UNIT OBJECTIVES

Orbital Atherectomy Treatment of Severely Calcified Coronary Lesions: Two Year Results of the ORBIT II Trial and Long-Term Economic Analysis

Jeffrey W. Chambers*, Richard A. Shlofmitz, Christopher Kim, Arthur C. Lee, Lou Garrison, Philippe Généreux

*Metropolitan Heart and Vascular Institute, Mercy Hospital, Minneapolis, Minnesota

Faculty Disclosures

•  Speaker's name: Jeffrey Chambers ! I have the following potential conflicts of interest to report:

–  Consultant: Cardiovascular Systems, Inc.

Risk Factors for Arterial Calcification

Advanced Age

•  40.3M 65+ years old in U.S.1

•  85+ age group is fastest growing in U.S.2

Type I & II Diabetes

•  Up to 26M in U.S.3

•  Diabetes is fastest growing health problem in U.S.4

Kidney Disease

•  Up to 31M in U.S.5

•  Diabetes is leading cause of kidney failure3

Intra-arterial Calcium

1. U.S. Census Bureau Website. http://www.census.gov/prod/cen2010/briefs/c2010br-03.pdf. Accessed July 30, 2013. 2. Older Americans 2012 Report Found on Federal Interagency Forum on Aging-Related Statistics Website. http://www.agingstats.gov/agingstatsdotnet/Main_Site/Data/2012_Documents/Docs/EntireChartbook.pdf. Accessed August 14, 2013. 3. 2011 National Diabetes Fact Sheet Found on American Diabetes Association Website .http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf.Accessed August 14, 2013. 4. Diabetes Fact Sheet Fund on American Diabetes Association Website. http://main.diabetes.org/stepup/diabetes_facts.pdf. Accessed August 14, 2013. 5. American Kidney Fund Website. http://www.prnewswire.com/news-releases/american-kidney-funds-annual-gala-the-hope-affair-celebrates-40-years-of-caring-on-october-25-along-with-spokesperson-laila-ali-131975873.html. October 17, 2011. Accessed July 30, 2013.

Challenges Treating Severely Calcified Coronary Lesions

§  Respond poorly to angioplasty1

§  Difficult to completely dilate2

§  Prone to dissection during balloon angioplasty or predilatation1

§  Preclude stent delivery to the desired location2,3

§  Can prevent adequate stent expansion → stent thrombosis4

§  May result in stent malapposition5

§  Insufficient drug penetration and subsequent restenosis6

7

Shows incomplete apposition, incomplete expansion and an edge tear.

8

1.  Fitzgerald PJ, et al. Circulation. 1992;86:64-70. 2.  Cavusoglu E, et al. Cathet Cardivasc Intervent. 2004;62:485-498. 3.  Gilutz H, et al. Cathet Cardiovasc Intervent. 2000;50:212-214.

4.  Moussa I, et al. Circulation. 1997;96:128-136. 5.  Mosseri M, et al. Cardiovasc Revasc Med. 2005;6:147-53. 6.  Ichihashi S, Kichikawa K. Ther Clin Risk Manag. 2014;10:467-474.

7.  Buckley CJ. Vascular Disease Management. 2011;8:87-92. 8.  Ullah M, et al. Cariovasc J. 2014;6:149-163.

Coronary Calcium Is A Predictor Of Worse Outcomes with Second Generation DES

2.8%1.8%

7.3%6.0%

1.7%

12.9%

4.2%2.8%

7.6% 8.2%

2.9%

15.3%

6.3%

4.0%

9.4% 8.7%

1.9%

19.9%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

14.0%

16.0%

18.0%

20.0%

Death Cardiac  death MI TLR ARC  Definite  ST MACE

None/Mild Moderate Severe

p = 0.01

p = 0.003

p = 0.0001

p = 0.22 p = 0.002

p = 0.002

HORIZONS-AMI and ACUITY CORONARY CALCIUM AND OUTCOMES 1-YEAR POST-PCI 6,855 Patients Enrolled: 3,268 STEMI and 3,587 N-STEMI

Généreux, P. et al. J Am Coll Cardiol 2014;63(18):1845-54

Diamondback 360® Coronary Orbital Atherectomy System

Device Features • Simple device setup • Microsecond feedback

to changes in loading •  135cm usable length

On-handle speed control •  Low (80K) and High Speed (120K)

Power on/off switch •  8 cm axial travel

Electric motor powered handle

6Fr Guide Compatible Saline Sheath

Saline Infusion Pump •  Mounts directly on to an IV pole •  Provides power •  Delivers fluid •  Includes saline sensor

ViperSlide® Lubricant •  ViperSlide reduces friction

during operation •  20ml ViperSlide per liter of

saline

Eccentric diamond

coated crown

0.012 Viper Wire

Actual results may vary depending on device-to-lumen ratio, run time and speed, and plaque morphology.

