More Questions Remain About the Role of Statins in Pediatric Heart Transplant

Statin therapy—a well-utilized strategy to manage cardiac allograft vasculopathy (CAV), a common long-term complication in heart transplantation—may not provide the same benefits in younger pediatric heart transplant recipients.

The authors of a recent study concluded that there are likely underlying factors at play in the development of CAV in children that could explain why younger patients don’t appear to respond as favorably to statins compared to adults.

They published their findings in The Journal of Heart and Lung Transplantation.

CAV and long-term survival outcomes

Despite considerable progress in pediatric heart transplantation over the past three decades, long-term graft survival outcomes have remained relatively stagnant. Experts say CAV is a significant barrier to long-term survival in recipients, making it a vexing issue within the pediatric heart transplant community.

Following a post-transplant CAV diagnosis, graft survival is approximately 50% at five years. In addition to being difficult to diagnose, there are no good strategies to prevent or delay its progression, according to pediatric cardiologist and first author Madeleine Townsend, MD.

And while the use of statins to prevent or delay CAV is well-supported in adult heart transplant, its benefits are less certain in children.

Statin use in kids: The pediatric literature is mixed

“The adult literature is compelling that statins improve all-cause mortality and decrease the development of CAV, among other things, including in a recent meta-analysis. But the pediatric literature is much more mixed,” notes Dr. Townsend.

Two decades of data support its use and safety in children undergoing heart transplantation. The International Society for Heart and Lung Transplantation guidelines also recommend consideration of statins in both adults and children. Despite this, statin use for pediatric heart transplant recipients has yet to be unanimously embraced, owing to the lack of evidence demonstrating its benefit.

Most of the studies pediatric heart transplant studies have been limited to observational, single-center experiences. “Some single-center studies have shown the benefit of statin initiation with different regimens and timing. But the largest study to date, which used the Pediatric Heart Transplant Society [PHTS] registry, found that statin use was actually associated with worse survival,” adds Dr. Townsend.

Although she notes, the authors acknowledged the data could be confounded by higher-risk patients being put on statins, resulting in worse outcomes irrespective of statin use.

Teasing out the outcomes

Using the PHTS registry, Dr. Townsend and colleagues set out to better understand contemporary trends in statin use and their association with CAV development. Given the limitations of the previous PHTS analysis, they hoped to tease out whether the higher-risk individuals had worse outcomes or whether the medication had any mediating effect.

“We used a few different statistical approaches to get at that question,” notes Dr. Townsend.

First, they extracted records from patients younger than 17 at the time of the primary heart transplant who were at least three years or more post-transplant without incidence of CAV. Based on their statin regimen, or lack thereof, they were classified as consecutive, intermediate or absent.

A secondary analysis focused on a 10-year-old and older cohort was also conducted as statins are more widely utilized in older patients, thus, offering more robust data on graft loss, CAV and rejection.

In addition to the Cox regression models, the team also used propensity score matching on the 10 and older cohort to compare outcomes with respect to CAV development and graft loss. Specifically, they examined those with a consistent statin regimen in the first three years following transplant versus those who did not receive statins.

Findings: No difference in CAV outcomes, inconsistent use across centers

Ultimately, the authors reported finding no difference in graft loss, time to first diagnosis of CAV, or time of first rejection among any of the statin use groups.

“I think we can finally put to rest, in all the different types of analyses we did, that statin use is not causing worse outcomes — or is at least not correlated with worse outcomes. But we also didn’t find that it’s improving outcomes in terms of graft loss or overall survival either.”

The study also found that statin use continues to be inconsistent across pediatric heart transplant centers—undoubtedly a reflection of the lack of consensus. However, there was an upward use trend in those age 10 and older.

“It’s a little disappointing,” she says, “given how strong the adult literature is.” But it speaks to the challenges often found in pediatric research.

“Short of a randomized control trial, which might need to be the next step, it’s very hard to piece out how pediatric patients are treated because they represent a diverse age range: an infant versus a 5-year-old versus a 17-year-old are all so different.”

Further, though the PHTS dataset is the most robust collection of its kind, much has changed in heart transplant medicine in the last several years. Dr. Townsend says current practice might not be accurately reflected in the long-term outcomes data for decades to come.

“Without granular data on the timing of statin initiation, it’s possible we aren’t able to truly suss out its effect in pediatric heart transplant.”

The bottom line? It’s safe to put children on statins, but it’s still not clear how effective they are. However, for older pediatric patients, who are nearing adulthood, there may be a benefit, and the adult literature can be a useful guide for management.

Another process at play?

Dr. Townsend also hints that something else might be in play. “The processes involved in CAV and the effects of statins may be different in children versus adults,” she says. “We suspect CAV in children is likely driven much more by immune-mediated factors, but the jury is still out on how we can best modify CAV in children.”