David E. Kandzari, MD, FACC, FSCAI Chief Scientific Officer Director, Interventional Cardiology...
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Transcript of David E. Kandzari, MD, FACC, FSCAI Chief Scientific Officer Director, Interventional Cardiology...
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
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
Urban TCT 2015; NEJM 2015
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
Urban TCT 2015; NEJM 2015
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
Valgimiglli ACC 2015; NEJM 2015
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
Valgimiglli ACC 2015; NEJM 2015
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
Valgimiglli ACC 2015; NEJM 2015
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
Valgimiglli ACC 2015; NEJM 2015
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
Kereiakes TCT2015; Ellis et al. NEJM 2015
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
Kereiakes TCT2015; Ellis et al. NEJM 2015
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
Jolly ACC 2015; Jolly et al. NEJM 2015
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
Jolly ACC 2015; Jolly et al. NEJM 2015
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
Jolly TCT 2015; Jolly et al. Lancet 2015
TOTAL
OR 0.90 (95% CI 0.79-1.02) P=0.10
TOTALUpdated Meta-analysis N=20,352, Stroke
Jolly TCT 2015; Jolly et al. Lancet 2015
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