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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Effect of fondaparinux 2.5 mg once daily on mortality: a meta-analysis of phase III randomized trials of venous thromboembolism prevention

John W. Eikelboom*

Thrombosis Service, McMaster Clinic, Hamilton Health Sciences-General Hospital, Hamilton, ON, Canada

* Corresponding author. Tel: +11 905 521 2100; fax: +11 905 521 1551. E-mail address: eikelbj{at}mcmaster.ca


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: Fondaparinux significantly reduces death in patients with acute coronary syndromes. The effect of fondaparinux on mortality when used for prevention of venous thromboembolism is unknown. We performed a meta-analysis to examine the effect of fondaparinux 2.5 mg once daily on mortality in phase III randomized trials of venous thromboembolism prevention.

Methods and results: Eight trials involving 13 085 patients undergoing major orthopaedic or abdominal surgery or medical patients were included. In five trials, fondaparinux was compared with low-molecular-weight heparin (LMWH); in three trials, the comparator was placebo. The primary efficacy outcome was all-cause mortality up to day 30. The incidence of death was 1.6% (105/6538) in patients treated with fondaparinux compared with 2.1% (134/6547) in patients treated with placebo or LMWH [odds ratio (OR) 0.79; 95% confidence interval (CI) 0.60 to 1.01, P = 0.058; P for heterogeneity = 0.58]. Results were consistent irrespective of whether the comparator was placebo (2.0 vs. 2.6%, OR 0.77; 95% CI: 0.46–1.26) or LMWH (1.5 vs. 1.9%, OR 0.78; 95% CI: 0.58–1.06).

Conclusion: The one-fifth reduction in mortality with fondaparinux suggested in randomized trials of venous thromboembolism prevention is not statistically significant, but is externally consistent with the reduction in mortality observed in registry studies and in randomized trials of fondaparinux in patients with acute coronary syndromes.

Key Words: Fondaparinux • Low-molecular-weight heparins • Clinical trial • Mortality • Thromboprophylaxis • Venous thromboembolism


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
Venous thromboembolism affects 1 to 2 per 1000 people in the general population each year,1,2 and is associated with one out of every 10 deaths in the general population in Europe.3 Effective methods are available for the prevention of venous thromboembolism, but very few treatments have been shown to reduce mortality (Table 1). Most randomized trials have been underpowered to demonstrate an effect of thromboprophylaxis on mortality and it is estimated that ~30 000 patients would be needed to reliably detect a 50% difference in mortality between two thromboprophylaxis methods.4 Meta-analyses can provide more reliable estimates of treatment effect than individual trials because they have greater statistical power, and thus represent an alternative approach to determining whether thromboprophylaxis reduces mortality. A meta-analysis of surgical thromboprophylaxis trials showed that unfractionated heparin (UFH) compared with control (placebo or no treatment) reduced the risk of death by 22% (P < 0.02).5 There was no significant reduction in death in meta-analyses of surgical trials comparing low-molecular-weight heparin (LMWH) or vitamin K antagonists with placebo/untreated control,6,7 or comparing anticoagulants with no anticoagulants in medical patients with restricted mobility.8,9 No study comparing LMWH with active comparator has demonstrated an effect on death in any clinical setting.


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  		Table 1 Effect of various thromboprophylaxis strategies in reducing mortality: summary of evidence5–9,22–24

 
Fondaparinux is the first selective inhibitor of activated coagulation factor X (Xa) approved for clinical use. In patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS), fondaparinux 2.5 mg once daily compared with enoxaparin 1 mg/kg twice daily reduced the risk of death by 17% at 30 days and by 11% at 180 days (Figure 1).10 In patients with ST-segment elevation myocardial infarction, fondaparinux 2.5 mg once daily compared with placebo or intravenous UFH reduced the risk of death by 13% at 30 days and by 14% at 180 days (Figure 1).11 Fondaparinux has also been extensively evaluated in multiple randomized trials for the prevention of venous thromboembolism in surgical and medical patients, but an effect on mortality was not demonstrated in individual trials. We performed a meta-analysis of phase III randomized trials comparing fondaparinux 2.5 mg once daily with placebo or approved doses of LMWH to examine the effect of fondaparinux on mortality.


Figure 1
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  		Figure 1 Mortality in patients with non-ST elevation acute coronary syndromes or ST-elevation myocardial infarction treated with fondaparinux 2.5 mg once daily in the randomized, double-blind OASIS-5 (A) and OASIS-6 trials (B), respectively10,11.

 

   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Study selection
We included all randomized, double-blind, phase III trials comparing a once daily 2.5 mg dose of fondaparinux with placebo or anticoagulant control for the prevention of venous thromboembolism in which mortality at 30 days was reported. The type of comparator, duration of treatment, or duration of follow-up was not used to determine eligibility of studies for inclusion. Uncontrolled studies or studies which did not use a 2.5 mg dose of fondaparinux were excluded.

Search strategy
Potentially eligible studies were identified by a computer-assisted search of the MEDLINE database, using the following keywords: fondaparinux, pentasaccharide, randomized, and controlled trial. The reference lists of original articles and review papers were also examined.

Data extraction
Since no other studies than those designed by the pharmaceutical companies (Sanofi-Synthelabo then GlaxoSmithKline) developing the drug fondaparinux were identified, the patient data were extracted from the fondaparinux integrated clinical trials database. Data were extracted on trial design, baseline characteristics, interventions, and outcome at 30 days.

Outcome measures
The primary outcome of the meta-analysis was all-cause mortality at 30 days, where day 1 corresponded to the day of randomization.

Statistical analyses
An individual patient meta-analysis was performed using a fixed effects model with the analyses stratified by trial and based on an intention-to-treat approach. The homogeneity of the treatment effect between studies was assessed using the Breslow-Day homogeneity of odds ratio test. The odds ratios (OR) were estimated with two-sided 95% confidence intervals (CI). An OR equal to one indicates no difference between the treatments, less than one indicates that fondaparinux is better, and more than one that the comparator is better.

A sensitivity analysis was performed in which data from the one extended-duration prophylaxis study were excluded to assess its influence on the overall result.

Subgroup analyses were performed according to the type of comparator (i.e. fondaparinux vs. placebo and fondaparinux vs. LMWH) in order to evaluate the internal consistency of results. All statistical analyses were performed using SAS software, version 8.02 (SAS Institute Inc., Cary, NC, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Trials
Eight trials involving a total of 13 085 patients were included (Table 2). Seven trials, performed in 12 236 patients (93.5%), were performed in a surgical context,12–18 and one trial (849 patients, 6.5%) was performed in acutely ill medical patients with restricted mobility.19 Among the surgical trials, five studies were performed in major orthopaedic surgery,12–16 and two studies in major abdominal surgery.17,18


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  		Table 2 Main characteristics of the trials included in the meta-analysis

 
Patient population
The major orthopaedic surgery trials included patients who were scheduled for primary elective total hip replacement surgery, revision of at least one component of a previously implanted total hip prosthesis, elective major knee surgery, or surgery for a fracture of the upper third of the femur.12–16 One of the trials in abdominal surgery included high-risk patients who were expected to undergo an abdominal surgery lasting longer than 45 min while under general anaesthesia and aged over 60 years or aged over 40 years with one or more additional risk factors for thromboembolic complications.17 The qualifying risk factors were obesity, a history of venous thromboembolism, congestive heart failure (NYHA class III or IV), chronic obstructive pulmonary disease, inflammatory bowel disease, or surgery for cancer. In the other abdominal surgery trial, eligible patients were aged over 40 years, weighed over 50 kg, and were scheduled to undergo abdominal surgery expected to last longer than 45 min.18 The medical thromboprophylaxis trial included patients aged at least 60 years who were expected to require bed rest for at least four days and who were acutely ill with congestive heart failure (NYHA class III or IV), acute respiratory illness in the presence of chronic lung disease, or with clinically diagnosed acute infections or inflammatory disorders such as arthritis, connective tissue diseases, and inflammatory bowel disease.19 In all the trials, patients with contraindications to anticoagulation, including those at high risk of bleeding or with high serum creatinine concentration (>180 µmol/L), were excluded.

