The burden of HF can be affected only by drastically decreasing its incidence, and as such, it is crucial to identify the primary drivers for this problem and develop/implement population-level preventive strategies. To aid in this goal, the American College of Cardiology/American Heart Association adopted a new stage-based system for the classification of HF in 2001 (Table 26–2). In this approach, stage A included patients without structural cardiac disorders or HF symptoms, but with risk factors that clearly predispose carriers toward the development of HF (eg, hypertension, coronary artery disease, diabetes). Stage B included patients without HF symptoms, but with structural cardiac abnormalities (eg, left ventricular hypertrophy, prior myocardial infarction, valvular heart disease) that if untreated could progress to symptomatic HF. Stages C and D included the symptomatic HF patients. This new classification added a useful dimension to the understanding of HF by recognizing that there are established risk factors and structural prerequisites for the development of the clinical syndrome and that therapeutic interventions performed even before the appearance of left ventricular dysfunction or symptoms can prevent the development of HF.
Table 26–2. Staging System in the Classification of Heart Failure ||Download (.pdf)
Table 26–2. Staging System in the Classification of Heart Failure
Clinical Heart Failure
Symptoms (NYHA Functional Class)
Population Estimate from NHANES (millions)1
Population Estimate: Adults > Age 45 from Olmsted County (%)2
(Marked symptoms despite maximal therapy)
(Shortness of breath, fatigue, reduced exercise tolerance)
(Prior myocardial infarction, left ventricular hypertrophy, valvular disease, etc.)
High Risk for Developing HF
(Hypertension, coronary disease, diabetes, obesity, etc.)
Because nearly 33% of adults in the United States have hypertension and due to the high PAR of hypertension in HF in both men and women, aggressive control of blood pressure is the most effective approach to reduce the incidence of HF. Primary prevention trials have shown up to a 50% reduction in the incidence of HF in patients with hypertension who are treated with thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and most β-blockers and calcium channel blockers.
The roles of coronary artery disease and myocardial infarction as major antecedents of systolic HF have been well established. Therapy with ACE inhibitors has been shown to reduce the risk of developing HF in patients with stable coronary artery disease, while therapy with ACE inhibitors, ARBs, β-blockers, and mineralocorticoid receptor blockers (MRBs) have been shown in several randomized trials to reduce the risk of progression to symptomatic HF in patients with myocardial infarction and asymptomatic left ventricular systolic dysfunction.
Diabetes mellitus has been consistently associated with a two- to fivefold increase in the risk of HF, especially in women. Although several studies have shown an 8–16% increase in the risk of hospitalizations for HF for every 1% increase in hemoglobin A1c, the optimal treatment strategy (eg, insulin versus metformin versus sulfonylureas versus thiazolidinediones) is currently unknown.
It is widely believed that HF management should include dietary sodium and fluid restriction, recommendations endorsed by all national and international guidelines. Most current recommendations are for 2000–3000 mg/day sodium for all HF patients and for less than 2000 mg/day with some degree of fluid restriction (1500–2000 mL/day) for HF patients with volume overload. Given the possibility that increased sodium intake leads to increased fluid retention in HF, it has been assumed that a low-sodium diet would improve outcomes in HF patients. However, the data on which these recommendations are drawn are limited, and the few clinical trials conducted to date have produced inconsistent findings. The new American Heart Association recommendations for 1500 mg/day sodium appear to be appropriate for patients with stage A and B, because of the data linking sodium intake with incidence of hypertension and HF. However, there are insufficient data to support a certain level of sodium or fluid intake in symptomatic HF patients (stages C and D).
Physical Activity and Exercise Training
For decades, exercise testing and exercise training were considered dangerous in patients with systolic HF because of concerns about exacerbating HF symptoms, potential deleterious effects on ventricular function, and the possibility of severe ventricular arrhythmias and cardiac arrest. Recent work has shown that exercise training in these patients is associated with improved response to pharmacologic vasodilators, improved endothelial function, improved skeletal muscle metabolism and performance, and attenuation of the activation of the overactive muscle ergoreflex. The large randomized trial, Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION), showed that in patients with symptomatic systolic HF exercise training was safe (no increase in arrhythmias over usual care) and was associated with a significant decrease in hospitalizations for HF and an improvement in the patients' well-being and in exercise capacity. Thus, all patients with systolic HF should be prescribed an exercise training program in addition to evidence-based pharmacologic therapy.
