The last 50 years have witnessed great strides in the management of HFrEF. The treatment of symptomatic heart failure that evolved from a renocentric (diuretics) and hemodynamic therapy model (digoxin, inotropic therapy) ushered in the era of disease-modifying therapy with neurohormonal antagonism. In this regard, RAAS blockers and beta blockers form the cornerstone of pharmacotherapy and lead to attenuation of decline and improvement in cardiac structure and function with consequent reduction in symptoms, improvement in QOL, decreased burden of hospitalizations, and a decline in mortality from both pump failure and arrhythmic deaths (Fig. 253-3).
Progressive decline in mortality with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) or angiotensin receptor neprilysin inhibitors (ARNIs), beta blockers, mineralocorticoid receptor antagonists, and balanced vasodilators (*selected populations such as African Americans); further stack-on neurohormonal therapy is ineffective or results in worse outcome; management of comorbidity is of unclear efficacy. EPO, erythropoietin; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; PUFA, polyunsaturated fatty acid; SSRI, selective serotonin reuptake inhibitor.
Meta-analyses suggest a 23% reduction in mortality and a 35% reduction in the combination endpoint of mortality and hospitalizations for heart failure in patients treated with ACEIs. Patients treated with beta blockers provide a further 35% reduction in mortality on top of the benefit provided by ACEIs alone. Increased experience with both agents in a broad range of patients with HFrEF has demonstrated the safety of ACEIs in treating patients with mild renal insufficiency and the tolerability of beta blockers in patients with moderately controlled diabetes, asthma, and obstructive lung disease. The benefits of ACEIs and beta blockers extend to advanced symptoms of disease (NYHA class IIIb–IV). However, a substantial number of patients with advanced heart failure may not be able to achieve optimal doses of neurohormonal inhibitors and require cautious reduction in dose exposure to maintain clinical stability. Such individuals with lower exposure to ACEIs and beta blockers represent a high-risk cohort with poor prognosis.
Class Effect and Sequence of Administration
ACEIs exert their beneficial effects in HFrEF as a class; however, the beneficial effects of beta blockers are thought to be limited to specific drugs. Beta blockers with intrinsic sympathomimetic activity (xamoterol) and other agents, including bucindolol, have not demonstrated a survival benefit. On the basis of investigations, beta blocker use in HFrEF should ideally be restricted to carvedilol, bisoprolol, and metoprolol succinate—agents tested and proven to improve survival in clinical trials. Whether beta blockers or ACEIs should be started first was answered by the Cardiac Insufficiency Bisoprolol Study (CIBIS) III, in which outcomes did not vary when either agent was initiated first. Thus, it matters little which agent is initiated first; what does matter is that optimally titrated doses of both ACEIs and beta blockers be established in a timely manner.
A trial has indicated that higher tolerated doses of ACEIs achieve greater reduction in hospitalizations without materially improving survival. Beta blockers demonstrate a dose-dependent improvement in cardiac function and reductions in mortality and hospitalizations. Clinical experience suggests that, in the absence of symptoms to suggest hypotension (fatigue and dizziness), pharmacotherapy may be up-titrated every 2 weeks in stable ambulatory patients as tolerated.
Aldosterone antagonism is associated with a reduction in mortality in all stages of symptomatic NYHA class II to IV HFrEF. Elevated aldosterone levels in HFrEF promote sodium retention, electrolyte imbalance, and endothelial dysfunction and may directly contribute to myocardial fibrosis. The selective agent eplerenone (tested in NYHA class II and post–myocardial infarction heart failure) and the nonselective antagonist spironolactone (tested in NYHA class III and IV heart failure) reduce mortality and hospitalizations, with significant reductions in sudden cardiac death (SCD). Hyperkalemia and worsening renal function are concerns, especially in patients with underlying chronic kidney disease, and renal function and serum potassium levels must be closely monitored.
