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Discussion summary: key clinical questions
Philippe Lechat* and
Ronnie Willenheimer, (Symposium Chairmen)
Service de Pharmacologie, Hôpital Pitié-Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France
* Corresponding author. Tel: +33 1 42 16 16 82; fax: +33 1 42 16 16 88. E-mail address: philippe.lechat{at}psl.ap-hop-paris.fr
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Can the benefits of beta-blockade in CHF be considered a class effect?
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It is probable that the efficacy of beta-blockers in CHF is
attributable to beta
1-blockade. However, there are differences
between beta-blockers in their pharmacological properties, which
may translate into differences in effects on morbidity, mortality,
quality-of-life, and physical function. The European Society
of Cardiology guidelines clearly state that the only beta-blockers
proven to reduce morbidity and mortality in large randomized
trials are bisoprolol, carvedilol, metoprolol succinate CR/XL,
and nebivolol, and that these are the agents from which physicians
should choose.
1
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Could beta-blockers and ACE-inhibitors be initiated simultaneously in CHF?
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A survey of the audience through interactive voting revealed
this to be a surprisingly widespread practice. However, as the
panel pointed out, simultaneous initiation has never been examined
in a randomized controlled outcome trial, and therefore cannot
be considered evidence-based. Moreover, there are potential
problems in trying to uptitrate two drugs simultaneously. The
risk of side-effects is greater, and if they occur, the physician
will not know which drug should be reduced in dose or withdrawn
(particularly in the setting of a double-blind study). In addition,
the dose titration schedules for ACE-inhibitors and beta-blockers
differ.
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Could both treatments be combined in a single pill?
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As explained above, simultaneous initiation cannot be recommended
on the basis of current evidence. However, as compliance is
likely to be better with fewer pills, it is conceivable that
a range of fixed combinations of an ACE-inhibitor and a beta-blocker
might be developed for use in patients who have been stabilized
on combined treatment.
However, the problem of what to do in the case of side-effects attributable to only one of the component of the pill would remain.
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How important is it to adhere to the target doses of beta-blockers used in clinical trials?
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The principles of evidence-based medicine indicate that we should
aim for the target doses used in clinical trials, but it should
be recognized that such doses are unachievable in some patients,
particularly elderly frail individuals. It should also be remembered
that 60–70% of the patients who should have a beta-blocker,
currently do not receive one.
2,3 So, it might reasonably be
said that a low dose is better than no dose. Mortality reduction
has been shown for bisoprolol and metoprolol across a range
of dose levels.
4,5 However, it is important to aim for maximal
beta
1-receptor occupancy in the individual patient, which may
be assumed to be reached at the maximal tolerated dose.
The critical steps are to:
- Prescribe a beta-blocker in all CHF patients in whom there is no specific contra-indication
- Slowly titrate the dose upwards, stopping only when either the target or the maximum tolerated dose is reached
- Lower the dose where necessary in preference to withdrawing the beta-blocker altogether, as analysis of CIBIS-II data shows that withdrawal is associated with increased mortality.5
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Can we achieve target doses of both the beta-blocker and the ACE-inhibitor?
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It may sometimes be difficult to reach target doses of both
drug classes, which is why it is important for physicians to
know that, based on CIBIS-III, they have the option to start
treatment with either a beta-blocker or an ACE-inhibitor. There
is clear evidence that the first-initiated drug is likely to
reach a higher dose.
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What factors can contribute to the successful initiation of beta-blockers?
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‘Start low and go slow’ should be the rule, and
the dose and speed of uptitration should be individualized.
Patients should be warned not to expect an immediate improvement
in their symptoms—some transient worsening is to be expected,
and does not usually mean that the beta-blocker should be withdrawn.
Rather, the concomitant medication, for example diuretics, glycosides
should be adjusted and/or the beta-blocker dose temporarily
reduced.
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Is there a clearly defined subgroup of patients in whom beta-blockers should be initiated first?
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There is no evidence-based answer to this question—the
CIBIS-III subgroup analysis did not identify any subgroup who
benefited more from beta-blocker first.
6 However, some experts
suggest that early beta-blockade is particularly desirable in
patients at increased risk of sudden cardiac death (those with
tachycardia or with a history of arrhythmias). Patients who
are at an early stage of CHF are also at high-risk of sudden
cardiac death. In any case, all post-myocardial infarction patients
have a clear indication for starting beta-blockade as early
as possible for secondary prevention.
1 Patients with impaired
renal function may also be considered for treatment initiation
with a beta-blocker.
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Can beta-blockers be used in patients with chronic obstructive pulmonary disease (COPD)?
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Selective beta
1-blockers can be used safely and effectively
in COPD, and are not contra-indicated. However, they are contra-indicated
in asthma. As patients with COPD sometimes also have a degree
of reversible bronchoconstriction, beta-blockers should be initiated
at a low dose, uptitrated slowly, and the patient monitored
carefully for adverse events.
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Is 6 months of monotherapy used in CIBIS-III appropriate for everyday clinical practice?
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This rather prolonged period of monotherapy was necessary in
CIBIS-III to allow an effective statistical comparison of the
two treatment strategies, but no study to date has investigated
how long the interval should be between initiation of each drug.
In everyday practice, the second agent should be introduced
as soon as the patient is stabilized on the maximal tolerated
or target dose of the first therapy.
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Why was enalapril chosen as the ACE-inhibitor in CIBIS-III?
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Although, quite an old drug, enalapril is the ACE-inhibitor
for which there is the greatest body of evidence in CHF. ESC
guidelines do not state which ACE-inhibitor should be used,
but the major CHF trials cited as leading to this recommendation
are CONSENSUS,
12 the SOLVD treatment trial,
13 V-HEFT II,
14 and
ATLAS.
