Presentation on theme: "One-Year Outcome of a Trial Comparing"— Presentation transcript:
1 One-Year Outcome of a Trial Comparing Second Generation Drug-eluting Stents UsingEither Biodegradable Polymer or Durable PolymerThe NOBORI Biolimus-Eluting versusXIENCE/PROMUS Everolimus-eluting Stent Trial (NEXT)Masahiro Natsuaki, MDKyoto University Graduate School of MedicineKen Kozuma, MD; Takeshi Morimoto, MD, MPH; Kazushige Kadota, MD;Toshiya Muramatsu, MD, Yoshihisa Nakagawa, MD, Takashi Akasaka, MD;Keiichi Igarashi, MD; Kengo Tanabe, MD; Yoshihiro Morino, MD; Tetsuya Ishikawa, MD;Hideo Nishikawa, MD; Masaki Awata, MD; Masaharu Akao, MD; Hisayuki Okada, MD;Yoshiki Takatsu, MD; Nobuhiko Ogata, MD; Kazuo Kimura, MD; Kazushi Urasawa, MD;Yasuhiro Tarutani, MD; Nobuo Shiode, MD; and Takeshi KImura, MDOn behalf of the NEXT InvestigatorsThank you chairman. Ladies and gentlemen.On behalf of the NEXT trial investigators, it is my great pleasure and honor to present the result of NEXT trial at ACC late-breaking clinical trials session.
2 Disclosures Masahiro Natsuaki, MD Study Sponsor of the NEXT Trial None.Study Sponsor of the NEXT TrialTerumo JapanTerumo Japan is a study sponsor of the NEXT trial.
3 BackgroundThe COMPARE II trial demonstrated non-inferiority of biolimus-eluting stent (BES) relative to everolimus-eluting stent (EES) in terms of a composite of cardiac death, non-fatal myocardial infarction (MI) and clinically-driven target-vessel revascularization (TVR) at 1 year.Kaplan-Meier Cumulative Event Curves for the Primary Endpoint at 1 yearP non-inferiority<0.0001The COMPARE II trial demonstrated non-inferiority of biolimus-eluting stent, BES, relative to everolimus-eluting stent, EES, in terms of a composite of cardiac death, non-fatal MI and clinically-driven TVR at 1 year.Smits PC, et al. Lancet Jan 29. Epub ahead of print.
4 BackgroundOn the other hand, non-inferiority of BES relative to sirolimus-eluting stent was not demonstrated in the SORT-OUT V trial in terms of a composite of cardiac death, MI, definite stent thrombosis and TVR at 9 months.The results of these trials were inconsistent and it is still unknown whether the biodegradable polymer BES has the efficacy- and safety-profile equivalent to or even better than the durable polymer EES.On the other hand, non-inferiority of BES relative to sirolimus-eluting stent was not demonstrated in the SORT-OUT V trial.The results of these trials were inconsistent and it is still unknown whether the biodegradable polymer BES has the efficacy- and safety-profile equivalent to or even better than the durable polymer EES.P non-inferiority=0.06Christiansen EH, et al. Lancet Jan 29. Epub ahead of print.
