Antithrombotic Prophylaxis For Multiple Myeloma Patients Receiving Immunmodulator: A Systematic Review

Objectives: To evaluate the efficacy and safety of thromboprophylaxis for multiple myeloma(MM) patients treated with thalidomide or lenalidomide.Methods : Randomized controlled trials(RCTs) or prospective cohort studies on thromboprophylaxis for multiple myeloma patients treated with immunomodulator(thalidomide or lenalidomide) in any language were sought using the following sources: CBM, Central, CNKI, Embase, Pubmed, Clinicaltrial(up to July 2015). Two reviewers independently indentified the eligible studies according to the inclusion criteria and exclusion criteria, assessed the studies’ methodological quality using the Newcastle-Ottawa Quality Assessment scale(NOS) for prospective cohort studies and the Risk of Bias Assessment Tool(Cochrane Handbook) for RCTs, respectively, and analysed the data using the Rev Man software 5.3. The primary outcomes were venous thromboembolic(VTE) events(deep vein thrombosis or pulmonary embolism),arterial thromboembolic events(acute myocardial infarction, stoke or arterial thrombosis), deaths(any death and deaths as a result of pulmonary embolism, acute myocardial infraction or stoke). The second outcomes were major or minor bleeding events, other complications related to thromboprophylaxis, drop-outs or withdrawals for any reason.Results: Five RCTs and ten prospective cohort studies out of 253 identified references were included in the systematic review. No full text publication was available for 2 of these 15 studies. NOS scores were 7 or 8 for the included 10 prospective cohort studies and overall risk of bias was low. They compared aspirin(ASA), low-molecular-weight heparin(LMWH), warfarin with no thromboprophylaxis respectively. The risk ratios(RRs) of VTE events were 0.28(0.18, 0.46), 0.53(0.39, 0.71) and 0.72(0.53, 0.99), respectively. The numbers need to treat(NNTs) were 2.15, 7 and 5.34, respectively. These results showed that ASA, LMWH and warfarin were effective in reducing the incidence of VTE events. Other outcomes were not analyzed because of the incomplete data. Five RCTs met the inclusion criteria. Two of them were of high quality, the risk of bias was low. Other three were not and the risk of bias was high. These RCTs compared ASA with enoxaparin, ASA with warfarin and warfarin with enoxaparin,respectively. The RRs of VTE events were 1.57(0.99, 2.49), 0.94(0.61, 1.45) and 1.61(0.98, 2.65),respectively. The NNTs were 59, 260 and 40, respectively. Enoxaparin was superior to either ASA or warfarin in reducing the incidence of VTE events although the difference was not statistically significant. The incidence of VTE events in ASA and warfarin was similar. The RRs of arterial thromboembolic events were 0.88(0.34,2.26), 2.65(0.71, 9.92) and 0.33(0.09, 1.22), respectively. The NNTs were 709, 121 and 97.5, respectively. Warfarin was superior to either ASA or enoxaparin in reducing the incidence of arterial thromboembolic events although the difference was not statistically significant. The incidence of arterial thromboembolic events in ASA and enoxaparin was similar. For death outcomes, only Palumbo A 2011 study reported 4deaths(ASA was 1/220, enoxaparin was 1/219, warfarin was 2/220). The RRs of bleeding events were 2.05(0.94, 4.50), 4.47(1.52, 13.12) and 0.79(0.21, 2.94),respectively. The bleeding event incidence in ASA group was higher than in warfarin or in enoxaparin group although difference was statistically significant only between ASA and warfarin. The incidence of bleeding event in warfarin and enoxaparin was similar. For other adverse effects, only Larocca A 2012 study reported that 4 patients who recevied ASA experienced a superficial venopathies. Other complications were not reported. The RRs of drop-outs were 1.49(0.97, 2.29), 0.76(0.51, 1.13) and 1.76(1.13, 2.74) for ASA vs enoxaparin, ASA vs warfarin and warfarin vs enoxaparin,repectively. The drop-out in enoxaparin group was lower than in warfarin or in ASA group, and the difference between enoxaparin and warfarin was statistically significant.Conclusion: ASA, LMWH and warfarin were all effective in reducing the incidence of VTE events for MM patients receiving thalidomide or lenalidomide. However, no evidence was found in reducing the incidence of arterial thromboembolic events.Head to head RCTs showed that enoxaparin seem to be superior to either ASA or warfarin in reducing the incidence of VTE events with fewer bleeding events and withdraws. But for arterial thromboembolism prophylasis, warfarin seem to be superior to enoxaparin.