Andrew Grant and Mazen Hanna
The management of heart failure (HF) depends on the underlying mechanism. This chapter focuses on the treatment of HF related to left ventricular (LV) systolic dysfunction, the best understood and studied nonvalvular cause of HF. LV dysfunction is generally defined by a reduction in left ventricular ejection fraction (LVEF).
We briefly discuss lifestyle measures and then review established pharmacotherapy. Trial evidence is summarized where appropriate. Current guideline recommendations from the American College of Cardiology1 and the Heart Failure Society of America2 are cited in each section with some changes in wording for clarity. Where guidelines are quoted, the strength of the recommendation is given, followed by the level of evidence in parentheses (e.g., I,C refers to a class I recommendation with level of evidence C). Discussion of surgical treatments and device-based therapies for HF can be found elsewhere in this book.
LIFESTYLE MEASURES
Sodium Restriction
Retention of sodium is an important aspect of the pathophysiology of HF and occurs due to overactivation of the sympathetic and renin–angiotensin–aldosterone systems (see Chapter 15). It is felt for this reason that limitation of salt intake reduces HF symptoms. The typical recommendation is that patients adhere to a diet of <2 g/day of sodium from all sources.
ACC Guideline1
Sodium restriction is indicated in patients with current or prior symptoms of HF and reduced LVEF who have evidence of fluid retention (I, C).
Fluid Restriction
Fluid balance is generally monitored closely during hospitalization for HF. This can be difficult to achieve in the outpatient setting. For those with serum sodium levels <130, however, a fluid restriction of 2 L/day (and sometimes 1.5 L) may be advisable.
HFSA Guidelines2
Restricted fluid intake is recommended for HF patients with moderate hyponatremia (serum Na <130) (I equivalent, C).
Restricted fluid intake should be considered among HF patients without significant hyponatremia who demonstrate fluid retention that is difficult to control with sodium restriction and diuretic therapy (IIa equivalent, C).
Exercise
HF patients are generally counseled to engage in regular physical exercise within the limits of their symptoms. For those with a recent myocardial infarction (MI) or high burden of coronary artery disease, the usual recommendations on cardiac rehabilitation and exercise should be followed.
Clinical Trials
Multiple small trials had suggested that exercise training is associated with improved functional capacity, decreased HF hospitalizations, and possibly a decrease in mortality.3–5 In a meta-analysis, it has also been shown to have a favorable effect on LV remodeling.6
The HF-ACTION trial evaluated the effect of aerobic exercise in 2,331 patients with stable HF and LV dysfunction.7 Patients randomized to regular exercise had a greater improvement in peak oxygen consumption and 6-minute walk distance. In contrast to previous smaller trials, there was no difference in all-cause mortality or hospitalization after a mean follow-up of 30 months.
ACC Guideline1
Exercise training is recommended as an adjunctive approach to improve clinical status in ambulatory patients with current or prior symptoms of HF and reduced LVEF (I, B).
MEDICAL THERAPY IN CHRONIC HEART FAILURE
Neurohormonal Blockade
Activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system leads to adverse physiologic effects in HF. Medications that block or dampen these effects include beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, AT1 receptor blockers (ARBs), and aldosterone antagonists. These medications have become an important cornerstone of contemporary HF management. It is recommended that these agents, particularly ACE inhibitors and beta-blockers, be considered in all HF patients and that they be titrated to achieve the doses used in clinical trials or to maximal tolerated doses.
Beta-Blockers
Mechanism of Action There are a number of proposed mechanisms by which beta-adrenergic blockers have been theorized to be beneficial in HE. Over time, they improve the efficiency of beta-adrenergic signaling, and some agents in this class restore a more normal distribution of beta-receptors on the cell surface. Hemodynamic and cellular effects include reduced wall tension, inhibition of adverse remodeling, and prevention of myocyte apoptosis.8Beta-blockers have a favorable impact on ventricular remodeling in both ischemic and nonischemic cardiomyopathies.9
Clinical Trials Multiple large-scale RCTs have shown beta-blockers to improve symptoms and reduce mortality in HF (Table 16.1).10–14 It should be noted that the nonselective beta-blocker bucindolol was also studied in the BEST trial, which showed no significant improvement in mortality.15 This agent has a significant degree of intrinsic sympathomimetic activity.
TABLE
16.1 Landmark Trials Evaluating the Effect of Beta-Blockers on Clinical Outcomes in HF
Cautions
Bradycardia can occur due to sinus node slowing and/or AV block.
Initiation of beta-blockers during acute HF decompensation can worsen symptoms due to negative inotropy.
ACC Guidelines1
Beta-blockers are indicated in patients with current or prior symptoms of HF and reduced LVEF (I, A).
Beta-blockers are indicated in patients with asymptomatic LV dysfunction (I, A).
Agents demonstrated to be beneficial in HF include carvedilol, bisoprolol, and metoprolol succinate.
Angiotensin Converting Enzyme Inhibitors
Mechanism of Action These agents block the ACE, preventing conversion of angiotensin I to angiotensin II (see Fig. 6.3). The role of angiotensin II in HF is discussed in detail in Chapter 15. By preventing the formation of angiotensin II, ACE inhibitors decrease vasoconstriction, increasing arterial compliance. The resulting decrease in vascular resistance unloads the failing left ventricle. ACE inhibitors reduce adverse structural changes such as ventricular hypertrophy and dilation, even among patients without overt HF.16,17 At a microscopic level, they have also been shown to reduce fibrosis.18
Clinical Trials Numerous published trials have demonstrated reductions in cardiovascular endpoints including mortality using ACE inhibitors in patients across the spectrum of HF (Table 16.2).19–23 ACE inhibitors have also been studied extensively in the setting of MI complicated by LV dysfunction or HF. Three key trials are summarized in Table 16.3.24–26
TABLE
16.2 Landmark Trials of ACE Inhibitors in chronic HF or LV Dysfunction
aSome patients were enrolled on the basis of increased LV end-diastolic diameter or cardiothoracic ratio; mean LVEF was 0.29. ISDN = isosorbide dinitrate.
TABLE
16.3 Landmark Trials of ACE Inhibitors in LV Dysfunction or HF Post-MI
Cautions
Angioedema is a rare but serious complication of ACE inhibitors.
Hyperkalemia can occur, especially in combination with ARBs or spironolactone.
Renal dysfunction can be exacerbated by ACE inhibitors.
