The Interventional Trials of the Year: (TCT, AHA, and ACC)

Transcription

1 The Interventional Trials of the Year: (TCT, AHA, and ACC) Roxana Mehran, MD Associate Professor of Medicine Columbia University Medical Center Cardiovascular Research Foundation New York City

2 The best of LBCT Adjunct Pharmacology ACS, AMI (ACUITY 30-day, 1 Year, ISAR-REACT REACT 2) DES in AMI (TYPHOON, PASSION), DES in the real world (SORT OUT), DES in Bifurcations (Nordic Bif study) New Drug-Eluting Stents (ZOMAXX I, SPIRIT III, ENDEAVOR Safety, RESOLUTE, and ABSORB) Anti PCI Trials! (OAT and COURAGE)

3 The best of LBCT Adjunct Pharmacology ACS, AMI (ACUITY days, 1 Year, (ISAR-REACT REACT 2) DES in AMI (TYPHOON, PASSION), DES in the real world (SORT OUT), DES in Bifurcations (Nordic Bif study) New Drug-Eluting Stents (ZOMAXX I, SPIRIT III, ENDEAVOR Safety, RESOLUTE, and ABSORB) Anti PCI Trials! (OAT and COURAGE)

4 A Prospective, Randomized Trial of Bivalirudin in Acute Coronary Syndromes 30- day (ACC-06), and Final One-Year Results (ACC-07) from the ACUITY Trial Gregg W. Stone MD for the ACUITY Investigators

5 Study Design First Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Moderate and high risk ACS (n=13,819) Aspirin in all Clopidogrel dosing and timing per local practice R* UFH/Enox + GP IIb/IIIa (n=4,603) Bivalirudin + GP IIb/IIIa (n=4,604) Bivalirudin Alone (n=4,612) Angiography within 72h Medical management PCI CABG 33% 56% 11% *Stratified by pre-angiography thienopyridine use or administration

6 Primary Endpoint Measures (ITT) 30 Days UFH/Enoxaparin + GPI vs. Bivalirudin + GPI Primary endpoint Risk ratio ±95% CI Bival UFH/Enox + IIb/IIIa + IIb/IIIa RR (95% CI) p value (non inferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.8% 11.7% 1.01 ( ) 7.7% 7.3% 1.07 ( ) 5.3% 5.7% 0.93 ( ) < < Bivalirudin + IIb/IIIa better UFH/Enox + IIb/IIIa better Stone GW et al. NEJM 2006;355:

7 Primary Endpoint Measures (ITT) 30 Days UFH/Enoxaparin + GPI vs. Bivalirudin Alone Primary endpoint Risk ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa RR (95% CI) p value (non inferior) (superior) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 10.1% 11.7% 0.86 ( ) 7.8% 7.3% 1.08 ( ) 3.0% 5.7% 0.53 ( ) < <0.001 <0.001 Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW et al. NEJM 2006;355:

8 Patient Follow-up at 1-Year* All patients N = 13,819 R Heparin + IIb/IIIa 4,603 Bivalirudin + IIb/IIIa 4,604 Bivalirudin alone 4, Withdrawn 62 Lost to follow-up 33 Withdrawn 69 Lost to follow-up 25 Withdrawn 66 Lost to follow-up Heparin + IIb/IIIa 4,516 (98.1%) 1-year FU Bivalirudin + IIb/IIIa 4,502 (97.8%) 1-year FU Bivalirudin alone 4,521 (98.0%) 1-year FU *Endpoints adjudicated: Composite ischemia (death, MI, unplanned revasc) and stent thrombosis

9 Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Ischemic Composite (%) UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone day Estimate 7.4% 7.8% 7.9% Days from Randomization P (log rank) year Estimate 16.3% 16.5% 16.4% P (log rank) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 ( ) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 ( ) p=0.55

10 Mortality: 524 total deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Mortality (%) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 ( ) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 ( ) 30 day Estimate P (log rank) 1 year Estimate P (log rank) p= UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone 1.4% 1.6% 1.6% % 4.2% 3.8% Days from Randomization

11 Impact of MI and Major Bleeding (non-cabg) in the First 30 Days on Risk of Death Over 1 Year 1 year Estimate 30 Both MI and Major Bleed (N=94) 28.9% Major Bleed only (without MI) (N=551) 12.5% MI only (without Major Bleed) (N=611) 8.6% No MI or Major Bleed (N=12,557) 3.4% 28.9% 25 Mortality (%) % 8.6% 3.4% Days from Randomization

