13 Heart Failure Controversies

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From: Contemporary Cardiology: Cardiac Drug Therapy, Seventh Edition M. Gabriel Khan © Humana Press Inc., Totowa, NJ

13 Heart Failure Controversies

MANAGEMENT OF HEART FAILURE PRESERVED EJECTION FRACTIONS (HFPEF)

The prevalence of heart failure (HF) rises from 2% to 3% at age 65 to more than 50%

in persons older than age 80. Many of these patients have HFPEF. The condition is not uncommon in elderly women, most of whom have hypertension, diabetes mellitus, or both and often coronary heart disease (CHD). However, CHD more commonly causes systolic heart failure (SHF). Atrial fibrillation is common in the elderly, and ventricular rates even when not very rapid (120–140) may precipitate HF with a preserved ejection fraction (EF).

Is it preferable to adopt the term HFPEF rather than diastolic HF? Not all patients with HFPEF show definite diagnostic diastolic abnormalities. Controversies abound, however, among the experts.

Mauer et al. (1) stated that HF with normal ejection fraction (HFNEF) is preferred over the term diastolic heart failure (DHF) mainly because

• Doppler-derived diastolic parameters do not provide specific information on intrinsic pas- sive diastolic properties; thus, diastolic dysfunction cannot be diagnosed reliably by Dop- pler echocardiography.

• Delayed relaxation and/or stiffened passive properties may not be the unifying pathophys- iologic mechanisms in all patients who present with HF and normal EF.

Nonetheless, abnormal diastolic function is a common cause of HFPEF.

Oh et al. (2) criticized Mauer and colleagues and emphasized that diastolic HF is easily diagnosed by echocardiography in a patient with a preserved left ventricular (LV)EF with evidence of abnormal relaxation, decreased compliance, increased filling pressure, and normal LV dimensions. However, Oh et al. describe the situation that exists in most sophis- ticated diagnostic laboratories with highly trained echocardiographers and clinicians and that does not represent the real world of medicine.

The American College of Cardiology/American Heart Association (ACC/AHA) guide- lines of 2001 stated that it is difficult to be precise about the diagnosis of diastolic HF (3).

This difficulty still exists in 2007 and is unlikely to change substantially in the near future.

The incidence of this condition is stated to be approx 33% or more of all HF patients.

Allowing for diagnostic errors, the incidence is probably <25% for all patients with HFPEF.

More than 66% of HFPEF instances are represented by DHF.

The diagnosis of definite diastolic HF can be made if typical signs, symptoms, and

radiologic features of HF, as well as elevated brain naturietic peptide (BNP), are docu-

mented in the presence of normal LV systolic function within 1–2 d of the episode, in the

absence of valvular disease or atrial fibrillation and there is objective evidence of dias-

tolic dysfunction at echocardiographic assessment: EF > 50%; abnormal LV relaxation,

filling, diastolic distensibility, or stiffness and normal LV volumes.

(2)

The diagnosis of probable diastolic HF can be made by using the criteria of Vasan and Levy criteria (4). A study by Zile and colleagues (5) indicated that it is possible to make the diagnosis of definite diastolic HF provided that there is evidence of mild LV hypertrophy.

• The ACC/AHA guidelines of 2005 note the controversy by stating that there have been several proposed criteria by which clinicians and investigators may define HFPEF (6):

• The diagnosis is based on the finding of typical symptoms and signs of HF in a patient with a normal LVEF and no valvular abnormalities on echocardiography.

• A definitive diagnosis requires the finding of: an elevated LV filling pressure in a patient with normal LV volumes and contractility; usually the rate of ventricular relaxation is slowed (6).

• It is surprising that the magic number for normal EF is not stated in the guidelines; it would be wise to use >50% as a cutoff rather than 45%, allowing for errors in echo- cardiographic assessment.

• In addition, it is crucial to exclude other possible explanations or disorders that may present in a similar manner.

Differential diagnosis and mimics include:

• Incorrect diagnosis or incorrect measurement of EF. The echocardiographic assessment of EF is fraught with errors but remains a useful guide to diagnosis and management of systolic HF.

• Valvular disease.

• Pericardial constriction and left atrial myxoma are rare and do not genuinely represent HFPEF; in this setting there is simply restriction to ventricular filling.

