Fondaparinux Sodium Compared With Low‐Molecular‐Weight Heparins for Perioperative Surgical Thromboprophylaxis: A Systematic Review and Meta‐analysis

Abstract

Background

Fondaparinux sodium has been compared with low‐molecular‐weight heparins (LMWH) in randomized controlled trials for perioperative surgical thromboprophylaxis. However, the results from these studies are inconsistent in terms of efficacy and safety to reach a clinical decision. The objective of this study was to systematically review the randomized controlled trials comparing the efficacy and safety of fondaparinux and LMWH for perioperative surgical thromboprophylaxis.

Methods and Results

Systematic search in various databases was done to identify randomized controlled trials comparing fondaparinux and LMWH published during the years 2000 to 2017. Outcomes of interest in this study included venous thromboembolism up to day 15, all‐cause mortality up to day 90, major bleeding, and minor bleeding during the treatment period. Analyses were performed with the relative odds based on a random‐effects model using Mantel‐Haenszel statistics. Results were presented as odds ratios with their 95% CIs. The assessment of study quality was performed as per Cochrane collaboration. After screening 10 644 articles, 12 randomized controlled trials including 14 906 patients were included in the final analyses. Pooled analyses showed the odds of venous thromboembolism in the fondaparinux group were 0.49 times the odds in LMWH group (OR=0.49 [0.38–0.64]). However, the odds of major bleeding in the fondaparinux group were 1.48 times the odds in the LMWH group (OR=1.48 [1.15–1.90]).

Conclusions

Fondaparinux was associated with a superior efficacy in terms of reduction of venous thromboembolism in this meta‐analysis. However, it was also associated with increased odds of major bleeding.

Clinical Perspective

What Is New?

• Meta‐analyses during the past years have compared fondaparinux sodium with low molecular weight heparins (LMWH) for thromboprophylaxis in orthopedic surgeries; however, the literature lacks a systematic comparison of these drugs in different types of surgeries altogether.

• Among the randomized controlled trials, both drugs have been compared for surgical thromboprophylaxis; nevertheless, the findings are not consistent in terms of efficacy and safety.

• This study systematically reviews the randomized controlled trials comparing safety and efficacy of fondaparinux and LMWHs for perioperative surgical thromboprophylaxis for better clinical judgment.

What Are the Clinical Implications?

• In this study, fondaparinux was associated with lower odds of venous thromboembolism compared with LMWH, but both groups were similar in terms of reduction of symptomatic venous thromboembolism and all‐cause mortality.

• Fondaparinux was also associated with increased risk of major bleeding, especially surgical site bleeding, compared with LMWH.

• This analysis suggested a trade‐off between safety and efficacy when fondaparinux is used over LMWH; however, net clinical benefit (venous thromboembolism + major bleeding) was in favor of fondaparinux compared with LMWH.

Introduction

Venous thromboembolism (VTE) is a leading cause of preventable death among patients undergoing surgical intervention.1 Major factors contributing to development of VTE among surgical patients may include variations in the flow of blood in the veins (circulatory stasis), changes in the vessel wall because of any injury during the procedure (vascular damage), and any variation in the composition of blood (hypercoagulability). These complex mechanisms interplay in the progression of VTE.2 A majority of patients undergoing surgeries possess at least 1 risk factor of VTE,3 making VTE a significant cause of healthcare and financial burden.4, 5

VTE is the most common postoperative complication following surgeries.2 VTE has been reported to be associated with long‐term sequelae such as chronic leg ulcers and venous insufficiency,6 which could be life threatening. Thus, surgical thromboprophylaxis is strongly recommended by the American College of Chest Physicians.7 Pharmacological prophylaxis is effective, yet VTE still occurs frequently.8 Hence, there is a need to improve thromboprophylaxis for surgical patients at risk for VTE.

Among patients undergoing surgical interventions, the management of anticoagulation is challenging, as underlying surgical procedures are associated with bleeding complications, which could be augmented further by anticoagulation for thromboprophylaxis. Thus, a balance between thrombosis prevention and devastating operative site bleeding is crucial in this population.9 Conventional therapy such as low‐molecular‐weight heparins (LMWHs) has been used for many years; nevertheless, factor Xa inhibitors are desired because they are more selective in their action.10 Fondaparinux is the first approved drug among factor Xa inhibitors,11 which has been compared with LMWH in various clinical trials; however, results are inconsistent in terms of efficacy and safety.6, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 This meta‐analysis was performed to examine existing clinical evidence on efficacy and safety of parenteral fondaparinux and LMWH for perioperative surgical thromboprophylaxis in patients at high risk for VTE.

