The Microport FIREBIRD Polymer-based Sirolimus- Eluting Stent Clinical Trial Program Update: The FIC and FIREMAN Registries Junbo Ge, MD, FACC, FESC, FSCAI On behalf of Runlin Gao (FIC PI) and Haichang Wang (FIREMAN PI)
Final Clinical and Angiographic Results From a Nationwide Registry of FIREBIRD Sirolimus- Eluting Stent: Firebird In China (FIC) Registry (PI R. Gao) A Prospective Multicenter Study to Evaluate Long Term Efficacy and Safety of the FIREBIRD Sirolimus Eluting Stent in Patients with CoMplex CoronAry LesioNs(FIREMAN) (PI H. Wang)
Disclosure Statement of Financial Interest I, (Junbo Ge) DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation.
Aim of the FIC Post-marketing surveillance registry to determine: Safety and efficacy of FIREBIRD SES in routine clinical practice in Chinese population Aim of the FIREMAN To evaluate the long term efficacy, safety and angiographic outcomes of FIREBIRD Sirolimus-eluting stent for the treatment of complex coronary lesions (off-label use)
Study Design(FIC) All patients receiving >= 1 Firebird SES are enrolled after informed consent was signed Patients implanted other stents and had previous MI within 1 week are excluded Clinical FU at 30-day, 6- and 12-month Target recruitment = 1500 patients Angiographic follow-up at 9 months for 50% enrolled patients
Pre-defined Objectives(FIC) Primary MACE (Cardiac death, nonfatal MI, and target lesion revascularization) @ 12-month Secondary In-stent and in-segment binary Restenosis rates, late loss @ 9-month
Patient Enrollment (FIC) patients 1600 1200 800 400 0 August 64 September 158 372 October November 646 December 1138 January 1569 First patient in Jul. 13, 2005 Last patient in Jan. 31, 2006
Study Flow - Clinical (FIC) De-registered* (n=8) Enrolment, n=1569 Study population, n=1561 30 days FU, n=1553 (99.5%) 12 months FU, n=1426 (91.4%) * non-studied stent (n=5), AMI patients (n=3)
Baseline Demographics (FIC) Patients 1561 Age (yrs) 62.3±11.0 28~88 Male 70.5% 1101/1561 Prior MI 31.4% 490/1561 Prior PCI 16.8% 262/1561 Prior CABG 2.0% 31/1561 Diabetes 24.2% 378/1561 -IRDM 13.2% 50/378 Hypertension 62.3% 973/1561 Hyperlipidemia 30.4% 474/1561 Positive Family History 6.9% 108/1561 Current Smoker 37.6% 587/1561 Unstable Angina 70.0% 1092/1561
Target Lesion Distribution (FIC) 50 40 30 20 10 0 46.4 Target Vessel 29.8 22.4 1.1 0.3 LM LAD LCx RCA Graft
ACC/AHA Lesion Classification (FIC) 44.8% n=1045 n=164 n=423 7.0% 18.2% A B1 B2 C 30.0% n=698
Lesion Characteristics (FIC) Target Lesion (n=2330) Target lesions per patient, n 1.49 De Novo, n (%) 2240 (96.1) In-stent restenotic lesion, n (%) 69 (3.0) Total occlusion, n (%) 281 (12.1) Ostial lesion, n (%) 385 (16.5) Bifurcation, n (%) 316 (13.6) Moderate to severe angle, n (%) 160 (6.9) Reference Vessel Diameter by visual estimation, mm 2.97±0.43 Lesion length by visual estimation, mm 24.9±15.3 Diameter stenosis @baseline by visual estimation, % 86.3±10.5
Procedural Results (FIC) Target lesion, n=2330 Direct stenting, n (%) 701 (30.1) Length of stent, mm 29.2±15.4 Stents overlapping, n (%) 489 (21.0) Stents post-dilatation, n (%) 537 (23.1) Bifurcation treated by 2 stents, n (%) 58 (18.4) Residual stenosis by visual estimation, % 1.0±6.3 Dissection during procedure, n (%) 24 (1.0) Thrombosis during procedure, n (%) 14 (0.6) Procedural success per lesion, n (%) 2327 (99.9) Procedural success per patient, n (%) 1558 (99.8)
