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OVERVIEW
The development of clinical heart failure (HF) is a progressive process that can be initiated by a variety of conditions that alter cardiac performance either by directly injuring the myocardium or imposing an increase in loading conditions. When this occurs, neurohormonal systems are activated in an attempt to augment cardiac output and tissue perfusion. Although activation of the reninangiotensin-aldosterone and sympathetic nervous system (SNS) may help to maintain circulatory homeostasis over the short run, it is clear that their sustained effects have adverse consequences on cardiac structure and function that ultimately result in progression of disease and clinical deterioration.
One of the fundamental strategies of HF management is to interrupt maladaptive neurohormonal activation by blocking production of effector peptides or preventing the action of these molecules with their target receptor. There is now convincing evidence that this strategy results not only in symptomatic improvement,but also significant reduction in morbidity and mortality.
The present chapter describes the use of neurohormonal blocking agents in the treatment of HF with particular focus on practical aspects related to their initiation, uptitration, and long-term maintenance. The classes of drugs that will be discussed are the angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), b-blockers, and aldosterone antagonists.
INHIBITORS OF THE RENIN-ANGIOTENSIN SYSTEM
Initial activation of the renin-angiotensin system (RAS) involves secretion of renin by the kidney in response to hypoperfusion resulting from intravascular volume depletion or low cardiac output. The fact that renin secretion is enhanced by adrenergic stimulation of the kidney highlights the interaction and synergism between various neurohormonal systems. Renin cleaves angiotensinogen, initiating a cascade that concludes in the generation of angiotensin II (AngII), the main effector molecule of the RAS. The effects of AngII are mediated by its interaction with its Type I (AT1), and Type II (AT2) receptors. Of these, the AT1mediates most known physiologic effects of AngII. AngII-AT1-receptor effects result in sodium (Na+) retention, vasoconstriction, norepinephrine (NE) secretion, and aldosterone release. AT1-receptor activation also has direct trophic effects on cardiac myocytes and stimulates fibroblasts to increase extracellular matrix production. These latter effects, in particular, contribute to the adverse remodeling that results in progressive left ventricular (LV) dysfunction. In experimental animal models, blocking AngII-AT1-receptor interactions attenuates this maladaptive process. Pharmacologically, this is accomplished by inhibiting ACE from cleaving AngI to AngII or by direct antagonism of the AT1 receptor. The application of ACE inhibitors and AT1-receptor blockers has been shown in human HF trials to inhibit remodeling, ameliorate symptoms, improve hemodynamics, reduce hospitalizations, and prolong survival.
Angiotensin-Converting Enzyme Inhibitors in Chronic Heart Failure
Clinical Evidence
ACE inhibitors were the first class of neurohormonal blocking agents that were shown to have a mortality benefit in patients with chronic HF and left ventricular dysfunction (LVD). The randomized, placebo-controlled trial (RCT), Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), was a seminal study, which established the concept that ACE inhibitors have favorable effects on the clinical course of HF.1 In this study, after 6 months of treatment, enalapril reduced mortality in patients with advanced HF by 40% relative to placebo. Improved survival, reduced hospitalization, and other clinical benefits have also been reported in the Studies Of Left Ventricular Dysfunction (SOLVD) trials and other studies encompassing a broader spectrum of HF patients and using a variety of different ACE inhibitors (see Table 10-1).2,3 The Assessment of Treatment with Lisinopril and Survival (ATLAS) trial demonstrated that the effects of ACE inhibitors appear to be dose dependent, at least for a combined morbidity/mortality endpoint.
How to Use Angiotensin-Converting Enzymes Inhibitors in Chronic Heart Failure
Inhibition of the RAS is a cornerstone of neurohormonal treatment of HF and it is now widely accepted that all patients with LV dysfunction should receive an ACE inhibitor titrated to the target dose, unless such treatment is contraindicated (see Table 10-2). Treatment with ACE inhibitors is usually initiated at a low dose that can then be rapidly uptitrated. When patients are being treated in-hospital, this is usually completed within a matter of days, while in outpatients a more gradual approach is taken. The major limiting factors for the initiation and uptitration of ACE inhibitors are hypotension, impaired renal function, and elevated serum potassium (K+) levels. In general, advised practice is to initiate and uptitrate ACE inhibitors in patients with systolic pressures ≥80 mm Hg, limiting uptitration only by the development of symptomatic hypotension rather than by a level of blood pressure, per se. Patients at greatest risk for developing symptoms for low blood pressure include those (1) with borderline pressure to begin with, (2) who have recently undergone extensive diuresis, (3) with New York Heart Association (NYHA) functional Class IV symptoms, and/or (4) who have low levels of serum Na+. If symptomatic hypotension occurs, initial management includes a reduction of other vasodilators and diuretics (see Patient Monitoring and Management later in the chapter). The basic chemistry panel should be drawn within a few days following ACE inhibitor initiation to assess renal function and serum K+. These measurements should be repeated periodically thereafter with the frequency determined by the stability of the patient and the initial levels of creatinine and K+. If serum K+ levels >4.5 mEq/L, amount of potassium replacement should be reduced. When this proves insufficient, addressing sources of potassium in the diet and discontinuing supplemental K+ may be necessary. When the K+ levels >5.5 mEq/L despite these measures, halving (or greater) of the ACE inhibitor dose is usually recommended. In some patients, ACE inhibitors cannot be continued because of persistent hyperkalemia.