15 As all except ATLAS used enalapril, this seemed an
appropriate choice of ACE-inhibitor for CIBIS-III.
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Can long-term monotherapy with a beta-blocker ever be recommended in CHF?
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The panel was clear—combination therapy with an ACE-inhibitor
(and/or ARB) and a beta-blocker is the best option for reducing
morbidity and mortality. However, a period of monotherapy cannot
be avoided at the start of treatment, and CIBIS-III has shown
that this can be with either class of agent. CIBIS-III was not
designed to examine what happens if beta-blocker therapy is
continued alone, without the addition of an ACE-inhibitor. It
therefore provides no evidence on the efficacy or safety of
beta-blocker therapy alone, beyond 6 months. Combined therapy
should therefore continue to be used in accordance with ESC
guidelines,
1 unless the patient cannot tolerate it. There is
evidence that the combination of both agents provides the greatest
benefit to the patient.
The only patient in whom continued monotherapy can be recommended are those who are completely unable to tolerate the second agent at any dose, and the number of such cases should be few.
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Why were both per-protocol and intention-to-treat analyses of the primary endpoint reported in CIBIS-III?
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The choice of analysis in a study such as CIBIS-III is controversial.
Clinicians will be familiar with the concept of intention-to-treat
analysis (which includes all randomized patients, whether or
not there were protocol violations). This is considered to represent
the realities of clinical practice and is the most rigorous
way of comparing treatments in superiority trials (the most
usual type of drug efficacy study). However, per-protocol analysis
is widely accepted as the appropriate analysis for non-inferiority
trials. In this instance, it is argued that it is most appropriate
to look only at the patients who actually received the drug
as specified in the protocol as this is the most conservative
approach for non-inferiority testing. However, this approach
was mainly developed for comparing the pharmacokinetic characteristics
of generic drugs with those of proprietary agents in short-term
studies. Non-inferiority trials with mortality and morbidity
endpoints are a relatively new and continuously developing area
of research, and the appropriate analysis is still a topic of
debate. Therefore, both types of analysis were reported for
the primary endpoint of CIBIS-III. Most importantly, the result
with regard to the primary endpoint was quite similar in the
intention-to-treat and the per-protocol analysis. Secondary
endpoints were evaluated by intention-to-treat.
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Why was CIBIS-III not double-blind?
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CIBIS-III was a prospective, randomized, open, blinded endpoint
evaluation (PROBE) trial.
7 An open design was used in case of
necessary dose adjustments of either drug during the combined
study phase. Such adjustments might be required, for example,
if side-effects occurred. If both treatments were masked, it
would have been virtually impossible for the investigators to
make such multiple adjustments for the two drugs separately.
Another advantage of the open design is that it resembles real-life
clinical practice. Note, however, that the design was only open
with respect to the patients and the treating physicians; a
blinded evaluation of the endpoints was performed by an independent
endpoint committee. There is an increasing trend towards PROBE-design
studies, as they are easier to conduct and resemble clinical
practice. Many recent phase IV studies on, for example, antihypertensive
drugs have used the PROBE design. Patient and/or investigator
bias is of course a possibility with the open nature of the
PROBE design. However, in a study such as CIBIS-III utilizing
a strict randomization procedure and precisely predefined ‘hard’
endpoints such as mortality and cardiovascular events, this
source of bias can be largely avoided using a blinded end-point
assessment by experienced independent experts, otherwise not
involved in the conduct of the study, who adhere to strict endpoint
evaluation guidelines.
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Why did CIBIS-III not include NYHA Class IV patients?
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CIBIS-III only recruited previously untreated and clinically
stable patients without clinically relevant fluid retention,
so it would have been nearly impossible to include NYHA Class
IV patients. Indeed, it may be argued that very few true NYHA
Class IV patients have been included in previous trials. Even
COPERNICUS, which was designed to include patients with severe
CHF, had a relatively low mortality in the placebo group compared
with what would have been expected in NYHA Class IV.
8 Beta-blocker
therapy should not, of course, be initiated in unstable patients
(many NYHA IV patients are unstable) with decompensated or recently
recompensated heart failure.
Conflict of interest: None declared.
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References
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- Swedberg K, Cleland J, Dargie H . Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 1115–1140.[Free Full Text]
- Komajda M, Follath F, Swedberg K . The EuroHeart Failure Survey programme–a survey on the quality of care among patients with heart failure in Europe. Part 2: treatment. Eur Heart J 2003; 24: 464–474.[Abstract/Free Full Text]
- Cleland JG, Cohen-Solal A, Aguilar JC . Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): an international survey. Lancet 2002; 360: 1631–1639.[CrossRef][Web of Science][Medline]
- Wikstrand J, Hjalmarson A, Waagstein F . Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 2002; 40: 491–498.[Abstract/Free Full Text]
- Simon T, Mary-Krause M, Funck-Brentano C, Lechat P, Jaillon P. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study (CIBIS-II). Eur Heart J 2003; 24: 552–559.[Abstract/Free Full Text]
- Willenheimer R, van Veldhuisen DJ, Silke B . Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence. Results of the Randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation 2005; 12: 2426–2435.
- Hansson L, Hedner T, Dahlof B. Prospective randomized open blinded end-point (PROBE) study. A novel design for intervention trials. Prospective Randomized Open Blinded End-Point. Blood Press 1992; 1: 113–119.[Medline]
- Packer M, Coats AJ, Fowler MB . Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658.[Abstract/Free Full Text]
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