Dabigatran: Drug Whys
Widespread use, extensive marketing, and significant media coverage mandate that EMS providers be informed about this drug
By Mike McEvoy
Generic Name: Dabigatran (no generic available, U.S. patent expires in February 2018)
Common U.S. Brand Names: Pradaxa® (Boehringer Ingelheim Pharmaceuticals, USA)
Popularity: Too new to rank
Treatment Uses — Prevention of blood clots and thromboembolic events associated with atrial fibrillation. Also used for treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) as well as prevention of post-operative blood clots (thromboembolism) following total hip and knee replacements.
Dabigatran should not be used in patients with prosthetic heart valves. There are several recent reports of prosthetic heart valve patients switched from warfarin to dabigatran who subsequently developed major clots on their mechanical heart valves, requiring emergency surgery and valve replacement.
Atrial fibrillation affects 1 percent to 2 percent of the population and is the most common sustained rhythm alteration seen. One in five strokes is attributed to atrial fibrillation and patients with a-fib have a five times greater stroke risk.
At least one-third of patients with atrial fibrillation are not prescribed anticoagulants even though it reduces their incidence of stroke by 60 to 80 percent. Strokes resulting from atrial fibrillation tend to be more damaging and patients who survive are likely to have additional strokes. EMS providers reviewing medication lists of patients with atrial fibrillation who fail to find an anticoagulant should advise the patient to discuss this with their health care practitioner.
The anticoagulation mainstay for centuries has been warfarin (Coumadin®). Dosing of warfarin is individualized for each patient, adjusted by measuring blood prothombin time (PT). Wide variations in laboratory controls led the World Health Organization in 1983 to develop a system that standardized PT for oral anticoagulant therapy using a control standard called International Normalized Ratio (INR).
An INR of 1.0 times the control indicates no depression of clotting factors, whereas 2 to 3 times control is considered therapeutic for most purposes. Certain heart valves with higher clotting risk require an INR as high as 3.5. There is a markedly increased risk of bleeding when the INR is above 4. Routine INR blood testing is costly and time consuming.
Keeping INR within the desired therapeutic range can be challenging; some 40% cannot maintain INRs within the recommended range of 2.0 to 3.0 (target 2.5). Different brands of warfarin have different degrees of bioavailability, health and diet can significantly increase or decrease INR, and compliance with routine lab work is not always ideal.
Dabigatran works through a different mechanism than warfarin and does not require blood testing or periodic dose adjustment. This has been very appealing to some patients and prescribers. Additionally, in studies comparing dabigatran to warfarin, patients with atrial fibrillation had less strokes and blood clots with an overall similar risk of serious bleeding. GI bleeds occurred more often and intracranial bleeding less often with dabigatran compared to warfarin.
"Drug Whys" has never covered a drug as new on the market as dabigatran. However, widespread use, extensive marketing, and significant media coverage mandate that EMS providers be informed about this drug.
Most importantly, there is no reversal agent or antidote for dabigatran; this can be a major challenge when managing traumatic injuries and hemorrhage. To date, hemodialysis is the only effective means of reversing the anticoagulant effects of dabigatran and this is difficult to perform in an unstable, actively bleeding patient.
Unlike other anticoagulants which work by depleting or lowering levels of circulating clotting factors, dabigatran is a direct thrombin inhibitor meaning that it directly inhibits the ability of circulating clotting factors to work.
Patients on warfarin or aspirin who bleed can be given replacement clotting factors. When additional clotting factors are given to patients taking dabigatran, the drug renders those replacement clotting factors ineffective as well.
Cost wise, dabigatran is expensive compared to warfarin. However, time is saved by eliminating lab tests to adjust dosing. Compliance may be more difficult with twice daily dosing of dabigatran versus once a day for warfarin.
If bleeding occurs, either from traumatic injury or spontaneously, there is no reversal agent for dabigatran. For patients who have difficulty maintaining therapeutic INR levels on warfarin or live far away from monitoring labs, dabigatran may be a reasonable alternative. If cost is a concern, patients don’t mind routine blood tests, and INR is consistently in therapeutic range, warfarin continues to be a reasonable choice.
Dosing and Administration — Dosing recommended for adult patients with atrial fibrillation is 150 milligrams taken by mouth twice daily. Dabigatran is not approved in the U.S. for prevention of post-operative blood clots but doses of 220 milligrams given once daily are approved in other countries.
There is not a 110milligram dose sold in the U.S. but one 150 milligram and one 75 milligram capsule closely approximate this dose. The safety of dabigatran in pediatric patients has not been established. Dabigatran can be taken without regard to food/meals.
As with other drugs that have potentially serious side effects, the FDA requires prescribers to have Risk Evaluation and Mitigation (REMS) in place, including dispensing the medication with a medication guide (see: www.fda.gov/Drugs/DrugSafety/ucm085729.htm).
