European Heart Journal (2008) 29, 324–331 CLINICAL RESEARCH

doi:10.1093/eurheartj/ehm616 Coronary heart disease

The role of fondaparinux as an adjunct

to thrombolytic therapy in acute
myocardial infarction: a subgroup analysis
of the OASIS-6 trial
Ron J.G. Peters 1*, Campbell Joyner 2, Jean-Pierre Bassand 3, Rizwan Afzal 4,
Susan Chrolavicius 4, Shamir R. Mehta 4, Jonas Oldgren5, Lars Wallentin 5,
Andrzej Budaj 6, Keith A. Fox 7, and Salim Yusuf 4 for the OASIS-6 investigators
1
Department of Cardiology, Academic Medical Center, Room F3-236, P.O. Box 22660, 1100 DD Amsterdam, The Netherlands; 2Division of Cardiology, University of Toronto and
Sunnybrook Health Sciences Centre, Toronto, ON, Canada; 3Division of Cardiology, University of Besancon, Besancon, France; 4Population Health Research Institute and
Department of Medicine, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; 5Uppsala Clinical Research Center, Uppsala University Hospital, Uppsala,
Sweden; 6Division of Cardiology, Grochowski Hospital, Warsaw, Poland; 7Cardiovascular Research Division, University of Edinburgh, Edinburgh, UK

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Received 15 September 2006; revised 11 December 2007; accepted 13 December 2007

Aims No antithrombotic therapy has been shown to reduce mortality when used with thrombolytics in acute myocardial
infarction (AMI). In the OASIS-6 trial, fondaparinux significantly reduced mortality and reinfarction without increasing
bleeding in 12 092 patients with acute ST elevation MI.
.....................................................................................................................................................................................
Methods We report the results of a subgroup analysis in the 5436 patients (45%) receiving thrombolytics. According to local
and results practice, 4415 patients did not have an indication for unfractionated heparin (stratum 1) and 1021 did (stratum 2).
Fondaparinux reduced the primary study outcome of death or MI at 30 days [Hazard ratio (HR) 0.79, 95% confidence
interval (CI) 0.68 –0.92] with consistent reductions in both mortality (HR and CI) and reinfarction (HR and CI). There
was a non-significantly lower rate of stroke (HR 0.77, CI 0.48–1.25). The risk of severe bleeding was significantly
reduced (HR 0.62, CI 0.40–0.94), and thus the balance of benefit and risk (death, MI and severe haemorrhage)
was clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67–0.90). Results were consistent in the two strata, by
the different types of thrombolytics and across various time intervals from symptom onset to treatment.
.....................................................................................................................................................................................
Conclusion In STEMI patients treated with thrombolytic agents (predominantly streptokinase), fondaparinux significantly reduced
the risk of death, re-MI and severe bleeds.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Acute myocardial infarction † Thrombolytic therapy † Antithrombotic therapy

recommend the administration of UFH with fibrin specific (FS)

Introduction
Thrombolytic therapy for acute myocardial infarction (AMI)
presenting with ST segment elevations (STEMI) routinely includes
aspirin and more recently clopidogrel. The role of antithrombin
agents in this setting remains unclear. With non-fibrin specific
(NFS) thrombolytic agents, administration of unfractionated
heparin (UFH) provides no clinical benefit but increases the risk
of bleeding complications.1,2 Although contemporary guidelines
thrombolytic therapy, there are no data that such therapy
reduces mortality or morbidity, and that the benefits outweigh
the increased risk of bleeding.3 – 5 A recent trial in patients
treated with FS agents indicated that enoxaparin reduces the risk
of reinfarction as compared to UFH, without a significant reduction
in mortality, but with an increased risk of major bleeding, including
intracranial haemorrhage (ICH) and other fatal bleeds.6 A large
trial of reviparin compared with placebo indicates a reduction in

