This quiz feedback provides an opportunity to revisit the BPJ 38 (September, 2011) article "The use of dabigatran in general practice: a cautious approach is recommended"

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The majority of respondents correctly answered that renal excretion is the dominant elimination pathway for dabigatran. Up to 80% of circulating unchanged dabigatran and small amounts of dabigatran glucuronides are excreted via the kidneys. It is for this reason that creatinine clearance should be checked in all patients before treatment with dabigatran. Only 20% of dabigatran is eliminated via the liver.

Dabigatran is a relatively new medicine, so knowledge on its medicine and dietary interactions is still in its infancy. To date few significant interactions have been reported.

Agents that may increase dabigatran plasma concentration include; amiodarone, verapamil, digoxin, ketoconazole, clarithromycin

Agents that may decrease dabigatran plasma concentration include;, rifampicin, carbamazepine, St John’s Wort and possibly antacids and some PPIs.

Dabigatran is contraindicated in patients receiving systemic ketoconazole. Some experts advise that patients take dabigatran at least two hours before antacids, amiodarone and verapamil or use an alternative medicine.

The majority of respondents correctly stated that dyspepsia is a commonly reported adverse effect with dabigatran. In the RE-LY trial, 11.8% of people taking dabigatran 110 mg, twice daily, and 11.3% of patients taking dabigatran 150 mg, twice daily, experienced dyspepsia compared with 5.8% in patients taking warfarin.

Adverse effects such as blurred vision, dry mouth and drowsiness are common with anticholinergic medicines but are not a common adverse effect of dabigatran.

The use of dabigatran with systemic ketoconazole is contraindicated because clinical trials have shown that this combination increases the maximum plasma concentration of dabigatran by approximately 150%.

Creatinine clearance should be checked in all patients before treatment with dabigatran because patients with severe renal impairment (creatinine clearance < 30 mL/min) should not be prescribed dabigatran. Caution is also advised in patients with creatinine clearance 30 - 50 mL/min.

Although hepatotoxicity has not been demonstrated with dabigatran, caution is advised when used in patients with severe liver disease. Patients with active liver disease or persistently raised liver enzymes (> two times upper limit of normal) were excluded from clinical trials so no treatment experience is available in this subpopulation of patients and therefore use of dabigatran is not recommended in this population.

Antiplatelet medicines (e.g. aspirin, clopidogrel) and NSAIDs (both conventional and Cox-2) should be used with caution in people taking dabigatran because the risk of bleeding can be increased.

The current recommended doses of dabigatran are:

For the prevention of stroke in people with non-valvular atrial fibrillation:

• 150 mg, twice daily, for patients with a creatinine clearance of >30mL/min
• 110 mg, twice daily, for patients aged ≥ 80 years (because of the likelihood of an age-related decline in renal function)

For VTE prophylaxis following major orthopaedic surgery (usually 10-35 days depending on the surgery):

• 220 mg (2 × 110 mg tablets), once daily, for patients with creatinine clearance > 50 mL/min
• 150 mg ( 2 × 75 mg tablets), once daily, for patients with creatinine clearance 30 – 50 mL/min

As current recommendations stand, patients with severe renal impairment (i.e. creatinine clearance < 30 mL/min) should not be prescribed dabigatran and patients with a creatinine clearance between 30 and 50 mL/min should be prescribed 150 mg twice daily unless they are aged ≥ 80 years.

It appears that many respondents would be tempted to prescribe a lower dose of dabigatran for patients with a creatinine clearance between 30 and 50 mL/min. Patients with moderate renal impairment may be at an increased risk of bleeding due to reduced dabigatran excretion - this is especially the case if other risk factors such as a low body weight are present. However, there is no evidence that the 110 mg dose is safer and it is likely to be less effective than the 150 mg dose. The decision whether to prescribe a lower dose of dabigatran for such patients should be individualised. It is possible that dosing recommendations for this group of patients will be revised in the future as more evidence and experience becomes available.

The eGFR or creatinine clearance needs to be checked prior to starting dabigatran. Most laboratories report eGFR automatically with serum creatinine results, and eGFR can be used as an estimate of renal function. However, eGFR may not be a good estimate of renal function in people at extremes of body size (BMI < 18.5 or > 30 kg/m²) or in older people. In this case, an estimate of creatinine clearance is preferable, determined using a hand held or electronic calculating tool or by using the Cockcroft-Gault equation.

