After this report was updated, the Food and Drug Administration approved an oral direct factor Xa inhibitor, rivaroxaban, for the prevention of deep vein thrombosis, which may lead to pulmonary embolism, in patients undergoing knee or hip replacement surgery.¹⁹⁹ Four phase III trials have been completed at this time.^200-203 Since this drug did not carry an FDA approved indication until recently, rivaroxaban did not meet the inclusion criteria and was not included in this report. We find these trials relevant since they provide new information for an additional between class comparison (oral direct factor Xa inhibitor versus injectable low-molecular weight heparin) in Key Question 5. The main findings of the four trials and the outcomes reported in these trials that are consistent with the methodology of this report are described here.

The four Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism (RECORD) trials compared various regimens of rivaroxaban and enoxaparin, in total hip or knee replacement surgery (Table 16). All four trials were determined to be of good methodological quality and all evaluated either a per-protocol, modified intention to treat, or safety population for a given outcome.

Table 16

The RECORD trials.

RECORD 1²⁰⁰: Thiss trial was designed to evaluate extended duration prophylaxis in total hip replacement surgery and randomized 4,541 patients to receive either rivaroxaban or enoxparin (Table 16). The mean duration of followup was 33.4 days and 33.7 days in the rivaroxaban and enoxparin groups, respectively. Symptomatic venous thromboembolism was not significantly different in the rivaroxaban group compared with enoxaparin during the treatment [risk difference (RD) -0.1 (-0.6 to 0.1)] or followup [RD -0.1 (-0.4 to 0.1)] period. Major venous thromboembolism was a composite of proximal deep vein thrombosis, nonfatal pulmonary embolism or death from venous thromboembolism. The risk of major venous thromboembolism was significantly decreased in the rivaroxaban group compared with enoxparin [RD -1.7 percent (-2.5 to -1.0)]. Death during treatment [RD 0.0 (-0.4 to 0.4)] or death during followup [RD 0.1 (-0.2 to 0.4)] was not significantly different in the rivaroxaban group compared with enoxaparin. Nonfatal pulmonary embolism was not significantly different in the rivaroxaban group compared with enoxaparin [RD 0.2 (-0.1 to 0.6)].

The risk of total deep vein thrombosis [RD -2.7 (-3.7 to -1.7)] or proximal deep vein thrombosis [RD -1.9 (-2.7 to -1.2)] was decreased with rivaroxaban compared with enoxaparin although the risk of distal deep vein thrombosis was not significantly impacted [RD -0.7 (-1.5 to 0.0)]. There was no difference in the risk of major bleeding in the rivaroxaban group compared with enoxaparin [RD 0.2 (-0.1 to 0.5)]. The incidence of nonmajor bleeding was similar in both groups; rivaroxaban 128/2209 (5.8 percent), enoxaparin 129/2224 (5.8 percent), (p=0.955). There was one death from bleeding (0.05 percent) in the rivaroxaban group and none in the enoxparin group (p=0.995). Two cases (0.09 percent) of bleeding leading to reoperation occurred in the rivaroxaban group while 1 case (0.04 percent) occurred in the enoxaparin group (p=0.995).

RECORD 2²⁰¹: This trial was designed to evaluate extended duration prophylaxis with rivaroxaban to short-term prophylaxis with enoxaparin in total hip replacement surgery (Table 16). A total of 2,509 patients were randomized to receive either rivaroxaban or enoxparin and the mean duration of followup was 33.5 days and 12.4 days in the rivaroxaban and enoxparin groups, respectively. Symptomatic venous thromboembolism was significantly decreased in the rivaroxaban group compared with enoxaparin during treatment [absolute risk reduction (ARR) 1.0 (0.3 to 1.8)] but not during the followup period [ARR 0.1 (-0.2 to 0.4)]. Major venous thromboembolism was a composite of proximal deep vein thrombosis, nonfatal pulmonary embolism or death from venous thromboembolism. The risk of major venous thromboembolism was significantly decreased in the rivaroxaban group compared with enoxparin [ARR 4.5 (3.0 to 6.0)]. Death during treatment [ARR 0.5 (-0.2 to 1.1)] or death during followup [ARR 0.2 (-0.1 to 0.6)] was not significantly different in the rivaroxaban group compared with enoxaparin. Nonfatal pulmonary embolism was not significantly different in the rivaroxaban group compared with enoxaparin [ARR 0.3 (-0.2 to 1.1)].

The risk of total deep vein thrombosis [ARR 6.5 (4.5 to 8.5)], proximal deep vein thrombosis [ARR 4.5 (2.9 to 6.0)] and distal deep vein thrombosis [ARR 2.0 (0.7 to 3.3)] was decreased with rivaroxaban compared with enoxaparin. One major bleeding episode occurred in each group (0.08 percent in each group, p=0.480) and there were no fatal bleeding events or bleeding leading to reoperation events. The incidence of nonmajor bleeding was 80/1228 (6.5 percent) in the rivaroxaban group and 67/1229 (5.5 percent) in the enoxaparin group (p=0.305).