Methods

The authors declare that all supporting data are available within the tables, figures, and online supplemental material of this manuscript. This systematic review and meta‐analysis followed the guidelines published by Cochrane Collaboration. We used the Preferred Reporting Items for Systematic Review and Meta‐analysis 200922 checklist (Table S1) for transparent reporting of this study.

Study Protocol

We developed a protocol for systematic review and meta‐analysis to assess overall risk factors as per Virchow's triad (Data S1). However, this paper was developed to specifically address perioperative surgical thromboprophylaxis considering its management very crucial and challenging for this patient population.9

Eligibility Criteria

Type of Studies

Only head‐to‐head randomized controlled trials (RCTs) comparing fondaparinux with LMWHs published in English, and meeting the study inclusion criteria were taken into consideration. LMWHs included enoxaparin sodium, dalteparin sodium, nadroparin calcium, parnaparin sodium, and tinzaparin sodium. Potential studies in other languages were searched for abstracts in English. Studies were included if published between January 2000 and December 2017. This period was selected because the first clinical trial of fondaparinux comparing LMWH was published in 2001.11

Participants

RCTs were considered eligible if they included both male and female adults aged ≥18 years old. RCTs enrolling patients undergoing major orthopedic surgeries (eg, total hip replacement, total knee replacement, or hip fracture surgeries), major general surgeries (eg, abdominal surgery, cancer surgery), and related surgical immobility proven to be a risk factor for the development of VTE were included in the analyses.

Interventions

The interventions compared in this review were subcutaneous fondaparinux and subcutaneous LMWHs at titrated dose/manufacturer's recommended dose as per body weight or at the standard dose as per the country of interest. Studies in which the assessment was done up to 15 days after surgery were only taken into consideration for inclusion. Assessment period was chosen as 15 days, as the increased risk of VTE has been cited to be during the first 2 weeks.23, 24, 25

Information Sources

We conducted a systematic search of the databases (Embase, PubMed, The Cochrane Central Register of Control Trials, ProQuest‐Direct, Science Direct, Clinicaltrials.gov), and conference proceedings to find RCTs evaluating fondaparinux and LMWH for the prophylaxis of VTE. Trials presented in conference proceedings but not published were searched for full‐text results. When full‐text results were not available, the reviewers contacted the authors of the unpublished studies via email to request trial results and full‐text manuscripts if available. The reference lists of all identified trials and review articles were hand searched to find any additional trials.

Search

The complete search strategy can be found in Table S2.

Study Selection

Covidence,26 an online systematic review platform (www.covidence.org) was used to initially screen articles on the basis of the title and abstract. Records were imported from various databases into Covidence, where duplicates were removed. Two review authors (A.K., A.T.) independently screened the titles and abstracts of identified citations for potential eligibility. Full texts of articles retrieved were judged potentially eligible by at least 1 review author.

Data Collection Process

Both review authors then independently screened the full‐text article for eligibility using an explicit inclusion and exclusion criteria. The screening process was documented in Preferred Reporting Items for Systematic Review and Meta‐analysis flow chart of study selection (Figure 1). A data extraction form was developed in the Covidence web platform to extract the information from relevant clinical trials. Both review authors independently extracted data from each included study. Any disagreements were resolved by discussion or by consulting a third reviewer (WW). After consensus, both reviewers analyzed the resulting papers in full text independently.

Figure 1.

Preferred reporting items for systematic reviews and meta‐analyses (PRISMA) flow chart for study selection.

Data Items

The primary efficacy outcome of this study was VTE defined as the composite of symptomatic and asymptomatic deep vein thrombosis (DVT) and pulmonary embolism (PE). We also reported symptomatic VTE and PE as an independent outcome, considering it to be an important predictor of death. Considering the differential risk of proximal and distal DVT on PE and death, the events of proximal and distal DVT were also reported separately. Included studies assessed patients for DVT by systematic bilateral ascending venography of the legs, magnetic resonance venography, or d‐dimer test. PE was assessed by a lung scan, pulmonary angiography, and helical computed tomography or at autopsy. All‐cause mortality at day 90 after surgery was also reported. Mortality assessment at 90 days was chosen, as increased risk of VTE‐related mortality has been indicated as 60 to 90 days following surgeries.12 The safety outcome was the incidence of major bleeding, a composite outcome that included fatal bleeding; bleeding that was retroperitoneal, intracranial, or intraspinal or that involved any other critical organ; bleeding leading to reoperation; or overt bleeding, with hemoglobin level declined >2 g/dL, or requirement of transfusion of ≥2 units of blood as reported in major clinical trials.11, 12, 15, 27 Safety measures also included minor bleeding, which included any bleeding event not qualified as major bleeding. To assist clinical decision making, we also reported net clinical benefit in which we combined VTE and major bleeding events for each study.

