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Dabigatran Demystified
What Warfarin Patients Should Know About this New Anticoagulant

Henry I. Bussey, Pharm.D.
Edith A. Nutescu, Pharm.D.
Marie Bussey
February, 2012

Late in 2010, the FDA approved a new anticoagulant drug called dabigatran (brand name Pradaxa) for the prevention of stroke in patients with an irregular heart beat called atrial fibrillation (AF). This medication is the first orally-administered alternative to warfarin (brand name Coumadin) to be approved by the FDA in the more than 60 years since warfarin became available. The attention that dabigatran has drawn is, in large part, due to the fact that frequent blood tests and dosage adjustments are not required for this medication as is the case with warfarin. Much has been written about this new drug in both the news media and medical literature. Most of the published information, however, has been directed at health care professionals or those with an interest in health care costs and pharmaceutical marketing. Little has been done to communicate to patients on warfarin (brand name Coumadin) what they should know about this new medication. This article will attempt to cover the key points that a patient taking warfarin should know about dabigatran.

What are some major differences between taking dabigatran and taking warfarin?

If you are currently taking warfarin, then you probably know that the correct dose of warfarin has to be determined for each individual and may change from time-to-time. Factors that may require a change in warfarin dose include such things as changes in diet, use of dietary supplements, physical activity, illness, alcohol use, smoking practices, and other issues. When taking warfarin, you should have a blood test called the INR checked at least once every four weeks, and your clinician will adjust your warfarin dose as necessary to keep your INR in the target range, which is usually 2.0-3.0.

Dabigatran is a new medication that works differently than warfarin. Your body produces a chemical called thrombin that is needed in order to form a blood clot. Dabigatran helps to prevent blood clots by blocking the effect of thrombin.

Dabigatran comes as two standard doses in the U.S. Most patients on dabigatran take 150 mg two times a day. Some patients require a lower dose, however. In patients whose kidneys do not work as well as they should, dabigatran may build up in the blood stream since the kidneys cannot eliminate the drug from the body as fast as they should. Patients whose kidneys do not work well take 75 mg of dabigatran twice a day. In Canada and other countries, a 110 mg capsule is available, but this size was not approved by the U.S. FDA.

Regardless of the dose, with dabigatran, you take a capsule twice a day, and there is no blood test to measure the effect of the drug. The capsule formulation, however, presents some rather unique considerations. When taken as prescribed, less than 10% of the dose is absorbed into the blood stream. The capsule should NOT be opened before taking the dose (such as sprinkling the contents of the capsule on food) because the amount of drug absorbed is substantially increased. Absorbing a larger amount of the drug would be expected to result in an elevated drug concentration and an increased risk of bleeding. The medication also is subject to being degraded by moisture and, therefore, must be stored in the original bottle, which should be kept tightly closed. Once the original bottle is opened, the initial FDA approval called for the capsules to be used within 30 days or discarded. More recently, the FDA has been considering extending that time frame to 60 days. This susceptibility to moisture also means that the capsules cannot be stored in another container such as a typical prescription vial or a “weekly pill box,” as is often used by warfarin patients to enhance adherence to the dosing schedule. This issue has led some to suggest that it may be preferable to use dabigatran that is “strip packaged” where each capsule is sealed separately. This type of packaging would seem a reasonable option as long as the integrity of the strip packaging is maintained to be moisture proof.

Except for the special storage and handling issues addressed above, taking dabigatran is simple and not having a blood test every few weeks may sound appealing. On the other hand, fingerstick devices are readily available such that if you are taking warfarin, your INR can be checked with a quick stick of your finger rather than a traditional blood draw. Additionally, there is no way to monitor the effect of dabigatran, and there is no easy way to reverse the effect of dabigatran if bleeding should occur. If you take too much warfarin and bleeding occurs, the effects of warfarin can be reversed by administering vitamin K or, if more urgent reversal is needed, by administering clotting factors.

What are some potential side effects of taking dabigatran?

In the study mentioned above, more patients stopped taking dabigatran than stopped taking warfarin, and a significant reason for discontinuation was a higher rate of “dyspepsia” (or upset stomach). If an upset stomach occurs, patients should contact their prescribing clinician and should NOT stop the medication on their own. If you stop taking dabigatran, you increase your risk of having a stroke or other blood clot related event.

Dabigatran requires an acid environment in order to be absorbed in the body. As such, many experts believe that the upset stomach is due to the acid that is combined with the drug in the capsule. Another possibility is that the upset stomach is due to the fact that more than 90% of the drug is not absorbed and remains in the stomach and intestines (the gastro-intestinal or “GI” tract). The large amount of drug that stays in the GI tract also may explain a higher risk of GI bleeding seen with dabigatran. Patients who experience any bleeding, of course, should contact their prescribing clinician immediately.

What drugs are known to interact with dabigatran?

Although dabigatran is thought to have fewer and less clinically-significant drug interactions than what has been seen with warfarin, a few significant interactions have been identified. It also is worth noting that the lack of a blood test to monitor dabigatran makes it difficult to determine if a given patient is experiencing a drug interaction. Specific drug interactions that have been identified were reviewed recently in an article by Nutescu, et. Al. and are summarized below. Most of the potentially significant drug interactions with dabigatran appear to be related to the way the interacting drug affects the activity of something in the body called a P-glycoprotein. The P-glycoprotein is basically a pump that works to pump dabigatran back into the intestines. Some drugs prevent the P-glycoprotein from pumping dabigatran back into the intestines, so more dabigatran stays in the blood, which may increase the risk of bleeding. Alternatively, some drugs cause the P-glycoprotein to pump more dabigatran back into the intestines, so less dabigatran remains in the blood. With less dabigatran in the blood, the risk of stroke may increase. Exactly how much of a change in dabigatran blood levels is acceptable is not known. Since worsening kidney function can also lead to an increase in dabigatran blood concentration, it would seem logical to use the data on drug interactions together with how well the patient’s kidneys are working in trying to determine how significant various drug interactions may be.

