Circulation January 24, 2017 Issue

 


Dr Carolyn
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 Centre and
Duke-National University of Singapore. In just a moment, we're
going to be discussing new results of the pioneer trial, and the
patient with atrial fibrillation who undergoes intracoronary
stenting, a familiar conundrum. What's the role of NOACs? Is
there still a role for full-dose triple therapy with warfarin?
First, here's your summary of this week's journal.


The first paper tells us about the clinical impact of left atrial
appendage closure. Dr. Melduni and colleagues from the Mayo
Clinic in Rochester, Minnesota, studied 9,792 patients undergoing
bypass or valve surgery between 2000 and 2005. They used
propensity score matching to estimate the association of left
atrial appendage closure with early post-operative atrial
fibrillation- defined as atrial fibrillation within 30 days of
surgery- ischemic stroke, and mortality. They found that after
adjustment for treatment allocation bias, left atrial appendage
closure during routine cardiac surgery was significantly
associated with an increased risk of early post-operative atrial
fibrillation, and did not influence the risk of stroke or
mortality.


They therefore concluded that it remains uncertain whether
prophylactic exclusion of the left atrial appendage is warranted
for stroke prevention during non-atrial-fibrillation-related
cardiac surgery.


The next study provides pre-clinical evidence that genes on sex
chromosomes may contribute to the sexual dimorphism of abdominal
aortic aneurysms. That is, we well know that abdominal aortic
aneurysm is a male-predominant disease. Now, in this paper, by
first author Dr. Alsiraj, corresponding author Dr. Cassis and
colleagues from the University of Kentucky, female
LDL-receptor-deficient mice, with an XX or XY sex chromosome
complement, were infused with angiotensin II for 28 days to
induce abdominal aortic aneurysms. DNA microarrays were performed
on the abdominal aortas, and to mimic the males, the female mice
were administered a single dose of testosterone.


They found that an XY sex chromosome complement, in phenotypic
females, profoundly influenced aortic gene expression profiles
and promoted abdominal aortic aneurysm severity. When XY females
were exposed to testosterone, aneurysm rupture rates were
striking. The mechanisms for augmented abdominal aortic aneurysm
severity in XY females included increased inflammation, augmented
matrix metalloproteinases, and oxidative stress. These results,
therefore, demonstrate that genes on the sex chromosomes regulate
aortic vascular biology and contribute to sexual dimorphism of
aortic abdominal aneurysms. Sex chromosome genes may therefore
serve as novel targets for sex-specific abdominal aortic aneurysm
therapeutics.


The next two studies shed light on the mechanism of action of
PCSK9 monoclonal antibodies on lipoprotein metabolism. In the
first study, Dr. Watts and colleagues from University of Western
Australia carried out a two-by-two factorial trial, of high-dose
atorvastatin versus evolocumab on stable isotope tracer kinetics
in 81 healthy, normal lipidemic, non-obese men.


They found that both atorvastatin and evolocumab independently
accelerated the fractional catabolism of VLDL apoB, IDL apoB, and
LDL apoB. On the other hand, evolocumab, but not atorvastatin,
also decreased the production rate of IDL apoB and LDL apoB. The
reduction of LDL apoB and LDL cholesterol was significantly
greater with a combination versus either mono-therapy. In
summary, they found that in healthy, normal lipidemic men,
evolocumab decreased the concentration of atherogenic
lipoproteins, particularly LDL, by accelerating their catabolism,
and by reducing IDL and LDL production. The latter effects are
incremental to statins.


The second paper to deal with this topic comes from Dr. Ginsberg
and colleagues from Columbia University in New York, who studied
18 participants, this time 10 of whom were women, who completed a
placebo-controlled two-period study, receiving two doses of
placebo followed by five doses of alirocumab. These authors found
that alirocumab decreased LDL cholesterol and LDL apoB by
increasing IDL and LDL apoB fractional clearance rates, and by
decreasing LDL apoB production rates. These results were
consistent with increases in LDL receptors available to clear IDL
and LDL from the blood during PCSK9 inhibition. These two papers
are discussed in a beautiful accompanying editorial by Dr. Chris
Packard from University of Glasgow. In his editorial entitled
"Unpacking and Understanding the Impact of PCSK9 Inhibitors on
Apolipoprotein B Metabolism." Those were your highlights! Now for
our feature discussion.