Known bilateral renal artery stenosis is a contraindication to ACE inhibitors.
ACE inhibitors should not be used during pregnancy.
ACE inhibition leads to increased levels of bradykinin—in some patients, this is associated with the development of dry cough.
ACC Guidelines1
ACE inhibitors are indicated in patients with current or prior symptoms of HF and reduced LVEF (I, A).
ACE inhibitors should be used in patients with reduced LVEF in the absence of symptoms (I, A).
Angiotensin Receptor Blockers
Mechanism of Action Angiotensin can be produced by other proteases besides ACE. Furthermore, although angiotensin II action on AT1 receptors leads to vasoconstriction and adverse remodeling, action on AT2 receptors may actually have beneficial antifibrotic effects.27 These findings helped suggest the idea that using a selective ARB may be beneficial in HF.
Clinical Trials—ACE Inhibitor-Intolerant Patients The CHARM Alternative trial enrolled 2,028 patients with HF who were intolerant of ACE inhibitors and randomized them to candesartan or placebo.28 There was a significant reduction in the rate of the primary endpoint of death or HF hospitalization at 34 months in the candesartan group (33% vs. 40% with placebo).
Clinical Trials—Comparison to ACE Inhibitors The data from head to head trials comparing ACE inhibitors and ARBs in HF are mixed (Table 16.4). The ELITE I trial suggested a significant hard-endpoint benefit of using losartan rather than captopril in HF.29 This finding was not reproduced in the larger follow-up ELITE II trial.30 The OPTIMAAL study in post-MI patients showed the opposite result with a trend toward captopril being superior to losartan with respect to major cardiovascular events.31 The VALIANT study compared the ACE inhibitor captopril, the ARB valsartan, and a combination of the two in post-MI patients with HF or LV dysfunction.32 In this study, there was no difference between groups with respect to rates of death or HF hospitalization.
TABLE
16.4 Landmark Trials Comparing ARBS to ACE Inhibitors in HF
a4,909 valsartan and 4,909 captopril; combination arm with 4,885 excluded here.
EDD=end diastolic diameter; LV LVEF <0.35 or EDD >65 mm present in only 13.6% of patients.
c28% had no symptoms and mean LVEF was 0.35.
Clinical Trials—Combination with ACE Inhibitors Several trials have tested the effects of adding ARB therapy to patients already stabilized on ACE inhibitors (Table 16.5). CHARM added randomized patients already taking ACE inhibitors to the addition of candesartan or placebo.33 This trial showed a significant reduction in death and HF hospitalization in patients receiving candesartan. The ValHeft trial randomized patients to valsartan or placebo in addition to regular HF therapy.34 More than 92% of patients were on an ACE inhibitor at baseline which was continued. In the overall trial, there was no mortality difference between groups, but patients receiving valsartan had a significant reduction in HF hospitalization. As mentioned above, the VALIANT study compared the combination of valsartan and captopril to the use of either agent alone.32 The 4,885 patients who received the combination of ACE inhibitor and ARB had mortality rates and HF hospitalization rates that were identical to those of the captopril alone group.
TABLE
16.5 Landmark Trials of the Addition of an ARB to an ACE Inhibitor in HF
a4,909 captopril alone and 4,885 combination; 4,909 patients on valsartan alone excluded here.
bRequired either LVEF < 0.40 or overt HF; 28% had no symptoms and mean LVEF was 0.35.
Cautions
Angioedema can occur with ARBs but much less commonly than with ACE inhibitors.
Cough caused by ACE inhibitors is not seen with ARBs.
Otherwise, the side effect profile of ARBs is much like that of ACE inhibitors.
ACC Guidelines1
ARBs are indicated for ACE inhibitor-intolerant patients with HF and reduced LVEF (I, A).
In patients with reduced LVEF but no symptoms of HF who are intolerant of ACE inhibitors, an ARB should be used if the etiology is ischemic (I, B) and is reasonable if the etiology is nonischemic (Ila, C).
ARBs are a reasonable first-line alternative to ACE inhibitors in patients with HF and reduced LVEF (Ila, A).
The addition of an ARB to an ACE inhibitor and beta-blocker can be considered in persistently symptomatic HF patients with reduced LVEF (IIb, B).
Aldosterone Antagonists
Mechanism of Action Spironolactone was originally used as a potassium-sparing diuretic. It blocks mineralocorticoid receptors in the kidney, preventing reabsorption of sodium and excretion of potassium in the distal convoluted tubule. Because aldosterone production is upregulated in HF (see Chapter 15), it becomes an obvious target for therapies. Spironolactone also has some androgen blocking activity, which can lead to adverse effects such as breast tenderness and gynecomastia. Eplerenone is more selective for the aldosterone receptor and does not have these same side effects.
Clinical Trials The RALES trial firmly established the benefits of aldosterone antagonism in patients with severe symptomatic HF and reduced LVEF35 The EPHESUS trial studied only post-MI patients with resulting LV dysfunction.36 In an effort to include higher risk patients, the investigators required patients to have either symptomatic HF or diabetes. The recently published EMPHASIS study may expand the use of these agents in patients with less symptomatic HF, although these findings have yet to be incorporated into national guidelines.37 These three trials are summarized in Table 16.6.
TABLE
16.6 Landmark Trials of Aldosterone ALandmark Trials of Aldosterone and Post-MI LV Dysfunction
Cautions
Caution should be used in patients with renal dysfunction.
Hyperkalemia (Should not be prescribed if K > 5 mM)
Spironolactone can be associated with breast tenderness and gynecomastia.
ACC Guidelines1
An aldosterone antagonist is recommended in selected patients with NYHA III or IV symptoms of HF and reduced LVEF who can be monitored for preserved renal function and normal potassium concentration (I, A).
Creatinine should be ≤2.5 in men or ≤2.0 mg/dL in women.
Potassium should be ≤5.0 mEq/L.
Other Vasodilators
Afterload reduction of the LV in chronic HF decreases wall tension and improves forward stroke volume. Preload reduction with venous vasodilator therapy helps to decrease LV filling pressures and improve symptoms.
Hydralazine and Nitrates
Mechanism of Action Hydralazine increases intracellular cGMP promoting smooth muscle relaxation leading to vasodilation. It acts primarily in the arterioles, decreasing blood pressure and LV afterload. It is often given in conjunction with nitrates in HF because of a synergistic activity on the nitric oxide pathway and more sustained clinical effect. The combination of hydralazine and a nitrate leads to lower LV filling pressure and an increase in cardiac output.