A change in creatinine can be anticipated in the elderly and those patients with limited renal reserve. Increases in creatinine of <30% are generally considered acceptable if there is no clinical evidence of progressive fluid overload or associated hyperkalemia. “Dry” patients who develop renal insufficiency can be treated by cautiously decreasing the diuretic dose by 25–50%. The strict use of a daily weight log to detect changes in volume status can also be of value in adjusting the diuretic dose during this period in order to maintain euvolemia in HF patients. When hyperkalemia occurs it is critical to review the patients’ medications and to eliminate or reduce contributing medications, such as nonsteroidal anti-inflammatory drugs (NSAIDs), K+ sparing diuretics, or K+ replacement.
Angiotensin-Converting Enzyme Inhibitors Postmyocardial Infarction
Clinical Evidence
Based on the results of studies in experimental animal models, their efficacy in chronic HF and the results of initial studies demonstrating a favorable impact on post-myocardial infarction (post-MI) cardiac remodeling, the effects of ACE inhibitors on the clinical course of post-MI patients were evaluated in a series of large well-designed RCTs. These trials, Survival and Ventricular Enlargement (SAVE), Acute Infarction Ramipril Efficacy (AIRE) and Trandolapril Cardiac Evaluation (TRACE), Survival of Myocardial Infarction Long-term Evaluation (SMILE), included patients with evidence of LV dysfunction and/or HF following an MI (summarized in Table 10-3) and demonstrated significant reductions in all-cause mortality, hospitalization, progressive HF, and other relevant cardiovascular (CV) endpoints.4–6 As a result, the use of ACE inhibitors has emerged as a cornerstone of long-term medical therapy for patients with post-MI LV dysfunction.
How to Use ACE Inhibitors in the Post-Acute Myocardial Infarction Patient
Following an acute myocardial infarction (AMI), all patients should undergo assessment of LV function. Those patients with an ejection fraction (EF) <40% or symptoms of HF should be started on an ACE inhibitor (along with other therapies including aspirin, a statin, and b-adrenergic receptor blocker). It is advisable that treatment be initiated prior to hospital discharge both in order to increase the likelihood that this beneficial form of therapy will be used and to provide early protection to the MI survivor. In fact, studies such as GISSI-3 and ISIS-4 indicate that the benefits and early initiation of ACE inhibitors post-MI are substantial.8,9 While in-hospital, a short acting ACE inhibitor such as captopril is usually initiated at a low dose (e.g., 6.25 mg thrice daily). The dosage is then rapidly increased over a period of days to the target dose of 150 mg daily. Switching to a longer acting ACE inhibitor at the time of discharge can simplify the patients’ medical regimen and improve compliance. Careful monitoring of blood pressure, serum creatinine, and potassium levels is mandatory during the initiation and uptitration of ACE inhibitors in post-MI patients.
Angiotensin Receptor Blockers in Chronic Heart Failure
Clinical Evidence
The use of ARBs in chronic HF offers an alternative approach to blocking RAS. The main theoretical advantage would appear to be the ability of the ARBs to block effects of AngII, regardless of whether the peptide is generated by the action of ACE or through alternative pathways that appear to predominate in the tissue-based RAS. Unlike ACE inhibitors, ARBs do not enhance bradykinin (BK) levels by inhibiting ACE-mediated breakdown of this peptide. Whereas this latter effect has been associated with the excess cough seen with the ACE inhibitors, BK accumulation may contribute to the beneficial effects of the ACE inhibitors since it has vasodilating and antigrowth properties.
Although ACE inhibitors are the foundation of contemporary HF therapy, clinical trials (see Table 10-4) have established an important supporting role for ARBs. Evaluation of Losartan in the Elderly (ELITE II) compared the effect of losartan to that of captopril in patients with chronic HF and LV dysfunction.10 Although the results failed to demonstrate the superiority of the ARB, it did provide evidence that losartan was better tolerated. The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Alternative study studied the effects of candesartan in ACE inhibitor-intolerant patients with symptomatic HF and LV systolic dysfunction.11 The results demonstrated a highly favorable effect on the combined endpoint of CV mortality and HF hospitalization. These studies, along with an analysis of patients in Valsartan Heart Failure Trial (Val-HeFT) who were not receiving ACE inhibitors, provide convincing evidence of the efficacy of ARBs in systolic HF and establish their place as an alternative therapy in ACE-intolerant patients.12 Both Val-HeFT and the CHARM-Added study evaluated the impact of adding an ARB in addition to a therapeutic regimen that already included an ACE inhibitor.13 In each study, there was a significant reduction in the primary composite endpoint of morbidity and mortality. The CHARM-Added study, in which high doses of candesartan were used, also showed a 15% reduction in CV mortality with the addition of the ARB. While there was suggestion from post-hoc analysis of Val-HeFT that the addition of an ARB to a regimen that already included an ACE inhibitor and b-blocker might have adverse consequences, this possibility was not confirmed in the predesignated analysis of this interaction in the CHARM-Added study.
