October 1, 2024 • 23 mins
For CME Information and to Claim Your Credit: www.iridiumce.com/hf
Host:
- Dr. Bob Underwood
Guest:
- Dr. Deepak Bhatt
- Director of Mount Sinai Heart
- Dr. Valentin Fuster Professor of Cardiovascular Medicine at Icahn School of Medicine
Supported by:
- Independent educational grant from Merck, Sharp, and Dohme
Episode Overview:
In this episode, Dr. Bob Underwood and Dr. Deepak Bhatt discuss novel heart failure medications for both heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). They explore the latest advancements in treatment, including the four pillars of heart failure care and emerging medications like SGLT2 inhibitors and ARNI, backed by key clinical trials.
Key Takeaways:
- Four Pillars of Heart Failure Treatment:
- The core therapies for HFrEF include beta-blockers, ACE inhibitors or ARNI, mineralocorticoid receptor antagonists (MRAs), and SGLT2 inhibitors. Each plays a distinct role in improving heart failure outcomes, reducing hospitalizations, and decreasing mortality.
- SGLT2 Inhibitors:
- Originally developed for diabetes, SGLT2 inhibitors now show significant heart failure benefits in both HFrEF and HFpEF patients, regardless of diabetes status. Key trials, such as DAPA-HF and EMPEROR, highlight their efficacy.
- ARNI (Sacubitril/Valsartan):
- Trials like PARADIGM-HF and PIONEER-HF established ARNI as a key therapy in reducing cardiovascular deaths and hospitalizations in patients with HFrEF, with potential benefit in those with lower ejection fractions within HFpEF.
- GLP-1 Receptor Agonists:
- Medications like semaglutide, primarily used for diabetes and obesity, are now being investigated for their benefits in heart failure, particularly HFpEF, through trials like STEP-HFpEF, which show improvements in patient symptoms and quality of life.
- 2022 Guidelines for Heart Failure:
- The updated AHA/ACC/HFSA guidelines emphasize the four pillars of heart failure care for HFrEF and recommend expanding SGLT2 inhibitor use for HFpEF. They highlight the importance of integrating new treatments to optimize patient outcomes.
Follow Us:
Stay updated on upcoming MedEd threads and CME programs by following Iridium on X, Facebook, and LinkedIn.
Mark as Played
Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
Dr.Bob Underwood (00:01):
Welcome to Advancing Worsening Heart
Failure Treatment, exploringcutting edge therapies and
addressing disparities. I'mdoctor Bob Underwood, and I am
joined today by my esteemedcolleague, who is the director
of Mount Sinai Heart and the 1stdoctor Valentine Fooster
professor of cardiovascularmedicine at Icahn School of
Medicine in New York, doctorDeepak Bhatt. Doctor Bhatt's
(00:25):
relevant financial relationshipscan be found at iridiumce.com/
hf. This educational activity issupported by an independent
educational grant from Merck,Sharp, and Dome. We would like
to thank them for their supportof this initiative.
This learning objective for thisprogram is summarize the novel
(00:47):
heart failure medications andtheir treatment indications for
heart failure with reducedejection fraction or HFREF, and
heart failure with preservedejection fraction, which we more
commonly refer to as HFEF.Doctor Bott, thanks for joining
us today.
Dr.Deepak Bhatt (01:04):
It's great to be with you.
Dr.Bob Underwood (01:05):
Absolutely. And so to start off, can you
give us some information on thedifferent classes of medications
for heart failure?
Dr.Deepak Bhatt (01:14):
Absolutely. So they're generally speaking, 4
classes of medications, betablockers, drugs that target
angiotensin, things like ACEinhibitors, angiotensin receptor
blockers, RNA, mineral,corticoid receptor antagonists,
or MRAs as they're sometimesabbreviated and sodium glucose,
co 2 inhibitors, SGLT 2inhibitors as they're often
(01:37):
referred to. The ACE inhibitors,RNA, MRA also along with the
angiotensin receptor blockers orARBs target the renin
angiotensin aldosterone systemor RA system. The SGLT 2
inhibitors block uptake ofglucose to the proximal tubules
of the kidney. This leads toexcretion of glucose and sodium
(01:57):
in the urine with resulted inatherotic and diuretic effects.
But it's not just that.Sometimes people think, oh, it's
just the sugar and salt in theurine. And that's part of it,
but it's also an improvement incardio energetics. Yeah. There's
a heart failure benefit with theSGLT 2 inhibitors, including
reductions in the composite ofcardiovascular death and
hospitalization for heartfailure in some cases, even in
(02:19):
CV death, alone as an endpoint,especially in sicker heart
failure patients.
And these benefits are seen bothin patients with diabetes, the
SGLT2 inhibitors were initiallydeveloped for diabetes, but also
in patients with heart failurewithout diabetes, quite
important. And also in patientsyou are alluding to have ref and
have peth in both those types ofheart failure. So pretty
(02:42):
remarkable and relatively stillnew development with the SGLT2
inhibitors as heart failuredrugs, not just diabetes drugs
anymore. The glucagon likepeptide 1 receptor agonist or
the GLP-one receptor agonist asthey're often called, were
originally used to treat type 2diabetes, really good diabetes
drugs, pretty good, glycemiccontrol in fact that they
(03:05):
provide. But in the context ofthis conversation, they were
also found to protect againstcardiovascular events in person
with diabetes, at least some ofthe drugs in the class, not
every drug in the class, andalso provide cardiovascular
benefits in people that wereoverweight or obese with
established cardiovasculardisease.
So very important. And alsofound to have benefit in
(03:25):
patients with HFpEF that wereoverweight or obese in improving
things like the Kansas CityCardiomyopathy questionnaire in
terms of how patients feel andBNP levels. This was shown in
the step HFpEF trial.