Treatment of Sleep-Disordered Breathing
Sleep-disordered breathing is common in systolic HF patients and is associated with adverse prognosis. Continuous positive airway pressure is the major treatment, especially if obstructive rather than central sleep apnea predominates, and its use has been associated with improvement in symptoms and ejection fraction. Adequate suppression of central sleep apnea by positive airway pressure may also be associated with improved survival. Bilevel positive airway pressure may be preferable over continuous pressure in patients who experience expiratory pressure discomfort. Adaptive (or auto) servo ventilation, which adjusts the positive airway pressure depending on the patient's airflow or tidal volume, may be useful in HF patients if continuous pressure is found ineffective.
The mechanical removal of fluid from the vasculature is accomplished by applying hydrostatic pressure across a semipermeable membrane, resulting in isotonic plasma water separation from blood; thus, large amounts of fluid can be removed without affecting serum concentration of electrolytes and other solutes. Several small studies in HF patients have shown that ultrafiltration was associated with relief of congestive symptoms, improved exercise capacity, lower intracardiac filling pressures, and improved pulmonary function and neurohormonal levels. In recent years, ultrafiltration gained immense popularity in the treatment of hospitalized patients with HF and volume overload, and it has been increasingly used even in outpatient settings in HF patients at risk for readmission. However, in the recently published Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARESS-HF) trial, the use of a stepped diuretic algorithm was superior to a strategy of ultrafiltration for the preservation of renal function, with a similar amount of weight loss. Due to the possible side effects related to the ultrafiltration therapy, it should be reserved only for inpatients with HF and volume overload with preserved renal function who are not responding adequately to high-dose diuretic therapy.
Bart BA, et al; Heart Failure Clinical Research Network. Ultrafiltration in decompensated heart failure with cardiorenal syndrome. N Engl J Med
Gupta D, et al. Dietary sodium intake in heart failure. Circulation
O'Connor CM, et al; HF-ACTION Investigators. Efficacy and safety of exercise training in patients with chronic heart failure: HF-ACTION randomized controlled trial. JAMA
Sharma BK, et al. Adaptive servoventilation for treatment of sleep-disordered breathing in heart failure: a systematic review and meta-analysis. Chest
Pharmacologic Treatment: Life-Saving Therapies
The pharmacologic treatment of symptomatic systolic HF has evolved substantially in the past 40 years, with neurohormonal antagonists becoming the mainstay of treatment due to marked improvements in morbidity and mortality.
Inhibition of ACE in HF results in an increase in the cardiac output, with concomitant decrease in ventricular filling pressures and pulmonary and systemic vascular resistances, without an increase in the heart rate. Over time, ACE inhibition leads to a decrease in left ventricular end-systolic and end-diastolic dimensions, a reduction in the incidence of ventricular arrhythmias, and continuous and sustained improvements in symptoms (occurring as early as 2 weeks), exercise duration, and quality of life. The most significant benefit of therapy with ACE inhibitors is the 20% increase in survival seen in all patients with systolic HF and in all patients with left ventricular systolic dysfunction after myocardial infarction, even in those without symptoms or signs of HF.
ACE inhibitors should be used in conjunction with β-blockers and MRBs as part of the “triple therapy” in order to achieve the maximal symptomatic improvement and survival benefit, and with a diuretic to maintain the sodium balance and prevent the development of fluid overload. The highest tolerated ACE inhibitor dose should be achieved, as clinical trials have shown improved HF outcomes at higher doses. Once the drug has been titrated (Table 26–3), patients can usually be maintained on long-term therapy with little difficulty. The need to decrease the ACE inhibitor dose due to hypotension and/or renal dysfunction may signal the development of end-stage HF and the need for advanced therapies (ie, ventricular assist devices, heart transplantation). Renal function and serum potassium should be assessed within 2 weeks of initiating therapy and every 3 months thereafter.