Risk of Bias in Individual Studies

The assessment of methodological quality of included studies was done using The Cochrane Collaboration's “Risk of Bias” tool. Domains were classified as “low risk,” “high risk,” or “unclear risk” as per Cochrane Handbook for Systematic Reviews of Interventions.28

Summary Measures

All the outcomes in this analysis were binary. Relative treatment effects for each comparison were expressed as odds ratio (OR) with 95% CI. The pooled data for each outcome were used to create a “Forest Plot.” The individual participant was the unit of analysis. Finally, we also presented the primary outcomes using L'Abbe plots as a tool to look at the direction of pooled effect graphically and to compare the event rates in fondaparinux compared with LMWH.

Synthesis of Results

Data were analyzed using Mantel‐Haenszel statistics. Chi‐square tests and I2 statistics were used to assess heterogeneity. As the studies included in this meta‐analysis were from different countries, which might cause unexplained heterogeneity, we used a random‐effects model for summary statistics.29

Risk of Bias Across Studies

The reporting bias was assessed by use of a “funnel plot” to examine the relationship between treatment effects and their inverted standard errors.30 Funnel plots were presented only if there were at least 10 studies in any subgroup to maintain power to distinguish chance from real symmetry.28

Additional Analyses

Subgroup Analysis

Subgroup analysis was conducted in which studies from different continents were pooled together to see any difference in the results compared with primary analyses. We also reported a subgroup analysis comparing only postoperative thromboprophylaxis to control for possible bias caused by different timings of anticoagulation.

Sensitivity Analysis

The primary analyses included data from all patients in the trials during the period of randomly allocated treatment. A sensitivity analysis was performed to explore the effect that risk of bias had on estimates of treatment effects. The effect on the primary outcome was explored using sensitivity analyses by eliminating studies that were at a high risk of bias, had used a dose other than that recommended, did not clearly list the dose, or did not have the full text available. As some included studies in this meta‐analysis had a small number of events, we used the recommended Peto method31 for pooled analyses during sensitivity analyses. All statistical analyses in this meta‐analyses were performed using Review Manager32 (RevMan 5.3) and STATA33 version 15.1.

Results

Study Selection

A total of 10 644 citations were identified; 5923 duplicate studies were removed, leaving 4721 studies for screening. After screening the full text, 18 studies were retrieved and reviewed. Six of these 18 studies were subsequently excluded because they did not meet the RCT study design criteria or were duplicate publications. The final analysis included 12 studies (Figure 1).

Study Characteristics

The 12 studies6, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 captured data on 14 906 patients for analysis. All 12 studies compared fondaparinux with LMWHs at titrated dose/manufacturer recommendation for surgical thromboprophylaxis. Six of these studies6, 11, 12, 15, 18, 19 were multicenter RCTs while the remaining 613, 14, 16, 17, 20, 21 were single‐center RCTs (Table). Four studies each were conducted in North American11, 12, 16, 18 and Asian countries.13, 14, 17, 20 Three studies11, 12, 21 were conducted in European countries, and 1 study was multinational. Average assessment day of VTE was the ninth day in this meta‐analysis.

Table 1.

