Heart Failure

[mazen]

Acute vs. chronic heart failure
The clinical manifestations depend on the speed with which the syndrome
develops. Acute heart failure is often used to describe the patient with
acute-onset dyspnea and pulmonary edema, but it can also apply to cardiogenic
shock where the patient is hypotensive and oliguric. Compensatory
mechanisms have not yet become operative.
Acute deterioration may be a consequence of myocardial infarction
(MI), arrhythmia, or acute valve dysfunction (e.g., endocarditis).
Systolic vs. diastolic heart failure
Most patients with heart failure have impaired LV systolic function: there
is a failure of the LV to eject blood.
However, there is a group of patients with signs and symptoms of heart
failure but apparently preserved LV systolic function. These patients are
said to have diastolic heart failure: there is an abnormality in the ability of
the LV to fi ll in diastole. This may be transient (e.g., acute ischemia) or
persistent (restrictive or infi ltrative cardiomyopathy, or LVH).
Right vs. left heart failure
Right and left heart failure refers to whether the patient has either predominantly
systemic venous congestion (swollen ankles, hepatomegaly)
or pulmonary venous congestion (pulmonary edema), respectively.
These terms do not necessarily indicate which ventricle is most seriously
affected.
Fluid retention in heart failure is due to a combination of factors: reduced
GFR (glomerular fi ltration rate) and activation of the renin–angiotensin–
aldosterone system and sympathetic system. However, there are causes for
swollen ankles other than heart failure (gravitational disorder, e.g., immobility;
venous thrombosis or obstruction; varicose veins; hypoproteinemia,
e.g., nephrotic syndrome or liver disease; or lymphatic obstruction; see
also Box 5.1).
High-output vs. low-output heart failure
A variety of high-output states may lead to heart failure, e.g., thyrotoxicosis,
Paget’s disease, beriberi, and anemia. High-output failure is characterized
by warm extremities and normal or widened pulse pressure.
In contrast, low-output states are characterized by cool, pale extremities,
cyanosis due to systemic vasoconstriction, and low pulse volume.
The mixed venous oxygen saturation (a marker of the ability of the
heart to deliver oxygen to the metabolizing tissues) is typically abnormally
low in low-output states but normal or even high in high-output states

Conditions mimicking heart failure
• Obesity
• Chest disease, including lung,
diaphragm, or chest wall
• Venous insuffi ciency in lower limbs
• Drug-induced ankle swelling (e.g.,
dihydropyridine calcium blockers)
• Drug-induced fl uid retention
(e.g., NSAIDs)
• Hypoalbuminemia
• Intrinsic renal disease
• Intrinsic hepatic disease
• Pulmonary embolic disease
• Depression and/or anxiety
disorders
• Severe anemia
• Thyroid disease
• Bilateral renal artery stenosis

[mazen]

Diuretics in heart failure
Diuretics are used for the symptomatic treatment of fl uid overload (either
pulmonary congestion or peripheral edema). With the exception of aldosterone
antagonists, there are no randomized, controlled trials that have
shown any prognostic benefi t. However, they do improve symptoms and
may slow the progression of LV remodeling.
Loop diuretics (furosemide, bumetanide, and torsemide) are the most
effective. Use the lowest dose that controls symptoms effectively.
If there is insuffi cient response to diuretic, a combination of a loop diuretic
and a thiazide diuretic can be used (see Box 5.4). Thiazides reduce
magnesium absorption and hypomagnesaemia may occur with prolonged
use.
Potassium-sparing diuretics (amiloride and triamterene) used alone do
not achieve a net negative Na+ balance, as Na+ retention in HF occurs
proximal in the tubule. They should be used with caution in conjunction
with ACE inhibitors and spironolactone (may result in hyperkalemia).
In “diuretic resistance,” the effectiveness of loop diuretics may decrease
with worsening HF. This is due to a variety of factors, including reduced
bioavailability of oral drug, excessive dietary salt intake, compensatory
hypertrophy of the distal tubule increasing Na+ reabsorption, other drugs
(e.g., NSAIDs or COX-2 inhibitors), and reduced renal perfusion pressure
by volume depletion.
This can be managed by switching to IV diuretics (perhaps by continuous
infusion) and/or adding in a thiazide. In hospitalized patients, treatments
such as IV dopamine at low dose and even short-term infusion of nesiritide
(human BNP) have been shown to enhance effects of diuretics.
Table 5.4 Diuretics dosages for treating heart failure
Loop diuretics Initial dose Maximum dose
Furosemide 20–40 mg qd or bid Titrate to achieve dry
weight (up to 400 mg daily)
Bumetanide 0.5–1 mg qd or bid Titrate to achieve dry
weight (up to 10 mg daily)
Torsemide 10–20 mg qd or bid Titrate to achieve dry
weight (up to 200 mg daily)
Thiazides
Hydrochlorothiazide 25 mg qd 50–75 mg daily
Metolazone 2.5 mg qd 10 mg daily
Indapamide 2.5 mg qd 2.5 mg daily


