Beyond Access Site Bleeding: Incidence, Sources, and Impact of Antithrombotic Therapy in the PCI Patient

1. Beyond Access Site Bleeding:
Incidence, Sources, and Impact
of Antithrombotic Therapy in the
PCI Patient
A Combined Analysis of 17,393 Patients REPLACE-2,
ACUITY and HORIZONS-AMI
Freek Verheugt, Steven Steinhubl, Harald Darius, Martial Hamon, Gabriel
Steg, Marco Valgimigli, Steven Marso, Sunil Rao, Anthony Gershlick
Onze Lieve Vrouwe Gasthuis, Amsterdam
Verheugt JACC Cardio Interv 2011;4:191-7:

2. How Does Access Site Impact Major
Bleeding Rates in PCI Patients?
● Meta-analysis of 18 randomized trials (5 had no bleeding events)
of femoral versus radial access involving 4,458 patients
undergoing angiography or PCI
Major Bleeding
Radial access reduced
major bleeding by
73%, with a trend for
reductions in the
composite of death,
MI, or stroke (2.5%
vs 3.8%, P = .058)
Jolly SS. Am Heart J 2009;157:132-40.

3. Non-CABG bleeding* in PCI-treated
ACS patients
84%
Radial
88% Access
6 Femoral
Access
5
% Protocol Major Bleed
4
3
5.4
4.7
2 4.1
3.1
1 2.1
0
ACUITY EARLY ACS SYNERGY OASIS 5 ABOARD
30 Days 120 hours 30 Days 30 Days 30 Days
*Bleeding Scales: ACUITY TIMI Maj+Min TIMI Maj ESSENCE STEEPLE
Stone N EJM 2006;355:2203-16; Giugliano NEJM 2009;360:2176-90; SYNERGY JAMA. 2004;292:45-54; Mehta JACC2007;50:1742–51 Cayla Heart 2011

4. Purpose
Data from over 17,300 patients undergoing a PCI for
a wide variety of clinical diagnoses in 3 large-scale
randomized trials was analyzed to identify
• the relative incidence of access site and non-
access site related bleeding
• the association of these events with 1-year
mortality and
• the relative impact of randomized antithrombotic
therapy (bivalirudin versus heparin + GPIIb/IIIa
antagonist) on each type of bleeding
Verheugt JACC Cardio Interv 2011;4:191-7:

5. Analysis Population:
● All PCI patients (ITT) from:
REPLACE-2 N = 6,002
ACUITY N = 7,789
HORIZONS N = 3,602
N = 17,393
● For antithrombotic comparisons the bivalirudin + GPIIb/IIIa
arm (n=2609) of ACUITY was excluded, N= 14,784 patients
Verheugt JACC Cardio Interv 2011;4:191-7:

6. Patient Characteristics N=17,393
Age (years) 62.3 ± 11.4
Age ≥ 75 years (%) 16.0%
Weight (kg) 85.6 ± 17.8
Female (%) 25.7%
Diabetes (%) 25.1%
Current Smoker (%) 32.3%
CrCl < 60 17.0%
Hypertension 63.5%
Anemia 8.%
Prior PCI 31.6%
Prior CABG 14.8%
Presenting Diagnosis
STEMI 20.7%
NSTEMI 30.0%
Unstable Angina 29.5%
Stable Angina 8.6%
Other 11.2%
Verheugt JACC Cardio Interv 2011;4:191-7:

7. Procedural Characteristics N=17,393
Balloon/Atherectomy only 6.5%
Stent
Bare metal only 50.9%
Any drug-eluting 58.2%
Multivessel intervention 12.6%
Femoral artery access site* 92.9%
Radial artery access site* 7.1%
Baseline medications
Aspirin pre-angiography 98.0%
Thienopyridine pre- 80.0%
angiography
Statins 49.9%
* Access site was not documented in REPLACE-2 but assumed to be femoral
Verheugt JACC Cardio Interv 2011;4:191-7:

8. Sources of Bleeding
• Access/puncture
• Retroperitoneal
• Intracranial
1. Access Site Only
• Intraocular
2. Both Access and • Gastrointestinal
Non-Access • Genitourinary
• Pleural
3. Non-Access Site Only • Pulmonary
4. No Identified Location • Head and Neck
• Epistaxis
• Hemoptysis
Bleeding location was determined locally by the • Hematemasis
investigators and recorded on the case report form • Gingival
• Other
Verheugt JACC Cardio Interv 2011;4:191-7:

9. Sources and Incidence of Bleeding
● Pooled analysis REPLACE-2, ACUITY, HORIZONS-AMI, N=17,393
No
Location Non-­‐Access
Site
O nly
Both Access
Site
O nly
6
5.2% 5.3% (n=925)
5
1.5 1.6
(281) Non- access
Percentage (%)
4 site bleeds are
0.5 3.3% 61.4% of TIMI
0.8
(142)
3 0.7 bleeding
0.8
(145)
events
2 1.6%
2.5 0.5
1 0.2 2.1 2.1%
0.2 Access site
0.7 only accounts
0
for 38.6%
Protocol
Major TIMI
Major TIMI
Major
+
Minor
The safety and effectiveness of bivalirudin have not been established in patients with ACS who are not undergoing PTCA or PCI
Verheugt JACC Cardio Interv 2011 4:191-7, Steinhubl GISE 2009

