Randomized, Blinded Trial Comparing Fondaparinux With

Unfractionated Heparin in Patients Undergoing

Contemporary Percutaneous Coronary Intervention
Arixtra Study in Percutaneous Coronary Intervention: A Randomized
Evaluation (ASPIRE) Pilot Trial
Shamir R. Mehta, MD, MSc; Philippe Gabriel Steg, MD; Christopher B. Granger, MD;
Jean-Pierre Bassand, MD; David P. Faxon, MD; Jeffrey I. Weitz, MD; Rizwan Afzal, MSc;
Bonnie Rush; Ron J.G. Peters, MD; Madhu K. Natarajan, MD; James L. Velianou, MD;
David M. Goodhart, MD; Marino Labinaz, MD; Jean-Francois Tanguay, MD;
Keith A.A. Fox, MBChB; Salim Yusuf, DPhil; for the ASPIRE Investigators*
BackgroundFactor Xa plays a central role in the generation of thrombin, making it a novel target for treatment of arterial
thrombosis. Fondaparinux is a synthetic factor Xa inhibitor that has been shown to be superior to standard therapies for
the prevention of venous thrombosis. We performed a randomized trial to determine the safety and feasibility of
fondaparinux in the percutaneous coronary intervention (PCI) setting.
Methods and ResultsA total of 350 patients undergoing elective or urgent PCI were randomized in a blinded manner
to receive unfractionated heparin (UFH), 2.5 mg fondaparinux IV, or 5.0 mg fondaparinux IV. Randomization was
stratified for planned or no planned use of glycoprotein (GP) IIb/IIIa antagonists. The primary safety outcome was total
bleeding, which was a combination of major and minor bleeding events. The incidence of total bleeding was 7.7% in
the UFH group and 6.4% in the combined fondaparinux groups (hazard ratio, 0.81; 95% confidence interval, 0.35 to
1.84; P0.61). Bleeding was less common in the 2.5-mg fondaparinux group compared with the 5-mg fondaparinux
group (3.4% versus 9.6%, P0.06). The composite efficacy outcome of all-cause mortality, myocardial infarction,
urgent revascularization, or need for a bailout GPIIb/IIIa antagonist was 6.0% in the UFH group and 6.0% in the
fondaparinux group, with no significant difference in efficacy among the fondaparinux doses compared with UFH.
Coagulation marker analysis at 6 and 12 hours after PCI demonstrated that fondaparinux was superior to UFH in
inducing a sustained reduction in markers of thrombin generation, as measured by prothrombin fragment F1.2 (P0.02).
ConclusionsIn this pilot study of patients undergoing contemporary PCI, factor Xa inhibition with the synthetic
anticoagulant fondaparinux in doses of 2.5 and 5.0 mg was comparable to UFH for clinical safety and efficacy outcomes.
These data form the basis for further evaluation of fondaparinux in arterial thrombosis. (Circulation. 2005;111:13901397.)
Key Words: angioplasty stents anticoagulants complications

nfractionated heparin (UFH) has traditionally been used to

prevent complications in patients undergoing percutaneous
coronary intervention (PCI).1,2 UFH exerts its anticoagulant effect
by catalyzing the inhibition of thrombin and factor Xa by antithrombin. UFH has several important limitations, including its unpredictable anticoagulant effect necessitating careful laboratory monitor-

ing, high protein binding, and inactivation by platelet factor 4.3 To

overcome some of these limitations, newer agents with more
predictable anticoagulant effect and with greater antifactor Xa
activity are being evaluated. Factor Xa occupies a pivotal role in the
clotting cascade because it is the final common pathway linking the
intrinsic and extrinsic systems leading to the generation of thrombin,

Received July 19, 2004; revision received December 13, 2004; accepted December 21, 2004.
From McMaster University and the Population Health Research Institute (S.R.M., J.L.W., R.A., B.R., M.K.N., J.L.V., S.Y.), Hamilton Health Sciences,
Hamilton, Canada; Hpital Bichat (P.G.S.), Paris, France; Duke Clinical Research Institute (C.B.G.), Durham, NC; Centre Hospitalier Universitaire Jean
Minjoz (J.-P.B.), Besancon, France; University of Chicago (D.P.F.), Chicago, Ill; Academic Medical Center (R.J.G.P.), Amsterdam, the Netherlands;
Foothills Medical Center (D.M.G.), Calgary, Canada; Ottawa Heart Institute (M.L.), Ottawa, Canada; Montreal Heart Institute (J.-F.T.), Montreal,
Canada; and the Royal Infirmary (K.A.A.F.), Edinburgh, Scotland.
*The online-only Data Supplement, which contains information about the participating clinical centers, committees, and sponsors of ASPIRE,
can be found with this article at http://www.circulationaha.org.
Correspondence to Dr Shamir R. Mehta, Interventional Cardiology, Hamilton Health Sciences, General Division, 237 Barton St E, Hamilton, Ontario,
Canada L6K 1B8. E-mail smehta@mcmaster.ca
2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