Today we are going to be discussing one of the most common
conundrums in all of cardiovascular medicine, and that is the
care of patients with atrial fibrillation who also need
percutaneous coronary intervention. Of course, both dual
antiplatelet therapy and oral anticoagulation therapy would be
indicated to reduce the risk of stent thrombosis and
thromboembolism in atrial fibrillation, respectively. However,
with the intensification of the anti-thrombotic regimen, there is
the inevitable trade-off with more bleeding. Now, to discuss
this, we have the first and corresponding author on a very novel
study of the pioneer trial, and that is Dr. Michael Gibson, from
Harvard Medical School and Beth Israel Deaconess Medical Center.
We also have the editorialist for this very exciting paper, Dr.
Deepak Bhatt from Brigham and Women's Hospital, and finally, we
have Dr. Dharam Kumbhani, associate editor from UT Southwestern.
Welcome, gentlemen!


Dr Deepak
Bhatt:           Thank
you.


Dr Michael
Gibson:         
Thanks.


Dr Dharam Kumbhani:   Thank you.


Dr Carolyn
Lam:               
So, Michael, could I start with you? This is a sub-study of the
pioneer study. Could you tell us how this is different from the
primary results, what were you looking for, and what you found?


Dr Michael
Gibson:          As
you know, as [inaudible 00:07:40] said, we have a lot of bleeding
with conventional triple therapy, and we used two regimens to try
and reduce that bleeding. One was a reduced dose of rivaroxaban,
15 milligrams, plus thienopyridine. The other strategy was baby
dose rivaroxaban, 2.5 milligrams twice a day, plus DAPT. What we
found in the overall study was a significant reduction in
bleeding- from, say, 26.7% down to 18% for riva plus DAPT- that's
the baby dose plus DAPT- and down to 16.8% for the 15 milligrams
of riva plus the thienopyridine.


You'd have to treat about 11 to 12 patients to prevent one
significant bleeding event. That's the mainstay. What we found in
this very, very important sub-study is that that was associated
with reduction in hospitalization. All-cause hospitalization was
reduced, and cardiovascular hospitalization went down from 28.4%
to about 20% for the two regimens. Bleeding with hospitalization
went down, from 10.5% to about 6%. At the end of the day, you'd
only have to treat 10 to 15 people to prevent one
hospitalization, so from a health economic perspective, and from
a patient viewpoint and hassle perspective, this was very
important.


Dr Carolyn
Lam:               
In fact, Michael, I would say from a clinician-cardiologist
perspective, these results are really very applicable. In fact, I
really like, in the accompanying editorial, what Deepak wrote,
that it may be one of those rare occasions where a sub-study
provides very clinically meaningful information compared to the
primary study. Deepak, would you like to elaborate a little bit
more about that?


Dr Deepak
Bhatt:            
Sure. A really great point that you've raised. It wasn't, in
fact, a sub-study we're talking about in Circulation. It was an
analysis from the overall trial, looking at a different endpoint
than the primary endpoint, the hospitalization, and the composite
of hospitalization and mortality. I think that's a very important
endpoint. If it were a heart failure trial, for example, that's
the endpoint everyone would hone in on- mortality and
hospitalization. The fact that that was significantly reduced, I
think, is very clinically meaningful. Mike mentioned the economic
implications, which for sure are there, by reducing
hospitalizations and re-hospitalizations.


The impact on cardiovascular hospitalizations- the reduction
there- I find particularly remarkable. The reduction in bleeding,
of course, is good, and in its own right has a great deal of
value, but the additional reduction in cardiovascular
hospitalizations, I think, is quite reassuring for those that are
worried about the efficacy of the two experimental regimens that
he and his colleagues studied. Sure, the trial's not powered in
each individual sub-group for rare events like stroke, but the
fact that CV hospitalizations are not increased, and in fact
reduced, tells me that this is a winning strategy or strategies.


Dr Carolyn
Lam:               
Right. Michael, another issue, though- this is open label, and I
suppose one of the criticisms could be that there is a bias for
clinicians managing patients on the traditional Vitamin K
antagonist to maybe hospitalize patients more for some reason.
What is your response to that?


Dr Michael
Gibson:         
That is always the criticism of an open label trial, but again,
the events were adjudicated, and for the heart events, that's
done in a blinded fashion, so it's reassuring that there was a
blinded assessment of the heart events.


Dr Carolyn
Lam:               
True. How about comments on generalizability? I mean, what do you
think? Trial setting, real world ...


