1. Key Clinical Trials 2015
Impact Trials That Influence Clinical Practice
David E. Kandzari, MD, FACC, FSCAI
Chief Scientific Officer
Director, Interventional Cardiology
Piedmont Heart Institute
Atlanta, Georgia

2. Disclosure
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 Relationship Company
Grant/Research Support Abbott Vascular, Boston Scientific, Medtronic CardioVascular, Biotronik, Thoratec
Consulting Fees/Honoraria Boston Scientific Corporation, Medtronic CardioVascular
Major Stock Shareholder/Equity None
Royalty Income None
Ownership/Founder None
Intellectual Property Rights None
Other Financial Benefit None

3. Acute Myocardial Infarction Structural Heart Disease
Key Clinical Trials
SEARCH: ACC/AHA/TCT/ESC/EUROPCR/HRS/STS/ATS Late Breaking Clinical Trials, theheart.org, Cardiobrief.org, clinicaltrialresults.org, NEJM, Lancet, JAMA, JACC, Circulation….
Pharmacology
DES and PCI Trials
Acute Myocardial Infarction
Structural Heart Disease
FDA: Thumbs Up in an Election Year

4. Randomized Trials of DAPT Duration After PCI
RESET N=2117
OPTIMIZE N=3119
EXCELLENT N=1443
ISAR-SAFE N=4000
ARCTIC Interrupt N=1259
PRODIGY N=2014
ITALIC N=1850
DAPT BMS N=1687
DAPT DES N=9961
DES LATE N=5045
32,495 Randomized Patients
6 Months
1 Year
18 Months
2 Years
30 Months
3 Years

5. DAPT Trial
Component Endpoints
Mauri et al. NEJM 2014 5

6. DAPT Trial
Bleeding Events, Months
Mauri et al. NEJM 2014 6

7. Treatment Effect According to ACS Status Myocardial Infarction Type, 12-30 M follow-up
All Randomized Subjects (N=11648)
Stent Thrombosis-Related
Myocardial Infarction
Non-Stent Thrombosis-Related
Myocardial Infarction
P=0.04
P=0.04
P<0.001
P<0.001
Interaction P=0.86
Interaction P=0.24

8. DAPT Trial Stent Thrombosis, DES vs BMS 8
Kereiakes et al. JAMA. 2015;313(11): 8

9. Treatment Duration by Stent Type Interaction on Stent Thrombosis
( )
HR 0.49
( )
Kereiakes et al. JAMA. 2015;313(11):

10. PEGASUS TIMI 54 Benefit of DAPT For Secondary Prevention 10
Sabatine et al. ACC 2015 10

11. PEGASUS TIMI 54 Benefit of DAPT For Secondary Prevention 11
Sabatine et al. ACC 2015 11

12. PEGASUS TIMI 54 DAPT For Secondary Prevention 12
Sabatine et al. ACC 2015, NEJM 2015 12

13. LEADERS FREE Trial DCS vs BMS in HBR PCI Patients
94.9%
N=2,466 %
100
SAPT 80 60 40
9.5% 20
DAPT 30 90
180
270
390
Day Since Randomization
Urban TCT 2015; NEJM 2015

14. LEADERS FREE Trial Primary Efficacy Endpoint: Clinically Driven TLR%
N=2,466 12
9.8% 9
Cumulative Percentage with Event 6
5.1% 3
p for superiority < 0.001 90
180
270
390
Days
Number at Risk
DCS
1221
1167
1130
1098
1053
BMS
1211
1131
1072
1034
984
Urban TCT 2015; NEJM 2015

15. LEADERS FREE Trial Primary Safety Endpoint: Cardiac Death, MI, Stent Thrombosis% 15
12.9% 12 9
9.4%
Cumulative Percentage with Event 6 3
p = for superiority 90
180
270
390
Days
Number at Risk
DCS
1221
1146
1105
1081
1045
BMS
1211
1115
1066
1037
1000
Urban TCT 2015; NEJM 2015

