1

IV NTG and nitroprusside

(a mixed arterial and venous dilator) are also used in hospitalized patients with acute

HF exacerbations. The role of these vasodilators in HFpEF is not well studied.

OTHER INOTROPIC AGENTS

IV dopamine and dobutamine, which are sympathomimetics, and milrinone

(phosphodiesterase inhibitor) are used in acutely decompensated HF (see Chapter

17, Shock). They are associated with an increased incidence of mortality but

frequently used short term for ADHF. Both dobutamine and milrinone are used

chronically in some stage D patients.

Initial positive hemodynamic effects during the first few weeks to months of

therapy are followed by increased mortality with continued therapy when compared

with placebo. This is related to proarrhythmic effects. Inotropic drugs are

contraindicated in HFpEF.

CALCIUM-CHANNEL BLOCKERS

Amlodipine, felodipine, isradipine, nifedipine, and nicardipine are examples of

dihydropyridine calcium-channel blockers with arterial vasodilating effects.

Compared with the nondihydropyridine calcium-channel blockers (verapamil and

diltiazem), they have minimal negative inotropic properties. Only amlodipine

72 and

felodipine

73 have been documented to be safe in HF, but only a small subset of

patients with nonischemic dilated cardiomyopathy actually

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p. 272

had a beneficial effect of improved survival with amlodipine.

72 Verapamil and

diltiazem are safe to use in HFpEF and may improve symptoms by reducing HR and

allowing more time to fill the ventricle, but should be avoided in patients with

HFrEF due to their negative inotropic effects.

IMPLANTABLE CARDIOVERTER-DEFIBRILLATOR

Ventricular arrhythmias are common in patients with HF ranging from asymptomatic

ventricular premature beats to sustained ventricular tachycardia, ventricular

fibrillation, and sudden cardiac death (SCD). SCD is highest in patients with severe

HF symptoms, or stage D HF.

1 Patients with previous cardiac arrest or documented

sustained ventricular arrhythmias have a higher risk of future events. An implantable

cardioverter-defibrillator (ICD) implantation is indicated for secondary prevention

of SCD in HF patients who have good clinical function and prognosis and low EF

and experience syncope of unknown origin, as well as in a small subset of HF

patients who are awaiting a planned cardiac transplant. The ACC/AHA guidelines

1

also recommend ICD for primary prevention of SCD in patients with nonischemic

dilated cardiomyopathy or ischemic heart disease at least 40 days after MI, EF of

35% or less despite optimal drug therapy, with mild to moderate symptoms of HF

and in whom survival with good functional capacity is otherwise anticipated to

extend beyond 1 year (see Case 14-5, Question 4, for detailed discussion).

CARDIAC RESYNCHRONIZATION

CRT is a therapeutic approach for treating patients with ventricular dyssynchrony

(defined as a QRS duration of at least 120 ms). Selected HF patients benefit from

simultaneous pacing of both ventricles (biventricular pacing), or of one ventricle in

patients with bundle branch block. The rationale for using CRT is that dyssynchrony

causes ventricular remodeling and worsens HF. CRT can be used alone or with an

ICD device. Several clinical trials with CRT or CRT-D 74–77

(cardiac

resynchronization defibrillator therapy) have demonstrated improvements in HF

functional status, survival, and reduction in hospitalizations. The approved indication

for cardiac CRT-D includes patients with NYHA class II or ischemic class I HF,

with an EF of less than 30% and a QRS duration of longer than 130 ms, and left

bundle branch block. These indications are based on results

75 which showed a

significant reduction in HF events among patients with mild HF symptoms with CRTD compared with ICD alone. Current guidelines

1 support the use of CRT in patients

with NYHA class II, III or ambulatory IV symptoms on GDMT, LVEF of 35% or

less, and LBBB with a QRS ≥150 ms (see Case 14-6, Questions 1 and 2).

LEFT VENTRICULAR ASSIST DEVICES

A left ventricular assist device (LVAD) is a battery-operated, mechanical pump that

is surgically implanted to maintain the pumping ability of the heart. Clinical trials

using LVADs have shown improvement in survival and quality of life. For patients

with end-stage HF, LVADs are used as a bridge to transplant or as destination

therapy, which is permanent device implantation for patients who are not candidates

for a transplant.