Diamondback 360® Coronary Orbital Atherectomy System

Diamondback 360® OAS Mechanism of Action

Actual  results  may  vary  depending  on  device-­‐to-­‐lumen  ra5o,  run  5me  and  speed,  and  plaque  morphology.  

v  Differen'al  orbital  sanding:  v  Increased  speed    =  Increased  centrifugal  force  v  Greater  centrifugal  force  =  Larger  orbital  diameter  

v  Con'nuous  flow  of  blood  and  saline  during  orbit    v  Minimizes  thermal  injury  v  Poten5ally  decreases    no-­‐reflow  and  peri-­‐procedural  

cardiac  enzyme  eleva5on    

v  The  crown  treats  the  en're  lumen  and  different  vessel  diameters  can  be  treated  based  on  orbi'ng  speed   So#  components  (plaque/

2ssue)    flex  away  from  crown  

Crown  will  only  sand  the  hard  components  of  

plaque  

OAS Treatment Effect Orbital  atherectomy  is  a  5me-­‐dependent  therapy  

Orbit  in  a  Carbon  Block  Model  System  

2-year follow-up#

(N=419/440)

1-year follow-up†

(N=433/440)

30 day follow-up*

(N=437/440)

N=443 enrolled in

49 U.S sites

ORBIT II Study Design

Chambers  JW,  et  al.  JACC  Cardiovasc  Interv.  2014;7:510-­‐8.  

To  evaluate  safety  and  efficacy  of  the  Diamondback  Coronary  OAS  to  prepare  de  novo,  severely  calcified  coronary  lesions  for  enabling  stent  placement  

–  Prospec5ve,  mul5-­‐center  trial  –  Single  arm  -­‐    As  there  are  no  FDA-­‐approved  percutaneous  treatments  for  pa5ents  with  

severely  calcified  lesions.  

•  Primary Safety Endpoint: MACE (MI= CK-MB>3x ULN, TVR, Cardiac Death)

•  Primary Efficacy Endpoint: Procedural Success -  Success in facilitating stent delivery with a final residual stenosis of <50% (as determined by

Angiographic Core Lab) and free from in-hospital MACE

*438  subjects  per  Kaplan  Meier  were  at  risk/events  †430  subjects  per  Kaplan  Meier  were  at  risk/events  #354  subjects  per  Kaplan  Meier  were  at  risk/events  

ORBIT II Inclusion/Exclusion Criteria

Chambers JW, et al. JACC Cardiovasc Interv. 2014;7:510-8.

Key  Inclusion:  •  The  target  lesion  must  have  fluoroscopic  or  IVUS  evidence  of  severe  calcium:  

Presence  of  radiopaci2es  noted  without  cardiac  mo2on  prior  to  contrast  injec5on  involving  both  sides  of  the  arterial  wall  with  calcifica5on  length  of  at  least  15  mm  and  extend  par5ally  into  the  target  lesion  or  presence  of  ≥  270°of  calcium  at  one  cross  sec5on  via  IVUS  

•  The  target  vessel  reference  diameter  ≥  2.5  mm  and  ≤  4.0  mm  and  lesion  must  not  exceed  40  mm  in  length    

 Key  Exclusion:  •  Diagnosed  with  chronic  renal  failure  (CR  >2.5  mg/dl)  unless  under  hemodialysis  •  Evidence  of  current  LVEF  ≤25%    •  More  than  1  lesion  requiring  interven5on  unless  the  lesions  are  staged      •  In-­‐stent  treatment  •  Target  lesion  is  an  os2al  loca2on,  bifurca2on  or  has  a  ≥  1.5  mm  side  branch  •  Target  lesion  has  thrombus  or  dissec2on  •  Angio  evidence  of  dissec5on  prior  to  ini5a5on  of  OAD  

ORBIT II Demographic & Lesion/Vessel Characteristics

Chambers JW, et al. JACC Cardiovasc Interv. 2014;7:510-8.

Demographics N=443 Male 64.6% Age (yrs) 71.4 History of diabetes mellitus 36.1% History of CABG 14.7% History of dislipidemia 91.9% History of hypertension 91.6% Smoker (current or previous) 66.1% Vessel & Lesion Characteristics N=440 Mean pre-procedure target lesion length 18.9 mm Mean pre-procedure minimum lumen diameter 0.5 mm Mean pre-procedure percent stenosis 84.4%

Types of stents n=542 BMS 11.8% DES 88.2%

ORBIT II Study Objective – Efficacy

Chambers JW, et al. JACC Cardiovasc Interv. 2014;7:510-8.