Description of Included Studies in the Meta‐analysis

Characteristics of the Included Studies								Number of Patients		Mean Age in Years		Sex (M/F)		Mean Weight/BMI
Study	Type of Surgery	N=14 906	Clinical Trial Setting	FPX Dose	LMWH Dose	Assessment Day Post‐Surgery	Duration of Prophylaxis	FPX	LMWH	FPX	LMWH	FPX	LMWH	FPX	LMWH
Turpie, 200119	Elective hip replacement surgery	n=437	Multicentered, double blind RCT	3.0 mg OD	Enoxaparin 30 mg BD	10th day	5–10 days	177	260	66	66	80/97	123/137	80/NA	81/NA
Bauer, 200118	Elective major knee surgery	n=1034	Multicentered, double‐blind RCT	2.5 mg OD	Enoxaparin 30 mg BD	11th Day	5–9 days	517	517	67.5	67.5	204/313	223/294	89/31.5	88/30.9
Erikss‐on, 200111	Hip‐fracture surgery	n=1673	Multi‐centered, double‐blind RCT	2.5 mg OD	Enoxaparin 40 mg OD	11th day	5–9 days	831	842	76.8	77.3	187/644	224/618	64.3/23.8	64.223.6
Turpie, 200212	Total hip replacement	n=3841	Multicentered, double‐blind RCT	2.5 mg OD	Enoxaparin 30 mg BD	11th day	5–9 days	1915	1926	67	67	942/973	897/1029	80.6/28	79.6/27.6
Lassen, 20026	Elective hip replacement surgery	n=4100	Multicentered, double‐blind RCT	2.5 mg OD	Enoxaparin 40 mg OD	11th day	5–9 days	2048	2052	66.4	67	889/1159	875/1177	75/26	75/26.55
Agnelli, 200515	High‐risk abdominal surgery	n=2858	Multicentered, double‐blind RCT	2.5 mg OD	Dalteparin 5000 IU OD	10th day	5–9 days	1433	1425	66	65	788/645	796/629	74.2/26.3	74.3/26.3
Sasaki, 200914	Hip fracture surgery	n=76	Single‐centered, open‐label RCT	2.5 mg OD	Not disclosed	14th day	14 days	38	38	79.2	80.2	8/30	9/29	NA/21.3	NA/20.35
Yokote, 201117	Total hip replacement	n=167	Single‐centered, single‐blind RCT	2.5 mg OD	Enoxaparin 20 mg BD	11th day	10 days	84	83	63	64	14/70	16/67	NA/22.5	NA/23.0
Argun, 201321	Elective Hip and Knee Arthroplasty	n=108	Single‐centered, open‐label RCT	2.5 mg OD	Nadroparin 2850 IU OD	5th day	Not disclosed	55	53	58.7	60	34/21	33/20	NA/NA	NA/NA
Shen, 201420	Esophagectomy	n=116	Single‐centered, open‐label RCT	2.5 mg OD	Nadroparin 4100 IU OD	Undisclosed‐Abstract only	Not disclosed	NA	NA	NA	NA	NA	NA	NA/NA	NA/NA
Steele, 201516	Bariatric surgical patients	n=198	Single‐centered, double‐blind RCT	5.0 mg OD	Enoxaparin 40 mg BD	14th day	Duration of hospital stay (Average: 2.5 days)	100	98	40.4	41.8	16/84	16/82	NA/NA	NA/NA
Hata, 201613	Uro‐oncological surgery	n=298	Single‐centered, single‐blind RCT	2.5 mg OD	Enoxaparin 2000 IU BD	5th day	5 Days	152	146	63.9	64.7	144/8	138/8	NA/23.9	NA/23.7

BMI indicates body mass index; FPX, fondaparinux sodium; LMWH, low‐molecular‐weight heparin; RCT, randomized controlled trial.

Risk of Bias Within Studies

Eight of the studies6, 11, 12, 13, 15, 16, 18, 19 were funded by pharmaceutical industries, which could have been a source of bias. These studies were indicated to be at high risk of bias. Review authors’ judgment about each risk is presented by a “risk of bias graph” and a “risk of bias summary” for each study in Figures 2 and 3, respectively. A detailed description of the risk of bias can be found in Data S2 and Data S3.

Figure 2.

Risk‐of‐bias graph: review authors’ judgments about each risk‐of‐bias item presented as percentages across all included studies.

Figure 3.

Risk‐of‐bias summary: review authors’ judgments about each risk‐of‐bias item for each included study.

Results of Individual Studies

Summary data for each study are indicated in Table and Data S3.

Synthesis of Results

Efficacy Outcome

Venous thromboembolism up to postoperative day 15

All 12 trials reported on the outcome measure of VTE; 243 of 4309 patients had VTE in the fondaparinux group versus 471 of 4357 patients in the LMWH group. The odds of VTE in the fondaparinux group were 0.49 times the odds of VTE in the LMWH group (OR, 0.49; 95% CI, 0.38–0.64; P<0.001; Figure 4. Sensitivity analysis (Figure S1) did not impact the effect size (OR, 0.50; 95% CI, 0.42–0.58; P<0.001). The L'Abbe plot (Figure 5) shows that most of the studies lie in the bottom right (under the null effect line) of the plot. This indicates that the VTE event rates were higher in the LMWH group compared with fondaparinux. The overall trendline (OR line) shows that fondaparinux has a protective effect against VTE compared with LMWH. Reporting bias was not evident, as the funnel plot was symmetric (Figure S2).

Figure 4.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for venous thromboembolism up to postoperative day 15.

Figure 5.

Comparison of events rates of venous thromboembolism in fondaparinux and low‐molecular‐weight heparins (LMWH) group.