The landmark trial REMATCH78

(Randomized Evaluation of Mechanical

Assistance for the Treatment of Congestive Heart Failure) found that end-stage HF

patients who received an LVAD (HeartMate XVE) had a 52.1% chance of surviving

1 year, compared with a 24.7% survival rate for patients who received optimal

medical therapy. At 2 years, the survival was 23% for the LVAD patients versus 8%

for those receiving medical therapies. However, these survival rates were much

lower than those seen with transplantation. Advances in technology led to the

introduction of the second-generation devices, notably HeartMate II, which was

approved as a bridge to transplant in 2008.

79

In January 2010, the HeartMate II

(continuous flow), a smaller device, was approved for destination therapy. In a headto-head comparison with the first-generation HeartMate XVE (pulsatile flow), 1- and

2-year survival rates were 68% and 58% with HeartMate II versus 55% and 24%

with HeartMate XVE.

80 Adverse events were less frequent with the continuous-flow

device and patients reported significant improvements in their quality of life.

Recently, a new novel pump called HeartWare left ventricular assist device (HVAD)

was tested in patients awaiting cardiac transplantation with refractory and advanced

HF. This device is small and can be directly implanted into the pericardial sac. The

nonrandomized ADVANCE trial

81

(Evaluation of the HVAD for the Treatment of

Advanced Heart Failure) enrolled 140 patients who received HVAD compared with

499 patients who received an LVAD. The primary end points were survival and

success rates at 180 and 360 days after implantation. At 180 days the survival was

92.0% for the HVAD group and 90.1% for the control group ( p < 0.001). There was

less bleeding and fewer infections reported with HVAD; however, the incidence of

stroke was higher. New clinical trials are being designed and conducted to evaluate

adverse events between HVAD and HeartMate II. Until further improvements are

implemented and demonstrated, cardiac transplantation remains the gold standard for

the treatment of end-stage HF.

NEW THERAPIES IN HFREF

Ivabradine

There is considerable evidence of an association between elevated HRs (HRs >80

beats/minute [bpm]) and increased risk of mortality in patients with HF. The HF

trials with β-blockers demonstrated increased mortality with elevated baseline

resting heart rates (RHR) >90 bpm.

82,83 Post hoc analysis of CHARM84 showed that

increased RHR was an independent predictor of mortality regardless of LV function

or use of β-blockers. A subsequent meta-analysis of HF trials

85 showed an

association between the magnitude of HR reduction and survival benefit.

Ivabradine is a selective I

f

(“funny current”) inhibitor which lowers HR by acting

on the sinoatrial node. In 2010, the Systolic Heart Failure Treatment With the I

f

Inhibitor Ivabradine Trial (SHIFT)

86 provided evidence for the benefit of HR

lowering in patients with HF. SHIFT randomized 6,558 patients with symptomatic

HF to ivabradine versus placebo. Patients had an EF ≤35%, normal sinus rhythm

with a HR of ≥70 bpm, and at least one hospitalization for HF within the previous

year. In addition to background treatment, which generally included a β-blocker,

patients received either ivabradine to maintain a RHR between 50 and 60 bpm, or

placebo. During a median 23 months of follow-up, patients in the ivabradine group

had an 18% decrease in risk for CV death or hospitalization (hazard ratio, 0.82; p <

0.0001). Ivabradine significantly reduced the risk of hospitalization for worsening

HF and death due to HF, but did not have a significant effect on all-cause mortality.

Ivabradine was well tolerated with relatively few adverse events, although

significantly more than placebo. The most common adverse events were bradycardia

and visual disturbances.

In April 2015, the FDA approved ivabradine (Corlanor) for symptomatic chronic

HF with LVEF ≤35%, to reduce the risk of hospitalization for worsening HF in

adults. Because ivabradine did not reduce all-cause mortality, its broader application

in clinical practice will emerge as more evidence becomes available.The 2016

ACC/AHA/HFSA update on 2013 HF guidelines notes that ivabradine can be

beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class

II–III) stable chronic HFrEF (≤35%) who are receiving maximal GDMT, including a

β-blocker at maximum tolerated dose, and in sinus rhythm with a heart rate of greater

than or equal to 70 bpm at rest. It received a class IIa recommendation, level of

evidence B-R.