DOI: 10.1161/01.CIR.0000158485.70761.67

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Mehta et al
thus making it an attractive target for the development of new
anticoagulant agents.3
Fondaparinux is a synthetic, pure factor Xa inhibitor that is
structurally similar to the antithrombin binding site of heparin
and low-molecular-weight heparin (LMWH). In contrast to
heparins, fondaparinux selectively binds to antithrombin and
causes rapid and predictable inhibition of factor Xa. Fondaparinux has a half-life of 15 hours, with linear pharmacokinetics
and low interindividual and intraindividual variability, thus
obviating the need for laboratory monitoring.4 Fondaparinux
has been evaluated extensively for the prevention of venous
thrombosis in patients undergoing orthopedic surgery, where
it was shown to be consistently more effective than
LMWH.59 For the treatment of deep vein thrombosis or
pulmonary embolus, fondaparinux was at least as effective as
enoxaparin or UFH, respectively.10,11 In arterial thrombosis,
an early study of patients undergoing PCI treated with 12 mg
fondaparinux demonstrated feasibility with few complications.10 Subsequent dose-finding phase II trials in patients
with acute coronary syndromes (ACS) have suggested that
doses as low as 2.5 mg may be optimal from both a safety and
efficacy perspective.11,12
To explore the feasibility and safety of fondaparinux at
doses of 2.5 and 5.0 mg given intravenously in patients
undergoing contemporary urgent or elective PCI, we conducted a pilot phase II, randomized, multicenter, blinded trial
of these 2 doses compared with UFH.

Methods
The Arixtra Study in Percutaneous coronary Intervention: a Randomized Evaluation (ASPIRE) Trial was a randomized, blinded, multicenter phase II trial comparing 2 intravenous doses of fondaparinux
(2.5 and 5.0 mg) with UFH. Twenty-two centers from Canada,
France, and the United States participated in the trial (see online-only
Data Supplement for names of centers).

Patient Population
Patients 21 years of age and able to provide informed consent were
eligible if they were undergoing urgent or elective PCI for ACS
(including primary PCI for ST-segment elevation myocardial infarction [STEMI]) or stable angina. Exclusion criteria included an
activated clotting time 200 seconds immediately before PCI, use of
LMWH within 6 hours of PCI, currently receiving an oral anticoagulant with an international normalized ratio 1.8, thrombolytic
therapy for STEMI in the previous 24 hours (ie, rescue PCI), active
internal bleeding or a history of hemorrhagic diathesis, pregnancy or
intent of pregnancy, absolute contraindication to anticoagulation,
participation in other clinical research studies involving the evaluation of other investigational drugs or devices within 30 days of
enrollment, or prior participation in this trial.

Study Organization
Patients were recruited between June and November 2003. The
ethics review board at each institution approved the study, and all
patients gave written, informed consent. The study was organized
and coordinated and all the data were managed and analyzed by the
Canadian Cardiovascular Collaboration Project Office, McMaster
University, Hamilton, Canada. A steering committee consisting of
national coordinators oversaw the study. The data were periodically
reviewed by an independent data and safety monitoring board. An
independent events adjudication committee adjudicated all primary
outcome events (see the online-only Data Supplement for names of
committee members).

Fondaparinux in PCI

1391

Study Protocol
We randomly assigned patients to receive fondaparinux (2.5 or 5.0
mg IV) or UFH. Randomization was stratified for planned use of a
glycoprotein (GP) IIb/IIIa antagonist, which was given as per local
practice. The dose of UFH was 100 U/kg without a GPIIb/IIIa
antagonist or 65 U/kg with a GPIIb/IIIa antagonist. Permuted block
randomization was used and was performed by using sealed envelopes on NCR paper, ensuring adequate concealment of treatment
allocation. Before commencement of the trial, each center identified
an unblinded anticoagulation coordinator, whose role it was to open
the randomization envelope and prepare the study drug, which was
identical in appearance for all treatment groups. All other personnel
were blinded to treatment allocation. The activated clotting time and
activated partial thromboplastin time were not routinely monitored
because fondaparinux has no effect on these tests, and the doses of
UFH selected were those routinely used. Markers of periprocedural
myonecrosis (creatine kinase [CK], CK-MB, and troponin) and an
ECG were determined systematically in all patients before PCI and
at 6 to 8 hours and 12 to 14 hours after PCI. Vascular access site
sheaths were removed immediately after the procedure when a
vascular closure device was used or when a radial artery approach
was used. Sheaths were otherwise removed 6 hours after the
procedure.

