Circulation January 9, 2018 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 Center and Duke‐National University of Singapore. Our
featured discussion this week focuses on the new 2017 ACC/AHA
high blood pressure guidelines, and the potential impact of these
guidelines on the U.S. population. A must listen, coming right up
after these summaries.


The first original paper this week provides insights into how
extracellular matrix remodeling contributes to in‐stent
restenosis and thrombosis. First author, Dr. Suna, corresponding
author, Dr. Mayr, and colleagues from King's College London,
implanted bare metal and drug‐eluting stents in pig coronary
arteries with an overstretch and then harvested the stented
segments up to 28 days poststenting for proteomics analysis of
the media and neointima.


The authors found significant differences by proteomics in the
extracellular matrix of coronary arteries after stent
implantation. Most notably, an upregulation of aggrecan, a major
extracellular matrix component of cartilaginous tissues that
confers resistance to compression. In fact, this study provided
the first evidence implicating aggrecan and aggrecanases in the
vascular injury response after stenting. This opens a door to
consideration of aggrecanase activity as new drug targets that
may alter extracellular matrix remodeling in the vasculature.


The next paper tells us that empagliflozin could address a
significant unmet need in patients with chronic kidney disease.
First and corresponding author, Dr. Wanner, from Wurzburg
University Clinic in Germany investigated the effects of
empagliflozin on clinical outcomes in patients with chronic
kidney disease in the EMPA‐REG OUTCOME trial, where patients with
type 2 diabetes, established cardiovascular disease, and an eGFR
above 30 at screening were randomized to receive empagliflozin or
placebo, in addition to standard of care.


In the current study, prevalent kidney disease was defined as an
eGFR of less than 60 or urine albumin/creatinine ratio of more
than 300 at baseline. In these patients, empagliflozin reduced
the risk of cardiovascular death by 29% compared with placebo,
reduced the risk of all‐cause mortality by 24%, and reduced the
risk of hospitalization for heart failure by 39%, and the risk of
allcause hospitalization by 19%.


The effects of empagliflozin on these outcomes were independent
of renal function or albuminuria status at baseline. Furthermore,
the adverse event profile of empagliflozin was similar across
subgroups by renal function at baseline. Adverse events of
particular concern in this population, such as urinary tract
infection, acute renal failure, hypokalemia or fractures, lower
limb amputations or hypoglycemia were not increased with
empagliflozin compared to placebo.


The next study provides mechanistic insights into exercise
intolerance in heart failure with preserved ejection fraction or
HFpEF. First author, Dr. Houstis, corresponding author, Dr. Lewis
and colleagues from Massachusetts General Hospital, investigated
the mechanism of exercise intolerance in 79 patients with HFpEF
and 55 controls referred for cardiopulmonary exercise testing who
were also studied with invasive monitoring to measure
hemodynamics, blood gases and gas exchange during exercise.


These measurements were used to quantify six steps of oxygen
transport and utilization in each HFpEF patients, identifying the
defective steps that impaired each one's exercise capacity. The
authors then quantified the functional significance of each
pathway defect by calculating the improvement in exercise
capacity that a patient could expect from correcting the defect.


The authors found that the vast majority of HFpEF patients
harbored defects at multiple steps of the pathway, the identity
and magnitude of which varied widely. Two of these steps, namely,
cardiac output and skeletal muscle oxygen diffusion were impaired
relative to controls by an average of 27% and 36% respectively.
Due to interactions between a given patient's defects, the
predicted benefit of correcting any single defect was often
minor. At the individual level, the impact of any given pathway
defect on a patient's exercise capacity was strongly influenced
by comorbid defects.


The authors concluded that a personalized pathway analysis could
identify patients most likely to benefit from treating a specific
defect. However, the system properties of oxygen transport favor
treating multiple defects at once, such as, with exercise
training.


What are the potential benefits or risks of intensive systolic
blood pressure lowering in individuals with a low diastolic blood
pressure? Well, the final paper today tells us. In this study by
first and corresponding author, Dr. Beddhu, and colleagues from
Salt Lake City in Utah, a post hoc analysis of the SPRINT trial
was performed. Remember that the SPRINT trial was a randomized
control trial that compared the effects of intensive versus
standard systolic blood pressure control in older adults with
high blood pressure at increased risk of cardiovascular disease.
The current post hoc analysis examined whether the effects of the
systolic blood pressure intervention differed by baseline
diastolic blood pressure.