Demonstrate that the OAS successfully facilitates stent deployment in severely calcified coronary lesions

Successful Stent delivered: 97.7% Less than 50% residual stenosis: 98.6%

ORBIT II Study Objective – Safety Demonstrate that the OAS is safe in treating de novo, severely calcified coronary lesions

0.2% 1.4%

9.7% 10.4%

2.8%

4.4%

6.0%

1.3%

2.3%

3.0%

0.0%

5.0%

10.0%

15.0%

20.0%

Cardiac death TVR MI* MACE

30 Days 30 Days to 1 year 1 year to 2 years

4.3%

8.1% 9.7%

19.4%

*Per protocol analysis. Based on reported CK-MB > 3X ULN.

ORBIT II Study Objective – Safety Demonstrate that the OAS is safe in treating de novo, severely calcified coronary lesions

*Not per protocol analysis. Clinically driven evaluation based on CEC adjudication of MI.

0.2% 1.4%

9.7% 10.2%

2.8%

4.4%

1.2%

6.2%

1.3%

2.3%

3.0%

0.0%

5.0%

10.0%

15.0%

20.0%

Cardiac death TVR MI* MACE

30 Days 30 Days to 1 year 1 year to 2 years

4.3%

8.1%

10.9%

19.4%

ORBIT II 2-Year Cardiac Death

4.3%

ORBIT II 2-Year TVR/TLR Outcomes

TLR: 6.2% TVR (non-TLR): 2.9%

TVR/TLR: 8.1%

ORBIT II 1 and 2 year TVR/TLR Rates within Range of DES Literature*

  1-year   2-year     TVR   TLR   TVR   TLR  ORBIT II—all stent types   1.9%   4.7%   2.9%   6.2%  ORBIT II—DES only   1.6%   3.4% 2.7% 5.2% ROTAXUS—RA  +  DES1   NR   NR 19.6% NR DES RCT—severe Ca2+ included   0.7-7.6%2   0.0-7.8%3   3.7-14.9%4   3.5%-11.0

%5  

*Literature search of coronary drug eluting stent (DES) randomized controlled trials (RCT) is on file at CSI. This summary table shows the TVR/TLR events as presented in the literature, but is not a direct device-to-device comparison since the studies described vary in design.

1.  Abdel-Wahab M, et al. Rotational atherectomy before paclitaxel-eluting stent implatation in complex coronary lesions: Two-year clinical outcome of the randomized ROTAXUS trial. Presented at EuroPCR 2013--Paris, France.

2.  COMPARE (Lancet. 2010;375:201-9.), DESSERT (Am J Cardiol. 2008;101:1560-6.), ESSENCE-DIABETES (Circulation. 2011;124:886-92.), EXAMINATION (Lancet. 2012;380:1482-90.), EXCELLENT (J Am Coll Cardiol. 2011;58:1844-54.), LONG-DES III (JACC Cardiovasc Interv. 2011;4:1096-103.), MISSION (Am J Cardiol. 2010;106:4-12.), PRISON II (Circulation. 2006;114:921-8.), RESET (Circulation. 2012;126:1225-36. ), RESOLUTE (J Am Coll Cardiol. 2011;57:2221-32.), SESAMI (J Am Coll Cardiol. 2007;49:1924-30.),TWENTE (J Am Coll Cardiol. 2012;59:1350-61.), ZEST (J Am Coll Cardiol. 2010;56:1187-95.)

3.  COMPARE (Lancet. 2010;375:201-9.), DESSERT (Am J Cardiol. 2008;101:1560-6.), ESSENCE-DIABETES (Circulation. 2011;124:886-92.), EXAMINATION (Lancet. 2012;380:1482-90.), EXCELLENT (J Am Coll Cardiol. 2011;58:1844-54. ), ISAR Left Main (J Am Coll Cardiol. 2009;53:1760-8.), KOMER-AMI (EuroIntervention. 2011;7:936-43.), LONG-DES III (JACC Cardiovasc Interv. 2011;4:1096-103.), MISSION (Am J Cardiol. 2010;106:4-12.), PASEO (JACC Cardiovasc Interv. 2009;2:515-23.), PRISON II (Circulation. 2006;114:921-8.), PROSIT (Catheter Cardiovasc Interv. 2008;72:25-32.), RESET (Circulation. 2012;126:1225-36.), RESOLUTE (J Am Coll Cardiol. 2011;57:2221-32.), SESAMI (J Am Coll Cardiol. 2007;49:1924-30.), TWENTE (J Am Coll Cardiol. 2012;59:1350-61.), ZEST (J Am Coll Cardiol. 2010 ;56:1187-95.)

