Circulation March 15, 2022 Issue

This week, join author Tristram Bahnson and Associate
Editor Changsheng Ma as they discuss the article "Association
Between Age and Outcomes of Catheter Ablation Versus Medical
Therapy for Atrial Fibrillation: Results from the CABANA
Trial."


Dr. Carolyn Lam:


Welcome to Circulation On The Run, your weekly podcast summary
and backstage pass to the journal and its editors. We're your
co-hosts. I'm Dr. Carolyn Lam, Associate Editor from the National
Heart Center and Duke National University of Singapore.


Dr. Greg Hundley:


And I'm Dr. Greg Hundley, Associate Editor, Director of the Poly
Heart Center at VCU Health in Richmond, Virginia.


Dr. Carolyn Lam:


Guess what, Greg? For today's feature paper, we are going to be
looking at a very interesting analysis from the CABANA trial,
this time, looking at the association between age and outcomes of
catheter ablation versus medical therapy for atrial fibrillation.
Cool, huh? Okay, but first, let's go through some other important
papers in today's issue. Why don't I let you go first?


Dr. Greg Hundley:


Well, Carolyn, my first paper pertains to the cost effectiveness
of coronary artery bypass surgery, and it comes to us from the
STICH trial.


Dr. Carolyn Lam:


Ah, very important question, but please remind us what the STICH
trial is again.


Dr. Greg Hundley:


Right, Carolyn. So the Surgical Treatment for Ischemic Heart
Failure trial, or STICH demonstrated that coronary artery bypass
grafting reduced all-cause mortality rates out to 10 years
compared with medical therapy alone in patients with ischemic
cardiomyopathy and reduced left ventricular function, defined as
an ejection fraction of less than or equal to 35%. Now in this
study, the authors led by Dr. Derek Chew at University of Calgary
examined the economic implications of these results using a
decision-analytic patient-level simulation model to estimate the
lifetime costs and benefits of CABG versus medical therapy alone,
using patient-level resource use and clinical data collected from
the STICH trial.


Dr. Carolyn Lam:


Again, really important study. And what did they find?


Dr. Greg Hundley:


Right, Carolyn. So first, using their patient-level simulation
model incorporating resource use and clinical data collected from
the STICH trial, they found that coronary artery bypass grafting
was estimated to cost $63,989 per quality-adjusted life year gain
compared to medical therapy alone. Second, in STICH eligible
patients with left ventricular ejection fraction of less than 35%
in coronary artery disease amenable to CABG, routine use of CABG
increased the quality-adjusted life expectancy compared to
medical therapy alone for an increased cost within current
benchmarks for good value in healthcare within the United States.
Then finally, Carolyn, together with the improved clinical
outcomes seen in the 10 year extended follow-up of STICH, the
findings in this study provide additional economic support for
the use of coronary artery bypass grafting in patients with
ischemic cardiomyopathy eligible for STICH.


Dr. Carolyn Lam:


Wow, thanks Greg. Well, this next study contributes to the
understanding of the effect of lifestyle and genetic risk on the
lifetime risk of coronary heart disease. Interesting? Well,
listen up. This is from Dr. deVries from UT Health Science Center
at Houston and colleagues who aimed to quantify remaining
lifetime risk and years free of coronary heart disease according
to polygenic risk and the AHA's Life's Simple 7 guidelines in the
population base cohort of ARIC. As a reminder, the Life's Simple
7 by the AHA consists of smoking status, body weight, total
cholesterol, blood glucose, blood pressure, physical activity,
and diet.


Dr. Greg Hundley:


Ah, Carolyn. So genes versus lifestyle. So what did they find?


Dr. Carolyn Lam:


Participants with high polygenic risk may offset their lifetime
risk of coronary heart disease by up to 50% through managing
their health according to the Life's Simple 7's recommendations,
depending on ancestry. Individuals with high polygenic risk
scores and ideal Life's Simple 7 scores had 4.5 to 20 more
coronary heart disease free years than individuals with high
polygenic risk scores, but low Life's Simple 7 scores and again,
depending on ancestry. Appropriate management of lifestyle and
clinical risk factors of coronary heart disease play larger roles
in the overall lifetime risk of coronary heart disease than
presently available genetic information. Thus, communicating the
effects of Life's Simple 7 measures and polygenic risk on
coronary heart disease in terms of absolute risk may have
important implications for education, policy, and environmental
changes, which can benefit not only high risk individuals, but
the whole population.


Dr. Greg Hundley:


Wow, Carolyn, really informative study and so nicely summarized.
So Carolyn, my next paper comes to us from the world of
preclinical science and it's from Professor Yan from Shanghai,
Ruijin University School of Medicine. So Carolyn, previous
studies have suggested that mitochondrial dysfunction plays
critical roles in the progression of heart failure. However, the
underlying mechanisms often remain unclear. Now since kinases
have been reported to modulate mitochondrial function team
investigated the effects of dual specificity tyrosine regulate
kinase one B on mitochondrial, bio energetics, cardiac
hypertrophy, and heart failure.


