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CRT Clinical Trials: What We Know And Why
William Abraham, MD
Ohio State University
Columbus, OH
But the good news is you all know the data, and one of the things that
Cecelia and the meeting organizers asked me in particular to talk about is
how we measure response to CRT. So we will talk a little bit about what we
know, who CRT is currently indicated for, and we are going to look at
possible definitions of nonresponse or inadequate response, and I believe
that is one of the objectives is to move to some consensus in terms of that
definition.
So let’s start with what we know. We know that cardiac resynchronization
therapy is an effective form of therapy for patients with New York Heart
Association class III and class IV heart failure. The weight of evidence
supporting current practice and our current guideline recommendations is
summarized on this slide. More than 4000 patients have been evaluated in
landmark randomized controlled trials; in fact, the leadership for most of
those trials is with us in this room. These trials have demonstrated consistent
improvements in quality of life, functional status, and exercise capacity. They
have provided strong evidence for reverse remodeling, the ventricle gets
smaller and stronger, and functional mitral regurgitatio n is diminished, and
there are reductions in both heart failure and all cause morbidity and
mortality.
So I will just show you two or three slides to provide some data to support
what was summarized on the prior slide. This slide depicts the effects of CRT
on quality of life and functional status f rom four of our landmark trials, which
includes the MUSTIC trial, Drs. Daubert, Linde, and others in this room,
MIRACLE, CONTAK-CD, and MIRACLE ICD, and you can see in terms of
quality of life and New York Heart Association functional class ranking, very
consistent improvements.
Similarly, these trials have demonstrated consistent improvement on exercise
capacity, whether that be measured by the six-minute hall walk distance, or
the change in peak oxygen consumption. We have data from MIRACLE and
now from many, many other studies that demonstrate the effects of CRT to
produce reverse remodeling, improvements in the ejection fraction,
reductions in mitral regurgitation, reductions in LV volumes including both LV
and diastolic, and then systolic volumes and dimensions.
And then finally, from the very large CARE -HF study from our colleagues in
Europe, the first demonstration that CRT alone without a defibrillator prolongs
life, prolongs survival, morbidity and mortality is markedly reduced in patients
randomized to CRT plus optimal medical therapy versus CRT alone.
So it is this, these types of data, that have led to the following guideline
recommendations for heart failure. Here are the patients who currently should
receive CRT on the basis of those studies. A class I indication supported by
multiple randomized controlled trials, so a level of evidence graded as A, that
patients with LV ejection fractions less than or equal to 35% in sinus rhythm
and with New York Heart Association functional class III or ambulatory class
IV symptoms, despite recommended optimal medical therapy and who have
cardiac dyssynchrony currently defined as a QRS duration greater than 120
msec should receive CRT with or without an ICD, unless cont raindicated. So
that covers the patients with sinus rhythm.
There is now also a class IIA recommendation; the level of evidence here is
graded as B because it comes from either small randomized controlled trials
or from observational studies supporting the use of cardiac resynchronization
therapy in patients with atrial fibrillation. And I won’t read this guideline
recommendation to you because it is identical to the one shown on the
previous slide with the exception of specifying atrial fibrillation rather than
normal sinus rhythm.
And then there is additionally a class IIA recommendation in the guidelines
for patients who have a frequent dependence on, or an indication for
ventricular pacing. Here, the level of evidence is C; this really means that the
recommendation is based on consensus and some of the randomized
controlled trials to actually support this recommendation are still ongoing.
Now, in addition, we know that we are on the verge of an expansion of the
clinical indication for cardiac resynchronization therapy into a group of
patients with either asymptomatic or only mildly symptomatic heart failure,
and this slide summarizes the weight of evidence supporting an indication for
those patients. More than 3,000 patients evaluated in landmark randomize d
controlled trials, most of those patients to date studied in either the
REVERSE or the MADIT-CRT trial. These studies have also provided strong
evidence for reverse remodeling and demonstrated improvements in
functional status and outcomes as measured by either a clinical composite
endpoint or the combined endpoint of heart failure or cardiovascular morbidity
and all cause mortality.
Just very briefly because you already know the data, we will take a look at
one slide from REVERSE and a couple of slides f rom MADIT-CRT. Here are
the REVERSE data at 24 months from Drs. Linde, Daubert and others that
demonstrate a statistically significant improvement in the percent of patients
who are worsened over 24 months randomized to CRT versus no CRT. So
you see that a greater percentage of patients are improved or unchanged, a
lesser percent of patients are worsened, compared to those patients who are
randomized to no cardiac resynchronization therapy.