16. NSTEACS or STEMI with Invasive Management Unfractionated Heparin
MATRIX
NSTEACS or STEMI with Invasive Management
Aspirin+P2Y12 blocker
N=8,404
1:1 at Presentation
Trans-Radial Access
ACCESS
Trans-Femoral Access
N=7,213
1:1 at PCI
Bivalirudin
Bailout GPI
Unfractionated Heparin
with planned or bailout GPI
Post PCI Bivalirudin
No Post PCI Bivalirudin
ANTITHROMBIN
Valgimiglli ACC 2015; NEJM 2015

17. No significant differences in any recurrent MI or stroke
MATRIX
Primary Endpoint 1: Death, MI, Stroke at 30 days
10.9%
10.3%
UFH
*GP 2b3a 26% vs 5%
Bivalirudin
RR: 0.94; 95% CI: ; P=0.45
No significant differences in any recurrent MI or stroke
Valgimiglli ACC 2015; NEJM 2015

18. MATRIX All-Cause, Cardiac, Vascular and Non-CV Mortality RR:0.70
( )
P=0.037
RR: 0.68
( )
P=0.032
2.3% %
1.7%
UFH
Bivalirudin
Valgimiglli ACC 2015; NEJM 2015

19. MATRIX
Primary Endpoint 2: Death, MI, Stroke and BARC 3 or 5 Bleeding at 30 days
12.4%
11.2%
RR: 0.89; 95% CI: ; P=0.122
UFH
Bivalirudin
Valgimiglli ACC 2015; NEJM 2015

20. MATRIX Bleeding Endpoints: BARC, GUSTO, TIMI, Access vs Non-Access
RR: 0.61
P=0.002
RR: 0.50
P=0.005
RR: 0.53
P=0.027
RR: 0.61
P=0.07
RR: 0.59
P=0.0016
RR: 0.31
BARC 3 or 5
Major or minor
Moderate or severe
Valgimiglli ACC 2015; NEJM 2015

21. MATRIX Stent Thrombosis
P=0.27
RR: 1.28
P=0.23
RR: 1.53
P=0.10
RR: 1.99
P=0.048
RR: 1.71
P=0.34
RR: 1.37
P=0.54
RR: 1.21
1.4%
Definite Stent Thrombosis
Definite/Probable Stent ST
No reduction in stent thrombosis or MI with prolonged bivalirudin
Valgimiglli ACC 2015, ESC 2015; NEJM 2015

22. MATRIX Radial vs Femoral, MACE and NACE
10.3%
8.8%
Outcome
Radial
Femoral
HR (95% CI)
P value
All Mortality
1.6
2.2
0.72 ( )
0.045
CV Mortality
1.5
2.1
0.75
( )
0.08
BARC 3/5 Bleeding
2.3
0.67 ( )
0.013
Access Site
0.4
1.1
0.37 ( )
0.0004
Non-access Site
1.2
N/A
0.68
15% significant reduction at nominal 5% alpha
which is however NOT significant at the pre-specificed
alpha of 2.5%
Crossover:
5.8% vs 2.3%
P<0.001
PCI Failure
6.3% vs 6.1%, P=0.77
11.7%
9.8%
NNTB: 53
Valgimiglli ACC 2015; Lancet 2015

23. 1 and 2 Year Clinical Outcomes
ABSORB II
1 and 2 Year Clinical Outcomes
Absorb N=335
∆Years 1-2
Xience N=166
P Value
TLF
7.0
∆2.2
3.0 —
0.07
Cardiac Death
0.6
∆0.6
0.55 MI
5.8
∆1.6
2.4
∆1.2
0.10
ID-TLR
2.7
∆1.5
1.8
0.76
Stent Thrombosis
1.5
0.17
No differences in freedom from angina, angina frequency or physical limitation at 6 and 12 months
Chevalier, TCT 2015
Serruys ACC 2011

