The end of the heparin pump?

Antithrombotic therapy with intravenous unfractionated heparin has been the mainstay of early treatment of patients with venous thromboembolic disease and unstable angina. On a typical medical ward several patients will be attached to syringe drivers containing heparin. Management of these patients is time consuming: heparin infusions have to be made up daily, intravenous cannulas resited, blood samples analysed for monitoring of coagulation control, and doses adjusted on the basis of these results. The potential for dosing errors is high: even in trials with criteria for dose monitoring, over 60% of patients are overanticoagulated or underanticoagulated 24 hours after the start of heparin therapy.¹ Newer low molecular weight heparins are much easier to administer, but do they have other advantages over unfractionated heparin?

The benefit of heparin treatment to patients with venous thromboembolic disease and unstable angina has been shown in several trials. In the only placebo controlled trial of heparin in pulmonary embolism the mortality rate was so much lower in treated patients that the trial was stopped.² In unstable angina several randomised trials have indicated a trend towards reduced risk of death and non-fatal myocardial infarction in patients treated with aspirin and heparin compared with aspirin alone. A meta-analysis of these trials indicated a relative risk reduction of 33% with combined aspirin and heparin in patients whose absolute risk of death or myocardial infarction is 14% in the first three months.³

Conventional unfractionated heparin refers to a family of mucopolysaccharides of varying chain length and composition which are not separated into their component parts. Heparin forms a high affinity complex with antithrombin III, which inhibits thrombin and activated factors X, IX, and XI, depending on the chain length of the heparin molecule. Unfractionated heparin has an antifactor Xa:antithrombin ratio of 1:1. Over the past decade a family of low molecular weight heparins has been developed, based on the principle that inhibiting the earlier amplification stages of the coagulation cascade will provide more effective anticoagulation. These molecules have an antifactor Xa:antithrombin ratio of 2:1 to 4:1. Low molecular weight heparins have several other theoretical therapeutic advantages: higher bioavailability after subcutaneous injection, longer half life, and a lower propensity to induce thrombocytopenia. Haemorrhagic complications may also be reduced because, in contrast with unfractionated heparin, low molecular weight heparins have lower affinity for von Willebrand factor, have a weaker inhibitory effect on platelet function, and are less prone to increasing vascular permeability. Their high bioavailability and antifactor Xa activity confer a predictable dose response, which allows administration on a per kilogram basis without the need for routine anticoagulation monitoring. Indeed, most preparations can be administered by weight adjusted twice daily injection.

But are these preparations as effective as unfractionated intravenous heparin? Trial evidence is accumulating that they are. In patients with unstable angina or non-Q wave myocardial infarction, the FRIC and ESSENCE studies showed, respectively, that dalteparin and enoxaparin are at least as effective as unfractionated heparin at preventing death, myocardial infarction, and recurrent angina.⁴,⁵ Neither study used anticoagulant monitoring in patients receiving the low molecular weight preparation, and there was no difference between groups in the incidence of major and minor haemorrhagic complications. However, no trial evidence currently exists to support the use of low molecular weight heparins as an adjunct to thrombolysis.

Low molecular weight heparins are effective in treating venous thromboembolic disease. In a study of 432 patients with proximal deep venous thrombosis intermittent subcutaneous logiparin substantially reduced the incidence of death and major haemorrhage compared with intravenous unfractionated heparin.⁶ Similar results are seen with fraxiparine; enoxaparin and dalteparin are at least as safe and effective as unfractionated heparin.⁷ Furthermore, patients can be taught to administer low molecular weight heparins at home, and there are clear economic advantages in reducing the time in hospital.⁸,⁹ Finally, subcutaneous tinzaparin has recently been shown to be as safe and effective as unfractionated heparin in managing the early phase of acute pulmonary embolism in hospital.¹⁰

The practical advantages of low molecular weight heparins are less compelling for thromboembolism prophylaxis, since in this setting unfractionated heparin is also administered subcutaneously and anticoagulant monitoring is not required. However, a recent meta-analysis of 22 trials of low molecular weight heparins for prophylaxis against venous thromboembolism in orthopaedic surgery showed that they are better and safer than unfractionated heparin and warfarin.¹¹ In some high risk settings, for example after major trauma, low molecular weight heparins may be better than unfractionated heparin.¹²

Although low molecular weight heparins are more expensive than unfractionated heparin, cost savings are likely through savings in consumables and staff time. Their economic impact must also be assessed in terms of the effect on complications of unstable angina and the cost of subsequent procedures: a cost benefit analysis from the United Kingdom subgroup in the ESSENCE study estimated savings of over £2300 per 100 patients treated with enoxaprin.¹³

Caution is clearly needed when considering practical procedures such as arterial sampling or central venous line insertion in patients treated with low molecular weight heparin—no infusion pump is present as a reminder that the patient is receiving anticoagulant therapy. Furthermore, guidelines need to be established for safe timing of arterial sheath removal after coronary angiography and intervention in patients treated with low molecular weight heparin. Also, important differences exist in the properties of the different preparations: they are not interchangeable, and regimens proved in trials should be used for those specific clinical applications. Moreover, in certain circumstances it is sensible to use intravenous heparin because it can be discontinued abruptly—for example, in patients with mechanical valves undergoing surgery or in patients at high risk of bleeding. Nevertheless, and with these caveats, it is time to abandon the heparin pump for the prophylaxis and treatment of venous thromboembolic disease and for managing patients with unstable angina.