Treatment of Calcified Coronary Lesions: Insights from Randomized Trials David J. Cohen, M.D., M.Sc. Director of Cardiovascular Research Saint Luke’s Mid America Heart Institute Professor of Medicine, University of Missouri-Kansas City CRT 2017- 8 mins

Disclosures Grant Support/Drugs Grant Support/Devices Daiichi-Sankyo - Merck Astra-Zeneca Grant Support/Devices Edwards Lifesciences - Abbott Vascular Medtronic - Boston Scientific Biomet - CSI Consulting/Advisory Boards Medtronic - Astra-Zeneca Edwards Lifesciences - Cardinal Health DJC: 2/17

Calcified Lesions Background Calcified lesions are common among patients undergoing PCI prevalence ranges from 10-30% depending on the definition and patient population (ACS vs. chronic CAD) PCI in pts with calcified lesions is associated with… Reduced rates of procedural success Worse long-term outcomes, mainly related to more frequent repeat revascularization (? ‘d mortality) PCI in pts with calcified lesions is also associated with higher short- and long-term costs

Medicare Calcified Lesion Study Patient population derived from Medicare data and includes all pts aged > 65 who underwent attempted PCI in 2011-12 Patients with “severely calcified” lesions identified by specific ICD-9 code (414.4) Propensity-matching (4:1) used to balance baseline characteristics Calcified: 2,276 Non-Calcified: 9,104 Clinical outcomes (death, MI, repeat revasc, hospitalization) and costs assessed through 1-year f/u Baron SJ, et al. CRT 2016

Clinical Outcomes at 1 year Count per 100 patients Calcified (n=2,276) Non-Calcified (n=9,104) P value Death 9.4 9.7 0.657 Myocardial Infarction 27.2 24.9 0.415 Repeat Revascularization PCI CABG 13.6 11.7 1.9 10.7 9.3 1.3 0.020 0.037 0.152 Repeat Hospitalization Cardiovascular Non-Cardiovascular 66.1 43.2 68.4 47.4 0.595 0.214 Outpatient Visit 827.9 829.4 0.939 Baron SJ, et al. CRT 2016

Medicare Costs Calcified Non-Calcified Difference (95% C.I.) P value Index Hosp. $25,236 $22,668 2568 (1881 to 3256) < 0.001 Repeat CV Hosp. With Revasc. Without Revasc. Total $3,551 $6,211 $9,763 $2,577 $7,226 $9,803 974 (175 to 1774) -1015 (-2520 to 490) -40 (-1810 to 1729) 0.016 0.186 0.964 Non-CV Hosp. $5,842 $5,291 893 (-1198 to 2301) 0.536 Outpatient Care $13,737 $12,071 1666 (-681 to 4014) 0.164 Total 1-year Cost $54,579 $49,833 4746 (790 to 8702) 0.018 * Propensity matched analysis Baron SJ, et al. CRT 2016

Unresolved Question Does plaque modification/lesion preparation in patients with calcified lesions lead to improved long-term outcomes?

ROTAXUS Trial 240 patients undergoing PCI for moderate or severely calcified lesion Moderate Ca++  radioopacity noted only during cardiac motion Severe CA++  radioopacity noted without motion and including both sides of vessel Randomized to rota/stenting vs. standard PTCA/stenting (TAXUS stent) Rotablator performed with burr:artery ratio 0.5-0.7 Primary endpoint = angiographic late loss

Baseline Characteristics ROTAXUS Baseline Characteristics RA + PES (n=120) Std. PES (n=120) Age 70.5 71.8 Male 72.3% 81.7% Diabetes 27.7% 26.8% Current smoker 20.2% 13.5% Renal Failure 4.2% 6.7% Prior CABG 7.6% 12.6% Multilesion PCI 19.3% 27.1% Presentation Stable CAD 85.7% 86.4% Unstable Angina 14.3% 13.6% P= NS for all comparisons Abdel-Wahab M, et al. JACC Intv 2013;6:10-19

Angiographic Characteristics ROTAXUS Angiographic Characteristics RA + PES (n=146) Std. PES (n=176) Vessel Treated LM 2.1 1.1 LAD 69.2 63.1 LCx 4.8 12.5 RCA 24.0 23.3 Severe Calcification 44.5% 49.1% Lesion Length 19.5 mm 18.0 mm Ref Vessel Diameter 2.7 mm 2.8 mm RA + PES (n=146) Std. PES (n=176) Vessel Treated LM 2.1 1.1 LAD 69.2 63.1 LCx 4.8 12.5 RCA 24.0 23.3 Severe Calcification 44.5% 49.1% Lesion Length 19.5 mm 18.0 mm Ref Vessel Diameter 2.7 mm 2.8 mm Lesion based analysis Abdel-Wahab M, et al. JACC Intv 2013;6:10-19

