Sep 19, 2016
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.