How to Use Angiotensin Receptor Blockers in Chronic Heart Failure with Left Ventricular Dysfunction
In starting ARB therapy, one follows similar guidelines to those summarized above in regards to the initiation of ACE inhibitors. The ARB is started at a low dose (see Table 10-5). Potassium supplementation is decreased by 25–50% if K+ >4.5 mEq/L. A history of symptomatic hypotension is sought and K+ and renal function are remeasured at 1 week. If systolic blood pressure (SBP) >80 and the patient does not have symptoms of orthostasis, continue to uptitrate the dose.
Angiotensin Receptor Blockers in Acute Myocardial Infarction
Clinical Evidence
The Optimal Trial in Myocardial Infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL) and Valsartan in Acute Myocardial Infarction (VALIANT) trials have helped to define the role of ARBs in the post-MI patient. OPTIMAAL was a head-to-head comparison between losartan and captopril in post-MI patients with LV dysfunction.14,15 For the primary endpoint of all-cause mortality, there was an insignificant trend in favor of the ACE inhibitor, but there was evidence that the ARB was better tolerated with a lower rate of discontinuation (17% vs. 23%, P < 0.0001). This study has been criticized, however, based on the low dose and delayed titration schedule for the ARB. VALIANT examined the efficacy of captopril, valsartan, and their combination therapy in patients with post-MI LV dysfunction. The study demonstrated “noninferiority” of the ARB, valsartan, to ACE inhibitor therapy. Treatment with the combination of valsartan and captopril provided no additional morbidity or mortality benefit and resulted in an increased incidence of adverse events. These trials established ARBs as an alternative agent in the ACE inhibitor-intolerant patient with post-MI LV dysfunction.
How to Use Angiotensin Receptor Blockers in the Post-Acute Myocardial Infarction Patient
When selecting an ARB (or replacing an ACE inhibitor) for treatment of post-MI LV dysfunction, the drug should be started in conjunction with other treatments including a b-adrenergic receptor blocker, aspirin, and a statin. In patients with elevation of creatinine due to the effects of the contrast load delivered during emergency angiography, initiation of therapy should be delayed until creatinine stabilizes. Treatment is usually initiated in a monitored environment, prior to hospital discharge, but this degree of caution is not necessary since serious immediate side effects are rare. When the drug is started in the in-patient setting, rapid titration to target can be accomplished with minimal risk. Management of hypotension and other issues (with the exception of cough and angioneurotic edema) are similar as with ACE inhibitors and are managed in a similar manner.
Patient Monitoring and Management of Adverse Effects During Chronic Therapy with Angiotensin-Converting Enzymes Inhibitors and/or Angiotensin Receptor Blockers
Hypotension
Initially, one should confirm that new symptoms of dizziness and fatigue correspond to a reduction in SBP (usually to <80 mm Hg) or that orthostatic hypotension (a decrease in SBP or diastolic blood pressure [DBP] of 20 or 10 mm Hg, respectively, within 3 minutes after standing) is present.16
Although hypotension is a well-recognized side effect of ACE inhibitors and ARBs, symptoms may be due to other agents as shown in the SOLVD prevention study where the incidence of hypotension was reported as 57% in ACE inhibitor-treated patients and 50% in the placebo group.3 Combination therapy with an ACE inhibitor and ARB is more likely to cause hypotension than a single drug. In VALIANT, hypotension was reported in 18.2% of patients on combination RAS blockade compared to 15.1% and 11.9% in the groups randomized to valsartan or captopril, respectively.15 Overall, the discontinuation rate was low with 1.9%, 1.4%, and 0.8% of patients in the valsartan-captopril, valsartan, and captopril groups, respectively. In patients with symptomatic hypotension, it is essential to assess volume status (by assessing weight, estimating jugular venous pressure [JVP], measuring serum bicarbonate, blood urea nitrogen [BUN], and creatinine levels). If the patient is volume depleted, decrease the diuretic dose by 25–50%. If the patient is euvolemic and receiving other vasodilators, reduce or eliminate these medications wherever possible. Hypervolemic and hypotensive patients may require hospitalization for decompensated congestive heart failure (CHF). If hypotension persists in the ambulatory patient, decrease the RAS blocker dose and attempt to titrate back to target in 2–3 weeks.
Progressive Renal Dysfunction
ACE inhibitors and ARBs decrease intraglomerular pressure, an effect that results in decreased filtration of renal plasma flow through the glomeruli (GFR). In patients who develop increases in creatinine while receiving an ACE inhibitor or ARB, it is important to consider reversible etiologies of azotemia including volume depletion, medications (NSAIDs, antibiotics), and post-renal outflow obstruction. If no reversible etiology is identified and a >30% increase occurs, reduce the dose of the ACE inhibitor or ARB by 50%.
Hyperkalemia
Patients receiving either an ACE inhibitor, an ARB, or, particularly, the combination are at increased risk for hyperkalemia. The groups receiving low-and high-dose lisinopril from the ATLAS trial reported a 4% and 6% incidence of hyperkalemia, respectively. However, only 0.2% and 0.4% of these patients required eventual ACE inhibitor discontinuation. If K+ rises to >5.5 mEq/L, discontinue concurrent K+ supplements or K+ sparing diuretics, such as spironolactone or eplerenone. Patients receiving dual therapy with an ARB and ACE inhibitor should discontinue one of these agents. If these measures are ineffective, decrease the ACE inhibitor dose by 50% and repeat serum chemistries in 1 week.