RECORD 3²⁰²: This trial was designed to evaluate the use of rivaroxaban compared with once daily enoxaparin for venous thromboembolism prophylaxis in total knee replacement surgery (Table 16). A total of 2,556 patients were randomized to receive either rivaroxaban or enoxparin and the mean duration of followup was 11.9 days and 12.5 days in the rivaroxaban and enoxparin groups, respectively. Symptomatic venous thromboembolism was significantly decreased in the rivaroxaban group compared with enoxaparin during treatment [RD -1.3 (-2.2 to -0.4)] but not during the followup period [RD 0.2 (-0.3 to 0.6)]. Major venous thromboembolism was a composite of proximal deep vein thrombosis, nonfatal pulmonary embolism or death from venous thromboembolism. The risk of major venous thromboembolism was significantly decreased in the rivaroxaban group compared with enoxparin [RD -1.6 (-2.8 to -0.4)]. Death during treatment [RD -0.2 (-0.6 to 0.2)] or death during followup [RD -0.3 (-0.8 to 0.0)] was not significantly different in the rivaroxaban group compared with enoxaparin. Nonfatal pulmonary embolism was not significantly different in the rivaroxaban group compared with enoxaparin [RD -0.3 (-0.8 to 0.0)].

The risk of total deep vein thrombosis [RD -8.4 (-11.7 to -5.2)] and distal deep vein thrombosis [RD-7.3 (-10.4 to -4.3)] was decreased with rivaroxaban compared with enoxaparin but the risk of proximal deep vein thrombosis was not significantly impacted [RD -1.1 (-2.3 to 0.1)]. No significant difference in the rate of major bleeding during treatment was found, with 7/1220 (0.6 percent) cases in the rivaroxaban group and 6/1239 (0.5 percent) in the enoxaparin group (p=0.77). No fatal bleeding episodes occurred. Five cases (0.4 percent) of bleeding leading to reoperation occurred in the rivaroxaban group and 4 cases (0.3 percent) occurred in the enoxaparin group (p=0.981). The incidence of nonmajor bleeding was 53/1220 (4.3 percent) in the rivaroxaban group and 54/1239 (4.4 percent) in the enoxaparin group (p=0.935).

RECORD 4²⁰³: This trial was designed to evaluate the use of rivaroxaban compared with twice daily enoxaparin for venous thromboembolism prophylaxis in total knee replacement surgery (Table 16). A total of 3,148 patients were randomized to receive either rivaroxaban or enoxparin and the mean duration of followup was 11.7 days and 11.0 days in the rivaroxaban and enoxparin groups, respectively. Symptomatic venous thromboembolism was not significantly different in the rivaroxaban group compared with enoxaparin during treatment [RD -0.47 (-1.16 to 0.23)] or during the followup period [RD 0.00 (-0.32 to 0.32)]. Major venous thromboembolism was a composite of proximal deep vein thrombosis, nonfatal pulmonary embolism or death from venous thromboembolism. The risk of major venous thromboembolism was not significantly different in the rivaroxaban group compared with enoxparin in both the per-protocol [RD -0.37 (-1.34 to 0.60)] and modified intention to treat populations [RD -0.80 (-1.82 to 0.22)]. Death during treatment [RD -0.07 (-0.46 to 0.30)] or death during followup [RD 0.06 (-0.35 to 0.50)] was not significantly different in the rivaroxaban group compared with enoxaparin. Pulmonary embolism [RD -0.20 (-0.75 to 0.30)] and nonfatal pulmonary embolism [RD -0.27 (-0.8 to 0.21)] was not significantly different in the rivaroxaban group compared with enoxaparin.

Asymptomatic deep vein thrombosis occurred in 55/965 (5.7 percent) of rivaroxaban patients and 76/959 (7.9 percent) of enoxaparin patients (p=0.065). Of those cases, 3 and 13 were proximal (p=0.08) and 52 and 63 were distal (p=0.08), in the rivaroxaban and enoxaparin groups respectively. Symptomatic deep vein thrombosis occurred in 6/965 (0.6 percent) of rivaroxaban patients and 10/959 (1.0 percent) of enoxaparin patients (p=0.444). No significant difference in the rate of major bleeding during treatment was found, with 10/1526 (0.7 percent) cases in the rivaroxaban group and 4/1508 (0.3 percent) in the enoxaparin group (p=0.1096). One fatal bleeding episode (0.07 percent) occurred in the rivaroxaban group and none in the enoxaparin group (p=0.995). Five cases (0.3 percent) of bleeding leading to reoperation occurred in the rivaroxaban group and 2 (0.1 percent) occurred in the enoxaparin group (p=0.459). The incidence of nonmajor bleeding was 155/1526 (10.2 percent) in the rivaroxaban group and 138/1508 (9.2 percent) in the enoxaparin group (p=0.381).