Background
Central lines are thin flexible tubes that are inserted into a person’s vein to provide medical care. They are used to deliver medicines, fluids or nutrients (to feed the patient) directly into the bloodstream. However, they can cause the blood to clot (form into a small lump). This prevents blood from flowing normally in the blood vessels. Blood clots can cause symptoms such as pain or swelling, but can also happen without any symptoms. They can lead to serious health problems and death, if they move and become stuck in major veins or in the lungs.
Since the 1990s, blood clots in children in general have become more common, notably due to the rise in blood clots in children treated with central lines. We reviewed the existing research to find out if giving children a blood thinning medicine called low molecular weight heparin (LMWH) protects against blood clots. We also wanted to know whether LMWH increases the risk of minor or severe bleeding, death or other unwanted (adverse) side effects.
What did we find?
We searched the scientific literature in May 2019. We found two studies (one more than when we last searched in 2014). The studies compared what happens in children (aged up to 18 years old) treated using central lines who received LMWH and those who did not. A total of 1135 children were followed for between 30 and 64 days. During that time, the number of blood clots, bleeding episodes and deaths were recorded. One study also looked at the number of deaths five years after treatment.
The two studies we found did not allow us to determine with certainty whether or not LMWH protects children with central lines from getting blood clots (with or without symptoms).
The studies also did not allow us to determine whether children on LMWH were more likely to experience bleeding (minor or severe), or whether LMWH increases or reduces the risk of death.
The two studies did not report any additional adverse effects caused by LMWH.
Certainty of the evidence
We judged the certainty of the evidence to be low for blood clots, low for major bleeding, very low for minor bleeding, and low for mortality. The certainty of the evidence was low or very low because:
⦁ there were differences in the way blood clots, bleeding and mortality were measured between studies;
⦁ there were few studies and events; and
⦁ the researchers and children in the studies knew who was receiving LMWH and who was not, which can influence results.
It is likely that future studies will have an important impact on our understanding of the role of LMWH to prevent blood clots and its side effects.
Conclusion
We need more studies on whether LMWH prevents blood clots in children who are treated using central venous lines.
Pooling data from two RCTs did not provide evidence to support the use of prophylactic LWMH for preventing CVC-related thrombosis in children (low-certainty evidence). Evidence was also insufficient to confirm or exclude a difference in the incidence of major and minor bleeding complications in the LMWH prophylaxis group compared to low-dose UFH (low and very low certainty respectively). No evidence of a clear difference in overall mortality was seen. Studies did not report on the outcomes catheter occlusion, days of catheter patency, episodes of CRBSI and other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis). The certainty of the evidence was downgraded due to risk of bias of the included studies, imprecision and inconsistency, preventing conclusions in regards to the efficacy of LMWH prophylaxis to prevent CVC-related thrombosis in children.
The prevalence of children diagnosed with thrombotic events has been increasing in the last decades. The most common thrombosis risk factor in neonates, infants and children is the placement of a central venous catheter (CVC). It is unknown if anticoagulation prophylaxis with low molecular weight heparin (LMWH) decreases CVC-related thrombosis in children. This is an update of the Cochrane Review published in 2014.
To determine the effect of LMWH prophylaxis on the incidence of CVC-related thrombosis and major and minor bleeding complications in children. Further objectives were to determine the effect of LMWH on occlusion of CVCs, number of days of CVC patency, episodes of catheter-related bloodstream infection (CRBSI), other side effects of LMWH (allergic reactions, abnormal coagulation profile, heparin-induced thrombocytopaenia and osteoporosis) and mortality during therapy.
The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov trials registers to 7 May 2019. We undertook reference checking of identified trials to identify additional studies.
We included randomised controlled trials (RCTs) and quasi-randomised trials comparing LMWH to no prophylaxis (placebo or no treatment), or low-dose unfractionated heparin (UFH) either as continuous infusion or flushes (low-dose UFH aims to ensure the patency of the central line but has no systemic anticoagulation activity), given to prevent CVC-related thrombotic events in children. We selected studies conducted in children aged 0 to 18 years.
Two review authors independently identified eligible studies, which were assessed for study methodology including bias, and extracted unadjusted data where available. In the data analysis step, all outcomes were analysed as binary or dichotomous outcomes. The effects of interventions were summarised with risk ratios (RR) and their respective 95% confidence intervals (CI). We assessed the certainty of evidence for each outcome using the GRADE approach.
One additional study was included for this update bringing the total to two included studies (with 1135 participants). Both studies were open-label RCTs comparing LMWH with low-dose UFH to prevent CVC-related thrombosis in children. We identified no studies comparing LMWH with placebo or no treatment. Meta-analysis found insufficient evidence of an effect of LMWH prophylaxis in reducing the incidence of CVC-related thrombosis in children with CVC, compared to low-dose UFH (RR 0.68, 95% CI 0.27 to 1.75; 2 studies; 787 participants; low-certainty evidence). One study (158 participants) reported symptomatic and asymptomatic CVC-related thrombosis separately and detected no evidence of a difference between LMWH and low-dose UFH (RR 1.03, 95% CI 0.21 to 4.93; low-certainty evidence; RR 1.17, 95% CI 0.45 to 3.08; low-certainty evidence; for symptomatic and asymptomatic participants respectively). There was insufficient evidence to determine whether LMWH impacts the risk of major bleeding (RR 0.27, 95% CI 0.05 to 1.67; 2 studies; 813 participants; low-certainty evidence); or minor bleeding. One study reported minor bleeding in 53.3% of participants in the LMWH arm and in 44.7% of participants in the low-dose UFH arm (RR 1.20, 95% CI 0.91 to 1.58; 1 study; 158 participants; very low-certainty evidence), and the other study reported no minor bleeding in either group (RR: not estimable). Mortality during the study period was reported in one study, where two deaths occurred during the study period. Both were unrelated to thrombotic events and occurred in the low-dose UFH arm. The second study did not report mortality during therapy per arm but showed similar 5-year overall survival (low-certainty evidence). No additional adverse effects were reported. Other pre-specified outcomes (including CVC occlusion, patency and CRBSI) were not reported.