Cough
ACE inhibitor-associated cough is estimated to occur in 5–10% of treated patients and may require discontinuation of therapy. Before considering a medication change, confirm that the cough is not a result of progressive HF, exacerbation of reactive airway disease, chronic obstructive pulmonary disease (COPD), or upper respiratory infection. In ATLAS, the low-and high-dose lisinopril group reported an incidence of cough of 13% and 11%, respectively, suggesting that cough is not dose related. In our experience, there is usually not a benefit in switching from one ACE inhibitor to another. If no other cause is identified and the patient cannot tolerate the cough, we recommend changing to an ARB.
Angioneurotic Edema
Angioneurotic edema is a rare adverse event occurring in 0.1–0.5% of patients treated with an ACE inhibitor.14,15,17 The incidence appears to occur more frequently in African Americans.18 Angioneurotic edema is very unlikely with ARBs but it does occur. When this characteristic interstitial fluid accumulation occurs in patients receiving an ACE inhibitor, our usual practice is to stop the ACE inhibitor and replace it with an ARB unless the syndrome included airway obstruction. In that case, we exclude both classes of drug from the patients’ regimen and seek alternative therapies such as the combination of nitrates and hydralazine.
Contraindication in Pregnancy
Numerous case reports of RAS inhibition suggest the potential for organodysplasia and fetal renal dysfunction in both human and animal models.19 These risks are greatest in the second and third trimester of pregnancy and once pregnancy is recognized it is imperative to discontinue ACE inhibitor or ARB therapy. These medications should be used with caution in women of reproductive age not using birth control.
ACE Inhibitor and Aspirin Therapy
The question of whether or not there is an interaction between aspirin and RAS inhibition in HF has not been prospectively studied. Analyses of HF patients from SOLVD suggest that concurrent use of aspirin diminished the mortality benefit of ACE inhibitors. It is proposed that aspirin attenuated ACE inhibitor-mediated vasodilatation.20 These findings were not reproduced in a meta-analysis, including data from SOLVD, and the authors concluded that ACE inhibitor treatment reduced mortality in HF patients regardless of whether concurrent aspirin therapy was administered.21 It is our practice to continue low-dose, aspirin therapy in patients receiving an ACE inhibitor or ARB, particularly if there is a history of coronary disease or the patient is post-MI.
The Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers in Special Populations
Diabetes Mellitus
Diabetes is an independent risk factor for death from HF and it contributes to vascular inflammation, endothelial dysfunction, and to an increase in “oxidative stress.”22 In diabetic hypertensives, ACE inhibitors and ARBs have been shown to reduce progression of renal dysfunction.23–25 The Heart Outcomes Prevention Evaluation (HOPE) and Microalbuminuria Cardiovascular and Renal Outcomes-HOPE (MICRO-HOPE) trials enrolled diabetic patients with a prior CV event or a single CV risk factor and randomized them to ramipril or placebo.26,27 Treatment with ramipril resulted in a 24% and 37% relative reduction in all-cause mortality and CV death, respectively. HOPE excluded patients with HF, but treatment with ramipril reduced the relative risk of HF in the diabetic population by 20%. TRACE, a similarly designed study that included HF patients, concluded that ACE inhibitor treatment reduced mortality and progressive HF to a greater extent in diabetic than their nondiabetics counterparts.28 Overall, it appears that whereas all patients with HF and LVD benefit from treatment with an RAS blocker, this benefit is more pronounced in diabetic patients.
Heart Failure with Preserved Left Ventricular Function
The optimal treatment for patients with HF and preserved LV systolic function remains poorly defined. The CHARM-Preserved trial was designed to address this question and enrolled NYHA functional Class III–IV, or Class II patients with recent hospitalization and an LVEF >40%.29 Patients were randomized to candesartan or placebo in addition to background therapy with ACE inhibitor (20%), b-blocker (55%), and spironolactone (11%). There was a nonsignificant trend toward a reduction in the combined endpoint of CV mortality and hospitalization for HF. Hospitalizations for HF were significantly reduced by the ARB. This modest trend came at a significant increase in the risk of hypotension, renal insufficiency, and hyperkalemia. Thus, at this time the value of RAS blockade in HF with preserved LV function is uncertain. The ongoing irbesartan in HF with preserved systolic function (I-PRESERVE) trial should help resolve this issue.30
Race
Many of the trials investigating the impact of RAS blockers were performed in Northern Europe and enrolled only a small numbers of black or African American patients. Data from the Val-HeFT II comparing the effects of enalapril to the combination of hydralazine and isosorbide dinitrate (ISDN) suggested a diminished effect of enalapril on blood pressure and mortality in African Americans versus the Caucasian subgroup, or alternatively an enhanced response to hydralazine-ISDN not present in Caucasians.31 A retrospective analysis of the data collected from the SOLVD trial (conducted mostly in the United States) suggests that African Americans with impaired LV function are at greater risk of death and progressive HF than their Caucasian counterparts.32 This data set, however, also concluded that African American patients experienced an equivalent risk reduction when treated with enalapril. Despite contradictory and incomplete data, we recommend the use of ACE inhibitors and ARBs in the African American population for the same indications and in the same way as in other patients.
