systolic dysfunction clinical /hemodynamic guide for...
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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
ec
rea
se
in
Mo
rta
lity
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
Kap
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve R
ate
s (
%)
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
lan
-Meie
r E
sti
mate
of
Cu
mu
lati
ve R
ate
s (
%)
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
ec
rea
se
in
Mo
rta
lity
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
Cu
mu
lativ
e R
ate
of N
on
-Te
rmin
al E
ven
ts
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
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
Cu
mu
lativ
e R
ate
of N
on
-Te
rmin
al E
ven
ts
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
1.1
1.2
1.3
1.4
1.5
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
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