* Corresponding author: Tel: þ31 20 5666952, Fax: þ31 20 5669747. Email: r.j.peters@amc.uva.nl
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org.
Role of fondaparinux as an adjunct to thrombolytic therapy in AMI
mortality, and reinfarction, but with an excess in intracranial and
other major bleeding.7 However, reviparin is not available in
many countries, and the company has not sought regulatory
approval for AMI. Thus, for patients treated with thrombolytic
therapy, in most countries, there is no anticoagulant available
that has demonstrated a reduction in mortality, with an acceptable
safety profile. Therefore, there is a need for antithrombotic agents
that reduce death and recurrent MI without increasing the risk of
bleeding or strokes.
The recent OASIS (Organization for the Assessment of Strat-
egies for Ischaemic Syndromes) 6 trial demonstrated that fonda-
parinux, a synthetic pentasaccharide, when compared with
standard therapy (either placebo or UFH), reduced the incidence
of death and MI in STEMI patients treated with either primary per-
cutaneous coronary intervention (PCI), thrombolysis, or no reper-
fusion thereapy. Since the balance between benefit and risk is likely
dependent on the type of reperfusion therapy, we explored the
efficacy and safety of fondaparinux in the subgroup of patients
treated with thrombolytic therapy.
Methods
OASIS-6 was a randomized, double blind trial of fondaparinux vs. usual
care in 12 092 patients with STEMI, enrolled within 24 h of symptom
onset.8 This time window was reduced to ,12 h after 4300 patients
had been enrolled, based on the results of the CREATE trial which
indicated little benefit in those randomized beyond 12 h.5 At the
time of this decision, we had no knowledge of any interim results
from OASIS-6. Patients with contraindications to anticoagulation,
including those at high risk of bleeding, receiving oral anticoagulants,
or with creatinine levels .265.2 mg/dL (3.0 mmol/L), were excluded.
Randomization was stratified by indication for the use of UFH based
on the investigator’s judgment. Thus, the trial reflects the uncertainty
on the value of UFH, and consequently the variability of its use in clini-
cal practice. Overall, in stratum 1 (no indication for UFH) 5658 patients
were enrolled, whereas 6434 patients were enrolled in stratum 2 (indi-
cation for UFH, e.g. intended use of FS thrombolytic, patients not eli-
gible for fibrinolytics but eligible for antithrombotics, or those
scheduled for primary PCI). Patients in stratum 1 were assigned to
receive blinded fondaparinux 2.5 mg (or 5.0 mg in case of PCI
without the use of a glycoprotein 2b/3a inhibitor) initially intrave-
nously, and then subcutaneously once daily or matching placebo on
subsequent days for up to 8 days or hospital discharge, if earlier.
Patients in stratum 2 were assigned to receive either blinded fondapar-
inux or matching placebo (initial dose intravenous and subsequent
doses subcutaneously) for up to 8 days or hospital discharge. Those
in the control group received UFH bolus injection of 60 IU/kg followed
by an infusion of 12 IU/kg per hour for 24 – 48 h. Equivalent placebo
bolus and injections were used in the fondaparinux group. Thus, in
stratum 2 a comparison is made of two active treatments. The
maximum dose of the bolus was 4000 IU and maximum initial infusion
rate of 1000 IU/h for patients weighing more than 70 kg and adjusted
to maintain activated partial thromboplastin time within the thera-
peutic range of 1.5 – 2.0 times control. Higher doses could be used
during PCI.
The primary outcome of the study was death or MI at 30 days. All
patients were followed for a minimum of 3 and a maximum of 6
months. Consequently, ‘study end’ in this report indicates a follow-up
of 3 – 6 months. The definition of reinfarction and the classification of
deaths and haemorrhages have been previously published.6 In the main
325
trial, two approaches for classifying bleeding complications were used.
In the current analysis, we use the classification of bleeding that allows
comparison with the thrombolysis in myocardial infarction trials.9 We
subdivided all bleeding episodes into ‘severe’ [fatal haemorrhage, ICH,
cardiac tamponade, or a clinically significant haemorrhage with a
decrease in haemoglobin (Hb) of 5 g/dL, with each blood transfusion
unit counting for 1.0 g/dL of Hb], ‘minor’ (clinically overt haemorrhage
with decrease in Hb 3.0– 5.0 g/dL that did not meet criteria for severe
haemorrhage, with each blood transfusion unit counting as the equiv-
alent of a 1 g/dL of Hb), and ‘other’.
Statistical analysis
Treatment effects, as measured by hazard ratio (HR) and two-sided
95% confidence interval (CI), were derived with Cox’s proportional
hazard model, stratified by the indication for UFH. No P-values for
comparisons of active treatment vs. controls are presented in this
paper, as these represent subgroup results. Instead HRs and their
CIs are presented, and where appropriate tests for heterogeneity.
Because several subgroup analyses were conducted, the pre-specified
two-sided level to test for interactions between subgroups was 0.01.
The primary interest of the present analysis was the efficacy and
safety of fondaparinux compared with control (placebo or UFH) in
the subset of patients who were treated with thrombolytic therapy.
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Therefore, the primary outcomes of the main trial were used, i.e.
the rates of death, MI, or severe bleeding at 30 days.
In addition to the two strata by indication for use of UFH, pre-
specified subgroups included age (above and below the median), sex,
initial reperfusion strategy (thrombolytic, primary PCI, or neither),
time to reperfusion therapy from symptom onset, GRACE (Global
Registry of Acute Coronary Events) risk score16 (above or below
the median), and pre-randomization heparin use. This report is con-
fined to patients who were treated with thrombolytic therapy. The
analysis of the combined efficacy and safety outcomes, including
death, MI, and severe bleeding, was pre-specified, as well as an analysis
of the combined efficacy outcome of death, MI, and stroke.
The statistical analyses were performed at the Population Health
Research Institute SAS version 9.1 was used for analysis (SAS Institute
Inc., Cary, NC, USA).
Results
Overall results
The results of the OASIS-6 trial, including the randomization pro-
cedure and a flow diagram of the selection of patients, have been
previously published and are briefly summarized here. Overall, the
primary outcome of death or reinfarction at 30 days was signifi-
cantly reduced by fondaparinux, from 11.2% in the control group
to 9.7% in the fondaparinux group (HR, 0.86; 95% CI, 0.77– 0.96;
P ¼ 0.008). Of the12 092 patients included, 2867 (23.7%) did not
receive any reperfusion therapy. Primary PCI was performed in
3789 patients (31.3%), whereas thrombolytic therapy was used
in 5436 patients (45%).
Patients receiving thrombolytic agents
Of the 5436 patients who received thrombolytic therapy, 4415
patients did not have an indication for heparin therapy (stratum 1)
and 1021 did (stratum 2) (Tables 1 and 2). Streptokinase was
the most commonly used thrombolytic agent (73%). In stratum
1, 4395 patients (99.6%) received a NFS thrombolytic agent
326 R.J.G. Peters et al