Clinical Trials The original V-HeFT study compared a combination of hydralazine and isosorbide dinitrate (ISDN) with placebo in patients with HF and reduced LVEF.38 It showed a significant mortality reduction to 26% at 2 years from 34% in the placebo arm.
V-HeFT II compared the same combination of hydralazine and ISDN to the ACE inhibitor enalapril.22 Event rates in the hydralazine and ISDN arm of V-HeFT II were similar to those of V-HeFT, with a 2-year mortality of 25%. The enalapril arm, however, had an even lower mortality rate of 18% at 2 years.
In the V-HeFT II trial, there appeared to be less benefit of ACE inhibitor over hydralazine and nitrates among black patients. The A-HeFT trial enrolled patients self-described as African American to directly test the utility of adding hydralazine and ISDN when symptoms persisted on ACE inhibitors.39 The trial was discontinued early after a mean follow-up of 10 months because of a significant reduction in mortality in the group treated with hydralazine and ISDN (6.0% vs. 10.2% in placebo).
Cautions
Use of phosphodiesterase inhibitors such as sildenafil for erectile dysfunction in combination with nitrates is contraindicated because of the risk of hypotension.
Methemoglobinemia is a rare but serious side effect of nitroglycerin.
Headache is a common side effect of nitrates.
ACC Guidelines1
Hydralazine and a nitrate could be considered in patients with HF and decreased LVEF who are intolerant of ACE inhibitors and ARBs (IIb, C).
Hydralazine and a nitrate should be used in self-identified African American patients with HF and decreased LVEF who have persistent moderate or severe symptoms despite treatment with a beta-blocker, an ACE inhibitor, and a diuretic (I, B).
Calcium Channel Blockers
Mechanism of Action In general, calcium channel blockers are not recommended in HF and impaired LV function. The more cardioselective diltiazem and verapamil in particular are contraindicated because of their negative inotropic properties. The dihydropyridines, on the other hand, act more peripherally causing vasodilation and reducing blood pressure.
Clinical Trials The MDPIT trial evaluated the benefits of diltiazem in patients who had suffered a MI. Among patients with pulmonary edema on chest x-ray, use of diltiazem was associated with higher cardiac mortality.40 The PRAISE-I study compared amlodipine to placebo in patients with HF and reduced LVEF41 It showed a trend toward a decrease in the combined endpoint of death or CV hospitalization among patients randomized to amlodipine. This difference was significant among the subset of patients with a nonischemic cardiomyopathy. The subsequent PRAISE-II trial enrolled only patients with nonischemic-dilated cardiomyopathies and randomized them to amlodipine or placebo. There was no difference in outcomes found. Small randomized trials of amlodipine42 and nifedipine43 have shown mixed results with respect to exercise tolerance with these agents.
Cautions
Nondihydropyridine calcium channel blockers diltiazem and verapamil have negative inotropic effects and are considered contraindicated in HF.
Amlodipine and nifedipine can be associated with edema and increased fluid retention.
ACC Guidelines1
Calcium channel blockers should not be used as routine treatment in patients with current or prior symptoms of HF and reduced LVEF (III, A).
Alpha-blockers
The ALLHAT trial showed increased rates of HF in patients randomized to the alpha-blocker doxazosin compared to other antihypertensives.44 Alpha-blockers continue to be used as add-on therapy in patients with HF and refractory hypertension despite maximal doses of indicated drugs. The use of alpha-blockers in HF is not specifically mentioned in the ACC or HFSA guidelines.
Digitalis Glycosides
Preparations of digitalis have been used for centuries in the treatment of cardiovascular diseases. Digoxin is primarily used for rate control of atrial fibrillation, but it has an important role in the management of symptomatic HF in selected patients in sinus rhythm as well.
Digoxin
Mechanism of Action Digoxin acts via a number of different mechanisms. The primary effect has long been felt to be blockade of the Na/K ATPase in cardiac myocytes (see Chapter 6). This leads to an increase in intracellular calcium available for contraction and therefore to an increase in inotropy. Effects in other tissues lead to digoxin having sympatholytic and parasympathomimetic effects. It is now felt that the neurohormonal blockade activities of digoxin may play an important role in the long-term clinical benefits of its use.
Clinical Trials The Digitalis Investigation Group (DIG) trial studied the effects of digoxin in comparison to placebo in 6,800 patients with HF and decreased LVEF45 There was no significant difference between groups in the rates of mortality at a mean follow-up of 37 months. There was, however, a significant decrease in hospitalization for worsening HF in the digoxin group (26.8% vs. 34.7% in placebo).
Withdrawal Trials Several trials have tested the effects of withdrawing digoxin from stable patients on more contemporary HF treatment. The PROVED study randomized 88 patients with symptomatic HF on digoxin to continuation or withdrawal.46 Discontinuation of digoxin resulted in higher rates of treatment failure and decreased exercise tolerance. The RADIANCE study similarly randomized 178 patients to continuation of digoxin or withdrawal of the agent for 12 weeks and initiation of placebo.47 Patients in the placebo arm had higher rates of crossover to active treatment. In this study, they also showed significant worsening of symptoms and exercise tolerance.
Monitoring of Levels Digoxin toxicity is a major concern among HF patients, particularly the elderly and those prone to electrolyte disturbances. Digoxin toxicity is most common with serum levels >2.0, but can occur at lower levels. A post hoc analysis of the DIG trial demonstrated an interaction between serum digoxin levels and all-cause mortality.48
Cautions
Digoxin toxicity is a life-threatening complication of treatment with numerous manifestations.
Hypokalemia, hypomagnesemia, hypercalcemia, and acute renal failure can all precipitate digoxin toxicity.
ACC Guideline1
The use of digoxin is reasonable in patients with current or prior symptoms of HF and decreased LVEF (IIa, B).
HFSA Guideline2
Serum digoxin levels should be maintained <1.0 ng/mL (generally 0.7 to 0.9 ng/mL).
Investigational Agents
Many other agents have been tested or are under investigation for the treatment of HF. Several agents and classes with recent publications are briefly discussed below.