5

ANGIOTENSIN RECEPTOR-NEPRILYSIN INHIBITOR

The NP hormones are responsible for both natriuresis and diuresis and are broken

down by the neutral endopeptidase neprilysin,

p. 272

p. 273

which also degrades angiotensin II. Several neprilysin inhibitors (ecadotril,

candoxatril, omapatrilat) have been developed to target this pathway in order to

increase concentrations of NPs. Unfortunately, lack of efficacy and side effects led to

discontinuation of their development. A new drug sacubitril/valsartan (Entresto) has

shown improved outcomes with few adverse effects in patients with HFrEF.

Sacubitril/valsartan is an angiotensin receptor-neprilysin inhibitor (ARNI), a unique

combination with an ARB (valsartan) and a neprilysin inhibitor (sacubitril). Because

neprilysin also breakdowns angiotensin II, a neprilysin inhibitor should be given in

combination with a RAAS inhibitor. Sacubitril/valsartan provides a dual mechanism

of action in HF by inhibiting the renin–angiotensin–aldosterone axis and augmenting

several endogenous NPs. This mechanism has not been addressed by other HF

therapies.

This was tested in a randomized, double-blind trial “Prospective comparison of

Angiotensin Receptor neprilysin inhibitors with Angiotensin converting enzyme

inhibitors to Determine Impact on Global Mortality and Morbidity in Heart Failure”

(PARADIGM-HF)

83

that compared sacubitril/valsartan (400 mg daily) to enalapril

(20 mg daily) in patients with a LVEF <35% and elevated BNP levels, almost all of

whom were in NYHA class 2 to 3. At baseline, most patients in both groups were

receiving the recommended pharmacologic treatment for HFrEF. At 3.5 years of

follow-up, there was a significant reduction in the primary outcome of CV death or

HF hospitalization in the sacubitril/valsartan group (21.8%) versus the enalapril

group (26.5%). Patients receiving sacubitril/valsartan had lower rates of

hyperkalemia, renal dysfunction, and cough, but higher rates of hypotension. Fewer

patients in the sacubitril/valsartan group required treatment intensification and use of

advanced therapies (inotropes, assist devices, cardiac transplantation) when

compared with enalapril.

ACEIs have had a class I recommendation based on their magnitude of CV

mortality prevention (18%) in HF. The finding that sacubitril/valsartan has a superior

effect on CV mortality compared to enalapril lends support that an ARNI could

replace ACEI and ARBs in patients with HFrEF who remain symptomatic despite

being on optimal GDTM. However, it should be noted that fewer patients in both

groups had CRT or ICD therapy compared to contemporary treatment in the United

States. This is the first study which used substitution of an ACEI rather than an addon strategy in chronic HF. Even though the ARNI clearly met the criteria for clinical

superiority when compared with conventional therapy, the benefits have to be

weighed against the side effect profile. In clinical practice, the frequency of the side

effects (hypotension, angioedema) may be more pronounced due to a more

complicated patient population. The drug was approved by FDA in 2015 for NYHA

class I–IV. Post-marketing surveillance will determine the safety of

sacubitril/valsartan. A cost–benefit analysis would also be of use.

The 2016 ACC/AHA/HFSA update on 2013 HF guidelines recommends an ARNI

in patients with chronic symptomatic HFrEF (NYHA class II or III) who tolerate an

ACE inhibitor or ARB, in order to further reduce morbidity and mortality. It has a

class I, level of evidence B-R recommendation.

5 The guidelines also state that ARNI

should not be combined with ACE inhibitors and a 36-hour washout period is

required between these two therapies to minimize the risk of angioedema.

Given the positive results of the Paradigm trial, the benefit of sacubitril/valsartan

in HFpEF patients is being evaluated in an ongoing study: “Efficacy and Safety of

LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure

Patients With Preserved Ejection Fraction (PARAGON–HF).”

88 The primary end

point is to determine whether sacubitril/valsartan can reduce CV death or total HF

hospitalizations in patients with HFpEF.