Blood Analysis
An additional blood sample was taken at baseline (before PCI) and
at 6 and 12 hours after PCI from 233 patients. All samples were
immediately processed, stored at 70C, and shipped in dry ice to
the Canadian Cardiovascular Collaboration Project Office. Samples
were analyzed in the Coagulation Core Laboratory at the Henderson
Research Centre, Hamilton, Canada. Baseline characteristics and
outcomes in patients providing blood samples were similar to those
of the overall population. Plasma was analyzed for prothrombin
fragment 1.2 (F1.2), thrombin-antithrombin complex (TAT),
P-selectin, D-dimer, factor VIIa, and antifactor Xa levels. F1.2 and
TAT were assayed with commercial ELISA kits from Dade Behring.
Factor VIIa was measured with a commercially available kit (Staclot
VIIa-rTF, Diagnostica Stago). P-selectin antigen was measured with
a commercial assay from R&D Systems. D-dimer was measured with
an automated microlatex assay (MDA D-dimer, BioMerieux). Anti
factor Xa levels were measured by an amidolytic assay with the
Stachrom heparin kit (Diagnostica Stago) according to the method of
Teien et al.13 Fondaparinux, which has a specific activity of 700
antifactor Xa units per milligram, was used as the standard in this
assay.

Study Outcomes
The primary analysis was related to safety and consisted of the
composite of major and minor bleeding (total bleeding) events 48
hours after PCI. Major bleeding was defined as clinically overt
bleeding with one of the following criteria: fatal, symptomatic
intracranial hemorrhage, retroperitoneal hemorrhage, intraocular
hemorrhage, or a fall in hemoglobin of 3.0 g/dL, with each blood
transfusion unit counting for 1.0 g/dL of hemoglobin, or transfusion
of 2 U of blood. Minor bleeding was defined as any other clinically
overt bleed not meeting the definition for major bleeding. The
principal efficacy measure was a composite of clinical outcomes,
including death, MI, urgent revascularization, and bailout use of a
GPIIb/IIIa antagonist. Diagnosis of myocardial (re)infarction after
PCI was made on the basis of a CK-MB or a CK value 3 times the
upper limit of normal or an increase by at least 50% over the
previous valley level; new, significant Q waves of 0.04 second
duration in 2 or more contiguous leads; new, persistent ST-segment
elevation; or new left bundle-branch block. In patients presenting
with STEMI, myocardial reinfarction was defined as recurrent chest
discomfort associated with new ST-segment elevation or reelevation
of CK or CK-MB to 50% of the previous valley level. Urgent
revascularization was defined as ischemic symptoms that resulted in
either urgent repeated PCI or coronary artery bypass graft surgery.
Need for a bailout GPIIb/IIIa inhibitor was defined as an urgent need

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March 22, 2005

for a GPIIb/IIIa inhibitor because of an acute (or suspected acute)

complication of PCI. This outcome event applied only to those
patients who did not receive a planned upfront GPIIb/IIIa inhibitor.
Abrupt closure was defined as TIMI 0 or 1 flow in a target vessel that
had TIMI 2 or 3 flow at any time from enrollment to hospital
discharge, documented by angiography. An additional objective of
the study was to assess the impact of fondaparinux on coagulation
markers. An independent clinical events committee that was blinded
to treatment allocation adjudicated all major safety and efficacy
outcomes.

TABLE 1.

Baseline Clinical and Lesion Characteristics

UFH
(n117)

Fondaparinux
2.5 mg
(n118)

Fondaparinux
5.0 mg
(n115)