The MADIT-CRT trial, which randomized just over 1,800 patients, confirmed
the effects of resynchronization therapy in this class I and class II population,
demonstrating a reduction in heart failure –free, or an improvement in heart
failure–free survival. Overall, there was about a 30% improvement in survival
in these patients randomized to cardiac resynchronization therapy.
I am certain that you are all aware of the subgroup analysis. This was part of
the primary paper, the primary report, of the MADIT-CRT trial that
demonstrated a couple of curious findings. One was that the benefits of CRT
in this population appear to be most evident, most prominent in the class II
patients, a little bit tougher to show that the confidence intervals are broad
for class I and cross the line of unity, and there appear to be no beneficial
effect in patients with QRS durations less than 150 msec. It appeared that the
entire benefit was seen in patients with QRS durations greater than 150
msec.
And while the US guidelines have not yet caught up with these data, the
European guidelines have, and so, based on the ESC heart failure guideline,
specifically, the update on the use of devices for heart failure just released a
couple of months ago, Ken Dickstein and others, there is now a class I
indication with a level of evidence graded to be A, supporting the expansion
of the indication for CRT into mildly symptomatic heart failure patients.
And you will see that, and this is part of what we have wrestled with and may
become part of our discussion today, based on the MADIT-CRT and
REVERSE data, which patients should actually get CRT? Well, the European
Guideline Committee decided that this should be recommended to patients
who have a reduced ejection fraction, less than or equal to 35%. Interesting
cutoff; it agrees with the current guideline recommend ation for class III and
class IV patients, but remember that MADIT-CRT enrolled patients with
LVEFs less than 30%, and REVERSE less than 40%. So this represents a
compromise of the two, it falls right in-between, and it provides consistency
with our current guideline for class III and class IV heart failure.
They also, and I am not sure where the II dropped out, but that should say
New York Heart Association functional class II, so the European Guideline
Writing Committee did not extend this indication to c lass I patients on the
basis of currently available clinical trials. So they specified New York Heart
Associational functional class II patients, and also limited this to patients with
QRS durations greater than or equal to 150 msec. So that is the consensus of
the European Guideline Writing Group or Committee, on the basis of currently
available data.
Well, now let’s talk a little bit about how we define response to CRT in our
patients. If we look at clinical trials, while the clinical trials really run th e
gamut from assessing quality of life to New York Heart Association functional
class ranking, exercise capacity including six-minute hall walk and metabolic
exercise testing, cardiac remodeling, morbidity and mortality, when we look at
studies that have emerged either from single centers or large multicenter,
and, in some instances, multinational studies, that have tried to evaluate this
issue of CRT responsiveness, the most common endpoints used for
assessing response in CRT clinical trials have been the heart failure clinical
composite response, which was first described, the methodology published in
the Journal of Cardiac Failure in 2001 from Milton Packer, and remodeling,
particularly changes in left ventricular end-systolic volume or LVESV index.
For those of you who are not fully familiar with the clinical composite
response, its definition is shown on this slide. It incorporates measures of
both patient well-being or functional status, the New York Heart Association
functional class ranking and the patient global assessment, as well as heart
failure disease–specific morbidity, heart failure hospitalization, and all -cause
mortality.
So patients are judged to be improved if they have an improvement in New
York Heart Association functional class ranking, or an improvement in patient
global assessment; they are worse if they die, if they experience worsening
heart failure leading to hospitalization or permanent withdrawal of the
therapy, or if they experience worsening of New York Heart Association
functional class ranking or patient global assessment; and if they don’t meet
either of those two definitions, they are judged to be unchanged.
So let’s look at how this clinical composite endpoint performs in clinical trials
of cardiac resynchronization therapy. And in fact, this was the first trial to
prospectively evaluate the clinical composite response to cardiac
resynchronization therapy, and it has been widely cited as forming the basis
for the assertion that about a third of patients don’t respond to cardia c
resynchronization therapy. The data come from the MIRACLE trial, and this
demonstrated in the CRT arm that about 65% of patients were improved,
according to this clinical composite response definition; about 18% of
patients were unchanged; and 17% were worsened.
So that was our first experience with this clinical composite response in heart
failure. But remarkably, in now many studies that have reevaluated this over
the past decade, the results have been strikingly similar.
So let me just show you one example. Here are the data from the PROSPECT
trial, which evaluated the clinical composite response as one of its primary
endpoints; the second was LV end-systolic volume. And you will see that the
data, shown on the left-hand figure, are almost identical to those seen in the
MIRACLE trial. And we have seen this at least in the class III and IV heart
failure population, we have seen this emerge time and time and time again.
So by this definition, at six months follow-up, you get about 65%-70% of
patients demonstrating improvement with cardiac resynchronization therapy.
So that is what we do, or that is what our experience is, in clinical trials, and
those are two definitions of response to CRT which have been widely used in
investigations.
What about in the real world? And I am just going to conclude with a brief
summary of this survey that was done of participating sites in the FREEDOM
trial. The FREEDOM trial was a very large multinational randomized study
which evaluated optimization strategies in CRT. But at the onset or outset of
the FREEDOM study, a survey was conducted at the participating centers,
essentially to ask them, how do you define responsiveness to CRT?
So there were 117 centers from 16 countries which participated in, or
provided answers to, the survey. This represented nearly 80% of the 150
participating freedom centers. So we got a really good response rate to these
surveys. And again, questions in the survey focused on the period of time
when CRT responds was assessed. We wanted to know when did people sort
of make that judgment, was the patient improved or unchanged or worsened?
We also wanted to know what criteria they used to form that judgment. Were
they using echocardiograms or New York Heart Association class or some
subjective impression of how the patient was doing, their symptoms and so
on and so forth?
And we also asked them the percent of patients responding to CRT and then
ultimately when and how CRT is optimized. And I am going to tell you the
answer to the third bullet point because I forgot to include the slide in the
presentation. I meant to because it turned out that no matter how, no matter
what definition that the center was using, whether it be a single criteria or a
multiple criteria, whether it be subjective or an echo, no m atter how the
center defined responsiveness to CRT, when you asked them what
percentage of your patients respond to CRT, regardless of the criteria used,
the number was 70%, turned out to look just like what we see in the clinical
trials. So our real world clinical experience or impression of responsiveness
to CRT is virtually identical to that which has been seen in clinical trials.
Well, let’s take a look at what people are using in the real world as we enter
into our own discussion of how to define respo nsiveness to CRT, when and
how do people, clinicians assess the response to CRT? So in answer to the
period of time when CRT responds is assessed, while there may have been
device follow-up, and certainly was in most patients device follow -up which
occurred before this period, the first follow-up which involved a clinical
assessment of how the patient was doing, generally occurred between two
and six months after CRT implant.
The mean duration for this first follow-up was about four months, and it
turned out that the majority of centers indicated that CRT response was
assessed during this first follow-up time period. So most clinicians are
assessing how well patients are doing, how well or how poorly patients are
doing with CRT, somewhere between two and six months, on average at
about four months, that is when they are making that determination, has this
patient derived some benefit from cardiac resynchronization therapy?
Now, what criteria were used to assess CRT response? Sixty-three percent of
the centers used a single criterion. I am going to show you what that was
likely to be, or how that turned out in the survey, and 37% of the centers used
multiple criteria. So what were the results here? The most common single
criterion used in 95% of cases was to as sess CRT response with a measure
of either symptoms or functional status, and here is the breakdown: 49% of
those centers surveyed said that they used a single criterion and it was the
New York Heart Association functional class ranking. If the New York Heart
Association class improved, the patient was improved, if it did not improve,
they were worsened, and I am sorry, they were unchanged; and if it
worsened, they were worsened.
Thirty-one percent of centers said it was subjective symptoms; it was simply
what the patient told them, if the patient said, my symptoms are better, or my
symptoms are worse, or my symptoms are unchanged. Seven percent used a
formal quality of life assessment; 7% used a formal six -minute hall walk
study; 4% of centers used a subjective evaluation of exercise capacity; and
2% performed formalized metabolic exercise testing as their single criterion
for judging the responsiveness to CRT.
As a single criterion, cardiac structure and function, and this surprised me in
the survey, was only used in 5% of cases. I thought, quite frankly, and
certainly in my experience, we think about the echo a lot; we do serial echoes
in these patients and what happens to remodeling seems to mean a lot to us,
but it did not mean as much to a lot of other c enters because as a single
criterion in that 63% of centers that only used one criterion to determine CRT
responsiveness, the echo was only used 5% of the time. And the most
common echo parameters were LV volumes and LV ejection fraction.
And if we look at the centers, the 37% of centers that used more than one
criterion to judge responsiveness to CRT, the most common combination of
parameters used was New York Heart Association class and either LVEF or
LV end-systolic volume, so a combination of those things were looked at to
judge the responsiveness to CRT.
So that ends my formal presentation and tells you a bit of where we are
currently with CRT, and some of the challenges we have in defining CRT
responsiveness. Thank you.