Are Benefits of Fondaparinux Maintained According to Various Procedural Strategies?

1

• Are Benefits of Fondaparinux Maintained
  According to Various Procedural Strategies?
• Insights from OASIS 5

2
Prognostic Impact of Major Bleeding in Patients
With Acute Coronary Syndromes
Pooled Relative Risks of Mortality Increase
Random-effects Meta-analysis of 10 Studies
No Major Bleeding
Major Bleeding
Study
RR (95 CI)
Random Effects Model
Deaths. No. / Patients. No.
Ali et al 2004
9/89 24/931
3.92 1.88. 8.18
Eikelboom et al 2006
60/470 833/33676
5.16 4.04. 6.60
Feit et al 2007
10/194 9/5807
33.26 13.67. 80.92
Kinnaird et al 2003
44/588 54/8992
12.46 8.44. 18.39
Lenderink et al 2004
18/98 120/7702
11.79 7.49. 18.55
Manoukian et al 2007
47/644 159/13175
6.05 4.41. 8.29
Moscucci et al 2003
85/546 624/15348
3.83 3.10. 4.72
Rao et al 2005
79/307 549/19110
8.96 7.28. 11.02
Segev et al 2005
15/79 86/5763
12.72 7.71. 21.01
Yusuf et al 2006
83/629 545/19449
4.71 3.79. 5.85
Total (95 CI)
450/3644 3003/129953
7.60 5.55. 10.40
Test for overall effect Z 12.65 (P lt 0.00001)
0.01
0.1
1
10
100
N133.597 patients Major Bleeding 2.7
Lower Mortality
Higher Mortality
RR (95 CI)
(in hospital or 30-Day)
Hamon M. et al. EuroIntervention 2007
A Systematic Review and Meta-analysis
3
Entry site complications Radial vs Femoral
Meta-analysis of randomized studies
Pooled Relative Risks of Access site
complications Decrease
Random-effects Meta-analysis of 17 Studies
Study
Radial
Femoral
RR (random)
RR (random)
n/N
n/N
95 CI
95 CI
ACCESS
0/300 6/300
0.08 0.00. 1.36
Achembach
0/152 4/155
0.11 0.01. 2.09
BRAFE Stent
1/56 3/56
0.33 0.04. 3.11
CARAFE
0/140 2/70
0.10 0.00. 2.07
FARMI
2/57 11/57
0.18 0.04. 0.78
Gorge
1/214 1/216
1.01 0.06. 16.03
Grinfeld
0/138 3/141
0.15 0.01. 2.80
Mann 1996
0/76 4/76
0.11 0.01. 2.03
Mann 1998
0/74 3/68
0.13 0.01. 2.50
Moriyama
0/108 3/92
0.12 0.01. 2.33
OCTOPLUS
3/192 12/185
0.24 0.07. 0.84
OUTCLAS
0/322 1/322
0.33 0.01. 8.15
RADIAL-AMI
1/25 1/25
1.00 0.07. 15.12
RADIAMI
0/50 3/50
0.14 0.01. 2.70
Reddy
0/25 1/50
0.65 0.03. 15.50
TEMPURA
0/77 2/72
0.19 0.01. 3.83
Tian
0/189 2/195
0.21 0.01. 4.27
Total (95 CI)
8/2195 62/2130
0.22 0.12. 0.39
Test for overall effect Z 5.09 (P lt 0.00001)
Incidence 0.36 vs 2.9 RR 0.22 0.12-0.39. 78
reduction NNT 39
0.001
0.01
0.1
1
10
100
1000
Favours Radial
Favours Femoral
Adapted and updated from Agostoni et al J Am Coll
Cardiol 2004
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PCI Population in Oasis 5 during treatment period
(Access sub-study analysis)
Impact of TRI on efficacy and bleeding in ACS
patients treated with a contemporary
pharmacological regimen?
5565 PCI patients
4971 Femoral access
594 Radial access
2519 Fondaparinux
2452 Enoxaparin
319 Fondaparinux
275 Enoxaparin
Post hoc analysis to examine the impact of the
TRA vs TFA on PCI-related major bleeding and
patientsoutcomes
Patients randomized and that got treatment up
to discharge or up to 8 days Patients with
deferred PCI, brachial access or whose records
lacked access-site information excluded
5
Baseline Clinical Characterstics
TFA 89 and TRA 11
75