Dr.Bob Underwood (03:38):
Yeah. Absolutely. And we'll dig a
deeper dive into that particularclass of medicine here in a
little bit. Really some greatstuff coming out. So
cecubatrialvalsartan is approvedfor patients with chronic heart
failure.
So can you describe the clinicaltrials that led to best
approval, noting specificdifferences in left ventricular
ejection fraction among thesetrials?
Dr.Deepak Bhatt (04:00):
Yeah, absolutely. So
Sacubutrivalsartan is an ARTI Imentioned before this class of
Asian. And right now it'sactually in terms of what's
available, the only, drug inthat class. There are clinical
trials that support its use inHFrEF and, to an extent in HFEF.
It does have some labelingthere, where the data are
(04:20):
stronger for HFEPF.
And even in the HFEPF patients,it's ones that have lowish,
ejection fraction where thereseems to be benefit. But at any
rate, the paradigm heart failuretrial examined
sacubutrovalsartan versusenalapril in patients with left
ventricular ejection fractionless or equal to 35%. So these
were folks with a history ofheart failure, elevated
(04:41):
natriuretic peptides, trialexamined cardiovascular deaths
and hospitalization for heartfailures, well designed, well
done trial. And the primaryendpoint showed a significant
20% relative risk reduction andpretty sizable absolute risk
reduction as well. And the endpoint I mentioned for
Sacagbutrovalvastatinib versusenalapril.
(05:03):
So that's pretty good in itsown, right? But there was also a
lower rate of death in thosethat were randomized to
Sacagbutrovalvastatinib versusenalapril. So really important
results, overall. There was alsothe pioneer heart failure trial
that examined patients with LVEFof less than equal to 40%,
(05:24):
comparing sacubutrovalvastartwith enalapril. And this was
looking at patients that hadcome in with worsening heart
failure and fluid overload.
Patients were enrolled 24 hoursto 10 days after initial
presentation at a hospital. Theprimary endpoint here wasn't so
much a clinical one. It waschange in NT proBNP, but, there
were exploratory endpoints tolook at clinical endpoints,
(05:46):
things like cardiovasculardeaths and hospitalization for
heart failure. Bottom line, thebiochemical endpoint reduction
in T proBNP was significantlybetter, in the Sacubutro
Wellsartan arm. And in terms ofhospitalization for heart
failure, or I should sayrehospitalization for heart
failure, that was also lower inpatients randomized to Sacubutro
(06:10):
Wellsartan.
And the final trial I'll mentionat least right now is PARAGON
Heart Failure. This was inpatients with an ejection
fraction greater than or equalto 45%. So half path, but again,
one can debate in that range,whether it was truly patients
with, slightly reduced ejectionfraction or truly preserved. It
was an admixture. Here was acomparison of
(06:30):
sacubutrialvalsartan andvalsartan.
Again, patients with heartfailure. And this was a trial
that examined once morecardiovascular deaths and
hospitalization for heartfailure. So heart failure
related endpoints. And here, theprimary endpoint was lower with
Sacobutro, valsartan, about 13%lower, but the p value was right
(06:51):
on the fence, 0.059. So strictlyspeaking, a trial that was not
statistically significant, butthe treatment effect, if one is
willing to go beyond the p valuethere did appear to be driven by
reductions in heart failure,hospitalization, and appeared to
be in patients in the lowerrange of EF within that sort of
(07:12):
low normal range that wasenrolled in the trial.
So I think when viewed and ifthis were the only trial of
Sacubutro valsartan, then Idon't know that we could hang
our hat on it, but coupled withthe other trials I mentioned,
particular paradigm heartfailure, looks like if the EF is
low or lowish, there's a degreeof benefit with
shakbutrovalvesartan. Most markwhere the EF is truly low, that
(07:35):
is half ref.
Dr.Bob Underwood (07:37):
Yeah. Yep. Great trials. And I think you're
right. Looking at them incombination with one another
really supportive.
So how have these clinicaltrials informed which patients
can be treated withsuccubitrofloxet valsartan?
Dr.Deepak Bhatt (07:50):
Yeah. Great question. So the drug is now
approved. It's indicated toreduce the risk of
cardiovascular death that heartfailure hospitalizations in
patients with chronic heartfailure. And the benefits are
more evident in patients with anEF that's below NOBL.
So that's really where it fitsin. And it's one of the 4
pillars now, I think of heartfailure therapies, While one can
make an argument to use drugslike ACE inhibitors and ARBs,
(08:14):
really now assuming that costisn't prohibitive or there are
side effect issues, if thepatient can instead be on an
ARNI, that's probably the way togo and provides the absolute
best care along with the otherpillars of heart failure
therapy. That is beta blockers,SGLT 2 inhibitors, neural
corticoid receptor antagonists.
Dr.Bob Underwood (08:33):
Sure. So you've also done some work with
SGLT 2 inhibitors. So can youdescribe the 3 SGLT 2 inhibitors
available for the treatment ofheart failure and the clinical
trials that led to the approvalof these medications?
Dr.Deepak Bhatt (08:50):
Sure. I mean, there are a lot of trials.
There's been an explosion ofdata with the SGLT two numbers.
Once more, these were approvedavailable great data as diabetes
drugs for the most part toseveral drugs in the class. But
now specifically, let's talkabout heart failure and 3 drugs
that I think are most relevantare dapagliflozin,
empagliflozin, andsotagliflozin.
(09:11):
Sotagliflozin isn't SGLTtrinibre, but it's also an SGLT1
inhibitor. So it's got a littlebit of a different mode of
action, but they all share theSGLT2 inhibition. And most would
say they're all part of thatclass, but the SGLT1 might add a
little bit something differentin terms of reduction in
(09:31):
atherosclerotic events, but thatmay be a topic for another day.
But as far as dapagliflozingoes, it was studied in DAPA
heart failure and in deliver inpatients essentially with HFrEF
and HFF respectively.Dapagliflozin was compared with
placebo.