(streptokinase n ¼ 3829, urokinase n ¼ 566). In stratum 2, 855 therapy, and consequently with the combined subgroups of
patients (83.7%) received a FS thrombolytic agent (tPA n ¼ 214, patients who were not treated with primary PCI (Figure 2). An
rPA n ¼ 259 and tNK n ¼ 380). Consequently, control treatment analysis by type of thrombolytic agent (FS vs. NFS) showed con-
with NFS thrombolytics was placebo in 96.4%, with FS thromboly- sistency of efficacy and safety outcomes in the two second order
tics it was heparin in 97.7%. subgroups (Figure 3). In NFS thrombolytics: death or MI 10.7%
Baseline characteristics of all patients and those treated with with fondaparinux vs. 13.8% in the control group (receiving
thrombolytics are presented in Tables 3 and 4. Medications used placebo in 96.4%) (HR 0.76, 95% CI 0.64–0.90); in FS
after randomization included beta-blockers (83.6%), ACE inhibitors
(78.4%), and statins (72.2%), with no differences between sub-
groups. Antithrombotic therapies started after randomization are Table 3 Baseline characteristics and medications
presented in Tables 5 and 6. Rescue PCI was performed in 46 within 7 days prior to randomization
patients (2.1%) in stratum 1 and 59 patients (2.8%) in stratum
2. Outcomes at 30 days (primary study outcome) are presented All patients, Thrombolytic
in Table 7 and in Figures 1 –2. In patients treated with thrombolytic n 5 12 092 therapy, n 5 5436
................................................................................
agents, lower event rates were observed with fondaparinux for Age (years, mean, SD) 61.5 (12.2) 60.1 (12.1)
each of the individual and composite outcomes, including stroke, Male (%) 72.3 74.9
with HRs varying between 0.74 and 0.80. The primary outcome Previous MI (%) 12.6 12.3
(death and MI at 30 days) was reduced from 13.6 to 10.9% (HR PCI (%) 3.0 2.0
0.79, 95% CI 0.68–0.92). In stratum 1, the primary endpoint was CABG (%) 1.2 0.9
reduced from 13.8 to 10.8% (HR 0.77, 95% CI 0.65– 0.91), in Other CAD (%) 20.5 20.9
stratum 2, it was reduced from 12.3 to 11.2% (HR 0.91, 95% CI Fam. hx. of CAD (%) 13.0 11.2
0.63 –1.30). All CIs include the overall result, and there was no

