Pentasaccharides for the prevention of venous blood clots

Background

Venous thromboembolism (VTE) is a condition in which people develop blood clots in their veins. It includes deep vein thrombosis (DVT) and the potentially fatal pulmonary embolism (PE). VTE occurs in more than 10% of patients in hospital and is the third most frequent cause of death among them. Therefore, effective prevention is necessary for people who are at high risk of VTE. The standard method of prevention involves use of an anticoagulant, for example, low molecular weight heparin (LMWH) or warfarin, among orthopaedic patients. In recent years, another type of anticoagulant, pentasaccharide, has shown good anticoagulative effect in clinical trials. Three types of pentasaccharides are available, namely, short-acting fondaparinux, long-acting idraparinux and idrabiotaparinux.

Key results

Our systematic review included 25 studies involving 21,004 participants (current until March 2016). We found no studies on long-acting idraparinux nor idrabiotaparinux for prevention of VTE. Therefore, we included only studies on short-acting fondaparinux for prevention of VTE.

Moderate to high quality evidence shows that fondaparinux is effective for short-term prevention of VTE when compared with placebo. It can reduce total VTE, DVT, total PE and symptomatic VTE and shows no difference in the number of deaths when compared with placebo. Low to moderate quality evidence shows that fondaparinux is effective for short-term prevention of VTE when compared with LMWH. It can reduce total VTE and total DVT and shows no difference in the number of deaths when compared with LMWH. At the same time, however, fondaparinux increases major bleeding when compared with placebo and LMWH. Therefore, when fondaparinux is chosen for the prevention of VTE, attention should be paid to the person's bleeding risk. Most of the data were obtained from studies on patients undergoing orthopaedic surgery. Therefore, the conclusion pertains predominantly to these patients. Data on fondaparinux for other medical conditions such as internal, medical and abdominal surgery are sparse.

Quality of evidence

We downgraded the quality of the evidence because of small numbers of events causing imprecision, and differences and inconsistency between studies. We need additional high-quality clinical trials to confirm the efficacy and safety of fondaparinux.

Authors' conclusions: 

Moderate to high quality evidence shows that fondaparinux is effective for short-term prevention of VTE when compared with placebo. It can reduce total VTE, DVT, total PE and symptomatic VTE, and does not demonstrate a reduction in deaths compared with placebo. Low to moderate quality evidence shows that fondaparinux is more effective for short-term VTE prevention when compared with LMWH. It can reduce total VTE and total DVT and does not demonstrate a reduction in deaths when compared with LMWH. However, at the same time, moderate to high quality evidence shows that fondaparinux increases major bleeding when compared with placebo and LMWH. Therefore, when fondaparinux is chosen for the prevention of VTE, attention should be paid to the person's bleeding and thrombosis risks. Most data were derived from patients undergoing orthopaedic surgery. Therefore, the conclusion predominantly pertains to these patients. Data on fondaparinux for other clinical conditions are sparse.

Read the full abstract...
Background: 

Venous thromboembolism (VTE) is a common condition with potentially serious and life-threatening consequences. The standard method of thromboprophylaxis uses an anticoagulant such as low molecular weight heparin (LMWH) or warfarin. In recent years, another type of anticoagulant, pentasaccharide, an indirect factor Xa inhibitor, has shown good anticoagulative effect in clinical trials. Three types of pentasaccharides are available: short-acting fondaparinux, long-acting idraparinux and idrabiotaparinux. Pentasaccharides cause little heparin-induced thrombocytopenia and are better tolerated than unfractionated heparin, LMWH and warfarin. However, no consensus has been reached on whether pentasaccharides are superior or inferior to other anticoagulative methods.

Objectives: 

To assess effects of pentasaccharides versus other methods of thromboembolic prevention (thromboprophylaxis) in people who require anticoagulant treatment to prevent venous thromboembolism.

Search strategy: 

The Cochrane Vascular Information Specialist (CIS) searched the Specialised Register (last searched March 2016) and the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 2). The CIS searched trial databases for details of ongoing and unpublished studies. Review authors searched LILACS (Latin American and Caribbean Health Sciences) and the reference lists of relevant studies and reviews identified by electronic searches.

Selection criteria: 

We included randomised controlled trials on any type of pentasaccharide versus other anticoagulation methods (pharmaceutical or mechanical) for VTE prevention.

