Where do the new drugs fit in HF care

Ileana L. Piña, MD, MPHProfessor of Medicine, Epidemiology and Population Health

Albert Einstein College of MedicineAssociate Chief of Cardiology for Academic Affairs

Montefiore-Einstein Medical CenterBronx, NY

Graduate VA Quality Scholar

New Targets / Trials (looking at the syndrome from different angles)

• New vasodilators /GMPc modulators

• Synthetic natriuretic peptides

• Sinus node inhibition for heart rate reduction

• NEP inhibitors(+ ARB) (ARNI)

• Binders of actin-myosin

• Novel non-steroidal MRA’s

• CSA therapy? Will new agents also limit our use?

New Vasodilators

Relaxin Mechanisms of Action

• Vasodilation• NO, cGMP effectors• Induction of NOS II/III• Upregulation of endothelial endothelin

type B receptor, which mediates vasodilation

• Preferential dilation of constricted vessels• Relaxin-upregulated ETB receptors act as

vasodilating ET-1 sink

• Anti-inflammatory• Down-modulation of inflammatory

cytokines linked to outcome in HF (TNF-, TGF-)

• Other: Anti-ischemic, Anti-apoptotic, Anti-fibrotic

Relaxin Receptor LGR7

Serelaxin: RELAX-AHF Trial Results1,2

Symptoms CV Death

1. Metra M, et al. J Am Coll Cardiol. 2013;61(2):196-206. 2.Teerlink JR, et al. Lancet. 2013;381(9860):29-39; with permission.

Serelaxin and Lab values

1. Metra M, et al. J Am Coll Cardiol. 2013;61(2):196-206. 2.Teerlink JR, et al. Lancet. 2013;381(9860):29-39; with permission.

Synthetic Natriuretic Peptides

Ularitide

• Ularitide is the pharmacologic version of urodilatin

• 32 amino acid hormone of the natriuretic peptide family, secreted from the distal tubule of the kidney

• Binding to the natriuretic peptide receptor A

• stimulation of guanylate cyclase,

• In acute heart failure, • systemic organ perfusion

• Phase II trial completed

Binders of actin-myosin

ATOMIC-AHFOmecamtiv Mecarbil (OM) is a Novel Selective Cardiac Myosin Activator

Malik FI, et al. Science 2011; 331:1439-43.

Adapted from ATOMIC-HF results presentation available at www.clinicaltrialresults.org/Slides/ESC%202013/Teerlink_ATOMIC.ppt. Accessed January 27, 2015

Mechanochemical Cycle of Myosin

Omecamtiv mecarbilincreases the entry rate of

myosin into the tightly-bound, force-producing

state with actin“More hands pulling on the

rope”

Increases duration of systole

Increases stroke volume

No increase in myocyte calcium

No change in dP/dtmax

No increase in MVO2

Force production

ATOMIC-HFPrimary Efficacy Endpoint

Response Rate Ratio*

1.03 1.15 1.23

95% CI (0.79, 1.35) (0.90, 1.47) (0.97, 1.55)*Ratio of response rate to Pooled Placebop-value of a CMH test among all 3 Placebo arms = 0.32

Overall p-value = 0.33

Dysp

no

ea

Re

sp

on

se

Rate

(% R

esp

on

de

rs)

41% 42%

47%

51%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

55%

PooledPlacebo

OM Cohort 1 OM Cohort 2 OM Cohort 3

Dyspnea Response (Likert Scale)Pooled Placebo

Adapted from ATOMIC-HF results presentation available at www.clinicaltrialresults.org/Slides/ESC%202013/Teerlink_ATOMIC.ppt.

Potassium Binders

23

Normal Range

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0Pre

dic

ted

Pro

bab

ility

of

Mo

rtal

ity

Levels of Serum Potassium (mEq/L)

Adjusted Mortality* by Serum K+ Level in Patients 45 to 64 Years and ≥65 Years With and Without Comorbid Illness

*Evaluated through de-identified medical records (2007-2012) of individuals with ≥2 mEq/L serum K+ readings (Humedica, Cambridge, MA). Spline analyses were performed to assess mortality at 0.1 mEq/L increments of serum K+ after adjusting for covariates and interactions. Comorbid patients are those with diabetes, heart failure , CKD stages 3-5, cardiovascular disease, or hypertension.