Sympathetic Nervous System Blockade
The SNS primarily functions during stress or exercise to maintain or elevate blood pressure and tissue perfusion through a cascade of selective a- and b-stimulation that increases heart rate and myocyte contractility and helps regulate peripheral vascular resistance. SNS action is potent and rapid in onset. Its short-term role in maintaining circulatory homeostasis is complemented by the intermediate and long-term effect of the RAS and aldosterone system. A reduction in cardiac function disturbs this balanced system and results in persistent sympathetic activation and elevation of serum catecholamines. The pathologic milieu of excess catecholamines results in an increase in afterload as well as a variety of direct effects on the heart including b-receptor downregulation, alteration of myocyte phenotype and compromised cell viability. If this sympathetic activation is unopposed, cardiac remodeling is enhanced and HF progresses. Chronic b-receptor stimulation contributes to increased mortality from pump failure as well as sudden death from arrhythmia. The consequences of chronic SNS activation, however, can be ameliorated by b-adrenergic receptor blockade.
Adrenergic receptor antagonists are a diverse class and can be classified by their variable selectivity on a1 and a2, and b1 and b2 receptor subtypes and other ancillary properties (see Table 10-6). Given the diversity in pharmacology between adrenergic blocking agents, it is not warranted to describe the beneficial effects of a single agent as being due to a “class effect” as is done with ACE inhibitors. For the latter, the bulk of evidence would suggest that the effects of the ACE inhibitor can be generalized to all drugs within the class and it is our practice to use the ACE inhibitors interchangeably. For b-blockers, however, we recommend using only specific b-receptor antagonists proven to reduce morbidity and mortality in RCTs in HF or post-MI.
How to Use b-Antagonists in Chronic Heart Failure
Despite the fact that clinical evidence clearly demonstrates that select b-blockers reduce morbidity and mortality in patients with HF, registry data indicate that these drugs remain underutilized in the population at risk. The Initiation Management Predischarge process for Assessment of Carvedilol Therapy for Heart Failure (IMPACT-HF) trial confirmed that b-receptor antagonists can be safely initiated in patients hospitalized for HF prior to discharge.37 Predischarge initiation significantly increased b-blocker utilization when compared to initiation in the ambulatory setting. The criteria for introduction of a b-blocker are the same as in the outpatient setting. Thus, the drugs can and should be started in all patients with symptomatic HF due to systolic dysfunction as soon as they reach (or are approaching) the euvolemic state in the absence of contraindications such as symptomatic hypotension or bradycardia, active bronchospastic disease, or conduction disease greater then first-degree atrioventricular (AV) block.
Before initiating therapy, we recommend documenting the patients’ euvolemic or “dry weight.” Patients who do not tolerate the initial dose (see Table 10-6) due to increasing fluid retention, bradycardia (<60 beats/min) or symptomatic hypotension, or SBP <80 mm Hg, can be challenged with half of the initial dose. The dose should be uptitrated approximately every 2 weeks, but some patients will require a longer titration period. It is not uncommon for patients with severe HF to become somewhat more symptomatic before improving. A period of 3–6 months to achieve maximal tolerated or target dose is not uncommon in these severely ill patients. Most patients, however, are easily titrated up to target dose and surprisingly few experience even transient symptoms of worsening HF as catecholamine stimulation of the heart is progressively blocked.
In patients who develop evidence of decompensation secondary to fluid retention, we usually reduce the dose of b-blocker by half and double their diuretic dose for 3 days with careful monitoring of body weight, creatinine, and electrolytes. We then resume uptitration of the b-blocker over the next 2–3 weeks. In rare cases, patients will develop hypotension, fluid retention, and rapid progression of HF during the initiation/uptitration phase. These individuals usually require hospitalization for acute HF exacerbation (see below).
In patients with symptomatic hypotension, it is our practice to treat this side effect using one or more of the following approaches: (1) eliminate other nonessential vasodilators (e.g., calcium channel blockers); (2) alternate the dosing of RAS blockers in the morning with b-receptor blockers in the evening (when once daily formulations of these agents are being used) or, when both drugs are given on a bid regimen, separate the dosing of the agents by 1–2 hours; (3) administer the b-blocker with meals when its absorption (e.g., carvedilol) can be delayed by this approach; (4) consider reducing the diuretic dose if the patient is euvolemic; and (5) temporarily reduce the dose of RAS blockers. Since blood pressure often improves over time with b-blockers, the RAS blockers can often be increased to target dose at a later date. Patients who develop bradycardia should be queried for a history of syncope or presyncope. Asymptomatic patients without AV block and exertional HR >55 require no further intervention. Patients with severe HF and symptomatic bradycardia, or evidence of AV block that limits initiation and/or uptitration of a b-blocker can be considered for a permanent pacemaker.38
How to Select a b-Receptor Blocker in Heart Failure
The discordant results of BEST, which showed no benefit of bucindolol therapy, and COPERNICUS that demonstrated a mortality reduction in NYHA Class IIIb–IV patients, support the concept that the benefits of b-blockade should not be considered a class effect.39 COMET tested this hypothesis in patients with mainly NYHA Functional Class II and III HF.40 Patients were randomized and titrated to a target dose of 25 mg bid of carvedilol or 50 mg of metoprolol tartrate bid. Treatment with carvedilol conferred a 17% reduction in all-cause death relative to metoprolol tartrate. These data emphasize the importance of selecting only specific agents proven to reduce morbidity and mortality in RCTs. Unlike the results of clinical trials with ACE inhibitors, which indicated that the beneficial effects of these drugs could be considered a “class effect,” only three b-receptor antagonists have been shown to reduce mortality in HF patients: carvedilol, metoprolol succinate (e.g., Toprol XL, a longer acting formulation of metoprolol), and bisoprolol. Thus, only these three b-receptor blocking agents should be used in the treatment of patients with symptomatic HF due to LV systolic dysfunction.