• Episodic or reversible systolic HF, which is not uncommon.

• Severe hypertension can cause both systolic HF and HFPEF.

• Myocardial ischemia more commonly causes systolic HF but can cause a combination of both types of HF and rarely pure HFPEF.

• Cor pulmonale.

• Diastolic dysfunction of uncertain origin.

Age and the diseases listed appear to cause changes in crosslinking of intercellular connective tissue. The heart fills less and empties less, and the percentage ejected may be relatively normal but the stroke output and cardiac index are decreased; thus, the renin- angiotensin-aldosterone system (RAAS) is stimulated. Systolic dysfunction impairs the ability of the left ventricle to relax and fill at low pressure (7). Thus, systolic dysfunction is a principal cause of diastolic dysfunction (8).

Treatment

There are no tested proven therapies for HFPEF or for most patients who have DHF.

Importantly, the treatment of HFPEF is treatment of the cause. With systolic HF, medi- cations help considerably to improve outcomes versus DHF, in which medications are unproved except for symptomatic improvement enhanced by judicious diuretic therapy.

The following are the ACC treatment guidelines (6), with my additions in italics.

In the absence of randomized controlled trials (RCTs), the management of patients with HFPEF is based on the following:

• The judicious use of diuretics (class I) recommended to relieve symptoms.

• Beta-blockers decrease heart rate and the longer diastolic interval might improve ventric- ular filling (class II).

• Angiotensin-converting enzyme (ACE) inhibitors (class II) may be used to minimize symp-

toms of HF but with a level of evidence (C) that does not mean they are well-established

therapy.

(3)

• Digoxin receives a similar class IIb recommendation (level of evidence C).

• The main reliance is on improved control of blood pressure (BP), reduction in heart rate in patients with atrial fibrillation and aggressive management of CHD.

• There is no mention of the use of aldosterone antagonists. Spironolactone and eplerenone provide salutary effects on ventricular function and I strongly recommend their use as we await the results of RCTs. (See Chapters 7 and 12.)

• Caution: Because a decrease in preload exists, the overzealous use of preload-reducing agents, including loop diuretics, ACE inhibitors, and nitrates, may cause hemodynamic and clinical deterioration. Usually dosages are 50–75% lower than those used for systolic HF, and diuretics except eplerenone 25 mg may not be required except during the symp- tomatic congestive phase that may last a few weeks. Loop diuretics are contraindicated in pericardial diseases and restrictive cardiomyopathy and relatively contraindicated in hyper- trophic cardiomyopathy (HCM) and in hypertensive HCM of the elderly with impaired ven- tricular relaxation (9).

P

REVENTION IS

C

RUCIAL

• Aggressive drug therapy is important to control BP, as is prevention of left ventricular hypertrophy (LVH): low-dose ACE inhibitors, beta-blockers, and diuretics including 25 mg eplerenone or spironolactone prevent and cause regression. Calcium antagonists and alpha-blockers do not.

D

RUG

T

REATMENT OF

D

IASTOLIC

HF

IS

G

OVERNED BY THE

U

NDERLYING

D

ISEASE

: H

YPERTENSIVE

LVH

AND

C

HRONIC

CHD

1. A diuretic at low dosage: approx 50% lower than for systolic HF, e.g., furosemide 40 mg daily for a few days, then 20 mg daily during the congestive phase, and then on alternate days.

2. An ACE inhibitor, also at low dosage, approx 50% less than for systolic HF, can speed the rate of LV relaxation and improve diastolic function.

3. A beta-blocker low dose to decrease heart rate, which allows a longer diastolic filling phase.

Beta-blockers are necessary to influence the underlying disease favorably, e.g., ongoing ischemia in CHD. Ischemia contributes to diastolic dysfunction. However, beta-blockers slow the rate of LV relaxation and may impair diastolic function. Also they can be danger- ous in patients with chronotropic incompetence. Consideration should be given to inser- tion of a permanent pacemaker in those with chronotropic insufficiency who are otherwise not able to tolerate beta-blockade

4. Spironolactone and eplerenone can favorably modify myocardial collagen and the devel- opment of fibrosis and have a role in therapy. RCTs are under way. A 25-mg dose of spiro- nolactone or eplerenone 25–50 mg is advisable (see cautions for use in Chapter 7 and later in this chapter).