Comorbid ≥65 yr95% Conf Limits

Comorbid 45-64 yr95% Conf Limits

Control ≥65 yr 95% Conf Limits

Control 45-64 yr95% Conf Limits

Reference: Pitt B, et al. American Heart Association (AHA). 2014 Poster Presentation.

Increases in mortality remained after adjustments for

demographic characteristics and comorbidities

24

Low K+ Diet Is the First Step in Chronic Management, but Compliance Is Difficult

1. Foods rich in potassium content are pervasive and all encompassing

2. Consequently, strictly adhering to a low potassium diet exerts a toll on the patient’s quality of life

ZS-9

•ZS-9 is an insoluble, non-absorbed zirconium

silicate designed to preferentially trap K+ ions in

order to lower and maintain control

of serum K + levels.

• ZS-9 is passed through the GI tract and

eliminated in the stool.

• ZS-9 uses technology that mimics natural

ion channels to make it difficult for ions

other than potassium to enter its crystalline

structure.

Because of ZS-9’s high selectivity for K+, no clinically significant changes in sodium, magnesium,calcium

ZS-9 rapidly lowers serum potassium to normal levels (media time to normalization is 2.2 hours.

Across all doses studied, ZS-9 consistently maintains normokalemia: 5g-80%, 10g-90%, 15g 94%.

Patiromer

• Patiromer for oral suspension is

designed for the binding and removal

of K+ from the GI tract, particularly

the colon.

• Patiromer is a non-specific organic,

potassium-binding polymer.

.

• Patiromer is insoluble in typical

solvents and is believed to pass

through the GI tract without being

metabolized or broken down.

.

• Slow onset of action may limits its use

in the acute setting.

Device Therapy for Stage C HFrEF (cont.)Recommendations COR LOE

ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF at least 40

days post-MI with LVEF ≤35%, and NYHA class II or III symptoms on chronic GDMT, who are

expected to live ≥1 year*I A

CRT is indicated for patients who have LVEF ≤35%, sinus rhythm, LBBB with a QRS ≥150 ms

I

A (NYHA class

III/IV)

B (NYHA class

II)

ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF at least 40

days post-MI with LVEF ≤30%, and NYHA class I symptoms while receiving GDMT, who are expected

to live ≥1 year*I B

CRT can be useful for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with a QRS

≥150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT. IIa A

CRT can be useful for patients who have LVEF ≤35%, sinus rhythm, LBBB with a QRS 120 to 149 ms,

and NYHA class II, III or ambulatory IV symptoms on GDMTIIa

B

CRT can be useful in patients with AF and LVEF ≤35% on GDMT if a) the patient requires ventricular

pacing or otherwise meets CRT criteria and b) AV nodal ablation or rate control allows near 100%

ventricular pacing with CRT

IIa B

Recommendations COR LOE

CRT can be useful for patients on GDMT who have LVEF ≤35%, and are undergoing new or replacement

device with anticipated (>40%) ventricular pacing IIa C

An ICD is of uncertain benefit to prolong meaningful survival in patients with high risk of nonsudden death

such as frequent hospitalizations, frailty, or severe comorbidities*IIb

B

CRT may be considered for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with QRS

120 to 149 ms, and NYHA class III/ambulatory class IV on GDMT IIb B

CRT may be considered for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with a QRS

≥150 ms, and NYHA class II symptoms on GDMT IIb B

CRT may be considered for patients who have LVEF ≤30%, ischemic etiology of HF, sinus rhythm, LBBB

with a QRS ≥150 ms, and NYHA class I symptoms on GDMT IIb C

CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB pattern with QRS

<150 ms

III: No

BenefitB

CRT is not indicated for patients whose comorbidities and/or frailty limit survival to <1 year III: No

BenefitC

Device Therapy for Stage C HFrEF (cont.)