5 Nobori® Biolimus-eluting Stent Nobori® biolimus-eluting stent is a stainless steel alloy stent with relatively thick strut (120μm).Drug and polymerBiolimus A9, a highly lipophilic analogue of sirolimus,and biodegradable polymer (poly-lactic acid)are coated only on the abluminal side.Nobori biolimus-eluting stent is a stainless steel alloy stent with relatively thick strut.Regarding the drug and polymer, biolimus A9, a highly lipophilic analogue of sirolimus, and biodegradable polymer, poly-lactic acid, are coated only on the abluminal side.BiolimusPoly-lactic acid
6 NEXT Trial(NOBORI Biolimus-Eluting versus XIENCE/PROMUS Everolimus-eluting stent Trial)Multicenter, randomized, non-inferiority trial comparing BES with EES3200 patients scheduled for PCI using drug-eluting stentNo Exclusion Criteria (All-comer Design)Randomization 1:1Stratified by:CenterDiabetesParticipation in the imaging sub-studiesNobori(Biolimus-eluting stent)(1600 patients)XIENCE V/ PROMUS(Everolimus-eluting stent)(1600 patients)NEXT trial is a muticenter, randomized, non-inferiority trial comparing BES with EES.3200 patients scheduled for PCI using drug-eluting stents were randomly assigned to either Nobori biolimus-eluting stent or XIENCE/PROMUS everolimus-eluting stent without any exclusion criteria.Follow-up at 1, 2, and 3 yearsImaging Sub-studies at 8-12 months:Angiography (500 patients), IVUS/OCT (120 patients), Endothelial function (100 patients)(Scheduled follow-up angiography by local site protocol was allowed beyond 240 days. )
7 Primary Endpoints and Sample Size Calculation Primary Efficacy Endpoint: Any Target-lesion Revascularization (TLR) at 1 yearPrimary Safety Endpoint:Death or Myocardial Infarction at 3 yearsSample size calculation: Estimated TLR rate at 1 year in the EES group: 6.9% Non-inferiority margin of 3.4% and one-sided type I error of patients would yield > 95% power to detect non-inferiority.A total of 3200 patients were to be enrolled considering possible drop-out during follow-up.Primary efficacy endpoint was any target lesion revascularization at 1 year.Primary safety endpoint was death or MI at 3 years.Assuming a 6.9% of TLR rate in the EES group, 3000 patients would yield more than 95% power to detect non-inferiority with a non-inferiority margin of 3.4%.A total of 3200 patients were to be enrolled considering possible drop-out.
8 Angiographic Primary Endpoint and Sample Size Calculation Primary Angiographic Endpoint:In-segment Late Loss at 8-12 MonthsSample size calculation:Estimated in-segment late loss in the EES group: 0.04 ± 0.49 mm (Cypher PMS Japan) Non-inferiority margin of mm (SPIRIT III trial) and one-sided type I error of patients would yield 97% power to detect non-inferiority.A total of 500 patients were to be enrolled considering possible drop- out from the follow-up angiography.We also conducted angiographic substudy.Primary angiographic endpoint is in-segment late loss at 8-12 months.Assuming a 0.04mm of late loss in the EES group, 400 patients would yield 97% power to detect non-inferiority with a non-inferiority margin of 0.195mm.A total of 500 patients were to be enrolled considering possible drop-out.
9 Between May and October 2011, 3241 patients were enrolled and randomized from 98 Japanese centers. After excluding 6 patients who withdrew consent, ITT population consisted of 3235 patients, 1617 patients in BES group and 1618 patients in EES group.1-year clinical follow-up was achieved in 99.2% of patients.Angiographic substudy included 528 patients.
10 Baseline Patient Characteristics Biolimus-eluting stentEverolimus-PNo. of patients16171618Age (years)69.1 ± 9.869.3 ± 9.80.49Age>= 75 years31 %34 %0.052Male gender77 %0.76Body mass Index (kg/m2)24.1 ± 3.724.2 ± 3.50.55Diabetes46 %0.85Insulin-treated10 %11 %0.73Hypertension81 %82 %0.81Current smoker19 %18 %0.71Statin use75 %0.47Prior PCI50 %51 %0.9Prior CABG5.3 %4.8 %0.52Baseline patient characteristics were well balanced between the 2 groups.The Mean age of patients was 69 years and diabetes was highly prevalent, 46% in each group.
11 Everolimus-eluting stent Baseline Patient CharacteristicsBiolimus-eluting stentEverolimus-eluting stentPNo. of patients16171618Clinical diagnosis0.62Acute myocardial infarction5.1 %4.5 %Unstable angina12 %11 %Stable coronary artery disease83 %84 %Prior myocardial infarction28 %0.81Prior stroke10 %0.43Heart failure13 %0.13Hemodialysis6.5 %5.2 %0.11Peripheral vascular disease9.7 %0.1Multivessel disease51 %0.9SYNTAX score10 (6-17)(N=1494)10 (6-16)(N=1506)0.17Despite the all-comer trial design, patients with AMI were included only 5.1% of patients in the BES group and 4.5% in the EES group.The SYNTAX score was relatively low in both groups.