RAAS THERAPY AND NEUROHORMONAL “ESCAPE”
Neurohormonal “escape” has been witnessed in patients with HFrEF by the finding that circulating levels of angiotensin II return to pretreatment levels with long-term ACEI therapy. ARBs blunt this phenomenon by binding competitively to the AT1 receptor. Meta-analysis of 24 randomized trials demonstrated the superiority of ARBs to placebo in patients with intolerable adverse effects with ACEIs and their non-inferiority in all-cause mortality or hospitalizations when compared with ACEIs. The Valsartan Heart Failure Trial (Val-HeFT) suggested that addition of valsartan in patients already receiving treatment with ACEIs and beta blockers was associated with a trend toward worse outcomes. Similarly, adding valsartan to captopril in patients with heart failure after myocardial infarction who were receiving background beta blocker therapy was associated with an increase in adverse events without any added benefit compared with monotherapy for either group. Thus, the initial clinical strategy should be to use a two-drug combination first (ACEI and beta blocker; if beta blocker intolerant, then ACEI and ARB; if ACEI intolerant, then ARB and beta blocker). In symptomatic patients (NYHA class II–IV), an aldosterone antagonist should be strongly considered, but four-drug therapy should be avoided.
A recent trial called the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) tested a direct renin inhibitor, aliskiren, in addition to other heart failure medications, within a week after discharge from a hospitalization for decompensated HFrEF. No significant difference in cardiovascular death or hospitalization at 6 or 12 months was noted. Aliskiren was associated with a reduction in circulating natriuretic peptides, but any disease-modifying effect was overcome by excessive adverse events including hyperkalemia, hypotension, and renal dysfunction. These studies point to the limits achieved with RAAS modulation in this clinical syndrome.
The combination of hydralazine and nitrates has been demonstrated to improve survival in HFrEF. Hydralazine reduces systemic vascular resistance and induces arterial vasodilatation by affecting intracellular calcium kinetics; nitrates are transformed in smooth muscle cells into nitric oxide, which stimulates cyclic guanosine monophosphate production and consequent arterial-venous vasodilation. This combination improves survival, but not to the magnitude evidenced by ACEIs or ARBs. However, in individuals with HFrEF unable to tolerate RAAS-based therapy for reasons such as renal insufficiency or hyperkalemia, this combination is preferred as a disease-modifying approach. A trial conducted in self-identified African Americans, the African-American Heart Failure Trial (A-Heft), studied a fixed dose of isosorbide dinitrate with hydralazine in patients with advanced symptoms of HFrEF who were receiving standard background therapy. The study demonstrated benefit in survival and hospitalization recidivism in the treatment group. Adherence to this regimen is limited by the thrice-daily dosing schedule.
NOVEL NEUROHORMONAL ANTAGONISM
Despite an abundance of animal and clinical data demonstrating deleterious effects of activated neurohormonal pathways beyond the RAAS and sympathetic nervous system, targeting such pathways with incremental blockade has been largely unsuccessful. As an example, the endothelin antagonist bosentan is associated with worsening heart failure in HFrEF despite demonstrating benefits in right-sided heart failure due to pulmonary arterial hypertension. Similarly, the centrally acting sympatholytic agent moxonidine worsens outcomes in left heart failure. The combined drug omapatrilat hybridizes an ACEI with a neutral endopeptidase inhibitor, and this agent was tested in the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE) trial. This drug did not favorably influence the primary outcome measure of the combined risk of death or hospitalization for heart failure requiring intravenous treatment. The risk of angioedema was notably higher with omapatrilat than ACEIs alone.
More recently, the introduction of LCZ696, an ARB (valsartan) with an endopeptidase inhibitor (sacubitril), has shown a survival benefit in a large trial versus ARB alone. The drug, referred to as an angiotensin receptor–neprilysin inhibitor (ARNI) (and denoted Entrezto), was tested in the PARADIGM-HF trial as an alternate to optimally dosed ACEI and demonstrated an incremental improvement in survival when compared to ACEI alone. Most guidelines now advocate switching ACEI to this drug as a standard in patients with mild-moderate systolic heart failure when they remain symptomatic despite fully tolerated doses of conventional therapy.
Table 253-2 lists the common neurohormonal and vasodilator regimens for HFrEF.
