ROTAXUS A Prospective, Randomized Trial of High-Speed Rotational Atherectomy Prior to Paclitaxel-Eluting Stent Implantation in Complex Calcified Coronary Lesions Gert Richardt, MD, PhD Herzzentrum Segeberger Kliniken Bad Segeberg, Germany

Disclosure Statement of Financial Interest Grant/Research Support Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit Boston Scientific Boston Scientific, Cordis J&J, Abbott Vascular, Medtronic None Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany

Background (I) DES have shown favourable results when implanted in complex lesions and patients. Calcified coronary lesions can pose special problems, and may prevent stent delivery or expansion and increase the likelihood of stent thrombosis and/or restenosis. Calcified lesions may form a particular threat to DES, as damage to the polymer/drug coating and inadequate diffusion of the drug may decrease DES effectiveness.

Background (II) Rotational atherectomy can effectively modify calcified plaques and facilitate stent delivery and expansion. However, rotablation causes additional vessel injury with increased neointimal formation when used as a stand- alone therapy or combined with bare-metal stents. Elective rotablation followed by DES implantation can be a rational complementary concept in complex calcified lesions, but this is not supported by randomized controlled studies.

Objective of the ROTAXUS trial.. to evaluate whether routine rotablation prior to PES implantation is more effective than the standard of care (stenting without rotablation) in the setting of complex calcified coronary artery disease.

ROTAXUS: Study Details Design -Prospective, randomized, active-controlled clinical trial Participating Centers -Heart Center, Segeberger Kliniken, Bad Segeberg, Germany -Heart Center Bad Krozingen, Bad Krozingen, Germany -University Hospital Hamburg-Eppendorf, Hamburg, Germany Study Chair Gert Richardt Heart Center Bad Segeberg, Germany Principal Investigators Mohamed Abdel-Wahab Ahmed A. Khattab Independent Data Safety and Monitoring Board Independent QCA Core Lab (ISAR Research Center, Munich, Germany) Independent Statistical Core Lab (Derek Robinson, Sussex, UK)

Inclusion Criteria Clinical inclusion criteria 1.Age above 18 years 2.Angina and/or reproducible ischemia 3.Informed written consent Angiographic inclusion criteria First degree criteria (all) 1.De-novo lesion in a native coronary artery 2.Moderate to severe calcification Second degree criteria (at least one) 1.Ostial location 2.Bifurcational lesion 3.Long lesion (≥ 15mm)

Exclusion Criteria Clinical exclusion criteria 1.Myocardial infarction within 4 weeks 2.Left ventricular ejection fraction < 30% 3.Limited long term prognosis Angiographic exclusion criteria 1.Unprotected left main lesions 2.Coronary artery bypass graft stenoses 3.In-stent restenoses 4.Chronic total occlusions 5.Target vessel thrombus 6.Target vessel dissection

Endpoints Primary endpoint In-stent late lumen loss at 9 months Secondary endpoints 1.Major adverse cardiac events (MACE) 2.Definite stent thrombosis 3.In-segment late lumen loss 4.In-segment binary restenosis 5.Angiographic success 6.Strategy success (angiogr. success without crossover or stent loss) 7.Procedural duration 8.Contrast amount

Sample Size Calculation Hypothesis Rotablation prior to paclitaxel-eluting stent treatment will be superior to stenting without rotablation in reducing the late lumen loss at 9 months Assumption Late loss (primary endpoint) will be reduced from 0.5 ± 0.5 mm in the control group to 0.3 mm in the rotablation group Power of 80% One-sided alpha-level of 0.05 Random sequence 1:1 Needed total number of patients/lesions: 198 Analysis by intention-to-treat

ROTAXUS 240 patients enrolled between August 2006 and March 2010 at 3 clinical sites in Germany 240 patients analyzed with complete in-hospital follow-up Angiographic follow-up at 9 months in 80.5% (N=190) Clinical follow-up at 9 months in 96.2% (N=227) 1:1 randomization PTCA + PES (N=120) Rota + PES (N=120) - 2 patients died in-hospital - 6 patients withdrew consent - 5 patients lost at follow-up

Baseline Characteristics (I) Rota + PES n = 120 PTCA + PES n = 120 P Value Age (years)70.5± ± Males86 (72.3%)96 (81.7%)0.13 BMI (kg/m 2 )27.9± ± Diabetes mellitus33 (27.7%)32 (26.8%)0.88 Hypertension106 (89.1%)95 (79.8%)0.05 Dyslipidemia91 (76.5%)87 (73.1%)0.55 Current smokers24 (20.2%)16 (13.5%)0.17 Family history of CAD39 (32.8%)44 (37.0%)0.50 Chronic renal failure5 (4.2%)8 (6.7%)0.40 Previous MI38 (31.9%)29 (24.4%)0.20 Previous PCI44 (37.0%)39 (32.8%)0.50 Previous CABG9 (7.6%)15 (12.6%)0.20