These are patients again withheart failure class 2, the 4
(09:53):
elevated NT proBNP. So they havereal heart failure evidence of
it. The primary endpoint wasonce more are these composites
of heart failure relatedendpoints. In this case, heart
failure, hospitalization, urgentvisits for heart failure,
cardiovascular death, anddapagliflozin significantly
reduced that endpoint in theDAPA heart failure trial of
(10:15):
patients with EF less or equalto 40%. It was a hazard ratio of
about 0.74 statisticallysignificant.
And the deliver trial with an EFgreater than 40%, there has
ratio of 0.82. So again,statistically significant. So
similar or significant degree ofrisk reduction. And for that
reason, dapagliflozin isindicated to reduce the risk of
(10:36):
cardiovascular death andhospitalization due to heart
failure in patients with heartfailure. As far as epagliflozin
goes, that was studied in EPRAreduced and EPRA Preserved,
HFref and HFpEF respectively,trials of epigliflozin versus
placebo.
Again, patients with heartassociation class 2 to 4,
primary endpoint, similarendpoint of cardiovascular death
(10:56):
or heart failurehospitalization. Once more in
both trials, they were positive.That is an EMPEROR reduced a
significant reduction, has ratioof about 0.7, statistically
significant in the EMPERORPreserve trial. Again, that's
the one with EFs greater than40%, hazard ratio of around
0.79, once more statisticallysignificant. Therefore,
(11:20):
emagliflozin is indicated toreduce the risk of
cardiovascular death thanhospitalization due to heart
failure in patients with heartfailure.
And then finally, sotagliflozinwas studied in SOLUS worsening
heart failure, sotagliflozinversus placebo. Here, the trial
was patients specifically alsowith diabetes and admitted with
acute decompensated heartfailure. We actually intended to
(11:42):
ultimately enroll patients,without diabetes as well, but
the trial ended before we had achance to do that. The primary
outcome was the composite oftotal events consisting of
cardiovascular deaths,hospitalization for heart
failure, urgent heart failurevisits. The primary outcome once
more is significant benefit, hasa ratio 0.67, very statistically
(12:04):
significant.
And I'll point out that in termsof numbers needed to treat, it
was about 4 patients that neededto be treated for about a year
to prevent one event. So it justshows that in a very high risk
population, such as thoseadmitted with acute
decompensated heart failure andsoloist really large, not only
relative risk reductions, butabsolute risk reductions. And
(12:27):
for that reason, sotagliflozinis indicated in adults with
heart failure to reduce the riskof cardiovascular death,
hospitalizations for heartfailure, or ocean heart failure
visits. Importantly, the labeldoesn't actually just say
diabetes, even though our trialactually included patients with
diabetes. There's another trialof sotagliflozin where there was
a reduction in heart failure,but also in MACE atherosclerotic
(12:48):
events.
Maybe that's due to the SGLT1mechanism that was scored trauma
that was patients with chronickidney disease. So that's the
story in a nutshell for SGLT2inhibitors and the setting of
heart failure.
Dr.Bob Underwood (13:02):
And some just wonderful information about that
particular class of medication.So let's make a transition over
to aldosterone agonist. What canyou tell us about some of the
medications that are availableand how they work?
Dr.Deepak Bhatt (13:14):
Yeah. Absolutely. So this is, again,
one of the four pillars of heartfailure care. Spironolactone is
the agent with the most evidencein terms of being around for a
while and being effective,certainly in patients with heart
failure with reduced ejectionfraction, lots of older data and
trials that support that.Despite that lots of registries
show that it's under utilized inthe context of HFREF.
(13:37):
But what about HFpEF? There'smore recent data for
spironolactone from the top capstudy or the top cap trial,
spironolactone versus placebo.This was patients with an EF
grade or equal to 45% that hadheart failure. The primary
outcome was death fromcardiovascular causes, aborted
cardiac arrest, hospitalizationfor heart failure. And the
(14:00):
trial, strictly speaking overallwas not positive.
The hazard ratio was 0.89, butthe P value wasn't significant.
So, that makes it a little toughto go beyond the primary
endpoint. There was, I would saya signal of benefit on
components of the endpoint, likehospitalization for heart
failure, where it looked like itwas lower. There were some post
(14:21):
hoc analyses that were done thatsuggested maybe there is a
benefit if you excluded certaincountries where it looked like
there were protocol violationsand maybe the patients that got
admitted didn't really haveheart failure. And maybe those,
countries and the sites in thosecountries were doing some funny
stuff in terms of trial conduct.
So if you're willing to draw outthose particular countries, it
(14:43):
looked like the remainingcountries, there was a
significant benefit. So withsome caveats, it looks like
there's probably somethingthere, but need more data.
There's more research going onthough, with respect to MRAs,
melocorticoid receptor,antagonist and heart failure
receptor. The FIND ARTS trial isinvestigating a non steroidal
neural corticoid receptorantagonist, spironolactoid is a
(15:05):
steroidal one. The agent beingstudied there is phenerinone in
patients with HFpEF.
So that trial will hopefullyreport out sometime not too far
in the future. And we'll knowwith greater certainty whether
this class of agents truly doeswork in HFpEF.
Dr.Bob Underwood (15:21):
Thanks for that. So the last medication
we'll discuss in this section isGLP 1 receptor agonists or
semaglutide. So would youdescribe the results of the step
half pheff clinical trial forus?
Dr.Deepak Bhatt (15:35):
Sure. And I'm glad we're talking about the GLP
one receptor agonist again, andyou specifically said
semaglutide. I think it's right.Sometimes doctors like to talk
about classes of agents with theSGLT 200 Brazil seem pretty good
with respect to heart failurereductions With the GLP 1
receptor agonist, not all ofthem provide cardiovascular
benefits. So really not fair totalk about them as a class.
(15:57):
They're all great diabetesdrugs, but not necessarily all
great cardiac drugs. Exactly whythat's a topic for another day.
