Medical researchers are usually so cautious about characterizing results that when sober cardiologists use phrases like “very excited” and “a home run” and even “a new era,” you pay attention.
What’s causing this ripple is the emergence of new anticoagulant drugs, or blood thinners. Dabigatran (brand name Pradaxa) has already won Food and Drug Administration approval; rivaroxaban (Xarelto) has been endorsed by an F.D.A. advisory panel and awaits a final decision in November. A third drug, apixaban (Eliquis), exceeded investigators’ expectations in global clinical trials, according to findings just reported in The New England Journal of Medicine, and the manufacturer will seek F.D.A. approval by year’s end.
“The results are clear, so we’d expect the review process to be fairly rapid,” said Dr. Christopher Granger, the Duke University cardiologist who led the trials. A fourth new anticoagulant, edoxaban, is in advanced clinical trials.
As these medications hit the market, assuming most will, they’re likely to begin edging out warfarin, for 50 years the standard drug used to prevent strokes in people with atrial fibrillation. That’s what’s causing the cheers, though there are also some less-than-cheerful prospects.
A brief primer: Atrial fibrillation, a heart arrhythmia that can create blood clots, is thought to cause about one in five strokes in the United States. The condition increases steadily with age, so the number of people coping with it will rise along with the sheer numbers of older Americans.
Warfarin (Coumadin) reduces stroke risk from atrial fibrillation by about 60 percent, by thinning the blood so it’s less likely to clot. Along with blood pressure drugs, warfarin is one of the reasons that stroke deaths have declined sharply in recent decades.
But “the saying is that warfarin is the drug people love to hate,” said Dr. Jessica Mega, a cardiologist at Brigham and Women’s Hospital in Boston and author of an editorial in The New England Journal of Medicine hailing “a new era”. “It’s very unpopular.”
That’s because it affects individuals so differently that patients require careful monitoring; they typically have blood drawn each month to be sure the blood remains the proper consistency. “You want it thin enough that the drug is effective — you won’t form clots — but not so thin you’re going to bleed if you bump your head on the kitchen cabinet,” Dr. Mega said. If a doctor finds the monthly results unsatisfactory and adjusts the warfarin dose, the patient has to return for still another test.
“It’s a very labor-intensive medication,” Dr. Mega said. “People get fatigued, and they don’t want to do it anymore.”
Moreover, warfarin doesn’t play well with other drugs, from antibiotics to some blood pressure meds. Users even have to be mindful of what they eat (no bingeing on kale). And while some bleeding caused by warfarin — bruising, say, or nosebleeds –- is simply problematic and unpleasant, doctors particularly worry about bleeding into the brain. An intracranial hemorrhage can be fatal or disabling, as bad as the problems that warfarin was supposed to prevent.
That happens very rarely, it should be said. “It’s a low-frequency event, but it’s devastating,” Dr. Mega said.
So the goal in evaluating the new drugs has been to ascertain “noninferiority.” They didn’t have to be more effective than warfarin, which works quite well; they just have to be easier to take and no more likely to cause bleeding. That is benefit enough to seek F.D.A. approval.
Apixaban did well by those measures, the researchers found. In a randomized study of more than 18,000 people (median age: 70) with atrial fibrillation and at least one other risk factor for stroke, major bleeding occurred in 2.13 percent of patients in the apixaban group per year, significantly less than the 3.09 percent in the warfarin group. Apixaban significantly reduced bleeding in general, and brain bleeds in particular, compared with warfarin. And patients were able to skip the monthly monitoring. (Bristol-Myers Squibb and Pfizer, which hope to market apixaban, financed the study.)
But what caused excitement at the recent meeting of the European Society of Cardiology in Paris was that apixaban, a twice-daily pill, went beyond noninferiority. It prevented 21 percent more strokes than warfarin over the 1.8 years of the study and reduced deaths from any cause by 11 percent, in addition to reducing major bleeding incidents by nearly a third. “That’s a home run,” said Dr. Mega.
The other new drugs had similar benefits, she added: “Across all these trials, they make a whopping reduction in the risk of hemorrhagic stroke.” They have fewer dangerous interactions with other drugs as well. And although some drugs are less effective in the elderly, “one sees very clear findings of lower rates of stroke and bleeding among the elderly” in the apixaban study, Dr. Granger said.
The less-than-cheerful news is how much more the new meds cost than warfarin. Coumadin retails for about $1.50 a day, depending on dose. The generic goes for less than $10 a month at some big chains. By contrast, apixaban is expected to sell for $7 a day, a stiff price for patients on fixed incomes, even if they have Medicare Part D. “They fall into the doughnut hole fairly quickly,” Dr. Granger said.
Perhaps analysts will determine that cost savings of the new anticoagulants — at least a dozen monthly tests people no longer have to undergo, plus fewer strokes — will compensate for the higher costs.
Or maybe the competitive market will work the way it’s supposed to, with several new drugs entering the market in a short time creating downward pressure on costs. “We may be able to persuade pharmaceutical companies that it’s better to have broader use at lower prices than less use at higher prices,” Dr. Granger said.
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