Kovacs 2003.

Methods	Study design: randomized controlled clinical trial. Method of randomization: the randomization sequence was computer‐generated by the trial statistician. Also the randomization was stratified by study center and the presence of active malignant disease. Concealment of allocation: yes. The details of the randomization sequence, which were not known to the investigators or to the study coordinator, were contained in sets of sequentially numbered, opaque, sealed envelopes. The outside of each envelope was marked only with the name of the hospital, whether the participant had a malignant condition, and a participant number. Blinded: double (physician‐patient). Power calculation: we calculated that 92 participants per group would be required to show a 0.5‐day difference in time to a therapeutic INR (90% power; two‐sided α = 0.05). Number of participants randomly assigned: 201. Number of participants analyzed: 201. Number of withdrawals and reasons: none. Intention‐to‐treat analysis: yes. Source of funding: not stated. Potential financial conflicts of interest:none disclosed.
Participants	Country: Canada. Number of centers: 4. Location: thrombosis clinics of four Canadian academic centers. Source of participants: Canada. 10‐mg nomogram group: 104 participants. 5‐mg nomogram group: 97 participants. Age: mean age ± SD, years. 10‐mg nomogram group: 55 ± 17.4. 5‐mg nomogram group: 55.6 ± 17.2. Sex: men/women, n/n 10‐mg nomogram group: 65/39. 5‐mg nomogram group: 47/50. Inclusion criteria: outpatients, older than 18 years and with a diagnosis of objectively confirmed acute VTE:DVT or PE. Exclusion criteria: participants with baseline INR > 1.4, had thrombocytopenia (platelet count < 50 × 109 cells/mL), were younger than 18 years of age, required hospitalization, had received oral anticoagulant therapy within the previous two weeks, or were at high risk for major bleeding (as judged by the attending physician).
Interventions	Treatment(s): Intervention: 104 participants were assigned to the 10‐mg nomogram group. Control: 97 participants were assigned to the 5‐mg nomogram group. Treatment was initiated on the first day (day 1) with subcutaneous low molecular weight heparin (dalteparin 200 U/kg of body weight) or tinzaparin (175 U/kg). Low molecular weight heparin was continued for a minimum of five daily injections until the INR was therapeutic (> 1.9). Duration: 90 days. If a patient did not have a therapeutic INR by day 5, the INR was measured daily until it was therapeutic. Local attending physicians directed management of warfarin monitoring from day 8 to day 90.
Outcomes	Proportion of participants whose INRs were within the therapeutic range (2.0 to 3.0) on the fifth day: n (%) 10‐mg nomogram group: 86 (83%). 5‐mg nomogram group: 45 (46%), P < 0.001. Incidence of RVTE within 90 days of diagnosis: n (%) 10‐mg nomogram group: 3 (2.9%). 5‐mg nomogram group: 0 (0%), P = 0.09. Incidence of major bleeding within 90 days of diagnosis: n (%) 10‐mg nomogram group: 1 (0.96%). 5‐mg nomogram group: 1 (1.03%).
Notes	To add any information: Outcomes not included at protocol: Proportion of participants with INR > 3 in the first 4 weeks: n (%) 10‐mg nomogram group: 81 (77.88%). 5‐mg nomogram group: 84 (86.60%), P > 0.2. Proportion of participants with INR > 5 in the first 4 weeks: n (%) 10‐mg nomogram group: 9 (8.65%). 5‐mg nomogram group: 11 (11.34%), P > 0.2. Mortality at 90 days: n (%) 10‐mg nomogram group: 0. 5‐mg nomogram group: 1 (10.31%). The study included participants with cancer: n (%) 10‐mg nomogram group: 26 (25%). 5‐mg nomogram group: 22 (23%). This study was limited in its power for safety assessment. Invitation to authors to add and audit review data: not necessary.
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomization sequence was computer‐generated by the trial statistician.
Allocation concealment (selection bias)	Low risk	The details of the randomization sequence were contained in sets of sequentially numbered, opaque, sealed envelopes. The outside of each envelope was marked only with the name of the hospital, whether the participant had a malignant condition, and a participant number.
Blinding (performance bias and detection bias) All outcomes	Low risk	Double (physician‐patient): An adjudication committee consisting of three study investigators evaluated all clinical events in a blinded fashion, and end points were determined by consensus.
Incomplete outcome data (attrition bias) All outcomes	Low risk	All participants were followed for three months. Losses to follow‐up: none.
Selective reporting (reporting bias)	Low risk	All prespecified outcomes were reported.
Other bias	Low risk	Probably free of other bias sources.