Prevention of occlusion of small veins in the liver after blood-forming stem cell transplantation

Review Question

We reviewed evidence about the effects of medications to prevent blockage of small veins in the liver (veno-occlusive disease or VOD) in people who undergo blood-forming stem cell transplantation (HSCT).

Background

People undergoing HSCT can develop VOD, a severe complication which may lead to their death. Various medications with different mechanisms of action have been tried to prevent VOD. These prophylactic measures include heparin, low molecular weight heparin (LMWH), danaparoid, ursodeoxycholic acid, prostaglandin E1 (PGE1), glutamine, antithrombin III, defibrotide and fresh frozen plasma (FFP). Many transplant centres routinely administer these preventive measures, especially for people at high risk.

Study Characteristics

We included 14 randomised controlled trials (RCTs). Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or the same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma with or without additional treatment versus no treatment or the same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin alone. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with a wide age range and disease spectrum undergoing HSCT. The evidence is current as of January 2015.

Key Results

Ursodeoxycholic acid may reduce the occurrence of VOD, deaths from all causes and deaths due to VOD, but there was no evidence of a difference in overall survival. There was no evidence of difference in occurrence of VOD between treatment and control groups for heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There was no evidence of difference in survival between treatment and control groups for heparin and defibrotide. There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life for any trials. Eleven trials reported adverse effects. There was no evidence of a difference in adverse events among treatment groups, except for one trial showing that defibrotide resulted in more adverse events compared with no treatment.

Quality of the Evidence

The quality of evidence for all outcomes was low to very low, because of high risk of bias in study design, results inconsistent across studies and imprecision of results.

Conclusion

There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, overall mortality and mortality due to VOD in people undergoing HSCT. However, the most effective treatment is not well-defined. There is insufficient evidence to support the use of heparin, low molecular weight heparin, defibrotide, glutamine, FFP, antithrombin III, and prostaglandin E1. Further high-quality research is needed.

Authors' conclusions: 

There is low or very low quality evidence that ursodeoxycholic acid may reduce the incidence of hepatic VOD, all-cause mortality and mortality due to VOD in HSCT recipients. However, the optimal regimen is not well-defined. There is insufficient evidence to support the use of heparin, LMWH, defibrotide, glutamine, FFP, antithrombin III, and PGE1. Further high-quality RCTs are needed.

Read the full abstract...
Background: 

Hepatic veno-occlusive disease (VOD) is a severe complication after haematopoietic stem cell transplantation (HSCT). Different drugs with different mechanisms of action have been tried in HSCT recipients to prevent hepatic VOD. However, it is uncertain whether high-quality evidence exists to support any prophylactic therapy.

Objectives: 

We aimed to determine the effects of various prophylactic therapies on the incidence of hepatic VOD, overall survival, mortality, quality of life (QOL), and the safety of these therapies in people undergoing HSCT.

Search strategy: 

We searched the Cochrane Central Registe of Controlled Trials (CENTRAL), MEDLINE, EMBASE, conference proceedings of three international haematology-oncology societies and two trial registries in January 2015, together with reference checking, citation searching and contact with study authors to identify additional studies.

Selection criteria: 

We included randomised controlled trials (RCTs) comparing prophylactic therapies with placebo or no treatment, or comparing different therapies for hepatic VOD in people undergoing HSCT.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included 14 RCTs. Four trials (612 participants) compared ursodeoxycholic acid with or without additional treatment versus placebo or no treatment or same additional treatment. Two trials (259 participants) compared heparin with no treatment. Two trials (106 participants) compared low molecular weight heparin (LMWH) with placebo or no treatment. One trial (360 participants) compared defibrotide with no treatment. One trial (34 participants) compared glutamine with placebo. Two trials (383 participants) compared fresh frozen plasma (FFP) with or without additional treatment versus no treatment or same additional treatment. One trial (30 participants) compared antithrombin III with heparin versus heparin. One trial compared heparin (47 participants) with LMWH (46 participants) and prostaglandin E1 (PGE1) (47 participants). No trial investigated the effects of danaparoid. The RCTs included participants of both genders with wide age range and disease spectrum undergoing autologous or allogeneic HSCT. Funding was provided by government sources (two studies), research fund (one study), pharmaceutical companies that manufactured defibrotide and ursodeoxycholic acid (two studies), or unclear source (nine studies). All RCTs had high risk of bias because of lack of blinding of participants and study personnel, or other risks of bias (mainly differences in baseline characteristics of comparison groups).

Results showed that ursodeoxycholic acid may reduce the incidence of hepatic VOD (risk ratio (RR) 0.60, 95% confidence interval (CI) 0.40 to 0.88; number needed to treat for an additional beneficial outcome (NNTB) 15, 95% CI 7 to 50, low quality of evidence), but there was no evidence of difference in overall survival (hazard ratio (HR) 0.83, 95% CI 0.59 to 1.18, low quality of evidence). It may reduce all-cause mortality (RR 0.70, 95% CI 0.50 to 0.99; NNTB 17, 95% CI 8 to 431, low quality of evidence) and mortality due to hepatic VOD (RR 0.27, 95% CI 0.09 to 0.87; NNTB 34, 95% CI 16 to 220, very low quality of evidence). There was no evidence of difference in the incidence of hepatic VOD between treatment and control groups for heparin (RR 0.47, 95% CI 0.18 to 1.26, very low quality of evidence), LMWH (RR 0.27, 95% CI 0.06 to 1.18, very low quality of evidence), defibrotide (RR 0.62, 95% CI 0.38 to 1.02, low quality of evidence), glutamine (no hepatic VOD in either group, very low quality of evidence), FFP (RR 0.66, 95% CI 0.20 to 2.17, very low quality of evidence), antithrombin III (RR 0.13, 95% CI 0.01 to 2.15, very low quality of evidence), between heparin and LMWH (RR 1.96, 95% CI 0.80 to 4.77, very low quality of evidence), between heparin and PGE1 (RR 1.20, 95% CI 0.58 to 2.50, very low quality of evidence), and between LMWH and PGE1 (RR 0.61, 95% CI 0.24 to 1.55, very low quality of evidence). There was no evidence of difference in survival between treatment and control groups for heparin (92.6% vs. 88.7%) and defibrotide (HR 1.04, 95% CI 0.54 to 2.02, low quality of evidence). There were no data on survival for trials of LMWH, glutamine, FFP, antithrombin III, between heparin and LMWH, between heparin and PGE1, and between LMWH and PGE1. There were no data on quality of life (QoL) for any trials. Eleven trials reported adverse events. There was no evidence of difference in the frequency of adverse events between treatment and control groups except for one trial showing that defibrotide resulted in more adverse events compared with no treatment (RR 18.79, 95% CI 1.10 to 320.45). These adverse events included coagulopathy, gastrointestinal disorders, haemorrhage and microangiopathy. The quality of evidence was low or very low due to bias of study design, and inconsistent and imprecise results.

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