The authors found that there were U‐shaped relationships of
baseline diastolic blood pressure with the primary cardiovascular
disease outcome and all‐cause death. However, the beneficial
effects of intensive systolic blood pressure lowering on the
primary cardiovascular disease outcome in all‐cause death were
not modified by baseline level of diastolic blood pressure.


Increased risk of kidney events and serious adverse effects of
the intervention were consistent across baseline diastolic blood
pressure quintals. Therefore, there was no evidence that the
benefit of intensive systolic blood pressure lowering differed by
baseline diastolic blood pressure levels.


These findings suggest that the reason for the observed
associations of worse outcomes with lower diastolic blood
pressure was due to underlying processes, such as increased
arterial stiffness that lead to a decline in diastolic blood
pressure, rather than the level of diastolic blood pressure per
se. Furthermore, lower levels of diastolic blood pressure within
the ranges examined in SPRINT, should not be an impediment to
intensive treatment of hypertension, at least in those without
diabetes or stroke.


Well, that wraps it up for our summaries. Now for our feature
discussion. The ACC/AHA guidelines for the management of
hypertension in adults has really been a hot topic. Just
published this year, and it really updates the seventh JNC
report, which was published in 2003. Well, today's feature paper
deals directly with a comparison of these two guidelines and how
it may impact our practice.


I'm so pleased to have with us today the first and corresponding
author of this paper, Dr. Paul Muntner, from University of
Alabama at Birmingham and a very familiar wonderful voice, Dr.
Wanpen Vongpatanasin, associate editor from UT Southwestern.
Welcome!


Dr. Paul Muntner: Hi. Thank you for having me.


Dr. Wanpen Vongpatanasin: Hi, Carolyn.


Dr. Carolyn Lam: Paul, could I ask for you to start by painting
the differences between the 2017 ACC/AHA guidelines and the JNC
7? We understand you were part of writing the guidelines, so who
better than to draw our attention to the main differences.


Dr. Paul Muntner: I think that the new guideline, the ACC/AHA
guideline, it was fairly comprehensive included 15 chapters, so
there's a lot of new information in the guideline, everything
from a dedicated section on the measurement of blood pressure to
aspects of patient care.


The manuscripts featured in "Circulation" in this issue is
focused on, in the past, there's different blood pressure
thresholds in the guideline for defining hypertension, as well as
recommendations for antihypertensive medication treatments, as
well as blood pressure goals.


As everyone probably knows form JNC 7, hypertension was defined
as a systolic blood pressure greater than or equal to 140 mmHg
and/or a diastolic blood pressure greater than or equal to 90
mmHg, versus in the 2017 ACC/AHA guideline, these were lowered to
130/80.


In terms of treatment recommendations, there's really a
fundamental shift with the new guideline, where the new guideline
focuses not just on blood pressure levels, but also on overall
cardiovascular disease risk. So going to the new guideline,
people are recommended treatment if their blood pressure is above
140/90 but also there's a group with a blood pressure in the 130
to 139 range for systolic blood pressure, of 80 to 89 mmHg for
diastolic blood pressure, who are recommended treatment if they
have a high cardiovascular disease risk.


Finally, I'll just finish with this last note is that blood
pressure control for people taking antihypertensive medication is
now 130/80 so a goal blood pressure for people taking
antihypertensive medication is systolic blood pressure less than
130 mmHg, and a diastolic blood pressure less than 80 mmHg.


Dr. Carolyn Lam: That was beautifully explained. Paul, I just
really loved table 1 of your paper, and I want to refer our
audience to it. It so nicely summarizes the differences between
the 2017 guidelines and JNC 7. At risk of oversimplifying, when
you compare the two in this approach, it's sort of comparing
using a cardiovascular risk in conjunction with blood
pressure‐type approach with a blood pressureonly number approach,
isn't it?