Dr. Carolyn Lam:


Wow. Okay. So what did they find Greg?


Dr. Greg Hundley:


Right, Carolyn. So this team found that Dual Specificity
Tyrosine-Regulated Kinase 1B, our DYRK1B expression was clearly
up regulated in failing human myocardium as well as in
hypertrophic mirroring hearts and cardiac specific DYRK1B over
expression resulted in cardiac dysfunction, accompanied by a
decline in the left ventricular ejection fraction, as well as the
fraction shortening. And it increased left ventricular myocardial
fibrosis. Carolyn in striking contrast to DYRK1B over expression,
the deletion of DYRK1B mitigated tack-induced cardiac hypertrophy
and heart failure. In addition, the authors found that DYRK1B was
positively associated with impaired mitochondrial bio-energetics
by directly binding with stat three to increase its
phosphorylation and nuclear accumulation. Thereby ultimately
contributing toward the down regulation of PG C one alpha. Now,
furthermore, the inhibition of DYRK1B or stat three activity
using specific inhibitors was able to restore cardiac performance
by rejuvenating mitochondrial bio-energetics.


Dr. Carolyn Lam:


Cool, Greg. So could you give us a take home?


Dr. Greg Hundley:


Right. So in summary then, Carolyn, taken together, the findings
of this study provide new insights into the previously
unrecognized role of DYRK1 beta in mitochondrial bio-energetics
and the progression of cardiac hypertrophy in heart failure.


Dr. Carolyn Lam:


Fantastic. Thanks, Greg. Well, other papers in today's issue
include an exchange of letters between Doctors Nie and Wollert on
the article myeloid derived growth factor protects against
pressure overload induced heart failure by preserving
sarcoplasmic reticulum calcium, ATPase expression in
cardiomyocytes. There's an AHA update [AHA Advocacy Page] paper
by Dr. Churchwell on improving heart health through value-based
payment. An ECG Challenge by Dr. Murphy on a “Curious ECG
Morphology of a Cardiac Device.” An On My Mind paper by Dr.
Figtree on “Sublingual Nitrates for Patients as a Default in the
Post ACS Discharge Pack. Is the Time for a Rethink?”


Dr. Greg Hundley:


Right? Carolyn. Boy, this issue is really packed with great
articles. There's a Perspective piece from Professor Stewart
entitled “Myocardial Edema Provides A Link Between Pulmonary
Arterial Hypertension and Pericardial Effusion.” There's a
wonderful Frontiers in medicine piece from Professor Kandzari
entitled “A Clinical Trial Design Principles and Outcomes
Definitions for Device-Based Therapies for Hypertension: A
Consensus Document from the Hypertension Academic Research
Consortium.” And then finally, Carolyn, there's a Research Letter
from Professor Wold entitled “E-Cigarette Aerosol Reduces Left
Ventricular Function in Adolescent Mice. Well, Carolyn, how about
we get onto those results from the CABANA trial?”


Dr. Carolyn Lam:


Let's go, Greg.


Dr. Greg Hundley:


Well, listeners, we are now here for our feature discussion and
we have with us today, Dr. Tristram Bahnson from Duke University
and one of our own Associate Editors, Dr. Changsheng Ma from
Beijing. Welcome gentlemen. Tristram, we will start with you
first. Could you describe for us some of the background
pertaining to this particular research study and what was the
hypothesis that you wanted to address?


Dr. Tristram Bahnson:


Sure. Being an active electrophysiologist, a challenge we've had
over the years is to try to figure out for whom catheter ablation
would be a preferred therapy. I've had the privilege of being
part of the CABANA study team over the last several years. As
listeners might recall, the CABANA trial was a very large trial
looking specifically at hard endpoints, including mortality, to
try to determine whether or not catheter ablation provides
significant benefits to patient. Apart from what we already knew
over the years, which is the catheter ablation was more effective
than drug therapy to reduce AFib recurrences. That study, the
CABANA proper study was published in 2019.


Dr. Tristram Bahnson:


In the course of that study, pre-specified subgroup analyses were
done initially reporting unadjusted outcomes for important
clinically relevant subgroups. We found in that initial study
that patients with heart failure, minorities, and patients of
young age in particular appeared to do better with catheter
ablation than with drug therapy. So with that as background, the
CABANA study team embarked to focus on each of those subgroups
and the heart failure paper was published in 2021, the minorities
paper also in 2021 and the subject of our discussion now, the
relationship between age and outcome in the CABANA study cohort
is a subject of study today.


Dr. Greg Hundley:


Describe just quickly Tristram the hypothesis you wanted to test
here and then in order to test that hypothesis, what was the
study population that you included and what was your study
design?


