Circulation October 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. Sacubitril-valsartan reduces
the risk of cardiovascular mortality among patients with heart
failure with reduced ejection fraction. However, what are its
effects on kidney function and cardiac biomarkers in people with
moderate-to-severe chronic kidney disease? Well, stay tuned to
find out, as we will be discussing the results of the UK Harp III
Trial, right after these summaries.


                                               
The first original paper this week reveals that inhibition of a
long non-coding RNA may serve as a novel molecular therapy for
aortic aneurysms. First author, Dr Li, corresponding author, Dr
Maegdefessel from Technical University Munich, and colleagues,
identified the long non-coding RNA H-19 with functional relevance
in experimental aortic aneurysm progression in two mirroring
models, a novel genetically mutated mini-pig model, as well as
end-stage human disease. They found that H-19 mediated expression
levels of the transcription factor hypoxia inducible factor
1-Alpha. Which, in the chronic hypoxic environment of an
aneurysm, triggers apoptosis in aortic smooth muscle cells. This
study, therefore, introduces inhibition of H-19 as a novel
molecular therapy to limit smooth muscle cell death in
progressing aortic aneurysms.


                                               
The next study provides insights into molecular mechanisms
underlying heart failure progression in chronic pressure
overload. Co-first author, Dr Chiang and Alsina, co-corresponding
authors, Dr Heck, from Utrecht University, and Dr Wehrens, from
Baylor College of Medicine, and their colleagues developed a
novel and unbiased way to comprehensively study protein
phosphatase 1 or PP1 interactors in a mouse model of progressive
heart failure induced by elevated afterload. This so-called PP1
interaction enabled simultaneous interrogation of multiple
pathways relevant to heart failure pathogenesis. They found nine
specific PP1 interactors that were strongly associated with heart
failure progression. Among these, the PP1 regulatory subunit 7
was shown to play a central role by regulating the PP1
interaction, and by acting as a competitive molecular sponge of
PP1.


                                               
In clinical trials of direct oral anticoagulants for atrial
fibrillation, patients with end stage kidney disease on dialysis
were excluded. Today's study answers the question, "What are the
outcomes with Apixaban in dialysis dependent end stage kidney
disease patients with atrial fibrillation?"


                                               
Co-corresponding authors Dr Siontis and Dr Saran from University
of Michigan and their colleagues performed a retrospective cohort
study of Medicare beneficiaries included in the United States
Renal Data System from 2010-2015. All eligible patients were
those with end stage kidney disease and atrial fibrillation
undergoing dialysis who had initiated treatment with an oral
anticoagulant.


                                               
In prognostic score-matched analysis, Apixaban was associated
with lower rates of major bleeding compared with Warfarin,
whereas there was no difference in stroke or systemic embolism.
Patients on standard dose of Apixaban of 5 mg had a lower rate of
stroke and death compared to those on reduced dose Apixaban of
2.5mg. Thus, Apixaban may be associated with superior safety and
comparable effectiveness outcomes as Warfarin in dialysis
patients with atrial fibrillation. However, these findings
require confirmation in a randomized trial setting.


                                               
Does Canagliflozin have benefits in people with chronic kidney
disease, including those with an Estimated Glomerular Filtration
Rate, or EGFR, between 30 and 45, in whom the drug is currently
not approved? First author Dr Neuen, corresponding author Dr
Perkovic from the George Institute of Global Health, and their
colleagues performed a secondary analysis of the CANVAS Program
to describe outcomes in participants with and without chronic
kidney disease, as well as according to baseline kidney function
as measure by EGFR.


                                               
They found that the effect of Canagliflozin on HbA1c was
progressively attenuated at lower EGFR levels, but blood pressure
and body weight reductions were comparable. The reduction in risk
of major adverse cardiovascular events, hospitalization for heart
failure and progression of kidney disease appeared similar across
different levels of kidney function, down to an EGFR of 30.
Safety outcomes were also mostly consistent, but the risk of
hypoglycemia may increase as EGFR declines.


                                               
That wraps it up for our summaries, now for our feature
discussion.


                                               
Cubitalis-valsartan improves outcomes in patients with heart
failure with reduced ejection fraction, and we know that from the
Paradigm trial, but what about its effects on kidney function and
cardiac biomarkers in people with chronic kidney disease?


                                               
Well, this week's feature paper provides important randomized
trial data addressing this question. To discuss it, we have none
other than the first and corresponding author, Dr Richard Haynes
from University of Oxford, as well as our editorialist for the
paper, Braden Manns and Matthew James, both from University of
Calgary and in addition, we have Dr Justin Ezekowitz, associate
editor who manages paper, and Justin is from University of
Alberta.


                                               
Welcome gentlemen, we have a full house. Richard, could you start
by sharing about your trial and your findings?


Dr Richard
Haynes:          So,
the trial was called UK Harp-III, and it was really a pilot
trial, just to work to investigate the effects of
Cubitalis-valsartan on patients with chronic kidney disease, and
in particular to see what it did for their kidney function in the
short term, and also what it did to other measures of interest
like their blood pressure and cardiac biomarkers.


                                               
It was a randomized control trial double blind, among just over
400 people with chronic kidney disease, and we compared
Cubitalis-valsartan with Irbesartan, which is standard of care
for most of these patients. Our primary outcome was really to
look at the effects of these drugs on kidney function when it was
being precisely measured in hospitals. We found, actually, that
Cubitalis-valsartan had very similar effects to Irbesartan on
kidney function. So, there was no real difference in kidney
function at any point in the trial between patients who were
allocated the Cubitalis-valsartan or those allocated Irbesartan.


Dr Carolyn
Lam:               
Richard, the way you described it I'm sure you're prepared for
this question so why Irbesartan as the control versus Valsartan?


Dr Richard
Haynes:         
That's a very good question and a question asked quite often.
There were six of one and half a dozen of the other. We could
have chosen Valsartan. The difficulty with that is that Valsartan
doesn't have a license indication for the treatment of chronic
kidney disease so if we found a difference people might have said
we just chosen an inferior comparator, so we chose Irbesartan
because that does have an indication for the treatment of
proteinuria kidney disease and obviously that leaves us open for
the question about how different Valsartan and Irbesartan are. My
opinion is they might be subtly different, but I don't think the
difference is big enough to really impact these results in any
meaningful way.


Dr Carolyn
Lam:               
Indeed, and I know Braden and Matthew you have thought about it a
lot. Congratulations on the beautiful editorial. I love the way
you set the context in the heart failure world where perhaps we
have noted something different with regards to kidney function.
Would either of you like to start the ball rolling with
discussing that?


Matthew
James:             
Sure, this is Matthew James. So really the Paradigm Heart Failure
Trial is a very important place to start in thinking about the
effect of these medications on kidney function. That was a very
large trial that did report changes in estimated Glomerular
Filtration Rate and did show a small but statistically
significant change in kidney function between the
Sacubitril-valsartan arm and the control arm. There are many
potential mechanisms for that, but it is important to realize
that there were limitations in the population specifically around
chronic kidney disease due to the level of kidney function that
the patients were enrolled in to the study. So, some of the
patients with more advanced chronic kidney disease wouldn't have
been included in the Paradigm Heart Failure Trial so this trial
is actually giving us more information about patients with kidney
disease who we would expect to be at higher risk of seeing
progressive loss of kidney function or progression of their
kidney disease.


Dr Carolyn
Lam:               
Thanks for setting that up and just to clarify for the audience
here so in Paradigm EGFR went down to 30 right, and here in UK
Harp we are talking about measured GFR down to 20. Am I right?


Dr Richard
Haynes:         
Eligibility was actually determined by the EGFR, the estimated
GFR.


                                               
Yeah it went down to 20, up to 60. We also had a much more
proteinuria in the patients in Paradigm.


Dr Carolyn
Lam:               
Right, and do you have a take Richard on why the results seem
different from at least the secondary analysis that Milton Packer
wrote about on its effects on kidney function in Paradigm?


