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  • Definition of Heart Failure. There is no single definition of heart failure. Classically, heart failure is understood as the situation when the heart is incapable of maintaining a cardiac output adequate to accommodate the body’s metabolic requirements and the venous return. This concept is ambiguous and incomplete, however, because heart failure is a composite of clinical symptoms, physical signs, and abnormalities on the hemodynamic, neurohormonal, biochemical, anatomic and cellular levels. In addition, the actual cardiac output, venous return or absolute metabolic requirements are not usually measured in clinical practice. Heart failure is a syndrome characterized by symptoms and physical signs which are secondary to a change in function of the ventricles, valves or load conditions. Braunwald E.: Heart Diseases. W.B. Saunders Co. 1992.
  • Important Concepts. Clinical stages in the evolution of heart failure Heart failure is a continuous spectrum of changes, from the subtle loss of normal function to the presence of symptoms refractory to medial therapy. The patient with cardiomyopathy may maintain overall normal ventricular function; the progression of dysfunction may be sudden or gradual. Asymptomatic ventricular dysfunction is characterized by the absence of symptoms or decline in functional capacity, even in the absence of treatment. It may be associated with different changes in cardiac physiology, including ventricular dilatation, regional wall motion abnormalities, and decreases in the LV ejection fraction and of other parameters of ventricular function. The absence of symptoms may be explained by the heart’s functional reserve capacity and by the activation of compensatory mechanisms opposing the deterioration of cardiac function. In compensated heart failure the symptoms are controlled by medical therapy. In decompensated heart failure, symptoms persist despite usual therapy and are refractory to adjustments in drugs and dosages.
  • Pathophysiology of Congestive Heart Failure. Determinants of ventricular function. Ventricular function, and cardiac function in general, depends upon the interaction of four factors that regulate the volume of blood expelled by the heart (the cardiac output): contractility, preload, afterload, and heart rate. The first three determine the volume of blood expelled with each beat (the stroke or ejection volume), while the heart rate affects the cardiac output by varying the number of contractions per unit time. These four factors, which are intrinsic regulators of heart function, are all influenced by the nervous system. In the failing heart, especially in ischemic heart disease, it is also important to consider some purely mechanical factors, such as the synergy of ventricular contraction, the integrity of the septum, and the competence of the atrioventricular valves.
  • Treatment of Heart Failure. Objectives The objectives of treatment of the patient with heart failure are many, but they may be summarized in two principles: decrease symptoms and prolong life. In daily practice, the first priority is symptom control and the best plan is to adjust to the individual patient’s particular circumstances over the course of therapy. Nevertheless, the rest of the listed objectives should not be forgotten, as medical therapy now has the potential for decreasing morbidity (hospital admissions, embolism, etc.), increasing exercise capacity (all of the usually prescribed drugs), improve the quality of life, control neurohormonal changes (ACE-I, beta blockers), retard progression (ACEI) and prolong life.
  • Treatment of Heart Failure. Correction of aggravating factors Often a lack of response to conventional therapy for heart failure is due to the presence of uncorrected aggravating or precipitating factors. It is important to always consider the possibility of such factors, particularly in cases of refractory failure. AF: atrial fibrillation.
  • Treatment of Heart Failure. Drugs This is a simple and pragmatic classification of the vast numbers and types of medications in the pharmacopoeia for the treatment of heart failure.
  • Treatment of Heart Failure. Theoretical hemodynamic effects of different drugs for heart failure Effects of different treatments on the relationship between ventricular filling pressure (LVEDP) and stroke volume. Diuretics (D) and venous vasodilators (V) decrease the ventricular filling pressure in patients with heart failure and normal or elevated LVEDP, but except in patients with marked elevation of LVEDP, the stroke volume does not change. The pure arterial vasodilators (A) produce an increase in the stroke volume in patients with failure and an elevated LVEDP. Inotropic drugs (I) increase the stroke volume with a lesser effect of the ventricular filling pressure.
  • Treatment of Heart Failure. Effect of the principle pharmacologic groups on the majority of symptoms, reduction in mortality, prevention of symptom development and control of neurohormonal abnormalities. The drugs which control neurohormonal abnormalities include ß-blockers, ACE inhibitors, dopaminergic receptor stimulants, and digoxin.
  • Treatment of Heart Failure. Treatment scheme according to the degree of heart failure Patients with asymptomatic ventricular dysfunction should receive ACEI when the LVEF is significantly reduced, and clearly if it is less than 35%. In the presence of symptoms of heart failure, diuretics or neurohormonal inhibitors should be added. The use of digoxin remains controversial. In more advanced stages, in the presence of poorly controlled symptoms, newer drugs can be tried, reserving the inotropes for patients whose symptoms are uncontrollable with other medications. In any case, secondary prevention and assisting the patients in adapting to their limitations should remain in mind.
  • Treatment of heart failure. Diuretics: Classification and mechanisms of action Diuretics are drugs which eliminate Na and water by acting directly on the kidney. This category does not include other drugs with principle actions different from the diuretics, but which increase diuresis by improving heart failure or by mechanisms on the kidney which are incompletely understood. The diuretics are the primary line of therapy for the majority of patients with heart failure and pulmonary congestion. Diuretics (loop, thiazides and potassium-sparing) produce a net loss of Na and water acting directly on the kidney, decrease acute symptoms which result from fluid retention (dyspnea, edema). Diuretic drugs are classically divided into three groups: 1) thiazides, 2) loop diuretics and 3) potassium-sparing. Thiazide diuretics inhibit the active transport of Cl-Na in the cortical diluting segment of the ascending limb of the Loop of Henle. Loop diuretics inhibit the transport of Cl-Na-K in the thick portion of the ascending limb of the Loop of Henle. Potassium-sparing diuretics inhibit the reabsorption of Na in the distal convoluted and collecting tubules.
  • Treatment of heart failure. Diuretics: Mechanism of action of the thiazides The thiazides are diuretics of intermediate potency, excreting 5-10% of the filtered fraction of Na. The act from the luminal surface inhibiting the active transport of Cl and the subsequent diffusion of Na and water in the cortical diluting segment of the ascending portion of the loop of Henle. The also increase elimination of K by increasing the exchange of Na/K in the distal convoluted tubule and increase the urinary elimination of HCO 3 by inhibiting carbonic anhydrase. In addition they increase tubular reabsorption of uric acid, Ca and Mg. There are important differences in the strength and duration of diuretic action depending on which thiazide is used.
  • Treatment of heart failure. Diuretics Mechanism of action of loop diuretics Loop diuretics are the strongest, prompting the excretion of 15-20% of the filtered Na + . They act in the thick segment of the ascending loop of Henle, inhibiting the cotransport of Cl - -Na + -K + at the luminal surface. They also increase the elimination of K + , as the increase in Na that reaches the distal convoluted tubule stimulates its exchange for K + and H + ; in addition, they also stimulate the secretion of renin and the production of aldosterone which augments the elimination of K + . By inhibiting carbonic anhydrase, they increase the urinary elimination of HCO - 3 . They also increase elimination of Ca ++ and Mg ++ . GFR: glomerular filtration rate; PGS: prostaglandins; NSAIDs: nonsteroidal anti-inflammatory drugs.
  • Treatment of heart failure. Diuretics: Mechanism of action of potassium-sparing diuretics Potassium-sparing diuretics inhibit reabsorption of Na + at the level of the distal convoluted tubule and the collecting duct and its exchange for K + or H + . Their diuretic strength is slight, as the fraction of Na eliminated is no more than 5%. Spironolactone is a competitive antagonist of aldosterone, interfering with its induction of synthesis of proteins which specifically facilitate Na reabsorption. As a result, its diuretic action depends on the role that aldosterone plays in the retention of water and Na. Triamterene and amiloride block the exchange of Na + -K + /H + , but their effect is independent of the levels of aldosterone. All of these drugs moderately increase the renal excretion of Na + , Cl - and HCO - 3 , at the same time that they diminish the excretion of K + , H + and ammonium, and may therefore cause hyperkalemia and hypochloremic acidosis.
  • Treatment of heart failure. Diuretics: Mechanisms of action Diuretics decrease volume and preload, and as a result are very effective at improving the signs of pulmonary and systemic venous congestion. They do not change the cardiac output (CO), but CO may fall if an excessive decrease in preload occurs. They slightly improve arterial distensibility, but this effect is of no clinical relevance. The main drawback to diuretics use is their effect on the neurohormonal milieu, increasing the plasma levels of noradrenaline (NA), angiotensin II (Ang II) and aldosterone, and the plasma renin activity (PRA).
  • Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Thiazide and loop diuretics create electrolyte imbalances: hypovolemia, hyponatremia, hypokalemia, hypomagnesemia, hypercalcemia and metabolic alkalosis. They also create metabolic changes (hyperglycemia, hyperuricemia, gout, increase in LDL-cholesterol and triglycerides), impotence and menstrual cramps. Hypokalemia can be treated with K + supplements or with the simultaneous use of potassium-sparing diuretics. Cutaneous allergic reactions (rash, pruritis) are frequent. In addition, these are cross-reactions between the various thiazides (except chlorthalidone) and because of their chemical resemblance, with furosemide and bumetanide. Thiazides can aggravate myopia in pregnant women.
  • Treatment of heart failure. Diuretics: Adverse effects of thiazide and loop diuretics Known adverse reactions include parenchymal (pancreatitis, cholestatic jaundice, hemolytic anemia, thrombocytopenia), gastrointestinal effects (ethacrynic acid), myalgias (bumetanide, piretanide) and muscle cramps related to electrolyte disorders. Loop diuretics are associated with ototoxicity with loss of hearing and balance and these are more frequent in patients with renal insufficiency or with concomitant use of aminoglycoside antibiotics. They may also cause interstitial nephritis.
  • Treatment of heart failure. Diuretics: Adverse reactions to potassium-sparing agents The main adverse reaction to these agents is hyperkalemia, which occurs mostly in patients with renal failure, particularly if they are also receiving ACE inhibitors. They may also create metabolic acidosis, muscle cramps and weakness, and cutaneous allergic reactions.
  • Treatment of heart failure. Digoxin: Mechanism of action Digoxin attaches to specific receptors which form a part of the enzyme, Na + /K + -dependent ATP-ase (sodium pump), inhibiting it. This blockade produces a progressive increase in the intracellular concentration of Na, which in turn activates the exchange of Na + -Ca ++ and increases the influx of Ca ++ and its intracellular concentration, [Ca ++ ]i. This increase in the [Ca ++ ]i at the level of the contractile proteins explains the resultant increase in cardiac contractility.
  • Treatment of heart failure. Digoxin: Pharmacokinetics Oral absorption is 60-75% of the administered dose; when given by this route, maximal levels are reached after 30-90 minutes and its action is maximal after 3-6 h. When given i.v., onset of action is at 5-30 min and this reaches its maximum at 2-4 h. It is approximately 25% bound to plasma proteins and is widely distributed through the body, crossing the blood brain barrier and the placenta. It accumulates in skeletal muscle, liver and heart, where it may reach concentrations that are 10 to 50 times higher than serum levels. This explains why hemodialysis eliminates little of the digoxin load in digoxin toxicity. Cardiac uptake of digoxin increases in patients with hypokalemia and decreases in the presence of hyperkalemia, hypercalcemia or hypomagnesemia. Digoxin undergoes very little biotransformation, and is mainly eliminated through glomerular filtration and somewhat by tubular secretion. In patients with renal insufficiency, the half life of digoxin increases 2-4 times, so that the maintenance dose must be determined according to the creatinine clearance, generally requiring half of the usual dose and, in severe cases, intermittent dosing.
  • Treatment of heart failure. Digoxin: Digitalization strategies The dose of digoxin should be individualized according to age, renal function, severity of the circumstances and the existence of factors which modify the patients’ sensitivity to digoxin, and the dose then adjusted according to clinical response. The time required to reach stable serum levels is 5 half-lives, that is, 7 days. Loading can be accomplished: a) Rapidly, by i.v. (12-24 hours). This is not advisable except in cases of emergency, as it does not allow individualization of the treatment and increases the risk of cardiac toxicity. b) Slowly, via the oral route (5 days for digoxin), which carries less risk. Once loading is accomplished, the maintenance dose must be determined, and should correspond to the amount of digoxin which is eliminated daily (30% of the initial digoxin dose). In the majority of adults, the maintenance dose of digoxin is 0.25 mg/day; in patients with atrial fibrillation the dose may be increased to 0.375-0.5 mg/day, while in the elderly and in patients with renal failure it may need to be reduced to 0.125 mg/day and with anuria to 0.125 mg every 48 h.
  • Treatment of heart failure. Digoxin: Hemodynamic effects Digoxin increases contractile force, maximal shortening velocity (dp/dt max) and the cardiac output, decreases the LV filling pressure and volume, the pulmonary capillary wedge pressure, wall stress and the cardiothoracic ratio. Digoxin displaced the ventricular function curve up and to the left, meaning that it increases the cardiac output at any filling pressure. All of these effects explain when digoxin decreases the signs of congestion and peripheral hypoperfusion in the patient with heart failure. The increase in cardiac output reduces the heart rate, the peripheral vascular resistance, and offsets the increased myocardial demand for oxygen that the increase in contractility might create.
  • Treatment of heart failure. Digoxin: Neurohormonal effects Digoxin, at the doses which augment cardiac contractility, restores the inhibitory effect of the arterial baroreceptors and markedly inhibits the activity of the sympathetic nervous system, which can be seen in the reduction of plasma levels of noradrenaline, the activity of peripheral sympathetic system, and the activity of the renin-angiotensin- aldosterone system (RAAS). This neurohormonal inhibition reduces the heart rate, the peripheral vascular resistance and the signs of congestion and peripheral hypoperfusion in the patient with heart failure. This creates the question to what point do the beneficial effects of digoxin reflect its positive inotropic quality. Digoxin also decreases the reabsorption of Na and water; this natriuretic action, secondary to the increase in cardiac output, increases renal perfusion and the glomerular filtration rate , decreasing renal vasoconstriction and the activation of the RAAS.
  • Treatment of heart failure. Digoxin: Effect on morbidity The RADIANCE trial (multicenter, randomized, double-blind on the efficacy and safety of stopping digoxin in patients with heart failure who were receiving treatment with ACEI) analyzed clinical evolution in 178 patients with heart failure of functional classes II-III and LVEF < 35% treated with digoxin and diuretics and ACEI. Patients either maintained their dose of digoxin between 0.125-0.5 mg/d with serum levels of 0.7-2.0 ng/ml or were given placebo instead. After 100 days of treatment, digoxin withdrawal produced a significant worsening in heart failure which was greater than that observed in the group of patients in whom digoxin was maintained. Packer M et al (RADIANCE). N Engl J Med 1993;329:1
  • Treatment of heart failure. Digoxin: Effect on survival The results obtained from 3 controlled studies which included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality was similar in the group of patients with placebo. The results of the Digitalis Investigator Group-DIG study, which included 7788 patients with heart failure in sinus rhythm, functional class II-III and LVEF < 45%. The patients were treated with digoxin or placebo, in addition to conventional therapy over a mean of 37 months (28 - 58 months). No differences in mortality were observed between the two treatment groups. Am Coll Cardiol 1996
  • Treatment of heart failure. Digoxin: Effect on long term course The results obtained in 3 controlled studies that included patients at low risk (The German and Austrian Xamoterol Study Group, 1988; The Captopril-Digoxin Multicenter Research Group, 1988; DiBianco et al., 1989) indicate that the mortality were similar in both treatment groups. In the DIG study (Digitalis Investigator Group), the survival of 7788 patients with heart failure classes II-III and LVEF < 45% and sinus rhythm treated over 37 months (28 - 58) with digoxin, to determine if it increased or decreased the mortality of patients with symptoms of heart failure. There was no observed effect on survival, but it decreased slightly the number of admissions for cardiovascular causes and also increased the incidence of serious arrhythmias and episodes of acute myocardial infarction. The results of this study probably demand redefinition of the indication for the use of digoxin in patients with heart failure.
  • Treatment of heart failure. Digoxin: Clinical uses Digoxin is the drug of choice for patients with heart failure associated with atrial fibrillation/flutter with rapid ventricular response. Accompanied by diuretics and ACEI it is also useful in patients in sinus rhythm with systolic heart failure. The best results are obtained when cardiomegaly (cardiothoracic index > 60%) and important systolic dysfunction (LVEF < 40%, symptoms at rest, third heart sound) are present. It is also useful in patients who do not respond to diuretics and vasodilators and in severe heart failure associated with hypotension when vasodilators are contraindicated. Digoxin is more effective in heart failure with low cardiac output associated with cardiomyopathies, ischemic cardiomyopathy, arterial hypertension or rheumatic valvular disease with left ventricular failure. It is relatively inefficacious in heart failure with high cardiac output (associated with hyperthyroidism, anemia, arteriovenous fistulas, glomerulonephritis or Paget’s disease) and in heart failure secondary to hypertrophic cardiomyopathy. The results of the study of survival with digoxin require a reassessment of the indications for digoxin use in patients with heart failure. Probably digoxin will become a second-line drug, and its use may be restricted to patients with refractory symptoms, except in patient with rapid atrial fibrillation.