80
.
0

70

Femoral 4971
70
.
0

Radial 594
60
.
0

50
.
0

40
.
0

24

30
.
0

22

20

17

17

15

20
.
0

9

7

7

4

10
.
0

0
.
0

Male
Diabetes
Heart Failure
Prior MI
Prior PCI
Prior CABG
plt0.05
6
Similar High-risk Features in both Femoral and
Radial access groups
71.9
80

68.1
70

60

43.8
41.6
50

40

30

Troponin Positive ST Depression gt 1mm
20

10

0

Femoral
Radial
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Treatment Recommendations1 and Oasis 5 PCI
Patients

• ESC Guidelines for the management of NSTEACS Eur
  Heart J 2007281598-1660
• Plt0.05 for ACEI and GPI

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High revascularization success rate whatever the
vascular access
7944 lesions
7095 with femoral access
849 with radial access
3585 under Fondaparinux
3510 under Enoxaparin
460 under Fondaparinux
389 under Enoxaparin
92.1
91.7
93.7
94.6
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Procedural DetailsStenting by Access site
Percutaneous coronary interventions (analysis per
lesion)
92.9
91.6
1.00
0.90
70.5
70.7
0.80
0.70
0.60
0.50
30.0
0.40
25.4
0.30
0.20
8.4
7.1
0.10
0.00
Any stent
Bare stent
Drug Eluting Stent
No
Plt0.05
10
Most PCIs performed within 72 hours
At day 3 75 in femoral group At day 3 71 in
radial group
PCI per day
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Endpoint Measures at Day 9
Radial vs. Femoral
Endpoint
Femoral (n4971)
Hazard ratio 95 CI
Radial (n594)
p-value
HR (95 CI)
Net clinical outcome
11.4
8.6
0.74 (0.56-0.99)
0.043
Death/MI/RI
8.5
7.9
0.93 (0.69-1.26)
0.649
Major bleeding
3.7
1.0
0.27 (0.12-0.62)
0.002
0
1
2
Radial better
Femoral better
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Endpoint Measures at Day 30
Radial vs. Femoral
Endpoint
HR (95 CI)
Femoral (n4971)
Hazard ratio 95 CI
Radial (n594)
p-value
Net clinical outcome
12.8
9.1
0.70 (0.53-0.93)
0.013
Death/MI/RI
9.5
8.4
0.88 (0.66-1.18)
0.399
Major bleeding
4.1
1.2
0.28 (0.13-0.60)
lt0.001
0
1
2
Radial better
Femoral better
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Endpoint Measures at 6 months
Radial vs. Femoral
Endpoint
HR (95 CI)
Femoral (n4971)
Hazard ratio 95 CI
Radial (n594)
p-value
Net clinical outcome
15.9
11.1
0.69 (0.53-0.88)
0.003
Death/MI/RI
12.3
10.1
0.82 (0.63-1.07)
0.14
Major bleeding
4.8
1.5
0.31 (0.16-0.61)
lt0.001
0
1
2
Radial better
Femoral better
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Endpoint Measures Radial vs Femoral
Death, MI, RI
Femoral
Radial
Death, MI, RI
14
12.3
12
10.1
9.5
10
8.5
8.4
7.9
8
6
4
2
0
day 9
day 30
day 180
Primary endpoint of the study
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Mortality at 6 Months
Radial vs. Femoral
3.4
0.03
2.4
0.02
Cumulative Hazard
HR 0.68 95 CI 0.43-1.07 p0.09
0.01
Non-adjusted HR 0.68 0.40-1.18 p0.17
NNT100
0.0
0
30
60
90
120
150
180
Days
16
Primary endpoint Death, MI, RIin PCI patients
at Day 9
(during blind study drug administration)
P 0.77
P 0.47
HR 1.08 95 CI 0.62-1.89
HR 1.07 95 CI 0.89-1.30
8.2
8.8
8.0
7.8
(N275)
(N319)
(N2452)
(N2519)
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Protocol Major Bleeding in PCI patients at Day 9
(during blind study drug administration)
P 0.85
P lt0.001
HR 0.86 95 CI 0.17- 4.26
HR 0.44 95 CI 0.32- 0.60
5.1
2.3
1.1
0.9
(N275)
(N319)
(N2452)
(N2519)
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GPIs use in PCI patientsEndpoints Measures at
day 9during blind study drug administration
5595 patients
GPI 2397 (43)
GPI- 3198 (57)
1173 Enoxaparin
1224 Fondaparinux
1568 Enoxaparin
1630 Fonaparinux
Enoxaparin
Fondaparinux
Major Bleeding HR 0.51 (95 CI, 0.34-0.78)
Major Bleeding HR 0.37 (95 CI, 0.24-0.58)
GPI
GPI-
P0.002
plt0.001
19
GPIs use in PCI patientsEndpoints Measures at
day 9Comparing Radial vs Femoral
5565 patients
GPI 2389 (43)
GPI- 3176 (57)
2057 femoral
332 Radial
2914 Femoral
262 Radial
Femoral
Radial
GPI
GPI-
P0.08
P0.08
P0.02
P0.03
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ConclusionsInsights from OASIS 5