But with respect to semaglutide,it was studied in the STEP HFEF
study. So looking at patientswith heart failure with
preserved ejection fraction EFgreater than equal to 45%. These
different trials have slightlydifferent cut points for exactly
(16:17):
what HFEF is, but here it's whatI just said.
And here semaglutide wascompared versus placebo.
Patients had a BMI of 30 ormore, so they are obese. And the
primary outcome was change frombaseline in the KCCQ, that's the
Kansas City Cardiomyopathyquestionnaire, a way of seeing
how are patients with heartfailure feeling, how are they
(16:39):
doing? So not sort of a hardendpoint like cardiovascular
death or hospitalization forheart failure, but an important
patient centric endpoint. Alsochange in body where it was
examined.
Other secondary outcomes werethings like 6 minute walk
distance and looking at someclinical endpoints as part of
the composite along with some ofthe other endpoints that I
(16:59):
already alluded to. And bottomline is there was a significant
difference benefit with thesemaglutide with respect to KCCQ
that is in terms of how patientsfelt. It was a change that was
felt to be clinicallysignificant, not just
statistically significant. Therewas also a change in body weight
that was significant withsemaglutide that is consistent
(17:22):
with what was already done withthe ability of this drug to
cause a substantial amount ofweight loss. So that is
something patients obviouslylike.
Sometimes it can help withadherence. There are also
improvements in the 6 minutewalk distance and also in the
composite of clinical and otherendpoints that I alluded to. So
overall positive trial, not aclinical endpoint outcome trial
(17:46):
per se, but still lots of otherclinically relevant endpoints
being favorably influenced. Andsemaglutide is approved for
adults with type 2 diabetes,either alone or if they also
have cardiovascular disease.It's also approved for chronic
weight management in folks witha BMI greater than 30 or equal
to 27 with other comorbidities.
(18:08):
So a useful addition to theargumentarium. Yeah. Great drug
for diabetes, for obesity, forfolks at elevated cardiovascular
risk with obesity. And also nowit turns out for heart failure
preserved ejection fraction.Once more with the caveat that
this wasn't a classiccardiovascular outcome trial
looking at heart end points.
Dr.Bob Underwood (18:28):
Right. Right. But definitely some good
indications for that particularmedication in multiple
categories. So let's move on. So2022 American Heart Association,
American College of Cardiologyor ACC, and the Heart Failure
Society of America, HFSAreleased updated guidelines.
So what can you tell us are thebig takeaways for the 2022
(18:52):
guidelines?
Dr.Deepak Bhatt (18:52):
Yeah, absolutely. It really centers
upon the 4 pillars of care forheifera. Obviously you're gonna
use diuretics, even though ingeneral, they're not been shown
to reduce things like mortality.Although it sort of depends what
you call a diuretic, but the 4pillars beyond just decongesting
patients are ARNEs ACEinhibitors or angiotensin
(19:14):
receptor blockers should use oneof those. And as I said, with a
preference towards ARNI's,assuming lead cost or side
effects are an issue, betablockers are another pillar.
The mineralocorticoid receptorantagonists are yet another
pillar and they do have adiuretic effect obviously.
That's why when I was alludingto diuretics, I really meant
things like the loop diureticshaven't been shown to influence
(19:35):
hard endpoints. They're usedjust for deep congestion. The
MRAs are a bit special that way.The SGLT2 inhibitors are the
latest addition to the 4 pillarsof care.
So those are the 4 pillars ofcare, very strong evidence
based, guideline endorsement, soforth. In clinical practice
beyond that, if patients are all4 pillars of care, optimally
dosed to the extent they cantolerate without side effects
(19:57):
and so forth, still havingproblems with symptomatic heart
failure readmissions for heartfailure, then agents such as
ericiguat are potentialadditions to the armamentarium
for patients with heart failure,reduced ejection fraction. Now
with patients with heartfailure, more in that mid range
of ejection fraction, not quiteHFF, not quite HFF, there as
(20:17):
well as SGLT2 inhibitors wouldbe recommended. And there is
likely a role for RNAs, ACEinhibitors, ARBs,
mineralocorticoid receptorantagonists, especially if
they're at that lower range ofwhat we're saying is mid range.
So, and if they're closer toabnormal, there does seem to be
benefit.
The same seems to be true ofbeta blockers as well. And in
(20:38):
HFpEF, the evidence is reallystrong as for SGLT2 inhibitors.
One can consider RNAs and MRAs.As I said, there are some
caveats to the data where withrespect to RNA, as I alluded to,
the trial was clearlystatistically significant, but
there were a lot of signals ofpositivity. And with respect to
MRAs, again, top cat strictlyspeaking, not statistically
(20:59):
significant, but if you'rewilling to go on this post hoc
analysis, it looked like theremight be something there as well
for drug that's generic andrelatively cheap.
So this is really, I think thekey things to remember the
possibilities for HFREF andHFEF, we've come a long way in
terms of medical therapy andoptions that are evidence based.
Dr.Bob Underwood (21:19):
Yeah. The 2,292 guidelines have a huge
amount of information. And sothanks for summarizing your key
takeaways. I think people willfind that really, really
valuable. As we close anythingelse you'd like to add for this
particular segment?
Dr.Deepak Bhatt (21:32):
I think the most important point is that
medicine is ever static, andthat seems to be especially true
with heart failures, but so muchnew data that's come out. And I
think it's important to try tostay on top of all of the data
because it really can benefitpatients in terms of how they
feel, in terms of how they do,in terms of heart endpoints,
(21:52):
like hospitalization for heartfailure and even cardiovascular
death in some cases all causemortality. The approaches do
involve polypharmacy. One doesneed to be mindful of side
effects and and cost and thatsort of thing. But having said
that, in HFREF, we really aretrying to embrace the 4 pillars
of care, starting therapy asquickly as possible, again,
(22:14):
assuming it's tolerated.