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Stroke (%) 6.6 5.9
statistical heterogeneity among these subgroups. Results in the Hypertension (%) 54.4 51.0
two strata at 30 days are presented in Figure 2. There was consist- Heart failure (%) 13.9 14.6
ent benefit whether the control treatment was placebo or UFH. Diabetes (%) 17.8 17.9
The results in the subgroup of patients who received thromboly- Aspirin (%) 61.8 53.2
tics were consistent with patients who received no reperfusion Clopidogrel/ticlopidine (%) 46.5 8.4
Non-study UFH (%) 14.8 6.8
LMWH (%) 1.8 1.6
Table 1 Numbers of patients who received GPIIb/IIIa (%) 1.9 0.3
thrombolytic therapy Oral anticoagulants (%) 0.2 0.2
Mean + SD Mean + SD
OASIS-6 Stratum I Stratum II Total Heart rate (b.p.m.) 76 + 14.5 76.5 + 14.6
...................... ..................
Placebo Fonda UFH Fonda Diastolic BP (mmHg) 81.4 + 14.4 81.2 + 14.3
2835 2823 3221 3213 12 092 Systolic BP (mmHg) 134.1 + 23.4 132.5 + 23.0
................................................................................ Weight (Kg) 75.4 + 14.5 73.4 + 14.0
Non-fibrin specific 2216 2179 83 83 4561 BMI (Kg/mm2) 26.5 + 4.3 26.1 + 4.3
thrombolytics
Onset to randomization (h) 6.6 + 5.3 5.7 + 4.3
Fibrin specific 9 11 436 419 875
thrombolytics
UFH, unfractionated heparin; LMWH: low-molecular weight heparin; GPIIb/IIIa:
Any thrombolytic 2225 2190 519 502 5436 glycoprotein IIb/IIIa; MI, myocardial infarction; CAD, coronary artery disease; PCI,
percutaneous coronary intervention; CABG, coronary artery bypass grafting; BMI:
UFH, unfractionated heparin. body mass index; BP: blood pressure.

Table 2 Study endpoints at 30 days by type of thrombolytic agent

Death/MI n Control, n (%) Fondaparinux, n (%) HR 95% CI P-value for interaction

...............................................................................................................................................................................
Death/MI
NFS lytics 4561 318 (13.8) 241 (10.7) 0.76 0.64 0.90 0.175
FS lytics 875 54 (12.1) 52 (12.1) 1.01 0.69–1.48
Severe haemorrhage
NFS lytics 4561 45 (2.0) 27 (1.2) 0.60 0.37–0.97 0.846
FS lytics 875 11 (2.5) 7 (1.7) 0.67 0.26–1.73

FS, fibrin specific thrombolytic agents; NFS, non-fibrin specific thrombolytic agents; HR, hazard ratio; 95% CI, 95% confidence interval.
Role of fondaparinux as an adjunct to thrombolytic therapy in AMI 327

