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Clinical Cardiology: New Frontiers
New Therapeutic Options in Congestive Heart Failure
Part II
John McMurray, MD, FRCP, FESC; Marc A. Pfeffer, MD, PhD
T
he second part of this review deals with newer, nonneurohumoral, pharmacological approaches to congestive
heart failure (CHF) and nonpharmacological interventions in
heart failure patients with low left ventricular ejection fraction (LVEF) as well as potential treatments for CHF with
preserved LV systolic function. An algorithm summarizing
current, evidence-based therapy is also provided.
Experimentally, MMP inhibition reduces ventricular dilatation, although theoretical concerns remain about this therapeutic approach in patients.5
Antithrombotic Therapy
At present, there is no indication for warfarin in patients with
CHF in sinus rhythm, although there are obvious theoretical
reasons why antithrombotic therapy might be of benefit. The
place of aspirin in patients with coronary heart disease and
CHF has been challenged because of a possible interaction
with ACE inhibitors (whereby aspirin attenuates the effects of
ACE inhibitors).6 Unfortunately, the only outcome data
available to address this issue come from retrospective
analyses of the large ACE inhibitor trials. By far the largest
such analysis, pooling the 3 long-term postinfarction trials
with the 2 Studies of Left Ventricular Dysfunction (SOLVD)
trials, did not identify any significant treatment interaction
between aspirin and ACE inhibitors.6 Clopidogrel has an
antiplatelet effect comparable to that of aspirin but does not
interact with ACE inhibitors. To attempt to clarify the
optimum antithrombotic strategy in patients with CHF, the
Warfarin and Antiplatelet Therapy in Chronic Heart Failure
(WATCH) trial is comparing open-label warfarin (target INR
2.5 to 3.0) with double-blind aspirin (162 mg QD) or
clopidogrel (75 mg QD) in ⬇4500 patients with NYHA class
II to IV CHF and an LVEF ⱕ0.35. The primary end point is
a composite of death, nonfatal MI, and nonfatal stroke. Until
the results of WATCH are available, low-dose aspirin remains the antiplatelet agent of choice in patients with CHF
and atherosclerotic disease and should usually be coprescribed with an ACE inhibitor.
Anticytokine and Immunomodulating Therapy
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Cytokines, such as tumor necrosis factor, are produced in
increased amounts in a variety of tissues in patients with
CHF.1 Higher plasma cytokine concentrations are associated
with a worse prognosis.1 Experimentally, cytokines depress
myocardial contractility, cause myocyte death, and induce
heart failure.1 There is some evidence that anticytokine
interventions improve ventricular function and clinical status
in CHF.2,3 Two parallel trials (Randomized Etanercept North
American Strategy to Study Antagonism of Cytokines
[RENAISSANCE] and Research into Etanercept Cytokine
Antagonism in Ventricular Dysfunction Trial [RECOVER],
pooled as the Randomized Etanercept Worldwide Evaluation
[RENEWAL] program) examining the effect of the anti–
tumor necrosis factor agent etanercept on morbidity and
mortality in CHF, however, were recently discontinued because of futility (Table). Even more recently, a placebocontrolled phase II trial with an alternative anti–tumor necrosis factor chimeric monoclonal antibody, infliximab, was
stopped early because of higher rates of mortality and
hospitalization in the active-therapy group. Whether this
means that the cytokine hypothesis is invalid, that etanercept
and infliximab were the wrong drugs to use (or were used
incorrectly), that inappropriate patients were chosen, or that
the study designs were flawed is unknown.
Metabolic Interventions
The concept of CHF as a state of myocardial “energy
starvation” has been advocated by Katz.7 Ranolazine is a
partial fatty acid oxidation inhibitor that has demonstrated
efficacy in patients with angina pectoris.8 A morbidity/
mortality trial with ranolazine is being considered in CHF.