Dr Richard
Haynes:          I
do have a take. I'm really interested to hear what Braden and
Matthew thought. My take was that probably when you've got heart
failure one of the major determinants of how well your kidneys
work is actually how well your heart is working. That is probably
one of the major determinants in that setting and because we know
Sacubitril-valsartan has such beneficial effects on cardiac
function in people with heart failure perhaps it's not surprising
that it then is protected by kidney function a little bit better
than people given Enalapril in Paradigm. However, in UK Harp III,
we had a group of patients whose kidney had very definite kidney
disease and probably the determinants of kidney progression quite
different and having any impact on their heart function probably
wouldn't really be noticed because the effect of their kidney
disease would outweigh that. Perhaps, Sacubitril-valsartan
doesn't have any beneficial effects on the kidney itself. As far
as we can tell, from what is a relatively small and a relatively
short trial.


Dr Carolyn
Lam:               
Justin, I mean you come from the heart failure world too just
like me. What was your take?


Dr Justin Ezekowitz:        I
think there are a number of features here we should take a step
back and think about. Number one is as Richard outlined there is
a lot more proteinuria here than would typically be seen in a
heart failure related population. So, the comparator between the
two groups, while similar in overlap while co-manage these
patients is somewhat different in terms of what the result we are
looking for. So, you know, it brings to mind that what we look at
in the secondary analysis in for example Paradigm, is simple EGFR
creatinine changes versus here we are looking at a much more
sophisticated measure of GFR plus also looking at a comparator
that is known to reduce proteinuria and I would say stabilize or
not change or prevent their progression of renal disease in the
larger trials in the renal population. So, it's a slightly
different population, a slightly different comparator as well.
The importance in the choice of comparators becomes really
important when we are looking for this specific effect.


                                               
Now, to Richard's point, which he opened with, which is talking
about this as a pilot project to a larger outcome trial, it is
hard to know whether or not the effects that Richard and his team
on the NT-proBNP, troponin, and other effects would play out in
the larger cardiovascular outcomes trial that would be
potentially different results than simply a GFR change or
proteinuria change. I would be interested in Richard's thoughts
on that and Matt and Braden's as well.


Matthew
James:             
Maybe we can also get add another question to Richard which this
was a really well-done study and you talked about it being
relatively small and certainly by heart standards this was a
relatively small pilot study with a limited duration of follow
up. By kidney standards, this is a fairly this would be a usual
sized clinical trial and so getting all these patients in the
trial was a wonderful result to start with and while the study
wasn't directly looking at safety of these medications, there is
some I think assurance we have some tolerability data at least
with this medication and the challenge as Richard would well know
in managing patients with chronic kidney disease once they
developed more advanced chronic kidney disease GFR is less than
30 is often difficult to use medications because of side effects,
high potassium, and things. The most challenging types of
patients we see are patients with lower levels of kidney function
and with low ejection fractions. So at least this paper provides
some hope that we've got a medication that is reasonably well
tolerated in that population.


                                               
I think that when Richard talks about this being a pilot study
where a lot of patients, in fact patients with chronic kidney
disease are much more likely to die from heart disease than they
are to develop end stage renal disease. For many types of
patients that is true at least. So, we are often thinking about
what medications could be used to improve cardiovascular
outcomes. So, in that sense, again given that the majority of the
structural heart disease is not necessarily reduced heart
function but is left ventricular hypertrophy I'm sure, and
perhaps Richard has some comments as to the next study that might
be considered given this medication seemed tolerable. It didn't
have the effects that were perhaps hoped on progression although
in the Paradigm sub study there was only a difference of 0.5 ml
per minute and they were powered to detect 3 ml per minute in
this study but actually the immediate hemodynamic drop was about
3 ml per minute and then kidney function was relatively stable
thereafter. So hard to imagine this study would have showed a
difference in kidney function now in retrospect but potentially
this opens up some additional studies to look at cardiovascular
outcomes in patients with chronic kidney disease who don't have
reduced ejection fraction.


Dr Richard
Haynes:          I
think that's a really good point. I think it would be fascinating
to see the results of the Paradigm Trial with
Sacubitril-valsartan in patients with heart failure and preserved
ejection fraction. Nevertheless, I think this trial does raise
the hypothesis that this might be a drug that could improve
regardless of whether it has any effect on the kidney or not. It
could be possibly be used for improving cardiac outcomes but I
just don't think the trial that we've done is enough to justify
that at the moment. I think it's a good indicator that it may
well work, but I think before anybody could recommend that with
much enthusiasm I think it would require a large outcomes trial
but focusing quite rightly on cardiovascular outcomes in people
with chronic kidney disease which as Matthew said is actually the
major burden of disease in those patients.