Table 4 Incidence of death and MI at 30 days by type of thrombolytic agent

Death/MI n Control, n (%) Fondaparinux, n (%) HR 95% CI P-value for interaction

...............................................................................................................................................................................
Death/MI
NFS lytics 4561 260 (11.3) 194 (8.6) 0.75 0.62–0.90 0.046
FS lytics 875 33 (7.4) 39 (9.1) 1.24 0.78–1.97
MI
NFS lytics 4561 71 (3.3) 57 (2.6) 0.80 0.56–1.13 0.359
FS lytics 875 26 (6.1) 14 (3.5) 0.57 0.30–1.08

FS: fibrin specific thrombolytic agents, NFS: non-fibrin specific thrombolytic agents, HR: hazard ratio, 95% CI: 95% confidence interval.

Treating a 1000 patients will prevent 32 deaths, MI, strokes, or

Table 5 Additional antithrombotic medications used a severe bleeding complication compared with standard treatment.
from randomization to discharge Of note, these benefits led to a reduction in mortality. Thus, fon-
daparinux is the only antithrombotic that has been demonstrated
Overall Thrombolytic
........................ ...................... to reduce mortality in patients receiving thrombolytic therapy
n Per cent n Per cent without an increase in bleeding or strokes.
................................................................................
Further subdivision of patients according to heparin use or type

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Randomized 12 092 100% 5436 100%
of thrombolytic agent demonstrates consistency of effects.
Aspirin 11680 96.6% 5248 96.5%
However, the number of patients in stratum 2 and in the subgroup
Non-study UFH 1332 11.0% 565 10.4%
with FS are relatively modest and the CIs for the HRs for both effi-
LMWH 706 5.8% 261 4.8%
cacy and safety are wide (Figures 2–3). However, the point esti-
GPIIb/IIIa inhibitors 1892 15.6% 183 3.4%
mates are consistent with those observed in the overall trial
Bivalirudin or hirudin 12 0.1% 3 0.1%
(internal consistency), and CIs of all subgroup results include the
Clopidogrel 6500 53.8% 2352 43.3%
overall trial result (Figure 2).10 In addition, the results are consistent
Ticlopidine 1037 8.6% 214 3.9%
with the findings in the OASIS-5 study where fondaparinux was
Oral anticoagulants 288 2.4% 137 2.5%
superior to enoxaparin (which is likely superior to UFH) in redu-
cing death and strokes and was associated with less bleeding
UFH, unfractionated heparin; LMWH: low-molecular weight heparin; GPIIb/IIIa:
glycoprotein IIb/IIIa. (external replication). Furthermore, the reductions in the risk of
bleeding in those receiving thrombolytics, and the various sub-
groups defined here would favour the use of fondaparinux since
thrombolytics: death or MI 12.1% with fondaparinux vs. 12.1% in bleeding is associated with increased mortality. Therefore, our
the control group (receiving UFH in 97.9%) (HR 1.01, 95% CI findings suggest that fondaparinux improves the results of throm-
0.69–1.48). bolytic therapy, compared with either placebo or UFH, and irre-
The risk of severe bleeding was also reduced by fondaparinux spective of the type of thrombolytic used. To be certain,
(1.3% vs. 2.1%, HR 0.62, 95% CI 0.40 –0.94), and thus the however, a large trial would be required, evaluating fondaparinux
benefit-risk balance of death, MI and severe haemorrhage was and UFH in patients treated with FS agents.
also clearly reduced by fondaparinux (HR 0.77, 95% CI 0.67 – The reduction in bleeding when compared with placebo (25 vs.
0.90, Table 7). Outcomes at study end (3–6 months) show a 39 cases in stratum 1) was unexpected. Analysis by location of
similar pattern and the reduction in death and MI persisted to bleeding revealed a reduction in several types of serious bleeding
study end (Figure 1). Results were consistently observed at differ- complications including gastrointestinal bleeds, surgical bleeds,
ent times from onset to randomization (data not shown). Similarly, and cases of cardiac tamponade. By preventing ischaemic events,
the risk of severe haemorrhage was reduced by fondaparinux inde- fondaparinux may have prevented invasive procedures with their
pendent of the time from onset to randomization (data not associated risk of bleeding. The apparent reduction may also be
shown). due to the play of chance or, if real, due to a mechanism that is
yet to be defined. In any case, our data, when interpreted conser-
vatively confirm that fondaparinux does not increase the risk of
Discussion bleeding, a position that is consistent with the markedly lower
Our data demonstrate that fondaparinux significantly reduced the rates of bleeding with fondaparinux compared with enoxaparin
risk of death and MI, with a trend towards fewer strokes in STEMI seen in OASIS-5.
patients treated with thrombolytic therapy. In addition, there was a Contemporary guidelines recommend the routine adminis-
reduction in severe bleeding, so that the pre-specified outcome tration of UFH in STEMI patients treated with FS thrombolytic
balancing efficacy and safety was clearly reduced by fondaparinux. agents., This is largely based on three small trials indicating
328 R.J.G. Peters et al

