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Patients with CHF should have their cardiovascular risk factors modified aggressively. Hypertension is strongly linked to the development of CHF and should be aggressively treated (Vasan and Levy, 1996). The target BP should be 130/85 mm

Hg or less, except in diabetic patients, in whom the target is lowered to 125/85 mm Hg or less.

Control of dyslipidemia and diabetes is also very important in the management of patients with CHF. Screening for sleep apnea and thyroid disease and aggressively treating these conditions need to be done. The avoidance of alcohol, illicit drug use, and smoking is strongly advised. Losing weight and establishing a routine exercise program are also important preventive measures in the CHF patient. Patients with a history of heart palpitations need to be evaluated for tachycardia because this is a well-established risk factor for cardiomyopa-thy and CHF. If patients have daily palpitations, a 24-hour Holter monitor is sufficient to help establish the type of arrhythmia. On the other hand, if palpitations occur infrequently (a few times per month), an "event care" monitor is more useful because patients can keep this type of monitor with them at home for a month and record the arrhythmia as it occurs. If palpitations are very infrequent, it is unlikely that they will be contributing to tachycardia-induced cardiomy-opathy, but their diagnosis can be made with an implantable loop recorder, typically done by the electrophysiologist.

KEY TREATMENT

Control of systolic and diastolic hypertension in accordance with established guidelines is strongly indicated in the CHF patient (ACC/AHA guidelines; SOR: A).

Pharmacologic Therapy Diastolic Dysfunction

Diastolic dysfunction is typically diagnosed by echocar-diography. It is characterized by dyspnea and CHF with normal left ventricular systolic function but impaired relaxation. Conditions that increase left ventricular (LV) stiffness include CAD, hypertension, diabetes, valvular heart disease, and age (Ewy, 2004). Patients with LV diastolic dysfunction need to be treated with aggressive BP control and diuretics, beta blockade, or nondihydropyridine CCBs (diltiazem or verapamil). ACE inhibitors or ARBs can have long-term value in reducing LVH and theoretically may improve LV compliance (Mandinov et al., 2000).

Left Ventricular Systolic Dysfunction

Patients with asymptomatic LV dysfunction (Stage B, ACC/ AHA classification) benefit significantly from ACE inhibitors and beta blockade. The correction of anatomic abnormalities that are linked to LV systolic dysfunction is also important, including severe mitral or aortic insufficiency and aortic stenosis. Periodic follow-up of these patients is indicated, with serial assessment of LV function using echocardiography or isotope ventriculography (IVG). Patients with familial LV systolic dysfunction need to have their immediate family members screened for asymptomatic cardiomyopathy.

Symptomatic LV systolic dysfunction (Stage C, ACC/AHA classification) requires intensive pharmacologic treatment and close follow-up. Echocardiography or IVG is typically done to monitor LVEF over time, generally every 6 months or less frequently if a patient is clinically stable. An IVG provides a more accurate assessment of ejection fraction (within + 3%

variability in reading) than an echocardiogram but is more expensive. Whether an echocardiogram or an IVG is ordered depends on the patient's clinical presentation, history, and the management approach of the treating physician. Diuretics are important in the hypervolemic patient, and digoxin improves symptoms in patients with clinical evidence of CHF or symptomatic, severely reduced LV function. No data, however, support that a diuretic or digoxin alters a patient's long-term survival. Current therapies known to impact a person's mortality are summarized next (Cohn, 1996; Hunt et al., 2001; Packer et al., 1999). Table 27-9 lists drugs and dosages in treating patients with congestive heart failure.

Although there is no one way to start pharmacologic therapy for CHF patients, it is advisable that patients be started on a small dose of beta blockers, ACEI, or both. Diuretics are generally reserved for patients who are fluid overloaded. Caution needs to be exerted when a diuretic and an ace inhibitor are started simultaneously as hypotension could occur and serum creatinine levels can rise markedly. Beta blockers (Hori, 2004) and ACE inhibitors (Majumdar, 2004) need to be titrated to the maximum tolerated dose in order to achieve maximal therapeutic efficacy.

Angiotensin-Converting Enzyme Inhibitors

Angiotensin-converting enzyme inhibitors (ACEIs) reduce mortality by an absolute 4% and relative 15% to 20% in patients with LV systolic dysfunction (LVEF <40%). In addition, ACEIs reduce the combined end point of morbidity (heart failure hospitalizations) and mortality by 30% to 35%. Despite the benefits of ACE inhibitors (Wong et al., 2004), mortality from CHF remains at 50% within 5 years of the diagnosis and 30% of patients are rehospitalized within 3 months.