Dr Justin
Ezekowitz         I think
the question remains though is if as a pilot trial at that time
as a longer-term trial would there be any difference because the
mechanism of action of Sacubitril is different from that of
Irbesartan and that was also shown in the nice table you have in
the supplemental file which talks about the Sacubrital lapse
concentration going up with the lower GFR's. So, there is the
potential for those small subgroups where the GFR is lower they
may have a substantial benefit over a longer period of time, not
measured necessarily by GFR but measured by clinical outcomes. I
think that is where the balance of getting the pilot trial versus
a longer follow-up clinical outcomes trial is really important to
get.


                                               
I may actually just state one other thing or two. First, it's
really important to investigate or initiate a trial and this is
one of critical parts of why we do clinical trials. Medicine
tests the effects initially a pilot and then hopefully a larger
trial.


                                               
The second is the importance of randomization here. We all think
that the shiny new medications are important but getting
randomization in trials like this done are really advanced
knowledge, so we know what to do with the medication if we are
faced with it or if we want to make an important choice for a
patient that we can really make a point for the patient that we
will base it on the best scientific knowledge.


                                               
The third point that I would just come back to something else
that we have not talked about yet is this overall is a neutral
trial. There are no major effects that were seen but the
importance of getting a neutral trial done and published is
really critical as this advances the field potentially, so others
can now decide what to do and perhaps launch larger trials with
cardiovascular outcomes or decide to do a different comparator or
different other tasks forward. So, this one we emphasize it is
critically important to get these types of trials done and then
published.


Dr Carolyn
Lam:               
You know Justin, I couldn't have said it better and completely
echo your words. We are so proud to be publishing your paper
Richard and that beautiful editorial in circulation. So, I'm just
going to wrap up then because in the absence of better data at
the moment what is the main take home message of this trial for
patients with CKD right now and their care providers. I would
love to start with Braden because you wrote about it in the
editorial as well. What do you think of the take home messages?


Braden
Manns:                
Well again I think that we often struggle when peoples GFRs are
in the 20 to 30 range with identifying a medication that's
tolerable particularly in the context of people with reduced
ejection fraction. I must say personally I would now be
comfortable using this medication in patients with reduced
ejection fraction who remain symptomatic who have GFRs in the 20
to 30 range. Those patients aren't that common but feel
comfortable now using that type of medication there despite the
fact that most patients weren't necessarily enrolled in the
Paradigm study. A much larger population though of patients with
structural heart disease but not reduced ejection fraction who
have chronic kidney disease. It is not clear to me where this
medication fits in the armamentarium. As Justin says it certainly
wouldn't use this in preference to an ace inhibitor or an
angiotensin receptor blocker at this point. So, it's hard to know
where it fits without some larger studies looking at cardiac
outcomes.


Matthew
James:             
I agree with Braden. I think we are already seeing this
medication now enter practice here in Canada. There is this
overlap in population between the patients with kidney disease
and impaired left ventricular ejection fraction, so this is
actually very helpful for us when we see these patients in
practice around the appropriateness of continuing these
medications in this patient population.


Dr Justin Ezekowitz:       
So, I think it's critically important to remember the take home
message here is to do proper clinical trials and then do again
the large trial because without that would not really advance in
knowledge. There could be a huge value to a newer medication or
potentially the old ones are still just as good as we if we
continue them safely.


Dr Richard
Haynes:          I'd
like to echo what everybody said already really. I mean I think
what Justin just said trial is the key. We can't get away from
the need for randomized control trials. I'm pleased that we've
managed to deliver this one. In terms of a clinical take home
message I think if I was a patient with kidney disease and heart
failure, especially with reduced ejection fraction, I hope that I
would feel a bit more comfortable to take this drug now knowing
is it going to benefit me from a cardiovascular point of view it
doesn't seem it is going to do my kidneys any harm either. So,
hopefully it will reassure more patients that they can yield the
benefits of a trial this drug has.


Dr Carolyn
Lam:               
Great stuff! Thank you so much gentlemen. This has been such an
enlightening conversation.


                                               
Thank you very much to audience for joining us today. You've been
listening to Circulation on the Run. Don't forget to tune in
again next week.