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David J. Moliterno, MDProfessor and Chairman
Department of Internal Medicine
The University of KentuckyLinda and Jack Gill Heart Institute
Intravenous Antithrombotic Agents: Before,
During, Instead of the Cath Lab
Conflict of Interest Statement
“Intravenous Antithrombotic Agents: Before, During, Instead of
the Cath Lab”
David J. Moliterno, MD
DSMB: Janssen Pharmaceuticals (GEMINI Study)
Research Grant: Astra Zeneca (Steering Committee: TWILIGHT Study)
What are the immediate goals?
Prevent peri-procedural thrombosis
Minimize bleeding risk
Are there any unique thrombotic risks?
Are there unique bleeding risks?
Are their drug-drug interactions?
What is available and lab experience?
What are the cost implications?
Are there relevant future events to
consider?
IV Antithrombotic Choices
Admission to Angiography Time
Capodanno D, Angiolillo DJ. Circ Cardiovasc Inter 2015
Delayed drug absorption
Intravenous Antithrombotics
Antiplatelets
Aspirin
Thienopyridines
• Clopidogrel• Prasugrel• Ticagrelor• Cangrelor
GP IIb/IIIa
• Abciximab• Eptifibatide• Tirofiban
Antithrombins
Heparin
LMWH
• Dalteparin• Enoxaparin• Fondaparinux
DTI
• Lepirudin• Bivalirudin• Argatroban• Dabigatran
Numerous Class I Permutations
Aspirin: (3 options)
• None; low; high first dose
Thienopyridines: (12 options)• Cangrelor alone or in transition• Clopidogrel, Prasugrel, Ticagrelor• Short or long DAPT course
Antithrombin (4 options)
• Heparin, LMWH, Fondaparinux• Bivalirudin
Oral factor IIa or Xa inhibitors (#? of options)
Antithrombotic Options
2014 ESC/EACTS Guidelines
Windecker S et al. Eur Heart J 2014;35:2541-2619
2014 ESC/EACTS Guidelines
Windecker S et al. Eur Heart J 2014;35:2541-2619
Roffi M et al. Eur Heart J 2016;37:267-315
ESC Guidelines
Anticoagulation in NSTEMI
Roffi M et al. Eur Heart J 2016;37:267-315
Zeymer U et al. Eur HeartJ 2016;37:3376-3385
Anticoagulation During PCI
Zeymer U et al. Eur HeartJ 2016;37:3376-3385
Anticoagulation During PCI
Zeymer U et al. Eur HeartJ 2016;37:3376-3385
Anticoagulation During PCI
Zeymer U et al. Eur HeartJ 2016;37:3376-3385
Anticoagulation During PCI
SYNERGY Trial Investigators. JAMA 2004;292:45-54
30-Day Death or MI
TIMI Major TIMI Minor
14.0%
7.6%
9.1%
12.3%12.5%
15%
12%
9%
6%
0
3%
UFH Enoxaparin
P=0.008
Bleeding
Days from Randomization
Enoxaparin 14.0%
UFH 14.5%
N=10,027
Hazard Ratio, 0.96
(95% CI, 0.86-1.06)
15100 5 20 25 30
0
20%
10%
15%
5%
SYNERGY
Crossovers from LMWH to UFH
Death/MI
40%
30%
20%
10%
0%
Transfusion
13.5%15.3%
The SYNERGY Trial Investigators. JAMA 2004;292:52
17.4%
30.2%
Eve
nts
SYNERGY
No Crossover Crossover
TIMI Major Bleeding Among Crossovers
15%
9%
6%
3%
0%
White HD et al. Am Heart J 2006;152:1042
Eve
nts
12%
2.5%
3.7%
8.6%7.8%
OR = 3.89P = 0.002