Several trials have noted a mortality reduction with ACEIs in patients with clinical evidence of CHF after sustaining an MI (Kober et al., 1995). The Acute Infarction Ramipril Efficacy Study (AIRE) showed a 27% (p = 0.002) reduction in the 30-month cumulative mortality with ramipril over placebo in post-MI CHF patients. Furthermore, trandolapril reduced mortality by 22% (p = 0.01) in patients with reduced left ventricular function after an MI (Kober, 1995). Guidelines also emphasize the use of ACEIs in patients with asymptomatic LV dysfunction and history of MI. These patients are at high risk of developing LV remodeling and CHF several months after the initial insult (Jessup, 2003).

KEY TREATMENT

ACE inhibitors are recommended in all patients with CHF and left ventricular dysfunction unless a contraindication exists. ACEIs should be used in all patients with history of MI and asymptomatic reduced LV function regardless of ejection fraction. ACC/AHA guidelines (SOR: A).

Angiotensin Receptor Blockers

Key Point

• Angiotensin receptor blockade can be used in patients being treated with digitalis, diuretics, and a beta blocker and who cannot be given an ACE inhibitor because of cough or angioedema (ACC/AHA guidelines; SOR: A).

Table 27-9 Selected Drugs and Dosages in Treatment of Congestive Heart Failure

Early studies comparing ARBs and ACEIs in the management of CHF patients suggested that an ARB was as safe, effective, and tolerable as an ACEI. In the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study, 768 patients (NYHC II-IV, LVEF <40%) received candesartan, candesartan plus enalapril, or enalapril alone for 43 weeks (McKelvie et al., 1999). Left ventricular cavity size increased less and BNP levels decreased more with combination therapy compared to ARB or ACEI alone. In the Losartan Heart Failure Survival Study (ELITE II), 3152 patients (>60 years old; NYHC II-IV; LVEF <40%) were randomly assigned to losartan (1578 patients) titrated to 50 mg once daily or captopril (1574) titrated to 50 mg three times daily (Pitt et al., 2000). There were no differences in all-cause mortality or sudden death between the two groups. In a subset of the Val-HeFT (Valsartan in Heart Failure Trial) trial of patients intolerant to ACEI, valsartan (titrated to 160 mg twice daily) reduced both all-cause mortality and combined mortality and morbidity compared with placebo (17.3% vs. 27.1%, p = 0.017; and 24.9% vs. 42.5%, p <0.001, respectively) (Maggioni et al., 2002). In this trial, adding an ARB (valsartan) to an ACEI in CHF patients (LVEF<40%) did not reduce mortality further, whereas the combined end point of mortality and morbidity was reduced by about 27.5%, mostly from a reduction in CHF hospitalizations (Cohn et al., 2001).

In the Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM) trial, candesartan (titrated to 32 mg once daily) significantly reduced cardiovascular deaths and hospital admissions for CHF (Pfeffer et al., 2003). In the "overall programme" of this study, which included both preserved and reduced LV function, total mortality was not reduced compared to placebo. However, in a subset analysis, patients with symptomatic heart failure and reduced LV function (<40%), candesartan significantly reduced all-cause mortality, cardiovascular death, and CHF hospitalizations when added to standard therapies, including ACEIs, beta blockers, and aldosterone antagonists (Young et al., 2004). These patients should have their BP, creatinine, and serum potassium carefully monitored. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) randomized patients 0.5 to 10 days after an acute MI with reduced LV function to valsartan (4909 patients) titrated to 160 mg twice daily, valsartan (80 mg twice daily) plus captopril (50 mg three times daily) (4885 patients), or captopril (4909 patients) titrated to 50 mg three times a day in addition to standard therapy (Pfeffer et al., 2003). Valsartan was equally effective as captopril in reducing all cause mortality. For reasons that remain unclear, combining valsartan with captopril did not improve survival compared to either capto-pril or valsartan alone but did increase adverse events.

Currently the recommendation is to use an ACEI as first line therapy to treat CHF patients. However, a growing body of evidence suggests that an ARB could be as effective as an ACEI in the treatment of heart failure patients with reduced left ventricular function.

