Table 2.
Efficacy and Safety Outcomes.*
| Outcome Efficacy | FXI-ASO, 200 mg (N = 134) | FXI-ASO, 300 mg (N = 71) | Enoxaparin, 40 mg (N = 69) |
|---|---|---|---|
| Primary efficacy outcome: total venous thromboembolism — no. (% [95% CI])† | 36 (27 [20 to 35]) | 3 (4 [1 to 12]) | 21 (30 [20 to 43]) |
| Risk difference, FXI-ASO vs. enoxaparin — % (upper limit of 90% CI) | −4 (5) | −26 (−18) | — |
| Risk difference, FXI-ASO vs. enoxaparin — % (upper limit of 95% CI) | −4 (8) | −26 (−16) | — |
| P value for superiority of FXI-ASO to enoxaparin | 0.59 | <0.001 | — |
| Secondary efficacy outcomes: components of the primary efficacy outcome — no. (%) | |||
| Symptomatic venous thromboembolism | 2 (1) | 0 | 1 (1) |
| Asymptomatic deep-vein thrombosis | 34 (25) | 3 (4) | 20 (29) |
| Proximal deep-vein thrombosis | 7 (5) | 1 (1) | 4 (6) |
| Distal deep-vein thrombosis | 29 (22) | 2 (3) | 17 (25) |
| Exploratory efficacy outcome: extent of venous thrombosis on venography | |||
| Patients with deep-vein thrombosis — no. (%) | 36 (27) | 3 (4) | 21 (30) |
| Extent of deep-vein thrombosis — no. | |||
| Bilateral‡ | 2 | 0 | 2 |
| Confluent distal into proximal | 6 | 0 | 2 |
| Isolated proximal | |||
| Large: ≥10 cm | 0 | 0 | 1 |
| Small: <10 cm | 0 | 1 | 0 |
| Isolated distal | |||
| Extensive: ≥2 veins | 16 | 0 | 7 |
| Limited: <2 veins | 12 | 2 | 9 |
| Outcome Safety§ | FXI-ASO, 200 mg (N = 144) |
FXI-ASO, 300 mg (N = 77) |
Enoxaparin, 40 mg (N = 72) |
|---|---|---|---|
| Principal safety outcome: major or clinically relevant nonmajor bleeding — no. (% [95% CI]) | 4 (3 [1 to 7]) | 2 (3 [<1 to 9]) | 6 (8 [3 to 17]) |
| Risk difference, FXI-ASO vs. enoxaparin — % (95% CI) | −6 (−12 to 1) | −6 (−13 to 2) | |
| P value by Fisher’s exact test, FXI-ASO vs. enoxaparin | 0.09 | 0.16 | |
| Major bleeding — no. (% [95% CI])¶ | 0 [0 to 2.5] | 1 (1 [<1 to 7]) | 0 [0 to 5.0] |
| Clinically relevant nonmajor bleeding — no. (% [95% CI]) | 4 (3 [1 to 7]) | 1 (1 [<1 to 7]) | 6 (8 [3 to 17]) |
| Receipt of blood transfusion — no. (%) | 55 (38) | 22 (29) | 23 (32) |
| Adverse events — no. of patients (%) | |||
| ≥1 adverse event | 114 (79) | 62 (81) | 47 (65) |
| Serious adverse event‖ | 3 (2) | 1 (1) | 0 |
| Any adverse event resulting in permanent discontinuation of study drug** | 1 (1) | 1 (1) | 0 |
| Injection-site–related adverse event†† | 32 | 25 | 2 |
Efficacy outcomes were assessed in the per-protocol efficacy population, which comprised all patients who received at least one dose of study medication and who could be evaluated for the primary efficacy outcome, with the exclusion of patients with major protocol violations. Safety outcomes were assessed in the safety population, which included all patients who received at least one dose of study medication. CI denotes confidence interval.
Total venous thromboembolism was a composite of asymptomatic deep-vein thrombosis (detected by mandatory bilateral venography), objectively confirmed symptomatic venous thromboembolism, fatal pulmonary embolism, or unexplained death for which pulmonary embolism could not be ruled out. None of the patients had a pulmonary embolism.
In the 200-mg FXI-ASO group, one patient had bilateral distal deep-vein thrombosis and one patient had distal deep-vein thrombosis confluent to the popliteal vein in the right leg and distal deep-vein thrombosis alone in the left leg; in the enoxaparin group, one patient had bilateral distal deep-vein thrombosis and one patient had bilateral distal deep-vein thrombosis confluent to the proximal veins.
The safety outcomes reported here include data from the first administration of the study drug to study day 136 (end of the study). The observation period in the FXI-ASO groups was longer than that with enoxaparin because the FXI-ASO injections were started on day 1 (36 days before surgery) and continued to day 39 (3 days after surgery), and patients in the 300-mg group received two injections per dosing. In the enoxaparin group, the injections started on the day of surgery or the day before.
One episode of surgical-site hematoma requiring drainage occurred in a patient in the 300-mg FXI-ASO group.
In the 200-mg FXI-ASO group, the serious adverse events were transient ischemic attack (in one patient), fistula of the postoperative scar (in one patient), and ligature fistula (in one patient); in the 300-mg FXI-ASO group, one patient had a periprosthetic infection. All these events were considered by the investigators as unlikely to be related or as unrelated to FXI-ASO therapy.
The reasons for discontinuation were itching and worsening of preexisting arterial hypertension (one patient in the 200-mg FXI-ASO group) and bleeding from the surgical site (one patient in the 300-mg FXI-ASO group).
Injection-site adverse events included one or more of the following: erythema, pain, pruritus, swelling, and hematoma.