Data collection and analysis: 

Two review authors independently selected trials, assessed methodological quality and extracted data in predesigned tables.

Main results: 

We included in this review 25 studies with a total of 21,004 participants. All investigated fondaparinux for VTE prevention; none investigated idraparinux or idrabiotaparinux. Studies included participants undergoing abdominal surgery, thoracic surgery, bariatric surgery or coronary bypass surgery; acutely ill hospitalised medical patients; people requiring rigid or semirigid immobilisation; and those with superficial venous thrombosis. Most studies focused on orthopaedic patients. We lowered the quality of the evidence because of heterogeneity between studies and a small number of events causing imprecision.

When comparing fondaparinux with placebo, we found less total VTE (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.15 to 0.38; 5717 participants; 8 studies; I2 = 64%; P < 0.00001), less symptomatic VTE (RR 0.15, 95% CI 0.06 to 0.36; 6503 participants; 8 studies; I2 = 0%; P < 0.0001), less total DVT (RR 0.25, 95% CI 0.15 to 0.40; 5715 participants; 8 studies; I2 = 67%; P < 0.00001), less proximal DVT (RR 0.12, 95% CI 0.04 to 0.39; 2746 participants; 7 studies; I2 = 64%; P = 0.0004) and less total pulmonary embolism (PE) (RR 0.16, 95% CI 0.04 to 0.62; 6412 participants; 8 studies; I2 = 0%; P = 0.008) in the fondaparinux group. The quality of the evidence was moderate for total VTE, total DVT and proximal DVT, and high for symptomatic VTE and total PE.

When fondaparinux was compared with LMWH, analyses indicated that fondaparinux reduced total VTE and DVT (RR 0.55, 95% CI 0.42 to 0.73; 9339 participants; 11 studies; I2 = 64%; P < 0.0001; and RR 0.54, 95% CI 0.40 to 0.71; 9356 participants; 10 studies; I2 = 67%; P < 0.0001, respectively), and showed a trend toward reduced proximal DVT (RR 0.58, 95% CI 0.33 to 1.02; 8361 participants; 9 studies; I2 = 53%; P = 0.06). Symptomatic VTE (RR 1.03, 95% CI 0.65 to 1.63; 12240 participants; 9 studies; I2 = 35%; P = 0.90) and total PE (RR 1.24, 95% CI 0.65 to 2.34; 12350 participants; 10 studies; I2 = 0%; P = 0.51) indicated no difference between fondaparinux and LMWH. The quality of the evidence was moderate for total VTE, symptomatic VTE, total DVT and total PE, and low for proximal DVT.

We showed that fondaparinux increased major bleeding compared with both placebo and LWMH (RR 2.56, 95% CI 1.48 to 4.44; 6659 participants; 8 studies; I2 = 0%; P = 0.0008; moderate-quality evidence; and RR 1.38, 95% CI 1.09 to 1.75; 12,501 participants; 11 studies; I2 = 24%; P = 0.008; high-quality evidence, respectively). All-cause mortality was not different between fondaparinux and placebo or LMWH (RR 0.76, 95% CI 0.48 to 1.22; 6674 participants; 8 studies; I2 = 14%; P = 0.26; moderate-quality evidence; and RR 0.88, 95% CI 0.63 to 1.22; 12,400 participants; 11 studies; I2 = 0%; P = 0.44; moderate-quality evidence, respectively).

One study compared fondaparinux with variable and fixed (1 mg per day) doses of warfarin after elective hip or knee replacement surgery and showed no difference in primary and secondary outcomes between fondaparinux and both variable and fixed doses of warfarin. The quality of the evidence was very low. One small study compared fondaparinux with edoxaban in patients with severe renal impairment undergoing lower-limb orthopaedic surgery and reported no thromboembolic events, major bleeding events or deaths in either group. The quality of the evidence was very low. One small study compared fondaparinux with mechanical thromboprophylaxis. Results showed no difference in total VTE and total DVT between fondaparinux and mechanical thromboprophylaxis. This study reported no cases pertaining to the other outcomes of this review. The quality of the evidence was low.

There were insufficient studies to permit meaningful conclusions for subgroups of clinical conditions other than orthopaedic surgery.

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