SAXOPHONE Bolsters Apixaban for Pediatric Heart Disease

There were low rates of bleeding and no thromboembolic events with either the DOAC or standard-of-care anticoagulation.

SAXOPHONE Bolsters Apixaban for Pediatric Heart Disease

Apixaban is a safe option for pediatric patients with a variety of congenital or acquired heart diseases who require chronic anticoagulation for thromboprophylaxis, the randomized SAXOPHONE study shows.

After a year of treatment, there were low overall rates of bleeding with both apixaban (Eliquis; Bristol Myers Squibb) and standard-of-care anticoagulation with warfarin or low-molecular-weight heparin and no thromboembolic events in either group, according to researchers led by R. Mark Payne, MD (Indiana University School of Medicine, Indianapolis).

Moreover, “predictable therapeutic drug levels were achieved with weight-based dosing,” they report in a study published online ahead of the December 12, 2023, issue of the Journal of the American College of Cardiology.

There’s long been a need for a less-cumbersome way to provide chronic anticoagulation to children with heart disease who need it, Payne told TCTMD, noting that warfarin and low-molecular-weight heparin—though effective—have various drawbacks. Parents balk at heparin injections for their children and prefer oral medications, like warfarin. But warfarin requires frequent blood tests to ensure it remains within the therapeutic range and comes with potential restrictions on what children can eat and what activities they can pursue.

“It makes it burdensome and sometimes very erratic to put children on current standard-of-care anticoagulation,” Payne said.

Apixaban and other direct oral anticoagulants (DOACs), which avoid some of the issues with warfarin and heparin, have proven to be safe and effective in adults, raising the possibility of using them in the pediatric population. Prior studies suggest that DOACs may be safe and effective in children and teens, but additional trials remain a high priority, according to the researchers.

There were no surprises that would stop the forward motion of apixaban moving into pediatric heart disease. R. Mark Payne

SAXOPHONE was a phase II, open-label trial conducted at 33 centers in 12 countries. Investigators randomized 192 patients ages 28 days to less than 18 years (mean age 7.8 years; 46.9% female) who had either congenital or acquired heart disease and an indication for chronic thromboprophylaxis 2:1 to apixaban with weight-based dosing or standard-of-care anticoagulation with warfarin or low-molecular-weight heparin. Most patients (74%) had single ventricle disease, 14% had Kawasaki disease with aneurysms, and 12% had other forms of congenital or acquired heart disease.

The primary endpoint of the trial was adjudicated major or clinically relevant nonmajor bleeding, and there was one such event in the apixaban group and three with warfarin or low-molecular-weight heparin (0.8% vs 4.8%), a nonsignificant difference.

The rate of any bleeding was higher in the apixaban arm (100.0 vs 58.2 per 100 person-years), although much of that difference was driven by events in 12 participants who each had four or more minor bleeds; 47.1% of those were minor nosebleeds. The proportion of participants with any bleeding was similar in the apixaban and control arms (37.3% vs 37.1%).

Pharmacokinetic/pharmacodynamic analyses showed that the weight-based dosing of apixaban used in the trial resulted in drug exposures consistent with what has been seen in adults.

“These important findings support the use of apixaban as safe and potentially a more convenient alternative to current standard-of-care anticoagulants for thromboprophylaxis in children with heart disease,” Payne et al write.

Data Not Surprising, but Important

In an accompanying editorial, Craig Mullen, MD, PhD (University of Rochester, NY), said the study “will prove useful not only to pediatric cardiologists but all pediatricians who need to treat pediatric patients with anticoagulation.”

The findings aren’t surprising considering the adult studies comparing DOACs with warfarin or heparin, but “they are important because they provide good data on the pharmacokinetics and pharmacodynamics of apixaban in children dosed according to weight,” he adds.

Though DOACs address some of the issues with warfarin and heparin that impact quality of life for patients and physicians alike, they do come with a risk of bleeding and potential drug-drug interactions, Mullen says. He noted, too, that “the lack of routine lab monitoring for apixaban may make it more difficult to assess effectiveness or toxicity until the patient clots or bleeds.”

Moreover, he says, there are some practical problems that could stand in the way of a switch from standard-of-care anticoagulation to apixaban in pediatric patients—namely, the lack of availability of the lower-dose capsules used in this study and the higher cost of apixaban, which will weigh on cost-effectiveness considerations.

Nonetheless, Mullen said, the investigators “should be congratulated for their work and for providing important information for pediatric cardiologists and hematologists that will allow them to dose this drug with confidence.”

Indeed, Payne said, “there were no surprises that would stop the forward motion of apixaban moving into pediatric heart disease.”

There are specific clinical scenarios in which standard options should still be the go-to—in patients with mechanical valves in the aortic position, for instance—but “otherwise, I think that DOACs such as apixaban can take the place of warfarin with relative safety,” he added.

As for the effect on thromboembolic events, “we didn’t have adequate numbers and could never get adequate numbers to test for efficacy,” Payne said. “However, we did not have any events of thromboembolism at the doses that we were using. So it was safe, and dosing was predictable. I think chronic long-term use will show that it is as efficacious as warfarin has been, but that study has not been done and I don’t know that it ever will be.”

Payne cautioned that these results do not apply to patients who have an established thrombus, noting that warfarin or low-molecular-weight heparin should still be considered the preferred options in that situation.

Todd Neale is the Associate News Editor for TCTMD and a Senior Medical Journalist. He got his start in journalism at …

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  • The trial was supported by the Bristol Myers Squibb/Pfizer Alliance (financing, drugs, data and adjudication, trial design, editorial support) and the National Heart, Lung, and Blood Institute (NHLBI)-funded Pediatric Heart Network (PHN; trial design input, Data and Safety Monitoring Board, additional committee and logistical support.
  • Payne reports having received grants or contracts from the National Institutes of Health (NIH)/NHLBI, the Friedreich Ataxia Research Alliance, and the Additional Ventures nonprofit organization; having received royalties or licenses from inventions through Wake Forest University, Larimar Therapeutics, and Indiana University; having received consulting fees from Larimar Therapeutics Inc.; having received support for attending meetings or travel from Indiana University School of Medicine; having two patents pending at Indiana University School of Medicine; being chair or serving on the Data and Safety Monitoring Board for an NIH study on Friedreich Ataxia; having served on the scientific advisory board for the Friedreich Ataxia Research Alliance; and having stock in Larimar Therapeutics, Inc.
  • Mullen reports no relevant conflicts of interest.