Mean age, y

62.3

63.6

63.6

Sex, % male

79

75

79

ST-segment elevation, %

0.9

5.1

ST-segment depression, %

5.2

5.1

8.7

Statistical Analysis

T-wave inversion, %

24.8

22.1

28.7

The purpose of this pilot study was to assess the feasibility of using
fondaparinux during PCI and to explore the risk (either bleeding or
periprocedural clinical complications) to guide the conduct of much
larger studies. We acknowledged a priori that smaller differences
among the groups would not be detectable given the modest sample
size. With 300 patients and a composite rate of major and minor
bleeding in the UFH group of 6%, the study would have 80%
power to detect a relative risk of 2.95 at a 2-tailed (type I error) of
5%. The study eventually randomized 350 patients, which provided
80% power to detect a relative risk of 2.77 in total bleeding, with an
event rate in the UFH group of 7.7% and a 2-tailed of 5%.
All analyses were based on the intention-to-treat principle. The
primary safety and efficacy analyses used the time-to-first event with
Cox proportional-hazards models stratified by planned or no planned
GPIIb/IIIa inhibitor use. The point estimate of the hazard ratio (HR)
of fondaparinux (both doses combined) versus UFH and its associated 2-sided 95% confidence interval (CI) was calculated. Comparisons of both fondaparinux dosages separately against UFH as well
as against each other were also done. Separate analyses were
conducted to compare treatment groups in patients receiving GPIIb/
IIIa inhibitors and those not receiving these agents. Because of the
modest sample size, there were some imbalances in baseline characteristics. Because the study was randomized, these imbalances
were, by definition, due to chance alone. All of these characteristics
were entered into a Cox proportional-hazards model to determine
whether they were associated with the primary safety and efficacy
outcomes, regardless of treatment allocation. Only those baseline
characteristics that were associated with the outcomes were chosen
as covariates in the models. These covariates were age, sex, and
ST-segment depression.
Coagulation data are presented as geometric means and were
analyzed by ANOVA on logarithmically transformed measures. The
F test was used to determine the significance of treatment effect.
Adjustment for baseline coagulation factor levels was performed by
ANCOVA.

Diabetes, %

24.8

26.3

21.7

Previous CABG, %

4.3

8.5

8.5

12.2

Previous PCI, %

28.2

32.2

22.6

Previous MI, %

50.4

40.7

47.0

2.6

4.2

4.3

Stable angina

17.9

21.2

19.1

After ACS

81.2

77.1

79.2

0.9

1.7

1.7

Previous stroke, %
Reason for PCI, %

Primary PCI
Lesion location, %
SVG

1.2

3.0

3.2

LAD

29.3

34.5

34.0

Circumflex

31.7

23.8

21.8

RCA

37.8

37.5

40.4

8.5

8.3

10.3

Stent, %

93.3

91.7

94.9

Drug-eluting stent, %

24.4

25.0

16.7

6.1

8.3

7.7

Preprocedural angiographic
thrombus, %

TIMI 0 flow before PCI, %

CABG indicates coronary artery bypass graft surgery; SVG, saphenous vein
graft; LAD, left anterior descending coronary artery; and RCA, right coronary
artery.

Overall, we randomized 350 patients: 117 to UFH, 118 to 2.5

mg fondaparinux, and 115 to 5.0 mg fondaparinux. No patient
was lost to follow-up. The most common reason for undergoing PCI was after presentation with an ACS (79%).
Primary PCI for STEMI was performed in 0.9% of UFH
patients and 1.7% in each of the fondaparinux groups.

bus (8.5% versus 10.3%). Patients in the 2.5-mg fondaparinux group more frequently had prior stroke (2.6% for UFH
versus 4.2% for fondaparinux), heart failure (2.4% versus
9.3%), diabetes (24.8% versus 26.3%), left main PCI (0%
versus 1.2%), and saphenous vein graft PCI (1.2% versus
3.0%) compared with those in the UFH group. The 2.5 mg
fondaparinux group also had a greater proportion of women
(21% for UFH versus 25% for fondaparinux). Given these
differences in baseline characteristics, adjusted HRs for main
outcomes are presented. Concomitant medications were similar among the groups and are shown in Table 2.

Baseline Characteristics

Clinical Outcomes

Baseline characteristics were generally well matched between

the groups, with the exception of a few chance imbalances in
some key variables (Table 1). Patients in the fondaparinux
groups were older than the UFH group. Compared with UFH,
there were more patients in the 5.0-mg fondaparinux group
with prior coronary artery bypass graft surgery (8.5% for
UFH versus 12.2% for fondaparinux), intervention on saphenous vein grafts (1.2% versus 3.2%), TIMI 0 flow/total
occlusions (6.1% versus 7.7%), major ST-segment depression
(0.9% versus 2.6%), and preprocedural angiographic throm-

Bleeding
There were fewer patients in the fondaparinux groups who
experienced total bleeding compared with the UFH group
(6.4% versus 7.7%; HR, 0.81; 95% CI, 0.35 to 1.84;
P0.61; Figure 1). When adjusted for baseline characteristic imbalances that were associated with this outcome
(age, sex, and ST-segment depression), there was a trend
toward a 22% relative risk reduction in bleeding (HR, 0.78;
95% CI, 0.34 to 1.80; P0.56). There was no significant
difference in bleeding between the 2 doses of fondaparinux

Results

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Mehta et al
TABLE 2.

