Table 1.
Description of studies used in the derivation of the PT‐adjustment functions and description of studies for which the PT‐adjustment function was applied
| Description of studies used in the derivation of the PT‐adjustment function | |||||
|---|---|---|---|---|---|
| Indication | Prevention of VTE in patients undergoing hip or knee replacement surgery | Treatment of VTE | AF | ||
| Study | ODIXa‐HIP2 | ODIXa‐KNEE | ODIXa‐DVT | EINSTEIN‐DVT | ROCKET AF |
| Study number | 10944 | 10945 | 11223 | 11528 | AFL3001 |
| ClinicalTrials.gov identifier | NCT00398905 | NCT00402467 | NCT00839163 | NCT00395772 | NCT00403767 |
| Phase | II | II | II | II | III |
| N (n with valid PK and PT samples) | 553 (508) | 501 (322) | 470 (437) | 400 (351) | 161 (161) |
| Number of PK samples per patient, median (range) | 4 (1–10) | 4 (1–10) | 8 (1–9) | 3 (1–5) | 5 (2–15) |
| Number of PT samples per patient, median (range) | 7 (2–12) | 6 (1–10) | 9 (3–9) | 4 (1–5) | 7 (3–18) |
| Dose (mg) and regimen | 2.5, 5, 10, 20, 30 b.d. Dose‐ranging | 2.5, 5, 10, 20, 30 b.d. | 10, 20, 30 b.d. 40 o.d. | 20, 30, 40 o.d. Dose‐ranging | 20 (15 in patients with CrCl 30–49 mL/min) o.d. |
| Treatment duration | 9 ± 2 days | 8 ± 2 days | 12 weeks | 12 weeks | Median 590 days |
| Description of studies for which the PT adjustment was applied | ||||||
|---|---|---|---|---|---|---|
| Indication | Prevention of VTE in patients undergoing hip or knee replacement surgery | Treatment of VTE | AF | |||
| Study | RECORD1 | RECORD2 | RECORD3 | RECORD4 | EINSTEIN‐DVT/PE | ROCKET AF |
| Study number | 11354 | 11357 | 11356 | 11355 | 11702 | AFL3001 |
| ClinicalTrials.gov identifier(s) | NCT00329628 | NCT00332020 | NCT00361894 | NCT00362232 | NCT00440193/NCT00439777 | NCT00403767 |
| Phase | III | III | III | III | III | III |
| Number of patients for ER analysis | 2,183 | 1,197 | 1,191 | 1,526 | 4,130 | 7,111 |
| Number of patients with PT adjustment | 2,059a | 1,051a | 1,081a | 1,102a | 3,582b | 5,681c |
| Number of PT samples per patient without baseline samples, median (range) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 2 (1–3) | 2 (1–5) | 2 (1–3)d |
| Dose (mg) and regimen, and treatment duration | 10 o.d. 35 ± 4 days | 10 o.d. 35 ± 4 days | 10 o.d. 12 ± 2 days | 10 o.d. 12 ± 2 days | 15 b.d. for 3 weeks followed by 20 o.d. for 3, 6, or 12 months | 20 o.d. (15 o.d. for patients with moderate renal impairment); median 590 days |
AF, atrial fibrillation; b.d., twice daily; CrCl, creatinine clearance; DVT, deep vein thrombosis; ER, exposure–response; o.d., once a day; PE, pulmonary embolism; PK, pharmacokinetic; PT, prothrombin time; VKA, vitamin K antagonist; VTE, venous thromboembolism.
aAcross studies of patients undergoing hip or knee replacement surgery, data from 5,293 patients were used for PT adjustment. In 24 cases, a missing covariate value was imputed. PT measurements under the influence of VKA were excluded, as were PT measurements <72 hours postsurgery. In this early postsurgery phase, neither PK nor PT data reflect a steady‐state PK/PT relationship. A median of two samples per participant were available. bIn 30 cases, a missing covariate value was imputed. For eight patients, no information on comedication intake was available for the 20 mg o.d. phase; these patients were treated as nonusers in this phase. PT measurements under the influence of VKA were excluded, as were PT measurements in the initial 3‐week 15 mg b.d. treatment period. PT measurements in the first 3 days, after the switch from 15 mg b.d. to 20 mg o.d. treatment, were also excluded because they cannot be assumed to reflect a 20 mg o.d. steady‐state PK model. A median of two samples per participant were available. cIncludes the subset of patients with PT measurements (including the 161 patients from the PK subgroup). In 13 cases, a missing covariate value was imputed. A median of two samples per participant were available. dFor patients not in the PK subset.