5. Digoxin is not generally recommended except for patients with atrial fibrillation to control rate and in patients with mixed SHF and HFPEF (see digoxin discussion in Chapter 12).

• HCM, restrictive infiltrative disease, constrictive pericarditis, amyloid, and other dis- eases in the absence of hypertension and LVH are difficult to treat with drugs: hypoten- sion and deterioration may be precipitated by diuretics, nitrates, and ACE inhibitors;

calcium antagonists have no role (10).

DIGOXIN IS NOT USEFUL FOR HFPEF: TRUE OR FALSE?

The guidelines have demoted digoxin to a class IIa recommendation (6). Ahmed et al.

(11) did a comprehensive post hoc analysis of the randomized controlled Digitalis Inves-

tigation Group trial (n = 7788) (12) and focused on 5548 patients: 1687 with digoxin levels

drawn randomly at 1 mo, and 3861 placebo patients, alive at 1 mo.

(4)

Findings: Digoxin at 0.5–0.9 ng/mL reduced mortality and hospitalizations in all HF patients, including those with HFPEF. At higher serum concentration, digoxin reduced HF hospitalization but had no effect on mortality or all-cause hospitalizations.

Importantly, digoxin is the only HF agent that does not decrease BP. Systolic BP < 100 mmHg is a common problem in clinical practice when proven agents (ACE inhibitor, diuretic, and beta-blocker) are combined. Digoxin provides salutary effects including reduction in mortality and hospitalizations for recurrent HF in patients with SHF class III–IV with enlarged LV provided levels are maintained at 0.5–0.9 ng/mL.

IS CHARM-PRESERVED A CLEAR STUDY OF HFPEF?

It must be emphasized that the EF should be >50% determined within 3 d of the episode of HF to be diagnostic of HFPEF. Thus, Candesartan in Heart Failure Assessment in Reduc- tion of Mortality (CHARM)-Preserved (13), which studied patients with EF > 40%, was not a true study of patients with HFPEF. An EF of 40–45% cannot be assumed to be normal LV systolic function.

• CHARM-Preserved randomized 3025 patients with EF > 40%. There was an 18% reduc- tion in the number of patients with investigator-reported hospitalizations for HF with candesartan (230 versus 279, p = 0.017), but there was no decrease in deaths (13).

• The primary end points of cardiovascular disease (CVD) death and hospitalization were not met (11%, p = 0.051; total hospitalization, 912 patients versus 922, p = 0.99). Thus, CHARM-Preserved is flawed.

DOES AN ACE INHIBITOR

COMBINED WITH AN ARB IMPROVE OUTCOMES?

The Valsartan Heart Failure Trial (Val-HeFT) compared valsartan (160 mg/d) + ACE inhibitor with placebo in approx 5000 patients with class II–III HF. There was a 28%

reduction in hospitalization for HF, but no reduction in mortality (14).

• Importantly, in 794 patients given an ACE inhibitor, a beta-blocker, and valsartan, there was a significant increase in mortality (129 versus 97 deaths; hazard ratio [HR], 1.42; 95%

confidence interval [CI], 1.09–1.85, p = 0.009), compared with 806 patients treated with an ACE inhibitor, a beta-blocker and placebo. Beta-blocker therapy is an integral compo- nent of HF therapy. An angiotensin receptor blocker (ARB) added to ACE inhibitor/beta- blocker therapy is not advisable. Extensive RAAS blockade appears to be harmful (14).

CHARM-Added (15) used the same entry criteria as Val-HeFT: mainly patients with class III HF and virtually no class IV patients.

• Enalapril, lisinopril, captopril, and ramipril were given. The mean daily doses of these drugs in the candesartan group were 16.8, 17.7, 82.2, and 6.8 mg, respectively; in the placebo group they were 17.2, 17.7, 82.7, and 7.3 mg, respectively.

• The trialists stated that they thought 96% of patients in each group were receiving optimum doses of ACE inhibitor at randomization.

• In addition, a subclinical low dose of ACE inhibitor was used. The trial results, therefore are not clinically acceptable.

• 483 (38%) patients in the candesartan group and 538 (42%) in the placebo group experi- enced the primary outcome of cardiovascular death or admission to hospital for CHF (unadjusted HR 0.85; 95% CI, 0.75–0.96; p = 0.011).