Concomitant Medications
UFH
(n117)

Fondaparinux
2.5 mg
(n118)

Fondaparinux
5.0 mg
(n115)

98.3

95.8

94.8

Before PCI

87.2

90.7

89.6

6 Hours before PCI

29.9

43.2

37.4

Aspirin, %
Clopidogrel, %

GPIIb/IIIa antagonist, %

55.6

59.3

59.1

Abciximab

13.7

14.4

15.7

Eptifibatide

28.2

30.5

27.8

Tirofiban

14.5

12.7

16.5

-Blockers, %

82.9

74.6

86.1

ACE inhibitors, %

61.5

61.0

58.3

Statins, %

86.3

79.7

78.3

ACE indicates angiotensin-converting enzyme.

and UFH (Table 3); however, there was a nonsignificant

trend toward a lower rate of bleeding with the lower dose
of fondaparinux compared with the higher dose (3.4%
versus 9.6%; relative risk, 0.33; 95% CI, 0.10 to 1.04;
P0.06). The results were similar in patients who received
a planned intravenous GPIIb/IIIa antagonist and those with
no planned intravenous GPIIb/IIIa antagonist (Table 3).
Major bleeding was low overall, with no significant
differences among the groups. Components of the bleeding
composite, including need for blood transfusion 2 U and
intracranial hemorrhage, also were infrequent. There were
nonsignificantly fewer vascular site complications, including large hematomas and pseudoaneurysms, in the
fondaparinux groups compared with UFH (Table 3).
Efficacy Outcomes
The predefined composite outcome to assess efficacy (allcause mortality, MI, urgent revascularization, and need for
bailout GPIIb/IIIa antagonist) was similar between the combined fondaparinux and UFH groups (6.0% versus 6.0%; HR,
1.02; 95% CI, 0.41 to 2.52; P0.97; Figure 1). When

Fondaparinux in PCI

1393

adjusted for baseline characteristic imbalances that were

associated with this outcome (age, sex, and ST-segment
depression), there was a nonsignificant 17% relative risk
reduction in the composite efficacy outcome (HR, 0.83; 95%
CI, 0.33 to 2.09; P0.69). There was no obvious dose
response with respect to efficacy between the 2 fondaparinux
groups. Individual components of the efficacy composite
outcome were also similar among the groups, with no
significant differences in the rate of events among those
receiving and those not receiving a planned GPIIb/IIIa
antagonist (Table 3).
Angiographic Findings
Procedural success rates were high and similar across the
groups: 96.3% for UFH, 96.5% for 2.5 mg fondaparinux, and
98.4% for 5.0 mg fondaparinux (Table 4). There was no
significant difference among the groups in the proportion of
patients with side-branch closure, dissection, or persistent
residual stenosis. There was 1 case of abrupt closure and 1
case of reported angiographic thrombus in the UFH group, 3
and 6 cases respectively in the 2.5-mg fondaparinux group,
and 0 and 5 cases respectively in the 5.0-mg fondaparinux
group (PNS). Despite this, the 2.5-mg fondaparinux group
tended to have fewer clinical events, including periprocedural
MI (7 in the UFH group versus 4 in the 2.5-mg fondaparinux
group).
Coagulation Data
Fondaparinux produced a greater reduction in prothrombin
F1.2, a marker of thrombin generation, at 6 and 12 hours after
PCI, than did UFH (Table 5, Figure 2). There was no
difference in P-selectin levels between the fondaparinux and
UFH groups at either time point. There was a small increase
in D-dimer levels in the 2.5-mg fondaparinux group at 6 hours
but not at 12 hours. There was no increase in D-dimer levels
in the UFH or 5.0-mg fondaparinux groups. There was a
greater reduction in the levels of factor VIIa observed in both
fondaparinux groups at 6 and 12 hours compared with UFH
(Table 5). Mean antifactor Xa levels (with fondaparinux as
a standard) at 6 hours after PCI were 0.21 and 0.38 mg/L for
the 2.5- and the 5.0-mg doses, respectively.

