New Strategies For Treating Patients With Chronic Heart Failure

Transcription

1 New Strategies For Treating Patients With Chronic Heart Failure Barry Greenberg MD Professor of Medicine Director, Advanced Heart Failure Treatment Program University of California, San Diego

2 Disclosures Consultant GSK, Corventis, BiogenIdec Speakers Bureau - GSK, Merck, Scios, Novartis

3 New Strategies For Treating Patients With Chronic Heart Failure Prevention Pathogenesis and medical therapy Emerging role of devices Strategies for improving outcomes New therapeutic approaches

4 Heart Failure Rages Through American Cities

5 Epidemiology of Heart Failure in the US Prevalence (millions) Incidence: 10 per 1000 population after age 65 Over 1 million hosp DCs annually More deaths from heart failure than from all forms of cancer combined * *Rich M. J Am Geriatric Soc. 1997;45: Rosamond W, et al. Heart Disease and Stroke Statistics 2007 Update. Circulation. 2007;115:

6 CHF = chronic heart failure; AP = angina pectoris; DM = diabetes mellitus; LVH = left ventricular hypertrophy; VHD = valvular heart disease; HTN = hypertension; MI = myocardial infarction Levy et al. JAMA. 1996;275:1557. Population-Attributable Risks DM 6% LVH 4% VHD 7% Men for Development of HF HTN, diabetes and/or CAD AP 5% MI 34% accounts for ~90% of HF HTN 39% Women LVH 5% VHD 8% DM 12% AP 5% MI 12% MI 12% HTN 59% HTN 59% Population-attributable risk defined as: (100 x prevalence x [hazard ratio 1])/(prevalence x [hazard ratio 1] + 1)

7 The Boys Go Out For A Heart Healthy Lunch

8 And Then Walk the Dog For Exercise

9 Adults With Diagnosed Diabetes* 1990 No data available Less than 4% 4%-6% Above 6% *Includes women with a history of gestational diabetes. Mokdad AH, et al. Diabetes Care. 2000;23(9):

10 Adults With Diagnosed Diabetes* %-6% Above 6% *Includes women with a history of gestational diabetes. Mokdad AH, et al. JAMA. 2001;286(10):

11 HTN in America Increased 30% Last Decade Hypertensive Adults, burden, millions ± SE 0 P<0.001 Years 65.2 Population, millions Population, millions Fields LE et al. Hypertension. 2004;44: Majority of U.S. Hypertensives Not at <140 mmhg Goal Not Meeting Goal SBP Range, mmhg Adapted from Whyte JL et al. J Clin Hypertens. 2001;3:

12 Treating Hypertension to Prevent HF Aggressive blood pressure control: Decreases risk of of new HF by by ~ 50% 56% in in DM2 Aggressive BP control in patients with prior MI: Decreases risk of new HF by ~ 80% Lancet 1991;338:1281: (STOP-Hypertension) JAMA 1997;278:212-6 (SHEP) UKPDS Group. UKPDS 38. BMJ 1998;317:

13 Management of Patients with Known Atherosclerotic Disease But No HF Treatment with ACE inhibitors decreases the risk of CV death, MI, stroke, or cardiac arrest. NEJM 2000;342: (HOPE) Lancet 2003;362:782-8 (EUROPA) % MI, Stroke, CV Death % MI, CV Death, Cardiac Arrest HOPE Placebo Ramipril 22% rel. risk red. p < Years EUROPA Placebo Perindopril 20% rel. risk red. p = Years

14 Take Home Messages Heart failure is preventable (if we really try)!

15 Remodeling Is The Major Cause of Progressive Cardiac Dysfunction 6 months post-mi 14 months post-mi

16 Effect of Remodeling on Survival in HF Patients Quinones M, Greenberg B et al. J Am Coll Cardiol 2000;35:

17 Neurohormonal Activation in HF Median Plasma Norepinephrine (pg/ml) 600 P= P= Control Prevention* Treatment SOLVD Median Plasma Renin Activity (pg/ml) Control P=.03 Prevention* P=.0003 Treatment Median Plasma ANF (pg/ml) P<.0001 P= Median Plasma AVP (pg/ml) P=.006 P= Control Prevention* Treatment 0 Control Prevention* Treatment *Prevention trial: assessed prevention of HF in asymptomatic patients (n=151); Treatment trial: assessed reduction in mortality in symptomatic patients (n=81). Francis et al. Circulation ;82:

18 ACEIs Inhibit LV Remodeling: SOLVD Echo Sub-study Greenberg B et al. Circulation 91: , 1995

19 ACEIs Reduce Mortality in HF Mortality Trial ACEI Controls RR (95% CI) Chronic HF CONSENSUS I SOLVD (Treatment) SOLVD (Prevention) 39% 54% 0.56 ( ) 35% 40% 0.82 ( ) 15% 16% 0.92 ( ) Post MI SAVE AIRE TRACE 20% 25% 0.81 ( ) 17% 23% 0.73 ( ) 35% 42% 0.78 ( ) SMILE 5% 6.5% 0.75 ( ) Average 21% 25% The Heart Outcomes Prevention Study Investigators. Lancet. 2000;355:

20 Addition of β-blockers to ACEIs Reduces Mortality in Heart Failure Probability of Survival Survival US Carvedilol Trials 65% P<.001 Carvedilol (n=696) Placebo (n=398) Days % P<.0001 CIBIS-II Placebo (n=1,320) Bisoprolol (n=1,327) Cumulative Mortality (%) Survival (%) % P=.0062 (adjusted) MERIT-HF Placebo (n=2,001) Metoprolol CR/XL (n=1,990) Days 35% P=.0014 (adjusted) COPERNICUS Carvedilol (n=1,156) Placebo (n=1,133) Days Packer M et al. N Engl J Med. 1996;334: MERIT-HF Study Group. Lancet. 1999;253: CIBIS-II Investigators. Lancet. 1999;353:9-13. Packer M et al. N Engl J Med. 2001;344: Months 18 21

21 Trials With Aldosterone Antagonists Primary Endpoint: All-Cause Mortality Trial Placebo Aldosterone Antagonist Hazard Ratio Log-rank P Value EPHESUS 554/3, /3, (.75,.96).008 RALES 386/ / (.60,.82) <.001 Pitt B. N Engl J Med. 2003;348: Pitt B. N Engl J Med. 1999;341:

22 Take Home Messages Most heart failure is preventable (if we really try)! Neurohormonal activition causes remodeling inhibition improves outcomes.

23 Heart Failure Related Deaths: Impact Of Contemporary Therapy % Deaths at 2 years % (85%) -4.9% (60%) Major Opportunity Pump Failure Sudden Death 2 0 No ACEI or BB ACEI and BB 24 month data from placebo arm of ValHeft Cohn J, et al. J Cardiac Failure 2003; 9:5 (suppl):s87

24 Arrhythmic Death Can Be Prevented

25 SCD-HeFT: Mortality 0.4 HR 97.5% CI P Value Amiodarone vs Placebo ICD Therapy vs Placebo Mortality Rate Placebo ICD Therapy Amiodarone ICD=implantable cardioverter defibrillator. Bardy GH. N Engl J Med. 2005;352: Months of Follow-Up

26 ICD Use in Patients Hospitalized With History of Chronic HF and LVEF < 30% Baseline Q1 Q2 Q3 Q4 P trend = ICD in LVEF <= 30% Data from 97 GWTG-HF hospitals and 18,516 HF patients were collected from 1/05-3/06 Fonarow GC et al. AHA 2006 abstract

27 Ventricular Dyssynchrony Abnormal ventricular conduction resulting in a mechanical delay Present in 15% to 30% (or more) of HF patients Wide QRS (IVCD); typically LBBB morphology Impaired systolic and diastolic function Worsening mitral regurgitation ECG depicting interventricular conduction delay IVCD=interventricular conduction delay; LBBB=left bundle branch block.

28 CARE-HF: CRT Long-Term Outcomes Primary Endpoint All-Cause Mortality or Hospitalization for Major Cardiovascular Event P< % 50% 40% 30% 20% 10% 0% 39% 55% Secondary Endpoint All-Cause Mortality P< % 30% CRT Control CRT Control Median LV ejection fraction was 25% Of the 409 patients randomized to the CRT device, 95% had a successful implantation The primary endpoint of allcause mortality or hospitalization for a major CV event occurred less frequently in the CRT group than in the medical therapy alone group (HR 0.63, 95% CI ) The major secondary endpoint of all-cause mortality was also lower in the CRT group (HR 0.64, 95% CI ) Cleland JG, et al. N Engl J Med. 2005;352:

29 CRT: Areas of Uncertainty Atrial fibrillation RBBB Mild (NYHA Class II) or end-stage HF Efficacy in patients with narrow QRS Prospectively defining who will and who won t respond to CRT RBBB=right bundle branch block; CRT=cardiac resynchronization therapy. Mehra MR, Greenberg BH. J Am Coll Cardiol. 2004;43:

30 Take Home Messages Most heart failure is preventable (if we really try)! Neurohormonal antagonists inhibit remodeling and improve HF outcomes. Devices provide incremental benefits when added to optimal medical therapy.

