Intravenous Agents: Before, During, Instead of the Cath Lab

David J. Moliterno, MD Professor and Chairman Department of Internal Medicine

The University of Kentucky Linda and Jack Gill Heart Institute 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) IV Antithrombotic Choices

 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? Admission to Angiography Time

Capodanno D, Angiolillo DJ. Circ Cardiovasc Inter 2015 Delayed drug absorption Intravenous

Antiplatelets

 LMWH • • Dalteparin • • Enoxaparin • • •  DTI  GP IIb/IIIa • Lepirudin • • • • • • Antithrombotic Options

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

(4 options) • Heparin, LMWH, Fondaparinux • Bivalirudin

 Oral factor IIa or Xa inhibitors (#? of 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 ESC Guidelines

Roffi M et al. Eur Heart J 2016;37:267-315 Anticoagulation in NSTEMI

Roffi M et al. Eur Heart J 2016;37:267-315 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

Zeymer U et al. Eur HeartJ 2016;37:3376-3385 SYNERGY

30-Day Death or MI Bleeding

20% 15% UFH Enoxaparin

UFH 14.5% 12% 12.5% 15% 12.3% P=0.008 14.0% 9% Enoxaparin 14.0% 9.1% 10% 7.6% 6%

5% 3% N=10,027 Hazard Ratio, 0.96 (95% CI, 0.86-1.06) 0 0 0 5 10 15 20 25 30 Days from Randomization TIMI Major TIMI Minor

SYNERGY Trial Investigators. JAMA 2004;292:45-54 SYNERGY

Crossovers from LMWH to UFH

40% No Crossover Crossover

30% 30.2%

20% Events 17.4% 15.3% 10% 13.5%

0% Death/MI Transfusion

The SYNERGY Trial Investigators. JAMA 2004;292:52 SYNERGY: PCI Cohort

TIMI Major Bleeding Among Crossovers

15% No Crossover Crossover

12% OR = 3.89 OR = 2.68 P = 0.002 P < 0.001 9% 8.6%

Events 7.8% 6%

3% 3.7% 2.5% 0% UFH → LMWH LMWH → UFH (n = 70) (n = 295)

White HD et al. Am Heart J 2006;152:1042 HORIZONS-AMI

30-Day Endpoints 16% Heparin (n=1802) RR=0.76 P=0.005 Bivalirudin (n=1800) 12% 12.1% RR=0.60 P<0.001 8% 9.2% 8.3%

RR=0.66 5.5% 5.5% 4.9% 4% P=0.047

3.1% 2.1% 0 Death/MI/uTVR Death/MI/ All Death Major Major Bleeding uTVR Bleeding

Stone GW et al. N Engl J Med 2008;358:2218-2230 ISAR-REACT 3

30-Day Endpoints

12% Heparin (n=2281) RR=0.94 P=0.57 Bivalirudin (n=2289) 9% 8.7% 8.3%

6% RR=0.66 P=0.008 5.9% 5.6% 5.0% 4.8% 4.6% 3% 3.1%

0 Death/MI/uTVR Death/MI/ MI Major Major Bleeding uTVR Bleeding

Kastrati et al. N Engl J Med 2008;359:688 Major Bleeding by Access Site

HORIZONS ACUITY 12%

Heparin + GPI 10% Heparin + GPI Bivalirudin Bivalirudin

8% 8.6%

6%

5.1% 4%

3.4% 2% 2.7% 2.7%

1.1% 0.9% 0 0.7% Femoral Radial Femoral Radial n=3,371 n=226 n=11,989 n=798 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

30-Day Events

Randomization to Randomization to Outcome Bivalirudin Better Heparin Better OR (95% CI) P (n = 13,255) (n = 12,569)

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

0 1 2

Bavry A et al. PlosOne 2015;10:e0127832 CHAMPION Trials

Steg PG et al. Lancet 2013;382:1981-1992 CHAMPION Trials 48-Hour 30-Day Death, MI, IDR, ST Death, MI, IDR, ST 10% 10%

8% OR=0.81 8% OR=0.89 (0.71-0.91) (0.81-0.98) P=0.0007 P=0.001 6% 6% 5.9% 5.2% 4% 4.7% 4% 3.8%

2% 2%

0 0 Clopidogrel Cangrelor Clopidogrel Cangrelor n=12,542 n=12,565 n=12,542 n=12,565

Steg PG et al. Lancet 2013;382:1981-1992 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

Steg PG et al. Lancet 2013;382:1981-1992 CHAMPION Trials ACUITY Blood Major Bleeding Transfusions 10% 5%

8% OR=1.53 4% (1.34-1.76) P<0.0001 6% 3%

OR=1.29 4% 4.2% 2% (0.94-1.76) P=0.115 2.8% 2% 1%

0.6% 0.7% 0 0 Clopidogrel Cangrelor Clopidogrel Cangrelor n=12,542 n=12,565 n=12,542 n=12,565

Steg PG et al. Lancet 2013;382:1981-1992 CHAMPION Trials

Steg PG et al. Lancet 2013;382:1981-1992 Optimal Anticoagulation—does it exist?

Bleeding

Thrombosis

intensity x duration Summary

• 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 , before exploring the next