Baseline characteristics
The median age of the patients was 69 years; 31.2% were aged 75 years or more (Table 3). Most patients were women (56.1%), and 28.4% of all patients reported a history of cancer.


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  		Table 3 Patient characteristics

 
Interventions
The dosage regimens of fondaparinux and comparators are shown in Table 2. Five trials, involving a total of 10 271 patients (78.5%) compared fondaparinux with LMWH. Four trials involving 2814 patients (21.5%) compared fondaparinux with placebo. Two LMWH agents, enoxaparin and dalteparin, were used as comparators.

In surgical studies, the protocol required that the first injection of fondaparinux be administered 6 ± 2 h postoperatively, and the second injection at least 12 h after the first, but no more than 24 h after surgical closure.12–18 In six surgical trials, fondaparinux and comparators were given for 5 to 9 days post surgery; patients were then followed for 35 to 49 days after major orthopaedic surgery, or 28 to 32 days after abdominal surgery.12–15,17,18 In a single trial of extended-duration thromboprophylaxis after hip fracture surgery, patients received fondaparinux for 7 ± 1 days in an open fashion, after which they received fondaparinux or placebo for an additional 21 ± 2 days, for a total duration of treatment of 25 to 31 days; follow-up was up to 32 days after surgery.16 In the trial of medical patients, fondaparinux or placebo were administered for 6 to 14 days; follow-up was continued up to day 32.19 In all the studies, the extension of prophylaxis with non-study drugs and treatment of venous thromboembolism arising during the study were left to be discretion of the local investigator.

All-cause mortality
Fondaparinux compared with control was associated with a non-significant 21% reduction in risk of all-cause mortality, from 2.1% in the control group to 1.6% in the fondaparinux group, corresponding to an absolute difference of –0.44% (95% CI: –0.90 to 0.02) and an OR of 0.79 (95% CI: 0.60 to 1.01, P = 0.058; P for heterogeneity = 0.58) (Table 4 and Figure 2). Excluding the trial of extended thromboprophylaxis after hip fracture surgery, the respective figures were 2.1% in the control group and 1.6% in the fondaparinux group [OR (95% CI): 0.78 (0.59 to 1.01), P = 0.063; P for heterogeneity = 0.466].


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  		Table 4 Effect of fondaparinux on mortality

 

Figure 2
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  		Figure 2 Effect of fondaparinux on mortality. CI, confidence interval; HFS, hip fracture surgery; LMWH, low-molecular-weight heparins; OR, odds ratio; MKS, major knee surgery; THR: total hip replacement.

 
Subgroup analyses
The reduction in mortality associated with the fondaparinux administration was consistent, irrespective of whether the comparator was placebo [2.6 vs. 2.0%, OR: 0.77 (0.46 to 1.26)] or LMWH [1.9 vs. 1.5%, OR: 0.78 (0.58 to 1.06)] (P for heterogeneity across subgroups = 0.97).


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
Our meta-analysis suggests a one-fifth reduction in risk of mortality with fondaparinux 2.5 mg once daily compared with placebo or LMWH when used for the prevention of venous thromboembolism in surgical or medical patients. The reduction in mortality is not statistically significant by conventional criteria, but is remarkably consistent with the reduction in mortality seen with fondaparinux in patients with acute coronary syndromes and was evident irrespective of whether the comparator was placebo or active control, without any statistical evidence of heterogeneity.