Phosphodiesterase Inhibitors
LV dysfunction with HF is a major secondary cause of pulmonary hypertension (type 2 by the current classification scheme). There are theoretical concerns that reducing pulmonary pressures in patients with left-sided HF could lead to increased pulmonary edema. Nevertheless, there is interest in using selective pulmonary arterial vasodilators in HF. Several small trials have shown hemodynamic benefit and increased exercise tolerance.49,50
Polyunsaturated Fatty Acids
Epidemiologic studies have linked consumption of polyunsaturated fatty acids (PUFAs) with decreased rates of adverse cardiovascular events.51 GISSI-HF randomized 6,975 patients with symptomatic HF (>90% of whom had LVEF < 0.40) to omega-3 PUFA or placebo.52 At a follow-up of 3.9 years, there was a statistically significant reduction in allcause mortality (27% vs. 29% in placebo).
Ivabradine
This medication has selective inhibitory effects on the sinus node. It was postulated as the basis of the SHIFT study that controlling heart rate with such an agent in HF patients unable to tolerate maximal beta-blocker doses may be beneficial. SHIFT randomized 6,558 patients to receive ivabradine or placebo in addition to conventional HF therapy.53 Although there was a significant reduction in cardiovascular death or HF hospitalization, the trial has been criticized for underdosing of beta-blockers. The argument is that slowing the sinus node rate may be beneficial but could have been achieved by uptitration of beta-blockers to maximal doses.
Treatment of Related Conditions
Anemia and Iron Deficiency
Anemia is commonly associated with HF, and normalization of hemoglobin may be associated with increased exercise tolerance. There is evolving evidence to suggest that there may be symptomatic benefit to treatment of iron deficiency in HF even in the absence of anemia.
Clinical Trials The STAMINA-HF trial examined the effects of darbapoetin alpha in 319 patients with HF and anemia.54
Treatment resulted in a significant increase in hemoglobin levels but had no significant impact on mortality or hospitalization rates.
FAIR-HF enrolled 459 patients with symptomatic HF and decreased LVEF who had iron deficiency defined as ferritin <100 µg/L (or <300 µg/L with transferrin saturation <20%).55 Only half of the patients had anemia (defined as hemoglobin <12.0 g/dL). Randomization was to a regimen of intravenous iron to achieve iron repletion or placebo. Iron therapy was associated with improved self-reported quality of life and symptom status at 24 weeks, both among anemic and nonanemic irondeficient HF patients.
ACC Guidelines1
Increasing erythropoiesis in HF patients with decreased LVEF is not well established (IIb, B).
Iron supplementation therapy “is undergoing further investigation.”
Rhythm Control for Atrial Fibrillation
Atrial fibrillation is a common arrhythmia in patients with HF and LV dysfunction. This topic is discussed in detail elsewhere in this text. The AF-CHF study of 1,376 patients with HF and EF <0.35 did not show any difference between ratecontrol and rhythm-control strategies with respect to mortality or worsening HF.56
ACC Guideline1
It is reasonable to adopt either a rate control strategy or a rhythm control strategy in patients with HF and reduced LVEF who develop atrial fibrillation (IIa, A).
Anticoagulation for Prevention of Stroke
HF is a prothrombotic condition, associated with increased levels of fibrinogen, D-dimer, and antithrombin.57,58 Stasis of blood within a poorly contracting left ventricle also contributes to the formation of clot. As such, rates of stroke and systemic embolus are higher in patients with LV systolic dysfunction.59
Clinical Trials The WATCH study compared ASA, clopidogrel, and warfarin in 1,587 patients with LV systolic dysfunction.60 This study demonstrated a significant reduction in ischemic stroke among warfarin patients, but this was offset by an increase in rates of intracranial hemorrhage. It should be noted that the study was underpowered due to poor enrollment. The HELAS study enrolled 197 patients with HF and decreased LVEF.61 Patients with nonischemicdilated cardiomyopathies were randomized to warfarin or placebo. Those with ischemic heart disease were randomized to ASA 325 mg QD or placebo. At 2 years of follow-up, there was no difference between the groups in rates of embolic events. The WARCEF trial comparing warfarin to placebo is ongoing.
ACC Guideline1
Anticoagulation for prevention of stroke or systemic embolus is not well established in HF patients with reduced LVEF in the absence of other indications for anticoagulation (IIb, B).
MEDICAL THERAPY IN ACUTE HEART FAILURE
Supportive Treatment
HF decompensation is a spectrum from progression of exertional symptoms to cardiogenic shock with florid pulmonary edema. The general principles of Advanced Cardiac Life Support apply to the initial stabilization of patients presenting with acute HF syndromes.
HFSA Guidelines2
Supplemental oxygen should be administered for all patients with acute HF who demonstrate hypoxia (I equivalent, C)
Positive pressure ventilation may be considered for severely dyspneic patients with pulmonary edema (IIb equivalent, A)
Admission to Hospital
The decision about when to admit a patient with decompensated HF is a complex one. The following lists of clinical parameters (modified from Table 12.1 of the HFSA 2010 guidelines)2 is not meant to be exhaustive.
Features of acute decompensation for which admission to hospital is recommended:
Hypotension
Resting tachypnea or hypoxia
Altered mentation
Worsening renal function
Hemodynamically unstable arrhythmia
Acute coronary syndrome
Features of acute decompensation for which hospitalization should be considered:
New diagnosis of HF with congestion
Worsening pulmonary or systemic congestion
Major electrolyte disturbances
Pneumonia, pulmonary embolus, diabetic ketoacidosis, and stroke/transient ischemic attack
Repeated defibrillator discharges
Invasive Hemodynamic Monitoring
Invasive hemodynamic assessment with a pulmonary artery catheter is performed for a number of different indications in HF patients, including assessment of pulmonary hypertension, and pretransplant workup. In the context of acute HF exacerbation, placement of a PA catheter can help distinguish HF from other causes of hypoxia or hypotension. It also allows careful titration of vasoactive medications to hemodynamic parameters.
Clinical Trials A large observational study in the medical intensive care unit (ICU) showed an increase in mortality in patients who received invasive monitoring with a pulmonary artery catheter.62 A meta-analysis of small trials using PA catheter-guided therapy in the ICU showed no improvement in hospital stay or mortality with this strategy.63 The ESCAPE trial randomized 433 patients with acute decompensated HF to invasive hemodynamic monitoring or usual care.64 There was no significant difference between the two groups with respect to the primary endpoint of days alive out of hospital.
ACC Guidelines1
Invasive hemodynamic monitoring should be performed in patients with respiratory distress or systemic hypoperfusion in whom intracardiac filling pressures cannot be adequately assessed clinically (I, C).