• Cardiovascular death in the treated group was 302 (23.7%) versus 347 (27.3%) in the

placebo group, a nonclinically significant reduction of 12.5%.

(5)

• In patients treated with beta-blockers in addition to an ACE inhibitor, 175 (25%) of 702 died in the candesartan group, and 195 (27%) of 711 died in the placebo group (HR, 0.88;

95% CI, 0.72–1.08; p = 0.22) (15). Perhaps the combination is not as dangerous as was observed with valsartan, but harmfulness cannot be excluded.

• Hyperkalemia was observed in 3% of treated patients and 1% in the placebo arm; caution is required.

• The combination of an ACE inhibitor and an ARB is not advisable. Also, patients should not receive aldosterone antagonists when this combination is used because the incidence of hyperkalemia is significantly increased. It is more beneficial to add an aldosterone antagonist to an ACE inhibitor than to add an ARB.

ALDOSTERONE ANTAGONISTS: USEFUL BUT HARMFUL?

In the Randomized Aldactone Evaluation Study (RALES), spironolactone 12.5–37.5 mg daily added to ACE inhibitor therapy for patients with class IV HF symptoms or class III symptoms and recent hospitalization decreased the risk of death from 46% to 35%

(30% relative risk reduction) over 2 yr, with 35% reduction in HF hospitalization (16).

Serum creatinine was below 2.5 mg/dL (220 µmol/L) in the main trial.

• Eplerenone in patients with LVEF < 40% and clinical evidence of HF or diabetes mellitus within 14 d of myocardial infarction (MI) decreased mortality from 13.6% to 11.8% at 1 yr (17). Hyperkalemia occurred in 5.5% of those treated with eplerenone compared with 3.9%

in the placebo arm. Hyperkalemia occurred in 10.1% versus 4.6% of patients with esti- mated creatinine clearance < 50 mL/min.

My advice is as follows:

• In HF patients treated with an ACE inhibitor or ARB, aldosterone antagonists should be used with caution and with close monitoring of estimated glomerular filtration rate (GFR) in patients with a serum creatinine of 1.2–1.4 mg/dL (104–124 µmol/L), especially in diabetics and the elderly; it is advisable to obtain an estimated GFR. A 24-h urine collec- tion for creatinine clearance is rarely required, but some caution is needed because the estimated GFR can be somewhat erroneous in patients over age 70 and in blacks.

• Aldosterone antagonists should not be combined with ACE inhibitors in patients with esti- mated GFR < 50 mL/min. Monthly monitoring of K

⁺

is advisable if used when the estimated GFR range is 50–60 mL/min, a finding that is common after age 70.

• It is now recognized that an aldosterone antagonist should not be combined with an ACE inhibitor in patients with more severe renal dysfunction: a serum creatinine > 1.5 mg/dL (132 µmol/L) or estimated GFR < 50 mL/min. Hyperkalemia is more frequent in type 2 diabetics with hyporeninemic hypoaldosteronism, and the combination of an aldosterone antagonist and an ACE inhibitor or an ARB is particularly harmful in the setting of signif- icant renal impairment.

HEART FAILURE IN BLACKS: DO DIFFERENCES EXIST?

• Heart failure has a 50% higher incidence in the black population than is observed in the general population.

• ACE inhibitors have not shown as great a benefit in black patients with HF as found in the white population. Also, angioedema is more common in black versus white patients treated with ACE inhibitors.

• In the Veterans Administration Heart Failure Trial (VHeFT), hydralazine combined with

isosorbide dinitrate was not shown to be significantly effective in reducing cardiac mor-

tality in mainly white patients (see Chapter 12).

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An RCT of 1050 black patients with class III/IV HF was conducted using isosorbide dinitrate and hydralazine along with a standard HF regimen. Treatment resulted in a 43%

decrease in total mortality, which led to premature termination of the trial. Time to first hospitalization was improved (18).

The combination of isosorbide dinitrate and hydralazine has a role in white patients with HF if ACE inhibitors and ARBs are contraindicated.

SHOULD THE ROLE OF NATRIURETIC PEPTIDES BE EXPANDED?