ACE Inhibitor or b-Receptor Blocker; Which One to Start First in Heart Failure Patients?
Historically, ACE inhibitors have been the initial neurohormonal agent added to the treatment regimen of HF patients based both on the fact that they were the first approved for clinical practice and that they can acutely improve cardiac function by providing afterload reduction. The latter property being of particular benefit in patients presenting with decompensated HF. In contrast, data supporting the use of b-receptor blockers in stable HF patients are relatively more recent and therefore, in practice, these agents are commonly instituted after the ACE inhibitor. However, clinical trial data indicate that the overall impact of b-blockers on the clinical course may be of greater magnitude than that of the RAS blockers and there is evidence from a small recent study that NYHA Functional Class II–III HF patients with idiopathic dilated cardiomyopathy may actually have better outcomes when initially treated with a b-blocker. In this study, patients receiving digoxin and diuretics were randomized to initial therapy of either carvedilol or perindopril, an ACE inhibitor. After 6 months, the carvedilol group was additionally treated with an ACE inhibitor and the perindopril group was started on carvedilol. A functional assessment at 6 and 12 months favored the group initially receiving carvedilol as these patients tolerated a higher dose of the b-blocker and required a lower dose of diuretic, and experienced significant symptomatic improvement and lower plasma NT-BNP.40 Although, this small study, in a nonischemic HF population, suggests that initial therapy with a b-receptor blocker might be preferable, this possibility needs to be further evaluated in a larger, more diverse population including patients with an ischemic etiology of their HF.
b-Receptor Blockers in Heart Failure and Post-Acute Myocardial Infarction
Clinical Evidence
Although the long term use of b-receptor antagonists in the post-MI patient has been demonstrated in RCTs to reduce mortality, sudden cardiac death, and reinfarction rate, registry data suggest that these agents are markedly underutilized in this population.42 This situation appears to be most pronounced in high risk patients with LV dysfunction.43 This is, at least in part, a consequence of the fact that high risk post-MI patients and/or those with evidence of LVD were generally excluded from the earlier post-MI b-blocker trials. The CAPRICORN trial, however, evaluated the use of b-receptor blockers in patients, with documented LV dysfunction, 3–21 days following AMI.44 In this study, all-cause mortality was reduced by 23% in patients who were randomized to the carvedilol-treated group. Of note is the fact that this improvement in outcome in the primary endpoint of the trial was seen in the context of contemporary therapy that included aspirin, statins, anticoagulants, revascularization (where deemed appropriate), and ACE inhibitors.
How to Use b-Antagonists in Post-AMI Patient with LV Dysfunction
In the post-MI period, all patients require imaging to evaluate LV function. Patients with reduced LV function should be considered for angiography and revascularization. All patients with depressed LVEF in this setting should receive a b-blocker regardless of the presence or absence of clinical HF. At the time of initiation of therapy, patients should be euvolemic, maintained on a stable dose of oral diuretics, and receiving an RAS blocker. If the initial dose is not tolerated (see Table 10-6) start the drug at half dose. Patients require ambulatory follow-up 7–10 days after hospital discharge and every 2 weeks thereafter as the b-blocker is uptitrated. This is accomplished by doubling the dose unless limited by symptoms of orthostasis, SBP <80, HR <60 or progressive HF.
In the case of bradycardia, discontinue other elective SA and/or AV nodal blocking agents, such as calcium channel blockers (CCB). If the patient is asymptomatic, HR >55 with effort and no evidence of AV nodal disease continue at the current dose and reevaluate in 2–3 weeks. Patients with AV nodal disease and symptomatic bradycardia should be considered for placement of a permanent pacemaker. In the case of hypotension, confirm adequate peripheral perfusion, evaluate for evidence of excess diuretics, and then consider withdrawing other vasodilators, adjust the timing of ACE inhibitor administration and b-blocker dosing and/or reduce the diuretic dose. If patients remain symptomatic, decrease the b-blocker dose by 50% and reevaluate shortly thereafter. Patients, who experience functional LV recovery, should continue on target therapy or maximal tolerated dose indefinitely.