Matrix Metalloproteinase Inhibitors
The constitution of the cardiac extracellular matrix depends
on the balance in activity of matrix metalloproteinases
(MMPs) and tissue inhibitors of metalloproteinases.4,5 Endstage heart failure is associated with increased collagenase
activity (increased expression of MMP-1 and MMP-9) and
reduced expression of tissue inhibitors of metalloproteinases.5
Inotropic Therapy
Previous experience with orally administered inotropic agents
was unfavorable. Mortality was increased by drugs with
From the Clinical Research Initiative in Heart Failure, University of Glasgow, Scotland (J.M.), and the Cardiovascular Division, Brigham and Women’s
Hospital, Boston, Mass (M.A.P.).
This is Part II of a 2-part article. Part I appeared in the April 30, 2002, issue of the journal (Circulation. 2002;105:2099 –2106).
Both authors have received research support for clinical trials and honoraria for advisory boards, lectures, and other activities related to a number of
the pharmacological agents mentioned in this review.
Correspondence to Dr John J.V. McMurray, Clinical Research Initiative in Heart Failure, University of Glasgow, Wolfson Building, Glasgow G12
8QQ, Scotland. E-mail [email protected]
(Circulation. 2002;105:2223-2228.)
© 2002 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
2223
DOI: 10.1161/01.CIR.0000014771.38666.22
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Circulation
May 7, 2002
Ongoing and Planned Trials of Pharmacological Agents in CHF
Trial Acronym/Name
Treatment Comparisons*
Low-LVEF CHF
Neurohumoral
antagonists
Alternative CHARM
Placebo vs candesartan (ACE-I–intolerant
patients)
Added CHARM
Placebo vs candesartan (ACE-I–treated
patients)
COMET
Carvedilol vs metoprolol
ENABLE
Placebo vs bosentan
ECHOS
Placebo vs nolomirole
OVERTURE
Enalapril vs omapatrilat
SENIORS
Placebo vs nebivolol (patients⬎70 years old)
Cytokine antagonists
RENEWAL (RECOVER
and RENAISSANCE)†
Placebo vs etanercept
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Antithrombotic agents
WATCH
Warfarin vs aspirin vs clopidogrel
Inotropic agents
ESSENTIAL
Placebo vs enoximone (␤-blocker–treated
patients)
REVIVE
Placebo vs levosimendan
Metabolic agents
Ranolazine
Placebo vs ranolazine
Normal-LVEF CHF
Neurohumoral
antagonists
Adenosine Agonists
Selective A1 adenosine receptor blockade may induce diuresis
and natriuresis in CHF without reducing glomerular filtration
rate.12 As such, this therapeutic approach could be of great
value in CHF patients with azotemia, a problem group
growing in size.
Targeting Pharmacological Therapy?
Patients with CHF may currently be prescribed many different antifailure therapies (diuretics, ACE inhibitors,
␤-blockers, spironolactone, digoxin) and potentially several
more in the future. They may also take multiple treatments for
concomitant problems. This polypharmacy is a cause of
concern, not least from the adherence point of view. There is
growing interest in the notion of targeting therapy either on
the basis of biological mechanisms or genetic makeup.13–15
Differential ethnic or racial responses to therapy may reflect
either or both of these factors. This subject has been the focus
of much recent interest and the source of considerable
controversy, with suggestions that African Americans may
respond less well to ACE inhibitor therapy and better to
hydralazine and isosorbide dinitrate combination therapy.16,17
There is conflicting evidence about racial or ethnic background and response to ␤-blocker therapy.18 –20 The African
American Heart Failure Trial (A-HeFT) will randomize
⬇600 black men and women with NYHA class III to IV CHF
to placebo or hydralazine and isosorbide dinitrate and evaluate clinical status and ventricular function.
Tailoring Pharmacological Therapy?
