Circulation September 20, 2016 Issue

 


Carolyn:
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. Today we will be diving
deep into issues of resistant hypertension, adherence to
anti-hypertensive medication, and renal denervation. All this by
looking closely at new data from the Renal Denervation for
Hypertension trial. First, here are your summaries of this week's
journal.


 
 
The first paper sought to answer these questions: How can we
better re-stratify patients with long QT syndrome type 3? You
will remember that as the type caused by a gain of function
mutation in the SCN5A sodium channel, and the type that has a
more lethal course than types 1 and 2. Another question is, are
we sure that beta blockers are effective in type 3 long QT
syndrome? Well the current study is by co-first-authors, Dr.
Wilde of Academic Medical Center, Amsterdam, and Dr. Moss from
University of Rochester School of Medicine and Dentistry, which
is the largest multi-center long QT type 3 syndrome cohort
described to date.


 
 
This study was designed to identify the risk and therapeutic
factors associated with cardiac events in patients. The risk
factors evaluated included clinical features such as age, gender,
ECG measurements, the mutation type, and the therapeutic effects
of beta blockers, other medications, and ICD. In almost four
hundred patients with type 3 long QT syndrome, 30% experienced at
least one cardiac event; that is syncope, aborted cardiac arrest,
or sudden death. The risk of a first cardiac event was directly
related to the degree of QT prolongation. Each 10 millisecond
increase in QTC up to 500 milliseconds was associated with a 19%
increase in cardiac events. Prior syncope doubled the risk of
life threatening events. Beta blocker therapy was associated with
an 83% percent reduction in cardiac events in females, however
the efficacy in males could not be conclusively determined due to
low number of events. The take-home message is, in your patients
with long QT syndrome type 3, recognize the very high risk
sub-population with prolonged QTC and a history of syncope.


 
 
The next paper is a basic science paper that reveals a novel way
in which mitochondrial dysfunction may be targeted in heart
failure. This paper is from first author Dr. Li, corresponding
author Dr. Tian, and colleagues from the Mitochondria and
Metabolism Center at University of Washington. These authors
previously found that elevation in the NADH to NAD ratio induces
mitochondrial protein hyperacetylation, and renders hearts highly
susceptible to stresses, and they showed this in a mouse model of
primary mitochondrial dysfunction caused by genetic defects. In
the current study they defined the molecular intermediaries
linking specific NAD sensitive hyperacetylation targets to the
development of heart failure, and further demonstrated the
relevance of these mechanisms in human heart failure.
Specifically, they identified that hyperacetylation of the
regulators of mitochondrial permeability transition poor and
malate-aspartate shuttle, mediates the increased susceptibility
to cardiac stresses. Further, expanding the cardiac NAD pool via
pharmacological or genetic approaches normalized the NADH to NAD
ratio, and thereby normalized protein acetylation in
hypertrophied and failing hearts. Importantly, these measures
improved cardiac function and reduced pathological hypertrophy in
mice. Thus, the clinical implication is that restoring the NADH
to NAD ratio may be an effective and translatable strategy to
treat mitochondrial dysfunction in heart failure.


 
 
The next study broadens our considerations of the benefits versus
risks of intensive anti-platelet therapy in patients with a prior
myocardial infarction, and really suggests that more intensive
anti-platelet therapy should be considered, not only to reduce
the risks of coronary events, but also to reduce the risk of
stroke. This is a paper from Dr. Bonaca and colleagues of the
TIMI study group from Brigham and Women's Hospital in Boston,
Massachusetts, who investigated the efficacy of ticagrelor, 60
milligrams twice a day, for reducing stroke in patients with a
prior myocardial infarction from the Pegasus-TIMI 54 trial.


 
 
You will remember that in the Pegasus-TIMI 54 trial, ticagrelor
was already shown to reduce the risk of major adverse
cardiovascular events when added to low-dose aspirin in stable
patients with prior MI. Of more than 14,000 patients randomized
to placebo or Ticagrelor, 213 experienced a stroke, 85% of which
were ischemic. 18% of strokes were fatal, and another 15% led to
either moderate or severe disability at 30 days. Ticagrelor
significantly reduced the risk of stroke, with a hazards ratio of
0.75, and this was driven by a reduction in ischemic stroke.
Hemorrhagic stroke occurred in nine patients on placebo and eight
patients on ticagrelor. Furthermore, a meta-analysis of four
placebo-controlled trials of more intensive antiplatelet therapy
in more than 44,800 patients with coronary disease confirmed a
marked reduction in ischemic stroke, with a combined hazards
ratio of 0.66. Thus this study really broadens our considerations
of benefits versus risks of intensive antiplatelet regimens for
the long-term secondary prevention in patients with patients with
prior myocardial infarction. It really highlights the broader
benefits in reducing ischemic stroke, and not just coronary
events. In summary, overall, for 1,000 patients initiated on
ticagrelor 60 milligrams twice daily for three years, 13 primary
endpoint events would be prevented, including approximately five
ischemic strokes. This benefit would come at a cost of nine TIMI
major bleeds, but no hemorrhagic strokes or fatal bleeds.


