David E. Kandzari, MD, FACC, FSCAI Chief Scientific Officer Director, Interventional Cardiology Piedmont Heart Institute Atlanta, Georgia [email protected]

David E. Kandzari, MD, FACC, FSCAI

Chief Scientific OfficerDirector, Interventional Cardiology

Piedmont Heart Institute Atlanta, Georgia [email protected]

Key Clinical Trials 2015Impact Trials That Influence Clinical Practice

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 RelationshipCompany

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

Key Clinical Trials

1 Pharmacology

2 DES and PCI Trials

3 Acute Myocardial Infarction

4 Structural Heart Disease

5 FDA: Thumbs Up in an Election Year

SEARCH: ACC/AHA/TCT/ESC/EUROPCR/HRS/STS/ATS Late Breaking Clinical Trials, theheart.org, Cardiobrief.org, clinicaltrialresults.org, NEJM, Lancet, JAMA, JACC, Circulation….

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

6 Months 1 Year 18 Months 2 Years 3 Years30 Months

32,495 Randomized Patients

Petrutiu, Simona

Should we add ZEUS to this list?

DAPT Trial Component Endpoints

Mauri et al. NEJM 2014

DAPT Trial Bleeding Events, 12-30 Months

Mauri et al. NEJM 2014

Non-Stent Thrombosis-RelatedMyocardial Infarction

Stent Thrombosis-RelatedMyocardial Infarction

ACS No ACS ACS No ACS0%

2%

4%

6%

8%

0.5% 0.3%

1.8% 1.9%1.9%

1.0%

3.3%

2.5%

Continued ThienopyridinePlacebo

Interaction P=0.86 Interaction P=0.24

Treatment Effect According to ACS Status Myocardial Infarction Type, 12-30 M follow-upAll Randomized Subjects (N=11648)

P<0.001 P<0.001

P=0.04 P=0.04

DAPT Trial Stent Thrombosis, DES vs BMS

Kereiakes et al. JAMA. 2015;313(11):1113-21.

9

Treatment Duration by Stent Type Interaction on Stent Thrombosis

HR 0.29(0.17-0.48)

HR 0.49(0.15-1.65)

Kereiakes et al. JAMA. 2015;313(11):1113-21.

