Dabigatran, Product Familiarisation Programmes, who benefits, who shouldn't get it?
An 88-year-old woman with a history of ischaemic heart disease, chronic kidney disease, type II diabetes mellitus and gastritis presented to the emergency department of an Australian tertiary hospital with melaena, symptomatic anaemia, haemoglobin of 61 g/L. Three weeks prior to the presentation she had been changed by her general practitioner from warfarin, on which she had previously been well controlled for more than 10 years, to dabigatran for stroke prevention for her atrial fibrillation. Why did this previously stable patient experience significant haemorrhagic complications so shortly after commencing the new medication?
Dabigatran has been approved for use in Australia by the Therapeutic Goods Administration (TGA) for the prevention of stroke and systemic embolisation in patients with non-valvular atrial fibrillation and at least one additional risk factor for stroke.1 It has been recommended for listing on the Pharmaceutical Benefits Scheme (PBS) by the Pharmaceutical Benefits Advisory Committee (PBAC) for this indication.2 Despite the PBAC's recommendation the Department of Health and Ageing (DOHA) has delayed its decision on the matter, commissioning further inquiry into the use of the drug. The Department's concerns included that the benefit of dabigatran observed in the landmark trial3 may not be reflected in the general Australian population, and that this may lead to over-prescription without adequate education for doctors, pharmacists or patients.4 Between June 2009 and October 2011 the TGA has received reports of 297 adverse events with the use of dabigatran, 70 of which were serious bleeding events.5 A similar picture has emerged in New Zealand.6 The TGA has subsequently issued two warnings, one on the bleeding risk of the dabigatran, and the other on the necessity of assessing renal function in those taking the drug.5,7 The high number of reported incidents, the delay on the PBS approval and personal experience with cases, such as that described earlier, raise questions about the appropriateness of the widespread prescription of dabigatran.
The pharmaceutical company marketing this medication embarked on a Product Familiarisation Programme (PFP) across the country, targeting specialists and general practitioners alike. Perhaps this was a response to the DOHA delay. While most public hospitals have strict rules on how PFPs should be conducted and monitored, it is less clear what occurs in community practice.8
Randomised clinical trials (RCTs) by their inherent design enrol a safe and homogenised sample population. It is not surprising that when translating the use of an anticoagulant to the broader population adverse events have occurred. Possibly this has influenced the pharmaceutical company to terminate prematurely their PFP (NSW Therapeutic Advisory Group, pers. comm., 2011).
Before the decision to prescribe dabigatran for stroke prevention is undertaken, a number of important issues must be considered.
Impaired renal function
As dabigatran is 80% renally excreted,9 care must be taken in its use in patients with impaired renal function. It is contraindicated in people with a creatinine clearance (CrCL) less than 30 mL/min. The company suggests considering the reduced dose of 110 mg twice daily for those with moderate renal impairment (CrCL of 30–50 mL/min),10 but it would be logical to make this recommendation mandatory. In the RE-LY trial the risk of bleeding events increased with decreasing CrCL, although this did not meet significant criteria.11 Impaired renal function was a likely contributor to the bleeding event in the our case. Accurate estimation of renal function is important for drug dosing. The Cockcroft-Gault equation and the Modification of Diet in Renal Disease equation (estimation of glomerular filtration rate (eGFR)) have both been validated for use in people of average age, weight and size, but are less robust for use in those in the extremes of those categories.12 Neither method has been validated for use in those over 80, particularly if lean body mass is not taken into account as with the eGFR.13 Our patient, described earlier, was significantly underweight. It is important to keep these inaccuracies in mind when deciding on drug use or dosing.
The bleeding rates with dabigatran increase with increasing age.11 In the RE-LY trial those over 75 on dabigatran had greater rates of major bleeding, extracranial bleeding, and gastrointestinal bleeding than those <75 years.11 Patients >75 years had significantly higher rates of gastrointestinal bleeding with both doses of dabigatran compared with warfarin like the case in question. Age did not have a significant effect on the lower rates of intracranial bleeding seen with both doses of dabigatran.11
Unlike warfarin, one of the major drawbacks of dabigatran is the lack of an effective antidote for use in the event of a severe bleeding event. Prothrombin complex concentrate did not correct prolonged coagulation assays in healthy volunteers, and there is no evidence to support its use in bleeding patients.14 It is not clear whether recombinant factor VIIa will be effective.15 This becomes a critical issue when urgent surgery is required.
At present there are no available laboratory tests that have been validated for monitoring of dabigatran. Situations do exist in which the ability to monitor its therapeutic effect would be potentially beneficial.16 In the case described monitoring dabigatran activity may have allowed for dose adjustment or cessation of the medication to prevent the haemorrhagic complication.
The commonly used APTT and PT are not suitable for the measurement of dabigatran effect. The thrombin clotting time is a sensitive test for determining if any dabigatran is present in a sample, however, because of great variation of results with different reagents used by different laboratories it has not been validated for use as a monitoring test.17 The test can only be used to tell if there is any dabigatran activity present, but not how much.
