Current Drug Therapy

Dabigatran: Will it change clinical practice?

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DOES DABIGATRAN NEED MONITORING? CAN IT EVEN BE MONITORED?

Dabigatran has a predictable pharmacodynamic effect, and current data indicate it does not need regular monitoring.18–20 However, one may need to be able to measure the drug’s activity in certain situations, such as suspected overdose, bleeding, need for emergency surgery, impaired renal function, pregnancy, and obesity, and in children.20

Dabigatran has little effect on the prothrombin time or the INR, even at therapeutic concentrations.19 Further, its effect on the activated partial thromboplastin time (aPTT) is neither linear nor dose-dependent, and the aPTT reaches a plateau and becomes less sensitive at very high concentrations. Therefore, the aPTT does not appear to be an appropriate test to monitor dabigatran’s therapeutic anticoagulant effect, although it does provide a qualitative indication of anticoagulant activity.18,19

The thrombin time is a very sensitive method for determining if dabigatran is present, but the test lacks standardization; the ecarin clotting time provides better evidence of the dose but is not readily available at most institutions.18,19,21

EVALUATED IN CLINICAL TRIALS

Dabigatran has been evaluated in a number of trials for its ability to prevent ischemic stroke and systemic embolization in patients with atrial fibrillation and to prevent and treat venous thromboembolism in surgical orthopedic patients, and in patients with acute coronary syndrome (Table 3).1–4,22–25

DABIGATRAN IS EXPENSIVE BUT MAY BE COST-EFFECTIVE

The estimated price of dabigatran 150 mg twice a day in the United States is about $6.75 to $8.00 per day.26,27

Warfarin, in contrast, costs as little as $50 per year.28 However, this low price does not include the cost of monitoring the INR (office visits and laboratory testing), and these combined expenses are much higher than the price of the warfarin itself.29 In addition, warfarin requires time-consuming management when bridging to a parenteral anticoagulant (for reversal of its anticoagulant action) before routine health maintenance procedures such as dental work and colonoscopy and interventional procedures and surgery. Any bleeding complication will also add to its cost and will be associated with a decrease in the patient’s perceived health and quality of life, but this is true for both drugs.30

In today’s health care environment, controlling costs is a universal priority, but it may be unfair to compare the cost of dabigatran with that of warfarin alone. The expense and morbidity associated with stroke and intracranial bleeding are high, and if patients on dabigatran have fewer strokes (as seen in the RE-LY trial with dabigatran 150 mg twice a day) and no added expense of monitoring, then dabigatran may be cost-effective.

Freeman et al31 analyzed the cost-effectiveness of dabigatran, using an estimated cost of $13.70 per day and data from the RE-LY trial. They concluded that dabigatran may be a cost-effective alternative to warfarin in preventing ischemic stroke in patients considered at higher risk for ischemic stroke or intracranial hemorrhage, ie, those with a CHADS2 score of 1 or higher or equivalent. (The CHADS2 score is calculated as 1 point each for congestive heart failure, hypertension, age 75 or older, and diabetes mellitus; 2 points for prior stroke or transient ischemic attack.)

As more new-generation oral anticoagulants become available (see below), the price of dabigatran will undoubtedly decrease. Until then, warfarin will remain a cost-effective and cost-saving drug that cannot yet be considered obsolete.

WHO SHOULD RECEIVE DABIGATRAN?

The ideal patient for dabigatran treatment is not yet defined. The decision to convert a patient’s treatment from warfarin to dabigatran will likely depend on several factors, including the patient’s response to warfarin and the physician’s comfort with this new drug.

Many patients do extremely well with warfarin, requiring infrequent monitoring to maintain a therapeutic INR and having no bleeding complications. For them, it would be more practical to continue warfarin. Another reason for staying with warfarin would be if twice-a-day dosing would pose a problem.

Dabigatran would be a reasonable choice for a patient whose INR is erratic, who requires more frequent monitoring, for whom cost is not an issue, and for whom there is concern about dietary or drug interactions.

Another consideration is whether the patient has access to a health care facility for warfarin monitoring: this is difficult for those who cannot drive, who depend on others for transportation, and who live in rural areas.

Additionally, dabigatran may be a cost-effective alternative to warfarin for a patient with a high CHADS2 score who is considered at a higher risk for stroke.31

In all cases, the option should be considered only after an open discussion with the patient about the risks and benefits of this new drug.

WHO SHOULD NOT RECEIVE IT?

Dabigatran is a twice-daily drug with a short half-life. No patient with a history of poor compliance will be a good candidate for dabigatran. Since there are no practical laboratory tests for monitoring compliance, one will have to reinforce at every visit the importance of taking this medication according to instructions.

Patients with underlying kidney disease will need close monitoring of their creatinine clearance, with dose adjustment if renal function deteriorates.

Additionally, one should use caution when prescribing dabigatran to obese patients, pregnant women, or children until more is known about its use in these populations.

ADVANTAGES AND DISADVANTAGES OF DABIGATRAN

In addition to its pharmacologic advantages, dabigatran demonstrated two other major advantages over warfarin in the RE-LY trial in patients with atrial fibrillation (Table 4). First, the rate of intracranial bleeding, a major devastating complication of warfarin, was 60% lower with dabigatran 150 mg twice a day than with warfarin—and lower still with dabigatran 110 mg twice a day.1 Second, the rate of stroke or systemic embolism was 34% lower in the group that got dabigatran 150 mg twice a day than in the group that got warfarin.

A reason may be that patients with atrial fibrillation and poor INR control have higher rates of death, stroke, myocardial infarction, and major bleeding.14 In most clinical trials, only 55% to 60% of patients achieve a therapeutic INR on warfarin, leaving them at risk of thrombosis or, conversely, bleeding.1,2,15,32 Dabigatran has predictable pharmacokinetics, and its twice-daily dosing allows for less variability in its anticoagulant effect, making it more consistently therapeutic with less potential for bleeding or thrombosis.1

The Canadian Cardiovascular Society included dabigatran in its 2010 guidelines on atrial fibrillation, recommending it or warfarin.33 The American College of Cardiology, the American Heart Association, and the Heart Rhythm Society now give dabigatran a class I B recommendation (benefit greater than risk, but limited populations studied) in secondary stroke prevention.34

On the other hand, major concerns are the lack of an antidote for dabigatran and a lack of experience in treating bleeding complications. Since dabigatran is not monitored, physicians may be uncertain if we are overdosing or undertreating. As we gain experience, we will learn how to treat bleeding complications. Until then, it will be important to anticipate this problem and to develop an algorithm based on the best available evidence in managing this complication.

Although the overall rates of bleeding in the RE-LY trial were lower with dabigatran than with warfarin, there were more gastrointestinal bleeding events with the 150-mg dose of dabigatran, which was not readily explained.

Further, the rate of dyspepsia was almost twice as high with dabigatran than with warfarin, regardless of the dose of dabigatran. There were also more dropouts in the 2nd year of follow-up in the dabigatran groups, with gastrointestinal intolerance being one of the major reasons. Therefore, dyspepsia may cause intolerance and noncompliance.1

Dabigatran must be taken twice a day and has a relatively short half-life. For a noncompliant patient, missing one or two doses will cause a reversal of its anticoagulation effect, leaving the patient susceptible to thrombosis. In comparison, warfarin has a longer half-life and is taken once a day, so missing a dose is less likely to result in a similar reversal of its anticoagulant effect.

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Proceedings of the 2010 Heart-Brain Summit

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