Presentation on theme: "Presenter Disclosure Information"— Presentation transcript:
1 Presenter Disclosure Information The following relationships exist related to this presentation:Consulting Fees: Medtronic Inc., St. Jude MedicalSpeaker Honoraria: Medtronic Inc., Sorin Group, St. Jude MedicalThere are my disclosures
2 Mrs chairmen, Ladies and gentlemen, Does Cardiac Resynchronization Therapy Prevent Disease Progression in NYHA Class I and II Heart Failure Patients?24 month results from the European cohortof the REsynchronization reVErses Remodeling inSystolic left vEntricular dysfunction trialJean-Claude Daubert, Rennes, FranceOn Behalf of the REVERSEInvestigators and CoordinatorsMrs chairmen, Ladies and gentlemen,On behalf of the REVERSE investigators and coordinators, I am very pleased to present the final results of the REsynchronization reVErses Remodeling in Systolic left vEntricular dysfunction trial.
3 REVERSE was a double-blind, parallel-arm controlled trial Purpose and DesignTo evaluate the long-term benefits of CRT in the European patients included in REVERSE and prospectively followed for 24 monthsRandomized, double-blind, parallel-arm controlled clinical trialThe purpose of the study was to assess the long-term clinical benefits of Cardiac resynchronization therapy in the 262 european patients included in REVERSE and who were prospectively followed for 24 monthsREVERSE was a double-blind, parallel-arm controlled trial
4 Inclusion Criteria NYHA Class II or I (previously symptomatic) QRS 120 msLVEF 40%; LVEDD 55 mmOptimal medical therapy (OMT)Without permanent cardiac pacingWith or without an ICD indicationTo be included in REVERSE, patients had to be stabilized in NYHA Class II or I. Class I patients had to be previously symptomatic in a higher NYHA Class, thus meaning ACC/AHA Class I-Stage CThey had to have a wide QRS, more than 120 msec, the evidence of LV dysfunction by ejection fraction less than 40% and LV dilatation.They had to be on optimal medical therapy as indicated in guidelines with stable drug regiment for at least 3 months
5 End PointsPrimary: HF Clinical Composite Response, comparing the proportion of patients worsened in CRT OFF vs. CRT ON groupsComposite includes: all-cause mortality, HF hospitalizations, crossover due to worsening HF, NYHA class, and the patient global assessment assessed in double blind mannerProspectively Powered Secondary: LV End Systolic Volume Index (LVESVi) comparing CRT OFF vs. CRT ON subjectsLVESVi assessed by core labs (1 in Europe, 1 in U.S)The primary endpoint of the study was the clinical composite response, a measure of clinical outcome that includes all-cause mortality, heart failure hospitalizations, crossover due to worsening heart failure, change in NYHA class and the patients global assessment assessed in double blind manner. For the purpose of REVERSE, we compared the proportion of patients worsened in CRT OFF versus CRT ON groupsTo analyze more specifically the effect on disease progression, we had a prospectively powered secondary endpoint of ventricular remodeling by the change in left ventricular endsystolic volume index. Echo data were analyzed in core centers
6 Actually, the study included two phases. Study SchematicBaseline AssessmentSuccessfulCRT ImplantCRT OFF(OMT ± ICD)112 Months:North American randomization complete (CRT recommended in all pts)24 Months: European randomization complete (CRT recommended in all pts)Randomized 1:2CRT ON(OMT ± ICD)2After initial assessment, all patients underwent an attempt to CRT device implantation, whether a CRT-D or a CRT-P according to the patient needs. The successfully implanted patients were randomized in a 1:2 ratio to CRT-OFF with the device programmed in an inhibited mode or CRT-ON.Actually, the study included two phases.All patients randomized in the trial participated in the first 12 months of the study, at which point North American patients learned their randomisation assignment. Before the study began, for health economics analysis purposes, it was decided to maintain all European patients blinded and in their randomly assigned for 24 months.Today we report the 24-month results of this entire European patient cohort.