Table 6 Primary endpoints at 30 days by stratum

n Control, n (%) Fondaparinux, n (%) HR 95% CI P-value for interaction

...............................................................................................................................................................................
Death/MI
Stratum 1 4415 308 (13.8) 237 (10.8) 0.77 0.65–0.91 0.414
Stratum 2 1021 64 (12.3) 56 (11.2) 0.91 0.63–1.30
Severe haemorrhage
Stratum 1 4415 42 (2.0) 27 (1.3) 0.65 0.40–1.05 0.680
Stratum 2 1021 14 (2.7) 7 (1.4) 0.52 0.21–1.29

FS: fibrin specific thrombolytic agents, NFS: non-fibrin specific thrombolytic agents, HR: hazard ratio, 95% CI: 95% confidence interval.

improved patency of the infarct-related coronary artery when

Table 7 Event rates by 30 days in patients who received intravenous UFH is added to FS thrombolytic agents.11 – 13
thrombolytic therapy. Kaplan –Meier and Cox PH However, in two of these trials, patients treated with intravenous
hazard ratios UFH did not receive aspirin10, whereas in the third study, in which
all patients received aspirin, there was only a modest impact of
Control, Fonda, HR 95% CI intravenous UFH on patency. All trials were too small to reliably
n 5 2744 n 5 2692
............ ............ assess the impact on clinical outcomes and on safety, and recent
n % n % trials of GP 2b/3a inhibitors have indicated that improved coronary

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................................................................................
patency need not result in a reduction in mortality, especially if
Death/MI 372 13.6 293 10.9 0.79 0.68– -0.92
bleeding or strokes are increased.14
Death 293 10.7 233 8.7 0.80 0.68– 0.95
A meta analysis of all available trials on a total of about 1450
MI 97 3.8 71 2.8 0.74 0.54– 1.00
patients evaluating the use of UFH with a FS thrombolytic agent
Stroke 38 1.5 29 1.1 0.77 0.48– 1.25
indicates no reduction in mortality or morbidity, but a clear
Death/MI/stroke 393 14.3 306 11.4 0.78 0.67– 0.91
excess in bleeding as compared to placebo.15
Severe haemorrhage 56 2.1 34 1.3 0.62 0.40– 0.94
The use of an anticoagulant in patients who have received strep-
Death/MI/severe 386 14.1 297 11.0 0.77 0.67– 0.90
tokinase has been evaluated in several large trials. In the ISIS 3 and
haemorrhage
GISSI 2 trials, there was no reduction in mortality, a small
MI, myocardial infarction.
reduction in recurrent MI in hospital (which was not sustained at
30 days), a tendency to increased ICH and a clear excess in

