Download Response to (resynchronization) therapy in chronic heart failure

EDITORIAL
European Journal of Heart Failure (2014) 16, 117–118
doi:10.1002/ejhf.53
Response to (resynchronization) therapy in
chronic heart failure: time for a different
approach
John Gierula and Klaus K. A. Witte*
Although chronic heart failure (CHF) remains an incurable syndrome of exercise intolerance, cardiac dysfunction and reduced
longevity, the last two decades have seen an unprecedented
improvement in the quality and quantity of life for patients diagnosed with CHF caused by left ventricular systolic dysfunction
(LVSD). One of the major advances has been cardiac resynchronization therapy (CRT), which can improve symptoms and prognosis in CHF patients with LVSD and conduction delay.1 Guidelines
describing the criteria for selection of CHF patients for CRT are
based upon large randomized, placebo-controlled studies demonstrating reduced hospitalization and mortality (over a finite time).3,4
In addition to these studies, there are hundreds of smaller, mostly
observational, studies using multiple imaging techniques and various measures of response to try to identify subgroups of patients
more or less likely to benefit from CRT. Thankfully, none of the proposed pre-assessment deselection techniques have been adopted
into international guidelines, and the indications remain resolutely
a broad QRS, left ventricular systolic dysfunction, and sinus rhythm.
The data presented by Versteeg et al.2 contribute to the increasing recognition of the pointlessness of trying to predict response
to CRT from baseline variables, with the only predictor of symptomatic response being a broad QRS complex. Furthermore their
data show that changes in echocardiographic variables are unrelated to changes in symptoms following CRT. These unique data
should not only stimulate discussion about the use of contemporary measures of response (often based upon arbitrary percentages
of change from baseline) and other surrogate outcomes in chronic
disease, but also question the use of cohort studies to deselect subgroups of patients previously included in prospective randomized
placebo-controlled trials.
The response of any individual to any intervention for a chronic
disease is variable and CHF is no different. Cardiac resynchronization therapy is associated with a greater symptomatic response
than medical therapy,5 yet many patients experience no improvement. Versteeg et al.2 show us that improvements in symptoms and
improvements in cardiac function tend not to occur together (only
30% have a response in both, although 80% have a response in
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Division of Cardiovascular and Diabetes Research, Leeds Institute of Genetics, Health and Therapeutics Multidisciplinary Cardiovascular Research Centre, University of
Leeds, UK
either domain), but should this concern us? In the race to select
patients with greatest ‘benefit’, it is often forgotten that stability
or a slowing of deterioration is a powerful effect of modern treatment for CHF but is impossible to observe from non-randomized
longitudinal cohort studies. Cohort studies are also unable to
address the ‘ceiling effect’ commonly seen in older patients with comorbidities and in younger patients with mild disease. In both situations, patients with an excellent clinical outcome are labelled as
‘non-responders’. For example the data by Versteeg et al.2 demonstrate the ceiling effect in patients with less severe disease, where
those with smaller heart dimensions are more frequently classed
as non-responders.
In a chronic disease of uncertain course, only a randomized
placebo-controlled trial offers clarity in terms of predictors of
outcome, as, rather than looking at the experiences of individuals,
one can compare outcomes in groups of patients displaying similar
features but exposed to different treatments. Without this one
cannot model what would have happened to the patient had they
received different treatment. Such an analysis from the CARE-HF
(Cardiac Resynchronization in Heart Failure)6 study showed that
not only do baseline symptoms not relate to mortality benefit, but
powerful markers such as baseline natriuretic peptides, and the
presence of mitral regurgitation also do not predict the benefit of
CRT on hard outcomes.7
If we are to use surrogate measures in evaluating a treatment, we
need to adopt a patient-orientated approach. Is an arbitrary degree
of improvement in a surrogate endpoint such as cardiac function
relevant to patients? On the other hand, although symptoms are
important to patients, and their severity,8,9 but not nature10 are
related to outcome, we cannot assume that a lack of change
following a particular treatment implies that it has no effect on
outcome. Equally, we must not assume that improving symptoms11
has a beneficial (or even neutral) effect on prognosis.12,13
Rather than using the data from Versteeg et al.2 to begin a costly
and distracting search for more obscure predictors with which to
deselect patients currently indicated for CRT, we should use them
to support an open and frank discussion with patients and their
*Corresponding author:Leeds Institute of Genetics, Health and Therapeutics, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Clarendon Way, Leeds, United
Kingdom, LS2 9JT. Tel: +44 1133926642, Fax: +44 1133925442. E-mail: [email protected]
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology
118
apy in three patients with chronic heart failure. All three gain
benefit from the implant procedure, but only patient 1 is classed
as a responder in a standard cohort study approach, and only
then if the improvement is of a specific magnitude. Reprinted from
Cubbon and Witte,1 BMJ 2009 with permission.
carers, preferably before the implant, about what CRT might and
might not do for them. Based upon large randomized studies, the
procedure extends average longevity by a year whether symptoms
or cardiac function improve or not, and although many patients
do feel better as a result of CRT, it seems that at the very least,
patients are likely to be less symptomatic at any given time-point in
the future than they would have been without the device (Figure 1).
Crucially, we must abandon the term ‘non-responder’ for all
treatments for CHF including CRT. Beta-blockers and angiotensinconverting enzyme inhibitors improve outcomes in patients with
CHF, but we do not question our prescription if symptoms or the
echocardiogram fail to improve, yet we label such patients as ‘nonresponders’ following CRT. Chronic heart failure remains a chronic
incurable disease and failure to improve does not mean failure of
treatment. If we explain this to patients at an early stage, we will
avoid the common pitfall of setting ourselves, our patients, and
their carers flawed and clinically irrelevant targets, which when not
achieved can have a negative effect everyone.
..................................................................................................................
Figure 1 The possible effects of cardiac resynchronization ther-
Editorial
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Funding
None.
© 2014 The Authors
European Journal of Heart Failure © 2014 European Society of Cardiology