12 Everolimus-eluting stent Baseline Lesion CharacteristicsBiolimus-eluting stentEverolimus-eluting stentPNo. of lesions20592010Target vessel location0.42LMCA2.4 %2.3 %LAD42 %LCx22 %24 %RCA33 %31 %Graft0.7 %0.9 %STEMI culprit lesions3.0 %2.9 %0.88Chronic total occlusion8.6 %7.9 %0.39In-stent restenosis11 %0.94Bifurcation lesions43 %45 %0.36Reference vessel size <= 2.75 mm60%62%0.25Lesion length > 18 mm43%42%0.51Baseline lesion characteristics were also well balanced between the 2 groups.Bifurcation lesions were found in 43% of patients in the BES group and 45% in the EES group.
13 Everolimus-eluting stent Procedural CharacteristicsBiolimus-eluting stentEverolimus-eluting stentPNo. of lesions treated per patient1.27 ± 0.561.24 ± 0.510.1No. of stentsPer patient1.59 ± 0.841.6 ± 0.830.74Per lesion1.29 ± 0.561.32 ± 0.60.13Total stent length (mm)33.0± 20.332.9 ± 20.70.8726.9 ± 15.127.2 ± 16.50.52Stent diameter (mm)2.88 ± 0.672.87 ± 0.640.7Direct stenting23 %0.93Maximum inflation pressure (atm)17.2 ± 4.516.9 ± 4.40.03Bifurcation 2-stent1.2 %1.0 %0.41IVUS use88%87%0.21Multivessel treatment13%11%Staged procedures27%0.77When we look at the procedural characteristics, the number of lesions treated per patient was 1.2 on average and total stent length per patient was approximately 33mm.Maximum inflation pressure was slight but significantly higher in the BES group..
14 Baseline QCA Data Variables ― no. (%) BES EES p-value Before procedure ( 1960 lesions)EES( 1930 lesions)p-valueBefore procedureLesion length ― mm19.5±12.819.3±13.10.7Reference vessel diameter ― mm2.62±0.62.61±0.570.49Minimal luminal diameter (MLD)― mm0.77±0.440.75±0.420.11Diameter stenosis (DS)― %71.0±14.671.4±14.60.4After procedureMinimal luminal diameter (MLD) ― mmIn stent2.51±0.482.47±0.460.006In segment2.08±0.562.07±0.53Diameter stenosis (DS) ― %9.7±7.910.0±7.90.2622.2±12.321.1±11.20.005Acute gain ― mm1.73±0.51.71±0.510.211.3±0.531.32±0.540.41Baseline QCA data were generally similar between the 2 groups.Lesion length was 19mm and reference vessel diameter was 2.6mm.
15 Procedural Results Acute Device Success Patient Success BES N=1970 EES 1962(99.6%)1928(99.6%)1565(96.8%)1565(96.7%)This slide shows the procedural results.Acute device success was defined as successful implantation of all the study stents attempted.Patients success was defined as successful procedure without any major in-hospital complications.Acute device success was achieved in 99.6% of patients in both groups.Patients success rate was also high and comparable between the 2 groups.BESN=1970EESN=1936BESN=1617EESN=1618Acute device success: Successful implantation of all the study stents attemptedPatient success: Successful procedure without any major in-hospital complicationsProcedural duration (min) : 72.6 ± 43.5 vs ± 43.4 (BES vs. EES, P=0.38)
16 Clinical Outcomes at 1-year Next, I would like to show you the results of clinical outcomes at 1-year.
17 Target-Lesion Revascularization Regarding the primary efficacy endpoint, the cumulative incidence of TLR was 4.2% in both groups.
18 Target-Lesion Revascularization (TLR) Non-inferiority Assessment for the Primary Efficacy EndpointTarget-Lesion Revascularization (TLR)BES 4.2% vs. EES 4.2%Pnon-inferiority <Difference: %Upper one-sided 95% CI: %In non-inferiority assessment for the primary efficacy endpoint, upper 95% confidence interval of the difference was 1.5%, which was clearly lower than pre-defined non-inferiority margin.Therefore, non-inferiority of BES relative to EES was demonstrated in terms of TLR.-1.0%0%1.0%2.0%3.0%3.4%Non-inferiority margin18
19 Adjudicated by the Angiographic Core Laboratory Proportion of EventsAdjudicated by the Angiographic Core Laboratory170(83%)121(91%)In this trial, all the angiograms of patients with TVR were to be analyzed by the angiographic core laboratory.Proportions of events adjudicated by the angiographic core laboratory were 83% of TVR events and 91% of TLR events.TVRN=204TLRN=133All the angiograms of patients with TVR were to be analyzed by the angiographic core laboratoryin an attempt to discriminate TLR from non-TLR TVR and to identify clinically-driven TLR.
