Canadian Journal of General Internal Medicine

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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.

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%.

Current standard medical therapies for HF include ACE

inhibitors, beta-blockers, and mineralocorticoid receptor

antagonists.

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.

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).

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.

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.

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).

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.

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.

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.

A meta-analysis showed

that comorbid AF in patients with HF was associated with

increased mortality.

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.

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.

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.

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.

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).

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.

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).

Emerging Therapies

Omecamtiv Mecbril

The use of inotropic agents in HF has not been shown to improve

mortality or reduce hospitalization.

Different mechanisms

to explain these observations have been proposed, including

triggering arrhythmias and increasing myocardial oxygen demand.

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.

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.

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.

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.

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.

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.

Riociguat is a sGC stimulator that has been

shown to be effective in the treatment of chronic thromboembolic

pulmonary hypertension and pulmonary arterial hypertension.

The VICTORIA trial (NCT02861534), a study of vericuguat,

another sGC stimulator, in patients with chronic HFrEF is still

ongoing.

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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