Pharmacological strategies to reduce periprocedural bleeding

Jonathan ByrneKing’s College Hospital

Delicate balancing act

Ischaemic compications

BleedingPatient factors

Procedural factors

Pharmacology

Increasing thrombotic risk usually parallels increased bleeding risk

Incr

easi

ng ri

sk o

f isc

hem

ic c

ompl

icat

ions

Incr

easi

ng ri

sk o

f ble

edin

g co

mpl

catio

ns

Benefit Risk

Pharmacological strategies to reduce bleeding during PCI

1. Reduced dose/no heparin

2. LMW versus unfractionated heparin

3. Newer synthetic anticoaculants

1. Bivalirudin versus heparin/GPI

2. Reduced dose GPI

Incr

easi

ng ri

sk o

f ble

edin

g co

mpl

catio

ns

Stable

ACS

High Risk ACS/PPCI

Low dose or ‘no’ dose heparin?

Current heparin dosages used in PCI are not based on randomised data

Current strategies include weight adjusted/ACT adjusted or fixed dose

Is it safe to use no heparin in selected ‘low risk’ patients?

CIAO Study700 stable, elective patients. Type A/B lesions. No adjunctive GPI use

3.7

Eve

nt ra

te

(%)

Higher procedural CK release in the heparin group (3.1 vs 1.7%)

Stabile JACC 2008

MACE Major Bleeding

Low fixed dose or weight adjusted?

.Retrospective analysis of 698 patients

Elective PCI

Weight adjusted vs fixed dose UFH (3000 units)

More complex angiographic lesions than CIAO

Kidambi Cardiovasc Ther 2010Similar levels of TnI release

FUTURA/ OASIS 8

FUTURA/OASIS 8 JAMA 2010

2026 high risk ACS patients within a larger cohort treated with fondaparinux

Fixed low dose heparin (50u/kg) compared with ACT guided weight adjusted (85u/kg), regardless of GPI use

Major outcome composite of major bleeding at 48 hours

5.8

4.7

Eve

nt ra

te (%

)

3.9

4.8

Peri-PCI bleeding/vascular access complications

Peri-PCI bleeding/death/MI/TVR

FUTURA/OASIS 8 JAMA 2010

No benefit with low dose heparin

Low use of GPI (20%)

~40% radial access

Small reduction in minor bleeds

STEEPLE- LMWH in elective PCI

Major or minor bleeding

Major Bleeding Minor bleeding

5.9

6.5

1.2 1.2

2.8

4.85.3

5.9

P=0.01

P=0.05

Monatalescot NEJM 2006

trend towards higher mortality in the low dose LMWH group

40% GPI use

Eve

nt ra

te (%

)

Meta-analysis of 13 RCTs

Dumaine Arch Intern Med 2007

Avoid crossover from one to the other..

White Am Heart J 2006

>2000 patients undergoing PCI in the SYNERGY study

Event rate (%)

3.7

2.8

5.4P=0.03

P=0.047

Synthetic Xa inhibitors in ACS…

Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin)Primary efficacy endpoint: 5.8% (fondaparinux) vs 5.7% (enoxaparin) Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)Major bleeding: 2.2% (fondaparinux) vs 4.1% (enoxaparin)

0 1 2 3 4 5 6 7 8 90.00

0.01

0.02

0.03

0.04

Days

Cum

ulat

ive

haza

rd

Death, MI, refractory ischaemia Major bleeding

Enoxaparin

Fondaparinux

HR 0.5295% CI 0.44, 0.61

p<0.001

0 1 2 3 4 5 6 7 8 90.00

0.01

0.02

0.03

0.04

0.05

0.06

Days

Cum

ulat

ive

haza

rd Enoxaparin

Fondaparinux

HR 1.0195% CI 0.90, 1.13

OASIS 5 N Engl J Med 2006

Mortality at 6 months

OASIS 5 N Engl J Med 2006

Days

Cum

ulat

ive

haza

rd0.

00.

020.

040.

06

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

HR 0.8995% CI 0.80, 1.00

p=0.05

Bivalirudin in ACS/STEMI

Paucity of data comparing heparin directly with bivalirudin (without GPI)

Doses of heparin used in most of the studies are higher than standard UK/European practice

ISAR REACT 3

4570 patients with stable/unstable angina (with no biomarker rise

Preloaded with 600mg clopidogrel

140υg/kg UFH compared with bivalirudin

Triple end-point; net clinical benefit (MACE + bleeding)

Kastrati N Engl J Med 2008

BCIS Autumn Meeting 2008, Stoke on Trent, UK

BCIS Autumn Meeting 2008, Stoke on Trent, UK

ISAR REACT 3a

• Lower dose (100units/kg) heparin in patients preloaded with clopidogrel

• ISAR react 3 heparin group used as historical control

• Same eligibility/exclusion criteria (biomarker negative ACS)

BCIS Autumn Meeting 2008, Stoke on Trent, UK

**Almost identical to those seen with bivalirudin in previous study

Kastrati ESC 2010

**

**

STEMI- HORIZONS AMID

eath

(%)

Dea

th (%

)

Time in DaysTime in Days

2.9%

1.8%

Heparin + GPIIb/IIIa inhibitor (n=1802)Bivalirudin monotherapy (n=1800)

0.3%0.2%

Cardiac

Non cardiac

HR [95%CI] =0.62 [0.40, 0.96]

P=0.029

Stone NEJM 2008

HORIZONS-AMI 30 day outcomes

Stone NEJM 2008

12.1

8.3

5.5

9.2

4.9 5.4

0

5

10

15

20

Net adverse clinical events

Major bleeding (non CABG)

MACE

30 d

ay e

vent

rat

es (%

)

Heparin + GPIIb/IIIa inhibitor (N=1802) Bivalirudin monotherapy (N=1800)

Reduced dose GPI?

• Early data (EPIC) suggested reduced bleeding but higher ischaemic complications with bolus abciximab

• EASY PCI (transradial) - clopidogrel loading. no difference between bolus/infusion of abciximab. Bleeding rates 0.5% (TRI)

• BRIEF PCI – ~700 patients (stable/ACS). Transfemoral. Clopidogrel preloaded. 2 hour versus 18 hour eptifibatide infusion

Major Bleeding Minor Bleeding

Event R

ate (%)

1

4.2

17.6

21.2

P=0.02

Lower major bleeding rates

~40% ACS 97% femoral access

Fung JACC 2009

Conclusions• Tailored treatment for individual patients to balance

thrombotic/bleeding risk.

• Stepwise approach to antithrombotics with increasing bleeding risk

• Avoid switching between antithrombins (except UFH from fondaparinux)

• Pharmacology should be coupled with other bleeding avoidance strategies (TRI in particular)