And with HFpEF, it's a new daywith data really showing clear
benefit of SGLT 2 inhibitors andpotential benefit of at least a
couple other classes where SGLT2 inhibitors may not be enough.
So lots of reasons to beoptimistic these days in the
care of our heart failurepatients.
Dr.Bob Underwood (22:32):
Yeah. It's great advances. Really is. So
doctor Bhatt, thank you so muchfor this informative discussion.
For me, it's been an honor tolearn from you today.
So we'd also like to thank Merckfor their support of this
program. And for the listeners,please claim your CME credit by
filling out the evaluation andthe post test. And don't miss
our next and final episode ofthis series where we will again
(22:56):
be speaking with doctor AaronMichos from Johns Hopkins. And
be sure to follow Iridium on x,Facebook, and LinkedIn to see
the corresponding MedEd threads.Thanks so much for being on.
Welcome to Advancing Worsening Heart
Failure Treatment, exploringcutting edge therapies and
addressing disparities. I'mdoctor Bob Underwood, and I am
joined today by my esteemedcolleague, who is the director
of Mount Sinai Heart and the 1stdoctor Valentine Fooster
professor of cardiovascularmedicine at Icahn School of
Medicine in New York, doctorDeepak Bhatt. Doctor Bhatt's
(00:25):
relevant financial relationshipscan be found at iridiumce.com/
hf. This educational activity issupported by an independent
educational grant from Merck,Sharp, and Dome. We would like
to thank them for their supportof this initiative.
This learning objective for thisprogram is summarize the novel
(00:47):
heart failure medications andtheir treatment indications for
heart failure with reducedejection fraction or HFREF, and
heart failure with preservedejection fraction, which we more
commonly refer to as HFEF.Doctor Bott, thanks for joining
us today.
Dr.Deepak Bhatt (01:04):
It's great to be with you.
Dr.Bob Underwood (01:05):
Absolutely. And so to start off, can you
give us some information on thedifferent classes of medications
for heart failure?
Dr.Deepak Bhatt (01:14):
Absolutely. So they're generally speaking, 4
classes of medications, betablockers, drugs that target
angiotensin, things like ACEinhibitors, angiotensin receptor
blockers, RNA, mineral,corticoid receptor antagonists,
or MRAs as they're sometimesabbreviated and sodium glucose,
co 2 inhibitors, SGLT 2inhibitors as they're often
(01:37):
referred to. The ACE inhibitors,RNA, MRA also along with the
angiotensin receptor blockers orARBs target the renin
angiotensin aldosterone systemor RA system. The SGLT 2
inhibitors block uptake ofglucose to the proximal tubules
of the kidney. This leads toexcretion of glucose and sodium
(01:57):
in the urine with resulted inatherotic and diuretic effects.
But it's not just that.Sometimes people think, oh, it's
just the sugar and salt in theurine. And that's part of it,
but it's also an improvement incardio energetics. Yeah. There's
a heart failure benefit with theSGLT 2 inhibitors, including
reductions in the composite ofcardiovascular death and
hospitalization for heartfailure in some cases, even in
(02:19):
CV death, alone as an endpoint,especially in sicker heart
failure patients.
And these benefits are seen bothin patients with diabetes, the
SGLT2 inhibitors were initiallydeveloped for diabetes, but also
in patients with heart failurewithout diabetes, quite
important. And also in patientsyou are alluding to have ref and
have peth in both those types ofheart failure. So pretty
(02:42):
remarkable and relatively stillnew development with the SGLT2
inhibitors as heart failuredrugs, not just diabetes drugs
anymore. The glucagon likepeptide 1 receptor agonist or
the GLP-one receptor agonist asthey're often called, were
originally used to treat type 2diabetes, really good diabetes
drugs, pretty good, glycemiccontrol in fact that they
(03:05):
provide. But in the context ofthis conversation, they were
also found to protect againstcardiovascular events in person
with diabetes, at least some ofthe drugs in the class, not
every drug in the class, andalso provide cardiovascular
benefits in people that wereoverweight or obese with
established cardiovasculardisease.
So very important. And alsofound to have benefit in
(03:25):
patients with HFpEF that wereoverweight or obese in improving
things like the Kansas CityCardiomyopathy questionnaire in
terms of how patients feel andBNP levels. This was shown in
the step HFpEF trial.
Dr.Bob Underwood (03:38):
Yeah. Absolutely. And we'll dig a
deeper dive into that particularclass of medicine here in a
little bit. Really some greatstuff coming out. So
cecubatrialvalsartan is approvedfor patients with chronic heart
failure.
So can you describe the clinicaltrials that led to best
approval, noting specificdifferences in left ventricular
ejection fraction among thesetrials?
Dr.Deepak Bhatt (04:00):
Yeah, absolutely. So
Sacubutrivalsartan is an ARTI Imentioned before this class of
Asian. And right now it'sactually in terms of what's
available, the only, drug inthat class. There are clinical
trials that support its use inHFrEF and, to an extent in HFEF.
It does have some labelingthere, where the data are
(04:20):
stronger for HFEPF.
And even in the HFEPF patients,it's ones that have lowish,
ejection fraction where thereseems to be benefit. But at any
rate, the paradigm heart failuretrial examined
sacubutrovalsartan versusenalapril in patients with left
ventricular ejection fractionless or equal to 35%. So these
were folks with a history ofheart failure, elevated
(04:41):
natriuretic peptides, trialexamined cardiovascular deaths
and hospitalization for heartfailures, well designed, well
done trial. And the primaryendpoint showed a significant
20% relative risk reduction andpretty sizable absolute risk
reduction as well. And the endpoint I mentioned for
Sacagbutrovalvastatinib versusenalapril.