Cumulative 30-day Clinical Outcomes (FIC) 0.9 0.6 0.3 0 n=3 0.19 N=1553 (99.5%), 100% monitoring n=2 0.13 n=3 0.19 n=5 0.32 n=1 0.06 0 n=11 0.71 cardiac death Non- Cardiac Death Q AMI NQ AMI TLR PCI TLR CABG MACE
Cumulative 12-month Clinical Outcomes (FIC) 4.5 3.0 1.5 0.0 n=12 0.84 cardiac death N=1426 (91.4%), 100% monitoring n=12 0.84 Non- Cardiac Death n=8 0.56 n=8 0.56 n=26 1.82 n=2 0.14 Q AMI NQ AMI TLR PCI TLR CABG n=51 3.58 MACE
MACE-free Survival at 12-month (FIC)
Stent Thrombosis (FIC) 0.56%, n=8, SIRIUS definition 1 0.98%, n=14, ARC definition 0.8 0.8 0.6 0.6 0.4 0.4 0.2 0.2 0 0 Thrombosis events Thrombosis events 1 Acute Sub-acute Late Definite/Confirmed Probable Possible
QCA at Baseline, n=585 (FIC) Mean±SD Median [Q1, Q3] Pre-procedure Reference vessel diameter, mm 2.68±0.40 2.66 [2.40, 2.99] Lesion length, mm 23.5±15.6 19.0 [12.7, 28.3] Diameter stenosis, % 72.1±14.8 69.0 [61.0, 79.0] Minimal lumen diameter, mm 0.75±0.43 0.80 [0.55, 1.04] Post-procedure Diameter stenosis, % In-stent 17.2±5.1 17.0 [14.0, 20.0] In-segment 21.8±7.3 21.0 [16.0, 26.0] Minimal lumen diameter, mm In-stent 2.51±0.37 2.47 [2.22, 2.75] In-segment 2.30±0.43 2.27 [1.99, 2.58] Acute gain, mm In-stent 1.76±0.45 1.69 [1.42, 2.02] In-segment 1.44±0.52 1.41 [1.11, 1.75] Stent/lesion length ratio 1.40±0.34 1.30 [1.19, 1.49]
QCA at 9-month Angiographic Follow-up, n=585 (FIC) Diameter stenosis, % Mean±SD Median [Q1, Q3] In-stent 20.9±10.1 19.0 [15.0, 23.0] In-segment 25.2±11.1 23.0 [18.0, 29.0] Minimal lumen diameter, mm In-stent 2.38±0.46 2.38 [2.09, 2.65] In-segment 2.19±0.48 2.17 [1.89, 2.51] Late lumen loss, mm In-stent 0.14±0.24 0.08 [0.02, 0.16] In-segment 0.11±0.26 0.05 [-0.01, 0.14] Follow-up duration: 252±89 days
Binary Restenosis, n=585 (FIC) 8 6 4 2 3.6 5.3 0 In-stent In-segment Binary Restenosis Rate, %
FIC Compared with China CYPHER Select Registry FIC, n=1561 CCSR, n=893* Reference vessel diameter, mm 2.68±0.40 2.80±0.42 Lesion length, mm 23.5±15.6 19.9±11.3 Diabetes mellitus, % 24.2 20.8 Cumulative MACE at 1-year, % 3.6 4.9 Cumulative cardiac death at 1-year, % 0.8 1.1 Cumulative AMI at 1-year, % 1.1 0.9 Cumulative TLR at 1-year, % 1.8 3.5 In-stent late lumen loss,mm 0.14±0.24 0.14±0.39 In-segment binary restenosis rate, % 5.3 9.6 * In CCSR (n=1189) study, 893 patients (75%) were treated by CYPHER Select stent exclusively
Baseline Firebird 2.5/23mm+3.0/23mm Case 3 Firebird 3.0/33mm 2
Angiographic follow-up Case 3
Conclusions (FIC) The registry enrolled patients with more complex lesions and multiple vessel disease which reflected daily clinical practice The procedural success rate is high (99.8%) At 12-month, cumulative cardiac death (0.84%), MI (1.12%), TLR (1.82%), MACE (3.58%), and thrombosis rate (0.56% with SIRIUS definition and 0.98% with ARC definition) are acceptable QCA revealed in-stent late loss 0.14±0.24mm, binary restenosis rates: in-stent 3.6%, in-segment 5.3% The safety and efficacy profiles of FIREBIRD SES are very similar to the results from China CYPHER Select Registry