20 Clinically-driven TLR Cumulative incidence of clinically-driven TLR was also similar, 3.0% in each groupFollow-up angiography was performed in 65% of patients within 1-year.Follow-up angiography was performed in 2103 patients (65%) within 1-year.
21 Target-Vessel Revascularization Cumulative incidence of target lesion revascularization was not significantly different between the 2 groups.
22 All-cause DeathCumulative incidence of all-cause death was low and similar, 2.6% in the BES group and 2.5% in the EES group.
23 Myocardial Infarction Cumulative incidence of myocardial infarction was also not significantly different.
24 Definite Stent Thrombosis Cumulative incidence of definite stent thrombosis was very low and not significantly different, 0.25% in the BES group and 0.06% in the EES group.
25 We conducted the pre-specified subgroup analysis for TLR comparing BES with EES. The treatment effect of BES compared with EES was not significant in any subgroups.
26 Angiographic Outcomes at 8-12 monthsNext, I would like to show you the results angiographic outcomes at 8-12months.
27 Cumulative Distribution Function Curves of Late Loss In-segment Late LossRegarding primary angiographic endpoint, in-segment late loss was 0.03mm in the BES group and 0.06mm in the EES group.
28 Non-inferiority Assessment for the Primary Angiographic Endpoint In-segment Late LossBES 0.03 mm vs. EES 0.06 mmPnon-inferiority <Difference: mmUpper one-sided 95% CI: mmIn non-inferiority assessment for the primary angiographic endpoint, upper 95% confidence interval of the difference was 0.05mm, which was clearly lower than the pre-defined non-inferiority margin..Therefore, non-inferiority of BES relative to EES was demonstrated in terms of in-segment late loss.-0.2 mm-0.1 mm0 mm0.1 mm0.195 mmNon-inferiority margin28
29 Cumulative Distribution Function Curves of Late Loss In-stent Late LossIn-stent late loss was also not significantly different between the 2 groups.
30 Follow-up QCA Data in Angiographic Sub-study Variables ― no. (%)BES(295 lesions)EES(293 lesions)p-valueFollow-up at 8-12 monthsBinary restenosis ― n (%)In segment21 (7.1%)22 (7.5%)0.86Location of restenosis― n (%)0.17Stent body10 (48%)6 (27%)Both edges5 (24%)5 (23%)Proximal edge2 (9.5%)4 (18%)Distal edge4 (19%)7 (32%)Restenosis pattern ― n (%)0.23Focal12 (57%)17 (77%)Diffuse6 (29%)3 (14%)Total occlusion1 (4.6%)ProliferativeStent fracture ― n (%)9 (3.1%)0.004Peri-stent contrast staining ― n (%)8 (2.7%)4 (1.4%)0.24In the follow-up QCA data, stent fracture was more often found in the BES group than in the EES group.However, there were no significant difference in the binary restenosis between the 2 groups.
31 Limitations Despite the all-comers trial design, the actual study population mostlyincluded patients with stable coronary artery disease.Actual 1-year rate of TLR was lower than expected due to less complexcoronary anatomy, leading to a relatively large non-inferiority margin.High prevalence of follow-up angiography based either on the currentstudy protocol or on the local site-protocols certainly inflated the rateof TLR.There were several limitations in this study.Despite the all-comers trial design, the actual study population mostly included patients with stable coronary artery disease.Actual 1-year rate of TLR was lower than expected due to less complex coronary anatomy, leading to a relatively large non-inferiority margin.High prevalence of follow-up angiography certainly inflated the rate of TLR.
