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Heart Failure: Novel and Emerging Therapies
Shiva Nandiwada, MD, Justin Ezekowitz, MBBCh MSc, Nawaf Al-Majed, MBBS MSc
About the Authors
Shiva Nandiwada, is with the Department of Medicine – University of Alberta. Edmonton. AB. Canada.
Justin Ezekowitz is with the Canadian VIGOUR Centre, University of Alberta. Edmonton. AB. Canada.
Nawaf Al-Majed is with the Mazankowski Alberta Heart Institute, University of Alberta. Edmonton. AB. Canada.
Corresponding Author: almajed@ualberta.ca
Submitted: January 29, 2020. Accepted: February 5. Published: April 8, 2020. DOI: 10.22374/cjgim.v15iSP1.419.
Abstract
Heart failure (HF) is increasing in prevalence and continues to have poor prognosis despite
using up-to-date guideline-directed medical treatment and device intervention. There is a dire
need for new therapies that can improve patient outcomes. New recently tested medical and
interventional therapies have proven effective in reducing the morbidity, mortality and improving
the quality of life for patients with HF and these therapies are discussed in details in this review.
Ongoing large-scale clinical trials are underway to determine the efficacy and safety of novel
therapies of HF. Development of these medical and interventional therapies are improving our
understanding of HF and paving the way to better clinical outcomes.
Résumé
La prévalence de l’insuffisance cardiaque (IC) augmente et le pronostic reste mauvais malgré
l’utilisation de traitements médicaux et de dispositifs d’intervention conformes aux directives les
plus récentes. Il y a un besoin urgent de nouvelles thérapies qui peuvent améliorer les résultats
des patients. De nouvelles thérapies médicales et interventionnelles récemment testées se sont
avérées efficaces pour réduire la morbidité et la mortalité et améliorer la qualité de vie des patients
atteints d’HF. Ces thérapies sont examinées en détail dans cette revue. Des essais cliniques à
grande échelle sont actuellement en cours pour déterminer l’efficacité et la sécurité des nouvelles
thérapies de l’HF. Le développement de ces thérapies médicales et interventionnelles améliore
notre compréhension de l’HF et ouvre la voie à de meilleurs résultats cliniques.
Heart failure (HF) is a complex syndrome that is increasing in
prevalence, and ranges from 1–2% across different countries and
regions.
1
Despite advances in therapy in the last two decades,
HF-related morbidity and mortality remains high. The one-
year mortality of patients with a new diagnosis of HF remains
as high as 19%.
2
Current standard medical therapies for HF include ACE
inhibitors, beta-blockers, and mineralocorticoid receptor
antagonists.
3
Recent additions to standard therapy include
neprylisin inhibitors for patients with HF with reduced ejection
fraction (HFrEF) and ivabradine for HFrEF patients with a heart
rate >70 beats per minute in normal sinus rhythm. Device-based
therapies such as internal cardiac defibrillator (ICD) implantation
and cardiac resynchronization therapy (CRT) have proven to be
effective in appropriately selected patient populations.
4
Within the last few years, new HF therapies have emerged
(Table 1). The purpose of this review is to outline some of the
emerging therapies that have proved efficacious and to shed
light on promising therapies that are still being evaluated in
randomized-controlled trials.
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Emerging Efficacious Therapies
SGLT-2 Inhibitors
Sodium-glucose co-transporter (SGLT)-2 inhibitors are among
the newest oral diabetes medications that have been proven to
be effective and safe in the treatment of type 2 diabetes mellitus
(T2DM).
5
Large scale RCTs of different SGLT-2 inhibitors have
found improvements in diabetic control, weight loss, systolic
blood pressure, albuminuria, and renal dysfunction.
6,7
A meta-
analysis of trials that assessed the effect of SGLT-2 inhibitors on
cardiovascular outcomes in patients with T2DM with coronary
artery disease found a moderate reduction in the risk of adverse
cardiovascular events.
8
Many of these studies also described a
reduction in rates of HF admission associated with the use of
these agents.
7–10
Subsequently, the Dapagliflozin and Prevention of Adverse
Outcomes in Heart Failure (DAPA-HF) trial aimed to determine
the efficacy of dapagliflozin in patients with HF irrespective of
presence or absence of diabetes. In this trial, 4744 patients with
LVEF <40%, NYHA class II-IV and an elevated NT-proBNP
were randomized to dapagliflozin 10 mg daily or placebo. All
patients received guideline-directed medical and device HF
therapy. The primary end point was a composite of worsening
HF (defined as unplanned hospitalization or urgent visit
requiring intravenous HF therapy) or cardiovascular death.