Procedural Outcomes ROTAXUS RA + PES Std. PES P-Value Procedure duration 66.4 mins 57.4 mins 0.05 Crossover to alt. strategy 4.2% 12.5% 0.02 Stents per lesion 1.3 NS Procedural Outcomes Perforation 1.7% 0.8% Stent Loss 0.0% 2.5% 0.08 Strategy Success 92.5% 83.3% 0.03 Angiographic Success 96.7% * Strategy success = angiographic success without crossover or stent loss Abdel-Wahab M, et al. JACC Intv 2013;6:10-19

Angiographic Outcomes ROTAXUS Angiographic Outcomes RA + PES Std. PES P-Value Post Procedure (in-stent) Acute gain, mm 1.56 ± 0.43 1.44 ± 0.49 0.01 MLD, mm 2.57 ± 0.38 2.55 ± 0.45 NS Diameter stenosis, % 10.8 ± 5.6 12.3 ± 7.9 0.04 9-Month Follow-up (in stent) Late Loss, mm* 0.44 ± 0.58 0.31 ± 0.52 2.14 ± 0.63 2.25 ± 0.62 22.0 ± 19.9 19.9 ± 19.6 Binary Restenosis 11.4% 10.6% RA + PES Std. PES P-Value Post Procedure (in-stent) Acute gain, mm 1.56 ± 0.43 1.44 ± 0.49 0.01 MLD, mm 2.57 ± 0.38 2.55 ± 0.45 NS Diameter stenosis, % 10.8 ± 5.6 12.3 ± 7.9 0.04 9-Month Follow-up (in stent) Late Loss, mm* 0.44 ± 0.58 0.31 ± 0.52 2.14 ± 0.63 2.25 ± 0.62 22.0 ± 19.9 19.9 ± 19.6 Binary Restenosis 11.4% 10.6% Abdel-Wahab M, et al. JACC Intv 2013;6:10-19

9-Month Clinical Outcomes ROTAXUS 9-Month Clinical Outcomes Rota/Stent Std. Stent P=NS for all comparisons Death MI TLR TVR Abdel-Wahab M, et al. JACC Intv 2013;6:10-19

Why Was ROTAXUS Negative? Calcified Lesions Why Was ROTAXUS Negative? Inclusion of moderately calcified lesions? Not enough ablation? (mean burr 1.5 mm) Crossovers are refractory lesions the ones that really benefit? Wrong endpoint? f/u MLD probably more appropriate as an angiographic surrogate Underpowered for clinical endpoints No true benefit?

Design Considerations for a Contemporary Trial Calcified Lesions Design Considerations for a Contemporary Trial Parameter Considerations Patient population Severe calcification vs. moderate/severe

Design Considerations for a Contemporary Trial Calcified Lesions Design Considerations for a Contemporary Trial Parameter Considerations Patient population Severe calcification vs. moderate/severe Comparator strategy PTCA/Stent or Rota/Stent

Design Considerations for a Contemporary Trial Calcified Lesions Design Considerations for a Contemporary Trial Parameter Considerations Patient population Severe calcification vs. moderate/severe Comparator strategy PTCA/Stent or Rota/Stent Primary endpoint Angiographic vs. Clinical

Design Considerations for a Contemporary Trial Calcified Lesions Design Considerations for a Contemporary Trial Parameter Considerations Patient population Severe calcification vs. moderate/severe Comparator strategy PTCA/Stent or Rota/Stent Primary endpoint Angiographic vs. Clinical Crossover permitted If not, may be challenging to enroll

Design Considerations for a Contemporary Trial Calcified Lesions Design Considerations for a Contemporary Trial Parameter Considerations Patient population Severe calcification vs. moderate/severe Comparator strategy PTCA/Stent or Rota/Stent Primary endpoint Angiographic vs. Clinical Crossover permitted If not, may be challenging to enroll Stent type 2nd gen DES vs. BVS

Calcified Lesions Summary/Conclusions Ablative techniques are an important adjunct to standard PTCA/stenting for treatment of refractory lesions and heavily calcified lesions Whether these approaches provide meaningful benefit compared with standard PTCA/stenting except for truly refractory lesions is unknown High quality clinical trials (most likely with clinically relevant endpoints) will ultimately be necessary to make the case for routine use of orbital atherectomy (or any other ablative techniques) in contemporary practice