Perioperative and acute coronary syndrome (ACS) settings
Like all the new anticoagulants and new anti-platelet drugs on or about to be available on the Australasian market, the treating team has to recognise these new medications (and their trade names) and stop them for an appropriate time before surgery or before conventional anticoagulation can start (in the case of ACS). Failure to identify these agents or surgery in the emergent situation will be extremely hazardous.
Dabigatran is given as the prodrug dabigatran etexilate, and this prodrug is a substrate for the efflux p-glycoprotein transporter. Inhibitors of p-glycoprotein, such as ketoconazole (most azoles), protease inhibitors, macrolides, calcineurin inhibitors, amiodarone and verapamil, can increase dabigatran plasma concentrations by decreasing the efflux of the drug into the gastrointestinal lumen.18 Strong inducers of p-glycoprotein, such as rifampicin, carbamazepine and phenytoin can reduce plasma concentrations and coadministration should be avoided.10 Given its indication for use in atrial fibrillation, particular caution must be used with the potential interactions with verapamil and amiodarone. Simultaneous initiation of dabigatran and verapamil is contraindicated, but the product information does recommend verapamil can be given 2 h after the dabigatran. The company does not recommend dose alterations in dabigatran with pre-existing treatment with amiodarone or verapamil,10 but it is likely less dabigatran will be required.10 No significant interaction was seen with digoxin, also a p-glycoprotein substrate.19
Approximately 40% of patients in the RE-LY trial took concomitant aspirin on enrolment,3 and about half of these continued to take it throughout the study. The combination of aspirin and dabigatran was associated with higher bleeding rates.11 Bleeding rates were also higher among people who received the combination of aspirin and clopidogrel throughout the study compared with those who did not receive combination antiplatelet therapy.11
Different international normalised ratio (INR) groups
The comparison of efficacy and safety between dabigatran and warfarin is altered by the success in achieving a therapeutic international INR with warfarin therapy.20 Overall the patients in the warfarin arm of the RE-LY trial had a mean Time in Therapeutic Range (TTR) of 64%. In centres with a high mean TTR (greater than 57.1%) there was no significant difference in the primary endpoint (the composite of stroke or systemic embolisation) or non-haemorrhagic stroke between either dose of dabigatran when compared with warfarin.20 Australian subjects had a mean TTR of 74%, which was exceeded only by Sweden.20 A similar picture emerges for major bleeding when comparing the high dose dabigatran (150 mg b.d.).
The lower 110 mg dose of dabigatran maintained a slightly lower total bleeding rate even in those with a high TTR, though all other bleeding subgroups were not significantly different.20 The lower rates of intracranial bleeding with dabigatran compared with warfarin were maintained for all populations of TTR.
Who should not and who should?
Those who have been prescribed with dabigatran should match the inclusion criteria of the major trial that proved the efficacy and safety of that drug. The RE-LY trial excluded those with creatinine clearance <30 mL/min, those with active liver disease, pregnancy and any patient with a condition that placed them at an increased risk of bleeding, including a history of gastroduodenal ulcer disease, recent or planned surgery, uncontrolled hypertension, a history of intracranial or gastrointestinal bleeding. Patients with a history of heart valve disease were also excluded.3 A knowledge of these exclusion groups is crucial as not only has dabigatran not been demonstrated to be efficacious in these groups, it has also not been proven to be safe.
In the trial the elderly and patients with impaired renal function had higher rates of bleeding and those with stable INRs did well with warfarin. So if well controlled on warfarin it makes no sense in changing these patients to dabigatran. There is an advantage for intracranial haemorrhage for dabigatran; however, we are unaware of any validated predictive model that is available to distinguish this group from the general bleeding risk.
There is a role for the use of dabigatran in patients with atrial fibrillation. We would propose that dabigatran would be useful in patients <75 years, who have normal renal function, few co-morbid medical conditions (i.e. not many concurrent medications), limited additional risks for bleeding. Here the decreased risk of intracranial bleeding is clinically advantageous and the lack of regular INR testing is convenient. Patients whose INR control is poor should also be considered for dabigatran.
No doubt this era of new anticoagulants and new anti-platelet medications is an advance. Despite the marketing it is the opinion of the authors that all anticoagulants must be considered to have a narrow or critical therapeutic range. In view of all the issues why would one market this new medication in general practice?
We require an effective antidote, clear national guidelines about who should be considered for dabigatran therapy, and a reliable, widely available laboratory monitoring test. Its cost-effectiveness is uncertain.21 The drug interaction story is yet to be played out in full. Guidelines on how clinicians deal with the multiple issues that patients on dabigatran can present with are now being produced.16,22
As more new medications are potentially held up by DOHA, pharmaceutical companies are considering PFPs or other forms of Medicines Access Programs. In our new world of Medicare Locals and Local Health and Hospital Networks, strict oversight of these programmes is essential.