Deep vein thrombosis up to postoperative day 15

The odds of total DVT in the fondaparinux group was 0.48 times the odds in the LWMH group (OR, 0.48; 95% CI, 0.38–0.61; P<0.001; Figure S3). The odds for proximal DVT in the fondaparinux group were 0.49 times the odds in the LMWH group (OR, 0.49; 95% CI, 0.29–0.84; P=0.009; Figure S4). As far as distal DVT was concerned, the odds in the fondaparinux group were 0.50 times the odds in the LMWH group (OR, 0.50; 95% CI, 0.39–0.64; P<0.001; Figure S5). Not much impact on effect size was observed during sensitivity analysis (Figures S6, S7, and S8). Reporting bias was not evident as presented by funnel plot (Figure S9).

Symptomatic VTE up to postoperative day 15

We observed 29 events among 5152 patients in the fondaparinux arm and 20 events among 5153 patients on LMWH. We did not observe any statistically significant difference between the 2 groups (OR, 1.33; 95% CI, 0.62–2.86; P=0.47; Figure S10).

Pulmonary embolism up to postoperative day 15

Sixteen events each among 5373 and 5425 patients on fondaparinux and LMWH, respectively, were observed. There was no difference between the PE events of the two arms (OR, 1.01; 95% CI, 0.49–2.11; P=0.97; Figure S11).

All‐cause mortality up to postoperative day 90

Six studies reported on number of deaths. Odds in the fondaparinux group were 0.87 times the odds in the LMWH group (OR, 0.87; 95% CI, 0.62–1.23; P=0.44), but results were statistically insignificant (Figure S12). Sensitivity analysis (Figure S13) did not impact the effect size.

Safety Outcome

Major bleeding during the treatment period

Nine studies reported on the incidences of major bleeding. The odds in the fondaparinux group for major bleeding were 1.48 times the odds in the LMWH group (OR, 1.48; 95% CI, 1.15–1.90; P=0.002; Figure 6. Sensitivity analysis did not have much impact on the effect size (OR, 1.49; 95% CI, 1.17–1.91; P=0.001; Figure S14). The L'Abbe plot (Figure 7) showed that most of the studies lie above the null effect line of the plot, which indicates that major bleeding event rates were higher in the fondaparinux group compared with the LMWH group. The overall trendline shows that LMWH has a protective effect against major bleeding compared with fondaparinux.

Figure 6.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for major bleeding during the treatment period.

Figure 7.

Comparison of events rates of major bleeding in fondaparinux and low‐molecular‐weight heparin (LMWH) group.

We also specifically looked at events of fatal bleeding and bleeding at surgical site between the 2 groups. For fatal bleeding, Agnelli et al15 reported 2 events each in both arms. Eriksson et al11 reported 1 event of fatal bleeding in LMWH, but no event of fatal bleeding was observed with fondaparinux in this study. As very few studies reported on fatal bleeding, pooled analysis could not be performed. However, for bleeding at the surgical site, we observed 82 events and 54 events in the fondaparinux arm and LMWH arm, respectively. In the pooled analysis, the odds of surgical site bleeding in fondaparinux were 1.43 times the odds in the LMWH arm (OR, 1.43; 95% CI, 1.01–2.04; P=0.05). The association was found to be statistically significant (Figure 8). The L'Abbe plot (Figure 9) shows that of 7 studies included in this analysis, 3 studies lie on the null effect line. However, the overall trendline shows that LMWH administration has a protective effect against surgical site bleeding compared with fondaparinux.

Figure 8.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for surgical site bleeding.

Figure 9.

Comparison‐of‐events rates of surgical site bleeding in fondaparinux and low‐molecular‐weight heparins (LMWH) group.

Minor bleeding during the treatment period

Nine studies reported minor bleeding (any bleeding event that did not meet the criteria for major bleeding previously defined). In the summary statistics, it was indicated that fondaparinux odds for minor bleeding were 1.13 times the odds in LMWH (OR, 1.13; 95% CI, 0.89–1.43; P=0.31); however, the results were not significant (Figure S15). Results were consistent following sensitivity analysis (Figure S16).

Net clinical benefit

Eight studies were included in this analysis. Pooled analysis showed significant difference in net clinical benefit in favor of the fondaparinux arm (OR, 0.66; 95% CI, 0.51–0.84; P=0.001; Figure 10. The L'Abbe plot (Figure 11) shows that most of the studies lie under the null effect line. This indicates that the net clinical benefit is higher in the fondaparinux group compared with LMWH. The overall trendline shows that fondaparinux is better than LMWH in terms of net clinical benefit.

Figure 10.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for net clinical benefit.

Figure 11.

Comparison‐of‐events rates of net clinical benefit in fondaparinux and low‐molecular‐weight heparins (LMWH) group.

Risk of bias across studies

Reporting bias was presented with funnel plots in the outcome variables above.