PATIENT EVALUATION

Signs and Symptoms

CASE 14-1

QUESTION 1: A.J., a 58-year-old man, is admitted with a chief complaint of increasing SOB and an 8-kg

weight gain. Two weeks before admission, he noted the onset of dyspnea on exertion (DOE) after one flight of

stairs, orthopnea, and ankle edema. Since then, his symptoms have worsened. He has also noted episodic bouts

of paroxysmal nocturnal dyspnea (PND), and he has been able to sleep only in a sitting position. A.J. reports a

productive cough, nocturia (two to three times a night), and edema.

A.J.’s other medical problems include a long history of heartburn, a 10-year history of osteoarthritis,

depression, and poorly controlled HTN. A family history of diabetes mellitus is also present.

Physical examination reveals dyspnea, cyanosis, and tachycardia. A.J. has the following vital signs: BP,

160/100 mm Hg; pulse, 90 bpm; and respiratory rate, 28 breaths/minute. He is 5 feet 11 inches tall and weighs

78 kg. His neck veins are distended. On cardiac examination, an S3

gallop is heard; the point of maximal

impulse is at the sixth intercostal space, 12 cm from the midsternal line. His liver is enlarged and tender to

palpation, and a positive hepatojugular reflux is observed. He is noted to have 3+ pitting edema of the

extremities and sacral edema. Chest examination reveals inspiratory rales and rhonchi bilaterally.

The medication history reveals the following current medications: hydrochlorothiazide (HCTZ) 25 mg every

day, ibuprofen 600 mg 4 times a day (QID), ranitidine 150 mg every night at bedtime, and citalopram 20 mg

every day. He has no allergies and no dietary restrictions.

Admitting laboratory values include the following:

Hematocrit, 41.1%

White blood cell count, 5,300/μL

Sodium (Na), 132 mEq/L

Potassium (K), 3.2 mEq/L

Chloride (Cl), 100 mEq/L

Bicarbonate, 30 mEq/L

Magnesium, 1.5 mEq/L

Fasting blood sugar, 100 mg/dL

Uric acid, 8 mg/dL

Blood urea nitrogen (BUN), 40 mg/dL

Serum creatinine (SCr), 0.8 mg/dL

Alkaline phosphatase, 44 units/L

Aspartate aminotransferase, 30 units/L

BNP, 1,364 pg/mL (normal <100 pg/mL)

Thyroid-stimulating hormone, 2.0 microunits/mL

The chest radiograph shows bilateral pleural effusions and cardiomegaly. What signs, symptoms, and

laboratory abnormalities of HF does A.J. exhibit? Relate these clinical findings to the pathogenesis of the

disease and to left-sided or right-sided HF.

Left-sided ventricular dysfunction primarily causes pulmonary symptoms, whereas

right-sided ventricular dysfunction causes signs of systemic venous congestion.

Although LV failure usually develops first, many patients present with signs of

biventricular failure. The signs and symptoms of both left-sided and right-sided

ventricular dysfunction are summarized in Table 14-4.

LEFT-SIDED HEART FAILURE (LEFT VENTRICULAR DYSFUNCTION)

Weakness, fatigue, and cyanosis result from decreased CO and compromised tissue

perfusion. If the LV is not emptied completely, pulmonary congestion occurs.

Dyspnea (labored or uncomfortable breathing) on exertion, a productive cough, rales

(crackles in the lung during auscultation), pleural effusions on chest radiograph, and

hypoxemia all result from pulmonary congestion. Pulmonary symptoms are

aggravated in the reclining position. Orthopnea or SOB in the supine position is

quantified by the number of pillows the patient must lie on to sleep comfortably. A.J.,

for example, could sleep only sitting upright. PND is characterized by SOB that

awakens the patient from sleep and is alleviated by an upright position.

p. 273

p. 274

Table 14-4

Signs and Symptoms of Heart Failure

Left Ventricular Failure Right Ventricular Failure

a

Subjective

DOE

SOB

Orthopnea (2–3 pillows)

PND, cough

Weakness, fatigue, confusion Peripheral edema

Weakness, fatigue

Objective

LVH Weight gain (fluid retention)

↓BP

EF <40%b Neck vein distension

RALES, S3

gallop rhythm Hepatomegaly

Reflex tachycardia Hepatojugular reflux

↑BUN (poor renal perfusion)

a

Isolated right-sided failure occurs with long-standing pulmonary disease (cor pulmonale) or after pulmonary

hypertension.

bEjection fraction normal in patients with diastolic dysfunction.

