intravenous antithrombotic agents: before, during, instead ... · david j. moliterno, md professor...

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

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

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



Stent Thrombosis



Major Bleeding



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


30-DayDeath, MI, IDR, ST

CHAMPION Trials


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


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

intravenous antithrombotic agents: before, during, instead ... · david j. moliterno, md professor...

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