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RE synchronization re VE rses R emodeling in S ystolic left v E ntricular dysfunction:

RE synchronization re VE rses R emodeling in S ystolic left v E ntricular dysfunction: Results of the REVERSE Trial Cecilia Linde, Stockholm, Sweden William T. Abraham, Columbus, U.S Michael R. Gold, Charleston, U.S. Jean-Claude Daubert, Rennes, France On Behalf of the REVERSE

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RE synchronization re VE rses R emodeling in S ystolic left v E ntricular dysfunction:

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  1. REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction: Results of the REVERSE Trial Cecilia Linde, Stockholm, Sweden William T. Abraham, Columbus, U.S Michael R. Gold, Charleston, U.S. Jean-Claude Daubert, Rennes, France On Behalf of the REVERSE Investigators and Coordinators

  2. Acknowledgments Steering Committee W. T. Abraham, J-C. Daubert (study initiator), M. Gold, C. Linde (coordinating clinical Investigator) Echo Core Labs Ghio, S, St. John Sutton, MG Adverse Events Advisory Committee D. Böcker, J. P. Boehmer, J. G. F. Cleland, M. Gold, J. T. Heywood, A. Miller (chair) Data Monitoring Committee J. Aranda, J. Cohn (chair), P. Grambsch; M. Komajda Investigators Austria: H. Mayr, A. Teubl; Belgium: R. Willems; Canada:C. Simpson; Czech Republic: J. Lukl; Denmark: H. Eiskjær, C. Hassager, M. Møller, T. Vesterlund; France: E. Aliot, P. Chevalier, J-C. Daubert, J-M. Davy, P. Djiane, H. Le Marec; Germany: G. Groth, G. Klein, T. Lawo, C. Reithmann; Hungary: T. Forster, T. Szili-Török; Ireland: R. Sheahan; Italy: S. Lombroso, M. Lunati, L. Padeletti, M. Santini; Netherlands: B. Dijkman; Norway: S. Færestrand, F. T. Gjestvang; Spain: I. Fernandez Lozano, R. Muñoz Aguilera, A. Quesada Dorador; Sweden: C. Linde, F. Maru, K. Säfström; United Kingdom: G. Goode;United States: U. Birgersdotter-Green, J. Boehmer, E. Chung, S. Compton, J. Dinerman, D. Feldman, R. Fishel, G. J. Gallinghouse, M. Gold, S. Hankins, J. Herre, M. Hess, E. Horn, S. Hsu, S. Hustead, S. Jennison, E. Johnson, W. B. Johnson, G. Jones, R. Malik, A. Merliss, S. Mester, S. Moore, N. Nasir, F. Pelosi, Jr., D. Renlund, K. Rist, R. Sangrigoli, R. Silverman, D. Smull, K. Stein, L. Stevenson, J. Stone, N. Sweitzer, D. Venesy, L. Zaman. Sponsor Medtronic Inc.

  3. Landscape of CRT Trials in NYHA I, II 2010: MADIT CRT Approx. 33 months, n=1820 2010: RAFT Minimum 18 months, n=1800 Primary Obj: mortality or HF events (i.e. HF hosp or IV therapy) 2008: REVERSE 12 months, n=610 Primary Obj: composite (total mortality and HF hospitalization) 2004: MICD II 6 months, n=186 Primary Obj: Packer’s HF Clinical Composite 2003: Contak CD 6 months, n =263 Primary Obj: Peak V02 Primary Obj: composite (mortality, HF hospitalization, and VT/VF)

  4. REVERSE Purpose and Design • To determine the effects of CRT with or without an ICD on disease progression over 12 months in patients with asymptomatic and mildly symptomatic heart failure and ventricular dysynchrony • Randomized, double-blind, parallel-controlled clinical trial

  5. Inclusion Criteria • NYHA Class II or I (previously symptomatic) • QRS  120 ms; LVEF  40%; LVEDD  55 mm • Optimal medical therapy (OMT) • Without permanent cardiac pacing • With or without an ICD indication