Table 26–3. Target Doses of Renin–Angiotensin–Aldosterone System Inhibitors in Heart Failure ||Download (.pdf)
The main adverse effects of the therapy are related to the angiotensin suppression (hypotension, increase in serum creatinine and potassium) and bradykinin potentiation (cough and angioedema). The initial hypotension responds to a decrease in the dose of diuretic, liberalization of salt intake, or initiation of a lower dose of ACE inhibitor. Hypotension can be delayed and prolonged with longer acting ACE inhibitors (enalapril and lisinopril), leading to decreased systemic perfusion and compromise of renal and cerebral functions, but is shorter in duration with captopril, which rarely compromises organ perfusion. Some patients may be very sensitive to the hypotensive effects of ACE inhibitors, particularly end-stage HF patients who are dependent on the RAAS for blood pressure maintenance. In general, treatment should be reassessed if serum creatinine increases above 3 mg/dL or if serum potassium increases above 5.5 mEq/L. Patients should not be given ACE inhibitors if they are pregnant, have a history of angioedema or anuric renal failure during a previous exposure to this class, or are severely hypotensive and at risk of immediate cardiogenic shock.
These agents block the angiotensin II receptor and inhibit the effects of angiotensin II produced not only through the classical ACE pathway, but also by the chymase pathway. Available ARBs block the angiotensin II type 1 receptors (associated with myocardial hypertrophy and remodeling) and enhance the activation of angiotensin II type 2 receptors, causing vasodilation. In addition, these effects are achieved without accumulation of bradykinin, which is considered to be responsible for some of the adverse reactions associated with the use of ACE inhibitors, such as cough or angioedema. Although the hemodynamic effects of ARBs are similar to those of ACE inhibitors, the randomized clinical trials have shown a consistent mortality benefit only in patients with systolic HF who are intolerant of ACE inhibitors. Candesartan was the only ARB that showed in clinical trials a 15% reduction in mortality when added to an ACE inhibitor. Use of ARBs in higher doses (see Table 26–3) in addition to ACE inhibitors and β-blockers is associated with symptomatic improvement and an overall modest 15% reduction in HF hospitalizations.
Despite treatment with ACE inhibitors or ARBs, patients with HF demonstrate elevated aldosterone levels, due to alternative stimuli for aldosterone synthesis (eg, adrenocorticotropic hormone or endothelin), potassium-dependent aldosterone secretion, and reduced aldosterone clearance. Spironolactone is a renal competitive aldosterone antagonist, inhibiting its effect by competing for the aldosterone-dependent sodium–potassium exchange site in the distal tubule cells. Eplerenone is a selective MRB that prevents the binding of aldosterone and is devoid of the painful gynecomastia seen in about 10% of men taking spironolactone. Multiple clinical trials have shown that use of MRBs in addition to ACE inhibitors and β-blockers in patients with systolic HF and a variety of symptoms (New York Heart Association functional class II–IV) leads to a 15–30% decrease in mortality (including a 20% decrease in sudden cardiac death immediately after a myocardial infarction), improvement in HF symptoms, and a 30–40% decrease in hospitalizations for HF. Due to these significant benefits in a variety of systolic HF patients, MRBs and not ARBs should be the drugs of choice in the initial triple therapy with ACE inhibitors and β-blockers. The use of MRBs should be restricted to those patients with an estimated glomerular filtration rate above 30 mL/min/1.73 m2 and with serum potassium below 5 mEq/L; potassium levels should be monitored within a week of initiation and at least every 4 weeks for the first 3 months and every 3 months thereafter. Although low, the risk of hyperkalemia is real with these agents and can lead to a significant increase in morbidity and mortality.
β-Adrenergic Receptor Blockers
β-Blockers act by inhibiting the adverse effects of the sympathetic nervous system activation in patients with systolic HF. Long-term benefits of β-blockade include an increase in ejection fraction, a decrease in left ventricular volumes and in mitral regurgitation, and a reversion of the left ventricle to a more elliptical shape. Administration of β-blockers is associated with an early deterioration in cardiac function (consistent with the negative inotropic effects), followed by return to baseline values after 1 month and an increase in the ejection fraction after 3 months of treatment with further improvement for up to a year. Although the exercise capacity may not be improved by objective assessments (CPET), β-blockers, when added to ACE inhibitors, lead to marked symptomatic improvement, translated in robust 18% decreases in hospitalizations for HF and 35% improvement in survival. Only three β-blockers (bisoprolol, carvedilol, and metoprolol succinate) have been consistently shown to improve symptoms and survival in clinical trials, and therefore, only these should be used in patients with systolic HF. As in the case of ACE inhibitors, use of the highest tolerated β-blocker doses is recommended due to improvement in outcomes. In direct comparison studies, carvedilol was associated with better survival than metoprolol tartrate; in addition, the incidences of myocardial infarction, stroke, atrial fibrillation, and diabetes were lower with the use of carvedilol. In patients with reactive airway disease, bisoprolol has been shown to improve the peak expiratory flow and be better tolerated compared to the other approved β-blockers.