12 ISAR- REACT 2 Trial 2022 High Risk ACS patients undergoing PCI Accelerating or rest angina within 48 hours with either: (1) Tn-T > 0.03 ugl or (2) new ischemic EKG changes Clopidogrel mg mg x 1 (> (> 2 hr hr pre pre PCI) PCI) mg/d mg/d x days days Abciximab (n=1012) Placebo (n=1010) Primary endpoint 30-day death, MI, MI, U-TVR Kastrati A et al. JAMA 2006;295:1531-8

13 ISAR-REACT REACT 2 30-day endpoints 15% 25% (p=0.03) 25% (p=0.03) Abciximab Placebo 10% 11.9% 10.5% 5% 8.9% 31% (p=ns) 8.1% 17% (p=ns) 1.6% 1.1% 1.0% 1.2% 0% D/MI/U-TVR Death MI U-TVR Kastrati A et al. JAMA 2006;295:1531-8

14 ISAR-REACT REACT 2 1ry endpt benefit with IIb/IIa and troponin elevation Tn-T >0.03 P=0.02 Benefit of abciximab restricted to subgroup with elevated Troponin at time of PCI TnT > 0.03 RR = 0.71 Tn-T 0.03 TnT 0.03 = 0.99 Similar findings in PURSUIT, CAPTURE, TACTICS RR Kastrati A et al. JAMA 2006;295:1531-8

15 The best of LBCT Adjunct Pharmacology ACS, AMI (ACUITY days, 1 Year, ISAR-REACT REACT 2) DES in AMI (TYPHOON, PASSION), DES in the real world (SORT OUT), DES in Bifurcations (Nordic Bif study) New Drug-Eluting Stents (ZOMAXX I, SPIRIT III, ENDEAVOR Safety, RESOLUTE, and ABSORB) Anti PCI Trials! (OAT and COURAGE)

16 TYPHOON 1 Endpoint: Target Vessel Failure 25% 20% % of Patients 15% 10% 5% 0% BMS SES 49% P = Time (days) Time (days) 712 pts within 12 hrs of AMI Randomized to SES vs. any approved BMS Primary endpoint: Target vessel failure (TV-related death, re-mi, or TVR) at 1 year Key issues Dual antiplatelet >6 months Angio. Substudy at 8 months in 210 pts (29% of overall) Benefit entirely due to reduced TLR (3.7 vs. 12.6%) no excess late MI or stent thrombosis Spaulding C et al. NEJM 2006;355:

17 PASSION 1 Endpoint: Death/MI/TLR BMS RR 0.63 (p=0.09) PES 12.8% 8.8% 619 pts presenting within 6 hrs or AMI at 2 study centers Randomized to PES vs. Bare Express Stent (double-blind) blind) Primary endpoint: Composite of death, MI, or TLR Patients managed according to standard practice without routine angiographic f/u Laarman GJ et al. NEJM 2006;355: Main Result: : No benefit on primary endpoint although trends toward lower TLR

18 SORT-OUT OUT Trial CYPHER (n=1065) Patients undergoing planned PCI with DES (n=2098) Primary Endpoint TAXUS (n=1033) Cardiac Death, MI, or TVR at 9 months Key Trial Features Involved all 5 university centers in Denmark Very high participation ~20% of all pts enrolled during recruitment period No mandatory angiographic or clinical f/u at all all events ascertained through national health database and death registry (true real world trial) Galloe A et al. TCT LBCT 2006

19 SORT-OUT Primary Endpoint: Cardiac Death, MI, TLR at 9 months Event-free Survival (%) 92.2% 91.4% Cypher TAXUS

20 Nordic Bifurcation Trial Patients undergoing PCI for a de novo bifurcation lesion (n=413) Stent Main Vessel + Side Branch (n=206) Stent Main Vessel Only (n=207) Primary Clinical Endpoint (6-months): Cardiac Death, MI, Stent Thrombosis, or TLR Angiographic Follow-up (8 months) Thuesen L et al. Circulation 2006;114:

21 Nordic Bifurcation 6-month Clinical Outcomes Outcome MV + SB MV only P-value 1 Composite 3.4% 2.9% NS Cardiac Death 1.0% 1.0% NS MI 0.5% 0.0% NS TVR 1.9% 1.9% NS Stent thrombosis 0.5% 0.0% NS Periprocedural MI (CKMB>3x) CCS class > 1 at 6 mos 18% 8.6% 8% 9.2% NS Thuesen L et al. Circulation 2006;114:

22 Nordic Bifurcation Angiographic Outcomes Outcome MV + SB MV only Main vessel Implications 5.1% 4.6% restenosis Side branch For treatment of bifurcation lesions, 11.5% 19.2% restenosis stenting the main vessel alone is equally effective as stenting both branches, yet Any restenosis 16.0% 22.5% offers substantial advantages in terms of risk, time, and cost P-value NS 0.06 NS Sidebranch occlusion 0.0% 0.5% NS Thuesen L et al. Circulation 2006;114:

23 The best of LBCT Adjunct Pharmacology ACS, AMI (ACUITY days, 1 Year, (ISAR-REACT REACT 2) DES in AMI (TYPHOON, PASSION), DES in the real world (SORT OUT), DES in Bifurcations (Nordic Bif study) New Drug-Eluting Stents (ZOMAXX I, SPIRIT III, ENDEAVOR Safety, RESOLUTE, and ABSORB) Anti PCI Trials! (OAT and COURAGE)

24 ZOMAXX I 401 patients Determined ineligible after randomization *De-registered (n=4) *De-registered (n=1) Withdrew consent ZoMaxx (n=199) ITT Population (N=396) TAXUS (n=197) 9-Month Clinical Follow-up (n=382) 9-Month Angiographic Follow-up (n=345) *no stent implantation attempted ZOMAXX I

25 Angiographic Results Primary Endpoint ZoMaxx (median) TAXUS (median) Median difference Upper 95% CI In-segment late loss 0.29 mm 0.22 mm 0.12* 0.21* * Met primary non-inferiority endpoint (based on non-parametric testing) ZOMAXX I

26 Angiographic Results ZoMaxx (n=170) Taxus (n=175) P-Value In-stent Late loss (mm) 0.67 ± ± 0.48 <0.001 Restenosis 12.9% 5.7% 0.03 In-segment Late loss (mm) 0.43 ± ± Restenosis 16.5% 6.9% ZOMAXX I

27 Clinical, Angiographic, and IVUS Results from the Pivotal U.S. Randomized SPIRIT III Trial of the XIENCE V Everolimus- eluting Coronary Stent System Gregg W. Stone, MD for the SPIRIT III Investigators

28 Study Algorithm 1002 pts enrolled at 65 U.S sites RVD 2.5 mm mm; Lesion length 28 mm Max. 2 lesions each in a different epicardial vessel Pre-rand: rand: ASA 300 mg, clopidogrel 300 mg load unless on chronic Rx Randomized 2:1 XIENCE V:TAXUS Stratified by diabetes and intent for 1 vs. 2 lesion treatment Pre-dilatation mandatory Everolimus-eluting XIENCE V Paclitaxel-eluting TAXUS Aspirin 80 mg QD for 5 years; Clopidogrel 75mg QD for 6 months Clinical f/u: 1, 6, 9 months and yearly for 1-5 years Angio f/u 8 mos; IVUS f/u 8 mos

29 100% Primary Endpoint: In-segment LL at 8 Months* (Analysis Lesion) % of Lesions 90% 80% 70% 60% 50% 40% 30% 20% 10% TAXUS: 0.28 ± 0.48 (n=134) XIENCE V: 0.14 ± 0.41 (n=301) P NI < P SUP = % In-segment Late Loss (mm) *F/U window ±28 days.

30 MACE Through 284 Days MACE (%) HR=0.56 [ ] P logrank = % 4.6% Days

31 Ischemia-driven TLR Through 284 Days Rate (%) HR=0.52 [ ] P logrank = % 2.6% Days

32 Two-Year Outcomes from the ENDEAVOR III Trial: A Randomized Trial of the Endeavor Zotarolimus- Eluting Stent Compared with the Cypher Eluting Stent Martin B. Leon, MD For the Endeavor III Investigators ACC 2007 i2 Symposium March 26, 2007 New Orleans, LA

33 Endeavor Clinical Trial Program ENDEAVOR I ENDEAVOR II ENDEAVOR II CA Registry ENDEAVOR III ENDEAVOR IV Endeavor Japan E-Five Registry PROTECT Phase I FIM 36 month results Double-blind blind Randomized Trial 24 month results Continued Access Safety 24 month results Endeavor vs. Cypher 24 month results Endeavor vs. Taxus 30 day results Single Arm Trial Enrollment completed Real-World Performance and Safety Evaluation Enrollment completed Endeavor vs. Cypher Safety Study 8,000 patient RCT