ACE inhibitors for heart failure
Angiotensin-converting enzyme (ACE) inhibitors signifi cantly improve the
survival and symptoms and reduce hospitalization of patients with moderate
and severe HF and LV systolic dysfunction. ACE inhibitors should
be used as fi rst-line therapy for patients with a reduced LV systolic function
(ejection fraction [EF] <40%–45%). The absolute benefi t is greatest in
patients with most severe heart failure.
In the absence of fl uid retention, ACE inhibitors should be given fi rst. In
patients with fl uid retention, diuretics may be added.
Furthermore, the dosage of ACE inhibitors should be up-titrated to the
dosages shown to be effective in large, controlled trials in heart failure,
and not titrated on the basis of symptomatic improvement alone (see
Table 5.5).
Asymptomatic patients with a documented LV systolic dysfunction benefi
t from long-term ACE inhibitor therapy. Large trials (SOLVD Prevention
Study, SAVE, and TRACE) have shown that asymptomatic patients, but
with left ventricular dysfunction, will have less development of symptomatic
heart failure and hospitalizations for heart failure.
ACE inhibitors may prevent further deterioration of LV function and
attenuate further cardiac dilatation. However, they do not consistently
reduce cardiac size.
Starting an ACE inhibitor
• Review diuretic dose and avoid excessive diuresis before treatment.
• Consider giving fi rst dose at night to minimize the hypotensive effect.
• Start with a low dose and build up to target levels.
• Stop treatment if there is a substantial deterioration in renal function
(see Table 5.6).
• Avoid NSAIDs and potassium-sparing diuretics.
• Check BP and Chem7 1–2 weeks after each dose increment and at
6-month intervals.
• Low BP (systolic <90 mmHg) is acceptable if patient is asymptomatic.

B-Blockers for heart failure
B-Blockers were once contraindicated in patients with heart failure.
However, several studies (Carvedilol studies, Merit-HF, COPERNICUS;
see Chapter 15) have shown that they are effective in reducing the risk of
sudden cardiac death (of the order of 30%).
B-Blockers are recommended for all patients with HF, whether due to
ischemic heart disease or not and irrespective of the severity of LV dysfunction
(NYHA classes II to IV).
The effect does not appear to be a class effect, and only metoprolol,
carvedilol, and bisoprolol can be recommended in HF.
B-Blockers should be initiated under careful physician monitoring, as
there may be an initial deterioration in heart failure symptoms. The drugs
are started at a low dose and up-titrated to target over a period of weeks
or months (see Table 5.7).
Starting a B-blocker (see Table 5.8)
• Patients should be on an ACE inhibitor if possible.
• Heart failure symptoms should be relatively stable before initiation.
• Start with a low dose and titrate up to target every 1–2 weeks if the
preceding dose was tolerated.
• Monitor patient for symptoms and signs of HF, bradycardia, and
hypotension.
• If symptoms worsen, increase dose of diuretics or ACE inhibitor
initially. The B-blocker dose may need to be decreased transiently.
• If patient is hypotensive, reduce dose of vasodilators and reduce dose
of B-blockers if necessary.
Table 5.7 Titration scheme for B-blockers
Drug First dose Increments Target dose
Carvedilol 3.125 mg bid 6.25, 12.5, 25, 50 50 mg daily
Bisoprolol 1.25 mg daily 2.5, 3.75, 5, 7.5, 10 10 mg daily
Metoprolol succinate 12.5 mg daily 25, 50, 100, 200 200 mg daily
NB: Carvedilol maximum dosage is 25 mg bid if there is severe heart failure. For patients with
mild–moderate heart failure, maximum dosage is 50 mg bid if weight is above 85 kg; otherwise
maximum dosage is 25 mg bid.


Angiotensin II receptor antagonists
for heart failure
Angiotensin II receptor blockers (ARBs) are often used in those patients
who do not tolerate an ACE inhibitor because of cough. In patients with
heart failure, ARBs are as effective as ACE inhibitors in reducing mortality
and morbidity.
One study (ValHeft II) showed that the combination of an ACE inhibitor
and valsartan was better than either drug alone. However, this benefi t was
reversed in patients also taking a B-blocker. This adverse effect was not
seen in the CHARM-Added Trial, which used the ARB candesartan.
When combined with ACE inhibitors, ARBs reduce HF hospitalizations.
In patients with heart failure and preserved LV systolic function (i.e.,
patients with diastolic dysfunction), the ARB candesartan reduces hospitalization
for HF.

