Use of an Algorithm for Administering Subcutaneous Heparin in the Treatment of Deep Venous Thrombosis

Methods

Patients

Eligible patients were consenting symptomatic outpatients who had a first episode of proximal venous thrombosis, as assessed by compression ultrasonography. Exclusion criteria were contraindications to anticoagulation, ongoing full-dose anticoagulant therapy, pregnancy, and poor life expectancy. The institutional ethical board approved the investigation.

Intervention

Patients were given an intravenous bolus of sodium heparin (Liquemin, Roche, Basel, Switzerland) and a subcutaneous injection of calcium heparin (Calciparina, Italfarmaco, Milan, Italy) in doses adjusted according to body weight (Table 1).

The first activated partial thromboplastin time (aPT) was done after 6 hours, and subsequent dose adjustments during the first 48 hours were scheduled twice daily according to the algorithm shown in Table 1. The aPT was performed in the mid-interval. Adjustments were arranged in “steps” to be run up or down according to aPT, regardless of body weight. The target aPT range (50 to 90 seconds) was calibrated to correspond to a heparin plasma level (as expressed by antifactor Xa [aXa] activity) of 0.35 to 0.70 U/mL.

To avoid unnecessary overanticoagulation [7, 8], an aXa assay was scheduled if the aPT was subtherapeutic 6 hours after the administration of 25 000 U of heparin. If the aXa level exceeded 0.35 U/mL, the heparin dose was not modified. After the first 48 hours, heparin administration was managed on the basis of daily aPT determinations.

Sodium warfarin therapy was begun on the first or second day and was continued for 12 weeks, with the dose adjusted to achieve an international normalized ratio of 2.0 to 3.0. Heparin therapy was discontinued if the international normalized ratio in patients who had received the study drug for at least 5 days was greater than 2.0 for 2 consecutive days.

Clinical Evaluation

Patients were examined daily for signs and symptoms of recurrent thromboembolism, bleeding, or the occurrence of heparin-induced thrombocytopenia (decrease in platelet count to <10⁹ cells/L or to >50% below the baseline count).

Follow-up visits were scheduled after 1 and 3 months. Patients were asked to return to the study center if clinical manifestations of recurrent thromboembolism occurred. Recurrent venous thromboembolism was diagnosed according to standard methods [9, 10]. Bleeding was defined as major if it was intracranial or retroperitoneal or was associated with a decrease in the hemoglobin level of at least 2.0 g/dL. Autopsy was intended for all decedents in whom pulmonary embolism could not be excluded.

Study Outcomes and Analysis

We determined the proportion of patients who achieved the therapeutic threshold (aPT ≥ 50 seconds) within 24 and 48 hours and the time elapsed from initiation of heparin therapy until achievement of the threshold aPT. We calculated the percentage of patients with supratherapeutic aPT that persisted for more than 12 hours. We also evaluated the rate of recurrent thromboembolism during heparin treatment and follow-up and the rate of major bleeding occurring during heparin treatment and during the following 48 hours.

Descriptive statistics were calculated according to standard methods; 95% CIs were estimated by using the exact method. The time from initiation of heparin therapy until achievement of the aPT threshold was calculated according to the Kaplan-Meier method.

Results

Patients

Twenty-seven of 97 eligible patients were excluded because of ongoing full-dose anticoagulant therapy (15 patients), contraindications to heparin (4 patients), refusal to participate (4 patients), poor life expectancy (3 patients), and pregnancy (1 patient). Thus, 70 patients were enrolled (25 men; median age, 65 years). Three patients weighed less than 50 kg, 21 weighed 50 to 70 kg, and 46 weighed more than 70 kg. Risk factors for thrombosis were identifiable in 51 patients: cancer (20 patients), prolonged immobilization (14 patients), recent trauma (9 patients), thrombophilia (5 patients), and estrogen therapy (3 patients).

Biological Outcomes

Eighty-seven percent of patients (61 of 70) achieved the aPT threshold within 24 hours, and 99% (69 of 70) achieved the threshold in 48 hours. Figure 1 shows the Kaplan-Meier curve for the heparin therapeutic threshold. Seven patients (10.0% [95% CI, 4.1% to 19.5%]) had supratherapeutic aPT that persisted for more than 12 hours. In 2 of the 4 patients who had a subtherapeutic aPT despite the administration of 25 000 U of heparin, the aXa assay showed a plasma heparin level greater than 0.35 U/mL.

