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Update in Heart Failure Management

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Chet Patel, MD
Duke University Medical Center

Published in: Health & Medicine

Update in Heart Failure Management

  1. 1. Update in Heart Failure Management Chetan B. Patel, MD Assistant Professor of Medicine Medical Director, Cardiac Transplant Program Associate Medical Director, Mechanical Circulatory Support Program Duke University Medical Center
  2. 2. Disclosures Consultant for Thoratec Corp. and Heartware Inc.
  3. 3. Outline Update in Medical Therapy  Ivabradine  LCZ696 Update in Device Therapy (LVAD)  Patient Selection  New Devices  Optimizing Outcomes
  4. 4. Ivabradine
  5. 5. Heart Rate: A Prognostic Risk Factor in Heart Failure Fox K, et al. Lancet 2008 Cardiovascular Death Heart Failure Hospitalization 1 y 2 y 1 y 2 y Heart Rate ≥70 bpm Heart Rate ≥70 bpm Patients with CAD and EF < 40%
  6. 6. Heart Rate Reduction and Mortality in Heart Failure Kjekshus J. Eur Heart J 1999. • Major criticism of COMET (carvedilol vs metoprolol)
  7. 7. Ivabradine Ivabradine selectively inhibits the “funny” current in the sinus node Slows HR independent of BB effect “less ngetive inotropy” Implications for patients with impaired stroke volume
  8. 8. To evaluate whether the If inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic HF 2. Left ventricular EF 35% 3. Heart rate 70 bpm and 4. Recommended therapy Systolic Heart failure treatment with the If inhibitor ivabradine Trial
  9. 9. Patients and Follow-up Median study duration: 22.9 months; maximum: 41.7 months 6558 randomized 3268 to ivabradine 3290 to placebo 3264 analyzed 1 lost to follow-up 3241 analyzed 2 lost to follow-up 7411 screened Excluded: 27 Excluded: 26
  10. 10. Mean heart rate reduction Mean ivabradine dose: 6.4 mg bid at 1 month 6.5 mg bid at 1 year 0 2 weeks 1 4 8 12 16 20 24 28 32 Months 90 80 70 60 50 67 75 75 80 64 Ivabradine Placebo Heart rate (bpm)
  11. 11. HR = 0.82 [95% CI 0.75-0.90] p<0.0001 0 6 12 18 24 30 Months 40 30 20 10 0 Ivabradine Placebo Primary Composite Endpoint: CV Death + HF hospitalization - 18% Cumulative frequency (%) Ivabradine ARR = 4.2% NNT = 24
  12. 12. Ivabradine n=449 (7.5%PY) Placebo n=491 (8.3%PY) HR = 0.91 p=0.128 0 6 12 18 24 30 Months 30 20 10 0 Ivabradine Placebo Cardiovascular Death Cumulative frequency (%)
  13. 13. Ivabradine n=514 (9.4%PY) Placebo n=672 (12.7%PY) HR = 0.74 [95% CI 0.66-0.83] p<0.0001 0 6 12 18 24 30 Months 30 20 10 0 Ivabradine Placebo Hospitalization for heart failure - 26% Cumulative frequency (%) Ivabradine
  14. 14. ESC Guidelines 2012  Ivabradine indicated for Sinus Rhythm and HR ≥ 70 bpm  Now approved in US (based on non- US study) McMurray JJV. EHJ 2012
  15. 15. LCZ-696
  16. 16. LCZ-696: A New Class - ARNI Vardeny O. JACC HF 2014
  17. 17. 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
  18. 18. Neprilysin inhibition alone Neprilysin inhibition + ACE inhibition Neprilysin inhibition + angiotensin receptor blockade Ineffective due to angiotensin potentiation Potentially dangerous due to angioedema How to Inhibit Neprilysin in Heart Failure
  19. 19. Key Entry Criteria  NYHA Class II-IV  EF ≤ 35-40%  Any use of ACE/ARB  Able to tolerate stable dose equivalent to enalapril 10 mg daily for ≥ 4 weeks  GDMT for beta-blockers and MRAs  SBP ≥ 95, eGFR ≥ 30 and K ≤ 5.4