 
 
That wraps it up for our summaries! Now for our feature paper.
Our feature paper today discusses a really important issue that
we face everywhere around the world, and that is the management
of resistant hypertension. We're taking a very interesting look
at the Renal Denervation for Hypertension trial, because we're
actually looking at the adherence to anti-hypertensive therapy,
and what we've learned in this trial. I'm so excited because I am
sitting right here with first and corresponding author Dr. Michel
Azizi, from Georges Pompidou hospital in Paris, France. Hello
Michel, thank you!


 
Michel:
Hello, Carolyn. Thank you also for the invitation to discuss
about the paper.


 
Carolyn:
We're also so lucky to have the associate editor who handled the
paper, Dr. Wanpen Vongpatanasin, associate editor from UT
Southwestern. Welcome, Wanpen.


 
Wanpen:
Hi, Carolyn.


 
Michel:
Hi, Wanpen.


 
Carolyn:
This whole issue of resistant hypertension, I'll tell you, to me
that means someone who's adequately treated, and despite all the
treatment that we can throw at them, they still have a blood
pressure that is above a certain level, right?


 
Michel:
Yes.


 
Carolyn:
But your study seems to tell us that that assumption, that
everyone's receiving treatment and still having high blood
pressure, may need to be questioned, so please tell us a little
bit more about what you found.


 
Michel:
This is a clinical trial where we compared the effect of renal
denervation to medical treatment, optimal medical treatment. We
standardized the anti-hypertensive treatment in the cohort of
patients with resistant hypertension, and then we followed them
on a monthly basis with home blood pressure monitoring. We also
increased the intensity of the treatment every month after
randomization between renal denervation against nothing, because
this is a probe trial, it is not a double blind trial. We gave
them the same treatment in both arms. At the end of the many
study we demonstrated that there was 6 millimeter of difference,
in terms of ABPM, in favor of renal denervation, against the same
medical treatment alone.


 
 
However, because this trial was an open trial, it was open to a
Hawthorne effect, and the possibility that patients or doctors
behave differently in each arm of the study. Those having renal
denervation may be more adherent to the treatment, and those not
being given the new therapy, not being really adherent to
treatment. This was an issue, so we specified analysis. We also
measured drug levels in urine after six months of followup, and
also assessed the exposure to each individual using a peptide in
urine, which is N-acetyl-serylaspartyl-lysyl-proline
(AcSDKP)/creatinine.


 
 
What we found after six months of followup in patients who really
participated to this trial, they were willing to participate to
the study, they signed an informed consent where it was written
that, indeed, we will monitor drug levels. They knew that we
would do this. They also knew that we will follow them very
carefully every month, et cetera, that we'll provide them home
blood pressure monitor for free. They had access to the same
doctor, same nurse, same everything. They could arrive at the
time they wanted in the morning for being investigated. After six
months of followup we found that more than half of these patients
did not take correctly their treatment, and even 15% of them, in
reality, took zero medication over seven medications. This was a
major, major surprise for us in this trial.


 
Carolyn:
I think that's one of the most significant findings, even in a
trial setting, that is such a lot of non-adherents,
anti-habitants, of therapy. It really makes us question when we
say someone has resistant hypertension, is it really that, or do
we have just a very non-compliant patient?


 
Michel:
Yes.


 
Carolyn:
Because it can only be worse in the real-world setting, isn't it?
Congratulations, that was a very striking message to me as well.
What was the other main finding that you wanted to ... ?


 
Michel:
The other finding was that the rate of non-adherence was similar
in both arms. That there was absolutely no influence of being
randomized to the renal denervation group or the medical
treatment group only. This means that the patients were not
influenced, and other physicians behaved similarly in both arms.
Because at the end you have exactly the same rate of
non-adherence to treatment. This is also very important.


 
Carolyn:
Yes, indeed. Wanpen, I was wondering what your thoughts were, and
take-home messages from this paper. We definitely thought it was
significant in the editorial board because you even commissioned
a wonderful editorial by Dr. David Calhoun on this. What are your
thoughts?