Preserved CHARM
Placebo vs candesartan
I-PRESERVE
Placebo vs irbesartan
PEP-CHF
Placebo vs perindopril
SENIORS
Placebo vs nebivolol
*New treatments tested against conventional background therapy (diuretic,
digoxin, ACE inhibitor, ␤-blocker) unless stated otherwise.
†Recently terminated prematurely because of “futility.”
␤-agonist (xamoterol) and phosphodiesterase (PDE) inhibiting activity (including milrinone, enoximone, vesnarinone,
and flosequinan). The precise mechanism underlying this
increased hazard is unknown but may reflect a proarrhythmic
effect of agents of this type. There has, however, been some
renewed interest in the use of PDE inhibitors at lower doses
and in combination with ␤-blockers.9 PDE inhibition may
facilitate the introduction of ␤-blockade, and ␤-blockade may
protect against the proarrhythmic effect of PDE inhibition.
New phase III morbidity/mortality trials with enoximone are
beginning. Similarly, levosimendan, a calcium-sensitizing
agent, has shown promise in acute heart failure, and further
trials are planned.10
Anemia as a Treatment Target?
There has been much recent interest in the finding that a high
proportion of patients with CHF are anemic and that correction of this anemia with iron supplementation and erythropoietin may improve symptoms and morbidity.11 Larger-scale
clinical trails are being considered.
In addition to knowing which therapies to give to patients, we
also need to understand better how to decide how much
treatment patients require. Trials to date have usually had
“target” doses of treatment, and these are the doses also
recommended in clinical practice. It has recently been suggested that plasma natriuretic peptide concentrations might
provide a simple biochemical means of tailoring therapy.21
Intensification of treatment, aimed at normalizing natriuretic
peptide concentrations, might improve outcome. The recent
availability of simple, rapid assays for natriuretic peptides
and near-patient testing kits make such an approach a realistic
one in ordinary clinical practice. Further exploration of this
therapeutic strategy is undoubtedly needed.
Frameworks for Implementation of
Pharmacological Therapy
A consistent finding across many countries is that evidencebased therapy for CHF (and other conditions) is frequently
underused.22,23 Even when therapy is prescribed, patients may
be nonadherent, probably in part because they are poorly
educated about their condition and its treatment. For these
and other reasons, better approaches to the organized and
systematic care of patients with CHF have been sought.22,23 A
number of randomized trials have shown that nurse- or
pharmacist-led, multidisciplinary intervention can improve
medium-term outcomes in CHF (mainly by reducing hospital
admissions).22,23 Although to date, the greatest effect seems to
be seen with home-based interventions, a number of questions remain unanswered about these new approaches. What
McMurray and Pfeffer
is the optimal timing, intensity, and duration of such interventions? Do these interventions have long-term benefits?
Are they cost-effective? What are the exact mechanisms of
their beneficial effects? Are programs of this type associated
with improved survival?
Treatments Targeted at Coronary Artery
Disease and Its Consequences in CHF
Many, if not the majority, of patients with CHF have
underlying coronary artery disease, and as alluded to above,
existing, successful therapies may exert some of their beneficial effects by preventing new acute coronary events (see
Part I). There is also much interest in specifically addressing
recurrent ischemia and hibernation as therapeutic targets in
CHF. Pharmacological and interventional strategies are under
investigation.
