Endpoints When Treating VT/VF in Patients with ICDs Programming Wojciech Zareba, MD, PhD

Transcription

1 Endpoints When Treating VT/VF in Patients with ICDs Programming Wojciech Zareba, MD, PhD Professor of Cardiology/Medicine Director of the Heart Research Follow Up Program, University of Rochester, Rochester, NY

2 Disclosures Research Grants: Boston Scientific - MADIT, MADIT II, MADIT-CRT, MADIT-RIT, MADIT-CHIC, MADIT-SICD Medtronic - LQTS ICD Registry Zoll, Inc - WEARIT II, WEARIT III, WED-HED Gilead Sciences - TEMPO, HARMONY, LQT3, HCM NIH - RAID, ARVC, LQTS

3 Trial ICD/CRT-D Trials Primary Endpoint MADIT Death SCD MADIT II Death SCD SCD-HeFT Death SCD DEFINITE Death SCD DANISH Death SCD DINAMIT Death SCD IRIS Death SCD Secondary Endpoint COMPANION HF event/death Death, HF event MADIT-CRT HF event/death Death, HF event RAFT HF event/death Death, HF Event

4 Cumulative Probability of VT/VF or Death by Treatment (CRT-D vs. ICD only) in patients with LBBB in MADIT-CRT Patients 2-year 3-year 31% 24% 23% 15% Zareba et al. Circulation 2011;123:

5 Probability of subsequent VT/VF/Death Ouellet et al. J Am Coll Cardiol 2012;60: MADIT-CRT: Cumulative probability of VT/VF/Death after first VT/VF requiring appropriate ICD therapy Unadjusted P= % at 1 year ICD CRT-D 60% at 2 years Years from 1st VT/VF Patients at Risk ICD (0.48) 24 (0.63) 8 (0.67) CRT-D (0.44) 33 (0.57) 7 (0.67)

6 Association of Rapid Rate NSVT >188 bpm with Cardiac Events in SCD-HeFT Chen et al. J Am Coll Cardiol 2013;61:2161 8

7 Antiarrhythmic Therapy in Patients with VT: Cardiac Resynchronization Therapy Pharmacological heart failure therapy Device programming VT ablation Cardiac sympathetic denervation Antiarrhythmic medications

8 Antiarrhythmic Therapy in Patients with VT: Cardiac Resynchronization Therapy Pharmacological heart failure therapy Device programming VT ablation Cardiac sympathetic denervation Antiarrhythmic medications ICD Documented VT/VF Endpoints Serve to Assess Efficacy and Safety of Antiarrhythmic Therapy in Patients with VT/VF

9 Cumulative Probability of VT/VF or Death by Treatment (CRT-D vs. ICD only) in patients with LBBB and Non-LBBB QRS Pattern in MADIT-CRT Patients HR=0.69 p<0.002 HR=1.11 p<0.574 LBBB Zareba et al. Circulation 2011;123: Non-LBBB P value for interaction = 0.028

10 Reduction in Cardiac Events in Carvedilol vs. Metoprolol Treated Patients from MADIT-CRT Study population HF/death VT/VF HR 95% CI P-value HR 95% CI P- value MADIT-CRT CRT-D and LBBB < Ruwald M et al. J Am Coll Cardiol. 2013;61:

11 Cumulative Probability of First Inappropriate Therapy by Treatment Group in MADIT-RIT by Arm Moss et al, NEJM 2012;367:

12 MADIT-RIT: Cumulative risk of high-rate appropriate therapy by programming arm

13 VANISH Trial: Ventricular Tachycardia Ablation versus Escalation of Antiarrhythmic Drugs Primary Outcome: death at any time or VT storm or appropriate shock from ICD after the 30-day treatment period Saap et al. N Engl J Med 2016;375:

14 VANISH Trial: Primary Outcome According to Receipt of Amiodarone during the Index Arrhythmia. Saap et al. N Engl J Med 2016;375:

15 Pharmacologic Antiarrhythmic Therapy for VT/VF

16 Pharmacological Trials in ICD Patients Trial Intervention Primary Endpoint Secondary Endpoint SOTALOL ICD (n=302) 1999 Sotalol Death or delivery of a first shock for any reason Appropriate ICD Shocks SHIELD (N=663) 2004 Azimilide, Placebo 1) all-cause shocks plus symptomatic tachyarrhythmias terminated by ATP and 2) all-cause shocks Appropriate ICD therapies, defined as shocks or VT terminated by ATP OPTIC (n=412) 2006 Sotalol, BB, amiodarone+bb Cumulative risk of ICD shocks Appropriate ICD shocks ALPHEE (n=486) 2011 Celivarone, Amiodarone, Placebo Time to first ICDtreated VT/VF (ATP or shock) or SCD Occurrence of ICD shocks (appropriate or inappropriate) or Death