Discussion

Figure 1. Primary safety and efficacy outcome: combined

fondaparinux vs UFH. When adjusted for age, sex, and
ST-segment depression (which were baseline characteristic
imbalances associated with primary outcomes), HR for total
bleeding was 0.78; 95% CI, 0.34 to 1.80; P0.56; and for
death/MI/urgent revascularization (UR)/bailout GPIIb/IIIa inhibitor, HR was 0.83; 95% CI, 0.33 to 2.09; P0.69.

The ASPIRE results suggest that fondaparinux in doses of 2.5

and 5.0 mg was comparable to UFH for clinical safety and
efficacy outcomes when given with or without planned use of
GPIIb/IIIa antagonists. Fondaparinux also produced greater
and more sustained suppression of thrombin generation after
PCI than did UFH.
The primary objective of the study was to determine the
safety of fondaparinux as assessed by rates of total bleeding
between the groups. Overall, the combined doses of fondaparinux demonstrated a nonsignificantly lower bleeding rate
and fewer vascular access site complications compared with
UFH. Although bleeding overall in the study was relatively
infrequent, the 2.5-mg fondaparinux group was associated
with the lowest rate of bleeding. Our study was performed on
a background of aggressive antiplatelet therapy, including
GPIIb/IIIa antagonists in 58%, preprocedural clopidogrel in
87%, and aspirin in 96% of patients, all of which are

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March 22, 2005

TABLE 3. Primary Safety and Efficacy Outcomes by Dose of Fondaparinux Overall and by Planned Use of Intravenous GPIIb/IIIa Antagonists
All Patients (n350)

Planned GP IIb/IIIa (n203)

UFH
Fonda 2.5 mg Fonda 5.0 mg
(n117)
(n118)
(n115)

UFH
(n65)

No Planned GP IIb/IIIa (n147)

Fonda 2.5 mg Fonda 5.0 mg

(n70)
(n68)

UFH
(n52)

Fonda 2.5 mg Fonda 5.0 mg

(n48)
(n47)

Safety
Total bleeding, n (%)

9 (7.7)

4 (3.4)

11 (9.6)

6 (9.2)

4 (5.7)

9 (13.2)

3 (5.8)

2 (4.3)

Major bleeding, n (%)

1 (0.8)

3 (2.6)

1 (1.4)

3 (4.4)

Minor bleeding, n (%)

9 (7.7)

3 (2.5)

8 (7.0)

6 (9.2)

3 (4.3)

6 (8.8)

3 (5.8)

2 (4.3)

1 (0.87)

1 (1.5)

Transfusion 2 U of blood,
n (%)
ICH, n (%)

1 (0.85)

1 (1.4)

Large hematoma, n (%)

22 (18.8)

16 (13.6)

19 (16.5)

10 (15.4)

8 (11.4)

9 (13.2)

12 (23.1)

8 (16.7)

10 (21.3)

Pseudoaneurysm, n (%)

1 (0.9)

0.0

0.0

1 (1.5)

7 (6.0)

5 (4.2)

9 (7.8)

3 (4.6)

3 (4.3)

4 (5.9)

4 (7.7)

2 (4.2)

5 (10.6)

1 (0.9)

MI, n (%)

7 (6.0)

4 (3.4)

9 (7.8)

3 (4.6)

3 (4.3)

4 (5.9)

4 (7.7)

1 (2.1)

5 (10.6)

UR, n (%)

1 (0.9)

2 (1.7)

1 (1.9)

2 (4.3)

Bailout GPIIb/IIIa, n (%)

2 (1.7)

1 (0.8)

3 (2.6)

2 (3.8)

3 (6.4)

Efficacy
Death/MI/UR/bailout, n (%)
Death, n (%)

Fonda indicates fondaparinux; ICH, intracranial hemorrhage; and UR, urgent revascularization.

ride as an Adjunct to fibrinoLYsis in ST-Elevation acute

myocardial infarction) study evaluating 3 doses of fondaparinux in alteplase-treated STEMI patients (4, 8, and 12 mg),
there did not appear be a clear dose response with respect to
efficacy.11 A trial of 5 doses of fondaparinux for the prevention of venous thrombosis in patients undergoing hip replacement suggested that a 2.5-mg dose would yield the most
favorable efficacy-safety profile.5 Data from those studies
taken in context with the results of ASPIRE suggest that the
2.5-mg dose is the most optimal dose to study in the phase III
ACS trials of fondaparinux.
The angiographic data largely support the clinical efficacy
data in the trial, with high procedural success rates (96.3% for
UFH, 96.5% for 2.5 mg fondaparinux, and 98.4% for 5.0 mg
fondaparinux). There were no significant differences in the
rates of abrupt closure, persistent residual stenosis, major
side-branch occlusion, or need for a bailout GPIIb/IIIa inhib-

