Strategie terapeutiche Strategies of Medical Therapy Mariell Jessup MD Professor of Medicine...

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 ??



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



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



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



Clark et al. BMJ 2007; 337:942 All cause mortality

Clark et al. BMJ 2007; 337:942

All cause hospitalization



Taylor et al. NEJM 2004; 351:2049 AHEFT

1050 patients

death 43%



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


• 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?


• 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


• 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

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Strategie terapeutiche Strategies of Medical Therapy Mariell Jessup MD Professor of Medicine...

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