Intensity of Heparin Anticoagulation as an Independent Predictor of 14-Day Recurrence after Deep Vein Thrombosis or Pulmonary Embolism: A Population-Based Cohort Study.

Background: Most trials of standard heparin and warfarin therapy used the 3- to 6-month cumulative incidence of venous thromboembolism (VTE) recurrence as the primary efficacy outcome. Consequently, the effect of heparin anticoagulation intensity on short-term VTE recurrence after controlling for other predictors of recurrence (e.g., active cancer, neurological disease with extremity paresis) is uncertain.

Objectives: To test standard heparin anticoagulation intensity, using activated partial prothrombin time (APTT) data, as an independent predictor of 14-day VTE recurrence.

Measurements: Using the resources of the Rochester Epidemiology Project, we identified all Olmsted County, MN residents with an incident deep vein thrombosis or pulmonary embolism over the 14-year period, 1984–1997 (n=1165). We followed each case (conditional on surviving one day) forward in time through their complete medical records in the community for first VTE recurrence. We collected date of incident VTE onset, start and stop dates of heparin and warfarin, and date, time and result of all APTT and platelet count values. Using these and other measures of standard heparin therapy as time-dependent variables, we tested the intensity of heparin anticoagulation as an independent predictor of 14-day VTE recurrence while controlling for other baseline characteristics using Cox proportional hazards modeling.

Results: Of the 1165 patients, 1026 (88%) and 989 (85%) received heparin and warfarin, respectively, and 254 (22%) developed recurrent VTE over 5461 person-years of follow-up; 23 recurred within 14 days. In the multivariate analysis, the independent predictors of 14-day recurrence included female gender (HR=3.06, 95%CI: 1.05, 8.91; p=0.04) and neurologic disease with extremity paresis (HR=6.01, 95%CI: 1.93, 18.66; p<0.01); the hazard of recurrence was marginally increased for active cancer (HR=2.21, p=0.13). Warfarin therapy (HR=0.44, p=0.11) and a therapeutic APTT within the first 24 hours of therapy (HR=0.41, p=0.08) were marginally protective, but age, body mass index, time interval between VTE onset and start of heparin, and other measures of heparin anticoagulation intensity (e.g., proportion of time in therapeutic APTT range, etc) were not predictors of recurrence. Three patients developed new and persistent thrombocytopenia beginning 2, 4 and 5 days after starting heparin, respectively and prior to VTE recurrence.

Conclusions: VTE recurrence is uncommon within 14 days after starting heparin therapy. Female gender and neurologic disease with extremity paresis are independent predictors of 14-day recurrence, and active cancer may be an additional predictor. Warfarin therapy and a therapeutic APTT within the first 24 hours may predict a reduced recurrence risk. However, other measures of heparin anticoagulation intensity were non-predictive. Heparin-induced thrombocytopenia may partially account for early VTE recurrence.