effective in patients undergoing PCI but also have the

potential to increase bleeding.14 17 Despite the use of these
multiple antithrombotic therapies, our trial suggests that a
large increase in bleeding is unlikely with the use of fondaparinux compared with a weight-adjusted dose of UFH.
The predefined efficacy composite outcome was similar
between the UFH and fondaparinux groups. Unlike bleeding,
there did not appear to be a dose-response relation between
efficacy and the 2 doses of fondaparinux. The lower dose of
fondaparinux seemed to yield the best point estimate in terms
of efficacy, although the overall number of events was small.
Similar findings were observed in the PENTUA (Pentasaccharide in Unstable Angina) study evaluating 4 doses of
fondaparinux ranging from 2.5 up to 12 mg in patients with
nonST-segment elevation ACS (NSTEACS), wherein the
2.5-mg dose appeared to be associated with the lowest event
rates.12 Also, in the PENTALYSE (synthetic PENTasacchaTABLE 4.

Angiographic Outcomes
All Patients (n350)

Planned GPIIb/IIIa (n203)

No Planned GPIIb/IIIa (n147)

UFH
(n117)

Fonda 2.5 mg
(n118)

Fonda 5.0 mg
(n115)

UFH
(n65)

Fonda 2.5 mg
(n70)

Fonda 5.0 mg
(n68)

UFH
(n52)

Fonda 2.5 mg
(n48)

Fonda 5.0 mg
(n47)

158 (96.3)

162 (96.5)

152 (98.4)

94 (96.9)

101 (95.3)

92 (97.9)

64 (95.5)

61 (98.4)

60 (96.8)

1 (0.9)

1 (0.8)

1 (1.9)

1 (2.1)

Abrupt closure, n (%)

1 (0.9)

3 (2.5)

3 (4.3)

1 (1.9)

Suspected angiographic
thrombus, n (%)

1 (0.9)

6 (5.1)

5 (4.3)

6 (8.6)

2 (2.9)

1 (1.9)

3 (6.4)

Side-branch closure, n (%)

1 (0.9)

1 (0.8)

2 (1.7)

1 (1.4)

1 (1.5)

1 (1.9)

1 (2.1)

1 (0.9)

1 (1.5)

Procedure success (per total lesions

attempted), n (%)
Persistent residual stenosis, n (%)
Dissection, n (%)

Unplanned stent, n (%)

Fonda indicates fondaparinux.

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Mehta et al

Fondaparinux in PCI

1395

TABLE 5. Geometric Means of Coagulation Factors at Baseline (Before PCI) and at 6 and 12 Hours
After PCI
UFH

Fondaparinux 2.5 mg

Fondaparinux 5.0 mg

MeanSE

MeanSE

MeanSE

Baseline

72

0.790.04

67

0.830.05

0.820.06

70

0.870.04

67

0.770.04

0.06

63

6h

0.08

62

0.740.05

0.08

0.02

12 h

68

0.900.05

0.11

67

0.770.05

0.06

62

0.700.07

0.12

0.01

Baseline

70

4.230.41

65

4.630.47

4.030.43

68

4.120.35

67

3.600.40

1.03

60

6h

0.11

60

2.980.31

1.05

0.19

12 h

68

4.140.53

0.09

67

3.110.48

1.52

62

3.370.55

0.66

0.22

Baseline

70

0.450.03

67

0.420.04

0.400.04

71

0.440.03

66

0.530.03

0.11

63

6h

0.01

62

0.440.03

0.04

0.043

12 h

69

0.460.04

0.01

65

0.540.05

0.12

60

0.420.06

0.02

0.18

Baseline

63

51.63.6

61

53.13.2

6h

66

56.42.8

3.5

39

12 h

66

58.03.7

6.4

Baseline

71

36.51.9

6h

71

34.81.3

1.7

12 h

70

33.21.9

3.3

F1.2, nmol/L

TAT, g/L

D-dimer,

g FEU/mL

Factor VIIa, U/mL

58

46.84.1

36.63.6

16.5

39

34.63.5

12.2

0.02

34

48.55.1

4.6

41

33.84.2

13.0

0.002

68

35.61.4

64

38.61.4

67

32.61.4

3.0

62

35.41.6

3.2

0.95

67

33.71.5

1.9

64

34.61.5

4.0

0.32

P-selectin, ng/mL

Fonda aXa, U/mL

6h

64
0.150.07
63
0.270.01

FEU indicates fibrinogen equivalent unit; fonda aXa, Fondaparinux antifactor Xa level.
is the mean of changes in marker levels from baseline to 6 or 12 hours after PCI for each patient.
*P represents difference in fonda aXa levels between 2.5- and 5.0-mg fondaparinux groups at 6 hours.

