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

Background Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction presenting as a prothrombotic disorder related to antibody-mediated platelet activation. It is a poorly understood 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 presenting a 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 adverse reactions such as HIT. We therefore sought to determine the relative impact of UFH and LMWH specifically on HIT in postoperative patients receiving thromboembolism prophylaxis. Objectives The objective of this review was to compare the incidence of HIT and HIT complicated by thrombosis in patients exposed to UFH versus LMWH in randomised controlled trials (RCTs) of postoperative heparin therapy. Search methods The Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (March 2012) and CENTRAL (2012, Issue 2). In addition, the authors searched LILACS (March 2012) and additional trials were sought from reference lists of relevant publications. Selection criteria We were interested in comparing the incidence of HIT occurring during exposure to UFH or LMWH after any surgical intervention. Therefore, we studied RCTs in which participants were postoperative patients allocated to receive UFH or LMWH, in a blinded or unblinded fashion. Eligible studies were required to have as an outcome clinically diagnosed HIT, 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 > 150 x 10(9)/L) occurring within five to 14 days after the surgery, with or without a thrombotic event occurring in this timeframe. Additionally, circulating antibodies associated with the syndrome were required 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 total two studies involving 923 participants met all the inclusion criteria and were included in the review. Pooled analysis showed a statistically significant reduction in the risk of HIT with LMWH compared with UFH (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.07 to 0.82; P = 0.02). This result suggests that patients treated with LMWH would have a relative risk reduction (RRR) of 76% in the probability of developing HIT compared with patients treated with UFH. Venous thromboembolism (VTE) complicating HIT occurred in 12 of 17 patients who developed HIT. Pooled analysis showed a statistically significant reduction in HIT complicated by VTE with LMWH compared with UFH (RR 0.20, 95% CI 0.04 to 0.90; P = 0.04). This result indicates that patients using LMWH would have a RRR of 80% for developing HIT complicated by VTE compared with patients using UFH. Arterial thrombosis occurred in only one patient who received UFH and there were no amputations or deaths documented. Authors' conclusions There was a lower incidence of HIT and HIT complicated by VTE in postoperative patients undergoing thromboprophylaxis with LMWH compared with UFH. This is consistent with the current clinical use of LMWH over UFH as front-line heparin therapy. However, conclusions are limited by a scarcity of high quality evidence. We did not expect the paucity of RCTs including HIT as an outcome as heparin is one of the most commonly used drugs worldwide and HIT is a life-threatening adverse drug reaction. To address the scarcity of clinically-relevant information on the topic of HIT as a whole, HIT should be included as an outcome in future RCTs of heparin, and HIT as an adverse drug reaction should be considered in clinical recommendations regarding monitoring of the platelet count for HIT.