Subgroup Analysis

A subgroup analysis was performed stratifying studies within each of the different continents to examine any difference in the effect sizes.

North American and Australian Population

Four studies were conducted on the North American and Australian continents. For VTE, the odds in the fondaparinux group were 0.47 times the odds in the LMWH group (OR, 0.47; 95% CI, 0.27–0.84; P=0.01; Figure 12. For major bleeding, the odds in the fondaparinux group were 2.09 times the odds in the LMWH group, but the association was not statistically significant (OR, 2.09; 95% CI, 0.89–4.89; P=0.09; Figure 13.

Figure 12.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for venous thromboembolism in the North American and Australian population.

Figure 13.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for major bleeding in the North American and Australian population.

European Population

Three studies were conducted on the European continent. Odds in the fondaparinux group were 0.40 times the odds in LMWH group for VTE (OR, 0.40; 95% CI, 0.31–0.52; P<0.001; Figure 14. For major bleeding, the odds in the fondaparinux group were 1.27 times the odds in the LMWH group but were not statistically significant (OR, 1.27; 95% CI, 0.85–1.91; P=0.25; Figure 15.

Figure 14.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for venous thromboembolism prophylaxis in the European population.

Figure 15.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for major bleeding in the European population.

Asian Population

Four of the trials were conducted on the Asian continent. The summary statistics indicated that the odds for VTE in the fondaparinux group were 0.52 times the odds in the LMWH group (OR, 0.52; 95% CI, 0.19–1.41; P=0.20; Figure 16. As only 2 studies with very few events of major bleeding were estimable for the meta‐analysis, summary statistics for major bleeding were not performed for Asian studies.

Figure 16.

Fondaparinux compared with low‐molecular‐weight heparins (LMWH) for venous thromboembolism in the Asian population.

Fondaparinux Versus LMWH in Postoperative Thromboprophylaxis

To estimate the effect of “timing of dose” on the results, we included only the studies in which thromboprophylaxis was given postoperatively in this subgroup analysis. We continue to find results similar to the main analyses. The odds in the fondaparinux group for VTE were 0.49 times the odds in the LMWH group (OR, 0.49; 95% CI, 0.28–0.87; P=0.02; Figure 17. At the same time, fondaparinux was associated with an increased risk of major bleeding compared with LMWH (OR, 1.95; 95% CI, 1.02–3.76; P=0.04; Figure 18.

Figure 17.

Postoperative fondaparinux compared with low‐molecular‐weight heparins (LMWH) for venous thromboembolism.

Figure 18.

Postoperative fondaparinux compared with low‐molecular‐weight heparins (LMWH) for major bleeding.

Discussion

Our study suggests a significant reduction of the risk of VTE associated with fondaparinux compared with LMWH for perioperative surgical thromboprophylaxis. This is consistent with the findings of a previous meta‐analysis conducted on 4 RCTs by Turpie et al27 in which better efficacy of fondaparinux over LMWH was indicated with a 45.3% reduction of risk of total VTE. In their meta‐analysis, Turpie et al focused only on the patients undergoing major orthopedic surgeries, whereas our meta‐analysis extends the current existing knowledge to overall surgical interventions. Among the RCTs and large cohort studies, PE has been cited as a major cause of death in patients with VTE.34, 35 To the reviewers’ knowledge, previous studies have not reported PE as an independent outcome. PE events were reported independently in our study, which could be useful in clinical decision making. Our results suggest no significant difference in the incidence of PE between fondaparinux and LMWH combining data across available published studies. Because the patients after randomization in each trial were given prophylaxis treatment, events of PE in these trials might have been small compared with real clinical practice.

This meta‐analysis reported a significant reduction in the risk of total DVT associated with fondaparinux compared with LMWH, which is consistent with the results of previous meta‐analyses.27, 36, 37 Studies have indicated proximal DVT as a substantial risk factor for PE and mortality.38 As almost half of the patients with proximal DVT suffer fatal PE if untreated,39, 40 detection and treatment of proximal DVT is important.40 Fondaparinux significantly reduced the risk of proximal DVT compared with LMWH in our study. To the best of our knowledge, the recent meta‐analyses did not report the results pertinent to the proximal DVT;36, 37 thus, our study improves the current knowledge in this discipline. Also, although proximal DVT has a 3‐fold higher risk of recurrent VTE than distal DVT,41 there is a high probability that distal DVT may extend to proximal DVT and increase the risk of PE and death.40 Our study indicated a significant reduction of distal DVT by fondaparinux. The observed differences in the efficacy in both drugs might be related to the selective inhibition of factor Xa by fondaparinux compared with LMWH (by which both factor Xa and IIa are inhibited). It could also be attributable to longer half‐life and the linear pharmacokinetic profile of fondaparinux.42

