Novel Anticoagulants Under the Fiscal Microscope

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Source: 201300043_Malone_DSC4640.jpg - DanielMalone
Daniel Malone, RPh, PhD, a pharmacy professor at the University of Arizona in Tucson, acknowledges that novel anticoagulants may be expensive but the prices aren't exorbitant, either. Source: The University of Arizona College of Pharmacy.

Novel oral anticoagulants (NOACs) may beat warfarin for cost-effectiveness, but does that mean they offer a genuinely good value? Physicians and payers might answer that question differently.

Heads or tails: warfarin or NOACs for preventing stroke in some atrial fibrillation patients? Talk with researchers who’ve asked that question, and it becomes clear that it is a coin toss. The decision comes down to the preference of the prescribing physician, shaped by his or her experience and views on efficacy and ease of use.

The picture doesn’t get much clearer when you add cost-effectiveness into the mix, but that’s where the conversation has been moving as U.S. healthcare continues to stress price considerations in clinical decision-making—and as the NOAC market, driven by aggressive direct-to-consumer marketing, grows by leaps and bounds.

Three FDA-approved drugs in the category have been duking it out with warfarin and each other: Bayer/Johnson & Johnson’s rivaroxaban (Xarelto), Boehringer Ingelheim’s dabigatran (Pradaxa), and, from Bristol-Myers Squibb and Pfizer, apixiban (Eliquis). In early 2015, Daiichi Sankyo’s edoxaban (Savaysa), also won FDA clearance, making it the fourth approved option. It may be closely followed by Portola/Merck’s betrixaban.

EvaluatePharma forecasts the NOAC market will expand by 11.5 percent annually until it hits $15.3 billion in sales by 2018. If that holds, there soon may be four or five blockbusters in one very lucrative drug category.

Sixty-year-old warfarin enjoys the benefits of familiarity, along with its reversibility when bleeding occurs or is likely, as in planned surgery. EvaluatePharma shows warfarin still captures more than 30 percent of the U.S. market, although rivaroxaban has displaced it as category leader for first-time anticoagulant prescriptions. But dosing remains difficult, food interactions are common and frequent monitoring for prothrombin time and international normalized ratio (INR) is required.

By contrast, the NOACs need little to no monitoring and carry less risk of causing brain hemorrhage and stomach bleeds. Clinically their biggest drawback is that they have no antidote—yet. At least two reversal agents have shown promise in trials.

As for price, the NOACs are steep while warfarin (Bristol-Myers Squibb’s Coumadin, generics from numerous factories) is cheap. This has some questioning the wisdom of rushing to replace the old with the new on a broad scale in a time of cost-containment, especially if the NOACs are not vastly safer and more efficacious than the established treatment.

Expensive but (sometimes) worth it

Harvard Medical School’s Niteesh K. Choudhry, MD, PhD, a hospitalist at Brigham and Women’s Hospital in Boston whose research concentrates on evaluating novel strategies for improving care quality while reducing costs, says the NOACs offer a game-changing therapy for many patients. However, they may not represent good value for the money (Circ Cardiovasc Qual Outcomes online Nov. 13, 2013).  

“Apixaban fell just below the $100,000 per quality-adjusted life year [QALY] threshold,” Choudhry explains. “That’s not bad in and of itself; it suggests that the drug may represent good value. But there are so many unknowns about how these drugs work in the real world and, when you subject an analysis of cost to sensitivity analyses and you re-run them, it’s not so clear. And, in fact, warfarin came out to be the winner in more simulations than apixaban. Hence our conclusion.”

He notes that, throughout healthcare, $50,000 remains the benchmark threshold for QALY more than 20 years after it was established.

In 2014 Choudhry and colleagues looked at trends in utilization of NOACs and the resulting economic outlays (Am J Med. 2014;127[11]:1075-1082). The study zeroed in on atrial fibrillation patients initiating an oral anticoagulant, and the data showed that rapid adoption of NOACs into clinical practice has high-cost consequences.

“In and of itself, use of these drugs may represent good clinical value,” says Choudhry. “In fact, as a practicing doctor, I have a lot of enthusiasm for these medications. Clinically, they represent a vast improvement over warfarin in many regards. But seeing the value is really sort of a societal judgment. As a whole, given limited budgets, which we are all unfortunately faced with, do these really represent overall good value for society? The answer is not exactly clear.”

Choudhry adds that analyses of cost-effectiveness tend to leave out long-term effects on payers. His research group showed that average patient out-of-pocket and insurance spending is more than fivefold and 15-fold higher, respectively, for NOACs compared with warfarin. “A six-month difference in total costs of $900 in our cohort translates into billions of dollars at a national level,” he says. “If we were to transition everyone from warfarin to one of the novel anticoagulants, it would probably drive up spending quite a bit. As we think about determining whether or not a new drug represents good value, I think we shouldn’t ignore the payer’s perspective.”

No news is good news? 

The line on the cost-effectiveness of the NOACs hasn’t changed much since spring of 2013, when a study showed that, for patients with nonvalvular atrial fibrillation and an increased risk of stroke, the three approved NOACs were all cost-effective alternatives to warfarin (Stroke 2013;44:1676-1681).