TABLE 253-2Pharmacologic Therapy and Target Doses in Heart Failure with Reduced Ejection Fraction ||Download (.pdf) TABLE 253-2 Pharmacologic Therapy and Target Doses in Heart Failure with Reduced Ejection Fraction
|Drug Class ||Generic Drug ||Mean Daily Dose in Clinical Trials (mg) ||Initiation (mg) ||Target Dose (mg) |
|Angiotensin-Converting Enzyme Inhibitors |
| ||Lisinopril ||4.5–33 ||2.5–5 qd ||20–35 qd |
|Enalapril ||17 ||2.5 bid ||10–20 bid |
|Captopril ||123 ||6.25 tid ||50 tid |
|Trandolapril ||N/A ||0.5–1 qd ||4 qd |
|Angiotensin Receptor Blockers |
| ||Losartan ||129 ||50 qd ||150 qd |
|Valsartan ||254 ||40 bid ||160 bid |
|Candesartan ||24 ||4–8 qd ||32 qd |
|Aldosterone Antagonists |
| ||Eplerenone ||42.6 ||25 qd ||50 qd |
|Spironolactone ||26 ||12.5–25 qd ||25–50 qd |
|Beta Blockers |
| ||Metoprolol succinate CR/XL ||159 ||12.5–25 qd ||200 qd |
|Carvedilol ||37 ||3.125 bid ||25–50 bid |
|Bisoprolol ||8.6 ||1.25 qd ||10 qd |
|Arteriovenous Vasodilators |
| ||Hydralazine isosorbide dinitrate ||270/136 ||37.5/20 tid ||75/40 tid |
|Fixed-dose hydralazine/isosorbide dinitrate ||143/76 ||37.5/20 qid ||75/40 qid |
|Angiotensin Receptor Neprilysin Inhibitor |
| ||Sacubitril-valsartan ||375 ||100 bid ||200 bid |
Ivabradine, an inhibitor of the If current in the sinoatrial node, slows the heart rate without a negative inotropic effect. The Systolic Heart Failure Treatment with Ivabradine Compared with Placebo Trial (SHIFT) was conducted in patients with class II or III HFrEF, a heart rate >70 beats/min, and history of hospitalization for heart failure during the previous year. Ivabradine reduced hospitalizations and the combined endpoint of cardiovascular-related death and heart failure hospitalization. The study population was not necessarily representative of North American patients with HFrEF since, with a few exceptions, most did not receive internal cardioverter-defibrillation or cardiac resynchronization therapy and 40% did not receive a mineralocorticoid receptor antagonist. Although 90% received beta blockers, only a quarter were on full doses. Whether this agent would have been effective in patients receiving robust, guideline-recommended therapy for heart failure remains unclear. In the 2012 European Society of Cardiology guidelines for the treatment of heart failure, clinically, Ivabradine should be considered in patients who remain symptomatic after guideline-based ACEIs, beta blockers, and mineralocorticoid receptor antagonists and with residual heart rate >70 beats/min. Another group in whom potential benefit may be expected includes those unable to tolerate beta blockers.
Digitalis glycosides exert a mild inotropic effect, attenuate carotid sinus baroreceptor activity, and are sympatho-inhibitory. These effects decrease serum norepinephrine levels, plasma renin levels, and possibly aldosterone levels. The DIG trial demonstrated a reduction in heart failure hospitalizations in the treatment group (patients with heart failure and sinus rhythm) but no reduction in mortality or improvement in QOL. Importantly, treatment with digoxin resulted in a higher mortality rate and hospitalizations in women than men. It should be noted that low doses of digoxin are sufficient to achieve any potentially beneficial outcomes, and higher doses breach the therapeutic safety index. Although digoxin levels should be checked to minimize toxicity and although dose reductions are indicated for higher levels, no adjustment is made for low levels. Generally, digoxin is now relegated as therapy for patients who remain profoundly symptomatic despite optimal neurohormonal blockade and adequate volume control.
Neurohormonal activation results in avid salt and water retention. Loop diuretic agents are often required because of their increased potency, and frequent dose adjustments may be necessary because of variable oral absorption and fluctuations in renal function. Importantly, clinical trial data confirming efficacy are limited, and no data suggest that these agents improve survival. Thus, diuretic agents should ideally be used in tailored dosing schedules to avoid excessive exposure. Indeed, diuretics are essential at the outset to achieve volume control before neurohormonal therapy is likely to be well tolerated or titrated.
CALCIUM CHANNEL ANTAGONISTS
Amlodipine and felodipine, second-generation calcium channel–blocking agents, safely and effectively reduce blood pressure in HFrEF but do not affect morbidity, mortality, or QOL. The first-generation agents, including verapamil and diltiazem, may exert negative inotropic effects and destabilize previously asymptomatic patients. Their use should be discouraged.
