Circulation February 14, 2017 Issue

 


Dr.
Lam:              
Welcome to Circulation on the Run, your weekly podcast summary
and backstage pass to the Journal and its editors. I'm Dr.
Carolyn Lam, associate editor from the National Heart Center and
Duke National University of Singapore. Our podcast is taking us
to Japan today where we will be talking about aspirin for primary
prevention in patients with diabetes. First, here's your summary
of this week's issue.


                               
The first study provides insight into the development of
neurologic injury in patients with single ventricles undergoing
staged surgical reconstruction. In this paper by Dr. Fogel and
colleagues from the Children's Hospital of Philadelphia, the
authors recognize that single ventricle patients experience
greater survival with staged surgical procedures culminating in
the Fontan operation, but experience high rates of brain injury
and adverse neurodevelopmental outcome. They therefore studied
168 single ventricle patients with MRI scans immediately prior to
bi-directional Glenn, prior to the Fontan, and then three to nine
months after the Fontan reconstruction. They found that
significant brain abnormalities were frequently present in these
patients and that the detection of these lesions increased as
children progressed through staged surgical reconstruction. In
addition, there was an inverse association of various indices of
cerebral blood flow with these brain lesions. This study
therefore suggests that measurement of cerebral blood flow and
identification of brain abnormalities may enhance recognition of
single ventricle patients at risk for poor outcomes, and possibly
facilitate early intervention.


                               
The next paper uncovers a unique mechanism underlying
arrhythmogenesis and suggests that the anti-epileptic drug
valproic acid may possibly be repurposed for anti-arrhythmic
applications. In this paper by first authors Dr. Chowdhury and
Liu and corresponding author Dr. Wang and colleagues from
University of Manchester UK. The authors used mouse models and
human induced pluripotent stem cells derived cardiomyocytes to
discover a new mechanism linking mitogen activated kinase-kinase
7 deficiency with increased arrhythmia vulnerability in
pathologically remodeled hearts. Mechanistically, mitogen
activated kinase-kinase-7 deficiency in the hypertrophied hearts
left histone deacetylase-2 unphosphorylated, and filamin A
accumulated in the nucleus, which then formed an association with
kruppel-like factor 4 preventing its transcriptional regulation.
Diminished potassium channel reserve caused repolarization delays
resulting in ventricular arrhythmias, and the histone
deacetylase-2 inhibitor, valproic acid restored potassium channel
expression abolishing the ventricular arrhythmias. This study
therefore provides exciting insights in developing a new class of
anti-arrhythmics specifically targeting signal transduction
cascades to replenish repolarization reserve, all for the
treatment of ventricular arrhythmias.


                               
Does the Mediterranean diet improve HDL function in high risk
individuals? Well, the next paper by first author Dr. Hernaiz,
corresponding author Dr. Fito and colleagues from Hospital Del
Mar Medical Research Institute in Barcelona, Spain addresses this
questions. The authors looked at a large sample of 296 volunteers
from the PREDIMED study and compared the effects of two
traditional Mediterranean diets, one enriched with virgin olive
oil, and the other with nuts to a low-fat control diet. They
looked at the effects of these diets on the role of HDL particles
on reverse cholesterol transport, HDL antioxidant properties, and
HDL vasodilatory capacity after one year of dietary intervention.
They found that both Mediterranean diets increased cholesterol
efflux capacity and improved HDL oxidative status relative to the
baseline. In particular, the Mediterranean diet enriched with
virgin olive oil decreased cholesterol ester transfer protein
activity, and increased HDL ability to esterify cholesterol,
paraoxonase-1, arylesterase activity, and HDL vasodilatory
capacity. They therefore concluded that adherence to a
traditional Mediterranean diet, particularly when enriched with
virgin olive oil, improves HDL function in humans.


                               
The final study tells us that among hospitalized medically ill
patients, extended duration Betrixaban reduces the risk of stroke
compared to standard dose enoxaparin. In this retrospective
sub-study of the APEX trial, Dr. Gibson and colleagues from Beth
Israel Deaconess Medical Center and Harvard Medical School in
Boston, Massachusetts randomized 7,513 hospitalized acutely ill
patients in a double-dummy, double-blind fashion to either
extended duration of the oral Factor Xa inhibitor Betrixaban at
80 mg once daily for 35 to 42 days, or standard dose subcutaneous
enoxaparin at 40 mg once daily for 10 days all for venous
thromboprophylaxis. They found that the extended duration
Betrixaban compared with enoxaparin reduced all cause stroke by
almost one half with a relative risk of 0.56 equivalent to an
absolute risk reduction of 0.43 percent and number needed to
treat of 232. The effect of Betrixaban on stroke was explained by
a reduction in ischemic stroke with no difference in hemorrhagic
stroke. The reduction in ischemic stroke was confined to patients
hospitalized with acute heart failure or non-cardioembolic
ischemic stroke.