Dr Michael
Gibson:         
Yeah, I think that's one of the advantages. This was very much a
real-world kind of study. It was truly done throughout the world.
We had a very broad entry criteria. Anyone who was getting a
stent put in- you didn't have to have ACS, although about half
the patients did. The only real exclusive criteria was you
couldn't have any bleeding or be profoundly anemic. You couldn't
have a stroke or [TIA 00:11:58] in the past. Other than that, it
made real-world practice in a lot of ways.


Dr Dharam Kumbhani:   This is Dharam. If I may ask both
the other people on the call, is ... Rivaroxaban is not FDA
approved, in these doses, for use. I'm wondering if they might
provide some comment, given the benefit that we see in this
trial, overall, what their thoughts are and what the next steps
might be.


Dr Carolyn
Lam:               
Sure. Maybe Michael, then Deepak?


Dr Michael
Gibson:         
Yeah, that's a good point. It is important to point out that
you'd need to check the prescribing information in your country.
In some countries- I think it's about 54 countries- the 2.5
milligram dose is available. It is approved for ACS, but is not
approved for a-fib. Then, you have a dose of 20 milligrams that's
approved worldwide for a-fib, but there are some countries- it's
important to note, in some countries, 15 milligrams is the full
dose that's approved- say, in Japan and Taiwan. There are
Japanese studies showing that 15 milligrams was not only safer
than warfarin, but more efficacious than warfarin in a trial like
J-ROCKET. You're right, the 15 milligram dose is available in the
US- it's approved for renal insufficiency, but at this time, it's
not labelled for the ACS or stented patient.


But again, physicians are at liberty to look at this data, which
is the first real data that we have to guide decision-making in
this setting, and they're at liberty to make their own choices.


Dr Deepak
Bhatt:            
Yeah, I would agree with that assessment, and emphasize ... Like
Mike said, it's an international audience for Circulation, so I
would say, look in your own country, and in many parts of Europe,
the 2.5 milligram rivaroxaban dose is available and approved for
ACS, and could therefore be used for this purpose, though not
strictly falling within the label indications. In the US, there's
the 15.


I think, if I just answer the previous question, the results are
very generalizable, and for doctors that critique that point, I'd
say, "Why didn't you enroll your patients in the trial?" There's
the RE-DUAL as well, that's ongoing, with dabigatran, AUGUSTUS
with apixaban, and I'm missing one that's also ongoing as well, I
think, but there are four different trials that are out there.
The Pioneer was the first to report ...


Dr Carolyn
Lam:               
I think you're thinking of the Entrust AF-PCI with Edoxaban.


Dr Deepak
Bhatt:            
The most recent one, yes. I forgot the acronym, there. If people
are really thinking that the results don't apply to their
patients, well, there are trials that are ongoing. Enroll your
patients. But to say, "Oh, my patients, I'm not going to enroll
them in the trial," and then say, "The results aren't
generalizable," I always find that an odd thing. I think the
results are very generalizable. The one word of caution I would
say, though, is to make sure to renally dose, as was done in the
trial. That is, there was a downward adjustment in dose from the
15 milligrams to the 10. In real life, we've seen in registries
with NOAC use, whether it's rivaroxaban or any of the others, a
lot of times, the renal function is not carefully monitored in
those patients that are on the fringe in terms of their renal
function, and that's the one situation NOACs can backfire, where
the dose isn't corrected for their degree of renal dysfunction.
Other than that one caveat, I think the results are quite
generalizable.


Dr Carolyn
Lam:               
Excellent comments. We should wrap up soon, but not before I want
to ask Dharam. Thank you for managing this beautiful paper. What,
to you, is the take-home message for clinicians out there?


Dr Dharam Kumbhani:   Yeah, it was an absolute honor
and delight to manage this, and I think the paper's great. The
editorial's great. It's gotten a great response. I think the
take-home message is that this is a very clinically relevant
question, and a very clinically relevant trial, and it shows that
the needle will be moving towards using non-VKA-based agents,
especially in patients such as this, who have both a-fib and PCI.
I think this is very exciting space, a very important space. This
trial suggests that if you use the strategy rivaroxaban low dose,
with or without a DAPT, that it is safer, both in terms of
mortality and bleeding, compared with what is traditionally being
used with warfarin plus DAPT. I think this was a very, very
exciting trial.


Dr Carolyn
Lam:               
Indeed, and congratulations to all three of you. Thank you so
much for joining me on Circulation On The Run. Thank you,
listeners, for joining us too, and don't forget to tune in next
week.