Figure 1 Kaplan– Meier curve: incidence of death and myocardial infarction in patients treated with thrombolytics
Role of fondaparinux as an adjunct to thrombolytic therapy in AMI
Figure 2 Primary efficacy outcome (death and myocardial infarction at 30 days) in the overall population and in the subgroups of non-primary
percutaneous coronary intervention treated patients
major bleeds.1,2 The GUSTO trial demonstrated that IV UFH was
not superior to subcutaneous UFH, but further increased bleed-
ing.16 Thus, the currently available evidence for the use of UFH
in patients receiving a FS thrombolytic and aspirin is weak, and
the data evaluating UFH in patients receiving streptokinase
clearly demonstrates no clinically important benefits, but an
excess of major bleeds, including intracranial bleeds. Comparison
of a new agent against UFH may therefore underestimate the
risk of bleeding complications, whereas the demonstration of effi-
cacy would be relatively unaffected. The above data have led to
variability of UFH use after thrombolytic therapy, and reflects
the uncertainty of the available data.
A recent meta analysis of trials comparing low-molecular weight
heparin (LMWH) and placebo (completed after the initiation of
OASIS-5 and -6), including the recently published CREATE study,
has shown a reduction in death (by 10%, 14 deaths per 1000)
and re-MI (by 25%, 6 per 1000) at the cost of seven major bleeding
complications (including ICH) per 1000 (all 30 days).11
A meta analysis of trials of LMWH vs. UFH (in over 5000
patients) has shown a 6% relative risk reduction in death at 30
days and a 35% relative risk reduction in re-MI (19 per 1000
patients treated) at 30 days, at the cost of three strokes per
1000 patients treated.11 Results from the more recent ExTRACT
study (n ¼ 20,506) are consistent with this meta analysis.4
However, LMWH is associated with a substantial increase in
329
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severe bleeding complications as compared to UFH, including
ICH and fatal bleeds.4,11
Our findings in this analysis of OASIS-6, of a non-significantly
lower rate of bleeding and strokes, and of a significantly lower
mortality with fondaparinux in patients receiving thrombolytic
therapy, as well as benefit in the subgroup not receiving reperfu-
sion therapy in the accompanying paper by Oldgren et al.,17 are
consistent with the findings of the OASIS-5 trial in patients with
non-ST elevation acute coronary syndrome (ACS), where fonda-
parinux was as effective as enoxaparin in the short term, but
was substantially safer.18 Therefore the two trials together
provide strong evidence of the benefits and safety of fondaparinux
in a broad group of patients with ACSs.
Limitations
The trial was not designed to have sufficient power to indepen-
dently examine the impact of fondaparinux in various subgroups
but, like most trials, was designed to have adequate power to
detect clinically important results based on the overall study popu-
lation. The separate analysis of the main types of reperfusion
therapy (primary PCI, thrombolytic and no reperfusion) was pre-
specified in our statistical analysis plan. However, further subgroup
analyses of those receiving thrombolytic agents should be inter-
preted with considerable caution, as the numbers of patients for
some of the analyses tend to become very small and potentially
330
Figure 3 Thirty day efficacy (death and myocardial infarction, top) and safety (severe haemorrhage, bottom) outcome in patients who
received thrombolytic therapy
unreliable, as the data are further or repeatedly subdivided in
different ways.19 – 22 The influence of the play of chance is exempli-
fied in Figure 2, where in non-reperfused patients the treatment
effect of fondaparinux compared with heparin appears larger
than compared with placebo. Therefore, the consistency of the
results in those receiving thrombolytic therapy with those of the
overall results should provide confidence in the robustness of
the findings, but any further subgroup analyses should be viewed
with caution.
Conclusion
The results of OASIS-6 demonstrate that overall, there is evidence
of benefit for fondaparinux without evidence of an increase in
bleeding risk. Subgroup analysis must be interpreted with
caution. However, in STEMI patients treated with thrombolytic
agents (predominantly streptokinase), fondaparinux significantly
improved overall outcome, both in short term and in long term,
with no evidence of heterogeneity by whether or not heparin
was used in the control arm. Fondaparinux was associated with a
unique safety profile, with no increase (and perhaps a decrease) in
severe haemorrhage, irrespective of the type of thrombolytic, and
compared with both heparin and placebo.
R.J.G. Peters et al
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Acknowledgement
However, the trial was conducted, data collected, and analysed
independently by the Population Health Research Institute and
the steering committee.
Conflict of interest: All authors have received honoraria and/or
consulting fees from the sponsors. None of the authors are share-
holders for any of these companies.
Funding
The OASIS-6 study was jointly funded by Sanofi-Aventis, Organon, and
GlaxoSmithKline.
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