  20. 20. 10,521 patients screened at 1043 centers in 47 countries 8399 patients randomized for ITT analysis LCZ696 (n=4187) At last visit 375 mg daily 11 lost to follow-up Enalapril (n=4212) At last visit 18.9 mg daily 9 lost to follow-up median 27 months of follow-up PARADIGM-HF: Patient Disposition
  21. 21. 0 16 32 40 24 8 Enalapril (n=4212) 360 720 10800 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 Kaplan-MeierEstimateof CumulativeRates(%) 914 LCZ696 (n=4187) HR = 0.80 (0.73-0.87) P = 0.0000004 Number needed to treat = 21 PARADIGM-HF: Cardiovascular Death or Heart Failure Hospitalization (Primary Endpoint)
  22. 22. Enalapril (n=4212) LCZ696 (n=4187) HR = 0.80 (0.71-0.89) P = 0.00008 Number need to treat = 32 Kaplan-MeierEstimateof CumulativeRates(%) 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 10800 180 540 900 1260 0 16 32 24 8 693 558 PARADIGM-HF: Cardiovascular Death
  23. 23. PARADIGM-HF: All-Cause Mortality 4187 4212 4056 4051 3891 3860 3282 3231 2478 2410 1716 1726 1005 994 280 279 LCZ696 Enalapril Enalapril (n=4212) LCZ696 (n=4187) HR = 0.84 (0.76-0.93) P=0.0009 Kaplan-MeierEstimateof CumulativeRates(%) Days After Randomization Patients at Risk 360 720 10800 180 540 900 1260 0 16 32 24 8 835 711
  24. 24. 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% %DecreaseinMortality 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%
  25. 25. HF-REF: The building blocks of therapy Tx VAD CRT ICD Beta-blocker MRAACEI/ARB Digoxin H-ISDNCABG
  26. 26. HF-REF: The building blocks of therapy Tx VAD CRT ICD Beta-blocker MRA Digoxin Ivabradine H-ISDNCABG ARNI Serelaxin
  27. 27. HF-REF: The building blocks of therapy • What is the right combination of beta blocker and Ivabradine? • When is the patient too sick for this drug (i.e when is the stroke volume too low?) • Do we switch patients from ACEi to ARNIs? • Is it the first line therapy? • Can we recover LV function with ARNIs?
  28. 28. The Evolution of Mechanical Support • Paracorporeal • Pneumatic • Pulsatile • Uni- or Biventricular • Implantable • Electric • Pulsatile • Large • Multiple moving parts • Implantable • Electric • Continuous flow • Axial design • Smaller • Single moving part • Implantable • Electric • Continuous flow • Centrifugal design • Smaller • Bearingless • Implantable • Electric • Continuous flow • Axial design • Smaller • Partial support
  29. 29. 0 20 40 60 80 100 120 140 160 180 2008 2009 2010 2011 2012 2013 2014 Total VADs Intracorporeal VADs (HM II / HVAD) • 2500 MCS implanted reported to INTERMACS • More LVADs than OHT in the US • Destination therapy >> Bridge to Transplant Growth of LVAD therapy Kirklin et al. JHLT 2015
  30. 30. 32 36 44 45 48 53 52 55 57 603 4 4 3 2 6 8 8 6 8 0 10 20 30 40 50 60 70 80 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Adult Pediatric Data Source: UNOS/OPTN/OTTR • Total heart transplants plateaued at 2200 in US • Major limitations include donor availability, restrictive selection criteria for recipients and donors • 40% transplant procedures now with prior MCS Continued growth of LVAD therapy
  31. 31. Improving Outcomes with Destination Therapy: Technological Advances Adapted from Colombo and Mancini, JACC 2015