β-Blockers should be prescribed to all patients with asymptomatic left ventricular systolic dysfunction and stable systolic HF unless they have a contraindication. Patients should be clinically stable, receive ACE inhibitors and MRBs, and receive diuretics as needed to control the fluid retention associated with adrenergic blockade. β-Blockers should be initiated at very low doses (in euvolemic, noninotrope-dependent patients) and increased gradually, typically at 2-week intervals, to achieve the target doses from published clinical trials (Table 26–4).
Table 26–4. Target Doses of β-Blockers in Heart Failure. ||Download (.pdf)
Table 26–4. Target Doses of β-Blockers in Heart Failure.
Starting Dose (mg)
Target Dose (mg)
CIBIS I, II, III
CAPRICORN, COPERNICUS, U.S. carvedilol trials
Treatment with β-blockers can be associated with fatigue and weakness, which usually resolve in a few weeks. Symptomatic bradycardia is a serious adverse effect that requires a decrease in the dose or sometimes cardiac pacing. Hypotension is a side effect seen especially with nonselective blockers such as carvedilol. Usually, it occurs within the first 48 hours of initiation of therapy and subsides with repeated dosing without any change in the dose. Administration of ACE inhibitors and diuretics at a different time of day than the β-blockers can minimize the hypotension and dizziness. Administration of β-blockers is contraindicated in patients with severe bronchospasm, systolic blood pressure below 85 mm Hg, symptomatic bradycardia, or advanced heart block in the absence of a pacemaker.
Nitrates have a greater effect on venous capacitance (venodilation) than on the arterial system, while hydralazine is a direct-acting smooth muscle relaxant that seems to dilate arterioles predominantly. Long-term administration of isosorbide dinitrate has been associated with significant improvements in hemodynamic parameters, exercise capacity, and relief of symptoms in moderate-to-severe systolic HF. When used in combination with nitrates, hydralazine has shown a short-term increase in cardiac output and decrease in ventricular filling pressure. Patients who have dilated left ventricles appear to have a better hemodynamic and clinical response than do patients with lesser degrees of enlargement. The combination therapy was tested in African Americans with systolic HF in the African-American Heart Failure Trial (A-HeFT) and was associated with a significant 43% improvement in survival and a 33% decrease in HF hospitalizations, when used in addition to ACE inhibitors, β-blockers, and spironolactone. These results led to the first approval of a combination drug pill based on self-identified ethnicity. When the endothelial nitric oxide synthase (through which the combination of drugs is thought to work) was genotyped, the benefits of the therapy were evident only in those patients who were homozygous for glutamic acid in position 298 (GLU298GLU). Although 80% of African Americans have this genomic variant (as shown in A-HeFT), studies have shown that up to 40% of Caucasians have the same genotype, leading to intriguing possibilities for future pharmacogenomically targeted therapies. Unfortunately, the therapy is not easily tolerated due to side effects. Nitrates can produce headaches, while hydralazine can be associated with flushing, palpitations, nausea, vomiting, myocardial ischemia, and lupus-like syndrome.
Yancy CW, et al. 2013 American College of Cardiology Foundation/American Heart Association guidelines for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol
. 2013; S0735-1097(13)02114-1.
