Abstract: We included a total of 22 trials (9137 participants) of which 15 were randomized trials (7762 participants). The overall risk of bias was mostly unclear or high due to selection and performance bias. We used GRADE to assess the quality of the evidence and this was downgraded from high to moderate or very low due to the risk of bias, imprecision or indirectness. The rate of PE in the studies comparing IPC alone with combined IPC and pharmacological prophylaxis was low, underpowering the analyses. The incidence of symptomatic PE was 0.79% with IPC, but ranged between 0.1 to 1% with combined IPC and pharmacological prophylaxis (OR 0.49, 95% CI 0.18 to 1.34; 12 studies, 3017 participants, moderate quality evidence). The incidence of DVT was 4.10% in the IPC group and 2.19% in the combined group showing a reduced incidence of DVT in favour of the combined group (OR 0.52, 95% CI 0.33 to 0.82; 11 studies, 2934 participants, moderate quality evidence). The addition of an anticoagulant to IPC, however, increased the risk of any bleeding compared to IPC alone; 0.66% (7/1053) in the IPC group and 4.0% (44/1102) in the combined group (OR 5.04, 95% CI 2.36 to 10.77; 7 studies, 2155 participants, moderate quality evidence). Major bleeding followed a similar pattern; 0.1% (1/1053) in the IPC group to 1.5% (17/1102) in the combined group (OR 6.81, 95% CI 1.99 to 23.28; 7 studies, 2155 participants, moderate quality evidence). We detected no difference between the type of surgery subgroups such as orthopedic and non-orthopedic participants for DVT incidence (P = 0.16). Tests for differences between type of surgery subgroups were not possible for PE incidence. Compared with pharmacological prophylaxis alone, the use of combined IPC and pharmacological prophylaxis modalities reduced the incidence of symptomatic PE from 2.92% to 1.20% (OR 0.39, 95% CI 0.23 to 0.64; 10 studies, 3544 participants, moderate quality evidence). The incidence of DVT was 6.2% in the pharmacological prophylaxis group and 2.9% in the combined group showing no difference between the combined and pharmacological prophylaxis groups (OR 0.42, 95% CI 0.18 to 1.03; 11 studies, 2866 participants, moderate quality evidence). Increased bleeding side effects were not observed for IPC when it was added to anticoagulation (bleeding: OR 0.80, 95% CI 0.30 to 2.14, very low quality evidence; major bleeding: OR 1.21, 95% CI 0.35 to 4.18, very low quality evidence, 3 studies, 244 participants). No difference was detected between the type of surgery subgroups for PE incidence (P = 0.68) or for DVT incidence (P = 0.10). Moderate quality evidence suggests that combining IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, decreases the incidence of DVT when compared to compression, and incidence of PE when compared to anticoagulation. Moderate quality evidence suggests that there is no difference between combined and single modalities in the incidence of PE when compared with compression alone and DVT when compared with anticoagulation alone. The quality of evidence for PE or DVT was downgraded to moderate due to imprecision or risk of bias in study methodology, highlighting the need for further research. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method of thromboprophylaxis. The quality of evidence for bleeding was downgraded to moderate due to indirectness or very low due to risk of bias in study methodology, indirectness and imprecision highlighting the need for further research. Nevertheless, the results of the current review agree with current guideline recommendations, which support the use of combined modalities in hospitalised patients (limited to those with trauma or undergoing surgery) at risk of developing VTE. More studies on the role of combined modalities in VTE prevention are needed.

Plain-language summary: We identified 22 trials with a total of 9137 participants to include in this review (current until May 2016). The mean age of participants, where reported, was 65.2 years. Most participants had either a high-risk procedure or condition. The predisposing conditions were orthopedic surgery in 12 studies and urology, cardiothoracic, neurosurgery, trauma, general surgery, gynaecology or other types of participants in the remaining studies. Compared to IPC alone, IPC plus medication did not show differences in the incidence (rate of new cases) of PE (12 studies with a total of 3017 participants). The incidence of DVT was reduced for IPC combined with medication when compared with IPC alone (11 studies with a total of 2934 participants). The addition of a medication to IPC, however, increased the risk for any bleeding compared to IPC alone, from 0.66% to 4.0%. Major bleeding followed a similar pattern, with an increase from 0.1% to 1.5%.Further analysis looking at different subgroups of participants (orthopedic and non-orthopedic participants) did not show any overall difference in DVT while it was not possible to assess differences between subgroups for PE. Compared with medication alone, combined IPC and medication reduced the incidence of PE (10 studies with 3544 participants). DVT incidence was not different between the medication and the combined IPC and medication group (11 studies with 2866 participants). No differences were observed in rates of bleeding (three studies with 244 participants). Further analysis looking at different subgroups of participants did not show any overall difference in incidence of PE and DVT between orthopedic and non-orthopedic participants. The findings of this review show moderate quality evidence and agree with current guideline recommendations supporting the use of combined IPC and pharmacological prophylaxis, compared with IPC or pharmacological prophylaxis alone, to reduce the incidence of DVT and PE in hospitalized patients. Moderate quality evidence suggests the addition of pharmacological prophylaxis to IPC, increased the risk of bleeding compared to IPC alone, a side effect not observed for IPC when added to pharmacological prophylaxis (very low quality evidence), as expected for a physical method for preventing blood clots. The quality of the evidence was downgraded from high to moderate or very low for risk of bias and imprecision and indirectness between the studies.