Baseline Characteristics (II) Rota + PES n = 120 PTCA + PES n = 120 P Value Unstable angina17 (14.3%)16 (13.4%)0.85 Left main disease11 (9.2%)8 (6.7%)0.47 Multivessel disease88 (74.0%) 1.0 LV ejection fraction (%)55.5± ± Ad-hoc PCI11 (9.3%)9 (7.6%)0.64 Multilesion PCI23 (19.3%)32 (27.1%)0.16 Unfractionated heparin49 (41.2%)70 (50.4%)0.15 Bivalirudin70 (58.8%)59 (49.6%)0.15 GP IIb/IIIa antagonists4 (3.4%)00.12

Angiographic Characteristics Rota + PES n = 146 PTCA + PES n = 176 P Value Location0.06 Left main (protected)3 (2.1%)2 (1.1%) Left anterior descending101 (69.2%)111 (63.1%) Left circumflex7 (4.8%)22 (12.5%) Right coronary artery35 (24.0%)41 (23.3%) Reference vessel diameter (mm)3.1±0.43.1± Lesion length (mm)20.6± ± Diameter stenosis %)81.5± ± Ostial location27 (18.5%)31 (17.6%)0.84 Bifurcation72 (49.3%)82 (46.6%)0.63 Moderate/severe tortuosity67 (46.2%)83 (47.2%)0.82 Severe calcification65 (44.5%)86 (49.1%)0.38 B2/C lesion137 (93.8%)152 (86.3%)0.03

Procedural Characteristics Rota + PES n = 146 PTCA + PES n = 176 P Value 7 Fr guiding catheter122 (83.6%)50 (28.4%)<0.001 Balloon predilatation130 (89.0%)160 (90.9%)0.58 Max. predil. balloon size (mm)2.5±0.32.6± Max. predil. balloon pressure (atm)13.6± ± Starting burr size (mm)1.5±0.2-- Max. burr size (mm)1.5±0.2-- Use of > 1 burr8 (5.5%)-- Rotational speed (RPM)165,947±8,919-- No. of stents / lesion1.3± Total stent length / lesion (mm)27.7± ± Balloon postdilatation92 (63.0%)116 (65.9%)0.86 Max. postdil. balloon size (mm)3.3±0.53.3± Max. postdil. balloon pressure (atm)21.7± ±

Procedural Outcome (I) Rota + PES n = 120 PTCA + PES n = 120 P Value Procedural duration (min)66.4± ± Fluoroscorpy time (min)22.8± ± Contrast amount (ml)201.0± ± Dissections4 (3.3%) 1.0 Perforations2 (1.7%)1 (0.8%)0.56 No/slow flow01 (0.8%)0.32

Procedural Outcome (II) p = 0.03 p = 0.08 p = 1.0 * Defined as <20% residual stenosis + TIMI 3 flow ** Defined as angiographic success with no crossover or stent loss p = 0.02

In-Hospital Outcome p = 0.17 * Defined as death, MI and TVR

QCA data: Index procedure Rota + PES n = 123 PTCA + PES n = 132 P Value Before procedure Lesion length (mm)19.56± ± Refernce vessel diameter (mm)2.67± ± Minimal lumen diameter (mm)1.01± ± Diameter stenosis (%)62.05± ± Immediately after procedure Minimal lumen diameter (mm) In-stent2.58± ± In-segment2.27± ± Diameter stenosis (%) In-stent10.43± ± In-segment17.68± ± Acute gain (mm) In-stent1.57± ± In-segment1.26± ±

Primary Endpoint In-Stent Late Lumen Loss at 9 Months

Primary Endpoint p = 0.01 In-Stent Late Lumen Loss at 9 Months

QCA data: 9-month reangiography Rota + PES n = 123 PTCA + PES n = 132 P Value Minimal lumen diameter (mm) In-stent 2.14± ± In-segment 1.91± ± Diameter stenosis (%) In-stent 22.01± ± In-segment 27.92± ± Late lumen loss (mm) In-stent 0.44± ± In-segment 0.36± ± Binary restenosis (%) In-stent 14 (11.4%)14 (10.6%)0.84 In-segment 15 (12.2%)17 (12.9%)0.87

Events at Follow-Up p = 1.0 * Defined as death, MI and TVR p = 0.78 p = 0.79 p = 0.73 p = 0.84 p = 0.46

Summary (I) Rotablation + PES implantation was not superior to balloon dilatation + PES implantation in reducing the primary endpoint of late lumen loss at 9 months in patients with complex calcified coronary artery disease. Rotablation (probably due to additional vessel trauma) rather decreased the efficacy of PES in reducing neointimal growth.

Summary (II) The superior acute gain obtained by rotablation was counterbalanced by an increased late loss resulting in a neutral effect on restenosis. Rotablation remains an important bail-out device for uncrossable or undilatable coronary lesions and can improve overall success of DES implantation.

Thank You ROTAXUS Heart Center, Bad Segeberg, Germany