PEGASUS TIMI 54Benefit of DAPT For Secondary Prevention

Sabatine et al. ACC 2015

Sabatine et al. ACC 2015

PEGASUS TIMI 54Benefit of DAPT For Secondary Prevention

PEGASUS TIMI 54DAPT For Secondary Prevention

Sabatine et al. ACC 2015, NEJM 2015

LEADERS FREE TrialDCS vs BMS in HBR PCI Patients

Urban TCT 2015; NEJM 2015

0 30 90 180 270 390

0

20

40

60

80

100

Day Since Randomization

SAPT

DAPT

94.9%

9.5%

% N=2,466

LEADERS FREE TrialPrimary Efficacy Endpoint: Clinically Driven TLR


0

90 180 270 390

Cum

ulati

ve P

erce

ntag

e w

ith E

vent

3

6

9

12

Days0

9.8%

5.1%

p for superiority < 0.001

Number at Risk

DCS 1221 1167 1130 1098 1053

BMS 1211 1131 1072 1034 984

%N=2,466

LEADERS FREE TrialPrimary Safety Endpoint: Cardiac Death, MI, Stent Thrombosis


0

90 180 270 390

Cum

ulati

ve P

erce

ntag

e w

ith E

vent

3

6

9

12

Days0

12.9%

9.4%

Number at Risk

DCS 1221 1146 1105 1081 1045

BMS 1211 1115 1066 1037 1000

p = 0.005 for superiority

15%

MATRIX

Valgimiglli ACC 2015; NEJM 2015

NSTEACS or STEMI with Invasive ManagementAspirin+P2Y12 blocker

Trans-Femoral Access

Unfractionated Heparin

with planned or bailout GPI

BivalirudinBailout GPI

Trans-Radial Access

ACCESS

1:1 at Presentation

1:1 at PCI

ANTITHROMBIN

N=7,213

Post PCI Bivalirudin

No Post PCI Bivalirudin

N=8,404

MATRIX


10.3%

10.9%

UFHBivalirudin

RR: 0.94; 95% CI: 0.81-1.10; P=0.45

Primary Endpoint 1: Death, MI, Stroke at 30 days

No significant differences in any recurrent MI or stroke

*GP 2b3a 26% vs 5%

MATRIX


1.7%

2.3%

UFHBivalirudin

All-Cause, Cardiac, Vascular and Non-CV Mortality

%

RR:0.70 (0.50-0.98) P=0.037

RR: 0.68 (0.48-0.97)P=0.032

MATRIX


Primary Endpoint 2: Death, MI, Stroke and BARC 3 or 5 Bleeding at 30 days

11.2%

12.4%

UFHBivalirudin

RR: 0.89; 95% CI: 0.78-1.103; P=0.122

MATRIXBleeding Endpoints: BARC, GUSTO, TIMI, Access vs Non-Access


P=0.07RR: 0.59 0.33-1.04

P=0.005RR: 0.53 0.34-0.83

BARC 3 or 5

P=0.008 RR: 0.610.42-0.88

P=0.0016RR: 0.31

0.11-0.85

P=0.002RR: 0.50 0.33-0.75 P=0.027

RR: 0.61 0.39-0.95

Major or minor Moderate or severe

MATRIXStent Thrombosis

Valgimiglli ACC 2015, ESC 2015; NEJM 2015

1.4%

P=0.048RR: 1.71 1.00-2.93

P=0.23RR: 1.53 0.76-3.09

P=0.10 RR: 1.990.85-4.66

P=0.27RR: 1.28

0.82-2.00 P=0.34

RR: 1.37 0.72-2.62

P=0.54RR: 1.21 0.66-2.22

Definite Stent Thrombosis Definite/Probable Stent ST

No reduction in stent thrombosis or MI with prolonged bivalirudin

MATRIXRadial vs Femoral, MACE and NACE

Valgimiglli ACC 2015; Lancet 2015

15% significant reduction at nominal 5% alphawhich is however NOT significant at the pre-specificedalpha of 2.5%

8.8%

10.3%

11.7%

9.8%

NNTB: 53

Crossover:5.8% vs 2.3%P<0.001

PCI Failure6.3% vs 6.1%, P=0.77

Outcome Radial Femoral HR (95% CI) P value

All Mortality 1.6 2.2 0.72 (0.53-0.99) 0.045

CV Mortality 1.5 2.1 0.75 (0.54 - 1.04) 0.08

BARC 3/5 Bleeding 1.6 2.3 0.67 (0.49-

0.92) 0.013

Access Site 0.4 1.1 0.37 (0.21-0.66) 0.0004

Non-access Site 1.1 1.2 N/A 0.68

ABSORB II1 and 2 Year Clinical Outcomes

Serruys ACC 2011Chevalier, TCT 2015

Absorb N=335 ∆Years 1-2 Xience

N=166 ∆Years 1-2 P Value

TLF 7.0 ∆2.2 3.0 — 0.07

Cardiac Death 0.6 ∆0.6 0 — 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 ∆0.6 0 — 0.17

No differences in freedom from angina, angina frequency or physical limitation at 6 and 12 months

ABSORB III 1 Year Target Lesion Failure

TLF Cardiac death TV-MI ID-TLR0

2

4

6

8

10

7.8

0.6

6.0

3.0

6.1

0.1

4.6

2.5

Absorb (N=1322)Xience (N=686)

1-Ye

ar T

LF (%

)

P=0.16

P=0.29

P=0.18

P=0.50

Kereiakes TCT2015; Ellis et al. NEJM 2015

ABSORB III Device Thrombosis at 1 Year


Absorb(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% 0.74% 0.21

- Probable (1 year ) 0.15% 0.00% 0.55

*One “definite ST” in the Absorb arm by ITT was in a pt that was treated with Xience