Major bleeding in institutionalized surgical patients in VTE prevention trials is a strong predictor of mortality.43 Our pooled analysis indicated a greater risk of major bleeding with fondaparinux compared with LMWH consistent with previous studies.36, 37 More importantly, we observed a significantly increased risk of bleeding at the surgical site with fondaparinux, which is of high clinical relevance.27 Turpie et al pointed out a significant risk of major bleeding by fondaparinux;27 however, they reported no difference in clinically relevant bleeding between the 2 groups. Major bleeding in our study was reported as per the standard definition reported in the first major clinical trials assessing the efficacy and safety of these comparators11 to produce the most current and comprehensive evidence. The association of fondaparinux with major bleeding might be linked to differences in timing of the administration of fondaparinux and LMWH as reported in the previous study.27 We conducted a subgroup analysis in which we included only postsurgical thromboprophylaxis to control for bias, which may be caused by different timings of fondaparinux and LMWH. However, we found the results similar to the main analysis.

Prior studies have pointed out heterogeneity in definitions of major bleeding across different clinical trials,44 which might lead to confusion among clinicians about bleeding risk associated with VTE prophylaxis.45 To assist with clinical decision making, the incidences of minor bleeding were also compared in our study, which has not been reported in any previous meta‐analyses36, 37 to the best of our knowledge. We observed a nonsignificant increased risk of minor bleeding with fondaparinux in comparison with LMWH. In case the patients undergoing surgeries are at increased risk of bleeding, these results may help the clinicians in decision making.

In our analysis, the incidence of all‐cause mortality up to day 90 was also compared between treatment arms, which was not reported in the recent meta‐analyses.36, 37 Although not statistically significant, reduction in the odds of mortality was associated with fondaparinux compared with LMWH. Another meta‐analysis that was conducted to report the effect on mortality considered LMWH and placebo in the same group compared with fondaparinux46 and reported a statistically nonsignificant 21% reduction in the odds associated with fondaparinux. This difference in the results might be attributable to the fact that of the 8 studies included in the meta‐analysis by Eikelboom et al,46 2 studies compared fondaparinux with placebo. These 2 studies accounted for 2158 patients among the 13 085 patients, which might have caused the difference in mortality between our meta‐analysis and meta‐analysis by Eikelboom et al.

A meta‐analysis of 173 case‐control studies reported a significant association of genetic factors with VTE.47 As our analysis included trials from different continents, we also tested if there were any differences in the outcomes by the population. In our subgroup analysis, a significant 60% and 53% reduction in the odds of VTE was associated with fondaparinux among the European and North American and Australian populations, respectively. We also reported a 48% reduction in VTE in the Asian population, which was nonsignificant. The North American and Australian population was found to be at a greater risk of major bleeding compared with other races. These findings might be related to the differences in genetic factors related to venous thrombosis such as factor V, prothrombin G20210A, prothrombin G11991A, PAI‐1 4G/5G, or alpha‐fibrinogen Thr312Ala in different populations.47 As gene mutations may lead to variable risk of VTE in different populations, we hypothesize that exposure to anticoagulants in different populations may also differentiate the risk of major bleeding. This particular finding of our study could act as a hypotheses for future researchers to explore more on the effectiveness and safety of these drugs in different patient populations using real‐world data, which could be a significant addition to the existing literature. It may also be hypothesized that the low dose of LMWH in Japanese studies might have contributed, at least to some extent, to difference in the odds ratios across countries.

Limitations

This study had several limitations. Reviewers had access to the full text of all of the studies included in this meta‐analysis except 1 study from China.20 Efforts to contact the principal investigators of this study were made but were unsuccessful; consequently, reviewers labeled this study as having “unclear bias” during study bias assessment. This study was excluded during the sensitivity analysis as well. The clinical trial by Sasaki et al14 compared the fondaparinux with the non‐fondaparinux group. This non‐fondaparinux group was considered to be the LMWH group, as all the major clinical trials11, 12, 18 considered LMWH as the comparator to fondaparinux. However, in the sensitivity analysis, this study was excluded and the results were consistent. The clinical trial by Steele et al16 used a double dose of both fondaparinux and LMWH as a titration to the weight (body mass index, 35–59 kg/m²) of the participants randomized in the clinical trial. This study was included in the analysis because the dose was doubled in both arms. Nevertheless, this study was excluded as well during the sensitivity analysis, with no meaningful change to the results. In the clinical trial by Hata et al,13 randomized patients received low‐dose (5000 IU) unfractionated heparin for thromboprophylaxis during the first 24 hours after surgery. Low‐dose unfractionated heparin was administered initially because in Japan neither fondaparinux nor LMWH are approved to be prescribed immediately after surgery.13 After 24 hours, patients received either fondaparinux or LMWH for 5 days postoperatively. As patients in both arms received low‐dose unfractionated heparin, outcomes might have been affected similarly in each group.