Konstam MA, et al; HEAAL Investigators. Effects of high-dose versus low-dose losartan
on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet
Krum H, et al. Medical therapy for chronic heart failure. Lancet
McNamara DM, et al. Endothelial nitric oxide synthase (NOS3) polymorphisms in African Americans with heart failure: results from the A-HeFT trial. J Card Fail
Zannad F, et al; EMPHASIS-HF Study Group. Eplerenone
in patients with systolic heart failure and mild symptoms. N Engl J Med
Pharmacologic Treatment: Symptomatic Therapies
Diuretics provide rapid symptomatic relief of congestive symptoms by promoting excretion of sodium and water and lowering plasma volume, thus reducing congestion in the pulmonary and systemic vascular beds and improving symptoms and functional capacity. Diuretics are tightly bound to plasma proteins and are actively secreted into the proximal tubular lumen. Loop diuretics inhibit the sodium/ potassium/chloride symporter in the ascending loop of Henle; thiazide-type diuretics affect the sodium/chloride transporter in the distal convoluted tubules; whereas potassium-sparing diuretics work at sites in the collecting duct to inhibit the sodium/potassium transporter. The loop diuretics increase sodium excretion by 20–25% and enhance free water clearance. Orally dosed furosemide has variable bioavailability (10–100% in patients with HF), whereas bumetanide and torsemide are absorbed more completely, with 80% bioavailability after oral dosing. Although thiazide diuretics have bioavailability of 60–70%, their action is limited if the glomerular filtration falls below 40 mL/min/1.73m2 (with the exception of chlorothiazide and metolazone). Furosemide and thiazides are renally excreted, whereas the liver metabolizes torsemide and bumetanide. Thiazides and distal tubule diuretics have longer half-lives that allow them to be given once daily or even every other day. Because the plasma half-life of loop diuretics ranges from 1 to 4 hours, once a dose of a loop diuretic has been administered, its effect dissipates before the next dose is given. During this time, the nephron avidly reabsorbs sodium, resulting in rebound sodium retention that nullifies the prior natriuresis. In order to counteract this, the loop diuretics have to be given twice daily. Despite rapid symptomatic improvement, several retrospective analyses of systolic HF trials have linked non–potassium-sparing diuretics with an increase in mortality. Therefore, the lowest dose that achieves the desired effect should be used.
Diuretics should be used in all patients with evidence of volume overload; in an acutely decompensated state, a higher dose or combination of oral diuretics or intravenous diuretics is needed to achieve euvolemia. Using too low a diuretic dose causes fluid retention, which can diminish the response to ACE inhibitors and increase the risk of treatment with β-blockers. Use of inappropriately high doses of diuretics leads to volume contraction and increased risk of hypotension and renal insufficiency with ACE inhibitors. Diuretic resistance can be overcome by the intravenous administration of diuretics (intermittent bolus or continuous infusions have the same efficacy), the use of diuretic combinations (eg, loop and thiazide), or use of intravenous diuretics with low dose dopamine. Volume depletion (resulting in hypotension and/or renal failure), hypokalemia, hypomagnesemia, and thiamine deficiency are the most common side effects of diuretics. Diuretics may also cause metabolic alkalosis, carbohydrate intolerance, hyperuricemia, hypersensitivity reactions, and acute pancreatitis.
Digoxin exerts its effects by inhibition of sodium-potassium adenosine triphosphatase in the myocardium (resulting in an increase in myocardial contraction), in the vagal afferent fibers (sensitizing the cardiac baroreceptors and reducing the sympathetic outflow), and in the kidney (reducing the renal tubular reabsorption of sodium). These observations have led to the hypothesis that the beneficial effects of digoxin in HF are due to the attenuation of the activation of neurohormonal systems. Clinically, the beneficial effects in patients with systolic HF and sinus rhythm include improved HF symptoms, increased exercise time, modestly increased ejection fraction, enhanced cardiac output, and decreased HF hospitalizations. The benefits of digoxin are higher in patients with more symptomatic HF (New York Heart Association functional class IV), cardiomegaly (greater cardiothoracic ratio on chest x-ray), or an ejection fraction below 25%. However, due to its narrow therapeutic index, digoxin has a bidirectional effect with improvement in HF mortality and increase in the non-HF (presumed arrhythmic) mortality. Retrospective analyses of the Digitalis Investigation Group (DIG) trial have suggested an increased mortality with serum concentration above 1 ng/mL, especially in women. Due to these considerations, digoxin has been reserved in systolic HF patients in sinus rhythm who are still symptomatic despite triple therapy with ACE inhibitors, β-blockers, and MRBs. In patients with systolic HF and atrial fibrillation, digoxin can be used to decrease the ventricular response, usually associated with improved symptoms. Although more rare than in prior decades, digitalis intoxication may occur in patients hospitalized for HF. Common findings are nausea, vomiting, anorexia, malaise, drowsiness, headache, insomnia, altered color vision, or arrhythmia. Cardiac arrhythmias (most commonly premature ventricular beats, junctional tachycardia, paroxysmal atrial tachycardia with block, bidirectional ventricular tachycardia) can be caused by digitalis and are facilitated by hypokalemia. Digoxin toxicity is usually confirmed by the reversal of symptoms or cessation of arrhythmias after withdrawal of digoxin therapy. Severe toxicity can be reversed quickly with digoxin immune Fab.