Dr. Paul Muntner: Right. I think that's a key important piece of
the new guideline and really CVD risk is used in conjunction with
blood pressure levels to guide the recommendation to initiate
antihypertensive medication. This decision was based on a wide
variety of data from randomized trials, observational studies, as
well as simulation or economic analyses that consistently showed
the benefits of considering an individual's overall
cardiovascular disease risk and providing effective and efficient
treatment for lowering blood pressure.


Dr. Carolyn Lam: Right. And you analyzed the impact of this in
the NHANES data in today's paper. Could you tell us a bit more
about that?


Dr. Paul Muntner: The U.S. National Health and Nutrition
Examination Survey, or NHANES, provides an opportunity to
generate national representative point estimates on the
prevalence of hypertension and treatment recommendations. So
we're able to use data on about 9500 U.S. adults. Each person
came in for a clinic examination where they had their blood
pressure measured three times, and they were asked about their
use of antihypertensive medication. What we found was the
prevalence of hypertension, or the percentage of U.S. adults with
hypertension according to the new guideline, is about 46%, which
compares to 32% according to the JNC 7 guideline, so really a big
increase in the prevalence of hypertension of about 14%. However,
by using the combination of risk and blood pressure, we're not
recommending treatment for everyone with hypertension but rather
people with hypertension with very high blood pressure as well as
those at high cardiovascular disease risk.


So antihypertensive treatment, pharmacological antihypertensive
treatment, is now being recommended for about 36% of U.S. adults
compared to 34% of U.S. adults according to JNC 7. The rest of
the people with hypertension are recommended nonpharmacological
therapies; exercise, diet, alcohol reduction, weight loss for
people who are overweight and obese.


Really, it's an opportunity to treat people with pharmacological
therapy if they're high risk. Then for people who aren't high
risk, there's an opportunity for nonpharmacological therapies, so
they can, hopefully, prevent the need for further treatment.


Overall, this equates to about 103 million U.S. adults with
hypertension, so it's a very large number. However, only about 82
million of these individuals are recommended pharmacological
antihypertensive treatment, so there's a big portion of the U.S.
population who have hypertension, have high blood pressure, yet
we think would benefit from nonpharmacological therapy.


Dr. Carolyn Lam: Wanpen, could I get you to chime in on what you
think of the clinical implications of today's paper?


Dr. Wanpen Vongpatanasin: I think that this paper gives us at
least reassurance that although we have 30 million more people
with hypertension now, not all of them have to be started on
medication right away. But it also put an emphasis on
cardiovascular risk assessment, which we as the cardiologist are
already doing this on a regular basis. It is a major step forward
to incorporate cardiovascular risks as another way to gauge how
people should be treated intensively, which we like that aspect
of it.


Dr. Carolyn Lam: I agree. I think it's reassuring because most
people think, "Oh, my goodness. We have got so much more
hypertensives to manage." But then it tells us that a
restratified approach really keeps it manageable, I suppose. But
Wanpen, did you have some specific concerns or questions?


Dr. Wanpen Vongpatanasin: We look at the people who by JNC 7
calls prehypertension, which it's now some of them turn out to be
a stage 1 hypertension. The question I have for Paul is that even
though guidelines call for nonpharmacologic treatment first, the
guidelines said give a try from three to six months, but what
happens after that if they're still not reaching the goal?


Would people on the guidelines propose drug treatment eventually
because, as you know, nonpharmacology treatment is easier said
than done. Even though you might be able to tackle some aspect of
it, but I doubt you can tackle everything; exercise, diet,
sodium, weight loss all at the same time in a three to six month
period.


Dr. Paul Muntner: It's a great question and it's something that
the guidelines really spent a lot of time considering and
reviewing the evidence. First, what the recommendation is that we
recommend nonpharmacological intervention as you mentioned and
the re‐evaluation. If the person's blood pressure remains in the
stage 1 hypertension range and they're not a high cardiovascular
disease risk, then they are recommended to continue attempts at
the nonpharmacological interventions.


I've been asked several times since the guideline has been
published, "What, are we supposed to just wait until people
become high risk?" And my viewpoint on this is, it's hard enough
to get people to adhere to their medications currently, let's be
judicious about this, focus on the high‐risk people, and maybe if
we can communicate with people that have high‐risk for
cardiovascular disease, we can work with patients to improve
medication adherence and really focus on the low‐risk people
in preventing the need for lifelong therapy.