  • Treatment of heart failure Digoxin: Contraindications The only absolute contraindication for digoxin use is the presence of digoxin toxicity. Relative contraindications include: a) presence of advanced A-V blocks without pacemaker, as incremental blockade of conduction through the A-V node increases the risk of complete A-V block; b) ventricular extrasystoles and tachycardias, as these may be aggravated; nevertheless, digoxin may be given if the patient’s extrasystoles are secondary to heart failure; c) marked bradycardia or sinus node disease without pacemaker; d) marked, uncontrolled hypokalemia, and e) patients with Wolff-Parkinson-White syndrome and atrial fibrillation.
  • Treatment of heart failure. Digoxin toxicity Digoxin has a narrow therapeutic margin, and digoxin intoxication remains relatively frequent although it has diminished somewhat as it has become better recognized and lower doses are being prescribed. Cardiac manifestations. Digoxin may cause any type of cardiac arrhythmia, although at times the ECG may be nonspecific. At the ventricular level, isolated or multifocal PVC’s, bigeminy, tachycardia and ventricular fibrillation may occur; at the supraventricular level, digoxin may induce extrasystoles and paroxysmal tachycardias which may result in atrial flutter or fibrillation. In addition, depression of sinoatrial node function may produce bradycardia and even complete sinoatrial block. It prolongs the refractory period and depresses conduction velocity across the A-V node (lengthens the PR interval on the ECG), thereby creating different grade of conduction block, which may precede the appearance of reentrant nodal tachycardias and nodal rhythms. Exacerbation of heart failure in patients treated with digoxin should raise the question of digoxin toxicity.
  • Treatment of heart failure. Digoxin intoxication Extracardiac adverse reactions: a) Gastrointestinal: anorexia, nausea, vomiting, diarrhea, weight loss. b) Nervous: depression, disorientation, confusion, delirium, neuritis and paresthesias. c) Visual changes: blurry vision, scotomas, yellow-green vision. d) Digoxin inhibits the metabolism of ß-estradiol and can produce signs of hyperestrogenism: gynecomastia and galactorrhea or vaginal plaques which may be confused with carcinoma in postmenopausal women.
  • Treatment of heart failure. Positive inotropic agents The use of inotropic agents in heart failure is intended to increase contractility and cardiac output to meet the metabolic needs of the body. Theoretically, their use should be greatest in heart failure associated with a decrease in systolic function and marked cardiomegaly, depression of ejection fraction and elevated left ventricular filling pressure. In addition to the cardiac glycosides, other positive inotropic agents include: a) the sympathomimetics, represented by the ß1 agonists (which stimulate cardiac contractility) and ß2-adrenergics (vasodilators). Both groups increase the intracellular concentration of cAMP by stimulating the activity of adenylate cyclase which converts ATP to cAMP; b) Phosphodiesterase inhibitors, which inhibit the enzyme that breaks down cAMP, increase cardiac contractility and have arteriovenous vasodilatory effect; c) other ionotropic drugs including glucagon and Na + channels agonists.
  • Treatment of heart failure. ß-adrenergic agonists: Classification In an attempt to find options to digoxin, in the 1980’s different positive inotropic drugs became available, among them ß-adrenergic agonists and phosphodiesterase III inhibitors. Both groups of drugs increase the intracellular concentration of cAMP; ß-adrenergic agonists by stimulating the activity of adenylate cyclase which converts ATP into cAMP, and the phosphodiesterase III inhibitors by inhibiting the breakdown of cAMP. The ß-adrenergic agonists can be classified according to the capacity for stimulating the cardiac ß1 receptors (increasing contractility and heart rate), ß 2 -vasodilatory receptors or both (mixed). SVR = Systemic vascular resistance
  • Treatment of heart failure Dopamine (DA) and dobutamine: Hemodynamic effects The hemodynamic effects vary, depending on the dose used: At low doses (0.2-2 µg/kg/min), DA stimulates DA 1 and DA 2 receptors, producing renal, mesenteric, cerebral and coronary vasodilatation. Renal vasodilatation increases glomerular filtration rate, urine production and renal excretion of Na; the majority of Na excretion seems to be due to a direct tubular action of DA and stimulation of DA 2 receptors that inhibit the liberation of aldosterone. Inhibition of sympathetic tone produced by the stimulation of DA 2 receptors explains why at these doses the arterial pressure decreases slightly and the heart rate remains the same or even falls. These doses are used for induction of diuresis, particularly in patients who do not respond to furosemide. At intermediate doses (2-5 µg/kg/min) DA also stimulates cardiac ß1 and ß 2 receptors, increasing contractility, heart rate and cardiac output at the same time as it decreases peripheral resistance (stimulation of DA 1 and ß 2 receptors). These doses are used in the treatment of heart failure without hypotension. At high doses (> 5 µg/kg/min) DA also stimulates a-adrenergic receptors, increasing peripheral resistance and blood pressure. In addition, the marked stimulation of the cardiac ß 1 receptors increases the heart rate and contractility, the myocardial O 2 demand, and may produce arrhythmias. These doses are only used in patients with severe hypotension and/or cardiogenic shock.
  • Treatment of heart failure. Inotropes: General problems Positive inotropic drugs which increase cellular levels of cAMP have important proarrhythmic effects and seem to accelerate the progression of heart failure. Their hemodynamic effects decreased with prolonged treatment which suggests that they should not be used for chronic treatment. Safety and efficacy increases when they are used in low doses, with which the increase in contractility is slight. This points out that their beneficial effects probably do not depend on their positive inotropic action. The reduction in neurohumoral activation produced by digoxin and ibopamine, the antiarrhythmic action of Vesnarinone or the vasodilatory effects of dopamine, dobutamine or PDE III inhibitors may be more important than the increase in contractility that until recently was though to be their utility in the treatment of heart failure. With the exception of digoxin, chronic administration of these drugs increases mortality, so their use, in low doses, should be restricted to patients with refractory heart failure, with persistent symptoms despite treatment with combinations of other drugs. As it is precisely the sickest patients who manifest the increase in mortality, treatment with inotropic drugs is not likely to prolong the survival of these patients.
  • Treatment of Heart Failure. Nitrates: Hemodynamic effects At therapeutic doses, nitrates produce venodilatation that reduces systemic and pulmonary venous resistances. As a consequence, right atrial pressure, pulmonary capillary pressure, and LVEDP decrease. The preload reduction improves the signs of pulmonary congestion and decreases myocardial wall tension and ventricular size, which in turn reduce oxygen consumption. With higher doses, nitrates produce arterial vasodilatation that decreases peripheral vascular resistance and mean arterial pressure, leading to a decrease in afterload, and thereby reduce oxygen consumption. This arterial vasodilatation increases cardiac output, counteracting the possible reduction caused by the reduction in preload caused by venodilatation. The overall effect on cardiac output depends on the LVEDP; when LVEDP is high, nitrates increase cardiac output, while when it is normal nitrates can decrease cardiac output. Nitrates can also produce coronary vasodilatation, as much through reducing preload as through a direct effect on the vascular endothelium. This vasodilatation can decrease the mechanical compression of subendocardial vessels and increases blood flow at this level. Additionally, nitrates reduce coronary vascular tone, overcoming vasospasm.