The median duration of follow up was 18.2 months. The results
showed that dapagliflozin therapy was superior to placebo
in reduction of the primary composite end point (16.3% vs.
21.2%; hazard ratio [HR]=0.74, 95% confidence interval [CI]:
0.65–0.85; number-needed-to treat [NNT] = 21, 95% CI: 15–38),
mostly driven by reduction in HF hospitalization (HR=0.70,
95% CI: 0.59–0.83). The HR of all-cause mortality was 0.83
(0.71 to 0.97) indicating that, if anything, dapagliflozin may be
Table 1. Summary of Novel and Emerging Heart Failure Therapies and the Evidence Supporting Their Use.
Drug/
Intervention
Clinical Trial Findings Comments
Emerging Efficacious Therapies
Sodium-glucose
Cotransporter-2
Inhibitors
DAPA-HF This study demonstrates reductions in composite
of cardiac death and HF hospitalization in
diabetic and non-diabetic patients with HFrEF.
The DELIVER (NCT03619213) and EMPEROR-
Preserved (NCT03057951) studies are ongoing to
assess the efficacy of SGLT-2 inhibitors in patients
with HFpEF
Transcatheter mitral
valve repair
COAPT Transcatheter MV repair for secondary mitral
regurgitation in patients with severe LV systolic
dysfunction reduced HF hospitalization and all
cause mortality.
Results are discrepant from MITRA-FR,
highlighting the importance of appropriate
patients selection.
Atrial Fibrillation
Ablation
CASTLE-AF Pulmonary vein isolation reduced composite
outcome of HF hospitalization and all cause
mortality in patients with moderate to severe LV
dysfunction who had failed or declined medical
rhythm or rate control.
Caution regarding external validity. Physicians
need to be careful in selecting appropriate
patients. No ongoing trials at present.
Potential Emerging Therapies
Omecamtiv Mecabril GALACTIC-HF This phase III trial is investigating the effect of
oral cardiac myosin activators on mortality and
time to first HF event in patients with chronic
HFrEF.
Vericiguat VICTORIA This trial is investigating the effect of oral soluble
guanylate cyclase stimulator on the composite of
cardiac death and HF hospitalization in patients
with LVEF < 45%.
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to severe mitral regurgitation and left ventricular ejection
fraction 20–50% were included. To be eligible, patients had
to have persistent symptoms despite maximal medical and
device therapy, they had to be non-surgical candidates, and
they required review by a HF team that focused on medical
therapy assessment. Patient with concomitant severe valvular
disease or with pulmonary hypertension were excluded. After
a median follow-up of 22.7 months, the primary end-point of
HF-hospitalization was lower in the intervention than standard
therapy group (HR=0.53; 95% CI: 0.40–0.70; NNT=1.3, 95% CI:
1.9–7.9) as was the secondary end point of all cause mortality
(HR=0.62; 95% CI; 0.46 - 0.82; NNT=5.9, 95% CI 3.9 - 11.7).
At 12 months follow-up, 96.6% of patients in the intervention
group were free of device-related complications.
17
It is noteworthy that the results of COAPT are not consistent
with results from MITRA-FR trial, where patients with secondary
mitral regurgitation were randomized to mitral valve clip in
addition to standard medical therapy or medical therapy alone.
In this trial, mitral valve clip was not shown to be of significant
benefit for the outcome of cause mortality or HF-hospitalization
(odds ratio [OR]=1.16, 95% CI: 0.73–1.84).
18
The discrepancy
in results between these seemingly comparable trials may be
explained by the severity of mitral regurgitation (less severe
in MITRA-FR based on echocardiographic measures), study
size and design, length of follow up, and reasons related to the
technique and safety of the procedure.
19
Nevertheless, they
highlight the caution that must be exercised in patient selection
for this complex procedure.
The COAPT trial has established the benefit and safety of
transcatheter mitral valve repair in selected patients with secondary
severe mitral regurgitation. However, the incorporation of this
procedure into standard care of eligible patients is currently
limited by uncertain cost-effectiveness and availability of skilled
practitioners.
Catheter Ablation for Atrial Fibrillation in HF Patients
Atrial fibrillation (AF) and HF often coexist and, collectively,
worsen the progression of both diseases.
20
Up to 37% of patients
with a new diagnosis of AF had HF and 57% of patients with
a new diagnosis of HF had AF.
21
A meta-analysis showed
that comorbid AF in patients with HF was associated with
increased mortality.