Treatment of Special Population
Diabetes Mellitus
Diabetic patients are at increased risk of developing HF and, when HF is present, they have an increased risk of death when compared to non-diabetics. An analysis of the diabetic subgroups from CIBIS, COPERNICUS, and MERIT-HF trials demonstrate that b-blocker treatment results in a mortality reduction in both diabetic and nondiabetic patients.45 Though the relative mortality reduction appeared greater in HF patients without diabetes, given that diabetics have a greater overall risk of death it seems reasonable to conclude that diabetics also receive a substantial benefit from b-blocker therapy.
There have been concerns that b-blockers exacerbate hyperglycemia and worsen other CV risk factors in diabetics. The GEMINI investigators explored the impact of a selective b1-receptor antagonist, metoprolol versus carvedilol, a nonselective agent with a1-receptor action and additional antioxidant activity, in high-risk hypertensive diabetic patients without HF.46 These patients received concurrent treatment with a RAS blocker. The agents were titrated to achieve good hypertensive control and after 5 months of treatment this had been achieved in over two-thirds of patients in both arms of the trial. At this time, however, the HbA1c in the metoprolol group had increased with no significant change in the carvedilol group. Though both agents were well-tolerated, carvedilol was shown at equal antihypertensive doses to have more favorable effects on metabolic parameters such as HbA1c, insulin sensitivity, and microalbuminuria compared to metoprolol.
Reactive Airway Disease
HF patients with comorbid airway disease may have restrictive or obstructive disease or components of both. In our experience, patients who carry a diagnosis of COPD often have little or no reactive airway component so that initiation/uptitration of b-blockers can be carried out without difficulty. Patients with reactive airway disease or who are being acutely treated with steroids should not be initiated on b-receptor antagonist therapy. However, because of the reduction in mortality associated with b-blockers, patients with RAD in whom bronchospasm is well-controlled can be considered for treatment using a selective b1-receptor antagonist. Given its nonselective activity that includes blockade of the b2-receptor, we generally avoid the use of carvedilol in the relatively small percentage of HF patients with well-documented RAD. Metoprolol succinate has selective action on the b1-receptor and is preferred in those patients with stable RAD. Patients with all but the most severe RAD tolerate treatment well and minor exacerbations can be managed in most cases with inhaled b2-receptor agonists.
Race-Based Therapeutics
The natural history of HF in the African American population is more likely to be a sequela of hypertensive heart disease than in the non-African American population. These patients are also more likely to have comorbid diabetes and LVH. Whether related to this or to other factors this subpopulation has been shown to have worse outcomes. Retrospective analysis of the African American cohort from the U.S. Carvedilol Heart Failure study group did not detect an impact of race on the benefits of therapy.47 Therefore, b-blockers are recommended as first-line treatment of all HF patients regardless of their race.
Application in Acute Decompensated HF
Patients with acutely decompensated HF already on b-blockers who are maintaining adequate peripheral and organ profusion can be continued on their current regimen or the dose can be reduced transiently to half of their outpatient regimen. This approach, however, does not apply to patients who require inotropes for support due to evidence of hypoperfusion. It is our usual practice to halve or discontinue the b-blocker dose while inotropic agents are being given. When an inotrope is given, we usually use milrinone as opposed to dobutamine since the effects of the latter are more likely to be influenced by the presence of b-blockade. b-blocker naïve patients should not be started on therapy acutely, but should receive their first dose prior to hospital discharge at the time when their clinical course has stabilized and they have achieved or are approaching the euvolemic state.
Aldosterone Blockade in Heart Failure and Post-Acute Myocardial Infarction
Aldosterone secretion, once thought to be solely under the regulation of AngII (via the AT1receptor), is now known to be influenced by norepinephrine, adrenocorticotropic hormone, nitric oxide, serum potassium levels, and BK. This RAS-independent secretion is the likely cause of the phenomena of “aldosterone escape,” which occurs after reduction of serum ATII levels by RAS inhibition or after interactions between AngII and its receptor have been blocked by an ARB.48 Aldosterone is secreted not only by the adrenal gland, but also from vascular endothelium, vascular smooth muscle, and other tissue. Aldosterone acts both systemically, on the widely distributed mineralocorticoid receptor and is synthesized locally, acting in a paracrine fashion in the brain, blood vessels, and heart.