BP, blood pressure; BUN, blood urea nitrogen; DOE, dyspnea on exertion; EF, ejection fraction; LVH, left

ventricular hypertrophy; PND, paroxysmal nocturnal dyspnea; SOB, shortness of breath.

Cardiac dilatation is observed on chest radiography as an enlarged cardiac

silhouette. The point of maximal impulse corresponds to the apex of the LV and is

visualized as an external pulsation on the left side of the chest. It is displaced

laterally and downward from its normal location at the fifth intercostal space, less

than 10 cm from the midsternal line. An S3 gallop rhythm denotes a third heart sound

often heard in close proximity to the second heart sound (closing of the aortic and

pulmonary valves) in HF. Rapid filling of the ventricles causes the S3 sound and, in

an adult, usually indicates decreased ventricular compliance. In patients with mitral

valve regurgitation, an S3 heart sound is common and denotes systolic dysfunction

and elevated filling pressure. Tachycardia is caused by compensatory increases in

sympathetic tone.

Weight gain and edema reflect sodium and water retention resulting from

decreased renal perfusion (see Pathogenesis section). As RBF and GFR decrease, a

disproportionate amount of BUN may be retained. This phenomenon is termed

prerenal azotemia and is detected by an elevated BUN to SCr ratio of greater than

20:1. A.J. has a ratio of greater than 40:1. Prerenal azotemia also can be caused by

dehydration and overuse of diuretics. Frequency of urination at night (nocturia) is

caused by improved perfusion of the kidney when the patient is lying down.

RIGHT-SIDED HEART FAILURE (RIGHT VENTRICULAR

DYSFUNCTION)

The signs and symptoms of right ventricular dysfunction are related either to

hypervolemia, valvular disease, or pulmonary HTN. The overall effect is elevation

in central venous pressure.

Dependent edema results from increased venous and capillary hydrostatic

pressure, causing a redistribution of fluid from the intravascular to interstitial spaces.

Ankle and pretibial edema are common findings after prolonged standing or sitting

because fluid tends to localize in the dependent portions of the body secondary to

gravitational forces. Sacral edema can be present in patients at bed rest. Edema is

subjectively quantified on a 1+ (minimal) to 4+ (severe) scale. A.J. has 3+ pitting

edema.

Hepatomegaly, hepatic tenderness, and ascites (fluid in the abdomen) arise from

hepatic venous congestion and increased portal vein pressure. Metabolism of drugs

highly dependent on the liver for elimination can be impaired by both the retrograde

venous congestion of the liver from right-sided HF and the decreased arterial

perfusion of the liver from left-sided HF. Congestion of the gastrointestinal tract

makes the patient anorectic.

Neck vein distension, primarily seen as internal jugular venous distension, denotes

an elevated jugular venous pressure.

How high the neck veins are distended while the patient is lying down and how

much the patient’s head has to be raised before the jugular venous distension

disappears gives the clinician a rough estimate of the patient’s central venous

pressure. Jugular distension in centimeters is measured as the vertical distance from

the top of the venous pulsation down to the sternal angle. Neck vein distension of less

than 4 cm when the patient is lying with the head elevated at a 45-degree angle is

considered normal for an average, healthy adult. Applying pressure to the liver can

cause further distension of the neck veins if hepatic venous congestion is present.

This phenomenon is termed hepatojugular reflux.

EJECTION FRACTION MEASUREMENT

CASE 14-1, QUESTION 2: Does A.J. have LVSD?

SOB, crackles on auscultation, neck vein distension, edema, and nearly all of

A.J.’s other signs and symptoms provide some important clues about the nature of the

underlying cardiac abnormalities; however, they are limited in evaluating structural

abnormalities. Some of these symptoms can be confused with other disorders,

especially reduced exercise intolerance, which is often a gradual process that

patients may fail to recognize and report. An enlarged heart on a chest radiograph

increases the suspicion of LVSD, but this finding can be absent in some patients with

LVSD and present in others with normal LV function. Some patients may be

asymptomatic with structural abnormalities.