Aldosterone Blockers

Aldosterone is secreted by the zona glomerulosa of the adrenal gland and is induced by AII, adrenocorticotropic hormone, and potassium. Aldosterone leads to sodium and water absorption and the excretion of potassium. Although AII is a dominant stimulus of aldosterone secretion (Weber, 2001), ACEI are not sufficient to block aldosterone secretion (McKelvie, 1999; Schjoedt, 2004). Until recently the role of aldosterone blockade in the management of patients with CHF has been unclear.

Two large trials investigated the role of aldosterone antagonists in CHF management. The Randomized Aldactone Evaluation Study (RALES) randomized patients with advanced CHF

Table 27-9 Selected Drugs and Dosages in Treatment of Congestive Heart Failure

Drug

Dosage

Angiotensin-Converting Enzyme Inhibitors

Enalapril

2.5 to 20 mg PO bid, max 40 mg/day, start at 2.5 mg qd

Captopril

12.5 to 50 mg PO tid, max 150 mg/day, start 6.25 to 12.5 mg PO tid

Ramipril

5 mg PO bid, max 10 mg/day, start at 2.5 mg PO bid

Lisinopril

5-20 mg PO qd, max 40 mg/day, start 2.5 to 5 mg PO qd

Perindopril

4-16 mg PO qd, max 16 mg/day, start 2 mg PO qd

Monopril

10-40 mg PO qd/bid, max 80 mg/day, start 10 mg PO qd

Angiotensin Receptor Blockers (for ACE Inhibitor-Intolerant Patients)

Losartan

25-100 mg PO qd, max 100 mg/day, start 25-50 mg PO qd*

Candesartan

8-32 mg PO qd, max 32 mg/day, start 16 mg PO qd"

Valsartan

40-160 mg PO bid, max 320 mg/day, start 40 mg PO bid

Irbesartan

75-300 mg PO qd, max 300 mg/day, start 75 mg PO qd"

Beta Blockers

Carvedilol

3.125-25 mg PO bid, max 50 mg PO qd, start 3.125 mg PO bid

Metoprolol succinate

12.5 to 200 mg PO QD, max 200 mg/day, start 12.5 mg PO qd

Metoprolol

12.5-100 mg PO bid, max 100 mg PO BID, start 12.5 mg PO bid'

Aldosterone Antagonists

Spironolactone

12.5-25 mg PO bid, max 50 mg/day, start 12.5 mg PO bid

Eplerenone

50 mg PO qd, max 50 mg/day, start 25 mg PO qdt

'Off-label use.

tFor CHF patients post-myocardial

infarction.

(LVEF <35%) to spironolactone (25 mg daily) or placebo in addition to standard therapy (Pitt et al., 1999). After a mean follow-up of 24 months, spironolactone reduced mortality by 30% through reducing progression of CHF and sudden cardiac death. In addition, patients who received spironolactone had a significant improvement in the symptoms of heart failure as assessed by NYHA functional class (p <0.001). Recurrent hospitalization from worsening CHF was also reduced by 35% (p <0.001). The Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) randomized patients with CHF (LVEF<40%), 3 to 14 days post-MI, to eplerenone (25-50 mg daily) or placebo (Pitt et al., 2001). At a mean follow-up of 27 months, eplerenone, a competitive, relatively selective mineralocorticoid receptor antagonist, reduced total mortality by 15% (p = 0.008), cardiovascular mortality or cardiovascular hospitalizations by 13% (p = 0.002), and sudden cardiac death by 21% (p = 0.03). Based on these trials, aldosterone antagonists are now considered to be a primary therapy in patients with LV dysfunction and CHF.

Beta-Adrenergic Blockade in Heart Failure

The activation of the sympathetic nervous system in patients with CHF leads to excess catecholamine secretion, which adversely affects myocardium and contributes to left ventricular remodeling and CHF.

Multiple beta blockers have been tested in CHF. Beta blockers have been shown to reduce mortality by approximately 35% when added to an ACEI in mild to moderate CHF (MERIT-HF with metoprolol succinate, U.S. trials with carvedilol, and CIBIS-II trial with bisoprolol) or in very advanced CHF (Copernicus trial with carvedilol) (Packer et al., 2001). Beta blockers also reduce hospitalizations by 33% to 38% and work in synergy with ACEIs to reduce cardiac remodeling, reduce cavity size, and improve ejection fraction (CIBIS-II, 1999; Fowler et al., 2001; MERIT-HF, 1999; Packer et al., 1996; Remme et al., 2004).