                               
This paper is accompanied by an editorial by Drs. Quinlan,
Eikelboom, and Hart in which they articulate three reasons that
they think these results are important. First, the results
demonstrated an unexpectedly high rate of new or recurrent
ischemic stroke during the first three months in hospitalized
medical patients receiving standard enoxaparin prophylaxis, the
rate being even higher in patients presenting with heart failure
or ischemic stroke. Secondly, the data demonstrated for the first
time that a NOAC reduces the risk of ischemic strokes in patients
without known atrial fibrillation. Thirdly, the effects of
Betrixaban on stroke were dose dependent, all of the benefits
were seen in those who received the 80 mg dose, whereas the 40 mg
dose did not provide advantages compared with enoxaparin or
placebo. While these results are encouraging, the editorialists
also warn that these are based on a post-hoc analysis and should
be considered hypothesis generating.


                               
Well, that brings it to the end of our summaries. Now for our
feature discussion.


                               
Today our feature discussion focuses on the exciting 10-year
follow up results of the Japanese Primary Prevention of
Atherosclerosis with Aspirin for Diabetes, or JPAD trial. I am
simply delighted to have with me first and corresponding author
Dr. Yoshihiko Saito from Nara Medical University, Japan. As well
as a familiar voice on this podcast, Dr. Shinya Goto associate
editor of Circulation from Tokai University in Japan. Welcome
gentlemen!


Dr.
Goto:            
I am very pleased to have this opportunity. I am always enjoy
listening your podcast, and this is very interesting topic of
aspirin in prevention cardiovascular event in patients with
diabetes, type II diabetes.


Dr.
Lam:              
I couldn't agree more, because the burden of cardiovascular
disease globally is actually shifting to Asia, and the burden of
diabetes especially, is one of the fastest growing in Asia. So a
very, highly relevant topic indeed. Could I start, Yoshi, by
asking you: these are the 10 year follow up results, what
inspired you to take a re-look at the original JPAD results and
to report this 10 year result?


Dr.
Saito:             
The American guidelines said that low-dose aspirin is recommended
to the type II diabetes patient for the primary prevention of
cardiovascular events who are older than 30 years old, and who
are not contraindicated to aspirin. That meant that almost all
type II diabetes patients were recommended to low dose aspirin.
However, at that time there was no direct [inaudible 00:09:49]
evidence for it. So we connected the prospective randomized
control trial that examined the effects of the low dose aspirin
on primary prevention of cardiovascular events in type II
diabetes patients without preexisting cardiovascular disease. The
name of this trial, JPAD trial, that stand for the Japanese
Primary Prevention of Atherosclerosis with aspirin in Diabetes.
We enrolled 2,539 patients who were assigned to the low dose
asprin group or the no aspirin group. So we followed them with a
median follow up period of 4.4 years.


                               
The results of the original JPAD trial were that low dose aspirin
reduced CV events by about 20%, but the reduction could not reach
statistical significance. So I don't know the exact reason, but
one is the reason is low statistical power, because event rate
was about one-third of the anticipated. Another reason is that
low dose aspirin really could not reduce cardiovascular events.
So we decided the extension of the follow up of the JPAD trial to
elucidate the efficacy and safety of long term therapy with low
dose aspirin in type II diabetes patients. This extension study
was named the JPAD 2 study. We followed them up to the median
follow up period of more than 10 years.


                               
In this time the JPAD trial study, we analyzed the patients in a
pod protocol method because the randomized control trial was
ended after 2008. Finally, we analyzed the 992 patients in the
aspirin group, and 1,168 patients in the no aspirin group who
retained the original allocations throughout the study period.
The primary endpoint were composite endpoint of cardiovascular
events including sudden cardiac death, the fatal and the
non-fatal coronary artery disease, fatal and non-fatal stroke,
peripheral vascular disease, and aortic dissection. This end
point is the same as the original JPAD trial. The main results
are the primary endpoints, 15.2% of patients occurred primary
endpoints in aspirin group, and 14.2% in the no aspirin group
occurred in the primary endpoints. So the primary endpoints rate
is singular in both groups, with the hazard ratio is 1.14 with a
95% CI is 0.91 to 1.42 with a p value of 0.2 by log-rank test. So
the low dose aspirin therapy could not reduce cardiovascular
events in the type II diabetes mellitus.


                               
We also analyzed these data by intention to treat analysis, the
results is singular. Again, the low dose aspirin therapy could
not reduce the cardiovascular event in type II diabetes mellitus.
However, I was told the hemorrhagic events, total hemorrhagic
events was singular in both groups, but gastrointestinal bleeding
of about 2% in the aspirin group but only 0.9% in no aspirin
group. That means our gastrointestinal bleeding is doubled in the
aspirin group compared with no aspirin group. This is the main
outcome of the JPAD and JPAD-2 trials.


