HeparinThis drug, an acidic glycosaminoglycan (sulfated mucopolysaccharide), is a highly effective antithrombotic agent. Clinical preparations vary over a molecular weight range of 5,000-25,000 daltons, but the native molecule is probably much larger. The drug acts by enhancing the effect of a naturally occurring inhibitor, antithrombin III, so that the inhibitor more efficiently combines with and inactivates a number of serine proteinases, notably thrombin (factor Ha), factor IXa, and factor Xa. Heparin works only when given parenterally and only in the presence of antithrombin III. Neither hepatic nor renal disease seems to interfere notably with the clearance of the drug. Heparin is currently obtained from either the lung or gut mucosa of animals and is available as either a sodium or calcium salt. There is no clear evidence to favor one preparation over another, although the calcium salt may yield slightly lower blood levels than the sodium salt for a given subcutaneous dose.

The unit of heparin is measured in animals using a biologic assay. Unit age may vary by as much as 50% on a weight basis, and consequently heparin is properly prescribed by units, not weight.

Heparin has a proved efficacy in the treatment of pulmonary embolism. The trial by Barritt and Jordan, which satisfies the criteria for a level I study, was completed before the advent of perfusion lung scanning and pulmonary angiography and has several flaws, but the much higher mortality rate (25%) in the placebo-treated patients, combined with the demonstration of autopsy-verified pulmonary embolism as the cause of death, is persuasive. Subsequent studies have attested to the reduced mortality rate when heparin was used to treat venous thromboembolic disease and to the high mortality rate when patients with pulmonary embolism did not receive anticoagulant therapy. Proximal deep venous thrombosis nearly always precedes pulmonary embolism. Although there is no placebo-controlled trial for heparin in the treatment of isolated deep venous thrombosis, this condition is usually treated in a fashion similar to that of pulmonary embolism. In contrast, it is not clear that isolated calf vein thrombosis requires anticoagulant therapy. Superficial thrombophlebitis in the absence of deep venous thrombosis is generally treated effectively with nonsteroidal antiinflammatory agents.

How Intensely to Administer Heparin

In the past 25 years a great deal of effort has been spent to maximize heparin’s safety and efficacy which was ordered via My Canadian Pharmacy (to find more information about My Canadian Pharmacy click here). Blood levels during administration of heparin are not easily predictable, and specific plasma Blood levelsassays for the drug have not been widely applied. The lack of a clear relationship between heparin dose and bleeding probably results from heparin’s variable interference with platelet function in patients. Under most circumstances, a 5-20% rate of hemorrhagic complications or an unexplained fall in hematocrit can be expected during heparin therapy. Since no hemostatic studies address the independent effect on bleeding of dose and response measured by in vitro coagulation tests, it is impossible to separate the influence of these two variables (dose and response) on bleeding risk. There is, however, some support from published studies for the commonly held clinical view that the risk of bleeding increases with increasing doses of heparin and with the hemostatic response reflected by in vitro coagulation tests, which are used to monitor heparin. O’Sullivan described the hemorrhagic risk of heparin therapy in 100 consecutive patients treated with continuous IV heparin, which was adjusted according to the results of the whole blood clotting time. Four patients had major hemorrhagic episodes and in three of these patients the results of whole blood clotting time was prolonged considerably above the upper limit of the targeted therapeutic range (three times control). The level of the anticoagulant effect, however, was not described in patients who did not bleed. Other studies have provided stronger evidence for a relationship between hemorrhage and the intensity of the anticoagulant effect. In the Urokinase Pulmonary Embolism Trial, bleeding occurred in 20% of the 30 patients whose blood clotting time was greater than 60 minutes but in only 5 of the 19 patients whose blood clotting time was less than 60 minutes (relative risk 4). Wilson and Lampman described 18 nonsurgical patients receiving heparin monitored by the whole blood clotting time. Ten of 18 patients (56%) who received excessive heparin (defined by a greatly prolonged whole blood clotting time) bled, whereas bleeding occurred in only 16% of patients who did not receive excessive heparin (relative risk 3.5).

