Circulation February 8, 2022

Please join author David Webb and Editorialist Steven
Smith as they discuss the original research article “Regular
Acetaminophen Use and Blood Pressure in People With Hypertension:
The PATH-BP Trial" and the editorial "Acetaminophen-Induced
Hypertension: Where Have All the "Safe" Analgesics
Gone?"


Dr. Carolyn Lam:


Welcome to Circulation On The Run, your weekly podcast summary
and backstage pass to the journal and its editors. I'm your host
today, Dr. Carolyn Lam, associate editor from The National Heart
Center in Duke National University of Singapore. And I'm so
missing my co-host Dr. Greg Hundley, who can't make it today, but
will be back next week. Now, I have the privilege of telling you
all about the exciting papers in today's issue, but before I even
get there, I need to let you know that coming right up is a
discussion you are not going to want to miss. It deals with an
issue that we encounter very commonly and perhaps should have
questioned many times, but haven't yet. What is it? Well, regular
acetaminophen use and its blood pressure effect. Acetaminophen,
what we commonly call paracetamol or Tylenol depending where
you're coming from, but have we ever stopped to really ask, does
this impact blood pressure? We're going to find out more in the
path BP trial coming right up, but first here are your summaries.


Dr. Carolyn Lam:


The first original paper I'd like to tell you about is a study
representing additional four years a follow up from the Danish
trial. Now recall that Danish was a trial that found that primary
prevention ICD implantation was not associated with an overall
survival benefit in patients with non-ischemic systolic heart
failure, doing a median follow-up of 5.6 years. Although, there
was a beneficial effect on all-cause mortality in patients aged
70 years or younger. Now, the current study led by Dr. Lars Køber
from Copenhagen University Hospital and colleagues showed that
during a median follow up of now 9.5 years, ICD implantation did
not provide an overall survival benefit in patients with
non-ischemic systolic heart failure. In patients age 70 years or
younger, however, ICD implantation was associated with a lower
incidence of all-cause mortality, cardiovascular death, and
sudden cardiovascular death.


Dr. Carolyn Lam:


The next original paper reports on pre-specified analyses from
the FIGARO-DKD trial assessing the impact of finerenone known on
clinically important heart failure outcomes. Now recall that
FIDELIO-DKD and FIGARO-DKD, in those trials finerenone, which is
a selective nonsteroidal mineralocorticoid receptor antagonist,
improved cardiovascular outcomes in patients with albuminuric
chronic kidney disease and type two diabetes. In the current
study, Dr. Filippatos from Attikon University Hospital in Athens,
Greece and colleagues presented the pre-specified analyses of
FIGARO-DKD describing novel heart failure related outcomes, which
were not previously published in finerenone studies, and these
included new onset heart failure. Different outcomes containing
first or total hospitalization for heart failure events in the
overall population. The results indicated that in patients with
chronic kidney disease and type two diabetes on a maximum
tolerated dose of renin-angiotensin system inhibitor therapy,
fenerenone reduced new onset heart failure and improved heart
failure related outcomes irrespective of history of heart
failure. This is the first indication that a nonsteroidal
mineralocorticoid receptor antagonist may provide benefit in a
population with chronic kidney disease and type two diabetes, in
which patients with heart failure with reduced dejection fraction
or symptomatic NYHA 2-4 were excluded, thus indicating that
patients with type two diabetes and chronic kidney disease at
risk of heart failure or with early stage heart failure may
indeed benefit from fenerenone treatment.


