Sobieraj et al. (2012), in the meta-analysis previously mentioned, also compared vitamin K antagonists (VKA) to LMWH in patients undergoing orthopedic surgery by pooling seven studies. They found that patients who received LMWH had fewer total DVT (RR 0.66, 95 % CI 0.55–0.79) and distal DVT events (RR 0.56, 95 % CI 0.43–0.73) with no significant difference in proximal DVT risk (RR 0.63, 95 % CI 0.39–1.00) but reported increased major bleeding (OR 1.92, 95 % CI 1.27–2.91), minor bleeding (RR 1.23, 95 % CI 1.06–1.43), and surgical site bleeding events (OR 2.63, 95 % CI 1.31–5.28).

Major efficacy end points such as symptomatic venous thromboembolism (OR 1.00, 95 % CI 0.69–1.46), pulmonary embolism (OR 1.11, 95 % CI 0.57–2.19), and nonfatal pulmonary embolism (OR 1.00, 95 % CI 0.20–4.95) showed similar benefits of therapy with LMWH and VKA (Table 4.1).

In particular when THR and TKR surgery were considered, meta-analysis highlights the following evidences for patients receiving LMWH: (1) patients undergoing THR and TKR surgery had fewer total DVT events (RR 0.61, 95 % CI 0.44–0.84 and RR 0.71, 95 % CI 0.57–0.87, respectively) and fewer distal DVT (RR 0.48, 95 % CI 0.30–0.78 and RR 0.60, 95 % CI 0.44–0.81, respectively); (2) patients undergoing THR (OR 1.91, 95 % CI 1.11–3.29) and TKR surgery (OR 1.93, 95 % CI 1.01–3.67) had more major and minor bleeding; and (3) patients in THR surgery had more surgical site bleeding and major surgical site bleeding (OR 2.56, 95 % CI 1.04–6.30).

Four studies evaluating fondaparinux in comparison to enoxaparin were meta-analyzed by Yoshida et al. (2013).

When primary efficacy end-points (defined as the frequency of any DVT, nonfatal pulmonary embolism or death from any cause) were analyzed, the results showed that fondaparinux had a positive and statistically significant effect if compared with enoxaparin (mixed doses) (RR 0.50, 95 % CI 0.39–0.63).

Nevertheless, considering the secondary efficacy outcomes, fondaparinux showed no significant difference if compared with enoxaparin. More specifically, the incidence of proximal DVT resulted reduced, but not significantly (RR 0.44, 95 % CI 0.19–1.02) and no significant difference was found in relation to pulmonary embolism (RR 1.06, 95 % CI 0.36,3.12), symptomatic DVT events (R.R 1.59, 95 % CI 0.51–4.90). As concerns safety outcomes, fondaparinux exhibited a higher any bleeding risk compared with enoxaparin (RR 1.27, 95 % CI 1.04–1.55). Similar results were observed in minor and major bleedings where fondaparinux proved to be associated with a higher risk (RR 1.06, 95 % CI 0.69–1.64 and RR 1.53, 95 % CI 0.92–2.55 respectively). Nevertheless heterogeneity limited the strength of these results (Table 4.1).

Systematic reviews and meta-analyses, addressed to evaluate LMWH efficacy and safety in comparison to oral direct factor Xa inhibitors, considered as a class of drug (Neuman et al. 2012 and Sobieraj et al. 2012), comparing the single drug rivaroxaban (Gómez-Outes et al. 2012; Hamidi et al. 2013; Yoshida et al. 2013) and apixaban (Gómez-Outes et al. 2012; Hamidi et al. 2013), are available.

Neumann et al. (2012) conducted a meta-analysis of 22 randomized, controlled trials performed on 32,159 patients undergoing hip or knee replacement (female sex 44.6–72.5 %; mean age 57.8–67.6 years), comparing different doses of different factor Xa inhibitors versus LMWH. Factor Xa inhibitors considered by these authors were apixaban, rivaroxaban, and edoxaban; YM150; and LY1517717, TAK442, razaxaban, and betrixaban. These authors reported any outcomes regarding mortality at the end of prophylaxis or during the follow-up period, symptomatic DVT, nonfatal pulmonary embolism, major bleeding, intracranial bleeding, and bleeding leading to reoperation. Eleven trials comprised patients undergoing total hip replacement, ten undergoing knee replacement, and only one undergoing either procedure.

