Anticoagulants: The Brave New World

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Novel anticoagulants offer physicians a welcome option to warfarin for treating patients with atrial fibrillation who are at risk of stroke. But proceed with caution until more data accumulate, so say a selection of experts.

Worldwide sales of anticoagulants are expected to double between 2011 and 2018, a reflection of the growing number of people who will develop atrial fibrillation. Atrial fibrillation’s prevalence increases with age. As a result, the number of people in the U.S. with this arrhythmia disorder is expected to top 50 million by 2050, according to the Centers for Disease Control and Prevention. Based on current treatment patterns, 4.5 percent of those people annually will experience a stroke.

Market Share

According to EvaluatePharma's World Preview 2018 report:

  • Of all major therapy categories, anticoagulants have the highest growth through 2018;
  • Worldwide sales will increase from $8.1 billion in 2011 to $16.8 billion in 2018;
  • Apixaban is expected to see a 244 percent compound annual growth rate (CAGR) through 2018;
  • Rivaroxaban will have a more modest 57 percent CAGR; and
  • Sales of rivaroxaban will increase 86 percent in the U.S.

For decades, physicians turned to vitamin K antagonists to prevent blood clots that cause strokes. It’s a pact with the devilish, given warfarin’s narrow therapeutic range and interaction with other medications and food. Three FDA approved drugs—dabigatran (Pradaxa, Boehringer Ingelheim), a thrombin inhibitor, and rivaroxaban (Xarelto, Janssen Pharmaceuticals/Bayer HealthCare) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), both direct factor Xa inhibitors—have entered the scene in recent years. Compared with vitamin K antagonists, they may have varying lower bleeding and stroke rates, depending on the drugs and dose.

But they, too, have drawbacks. “If someone comes to the hospital and may be taking one of those drugs, we don’t know if we can treat them with one of the clot-busting drugs if they are having a stroke,” says Larry B. Goldstein, MD, co-chair of guidelines on use of these novel agents for the prevention of stroke in patients with nonvalvular atrial fibrillation (Stroke 2012;43:3442-3453). “We also don’t have a good way of reversing these agents right now.”

The newer agents also cost significantly more, at approximately $2,000 to $3,000 a year compared with about $50 to $100 for warfarin. 

Some physicians and their patients have decided the benefits outweigh any downsides. Registry data show novel oral anticoagulants nipping into warfarin’s lead.  An analysis of the American College of Cardiology’s PINNACLE-AF registry released in 2012 found that 12.6 percent of atrial fibrillation patients in the U.S. prescribed an anticoagulant received a novel agent rather than warfarin. Also, a Danish registry-based study that evaluated the use of dabigatran in the first four months after its 2011 approval in Europe reported that physicians prescribed the drug in doses of either twice daily 110 mg or 150 mg to 5.2 percent of patients with atrial fibrillation (BMJ online May 3, 2013). 

With enough data and time for follow-up, registry data potentially will allow researchers to detect outcomes not seen in randomized clinical trials, according to registry developers. The registries will capture data from patient populations that were excluded or underrepresented in trials, reflecting real-world clinical practice. 

“Clinical trials have a unique role in that they can tell us with a lot of accuracy what the exact effect would be of a particular medicine,” says Thomas Maddox, MD, chair of the PINNACLE registry research and publications subcommittee. “In the case of these novel anticoagulants, we know precisely how much of a stroke risk and bleeding risk would be accompanied by its use in a fairly homogenous, well-described population.”

Event & Crude Incident Rates Per 100 Patient Years
Event & Crude
Source: BMJ online May 3, 2013 / VKA = Vitamin K antagonist

Besides being homogenous, clinical trials often lack sufficient numbers to reveal rare adverse events. PINNACLE now has more than 9 million patient encounters, with data collection ongoing.  “Many risks are relatively small,” adds Maddox, who is a cardiologist at the Veteran Affairs Eastern Colorado Health Care System in Denver. “You are not going be able to see a signal of harm until you get to a big enough sample size of patients to have enough events to have it pop up statistically.”

Rikke Sorenson, MD, a cardiologist at Copenhagen University