On October 19, 2010, the FDA approved a long-awaited new drug, dabigatran, expected to replace warfarin (Coumadin) as a better way to prevent blood clots in susceptible patients. This provides an opportunity to re-visit several issues that we have addressed before, including Big Pharma tactics, drug approval by the FDA, deciding what is adequate evidence, applying science to clinical practice, and making individual health care decisions based on evidence that is sometimes incomplete.
Background
Patients with atrial fibrillation, artificial heart valves, deep vein thrombosis, pulmonary embolism, antiphospholipid syndrome, and people undergoing certain types of surgery are at risk of blood clots, embolism, and stroke. They are currently being treated with rat poison. Warfarin (Coumadin) is an anticoagulant originally intended to kill rats. It inhibits the vitamin K dependent synthesis of several clotting factors. It saves human lives but is a mixed blessing. It takes several days to achieve therapeutic levels. Patients must be monitored with frequent blood tests to ensure that their prothrombin levels stay between an INR (international normalized ratio) of 2 and 3. When starting out, this means blood tests every couple of days. For some patients, dosage fluctuates and requires frequent adjustments; others can eventually drop down to a monthly blood test. Warfarin interacts with a long list of other drugs that raise or lower its blood levels. It interacts with many foods, and patients have to modify their diet. It can cause serious bleeding complications; while preventing thrombotic strokes it can cause hemorrhagic strokes. It is taken once daily. There is an antidote, vitamin K, that can reverse its effects promptly.
Warfarin is the 11th most prescribed drug in the US. Its benefits clearly outweigh its risks, but we wish the risks were fewer. We have yearned for a better option: something safer, something that would not require monitoring with blood tests, something that foods wouldn’t interfere with, something that would not interact with every other drug in the book. And now it seems we have it: a direct thrombin inhibitor called dabigatran.
The Advantages of Dabigatran
Dabigatran is a pill taken twice daily as a fixed dose. It is immediately effective, versus the slow, several day onset for warfarin. No monitoring is required: no blood tests. It doesn’t interact with foods. It only interacts with a few drugs that affect levels of P-glycoprotein (such as rifampin, verapamil, and ketoconazole). Randomized controlled trials (RCTs) have shown that it is more effective than warfarin in reducing strokes and embolism and that it is less likely than warfarin to cause major bleeding complications. The difference is relatively small: the number of patients who would need to be treated (NNT) with dabigatran (rather than warfarin) to prevent one hemorrhagic stroke is approximately 370.
The Disadvantages of Dabigatran
It must be taken twice a day instead of once. Consistent timing of doses is important, because its effects wear off quickly compared to warfarin (its half-life is 12-17 hours vs. 20-60 hours for warfarin). It is more likely to cause dyspepsia (indigestion) and gastritis, and has a higher rate of major gastrointestinal bleeding (1.51% compared to 1.02% for warfarin). It costs about ten times as much as warfarin, around $200 a month.
Clinical Trials
The evidence has been consistently favorable and statistically significant. In the RE-LY trial,over 18,000 patients with atrial fibrillation were randomized to adjusted-dose warfarin treatment or dabigatran in two fixed doses (110 or 150 mg twice daily).In another trial, dabigatran and warfarin were compared in 2564 patients with venous thromboembolism. A meta-analysis of 3 trials showed that it was equivalent to injectable enoxaparin for preventing blood clots in patients undergoing elective hip and knee surgery.
Big Pharma and the FDA
Dabigatran has been available in Canada and Europe since 2008, and has been approved there for other indications like prevention of blood clots during surgery. The FDA has approved it only for atrial fibrillation. The FDA will inevitably be criticized for not approving it sooner, for costing lives by not making a better therapy available more quickly to US citizens. But it will be criticized for approving it too soon if post-marketing studies show unexpected problems. They can’t win.
It’s being marketed as Pradaxa by Boehringer Ingelheim. They stand to make obscene amounts of money before their patent runs out, but they had to spend obscene amounts of money to develop it. If they could not make a substantial profit they would have no motivation to create new drugs like this that may save a substantial number of lives. They were already aggressively advertising “Coming Soon” before the product was available on the market. There have been many discussions in the medical literature, some of which may well have been prompted by the manufacturer. It is to the company’s advantage to spread the word quickly, but it is also to the advantage of the provider and patient to learn when a better therapy is available. Big Pharma and advertising aren’t all bad.
Concerns
The FDA relied heavily on the results of one study to approve dabigatran for patients with atrial fibrillation. We try never to rely on one study, but in this case the study was particularly large, multi-center, well-designed, and supported by other related information. On the other hand, the study left some unanswered questions. It was open-label rather than double blind. The rate of complications with warfarin was higher in this study than was expected from the experience of previous studies. Might optimum control of INR have improved the warfarin results and lessened the apparent advantage of dabigatran? The average age of subjects was 71: might younger patients have different outcomes? The study lasted 2 years; might there be more adverse effects with longer use? A hazard ratio subgroup analysis indicated that warfarin was better than dabigatran for patients without hypertension and for patients in Europe: does this mean anything, or is it just noise in the data?
Real-world use is different from use in controlled studies. More people will be taking it, younger people, people with other co-existing health conditions, people who are taking other medications, people who may not comply with directions, people with different diets and lifestyles, people with different ethnicity or genetics, etc. As more people take it, rare adverse effects may become apparent. Post-marketing surveillance will be essential.
It has only been approved for patients with atrial fibrillation. Inevitably, doctors will prescribe it for off-label uses to include everything else that warfarin is used for. This is justifiable, but it would be nice to have pertinent studies. It is possible that the benefits may not be as great for other conditions as for atrial fibrillation.
The one-size-fits-all single dose may not be appropriate for every individual.
Conclusion
Fixed doses of the oral direct thrombin inhibitor dabigatran (Pradaxa) were at least as effective and safe as adjusted-dose warfarin in patients with non-valvular atrial fibrillation followed for a median of 2 years. Dabigatran, which does not require dose adjustment and close monitoring, could replace warfarin for this indication and probably others as well, particularly in patients with poor INR control. To what extent gastrointestinal adverse effects will limit its long-term use remains to be determined.
This does not fall under so-called “alternative medicine,” but dabigatran is an example of what “alternative” medicine should mean: a scientifically plausible, evidence-based alternative to warfarin.
This article was originally published in the Science-Based Medicine Blog