Aldosterone acts on the distal nephron in the kidney to promote retention of Na+ and, simultaneously, secretion of K+. These effects contribute to fluid overload and also K+ depletion. The latter is of particular importance in the HF population and/or post-MI population who are already at increased risk of sudden cardiac death and who are often being treated with loop or thiazide diuretics that potentiate K+ loss. Local aldosterone production, within the heart, is believed to contribute to cardiac myocyte hypertrophy and interstitial fibrosis. An increase in the quantity of fibrous tissue in the heart decreases ventricular compliance and also, by disturbing the homogeneity of electrical conduction, creates a substrate for arrhythmias. In the vasculature, aldosterone contributes to endothelial dysfunction by impairing acetylcholine and NO-mediated vasodilatation. It also increases vascular inflammation by recruiting macrophages and promoting monocyte infiltration of vessel walls. The discovery of “aldosterone escape” following treatment with RAS blockers raised the possibility that direct aldosterone blockade might provide incremental benefits and protection for the HF population.48
Aldosterone Blockade in Chronic Heart Failure Patients with LV Dysfunction
The RALES trial evaluated the effects of spironolactone on all-cause mortality in patients with advanced HF symptoms and evidence of systolic dysfunction who were already receiving an ACE inhibitor as background treatment.49 Patients received spironolactone 25–50 mg qd, or placebo, in addition to contemporary therapy with diuretics (100%), digoxin (~75%), and an ACE inhibitor (~95%). However, b-blockers were used in only ~10% of patients. The trial was terminated early after a 30% relative mortality reduction was reported in patients randomized to spironolactone. There was a 29% relative reduction in sudden cardiac death and 36% reduction in death due to progressive HF. The risk of severe hyperkalemia was low, at 2%, in this carefully monitored group. RALES proved that spironolactone, when added to contemporary therapy in a carefully controlled setting with well-defined follow-up monitoring of renal function and electrolytes, is well-tolerated and provides substantial clinical benefit.
Aldosterone Blockade in Post-Acute Myocardial Infarction Patients with LV Dysfunction
The Eplerenone in Patients with Heart Failure Due to Systolic Dysfunction Complicating Acute Myocardial Infarction (EPHESUS) trial assessed the effects of aldosterone blockade following AMI in patients with LV dysfunction and HF.50 Patients with symptomatic HF were randomized 3–14 days after the index event to eplerenone, a selective mineralocorticoid receptor blocker, or placebo. Diabetics, a group at high risk for CV events, were enrolled after the index MI with or without symptoms of HF. Eplerenone was added to standard therapy that included diuretics (60%), ACE inhibitor (86%), and b-blocker (75%). Many of these patients were also receiving aspirin (88%) and a statin (47%). Despite the already comprehensive therapy that was being administered to these patients, treatment with eplerenone resulted in significant 15% all-cause and 17% CV mortality reductions. These findings indicate that following AMI, patients with impaired LV function and DM or HF should receive eplerenone to reduce their risk of death and hospitalization for HF. Moreover, the results of EPHESUS indicate that this approach is of incremental benefit even in the setting of background treatment with other neurohormonal blocking agents.
How to Use Aldosterone Blockers in Heart Failure and Post-Acute Myocardial Infarction Patients with LV Dysfunction
The use of aldosterone blockade in patients with HF requires careful monitoring of serum K+ and renal function. It should only be added once patients are on a stable dose of a diuretic, RAS blocker, and b-receptor blocker. Supplemental K+ should be reduced or discontinued unless serum K+ levels fall below the lower limit of the normal range followed up at 1 and 4 weeks following initiation dose of 25 mg. The dose should be cut in half if K+>5 mEq/L and discontinued if >5.5 mEq/L. At 4 weeks, if the eplerenone 25 mg/day is well-tolerated, increase the dose to 50 mg/day.
Adverse Events and Patient Monitoring
Monitoring for Hyperkalemia
In both the RALES and EPHESUS trials, there was a significant increase in the incidence of hyperkalemia in those patients treated with spironolactone or eplerenone compared with patients receiving placebo (2% vs. 1% and 5.5 vs. 3.9%, respectively). Notably, patients receiving placebo in the EPHESUS study were more likely to develop hypokalemia, an equally life-threatening electrolyte imbalance and this risk was significantly ameliorated by treatment with eplerenone. Following the publication of RALES, two groups documented a greater incidence of hyperkalemia and inadequate patient selection in both the community and an academic setting.51,52 Treating HF with aldosterone blockade has a narrow therapeutic index, requires strict monitoring, and is indicated only in high-risk patients or those with HF, post-MI with depressed LVEF, and/or diabetes. In patients with less severely symptomatic HF or in those whom some time has passed since an MI that resulted in reduced EF, the benefits of aldosterone antagonists is uncertain. In these settings, the potential benefits of treatment should be carefully weighed against the known risks.
Aldosterone antagonists should only be initiated in patients with serum Cr ≤2.5 mg/dL or K+ ≤5 mEq/L and on a stable regimen of an ACE inhibitor, b-receptor blocker, and loop diuretic. If the patient is currently receiving K+ supplementation, cut the dose by one-half. The risk for severe hyperkalemia can be mitigated by close monitoring of serum creatinine and potassium levels. For this purpose we use the “rule of ones” that is, measurement of renal function and serum electrolytes is carried out 1 day prior to and 1 week and 1 month after drug treatment is begun. In monitored patients who later develop Cr >4 mg/dL or K+>5.5 mEq/L, stop the medication. The medication should also be stopped during periods of acute illness causing dehydration or renal dysfunction. In more mild cases of hyperkalemia, K+ 5–5.5 mEq/L, decrease the dose by half or if only tolerating 12.5 mg, change to qd dosing.
Gynecomastia
Spironolactone has activity at the androgen and estrogen receptor, which can result in gynecomastia. In RALES, 9% of male patients were affected by this condition compared to a 1% incidence in the placebo group. Patients who develop gynecomastia on spironolactone should be switched to eplerenone, which has substantially lower affinity for the androgen, progesterone, and estrogen receptors and, which does not increase the likelihood of gynecomastia above that seen with placebo.50
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