When converting from warfarin to dabigatran, discontinue the warfarin and start dabigatran when the INR is less than 2. When converting from dabigatran to warfarin, time the start of the warfarin based on kidney function. In patients with normal renal function (CrCl greater than 50 mL/min), start warfarin 3 days before discontinuing dabigatran. In patients with mild renal insufficiency (creatinine clearance between 30 and 50 mL/min), start warfarin 2 days before discontinuing dabigatran and in patients with severe renal impairment (CrCl between 15 and 30 mL/min), start warfarin 1 day before discontinuing dabigatran.
In renal failure patients (CrCl less than 15 mL/min), no clear recommendations presently exist. Note that INR levels may be elevated by dabigatran and may not reflect the true effects of warfarin for 2 days following the discontinuation of dabigatran.
When switching from dabigatran to intravenous or parenteral anticoagulants, postpone the initiation of parenteral agents until 12 hours after the last dose of dabigatran in patients with creatinine clearances greater than 30 mL/min and 24 hours in patients with CrCl less than 30 mL/min.
When converting from parenteral anticoagulants, start dabigatran 0 to 2 hours before the next scheduled dose of the parenteral agent or at the same time as discontinuation of a continuous infusion (such as intravenous heparin).
Increased risk of bleeding from surgery or invasive procedures requires anticoagulants to be discontinued in advance whenever possible. Dabigatran should be discontinued 1 to 2 days prior to surgery in patients with normal kidney function (creatinine clearance greater than 50 mL/min) and 3 to 5 days prior to surgery in patients with impaired kidney function (CrCl less than 50 mL/min). For major surgery or spinal puncture procedures, longer times should be considered. Anticoagulation should be restarted as soon as possible following the procedure.
Dose adjustments of dabigatran are necessary in patients with impaired renal function. For patients with severe renal impairment (CrCl 15 to 30 mL/min), the recommended dose of dabigatran is 75 milligrams twice daily.
Dose adjustments are also needed for patients with moderate renal insufficiency taking certain antiarrhythmics and antibiotics. There are currently no dosing recommendations for patients with end stage renal disease (ESRD) or renal failure who may be receiving dialysis.
Overdoses of dabigatran can lead to serious bleeding. Treatment should be supportive. Hemodialysis can remove 60 percent of dabigatran over 2 to 3 hours and would likely be helpful in an overdose or bleeding emergency.
Pharmacology/Pharmacokinetics/Stability — After oral administration of a single dose of dabigatran on an empty stomach, peak blood levels are seen after 2 hours. Given with a high fat meal, peak blood levels are seen after 4 hours. The overall time to reach peak blood concentrations following an oral dose of dabigatran ranges from 1 to 6 hours.
Most (80 percent) dabigatran is excreted by the kidneys. The half-life (time to eliminate half of the drug from the body) is 12 to 17 hours. Clinically, most effects of dabigatran “wash out” or disappear 13 hours after the last dose.
There are no good human studies of dabigatran use during pregnancy. In animals, dabigatran increased risks of bleeding and stroke during pregnancy. It is not known whether dabigatran is excreted in breast milk; risks and benefits should be carefully considered in nursing mothers.
Dabigatran 150 milligram capsules have a light blue opaque cap imprinted with a black Boehringer Ingelheim logo and a cream colored opaque body imprinted with a black “R150.”
The 75 milligram capsules have a cream colored opaque cap also with a black company logo and a cream colored opaque body imprinted with “R75” in black. Dabigatran is highly susceptible to moisture (hence the individual blister packaging).
Once a bottle of dabigatran has been opened, the contents should be used within 4 months. To protect the contents from moisture, immediately and tightly close the bottle after each use. Bottles of dabigatran should be stored at room temperature (77 F), with excursions permitted between 59 and 86 F.
Capsules should be swallowed whole, not broken, chewed, or emptied into food. If a missed dose cannot be taken at least 6 hours before the next scheduled dose, it should be skipped.
Cautions and Warnings — The risk of bleeding is similar to other anticoagulants when compared with dabigatran. However, lack of a reversal agent can lead to serious and sometimes fatal effects when bleeding occurs in patients taking dabigatran.
Important Side Effects and Interactions — The most common and significant side effect of dabigatran is bleeding (16.6 percent, major 3.3 percent, life threatening 1.5 percent). Other side effects have included nausea, indigestion and diarrhea (35 percent versus 24 percent reported by patients on warfarin).
There are 70 drugs and drug classes specifically reported to interact with dabigatran. Virtually all are anticoagulants or drugs with anticlotting effects. The interaction is increased bleeding and potential for life threatening hemorrhage. No food-drug interactions involving dabigatran have been reported.
Average Costs – U.S.
• Pradaxa (brand name): $250 per month
• Warfarin (generic): $80 per month including INR testing, $30 with Wal Mart or Target prescription program*
*(Wal Mart® and Target include warfarin in their $4/month programs)
1. MICROMEDEX Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed September, 2012).
2. Albany Medical Center Pharmacy, Albany, New York.