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Saturday, January 14, 2012

Is Pradaxa (dabigatran) dangerous? Comparing Pradaxa, Xarelto and warfarin

Just today while poking through studies recently released, I came upon an article that added to my growing discomfort with using Pradaxa, an anticoagulant ("blood thinner") that is now being widely used as an alternative for warfarin (coumadin is the brand name) for people with atrial fibrillation in order to reduce their risk for stroke.

Atrial fibrillation is a condition in which the atrium (entry chamber) of the heart wiggles rather than beats, and is caused by high blood pressure, valve problems, alcohol abuse and a number of other factors. The wiggling rather than beating atrium can build up blood clots which can migrate into arteries all over the body, but most devastatingly in the brain to cause strokes. Taking an anticoagulant reduces this risk. But blood has a very good reason for clotting, and when it is inhibited from clotting, a person can bleed, sometimes catastrophically, from an injury or an ulcer or a weak area in the tissues of the body. Like the use of any drug, anticoagulant use involves considering whether risks are less than expected benefits. Warfarin, our old standard drug, required that we monitor the level of anticoagulation with a blood test about every month. This was annoying and resource consuming, but had the effect of keeping us in contact with our patients and of making them realize, monthly, that there was risk associated with taking the drug. It was not uncommon for the level to drop too low to be protective, or to rise to the point that serious bleeding could occur. Still, most patients did fine. The drug became generic a few years ago so its cost was not too significant, and insurance covered the blood tests and followup.

Pradaxa, on the other hand, requires no monitoring. It is dosed twice daily rather than once, as for warfarin, but it is great to not have to worry about monthly visits. Warfarin blocked the action of vitamin K, so could be reversed by eating foods with lots of vitamin K, so patients had to be careful with their diets. Pradaxa has no such restrictions. Because Warfarin blocked vitamin K as its main mechanism of action, giving high doses of vitamin K was pretty effective in stopping bleeding if a person was injured or needed surgery, and if we needed to reverse it even more quickly we could use blood plasma. In the case of Pradaxa, though, there is no known agent that reverses its effects, though its effects do fade in about 24 hours. Unlike warfarin which takes days to become effective, pradaxa works in less than an hour, which in some situations might be life saving.

I was a great fan of Pradaxa when it first came out because my patients really did hate to get regular blood tests with warfarin and sometimes their doses were very difficult to stabilize. I saw many bleeding complications over the years that I practiced with warfarin, and occasionally strokes when the dose was too low. I woke up to problems with Pradaxa when I went to an Advanced Trauma Life Support course and found that the surgeons who dealt with patients who are injured were very opposed to anticoagulants, especially ones that couldn't be reversed. Patients who had trauma to their heads or abdomens and were on such drugs would bleed and die and the surgeon would have to sit by and watch. The surgeons asked why internists like myself would push so strongly to get patients to take these drugs to reduce risk of stroke, when the patient might just as easily die of bleeding should they fall or be in a car accident.

The article that just came out was in the Archives of Internal Medicine this month and showed that patients who took Pradaxa were 1.33 times as likely as patients who took no anticoagulants, aspirin or warfarin to had heart attacks or near heart attacks. I have no real idea why this would be, but the study was large and performed at several centers, so apparently something about this drug may make microclots in the coronary arteries occur or make platelets more sticky. In any case, it sure makes me think twice about using it.

Just very recently another drug like Pradaxa was released for use, and it may be better. The brand name is Xarelto, generic name Rivaroxaban. This drug is dosed once daily and can be reversed with a blood product called prothrombin complex. Its official indications are broader than Pradaxa. It can be used both for atrial fibrillation and preventing blood clots in the legs of patients who have had hip or knee replacements. It's likely that both Pradaxa and Xarelto are good for any clotting condition, but the FDA is slow to expand its recommendations due to the fact that blood clotting conditions are very risky, and there are other drugs that have long histories of effectiveness.

The cost of these new anticoagulants is really steep. Drugstore.com quotes a price of $245 for a month's supply of Pradaxa, and looking at sources online for Xarelto, costs for that will be really similar. Warfarin only costs about 15 dollars a month, but monitoring and complications bring the cost up significantly in the big picture. Both of the new drugs are less likely to cause fatal bleeding than warfarin.

