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1 Exciting Times: Advances in Heart Failure Dana McGlothlin, MD Associate Professor of Medicine Advanced Heart Failure and Transplant Program Medical Director, CCU Overview HF Statistics Therapies for chronic HF Management of acute decompensated HF (ADHF) Intravenous inotropes, vasodilators, diuretics AVP antagonists Ultrafiltration Investigational HF therapies Surgical therapies Stem cells Advanced therapies for stage D HF Transplantation Mechanical assist devices Heart Failure Statistics in 2010 % US prevalence: 5.8 million US annual incidence: 670,000 Annual mortality: 282,754 Cost: $39.2 billion 15 0 HF increases with age 50 s 60 s 70 s >80 et al. Circulation 2010;121:e46-e215 Outpatient Inpatient Cost Distribution for HF Heart Failure Patients in US (millions) HF Prevalence Projections: An Increasing Problem *Rich M. J Am Geriatric Soc. 1997;45: American Heart Association Heart and Stroke Statistical Update American Heart Association. Heart Disease and Stroke Statistics 2003 Update. Dallas, Tx: American Heart Association; * 1

2 ACC/AHA Staging System Evidence-Based Treatment Across the Continuum of Systolic LVD and HF A B C D Stage High risk for developing heart failure (HF) Asymptomatic HF Symptomatic HF Refractory end-stage HF Hunt SA, et al. Circulation 2001;104: Patient Description Hypertension Coronary Optimal drug artery therapy disease Aspirin, ACE inhibitors, statins, β-blockers, Diabetes α-β-blockers mellitus (carvedilol) diabetic therapy Family history of cardiomyopathy Previous myocardial infarction Optimize drug therapy Left ICD if ventricular LV dysfunction (systolic) dysfunction present Asymptomatic valvular disease Known Optimize structural drug therapy heart disease Shortness ICD if LV dysfunction of breath (systolic) and fatigue present CRT (if QRS wide, LVEF<35%) Reduced exercise tolerance Optimize drug therapy IV inotropes ICD/CRT-D IABP Other devices (LVAD, ECMO) Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital withot specialized interventions) Control Volume Diuretics Renal Replacement Therapy* Aquaretics Ultrafiltration* *In selected patients Improve Clinical Outcomes ACEI Aldosterone β-blocker or ARB Antagonist or ARB CRT ± an ICD* HDZN/ISDN* Treat Residual Symptoms Digoxin What s new in medical therapy for HF? Ivabradine vs placebo in HF: SHIFT Study High resting heart rate is a risk factor for adverse outcomes Ivabradine is a selective sinus node inhibitor 6558 pts with stage C HF LV EF <35% HR > 70 bpm Hospitalized for HF in past year Stable HF meds Ivabradine vs placebo in HF: SHIFT Study Outcomes-promising! Outcomes in SHIFT CV death or HF hospitalization Death from heart failure Ivabradine, Placebo, n=3241 (%) n=3264(%) HR (95% CI) ( ) < ( ) HF hospitalization ( ) < CV death, HF hospitalization, or admission for nonfatal MI Swedberg K et al. Lancet ( ) 0.89) < SEs: fewer w/ ivabradine than PBO, except 5% had Sx brady w/ ivabradine vs 1% w/ PBO p 2

3 HFSA 2006 Practice Guideline (12.3, Table 12.3) Acute Decompensated Heart Failure (ADHF) Treatment Goals for Hospitalized Patients Improve symptoms, especially congestion and low-output symptoms Optimize volume status Identify etiology Identify precipitating factors Optimize chronic oral therapy; minimize side effects Identify who might benefit from revascularization Educate patients concerning medication and HF self-assessment Consider enrollment in a disease management program Strength of Evidence = C HFSA 2006 Practice Guideline ( ) Overview of Treatment Options for Patients with Acute Decompensated HF Fluid and sodium restriction Diuretics, especially loop diuretics Ultrafiltration/renal replacement therapy (in selected patients only) Parenteral vasodilators * (nitroglycerin, nitroprusside, nesiritide) Inotropes * (milrinone or dobutamine) *See recommendations for stipulations and restrictions. Adams KF, Lindenfeld J, et al. HFSA 2006 Comprehensive Heart Failure Guideline. J Card Fail 2006;12:e1-e122. More than 50% of Patients Have Little or No Weight Loss During Hospitalization Diuretics: Adverse Effects Patients (%) % N=26,757 6% 13% Fonarow GC. Rev Cardiovasc Med. 2003;4(suppl 7): % 33% 15% (<-20) (-20 to -15) (-15 to -10) (-10 to -5) (-5 to 0) (0 to 5) (5 to 10) (>10) Change in Weight (lbs) Current treatment options Loop diuretics IV inotropes Nitrates Nesiritide 3% 2% ADHERE Registry data Hypo K+, Na+, Mg+ (15-60%) Stimulation of neurohormonal activity Hyperuricemia (15-40%) Hypotension Alkalosis Ototoxicity GI upset Sharpe N. Heart failure. Martin Dunitz 2000;43 Kubo SH, et al. Am J Cardiol 1987;60:1322 MRFIT, JAMA 1982;248:1465 Pool Wilson. Heart failure. Churchill Livinston 1997;635 3