In summary, although none of these studies was designed to compare the effects on bleeding on either different doses of heparin or different levels of hemostatic reponse (level V studies), there is a suggestion that bleeding is more likely to occur when an in vitro test of coagulation is excessively prolonged.

The Relationship Between the Risk of Bleeding and the Method of Administering Heparin

Four randomized studies have compared the bleeding rate when heparin was administered by intermittent injection and by continuous infusion. Two of the studies (level I) reported that continuous heparin infusion was associated with a lower frequency of bleeding, 1% and 0% compared with 9% and 33%, and the third reported the trend toward reduced bleeding with continuous heparin (level II study) 5% compared with 10%. In the fourth study, there was a trend in the other direction (level II study). Patients receiving continuous infusion heparin available on My Canadian Pharmacy, however, also received a lower dose of heparin. Therefore, it is uncertain whether the difference noted in the rates of bleeding between patients randomized into continuous IV infusion and intermittent IV injection is related to the method of heparin administration or to the difference in the total dose of heparin given to the two groups.

Only one randomized trial evaluated the benefit of monitoring heparin therapy. In this study, patients received intermittent heparin injections, either with or without laboratory control using the APTT. There was no significant difference detected in the frequency of bleeding between the two groups (8% vs 10%), suggesting that when heparin is administered by intermittent injection, monitoring the response may not reduce the risk of bleeding.

There is increasing evidence that a minimum level of heparin anticoagulation must be maintained to achieve an effective antithrombotic state and that inadequate anticoagulant therapy results in anticoagulant therapyunacceptably higher rates of recurrent thromboembolism. Animal experiments support the concept that a minimum level of heparin of approximately 0.4 units/ml is necessary to interrupt an ongoing thrombotic process. The threshold level for adequate anticoagulant effect cannot be precisely predicted in individual patients. In practice an effective activation of the antithrombin system is usually inferred by prolongation of the activated partial thromboplastin time to at least 15-25 seconds beyond the baseline value. Ifa baseline is not available, the middle of the laboratory normal range may be used as the control. If the baseline value is shorter than the normal range, a prolongation of 2.0 times the baseline should be sought.

The major problem with constant IV therapy is the equipment and skilled care necessary to deliver it properly. More trials are needed comparing constant IV infusion to a similar dose administered subcutaneously every 8-12 hours.

If a minimum level of anticoagulation is required to prevent thrombotic extension, it follows that anticoagulant effect (antithrombotic state) should be monitored with an in vitro clotting test. Heparin requirements are usually greatest in the first few days after the acute thromboembolic event, and consequently therapy should be monitored most closely then. After the first few days, the monitoring test can usually be obtained daily. It is wise to check a platelet count every 3-4 days when administering heparin, since the drug can induce thrombocytopenia.’ This problem is uncommon. Heparin use commonly leads to mild reductions in the levels of circulating antithrombin III, and the drug on rare occasions has been reported to induce disseminated thrombosis. Long-term, high-dose heparin administration can lead to severe osteopenia.

If full-dose heparin is contraindicated for a patient with acute venous thromboembolism, as it would be for a patient with an actively bleeding CNS lesion, the only acceptable alternative is vena caval interruption or the insertion of a vena caval filter. Substitution of low-dose, prophylactic heparin for full-dose heparin in this setting is inappropriate.

How Long to Anticoagulate uAth Heparin

Heparin can be conveniently administered IV for 7-10 days while the patient is recovering in hospital. Unfortunately, such a short period of anticoagulation does not seem completely to interrupt the thrombotic process in many patients with acute venous thromboembolic disease. Specifically, 10-14 days of conventional IV heparin followed by low-dose subcutaneous heparin did not prevent recurrent venous thromboembolism. Consequently, many clinicians follow the initial course of heparin with coumarin derivatives for long-term oral anticoagulation. The alternative is to give heparin in a larger subcutaneous dose that maintains the anticoagulated state.