  • Treatment of Heart Failure. Nitrates: Functional capacity Effect of isosorbide 5-mononitrate on functional capacity (maximal exercise time) in chronic heart failure patients. TID dosing of 20mg is effective both short-term and overall compared to pre-treatment control. Jansen W et al. Med Welt 1982;33:1756
  • Treatment of Heart Failure. Nitrates: Survival Mortality curves of heart failure patients. In men with class II-III heart failure, the VHeFT-I study showed that for patients already treated with digoxin and diuretics, the combination of hydralazine (300mg/day) and isosorbide dinitrate (160mg/day) improved symptoms and functional status. More importantly, combination therapy was associated with a 23% reduction in mortality at 3 years; this effect was not seen in patients treated with prazosin (30mg/day). Selection of the treatment arms in this study was based on certain suppositions. The placebo group received digitalis and diuretics, and subsequent to this study the combination has been administered obligatorily in control groups. The combined administration of hydralazine (arterial vasodilator) and a nitrate (venodilator) was designed to provide equilibrated vasodilatation. Prazosin combined both arterial and venous vasodilatory capacities in one medication, and was initially assumed to be better than combination therapy. The lack of effect of prazosin was probably due to development of tolerance. Perhaps the most relevant finding of the study was that, in practice, the effects of a medicine on symptoms or hemodynamic effects do not correlate well with effects on overall survival. Veterans Administration Cooperative Study (VHefT-1). N Engl J Med 1986;314:1547
  • Treatment of Heart Failure. Nitrates: Tolerance Repetitive administration of nitrates over days is accompanied by a reduction in intensity and duration of its effects (tolerance), that obligates sequential increases in dose to obtain the desired effect. Nitrate tolerance appears with all nitrates, crosses over from one nitrate preparation to another (explaining the poor effect that IV NTG can have in patients on oral nitrate therapy), and is not dose dependent. Additionally, tolerance appears within 8-24 hours of administration of preparations that allow for maintenance of stable plasma nitrate levels (i.v., patch), but disappears rapidly (<48hrs) after stopping treatment. Increasing dosage does not overcome the tolerance effect. Tolerance can be avoided, however, by using the lowest effective dose, and by avoiding continuous plasma levels (drug-free periods).
  • Treatment of Heart Failure. Nitrates: Tolerance Tolerance can be minimized through intermittent dosing, using the lowest possible dose, and allowing for “drug-free periods”. Peaks and valleys of drug levels occur; during valleys the plasma concentration is less than the minimal effective concentration, which allows the vascular smooth muscle to recover its nitrate-sensitivity. For this reason it is recommended to use oral nitrates 2-3 times during the day and to remove the nitrate patches for a 12 hour period.
  • Treatment of Heart Failure. Nitrates: Tolerance Tolerance is related to the duration of the nitrate effects, such that the longer the half-life, the higher the risk that tolerance will occur.
  • Treatment of Heart Failure. Nitrates: Contraindications Nitrates are contraindicated in patients with histories of nitrate hypersensitivity, marked hypertension or shock, acute infarction with low filling pressures, and first-trimester pregnancy. They should also not be given to patients with anemia, increased intracranial pressure, severe aortic or mitral stenosis, cardiac tamponade, constrictive pericarditis or coronary thrombosis. Nitrates can aggravate angina in the setting of hypertrophic cardiomyopathy.
  • Treatment of Heart Failure. Nitrates: Use in Heart Failure Through venodilation, nitrates reduce LVEDP, PAD, and PCWP, thereby improving pulmonary congestion and exercise tolerance. The reduction in end-diastolic pressure and volume decrease wall tension and oxygen consumption. Cardiac output and arterial pressure are not significantly changed, although a decrease in the LVEDP of 12 mmHg can decrease cardiac output. Nitrates are particularly useful in patients with signs of pulmonary congestion (PCWP > 18 mm Hg) and normal cardiac outputs, or in patients with orthopnea and PND. Recommended doses are well tolerated and rarely cause reflex tachycardia or hypotension. In patients with acute heart failure accompanied by pulmonary edema nitroglycerine can be given sublingually or i.v. I.V. administration allows for immediate onset of action, and rapid disappearance of effect within 10-30 minutes of stopping the infusion. Patients receiving I.V. nitroglycerin should be monitored. In patients with low cardiac output, nitrates can be used in conjunction with arterial vasodilators, dopamine, or dobutamine. In the treatment of chronic heart failure preparations with long half-lives are used. Topical nitroglycerine and other nitrates administered qHS are effective in patients with orthopnea and PND.
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) :Mechanisms of action ACE-inhibitors competitively block the converting enzyme that transforms angiotensin I into angiotensin II. The reduction in angiotensin II levels explains its arteriovenous vasodilatory actions, as angiotensin II is a potent vasoconstrictor that augments sympathetic tone in the arteriovenous system. Additionally, angiotensin causes vasopressin release and produces sodium and water retention, both through a direct renal effect and through the liberation of aldosterone. Since converting enzyme has a similar structure to kinase II that degrades bradykinin, ACE-inhibitors increase kinin levels that are potent vasodilators (E2 and F2) and increase release of fibrinolytic substances such as tPA.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Mechanisms of action ACE-inhibitors cause arteriovenous vasodilatation. Venodilation is accompanied by reduction in PAD, PCWP, and LVEDP. Arterial vasodilatation decreases SVR and MAP and increases cardiac output, ejection fraction, and exercise tolerance. Heart rate and contractility do not change, and, thus, double product and myocardial oxygen demand are decreased. These effects are more noticeable in patients with low sodium levels, in whom there is an increased plasma renin activity. Vasodilatation is seen in various vascular territories: renal, coronary, cerebral, and musculoskeletal (increasing exercise capacity). Additionally, ACE-inhibitors cause diuretic and natriuretic effects that are a consequence of the inhibition of angiotensin II and aldosterone synthesis, as well as the increase in cardiac output and renal perfusion. It is now known that the magnitude and duration of blood pressure reduction correlates better with the activity of ACE in certain tissues (heart, vessels, kidney, adrenal, etc.) than with its plasma levels, which indicates that ACE-inhibitors act by inhibiting local tissue production of angiotensin II. Plasma levels of ACE are not good predictors of the magnitude of hemodynamic effects of ACE-inhibition.
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors: Effect on Mortality The effect of discontinuation of quinapril therapy on patients with class II-III heart failure in the Quinapril Heart Failure Trial is shown. At 20 weeks of treatment the group whose quinapril treatment was terminated had increased symptoms compared to the group who continued to receive quinapril therapy. The latter group maintained a stable functional status. This study, whose design was similar to PROVD and RADIANCE, again demonstrates the efficacy of ACE-inhibitors in the treatment of heart failure. Pflugfelder PW et al. J Am Coll Cardiol 1993;22:1557.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Advantages In class II-IV heart failure patients treated with diuretics and digitalis, ACE-inhibitors decrease symptoms, improve hemodynamics and functional class, and increase exercise tolerance. Additionally, they reduce left ventricular dimensions, improve the cardiothoracic index, improve renal function, and improve hyponatremia. More importantly, ACE-inhibitors are the best drugs to date for preventing expansion and dilatation of the left ventricle post infarction, thereby decreasing the number and duration of hospitalizations, and improving symptoms and survival. They also retard progression to heart failure in patients with asymptomatic ventricular dysfunction. ACE-inhibitors differ from other vasodilators in that they do not produce neurohormonal activation or reflex tachycardia, and tolerance to these agents does not seem to develop over time. ACE-inhibitors increase plasma renin, bradykinin, and angiotensin I activities, and reduce plasma and tissue levels of angiotensin II, and plasma levels of aldosterone and cortisol. ACE-inhibitors can also decrease plasma norepinephrine levels, especially after long-term therapy, which has been attributed to the suppression of the stimulating effect angiotensin II has on the synthesis and release of norepinephrine. ACE-inhibitors also reduce arginine-vasopressin levels.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival CONSENSUS. Prolonged administration of ACE-inhibitors reduces mortality in symptomatic heart failure. The first study to demonstrate this effect was CONSENSUS I. This graph shows the cumulative mortality curves of the treatment and placebo group in this randomized, double-blind trial. The study analyzed the effect of enalapril on prognosis of 253 patients with class IV heart failure, who also received digitalis, diuretics, and conventional vasodilators. At the end of 6 months of treatment, there was a clear-cut improvement in functional class, a reduction in the need for medications, and a 40% reduction in mortality (p<0.002). After 12 months the mortality reduction was 31% (p<0.001). Nonetheless, there were no differences in the incidence of sudden death between the two groups, or in the sub-group that received other conventional vasodilators. Another characteristic of this study was variability of the dose that was used for each patient (adjusted for tolerance and symptoms): 2.5-40mg/day. This aspect shows the importance of individualized treatment for heart failure patients. The CONSENSUS Trial Study Group. N Engl J Med 1987;316:1429.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival Mortality curves in patients with asymptomatic ventricular dysfunction in the SOLVD study. This study compared the effect of enalapril versus placebo in 4228 asymptomatic patients with EF < 35% who were previously untreated. Overall mortality was similar in both groups (15.8% vs. 14.8%, NS), but in the enalapril arm a reduction in development of clinical symptoms of heart failure or need for hospitalization was seen. Once again, patients with the lowest EF’s were those who benefited the most from therapy. The SOLVD Investigators. N Engl J Med1992;327:685
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) : Survival SOLVD study-symptomatic heart failure. Mortality curves in patients with clinical heart failure in the SOLVD treatment study. In this study, 2589 symptomatic heart failure patients with EFs<35% (90% in functional class II – III) were randomized to receive enalapril or placebo. Mortality over a 41 month follow-up period was 39.7% in the enalapril arm and 35.2% in the placebo arm (p<0.004). The mortality reduction was chiefly mediated through less progression of heart failure; deaths due to arrhythmia were not reduced. Additionally, the enalapril group required fewer hospitalizations for heart failure. The SOLVD Investigators. N Engl J Med 1991;325:293
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI): Survival SAVE (Survival and Ventricular Enlargement). Mortality curves in the SAVE study in patients with varying degrees of post-infarct ventricular dysfunction. In this study, 2231 patients with EF < 40% were randomized to receive captopril or placebo between 3 to 16 days after experiencing a transmural infarct. After 42 months, the captopril group had a significant reduction in overall mortality (-19%), number of reinfarctions (-25%), hospitalizations (-22%), and in the number of patients who developed clinical congestive heart failure. The mortality reduction appeared after 1 year of treatment. Pfeffer MA et al. Survival and Ventricular Enlargement (SAVE) Study. NEngl J Med 1992;327:669.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Survival Post-infarction studies. The results of the various studies that have compared ACE-inhibitors with placebo in the post-MI setting have differing results. Nonetheless, the benefit obtained in each study correlates with the degree of ventricular dysfunction of the selected patients. In this graph, the difference in mortality over time is seen in absolute terms (lives saved per 100 patients treated = % mortality in placebo group - % mortality in ACEI group/ follow-up time). Even though the studies demonstrated statistically significant differences between placebo and ACE-inhibitor therapy, the benefit of treatment is minimal in low-risk patients, probably not justifying its routine use in every post-MI patient (ISIS-4 and GISSI-3). Benefits are moderate in patients with higher risk (asymptomatic ventricular dysfunction) (SAVE and SMILE), and maximal in patients with sever ventricular dysfunction or clinical heart failure (TRACE and AIRE). ISIS-4: Lancet 1995; 345:669 GISSI-3: Lancet 1994;343:1115 SAVE: N Engl J Med 1992;327:669. SMILE: N Engl J Med 1992;332:80. TRACE: N Engl J Med. 1995; 333:1670. AIRE: Lancet 1993; 342: 821.