(05:03):
So that's pretty good in itsown, right? But there was also a
lower rate of death in thosethat were randomized to
Sacagbutrovalvastatinib versusenalapril. So really important
results, overall. There was alsothe pioneer heart failure trial
that examined patients with LVEFof less than equal to 40%,
(05:24):
comparing sacubutrovalvastartwith enalapril. And this was
looking at patients that hadcome in with worsening heart
failure and fluid overload.
Patients were enrolled 24 hoursto 10 days after initial
presentation at a hospital. Theprimary endpoint here wasn't so
much a clinical one. It waschange in NT proBNP, but, there
were exploratory endpoints tolook at clinical endpoints,
(05:46):
things like cardiovasculardeaths and hospitalization for
heart failure. Bottom line, thebiochemical endpoint reduction
in T proBNP was significantlybetter, in the Sacubutro
Wellsartan arm. And in terms ofhospitalization for heart
failure, or I should sayrehospitalization for heart
failure, that was also lower inpatients randomized to Sacubutro
(06:10):
Wellsartan.
And the final trial I'll mentionat least right now is PARAGON
Heart Failure. This was inpatients with an ejection
fraction greater than or equalto 45%. So half path, but again,
one can debate in that range,whether it was truly patients
with, slightly reduced ejectionfraction or truly preserved. It
was an admixture. Here was acomparison of
(06:30):
sacubutrialvalsartan andvalsartan.
Again, patients with heartfailure. And this was a trial
that examined once morecardiovascular deaths and
hospitalization for heartfailure. So heart failure
related endpoints. And here, theprimary endpoint was lower with
Sacobutro, valsartan, about 13%lower, but the p value was right
(06:51):
on the fence, 0.059. So strictlyspeaking, a trial that was not
statistically significant, butthe treatment effect, if one is
willing to go beyond the p valuethere did appear to be driven by
reductions in heart failure,hospitalization, and appeared to
be in patients in the lowerrange of EF within that sort of
(07:12):
low normal range that wasenrolled in the trial.
So I think when viewed and ifthis were the only trial of
Sacubutro valsartan, then Idon't know that we could hang
our hat on it, but coupled withthe other trials I mentioned,
particular paradigm heartfailure, looks like if the EF is
low or lowish, there's a degreeof benefit with
shakbutrovalvesartan. Most markwhere the EF is truly low, that
(07:35):
is half ref.
Dr.Bob Underwood (07:37):
Yeah. Yep. Great trials. And I think you're
right. Looking at them incombination with one another
really supportive.
So how have these clinicaltrials informed which patients
can be treated withsuccubitrofloxet valsartan?
Dr.Deepak Bhatt (07:50):
Yeah. Great question. So the drug is now
approved. It's indicated toreduce the risk of
cardiovascular death that heartfailure hospitalizations in
patients with chronic heartfailure. And the benefits are
more evident in patients with anEF that's below NOBL.
So that's really where it fitsin. And it's one of the 4
pillars now, I think of heartfailure therapies, While one can
make an argument to use drugslike ACE inhibitors and ARBs,
(08:14):
really now assuming that costisn't prohibitive or there are
side effect issues, if thepatient can instead be on an
ARNI, that's probably the way togo and provides the absolute
best care along with the otherpillars of heart failure
therapy. That is beta blockers,SGLT 2 inhibitors, neural
corticoid receptor antagonists.
Dr.Bob Underwood (08:33):
Sure. So you've also done some work with
SGLT 2 inhibitors. So can youdescribe the 3 SGLT 2 inhibitors
available for the treatment ofheart failure and the clinical
trials that led to the approvalof these medications?
Dr.Deepak Bhatt (08:50):
Sure. I mean, there are a lot of trials.
There's been an explosion ofdata with the SGLT two numbers.
Once more, these were approvedavailable great data as diabetes
drugs for the most part toseveral drugs in the class. But
now specifically, let's talkabout heart failure and 3 drugs
that I think are most relevantare dapagliflozin,
empagliflozin, andsotagliflozin.
(09:11):
Sotagliflozin isn't SGLTtrinibre, but it's also an SGLT1
inhibitor. So it's got a littlebit of a different mode of
action, but they all share theSGLT2 inhibition. And most would
say they're all part of thatclass, but the SGLT1 might add a
little bit something differentin terms of reduction in
(09:31):
atherosclerotic events, but thatmay be a topic for another day.
But as far as dapagliflozingoes, it was studied in DAPA
heart failure and in deliver inpatients essentially with HFrEF
and HFF respectively.Dapagliflozin was compared with
placebo.
These are patients again withheart failure class 2, the 4
(09:53):
elevated NT proBNP. So they havereal heart failure evidence of
it. The primary endpoint wasonce more are these composites
of heart failure relatedendpoints. In this case, heart
failure, hospitalization, urgentvisits for heart failure,
cardiovascular death, anddapagliflozin significantly
reduced that endpoint in theDAPA heart failure trial of
(10:15):
patients with EF less or equalto 40%. It was a hazard ratio of
about 0.74 statisticallysignificant.
And the deliver trial with an EFgreater than 40%, there has
ratio of 0.82. So again,statistically significant. So
similar or significant degree ofrisk reduction. And for that
reason, dapagliflozin isindicated to reduce the risk of
(10:36):
cardiovascular death andhospitalization due to heart
failure in patients with heartfailure. As far as epagliflozin
goes, that was studied in EPRAreduced and EPRA Preserved,
HFref and HFpEF respectively,trials of epigliflozin versus
placebo.
Again, patients with heartassociation class 2 to 4,
primary endpoint, similarendpoint of cardiovascular death
(10:56):
or heart failurehospitalization. Once more in
both trials, they were positive.That is an EMPEROR reduced a
significant reduction, has ratioof about 0.7, statistically
significant in the EMPERORPreserve trial. Again, that's
the one with EFs greater than40%, hazard ratio of around
0.79, once more statisticallysignificant. Therefore,
(11:20):
emagliflozin is indicated toreduce the risk of
cardiovascular death thanhospitalization due to heart
failure in patients with heartfailure.