  32. 32. Patient Selection: Stage D Heart Failure Ambulatory Critical Cardiogenic Shock 67 5 4 3 2 1 Inotropes VAD Transplant Hospice INTERMACS PROFILES NYHA III NYHA IVAMB NYHA IV INTERMACS, Interagency Registry for Mechanically Assisted Circulatory Support AHA/ACC Guidelines
  33. 33. INTERMACS Profile Level Status Time Frame UNOS Status Patient Characteristics Time Frame 1 Critical cardiogenic shock Hours 1A Continuous hemodynamic monitoring in ICU Require high-dose, continuous inotropic support, or mechanical support When suitable donor heart becomes available 2 Progressive decline Days to week 3 Stable but inotrope dependent Weeks 1B Require hospitalization and some continuous inotropic support or ongoing VAD therapy If no suitable 1A recipients 4 Recurrent advanced HF Weeks to few months if baseline restored 5 Exertion intolerant Weeks to months 2 Can be maintained successfully outside hospital If clinical deterioration occurs, status would change. Transplanted if no suitable 1A or 1B recipients available 6 Exertion limited Months, if nutrition and activity maintained 7 Advanced NYHA class III INTERMACS and UNOS Patient Profiles Ahmad T, Patel CB, Milano CA and Rogers JG. Circulation 2012.
  34. 34. Clinical Outcomes Based on INTERMACS Profile *Kirklin JK, et al JHLT 2012; 31:117-26.
  35. 35. ROADMAP • Prospective, non-randomized, observational • Ambulatory NYHA class IV • Peak VO2 < 14 ml/kg/min • Multiple hospitalizations • Treated with optimal medical therapy Presented by Estep, J. ISHLT Scientific Sessions, Nice France
  36. 36. • Low 30 day mortality in both groups (1 % mortality in LVAD group) • Higher survival in LVAD group (80% at 12 months)  74% in the post DT approval analysis • Improved functional status, depression scores and QOL despite more adverse events (stroke, GI bleeding) in LVAD
  37. 37. ENDURANCE Control Device: • Continuous flow axial pump • Sub-diaphragmatic placement • FDA approved for BTT in 2008, DT in 2010 Treatment Device: • Continuous flow centrifugal HVAD® Pump • Pericardial placement • FDA approved for BTT in 2012
  38. 38. 55.0% 57.4% Non-Inferiority P value = 0.0060 0 297 148 365 210 106 730 156 80 1095 33 19 Days HVAD Control 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% EventFreeRate HVAD (n=297) Control (n=148) Survival at two years free from disabling stroke (MRS >4 at 24-weeks post-stroke), and alive on the originally implanted device, or transplanted or explanted due to patient recovery ENDURANCE Presented by Pagani F. ISHLT Scientific Sessions, Nice France
  39. 39. HVAD (n=296) Control (n=149) Adverse Event No. of Patients No. of events EPPY (410.02PY ) No. of Patients No. of events EPPY (203.89PY) P value Bleeding GI Bleed 176 (59.5%) 103 (34.8%) 400 225 0.98 0.55 90 (60.4%) 51 (34.2%) 196 90 0.96 0.44 0.92 0.92 Cardiac Arrhythmia 111 (37.5%) 175 0.43 61 (40.9%) 82 0.40 0.54 Infection Driveline Exit Site Infection 201 (67.9%) 56 (18.9%) 452 72 1.10 0.18 92 (61.7%) 21 (14.1%) 182 25 0.89 0.12 0.21 0.23 Stroke Ischemic CVA Hemorrhagic CVA TIA 85 (28.7%) 50 (16.9%) 42 (14.2%) 24 (8.1%) 110 65 45 27 0.27 0.16 0.11 0.07 18 (12.1%) 13 (8.7%) 6 (4.0%) 7 (4.7%) 19 13 6 7 0.09 0.06 0.03 0.03 <0.001 0.021 0.001 0.24 Renal Dysfunction 43 (14.5%) 54 0.13 19 (12.8%) 22 0.11 0.67 Right Heart Failure 110 (37.2%) 129 0.31 39 (26.2%) 45 0.22 0.025* Pump Exchange 23 (7.8%) 27 0.06 20 (13.4%) 23 0.10 0.06 * There was no statistical difference in the rate of RHF in the sintered cohort vs . Control. ENDURANCE: Insights into Optimizing Care Presented by Pagani F. ISHLT Scientific Sessions, Nice France