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Pharmacological Reversal of
Myocardial Hiberation
A surprisingly high proportion of patients with CHF and
coronary artery disease have substantial areas of hibernating
myocardium.24 –26 The Carvedilol Hibernation Reversible
ISchaemia Trial: MArker of Success (CHRISTMAS) study is
attempting to determine whether the presence or absence of
hibernating myocardium predicts improvement in LVEF in
patients treated with carvedilol, ie, comparing the changes in
LVEF in the randomized nonhibernating versus hibernating
groups.26
Percutaneous and Surgical “Revascularization” in
Patients With Coronary Artery Disease and CHF
The safety and efficacy of myocardial revascularization,
especially surgical revascularization, is uncertain in CHF.25 A
number of small and uncontrolled series have suggested that
patients with large areas of viable myocardium may have a
low interventional risk and a large potential benefit from
revascularization.25 Consequently, 2 clinical trials are currently planned to address the impact of mechanical revascularization on outcome in such patients. One is the Heart
Failure Revascularization Trial–United Kingdom (HEARTUK) study, comparing percutaneous or surgical revascularization with optimal medical therapy, which will recruit
⬇800 patients and have a minimum follow-up of ⬇5 years
and a primary end point of all-cause mortality.25 A planned
US trial, Surgical Treatment for IsChemic Heart failure
(STICH), intends to address 2 hypotheses, one being the
revascularization hypothesis and the other an “LV reconstruction hypothesis.”27 The latter concerns the possibility that
surgical remodeling to achieve optimum LV shape and size
will also reduce morbidity and mortality in these patients.
Nonpharmacological Therapy for Low-LVEF
CHF: Exercise Training, Devices, and Surgery
Exercise Training
The short-term benefits of exercise training on functional
capacity, symptoms, neurohumoral activity, muscle performance, and baroreceptor function are well recognized. To
date, however, a definitive randomized trial studying the
New Therapeutic Options in CHF: Part II
2225
effect of exercise prescription on morbidity and mortality is
awaited.28
Biventricular (Multisite) Pacing
Patients with CHF often have abnormal electrical activation
of the myocardium, reflected as a prolonged PR interval
and/or QRS duration of the surface ECG. This electromechanical dyssynchrony may lead to suboptimal atrioventricular coupling, uncoordinated ventricular contraction, and
presystolic mitral regurgitation. Biventricular or multisite
pacing may “resynchronize” cardiac contraction and reduce
these abnormalities.29
Two relatively small, short-term trials, the MUltisite
STImulation in Cardiomyopathy (MUSTIC) and Multicenter
InSync Randomized Clinical Evaluation (MIRACLE) studies, have suggested that biventricular pacing can improve
symptoms and exercise capacity in patients with prolonged
QRS duration.30,31 Biventricular pacing may also lead to LV
reverse remodeling and a reduction in mitral regurgitation.
Long-term morbidity/mortality trials are either planned or
under way, including the Comparison Of Medical therapy
and Pacing ANd DefibrillatION in Chronic Heart Failure
(COMPANION) and CArdiac REsynchronisation in Heart
Failure (CARE-HF) trials.29
Implantable Cardioverter-Defibrillators
The Antiarrhythmics Versus Implantable Defibrillators
(AVID) and Multicentre Automatic Defibrillator Implant
Trial (MADIT) demonstrated that implantable cardioverterdefibrillators (ICDs) reduce mortality in patients with a low
LVEF and spontaneous or inducible ventricular arrhythmias.
