuretics of choice for mobilizing edema fluid; later they may be continued in low doses. In advanced CHF after chronic use, resistance may develop to even high ceiling diuretics: a thiazide/metolazone/spironolactone may be combined to overcome it.

Thiazide alone has very limited role in CHF. Diuretics:


·      Decrease preload and improve ventricular efficiency by reducing circulating volume.

·      Remove peripheral edema and pulmonary congestion.


Intravenous furosemide promptly increases systemic venous capacitance and produces rapid symptomatic relief. It has, in conjunction with vasodilators, virtually obviated the need for i.v. digitalization. Further, most mild cases can be maintained on diuretics without recourse to chronic digitalis therapy. However, diuretics do not influence the primary disease process in CHF, though they may dramatically improve symptoms. Despite decades of experience, no prognostic benefit has been demonstrated for diuretics. On the other hand, they may cause activation of renin-angiotensin system (RAS) which has adverse cardiovascular consequences. Chronic diuretic therapy tends to cause hypokalaemia, alkalosis and carbohydrate intolerance. Current opinion is to treat mild heart failure with ACE inhibitors/ARBs ± β blockers only, because they afford survival benefit, while diuretics may be added intermittently as needed. Chronic diuretic therapy should be reserved for relatively advanced cases with tendency to fluid retention when diuretic is stopped. Dose should be titrated to the lowest that will check fluid retention, but not cause volume depletion to activate RAS.




Vasodilators are used i.v. to treat acute heart failure that occurs in advanced cases, as well as orally for long-term therapy of chronic CHF, and have become the mainstay of anti-CHF measures. Vasodilators with differing profiles of arteriolar and venodilator action are available (see box).



1) Preload Reduction: Nitrates cause pooling of blood in systemic capacitance vessels and reduce ventricular enddiastolic pressure and volume. With reduction in size of ventricles, effectiveness of myocardial fibre shortening in causing ejection of blood during systole improves (Laplace relationship). Controlled i.v. infusion of glyceryl trinitrate affords rapid relief in acute left ventricular failure. However, a marked lowering of preload (by vasodilators + strong diuretics) may reduce output of a failing heart whose performance is dependent upon elevated filling pressure. Occurrence of nitrate tolerance limits their utility in routine treatment of CHF.


2) Afterload Reduction: Hydralazine dilates resistance vessels and reduces aortic impedance so that even weaker ventricular contraction is able to pump more blood; systolic wall stress is reduced. It is effective in forward failure when cardiac index (CI = min output/body surface area) is low (< 2.5 L/min/m2) without a marked increase in central venous pressure (< 18 mm Hg). Marked tachycardia and fluid retention limit long-term use of hydralazine monotherapy.


Trials of the three prototype calcium channel blockers verapamil, diltiazem and nifedipine in systolic dysfunction have been disappointing, even negative with occasional worsening of symptoms and increase in mortality. This may be due to reflex sympathetic activation (nifedipine) or negative inotropic property (verapamil, diltiazem).


Verapamil, however, is useful in diastolic dysfunction due to hypertrophic cardiomyopathy. Trials with long-acting and more vasoselective dihydropyridines (felodipine, amlodipine) have reported neither increase nor decrease in heart failure mortality; may be used for symptomatic relief in selected patients.


(iii) Pre and After Load Reduction: ACE inhibitors/ ARBs are orally active medium efficacy nonselective arteriovenous dilators, while Sod. nitroprusside is high efficacy i.v. dilator with equal action on the two types of vessels. These drugs act by both the above mechanisms. Titrated i.v. infusion of nitroprusside is employed in conjunction with a loop diuretic + i.v. inotropic drug to tideover crisis in severely decompensated patients. For symptomatic treatment of acute heart failure, choice of i.v. vasodilator (glyceryl trinitrate or hydralazine or nitroprusside) depends on the primary haemodynamic abnormality in individual patients.


In the long-term, survival benefit has been obtained only with a combination of hydralazine + isosorbide dinitrate or with ACE inhibitors/ ARBs; the latter performing better than the former. Only ACE inhibitors/ARBs alter the course of pathological changes in CHF (see Ch. No. 36); afford symptomatic as well as disease modifying benefits by retarding/reversing ventricular hypertrophy, myocardial cell apoptosis and remodeling. Prognostic benefits of ACE inhibitors/ARBs have been established in mild to severe (NYHA class I to IV) CHF as well as in patients with asymptomatic systolic dysfunction. They are thus recommended for all grades of CHF, unless contraindicated, or if renal function deteriorates.


