Systolic Dysfunction Clinical /Hemodynamic Guide for Management

New Medical and Interventional Therapeutic Challenges

Donna Mancini MD

Choudhrie Professor of Cardiology

Columbia University

Speaker Disclosure

• Amgen Speakers bureau

Heart Failure Management

Arnold JMO, Howlett JG, et al. Can J Cardiol 2007;23(1):21-45.

Beta blocker

Mineralocorticoid receptor

antagonist

Drugs That Reduce Mortality in Heart Failure With Reduced Ejection Fraction

ACE inhibitor

Angiotensin receptor blocker

Drugs that inhibit the renin-angiotensin system have modest effects on

survival

Based on results of SOLVD-Treatment, CHARM-Alternative,

COPERNICUS, MERIT-HF, CIBIS II, RALES and EMPHASIS-HF

10%

20%

30%

40%

0%

% D

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Are there recent changes in HF therapy??

• Drugs – 2003 Eplerenone approved for CHF

– 2005 Bidil approved for self identified black patients

– 2015 ivabradine (blocks SA node If channels for reduction of HR CHF pts in NSR w HR>70 W LVEF <35%

– 2015 Entresto-ARNI (ARB + Neprilysin Inhibitor)

Devices

– HMII (4/08 BTT;1/10DT),HW (6/13 BTT)

– mitral clip for degenerative MV (10/13)

– cardiomems (5/14),

There is hope for Heart Failure

Drugs Neprilysin Inhibitors Entresto Ivabradine Seralaxin Gene Therapy Serca2-Mydicar Devices LVADs Stem Cells miRNAs-antagomirs

PARADIGM Angiotensin–Neprilysin Inhibition versus Enalapril

in Heart Failure

John J.V. McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C. Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D.,

Ph.D., Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees

N Engl J Med Volume 371(11):993-1004

September 11, 2014

von Lueder Circulation: Heart Failure. 6(3):594-605, 2013 May.

NEP interrupts Alternative AII generating Pathway

Neprilysin Inhibition Potentiates Actions of Endogenous Vasoactive Peptides That Counter

Maladaptive Mechanisms in Heart Failure

Endogenous

vasoactive peptides

(natriuretic peptides, adrenomedullin,

bradykinin, substance P,

calcitonin gene-related peptide)

Inactive metabolites

Neurohormonal activation

Vascular tone

Cardiac fibrosis, hypertrophy

Sodium retention

Neprilysin Neprilysin

inhibition

OVERTURE in 2002

• 5770 Class II-IV HF pts

• Enalopril 10 mg po BID vs Omapatrilat 40 mg daily

• Omapatrilat inhibited ACE, aminopeptidase P and neprilysin

• No difference in outcome

• Hypotension and angioedema (0.5%) more frequent with Omapatriat

OVERTURE Time to death or hospitalization in the omapatrilat and enalapril groups.

Packer M et al. Circulation. 2002;106:920-926

Prospective comparison of ARNI with ACEI to

Determine Impact on Global Mortality and morbidity

in Heart Failure trial (PARADIGM-HF)

• LCZ696 40 mg sacubitril + 160 mg valsartan BID vs Enalopril 10 mg po BID

• Inclusion criteria:

• Class II-IV CHF

• LVEF <40%

• BNP >150 or >100 if CHF hospitalization the prior year

• Exclusion critera:

• BP < 100 systolic

• GFR < 30

• K>5.2

• h/o angioedema

• Primary endpoint CV mortality and CHF hospitalizations

• 8442 patients randomized 1:1 to LCZ696 vs enalopril

2 weeks 1-2 weeks 2-4 weeks

Single-blind run-in period Double-blind period

(1:1 randomization)

Enalapril

10 mg BID

100 mg BID

200 mg BID

Enalapril 10 mg BID

LCZ696 200 mg BID

PARADIGM-HF: Study Design

LCZ696

LCZ696

(n=4187) Enalapril (n=4212)

Age (years) 63.8 ± 11.5 63.8 ± 11.3

Women (%) 21.0% 22.6%

Ischemic cardiomyopathy (%) 59.9% 60.1%

LV ejection fraction (%) 29.6 ± 6.1 29.4 ± 6.3

NYHA functional class II / III (%) 71.6% / 23.1% 69.4% / 24.9%

Systolic blood pressure (mm Hg) 122 ± 15 121 ± 15

Heart rate (beats/min) 72 ± 12 73 ± 12

N-terminal pro-BNP (pg/ml) 1631 (885-3154) 1594 (886-3305)

B-type natriuretic peptide (pg/ml) 255 (155-474) 251 (153-465)

History of diabetes 35% 35%

Digitalis 29.3% 31.2%

Beta-adrenergic blockers 93.1% 92.9%

Mineralocorticoid antagonists 54.2% 57.0%

ICD and/or CRT 16.5% 16.3%

PARADIGM-HF: Baseline Characteristics

0

16

32

40

24

8

Enalapril (n=4212)

360 720 1080 0 180 540 900 1260

Days After Randomization

4187

4212

3922

3883

3663

3579

3018

2922

2257

2123

1544

1488

896

853

249

236

LCZ696

Enalapril

Patients at Risk

1117

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%)

