Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients

Review question

Is the incidence of heparin-induced thrombocytopenia lower in postoperative patients receiving thromboprophylaxis with low molecular weight heparin in comparison with patients receiving unfractionated heparin?

Background

Heparin is a natural agent used to prevent clot formation in the vessels. Two types of heparins are widely used, unfractionated heparin (UFH) and low molecular weight heparin (LMWH). Heparin-induced thrombocytopenia (HIT) is an adverse reaction that can occur during treatment with heparin. It is common in practice and its most important consequence is a paradoxical increase in the risk of clotting (thromboembolic) complications. A number of factors are thought to influence its frequency, including the type of heparin and the type of patient, with patients who have had a surgery at higher risk. We compared the risk of HIT in people who had had surgery and had been exposed to UFH or LMWH. A better understanding of this problem will allow safer management of postoperative patients who need thromboprophylaxis with heparin.

Key characteristics and results

High-quality evidence about HIT from randomised controlled trials (RCTs) is sparse. Only three RCTs with a total of 1398 participants were suitable for including in this review (current until May 2016). Postoperative patients given LMWH had a lower risk of HIT than those given UFH (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.07 to 0.73); low-quality evidence. The occurrence of HIT complicated by clotting was significantly lower in participants receiving LMWH compared with UFH (RR 0.22, 95% CI 0.06 to 0.84); low-quality evidence. Two cases of HIT would be avoided for every 100 people treated with LMWH instead of UFH. A case of clotting complications of HIT would be avoided for every 75 people treated with LMWH. The risk of HIT was consistently reduced in people undergoing major surgical procedures exposed to LMWH or UFH (RR 0.22, 95% CI 0.06 to 0.75); low-quality evidence. Although limited evidence is available, it appears that HIT induced by both types of heparins is common in people undergoing major surgical procedures (incidence greater than 1% and less than 10%).

These systematic results support clinical recommendations regarding platelet count monitoring for HIT.

Quality of the evidence

The evidence gathered in this review was considered of low quality. We downgraded the quality of the evidence because we had concerns about the risk of bias in the included studies and imprecision of the results. It was possible that patient prognosis or clinicians' preferences influenced the allocation of participants to receive one or another medication. This process should be implemented by chance to allow a fair comparison between the therapies. We were not confident that staff implementing the trials were not aware of which treatment participants were receiving, and it was possible that the incomplete reporting of data could have affected the estimates. The detection of HIT throughout the trials was also problematic, and we were not confident that it was performed adequately. The results may be correct, but they may be changed by future research.

Authors' conclusions: 

This updated review demonstrated low-quality evidence of a lower incidence of HIT, and HIT complicated by venous thromboembolism, in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. Similarily, the risk of HIT in people undergoing major surgical procedures was lower when treated with LMWH compared to UFH (low-quality evidence). The quality of the evidence was downgraded due to concerns about the risk of bias in the included studies and imprecision of the study results. These findings may support current clinical use of LMWH over UFH as front-line heparin therapy. However, our conclusions are limited and there was an unexpected paucity of RCTs including HIT as an outcome. To address the scarcity of clinically-relevant information on HIT, HIT must be included as a core harmful outcome in future RCTs of heparin.

Read the full abstract...
Background: 

Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction presenting as a prothrombotic disorder related to antibody-mediated platelet activation. It is a paradoxical immune reaction resulting in thrombin generation in vivo, which leads to a hypercoagulable state and the potential to initiate venous or arterial thrombosis. A number of factors are thought to influence the incidence of HIT including the type and preparation of heparin (unfractionated heparin (UFH) or low molecular weight heparin (LMWH)) and the heparin-exposed patient population, with the postoperative patient population at higher risk.

Although LMWH has largely replaced UFH as a front-line therapy, there is evidence supporting a lack of superiority of LMWH compared with UFH regarding prevention of deep vein thrombosis and pulmonary embolism following surgery, and similar frequencies of bleeding have been described with LMWH and UFH. The decision as to which of these two preparations of heparin to use may thus be influenced by harmful effects such as HIT. We therefore sought to determine the relative impact of UFH and LMWH on HIT in postoperative patients receiving thromboembolism prophylaxis. This is an update of a review first published in 2012.

Objectives: 

The objective of this review was to compare the incidence of heparin-induced thrombocytopenia (HIT) and HIT complicated by venous thromboembolism in postoperative patients exposed to unfractionated heparin (UFH) versus low molecular weight heparin (LMWH).

Search strategy: 

For this update, the Cochrane Vascular Information Specialist searched the Specialised Register (May 2016), CENTRAL (2016, Issue 4) and trials registries. The authors searched Lilacs (June 2016) and additional trials were sought from reference lists of relevant publications.

Selection criteria: 

We included randomised controlled trials (RCTs) in which participants were postoperative patients allocated to receive prophylaxis with UFH or LMWH, in a blinded or unblinded fashion. Studies were excluded if they did not use the accepted definition of HIT. This was defined as a relative reduction in the platelet count of 50% or greater from the postoperative peak (even if the platelet count at its lowest remained greater than 150 x 109/L) occurring within five to 14 days after the surgery, with or without a thrombotic event occurring in this timeframe. Additionally, we required circulating antibodies associated with the syndrome to have been investigated through laboratory assays.

Data collection and analysis: 

Two review authors independently extracted data and assessed the risk of bias. Disagreements were resolved by consensus with participation of a third author.

Main results: 

In this update, we included three trials involving 1398 postoperative participants. Participants were submitted to general surgical procedures, minor and major, and the minimum mean age was 49 years. Pooled analysis showed a significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.23, 95% confidence interval (CI) 0.07 to 0.73); low-quality evidence. The number needed to treat for an additional beneficial outcome (NNTB) was 59. The risk of HIT was consistently reduced comparing participants undergoing major surgical procedures exposed to LMWH or UFH (RR 0.22, 95% CI 0.06 to 0.75); low-quality evidence. The occurrence of HIT complicated by venous thromboembolism was significantly lower in participants receiving LMWH compared with UFH (RR 0.22, 95% CI 0.06 to 0.84); low-quality evidence. The NNTB was 75. Arterial thrombosis occurred in only one participant who received UFH. There were no amputations or deaths documented. Although limited evidence is available, it appears that HIT induced by both types of heparins is common in people undergoing major surgical procedures (incidence greater than 1% and less than 10%).

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