Included studies in our meta‐analysis were from different countries. Thus, we reported pooled analysis of these studies, which were from different clinical settings, that might have impacted the results. Studies were also subgrouped by population (eg, North American and Australian, European, and Asian population) as well to address this issue. Two RCTs12, 19 conducted in North America had some of their centers in Australia. We could not separate the American population from the Australian population because of the limitation to data access. Thus, we presented pooled analyses of these 2 populations. Our study considered all LMWHs in 1 group whether it was enoxaparin, nadroparin, or dalteparin. Nevertheless, it has been indicated by a meta‐analysis of 20 RCTs that all LMWHs produce similar relative safety and efficacy when compared for VTE prophylaxis.48 There was a difference in the dose of the LMWH in studies from different countries, which might have impacted the outcomes as well. Also, there was a difference in the duration of the prophylaxis. This limitation is justified because of the fact that with the time there is a variation in the guidelines for the prophylaxis of VTE.7, 49, 50, 51

Strengths

To our knowledge, this is the most current comprehensive meta‐analysis comparing subcutaneous fondaparinux with LMWH for perioperative surgical thromboprophylaxis. To maintain the high quality of systematic review, this study considered only randomized clinical trials in the analyses as per the Cochrane Handbook for Systematic Reviews of Interventions.28 We kept the definition of our outcomes consistent while analyzing the results. The cutoff point for the assessment of our study was set to 15 days. If any study among the included studies assessed the outcomes after 15 days, we excluded the event from our analysis. For example, Argun et al21 reported an event of proximal DVT at day 19 with LMWH, which was not considered in our summary statistics. Thus, we maintained consistency throughout our study. To present the most comprehensive and robust results, we conducted several sensitivity and subgroup analyses as well to assist with the best clinical decision.

Conclusion

The results of this systematic review and meta‐analysis suggest that fondaparinux is significantly better in terms of reduction of VTE (composite of DVT and PE) for perioperative surgical thromboprophylaxis. However, for the symptomatic VTE and all‐cause mortality, fondaparinux was not found to be superior to LMWH in this study. Clinicians should be aware of the higher risk of major bleeding, especially surgical site bleeding with fondaparinux compared with LMWH. Nevertheless, net clinical benefit as per this study was in favor of fondaparinux compared with LMWH.

Disclosures

None.

Supporting information

Data S1. Study Protocol

Data S2. Description of “Risk of Bias” Among the Included Studies

Data S3. Detailed Description of Each Included Study (DATA EXTRACTION FORM)

Table S1. PRISMA 2009 Checklist

Table S2. Search Strategy for Study Inclusion

Figure S1. Fondaparinux vs LMWH for venous thromboembolism up to day 15 (sensitivity analysis).

Figure S2. Funnel plot for “reporting bias” of venous thromboembolism up to day 15.

Figure S3. Fondaparinux vs LMWH for total deep vein thrombosis up to day 15.

Figure S4. Fondaparinux vs LMWH for proximal deep vein thrombosis up to day 15.

Figure S5. Fondaparinux vs LMWH for distal deep vein thrombosis up to day 15.

Figure S6. Fondaparinux vs LMWH for total deep vein thrombosis up to day 15 (sensitivity analysis).

Figure S7. Fondaparinux vs LMWH for proximal deep vein thrombosis up to day 15 (sensitivity analysis).

Figure S8. Fondaparinux vs LMWH for distal deep vein thrombosis up to day 15 (sensitivity analysis).

Figure S9. Funnel plot for “reporting bias” of total deep vein thrombosis up to day 15.

Figure S10. Symptomatic VTE up to post‐operative day 15.

Figure S11. Pulmonary embolism up to post‐operative day 15.

Figure S12. Fondaparinux vs LMWH for all‐cause mortality at day 90.

Figure S13. Fondaparinux vs LMWH for all‐cause mortality at day 90 (sensitivity analysis).

Figure S14. Fondaparinux vs LMWH for major bleeding during the treatment period (sensitivity analysis).

Figure S15. Fondaparinux vs LMWH for minor bleeding during the treatment period.

Figure S16. Fondaparinux vs LMWH for minor bleeding during the treatment period (sensitivity analysis).

(J Am Heart Assoc. 2019;8:e012184. DOI: 10.1161/JAHA.119.012184.)