22
This questions whether an emphasis
on rhythm control could provide clinical benefit to patients
with HF and comorbid AF. Other than amiodarone, and
sotalol for patients with left ventricular ejection fraction
>35%, antiarrhythmic medications are not suitable for patient
with HF.
23
In addition, sotalol is associated with significant
arrhythmias and amiodarone is associated with well-known
long-term side effects.
associated with less risk of all cause death. In a pre-specified
analysis of secondary endpoints, patients randomized to the
dapagliflozin group experienced a clinical improvement in
HF symptoms as assessed by the Kansas City Cardiomyopathy
Questionnaire (58.3% vs. 50.9%; odds ratio [OR]= 1.15, 95%
CI: 1.08 to 1.23). The safety of dapagliflozin was demonstrated
in this trial as there was no significant difference between the
treatment groups in regards to medication discontinuation,
volume depletion, renal side effects and risk of significant
hypoglycemia.
11
DAPA-HF demonstrated that dapagliflozin therapy in
patients with HFrEF is efficacious and safe in both diabetic
and, importantly, non-diabetic patients, suggesting that the
improvements seen in HF end points are independent of the
glucose lowering effects of this agent. Multiple physiological
mechanisms have been proposed to explain the cardiovascular
benefits of SGLT-2 inhibitors, including an osmotic diuretic
effect mediated by relative glucosuria, changes in myocardial
metabolism, changes in cellular ion transport, modulation of
renal function, and changes in sympathetic nervous system
activation.
12
Regardless of the exact mechanisms for each patient
or patient group, the effectiveness as seen by clinical trials is the
ultimate test of their utility.
Further studies are ongoing to characterize the efficacy of
SGLT-2 inhibitors in the treatment of other subsets of patients
with HF such as those with HFpEF. DELIVER (NCT03619213)
and EMPEROR-Preserved (NCT03057951) are phase III trials
that are in the process of evaluating the efficacy of dapagliflozin
and empagliflozin in addition to standard medical therapy in
patients with HFpEF.
Transcatheter Mitral Valve Repair
Secondary mitral regurgitation is a complication of left
ventricular dysfunction. Left ventricular dysfunction can result
in annular dilation and the tethering of chordae tendinae and
papillary muscles, leading to incomplete coaptation of the mitral
valve leaflets.
13
Secondary mitral regurgitation is a clinically
significant phenomenon associated with increased morbidity
and mortality.
14,15
To date, the management of these patients has
focused on symptom control, and surgery, when tested in small
randomized trials has shown no benefit or harm. Currently,
indications for mitral valve surgery in patients with secondary
mitral regurgitation include persistent NYHA III-IV symptoms
(class IIb) and mitral valve surgery in the setting of concomitant
other cardiac surgery (class IIa).
16
The COAPT trial randomized 614 patients with secondary
mitral regurgitation to the intervention group (transcatheter
mitral valve repair in addition to standard therapy) or standard
therapy alone. Symptomatic patients with HFrEF with moderate
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The CASTLE-AF trial enrolled 363 patients with left
ventricular ejection fraction < 35%, NYHA II-IV symptoms, and
paroxysmal or persistent AF in whom rhythm control could not
be achieved. These patients were randomized to catheter ablation
or medical rate or rhythm control. In the ablation arm, the aim
of catheter guided ablation was to isolate the pulmonary vein
and restore normal sinus rhythm. All patients received guideline
directed medical therapy and had an ICD implanted or CRT if
indicated. Patients in the medical therapy arm received standard
medical therapy for AF (30% rhythm control, 70% rate control).
Both groups received guideline-directed medical therapy for HF.
The primary outcome was a composite of all cause mortality
and hospitalizations for HF. Secondary outcomes included
mortality, hospitalization due to HF, cardiac death and CVA.
After a median follow-up of 37.8 months, the ablation therapy
arm showed a reduction in the composite primary endpoint
compared to the medical therapy arm (28.5% vs. 44.6%; HR=0.62;
95% CI: 0.43 - 0.87) as well as a reduction in all cause mortality
(HR=0.53), HF hospitalization (HR=0.56), and cardiovascular
death (HR=0.49). The safety of this procedure was not clearly
assessed in this trial.
24
Although the CASTLE-AF trial demonstrated the efficacy
of catheter ablation in the establishment of rhythm control in
carefully selected HF patients, it has important limitations. The
results of this trial are specific to patients who failed or refused
rhythm control and thus should not be generalized to all patients
with HF and AF. Moreover, the results are inconsistent with the
CABANA trial, which was not specific to a HF population, and
showed that catheter ablation in addition to standard medical
therapy did not improved the composite outcome of death,
disabling stroke, severe bleeding, or cardiac arrest at 12 months
(HR=0.86; 95% CI; 0.65 – 1.15).