Post hoc analysis of both trials suggested that the greatest
benefit was obtained in patients with the lowest LVEF.32,33
Other primary and secondary prevention studies with ICDs
are in general agreement with these findings, including the
MADIT-II trial, which was recently stopped prematurely
because of overwhelming evidence of a survival benefit in the
ICD group. Consequently, there is interest in the role of ICDs
in patients with CHF. One large study, the Sudden Cardiac
Death in Heart Failure Trial (SCD-HeFT), is comparing ICD
therapy with amiodarone treatment in ⬇2500 patients with
NYHA class II to III CHF and an LVEF ⱕ0.35. The primary
end point is all-cause mortality.32,33 COMPANION (see
above) is a 3-way comparison of medical therapy; medical
therapy plus biventricular pacing; and medical therapy,
biventricular pacing, and an ICD.29
Ventricular Assist Devices, Pumps, and Total
Artificial Hearts
There is renewed interest in mechanical support for, or
replacement of, the failing heart as a stand-alone therapy,
rather than as a bridge to transplantation. A detailed review of
this topic is beyond the scope of this review. The Randomized
Evaluation of Mechanical Assistance for Treatment of
Chronic Heart failure (REMATCH), however, showed that
implantation of an LV assist device can improve survival in
transplant-ineligible patients with end-stage CHF, but at the
expense of frequent infective and hemorrhagic complications.34 Recently, the first implantations of a newly config-
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May 7, 2002
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Treatment algorithm for patients with low-LVEF CHF. This treatment algorithm represents a summary of the main options available, and
the reader is referred to more extensive guidelines published elsewhere.51–53 Most patients will benefit from structured multidisciplinary
care. Lifestyle measures, such as smoking cessation, moderation of alcohol consumption, restriction of salt intake, healthy eating, and
regular exercise, are also of benefit. BVP indicates biventricular pacing; PCI, percutaneous coronary intervention; and LVAD, LV assist
device. (1) Diuretics are also indicated to control sodium and water retention. Combination therapy with a loop and a thiazide diuretic
(or metolazone) may be particularly effective in resistant cases. Patient self-adjustment of diuretic therapy should be taught and encouraged. (2) An angiotensin II type 1 receptor antagonist or blocker (ARB) can be used as an alternative to an ACE inhibitor if there is documented ACE inhibitor intolerance. (3) Some guidelines advocate the use of digoxin at an earlier stage. The Val-HeFT trial suggests that
the addition of an ARB may also be considered at this stage or an earlier stage in a patient intolerant of either an ACE inhibitor or a
␤-blocker. An ARB should not be combined with a ␤-blocker and an ACE inhibitor. (4) Other measures advocated by some include (a)
combination diuretic therapy [see (1)], (b) hemofiltration, (c) intravenous inotropic therapy, and (d) vasodilator therapy tailored according
to invasive hemodynamic measurements. (5) If there is intolerance, antiplatelet therapy should be given. (6) Amiodarone may be used
as an alternative to digoxin. (7) On the basis of the use of this agent in V-HeFT I and II and other studies. (8) On the basis of the apparent safety of this agent in PRAISE I and II. (9) Some advocate revascularization only when there is a substantial area of reversible myocardial ischemia. Some also advocate revascularization of symptomless ischemia when a substantial area of hibernating myocardium
can be demonstrated. Standard secondary preventive measures should be used in patients with coronary artery disease (smoking cessation, antiplatelet therapy, cholesterol lowering therapy, etc). (10) Nitrates are not of benefit in heart failure per se.
ured total artificial heart have taken place, using the device
not as a bridge to transplantation but rather as a mechanical
replacement for otherwise terminal CHF.
Molecular Approaches to Treatment: Cell and
Gene Therapy for CHF
Multiple recent reports suggest that there is an exciting
potential for gene therapy and cell therapy both in preventing
and in treating CHF.35–38 Similarly, new molecular pathways,
such as those that cause programmed cell death (apoptosis)
may also be important future treatment targets.38 – 40 At
present, however, these remain at an exploratory stage and
cannot be detailed here. They do, however, offer the possibility of revolutionizing therapy for CHF, for example, by
allowing fibrotic scar tissue to be replaced by new myocytes.
Current Recommendations for the Treatment
of Low-LVEF CHF
The Figure summarizes the current treatment of patients with
low-LVEF CHF, emphasizing the key role of ACE inhibitors
and ␤-blockers and highlighting some of the concomitant
problems that either reflect the cause of CHF (eg, coronary
heart disease) or arise as a complication of CHF (eg, atrial
and ventricular arrhythmias). This algorithm also maps the
focus of many of the investigational approaches summarized
in the preceding text.