4.  BASKET-PROVE (N Engl J Med. 2010;363:2310-9.), DES-Diabetes (JACC Cardiovasc Interv. 2011;4:310-6.), GISSOC II-GISE (Eur Heart J. 2010;31:2014-20.) 5.  DES-Diabetes (JACC Cardiovasc Interv. 2011;4:310-6.), GISSOC II-GISE (Eur Heart J. 2010 ;31:2014-20.), ISAR Left Main (J Am Coll Cardiol. 2009;53:1760-8.), PASEO (JACC Cardiovasc Interv. 2009;2:515-23.)

ORBIT II Diabetic Sub-analysis

Challenges of PCI in Patients with Diabetes: • Diabetics are at increased risk for severe coronary artery calcification1

• Compared to non-diabetics, diabetics have higher MACE post-PCI/stent placement2

1.  Raggi P, et al. J Am Coll Cardiol. 2004;43:1663-9. 2.  Mathew V, et al. Circulation 2004;109:476–80.

Aim: Evaluate 2-year safety outcomes in ORBIT II patients with or

without DM treated with the Diamondback 360 Coronary Orbital

Atherectomy System (OAS)

ORBIT II Diabetic Sub-analysis: Demographics and Lesion/Vessel Characteristics

Baseline characteristics

Baseline Characteristics* History of Diabetes

(N=160) No History of Diabetes

(N=283) P-value

Male 105/160 (65.6%) 181/283 (64.0%) 0.76 Age (years) 70.3 ± 0.7 (N=160) 72.0 ± 0.6 (N=283) 0.02 eGFR (mL/min/1.73m2) 77.3 ± 2.3 (N=160) 74.9 ± 1.5 (N=281) 0.55 History of dislipidemia 150/160 (93.8%) 257/283 (90.8%) 0.14 History of hypertension 154/160 (96.3%) 252/283 (89.0%) 0.01 History of stroke 16/160 (10.0%) 23/283 (8.1%) 0.75 History of MI 43/160 (26.9%) 56/283 (19.8%) 0.08 History of Angina 125/160 (78.1%) 223/283 (78.8%) 0.90 History of CABG 32/160 (20.0%) 33/283 (11.7%) 0.02 Smoker 0.10

Never 44/160 (27.5%) 106/283 (37.5%) Current 29/160 (18.1%) 46/283 (16.3%) Former 87/160 (54.4%) 131/283 (46.3%)

Vessel and Lesion Characteristics† N=159 N=281 Pre-procedure target lesion length (mm) 19.3 ± 0.7 18.7 ± 0.5 0.55 Pre-procedure minimum lumen diameter (mm) 0.5 ± 0.0 0.5 ± 0.0 0.82 Pre-procedure percent stenosis 84.3 ± 0.7 84.4 ± 0.5 0.86 *Number of subjects enrolled; †Subjects with OAS inserted; P-values from Wilcoxon rank-sum test (continuous parameters) and Fisher's exact

test (categorical parameters). Mean ± SE

ORBIT II Diabetic Sub-analysis: 2-Year Safety Outcomes

ORBIT II Safety Outcomes Through 2-Year Follow-Up History of Diabetes

No History of Diabetes P-value

2-year* MACE (%) 20.6 18.7 0.71

Cardiac death (%) 5.3 3.7 0.45

MI (CK-MB >3X ULN) (%) 8.1 10.6 0.40

TVR (%) 8.7 7.8 0.75 *Kaplan Meier methods used to estimate event rates p-values from Fisher’s exact test (In-hospital) and Cox Proportional Hazards Model (30-day and 1-year)

ORBIT II 1-Year Economic Analysis

•  From a facility or health system perspective, the total of projected cost-offsets in the first year in this elderly population would, on average, fully cover the cost of the OAS at $3,795 and possible extra $1,118 cost offset/savings. Thus, up to a total possible cost offset/ savings of $4,913 at 1-year.1

•  The OAS device offers good value at $11,895 per life

year gained far below the “high value” threshold of $50,000 per quality-adjusted life year (QALY).1,2

1.  Chambers JW, Garrison L, et al. The Potential Cost-Effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for Treating de novo, Severely Calcified Coronary Lesions: An Economic Modeling Approach. In Review at Therapeutic Advances in Cardiovascular Disease