914

LCZ696 (n=4187)

HR = 0.80 (0.73-0.87)

P = 0.0000002

Number needed to treat = 21

PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)

Enalapril (n=4212)

LCZ696 (n=4187)

HR = 0.80 (0.71-0.89)

P = 0.00004

Number need to treat = 32

Kap

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%)

Days After Randomization

4187

4212

4056

4051

3891

3860

3282

3231

2478

2410

1716

1726

1005

994

280

279

LCZ696

Enalapril

Patients at Risk

360 720 1080 0 180 540 900 1260 0

16

32

24

8

693

558

PARADIGM-HF: Cardiovascular Death

LCZ696

(n=4187)

Enalapril

(n=4212)

Hazard

Ratio

(95% CI)

P

Value

Primary

endpoint

914

(21.8%)

1117

(26.5%)

0.80

(0.73-0.87) 0.0000002

Cardiovascular

death

558

(13.3%)

693

(16.5%)

0.80

(0.71-0.89) 0.00004

Hospitalization

for heart failure

537

(12.8%)

658

(15.6%)

0.79

(0.71- 0.89) 0.00004

PARADIGM-HF: Effect of LCZ696 vs Enalapril on Primary Endpoint and Its Components

Subgroup AnalysesLCZ696 superior in all subgroups

LCZ696 (n=4187)

Enalapril (n=4212)

P Value

Prospectively identified adverse events

Symptomatic hypotension 588 388 < 0.001

Serum potassium > 6.0 mmol/l 181 236 0.007

Serum creatinine ≥ 2.5 mg/dl 139 188 0.007

Cough 474 601 < 0.001

Discontinuation for adverse event 449 516 0.02

Discontinuation for hypotension 36 29 NS

Discontinuation for hyperkalemia 11 15 NS

Discontinuation for renal impairment 29 59 0.001

Angioedema (adjudicated)

Medications, no hospitalization 16 9 NS

Hospitalized; no airway compromise 3 1 NS

Airway compromise 0 0 ----

PARADIGM-HF: Adverse Events McMurray JJV et al. N Engl J Med 2014;371:993-1004

In heart failure with reduced ejection fraction, when

compared with recommended doses of enalapril:

LCZ696 was more effective than enalapril in . . .

• Reducing the risk of CV death and HF hospitalization

• Reducing the risk of CV death by incremental 20%

• Reducing the risk of HF hospitalization by incremental 21%

• Reducing all-cause mortality by incremental 16%

• Incrementally improving symptoms and physical limitations

LCZ696 was better tolerated than enalapril . . .

• Less likely to cause cough, hyperkalemia or renal impairment

• Less likely to be discontinued due to an adverse event

• More hypotension, but no increase in discontinuations

• Not more likely to cause serious angioedema

PARADIGM-HF: Summary of Findings

10%

Angiotensin Neprilysin Inhibition With LCZ696 Doubles Effect on Cardiovascular Death of Current

Inhibitors of the Renin-Angiotensin System

20%

30%

40%

ACE inhibitor

Angiotensin receptor blocker

0%

% D

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18%

20%

Effect of ARB vs placebo derived from CHARM-Alternative trial

Effect of ACE inhibitor vs placebo derived from SOLVD-Treatment trial

Effect of LCZ696 vs ACE inhibitor derived from PARADIGM-HF trial

Angiotensin neprilysin inhibition

15%

Criticisms of study

• Dose of enalopril may not have been optimal; lower than used in clinical practice; valsartan at maximal dose

• Run in period of the study • Hypotension w ARNI • Neprilysin also breaks down beta amyloid which

builds up in Alzheimer’s; long term effect of this drug is unknown

• 20% reduction in events is really decrease from 26 to 22 % absolute reduction in endpoints

When to Transition from ARB/ACE to ARNI????

• Symptomatic on ACE/ARB

• Asymptomatic but volume overloaded on ACE/ARB with edema, JVD, rales- Consider switching to ARNI rather than increasing diuretic

Corlanor (Ivabradine )

• Corlanor is indicated to reduce the risk of hospitalization for worsening heart failure in patients with stable, symptomatic CHF w LVEF < 35%

• In sinus rhythm with resting HR >70 bpm on maximally tolerated doses of beta blockers or have a contraindication to beta blockers

Contraindications to Corlanor

• Atrial Fibrillation

• Acute Decompensated HF

• BP<90/50

• SSS, SA block, or CHB unless PM is present

• Resting HR<60

• Severe hepatic impairment

• Pacemaker dependence

Systolic Heart Failure Treatment with the If Inhibitor Trial (SHIFT)

• Mortality Morbidity Driven Trial of 6,505 patients w CHF

• Patients received Corlanor or placebo in addition to Standard of Care medications

• Dose started at 5 mg BID and titrated up or down to 7.5 mg BID or 2.5 mg BID depending on HR