Treatments for Preserved-LVEF CHF
As mentioned above, a substantial minority of patients with
the clinical syndrome of CHF appear to have “preserved” LV
systolic function (or at least a relatively normal LVEF).41,42
Sometimes these patients are considered to have diastolic
dysfunction, although there is no agreed-upon definition of
this, and the precise cardiac problem in these patients is
variable and frequently undefined.43– 46 Because many of
these patients have underlying atherosclerotic arterial disease,
hypertension, diabetes mellitus, LV hypertrophy, and atrial
fibrillation, however, it is hoped that inhibitors of the reninangiotensin-aldosterone system and sympathetic nervous system might be of benefit. Three morbidity/mortality trials
enrolling patients with normal LVEF CHF are under way, and
one is planned. One arm of the CHARM program (CHARM
McMurray and Pfeffer
Preserved) has fully recruited 3025 patients with an LVEF of
⬎0.40, randomized to placebo or candesartan.47 Another trial,
I-PRESERVE, is also planning to compare placebo with an
angiotensin-receptor antagonist (irbesartan) in patients with
CHF despite preserved LV systolic function. The Perindopril
for Elderly People with Chronic Heart Failure (PEP-CHF)
study intends to enroll ⬇1000 patients ⬎70 years of age with
CHF and no major LV systolic dysfunction (LVEF ⬍0.40 or
wall motion index ⬍1.4).48 Patients will receive double-blind
treatment with placebo or perindopril. The Study of the
Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors (SENIORS) trial is randomizing patients
ⱖ70 years of age with CHF, many of whom will have a
normal LVEF, to treatment with either placebo or nebivolol.
There will undoubtedly be more trials in this previously
neglected minority of patients with CHF.
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Challenges Ahead
Many other important questions cannot be discussed here in
detail. We still do not understand some of the most basic
aspects of drug development and trial design. Selecting a
dose, or range of doses, to test remains a relatively arbitrary
process and may have resulted in problems with a number of
the therapies discussed above. There is also the clinically
pressing problem of adding yet more treatments to a patient’s
existing therapy. Targeting therapy has been mentioned
earlier, but will the sponsors of large trials, the pharmaceutical industry, encourage this? Can we ethically find ways of
comparing proven therapies with new ones (even though that
may mean that patients do not receive the former during the
trial)? The Carvedilol ACE inhibitor Remodelling Mild heart
failure EvaluatioN (CARMEN) study, comparing the effect
of carvedilol alone, enalapril alone, and the combination of
both agents on LV function in 450 patients with an LVEF
⬍0.39 is one of few studies addressing this challenge.49 What
other moral and ethical problems will molecular and genetic
advances bring (embryonic stem cell research has already
been contentious)? Will conventional clinical trials with a
mortality end point become enormously large and prohibitively expensive as more effective therapies are added to
existing ones? We may need to think of not only new
approaches to trial design but also new end points for trials,
perhaps refocusing on patient well-being rather than just
adverse clinical events.50
Conclusions
The past 20 years have seen enormous progress in our
understanding of the pathophysiology of CHF and its treatment. Pathophysiological progress has suggested therapeutic
approaches, and the successes and failures of clinical trials
have refined pathophysiological concepts as well as the
science of trial design and conduct. The next 2 decades will
present at least as many challenges as the past 2 and perhaps
less prospect of the same enormous breakthroughs with
pharmacological agents. Nevertheless, our patients with CHF
can still expect further improvement in their quantity and
quality of life.
New Therapeutic Options in CHF: Part II
2227
Note Added in Proof
Both OVERTURE and ENABLE have recently completed and
reported. There was no significant difference in mortality between the omapatrilat and enalapril groups in OVERTURE.
Bosentan was not superior to placebo in ENABLE. Both of these
trials were presented at the “late-breaking trials hot-line” at
the American College of Cardiology Meeting in March 2002
(Atlanta, Ga).
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KEY WORDS: diastole
biology
䡲
heart failure
䡲
pharmacology
䡲
trials
䡲
molecular
New Therapeutic Options in Congestive Heart Failure: Part II
John McMurray and Marc A. Pfeffer
Circulation. 2002;105:2223-2228
doi: 10.1161/01.CIR.0000014771.38666.22
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