• Most PCIs in NSTE-ACS patients are currently
  performed within 72 hours of admission by
  trans-femoral approach (TFA).
• Compared to TFA, TRA is associated with similar
  rates of ischemia and significant reduction of
  major bleeding, leading to better net clinical
  outcome.
• Wether TRA by reducing major bleeding can impact
  event-free survival warrants a randomized trial
  adequately powered. OASIS 5 access sub-study
  posthoc analysis (non randomised),
  hypothesis-generating analysis rather than
  hypothesis-testing.
• A fondaparinux strategy
• - Provides similar rates of ischemia compared to
  Enoxaparin either by TRA or TFA
• - Reduces major bleeding and Improves net
  clinical outcome in TFA compared to an enoxaparin
  based regimen with or without GPI.

Modifiable factors Arterial access site
Antithrombotic regimen
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Identification of Risk Factors For Bleeding in
ACS Patients and Preventive actions
Risk Factors For Bleeding in ACS Patients Risk Factors For Bleeding in ACS Patients Risk Factors For Bleeding in ACS Patients
Patient related Procedural related Treatment related
Female gender Older Hypertension Obesity Low weight Renal failure Platelet low count Medical history (GI disease) Puncture site (femoral vs radial) Level of puncture (femoral) Larger arterial sheath Prolonged sheath time IABP placement Concomitant venous sheath Need for repeat intervention Over anticoagulation Type of anticoagulation (antiXa, direct thrombin inhibtor or LMWH and UFH) GP IIb/IIIa inhibitors Thrombolytic
Identification
Reducing Bleeding Risk Preventive Actions Reducing Bleeding Risk Preventive Actions Reducing Bleeding Risk Preventive Actions
Patient level Procedural level Treatment level
Patient information (coughing, heavy lifting to be avoided after femoral puncture) Nurse training for early recognition of retroperitoneal hemorrhage Perfect puncture site Angiographic control before closure device use Radial Access Different access sites for staged procedures Decrease size of arterial sheath ACT during procedures for anticoagulation monitorring Discontinuation of antithrombin after uncomplicated PCI New anticoagulant agents (Bivalirudin, Fondaparinux)
Prevention
Hamon M. et al. EuroIntervention 2007