New Anticoagulants May Give Warfarin a Run for Its Money
Atrial fibrillation (AF) soaks up $26 billion in the U.S. annually. This figure is only set to rise. The estimated three million AF patients in the U.S. likely will double in the next 25 years (Circ Cardiovasc Qual Outcomes, online May 3, 2011). Most physicians turn to warfarin as the drug of choice to prevent stroke in the AF population, but now that novel therapeutics like dabigatran and rivaroxaban are available, will warfarin continue to own the U.S. anticoagulant market?

For years, warfarin has been the lone wolf on the anticoagulant market, but recently agents such as dabigatran (Pradaxa, Boehringer Ingelheim), rivaroxaban (Xarelto, Bayer/Johnson & Johnson) and apixaban (Eliquis, Bristol-Myers Squibb) have entered as competition, and may be poised to give warfarin a run for its money. While warfarin has a multitude of shortcomings—a narrow therapeutic window, a shorter half-life, frequent International Normalized Ratio (INR) checks and numerous food-drug interactions—it works. In fact, warfarin has been shown to reduce stroke by almost 62 percent when compared with placebo (Ann Intern Med 1999;131:492-501).

“It’s always good to have choices,” says Sanjay Kaul, MD, MPH, director of the fellowship training program in cardiovascular diseases at the Cedars-Sinai Medical Center in Los Angeles. But clinicians may be more apt to stick with prescribing the familiar drug, unless a patient cannot tolerate it.

Warfarin: Is it here to stay?

While warfarin has limitations, it is cheap and many patients have positive outcomes on the drug. So, when should a clinician switch a patient over to dabigatran or rivaroxaban?

“If a patient with known AF presents to me in a stable fashion on warfarin, I’m not in a  hurry to switch him or her to a newer agent,” Jeffrey I. Weitz, MD, deputy chair of research at McMaster University in Hamilton, Ontario, says. “However, if the patient’s INR is erratic or unstable on warfarin, then he or she would be a good candidate for a newer agent.”

Strategies for the new AF patient are more difficult, notes Mintu P. Turakhia, MD, cardiac electrophysiologist at Stanford Hospital & Clinics and director of cardiac electrophysiology at Palo Alto VA Healthcare System in California. “For a patient already on warfarin, it becomes a challenge because we are making inferences about anticoagulation control and how it compares to other agents across patient populations,” Turakhia offers. Data suggest that patients with poor INR would have fewer safety events (less bleeding and stroke) on either rivaroxaban or dabigatran; however, it remains unclear how compliant patients will be with these once-daily or twice-daily doses.  

Currently, with the help of CHADS2 scores, clinicians can make a better decision as to whom to place on specific treatment strategies and in whom to tailor treatment to the individual patient. In a substudy of the RE-LY trial, Oldgren et al found higher CHADS2 scores to be linked to increased rates of stroke, systemic embolism, bleeding and mortality in AF patients who received anticoagulants (Ann Intern Med 2011;155:660-667). Of the 18,112 AF patients in RE-LY who received oral anticoagulants, those who had a CHADS2 score between 3 and 6 had a higher risk of experiencing a primary endpoint compared with those who had a CHADS2 score between 0 and 1, 2.24 percent vs. 0.93 percent, respectively. Now, CHADS2 scores can identify who might benefit from a more complex treatment or benefit from aspirin alone.

“It is time to consider, where possible, switching patients over to the newer anticoagulants,” Justin A. Ezekowitz, MD, director of the Heart Function Clinic at the University of Alberta Hospital in Canada, says. “It also comes down to patient preference. Some patients are comfortable on the same drug [warfarin] they have been on for years and managed well.”

While Ezekowitz says that there is much known about warfarin use in complicated patients or high-risk groups, the same can’t be said for these newer agents that have far less exposure in the clinical setting. “In these settings, clinicians may be a little gun shy to prescribe newer agents,” he notes.

“However, the time has come to consider what is best for patients and this may include the use of these drugs as a first-line treatment, which might include switching patients even if they are tolerating warfarin well,” he says.

At TCT.11, Matthew R. Reynolds, MD, MSc, of the health economics and technology assessment research group at Saint Luke’s Mid America Heart Institute in Kansas City, Mo., questioned when warfarin may still be useful. While he noted that it is tempting to say never, he offered four possible scenarios:
  • When newer agents are contraindicated, not tolerated or a lack proven efficacy;
  • When significant drug-drug interactions cannot be avoided;
  • When the incremental costs of new drugs are not justified by the incremental benefits; or
  • When INR control is excellent.

Dabigatran, for instance, is contraindicated in patients with renal insufficiency because it is 80 percent renally extracted. Also, the safety of these agents in valvular AF patients, those with mechanical heart valves and those with cardioversion or other rhythm control interventions, has not yet been established.

Can we RE-LY on dabigatran?

The FDA gave the green light to dagibatran after its advisory committee voted unanimously in favor of the drug’s potential to prevent stroke and blood clots in patients with non-valvular AF. However, there was an odd twist—the FDA approved the higher 150 mg dose and the lower 75 mg dose, but not the 110 mg dose.

A major benefit of warfarin has been the drug’s capability to reduce ischemic strokes, Kaul says. However, not only did the 150 mg dose of dabigatran reduce ischemic stroke, it also reduced hemorrhagic stroke. The 110 mg dose did not obtain approval because while it reduced hemorrhagic stroke, it did not shave off any ischemic stroke risk, Kaul says.

“If you count hemorrhagic stroke for assessment of efficacy, you cannot also count it for assessment of safety,” he adds. “While it’s true that the 110 mg dose of dabigatran is safer in terms of bleeding, it does not reduce ischemic stroke. Stroke, especially disabling stroke, is arguably far more important than bleeding complications.”

Last month, the FDA said it was evaluating post-market reports of serious bleeding events in patients taking dabigatran. Previously, in the U.S., the drug maker suggested that healthcare professionals assess a patient’s renal function by evaluating the creatinine level prior to starting dabigatran treatment.

While dabigatran data are mostly positive, there has been a slight increase of MI, dyspnea and gastrointestinal bleeds linked to the drug, making some consider it as a second-line treatment, Turakhia says. However, he adds that “dabigatran is an equally viable alternative to warfarin and should be administered depending on individual patient profiles and risk.”

One pitfall of dabigatran is its one-size-fits-all dosing, Turakhia notes. While with warfarin physicians can titrate the desired dose to the anticoagulation level, dabigatran’s dosing strategy makes it unclear whether the drug’s potency can be tolerated throughout various patient groups.

For example, a 280-pound white man would be given the same dose of dabigatran as a 79-pound Asian woman with borderline renal insufficiency. “We need to figure out which patients are going to be on margins of risk and in what situations titrating patients on warfarin might actually serve them better,” Turakhia notes.

Kaul deems dabigatran “a wonderful addition to the armamentarium,” but he doesn’t see it as a replacement for warfarin.

The road to rivaroxaban

In November 2011, the FDA approved rivaroxaban as a first-line, once-daily treatment for the prevention of stroke in non-valvular AF patients after rivaroxaban was shown in the ROCKET AF trial to reduce the rates of intracranial hemorrhage and fatal bleeding compared with warfarin, 0.5 percent vs. 0.7 percent and 0.2 percent vs. 0.5 percent, respectively (N Engl J Med, online September 2011). However, the drug, and the trial, received considerable flak.

The FDA’s Cardiovascular and Renal Drug Advisory Committee voted nine to two that rivaroxaban be recommended for approval; however, the majority said the drug should be a third-line treatment behind warfarin and dabigatran. Most questioned the ROCKET AF trial design, which did not stipulate the use of an algorithm to manage INR as had the RE-LY and ARISTOTLE trials.  

Kaul argues that rivaroxaban should have been approved only for individuals who cannot tolerate warfarin or who experienced side effects on dabigatran. Turakhia supports the FDA’s decision.

Patients enrolled in the ROCKET AF trial were sicker, making it more difficult to keep them in a good therapeutic range compared with healthier patients. “Many have criticized ROCKET AF for having poor INR control on warfarin, particularly when compared with RE-LY,” Turakhia says. But he suggests this is a strength of the trial because it demonstrated that patients with more comorbidities may actually be better positioned to have better outcomes on newer anticoagulants, like rivaroxaban and dabigatran, rather than attempting to keep their INRs in check with warfarin.

Apixaban approval looks imminent

Following in dabigatran and rivaroxaban’s footsteps, warfarin may soon have another rival: apixaban. The FDA assigned apixaban a priority review designation in late 2011 and plans to issue a decision by March 28, 2012.

In the ARISTOTLE trial, Granger et al reported that apixaban proved to be superior to warfarin for the prevention of stroke or systemic embolism in AF patients (N Engl J Med 2011;365:981-992). ARISTOTLE enrolled 18,201 AF patients with at least one risk factor for stroke and patients were randomized to receive either apixaban or warfarin. Apixaban was found to reduce the risk of stroke and systemic embolism by 21 percent, major bleeding rates by 31 percent and mortality by 11 percent. The rates of hemorrhagic stroke were also 49 percent lower with apixaban.

Results of the AVERROES trial, presented at the 2010 European Society of Cardiology (ESC) Congress, showed that apixaban decreased the risk of stroke, systemic embolism and bleeding in AF patients. In fact, the results were so good that the trial was stopped early. Researchers concluded that apixaban may be more effective than clopidogrel plus aspirin and at least as effective as warfarin.

At the 2011 ESC Congress, a substudy of the ARISTOTLE trial showed promise for apixaban in a subset. “Not only was apixaban noninferior or equivalent to warfarin, it was better for reducing mortality,” says Ezekowitz, the substudy’s lead author. “Apixaban caused fewer bleeds than warfarin. With apixaban, you can prevent stroke and death at a cost that does not include increased bleeding.”

Outstanding issues

Adding in quality adjusted life years and costs associated with INR checks, complications, long-term care linked to incidence of stroke or intracranial hemorrhage, among others, warfarin may not be cost-effective. Turakhia offers that these newer drugs will be well in the range of the standard incremental cost ratio.

C. Michael Gibson, MD, chief of clinical research in the cardiology division at Beth Israel Deaconess Medical Center in Boston, projected that the annual cost of dabigatran would be $2,884 vs. an annual cost of $1,761 for warfarin plus INR monitoring. However, this resulted in $33,274 per year life saved, due to the reduction of mortality. An additional assessment estimated that dabigatran would cost nearly $9 per day.

Another question, Weitz asks, will be how novel anticoagulants and antiplatelet agents fit together.

“We always have been worried about warfarin and the dual-antiplatelet drugs—aspirin and clopidogrel—and now new drugs such as prasugrel and ticagrelor,” Ezekowitz offers. When these two classes of drugs meet, a patient’s risk of bleeding is increased. Strategies will be necessary to address complex patients who may need triple therapy—an anticoagulant, aspirin and an antiplatelet.

“At the verge of a major sea change on how we manage patients with AF, we have three agents that could be used to replace warfarin. But, how will we choose?” Weitz asks. It will be difficult to decide without head-to-head trial comparisons of the drugs.  

As newer anticoagulants hit the market, physicians will be left asking: who will tolerate what’s best? Making the decision to prescribe a flight of drugs—anticoagulants, dual-antiplatelet therapy, etc.—will be complicated, as these drugs are not sufficiently interchangeable. A multidisciplinary approach to manage stroke prevention in AF patients may be necessary to understand the risks, the benefits and the most beneficial prevention strategy.