Aldosterone receptor antagonists in heart failure
Aldosterone levels are not reduced by ACE inhibitors, and these raised
levels produce myocardial fi brosis and predispose to arrhythmias.
In the RALES study, spironolactone (an aldosterone receptor antagonist)
produced a 30% reduction in total mortality of patients with severe
CHF (NYHA classes III and IV) compared with placebo.
Long-term usage of spironolactone is associated with gynecomastia,
impotence, and menstrual irregularities. Newer agents have less of these
antiandrogenic and progesterone-like effects.
Eplerenone was evaluated in EPHESUS (Eplerenone Post Acute
Myocardial Infarction Heart Failure Effi cacy and survival Study). Patients
with LVEF <40% were randomized to eplerenone or placebo 3–14 days
after acute MI. Eplerenone produced a signifi cant (15%) reduction in mortality.
Gynecomastia, breast tenderness, and impotence were no different
in the two groups.
Starting spironolactone
• Consider whether a patient is in severe heart failure (NYHA III–IV)
despite ACE inhibition and diuretics.
• Check serum K+ (<5·0 mmol/L) and creatinine (<2.8 mg/dL).
• Start 25 mg spironolactone daily (see Table 5.10).
• Check serum K+ and creatinine after 4–6 days.
• If at any time serum K+ >5–5.5< mmol/L, reduce dose by 50%. Stop it
if serum K+ >5.5 mmol/L.
• If after 1 month symptoms persist and K+<5.5 mmol/L, increase to
50 mg daily. Check serum potassium/creatinine after 1 week.
• If endocrine-related side effects of spironolactone are observed,
change to eplerenone.

Digoxin in heart failure
Digoxin is very useful controlling heart rates in supraventricular arrhythmias,
including AF, in patients with chronic HF. Its role in patients with
sinus rhythm, however, is less clear.
Two large digoxin withdrawal trials (RADIANCE and PROVED) demonstrated
that patients from whom digoxin was withdrawn were more
likely to be admitted with worsening HF.
The DIG trial enrolled 6800 patients with classes I to III HF with a mean
EF of 28%. This showed that there was no decrease in overall mortality in
the group given digoxin. There was a trend to a decrease in mortality due
to pump-failure, balanced by a slight increase in non-pump failure related
cardiac deaths. Digoxin reduced the number of hospitalizations for HF
signifi cantly.
Overall the clinical trials support the use of digoxin in patients in sinus
rhythm with mild to moderate HF for symptomatic control. Trough levels
should be maintained between 0.5–1.0 ng/mL.
Contraindications are signifi cant bradycardia; heart block, WPW.

Vasodilators in heart failure
Vasodilators are not a particularly effective method to improve the natural
history of chronic HF, but are useful for dealing with acute decompensation.
They are also useful in patients intolerant of both ACE-I and ARBs.
Nitrates are primarily venodilators, but are potent coronary vasodilators
making them useful in ischemic HF. Isosorbide dinitrate is the only
nitrate formulation that has been shown to increase exercise tolerance,
and in combination with hydralazine, prolongs survival in patients with
HF. The addition of hydralazine appears to attenuate nitrate tolerance by
acting as a reducing agent.



Phosphodiesterase inhibitors in heart failure
In large-scale placebo-controlled trials, selective type III phosphodiesterase
inhibitors (PDEI) are associated with an increase in mortality.
Individual agents like milrinone and enoximone produce sustained inotropic
and vasodilator effects when administered intravenously and are
useful in the short term in decompensated HF.
Positive inotropic support
Inotropes (e.g., dobutamine) can be used to limit very severe episodes of
heart failure or as a bridge to transplantation in end-stage heart failure.
While longer term inotropic therapy may improve a patient’s quality of
life, they also increase mortality and are therefore not recommended.
Antiplatelet agents and anticoagulants
There has been much controversy regarding the use of aspirin in patients
with CHF. As a general rule, NSAIDs are avoided because of their fl uidretaining
and renotoxic properties. It is also thought that the benefi cial
effect of ACE inhibitors is reduced by these drugs.
Generally, patients with ischemic heart disease as their underlying etiology
should be treated with aspirin.
Formal anticoagulation with warfarin is indicated for patients with heart
failure and atrial fi brillation (paroxysmal or persistent). It is also often used
in those with demonstrated LV thrombus or patients with very large LV
cavities where it is thought that the risk of LV thrombus formation is high.
There are, however, no randomized data to support this use.
Miscellaneous drugs for heart failure
Patients with CHF may require drug treatment for systems other than
the heart:
• Gout is a common problem. Acute fl are-ups should be treated with
colchicine followed by allopurinol once the acute event has settled.
• While most calcium channel antagonists are avoided in patients with
CHF, amlodipine has a neutral effect on prognosis and can be used for
the treatment of hypertension or angina.
• Anemia is frequently seen in CHF patients. Correction of this with IV
iron and erythropoietin has been shown to improve symptoms
In V-HeFT-II, enalapril was shown to be superior to hydralazine and
isosorbide dinitrate except in African Americans, where the opposite was
found: this is still under investigation.
Nesiritide (human brain natriuretic peptide, hBNP) infusion has been
shown to improve hemodynamics and clinical status in patients with
decompensated HF, and is less arrhythmogenic than dobutamine. It is in
trial as a subcutaneous injection for chronic HF.
Neutral endopeptidase inhibitors with or without intrinsic ACE-inhibitor
activity are being explored for the treatment of chronic HF as they prevent
the inactivation of ANP and BNP; promising small trials have been
followed by disappointing results in larger scale studies.
Although all three classes of calcium antagonists are effective arteriolar
vasodilators, none produces a sustained improvement in HF. All except
amlodipine appear to worsen symptoms.