itor because of thrombotic complications between each of the

fondaparinux groups and UFH. Angiographic complications
occurred with similar frequency in the groups receiving and
not receiving a planned GPIIb/IIIa antagonist. Suspected
angiographic thrombus was reported more frequently in the
fondaparinux groups, but this finding should be interpreted
with some caution, as it is often confused with dissection after
PCI18 22 (none of which were reported in ASPIRE). The
sensitivity for correctly characterizing an intraluminal filling
defect on angiography (thrombus, dissection, or both) is only
19% to 37%,16,17 suggesting that in most cases, it is misclassified. Whether the rates of angiographic thrombus are real,
owing to the play of chance or to the unexpectedly low rate
in the UFH group, can only be clarified in larger trials, which
are currently ongoing. The fact that procedural success rates
were similar in the 3 groups, with no apparent excess in
clinical events or rates of abrupt closure, is reassuring.
The coagulation factor analysis demonstrated that fondaparinux was superior to UFH in inducing a sustained, dosedependent reduction in thrombin generation up to 12 hours
after PCI without resulting in an increase in bleeding and with
fewer vascular access site complications. This reduction in
markers of thrombin generation may reflect the longer halflife of fondaparinux compared with UFH and could poten-

0.004*

tially have benefit in reducing the rate of thrombotic events

after PCI, particularly in complex or high-risk procedures. On
the other hand, we did note a small increase in D-dimer levels
in the 2.5-mg fondaparinux group at the 6-hour time point but
not in the 5-mg fondaparinux or UFH group. The clinical
significance of this finding remains elusive, as the 2.5-mg
fondaparinux group tended to have the lowest rates of
primary efficacy outcome. At present, there is no international standard for measurement of anti-factor Xa with
fondaparinux like those that are available for UFH and
LMWH. Therefore, the antifactor Xa levels achieved with
fondaparinux are not directly comparable with these other
agents.
The main limitation of our pilot study was the modest
sample size, which can only evaluate large differences in
event rates. Nevertheless, the study was designed as an
exploratory trial to assess any major hazard associated with
fondaparinux and to demonstrate its feasibility in the setting
of PCI before the conduct of larger studies. In this respect, the
goals of the study were met. More definitive data will emerge
from the Michelangelo OASIS (Organization to Assess Strategies for Ischemic Syndromes) 5 and 6 trials, evaluating
fondaparinux in NSTEACS and STEMI settings, respectively. In those trials, a large proportion of patients are

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1396

Circulation

March 22, 2005

nous doses of 2.5 and 5.0 mg appear promising, with no
excess in bleeding complications or clinical events compared with UFH. These data form the basis for further
evaluation of fondaparinux in a larger number of patients
in this setting.

Acknowledgments
Dr Mehta was supported by a Canadian Institutes of Health Research
new investigator award. We would like to acknowledge and thank all
of the site principal investigators and research coordinators who
recruited patients into this trial. Their names and affiliations can be
found in the online-only Data Supplement.

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Figure 2. Geometric means of coagulation factors at 6 and 12 hours

after PCI. Probability values represent 3-way comparison among
groups within each time point. Fonda indicates fondaparinux.

undergoing PCI (including primary PCI in OASIS 6) while

on fondaparinux.

Conclusions
In this pilot, randomized comparison of fondaparinux with
UFH in patients undergoing contemporary PCI, intrave-

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Randomized, Blinded Trial Comparing Fondaparinux With Unfractionated Heparin in

Patients Undergoing Contemporary Percutaneous Coronary Intervention: Arixtra Study
in Percutaneous Coronary Intervention: A Randomized Evaluation (ASPIRE) Pilot Trial
Shamir R. Mehta, Philippe Gabriel Steg, Christopher B. Granger, Jean-Pierre Bassand, David P.
Faxon, Jeffrey I. Weitz, Rizwan Afzal, Bonnie Rush, Ron J.G. Peters, Madhu K. Natarajan,
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Circulation. 2005;111:1390-1397
doi: 10.1161/01.CIR.0000158485.70761.67
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright 2005 American Heart Association, Inc. All rights reserved.
Print ISSN: 0009-7322. Online ISSN: 1524-4539

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