Felker GM, et al. Diuretics and ultrafiltration in acute decompensated heart failure. J Am Coll Cardiol
Pharmacologic Treatment: Other Therapies
Oral Phosphodiesterase-5 Inhibitors
Due to the chronic elevation in left ventricular filling pressures, a large number of systolic HF patients will develop secondary pulmonary hypertension. While the presence of fixed pulmonary hypertension has been shown to be a poor prognostic factor in patients undergoing heart transplantation, recent studies have suggested that improvement in pulmonary artery pressures with oral phosphodiesterase-5 inhibitors (ie, sildenafil, tadalafil) may lead to improvements in symptoms in HF patients. Although this hypothesis has been recently rejected in the Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People with Diastolic Heart Failure (RELAX) study, a large randomized trial will address the question in patients with systolic HF and pulmonary hypertension. Until the results of the PDE5 Inhibition with Tadalafil Changes Outcomes in Heart Failure (PITCH-HF) trial become available, it is prudent to use these drugs in patients with systolic HF and pulmonary hypertension, only if they are compensated and have a pulmonary capillary wedge pressure close to normal.
More than 80% of systolic HF patients have frequent and complex ventricular arrhythmias as documented by Holter monitoring, and 50% have frequent nonsustained ventricular tachycardia. In addition, 35–40% of patients have paroxysmal or persistent atrial fibrillation that can lead to HF exacerbation. Systolic HF patients frequently require some antiarrhythmic drugs in order to stabilize these arrhythmias. Due to the structural heart disease seen in HF, only some of the class III anti-arrhythmics (dofetilide and amiodarone) are safe to use. Although clinical trials have shown that amiodarone per se does not improve prognosis in systolic HF patients, they have also shown that it is a rather safe option. It can be administered acutely to control ventricular response in HF patients with atrial fibrillation, and its long-term use may restore and maintain sinus rhythm. Amiodarone may also be used to suppress symptomatic ventricular tachycardia in combination with β-blockers, especially in patients who are receiving frequent defibrillator shocks. Close monitoring for side effects is required. Dofetilide was shown to be effective in restoring sinus rhythm in patients with systolic HF and atrial fibrillation without adverse effects on overall survival. Treatment with dofetilide also decreased the overall and HF hospitalizations in the Danish Investigations of Arrhythmia and Mortality on Dofetilide (DIAMOND) study. However, dofetilide dosing has to be closely titrated, based on creatinine clearance and QT interval, requiring 72-hour inpatient monitoring. Dronedarone is a benzofuran-derivative class III antiarrhythmic drug with pharmacologic properties similar to amiodarone and should not be used in patients with systolic HF due to the increased mortality risk associated with the drug.
In patients with systolic HF and sinus rhythm, antithrombotic therapy has traditionally been considered for those with very low ejection fraction. However, a multitude of clinical trials have failed to show a clear benefit of this strategy in preventing strokes in these patients. As such, the decision to use an antiplatelet or anticoagulant must be individualized, taking into account the comorbidities of the patient (eg, presence of concomitant coronary artery disease or peripheral vascular disease). All patients with systolic HF and atrial fibrillation (even paroxysmal) should be anticoagulated with warfarin or newer antithrombotic agents (apixaban, dabigatran, or rivaroxaban) in order to prevent strokes.
Statins (3-Hydroxy-3-Methyl-Glutaryl–Coenzyme A Reductase Inhibitors)
Statins are the cornerstone of primary and secondary prevention for patients with coronary artery disease or vascular disease. Paradoxically, even though 70% of systolic HF patients have coronary artery disease, the role of statins in systolic HF is only marginal. Two large randomized clinical trials testing the role of rosuvastatin in this setting failed to show a benefit on mortality. Patients with underlying coronary artery disease experienced a reduction in cardiovascular hospitalizations, presumably by averting small myocardial infarctions due to plaque destabilization. As such, statins should only be used in patients with systolic HF and clinical coronary artery disease.