 
Wanpen:
In the United States, using the same technique, we found as much
non-adherence. I think there is a lot that we need to do and to
understand what caused non-adherence. The patient should not be
the only party that's to blame. I think that the doctor's as much
of a culprit here to try to tease out what's the barrier to the
treatment. Also, as pointed out by Dr. Calhoun, is that although
the trials show improvement in blood pressure in both groups, at
the end number of medications of patients in resistant
hypertension, they require to take four to five drugs to get the
blood pressure under control. I think this is going to be a
lifelong continuing medication treatment that the physicians have
to face, and to deal with the adherence problem as well. Just
lastly, I think that although people believe that doing drug
levels is only for research purpose, but many people don't
realize that actually many drug levels for anti-hypertensive
drugs actually is clinical available and can be ordered. It takes
a little bit more effort to order it, but it can be done, and
actually our center has been doing that already anyway.


 
Carolyn:
Wow. I cannot say that my center has been doing that in Asia, but
I really have to admit that this paper made me think about it.
Especially the editorial when he highlights it, the very unique
information that is provided by actually measuring the blood
levels. Michel, you were nodding your head vigorously when Wanpen
was saying that we should not just blame the patient. Tell me,
what are your thoughts, and how does this affect your clinical
practice?


 
Michel:
I fully agree with Wanpen. We have to now integrate the fact that
it's accessible, you can measure drug levels through technology,
with mass spectrometry, et cetera. This is very important to
integrate and to change our paradigm that we have to put in our
brain. We have to monitor drug levels. Using this technology we
have to establish a partnership with the patient.


 
 
I think the truth, also, is somewhere, as Wanpen said, we are
also culprits. If patients do not take their treatment, okay,
there may be some benefit and e have to look why they are not
taking pill treatment, but also we are culprits because we don't
listen to them, we don't take enough time, et cetera, et cetera.
But I think patients should not be only blamed, so it opens a new
possibility to discuss with the patient about the fact that we
didn't find the drug in levels in their urine, et cetera.


 
 
However, taking into account that there will be this toothbrush
effect, that is, "Patient, brush your teeth when you go to see
the dentist," you'll take the pills when you go to see the doctor
so you can be treated. This is one of the difficulties. However I
think it's a new possibility to discuss with the patient of his
or her difficulties in taking the pills. It gives us the
opportunity to discuss, to take time with our patients.


 
Carolyn:
It's really fascinating, you're talking from a system based in
Europe. You're based in Paris.


 
Michel:
Yes.


 
Carolyn:
Wanpen just said that she's doing it, and she's based in the US.
Do you now routinely, maybe, monitor these medication levels?


 
Michel:
Yes, yes, yes.


 
Carolyn:
Wow.


 
Michel:
In the hospital we have these mass spectrometer platforms, so we
have access to this, and we are working with the house authority
to have the reimbursement. Because I think it's important,
because if it's not reimbursed there is also a problem.


 
Carolyn:
Of course.


 
Michel:
We are working to see how it could be reimbursed for labs doing
these measurements.


 
Carolyn:
But this is for maybe selected resistant hypertensive patients
that are difficult to ... ?


 
Michel:
Yes, absolutely. Those very difficult to manage. I think, as a
rule of thumb, that after four or five drugs given to the
patient, if the patient-


 
Carolyn:
Yeah, we should start questioning, are they taking it.


 
Michel:
If the patients do not have secondary hypertension, we should
really start questioning ourself whether they are taking or not
the treatment, even if they are looking right in your eyes and
telling you, "Yes, doctor, I'm taking all the pills."


 
Carolyn:
Wanpen, how about the reimbursement issues and things like that
in the United States? How are you getting it done in your
institution?


 
Wanpen:
Actually the coding for doing drug levels, it's actually generic.
It's the same coding for Digoxin or Cyclosporine. They actually
don't care about what the name of the drug. Strangely, they're
coded by the technique, so that's how we go with it, but we have
to put in miscellaneous "other" for, we wanted to test for this.
That's how we get around it.


 
Carolyn:
Do you do that again routinely, or in selected patients that are
difficult to manage hypertensive?


 
Wanpen:
Obviously we have to be selective, so we select from people who
we would suspect are non-adherent, but they say they're taking
it. But if they already came in and made that they're not taking
the drug, there's no point doing that for the clinical purpose.
We're doing it for people who we suspect it, and we use it the
way ... Actually we shall describe very well, not only just to
find what drug they're not taking, because when they're not
taking, only about 30% are not taking everything, about 20% not
taking one or two drugs. When we drill down to that drug they
say, "I have side effects to beta blocker and I don't want to
tell my physician that I have problems taking it, but I just not
take it." I think that's what led us to pinpoint the problem a
little bit better with this technique.


 
Carolyn:
What a lot of practical advice, and congratulations once again
for very, very meaningful findings. I learned a lot this time. I
don't do this, and so I'm definitely going to think about this
much more because of your work. Thank you very much Wanpen,
Michel.


 
 
And thank you, listeners, for tuning in this time. Remember,
you're listening to circulation on the run. Listen in again next
week. Thanks.