LEVINE (1)

Comparing activated thromboplastin time with heparin assay in patients requiring large doses of heparin (1994)

Condition

Treatment of patients with acute VTE who require large daily doses of intravenous heparin

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Objective

To compare the monitoring of heparin therapy either by anti-factor Xa levels or by the aPTT in patients requiring 35,000 IU or more of intravenous heparin for the treatment of acute VTE

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Trial design

Randomized, controlled study with parallel groups
Active treatment: All patients (n=131) received an initial i.v. heparin bolus of 5000 IU followed by an infusion at a starting dose of 33,600 IU per 24 h (20,000 IU in 500 ml of ⅔ : ⅓ dextrose-saline infusion at 35 ml/h). The aPTT was measured 6 hours after the initiation of therapy, and the dosage was adjusted according to a standard nomogram. The following day, patients who required the equivalent of 35,000 IU of heparin or more were eligible for randomization to one of the 2 methods of monitoring the heparin therapy

  • Monitoring by heparin level: Heparin dosage was adjusted to maintain the anti-factor Xa level within the targeted range of 0.35–0.67 IU/ml (n=65)
  • Monitoring by aPTT: Heparin dosage was adjusted to maintain the targeted aPTT range of 60–85 s (n=66)

Both ranges were equivalent to a heparin level of 0.2–0.4 IU/ml by protamine titration

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Endpoints

Primary endpoints: recurrent venous thrombosis, PE, and bleeding
Secondary endpoints: heparin dosage, aPTT and anti-factor Xa levels

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Trial participants

131 patients with acute DVT, PE, or axillary vein thrombosis who required 35,000 IU or more of intravenous heparin by continuous infusion during the previous 24 hours

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Results

Primary outcome: 3 of 65 patients (4.6%) in the anti-factor Xa group experienced recurrent VTE compared with 4 of 66 (6.1%) patients in the aPTT group. Bleeding events occurred in one patient (1.5%) in the anti-factor Xa group and in 4 patients (6.1%) in the aPTT group

Secondary endpoints: During the first 4 days, the patients in the aPTT group required a significantly greater amount of heparin (p<0.001). The daily mean aPTT was subtherapeutic in patients in the anti-factor Xa group, and it was within the therapeutic range in the aPTT group. The daily mean anti-factor Xa levels for both groups were within the therapeutic range

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Summary

The incidence of recurrent VTE was similar in both treatment groups, and there was a non-significant trend for lower bleeding in patients monitored by anti-factor Xa levels. These findings indicate that in patients who are resistant by the aPTT assay, dosage escalation can be avoided without compromising efficacy, by performing a heparin assay and not increasing the dose if the heparin level is in the therapeutic range

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Reference

Levine MN, Hirsh J, Gent M, Turpie AG, Cruickshank M, Weitz J, Anderson D, Johnson M. A randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin. Arch Intern Med 1994;154:49-56

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Corresponding author

Mark Levine, MD, Hamilton Regional Cancer Centre, 699 Concession St., Hamilton, ON L8V 5C2, Canada

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