  40. 40. • Retrospective analysis of Medicare beneficiaries 2006-2011 • Continuous flow devices • Overall increase in survival over time • Inverse relationship with center volume • No change in readmissions • Readmission rate similar in higher and lower volume centers Center Volumes and Outcomes Khazanie et al. JACC, 2014
  41. 41. N= 71 with 156 readmissions (4year) , 19% of all readmissions related to bleeding N=83 with 224 readmissions ( 3 year) , 66 readmissions in 34 patients (30% overall) related to bleeding Ann Thorac Surg 2013;95:1276–81) J Am Coll Cardiol 2013;61:153–63
  42. 42. Increased intraluminal pressure Lower pulse pressure;hypoperfusion Angiodysplasia (Heyde’s Syndrome) GI Bleeding Decrease in HMW multimers leading to impaired anticoagulation Acquired vWD vWF fragments Impaired platelet aggregation Continuous Flow Device Non-Surgical Bleeding after Continuous Flow Pump Support
  43. 43. Reintroducing Pulsatility • Reintroducing pulsatility by reducing speed • Targeted anticoagulation • NOACs • Optimizing the management • Endoscopic evaluation • Admission requirement?Wever-Pinzon et al. Circulation Heart Failure, 2013 * HMIII in clinical trial
  44. 44. Pooled data from 3 Centers: Duke, Washington University, Cleveland Clinic 837 patients 896 HM 2 LVAD Thrombosis Starling RC et al. N Engl J Med 2013.
  45. 45. Overall Occurrence of CONFIRMED Pump Thrombosis at 3 Months. 4.7% March 2011 2.2% at 3 months January 2013 8.4% at 3 months Starling RC et al. N Engl J Med 2013.
  46. 46. Device modifications Sealed grafts/Bend relief GI bleeding and vWF deficiency Relaxed anticoagulation targets Reduced emphasis on post- operative bridging Aortic valve pathology Lower pump speed for AV opening Diagnosis and recognition of thrombosisMehra MR et al. JHLT, 2014
  47. 47. PREVENtion of HeartMate II Pump Thrombosis Through Clinical ManagemenT • Avoid low flow  Implant techniques  Create unobstructed blood flow path  Prevent migration  Avoid low speeds  Avoid high BP • Maintain adequate anticoagulation  Heparin bridging  Warfarin anticoagulation  Address patient compliance issues Objectives: Assess the incidence of HMII pump thrombosis in the current era when defined clinical practices are adopted (300 patients/20 sites)
  48. 48. Surgical Management of LVAD thrombosis
  49. 49. Late RV failure 50 • 13% of the total cohort developed late RHF • 6% early post operative (14-30 days of support) • 5% true late RHF (>180 days post implant) • Patients with late RHF had worse survival and greater frequency of re- hospitalizations compared to those without late RHF • Significantly lower QOL Data from the HMII clinical trial database; presented at ISHLT 2015, Nice, France
  50. 50. Innovations: Biventricular Support
  51. 51. Summary • LVAD therapy is growing and has become most prominent in a non-transplant eligible population • Technological advances and improved patient selection has resulted in an improvement in survival with continuous flow devices • Focus on managing progression of heart failure and VAD-related complications will further optimize outcomes • Need for collaborative care outside implanting centers

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