24. ABSORB III 1 Year Target Lesion Failure
P=0.16
P=0.18
P=0.50
P=0.29
Kereiakes TCT2015; Ellis et al. NEJM 2015

25. ABSORB III Device Thrombosis at 1 Year
(N=1322)
Xience
(N=686)
P value
Device Thrombosis (def*/prob)
1.54%
0.74%
0.13
- Early (0 to 30 days)
1.06%
0.73%
0.46
- Late (> 30 to 1 year)
0.46%
0.00%
0.10
- Definite* (1 year)
1.38%
0.21
- Probable (1 year )
0.15%
0.55
*One “definite ST” in the Absorb arm by ITT was in a pt that was treated with Xience
Kereiakes TCT2015; Ellis et al. NEJM 2015

26. ABSORB III Outcomes By QCA RVD 2.25
RVD <2.25 mm
(median 2.09 mm)
RVD ≥2.25 mm
(median 2.74 mm)
TLF: Pint diff = 0.31
ST: Pint diff = 0.12
1-Year Events (%)
TLF
TLF ST
TLF ST
# Events: 31 11 2 71 30 9 3
# Risk:
241
133
238
1067
542
1058
540
Kereiakes TCT2015; Ellis et al. NEJM 2015

27. TOTAL Study Design STEMI with Primary PCI ≤12 hours of symptom onset
Sample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction
1:1 Randomization between strategies
Routine Upfront Manual Thrombectomy
followed by PCI
PCI Alone
(only bailout thrombectomy)
Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days
Safety Outcome: Stroke ≤30 days
Bailout Thrombectomy allowed if PCI alone strategy fails:
Persistent TIMI 0 or 1 flow with large thrombus after balloon pre-dilatation
Persistent large thrombus after stent deployment at target lesion
Jolly ACC 2015; Jolly et al. NEJM 2015

28. TOTAL Primary Endpoint Outcomes
 Day 180
Thrombectomy
(N=5033) (%)
PCI alone
(N=5030) (%) HR
95% CI
P Value
CV death, MI, shock or class IV heart failure
347 (6.9%)
351 (7.0%)
0.99
0.86
CV death
157 (3.1%)
174 (3.5%)
0.90
0.34
Recurrent MI
99 (2.0%)
92 (1.8%)
1.07
0.62
Cardiogenic Shock
100 (2.0%)
0.92
0.56
Class IV heart failure
98 (1.9%)
90 (1.8%)
1.09
0.57
Direct stenting, TIMI 3 flow, ST resolution higher with thrombectomy and less distal embolization
Jolly ACC 2015; Jolly et al. NEJM 2015

29. TOTAL Primary Safety Outcomes
Thrombectomy
(N=5033) (%)
PCI alone
(N=5030) (%) HR
95% CI
P value
Stroke within 30 days
33 (0.7%)
16 (0.3%)
2.06
0.015
Stroke or TIA within 30 days
42 (0.8%)
19 (0.4%)
2.21
0.003
Stroke within 180 days
52 (1.0%)
25 (0.5%)
2.08
0.002
Jolly ACC 2015; Jolly et al. NEJM 2015

30. TOTAL Primary Endpoint at 1 Year
Jolly TCT 2015; Jolly et al. Lancet 2015

31. TOTAL Updated Meta-analysis N=20,352, All-Cause Mortality
OR 0.90 (95% CI ) P=0.10
Jolly TCT 2015; Jolly et al. Lancet 2015

32. TOTAL Updated Meta-analysis N=20,352, Stroke
2015 ACC/AHA/SCAI Guidelines Update on Primary PCI (Oct 21, 2015):
2011/2013 Routine Thrombectomy II A Class III
Bailout Thrombectomy Class II B
0.9% Thrombectomy vs. 0.6% PCI alone, OR 1.43 (95% CI ) P=0.03
Jolly TCT 2015; Jolly et al. Lancet 2015

