FDA Approval of Betrixaban Could Potentially Alter the Future of VTE Treatment

In June, the US Food and Drug Administration announced the approval of BEVYXXA (betrixaban) for the prophylaxis of venous thromboembolism (VTE) in hospitalized acute medical illness adult patients who are at risk for thromboembolic complications

due to moderate or severe restricted mobility and other risk factors for VTE.

Betrixaban is the first preventive VTE treatment available, produced by Portola Pharmaceuticals. It was approved based on data from a randomized, double-blind, multinational clinical trial, called Acute Medically Ill VTE Prevention with Extended-Duration Betrixaban (APEX).

The history of treating venous thromboembolism in patients dates back to at least the 1930s, when the anticoagulation medicine heparin was introduced to treat VTE. The disease consists of deep vein thrombosis (DVT) and pulmonary embolism (PE), and is most often seen after surgeries and hospitalization.

Since the 1930s, multiple other treatments have been introduced to treat deep vein thrombosis and/or pulmonary embolism, including enoxaparin (1993), dabigatran (2010), rivaroxaban (2011), apixaban (2014), and edoxaban (2015). For patients with cancer, low molecular weight heparin (LMWH) is used, usually administered as a subcutaneous injection.

However, despite these numerous treatments, none are approved for in-hospital and extended-duration VTE prophylaxis. There has never been a medication for prevention of VTE, despite its widespread effect on those at risk. According to data shared by the Centers for Disease Control and Prevention (CDC) in 2010, “The precise number of people affected by DVT/PE is unknown, although as many as 900,000 people could be affected (1 to 2 per 1,000) each year in the United States.”

Of that nearly 1 million, the CDC estimates that somewhere between 60,000 and 100,000 Americans die each year because of VTE, and that 10% to 30% die within a month of the diagnosis.¹

“For the first time, physicians will have a therapy to help reduce VTE in acutely ill medical patients during their transition from hospital to home, which may ultimately help reduce morbidity,” Alexander Cohen, M.B.B.S., M.Sc., M.D., FRACP, APEX Co-Principal Investigator and Co-Chairman of the APEX Executive Committee and Consultant Physician at Guy’s and St Thomas’ NHS Foundation, said of betrixaban in a Portola news release.

That reduction of VTE in patients who are already being treated for acute medical illness is why the FDA’s approval of betrixaban for the prophylaxis for VTE in hospitalized adult patients is huge step forward.

“We've had Xa inhibitors around for prevention of stroke in atrial fibrillation. We've had treatment of VTE. But now we have a medication for prevention of VTE, which is a really important thing,” Karol Watson, MD, professor of medicine and cardiology, co-director of Preventive Cardiology, director of Barbara Streisand UCLA Women’s Heart Health Program, UCLA, told MD Magazine. “The fact there could be something now to prophlyaxigance—that's huge, because of the downstream effects of VTE morbidity. It happens most commonly in older patients. They don't always recover, so having something than can prevent that is big.”

The trial compared extended during betrixaban over a 35- to 42-day period with short duration enoxaparin over a 6- to 14-day period, in the prevention of VTE in a population of 7,513 hospitalized patients that were at-risk for developing the disease.

In the trial, patients were exposed to one of two randomized study arms: betrixaban in a 160-mg oral initial dose, followed by 80-mg once daily for the 35- to 42-day period, coupled with a placebo injection for once daily for 6 to14 days; or enoxaparin in a 40-mg subcutaneous injection once daily for 6 to 14 days, coupled with a placebo tablet consumed orally once daily for 35 to 42 days.⁴

The form of absorption is one of the main differences with betrixaban and its potential relationship with patients it will be available to in terms of treatment quality. The APEX study showed its performance against enoxaparin, a subcutaneous injection medicine, in critically ill patients, when patients are not intubated, there may be preference for PO medicine over an injection.

“We do have plenty of patients who are ill, but not necessarily intubated, that do voice their opinion against injections, so this could be a preferred approach,” Puneet Gandotra, MD, FACC, director of the Cardiac Catheterization Lab at Southside Hospital, and assistant professor at Hofstra Northwell School of Medicine, told MD Magazine. “When they’re told the efficacy is similar, patients would probably prefer to take the pill form. As long as the physician mentions that both are acceptable, patients will be accepting. We have to make sure it’s an equivalent to other treatments, though.”

When compared to enoxaparin, betrixaban’s efficacy was measured by a composite outcome score made up of the occurrence of non-fatal PE, asymptomatic or symptomatic proximal DVT, or VTE-related death. The patients receiving betrixaban experiences these occurrences at a lower rate than enoxaparin, 4.4% to 6%, respectively (relative risk, 0.75; 95% CI, 0.61-0.91).

More than 50% of the patients that received either treatment experienced at least one adverse reaction, with bleeding-related incidents being the most common occurrence for those on betrixaban. The frequency of patients reporting serious adverse reactions was similar between betrixaban (18%) and enoxaparin (17%). The most frequent reason for treatment discontinuation was bleeding, with an incidence rate for all bleeding episodes of 2.4% and 1.2% for betrixaban and enoxaparin, respectively.

“Every time we deal with anticoagulants, or even antiplatelets, it's always a balancing act between efficacy against thrombosis, and safety against bleeding,” Watson said. “So, that's where we have to get really smart about risk assessment and figure out who's at risk most.”

According to a 2014 study titled Assessing Bleeding Risk in Patients Taking Anticoagulants, coauthors Marwa Shoeb, MD, MS, and Margaret Fang, MD, MPH, wrote that patients with VTE run a 7.2% risk of major bleeding, and a 1.31% of fatal bleeding, “with a case-fatality rate of 13.4% from major bleeding.”¹²

“Many people don't realize that bleeding is a serious disease,” Jared Huston, MD, assistant professor of surgery and science education at Hofstra Northwell School of Medicine told MD Magazine. “We don't really talk about it much, but it really impacts many different medical and surgical specialties.”

