Anticoagulants: The Brave New World

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 Hospital Gentofte in Hellerup, Denmark, and lead author of the Danish study, agrees that it is premature to spot adverse events in registry data. But the Danish study offered an early peek into prescribing habits. Physicians in the analysis generally complied with European Medicine Agency (EMA) guidelines when prescribing lower dose dabigatran, which is indicated for patients 80 years old or older or those with an increased risk of bleeding. But they were much more likely to go off label at the higher dose; only 55.5 percent of patients prescribed the 150 mg dose met EMA recommendations, a point of concern for Sorenson.

“It is important to fulfill the recommendations, at least in the beginning, to see in what patient groups you should more be aware of side effects,” she says.    

Sorenson attributes some of the off-label prescribing to noncardiologists who may not be aware of the EMA guidelines. Additionally, guidelines from the EMA and the European Society of Cardiology are comparable but not exactly the same, which may lead to some confusion. To be adherent to guidelines, prescribing had to meet both group’s standards in the study.

Sorenson and colleagues found that bleeding risk was increased in patients previously prescribed vitamin K antagonists who were switched to the 110 dose of dabigatran but not patients in the 150 mg group (who were younger and healthier) or vitamin K antagonist naïve patients. “This is a group of patients who have been not well regulated on vitamin K antagonists,” she says. “They are very difficult patients with severe illnesses and poor compliance.”

Goldstein, director of the Duke Stroke Center in Durham, N.C., notes that his center has already treated patients on novel oral anticoagulants who missed a dose or two, lost the drug’s protective powers and then experienced a stroke. “Reliability and patient compliance issues are no less important with these newer drugs than with warfarin,” he cautions.

He reiterates that having an option to vitamin K antagonists advances care for patients at risk of stroke, though. Some physicians are embracing the newer anticoagulants while others maintain a wait-and-see strategy until registry analyses provide evidence in addition to clinical trial data. That could happen within a year, according to Maddox.

But most physicians agree that there is one group of patients poised to benefit greatly from the addition of the newer therapies: those who are compliant on vitamin K antagonists yet still have difficulty staying within an acceptable international normalized ratio, which puts them at risk of thrombosis and stroke or bleeding. “These drugs may offer a distinct advantage in those particular patients,” Goldstein says.

Registries Help: Surveillance Snapshot

Cardiologists can turn to numerous resources to track outcomes once a novel anticoagulant has been approved but each has its strengths and weaknesses. Given their observational designs, registries and other surveillance programs cannot directly compare one treatment to another or establish causality.

But the ongoing gathering of data over time can be used to not only elucidate practice patterns but also help change them for the better, says Paul N. Casale, MD, chair of the steering committee for the American College of Cardiology's PINNACLE-AF registry and chief of the cardiology division at Lancaster General Health in Lancaster, Pa. Studies based on registry data can shed light on best practices and temporal trends.

"It is an iterative process," Casale says. "When we re-analyze the data in the registry we can see if the results of our first analysis change behavior and identify [practices] that lead to a better outcome. That is where the registries can be very helpful."

Registries also give participants insight on their own performance, including adherence to guidelines. "Are we delivering care [according] to the guidelines, and how is that care being delivered?" asks J. Brendan Mullen, senior director of Quality First Network with the ACC.

PINNACLE, which is part of the larger National Cardiovascular Data Registry, offers participants the incentive of feedback and facilitates participation by integrating data entry with an EHR. Those carrots are missing in surveillance databases such as the FDA's Sentinel and Mini-Sentinel, which tasks physicians with filling out administrative forms.

"The entire process is onerous," says Thomas Maddox, MD, chair of the PINNACLE registry research and publications subcommittee and a cardiologist at the Veteran Affairs Eastern Colorado Health Care System in Denver. "As a result, there is significant underreporting of adverse events to the FDA of medications and other interventions."

Data in the FDA programs may lack PINNACLE's breadth but what is reported is highly detailed. "For those events that are captured, there is rich, granular data around the patient and what happened," Maddox says.

Theoretically, collaborations across resources would help to make databases even more robust and reduce redundancies, according Mullen. For instance, Sweden boasts a comprehensive database on cardiovascular diseases but it is limited in size and diversity. If national registries can be harmonized—no small feat—potential payoffs include less fragmentation and more efficiency.

"Instead of publishing the parallel paper, can we jointly answer more sophisticated questions and faster by working together," Mullen says.