Targeting inflammatory cytokines such as tumor necrosis factor α (TNF-α) by using anticytokine agents such as infliximab and etanercept has been unsuccessful and associated with worsening heart failure. Use of intravenous immunoglobulin therapy in nonischemic etiology of heart failure has not been shown to result in beneficial outcomes. Nonspecific immunomodulation has been tested in the Advanced Chronic Heart Failure Clinical Assessment of Immune Modulation Therapy (ACCLAIM-HF) trial where ex-vivo exposure of a blood sample from systolic heart failure patients to controlled oxidative stress was hypothesized to initiate apoptosis of leukocytes soon after intramuscular gluteal injection of the treated sample. The physiologic response to apoptotic cells results in a reduction in inflammatory cytokine production and upregulation of anti-inflammatory cytokines. This promising hypothesis was not proven, although certain subgroups (those with no history of previous myocardial infarction and those with mild heart failure) showed signals in favor of immunomodulation.
Potent lipid-altering and pleiotropic effects of statins reduce major cardiovascular events and improve survival in non–heart failure populations. Once heart failure is well established, this therapy may not be as beneficial and theoretically could even be detrimental by depleting ubiquinone in the electron transport chain. Two trials, Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) and Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiac (GISSI-HF), have tested low-dose rosuvastatin in patients with HFrEF and demonstrated no improvement in aggregate clinical outcomes. If statins are required to treat progressive coronary artery disease in the background setting of heart failure, then they should be employed. However, no rationale appears to exist for routine statin therapy in nonischemic heart failure.
ANTICOAGULATION AND ANTIPLATELET THERAPY
HFrEF is accompanied by a hypercoagulable state and therefore a high risk of thromboembolic events, including stroke, pulmonary embolism, and peripheral arterial embolism. Although long-term oral anticoagulation is established in certain groups, including patients with atrial fibrillation, the data are insufficient to support the use of warfarin in patients in normal sinus rhythm without a history of thromboembolic events or echocardiographic evidence of left ventricular thrombus. In the large Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial, full-dose aspirin or international normalized ratio–controlled warfarin was tested with follow-up for 6 years. Among patients with reduced LVEF in sinus rhythm, there was no significant overall difference in the primary outcome between treatment with warfarin and treatment with aspirin. A reduced risk of ischemic stroke with warfarin was offset by an increased risk of major hemorrhage. Aspirin blunts ACEI-mediated prostaglandin synthesis, but the clinical importance of this finding remains unclear. Current guidelines support the use of aspirin in patients with ischemic cardiomyopathy.
Treatment with long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been shown to be associated with modestly improved clinical outcomes in patients with HFrEF. This observation from the GISSI-HF trial was extended to measurements of ω-3 PUFAs in plasma phospholipids at baseline and after 3 months. Three-month treatment with ω-3 PUFAs enriched circulating eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Low EPA levels are inversely related to total mortality in patients with HFrEF.
A growing body of evidence suggests an association between heart failure and micronutrient status. Reversible heart failure has been described as a consequence of severe thiamine and selenium deficiency. Thiamine deficiency has received attention in heart failure due to the fact that malnutrition and diuretics are prime risk factors for thiamine loss. Small exploratory randomized studies have suggested a benefit of supplementation of thiamine in HFrEF with evidence of improved cardiac function. This finding is restricted to chronic heart failure states and does not appear to be beneficial in the ADHF phenotype. Due to the exploratory nature of the evidence, no recommendations for routine supplementation or testing for thiamine deficiency can be made.
ENHANCED EXTERNAL COUNTERPULSATION (EECP)
Peripheral lower extremity therapy using graded external pneumatic compression at high pressure is administered in 1-h sessions for 35 treatments (7 weeks) and has been proposed to reduce angina symptoms and extend time to exercise-induced ischemia in patients with coronary artery disease. The Prospective Evaluation of Enhanced External Counterpulsation in Congestive Heart Failure (PEECH) study assessed the benefits of enhanced external counterpulsation in the treatment of patients with mild-to-moderate heart failure. This randomized trial improved exercise tolerance, QOL, and NYHA functional classification but without an accompanying increase in peak oxygen consumption. A placebo effect due to the nature of the intervention simply cannot be excluded.
The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study investigated short-term (3-month) and long-term (12-month) effects of a supervised exercise training program in patients with moderate HFrEF. Exercise was safe, improved patients’ sense of well-being, and correlated with a trend toward mortality reduction. Maximal changes in 6-min walk distance were evident at 3 months with significant improvements in cardiopulmonary exercise time and peak oxygen consumption persisting at 12 months. Therefore, exercise training is recommended as an adjunctive treatment in patients with heart failure.