Mechanical Circulatory Support

MCS use is beneficial in carefully selected* patients with stage D HFrEF in

whom definitive management (e.g., cardiac transplantation) or cardiac recovery

is anticipated or planned.

Nondurable MCS, including the use of percutaneous and extracorporeal

ventricular assist devices (VADs), is reasonable as a “bridge to recovery” or a

“bridge to decision” for carefully selected* patients with HFrEF with acute,

profound hemodynamic compromise.

Durable MCS is reasonable to prolong survival for carefully selected* patients

with stage D HFrEF.

I IIa IIb III

I IIa IIb III

I IIa IIb III

June 10, 2006 ASAIO

Duration of Mechanical Circulatory SupportMechanical Circulatory

Support

Very Short Time< 6 hours

During CPBSurgical Procedures

Short Time> 6 hours, ≤ 14 days

Failure to weanCardiogenic shock

Bridge to next therapyPending recovery (?)

Intermediate Time> 14 days, < 1 year

Pending recovery (?)Bridge to transplant

Long Time“forever”

“Destination therapy”

June 10, 2006 ASAIO

Short Time

• Failure to wean from CPB

• Cardiogenic shock (acute MI)

• Acute decompensation of chronic HF

• Pending recovery

– Post-partum

– Myocarditis

• First presentation of HF in an acute setting

Mechanical Assistance: Approved• ECMO

• Impella

• CentriMag

• HMII for BTT and DT

• HeartWare for BTT only

• HMIII in trial

Devices for “Acute Rescue”

• IABP

– Advantages:

• Cath lab or CCU

• Rapid access with experience

– Disadvantages

• Blood flow compromise to leg

• Temporary--may not be long enough for recovery

• Dissection with PVD

Impella

“…submitted the necessary IDE file on the Recover® LP 2.5 to FDA.”

•Acute myocardial infarction

•Cardiogenic shock

•Low output syndrome

•High risk PTCA

•Post PCI]

•Bridge to the next decision

Inflow

outlet

pump

June 10, 2006 ASAIO

Intermediate Time

• Pending recovery (?)

• Bridge to transplant

June 10, 2006 ASAIO

Bridge to Transplant

• Objective Performance Criteria (OPCs)

– Develop performance criteria for a defined set of clinical

outcomes

– Measure new device against these performance criteria

• Partial solution?

– OPC for survival (~70%)

– No OPCs for AEs

Mechanical Circulatory Support

• Bridge to transplantation

• Destination Therapy

– Palliation

– Recovery

• Explantation

• Transplantation eligibility

REMATCH Trial: All Cause Mortality

LV Assist

Device (n=68)

Control

(n=61)

P=0.001

6 12 18 240

100

80

60

40

20

0

30

Months

% E

ve

nt F

ree

Su

rviv

al

RR 0.52 (0.34,0.78)

N Engl J Med 2001; 345: 1435

8 mths

Worsening of nutritional state, end-organ and RH function

OperativeRisk

DeathFutile Implants

Successful Implants

Too Late

1-Year Survival

53 – 94%

1-Year Survival

6%

The Right Time for LVAD ImplantationKey to Survival after Destination Therapy

Optimizing Peri-operative Outcomes

Lab Ideal Pre-Implant Goals

Renal BUN < 50; Creatinine < 2.5; Urine output > 1 cc/kg/min × 6 hr

Coagulation INR < 1.2; Hgb > 10.0; Plt Ct > 150,000

Nutrition Albumin > 2.5; Pre-Albumin > 15 mg/dL; Transferrin > 250 mg/dL

Liver Function Bili < 2.5; ALT, AST < 2 times normal

Hemodynamic

RA < 12

PCW < 24

CI > 2.0

May require IABP multiple vasoactive drugs and fluid ultrafiltration to

achieve

May require IABP to optimize status