Omega-3 Polyunsaturated Fatty Acids
The use of omega-3 polyunsaturated acids in systolic HF patients leads to small improvements in left ventricular ejection fraction, reduction in left ventricular end systolic volumes and functional capacity, and a small 10% decrease in cardiovascular mortality and 7% decrease in risk for cardiovascular hospitalizations. The dose used in clinical trials of 1 g (850–882 mg eicosapentaenoic acid and docosahexaenoic acid as ethyl esters in the average ratio of 1:1.2) is much smaller than the dose used to treat hypertriglyceridemia and, therefore, more likely to be tolerated by patients.
Iron deficiency is quite frequent in patients with systolic HF, and several small studies and one large randomized trial showed improvements in symptoms, exercise capacity, and quality of life with intravenous ferric carboxymaltose. Intravenous iron therapy (there are several preparations available) is relatively safe and should be used for all patients with systolic HF who are iron deficient even in the absence of anemia (ferritin level < 100 mcg/L or 100–299 mcg/L if the transferrin saturation is < 20%).
Although anemia is common and portends poor prognosis in systolic HF, treatment with darbepoetin was not associated with improved survival or decrease in hospitalization in these patients. Moreover, patients treated with darbepoetin experience more thromboembolic events, and thus, the erythropoiesis-simulating agents should not be used or should be used very cautiously in systolic HF patients. In patients with decompensated HF and hemoglobin level < 10 g/dL, careful transfusion with packed red blood cells, while giving diuretics, has been shown to improve outcomes.
GISSI-HF Investigators, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet
Redfield MM, et al; for the RELAX Trial. Effect of phosphodiesterase- 5 inhibition on exercise capacity and clinical status in heart failure with preserved ejection fraction: a randomized clinical trial. JAMA
Swedberg K, et al; for the RED-HF Committees and Investigators. Treatment of anemia with darbepoetin-alfa in systolic heart failure. N Engl J Med
. 2013 Mar 28;368(13):1210-9.
Pharmacologic Treatment: Specific Therapies in Hospitalized Patients
The majority of hospitalized patients with systolic HF are volume overloaded and may require vasodilators in order to decrease the filling pressures and improve dyspnea. For faster action, intravenous options such as sodium nitroprusside, nitroglycerin, or nesiritide are available. Due to the frequent titration needed, sodium nitroprusside and nitroglycerin can only be used in the intensive care setting. Nesiritide (recombinant BNP) is an agent with vasodilator, natriuretic, and diuretic effects that does not require titration and that can be used in telemetry units. Although proven to be safe, it has been shown to only marginally improve symptoms in patients with decompensated systolic HF, and as such, its use has been very limited.
A minority of hospitalized systolic HF patients presents with very low cardiac output (“cold” profile) and require intravenous inotropes in order to maintain perfusion and diuresis. The two most frequently used agents are dobutamine and milrinone. Dobutamine augments cardiac contractility primarily via stimulation of β-adrenergic receptors and is a modest vasodilator, whereas milrinone exerts potent inotropic and direct vasodilator effects via phosphodiesterase inhibition in the myocardium and vasculature. While these agents are fairly effective, their use is associated with further myocardial injury (evidence of troponin release even in nonischemic cardiomyopathy), and they can precipitate fatal ventricular arrhythmias. Their use is best reserved for patients in need of a bridge to mechanical circulatory support or transplant or in those patients where palliative home hospice is entertained.
Mebazaa A, et al. Levosimendan vs. dobutamine
for patients with acute decompensated heart failure: the SURVIVE randomized trial. JAMA
O'Connor CM, et al. Effect of nesiritide
in patients with acute decompensated heart failure. N Engl J Med
The majority of patients with systolic HF experience ventricular arrhythmias, and as many as 50% of all deaths in this population are sudden in nature. Findings from large clinical trials have clearly shown that implantable cardioverter-defibrillators (ICDs) are the most effective therapy available to prevent sudden cardiac death in these patients at risk, and ICD treatment has become standard therapy for primary and secondary prevention of sudden cardiac death in addition to optimal medical therapy in patients with left ventricular ejection fraction below 35%. Only about 10% of patients implanted with ICDs have appropriate discharges (highlighting the poor predictive value of current selection algorithms based solely on ejection fraction), with another 20% of patients experiencing inappropriate shocks (leading to an increase in mortality), and with the vast majority not using them at all. Fortunately, better discrimination algorithms for supraventricular tachycardia and the optimal use of ventricular antitachycardia pacing have markedly decreased the frequency of inappropriate shocks in these patients.