And then finally, sotagliflozinwas studied in SOLUS worsening
heart failure, sotagliflozinversus placebo. Here, the trial
was patients specifically alsowith diabetes and admitted with
acute decompensated heartfailure. We actually intended to
(11:42):
ultimately enroll patients,without diabetes as well, but
the trial ended before we had achance to do that. The primary
outcome was the composite oftotal events consisting of
cardiovascular deaths,hospitalization for heart
failure, urgent heart failurevisits. The primary outcome once
more is significant benefit, hasa ratio 0.67, very statistically
(12:04):
significant.
And I'll point out that in termsof numbers needed to treat, it
was about 4 patients that neededto be treated for about a year
to prevent one event. So it justshows that in a very high risk
population, such as thoseadmitted with acute
decompensated heart failure andsoloist really large, not only
relative risk reductions, butabsolute risk reductions. And
(12:27):
for that reason, sotagliflozinis indicated in adults with
heart failure to reduce the riskof cardiovascular death,
hospitalizations for heartfailure, or ocean heart failure
visits. Importantly, the labeldoesn't actually just say
diabetes, even though our trialactually included patients with
diabetes. There's another trialof sotagliflozin where there was
a reduction in heart failure,but also in MACE atherosclerotic
(12:48):
events.
Maybe that's due to the SGLT1mechanism that was scored trauma
that was patients with chronickidney disease. So that's the
story in a nutshell for SGLT2inhibitors and the setting of
heart failure.
Dr.Bob Underwood (13:02):
And some just wonderful information about that
particular class of medication.So let's make a transition over
to aldosterone agonist. What canyou tell us about some of the
medications that are availableand how they work?
Dr.Deepak Bhatt (13:14):
Yeah. Absolutely. So this is, again,
one of the four pillars of heartfailure care. Spironolactone is
the agent with the most evidencein terms of being around for a
while and being effective,certainly in patients with heart
failure with reduced ejectionfraction, lots of older data and
trials that support that.Despite that lots of registries
show that it's under utilized inthe context of HFREF.
(13:37):
But what about HFpEF? There'smore recent data for
spironolactone from the top capstudy or the top cap trial,
spironolactone versus placebo.This was patients with an EF
grade or equal to 45% that hadheart failure. The primary
outcome was death fromcardiovascular causes, aborted
cardiac arrest, hospitalizationfor heart failure. And the
(14:00):
trial, strictly speaking overallwas not positive.
The hazard ratio was 0.89, butthe P value wasn't significant.
So, that makes it a little toughto go beyond the primary
endpoint. There was, I would saya signal of benefit on
components of the endpoint, likehospitalization for heart
failure, where it looked like itwas lower. There were some post
(14:21):
hoc analyses that were done thatsuggested maybe there is a
benefit if you excluded certaincountries where it looked like
there were protocol violationsand maybe the patients that got
admitted didn't really haveheart failure. And maybe those,
countries and the sites in thosecountries were doing some funny
stuff in terms of trial conduct.
So if you're willing to draw outthose particular countries, it
(14:43):
looked like the remainingcountries, there was a
significant benefit. So withsome caveats, it looks like
there's probably somethingthere, but need more data.
There's more research going onthough, with respect to MRAs,
melocorticoid receptor,antagonist and heart failure
receptor. The FIND ARTS trial isinvestigating a non steroidal
neural corticoid receptorantagonist, spironolactoid is a
(15:05):
steroidal one. The agent beingstudied there is phenerinone in
patients with HFpEF.
So that trial will hopefullyreport out sometime not too far
in the future. And we'll knowwith greater certainty whether
this class of agents truly doeswork in HFpEF.
Dr.Bob Underwood (15:21):
Thanks for that. So the last medication
we'll discuss in this section isGLP 1 receptor agonists or
semaglutide. So would youdescribe the results of the step
half pheff clinical trial forus?
Dr.Deepak Bhatt (15:35):
Sure. And I'm glad we're talking about the GLP
one receptor agonist again, andyou specifically said
semaglutide. I think it's right.Sometimes doctors like to talk
about classes of agents with theSGLT 200 Brazil seem pretty good
with respect to heart failurereductions With the GLP 1
receptor agonist, not all ofthem provide cardiovascular
benefits. So really not fair totalk about them as a class.
(15:57):
They're all great diabetesdrugs, but not necessarily all
great cardiac drugs. Exactly whythat's a topic for another day.
But with respect to semaglutide,it was studied in the STEP HFEF
study. So looking at patientswith heart failure with
preserved ejection fraction EFgreater than equal to 45%. These
different trials have slightlydifferent cut points for exactly
(16:17):
what HFEF is, but here it's whatI just said.
And here semaglutide wascompared versus placebo.
Patients had a BMI of 30 ormore, so they are obese. And the
primary outcome was change frombaseline in the KCCQ, that's the
Kansas City Cardiomyopathyquestionnaire, a way of seeing
how are patients with heartfailure feeling, how are they
(16:39):
doing? So not sort of a hardendpoint like cardiovascular
death or hospitalization forheart failure, but an important
patient centric endpoint. Alsochange in body where it was
examined.
Other secondary outcomes werethings like 6 minute walk
distance and looking at someclinical endpoints as part of
the composite along with some ofthe other endpoints that I
(16:59):
already alluded to. And bottomline is there was a significant
difference benefit with thesemaglutide with respect to KCCQ
that is in terms of how patientsfelt. It was a change that was
felt to be clinicallysignificant, not just
statistically significant. Therewas also a change in body weight
that was significant withsemaglutide that is consistent
(17:22):
with what was already done withthe ability of this drug to
cause a substantial amount ofweight loss. So that is
something patients obviouslylike.