25
Emerging Therapies
Omecamtiv Mecbril
The use of inotropic agents in HF has not been shown to improve
mortality or reduce hospitalization.
26
Different mechanisms
to explain these observations have been proposed, including
triggering arrhythmias and increasing myocardial oxygen demand.
27
Omecamtiv mecabril (OM) is a cardiac myosin activator that is
being studied for its potential to increase the stroke volume of
HF patients without some of the deleterious effects associated
with existing inotropic medications, and as such, not considered
an inotrope based on its mechanism of action.
28
In the myosin-actin contraction cycle, the hydrolysis of
myosin bound ATP to myosin bound ADP and phosphate
prepares myosin head-ATP-phosphate complex for binding with
actin filaments. By binding to the catalytic domain of the myosin
head and increasing the rate of ATP hydrolysis, OM increases
cardiac contractility by increasing the proportion of myosin heads
available for actin binding. In doing so, contractility is increased
without an increase in cardiomyocyte oxygen consumption or
intracellular calcium levels.
27–31
The ATOMIC-HF trial randomized 606 patients with acutely
decompensated HFrEF to a 48 hours intravenous infusion of
OM or placebo. Inclusion criteria specified that patients must
have a left ventricular ejection fraction< 40%, elevated BNP
(>400 pg/mL or > 600 pg/mL if they had AF), and persistent
dyspnea two hours after 40 mg furosemide infusion. No
difference in the primary end point of dyspnea relief between
the OM and placebo groups was observed, however, the OM
group demonstrated prolonged systolic ejection time (SET),
decreased end systolic left ventricular diameter, and higher
plasma troponin levels.
30
The COSMIC-HF trial, a phase II trial, was able to demonstrate
the pharmacokinetics and optimal oral dose of OM. In this
RCT, patients with symptomatic HFrEF were randomized to
20 weeks of placebo, 25 mg OM twice-daily, or 50 mg OM
twice-daily. Overall, oral OM therapy was shown to be safe
and well tolerated in patients with HFrEF.
28
The ongoing phase
III GALACTIC-HF study (NCT02929329) is investigating the
effects of OM in reducing cardiovascular death or HF events in
patients with chronic HFrEF. This phase III trial has enrolled
over 8,000 patients, randomized to dose titrated oral OM or
placebo therapy arms. The primary outcome of interest will
be the time to cardiac death or first HF event. The estimated
conclusion date is January 2021.
32
Vericuguat
In normal physiology, nitric oxide (NO) released by
endothelial cells regulates the development and tone of
vascular smooth muscle cells in the heart, kidney, and
circulatory system.
29,33
The release of NO from endothelial
cells increases the production of cGMP. Through a complex
signaling cascade, cGMP leads to reduced intracellular
calcium levels and vasomotor tone.
34
In HF, endothelial cell
dysfunction and increased levels of reactive oxygen species
result in decreased NO availability and deleterious vascular
smooth muscle dysregulation.
35,36
Soluble guanylate cyclase activators stimulate sGC independent
of NO signaling.
37
Riociguat is a sGC stimulator that has been
shown to be effective in the treatment of chronic thromboembolic
pulmonary hypertension and pulmonary arterial hypertension.
38
The VICTORIA trial (NCT02861534), a study of vericuguat,
another sGC stimulator, in patients with chronic HFrEF is still
ongoing.
39
More than 5000 patients with chronic HF with NYHA
II-IV symptoms, LVEF < 45%, HF hospitalization within 6 months,
and elevated BNP were randomized to placebo or vericiguat 2.5,
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5.0, or 10.0 mg PO daily. The primary outcome of interest is a
composite end-point of cardiac death or HF hospitalization.
Conclusions
Although our understanding of the genetics and etiology of
HF has improved in the last two decades, the prognosis of
patients diagnosed with HF has not changed appreciably.
Amongst the newly established therapies, SGLT-2 inhibitors
offer the promise of additional medical therapy that can be
applied to a general HF population with moderate to severe
left ventricular systolic dysfunction. Interventional therapies
such as the mitral valve clip and AF ablation may improve
important patient related outcomes; however, their applicability
is limited to highly selected patient populations. None of
these therapies have been strongly recommended by current
practice guidelines, but it is expected that this may change in
their next iteration. The ongoing large-scale studies of OM
and vericiguat outlined above offer the promise of improving
outcomes in patients with HF.
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