Dr. Carolyn Lam:


The next original paper shows for the first time, a role of the
nuclear receptor Rev-Erb, a key component of the circadian clock
in obesity. So, co-corresponding authors, Dr. Song from Chinese
Academy of Medical Sciences and Peking Union Medical College in
Beijing, China, as well as Doctors Zheng Sun, both from Baylor
College of Medicine, and their colleagues used mice with
cardiomyocyte specific Rev-Erb deletion that manifested
contractile dysfunction, cardiac dilatation, and heart failure.
And using these models, authors showed that there was a temporal
coordination between clock mediated anticipation and nutrient
induced response in myocardial metabolism at multiomic levels.
Obesity, together with insulin resistance via a high fat diet,
paradoxically improved dysfunction and fatty acid availability
from edibles lipolysis in the disrupted circadian mouse model
that Rev-Erb knockout. These elegant studies reveal a punitive
link between circadian regulation and nutrient induced responses
in the heart, potentially helping to explain the obesity paradox.
Cardiac molecular chronotropes may, therefore, be involved in
human dilated cardiomyopathy. And the implication is that
myocardial bioenergetics downstream of Rev-Erb may be a
chronotherapy target in treating patients with heart failure.
Now, all of this is discussed in an editorial by Dr. Inna
Rabinovich-Nikitin and Dr. Lorrie Kirshenbaum from Manitoba,
Canada.


Dr. Carolyn Lam:


The final original paper in today's issue is an important
translational paper, in which ZEB2, which is a master regulator
of epithelial to mesenchymal transition and is associated with
many cancers, has for the first time been identified as a new
coronary artery disease associated gene. This was first
identified by human Genome-wide Association studies, following
which the authors Dr. Quertermous from Cardiovascular Institute
Stanford and colleagues used smooth muscle cell specific deletion
of ZEB2 in mice, coupled with single cell transcriptomic and
epigenetic profiling of smooth muscle cells specific [inaudible
00:07:31] cells, and showed that ZEB2 dramatically alters cell
state trajectories of the smooth muscle cells through epigenetic
regulation of TGF-β and notch signaling. Lower ZEB2 in smooth
muscle cells resulted in atherosclerotic plaques with high risk
features. So what are the clinical implications? Well, therapies
that specifically regulate smooth muscle behavior can potentially
alter the risk of plaque rupture, and may be used to further
reduce the risk of myocardial infarction. Existing chemotherapies
and additional drugs in development that modulate the epigenetic
silencing, such as HDAC inhibitors or hypomethylating agents,
may, on the other hand, increase the risk of myocardial
infarction.


Dr. Carolyn Lam:


So very interesting paper. Wraps it up for our original papers,
and now onto what else there is in today's issue. There's an On
My Mind paper by Dr. Messerli on [entitled] “Why Are We Still
Prescribing ACE Inhibitors?” and a Research Letter by Dr. Simon
on one-year major cardiovascular events after restrictive versus
liberal blood transfusion strategy in patients with AMI and
anemia from the reality randomized trial. Well, that's it for the
summaries. Thanks for joining. And please hang on tight for this
next exciting feature discussion.


Dr. Carolyn Lam:


For today's feature paper, we are talking about a very familiar
medication. Believe it or not, it's just paracetamol, or
acetaminophen in its generic term. What we also call Tylenol in
the US. And I'm sure this is something that everybody recognizes
as one of the first line therapies that we take for chronic pain.
It's even over the counter. It's perceived as extremely safe, and
in particular, is as having little or no effect on blood
pressure. But is that correct? Ah, this paper, I have to tell you
audience, really sent chills up my spine. I learned so much from
it and I am so, so pleased to have with us the corresponding
author, Dr. David Webb from Queens Medical Research Institute in
Edinburgh, as well as our editorialists Dr. Steven Smith from
University of Florida in United States to discuss this very, very
important paper. David, if you don't mind if I start with you,
what made you look at this question? It's strikingly important,
but seemingly strikingly ignored until your study, so please tell
us about that.


Dr. David Webb:


So paracetamol, or acetaminophen, has a really long history going
back to the 1800s, and it replaced a drug that was removed called
phenacetin that caused significant toxicity. It didn't really
grow in use until about the 1980s, but from then on, it really
took off and now it's the most widely used and prescribed
analgesic in the world. There have been observational studies,
large ones, and small clinical trials that suggested an increase
in blood pressure. We undertook a systematic review in 2013 that
suggested this really needed to be a topic for a further study,
and so we undertook a randomized control trial to answer the
question of whether, in hypertensive subjects, paracetamol would
increase blood pressure.