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibits (ACEI) Indications. ACE-inhibitors probably constitute the cornerstone of drug therapy for heart failure, in that administration over time leads to amelioration of symptoms, beneficial hemodynamic changes, increased functional capacity, regression of structural changes, and, unequivocally, prolongation of survival. Thus, ACE-inhibitors are first-line therapy, not only in symptomatic heart failure patients, but also in patients with asymptomatic left ventricular dysfunction. The exact degree of ventricular dysfunction below which it is advisable to begin therapy with an ACE-inhibitor has not been defined; however, in general terms they can be helpful in patients with ejection fractions less than 35%.
  • Treatment of Heart Failure. Angiotensin Converting-Enzyme Inhibitors (ACEI) : Undesirable Effects These can be classified into two groups. One group includes those effects that are inherent to its mechanism of action, and therefore are common to all ACE-inhibitors. The other includes those effects that are related to the specific chemical structure of the drug. In this case, substitution of one ACE-inhibitor for another could possibly reduce the intensity of the adverse reaction (e.g. choosing an ACE-inhibitor without a sulfhydryl moiety).
  • Treatment of Heart Failure Angiotensin Converting-Enzyme Inhibitors (ACEI) Contraindications. There are few absolute contraindications for the use of ACE-inhibitors. The most important one is the presence of renal artery stenosis. The most frequent contraindication is intolerance of the drug. Hypotension, the presence of renal insufficiency, or hyperkalemia limits their use, or the ability to administer adequate doses, in up to 20% of patients.
  • Treatment of congestive heart failure. Angiotensin II inhibitors Angiotensin II has different effects mediated via specific receptors. There are two types of tissue receptors for angiotensin: AT1 and AT2. Stimulation of AT1 receptors has a proliferative and vasoconstrictor effect, while stimulation of AT2 receptors has the opposite effects, that is, vasodilatory and antiproliferative. In the treatment of heart failure, specific blockade of the AT1 receptors is desirable. Drugs which create a selective and competitive block of the AT1 receptors include:losartan, valsartan, irbersartan and candersartan.
  • Treatment of congestive heart failure. Angiotensin II inhibitors Drugs which create a selective and competitive block of the AT1 receptors include: losartan, valsartan, irbersartan and candersartan.
  • Treatment of congestive heart failure. Aldosterone inhibitors: Mechanism of action Aldosterone acts directly on specific receptors. At the renal level it produces retention of sodium and water, resulting in an increase in preload and afterload, edema formation and the appearance of symptoms of pulmonary and systemic venous congestion. In addition, it increases the elimination of potassium and magnesium, creating an electrolyte imbalance which may be responsible in part for cardiac arrhythmias. At the tissue level, aldosterone stimulates the production of collagen, being in large part responsible for the fibrosis that is found in hypertrophied myocardium and in the arterial walls of patients with heart failure. The beneficial effects of spironolactone derive from the direct and competitive blockade of specific aldosterone receptors. Aldosterone inhibitors therefore have three types of effects: - Diuretic effect, which is most noticeable when fluid retention and increased levels of aldosterone are present. - Antiarrhythmic effect, mediated by the correction of hypokalemia and hypomagnesemia. - Antifibrotic effect. This effect, demonstrated in animal models, can contribute to a decrease in the progression of structural changes in patients with heart failure.
  • Treatment of congestive heart failure. Aldosterone inhibitors: Indications Spironolactone has been used for several decades for its diuretic effect in heart failure. It is currently considered a second line diuretic, to be considered when more potent diuretics, such as the loop diuretics, are inadequate. Retention of K+ and Mg+ prompted by spironolactone has an antiarrhythmic effect which may be helpful in patients with low serum levels of those electrolytes. One indication is when potassium supplementation is required; in these cases, spironolactone administration is preferable. Finally, spironolactone, by virtue of its neurohormonal effects, probably influences the progression and prognosis of patients with heart failure. Its effect on survival is being assessed in a prospective study, compared to placebo (Randomized ALdactone Evaluation Study) in 1400 patients with chronic severe heart failure. The results of this will allow better definition of the indications for spironolactone in patients with chronic congestive heart failure.
  • Treatment of congestive heart failure. Aldosterone inhibitors: Contraindications The contraindications for spironolactone use include hyperkalemia and chronic renal insufficiency.
  • Treatment of congestive heart failure. Possible benefits of beta adrenergic blockers The use of ß-blockers in patients with heart failure is controversial. Nevertheless, this slide lists some of the potentially beneficial effects of these drugs for patients in heart failure.
  • Treatment of Heart Failure. Possible Benefits of Beta-Blockers In the Beta-Blocker Heart Attack Trial the decrease in mortality associated with propranolol use was found to be inversely related to the pre-treatment ejection fraction. Beta Blocker Heart Attack Trial (BHAT). JACC 1990;16:1327
  • Treatment of Heart Failure. Possible Benefits of Beta-Blockers Other indirect data that suggest a beneficial effect of beta-blocker use in heart failure or LV dysfunction can be found in the SAVE trial. In this study, 2231 patients with EF < 40% post-AMI were included. A retrospective analysis of overall mortality (at median 42 months of follow-up) showed the results that are on this slide. Mortality was lower in patients who received beta-blockers, regardless of randomization to placebo or ACE-inhibitor therapy. Mortality was lowest when beta-blocker therapy was combined with ACE-inhibitors, and maximal when neither drug was used. SAVE. Circulation 1995;92:3132
  • Treatment of Heart Failure. Possible Benefits of Beta-Blockers. Carvedilol has been tested in various studies of patients with mild to moderate heart failure, none of which were designed to evaluate its effect on mortality. In the Carvedilol Program in Heart Failure in the U.S., 1094 patients with heart failure were included. The patients received carvedilol in doses ranging from 3 to 50 mg/day. The program, which included 4 studies of clinical efficacy for FDA approval, was suspended before reaching its predetermined objectives, after a significant decrease in mortality in the carvedilol group was seen. In the Australian-New Zealand study 415 patients with mild heart failure were randomized to receive carvedilol or placebo. Carvedilol therapy was associated with a decrease in the combination of death or hospitalization of cardiac etiology. Packer M, et al. N Engl J Med 1996;334:1349 Sackner J, et al. Circulation 1995;92:I:395
  • Treatment of Heart Failure. Indications for Beta-Blocker Therapy In spite of more than 20 years of clinical investigation, the indication for beta-blockers in patients with heart failure has not yet been precisely established. Nonetheless, it is suggested that treatment be started with doses much lower than those used for the treatment of angina, and the dose should be increased slowly.
