are benefits of fondaparinux maintained according to various procedural strategies? insights from...
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Are Benefits of Fondaparinux Maintained According to Various Procedural Strategies?
Insights from OASIS 5
Martial Hamon, MD, FESCUniversity Hospital of Caen
Normandy, France
Pooled Relative Risks of Mortality Increase*Pooled Relative Risks of Mortality Increase*
Random-effects Meta-analysis of 10 Studies
Hamon M. et al. EuroIntervention 2007
Prognostic Impact of Major Bleedingin Patients With Acute Coronary Syndromes
A Systematic Review and Meta-analysis
(*in hospital or 30-Day)
Total (95% CI) 450/3644 3003/129953 7.60 [5.55. 10.40]
Study Major
Bleeding No MajorBleeding RR (95% CI)
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]
Test for overall effect: Z = 12.65 (P < 0.00001)
0.01 0.1 1 10 100
Lower Mortality Higher Mortality
Deaths. No. / Patients. No.
RR (95% CI)
Random Effects Model
N=133.597 patientsMajor Bleeding 2.7%
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
Adapted and updated from Agostoni et al J Am Coll Cardiol 2004
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 < 0.00001)
0.001 0.01 0.1 1 10 100 1000
Favours Radial Favours Femoral
Incidence: 0.36% vs 2.9%RR 0.22 [0.12-0.39]. 78% reductionNNT 39
PCI Population in Oasis 5 during treatment period (Access sub-study analysis)
5565 PCI patients*
4971 Femoral access 594 Radial access
2519 Fondaparinux 2452 Enoxaparin 319 Fondaparinux 275 Enoxaparin
* 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
Impact of TRI on efficacy and bleeding in ACS patients
treated with a contemporary pharmacological regimen?
Post hoc analysis to examine the impact of the TRA vs TFA on PCI-related: major bleeding and patients’outcomes
Baseline Clinical Characterstics
70%75%
24%20%
7% 7%
22%17% 17%15%
9%4%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
70.0%
80.0%
Male* Diabetes* Heart Failure Prior MI* Prior PCI Prior CABG*
Femoral = 4971Radial = 594
*p<0.05
TFA 89% and TRA 11%TFA 89% and TRA 11%
Similar High-risk Features in both Femoral and Radial access groups
Troponin Positive
ST Depression > 1mm
68.1%
43.8%
71.9%
41.6%
0%
10%
20%
30%
40%
50%
60%
70%
80%
Femoral Radial
Treatment Recommendations1 and Oasis 5 PCI Patients
89%
85%
69%
39%
92%
99%
88%
60%
89%
53%
95%
99%
0% 20% 40% 60% 80% 100%
ASA
Clopidogrel
GPI's
BB
ACEI
Lipid Lowering drugs
Radial
Femoral
1. ESC Guidelines for the management of NSTEACS Eur Heart J 2007;28:1598-1660[P<0.05 for ACEI and GPI]
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
0
20
40
60
80
100
Femoral0
20
40
60
80
100
Radial
92.1% 91.7% 93.7% 94.6%
91.6%92.9%
70.7% 70.5%
25.4%30.0%
8.4% 7.1%
0.00
0.10
0.20
0.30
0.40
0.50
0.60
0.70
0.80
0.90
1.00
Any stent Bare stent Drug Eluting Stent* No
Femoral = 7095Radial = 849
Procedural DetailsStenting by Access site
Percutaneous coronary interventions(analysis per lesion)
*P<0.05
Most PCI’s performed within 72 hours
0%
5%
10%
15%
20%
25%
30%
35%
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8
Femoral Radial
At day 3: 75% in femoral groupAt day 3: 71% in radial group
% PCI per day
Endpoint Measures at Day 9Endpoint Measures at Day 9RadialRadial vs. vs. FemoralFemoralRadialRadial vs. vs. FemoralFemoral
11.4%11.4%8.6%8.6% 0.74 (0.56-0.99) 0.043
Hazard ratioHazard ratio±95% CI±95% CI
Hazard ratioHazard ratio±95% CI±95% CIEndpoint
Net clinical outcome
Death/MI/RI
Major bleeding
Radial betterRadial better Femoral betterFemoral better
RadialRadial(n=594)(n=594)
FemoralFemoral(n=4971)(n=4971) HR (95% CI) p-value
8.5%8.5%7.9%7.9% 0.93 (0.69-1.26) 0.649
3.7%3.7%1.0%1.0% 0.27 (0.12-0.62) 0.002
0 1 2
Endpoint Measures at Day 30Endpoint Measures at Day 30
Radial vs. FemoralRadial vs. Femoral
12.8%12.8%9.1%9.1% 0.70 (0.53-0.93) 0.013
Hazard ratioHazard ratio±95% CI±95% CI
Hazard ratioHazard ratio±95% CI±95% CIEndpoint
Net clinical outcome
Death/MI/RI
Major bleeding
Radial betterRadial better Femoral betterFemoral better
RadialRadial(n=594)(n=594)
FemoralFemoral(n=4971)(n=4971)
HR (95% CI)p-value
9.5%9.5%8.4%8.4% 0.88 (0.66-1.18) 0.399
4.1%4.1%1.2%1.2% 0.28 (0.13-0.60) <0.001
0 1 2
Endpoint Measures at Endpoint Measures at 6 months6 monthsEndpoint Measures at Endpoint Measures at 6 months6 months
Radial vs. FemoralRadial vs. Femoral
15.9%15.9%11.1%11.1% 0.69 (0.53-0.88) 0.003
Hazard ratioHazard ratio±95% CI±95% CI