4 Arginine Vasopressin and CHF Arginine vasopressin (AVP) acts via V1a, V1b, and V2 receptors vasoconstriction, inotropic effects, H2O retention Neurohormal activation of AVP is clinically important Hyponatremia and hypervolemia AVP-2 receptor antagonism facilitates aquaresis without disturbances of electrolytes and EVEREST Trial: RCT of oral Tolvaptan 30mg qd vs PBO in pts hospitalized w/ ADHF 2 concurrent trials (Trial A: n=4048 pts and Trial B: n=2085 pts) in No. America, So. America, and Europe Primary endpoint: composite of changes in global clinical status and body weight at day 7. Results: Primary composite endpoint was met, improved many secondary endpoint HF signs and symptoms Selected Secondary end points in EVEREST outcomes trial End point Mean change in body weight at day 1 (kg) Patients showing improved dyspnea scores at day 1* (%) Mean change in serum sodium at days 1/7** (meq/l) Patients showing >2 grade improvement in edema* (%) Trial A Tolvaptan PBO p Trial B Tolvaptan PBO p < < < < / / *Limited to patients with symptom at baseline **Limited to patients with baseline levels <134 meq/l Konstam MA et al. American College of Cardiology 2007 Scientific Sessions; March 25, 2007; New Orleans, LA. Special Session Late-Breaking Clinical Trials I. Proportion Alive EVEREST: All-Cause Mortality Median follow-up 9.9 months Peto-Peto Wilcoxon Test: P=0.68 Months In Study HR 0.98; 95%CI ( ) Meets criteria for non-inferiority TLV 30 mg PLACEBO TLV PLC Proportion Without Event EVEREST: CV Mortality or HF Hospitalization Peto-Peto Wilcoxon Test: P= TLV PLC Months In Study HR 1.04; 95%CI ( ) TLV 30 mg PLACEBO

5 Ultrafiltration to Manage Congestion Ultrafiltration Does not remove sodium and other electrolytes (aquafiltration) Does not activate neurohormones Can safely improve hemodynamics Requires a central venous catheter and anticoagulation UNLOAD Trial: Freedom From Heart Failure Rehospitalization Device therapies for chronic HF Costanzo, M. R. et al. J Am Coll Cardiol 2007;49:

6 SCD Primary Prevention Trials in HF MADIT-I MADIT-IIII CABG Patch MUSTT DINAMIT CAT AMIOVERT Who Should Get an ICD? Nonischemic cardiomyopathy: NYHA class II to III sx LVEF < 35% Ischemic cardiomyopathy: NYHA class II to III sx LVEF < 35% At least 40 days post-mi (DINAMIT) No reversible ischemia No recent revascularization Bardy GH et al. NEJM ;352(3): Cardiac Resynchronization Therapy CRT: CARE-HF Trial Randomized, controlled trial of 813 patients Entry criteria: IVCD NYHA III or IV CHF LVEF <35% Outcomes: Decreased mortality: 8.1% vs 13.9% at 29 months At 90 days: Improved quality of life (NYHA class 2.1 vs 2.7) Cleland JGF, et al. NEJM 2005; 352(15):