  • Treatment of Heart Failure. Possible Benefits of Beta-Blockers The ideal candidate for beta-blocker therapy has not yet been established. Nonetheless, having other indications for beta-blocker therapy could be an initial criterion for selection. Examples of these indications include sinus tachycardia, ventricular arrhythmia, hypertension, or angina in a heart failure patient.
  • Treatment of Heart Failure. Beta-Blockers: Contraindications Contraindications to beta-blocker therapy in heart failure patients are the same as those for the general population.
  • Treatment of Heart Failure. Possible Benefits of Calcium-channel Blockers Calcium-channel blockers are theoretically useful in heart failure for a number of reasons, including their vasodilatory action and their anti-ischemic effect, but some have a negative inotropic effect that could be detrimental, and preclude their use.
  • Treatment of Heart Failure. Utility of Calcium-channel Blockers Use of calcium-channel blockers in patients with heart failure is still a subject of heated debate. Diltiazem is contraindicated, as are verapamil and nifedipine. It is likely that the newer dihydropyridines that have selective effects on vascular smooth muscle will be useful in treatment of heart failure. Amlodipine can be used to control myocardial ischemia in heart failure patients. In the PRAISE-2 trial, a trend towards a survival benefit was noted in the amlodipine-treated group.
  • Treatment of Heart Failure. Anticoagulants The goal of using anticoagulants in heart failure patients is to reduce the risk of systemic and pulmonary embolism. Anticoagulation should be reserved for patients with highest risk of embolization, who are indicated in this graph. Of the possible noted indications, the only ones that are NOT controversial at present are history of previous embolism and the presence of atrial fibrillation.
  • Treatment of Heart Failure. Antiarrhythmics Approximately half of deaths in heart failure patients are attributable to arrhythmia. Nonetheless, the use of antiarrhythmics is controversial. No trial to date has shown that these agents should be used in heart failure patients as a group. Only beta-blockers and amiodarone can be considered safe, and should be used in patients with malignant ventricular arrhythmias. Consideration of AICD implantation should be given in cases of sudden death related to VF, as long as ischemic arrhythmia or another reversible cause (electrolyte imbalance, for example).
  • Treatment of Heart Failure. Antiarrhythmics The use of antiarrhythmics in heart failure is controversial. In some studies, such as SWORD (post-infarction ventricular dysfunction), the administration of sotalol had to be suspended because of the finding of increased mortality in the treatment arm. Amiodarone is considered to be the most effective agent in the prevention of sudden death in patients with heart failure or ventricular dysfunction. This effect, however, has never been demonstrated unequivocally. In one of the most important studies, EMIAT, the administration of amiodarone did not provide an overall improvement in prognosis. Am Coll Cardiol 1996
  • Chronic chf

    1. 1. CHRONIC CONGESTIVEHEART FAILUREAmerican Heart Associationin collaboration withSociedad Española de Cardiologia June, 1999
    2. 2. Chronic Congestive Heart FailureCommittee on Post Graduate Education,Council on Clinical Cardiology,American Heart AssociationDeveloped in collaboration with theSociedad Española de CardiologiaPrepared by:Ann F. Bolger, MDJosé Lopez Sendón, MDThe content of these slides is current as of June, 1999. (Slide #62 updated 9/00)Future revisions will be posted on theAmerican Heart Association website (
    3. 3. Chronic Congestive Heart Failure DEFINITION“The situation when the heart isincapable of maintaining a cardiacoutput adequate to accommodatemetabolic requirements and thevenous return." E. Braunwald
    4. 4. Chronic Congestive Heart Failure EVOLUTION OF CLINICAL STAGES NORMALNo symptomsNormal exerciseAsymptomaticNormal LV fxn LV Dysfunction No symptoms Compensated Normal exercise Abnormal LV fxnCHF Decompensated No symptoms Exercise CHF Abnormal LV fxn Symptoms Refractory Exercise CHF Abnormal LV fxn Symptoms not controlled with treatment
    5. 5. Chronic Congestive Heart Failure DETERMINANTS OF VENTRICULAR FUNCTION CONTRACTILITY PRELOAD AFTERLOAD STROKE VOLUME- Synergistic LV contraction- LV wall integrity HEART- Valvular competence RATE CARDIAC OUTPUT
    6. 6. Chronic Congestive Heart FailureTREATMENT OBJECTIVES Survival Morbidity Exercise capacity Quality of life Neurohormonal changes Progression of CHF Symptoms
    7. 7. Chronic Congestive Heart Failure TREATMENTCorrection of aggravating factorsPregnancy EndocarditisArrhythmias (AF) ObesityInfections HypertensionHyperthyroidism Physical activityThromboembolism Dietary excess MEDICATIONS
    9. 9. Chronic Congestive Heart Failure DRUGS HEMODYNAMIC EFFECTS Normal A IStroke A+VVolume V D CHF Ventricular Filling Pressure
    10. 10. Chronic Congestive Heart FailurePHARMACOLOGIC THERAPY Improved Decreased Prevention Neurohumoral symptoms mortality of CHF Control DIURETICS yes ? ? NO DIGOXIN yes = minimal yes INOTROPES yes mort. ? noVasodil.(Nitrates) yes yes ? no ACEI yes YES yes YESOther neurohormonalcontrol drugs yes +/- ? YES
    11. 11. Chronic Congestive Heart Failure TREATMENTNormal Asymptomatic LV dysfunction EF <40% Symptomatic CHF ACEI NYHA II Symptomatic CHF Diuretics mild NYHA - III Neurohormonal Symptomatic CHF Loop inhibitors NYHA - IV Diuretics Digoxin? Inotropes Specialized therapy Transplant Secondary prevention Modification of physical activity
    12. 12. Chronic Congestive Heart Failure DIURETICS ThiazidesCortex Inhibit active exchange of Cl-Na in the cortical diluting segment of the ascending loop of Henle K-sparing Inhibit reabsorption of Na in the distal convoluted and collecting tubule Loop diureticsMedulla Inhibit exchange of Cl-Na-K in the thick segment of the ascending loop of Henle Loop of Henle Collecting tubule
    13. 13. Chronic Congestive Heart Failure THIAZIDES MECHANISM OF ACTION Excrete 5 - 10% of filtered Na+ Elimination of K Inhibit carbonic anhydrase: increase elimination of HCO3 Excretion of uric acid, Ca and Mg No dose - effect relationship
    14. 14. Chronic Congestive Heart Failure LOOP DIURETICS MECHANISM OF ACTION Excrete 15 - 20% of filtered Na+ Elimination of K+, Ca+ and Mg++ Resistance of afferent arterioles - Cortical flow and GFR - Release renal PGs - NSAIDs may antagonize diuresis
    15. 15. Chronic Congestive Heart FailureK-SPARING DIURETICSMECHANISM OF ACTION Eliminate < 5% of filtered Na+ Inhibit exchange of Na+ for K+ or H+ Spironolactone = competitive antagonist for the aldosterone receptor Amiloride and triamterene block Na+ channels controlled by aldosterone
    16. 16. Chronic Congestive Heart FailureDIURETIC EFFECTS Volume and preload Improve symptoms of congestion No direct effect on CO, but excessive preload reduction may Improves arterial distensibility Neurohormonal activation Levels of NA, Ang II and ARP Exception: with spironolactone