34 Endeavor Safety Analysis HCRI CEC and ARC Definitions 2yr K-M K M estimate 1.8% 1.6% HCRI CEC Definition ARC Definite + Probable ARC Definite + Probable + Possible 1.52% UB 95% CI 1.4% 1.2% 1.0% 0.8% 0.60% UB 95% CI 0.98% UB 95% CI 0.97% 0.6% 0.4% 0.54% 0.2% 0.30% 0.0% ENDEAVOR EI, EII, EII CA, EIII (n= 1316)

35 % QMI/Death Endeavor Safety Analysis 0 Composite of Death and QMI EI, EII, EII CA, and EIII vs. EII Driver P= (n=585) 0.2 (n=1302) In Hospital P= (n=594) 0.2 (n=1313) P= (n=591) 1.2 (n=1201) Endeavor Driver P= (n=589) 1.2 (n=1297) P= (n=579) 2.2 (n=679) 30 days 9 months 1 year 2 years

36 RESOLUTE 4 month Angiographic and IVUS Subset Professor Ian Meredith M.D., Ph.D., FACC, FRACP, FSCAI Monash Medical Centre and Monash University Melbourne, Australia Principal Investigator On behalf of the RESOLUTE Investigators

37 Endeavor Resolute BioLinx Polymer System Durable Hydrophilic Zotarolimus Hydrophobic Non-inflammatory

38 Clinical Trial Design Endeavor Resolute Stent Clinical/MACE Angio/IVUS Single De Novo Native Coronary Artery Lesions Lesion Length: 14-27mm Stent Diameters: 2.5, 3.0, 3.5mm Stent Lengths: 18, 24, 30mm (8/9mm bailout) Drug Dose: 1.6 µg/mm 2 stent surface area Antiplatelet therapy for 6 months Pre-dilatation required 130 Patients (includes 30 PK Sub-Study Patients) 12 Sites (New Zealand and Australia) 30d 4mo 6mo 9mo 12mo 2yr 3yr 4 yr 5 yr N=30 N=100 Primary Endpoint: Late lumen loss (in-stent) at 9 mths by QCA Secondary Endpoints: MACE at 30 days, 6, 9 and 12mths and IVUS and angiographic parameters at 9mths 30 pt Subset: 4mth MACE and angiographic, IVUS parameters 9 month results will be compared to an ENDEAVOR II DES cohort

39 Angiographic Results 4 Month Subset n=30 RVD (mm) Lesion Length (mm) MLD (mm) pre Acute Gain % DS ABR (%) post MLD (mm) 4 mo f/u Late Loss (mm) Late Loss Index In-stent 2.81± ± ± ± ± In-segment 2.90± ± ± ± ± ±

40 Late Breaking Clinical Trials I The ABSORB Trial Six Month Angiographic and IVUS results from this First-in-Man Evaluation of a Fully Bioabsorbable Everolimus-Eluting Coronary Stent Patrick W. Serruys, MD, PhD and John A. Ormiston, MD On behalf of the ABSORB Investigators Thoraxcenter, Erasmus Medical Center, Rotterdam, the Netherlands Auckland City Hospital, Auckland, New Zealand 24 th March :00-11:10 La Nouvelle Orleans C

41 BVS Stent Components BVS Bioabsorbable Stent Platform ML VISION Balloon SDS Everolimus Bioabsorbable Polymer Coating Note: BVS is currently in development at Abbott Vascular. Not available for sale

42 ABSORB: Study Design Single, de-novo lesion 3.0 mm n = 30 BVS Stent Sponsor: Abbott Vascular Primary Investigators: J Ormiston MD PW Serruys MD, PhD DSMB: J Tijssen PhD, T Lefèvre MD, P Urban MD CEC: C Hanet MD, D McClean MD, V Umans MD Angiographic and IVUS Corelab: Cardialysis (Rotterdam, NL) Prospective, open label, FIM 3.0 x 12mm stents (3.0 x 18mm* stents available after enrolment start and used in 2 pts) 6 sites EU, NZ Rotterdam, NL, Patrick Serruys (16) Krakow, PL, Dariusz Dudek (6) Auckland, NZ, John Ormiston (5) Arhus, DN, Leif Thuesen (3) Aalst, BE, Bernard de Bruyne St Denis, F, Bernard Chevalier

43 ABSORB Angiographic Late Loss EES ** : 0.07 ± 0.23mm (N=22) BVS: 0.44 ± 0.35mm (N=26) BMS*: 0.85 ± 0.36mm (N=27) * BMS loss from SPIRIT FIRST ( n=27 ) ** EES loss of pts with 3.0 x 18mm for single lesion from SPIRIT FIRST and II ( n=22 )