17 Ongoing/Unpublished Pharmacological Trials in ICD Patients Trial Intervention Primary Endpoint Secondary Endpoint SHIELD II (n=240) Azimilide, Placebo Time-to first unplanned adjudicated cardiovascular (CV) hospitalisation, CV emergency department (ED) visit or CV death. Death Time-to first allcause adjudicated shock Time-to first adjudicated outpatient ICDrelated appointment TEMPO (n=313) Eleclazine, Placebo Total number of ICD interventions (ATP or shock) at 24 weeks Arrhythmia burden (untreated and treated VTs) RAID (n=1,012) Ranolazine, Placebo Time to first ICDtreated VT/VF (ATP or shock) or Death VT/VF, Death, recurrent VT/VF

18 VT/VF Endpoints VT/VF requiring ICD therapy (ATP or shock) VT/VF requiring ICD therapy or death VT/VF requiring ICD shocks VT/VF requiring ICD shocks or death VT/VF and arrhythmic death or SCD VT/VF storms (usually defined as at least 3 episodes in 24 hours) Fast VT/VF treated and untreated, including NSVT Time to first event Cumulative number of events over time Rate of events over 100 person-years Eliminate expected VT/VF in terminal stage

19 Nonsustained Self-terminating VF is it an Endpoint?

20 ALPHEE Trial: Recurrent episodes of the primary end point (VT/VFtriggered ICD intervention or sudden death. Percentage of patients by number of events (limited to a maximum of 10 per patient) Kowey et al. Circulation 2011;124:

21 Mean cumulative number of the first 10 events per patient in ALPHEE Trial. Kowey et al. Circulation 2011;124:

22 Probability of subsequent VT/VF/Death Ouellet et al. J Am Coll Cardiol 2012;60: MADIT-CRT: Cumulative probability of VT/VF/Death after first VT/VF requiring appropriate ICD therapy Unadjusted P= ICD CRT-D Years from 1st VT/VF Patients at Risk ICD (0.48) 24 (0.63) 8 (0.67) CRT-D (0.44) 33 (0.57) 7 (0.67)

23 MADIT-CRT: Number of Patients with Repeated VT/VF Episodes

24 VT/VF Endpoints Determined by ICD Programming ICD programming should be uniform but many patients will have prior VT/VF and VT zone will be programmed bpm above previously documented VT which might range from bpm Not all VT episodes are synonymous with sudden cardiac death Appropriate ICD therapy but unnecessary is significantly reduced by delayed activation

25 Programming of Implantable Devices

26 Programming of Implantable Devices

27 CRM Device Generated Data Variables Algorithm - variable EGM Collections - reporting Data efficiency - memory and power limitations Integrated Sensors User specified programming

28 Language Is Everything! Definitions are critical! Machine algorithms increasingly complex Need for consistent interpretation of events International data acquisition the norm: geographic clinical practice variability Pre-specify the data available to the device event adjudication committee Consider sampling analysis/memory limitations

29 Analytic Complexity Appropriate Device Therapy Appropriate ATP therapy only (ATP without shock); Appropriate ATP and appropriate shock (at least one ATP and one shock) Appropriate shock only (no preceding or accompanying ATP) Inappropriate Device Therapy Inappropriate ATP only Inappropriate ATP therapy and inappropriate shock Inappropriate shock only Inappropriate ATP and appropriate ATP Inappropriate ATP and appropriate shock Inappropriate shock and appropriate shock Appropriate ATP and inappropriate shock Lack of Appropriate Device Therapy Sustained VT or VF without device therapy terminated spontaneously Sustained VT or VF without device therapy continuing under rate cut-off Sustained supraventricular arrhythmia (atrial fibrillation, other atrial rhythms) not treated with ATP or shock Other Causes of Lack of Appropriate Device Therapy VT undersensing VF undersensing Other explain Device therapy not delivered but not required Unable to determine - Insufficient or confounding interrogation data available to make determination

30 Questions Is VT burden the right endpoint? If yes at what rate VT? How to deal with VT/VF below VT thresholds? Should death be included or just cardiac death or sudden cardiac death as part of the primary endpoint? How to trust devices without adjudication?