There are differences in the antiadrenergic actions of p-adrenergic blocking drugs. The ratio of p2- and ar adrenergic receptors in the damaged heart changes compared to the normal myocardium (Bristow, 1993). p1 receptors are reduced and a1 receptors increased with little change in the p2 receptors. Almost 50% of the adrenergic receptors on the failing myocardium are p2 and a1, which are typically not affected by selective p1 blockade. Norepinephrine is known to exert negative effects through p1, p2, and a1 receptors. To test whether a nonselective p1, p2, or a1 blocker yields better mortality reduction than a pj blocker alone, the Carvedilol or Metoprolol European Trial (COMET trial) recruited 3029 patients with NYHC II-IV heart failure at 317 centers in 15 European countries (Torp-Pedersen et al., 2005; Poole-Wil-son et al., 2003). At 58 months, there was a 17% reduction in mortality with carvedilol compared to metoprolol tartrate (p = 0.0017). Despite the controversy about the adequacy of p-blockade and the use of the shorter-acting metoprolol tar-trate instead of the long-acting metoprolol succinate in this study, the data seem to favor the theory that the nonselec-tive adrenergic blockade is superior to the selective short-acting pj-receptor blockade in reducing mortality in the CHF patient.

Carvedilol (6.25-25 mg twice daily) was shown in the Gly-cemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol

Comparison in Hypertensives (GEMINI) study not to alter glycemic control in diabetic patients compared with meto-prolol tartrate (50-200 mg twice daily). Also, carvedilol did improve some components of the metabolic syndrome such as improving insulin sensitivity (Bakris et al., 2004). Carve-dilol appears to be a favorable drug in diabetic patients, in contrast to other selective beta blockers.

Aggressive titration of beta blockers is needed in patients with CHF. Higher levels of p-blockade are associated with better improvement of ejection fraction and greater reductions in cardiovascular hospitalizations (Hori et al., 2004; Bristow et al., 1996). A stepwise approach in titration of beta-blockade is generally followed with an increase in the dose every 2 weeks as tolerated until achieving the maximum tolerable dose.

KEY TREATMENT

Beta blockers (bisoprolol, carvedilol, and sustained-release metoprolol succinate) should be used in asymptomatic patients with a recent MI regardless of ejection fraction (SOR: A). Beta blockade should be used in all stable stage C patients unless contraindicated (ACC/AHA guidelines; SOR: A).

Miscellaneous Pharmacologic Therapy

Patients receiving ACE inhibitors might benefit from the addition of the combination of hydralazine and nitrates. ACC recommendations indicate that this treatment is likely to benefit African American patients with advanced CHF symptoms.

In addition to pharmacologic therapy, CHF patients should be instructed on dietary salt restriction (2 g sodium/day), daily weight monitoring (with reporting of 3-lb/wk weight increase to their physician), free water restriction to 1 L daily, smoking cessation, regular exercise, avoidance of alcohol intake, and aggressive treatment of hypertension and lipid disorders. Supplemental oxygen is needed in patients with oxygen saturation less than 92% on room air after ambulation. Finally, sleep apnea has been associated with CHF, and these patients need to be screened and aggressively treated for moderate to severe apnea. Patients with symptomatic CHF are best treated at a heart failure clinic to ensure appropriate therapy is administered by a specialized provider, to increase patient compliance, and to reduce recurrent hospi-talization. A heart failure clinic will also ensure that national benchmarks in management of CHF patients are met. These include the optimal utilization of ACEIs and beta blockers, documentation of LV function, and smoking cessation.

KEY TREATMENT

The combination of a fixed-dose of isosorbide dinitrate and hydralazine to a standard medical regimen for heart failure (HF), including ACE inhibitors and beta blockers, is recommended to improve outcomes for patients self-described as African Americans, with NYHA functional class III or IV HF. Others may benefit similarly, but this has not yet been tested (ACC recommendations; Jessup, 2009) (SOR: A).

Referral of patients with refractory end-stage HF to a HF program with expertise in the management of refractory HF is useful (ACC/ AHA guidelines; Jessup, 2009) (SOR: A).

Figure 27-14 Aortic valve stenosis with calcification as seen with two-dimensional Doppler echocardiography.
Figure 27-15 Bicuspic aortic valve.

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