Dr. Tristram Bahnson:


So the focus was on the relationship between age and outcome in
CABANA, and this was pre-specified substudy of the CABANA
population. So it's probably worthwhile going over who got into
the CABANA trial and to remind folks the CABANA trial enrolled
2,204 patients across 126 sites at 10 countries and randomized
them one to one to a treatment strategy of either catheter
ablation or drug therapy for simple traumatic atrial fibrillation
that in the judgment of the treating physicians warranted
therapy, patients had to have had at least two episodes of PAF or
one episode of persistent AFib documented by ECG or ambulatory
recordings within the six months prior to enrollment and they
hadn't have failed more than one anuric drug. In other words,
they would have to have been reasonable candidates for drug
therapy, should they be so randomized.


Dr. Tristram Bahnson:


In addition, patients that were less than 65 years of age, had to
have some additional factors that would increase the likelihood
that outcome events would occur. They had to have a CHADSVASC
score greater than one. That was not required of the older
subjects follow up was 48 and a half months for the population at
large, with the interportal range of follow up between 30 and 62
months. The patients had regular follow up every three months for
the first year and then six months thereafter. In addition, 1,240
patients received a recording device that allowed them to provide
either prescribed episodic recordings or recordings for when they
were symptomatic and they also provided 96 hour holters every six
months throughout the duration of the trial.


Dr. Tristram Bahnson:


So that's the population that we were working with. The study
design, as I said, focused on trying to tease out the
relationship between age and outcomes and the primary outcomes of
the CABANA trial included the primary outcome, which was a
composite. It included all cause mortality, disabling, stroke,
serious bleeding or cardiac arrest, and the key secondary
endpoints that were looked at included mortality and
cardiovascular hospitalization and AF recurrence.


Dr. Greg Hundley:


Very nice. Describe for us your results.


Dr. Tristram Bahnson:


So we actually took a deeper dive into the subgroup of age, and
we did a couple things that we thought would be valuable. One was
to consider age as a continuous variable because after all, it's
pretty arbitrary to bin people into age groups. I think the
initial analysis did so with the CABANA proper publication in
2019 to correspond with the break points that we use for
CHADSVASC scoring, but we elected to consider age as a continuous
variable and we also elected to do adjusted Cox proportional
hazard models to account for the various clinical factors that of
course varied with age, such as their CHADSVASC score, the
occurrence of structural heart disease, like valvular heart
disease or coronary disease, the proportion of women, which
typically increases with age and did so in this population. The
key endpoints that we examined were the CABANA endpoints,
including the primary composite endpoint of total mortality,
mortality, or CB hospitalization and AF recurrence.


Dr. Tristram Bahnson:


So at the end of the day, we had 766 patients who were less than
65, 1,130 that were between 65 and 74 and 308 that were greater
than 75. Mind you, CABANA admitted patients with any kind of
AFib. As a matter of fact, more than half of the study population
had persistent or longstanding persistent atrial fibrillation,
which is not typical of many studies that have been published,
looking at the relative benefits of catheter ablation. We had an
unexpected finding that was hinted at, at the initial CABANA
study and that was the benefit of catheter ablation was greatest
in the younger patients and the benefits of catheter ablation
relative to drug therapy seemed to decrease with advancing age at
enrollment, which was the age criterion that we based the
analysis this on and that this effect was primarily driven by
changes in mortality.


Dr. Tristram Bahnson:


For the composite endpoint in CABANA, which was total mortality,
serious stroke, serious bleeding and cardiac arrest, we saw that
the adjusted hazard ratio increased average of 27% for every
decade in advancing age, where the age was defined as that at
enrollment, and for the total mortality endpoint, the adjusted
hazard ratio increased an average of 46% for every 10 year
increment in age at enrollment. For all age groups, catheter
ablation was superior to drug therapy, a relative to a reduction
in AFib consistent with many other studies. The benefit was a
reduction in the adjusted hazard ratio of about 50%. So catheter
ablation was agnostic to age in terms of the benefit of reducing
AFib, but was not agnostic to age with result to these mortality
inclusive endpoints. We did notice that there was a trend towards
a relative benefit of drug therapy for the oldest age group, but
we interpreted that result with caution for a variety of reasons.
The oldest age group was least well represented and comprised
less than 10% of the CABANA population and less than half of the
next best well represented age group, which was the less than
65's.


Dr. Tristram Bahnson:


In looking carefully at the data, we could find no plausible
explanation for why the older age group might do better with drug
therapy. Again, it was not significant by an intention to treat
analysis, but there was a trend towards drug therapy getting
better with the oldest age group. We noticed that there was no
excess mortality in the old age group within six months of
treatment, so it didn't seem like it was related to some adverse
procedural effect. We saw no evidence of more advanced forms of
AFib in the oldest age group, because they had as good AFib
suppression as others, and had the same distribution of
paroxysmal versus persistent forms of AFib as the other age
groups. There was no difference in crossover after all, if more
patients in the old age group crossed over from drug to ablation
therapy, who might expect that to be a confounder.