31 Suboptimal Utilization of Evidence- Based HF Therapies in ADHERE LVEF Documented and.40 Patients Treated (%) ACE Inhibitor ARB β-blocker Diuretic Digoxin Outpatient HF Medication 46,272 patients hospitalized with HF; prior known diagnosis of systolic dysfunction HF; outpatient medical regimen. The ADHERE Registry [database]. Third quarter 2003 Benchmark Report (10/02 9/03). Scios Inc. Sunnyvale, California. September 2003.

32 Outpatient Adherence to β- Blocker Therapy Post Acute MI β-blocker Users (%) Discharged on β-blockers Not discharged on β-blockers Days Since Discharge Prescription data on 846 patients surviving acute MI were studied by the Tennessee Quality Improvement Organization. Butler J et al. J Am Coll Cardiol. 2002;40:

33 OPTIMIZE-HF: Use of Evidence-Based HF Therapy at Discharge in Eligible Patients Eligible Patients Treated (%) ACEI/ARB at Discharge (11,976/14,493) β-blocker at Discharge (13,032/15,675) Evidence-Based β-blocker (10,248/15,675) Aldosterone Antagonist (3,621/20,118) Statin (14,904/38,066) Warfarin (6,571/12,560) ACEI/ARB, β-blocker, and aldosterone antagonist use in eligible patients with LVSD; statin in HF patients with a history of CAD, PVD, CVD and/or diabetes; and warfarin use in patients with HF and atrial fibrillation. The OPTIMIZE-HF Registry [database]. Final Data Report. Duke Clinical Research Institute. July 2005.

34 Intra-Thoracic Impedance Changes With Lung Wetness Impedance Wetter Lungs Reduced Impedance Dryer Lungs Increased Impedance

35 Correlation of Impedance with Net Fluid Loss During HF Hospitalization Medtronic data on file

36 Tracking Intrathoracic Impedance Medtronic data on file More Fluid Less

37 Take Home Messages Most heart failure is preventable (if we really try)! Neurohormonal antagonists inhibit remodeling and improve HF outcomes. Devices provide incremental benefits when added to optimal medical therapy. New strategies are available to better manage HF patients.

38 Mechanical Therapy Smaller devices Less infection? Opportunity for explant

39 REMATCH Trial: All Cause Mortality 100 % Event Free Survival Control (n=61) LV Assist Device (n=68) P=0.001 N Engl J Med 2001; 345: Months RR 0.52 (0.34,0.78)

40 Limitations of Current LVAD Therapy Very expensive. Major commitment on the part of physicians, nurses and hospitals for continuing care. Small increase in survival rates after 2 years. Substantial risk of bleeding, infection and device malfunction requiring in-hospital care.

41 Mechanical Unloading Reverses The Heart Failure Phenotype Donor Myocytes Dilated CMP Post LVAD

42 Cell Transplantation For Treating HF End stage heart failure Undefined mechanisms Functional recovery of diseased hearts animals, human New Myocytes Possible Graft neonatal/adult CM embryonic stem cell bone marrow stem cell skeletal myoblast others GM fibroblast cardiac stem cells

43 BOOST Results Wollert KC et al. Lancet, July 2004

44 Cell Transplantation Which type of cell works best? Where, when and how to deliver? What can we do to enhance homing of transplanted cells and improve their survival? How does therapy improve cardiac fxn? Is cell transplantation safe?

45 Calcium Cycling Mediated by SERCA2a is Key to Cardiac Contraction End stage HF: reduced SERCA2a results in reduced contractility & elevated intracellular Ca 2+ Cardiac function correlates with SERCA2a level or function Recovery after LVAD or with β- blockers

46 MYDICAR : SERCA2a Gene Therapy for Heart Failure SERCA2a

47 Sheep Pacing Model of Heart Failure Absolute Median Change After 1 Month Sheep are paced at 180 bmp for 2 mo, gene transfer using V-Focus # percutaneous coronary artery infusion at 1 mo, evaluation at 2 mo Control MYDICAR TM Fractional Shortening -1% +11% Ejection Fraction -2% +19% Slope of ESPVR -0.7 mmhg/ml +1.2 mmhg/ml +dp/dt -259 mmhg/sec -25 mmhg/sec # Preovolos A, et. al. Extra Corpor Technol 2006;38(1):51-2.

48 Take Home Messages Most heart failure is preventable (if we really try)! Neurohormonal antagonists inhibit remodeling and improve HF outcomes. Devices provide incremental benefits when added to optimal medical therapy. New strategies are required to better implement effective HF treatment. HF treatment continues to evolve with the development of new drugs and devices.