Dr. Wanpen Vongpatanasin: That's great, I think that's really
helpful in clarifying this point. Because even if you say that 30
million doesn't need to be started on the drug right away, that
eventually have to be started on drug in six months, I think that
doesn't really give us a reassurance but, obviously, we still
have to continue to


work on these patients who are on the fence of
needing pharmacology intervention.


Dr. Paul Muntner: Right. I think what's interesting here is a lot
of people since the guideline has been published have said to me,
"Now this is done." I said, "No. Now we're really just starting.
Now is the most important part of the guideline, which is
implementation." And how are we going to implement the guideline,
which, as we were just discussing, isn't just about initiating
pharmacological therapy, but it's also about the
nonpharmacological therapies as well as medication adherence and
all these other issues that are in the guideline, proper
measurement of blood pressure, etc.


I think that now is going to be the most important time to really
have a big impact on our patients' lives by really using the
evidence and now that it's in the guideline, we're using the
evidence to direct treatment appropriately.


Dr. Carolyn Lam: Indeed, Paul. Just one thing. Along the lines of
implementation, how about the issue of the lower target BP, to
treat to? What did your study from NHANES show about that,
numbers reaching targets, and do you see that as an issue?


Dr. Paul Muntner: It's an interesting question because the
findings from our study found that it's currently over half of
U.S. adults according to the new guideline, over half of U.S.
adults on antihypertensive medication, have blood pressure above
the goal in the new guideline. So in our study, 53% of U.S.
adults taking antihypertensive medication had a blood pressure
above 130/80. This represents an increase from the JNC 7
guideline of people with blood pressure above 140/90, of course,
of about 14.4%. According to our estimates, there are about 8
million U.S. adults who are going to be recommended more
intensive antihypertensive medication.


The blood pressure of less than 130/80 is a uniform goal for all
people taking antihypertensive medication. This comes from
several meta‐analyses that have consistently shown the
cardiovascular and mortality risk reduction associated with
achieving a blood pressure of less than 130/80. I think there's
very firm evidence to stand on.


One interesting thing from the guidelines, it's in one of the
tables, and I think it's a very important point to make, is that
a lot of people who have above goal blood pressure, according to
the new guideline, they're only taking one or two classes of
antihypertensive medication. The vast majority of them are not
taking multiple classes of antihypertensive medication, so we
feel that these therapies can be optimized and we're not going to
be pushing people into antihypertensive polypharmacy but rather
they can receive substantial risk reductions without really
giving them too many additional pills.


Dr. Carolyn Lam: Wow. Really about implementation. Wanpen, did
you have any other comments before we close?


Dr. Wanpen Vongpatanasin: Yes, I think that is really interesting
to see also with these guidelines how is this going to be
embraced to the rest of the world. Actually, prior to this
guideline, at least hypertension control rate in the U.S. is
better than most countries, European countries, as well as in
Asia. But now even lowering the bar, we use the same criteria for
the rest of the world, that would be a lot worse control rate
than now. I think it will be challenging, not only in this
country but throughout the world.


Dr. Paul Muntner: That's a great point. Obviously, these
guidelines are U.S. guidelines, however, new European guidelines
should be coming out in 2018, is what I've heard. I think that
even though these guidelines were developed by the American
College of Cardiology and the American Heart Association, the
data that we're using really comes from worldwide evidence. The
evidence didn't stop at the borders. A lot of the evidence that
was used in choosing the blood pressure levels to define
hypertension, the blood pressure levels to recommend
pharmacological interventions, as well as the blood pressure
goals do come from other countries. A lot of data from Asia,
Europe, Australia, so I think that the data used in these
guidelines should be generalized when it's out of the United
States.


I think there may be challenges with implementing these
guidelines in different settings, and, obviously, a lot of things
will have to be tailored to where they will be implemented.
However, the overall goal is to reduce the burden of
cardiovascular disease and renal disease related to hypertension
and, hopefully, that can be a worldwide goal.


Dr. Carolyn Lam: What a great reminder. It is worldwide data,
worldwide evidence for a worldwide problem. Well, listeners, you
heard it right here on "Circulation on the Run." Thank you so
much for joining us today and don't forget to tune in again next
week.