ABSORB III Outcomes By QCA RVD 2.25


TLF ST TLF ST0%

5%

10%

15%

20%

12.9%

4.6%

6.7%

0.9%

8.3%

1.5%

5.5%

0.6%

Absorb Xience

RVD <2.25 mm(median 2.09 mm)

1-Ye

ar E

vent

s (%

)

RVD ≥2.25 mm(median 2.74 mm)

# Events: 31 11 11 2 71 30 9 3

# Risk: 241 133 238 133 1067 542 1058 540

TLF: Pint diff = 0.31ST: Pint diff = 0.12

TLF TLFTLF ST ST

TOTALStudy Design

Jolly ACC 2015; Jolly et al. NEJM 2015

PCI Alone(only bailout thrombectomy)

Routine Upfront Manual Thrombectomyfollowed by PCI

Primary Outcome: CV death, MI, cardiogenic shock and class IV heart failure ≤180 days

Safety Outcome: Stroke ≤30 days

1:1 Randomization between strategies

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

STEMI with Primary PCI ≤12 hours of symptom onsetSample size of 10,700 for 80% power to detect a 20% Relative Risk Reduction

TOTAL

TOTALPrimary Endpoint Outcomes


TOTAL

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 0.85-1.15 0.86

CV death 157 (3.1%) 174 (3.5%) 0.90 0.73-1.12 0.34

Recurrent MI 99 (2.0%) 92 (1.8%) 1.07 0.81-1.43 0.62

Cardiogenic Shock 92 (1.8%) 100 (2.0%) 0.92 0.69-1.22 0.56

Class IV heart failure 98 (1.9%) 90 (1.8%) 1.09 0.82-1.45 0.57

Direct stenting, TIMI 3 flow, ST resolution higher with thrombectomy and less distal embolization

TOTALPrimary Safety Outcomes


TOTAL

Thrombectomy (N=5033) (%)

PCI alone (N=5030) (%) HR 95% CI P value

Stroke within 30 days 33 (0.7%) 16 (0.3%) 2.06 1.13-3.75 0.015

Stroke or TIA within 30 days 42 (0.8%) 19 (0.4%) 2.21 1.29-3.80 0.003

Stroke within 180 days 52 (1.0%) 25 (0.5%) 2.08 1.29-3.35 0.002

TOTALPrimary Endpoint at 1 Year

Jolly TCT 2015; Jolly et al. Lancet 2015

TOTAL

TOTALUpdated Meta-analysis N=20,352, All-Cause Mortality


TOTAL

OR 0.90 (95% CI 0.79-1.02) P=0.10

TOTALUpdated Meta-analysis N=20,352, Stroke


TOTAL

0.9% Thrombectomy vs. 0.6% PCI alone, OR 1.43 (95% CI 1.03-1.99) P=0.03

2015 ACC/AHA/SCAI Guidelines Update on Primary PCI (Oct 21, 2015):

2011/2013 Routine Thrombectomy II A 2015 Class III

Bailout Thrombectomy

2015 Class II B

Simultaneous PCI of Non-Culprit Arteries During Primary PCIGuidelines and Evolution of Evidence

ESC Guidelines 2014

Class II APrimary PCI should be limited to IRA unless shock or persistent ischemia

ACC/AHA 2013

Class IIIPCI 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

DANAMI 3- PRIMULTI

Engstrom ACC 2015; Lancet 2015

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 (0.63-3.0) 0.43

Nonfatal MI 0.94 (0.47-1.9) 0.87

Repeat revascularization 0.31 (0.18-0.53) <0.001

2015 ACC/AHA/SCAI Guidelines Update on Primary PCI (Oct 21, 2015):

2011/2013 Class III 2015 Class II B

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

FDA 2015: Thumbs Up in An Election Year

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

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

— Approval for fempop disease

Impella RP, 2.5 January, March 2015

— Right ventricular support and high risk PCI

Rob Califf January, September 2015

— Appointed FDA Deputy Commissioner and then Presidential nomination for FDA Commissioner

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

Documents

David E. Kandzari, MD, FACC, FSCAI Chief Scientific Officer Director, Interventional Cardiology Piedmont Heart Institute Atlanta, Georgia [email protected]