The most feared complication of venous thromboembolism is fatal pulmonary embolism and the most important goal of thromboprophylaxis is to prevent death. An effect of thromboprophylaxis on death is difficult to demonstrate in clinical trials because death is relatively uncommon (1–3% in the present meta-analysis) and very large numbers of patients are needed. Thus, no individual trial to date has been adequately powered to demonstrate an effect of anticoagulant thromboprophylaxis on mortality. Furthermore, while UFH has been shown to reduce mortality when compared with placebo/untreated control based on a meta-analysis of trials conducted in the 1970s and 80s,5 no thromboprophylaxis strategy has been shown to reduce death compared with active control. Our results suggesting a consistent effect of fondaparinux on mortality irrespective of comparator are consistent with the results of a very large retrospective database analysis spanning 509 US hospitals that compared the efficacy and safety of fondaparinux, LMWH (enoxaparin or dalteparin) and UFH in 144 806 patients undergoing major orthopaedic surgery.20 In the latter study, fondaparinux compared with UFH or LMWH significantly reduced all-cause mortality by ~70 and 45%, respectively, (Figure 3) without any increase in bleeding risk.


Figure 3
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  		Figure 3 Effect of various anticoagulant drugs in reducing all-cause mortality in patients undergoing major orthopaedic surgery20. LMWH, low-molecular-weight heparins; UFH, unfractionated heparin.

 
The mechanisms through which fondaparinux may exert a beneficial effect on preventing death in trials of venous thromboembolism prevention merit further exploration. In patients at risk of venous thromboembolism, it seems reasonable to assume that fondaparinux prevents death by preventing fatal pulmonary embolism. However, fondaparinux is also highly effective for preventing recurrent myocardial infarction and stroke in patients with acute coronary syndromes,10,11 and arterial vascular events are believed to account for about one-half of all deaths following major orthopaedic surgery (60% of the population included in this meta-analysis underwent orthopaedic surgery).21 In order to address this issue, we are presently conducting, in a blinded fashion, an exploratory analysis on the effect of fondaparinux on cause-specific mortality, including cardiovascular mortality. The OASIS-5 trial demonstrated that fondaparinux compared with enoxaparin reduced all cause mortality by 17% at 30 days in patients with NSTE-ACS. More than 90% of deaths were cardiovascular deaths (96.3% of these deaths were clearly due to a cardiovascular cause and 3.7% were due to unknown causes).10 Fatal bleeding accounted for <10% of cardiovascular deaths (8.0% of all deaths at 9 days and 6% of all deaths at 30 days were due to bleeding), but at 180 days >90% of the excess deaths in patients treated with enoxaparin occurred in patients who also experienced bleeding. Therefore, we propose also to examine the impact of bleeding on death in venous thromboembolism prevention trials. Finally, a benefit of LMWH for preventing death has been demonstrated in cancer patients,22 and it is possible that fondaparinux exerts an effect on mortality in venous thromboembolism prevention trials by reducing cancer deaths.

The most important limitation of this study is that it represents a post hoc exploratory analysis that pooled data from randomized controlled trials performed in different clinical settings with different comparators. In addition, while the results are provocative, the reduction in mortality with fondaparinux was not statistically significant. For these reasons, our results should be considered hypothesis-generating rather than representing definite evidence of a mortality benefit of fondaparinux when used for the prevention of venous thromboembolism. Further analyses may clarify the mechanism of any effect of fondaparinux on mortality in venous thromboprophylaxis trials.

In conclusion, the results of our meta-analysis of trials using fondaparinux 2.5 mg once daily for the prevention of venous thromboembolism are consistent with the results obtained with fondaparinux 2.5 mg once daily in patients with acute coronary syndromes which demonstrated a 14 to 17% reduction in mortality at 30 days.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
The author gratefully acknowledges the expert statistical assistance of Timothy E. Rolfe (GlaxoSmithKline, Harlow, UK).

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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J. W. Eikelboom, D. J. Quinlan, and M. O'Donnell
Major Bleeding, Mortality, and Efficacy of Fondaparinux in Venous Thromboembolism Prevention Trials
Circulation, November 17, 2009; 120(20): 2006 - 2011.
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