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Figure 1. The second row of numbers along the x-axis shows the number of patients with an activated partial thromboplastin time less than 50 seconds. Cumulative proportion of patients reaching the therapeutic threshold (activated partial thromboplastin time ≥ 50 seconds) within 48 hours of the initiation of heparin therapy.

The mean (±SD) heparin doses administered were 39 700 ± 5300 U during the first day and 30 500 ± 10 800 U during the second day. No patient required less than 10 000 U or more than 30 000 U twice daily to prolong the aPT (or aXa) level. The median duration of heparin treatment was 6.5 days (range, 5 to 12 days).

Clinical Outcomes

During the initial period of heparin treatment and follow-up, thromboembolism recurred in three patients (4.3% [CI, 0.9% to 12%]). One of the three (age, 93 years) died of autopsy-proven pulmonary embolism within 5 days after heparin treatment began. Both the aPT and the international normalized ratio were in the therapeutic range. The two other patients had contralateral thrombosis (one after 8 weeks and one after 10 weeks), as assessed by compression ultrasonography. In all three patients, the aPT threshold had been achieved within 24 hours of initiation of heparin therapy.

No major bleeding episodes or heparin-induced thrombocytopenia occurred during heparin treatment (0% [CI, 0.0% to 5.0%]), and no patient was lost to follow-up. Five patients died during the follow-up period: Four died of cancer (one after 65 days, one after 72 days, one after 80 days, and one after 85 days), and one died of pleural hemorrhage that occurred 1 month after heparin therapy began.

Discussion

Our results suggest that the use of a weight-based algorithm for the subcutaneous injection of unfractionated heparin allows the rapid achievement of correct anticoagulation in almost all patients with deep venous thrombosis while avoiding prolonged periods of excessive anticoagulation. The therapeutic threshold was achieved within 24 hours in 87% of patients and within 48 hours in 99%. In only 10% of patients did supratherapeutic aPT persist for more than 12 hours. No patient had major bleeding or heparin-induced thrombocytopenia, and thromboembolism recurred in only three patients (4.3%). These results are consistent with those reported in recent studies done with either intravenous unfractionated heparin according to standardized guidelines or fixed-dose low-molecular-weight heparins [3-5, 11-13].

An intravenous loading dose was chosen because of the poor bioavailability of subcutaneous heparin [8], and weight-adjusted heparin doses were chosen because body weight is the single best predictor of individual heparin requirements [5, 14, 15]. The combination of an initial intravenous bolus and weight-adjusted heparin doses probably explains the high biological success rates achieved with our protocol, rates that are similar to those recently reported with the use of a weight-based intravenous heparin nomogram [5, 16].

Of interest, the mean daily amount of heparin required to prolong the aPT during the first 24 hours (almost 40 000 U) was greater than the dose (30 000 to 35 000 U) usually required to attain proper anticoagulation with intravenous administration [1, 3-5, 8]. The implication of this finding is that the common practice of injecting as much subcutaneous heparin as is commonly administered intravenously for the initial treatment of patients with thrombotic disorders is likely to produce insufficient anticoagulation, thereby increasing the likelihood of recurrent thromboembolism [17-19].

A few considerations deserve careful analysis. Because of a relatively small sample size and the lack of a control group, our results should be validated in other cohorts of patients to ensure external validity. In addition, because we confined our investigation to symptomatic outpatients with a first episode of venous thrombosis, widespread generalization of this therapeutic regimen requires proper evaluation in patients who develop thrombosis during hospitalization and in those presenting with pulmonary embolism or recurrent thromboembolism.

In conclusion, the use of a weight-based algorithm for the subcutaneous administration of unfractionated heparin may greatly simplify the initial treatment of venous thromboembolic disorders. It enables the early mobilization of patients with venous thrombosis and allows the early discharge of suitable patients. The relatively low cost of unfractionated heparin makes this approach attractive in comparison with the use of low-molecular-weight heparins. This strategy has major implications for the short-term treatment of a broad spectrum of conditions for which heparin is indicated, such as unstable angina and myocardial infarction.