7 Outcomes in CARE-HF: 409 CRT-treated patients as compared with 404 control patients Outcomes All-cause mortality/unplanned hospitalization for CV event Hazard ratio (95% CI) 0.63 ( ) 0.77) All-cause mortality 0.64 ( ) 0.85) All-cause mortality/hf hospitalization 0.54 ( ) 0.68) p < <0.001 CRT: Recommendations Indicated for patients with LBBB or IVCD and: LVEF < 35% Sinus rhythm NYHA III-IV IV symptoms despite optimal medical mgmt These patients are also candidates for ICD placement and should be considered for a dual- function device (CRT-D) J Am Coll Cardiol Sep 20;46(6): Cleland JGF et al. N Engl J Med 2005; 352: Surgical Therapies Surgical Ventricular Reconstruction: STICH Trial Rationale: Left ventricular remodeling after MI can lead to progression of HF and poor prognosis Surgical LV volume reduction may improve HF outcomes in pts with ICM STICH: Surgical Tx for IsChemic Heart failure 1000 pts with EF <35%, CAD amenable to CABG, incl LAD dz amenable to revasc Randomized to CABG alone vs CABG + SVR Primary outcome: Composite of death from any cause and hospitalization for cardiac causes Jones, RH. NEJM 2009;360(17):1705 7

8 Surgical Ventricular Reconstruction STICH Trial Jones, RH. NEJM 2009;360 STICH Trial STICH Trial 8

9 ACORN Novel Mechanical Anti-remodeling Therapies in Heart Failure: Cardiac Support Devices HeartNet PEERLESS HF Trial Multicenter RCT of 217 patients with chronic advanced HF despite max med/device therapy ACC/AHA Stage C HF Stable medical/device therapy x3 mo LVEF<35% Randomized to HeartNet device or continued med/device therapy Safety and efficacy Primary endpoints Pk VO2, 6 MWD, QoL at 6 mo Freedom from all-cause mortality at 12 mo Results Study halted early d/t lack of effect on clinical endpoints, including Pk VO2 Survival was equivalent between the two groups Modest effect on ventricular remodeling by echo parameters Presented at HFSA 2010 in San Diego Stem cell Transplant in chronic heart failure: STAR-heart trial Prevention and/or reversal of remodelling of the LV by cell therapy is a hot topic and has generated great interest Studies of skeletal myoblast transplantations in HF patients has been associated with serious safety concerns from arrhythmias (MAGIC and MARVEL-1) Prior human studies using autologous bone marrow cells (progenitor cells) have been conflicting, with fewer safety concerns, but data in chronic HF is lacking STAR-heart Study evaluated the changes in LV geometry and survival in chronic HF patients Open label study of 391 pts with LVEF <35% due to ICM enrolled between Strauer B et al. Eur J Heart Fail 2010;12: Study design: patient recruitment. Strauer, B. Eur J Heart Fail. 2010;12:721 Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org. 9

10 STAR-heart Study Results: Changes in LVEF Stem Cells in Chronic Ischemic HF: STAR Heart Survival Effect of bone marrow cell therapy on survival in patients with chronic ischaemic cardiomyopathy. Strauer B et al. Eur J Heart Fail 2010;12: Published on behalf of the European Society of Cardiology. All rights reserved. The Author For permissions please journals.permissions@oxfordjournals.org. Cardiac Transplantation Advanced therapies for ACC/AHA stage D HF Remains the most effective Tx for end- stage heart disease, although donor shortage limits its use 1-year survival: 86% (2002) 5-year survival: 71% 10-year survival: 46% Taylor et al. J Heart Lung Transplant 2003;22:

11 Trends in Heart Transplants (UNOS: ) Destination Therapy Trials Number of Transplants 2,500 2,000 1,500 1, ,363 2,107 2,199 2, Years Source: United Network for Organ Sharing (UNOS), scientific registry data. Fang JC NEJM 2009 Newer Devices on the Horizon Conclusions The prevalence of HF is increasing rapidly as the population grows older Proven therapies that reduce morbidity and mortality with HF are ACE-I/ARB, BB, Aldosterone antagonists, hydralazine, nitrates, CRT (for patients with IVCD), ICD Ivaradibine, a selective sinus node inhibitor, is showing some promise in the treatment of chronic HF Short term aquaresis with Tolvaptan can improve HF symptoms without electrolyte disturbances in ADHF but does not improve survival Ultrafiltration is a safe and effective way of treating congestion in ADHF without activing the neurohormonal system 11

12 Conclusions Surgical therapies for ventricular reconstruction and prevention of remodeling have not yet been effective Stem cell therapy (autologous bone marrow cells), not skeletal myoblasts is showing some efficacy in HF, probably by a paracrine mechanism rather than cell transformation, but needs to be tested in a RCT Thank You! Transplant still has the best outcomes for treatment of stage D HF, however VADs are the way of the future Stay tuned! 12