The quality of evidence is downgraded by study limitations (lack of/unclear allocation concealment and lack of blinding), by inconsistency (unexplained variability in results), and by imprecise results (few patients and wide confidence intervals).
A Cochrane review [Abstract] 1 included 4 studies with a total of 494 subjects to evaluate the efficacy of a 10-mg warfarin nomogram compared with a 5-mg warfarin nomogram among patients with venous thromboembolism (VTE). The proportion of participants who had achieved a therapeutic INR by day 5 was higher with 10-mg warfarin nomogram compared with 5-mg warfarin normogram (table T1), although there was substantial heterogeneity (I2 = 90%). A sensitivity analysis was performed using the random-effects model, and no difference was observed (RR 1.06, 95% CI 0.52 to 2.16). Each study was analyzed separately because it was not possible to perform a subgroup analysis. One study (n=201) showed significant benefit of a 10-mg warfarin nomogram for the proportion of outpatients with VTE who had achieved a therapeutic INR by day 5 (RR 1.78, 95% CI 1.41 to 2.25; NNTB = 3, 95% CI 2 to 4); another study (n=132) showed significant benefit of a 5-mg warfarin nomogram in outpatients with VTE (RR 0.58, 95% CI 0.36 to 0.93; NNTB = 5, 95% CI 3 to 28); the third study (n=50) showed no difference (RR 1.08, 95% CI 0.65 to 1.80). No difference was observed in recurrent venous thromboembolism, in major bleeding, or in minor bleeding (table T1).
| Outcome | Participnats (studies) | Assumed risk (5-mg warfarin nomogram) | Corresponding risk (10-mg warfarin nomogram) | RR (95% CI) |
|---|---|---|---|---|
| *fall in hemoglobin of > 20 g/L or transfusion of 2 or more units of red cells | ||||
| Therapeutic INR | 383 (3) | 473 per 1000 | 601 per 1000(497 to 729) | 1.27 (1.05 to 1.54) |
| Recurrent venous thromboembolism at 90 days | 312(2) | 17 per 1000 | 25 per 1000(7 to 95) | 1.48 (0.39 to 5.56) |
| Major bleeding at 14-90 days* | 494(4) | 17 per 1000 | 16 per 1000(4 to 58) | 0.97 (0.27 to 3.51) |
| Minor bleeding at 14-90 days | 243(2) | 50 per 1000 | 26 per 1000(8 to 92) | 0.52 (0.15 to 1.83) |
Clinical comment: Acute thromboembolism is treated with LMWH together with warfarin dose titration. LMWH treatment is effective and safe, and thus there is no hurry with warfarin titration.
Another Cochrane review [Abstract] 2 included 12 studies with a total of 1 656 subjects. The studies assessed the effectiveness of different initiation doses of warfarin in several different situations.
5 mg versus 10 mg (4 studies, n=355): There was no clear benefit between 10 mg versus 5 mg loading dose (Table T2).
| Outcome | Participants (studies) | Assumed risk (5 mg) | Corresponding risk (10 mg) | Relative risk (95% CI) |
|---|---|---|---|---|
| INR in-range by day 5 | 352 (4) | 571 per 1000 | 668 per 1000 (440 to 1000) | 1.17 (0.77 to 1.77) |
| INR in-range on day 5 (single INR measure) | 250 (2) | 504 per 1000 | 751 per 1000 (509 to 1000) | 1.49 (1.01 to 2.21) |
| INR in-range by day 5 (2 consecutive INR measures) | 102 (2) | 714 per 1000 | 614 per 1000 (443 to 850) | 0.86 (0.62 to 1.19) |
5 mg versus other doses (2 studies, n=322): Heart valve replacement patients (INR target 1.5 to 2.6) receiving 2.5 mg compared to 5 mg took longer to achieve the therapeutic range (2.7 versus 2.0 days, P < 0.0001) but were less likely to have a supratherapeutic INR (26% versus 42%, P < 0.05). Another study compared 5 mg with a calculated dose that took account of age, weight, serum albumin and active malignancy. Patients receiving the calculated dose achieved the target range quicker (4.2 days versus 5 days, P = 0.007), although there was no difference in other end points.
Age-adjusted: Two studies (n=192) compared age adjusted doses to 10 mg initiation doses. More elderly patients receiving an age adjusted dose achieved a stable INR compared to those receiving a 10 mg initial dose. In both studies significantly fewer patients on the age adjusted regimens had high out-of-range INRs.
Genotype loading : 4 studies (n=701) used genotype guided dosing in one arm of each trial. Three studies reported no overall differences; the fourth study, which reported that the genotype group spent significantly more time in-range (P < 0.001), had a control group whose INRs were significantly lower than expected.
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