Dr. Carolyn Lam:


Well, thank you for that background. I have to admit, I didn't
even know about the origins and that very first paper you talked
about, and this is really beautifully summarized as well in,
Steve, your beautiful editorial. But before we go there, David,
could you tell us about this path BP trial, what you did and what
you found?


Dr. David Webb:


So we were funded by the British Heart Foundation, and we under
took a randomized placebo controlled blinded study of one gram of
paracetamol given four times a day versus match placebo. And we
looked primarily at the gold standard ambulatory blood pressure
in patients with hypertension, a third off treatment, and two
thirds on treatment, and about a hundred, more than a hundred
patients took part in this study. It was a crossover study with
washout, and we saw that ambulatory blood pressure compared to
placebo treatment increased by five millimeters of mercury, which
is substantial. It's very similar to what we see with the
nonsteroidal anti-inflammatory drugs, the NSAIDs, which also have
effects mediated through prostaglandin metabolism, and that
increase of five millimeters of mercury would amount to an
increased cardiovascular risk, if sustained, of around 20%. Our
study was only for two weeks for practical reasons, but we have
no reason to think the effect would not last longer.


Dr. Carolyn Lam:


And David, just before we carry on, could you clarify a few
things? So, these patients did not have pain to enter, and did
they have hypertension, and were they on other medications for
hypertension?


Dr. David Webb:


Yeah, so they were patients with hypertension. They had to have
an entry average ambulatory blood pressure daytime of more than
135 over 85, but less than 150 over 95, so this is mild to
moderate hypertension. A third of them were not treated at the
time of the study, but went on to treatment, and two thirds were
already on treatment and stayed on their existing treatment. So
this is a study in both treated and untreated hypertension, and
we saw, although it wasn't powered to look at differences, we saw
similar effects in those who were treated and untreated.


Dr. Carolyn Lam:


So an incredibly important question and Dr. Smith, Steve if I
may, you wrote very nicely how the fact that this is individuals
with hypertension, but not having an indication of pain and so
on. It's really something we needed to look at this question
because pain can confound, I suppose, the measurement of blood
pressure and so on. So could you tell us a little bit more of why
this study is so important and what do you think its impact of
the findings will be?


Dr. Steven Smith:


Sure. Thank you, Carolyn. And first of all, I just say, I
appreciate you having me on and getting to discuss this really
interesting study by Dr. Webb and his team. I think it's a really
interesting study. As you may know now, acetaminophen has been
associated with blood pressure increases going back almost half a
century now and there have been a number of studies, not all have
been particularly strong studies and there's a number of
limitations to that literature, and I think I was really
fascinated by Dr. Webb's study because they really just asked a
simple question and did a well designed, robust study to try to
address that question and I think it provided some pretty
definitive results.


Dr. Steven Smith:


As I mentioned in the editorial, despite the fact that
acetaminophen has been associated with blood pressure increases
in the past, if you go look at Google or whatever, your favorite
search engine of choices, you'll find a number of articles right
at the top that seem to imply or directly state that
acetaminophen is perfectly safe for patients with high blood
pressure. And I think that's a concerning thing that the medical
information out there is implying or directly stating that
acetaminophen is perfectly fine for these patients and so, I'm
appreciative with the work that Dr. Webb is doing to try to bring
to light some of the risks of acetaminophen


Dr. Carolyn Lam:


Indeed. And I think it raises a lot of questions that you also so
nicely put in your editorial, and maybe this is the chance to ask
David directly. For example, what do you think are the
implications, in terms of generalizability, in chronic uses of
acetaminophen in lower or higher doses in people without
hypertension? I mean, this is a big and important issue. What do
you think, David?