Invasive hemodynamic monitoring is reasonable for HF patients with persistent symptoms despite initial therapy who have one of the following features: hypotension, worsening renal function, or need for IV vasoactive agents (IIa, C).
Invasive hemodynamic monitoring is reasonable in HF patients being considered for advanced therapies such as cardiac transplantation or mechanical circulatory support (IIa, C).
Decongestion
A longstanding focus of acute HF management has been on the rapid shift of fluid from the pulmonary interstitial space. This improves symptoms of dyspnea and oxygenation. Following this stabilization phase, efforts are generally made to remove further salt and water targeting peripheral edema and ascites.
Loop Diuretics
Mechanism of Action So-called loop diuretics act by blocking the Na/K/2Cl cotransporter in the Loop of Henle. They are potent inhibitors of sodium reabsorption in the nephron. The commonly used loop diuretics are furosemide, bumetanide, and torsemide (Table 16.7).
TABLE
16.7 Commonly Used Loop Diuretics and their Relative Dosing in Acute HF
Modified from Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American college of Cardiology Foundation/American Heart Association task force on practice guidelines developed in collaboration with the International Society of Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1–e90, Table 16.5, with permission from Elsevier.
Route of Administration During acute exacerbations of HF, intravenous formulations of diuretic are generally used. This route of administration provides a more reliable bio-availability because edema in the bowel wall can interfere with absorption of oral diuretics, especially furosemide. The effective dose conversion of oral to intravenous furosemide is approximately 2:1.65,66
It has been suggested that continuous IV infusions of loop diuretics are superior to intermittent boluses. The DOSE study67 compared these two strategies in a randomized, blinded trial of 308 patients. There was no difference between continuous infusion and intermittent bolus diuretics (every 12 hours) on dyspnea or renal function. The study was not powered for hard clinical endpoints, but there was no difference in death or rehospitalization at 60 days, nor was there a difference in length of initial hospital stay.
Sequential Nephron Blockade Addition of a diuretic from another class that acts more distally in the nephron is a well-established means of potentiating the effect of a loop diuretic.68 The classical agents used in this way have been thiazide diuretics such as hydrochlorothiazide and chlorthalidone. Metolazone is now commonly used in this fashion, with a simple daily or twice daily oral dosing regimen. Metolazone acts in a very similar way to the thiazide diuretics.
Concerns
Observational studies and retrospective analyses of randomized trials have shown a relationship between use of diuretics and increased mortality.69,70
Electrolytes need to be monitored carefully due to risks of hyponatremia, hypokalemia, and hypomagnesemia.
Prerenal azotemia can be precipitated by overdiuresis.
ACC Guidelines1
Patients admitted for HF with significant fluid overload should be treated with intravenous loop diuretics (I, C).
When diuresis is inadequate to relieve congestion, treatment should be intensified with higher doses of loop diuretic, addition of a thiazide or metolazone, or transition to a continuous infusion of loop diuretic (I, C).
Vasopressin Antagonists
Mechanism of Action Arginine vasopressin, or antidiuretic hormone, is a hormone released from the posterior pituitary that causes retention of free water and is important in regulation of serum sodium and osmolality. It also causes vasoconstriction (hence its name). Interest has emerged in targeting vasopressin as a potentially harmful upregulated hormone in HF. Tolvaptan is a selective vasopressin antagonist, blocking the V2 receptor. Its use should result in diuresis of more hypotonic fluid than is seen with loop diuretics.
Clinical Trials EVEREST was a trial of 4,133 patients hospitalized for acute decompensated HF comparing tolvaptan with placebo in addition to usual care.71 Patients treated with tolvaptan had more weight loss after 24 hours (1.8 kg vs. 1.0 kg with usual care) and at hospital discharge. At a mean of 10-month follow-up, there was no significant effect of tolvaptan on mortality or HF readmission rates. As expected, tolvaptan was associated with increased sodium levels among hyponatremic patients.
Adenosine Receptor Blockers
Mechanism of Action This class of medications blocks the adenosine receptor. Adenosine receptors are found in the afferent arterioles of the glomerulus and their stimulation has been posited to mediate worsening renal function in HF. There has been interest in the use of the selective A1 receptor blocker rolofylline to treat HF with acute kidney injury.
Clinical Trials The PROTECT study randomized, patients with acute HF and renal dysfunction to rolofylline or placebo in a 2:1 fashion.72 The primary endpoint, a composite of death, worsened HF, or renal dysfunction, was no different between the two groups. Rolofylline was associated with an increased risk of seizures.
Ultrafiltration
Mechanism of Action Ultrafiltration removes isotonic fluid from the circulation through an extracorporeal circuit. This can be carried out using standard central venous catheters or special peripheral IVs.
Clinical Trials The UNLOAD study compared veno-venous ultrafiltration to intravenous diuretics in 200 HF patients.73 Ultrafiltration resulted in a significantly greater 4.6 L fluid loss at 48 hours (vs. 3.3 L in the diuretic group). Interestingly, with this modest increase in weight loss, there were important effects on the rates of clinical endpoints in the intermediate term. Specifically, there were decreased 90-day rates of HF rehospitalization and unscheduled physician visits. It has been argued that this is because ultrafiltration decongests patients without the use of diuretics, which themselves have deleterious neurohormonal effects.74
ACC Guideline1
Ultrafiltration is reasonable in HF patients with refractory congestion not responding to medical therapy (IIa, B).
Vasodilators
Nitrates
Nitroglycerin has long been used for the treatment of acute decompensated HF. Nitroglycerin is biotransformed into nitric oxide, which activates guanylate cyclase and increases cGMP. This leads to smooth muscle relaxation and vasodilation. At low doses, nitroglycerin acts as a venodilator, at high doses as an arterial vasodilator. The benefits in HF are pulmonary decongestion and facilitation of diuresis. Large clinical trials comparing nitroglycerin to placebo in HF are lacking, however. The topical application of nitroglycerin can lead to skin irritation, and a rare complication of this drug is methemoglobinemia.
Nitroprusside is predominantly a systemic arterial vasodilator that decreases LV filling pressures by reducing the afterload imposed on the failing ventricle. Its use is more often limited by hypotension and the need for invasive monitoring in an ICU setting. There is also a theoretical risk of cyanide toxicity when nitroprusside is used at higher doses.