OR = 2.68P < 0.001
UFH → LMWH(n = 70)
LMWH → UFH(n = 295)
No Crossover Crossover
SYNERGY: PCI Cohort
Stone GW et al. N Engl J Med 2008;358:2218-2230
16%
12%
8%
4%
0
12.1%
2.1%
Heparin (n=1802)
Bivalirudin (n=1800)
Death/MI/uTVRMajor Bleeding
Death/MI/uTVR
All Death Major Bleeding
3.1%
9.2%
5.5%
8.3%
RR=0.76P=0.005
30-Day Endpoints
RR=0.60P
Kastrati et al. N Engl J Med 2008;359:688
12%
9%
6%
3%
0
8.7%
5.6%
Heparin (n=2281)
Bivalirudin (n=2289)
Death/MI/uTVRMajor Bleeding
Death/MI/uTVR
MI Major Bleeding
4.8%
8.3%
5.0%4.6%
RR=0.94P=0.57
30-Day Endpoints
RR=0.66P=0.008
3.1%
5.9%
ISAR-REACT 3
Radialn=226
Femoraln=3,371
3.4%2.7%
8.6%
5.1%
10%
8%
6%
4%
2%
0
12%
Heparin + GPI
Bivalirudin
HORIZONS
Radialn=798
Femoraln=11,989
0.7%1.1%
2.7%
0.9%
Heparin + GPI
Bivalirudin
ACUITY
Major Bleeding by Access Site
Bavry A et al. PlosOne 2015;10:e0127832
Bivalirudin Meta-analysis
15 PCI RCTs of bivalirudin versus heparin with 30-day outcome
N = 25,824 (STEMI, NSTEMI, and elective cases)
Similar intended use of GP IIb/IIIa inhibtors between groups
Bavry A et al. PlosOne 2015;10:e0127832
Bivalirudin Meta-analysis
Stent Thrombosis
Bavry A et al. PlosOne 2015;10:e0127832
Bivalirudin Meta-analysis
Major Bleeding
Bavry A et al. PlosOne 2015;10:e0127832
Bivalirudin Meta-analysis
Outcome OR (95% CI) P
MACE 7.7% 1.04 (0.94 – 1.14) 0.46
Major Bleeding 3.5% 0.80 (0.70 – 0.92) 0.001
NACE 10.8% 0.91 (0.84 – 0.99) 0.028
Stent Thrombosis 1.0% 1.49 (1.15 – 1.92) 0.002
Randomization to
Bivalirudin Better
(n = 13,255)
Randomization to
Heparin Better
(n = 12,569)
0 1 2
30-Day Events
CHAMPION Trials
Steg PG et al. Lancet 2013;382:1981-1992
8%
0
4%
Cangrelorn=12,565
2%
6%
10%
Clopidogreln=12,542
3.8%
4.7%
48-HourDeath, MI, IDR, ST
8%
0
4%
Cangrelorn=12,565
2%
6%
10%
Clopidogreln=12,542
5.2%
5.9%
OR=0.81
(0.71-0.91)
P=0.0007
OR=0.89
(0.81-0.98)
P=0.001
CHAMPION Trials
Steg PG et al. Lancet 2013;382:1981-1992
30-DayDeath, MI, IDR, ST
CHAMPION Trials
Steg PG et al. Lancet 2013;382:1981-1992
At 48 Hours
0.9% ARR
19% RRR
OR 0.81 (0.71-0.91)
P=0.007
At 30 Days
0.7% ARR
13% RRR
OR 0.87 (0.78-0.97)
P=0.001
8%
0
4%
Cangrelorn=12,565
2%
6%
10%
Clopidogreln=12,542
4.2%
2.8%
ACUITYMajor Bleeding
4%
0
2%
Cangrelorn=12,565
1%
3%
5%
Clopidogreln=12,542
0.7%0.6%
OR=1.53
(1.34-1.76)
P
CHAMPION Trials
Steg PG et al. Lancet 2013;382:1981-1992
Bleeding
Thrombosis
Optimal Anticoagulation—does it exist?
intensity x duration
• Summary—for ACS/PCI there are between 30 and 1200 different combinations of options for the anticoagulation strategy
• Ischemic events are lowered by 1-1.5% and bleeding events are increased by 1-1.5%
• Advice—become very knowledgeable and comfortable with one drug at a time and then with one combination of anticoagulants, before exploring the next
Summary