    17. 17. Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS Thiazide and Loop Diuretics Changes in electrolytes: Volume Na+, K+, Ca++, Mg++ metabolic alkalosis Metabolic changes: glycemia, uremia, gout LDL-C and TG Cutaneous allergic reactions
    18. 18. Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS Thiazide and Loop DiureticsIdiosyncratic effects: Blood dyscrasia, cholestatic jaundice and acute pancreatitisGastrointestinal effectsGenitourinary effects: Impotence and menstrual crampsDeafness, nephrotoxicity
    19. 19. Chronic Congestive Heart Failure DIURETICS ADVERSE REACTIONS K-SPARING DIURETICS Changes in electrolytes: Na+, K+, acidosis Musculoskeletal: Cramps, weakness Cutaneous allergic reactions : Rash, pruritis
    20. 20. Chronic Congestive Heart Failure DIGOXIN Na-K ATPase Na-Ca Exchange + Na K + Na+ Ca++ Myofilaments Ca++ K+ Na+ CONTRACTILITY
    21. 21. Chronic Congestive Heart Failure DIGOXINPHARMACOKINETIC PROPERTIES Oral absorption (%) 60 - 75 Protein binding (%) 25 Volume of distribution (l/Kg) 6 (3-9) Half life 36 (26-46) h Elimination Renal Onset (min) i.v. 5 - 30 oral 30 - 90 Maximal effect (h) i.v. 2-4 oral 3-6 Duration 2 - 6 days Therapeutic level (ng/ml) 0.5 - 2
    22. 22. Chronic Congestive Heart Failure DIGOXIN DIGITALIZATION STRATEGIES Maintenance Loading dose (mg) Dose i.v oral 12-24 h oral 2-5 d (mg)0.5 + 0.25 / 4 h 0.75 + 0.25 / 6 h 0.25 / 6-12 h 0.125-0.5 / d ILD: 0.75-1 1.25-1.5 1.5-1.75 0.25 / d ILD = average INITIAL dose required for digoxin loading
    23. 23. Chronic Congestive Heart Failure DIGOXIN HEMODYNAMIC EFFECTS Cardiac output LV ejection fraction LVEDP Exercise tolerance Natriuresis Neurohormonal activation
    24. 24. Chronic Congestive Heart Failure DIGOXIN NEUROHORMONAL EFFECTS Plasma Noradrenaline Peripheral nervous system activity RAAS activity Vagal toneNormalizes arterial baroreceptors
    25. 25. Chronic Congestive Heart Failure DIGOXINEFFECT ON CHF PROGRESSION 30 Placebo n=93 % DIGOXIN Withdrawal WORSENING 20 OF0.5 mg /dDIGOXIN: 0.125 - CHF p = 0.001(0.7 - 2.0 ng/ml) 10EF < 35%Class I-III (digoxin+diuretic+ACEI)Also significantly decreased exercisetime and LVEF. DIGOXIN n=85 0 RADIANCE 0 20 40 60 80 100 N Engl J Med 1993;329:1 Days
    26. 26. Chronic Congestive Heart Failure OVERALL MORTALITY 50 40 30 % Placebo 20 n=3403 p = 0.8 10 DIGOXIN n=3397 0DIG 0 12 24 36 48N Engl J Med 1997;336:525 Months
    27. 27. Chronic Congestive Heart Failure DIGOXIN LONG TERM EFFECTS Survival similar to placebo Fewer hospital admissions More serious arrhythmias More myocardial infarctions
    28. 28. Chronic Congestive Heart Failure DIGOXIN CLINICAL USES AF with rapid ventricular response CHF refractory to other drugs Other indications? Can be combined with other drugs
    29. 29. Chronic Congestive Heart Failure DIGOXIN CONTRAINDICATIONS ABSOLUTE: - Digoxin toxicity RELATIVE - Advanced A-V block without pacemaker - Bradycardia or sick sinus without PM - PVC’s and TV - Marked hypokalemia - W-P-W with atrial fibrillation
    30. 30. Chronic Congestive Heart Failure DIGOXIN TOXICITYCARDIAC MANIFESTATIONS ARRHYTHMIAS : - Ventricular (PVCs, TV, VF) - Supraventricular (PACs, SVT) BLOCKS: - S-A and A-V blocks CHF EXACERBATION
    31. 31. Chronic Congestive Heart Failure DIGOXIN TOXICITY EXTRACARDIAC MANIFESTATIONS GASTROINTESTINAL: - Nausea, vomiting, diarrhea NERVOUS: - Depression, disorientation, paresthesias VISUAL: - Blurred vision, scotomas and yellow-green vision HYPERESTROGENISM:
    32. 32. Chronic Congestive Heart FailurePOSITIVE INOTROPES CARDIAC GLYCOSIDES SYMPATHOMIMETICS Catecholamines ß-adrenergic agonists PHOSPHODIESTERASE INHIBITORS Milrinone Amrinone Piroximone Enoximone
    33. 33. Chronic Congestive Heart Failureß-ADRENERGIC STIMULANTS CLASSIFICATION B1 Stimulants Increase contractility Dobutamine Doxaminol Xamoterol Butopamine Prenalterol Tazolol B2 Stimulants Produce arterial vasodilatation and reduce SVRPirbuterol Rimiterol TretoquinolTerbutaline SoterenolCarbuterolFenoterol Salbutamol SalmefamolQuinterenol Mixed Dopamine
    34. 34. Chronic Congestive Heart Failure DOPAMINE AND DOBUTAMINE EFFECTS DA (µg / Kg / min) Dobutamine <2 2-5 >5Receptors DA1 / DA2 ß1 ß1 + α ß1Contractility ± ++ ++ ++Heart Rate ± + ++ ±Arterial Press. ± + ++ ++Renal perfusion ++ + ± +Arrhythmia - ± ++ ±
    35. 35. Chronic Congestive Heart Failure POSITIVE INOTROPES CONCLUSIONS May increase mortality Safer in lower doses Use only in refractory CHF NOT for use as chronic therapy
    36. 36. Chronic Congestive Heart Failure VASODILATOR DRUGS PRINCIPLES Normal Contractility Normal ContractilityCO VV AV Diminished Diminished Contractility Contractility PRELOAD AFTERLOAD
    37. 37. Chronic Congestive Heart Failure VASODILATORS CLASSIFICATION VENOUS Venous Vasodilatation Nitrates Molsidomine MIXED Calcium antagonists α-adrenergic Blockers ACEI Angiotensin II inhibitors K+ channel activators Nitroprusside Arterial ARTERIALVasodilatation Minoxidil Hydralazine
    38. 38. Chronic Congestive Heart Failure NITRATES HEMODYNAMIC EFFECTS1- VENOUS VASODILATATION Pulmonary congestion Ventricular size Preload Vent. Wall stress MVO22- Coronary vasodilatation Myocardial perfusion • Cardiac output3- Arterial vasodilatation • Blood pressure Afterload
    39. 39. Chronic Congestive Heart Failure NITRATES FUNCTIONAL CAPACITY 400 n=24 392 384 ** ** EXERCISE 300 267 TIME, seconds 200 100 Control 1ST 4 dose weeksJansen W et al ISOSORBIDE 5 - MONONITRATEMed Welt 1982;33:1756 20 mg / 8h
    40. 40. Chronic Congestive Heart Failure NITRATES 0.7 SURVIVAL Placebo (273) 0.6 Prazosin (183) Hz + ISDN (186) 0.5PROBABILITY 0.4OF 0.3DEATH 0.2 0.1 0VHefT-1 0 6 12 18 24 30 36 42N Engl J Med 1986;314:1547 MONTHS
    41. 41. Chronic Congestive Heart Failure NITRATES TOLERANCE " Decrease in the effect of a drug when administered in a long-acting form"Develops with all nitratesIs dose-dependentDisappears in 24 h. after stopping the drugTolerance can be avoided - Using the least effective dose - Creating discontinuous plasma levels
    42. 42. Chronic Congestive Heart Failure NITRATES TOLERANCECan be avoided or minimized - Intermittent administration - Use the lowest possible dose - Intersperse a nitrate-free intervalAllow peaks and valleys in plasma levels - Vascular smooth muscle recovers its nitrate sensitivity during the nadirs - Patches: remove after 8-10 h
    43. 43. Chronic Congestive Heart Failure NITRATES TOLERANCE H T A s.l. NTG O L L F ISDN E R L I 5-MN A I N F Percutaneous NTG C E E
    44. 44. Chronic Congestive Heart Failure NITRATES CONTRAINDICATIONS Previous hypersensitivity Hypotension ( < 80 mmHg) AMI with low ventricular filling pressure 1st trimester of pregnancy WITH CAUTION: Constrictive pericarditis i Intracranial hypertension e Hypertrophic cardiomyopathy
    45. 45. Chronic Congestive Heart Failure NITRATES CLINICAL USESPulmonary congestionOrthopnea and paroxysmal nocturnaldyspneaCHF with myocardial ischemiaIn acute CHF and pulmonary edema:NTG s.l. or i.v.