2.  Anderson JL, et al. Circulation. 2014;129:2329-45.

ORBIT II 1-Year Economic Analysis: Cost-Model Framework

1.  Chambers JW, Garrison L, et al. The Potential Cost-Effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for Treating de novo, Severely Calcified Coronary Lesions: An Economic Modeling Approach. In Review at Therapeutic Advances in Cardiovascular Disease

The potential cost-offsets due to OAS use fall into three major categories: v Reduced procedural costs related to the stent implantation (Index Event)

v Reduced revascularization events in the 30 days following the initial hospitalization (Days 1-30)

v Reduced revascularization events between day 30 and one year (Days 31-365)

De  Novo  Severely  Calcified  Lesion  

OAS  Treatment  Index  Event:    

Costs  Days  1-­‐30:    

MACE  Event  Costs  Days  31-­‐365:    

MACE  Event  Costs  

Standard  Treatment  

Index  Event:    Costs  

Days  1-­‐30:    MACE  Event  Costs  

Days  31-­‐365:    MACE  Event  Costs  

ORBIT II 1-Year Economic Analysis: Effectiveness Model Framework

1.  Chambers JW, Garrison L, et al. The Potential Cost-Effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for Treating de novo, Severely Calcified Coronary Lesions: An Economic Modeling Approach. In Review at Therapeutic Advances in Cardiovascular Disease

De  Novo  Severely  

Calcified  Lesion  

OAS  Treatment   1-­‐Year  Mortality   Life  -­‐Years  Lost  

Standard  Treatment   1-­‐Year  Mortality   Life  -­‐Years  Lost  

Effectiveness (the denominator in the cost-effectiveness ratio) is measured in two ways: v Patient survival at the end of year one v Life years gained over a lifetime horizon

ORBIT II 1-Year Economic Analysis

1.  Chambers JW, Garrison L, et al. The Potential Cost-Effectiveness of the Diamondback 360® Coronary Orbital Atherectomy System for Treating de novo, Severely Calcified Coronary Lesions: An Economic Modeling Approach. In Review at Therapeutic Advances in Cardiovascular Disease

2.  Anderson JL, et al. Circulation. 2014;129:2329-45.

      Range    

Arm/Parameter     Base Case   Low   High   Source  

Incremental Costs            

Cost of Device     $3,795   $3,795   $3,795   List price  

Index event cost     -$2,690   -$2,018   -$3,363   Calculated  

Day 1-30 MACE event

costs  

 -$1,180   -$885   -$1,475   Calculated  

Day 31-365 MACE

event costs  

 -$60   -$45   -$75   Calculated  

Total Differential     -$135   $848   -$1,118   Calculated  

Incremental Health

Outcomes  

         

1-year mortality     2.6%   1.0%   3.0%   Calculated  

Life-years gained     0.25   0.07   0.36   Calculated  

Cost-Effectiveness

Ratios  

         

Cost per life saved     Dominant*   $84,750   Dominant*   Calculated  

Cost per life-year saved    

Dominant*   $11,895   Dominant*   Calculated  

At  1-­‐year:  Fully  cover  the  cost  of  the  OAS  at  $3,795  and  possible  extra  $1,118  cost  offset/savings.    Thus,  up  to  a  total  possible  cost  offset/savings  of  $4,913.    

At  1-­‐year:  The  OAS  device  offers  good  value  at  $11,895  per  life  year  gained  far  below  the  “high  value”  threshold  of  $50,000  per  quality-­‐adjusted  life  year  (QALY).2  

*  Dominant  is  defined  by  lower  cost  and  lower  mortality,  which  implies  very  cost-­‐    effec5ve.;  MACE  =  Major  Adverse  Cardiac  Event  (MACE  Event  Rates—Target  Lesion  Revasculariza5on  (TLR)/Target  Vessel  Revasculariza5on  (TVR))  

Conclusions v  The coronary OAS utilizes a centrifugal sanding action and is the first

novel technology to receive FDA approval to specifically treat severely calcified lesions.

v  The ORBIT II trial met the primary safety and efficacy endpoints by a significant margin. Low rates of 2-year cardiac death (4.3%) and TVR (8.1%) were observed.

v  Low rates of MACE at two year post-procedure in both diabetic and non-diabetic. Further studies are needed to better understand the impact of diabetes on the treatment of calcific coronary artery disease.

v  Using the coronary OAS as a lesion preparation tool prior to stent implantation offers an effective treatment option with durable long term results and potential cost benefits in these complex patients with severely calcified coronary lesions.