EVENT Registry: DES increase Adverse Event Rates in off-label indications? Win HK et al. JAMA 2007;297:2001-9
A View from Emerging Markets: DES Penetration, Local Products, Operator Techniques and Tendencies in China
Off-label use by FDA of U.S. Definition of Complex Coronary Lesions by Protocol More complex and unapproved indications Very small vessels Very long lesions Chronic total occlusions Bifurcations Left main disease In-stent restenosis Multivessel disease Does Domestic DES increase adverse events in a more complex settings? Ostial Saphenous lesions vein grafts Severe Acute myocardial calcification infarction or angulation lesions
Study Algorithm(FIREMAN) Clinical follow-up Patient enrollment (2006.09-2007.07) n = 1078 1029 pts Enrolled 30 days 99.7% (1026/1029 pts) 6 months 98.7% (1016/1029 pts) 12months 97.2% (1000/1029 pts) Excluded pts due to hybrid stenting, n=49 (4.5%) Angiographic follow-up 8 months 51% (517/1013pts) Primary End Point : MACE at 12 months Secondary End Point:Binary Restenosis, Late loss at 8months, TVR, Stent thrombosis, Stroke at 12 months
Enrollment Information (FIREMAN) 1200 1075 1000 800 600 400 200 0 Sep- 06 52 12 94 Oct- 06 Nov- 06 167 Dec- 06 468 306 940 725 Jan- 07 Feb- 07 Mar- 07 Apr- 07 1039 May- 07 Jun- 07 1078 Jul- 07
Baseline Demographics (FIREMAN) Parameters n=1029 Age (years) 64.2±10.2 Male, n (%) 757 (73.57) Risk Factors CAD Family history, n (%) 107 (10.40) Pre-MI, n (%) 245 (26.20) Pre-PTCA, n (%) 166 (17.75) Hypercholesterimia, n (%) 192 (20.60) Hypertension, n (%) 669 (71.55) Smoking, n (%) 301 (32.26) Diabetes Mellitus, n (%) 235 (25.16) Insulin requiring, n (%) 171 (81.82) Non-insulin requiring, n (%) 38 (18.18) PCI Indications Silent ischemia, n (%) 10 (1.00) stable angina, n (%) 191 (19.00) unstable angina, n (%) 716 (71.24)
% 100 80 60 40 20 0 Frequency of Complex Coronary Lesions Criteria* (FIREMAN) 83.8 50.3 5.8 7.4 30.7 Mul t i - vessel CTO Smal l vessel Unprotected left mai n di sease Rest enosi s Total Target Lesions n=1678 14.9 1.4 7.39 Long l esi on Os t i al Bi f ur cat i on Sever e angul at i on 2.74 * Criteria are not mutually exclusive.
Percentage of Patients Implanted With Different Number of Stents Percentage of Patients Implanted With Different Number of Stents % 45 40 35 30 25 20 15 10 5 0 41.6 27.1 19.7 88.4% 6.6 Numbers of stents per patient Total stents implanted n=2261 Mean stents implanted n=2.23 3.7 0.9 0.3 0.1 0.1 1 2 3 4 5 6 7 8 9
Baseline QCA Results (FIREMAN) 1678 lesions in 1013 pts analyzed Pre-procedure In-stent In-segment Lesion length, mm 23.7±14.4 - Reference vessel diameter, mm 2.63±0.45 - Diameter stenosis, % 76.2±13.9 - Minimal lumen diameter, mm 0.64±0.41 - Post-procedure Reference vessel diameter, mm 3.04±0.43 - Diameter stenosis, % 17.5±6.4 15.0±4.7 Minimal lumen diameter, mm 2.33±0.47 2.58±0.39 Acute gain, mm 1.69±0.48 1.95±0.45
8-month QCA Results (FIREMAN) 874 Lesions in 517 pts(51%) analyzed In-stent In-segment Reference vessel diameter, mm 2.97±0.43 - Diameter stenosis, % 23.3±17.3 21.5±13.1 Minimal lumen diameter, mm 2.11±0.54 2.34±0.54 Late lumen loss, mm 0.21±0.40 0.23±0.36 Binary restenosis rate, % (n) 4.3 (38) 5.7 (50)