    47. 47. Chronic Congestive Heart Failure ACEI HEMODYNAMIC EFFECTS Arteriovenous Vasodilatation - PAD, PCWP and LVEDP - SVR and BP - CO and exercise tolerance No change in HR / contractility MVO2 Renal, coronary and cerebral flow Diuresis and natriuresis
    48. 48. Chronic Congestive Heart Failure ACEI FUNCTIONAL CAPACITY 100No 95 QuinaprilAdditional continued n=114 90Treatment p<0.001Necessary 85(%) Quinapril 80 stopped Placebo Class II-III n=110 75 2 4 6 8 10 12 14 16 18 20Quinapril Heart Failure TrialJACC 1993;22:1557 Weeks
    49. 49. Chronic Congestive Heart Failure ACEI ADVANTAGESInhibit LV remodeling post-MIModify the progression of chronic CHF - Survival - Hospitalizations - Improve the quality of lifeIn contrast to others vasodilators,do not produce neurohormonal activationor reflex tachycardia
    50. 50. Chronic Congestive Heart Failure ACEI SURVIVAL 0.8 0.7 Placebo 0.6PROBABILITY 0.5 p< 0.001OF 0.4 p< 0.002DEATH 0.3 Enalapril 0.2 0.1 0 CONSENSUS 0 1 2 3 4 5 6 7 8 9 10 11 12 N Engl J Med 1987;316:1429 MONTHS
    51. 51. Chronic Congestive Heart Failure ACEI SURVIVAL 50 p = 0.30 Placebo 40 n=2117 % 30 MORTALITY 20 Enalapriln = 4228 10 n=2111No CHF symptomsEF < 35 0 0 6 12 18 24 30 36 42 48SOLVD (Prevention)N Engl J Med 1992;327:685 Months
    52. 52. Chronic Congestive Heart Failure ACEI SURVIVAL 50 p = 0.0036 Placebo 40 n=1284 % 30 MORTALITY Enalapril 20 n=1285n = 2589CHF 10- NYHA II-III- EF < 35 0 0 6 12 18 24 30 36 42 48SOLVD (Treatment)N Engl J M 1991;325:293 Months
    53. 53. Chronic Congestive Heart Failure ACEI SURVIVAL 30 Asymptomatic ventricular Placebo dysfunction post MI n=1116 20 Mortality, Captopril n=1115 % 10n = 22313 - 16 days post AMIEF < 40 ² -19%12.5 --- 150 mg / day p=0.019SAVE 0N Engl J Med 1992;327:669 0 1 2 3 4 Years
    54. 54. Chronic Congestive Heart Failure ACEI SURVIVAL POST MI ACEI Benefit Pt SelectionISIS-4 Captopril 0.5 / 5 wk All with AMIGISSI-3 Lisinopril 0.8 / 6 wk All with AMISAVE Captopril 4.2 / 3.5 yr EF < 40 asymptomaticSMILE Zofenopril 4.1 / 1 yr Ant. AMI, No TRLTRACE Trandolapril 7.6 / 3 yr Vent Dysfx / Clinical CHF EF < 35AIRE Ramipril 6 / 1 yr Clinical CHF
    55. 55. Chronic Congestive Heart Failure ACEI INDICATIONS Clinical cardiac insufficiency - All patients Asymptomatic ventricular dysfunction - LVEF < 35 %
    56. 56. Chronic Congestive Heart Failure ACEI UNDESIRABLE EFFECTS Inherent in their mechanism of action - Hypotension - Dry cough - Hyperkalemia - Renal Insuff. - Angioneurotic edema Due to their chemical structure - Cutaneous eruptions - Neutropenia, - Dysgeusia thrombocytopenia - Proteinuria - Digestive upset
    57. 57. Chronic Congestive Heart Failure ACEI CONTRAINDICATIONS Renal artery stenosis Renal insufficiency Hyperkalemia Arterial hypotension Intolerance (due to side effects)
    58. 58. Chronic Congestive Heart Failure ANGIOTENSIN II INHIBITORS MECHANISM OF ACTION RENINAngiotensinogen Angiotensin I ACE Other paths ANGIOTENSIN II AT1RECEPTORBLOCKERS AT1 RECEPTORS AT2Vasoconstriction Proliferative Vasodilatation Antiproliferative Action Action
    59. 59. Chronic Congestive Heart Failure AT1 RECEPTOR BLOCKERS DRUGS Losartan Valsartan Irbersartan Candersartan Competitive and selective blocking of AT1 receptors
    60. 60. Chronic Congestive Heart FailureALDOSTERONE INHIBITORS Spironolactone ALDOSTERONECompetitive antagonist of thealdosterone receptor(myocardium, arterial walls, kidney) Retention Na+ Collagen Edema deposition Retention H2O Fibrosis Excretion K+ Arrhythmias - myocardium Excretion Mg2+ - vessels
    61. 61. Chronic Congestive Heart FailureALDOSTERONE INHIBITORSINDICATIONSFOR DIURETIC EFFECT• Pulmonary congestion (dyspnea)• Systemic congestion (edema) FOR ELECTROLYTE EFFECTS • Hypo K+, Hypo Mg+ • Arrhythmias • Better than K+ supplements FOR NEUROHORMONAL EFFECTS
    62. 62. Chronic Congestive Heart Failure ALDOSTERONE INHIBITORS CONTRAINDICATIONS • Hyperkalemia • Severe renal insufficiency • Metabolic acidosis
    63. 63. Chronic Congestive Heart Failureß-ADRENERGIC BLOCKERSPOSSIBLE BENEFICIAL EFFECTS Density of ß1 receptors Inhibit cardiotoxicity of catecholamines Neurohormonal activation HR Antihypertensive and antianginal Antiarrhythmic Antioxidant
    64. 64. Chronic Congestive Heart Failure ß BLOCKERS 50 SURVIVAL 40 ß Blocker Placebo 30 % 20 10 0 < 30% 30-40% > 40%BHATJACC 1990;16:1327 LV EJECTION FRACTION
    65. 65. Chronic Congestive Heart Failure ß BLOCKERS Mortality ß BLOCKER n=2231 YES No Yes 13.3% 24.3% ACEI No 19.5% 27.7%SAVECirculation 1995;92:3132
    66. 66. Chronic Congestive Heart Failure ß BLOCKERS CARVEDILOL4 studies in U.S.;1 in Australia/New ZealandU.S. studies with control groupMortality with Placebo 8.2% p < 0.0001Mortality with Carvedilol 2.9%Initial low doses, progressive
    67. 67. Chronic Congestive Heart Failureß-ADRENERGIC BLOCKERSINDICATIONS and UTILIZATION Not clearly established Begin with very low doses Slow augmentation of dose Slow withdrawal ?
    68. 68. Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS IDEAL CANDIDATE? Suspected adrenergic activation Arrhythmias Hypertension Angina
    69. 69. Chronic Congestive Heart Failure ß-ADRENERGIC BLOCKERS CONTRAINDICATIONS Hypotension: BP < 100 mmHg Bradycardia: HR < 50 bpm Clinical instability Chronic bronchitis, ASTHMA Severe chronic renal insufficiency
    70. 70. Chronic Congestive Heart FailureCALCIUM ANTAGONISTS POTENTIAL EFFECTS Antiischemic Peripheral Vasodilatation Inotropy
    71. 71. Chronic Congestive Heart Failure CALCIUM ANTAGONISTS POSSIBLE UTILITYDiltiazem contraindicatedVerapamil and Nifedipinenot recommendedVasoselective (amlodipine, nisoldipine),may be useful in ischemia + CHFAmlodipine may be useful in nonischemic CHF
    72. 72. Chronic Congestive Heart FailureANTICOAGULANTS PREVIOUS EMBOLIC EPISODE ATRIAL FIBRILLATION Identified thrombus LV Aneurysm (3-6 mo post MI) Class III-IV in the presence of: - EF < 30 - Aneurysm or very dilated LV Phlebitis Prolonged bed rest
    73. 73. Chronic Congestive Heart FailureANTIARRHYTHMICSSustained VT, with/without symptoms - ß Blockers - AmiodaroneSudden death from VF - Consider implantable defibrillator
    74. 74. Chronic Congestive Heart Failure ANTIARRHYTHMICS MORTALITY 15 13.6 ns 13.7 MORTALITY AT 2 YEARS 10 %n=14865-21d post MIAmiodarone 5200 mg/dFollow up 1 - 4 years 101 / 743 102 / 743 0 EMIATAm Coll Cardiol 1996 Placebo Amiodarone
    75. 75. Chronic Congestive Heart FailureAmerican Heart Associationin collaboration withSociedad Española de CardiologiaCHRONIC CONGESTIVEHEART FAILUREThe content of these slides is current as of June, 1999.Future revisions will be posted on theAmerican Heart Association website (