Dr. David Webb:


Sorry, Carolyn. Maybe I could start by just sticking to the
subjects of the study itself. I think what this tells us, and
it's important to recognize that there is very little evidence
that paracetamol provides benefit in chronic pain. It's not of
any value in low back pain. There seems to be no evidence that
it's particularly useful in cancer pain and in a wide range of
other forms of pain. The evidence for benefit is very limited, so
harms really matter where the benefit is small, and probably most
patients with chronic pain are not benefiting from the
paracetamol in terms of its analgesic effect. So cautiously
trying to withdraw treatment in these patients may well be a
benefit in terms of reducing cardiovascular risk. So that's for
what patients with hypertension. So beyond hypertension, that's a
bit more difficult because we didn't study that, but we looked at
a range of blood pressures.


Dr. David Webb:


And whilst we weren't powered to address this specifically, it
looks as though the effects are there for lower blood pressures
and for higher blood pressures. So, it would be nice to do the
direct study, but it looks as though this might be slightly more
general I support. We didn't look at people with chronic pain for
practical reasons, but as I say, there's very little evidence
that paracetamol is providing a benefit. I always thought that
paracetamol was a safe drug. I use it in my hypertension clinic.
And I think in my head, this is safer than using a nonsteroidal,
but they're less effective and they may be no safer. So I think
one needs to inform clinicians and their patients about the
relative safety of paracetamol when considering treatment for
chronic pain. You asked one other question. In the UK four grams
a day as a common dose. It is in many parts of the world as a
maximum dose. In the US, FDA has advised reducing to three grams
a day as the maximum dose. You can still give four grams a day,
but I think that's a helpful recommendation because this is very
likely to be a dose dependent effect. So the lower maximum dose
will to some extent protect subjects.


Dr. Carolyn Lam:


And Steve, would you agree with that? What would your take-home
message to the audience be, or what do you think are the most
important unanswered questions?


Dr. Steven Smith:


Yeah, it's a great question. If I could piggyback on David's
answer, I think one of the really interesting findings from this
study is that we see these blood pressure changes even after only
two weeks of therapy, so this is not something that requires some
chronic, very high dose of acetaminophen to start experiencing
these blood pressure changes. Obviously a lot of people are on
acetaminophen, as David mentioned all over the world. Many of
those patients, of course, are on it for chronic therapy, for
example, for osteoarthritis, but a lot take it much more
sporadically or for short term use. And I think it's telling that
we see these blood pressure changes pretty rapidly after starting
therapy.


Dr. Steven Smith:


As far as unanswered questions go, I think Dr. Webb summarized
some of those already, but I guess what I would add is we still
lack some clarity on what the ultimate outcomes of these blood
pressure changes are. Obviously we know that blood pressure is
highly correlated with adverse cardiovascular outcomes, as well
as other outcomes, but the data showing an increased
cardiovascular risk with acetaminophen is a little bit more
murky. And so I do think there's still some question as to how
this translates to increased cardiovascular risk, and I totally
agree with David that the evidence supporting efficacy of
acetaminophen is so weak at this point for most things, it may be
a moot point. We may want to just move on from acetaminophen to
the extent that we can, because it seems to have some risks, or
at least some concern for risks, without a lot of evidence.


Dr. Carolyn Lam:


Wow. Thank you so much, gentlemen, for this. It's just amazing
discussion, but even more so for publishing such an important
study and such an elegant editorial in our journal. I think this
is one that not only may change practice, but changes my personal
perception and things that I'm going to do immediately.


Dr. Carolyn Lam:


Thank you very much audience. I'm sure you agree. This was
incredible. Do tune in again next week for another episode of
Circulation On The Run.


Dr. Greg Hundley:


This program is copyright of the American Heart Association 2022.
The opinions expressed by speakers in this podcast are their own,
and not necessarily those of the editors or of the American Heart
Association. For more, please visit ahajournals.org.