  6. Study Schematic Baseline Assessment Successful CRT Implant CRT OFF (OMT ± ICD) 1 12 Months Randomized 1:2 2 CRT ON (OMT ± ICD) U.S., Canada: at 12 Months, all patients recommended CRT ON Europe: remain in randomization assignment for 24 Months, all patients recommended CRT ON at 24 months All Geographies: Follow-up 5 years

  7. End Points • Primary: HF Clinical Composite Response, comparing the proportion of patients worsened in CRT OFF vs. CRT ON groups • Composite includes: all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind manner • Prospectively Powered Secondary: Left Ventricular End Systolic Volume Index (LVESVi) comparing CRT OFF vs. CRT ON subjects • LVESVi is assessed by two core labs (1 in Europe, 1 in U.S)

  8. Enrollment and Randomization 684 Enrolled (2004-2006) -42 ineligible or withdrew 642 Implant Attempts -21 unsuccessful implants 621 Successful CRT Implants (97%) -11 exits after successful implant 610 Patients Randomized U.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%) CRT OFF191 Patients CRT ON419 Patients - 594/598 completed 12 month follow-up - 12 deaths - 0 lost to follow-up, 0 exits

  9. Baseline Characteristics (n=610)

  10. Baseline Characteristics (n=610)

  11. Primary End Point: Clinical Composite Response Pre-Specified Analysis Proportion Worsened 100% 16% 21% Worsened 80% 60% P=0.10 84% 40% 79% Improved / Unchanged 20% 0% CRT OFF CRT ON

  12. 100% 16% 21% 80% 30% 60% 39% 40% 54% 20% 40% 0% CRT OFF CRT ON Primary End Point: Clinical Composite Response Pre-Specified Analysis Proportion Worsened Conventional Analysis Distribution Worsened/Unchanged /Improved 100% 16% Worsened 21% Worsened 80% Unchanged 60% P=0.004 P=0.10 84% 40% 79% Improved / Unchanged Improved 20% 0% CRT OFF CRT ON

  13. Clinical Composite Response Details Note: Data in table is listed in hierarchical order (subjects are included only in one sub-category)

  14. Powered Secondary End Point: LVESVi(ml/m2) P<0.0001 115 110 105 ) 100 2 CRT OFF 95 D = -1.3 LVESVi (ml/m 90 85 CRT ON D = -18.4 80 75 70 Baseline 12 Months n=487

  15. Other Remodeling Parameters LVEDVi (ml/m2) P<0.0001 LVEF (%) P<0.0001 150 34 CRT OFF ∆ = -1.4 32 140 CRT ON ∆ = 3.8 30 130 28 120 CRT ON ∆ = -20.5 26 CRT OFF ∆ = 0.6 110 24 100 22 20 90 Baseline 12 Months Baseline 12 Months n=487

  16. Time to First HF Hospitalization % of Patients Hospitalized for HF P=0.03 Hazard Ratio=0.47 CRT OFF CRT ON Months Since Randomization Number at Risk CRT OFF 191 187 181 176 119 CRT ON 419 415 411 409 251

  17. Other Secondary End Points: QOL, 6MHW 6-Min Walk Test P=0.26 MN LWHF P=0.26

  18. Other Secondary End Points: NYHA P=0.06

  19. Safety • 97% implant success rate • 9.5 % LV-lead related complications • 66 in 59 / 621 successfully implanted patients • LV lead dislodgements, diaphragmatic stimulation, subclavian vein thrombosis, etc.

  20. Conclusion REVERSE is the first large, randomized, double-blind study to show that CRT in asymptomatic and mildly symptomatic heart failure patients on optimal medical therapy: • Reverses LV remodeling • Reduces the risk of heart failure hospitalization • May improve clinical outcome as assessed by the clinical composite response measure Note: FDA has not yet reviewed the clinical data to determine whether or not CRT systems are safe and effective in this patient population.

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