So the answer to the question "is Pradaxa dangerous?" is "of course!" which also is true of Xarelto and warfarin.

6 comments:

Anonymous said...

The label for Xarelto states " no antidote ", carries a black box warning for increased stroke when discontinuing and uncertainty if it is effective compared to well controlled warfarin since the rates were so low in the trial data. In the end it is good to have choice, but Pradaxa clearly has stronger outcomes data.

Janice said...

Prothrombin complex immediately and completely reverses the effects of xarelto (rivaroxaban) but doesn't work on pradaxa. (http://circ.ahajournals.org/content/early/2011/09/06/CIRCULATIONAHA.111.029017) The discontinuation issue has to do with the fact that when changing from Xarelto to warfarin we have to remember that it takes at least 3 days for warfarin to become effective, so the two should be overlapped.

Janice Boughton said...

I overheard nurses in the PCU talking about the cost of prothrombin complex. It goes under the brand names of Cofact, Octaplex and Beriplex, and I cannot find any info on its cost in the US. The nurses were saying something like $10,000, but that is hearsay. In England the cost is US equivalent of 75cents per unit and the dose is 50 units per kg which would be over $2000 for reversal dose. It's probably higher in the US.

Paul J. Molinaro, M.D., J.D. said...

Cost is just one factor... safety is another...

One of the big “selling” points for Pradaxa as opposed to warfarin is that the patient taking Pradaxa does not have to submit himself or herself to regular blood draws and dietary restrictions. What promoters of Pradaxa conveniently do not tell physicians and patients is that there is no commonly available antidote for a Pradaxa overdose. Thus, should a patient’s Pradaxa levels reach a toxic level, he or she has a good chance of bleeding to death while physicians watch helplessly. Pradaxa levels are effected by advanced age, renal (kidney) function, extremes in body weight, and drug-drug interactions (aspirin, ibuprofen, nonsteroidal antiinflammatory drugs, and many other drugs commonly used by patients). In addition, should a patient on Pradaxa require emergency surgery (as a result of a motor vehicle accident, for example), he or she will be subject to uncontrolled bleeding and have a poor chance of successfully undergoing surgery. According to the National Center for Biotechnology Information, “In early 2013, there is still no routine coagulation test suitable for monitoring these patients; specific tests are only available in specialized laboratories. In early 2013 there is no antidote for dabigatran, rivaroxaban or apixaban, nor any specific treatment with proven efficacy for severe bleeding linked to these drugs. Recommendations on the management of bleeding in this setting are based mainly on pharmacological parameters and on scarce experimen-Haemodialysis reduces the plasma concentration of dabigatran, while rivaroxaban and apixaban cannot be eliminated by dialysis.”

In the last few years, several thousand patients, who have suffered serious injuries including death, have sued Boehringer Ingelheim Pharmaceuticals, Inc., the manufacturer of Pradaxa for failing to warn patients and their physicians about the serious adverse events that may result from taking Pradaxa. Many of these suits also allege that Boehringer promoted Pradaxa as being safer than warfarin.

If your physician has prescribed Pradaxa for you, you should immediately discuss whether there are safer alternative drugs for you. After weighing the risks and benefits, you and your physician can determine what drug is best for you. If you have taken Pradaxa, and have suffered uncontrollable bleeding, you should (after receiving medical treatment) consult with an attorney who is experienced in handling such a matter.

- Paul

Paul J. Molinaro, M.D., J.D.
Attorney at Law, Physician

Janice Boughton said...

All of these drugs are dangerous, but studies suggest that the newer drugs, including pradaxa, are less likely to cause serious bleeding than warfarin. There is no reversal agent for pradaxa, but its half life is short, so unlike warfarin it gets out of the system on its own within a day. In practice, although warfarin can be reversed with vitamin K or fresh frozen plasma, it takes a long time, usually a day, to reverse its effects. It is always necessary to weigh the risks and benefits of the different options, including not using anticoagulants at all.

Paul J. Molinaro, M.D., J.D. said...

Good information, Janice Boughton. Thanks!
- Paul