Dr.
Lam:              
Thank you so much Yoshi, and really congratulations on such a
tremendous effort. I completely applaud the idea of looking at
the 10 year follow up trying to address the issue of whether or
not it was a lack of power that limited JPAD-1, but what you
found really reinforced what you found in JPAD-1, which is low
dose aspirin did not reduce cardiovascular events in the diabetic
group. They're still huge numbers, I'm so impressed that 85% of
the treatment assignment was retained. Then furthermore you even
showed increased gastrointestinal bleeding with aspirin. So
really remarkable results. Can I just ask, are you surprised by
the results, and how do you reconcile it with what was found in
the general population studies like the Physician Health Study,
or the US Preventive Services Task Force, where they really seem
to say that primary prevention aspirin works in the general
population when your risk is a certain amount?


Dr.
Saito:             
I think that we studied only the type II diabetes patients, so it
is not clear that our results are applied to the general
population, but our results is very much similar to the current
European guidelines and American guidelines.


Dr.
Lam:              
That's a very interesting point about diabetic versus
non-diabetic population and the utility of low dose aspirin.
Shinya, you brought this up before. What do you think?


Dr.
Goto:            
For the primary prevention population cohort study, aspirin
demonstrated 25% reduction of cardiovascular event. We are not
recommending aspirin for primary prevention due to the balance of
bleeding and cardiovascular protection, absolute risk. In Yoshi's
paper, in patients with type II diabetes aspirin evened that
[inaudible 00:16:13], and that is very important message he had
shown in this long term outcome randomized trial.


Dr.
Lam:              
Do you think that there are some pathophysiologic differences
when you study a diabetic versus non-diabetic population?


Dr.
Goto:            
Yes, that is a very important topic, and we have very nice review
paper by Dr. Domenico and Fiorito. In patients with diabetes the
platelet time over becomes relatively rapid as compared to
general population. New platelets come to blood and COX-1
inhibition by aspirin cannot reach to enough level in diabetes
patient. Still, this [inaudible 00:16:57] hypothesis, very
interesting hypothesis.


Dr.
Saito:             
I think so, I think so. That review that proposed the same
concept, their higher dose of aspirin as possibly effective for
diabetic patient.


Dr.
Lam:              
That's interesting. Are you planning any future studies Yoshi?


Dr.
Saito:             
Yeah, maybe two times study.


Dr.
Goto:            
But anyway, the event rate is currently very low than the old
[inaudible 00:17:28]. So the sample size should be huge. Huge
sample size is needed for the primary prevention setting to
analyze the effect of aspirin, so the number needed to treat in
the primary prevention setting is more than 1000. If diabetes
patient, aspirin is resistant to aspirin so the number needed to
treat is getting larger. So the sample size is getting larger and
larger. That is not practical to perform that clinical trial.


Dr.
Lam:              
That's a very good point that the contemporary trials like yours
are really challenged by the low event rates because of improved
preventive treatment across the board like high dose statins,
like very, very low LDL targets, and so on. That's a good point.
Actually, could I ask both of you gentlemen, and maybe Shinya you
can start, can you let us know what is it like to perform such a
large rigorous clinical trial in Japan? It must be a lot of
effort. Could you give us an idea?


Dr.
Goto:            
In Japan, medical care system is a little bit different from the
U.S. Every patient covered by the homogeneous health care system
so it means it is rather difficult to conduct a clinical trial. I
appreciate the effort by Professor Saito, Yoshi, it is extremely
difficult to conduct the study. Japan is relatively small island,
patient stick to the clinic so the long term follow up with
relatively low follow up can be expected. [inaudible 00:19:15]
number of patients is a challenge, and Yoshi did succeed it. We
can do that and due to the baseline therapy is quite homogenous,
impact of the clinical care like this has very strong impact.


Dr.
Lam:              
Exactly, and I share your congratulations once again to Yoshi for
really tremendous effort, important results. Thank you so much
Shinya for helping with this paper, and for really highlighting
how really important it is. Did anyone have anything else to add?


Dr.
Saito:             
Yes, I have one thinking, in respect to the Japanese clinical
trials. I think the Japanese evidence, as derived from Japanese
clinical studies is getting better and better in quality. Almost
all Japanese clinical trials enrolled only Japanese patients, so
the way the Japanese not so good at to organize the international
clinical trial because of the, one is the language problem, and
the other is funding problem. In Japanese funding agency, the
AMED, that is similar to the NIH in United States, but AMED is
not so strong as NIH so that they cannot give a bigger budget to
the Japanese clinicians. That is another problem to organize a
big clinical trial. The funding [inaudible 00:20:49]
apprenticeship without holding investigators are very, very
important to be better clinical situation in Japan, I think so.


Dr.
Lam:              
Thank you for listening to Circulation on the Run, don't forget
to tune in next week.