44 The best of LBCT Adjunct Pharmacology ACS, AMI (ACUITY days, 1 Year, (ISAR-REACT REACT 2) DES in AMI (TYPHOON, PASSION), DES in the real world (SORT OUT), DES in Bifurcations (Nordic Bif study) New Drug-Eluting Stents (ZOMAXX I, SPIRIT III, ENDEAVOR Safety, RESOLUTE, and ABSORB) Anti PCI Trials! (OAT and COURAGE)

45 OAT Trial 2166 stable patients with total occlusion of the Infarct-Related Artery at days following MI Patients at increased risk,, defined as an EF<50%, proximal occlusion of a major epicardial vessel with a large risk region, or both Randomization to PCI vs. Medical Therapy Primary Endpoint: death, reinfarction, or Class IV heart failure at 4 years Hochman et al, NEJM 2006; 355:

46 OAT Trial Cumulative 4-year 4 Rates P=NS for all PCI Medical Therapy Death/MI/CHF Re-MI NYHA IV CHF Hochman et al, NEJM 2006; 355:

47 OAT Trial 2166 stable patients 3-28 days post MI 100% occlusion 4 year F/U Death MI Class IV CHF PCI 17.2% Med 15.6%

48 OAT: Who Were They? Age 58 Class I 83% Throm.. Therapy 20% Time from MI to Randomization 8 days Stress test 27% Ischemia mild/none 90% SVD 82% (50% RCA) Stable, untreated, non-ischemic, single vessel, 1 week out of an MI Nothing to do with CTOs

49 COURAGE

50 COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Guideline-Driven Drug Evaluation

51 A North American Trial 19 US Non-VA Hospitals 15 VA Hospitals 50 Hospitals 2,287 patients enrolled between 6/99-1/04 16 Canadian Hospitals

52 Enrollment and Outcomes 3,071 Patients met protocol eligibility criteria 2,287 Consented to Participate (74% of protocol-eligible patients) 784 Did not provide consent Did not receive MD approval Declined to give permission - 97 Had an unknown reason 1,149 Were assigned to PCI group 46 Did not undergo PCI 27 Had a lesion that could not be dilated 1,006 Received at least one stent 1,138 Were assigned to medical- therapy group 107 Were lost to follow-up 97 Were lost to follow-up 1,149 Were included in the primary analysis 1,138 Were included in the primary analysis Primary endpoint: Death/non-fatal MI

53 Survival Free of Death from Any Cause and Myocardial Infarction 1.0 Optimal Medical Therapy (OMT) PCI + OMT Hazard ratio: % CI ( ) P = Years Number at Risk Medical Therapy PCI

54 Overall Survival 1.0 PCI + OMT 0.9 OMT Hazard ratio: % CI ( ) P = Number at Risk Years Medical Therapy PCI

55 Survival Free of Hospitalization for ACS OMT PCI + OMT Hazard ratio: % CI ( ) P = Number at Risk Years Medical Therapy PCI

56 Need for Subsequent Revascularization At a median 4.6 year follow-up, 21.1% of the PCI patients required an additional revascularization, compared to 32.6% of the OMT group who required a 1 st revascularization 77 patients in the PCI group and 81 patients in the OMT group required subsequent CABG surgery Median time to subsequent revascularization was 10.0 mo in the PCI group and 10.8 mo in the OMT group

57 Freedom from Angina During Long-term Follow-up Characteristic CLINICAL Angina free no. PCI + OMT OMT Baseline 12% 13% 1 Yr 66% 58% 3 Yr 72% 67% 5 Yr 74% 72% The comparison between the PCI group and the medical- therapy group was significant at 1 year ( P<0.001) and 3 years (P=0.02) but not at baseline or 5 years.

58 Important LBCTs Summary Trends in adjunctive pharmacology: stress value of clopidogrel,, downgrade IIb/IIIa inhibitors, consider bivalirudin as preferred anti-thrombin. thrombin. DES in AMI/Real world/bifurcations: early and intermediate results favor DES in AMI, and in real world patients, and for treating bifurcations use of one stent with provisional stenting of the SB seems more favorable New DES: Favor Xience V for efficacy and Endeavor for safety (preliminary); watch out for bioresorbables in the future Anti PCI: Patient selection/endpoint definitions will influence clinical outcomes. Read between the lines! There are no new findings in COURAGE, PCI relieves symptoms and improves QOL.