32 Conclusions In this large scale randomized controlled trial, BES was demonstratedto be non-inferior to EES with respect to 1 year TLR rate and 8-12months angiographic in-segment late loss.One-year clinical outcome after both BES- and EES-use was excellentwith low rate of TLR and very low rate of stent thrombosis.Long-term follow-up of the biodegradable polymer BES compared withthe durable polymer EES will provide crucial implications for the futuredevelopment of metallic drug-eluting stents. In conclusion ladies and gentlemen, in this large scale randomized controlled trial, BES was demonstrated to be non-inferior to EES with respect to1 year TLR rate and months angiographic in-segment late loss.One-year clinical outcome after both BES- and EES-use was excellent with low rate of TLR and very low rate of stent thrombosis.Long-term follow-up of the biodegradable polymer BES compared with the durable polymer EES will provide crucial implications for the future development of metallic drug-eluting stents.
33 Participating Centers Caress Sappro Tokeidai Memorial HospitalOji General HospitalCardio-vascular Center Hokkaido Ohno HospitalCaress Sappro Hokko Memorial HospitalHokkaido Social Insurance HospitalHokkaido Junkanki HospitalTeine Keijinkai HospitalAomori Prefectural Central HospitalIwate Prefectural Central HospitalIwate Medical University HospitalTohoku Kousei Nenkin HospitalSendai Open HospitalIwaki Kyoritsu General HospitalFukushima Medical University HospitalSaiseikai Kurihashi HospitalSaitama Cardiovascular and Respiratory CenterDokkyo Medical University Koshigaya HospitalNew Tokyo HospitalJuntendo University HospitalSakakibara Memorial HospitalNTT Medical Center TokyoThe Cardiovascular Institute HospitalMitsui Memorial HospitalTokyo Medical University HospitalTeikyo University HospitalTokyo Women's Medical University HospitalJuntendo University Nerima HospitalItabashi Chuo General HospitalSaiseikai Yokohama-city Eastern HospitalKanto Rosai HospitalYokohama Rosai HospitalTokai University HospitalYokohama City University Medical CenterKitasato University HospitalKanazawa Cardiovascular HospitalUniversity of Fukui HospitalFukui Cardiovascular CenterOgaki Municipal HospitalJuntendo University Shizuoka HospitalShizuoka General HospitalOkamura Memorial HospitalSeirei Hamamatsu General HospitalHamamatsu Medical CenterAichi Medical University HospitalTosei General HospitalToyota Memorial HospitalFujita Health University HospitalJapanese Red Cross Nagoya Daini HospitalChubu Rosai HospitalNagai HospitalMie University HospitalMie Heart CenterYokkaichi Social Insurance HospitalKoto Memorial HospitalShiga University of Medical Science HospitalKyoto University HospitalMitsubishi Kyoto HospitalNational Hospital Organization Kyoto Medical CenterKyoto Second Red Cross HospitalOsaka University HospitalSakurabashi Waranabe HospitalOsaka City General HospitalOsaka Saiseikai Noe HospitalOsaka City University HospitalOsaka Red Cross HospitalNational Cerebral and Cardiovascular CenterSumitomo HospitalHigashisumiyoshi Morimoto HospitalBell Land General HospitalKobe City Medical Center General HospitalKobe University HospitalKansai Rosai HospitalHyogo Prefectural Amagasaki HospitalHyogo College of Medicine HospitalTenri HospitalJapanese Red Cross Society Wakayama Medical CenterWakayama Medical University HospitalTottori University HospitalMatsue Red Cross HospitalThe Sakakibara Heart Institute of OkayamaKurashiki Central HospitalKawasaki Medical School HospitalHiroshima City HospitalFukuyama Cardiovascular HospitalTsuchiya General HospitalIwakuni Clinical CenterChikamori HospitalUnversity Of Occupational and Environmental Health JapanFukuoka Wajiro HospitalKurume University HospitalKokura Memorial HospitalKouseikai HospitalSaiseikai Kumamoto HospitalNational Hospital Organization Kumamoto Medical CenterKumamoto Rousai HospitalMiyazaki Medical Association HospitalTenyokai Central HospitalNational Hospital Organization Kagoshima Medical CenterFinally, we appreciate tremendous efforts of investigators in 98 participating centers.