7 Enrollment and Randomization 621 Successful CRT Implants 684 Enrolled ( )-42 ineligible or withdrew642 Implant Attempts-21 unsuccessful implants621 Successful CRT Implants(97%)-11 exits after successful implant610 Patients RandomizedU.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)In total, 610 patients were randomized, 191 to CRT OFF and 419 to CRT ONCRT OFF 191 PatientsCRT ON 419 PatientsC Linde et Al, JACC 2008; 52:
8 2D2)DMain Study: 12-Month Clinical Composite Response Powered Secondary Objective707580859095100105110115Baseline12 MonthsLVESVi (ml/m2)CRT OFFD= -1.3CRT ON= -18.4Pre-Specified AnalysisProportion Worsened12 Month Change in LVESVi100%40%80%54%Improved60%2)D39%40%Unchanged30%P<0.0001Let me just recapitulate the results of the main study observed at 12-months in the entire REVERSE populationAt 12-month, we failed to demonstrate a significant benefit on the primary endpoint as the percentage of worsening was 16% in CRT ON as compared to 21% with CRT OFF. The P value was 0.10.However we did show a highly significant decrease in the LV endsystolic index with CRT ON suggesting large reverse remodeling effect20%21%Worsened16%0%CRT OFFCRT ONP=0.10C Linde et Al, JACC 2008; 52:
9 Enrollment and Randomization 621 Successful CRT Implants 684 Enrolled ( )- 42 ineligible or withdrew621 Successful CRT Implants(97%)- 11 exits after successful implant610 Patients RandomizedU.S. 343 (56%); Europe 262 (43%); Canada 5 (<1%)CRT OFF 191 PatientsCRT ON 419 PatientsLet us now move to todays topic: the European cohort and the 24-month results262 patients were randomized in Europe. Please remind they remained blinded and in their randomly assigned group for 24 months82 were randomized to CRT OFF and 180 to CRT ON262 patients (Europe) followed for 24 monthsCRT OFF 82 PatientsCRT ON 180 Patients
10 Baseline Characteristics US/Can N=348Europe N=262P-valueAge (mean) yrs63.4 ± 11.361.3 ± 10.40.02Ischemic63%44%<0.0001NYHA II82%83%0.75ICD95%68%EF26.3 ± 7.227.1 ± 6.80.16LVEDD (mm)65.5 ± 8.468.8 ± 9.2QRS (ms)151 ± 21156 ± 230.008Beta-blockers96%94%0.13ACE-i/ ARB>99%0.00036-min. Walk (m)363 ± 134439 ± 103Here are the baseline characteristics of the patients. Please note there were some important differences between the European cohort and the rest of the REVERSE population at baseline. European patients were younger, had less ischemic etiology, had more dilated left ventricle, wider QRS and received more ACE-inhibitos or ARB than the North-american patients. They also walked longer on the six minute walk test. Note also the lower implantation rate of CRT-D devices in Europe, 68% versus 95%.
11 Primary End Point: Clinical Composite Response at 24-month % worsened 81%54%/27%66%29%/37%66%There are the results for the primary study endpoint at 24-month. The percentage of worsening was 19% in the CRT ON group as compared to 34% in the CRT OFF group. P value When comparing the entire distribution of worsened, unchanged and improved, the difference was still more significant with a P value of34%19%CRT OFFCRT ONEntire distribution analysis of worsened, unchanged and improved: P=0.0006
12 Primary End Point Clinical Composite Response % worsened over time Interestingly, and unlike the main study results the difference between the two study groups became statistically significant at the 6-month evaluation and continued to differ significantly and with a similar amplitude of difference over the entire follow-up period in favor of CRT ON assignmentPlease note also that worsening was attributable to death or heart failure hospitalization in 68% of the worsened patients in the CRT OFF groupWorsening attributed to death or HF hospitalization in 68%of worsened patients in the CRT OFF group
13 Powered Secondary End Point: LVESVi There are the results for the powered secondary endpoint. The highly significant difference observed in the main study at 12-month was also seen at 24-month in the European cohort. The mean final difference was 25 ml/square meter or 26% in favor of CRT ON. Please note a trend to worsening during the last 6 months of the study in the CRT OFF group.P-value compares 24-month changes.
14 Other Remodeling Parameters LVEDVi (ml/m2)LVEF (%)This slides shows the Left ventricular endiastolic volume index and LV ejection fraction over 24 months in the 2 study groups. Highly significant differences indicating ventricular reverse remodeling in favour of CRT were seen. ,P-values compare 24-month changes.
15 Other Secondary Endpoints: Functional Paramaters Finally and as expected in these mildly symptomatic or asymptomatic patients, we did not observe significant differences between the two groups for functional parameters: quality of life scores, exercise tolerance and symptoms,P-values compares 24-month changes.P-value compares 24-month NYHA.
16 Time to First HF Hospitalization or Death Finally CRT had a strong impact on the time to first heart failure hospitalization or death: a very classical endpoint for assessing any heart failure treatment. At 24-month, we observed a significant difference in favor of CRT ON assignment with a 38% relative risk reduction. The P value was REVERSE however was not powered as a mortality trialNumber at RiskCRT OFFCRT ON
17 ConclusionThe 24 month results of the European cohort of REVERSE show that CRT in asymptomatic and mildly symptomatic HF patients on optimal medical therapy:Improves clinical outcomeImproves ventricular structure and functionCRT thus modifies disease progression in NYHA Class I-II HF patientsNote: FDA has not yet reviewed the clinical data to determine whether or not CRT systems are safe and effective in this patient population.
18 Once again I would like to thank warmly all REVERSE investigators and AcknowledgmentsSteering CommitteeW. T. Abraham, J-C. Daubert (study initiator), C. Linde (coordinating clinical Investigator), M. GoldEcho Core LabsS. Ghio, M.G. St. John SuttonAdverse Events Advisory CommitteeD. Böcker, J. P. Boehmer, J. G. F. Cleland, M. Gold, J. T. Heywood, A. Miller (chair)Data Monitoring CommitteeJ. Aranda, J. Cohn (chair), P. Grambsch; M. KomajdaInvestigatorsAustria: 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.SponsorMedtronic Inc.Once again I would like to thank warmly all REVERSE investigators andall colleagues who participated in the various study committees, with a special attention to our principal investigator, Dr Cecila Linde