Hazard ratioHazard ratio±95% CI±95% CIEndpoint
Net clinical outcome
Death/MI/RI
Major bleeding
Radial betterRadial better Femoral betterFemoral better
RadialRadial(n=594)(n=594)
FemoralFemoral(n=4971)(n=4971)
HR (95% CI)p-value
12.3%12.3%10.1%10.1% 0.82 (0.63-1.07) 0.14
4.8%4.8%1.5%1.5% 0.31 (0.16-0.61) <0.001
0 1 2
Endpoint Measures: Radial vs Femoral
Death, MI, RI*
*Primary endpoint of the study
8.5%9.5%
12.3%
7.9% 8.4%
10.1%
0%
2%
4%
6%
8%
10%
12%
14%
day 9 day 30 day 180
Femoral Radial
Death, MI, RI
Mortality at 6 MonthsMortality at 6 MonthsRadial vs. FemoralRadial vs. Femoral
HR 0.6895% CI [0.43-1.07]p=0.09
DaysDays
Cu
mu
lati
ve H
azar
dC
um
ula
tive
Haz
ard
0.0
0.01
0.02
0.03
0 30 60 90 120 150 180
Non-adjusted: HR 0.68 [0.40-1.18] p=0.17Non-adjusted: HR 0.68 [0.40-1.18] p=0.17
3.4%
2.4%
NNT~100NNT~100Femoral
Radial
Primary endpoint: Death, MI, RIin PCI patients at Day 9
Radial Femoral
9 d
ay e
ven
ts (
%)
Enoxaparin Fondaparinux
P = 0.77 P = 0.47
(N=275) (N=319) (N=2452) (N=2519)
HR 1.0895% CI [0.62-1.89]
(during blind study drug administration)
HR 1.0795% CI [0.89-1.30]
8.0% 7.8% 8.2% 8.8%
Radial Femoral
9 d
ay e
ven
ts (
%)
Enoxaparin Fondaparinux
P = 0.85 P <0.001
(N=275) (N=319) (N=2452) (N=2519)
HR 0.8695% CI [0.17- 4.26]
(during blind study drug administration)
HR 0.4495% CI [0.32- 0.60]
1.1% 0.9%
5.1%
2.3%
Protocol Major Bleeding in PCI patients at Day 9
5595 patients
GPI +2397 (43%)
GPI-3198 (57%)
1173Enoxaparin
1224Fondaparinux
1568Enoxaparin
1630Fonaparinux
0
5
10
15
20
Death D/MI/RI Bleed Net Out.0
5
10
15
20
Death D/MI/RI Bleed Net Out.
GPI’s use in PCI patientsEndpoints Measures at day 9
during blind study drug administration
Major BleedingHR 0.51 (95% CI, 0.34-0.78)
P=0.002
GPI+ GPI-
p=<0.001
Major BleedingHR 0.37 (95% CI, 0.24-0.58)
Enoxaparin Fondaparinux
5565 patients
GPI +2389 (43%)
GPI-3176 (57%)
2057femoral
332Radial
2914Femoral
262Radial
0
5
10
15
20
Death D/MI/RI Bleed Net Out.0
5
10
15
20
Death D/MI/RI Bleed Net Out.
P=0.02
GPI+ GPI-P=0.08
P=0.03
P=0.08
GPI’s use in PCI patientsEndpoints Measures at day 9Comparing Radial vs Femoral
Femoral Radial
ConclusionsInsights from OASIS 5
I. Most PCI’s in NSTE-ACS patients are currently performed within 72 hours of admission by trans-femoral approach (TFA).
I. Compared to TFA, TRA is associated with is associated with similar rates of ischemiasimilar rates of ischemia and and significant significant reduction of major bleeding, reduction of major bleeding, leading to leading to better net clinical better net clinical outcome.outcome.
I. Wether TRA by reducing major bleeding can impact event-free survival warrants a randomized trial adequately powered. OASIS 5 access sub-study: post’hoc analysis (non randomised), hypothesis-generating analysis rather than hypothesis-testing.
II.II. A fondaparinux strategy:A fondaparinux strategy:- Provides similar rates of ischemia compared to Enoxaparin either by - Provides similar rates of ischemia compared to Enoxaparin either by TRA or TFATRA or TFA- Reduces major bleeding and Improves net clinical outcome in TFA - Reduces major bleeding and Improves net clinical outcome in TFA compared to an enoxaparin based regimen with or without GPI.compared to an enoxaparin based regimen with or without GPI.
Modifiable factors : Arterial access site & Antithrombotic regimenModifiable factors : Arterial access site & Antithrombotic regimen
Risk Factors For Bleeding in ACS Patients
Patient related Procedural related Treatment related
Female genderOlderHypertensionObesityLow weightRenal failurePlatelet low countMedical history (GI disease)
Puncture site (femoral vs radial)Level of puncture (femoral)Larger arterial sheathProlonged sheath timeIABP placementConcomitant venous sheathNeed for repeat intervention
Over anticoagulationType of anticoagulation (antiXa, direct thrombin inhibtor or LMWH and UFH)GP IIb/IIIa inhibitorsThrombolytic
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 siteAngiographic control before closure device useRadial AccessDifferent access sites for staged proceduresDecrease size of arterial sheath
ACT during procedures for anticoagulation monitorringDiscontinuation of antithrombin after uncomplicated PCINew anticoagulant agents (Bivalirudin, Fondaparinux)
Identification of Risk Factors For Bleedingin ACS Patients and Preventive actions
Hamon M. et al. EuroIntervention 2007
Identification
Prevention