The most useful method to diagnose HF with LVSD is by measuring the LVEF. All

patients with suspected HF should have an EF measured before beginning therapy

because the treatment strategies between HFrEF and HFpEF differ. Two-dimensional

echocardiography coupled with Doppler flow studies (Doppler echocardiogram) is

the diagnostic test of choice for measuring EF. This procedure uses sound waves to

visualize and measure ventricular wall thickness, chamber size, valvular function,

and pericardial thickness. EF is estimated based on changes in ventricular chamber

size between diastole and systole. This method of EF measurement is not as

technically accurate as that provided by ventriculography, but the procedure is more

comfortable for the patient and the correlation of the measured EF to that of the other

methods is acceptable.

Radionuclide left ventriculography (also called a multiple gated acquisition scan)

uses radiolabeled technetium as a tracer to measure LV hemodynamics. Although this

method is the most accurate measurement of EF, it is moderately invasive because it

requires venipuncture and radiation exposure. In addition, radionuclide scanning

does not provide information on the architecture of the left ventricle. Magnetic

resonance imaging and computed tomography are useful in evaluating ventricular

mass but do not provide EF data.

p. 274

p. 275

Subsequently, A.J. underwent an echocardiogram. The results were reported as

left ventricular hypertrophy (LVH) with mild to moderate depression of EF (30%–

40%). Because he has systolic dysfunction and classic congestive signs, he fits the

criteria for having congestive HF.

STAGES OF HEART FAILURE AND NEW YORK HEART ASSOCIATION

CLASSIFICATION

CASE 14-1, QUESTION 3: What stage of HF does A.J. exhibit according the ACC/AHA criteria? How

severe is A.J.’s disability according to the NYHA functional classification of HF?

The ACC/AHA staging scheme and the NYHA functional classification are

summarized in Figure 14-1.

4,29

Because A.J. has symptoms of HF and structural changes in cardiac architecture,

he is in ACA/AHA stage C. On admission, A.J. is in NYHA functional class III as

evidenced by a need to sleep upright and an inability to undertake even minimal

physical activity. It is important to recognize that HF can progress very slowly in

some patients and very rapidly in others. A patient with MI could move from stage A

to stage C.

PREDISPOSING FACTORS

CASE 14-1, QUESTION 4: What factors contributed to the cause of A.J.’s HF?

Age, HTN, MI, diabetes, tachycardia-induced cardiomyopathy, valvular heart

disease, and obesity are well-established major risk factors associated with the

development of HF. Other risk factors associated with HF are smoking, excessive

intake of alcohol, dyslipidemia, anemia, and chronic kidney disease.

89 There is

interest in biochemical and genetic markers that are associated with HF. CAD, and in

particular MI, is considered to be the most significant risk factor for HF in the

elderly. During the past decades, there has been an increase in the incidence of HF

after MI due to the increased survival after MI.

90

A.J. is especially vulnerable to HF because of his poorly controlled HTN, which

increases afterload. HTN can lead to LVH, which is a compensatory response to

increased afterload. LVH is associated with a higher risk of HF, especially in

younger individuals.

8 The lifetime risk for individuals developing HF with BP of at

least 160/90 mm Hg is double that for those with BP less than 140/80 mm Hg.

91

Preventive strategies directed toward earlier and more aggressive BP control can

reduce the incidence of HF by almost 50% and its associated mortality as well.

8

NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND SODIUM

CONTENT

Nonsteroidal antiinflammatory drugs (NSAIDs) exert their antiinflammatory effects

by inhibiting prostaglandins. Blocking prostaglandins leads to sodium reabsorption

and counteracts the beneficial effects of diuretics and ACEIs. Ibuprofen used for

A.J.’s arthritis contributes to sodium overload. Epidemiologic studies indicate that

NSAIDs exacerbate HF symptoms, resulting in hospitalizations for HF.

92–94

ACC/AHA practice guidelines recommend avoiding NSAIDs whenever possible in

patients with HF.

1

Another potential source of excess sodium is in IV formulations. Sodium chloride

is often used as a diluent for IV drug administration. Some parenteral antibiotics,

particularly nafcillin and ticarcillin, have high sodium content. Most prescription and

nonprescription drug labels carry a disclosure of sodium content.

A.J.’s HTN and HF are both poorly controlled and he has gained 8 kg. His clinical

presentation (orthopnea, dyspnea, SOB, lower extremity edema, elevated jugular

venous pressure) clearly indicates fluid overload. This could be a result of high-dose

ibuprofen use. His HCTZ should be replaced by a loop diuretic to enhance diuresis.

Also, an ACEI should be added to the current regimen for BP control. Once he is

euvolemic, the addition of a β-blocker before discharge should be considered.

Lowering the dose or preferably discontinuing all NSAIDs might reduce sodium

retention and allow ACEI therapy to be more effective. Acetaminophen is an

alternative for treating his osteoarthritis.

DIET

It is possible that A.J.’s diet contains a considerable excess of sodium from foods

such as canned soups and vegetables, potato chips, or overuse of salt at mealtime.

Dietary supplements and sports drinks can also be rich sources of sodium. He should

follow a controlled-sodium (2–3 g/day) diet. If salt substitutes are used, he should be

warned that they are high in potassium and could cause hyperkalemia if used

concurrently with potassium supplements, an aldosterone antagonist, or other

potassium-sparing diuretics.

Drug-Induced Heart Failure

CASE 14-1, QUESTION 5: What are the basic mechanisms by which drugs can induce HF, and how can an

understanding of these mechanisms be predictive of drugs to avoid in A.J.?

Drug-induced HF is mediated by three mechanisms: inhibition of myocardial

contractility (negative inotropic agents and direct toxins), proarrhythmic effects, or

expansion of plasma volume (Table 14-5). The latter category includes drugs that act

primarily on the kidney (to either alter RBF or increase sodium retention) or those

that increase total body sodium and water because of their high sodium content.

The most recognized negative inotropic agents are the β-blockers, which decrease

myocardial contractility and slow the HR. Both of these factors can compromise CO.

Other well-documented negative inotropic drugs include the nondihydropyridine

calcium- channel blockers (verapamil and diltiazem), and some antiarrhythmic agents

(disopyramide, flecainide, and dronedarone). The anthracyclines (daunorubicin and

doxorubicin) have a direct, dose-related cardiotoxicity that can be minimized by

limiting total cumulative doses to 500 mg/m2

.

95,96

(See Chapter 94, Adverse Effects of

Chemotherapy and Targeted Agents.) Cocaine and alcohol are cardiotoxins when

used chronically in large quantities or after an overdose. Drugs that increase the

incidence of arrhythmias will worsen HF if the abnormal rhythm compromises

cardiac functioning or output.

Drugs that promote sodium and water retention include NSAIDs, certain

antihypertensive drugs, glucocorticoids, androgens, estrogens, and licorice. Weight

gain, peripheral and pulmonary edema has been observed in patients with

pioglitazone and rosiglitazone.

97 Worsening of HF appears to be dose-dependent and

presumed to be at least partly caused by fluid retention. As a consequence, the

package inserts for pioglitazone and rosiglitazone recommend they not be

administered to patients with NYHA class III or IV HF and that they be used

cautiously in earlier stages of HF.

97 Saxagliptin has been also associated with an

increased risk of HF hospitalizations. The FDA has initiated an investigation to

further evaluate this risk.

98

TREATMENT

Therapeutic Objectives

CASE 14-1, QUESTION 6: What are the therapeutic goals in treating A.J.?

p. 275

p. 276

Table 14-5

Drugs that May Induce Heart Failure

Negative Inotropic Agents

β-Blockers

a Most evident with propranolol or other nonselective

agents

Less with agents with intrinsic sympathomimetic

activity (acebutolol, carteolol, pindolol); can also be

caused by use of timolol eye drops

Calcium-channel blockers

a Verapamil has most negative inotropic and AVblocking effects; amlodipine has least

Antiarrhythmics Disopyramide, flecainide, dronedarone

Direct Cardiotoxins

Cocaine, amphetamines Overdoses and long-term myopathy

Anthracycline cancer chemotherapeutic drugs Daunorubicin and doxorubicin (Adriamycin); dose

related; keep total cumulative dose <600 mg/m

2

Proarrhythmic Effects

Class IA, Class III antiarrhythmic drugs QT interval widening

Probable torsades de pointes

HF develops if disturbed rhythm compromises cardiac

functioning

Nonantiarrhythmic drugs Same mechanism as above

(See Crouch et al.