Hydralazine causes more marked renal vasodilatation; may be selected for patients with renal insufficiency who cannot tolerate ACE inhibitors. Severe CHF patients already receiving ACE inhibitors + digoxin + diuretic have obtained extra benefit from addition of hydralazine with or without a nitrate.


For reasons not known, the α1 blocker prazosin has not been able to afford prognostic benefit.


β-Adrenergic Blockers


Extensive studies over the past 25 years have now established the utility of β1 blockers (mainly metoprolol and bisoprolol) and the nonselective β + selective α1 blocker carvedilol in mild to moderate CHF treated with ACE inhibitor ± diuretic/digitalis.


A large number of randomized trials including Metoprolol in dilated cardiomyopathy trial (1993), US carvedilol trial (1996), MERITHF trial (1999), CIBISII trial (1999), CAPRICORN trial (2001), COPERNICUS trial (2002) have demonstrated subjective, objective, prognostic and mortality benefits of the above 3 β blockers over and above that afforded by ACE inhibitors + diuretic ± digitalis.


Though the immediate hemodynamic action of β blockers is to depress cardiac contractility and ejection fraction, these parameters gradually improve over weeks. After a couple of months ejection fraction is generally higher than baseline, and slow upward titration of dose further improves cardiac performance. The hemodynamic benefit is maintained over long-term and hospitalization/mortality due to worsening cardiac failure, as well as all cause mortality is reduced. The benefits appear to be due to antagonism of ventricular wall stress enhancing, apoptosis promoting and pathological remodeling effects of excess sympathetic activity in CHF, as well as due to prevention of sinister arrhythmias. β blockers decrease plasma markers of activation of sympathetic, renin-angiotensin systems and endothelin-1.


However, β blocker therapy in CHF requires caution, proper patient selection and observance of several guidelines:


·    Greatest utility of β blockers has been shown in mild to moderate (NYHA class II, III) cases of dilated cardiomyopathy with systolic dysfunction in which they are now routinely co-prescribed unless contraindicated.


·    Encouraging results (upto 35% decrease in mortality) have been obtained in class IV cases as well, but use in severe failure could be risky and needs constant monitoring.


·    There is no place for β blockers in decompensated patients. β blockers should be stopped during an episode of acute heart failure and recommenced at lower doses followed by up-titration after compensation is retored. Conventional therapy should be continued along with them.


·    Starting dose should be very low—then titrated upward as tolerated to target level (carvedilol 50 mg/day, bisoprolol 10 mg/day, metoprolol 200 mg/day) or near it for maximum protection.


·    A long acting preparation (e.g. sustained release metoprolol) or 2–3 times daily dosing to produce round the clock β blockade should be selected.


·    There is no evidence of benefit in asymptomatic left ventricular dysfunction.


Aldosterone Antagonist (Spironolactone) 


Over the past 2 decades it has been realized that rise in plasma aldosterone in CHF, in addition to its well known Na+ and water retaining action, is an important contributor to disease progression by direct and indirect effects:


a)  Expansion of e.c.f. volume increased cardiac preload.

b) Fibrotic change in myocardium worsening systolic dysfunction and pathological remodeling.

c) Hypokalemia and hypomagnesemia increased risk of ventricular arrhythmias and sudden cardiac death.

d)  Enhancement of cardiotoxic effect of sympathetic overactivity.


The aldosterone antagonist spironolactone is a weak diuretic (see Ch. No. 41), but can benefit CHF by antagonizing the above effects of aldosterone.


In addition to several small studies, a large Randomised aldactone evaluation study (RALES, 1999) conducted on 1663 NYHA class III and IV patients having left ventricular ejection fraction < 35% has confirmed the additional survival benefit (30%) of spironolactone when added to conventional therapy with ACE inhibitors + other drugs. A subsequent trial (EPHESUS, 2003) using another aldosterone antagonist eplerenone in post acute MI heart failure has further substantiated the mortality and anti-remodeling benefit over and above that of ACE inhibitors ± β  blockers.


Though ACE inhibitors themselves lower aldosterone levels, this effect is incomplete and short lasting. Current evidence suggests the following regarding spironolactone therapy in CHF:


·     It is indicated as add-on therapy to ACE inhibitors + other drugs in moderate-to-severe CHF.


·     It can retard disease progression, reduce episodes of decompensation and death due to heart failure as well as sudden cardiac deaths, over and above the protection afforded by ACE inhibitors/ARBs ± β blockers.


·  Only low doses (12.5–25 mg/day) of spironolactone should be used to avoid hyperkalaemia; particularly because of concurrent ACE inhibitor/ARB therapy.