Device therapy for heart failure
Clearly, patients fulfi lling the standard indications for permanent pacemaker
implantation should undergo this procedure. Wherever possible,
dual-chamber systems should be implanted to maintain atrioventricular
synchrony.
Implantable cardiac defi brillators (ICD)
ICDs are devices capable of recognizing ventricular arrhythmias (VT or
VF) and delivering a DC shock to terminate them. They are implanted in
the same way as pacemakers.
Several studies have shown that patients with impaired LV function benefi
t from their implantation. The MADIT II trial showed a 30% improvement
in survival in patients with ischemic heart disease and an ejection
fraction of <30%.
The SCD-HeFT trial enrolled patients with ischemic and with
nonischemic cardiomyopathies with an LVEF <35%. There was a similar
reduction in mortality in ischemic and nonischemic cardiomyopathy
patients who received an AICD compared with those patients receiving
amiodarone.
Cardiac resynchronization (CRT)
Many patients with CHF have bundle branch block (BBB) patterns on their
ECG, in particular LBBB. A wide QRS duration is associated with a worse
outcome in patients with CHF. LBBB results in delayed depolarization and
contraction of the lateral LV free wall, which is thought to contribute to
disease progression. Biventricular pacemakers are able to reduce this ventricular
dysynchrony by pacing the LV via a cardiac vein.
Current indications for implantation include severe symptoms (NYHA
III or IV), a broad QRS complex (>130 ms), and impaired LV function
(LVEF <35%). These indications alone, however, do not necessarily predict
patients who will benefi t from resynchronization. Current research is
assessing the value of using noninvasive imaging techniques (tissue Doppler
and MRI) to identify true inter- and intraventricular dysynchrony.
Studies in patients with HF undergoing cardiac resynchronization (CRT)
have shown an improvement in quality of life, improved exercise capacity
(6-minute walk test), and, in one study, improved survival.
Biventricular devices can now be combined with ICDs to further
improve the outlook of these patients.
The devices can be diffi cult to implant, require close and careful follow-
up, and are expensive, which has reduced their widespread use.


Surgery for heart failure
Valve surgery
Patients with valve disease as the source of their heart failure should be
considered for valve replacement surgery. This is discussed more fully in
Chapter 4 on valve disease.
Coronary artery bypass grafting (CABG)
Ischemic heart disease is the most common cause of heart failure in developed
countries. In some cases, these patients will have evidence of either
stress-induced ischemia or hibernation (muscle that has reduced function
due to reduced blood supply but is still viable).
Revascularizing these patients can lead to an improvement in cardiac
function.
Transplantation
Cardiac transplantation is reserved for those patients with end-stage
heart failure (see Table 5.11). It is a major undertaking for the patient,
who must be willing to undergo intensive treatment and be emotionally
capable of withstanding the uncertainties that occur before and after
transplantation.
There are a number of contraindications, listed below.
Contraindications for heart transplantation
• Persistent alcohol or drug abuse
• Treated cancer with remission and <5 years follow-up
• Systemic disease with multiorgan involvement
• Infection
• Fixed high pulmonary vascular resistance
Despite problems with rejection and complications of immunosuppressive
therapy (infection, hypertension, renal failure, malignancy) the 5-year survival
is of the order of 70%–80% with many patients returning to work.

Assist devices
Because of the lack of organ donors for cardiac transplantation, much
interest has been shown in the development of left ventricular assist
devices (LVAD) and mechanical hearts. LVADs are automatic pumps that
take over the work of the heart. They have been used as a bridge to transplantation
and as a bridge to recovery in those with potentially reversible
causes for their heart failure (e.g., post-viral).
The next stage up from these large devices is the implantation of a
permanent artifi cial heart. An example is the Jarvik 2000, which has been
successfully been implanted in a relatively small number of patients.