The RE-LY trial compared two doses of dabigatran (110 mg and 150 mg administered twice daily) to warfarin treatment (aiming for INR values of 2–3) in over 18,000 patients with atrial fibrillation.

RE-LY showed that compared to warfarin:

• Dabigatran 150 mg twice daily was found to be superior to warfarin and to dabigatran 110 mg twice daily for the prevention of stroke or systemic embolism.
• Dabigatran 110 mg twice daily produced no significant difference in the rate of stroke or systemic embolism compared to warfarin (i.e.non-inferior to warfarin).
• The rate of myocardial infarction was significantly higher in patients in the dabigatran 150 mg group, compared to those in the warfarin group.
•  There was no statistical difference in death from any cause between the drug treatment groups.

Both doses of dabigatran (not only the 110mg twice daily dose) were associated with fewer intracranial haemorrhages and other life-threatening bleeds when compared to warfarin.

The majority of respondents correctly identified that gastrointestinal bleeding events were significantly increased with dabigatran 150 mg compared with dabigatran 110 mg or warfarin.

The risk of life-threatening bleeding is significantly worse with warfarin compared with both doses of dabigatran.

In the RE-LY trial, the use of antiplatelet medicines increased the risk of bleeding when used concurrently with dabigatran or warfarin. Current expert opinion is that antiplatelet medicines such as aspirin and clopidogrel should not be used with dabigatran, although for some patients with complex medicine requirements, their use may be considered on a case by case basis.

If bleeding occurs in a patient taking dabigatran, the dabigatran should be immediately stopped and the source of the bleeding investigated. Unless the bleeding is mild, referral to secondary care is recommended.

Unlike with warfarin, no specific antidote is available to reverse the anticoagulant effects of dabigatran. Administration of vitamin K or an infusion of plasma will not reverse the anticoagulant effect. Treatment in secondary care may involve the use of oral charcoal (but only if ingestion of dabigatran was less than two hours previously), transfusion of blood products or clotting factors, use of anti-fibrinolytic agents intravenously and consideration of haemodialysis, particularly if there is moderate to severe renal impairment.

Oral tranexamic acid (15mg/kg four times a day), along with local haemostatic measures (e.g. compression) may be considered for the treatment of mild bleeding. Intravenous tranexamic acid is used in a secondary care setting for more severe bleeding.

Reporting is an essential part of monitoring for any medicine, but particularly new medicines, so prescribers are encouraged to report all adverse events regardless of whether the patient required hospitalisation.

When switching from warfarin to dabigatran, stop warfarin and start dabigatran when the INR is less than 2.0. No titration is necessary from a lower dose to higher dose.

Blood tests such as activated partial thromboplastin time (aPTT) and the thrombin time (TT) have no role in the monitoring or the fine tuning of dabigatran dosing. The aPTT has limited sensitivity and should only to be used as a guide to the management of patients with acute bleeding (to indicate whether there is anticoagulant activity present).

At present there is limited evidence and clinical experience with the use of dabigatran prior to surgery. It is anticipated that the risk of bleeding with dabigatran is likely to be similar to the risk for a patient taking warfarin.

Current recommendations include:

• For people with a standard risk of bleeding, dabigatran should be temporarily discontinued for 24 to 48 hours before elective surgical procedures
• For people at increased risk (e.g. older people, concomitant use of antiplatelet medicines, cardiac, respiratory or liver disease) or those having procedures with a high bleeding risk (e.g. any major surgery, spinal anaesthesia), dabigatran should be discontinued two to four days prior to the surgery. If the risk of bleeding is high, a normal aPTT result will indicate a lack of residual anticoagulant effect and so may be reassuring prior to major surgery.
• There is limited information about the use of dabigatran in situations such as dental extractions and minor surgery. In these situations, warfarin will sometimes be continued especially of the INR is at the lower end of the therapeutic range and the individual risk of bleeding is low. A similar assessment of risk can be applied to dabigatran, although bearing in mind that a bleeding event with dabigatran cannot be reversed.

The majority of respondents answered that people at moderate risk of bleeding should have their dabigatran stopped 24-48 hours prior to surgery. This time frame may be adequate for a patient with a standard risk of bleeding, but for a patient at increased risk, it might be preferable for the dabigatran to be stopped even sooner (e.g. two to four days prior to surgery). The same applies to patients prior to major surgery where it is suggested that dabigatran be stopped two to four days beforehand.