·   It may help restoration of diuretic response to furosemide when refractoriness has developed.


The onset of benefit of spironolactone in CHF is slow. It is contraindicated in renal insufficiency: carries risk of hyperkalemia—requires serum K+ monitoring. Gynaecomastia occurs in a number of male patients. However, spironolactone is a significant additional therapeutic measure in moderate-severe CHF with prognostic benefits.


Sympathomimetic Inotropic Drugs (see Ch. No. 9)


Drugs with β adrenergic and dopaminergic D1 agonistic actions have positive inotropic and vasodilator properties through activation of adenylyl cyclase which may be utilized to combat emergency pump failure.


Dobutamine (2–8 μg/kg/min) a relatively selective β1 agonist with prominent inotropic action is the preferred drug for i.v. infusion in acute heart failure accompanying myocardial infarction (MI), cardiac surgery as well as to tide over crisis in advanced decompensated CHF.


Dopamine (3–10 μg/kg/min by i.v. infusion) has been used in cardiogenic shock due to MI and other causes. While dobutamine does not raise (may lower) systemic vascular resistance and is preferred in heart failure, dopamine tends to increase afterload, especially at higher rates of infusion (>5 μg/kg/min) and has limited utility in patients who are not in shock. Low rates of dopamine infusion cause selective renal vasodilatation (D1 agonistic action)—improve renal perfusion and g.f.r. This can restore diuretic response to i.v. furosemide in refractory CHF. These drugs afford additional haemodynamic support over and above vasodilators, digitalis and diuretics, but benefits are shortlasting. Due to development of tolerance, these drugs have no role in the long-term management of CHF.


Phosphodiesterase III Inhibitors


Theophylline is a phosphodiesterase inhibitor that is nonselective for different isoforms of this enzyme which degrades intracellular cAMP and cGMP. Intravenous aminophylline had been used in past for acute left ventricular failure with limited benefits, but unacceptable toxicity.


Amrinone (Inamrinone)


It is chemically and pharmacologically distinct from digitalis and catecholamines. This bipyridine derivative is a selective phosphodiesterase III (PDE III) inhibitor. The PDE III isoenzyme is specific for intracellular degradation of cAMP in heart, blood vessels and bronchial smooth muscles. Amrinone increases myocardial cAMP and transmembrane influx of Ca2+. It does not inhibit Na+K+ATPase, and its action is independent of tissue catecholamines and adrenergic receptors.


The two most important actions of amrinone are positive inotropy and direct vasodilatation: has been called an ‘inodilator’. Compared to dobutamine, proportionately greater decrease in systemic vascular resistance is noted.


In CHF patients i.v. amrinone action starts in 5 min and lasts 2–3 hours; elimination t½ is 2–5 hours. It increases cardiac index, left ventricular ejection fraction and decreases peripheral vascular resistance, CVP, left ventricular end diastolic volume and pressure accompanied by mild tachycardia and slight fall in BP.


Adverse Effects


Thrombocytopenia is the most prominent and dose related side effect, but is mostly transient and asymptomatic.


Nausea, diarrhoea, abdominal pain, liver damage, fever and arrhythmias are the other adverse effects.




Though amrinone is active orally, its oral use in maintenance therapy of CHF has been abandoned, because efficacy was lost and mortality was increased in comparison to placebo.


It is indicated only for shortterm i.v. use in severe and refractory CHF, as an additional drug to conventional therapy with digitalis, diuretics and vasodilators.


Dose: 0.5 mg/kg bolus injection followed by 5–10 μg/kg/ min i.v. infusion (max. 10 mg/kg in 24 hours). AMICOR, CARDIOTONE 5 mg/ml (as lactate) 20 ml amp.


Milrinone Related to amrinone; has similar action but is more selective for PDE III, and is at least 10 times more potent. It is shorteracting with a t½ of 40–80 min.


Thrombocytopenia is not significant. In long term prospective trials, increased mortality has been reported with oral milrinone also. Milrinone is preferred over amrinone for shortterm use.


Dose: 50 μg/kg i.v. bolus followed by 0.4–1.0 μg/kg/min infusion.


PRIMACOR IV 10 mg/10 ml inj.


Nisiritide This recombinant brain natriuretic peptide (BNP) has been approved recently for i.v. use to relieve dyspnoea and other symptoms in refractory CHF, especially in patients prone to develop cardiac arrhythmias. It enhances salt and water excretion as well as produces vasodilatation. Additional haemodynamic and symptomatic improvement can be obtained for shortperiods.

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