10. Sources and incidence of bleeding
● Pooled analysis REPLACE-2, ACUITY, HORIZONS-AMI, N=17,393
No
Location Non-­‐Access
Site
Only Both Access
Site
Only
6
5.3% (n=925)
5 Non- access
1.6 site bleeds are
Percentage (%)
4
61.4% of TIMI
3.3%
0.8 bleeding
3
events
0.8
2
1.6%
Access site
1 2.1 2.1% only accounts
for 38.6%
0
TIMI
Major
+
Minor
The safety and effectiveness of bivalirudin have not been established in patients with ACS who are not undergoing PTCA or PCI
Verheugt JACC Cardio Interv 2011 4:191-7, Steinhubl GISE 2009

11. Incidence and source of bleeding
excluding access site
50
45.2
45
40
35
30
% of Patients
25
20 17.9
15
15
10.1
10 6.9
5 3.7
0.9
0
GI
Other
GU
Head and
Pulmonar
Intracrani
GU GI Head/Neck Pulmonary ICH Other No site
Location
Neck
No
al
y
Axis Title
Verheugt JACC Cardio Interv 2011;4:191-7:

12. 1-year Mortality Associated with
Bleeding and Source (unadjusted)
1-Year Relative Risk (95%
Mortality Confidence Interval)
(%)
Compared with No Bleed
p-value
No bleed
2.54
-
-
Access Site Only
6.16
2.33 (1.53 – 3.53)
<0.001
All Non-Access Site
14.4
5.40 (4.32 – 6.74)
<0.0001
Non-Access Only
14.1
5.52 (3.62 – 8.40)
<0.001
Both Access and
14.5
5.70 (3.78 – 8.61)
<0.001
Non-Access
Indeterminate
14.6
5.18 (3.82 – 7.03)
<0.001
Verheugt JACC Cardio Interv 2011;4:191-7: 12

13. Relative Risk of 1-year Mortality Associated
with Bleeding and Source (unadjusted)
6.0 P<0.0001 for all bleeding versus none
5.7
5.5 5.4
5.0 5.2
Relative Risk 1-Year Mortality
4.0
3.0
2.0 2.3
1.0
0.0
Access Only Both Non-Access No Location All Non-Access
Only
Verheugt JACC Cardio Interv 2011;4:191-7:

14. Risk for 1 year mortality
● 1-year mortality risk from non-access site bleeding vs access site =
HR 2.27 (95%CI 1.42-3.64), p=0.0007
Relative Risk P-Value
Unadjusted
Access site 2.33 (1.53 – 3.53) <0.0001
Non-access site 5.40 (4.32 – 6.74) <0.0001
Hazard ratio
Adjusted
Access site 1.82 (1.17–2.83) 0.008
Non-access site 3.94 (3.07–5.15) <0.0001
0 1 2 3 4 5 6 7
No Bleed TIMI Major + Minor Bleed
Verheugt JACC Cardio Interv 2011;4:191-7:

15. Impact of Antithrombotic Therapy on
Bleeding by Source
Relative Risk P-Value
TIMI Major + Minor Bleeding
Access Only 0.45 (0.35-0.59) <0.0001
Both 0.31 (0.19-0.49) <0.0001
Non Access Only 0.70 (0.47-1.05) 0.08
No Location 0.75 (0.58-0.96) 0.02
All non-access 0.62 (0.51-0.75) <0.0001
0 0.5 1 1.5 2
Bivalirudin better Hep + GPI better
Verheugt JACC Cardio Interv 2011;4:191-7:

16. Impact of Randomized Antithrombotic
Therapy on TIMI Bleeding by Location
Hep + Bivalirudin Relative Risk
GPI (%) (%)
Intracranial 0.04 0.03 0.66 (0.11-3.97)
GI 0.64 0.28 0.44 (0.26-0.74)
GU 0.64 0.28 0.44 (0.26-0.74)
NEENT 0.33 0.22 0.66 (0.35-1.24)
Pulmonary 0.18 0.05 0.31 (0.10-0.94)
Other 0.3 0.15 0.49 (0.24-1.01)
No location bleed 2.82 1.83 0.65 (0.52-0.80)
All Non-Access 3.66 2.27 0.62 (0.51-0.75)
0 0.5 1 1.5 2
Bivalirudin better Hep + GPI better
Verheugt JACC Cardio Interv 2011;4:191-7:

17. Conclusions
• Almost two-thirds of PCI patients with a TIMI major/minor bleed
involve a bleeding source unrelated to the access site.
• Bleeding, irrespective of the source, is significantly associated
with increased mortality at 1 year.
• Importantly, non-access bleeding is associated with >2X the risk
of mortality than is access bleeding.
• Randomization to bivalirudin resulted in a 38% reduction in TIMI
major/minor and a 43% reduction in TIMI major bleeding
• Bivalirudin vs heparin + a GPI significantly reduces all TIMI
bleeding events (~40%), and to a comparable degree regardless
of the bleeding location
• Bivalirudin would thus be expected to improve patient outcomes
irrespective of the individual patient s risk for access site bleeding
or use of transradial vs. femoral access
Verheugt JACC Cardio Interv 2011;4:191-7: