strategie terapeutiche strategies of medical therapy mariell jessup md professor of medicine...
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Strategie terapeutiche
Strategies of Medical Therapy
Mariell Jessup MDProfessor of Medicine
University of PennsylvaniaPhiladelphia, Pennsylvania
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Proven toimprove survivalin clinical trials ??
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Pfeffer, M. A. et. al. N Engl J Med 2003;349:1893-1906
Kaplan-Meier Estimates of the Rate of Death from Any Cause (Panel A) and the Rate of Death from Cardiovascular Causes, Reinfarction, or Hospitalization for Heart Failure (Panel B),
According to Treatment Group
VALIANT
Val-HeFT: Combined Morbidity Endpoint
ACEI/Beta-Blocker Subgroups PlaceboValsartan
0
10
20
30
40
50
ACEI (No)BB (No)
ACEI (Yes)BB (No)
ACEI (No)BB (Yes)
ACEI (Yes)BB (Yes)(N = 1606)(N = 3038) (N = 139)(N = 227)
47.0%
27.7%
36.3% 30.9%
34.8%
20.5% 22.0%25.5%
Mortality in the placebo arm of Val-HeFT by treatment group: 23-month mean follow-up
0
10
20
30
40
ACEI-/BB- ACEI+/BB- ACEI-/BB+ ACEI+/BB+
HF Therapy
%
Mortality
Sudden death
Pump Failure
7.4
2.5
2.0
11.9
6.1
4.5
7.5
8.9
3.013.2
12.3
6.1
11.9
22.519.4
31.6
Slide courtesy of J. Cohn
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Aldosterone Blockade in Heart FailureRALES: Randomized Aldactone Evaluation
Study
1663 pts NYHA III and IV, ave age 65 and LVEF 0.25, on ACEI and loop diuretic Randomized to Aldactone 25 mg PO qd vs PlaceboPitt NEJM 1999;341:709-17
0 10 20 30 40
Follow-up (months)
0
20
40
60
80
100Survival Proportion
Aldactone
Placebo
RR 0.73 (0.63-0.86)P=0.0001
n=822
n=841
Juurlink et al. NEJM 2004;351:543
after RALES: RX
Juurlink et al. NEJM 2004;351:543
after RALES::Death
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Role of ICDsMADIT-II (16% women)– NYHA IV excluded from MADIT I and II– No benefit of ICD for women– Other minorities not listed
SCD-HeFT (23% women, 24% non-white)– NYHA IV excluded– No benefit of ICD for women or non-whites
COMPANION (32% women, 15% class IV)
Redberg. JAMA 2007;298:1564
COMPANIONNYHA IV: 217/1520 patients
Lindenfeld et al. Circulation 2007;115:204
Death orhospitalization
JACC 2009; 53:765-73
CRT in Advanced Heart Failure
JACC 2009; 54: 600-607
CRT in Advanced Heart Failure
Am Heart J 2006; 151: 837-43
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Clark et al. BMJ 2007; 337:942 All cause mortality
Clark et al. BMJ 2007; 337:942
All cause hospitalization
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Taylor et al. NEJM 2004; 351:2049 AHEFT
1050 patients
death 43%
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
0
50
100
150
200
250
300
350
Status 1A Status 1B Status 2
Days
0102030405060708090
100
status 1A status 1B status 2
1 year3 year5 year
0
50
100
150
200
250
300
Type O Type A Type B Type AB
Days
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery
• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Co-morbid Conditions and HF
Myocardial Ischemia Contribution to LV dysfunction.
Atrial arrhythmias Worsens symptoms, decreases cardiac performance.
Anemia Common. Associated with worse outcome and increased symptoms.
Sleep apnea Common. Associated with arrhythmias, pulmonary hypertension, biventricular dysfunction.
Thyroid disorders Either hypo- or hyperthyroidism can exacerbate HF.
Depression Common. Worsens symptoms and complicates interpretation.
Arthritis Treatment with NSAIDs can exacerbate HF and renal dysfunction. Vioxx off market for ↑ CV events.
Diabetes Associated with CAD and hyperlipidemia. Treatment (metformin and glitizones) can complicate HF.
Hyperlipidemia Associated with CAD. Statin effect important?
Erectile dysfunction Common. Associated with depression, non-compliance. Worsens QOL.
Impact on outcomes or life quality.Co-morbidity
Circulation 2008;117:526 Correcting anemia?
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance
• Intravenous inotropes or BNP• Ultrafiltration• Mechanical circulatory support device
Circ HF 2009; 2:90-97
IV Inotropic Agents During Hospitalization for Decompensated Heart Failure
Cuffe MS et al. JAMA. 2002;287:1541–1547.
Ev
ent
Ra
te (
%)
Treatment Failure From Adverse
Event (48 h)
Sustained Hypotension
Acute MI Mortality
Milrinone
Placebo
Afib
P < 0.001 P < 0.001
P = 0.18
P = 0.004P = 0.19
12.6
2.1
10.7
3.21.5
0.4
4.6
1.5
3.82.3
0
5
10
15
20
OPTIME-CHF: In-hospital Adverse Events
Impact of Inotropes on Survival
0
20
40
60
80
100
0 3 6 9 12
Mo on Inotropic Therapy
Mo
rtal
ity
(%)
Placebo
Randomized IV Inotropes
Uncontrolled IV Inotrope
Oral Milrinone Class IV
REMATCH InotropeDependent
Oregon Series
Circulation 2003; 108:492-97
Continuous Outpatient Support with Inotropes
• 36 inotrope-dependent patients
• EF <0.20
• Class IV symptoms
• Hypoperfusion and end-organ dysfunction
• 46 rehospitalizations
• Median survival=3.4 months (0.2-26.3)
• Most patients died at home
51%
26%
6%
J Cardiac Failure 2003;9:180-7
REVIVE II
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0 15 30 45 60 75 90
Days Since Start of Study Drug Infusion
Pro
bab
ilit
y o
f S
urv
ivin
g
Levosimendan Placebo
Day 5 14 31 90
Placebo 1 5 12 35
Levosimendan 5 14 20 45
* Time to death by Cox proportional hazard model
Time to Death During 90 Days of Follow-up Period
FUSION II Study Design
Nesiritide* 1x/wk + Intensive Disease Management (n = 300)
Nesiritide* 2x/wk + Intensive Disease Management (n = 300)
Phase IIb
Double-blind
Randomized
Multi-center
n = 900
Placebo 2x/wk + Intensive Disease Management (n = 150)
Placebo 1x/wk + Intensive Disease Management (n = 150)
12 week treatment period
1° and 2° Endpoints
12 week blindedfollow-up period*Dosing: 2 g/kg bolus, then
0.01 g/kg /min infusion x 4-6 hours
Additional EndpointsYancy CW et al. Am Heart J 2007
FUSION II: Primary Composite Endpoint Through Week 12
Placebo Combined
N=306
Nesiritide Combined
N=605
*P-value
All cause mortality and CV/renal hospitalization†
36.8% 36.7% 0.79
All Cause Mortality 9.6% 9.5% 0.98
CV/renal hospitalization 33.9% 32.9% 0.95
*P value: NES vs. placebo stratified by dose group†Modified ITT: all treated ITT patients
Slide courtesy of C.Yancy
Advanced Heart Failure:after ACEI or ARB and beta-blockade
• add ARB if on ACEI• add Aldactone• evaluate for CRT/ICD• Disease management• consider hydralazine-nitrate• Heart transplant• Ventricular re-shaping or restraint surgery• Correct anemia or sleep disturbance• Intravenous inotropes or BNP• Ultrafiltration
• Mechanical circulatory support device
Mechanical Circulatory Support Devices
When the Failing, End-Stage Heart Is Not End-StageDale G. Renlund, M.D., and Abdallah G. Kfoury, M.D. NEJM, 2006
0
10
20
30
40
50
60
70
80
90
100
30d 6 mo 1 yr 2yr
BEST
CARE-HF
COMPANION
RALES
COPERNICUS
COPERNICUS-NO BB
Survival In NYHA IIIb
%
SLIDE COURTESY OF J. LINDENFELD
0
10
20
30
40
50
60
70
80
90
30 d 6 mo 1yr 2 yr
REMATCH
Post-REMATCH
Post-REMATCH
INTrEPID
HeartMate II
%
Survival for LVADSLIDE COURTESY OF J. LINDENFELD
Big Gap in Mortality
0
10
20
30
40
50
60
70
80
90
30 d 6 mo 1yr 2 yr
REMATCH
Post-REMATCh
Post REMATCH
INTrEPID
HeartMateII
0
10
20
30
40
50
60
70
80
90
100
30d 6 mo 1 yr 2yr
BEST
CARE-HF
COMPANION
RALES
COPERNICUS
COPERNICUS-NO BB
SLIDE COURTESY OF J. LINDENFELD
Big Gap in Stroke Risk
• Heart failure 1.8% first year after dx 5.0% at five years 0.8% per year in chronic HF ( Witt RJ et al J Cardiac Failure 2007;13:489)
• LVAD 19% to 5.2% year Post REMATCH ( Lietz K et al Circulation 2007;116; 497)
6 fold increase in risk of stroke
Difficult decisions of end stage heart failure:Mechanical Circulatory Support
A balance:
The risks of multi-systemorgan failure from
progressive heart failure(> 50% death in 1 year)
The risks ofsurgical intervention
for MCSD andongoing MCSD support
versus