“Everybody has been finding pretty much the same thing,” says study lead Daniel Malone, RPh, PhD, a pharmacy professor at the University of Arizona in Tucson. “The numbers vary slightly in terms of cost-effectiveness, depending upon the structure of the model and the assumptions made, especially with respect to warfarin. The prices are certainly not cheap, but they’re not sky-high, either.” He adds that, in his opinion, the rise of the NOACs represents a scientific breakthrough marked by a modest increase in cost vis-à-vis benefits.

Malone sees no dominant NOAC akin to atorvastatin (Lipitor, Pfizer) in the brand statin market. “You’re going to have more of a level playing field in this space,” he predicts. “We’ll probably see a new degree of comfort by the prescribers with these agents.”

Competition on a level playing field usually has a happy effect on pricing, at least from buyers’ point of view. Is that likely with the NOACs? Perhaps, says Malone, but the effect likely will come on the back end via rebates and bundling. “The manufacturers might use a market basket approach, as some of them are quite well known for doing that,” says Malone. “Some of the health plans may be able to get preferred pricing on one agent over the other. I don’t know of anybody who is doing a preferred agent, but someone may be—and, if so, it’s probably based solely on price.”

Viable alternatives with reservations 

Matthew Reynolds, MD, MSc, a cardiologist at the Lahey Clinic in Burlington, Mass., and director of economics and quality-of-life assessment at the Harvard Clinical Research Institute, is intrigued by ongoing research looking at use of the NOAC drugs in the setting of catheter ablation for atrial fibrillation.

“It’s an interesting area where the two intersect,” he says. “The standard in afib ablation before the NOACs were available had evolved to doing the procedures on warfarin, without any interruption of the warfarin. This seemed to produce much better results than stopping and starting warfarin and using some sort of bridging anticoagulant therapy. We’re slowly learning and trying to get some comfort level with doing these procedures in patients who take NOACs.”

Reynolds stresses that the NOACs pose no market threat to ablation. “The role of ablation procedures is about trying to control the arrhythmia and the symptoms that the arrhythmia causes, whereas the blood thinners are all about stroke prevention,” he says. “It may be the case that catheter ablation does something with respect to stroke prevention, but these things are not competing.”

Reynolds also offers an observation on NOAC perceptions vs. reality. “Atrial fibrillation is incredibly common, and a lot of atrial fibrillation patients are not managed by specialists,” he says. “I see a lot of people who clearly have spoken to their primary care physician, and they all got the same line. These patients come in and say, ‘I heard from my doctor that I shouldn’t take one of those because if I start to bleed nobody will be able to stop it.’”

For some patients, Reynolds notes, that’s a legitimate concern. But many internists may be ignoring the major message of all the clinical trials on NOACs, which is that they prevent ischemic stroke and they reduce the risk of intracranial bleeding relative to warfarin.

“Reversal agent or no reversal agent, that was a very consistent and very important finding from all the studies with all of the novels,” he says. “We’ll see what happens, but I think that fear about not having reversal agents will go away as soon as we have one.”

For Choudhry, the larger challenge is adherence, as some of the NOACs at some doses require a twice-a-day regimen and dabigatran needs to be kept in its original packaging in order not to disintegrate. So much for using reminder pillboxes.

“There are a couple of clinical considerations beyond unknown risks that we’ll only learn over time, with use, as happens sometimes with drugs,” says Choudhry. “And those are really the questions that I ask myself when thinking about prescribing these drugs. If money were no object for a given patient—cost-effectiveness doesn’t apply to individual patients as it does to the healthcare system as a whole—and if I had no concerns about adherence, then the use of these drugs would, for me, in the clinical context, represent a very viable and attractive alternative to warfarin.”

Cryoballoon Ablation’s Payment Quandary

In 2013, Matthew Reynolds, MD, MSc, a cardiologist at the Lahey Clinic in Boston and director of economics and quality-of-life assessment at Harvard, led a study that showed cryoballoon ablation provides increased quality-adjusted life expectancy compared with anti-arrhythmic drug therapy at reasonable additional cost, representing good value in patients with paroxysmal atrial fibrillation (Europace 2014;16[5]:652-659).

“We’re now into next-generation catheters,” says Reynolds. “Both radiofrequency and cryo systems have been updated and improved. And they’re not repeating the randomized trials because they don’t have to, frankly. But in both cases, there’s reason to believe that the new catheters may be more effective than, and equally safe as, the preceding ones.”

That’s the good news. The not-so-good news is that some payers have proven stubborn about looking past FDA’s years-old approval.

“Most of our payers are fine with it [the cryoballoon system], but there are some Blue Cross carriers in particular that won’t pay for it,” he says. “They’ll pay for catheter ablation using the standard radiofrequency catheter but won’t pay for the use of a balloon catheter—even though both of them went through similar randomized trials,” where they were compared to antiarrhythmic drugs and those randomized trials produced similar results.

Reynolds notes that the denials have continued even in the wake of evidence of their safety and effectiveness. The Blues argue that the approach is still experimental.

“They’re stonewalling.”