Nesiritide
Nesiritide is a recombinant form of human B-type natriuretic peptide. The VMAC study showed that nesiritide was associated with a greater reduction in LV filling pressures than nitroglycerin or placebo.75The ASCEND-HF trial tested the effect of this medication on symptoms and hard outcomes in acute decompensated HF.76 It enrolled 7,141 patients with acute HF and randomized them to nitroprusside or placebo in addition to usual care. The study did not show a significant reduction in death or hospitalization at 30 days. Nesiritide seemed to have favorable effects on patient dyspnea, but these trends did not meet the prespecified margin for statistical significance. Concerns about the safety of the agent were also not realized. Previous meta-analyses had suggested that nesiritide was associated with increased rates of worsening renal function.
ACC Guideline1
In patients with severely symptomatic fluid overload unresponsive to initial treatment with diuretics, it is reasonable to add a vasodilator such as nitroglycerin, nitroprusside, or nesiritide (IIa, C).
Other Agents
Morphine
Morphine sulfate has been used routinely in the management of acute HF for decades. It is postulated that morphine provides symptomatic benefit by alleviating air hunger, but also has an early effect on LV end-diastolic pressures and facilitates pulmonary vasodilation. Analysis of observational data from the ADHERE registry has shown a correlation between use of morphine in acute HF and higher rates of mortality.77 Morphine is not specifically discussed in the most recent ACC or HFSA guidelines.
Neurohormonal Blockade
As discussed earlier, the initiation of ACE inhibitor and beta-blocker therapy in chronic HF patients is usually deferred until a time of hemodynamic stability and (in the case of beta-blockers) relative “euvolemia.” This raises the question of when it is appropriate to continue these therapies in the setting of acute decompensation.
HFSA Guidelines2
Beta-blockers should be continued in most patients experiencing an exacerbation of HF unless they develop cardiogenic shock, refractory volume overload, or symptomatic bradycardia (I equivalent, C).
A temporary reduction of beta-blocker dose (generally by one-half) may be considered in the setting of acute HF exacerbation (IIa equivalent, C).
Inotropes
Inotropes are agents that increase myocardial contractility. Unfortunately, although many such medications have demonstrated immediate hemodynamic benefits, they have not as a group been shown to improve clinical outcomes in acute or chronic HF. In fact, in many cases they have been shown convincingly to increase the risk of adverse cardiovascular events including arrhythmia and death. The main indication for parenteral inotropes in HF is in the resuscitation of patients with cardiogenic shock. In this group, it is felt that end-organ dysfunction can be stabilized or improved by increasing cardiac output.
Dobutamine
Dobutamine is the prototypical inotrope of the adrenergic agonist class. By stimulating beta-1-receptors in the heart, it results in increased cardiac output. Effects on blood pressure are variable because beta-2-receptors and alpha-receptors in the vasculature are activated as well.
There are two studies comparing low-dose intermittent dobutamine with placebo in HF. One of these showed no significant impact on exercise tolerance, mortality, or time to HF readmission.78 The other trial (which has been published only in abstract form) was stopped early due to an excess of deaths in the dobutamine arm.79
Dopamine
Dopamine has complex pharmacologic actions. At low doses, its primary action is on dopamine receptors. At moderate doses, it acts on adrenergic receptors including beta-and alpha-receptors in the heart and vasculature. This gives dopamine the sometimes desirable property of raising blood pressure. It is often used for patients in cardiogenic shock with severe or symptomatic hypotension. Higher doses of dopamine result in relatively greater alpha-stimulation such that the vasopressor properties dominate.
The DAD-HF trial compared low-dose furosemide and low-dose dopamine to high-dose furosemide in patients with acute HF.80 The dopamine group had similar diuresis to the high-dose furosemide group, but with lower rates of renal dysfunction.
The SOAP II trial randomized 1,679 patients with shock to dopamine or norepinephrine as their initial vasopressor.81 The overall trial showed no difference in mortality between the two agents, but dopamine use was associated with more arrhythmic events. In a subanalysis of the 280 patients with cardiogenic shock, mortality was higher with dopamine than with norepinephrine.
Milrinone
Milrinone is a phosphodiesterase inhibitor. It leads to decreased breakdown of cAMP in cardiomyocytes. This increases the amount of calcium available for contraction. Clinical effects include an increase in cardiac output and heart rate. Like dobutamine, this agent can cause hypotension.
In the OPTIME-HF trial, 48-hour intravenous infusion of milrinone or placebo was added to standard therapy in 951 acute HF patients.82 In this study, milrinone was associated with higher rates of hypotension and arrythmias and no decrease was seen in the number of days hospitalized for cardiovascular causes.
Oral milrinone in severe HF has been studied in the PROMISE trial of 1,088 NYHA functional class III or IV patients.83 After a median follow-up of 6.1 months, there was a 34% relative increase in the rate of cardiovascular death. Rates of hospital admission, worsening HF, and drug discontinuation were also higher in the active treatment group.
Levosimendan
This agent binds selectively to troponin C and increases the response of myofilaments to calcium. This medication is not presently available for use in the United States.
The SURVIVE trial randomized 1,327 patients with acute decompensated HF requiring inotropes to dobutamine or levosimendan.84 There was a significant reduction in B-type natriuretic peptide at 24 hours, but there was no significant difference in the primary outcome of mortality at 180 days. Levosimendan was associated with higher rates of atrial fibrillation, hypokalemia, and headache.
ACC Guidelines1
Patients with hypotension and clinical evidence of hypoperfusion and elevated intracardiac filling pressures should be treated with a vasopressor or inotrope (I, C).
Inotrope use might be reasonable in patients with hypotension and low cardiac output without congestion (IIb, C).
Long-term continuous infusions of inotropes should not be used except as palliation for patients with end-stage HF (III, B).
Continuous infusion of a positive inotrope may be considered for palliation of symptoms in patients with refractory end-stage HF (IIb, C).
MEDICATIONS TO AVOID IN HEART FAILURE
A variety of medications can worsen symptoms of HF or precipitate decompensation. This can occur through one or more of the following mechanisms:
Direct toxicity to cardiac myocytes
Decreased inotropy due to myocardial depression
Increased sodium or fluid retention
Nonsteroidal Anti-inflammatory Drugs
Both nonselective and COX-2-selective nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with increased risks of HF exacerbation and mortality.85 Concerns have also been raised about the safety of using ASA in patients with HF. Early hemodynamic data suggested an interaction between ASA and ACE inhibitors. A meta-analysis of large trials did not show an impact of ASA use on the beneficial effects of ACE inhibitors.86 It is generally felt now that HF is not a contraindication to the use of ASA.1
Calcium Channel Blockers
Diltiazem and verapamil are relatively contraindicated in HF with decreased LVEF because of their negative inotropic properties (see above).