Betrixaban’s incidence rate for major bleeding episodes was not statistically significantly increased compared to enoxaparin, coming in a 0.67% and 0.57%, respectively.

“[Betrixaban] represents a major advance for the field of thrombosis. It is the first therapy to demonstrate a reduction in the incidence of VTE in these high-risk patients without a significant increase in major bleeding,” C. Michael Gibson, MD, APEX Executive Committee Member and Steering Committee Chairman, professor at Harvard Medical School, and PERFUSE Study Group Chairman, said in a Portola new release.

When it comes to VTE, bleeding events are very difficult to predict and identify, according to a 2016 study by FA Klok, MD, and colleagues, making the prevention of the disease extremely important, especially in older patients.

“It’s an inherit issue, and risk:benefit. We do know that the bleeding events are very low, and the long-term benefits of not getting DVT or PE are quite significant,” Gandotra told MD Magazine. “I think that with every one of these medicines coming to market, the primary focus is risk-benefit. If enoxaparin is accepted as a good medicine, then if something can show non-inferiority, it’s perfect. The risk of bleeding happens with plenty of other blood thinners, like Xarelto and Eliquis and others, so I’m not that concerned about it. Bleeding events are part of the game, so to say.”

VTE is also significantly more present in older patients than others. Where the average number of persons aged 18 to 39 hospitalized with VTE coming in at 54,034, the average number of VTE patients aged 60 or older is a staggering 350,208 per year in the US, per a CDC report and a study from 2012.¹⁰ This, coupled with the fact that elderly patients are the highest risk for incidence of comorbidities, is reason for concern among physicians and why prevention is so vital.

“It is so much better to prevent something than to worry about treating it, because there are certain things you can't get back fully functioning,” Watson told MD Magazine. “So, I think if you have someone at risk, it makes so much sense to think about preventing this.”

Currently, VTE risk is estimated at 20% for general surgical patients and 30% for those undergoing colorectal procedures. Per a 2013 study on VTE prophylaxis by Jonathan Laryea, MD, and Bradley Champagne, MD, “Pulmonary embolism (PE) is recognized as the most common cause of preventable hospital deaths, accounting for up to 200,000 deaths annually in the United States.”²

Existing prophylaxis for VTE consists of graduated compression stockings (GCS), intermittent pneumatic compression (IPC) devices, and the previously mentioned unfractionated heparin, LMWH, and fondaparinux, with most strategies for prevention utilizing a combination of these available interventions.

Laryea and Champagne found that patients using GCS alone developed DVT at a rate of 15%, decreased to 3% when combined with another method; IPC devices alone decreased the risk of DVT by 60%, but was still more effective when coupled with another method.

This provides for the combination of betrixaban with GCS or IPC devices to aid in the risk reduction of VTE in acute medically ill patients by a significant amount.

“I think that it’s all patient specific. At the end of the day we have to make sure it’s not a cookie-cutter approach. We’ll always combine treatments when we have to,” Gandotra told MD Magazine. “Even then, if one medicine versus another tends to work well in one instance, it doesn’t necessarily mean we have to use them in combination. It differs with patients as well. Some patients require one thing, others require another, especially due to comorbidities."

As for how it will fair, that remains to be seen. Gandotra told MD Magazine that he doesn’t anticipate betrixaban being used widely in a hospital setting for at least 6 months to a year. It is going to boil down to “the aggressiveness of the company and acceptance of the hospitals. It also has to be finically viable, which tends to drive lots of new drugs, frankly,” he said.

Of course, like with all medications, betrixaban doesn’t come without its precautions. Patients with prosthetic heart valves and hepatic impairment have not been evaluated for the use of betrixaban, so it is not recommended for these patients. Betrixaban is recommended in lower dosages for use in patients with severe renal impairment, concomitant P-glycoprotein inhibitors, and patients undergoing spinal or epidural anesthesia or puncture.

Additionally, the real-life results of the drug are the final question that remains to be answered. Despite success in the APEX trial, the drug still remains to be tested in a hospital setting, and now faces the challenge that all newly approved drugs face: the performance in real-life registry.

“I think overall that I think it’s a good step forward. I’m always skeptical about new medications until they show clinical efficacy in a real-life registry,” Gandotra said. “Post registries really are where you’ll see the efficacy and benefit. We see it in controlled trials, but we have to keep that in mind that there are situations we’ll see in hospitals that don’t occur in controlled situations. I think we’ll see it succeed, but we have to be conscious not to accept it right away.”

Moving forward, it appears the goal will be for future medicines to reduce the risk (of bleeding) as much as possible in the risk:benefit relationship for VTE prophylaxis. Other blood thinners have experimented with lower dosage levels to help decrease the risk of major bleeding events as much as possible. The industry continues to explore the possibilities of reducing that risk through dosage alterations, and the plan going forward appears to be continuing along that line.

“We will continue to come up with blood thinners have lower bleeding efficacy or lower doses,” Gandotra said. “All these new medicines coming through have lower doses, to see if we have the same efficacy with less bleeding. I’m not that concerned about it, bleeding events are part of the game, so to say.”

Portola plans to launch betrixaban between August and November 2017. The European Medicines Agency’s Committee for Human Medicinal Products is currently reviewing the drug. The FDA’s recommended dose of betrixaban is equal to that of the trial’s dosage, with an initial single dose of 160 mg followed by a once-daily 80 mg dose, taken for 35 to 42 days with food.

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