93

for a complete list) Often associated with drug interactions that inhibit

metabolism of the offending drug leading to higher than

desired plasma levels

Expansion of Plasma Volume

Antidiabetics

Na retention with pioglitazone and rosiglitazone

NSAID Prostaglandin inhibition; Na retention

Glucocorticoids, androgens, estrogens Mineralocorticoid effect; Na retention

Licorice Aldosterone-like effect; Na retention

Antihypertensive vasodilators (hydralazine, methyldopa,

prazosin, minoxidil)

↓Renal blood flow, activation of renin–angiotensin

system

Drugs high in Na+ Selected IV cephalosporins and penicillins

Effervescent or bicarbonate-containing antacids or

analgesics

Also liquid nutrition supplements

Unknown Mechanism

Tumor necrosis factor antagonists Multiple case reports of new-onset HF or exacerbation

of prior HF with etanercept and infliximab in patients

with Crohn’s disease or rheumatoid arthritis

aβBlockers and verapamil may be beneficial in diastolic HF. Carvedilol and metoprolol counteract autonomic

hyperactivity in systolic dysfunction.

AV, atrioventricular; HF, heart failure; IV, intravenous; Na, sodium; NSAID, nonsteroidal antiinflammatory drugs.

Cure is not a feasible therapeutic objective in patients with most forms of HF,

exceptions being patients who are candidates for cardiac transplantation or who have

certain forms of viral, alcohol-induced, or tachycardia-induced dilated

cardiomyopathy. The immediate objective for A.J. is to provide symptomatic relief

by reducing his complaints of SOB and PND, improve sleep quality, and increase

exercise tolerance. Parameters to measure success include reduced peripheral and

sacral edema, weight loss, slowing of the HR to less than 90 bpm, normalization of

BP, reduction of BUN, reduction of heart size on chest radiograph, decreased neck

vein distension, and loss of the S3 heart sound. Long-range goals are to improve

A.J.’s EF and quality of life including better tolerance of daily life activities, fewer

future hospitalizations, avoidance of side effects of his therapy, and ultimately, an

increased survival time. The achievement of these goals depends on the severity of

A.J.’s disease, his understanding of his disease, and his adherence to prescribed

interventions.

Diuretics

FUROSEMIDE AND OTHER LOOP DIURETICS

CASE 14-1, QUESTION 7: Bed rest and a 3-g sodium diet were ordered. The medical team decides to begin

furosemide for A.J. What is the rationale for using diuretics and what route, dose, and dosing schedule should

be used?

Excessive volume increases the workload of a compromised heart, and diuretics

are an integral part of therapy. This is especially true if volume overload is

symptomatic (dyspnea) as it is in A.J. Diuretics produce rapid symptomatic

improvement. They relieve pulmonary and peripheral edema within hours, whereas

the effects of ACEIs, β-blockers, and digoxin take days to months to be fully realized.

Diuretics, however, should not be used alone. Even when they are initially successful

in controlling symptoms and reducing edema, they are ineffective in maintaining

clinical stability for long periods without the addition of other drugs.

p. 276

p. 277

More importantly, activation of the RAAS and sympathetic nervous system in

response to diuresis could lead to HF progression.

All current guidelines recommend diuretic therapy, both acutely and chronically, if

clinical volume overload is evident, but further state that patients without edema can

be treated either intermittently or without diuretics.

1 Diuretics used on an intermittent

(as-needed) basis are titrated based on changes in weight gain, neck vein distension,

peripheral edema, or SOB. Patients with a good understanding of their disease can be

instructed to weigh themselves daily and start taking their diuretic if they gain more

than 1 to 2 lb in 1 day or 5 lb in 1 week or have leg or abdominal swelling. Diuretics

can be withheld as long as patients are at their target dry weight. In other cases,

diuretic-free intervals or weekends can be arranged. Even with these options, if the

patient has experienced volume overload at some time during the course of his or her

disease, either past or present, a diuretic should always be readily available.