Antiarrhythmic Medications
The SWORD study randomized 1,549 patients with reduced LVEF post-MI to sotalol or placebo.87 The trial was discontinued early because of increased rates of death among patients receiving active treatment. In the ANDROMEDA study, dronedarone was associated with increased mortality in patients with NYHA functional class III or IV HF and LV dysfunction.88 The only antiarrhythmic medications felt to be safe and appropriate for use in HF are amiodarone and dofetilide. Routine use of antiarrhythmic medications to prevent ventricular arrhythmias is not recommended.
Oral Hypoglycemics
The thiazolidinedione rosiglitazone has recently had restrictions placed on its use because of cardiovascular safety concerns. A large meta-analysis of trials of rosiglitazone showed a 43% increase in the risk of MI and a possible increase in mortality.89 The use of pioglitazone has not been demonstrated to have similar associations with these outcomes.
Metformin is another common oral hypoglycemic that is often avoided in HF patients because of concerns about lactic acidosis. Although lactic acidosis has not been convincingly associated with metformin, it was a rare but serious adverse effect of phenformin, another drug of the biguanide class.
Chemotherapy Agents
Anthracyclines, cyclophosphamide and a variety of other chemotherapy medications have been shown to have direct cardiotoxic effects. Where possible, these drugs should be avoided in patients with known HF or depressed LV function.
HEART FAILURE WITH PRESERVED LVEF
The majority of clinical trials in HF management have specifically excluded patients with normal LV function and preserved LVEF. There is a growing recognition that a large percentage of patients admitted with a diagnosis of HF have no evidence of LV dysfunction.90–93
The main focus of treatment in these patients is control of factors that may precipitate HF such as myocardial ischemia, hypertension, and arrhythmia.1
Angiotensin Receptor Blockers
CHARM Preserved studied the use of candesartan in 3,025 patients with HF and LVEF > 0.40.94 There was no significant difference between candesartan and placebo with respect to the primary endpoint of cardiovascular death or admission for HF A significant difference was seen in the secondary outcome of HF admission, however, with a relative risk reduction of 15%.
The I-PRESERVE study enrolled 4,128 patients with HF and LVEF >0.45.95 The primary outcome was a composite of death or hospitalization for cardiovascular reasons. At a mean follow-up of 50 months, there was no significant difference between irbesartan and placebo in the primary outcome or in rates of HF admission.
MONITORING AND FOLLOW-UP
Disease Management Programs
There is a growing interest in the development and implementation of disease management programs for HF. These are generally multidisciplinary programs that involve formal guidelines for inpatient management, structured discharge planning, and close post-discharge follow-up. In a meta-analysis of small trials, disease management programs were associated with a reduction in mortality and readmission for HF.96
Implantable Hemodynamic Monitors
Direct measurements of right ventricular and pulmonary artery pressures with implanted devices have been trialed in very small studies. In one study, patients had decreased rates of HF readmission when data from the invasive monitor was available to physicians.97 Certain implantable defibrillators have internal sensors that measure thoracic impedance as an estimate of lung water caused by cardiogenic pulmonary edema. The utility of monitoring such parameters is still being actively studied.98
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QUESTIONS AND ANSWERS
Questions
1. Which of the following lifestyle modifications has been demonstrated to decrease mortality in heart failure (HF) patients?
a. Sodium restriction to <2 g/day from all sources
b. Regular aerobic exercise 30 minute/day, 5 to 7 days/week
c. Fluid restriction to <1.5 L/day
d. Daily weights and blood pressure monitoring
e. None of these modifications
2. A 50-year-old female with a nonischemic-dilated cardiomyopathy is being followed for HF with NYHA functional class II symptoms. Her current medications are carvedilol 6.25 mg BID, enalapril 10 mg BID, eplerenone 25 mg QD, and furosemide 20 mg QD. On physical examination, her HR is 70 bpm, blood pressure is 104/72 mm Hg, and oxygen saturation is normal on room air. Her JVP is not elevated, she has a normal chest exam, and there is no peripheral edema. Her complete blood count, electrolytes, renal function, and thyroid indices are normal.
What is the recommended dietary fluid restriction for this patient?
a. <3 L/day
b. <2.5 L/day
c. <2.0 L/day
d. <1.5 L/day
e. No specific fluid restriction is indicated
3. A 36-year-old male presents with an acute inferior wall myocardial infarction (MI). He is admitted to the CCU following primary angioplasty to a dominant right coronary artery. His chest x-ray shows mild pulmonary edema, and left ventricular ejection fraction (LVEF) is 46% by ventriculography.
Following initial stabilization, his medications are metoprolol 25 mg twice daily, ASA 81 mg QD, clopidogrel 75 mg QD, fondaparinux 2.5 mg QD, and atorvastatin 80 mg QD. His heart rate is 64 beats per minute, blood pressure is 108/78 mm Hg, and oxygen saturation is normal on room air. Complete blood count, electrolytes, urea, and creatinine are normal.
Which of the following changes to his therapy would be most appropriate prior to discharge?
a. Increase clopidogrel to 75 mg BID.
b. Discontinue metoprolol.
c. Start ramipril 2.5 mg daily.
d. Start spironolactone 12.5 mg daily.
e. Start hydralazine 25 mg TID.
4. Which of the following statements is correct regarding the use of angiotensin receptor blockers (ARBs) in HF?
a. Side effects of angiotensin receptor blockers relate to increased levels of bradykinin.
b. An angiotensin receptor blocker is a reasonable first-line alternative to an ACE inhibitor in patients with HF and reduced LVEF.
c. An angiotensin receptor blocker should be considered in ACE inhibitor-intolerant patients with HF only in combination with an aldosterone antagonist.
d. An angiotensin receptor blocker should be considered in ACE inhibitor-intolerant patients with HF only in combination with a continuous positive inotrope.
e. An angiotensin receptor blocker should never be given to ACE inhibitor-intolerant patients because angioedema occurs with this class of agents as well.