In most trials, the European-approved dosage of enoxaparin (40 mg daily) was the comparator instead of the US-approved dosage (30 mg twice daily). Regarding doses of factor Xa inhibitors, 12 studies evaluated several doses, including high doses. In eight of the ten trials evaluating a single dose of factor Xa inhibitors, the dose used was low.

Timing of prophylaxis differed from studies: in particular, rivaroxaban was started 6 h after surgery in the majority of studies; apixaban was started 12–24 h after surgery.

The duration of follow-up varied from less than 14 days in 9 trials, 30–70 days in 12 trials, and reached 90 days in one trial.

The pooled effect estimate did not suggest important differences between oral factor Xa inhibitors in comparison to LMWH for all-cause mortality in patients (n = 31,702) having THR or TKR (OR 1.27, 95 % CI 0.63–2.55); risk difference, 0 fewer deaths per 1,000 patients [95 % CI, 1 fewer to 1 more death] or at the end of follow-up (OR 0.95, 95 % CI 0.55–1.63); risk difference, 0 fewer deaths per 1,000 patients [CI, 2 fewer to 1 more deaths]; conversely, the risk for symptomatic DVT is decreased by 4 events per 1,000 patients (OR 0.46, 95 % CI 0.30–0.70).

Regarding nonfatal pulmonary embolism, no important difference between factor Xa inhibitors and LMWH (OR 1.07, 95 % CI 0.65–1.73); risk difference, 0 fewer events [CI, 1 fewer to 2 more events per 1,000 patients], was found.

Data with a moderate strength of evidence showed that factor Xa inhibitors could increase the risk of bleeding by two major events per 1,000 patients. In a subgroup analysis, higher, but not intermediate or lower, doses of factor Xa inhibitors were associated with increased risk for bleeding (OR 2.50, 95 % [CI 1.38–4.53]; P = 0.02). The pooled effect estimate of bleeding that led to reoperation also increased (OR 1.62, 95 % CI 0.82–3.19).

In this meta-analysis, subgroup analysis showed an interaction between the doses used in the intervention group and the risk for major bleeding; high doses increased the risk for major bleeding (OR 2.50, 95 % CI 1.38–4.53); test for interaction across the 3 doses, P = 0.02 (Table 4.2).

According to Sobieraj’s meta-analysis (2012) of ten trials, compared with patients receiving factor Xa inhibitors, patients who received LMWH had more major venous thromboembolism (OR 2.64, 95 % CI 1.82–3.84), pulmonary embolism (OR 2.50, 95 % CI 1.08–5.78), total DVT (RR 2.05, 95 % CI 1.68–2.50), symptomatic DVT (RR 1.66, 95 % CI 1.04–2.64), proximal DVT (OR 2.62, 95 % CI 1.95–3.51), and distal DVT events (RR 2.14, 95 % CI 1.84–2.50) but fewer major bleeding events (OR 0.65, 95 % CI 0.49–0.86).

In particular when THR and TKR surgeries were considered, meta-analysis highlights the following evidences: as concerns major VTE events, patients undergoing THR and TKR surgeries had fewer events than patients receiving LMWH (OR 3.97, 95 % CI 2.17–7.24 and OR 2.04, 95 % CI 1.26–3.30, respectively). Patients receiving LMWH had more total DVT events than patients receiving factor Xa inhibitors in THR surgery (OR 2.24, 95 % CI 1.79–2.80) and in TKR surgery (RR 1.81, 95 % CI 1.44–2.28). Considering proximal and distal DVT events, patients undergoing to THR and TKR surgeries had more events (RR 2.29, 95 % CI 1.24–4.28 and RR 1.39, 95 % CI 1.00–1.94, respectively).