Angiographic Binary Restenosis (FIREMAN) 874 Lesions in 517 pts(51%) analyzed 10 8 6 4 2 % 4.3 Binary Restenosis Rate 0.8 1.5 5.7 0 In-Stent Proximal Edge Distal Edge In-Segment N=38 N=7 N=13 N=50
Clinical Events Up to 1-Year* (FIREMAN) 30 days 6 months 12 months MACE (%) 11 (1.1) 16 (1.6) 52 (5.1) Cardiac death (%) 2 (0.2) 5 (0.5) 6 (0.6) Non-fatal MI (%) 9 (0.9) 10 (1.0) 11 (1.1) TLR (%) 1 (0.1) 3 (0.3) 35 (3.4) TVR (%) 2 (0.2) 5 (0.5) 42 (4.1) Stent Thrombosis (%) 6 (0.6) 9 (0.9) 13 (1.3) Non-cardiac death (%) 1 (0.1) 3 (0.3) 9 (0.9) * unadjusted data
Clinical Events Up to 1-Year* (FIREMAN) % 5.5 5 4.5 4 3.5 3 2.5 2 1.5 1 0.5 0 0.2 0.5 30d 6months 12months 0.6 0.9 1.0 1.1 Cardiac Death Nonfatal MI TLR MACE 0.1 0.3 3.4 1.1 1.6 5.1 * unadjusted data
MACE/TLR-free Survival at 12 months (FIREMAN) 100 98 96 94 92 MACE-free Survival Rate 94.2% 100 98 96 94 92 TLR-free Survival Rate 97.9% 90 0 100 200 300 400 90 0 100 200 300 400 DAY DAY
Cardiac death/non-fatal MI-free Survival at 12 months (FIREMAN) 100 98 96 94 92 90 0 Cardiac Death-free Survival 99.4% Non-fatal MI-free Survival 96 94.92 90 100 200 300 400 0 100 200 300 100 98 99.2% 400 DAY DAY
1-Year Safety of Off-label Indications Stent Thrombosis Stent Thrombosis ARC Definite Stent thrombosis-free Rate(%) ARC ARC Total Probable Possible Acute( 24h) 1 1 0 2 (0.19%) Subacute(24h-30d) 2 2 0 4 (0.39%) Late (30d-1y) 2 3 2 7 (0.68%) Total 5(0.48%) 6(0.58%) 2(0.19%) 13 (1.26%) 100 98 96 94 92 90 0 DAY 98.7% 100 200 300 400
Dual Antiplatelet Treatment medication with Clopidogrel and ASA (%) 1.2 1 0.8 0.6 0.4 0.2 0 97.7 98.8 96.8 98.3 72.3 Clopidogrel Asprin 98.1 30ds 6months 12months follow-up times
Predictors of Cumulative Stent Thrombosis By Cox Regression Analysis Parameters HR(95%CI) P value Male 0.187(0.021~1.658) 0.132 Age 1.028(0.826~1.281) 0.802 Pre-MI 2.659(0.698~10.130) 0.152 Pre-PCI 1.114(0.193~6.434) 0.904 Hypercholesterima 0.572(0.110~2.980) 0.507 hypertension 1.026(0.302~3.490) 0.967 Diabetes 6.852(2.091~22.453) 0.001 Multi-vessel 0.532 (0.127~2.226) 0.388 Diffuse long 1.826(0.453~7.360) 0.397 Small vessel 4.844(1.198~19.594) 0.027 CTO 4.154(1.138~15.166) 0.031 Bifurcation 0.800(0.053~12.025) 0.872 Ostial 0.893(0.058~13.665) 0.935 Severe angulation 0.001(0.000~ ) 0.988 LM 0.001(0.000~ ) 0.992 Restenosis 1.719(0.139~21.278) 0.673
Conclusions (FIREMAN) One-year outcomes showed that FIREBIRD SES was effective and safe even in a selectively complex lesion settings. FIREBIRD SES was effective in reducing restenosis, similar to the results from pivotal DES trials. Off label FIREBIRD SES use was not associated with increased rates of stent thrombosis, similar to other global studies on stent safety. Diabetes, small vessel and CTO were the predictors of stent thrombosis at one year.
Summary The two registries of Microport Firbird stent showed FIREBIRD SES was effective and safe in real world PCI even in a selectively complex lesion settings. FIREBIRD SES was effective in reducing restenosis, similar to the results from pivotal DES trials. Off label FIREBIRD SES use was not associated with increased rates of stent thrombosis, similar to other global studies on stent safety. Diabetes, small vessel and CTO were the predictors of stent thrombosis at one year. Long-term (>1 yr) safety were expected for further investigations.