Sometimes it can help withadherence. There are also
improvements in the 6 minutewalk distance and also in the
composite of clinical and otherendpoints that I alluded to. So
overall positive trial, not aclinical endpoint outcome trial
(17:46):
per se, but still lots of otherclinically relevant endpoints
being favorably influenced. Andsemaglutide is approved for
adults with type 2 diabetes,either alone or if they also
have cardiovascular disease.It's also approved for chronic
weight management in folks witha BMI greater than 30 or equal
to 27 with other comorbidities.
(18:08):
So a useful addition to theargumentarium. Yeah. Great drug
for diabetes, for obesity, forfolks at elevated cardiovascular
risk with obesity. And also nowit turns out for heart failure
preserved ejection fraction.Once more with the caveat that
this wasn't a classiccardiovascular outcome trial
looking at heart end points.
Dr.Bob Underwood (18:28):
Right. Right. But definitely some good
indications for that particularmedication in multiple
categories. So let's move on. So2022 American Heart Association,
American College of Cardiologyor ACC, and the Heart Failure
Society of America, HFSAreleased updated guidelines.
So what can you tell us are thebig takeaways for the 2022
(18:52):
guidelines?
Dr.Deepak Bhatt (18:52):
Yeah, absolutely. It really centers
upon the 4 pillars of care forheifera. Obviously you're gonna
use diuretics, even though ingeneral, they're not been shown
to reduce things like mortality.Although it sort of depends what
you call a diuretic, but the 4pillars beyond just decongesting
patients are ARNEs ACEinhibitors or angiotensin
(19:14):
receptor blockers should use oneof those. And as I said, with a
preference towards ARNI's,assuming lead cost or side
effects are an issue, betablockers are another pillar.
The mineralocorticoid receptorantagonists are yet another
pillar and they do have adiuretic effect obviously.
That's why when I was alludingto diuretics, I really meant
things like the loop diureticshaven't been shown to influence
(19:35):
hard endpoints. They're usedjust for deep congestion. The
MRAs are a bit special that way.The SGLT2 inhibitors are the
latest addition to the 4 pillarsof care.
So those are the 4 pillars ofcare, very strong evidence
based, guideline endorsement, soforth. In clinical practice
beyond that, if patients are all4 pillars of care, optimally
dosed to the extent they cantolerate without side effects
(19:57):
and so forth, still havingproblems with symptomatic heart
failure readmissions for heartfailure, then agents such as
ericiguat are potentialadditions to the armamentarium
for patients with heart failure,reduced ejection fraction. Now
with patients with heartfailure, more in that mid range
of ejection fraction, not quiteHFF, not quite HFF, there as
(20:17):
well as SGLT2 inhibitors wouldbe recommended. And there is
likely a role for RNAs, ACEinhibitors, ARBs,
mineralocorticoid receptorantagonists, especially if
they're at that lower range ofwhat we're saying is mid range.
So, and if they're closer toabnormal, there does seem to be
benefit.
The same seems to be true ofbeta blockers as well. And in
(20:38):
HFpEF, the evidence is reallystrong as for SGLT2 inhibitors.
One can consider RNAs and MRAs.As I said, there are some
caveats to the data where withrespect to RNA, as I alluded to,
the trial was clearlystatistically significant, but
there were a lot of signals ofpositivity. And with respect to
MRAs, again, top cat strictlyspeaking, not statistically
(20:59):
significant, but if you'rewilling to go on this post hoc
analysis, it looked like theremight be something there as well
for drug that's generic andrelatively cheap.
So this is really, I think thekey things to remember the
possibilities for HFREF andHFEF, we've come a long way in
terms of medical therapy andoptions that are evidence based.
Dr.Bob Underwood (21:19):
Yeah. The 2,292 guidelines have a huge
amount of information. And sothanks for summarizing your key
takeaways. I think people willfind that really, really
valuable. As we close anythingelse you'd like to add for this
particular segment?
Dr.Deepak Bhatt (21:32):
I think the most important point is that
medicine is ever static, andthat seems to be especially true
with heart failures, but so muchnew data that's come out. And I
think it's important to try tostay on top of all of the data
because it really can benefitpatients in terms of how they
feel, in terms of how they do,in terms of heart endpoints,
(21:52):
like hospitalization for heartfailure and even cardiovascular
death in some cases all causemortality. The approaches do
involve polypharmacy. One doesneed to be mindful of side
effects and and cost and thatsort of thing. But having said
that, in HFREF, we really aretrying to embrace the 4 pillars
of care, starting therapy asquickly as possible, again,
(22:14):
assuming it's tolerated.
And with HFpEF, it's a new daywith data really showing clear
benefit of SGLT 2 inhibitors andpotential benefit of at least a
couple other classes where SGLT2 inhibitors may not be enough.
So lots of reasons to beoptimistic these days in the
care of our heart failurepatients.
Dr.Bob Underwood (22:32):
Yeah. It's great advances. Really is. So
doctor Bhatt, thank you so muchfor this informative discussion.
For me, it's been an honor tolearn from you today.
So we'd also like to thank Merckfor their support of this
program. And for the listeners,please claim your CME credit by
filling out the evaluation andthe post test. And don't miss
our next and final episode ofthis series where we will again
(22:56):
be speaking with doctor AaronMichos from Johns Hopkins. And
be sure to follow Iridium on x,Facebook, and LinkedIn to see
the corresponding MedEd threads.Thanks so much for being on.
Popular Podcasts
Stuff You Should Know
If you've ever wanted to know about champagne, satanism, the Stonewall Uprising, chaos theory, LSD, El Nino, true crime and Rosa Parks, then look no further. Josh and Chuck have you covered.
The Joe Rogan Experience
The official podcast of comedian Joe Rogan.
Dateline NBC
Current and classic episodes, featuring compelling true-crime mysteries, powerful documentaries and in-depth investigations. Special Summer Offer: Exclusively on Apple Podcasts, try our Dateline Premium subscription completely free for one month! With Dateline Premium, you get every episode ad-free plus exclusive bonus content.