In addition, a third of systolic HF patients experience intraventricular conduction abnormalities (eg, left bundle branch block) that lead to mechanical dyssynchrony and adversely affect the cardiac performance. Several clinical trials have shown that CRT as standalone treatment or combined with ICD in patients with systolic HF and ejection fraction below 35% significantly improves the ejection fraction, decreases ventricular volumes, improves HF symptoms, improves exercise tolerance, and decreases the hospitalization rate for HF, as well as cardiovascular and all-cause mortality. These benefits are seen across the spectrum of HF patients (New York Heart Association functional class I–IV) and are more evident in patients in sinus rhythm, with a left bundle branch block pattern, QRS duration greater than 150 ms, and an ejection fraction below 35%. Proper patient selection to meet these strict criteria, together with selection of a viable (noninfarcted) lateral wall and optimal placement of the coronary sinus pacing lead can markedly decrease the frequency of CRT “nonresponders” (estimated at about 40% of the population implanted). The value of periodic CRT optimization by adjusting the atrioventricular and intraventricular timing for pacing (either via device-specific algorithms or echocardiography) is still a matter of debate, although in several studies, it has been shown to improve symptoms and ventricular remodeling parameters.
Holzmeister J, et al. Implantable cardioverter defibrillators and cardiac resynchronisation therapy. Lancet
Moss AJ, et al. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med
Cardiac surgical approaches for patients with systolic HF have changed and matured over the last decade due to improved surgical techniques and as a result of several randomized clinical trials. Until recently, uncertainty still existed about the role and benefits of revascularization in patients with ischemic systolic HF. However, the Surgical Treatment of Ischemic Heart Failure (STICH) trial showed a 19% decrease in cardiovascular mortality and a 15% decrease in cardiovascular hospitalizations in patients undergoing coronary artery bypass surgery in addition to optimal medical therapy when compared to optimal medical therapy alone. Thus, patients with ischemic systolic HF should be evaluated for surgical (or possibly percutaneous) revascularization.
Many HF patients with decreased systolic function and coronary artery disease have apical aneurysms as result of prior myocardial infarctions. Based on case series, surgical aneurysm reduction was thought to be beneficial by making the left ventricular contraction more efficient; however, data from the STICH trial showed that the improvement in ventricular volume with surgical ventricular restoration did not translate into a measurable clinical benefit for the patients.
A large number of systolic HF patients develop functional mitral regurgitation as results of left ventricular enlargement. While data are more convincing for concomitant mitral valve repair at the time of coronary bypass surgery, several large case series showed that even in nonischemic patients, mitral valve repair with an undersized complete rigid annuloplasty ring and without alteration of the subvalvular apparatus can be performed safely with low operative mortality. At the present time, it is unknown if this operation will translate into reverse remodeling or improved clinical outcomes. Recently, percutaneous plication or repair of the mitral valve has become possible and may replace surgical approaches in the future.
Patients with advanced systolic HF who are not amenable to conventional pharmacologic, electrical, or surgical therapies should be considered for advanced surgical options. Although with the current advances in immunosuppression therapy, the 1-year survival after cardiac transplantation approaches 90% and 50% of patients survive more than 12 years, only about 2200 adult patients will get transplanted every year due to the lack of available organs. The strict evaluation of candidates for heart transplantation will address comorbid diseases such as pulmonary hypertension, kidney disease, diabetes, chronic obstructive lung disease, and cancers in an attempt to identify the candidates most likely to benefit long term from this therapy.
Left ventricular assist device implantation has been used as a bridge to recovery (in patients with acute myocarditis or postpartum cardiomyopathy), a bridge to transplant (for patients likely to wait extended period of time for an available organ) or destination therapy. The devices in current commercial use, ThoratecHeartMate II and HeartWare HVAD, are second- and third-generation devices that have good reliability and have transformed the field of mechanical circulatory support. While the surgical operation itself has become fairly standardized, the long-term postoperative care is complex, and the use of assisted circulation is associated with risk of complications such as gastrointestinal bleeding, right-sided HF, renal insufficiency, infection, and thromboembolic events.
Aaronson KD, et al; HeartWare Ventricular Assist Device (HVAD) Bridge to Transplant ADVANCE Trial Investigators. Use of an intrapericardial, continuous-flow, centrifugal pump in patients awaiting heart transplantation. Circulation
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