Avoiding adverse events with dabigatran by careful selection of eligible patients

Dabigatran is the first new oral anticoagulant for the prevention of embolism in patients with non-valvular atrial fibrillation (AF) that has been recently approved in Australia (Therapeutic Goods Administration, 1 April 2011) and New Zealand (PHARMAC, 1 July 2011), based on the results of the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy) study.1 It is an attractive alternative to warfarin because it has a rapid onset of action (2–3 hours), a wide therapeutic range, predictable pharmacokinetics (half-life of 12–17 hours), limited drug interactions and no food interactions. Unlike warfarin, these features allow fixed doses and no requirement for routine laboratory monitoring.1

The RE-LY study allocated patients with AF and at similar risk of stroke and bleeding to therapy with warfarin or one of two doses of dabigatran (150 mg twice daily or 110 mg twice daily). The most consistent and important clinical benefit of dabigatran found in the RE-LY study was the significant reduction in the incidence of intracranial haemorrhage when compared with warfarin. Other benefits were dose dependent — overall, the risk of embolic stroke was lower in patients taking 150 mg twice daily, while those taking 110 mg twice daily experienced less bleeding.1 For every 200 patients treated with 150 mg of dabigatran twice daily instead of warfarin, two intracerebral events were prevented (one ischaemic and one haemorrhagic stroke) at the cost of one extra major gastrointestinal haemorrhage.1 There was a trend towards a higher risk of major bleeding in patients aged over 75 years on the 150 mg dose.2

However, translating the RE-LY trial evidence into routine clinical practice and choosing the most suitable patients in whom to use dabigatran requires a modification of the usual clinical judgement about assessing anticoagulant bleeding risk. If major bleeding does occur with dabigatran, which happened in around 3% of patients per year in the RE-LY trial,1 unlike with warfarin, there is no accepted reversal agent or standardised routine laboratory test to guide decisions for clinical management.3,4

In contrast to warfarin, dabigatran is eliminated via the kidney, and impaired renal function results in drug accumulation.5 In the community, more than half of patients who develop AF are aged over 75 years,6 and older people are the most vulnerable to dabigatran accumulation because of an age-related decline in creatinine clearance (CrCl).5

The RE-LY trial was not designed or powered to assess the safety profile in older patients. Cases have recently been reported of older patients with poor renal function taking dabigatran who have had major life-threatening haemorrhage, with one event resulting in death.7,8

Safe dabigatran dosing depends on an assessment of CrCl. It should be noted that any simple method to estimate CrCl is neither reliable nor validated in older patients.9 One reason is that, with increasing age, there is a loss of muscle mass so that the serum creatinine will not increase proportionally to the decrease in renal function.9 Of the several formulas used for calculating the CrCl, the Cockcroft–Gault formula, which was used in the RE-LY trial, is the most appropriate one to use for dabigatran prescribing.9 A calculator using this formula is readily available online or as a smartphone application. It is derived from serum creatinine level, age, weight (ideal rather than total bodyweight) and sex.9 The widely available epidemiological tool for estimated CrCl (Modification of Diet in Renal Disease), which pathology laboratories routinely present when they report serum creatinine levels, is not recommended for dabigatran dosing.9 It overestimates CrCl because most older patients have a body surface area below the adjusted ideal value of 1.73 m2.

Patients with severe renal impairment (CrCl, < 30 mL/min) were excluded from the RE-LY study and should not be taking dabigatran.1 Patients with moderate impairment of renal function (CrCl, 30–50 mL/min) have an exposure to dabigatran that is about 50% higher for a given dose than for patients with normal renal function (CrCl, > 80mL/min).5 Care is required in patients aged over 75 years with this degree of moderate renal impairment, particularly those with low bodyweight, who may be taking a medication that significantly increases their dabigatran level (amiodarone, quinine and verapamil) or increases the risk of gastrointestinal haemorrhage (aspirin, clopidogrel or a long-acting non-steroidal anti-inflammatory agent).10 Patients whose therapy is changed from warfarin to dabigatran should not start taking dabigatran until the international normalised ratio (INR) is less than 2 because of dabigatran’s rapid onset of action.10 No data are available for the use of dabigatran in patients with AF and significant heart valve disorder (prosthetic or haemodynamically relevant), a high bleeding risk or recent surgery.

The availability of dabigatran means that for the first time in over 50 years, there is an alternative oral anticoagulant to warfarin, with much promise as a more convenient and effective drug to reduce the rate of stroke in patients with AF. We urge caution to avoid overenthusiastic use of dabigatran because there are limitations of extrapolating clinical trial data to the wider patient population, and limited postmarketing data. Particular care is required in older patients and those with renal impairment. Further studies are urgently required to provide data for appropriate laboratory testing and immediate anticoagulant reversal in patients who haemorrhage, who require surgery or who overdose with dabigatran.