The peptide is produced by both ventricles in response to increased wall stretch, volume overload, and hypertrophy. B-type natriuretic peptide (BNP) or amino-terminal pro-BNP has found a niche as an aid to the diagnosis of HF (19).

• However, is this test overused? Are costs justified? Is this test needed if there is a clear clinical diagnosis with radiologic confirmation of HF, and a cause for HF is identified?

The test is most useful in patients who present with acute dyspnea of unknown etiology, and particularly in those with probable HFPEF.

Consider the following:

• Age and female gender increase BNP levels.

• Levels decrease with obesity because BNP is metabolized by adipose tissue.

• A decrease in body mass index is accompanied by an increase not only in BNP but also in NT-pro-BNP.

• Decreased excretion from the kidney contributes to the elevated BNP in HF patients with renal dysfunction, especially in patients with an estimated GFR < 60 mL/min. Impor- tantly, >75% of individuals older than age 70 have an estimated GFR < 55 mL/min, and HF is a disease of the elderly.

• In studies of BNP, an estimated one in four study participants had a BNP level of 100–500 pg/mL, and approx 33% of these patients were subsequently determined to not have HF (19).

There are probably no false-positive BNP levels. If the BNP is elevated, consider the following:

• HF.

• A pulmonary-related problem: pulmonary embolism or other conditions causing right ven- tricular stretch increase levels.

• The kidneys are not eliminating it, particularly in the elderly patient.

• Severe myocardial ischemia may cause higher levels.

• Anemia: higher levels are found in anemia.

• Reduction in body mass.

• Assay types and demographics.

The Systolic Heart Failure Treatment Supported by BNP (STARS-BNP) trial indicated that a BNP-guided strategy of HF management resulted in improved clinical end points (20,21), but costs must be justified.

IS NESIRITIDE A USEFUL ADDITION?

Patients who cannot be weaned from intravenous to oral therapy may require continu-

ous infusion of dobutamine or nesiritide. The use of the peptide nesiritide is limited to

patients who are hospitalized with acute decompensated HF. Nesiritide may cause renal

dysfunction (22), however, and appears to increase mortality (23). Also, the drug causes

hypotension, which limits its use.

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ARE STATINS RECOMMENDED FOR PATIENTS WITH HEART FAILURE?

The PROVE IT-TIMI 22 study randomized 4162 patients, stabilized after acute coro- nary syndrome (ACS), to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 d after randomization was determined during a mean follow-up of 24 mo. Levels of BNP were measured at baseline (24).

• Atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (1.6% versus 3.1%; HR, 0.55; 95% CI, 0.35–0.85; p = 0.008) independently of a recurrent MI or prior history of HF (24).

• The risk of HF increased steadily with increasing quartiles of BNP (HR, 2.6; 95% CI, 1.2–

5.5; p = 0.016 for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (>80 pg/mL), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR, 0.32; 95% CI, 0.13–0.8; p = 0.014) (24).

• Scirica and colleagues concluded that intensive statin therapy reduces the risk of hospi- talization for HF after ACS with the most gain in patients with elevated levels of BNP (24).

The evidence for high-dose statin therapy inpatients with nonischemic HF, however, awaits the results of further studies. In a study by Sola et al. (25), the use of atorvastatin in patients with nonischemic HF improved LVEF and attenuated adverse LV remodeling.

The effects on soluble levels of several inflammatory markers with atorvastatin suggest, in part, mechanisms by which statins might exert their beneficial effects in nonischemic HF (25).

Ramasubbu and colleague point out that there are several ongoing large-scale clinical outcome trials in HF patients (Controlled Rosuvastatin Multinational Trial in Heart Fail- ure [CORONA], Gruppo Italiano per lo Studio della Sopravvivenza nell’Insufficienza Cardiaca [Italian Group for the Study of Survival in Cardiac Insufficiency; GISSI-HF], and RosUvastatiN Impact on Ventricular Remodelling Lipids and Cytokines [UNIVERSE]).

These should provide a more definitive answer to the expanded use of statins in HF patients (26).

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18. Taylor AL, Ziesche S, Yancy C, et al. Combination of isosorbide dinitrate and hydralazine in blacks with heart failure. N Engl J Med 2004;351:2049–2057.

19. Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:l6l.

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24. Scirica BM, Morrow DA, Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 Study. J Am Coll Cardiol 2006;47:2326–2331.

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