33. Simultaneous PCI of Non-Culprit Arteries During Primary PCI Guidelines and Evolution of Evidence
ESC Guidelines 2014
Class II A
Primary PCI should be limited to IRA unless shock or persistent ischemia
ACC/AHA 2013
Class III
PCI of non-IRA without hemodynamic compromise
PRAMI, N=465, NEJM 2013
65% reduction in CV death, nonfatal MI, refractory angina
CvLPRIT, N=296, JACC 2015
55% reduction in all-cause mortality, recurrent MI, heart failure, ischemia-driven revascularization
*Balanced reductions in both ischemic and repeat revascularization events

34. 2011/2013 Class III 2015 Class II B DANAMI 3- PRIMULTI
627 STEMI pts randomized to IRA PCI only vs IRA and FFR guided non-IRA PCI
Outcome
HR (95% CI)
P value
All-cause death
1.4 ( )
0.43
Nonfatal MI
0.94 ( )
0.87
Repeat revascularization
0.31 ( )
<0.001
2015 ACC/AHA/SCAI Guidelines Update on Primary PCI (Oct 21, 2015):
2011/2013 Class III Class II B
Engstrom ACC 2015; Lancet 2015

35. 2015 TAVR PARTNER I, 5 Year Outcomes ACC 2015
Similar all-cause mortality for HR TAVR vs SAVR (68% vs 64%, P=0.78) and similar stroke
No differences in AV gradient but even mild PVL associated with higher mortality
PARTNER II Sapien 3 ACC 2015, TCT 2015
30 days: HR mortality 2.2%, stroke 1.5%; Intermediate Risk mortality 1.1%, stroke 2.6%
1 year: 86% overall survival (HR, IR); More than halving of mortality at 30 days and 1 year compared with historical trials
CoreValve 2 and 3 Year Outcomes ACC 2015, TCT 2015
High Risk: Compared with SAVR, 2 year survival superior (22% vs 29%) and lower stroke (11% vs 17%)
Extreme Risk: Mortality or major stroke at 3 years, 52%
REPRISE II London Valve
1 year mortality 11.6% with no moderate or severe PVL
BRAVO TCT 2015
No reduction in bleeding or MACE with bivalirudin vs UFH
Reduced Leaflet Mobility and Thrombosis Risk NEJM 2015
Relationship to anticoagulation, imaging vs clinical phenomenon, device specific

36. FDA 2015: Thumbs Up in An Election Year
WATCHMAN October 2014, March 2015
3rd FDA Panel (approval); FDA approval as alternate to warfarin in high risk AF
BARD/Lutonix DCB October 2014
Approval for fempop disease
Heartflow October 2014
CT FFR functional assessment of anatomy
Admiral IN PACT January 2015
Impella RP, 2.5 January, March 2015
Right ventricular support and high risk PCI
Edoxaban (Savaysa) Oct 2014, January 2015
FDA Panel and then approval for AF and DVT
Ivabradine (Corlanor) April 2015
FDA approval for reduced HF hospitalization
Cangrelor (Kengreal) April 2015
FDA approval for PCI
Alrocumab (Praluent) July 2015
Evolocumab (Repatha) August 2015
Familial hyperlipidemia or CV risk not at lipid goal
LCZ696 (Entresto) August 2015
Reduced CV death and HF hospitalization for NYHA II-IV and reduced LVEF
Rob Califf January, September 2015
Appointed FDA Deputy Commissioner and then Presidential nomination for FDA Commissioner

37. Those Who Almost Made The List…
PREPIC2
IVC Filter/OAC vs OAC
N=399; No difference in symptomatic recurrent pulmonary embolism
MR CLEAN, ESCAPE, EXTEND IA, SWIFT
Retrievable Stent Thrombectomy/Fibrinolysis vs Fibrinolysis for Acute Stroke
Improved recovery, functional independence and possibly lower mortality
SPRINT
SBP Goal <120 vs <140 for moderate cardiovascular risk
Randomized trial (N=9,361) halted for 30% reduction in CV death/MI/CHF/stroke/ACS and 25% reduction in all-cause mortality
JAMA Int Med 2015
N=8,000; apple per day does not reduce doctor visits but associated with modest reduction in need for prescription drugs