Dabigatran etexilate

Some of the views expressed in the following notes on newly approved products should be regarded as preliminary, as there may have been limited published data at the time of publication, and little experience in Australia of their safety or efficacy. However, the Editorial Executive Committee believes that comments made in good faith at an early stage may still be of value. Before new drugs are prescribed, the Committee believes it is important that more detailed information is obtained from the manufacturer's approved product information, a drug information centre or some other appropriate source.

Pradaxa (Boehringer Ingelheim)
75 mg and 110 mg capsules
Approved indication: prevention of postoperative venous thrombosis
Australian Medicines Handbook section 7.1

Patients who have had major surgery on their legs are at risk of venous thrombosis. This risk can be reduced by anticoagulation with a heparin or an alternative such as fondaparinux. A disadvantage of these drugs is that they have to be given by injection, so patients may not continue them after leaving hospital. An oral anticoagulant, without the disadvantages of warfarin, might improve the effectiveness of prophylaxis.

Dabigatran is a direct inhibitor of thrombin which can be taken orally as a prodrug (dabigatran etexilate). By inhibiting thrombin, it blocks the conversion of fibrinogen to fibrin and thus reduces clot formation. It is given 1-4 hours after surgery.

In healthy people dabigatran etexilate is rapidly absorbed and converted to dabigatran. Absorption is slower initially in postoperative patients, but subsequently peak plasma concentrations of dabigatran are reached two hours after a dose. The half-life, 12 - 14 hours, is also slightly longer after surgery. Treatment begins with half the ongoing dose. Most of the dose is excreted as dabigatran in the urine. People with reduced renal function, such as some elderly patients, may require a lower dose. However if the creatinine clearance is under 30 mL/min, dabigatran is contraindicated.

A double-blind trial has compared dabigatran etexilate (220 mg and 150 mg daily) with a daily dose of subcutaneous enoxaparin 40 mg in 3494 people having total hip replacements. Treatment continued for 28-35 days until the patients had venography. However, many patients did not have venography so efficacy could only be assessed in 2651 patients. Death or venous thromboembolism occurred in 8.6% of the patients taking dabigatran 150 mg, 6% of those taking 220 mg and in 6.7% of the patients injected with enoxaparin.¹

The same drugs and doses were used in a study of 2076 patients having total knee replacements. Treatment continued for 6-10 days. As some patients did not have venography, efficacy was assessed in 1541 patients. Death or venous thromboembolism occurred in 40.5% of the patients taking dabigatran 150 mg, 36.4% of those taking 220 mg and 37.7% of the enoxaparin group.²

Bleeding is a major concern when anticoagulants are used following surgery, and there is no antidote for dabigatran. After hip replacement, significant bleeding occurred in 1.3% of the dabigatran 150 mg group and 2.0% of the 220 mg group. This was fatal for one patient in each group. In the enoxaparin group 1.6% of patients had significant bleeding, but there were no fatalities.¹ After knee replacement the incidence of major bleeding was 1.5% in the dabigatran 220 mg group and 1.3% in the 150 mg and enoxaparin groups.² To reduce the risk of a haematoma forming, dabigatran should be given for at least two hours following the removal of a spinal or epidural catheter.

Common adverse effects include nausea, vomiting, fever and constipation, but they occur irrespective of the treatment used. Routine monitoring is not required, but liver function should be checked before treatment as liver disease is a contraindication to dabigatran. Drugs which act on the P-glycoprotein transporter may alter the plasma concentration of dabigatran. These drugs include amiodarone, verapamil, clarithromycin and St John's wort. Quinidine is contraindicated. Anticoagulants and antiplatelet drugs such as clopidogrel are not recommended while the patient is taking dabigatran. Doses of aspirin above 75 mg daily increase the risk of bleeding. Non-steroidal anti-inflammatory drugs (NSAIDs) can be used for short-term analgesia, but there may be an increased risk of bleeding particularly if the NSAID has a long half-life.

The main studies of dabigatran have shown that it has similar efficacy to enoxaparin, however an American study found inferior efficacy. In the USA prophylaxis can be given as enoxaparin 30 mg twice daily. The study of 1896 patients having knee replacement found venous thromboembolism in 31-34% of the patients taking dabigatran but in only 25% of those given enoxaparin.³

The development of the first direct thrombin inhibitor, ximelagatran, was halted because of concerns about adverse effects on the liver. Hepatotoxicity has not yet emerged as a significant problem with the relatively short-term use of dabigatran. If its safety and efficacy are confirmed in more widespread use, oral dabigatran may be a cost-effective alternative to subcutaneous low molecular weight heparins.

manufacturer declined to supply data

The Transparency Score () is explained in New drugs: transparency', Vol 37 No 1, Aust Prescr 2014;37:27.

Note on references

At the time the comment was prepared, information about this drug was available on the web site of the Food and Drug Administration in the USA (www.fda.gov).