A Closer Look: A new blood thinner option
For the estimated 2 million Americans with atrial fibrillation who take the blood thinner warfarin to reduce their risk of stroke, there’s a new drug on the shelf — the first in two decades.
FOR THE RECORD
An earlier online version of this article incorrectly said the rate of stroke among patients in a clinical trial comparing dabigatran and warfarin was 0.10% (1 in 1,000) per year for patients taking 150 milligrams of dabigatran and 0.38% (nearly 4 in 1,000) for those on warfarin.
The Food and Drug Administration last month approved dabigatran (sold under the brand name Pradaxa) based on clinical trial data showing that it’s at least as effective as the old standby. The new drug offers practical advantages for patients, namely avoiding the frequent blood tests and dose adjustments required with warfarin (also known by its brand name, Coumadin).
“It’s a potential game-changer,” says Dr. Mintu Turakhia, a cardiologist at the Palo Alto VA Hospital and Stanford University.
The clinical trial was huge, comparing two doses of dabigatran with warfarin treatment in 18,113 patients across the globe and following them for two years. The rate of stroke was 34% lower in the high-dose group — 150 milligrams, which was the dose approved by the FDA — than in the warfarin group. Actual rates per year were 1.1% (11 in 1,000) for the group on 150 mg of dabigatran and 1.7% (17 in 1,000) for warfarin The study was published last year in the New England Journal of Medicine.
“There’s a lot of excitement about this drug,” says Dr. Noel Boyle, a UCLA cardiologist. “It’s the long-awaited alternative to warfarin.”
Uncertainties remain, however, as is always the case when a drug moves from clinical trials to wider distribution.
Here’s a closer look at stroke prevention treatment for high-risk patients.
How can people reduce their risk of stroke?
Risks include age, family history and personal history of stroke or heart attack. Of treatable risk factors, high blood pressure and atrial fibrillation rank as the big two. Others include heart failure and diabetes.
Atrial fibrillation is an abnormal heart rhythm, specifically a too-fast beating of the smaller chambers of the heart called the atria. Also called A-fib, the condition increases a person’s stroke risk by a factor of five.
The link between atrial fibrillation and stroke was established by the Framingham Heart Study about 30 years ago, Boyle says. In the late 1980s and early 1990s, several large clinical trials showed that the blood thinner warfarin — referred to by many patients as “rat poison” because it was first marketed as a pesticide — reduced the risk of stroke by about 66% compared with placebo in patients with A-fib, he says.
How do the treatment drugs work?
Clotting factors in the blood depend on the presence of vitamin K. By blocking the site where vitamin K usually acts, warfarin inhibits clotting.
However, patients taking warfarin must have their blood checked periodically because its effect on blood can be modified by foods and other drugs. For instance, when people eat foods rich in vitamin K — such as leafy greens, broccoli and Brussels sprouts — the extra vitamin K competes with warfarin and the blood’s clotting activity can increase to unhealthy levels. In addition, many other drugs — including aspirin, Cymbalta, Flomax, Lipitor and Plavix — interact with warfarin, changing its effectiveness.
“Because of these interactions, the safest way to manage warfarin treatment is by monitoring blood,” Turakhia says. Monitoring can be as frequent as every other day or as infrequent as once a month. Often, blood testing shows that the warfarin dose must be adjusted. Too much inhibition of clotting could cause bleeding problems; not enough inhibition means less protection against stroke.
Dabigatran is a direct thrombin inhibitor and acts at a different step in the coagulation process. Normally, thrombin promotes clotting by making blood platelets clump and by prompting tiny fibers to grow and catch the sticky clumps.
Dabigatran is not sensitive to diet or drug interactions, so patients don’t need blood testing and can take the same dose every day. This practical benefit can be huge to patients, because it reduces the burden of getting blood tests and then waiting for a provider to call back with a dose adjustment.
Dabigatran is not the only direct thrombin inhibitor to be tested for stroke prevention, but it’s the first to pass muster. The FDA did not approve an earlier candidate, ximelagatran, after liver damage was observed in 7% of patients taking it. Results from a new clinical trial, testing a drug called rivaroxaban, are to be presented this week at the American Heart Assn. conference in Chicago.
What are their potential side effects?
Thinning of the blood increases the risk that bleeding will get out of control, and the most concerning side effect of warfarin is bleeding in the brain. The risk of intracranial bleeding is so low that it’s hard to measure, but when it happens, the result can be as devastating as a stroke. Some experts estimate that there are fewer than five events per year for every 1,000 patients on warfarin, but the risk may increase with age and in people at greater risk of suffering falls — and thus, blows to the head.
The dabigatran trial found rates of bleeding problems were similar for both the 150 mg dose of dabigatran and warfarin — about 3% per year. But the rates of brain hemorrhage were lower for those taking dabigatran. In a subgroup of 3,623 patients who had a history of stroke, 30 people on warfarin had brain bleeding, compared with 13 in the dabigatran group. That study was published online last week in the journal Lancet Neurology.
In addition, a small increase in the rate of heart attack was observed in the dabigatran trial; that’s something many will be watching as the drug enters wider use. Boyle says about 20% of patients enrolled in the trial stopped taking the drug after two years because of stomach upset. Other unanticipated side effects might also emerge.
What are the cost considerations?
Warfarin is a cheap, generic drug that costs about $1 per day. The wholesale cost of a daily dose of dabigatran was set at $6.75, so with a typical 20% to 25% markup, the price will be around $8. It hit the shelves at Kaiser Permanente in Los Angeles last week at about $7, says Dr. Zahra Ajani, who is the director of stroke and cerebrovascular neurology there.
However, the price gap narrows — or may even disappear entirely — when all the costs are taken into account, Turakhia says. There are the related costs of treatment, such as the office visits and lab tests for blood monitoring required with warfarin. There are also costs associated with poor outcomes, such as the cost of care for stroke.
Turakhia co-authored a study this month in Annals of Internal Medicine that compared the cost-effectiveness of warfarin and dabigatran, taking account of all these factors. His team calculated that for a 65-year-old patient with A-fib and other risk factors for stroke, the lifetime cost of treatment came to $143,193 with warfarin and $168,398 for dabigatran. The analysis was done before the price was set for dabigatran and used a cost of $13 per day, so the true lifetime cost of the drug would be lower.
But even with a $25,000 difference, it’s not clear that warfarin is a bargain. “If warfarin costs less but you had a stroke or bleeding in the brain while on warfarin, then is it really a deal?” Turakhia says. “The answer is no, because the quality of that life is less than someone who has not had a stroke.”