Antacids and drugs to reduce acid secretion (for example: Pepcid): Dabigatran requires an acid environment in order for it to be absorbed into the blood stream. Medicines such as Pepcid that neutralize or suppress stomach acid have been shown to reduce absorprtion of dabigatran by approximately 11% to 35%. This degree of reduction in drug absorption is not thought to be clinically important.

Verapamil has been reported to more than double the blood concentration of dabigatran if the verapamil is given right before the dabigatran. However, there appears to be no interaction if the verapamil is taken at least 2 hours after the dabigatran dose. Use of a sustained release formulation of verapamil also may avoid this drug interaction.

Amiodarone and/or Dronedarone: Amiodarone and dronedarone are listed together because they are closely related chemically and both are used to treat atrial fibrillation. Amiodarone has been reported to increase dabigatran blood levels by approximately 65%. Additionally, data on file with Sanofi-Aventis suggest that dronedarone may cause a doubling of dabigatran blood levels. Amiodarone, however, also causes the kidneys to eliminate dabigatran from the body at a faster rate. As such, the initial increase in dabigatran blood levels may be offset by an increase in kidney elimination of the drug. Whether dronedarone has a similar effect on kidney elimination of dabigatran is not known at this time.

Other drugs that may increase dabigatran blood levels by preventing the P-glycoprotein from pumping dabigatran back into the intestines include Ketaconazole (150% increase), Quinidine (53% increase), Clarithromycin (19% increase), and Clopidogrel (30% increase) Rifampin is thought to cause the P-glycoprotein to pump more dabigatran back into the intestines, which causes a lowering of dabigatran blood levels. The data suggest that rifampin may cause a two-thirds reduction in dabigatran blood levels. A two-thirds reduction in dabigatran blood levels would be expected to cause a loss of anticoagulant effect, which would increase the patient’s risk of stroke.

The drugs mentioned above that cause the P-glycoprotein to increase or decrease its pumping rate should be considered a partial list. Whether other medications may produce interactions with dabigatran in this same way remains to be determined.

Lastly, it should be noted that non-steroidal anti-inflammatory drugs (NSAIDS)- such as ibuprofen and similar agents - as well as other antiplatelet agents (such as clopidogrel) and other anticoagulants can increase the bleeding risk with dabigatran without changing the blood level of the drug.

Can any warfarin patient switch to dabigatran?

No. When the FDA approves a drug, it approves it only for specific conditions. Currently dabigatran is approved only for patients with A.F. FDA approval was based largely on a single study that involved more than 18,000 patients who received either warfarin or one of two doses of dabigatran (110 mg twice daily or 150 mg twice daily). In the future, dabigatran may be approved for other indications in which blood clots may be a problem; but in order for such approval to be granted by the FDA, the manufacturer will have to conduct clinical trials and show benefit for the medication in patients who have the specific indication in question for anticoagulation.

Is dabigatran better than warfarin?

In order to get approval from the FDA, dabigatran had to go through “non-inferiority” trials. The purpose of a non-inferiority trial is to show that the investigational drug (in this case, dabigatran) is at least as safe and effective as the comparator drug (in this case, warfarin). The trials do not have to show that the new drug is better than the old drug. In the trial mentioned above, dabigatran 110 mg twice daily was “non-inferior” to warfarin in preventing strokes and had less bleeding than warfarin. The dose of 150 mg twice daily was actually found to be superior to warfarin in preventing strokes but with a similar rate of bleeding complications.

It also is important to understand that the studies look at group data. In other words, they have to show that the group on dabigatran does at least as well as the group taking warfarin. When one looks at individual data, however, the results sometimes look different. For example, 50% of warfarin-treated patients in the study mentioned above had their INRs in range 67% of the time or more. In such patients, the data suggest that warfarin is more effective and safer than dabigatran. On the other hand, when one compares data from the 25% of warfarin-treated patients with the poorest INR control (INRs in range less than 53% of the time), then dabigatran appears to be considerably safer and more effective.

Should I switch to dabigatran?

So, what’s the bottom line; should you make the switch? Patients with severe reduction in kidney function and those with significant liver disease should not take dabigatran because of a potential increased risk of bleeding. Otherwise, the answer as to whether you should switch is…it depends. Well-managed warfarin appears to be safer and more effective than dabigatran. So, if you are taking warfarin and have a good clinician management system in place such that your INR is usually in range and stable, then warfarin is probably safer and more effective for you than dabigatran would be. If, however, your INR is often out of control and measures to improve INR stability have not worked, then dabigatran may be a better option for you.

References

  1. Connolly SJ, Ezekowitz MD, Yusuf S, et al. RE-LY Steering Committee and Investigators. Dabigatran vs warfarin in patients with atrial fibrillation. New England Journal of Medicine 2009; 361:113-51
  2. Gage BF (2009) Can we rely on RE-LY? New England Journal of Medicine 2009; 361:1200-1202.
  3. Wallentin L, Yusuf S, Ezekowitz MD, et al (RE-LY investigators). Efficacy and safety of dabigatran compared with warfarin at different levels of international normalized ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 2010 376:975-83.
  4. Nutescu E, Chuatrisorn I, Hellenbart E. Drug and dietary interactions of warfarin and novel oral anticoagulants: an update. J Thromb Thrombolysis 2011; 31:326-343.
  5. fda.gov/Drugs/DrugSafety/ucm248746.htm (accessed last on May 13, 2011)
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