• Median F/U 23 months

SHIFT Inclusion/Exclusion Criteria

• Inclusion

• Sinus Rhythm

• Stable CHF x 4 wks

• NYHA Class II-IV

• LVEF < 35%

• HR>70

• CHF Hospitalization in the preceding year

• Exclusion

• MI w/in past 2 mo or scheduled revascularization

• V Paced> 40% of day

• Permanent Afib/flutter

• Severe or Uncontrolled HT

Baseline Characteristics

Ivabradine group (n=3241)

Placebo group (n=3264)

Age (years) 60.7 (11.2) 60.1 (11.5) Sex (male) 2462 (76%) 2508 (77%) Heart rate (bpm) 79.7 (9.5) 80.1 (9.8) SBP (mmHg) 122.0 (16.1) 121.4 (15.9) LVEF (%) 29·0% (5·1) 29·0% (5·2) NYHA class Class II 1585 (49%) 1584 (49%) Class III 1605 (50%) 1618 (50%) Class IV 50 (2%) 61 (2%)

Swedberg, Lancet 2010; Vol 376; p 875

Benefit derived from decrease in hospitalizations not mortality

When to Add Ivabradine?

• At maximum dose of B Blocker but still with a HR >70 bpm

• In NSR

• Not totally paced

• BP >90 systolic

Gene Therapy

• Target specific genetic defects – Hypertrophic CM

• >1400 mutations in 10 sacromere genes-Actin, myosin , troponin

– Dilated CM • Titin, LMNA, desmin, dystrophin

– Arrhythmogenic RV cardiomyopathy – Channelopathies – Restrictive CM

• Fabry’s, Glycogen storage diseases, mitochondrial defects

• Hope of the future is to correct Genetic defects—not there yet; many missense mutations

• Target downregulation of several key enzymes

SERCA2a: Validated Target for Treatment of CHF

• Cardiac SERCA2a protein and activity decline during heart failure

• Cardiac function correlates with SERCA2a level or function – Clinical recovery after LVAD – Treatment with -blockers

• Increase in SERCA2a activity via gene transfer improves contractility & survival – In isolated human end-stage cardiomyocytes – In rodents & independent large animal models of heart

failure in multiple labs

SERCA2a Target

36

Duration (Days)30 60 90 120 150 180 210 240 270 300 330 360 390

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DAY vs M0

DAY vs M1

DAY vs M2

DAY vs M3

Cumulative Clinical Event Rate Adjusted for Competing Event (Death, Tx, LVAD)

Biometrics 2000;56(2):554-62.

Circulation 2009; 119(7): 969-977.

*

Duration (Days)30 60 90 120 150 180 210 240 270 300 330 360 390

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DAY vs M0

DAY vs M1

DAY vs M2

DAY vs M3

P (N=14)

L (N=8) HR(CI)=0.40 (0.13, 1.21), p = 0.11

M (N=8) HR(CI)=0.44 (0.16, 1.24), p = 0.12

H (N=9) HR(CI)=0.12 (0.03, 0.49), p = 0.003

Devices

• New RV temporary support device Impella 2.5

• HMIII

• HW

• Biventricular Pacing

• Percutaneous Valve Repair

• Physiologic Monitoring

“Epidemic” of Heart Failure in the US

• 5.2 million cases

• 650,000 incidence cases/yr

• 1 million hospital admissions annually

• Rehospitalization rate of 25% within 1 month; 50% within 6 months

• 50% of patients diagnosed with heart failure will die in 5 years

• 300,000 deaths/yr

• Cost >$40 billion/yr

Timeline of Congestion

Trends over days

Pressures /sec

Champion Trial

Abraham W,Lancet 2011;377:658-666

• 550 patients w sensor implants

• All patients take daily readings

• Primary Endpoint Rate of HF hospitalizations

• 270 patients in treatment arm-hemodynamically guided therapy

• 280 control arm—standard therapy

Champion

• 37% reduction in HF hospitalizations over 15 months (p < 0.0001)

• In patients with HFpEF, 60% reduction in HF hospitalization over 15 months (p<0.0004)

• In patients with HFrEF, similar reductions in HF hospitalization in patients with and without a CRT device

COAPT Trial CV Outcomes Assessment of MitraClip Percutaneous Tx

for HF Pt with Fn MR

• 3+ functional MR

• Optimal Medical therapy

• Non surgical candidate

• NYHA Class II-IV

• LVEF between 20-50%

• LVEDD <7 cm

• 1 prior CHF hosp in the last year

• Exclusion Criteria

• Untreated CAD

• Recent CABG or PTCA

• Severe TV or AV disease

• Recent CVA

• Carotid stenosis >70%

• MV orifice area <4

• Leaflet anatomy-Ca, intercommisural MR

There is hope for Heart Failure

Drugs Neprilysin Inhibitors Entresto Ivabradine ??miRNAs-antagomirs ?? Seralaxin Physiologic Monitors Percutaneous Valve repairs LVADs ????Stem Cells

Sources of micro RNAs

Kumarswamy R; Circ Res113(6):676-89, 2013

Micro RNAs Short non coding RNAs which silence messenger RNA by pairing w messenger sites preventing protein translation Produced by necrotic; apoptotic cells . MicroRNAs (miR/miRNA) can have adverse or protective roles in cardiac remodeling Antagomirs: Chemically engineered oligonucleotide antagonists to miRNAs