Are Benefits of Fondaparinux Maintained According to Various Procedural Strategies?

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




Death/MI/RI

Major bleeding



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




Death/MI/RI

Major bleeding



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 (

%)


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)


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

Documents

Are Benefits of Fondaparinux Maintained According to Various Procedural Strategies?