5. Important side effects of the aldosterone antagonist eplerenone include all of the following except:
a. Renal dysfunction
b. Lightheadedness
c. Gynecomastia
d. Hypotension
e. Hyperkalemia
6. Which of the following statements about digoxin is correct?
a. Digoxin toxicity can be precipitated by hypokalemia, hypermagnesemia, or hypocalcemia.
b. Digoxin has been demonstrated to decrease rates of repeat hospitalization in HF patients, but at the expense of increased mortality.
c. During chronic therapy, digoxin levels should be monitored and maintained in the range of 1.5 to 2.0 ng/mL.
d. Digoxin acts by downregulating the expression of the gene coding for the cardiac Na+/K+ ATPase.
e. Digoxin has sympatholytic and parasympathomimetic properties.
7. A 46-year-old female is found to have an abnormal EKG at the time of a routine physical. She denies any symptoms, and has a normal physical examination. She has an echocardiogram performed that demonstrates an LVEF of 30%. A coronary angiogram is performed and is normal. She is diagnosed with a nonischemic-dilated cardiomyopathy. Based on the information provided, which of the following agents should be added to her medical regimen?
a. Eplerenone
b. Carvedilol
c. Nitroglycerin
d. Furosemide
e. Warfarin
8. A 72-year-old female with severe LV systolic dysfunction has chronic symptoms of HF with NYHA functional class III symptoms. She is admitted to hospital with worsening breathlessness and leg swelling. On examination, she is grossly volume overloaded. Her current medications include ASA 81 mg daily, lisinopril 5 mg daily, furosemide 40 mg daily, spironolactone 25 mg daily, and simvastatin 40 mg at bedtime.
What changes to her diuretic regimen would be most appropriate?
a. Increase furosemide to twice daily dosing.
b. Increase furosemide and change to intravenous formulation.
c. Add metolazone.
d. Discontinue furosemide and start hydrochlorothiazide.
e. No change
9. Which of the following statements regarding vasodilators in HF is correct?
a. The combination of hydralazine and isosorbide dinitrate has equivalent effects on mortality and repeat hospitalization to those of an ACE inhibitor in HF.
b. Nesiritide has been shown to lower intracardiac filling pressures in patients with decompensated HF but has not been shown to decrease mortality.
c. A dihydropyridine calcium channel blocker such as amlodipine or nifedipine is a reasonable alternative to an ACE inhibitor in HF.
d. Nitroprusside is a recombinant form of atrial natriuretic peptide.
e. Nitroglycerin acts by binding to nitric oxide reductase, causing venodilation.
10. You are asked to see a 56-year-old female with a history of cardiac sarcoidosis and severe LV dysfunction. She is treated with lisinopril, metoprolol, spironolactone, and furosemide. One week ago, she developed an acutely painful swollen ankle. She was seen by her family doctor and treated with colchicine and naproxen. She returned to the same doctor after 2 days and was started on amoxicillin and clavulinic acid. She has since developed worsening exertional breathlessness and presents to the emergency department in decompensated HF.
Which of her medications is most likely to have contributed to worsening HF?
a. Naproxen
b. Colchicine
c. Amoxicillin
d. Clavulinic acid
e. Metoprolol
Answers
1. Answer E: Although some studies have suggested a reduction in hard endpoints with aerobic exercise in HF, the large HF-ACTION trial did not show any effect on mortality. Other lifestyle measures in HF have not been studied in large clinical trials.
2. Answer E: No specific fluid restriction is suggested in the care of HF patients without refractory volume overload or hyponatremia.
3. Answer C: An ACE inhibitor should be used in all patients with HF complicating a MI. There is good evidence to continue a beta-blocker in this case. In the absence of significant LV systolic dysfunction, there is no established role for spironolactone here.
4. Answer B: The ACC gives a IIa recommendation for the use of ARBs as a first-line alternative to ACE inhibitors in patients with HF and reduced LVEF. Side effects of these agents are not related to increased bradykinin levels; this is a potential mechanism of the side effects of ACE inhibitors such as dry cough. In ACE inhibitor-intolerant patients, use of an ARB is a class I recommendation without qualification regarding the use of other agents. Rates of angioedema are considerably lower with ARBs than with ACE inhibitors.
5. Answer C: Eplerenone differs from spironolactone in that it has higher specificity for the aldosterone receptor. As a result, gynecomastia is not an important side effect of eplerenone. Hypotension with or without symptoms such as lightheadedness can be a side effect of any antihypertensive agent. It remains important to monitor for hyperkalemia and renal dysfunction.
6. Answer E: The pharmacology of digoxin and its complications are important board exam subjects. Digoxin has both sympatholytic and parasympathomimetic effects, making statement E correct. Digoxin toxicity can be precipitated by a variety of electrolyte disturbances; these include hypokalemia, hypomagnesemia, and hypercalcemia. Digoxin decreases rates of repeat hospitalization in HF; the effect on mortality is probably neutral. Target serum digoxin levels should be 0.7 to 0.9 ng/mL. The direct action of digoxin is blockade of the Na+/K+ATPase, not downregulation of its gene expression.
7. Answer B: Beta-blockers have a class I indication in nonischemic (and ischemic) cardiomyopathies with asymptomatic LV systolic dysfunction. Eplerenone and spironolactone may soon have expanded indications to include functional class II patients, but current guidelines endorse their use only in functional class III and IV patients. Asymptomatic patients were not included in any of these trials. Nitroglycerin and furosemide would be indicated for symptoms acutely or chronically. There is no recommendation to routinely prescribe anticoagulation in this setting.
8. Answer B: Increasing diuretic dose and switching to intravenous formulation at the time of hospitalization for acute decompensation is the specific recommendation in the Heart Failure Society of America guidelines. Increasing furosemide to twice daily dosing and adding metolazone remain reasonable considerations, and discontinuing furosemide and starting hydrochlorothiazide, or no change, are clearly incorrect.
9. Answer B: Nesiritide is effective in lowering LV end-diastolic pressure, but the large ASCEND-HF trial did not show any difference in mortality. The VHeFT II study showed enalapril to be superior to the combination of hydralazine and isosorbide dinitrate. Calcium channel blockers are not recommended as first-line treatment for HF patients. Nitroprusside is a nitrate, not a natriuretic peptide hormone like nesiritide. Nitroglycerin is converted into nitric oxide which activates guanylate cyclase.
10. Answer A: Nonsteroidal anti-inflammatory medications are a common precipitant of HF exacerbations. Colchicine, amoxicillin, and clavulinic acid are not major contributors to HF decompensation. Metoprolol and other beta-blockers can worsen symptoms of HF at the time of initiation, but this is not a new medication for this patient.