Dr. Tristram Bahnson:


We did see something that was very unusual and unexpected, which
is that the mortality of the oldest age group treated with drugs
was actually less than their mortality in catheter ablation,
which is the issue at hand, but also less than the other age
groups, which was unexpected and even less than all but the
youngest age group treated with catheter ablation. So we can't
explain this finding. It was not statistically significant. At
the end of the day, we don't believe that elderly patients who
have drug refractory AFib that is symptomatic should be denied
ablation.


Dr. Greg Hundley:


Well, thank you so much, Tristram, for these very intriguing
results. Changsheng, you have many papers that come across your
desk. What drew you to this particular paper?


Dr. Changsheng Ma:


Yes. Dr. Bunch and colleagues should be commanded for the
understand and taking important subgroup analysis of CABANA
study. There has also been interest in whether the risk and the
benefit of ablation may be modulated by patient age. The current
analysis suggests that the related benefit of ablation was
characterized for those less than 65 years of age are a tiny bit
by the increasing age. It is important to emphasize that the
current analysis result should not be interpreted to suggest that
the cancer ablation has less value in idly patients. As a casual
ablation must treated before recurrence across all age groups.


Dr. Changsheng Ma:


The current analysis is assuming we should know age related
increase in safety constant in patients and taking ablation
therapy. So we must be cautious not to over incorporate the
result of the sub-group analysis, especially in the context of
CABANA trial, treating in the permanent effect of ITT analysis.
So I think it can be a possible that reach age related gradings
in the relatively treatment benefits of the ablation is finding a
challenge. Secondly, the CABANA trial was not a oral subgroup
analysis. So the variation of treatment effect across the
different age group were in the further resource. That's my
opinion.


Dr. Greg Hundley:


Thank you very much. Well, gentlemen, what do you see is the next
study that needs to be performed in this sphere of research and
Tristram, we'll start with you.


Dr. Tristram Bahnson:


Well, clearly the clinical task at hand, for those of us who
treat patients is to advise patients about relative benefits of
therapy when there are choices at hand. And in the case of atrial
fibrillation, the fundamental choice obviously is whether or not
to pursue catheter ablation or to pursue medical therapy, either
for rhythm or rate control. An important part of that decision
making is to understand which patients would derive the most
benefit from one versus the other therapy. And that need is
perhaps the genesis of why we embarked on these subgroup
analysis, which admittedly need to be interpreted with caution
are not powered to give definitive results, but can certainly
help guide future research. So we have noted in the CABANA trial
that heart failure patients might do better and that's consistent
with other studies looking specifically at heart failure with
reduced ejection fraction. So we're contemplating additional
studies to help tease that population out since in CABANA, in
particular, our heart failure population was mostly those with a
preserved ejection fraction and clinical heart failure.


Dr. Tristram Bahnson:


With regard to age, I think it'll be important to do studies to
try to understand what factors resulted in the young patients
apparently doing better with ablation. Again, this is hypothesis
generating in terms of our result with this paper. So it'd be
very interesting to find out whether there are some subsets of
patients with younger ages or patients who have the relevant
characteristics of the young age patients who would derive
particular benefit from catheter ablation. This would obviously
require a variety of approaches, including prospective randomized
studies and carefully done population studies. So this issue
about which patients really derive a significant mortality
benefit it from catheter ablation is an important one that has
not yet been teased out completely.


Dr. Greg Hundley:


Thank you. And Changsheng, do you have anything to add?


Dr. Changsheng Ma:


Yes. I think two streams say it's a very important topic for, you
know, who have more and more, the older patients. So we need to
answer the question, how about the real influence of age on the
outcomes of the atrial fibrillation patients with ablation. So in
future, we should consider randomized trial, but I think it's
very difficult. So maybe we have to wait more and more, you know,
other study to have a trend, how about the outcome for all the
patients. It becomes too difficult for a new randomizedtrial.


Dr. Greg Hundley:


Very nice. Well listeners, we want to thank Dr. Tristram Bahnson
from Duke University and Dr. Changsheng Ma from Beijing for
bringing us the results from this substudy of the CABANA trial
indicating that the mortality related benefits of catheter
ablation for atrial fibrillation appeared to decrease for every
10 year increment in age, above the age of 65 years. Well, on
behalf of Carolyn and myself, we want to wish you a great week
and we will catch you next week on the run.


Dr. Greg Hundley:


This program is copyright of the American heart association,
2022. The opinions expressed by speakers in this podcast are
their own and not necessarily those of the editors or of the
American Heart Association for please visit ahajournals.org.