Improving adherence: It’s complicated

Abstract

This month’s installment of “The AJT Report” discusses effective strategies for addressing patients’ nonadherence to immunosuppression, and reports on the latest guidance concerning COVID-19 vaccination for pre- and posttransplant patients.

Focusing on patients with severe nonadherence to immunosuppression may be the most effective path to improved outcomes

The National Organ Transplant Act requires transplant centers to provide equitable access to transplantation. Implicit in the Act’s provisions is support for populations unable to adhere to immunosuppression. “Adherence is very important, as it is essential for successful transplant outcomes,” explains Keren Ladin, PhD, MSc, director of Research on Ethics, Aging, and Community Health (the REACH Lab) at Tufts University in Boston. Unfortunately, historical and structural inequalities affect many patients’ capabilities to be adherent, and thus the ability to be so is not equally distributed.

To address this inequity, transplant centers provide adherence interventions that support patients and serve as an adjunct to their personal social support. Such interventions may be informational, emotional, instrumental, motivational and/or in the form of paid support. Tangible, people-facing support may include pill loading services; remote help may be provided via telephone, video or text messaging. Many of these interventions not only make intuitive sense but have demonstrated efficacy. Eyal Shemesh, MD, chief of the Division of Behavioral and Developmental Health in the Department of Pediatrics at Mount Sinai Kravis Children’s Hospital in New York City, and his colleagues, for example, found that a remote intervention targeting immunosuppressant management in pediatric lung transplant recipients stabilized patients’ medication blood levels.¹

“Remote interventions are a really important part of the toolkit,” confirms Dr. Ladin. She notes, however, that there may be patients for whom telehealth is not optimal. Such patients may prefer community-based services such as housing, ride services, and help in visiting their transplant center. Although which patients will benefit from each type of intervention is not yet evident, Dr. Ladin expects that ultimately, a combination of remote and in-person services will be most effective.

Targeting Resources

Social workers work the front line of adherence interventions, evaluating social risk and providing educational services. They are, therefore, “stretched at transplant centers,” says Dr. Ladin. She notes that, typically, a small number of more challenging patients may disproportionately consume social workers’ time, but these patients may have the most to gain with improved adherence.

KEY POINTS.

• •Equitable access to transplant includes providing tangible and remote support for populations unable to adhere to immunosuppression and/or the medical regimen.
• •Social workers who evaluate social risk and provide educational support are stretched thin at transplant centers.
• •As transplant centers vary in their social support requirements, they also vary in their abilities to waitlist patients who lack their own support systems.
• •There is a catch-22 in that interventions that do not specifically target nonadherent patients may inadvertently cause harm.

“We are still quite limited in our ability to predict who will be adherent,” says Dr. Ladin. In an ideal world, centers that effectively identify these patients provide them with interventions. Unfortunately, some centers may decide not to list the patients who need significant support because they feel that they cannot adequately meet their needs.

Both clearer definitions and a greater capacity to provide supportive care may increase the number of patients waitlisted and transplanted. Because of this, Dr. Ladin and others have called for consensus conferences to develop clear, evidence-based guidelines.² However, given that people who are denied transplant may not contribute to data collection, such guidelines may not be fully informative. Moreover, if transplant horizons are expanded relative to psychosocial criteria, then the outcomes of these transplants should be tracked and assessed.

Dr. Ladin points out that sometimes, when transplant centers identify individuals who require psychosocial supports or interventions that cannot adequately be supported through transplant center interventions, they decline to waitlist them. In some instances, the screening process used to identify those most in need of intervention, in effect, works against the patient. She feels that social workers should systemize the process of evaluating patients. However, as with any effort at systematization that involves human beings, circumstances—and therefore, types and levels of need—will vary. Dr. Ladin also encourages the transplant community to be sensitive to the possibility that interventions, if not equitably distributed, may preserve or increase disparities.

Although transplant centers intend for interventions to reduce disparities, centers still need to identify those specific interventions that will make a difference. “What I am fascinated by,” says Dr. Shemesh, “is the selection bias issue.” Research studies, by their very nature, target individuals who are interested in and willing to participate in science, and who thus tend to be the most adherent patients. Results obtained using these patients may not be generalizable to nonadherent patients. A given intervention, for example, may increase adherence from 90% to 95% in a study population of patients who are very adherent to begin with, but may lead to zero clinical benefits for such adherent patients; however, that type of intervention may prove inappropriate and/or ineffective for the nonadherent patients who actually need those interventions but do not enroll in such research.

Potential for Harm

Interventions that do not specifically focus on extremely nonadherent patients may actually cause harm. Dr. Shemesh is concerned that the transplant community may not consider the possibility that patients may take more immunosuppressive medications as a result of such interventions and thus develop infections and other side effects of excessive immunosuppression. He points to a study recently published in the American Journal of Transplantation describing a randomized clinical trial testing the SystemCHANGE™ intervention, which taught kidney transplant recipients to use person-level quality improvement strategies to improve adherence.³ The study documented significant improvements in medication adherence but no significant effects on clinical outcomes. The investigators did note that as immunosuppressant medication adherence improved, recipients tended to be at higher risk for infection. According to Dr. Shemesh, this finding has been reproduced in other studies.

Dr. Shemesh wonders if too much immunosuppression may be a concern in adherence intervention studies, particularly if the study targets patients who are already adherent. These patients are not only the easiest to recruit into research and nudge toward greater adherence, but their increase in adherence is the least likely to be clinically meaningful and may even be harmful. “We must realize that behavioral interventions—like any intervention—could be harmful, and diligently monitor for such harm,” he says.

Dr. Shemesh calls on researchers who focus on adherence to turn their attention toward patients who have the worst problems and can be especially difficult to recruit into a clinical trial. A study by Dr. Shemesh and his colleagues attempted to address this problem. The team recruited pediatric lung transplant recipients with a Medication Level Variability Index ≥2.0—a level that indicated worrisome tacrolimus fluctuation. “The crux of the issue is patient selection,” stresses Dr. Shemesh. “If you are able to have a meaningful dialogue with those patients who are not engaged in care, that is a very good beginning. The specifics of what you do with the patients after you have been able to engage them may matter less.”

Given the limited resources and potential for harm, the trick for improving immunosuppression adherence seems to come down to identifying and targeting patients with severe nonadherence. This is especially important because providing adherence interventions to everyone is not only resource intensive, but also may not produce equitable or even desirable outcomes. Moreover, equity requires that patients at risk for nonadherence not be targeted for exclusion, but rather be appropriately assisted and listed for organs. As transplant centers look to meld these two intentions (targeting patients for effective interventions and not preventing them from the potential benefits of a transplant), they are finding that the path forward is complicated.

COVID-19 Vaccination Guidance for Transplant

Most transplant candidates and recipients fall under the “people at high risk for severe COVID-19 due to underlying medical conditions” description used by the phased distribution proposal of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices. Moreover, the American Society of Transplantation’s (AST) COVID-19 vaccination guidance (updated March 10) states that, because vaccination is likely to be beneficial, transplant candidates and recipients should be vaccinated when vaccines become available. The Society recommends receiving any of the currently authorized vaccines.

Waitlisted patients should ideally be vaccinated at least 2 weeks prior to transplant, although AST guidance states that transplantation should not be delayed because of the COVID vaccine schedule. Transplant recipients should not receive the vaccine within 1 month of transplant surgery but at any time thereafter. AST’s vaccination guidance acknowledges that patients with suppressed immune systems were not included in the clinical trials that evaluated the COVID-19 vaccines and, therefore, vaccine efficacy in the patient population is unclear. It notes, however, that not only have there have been no safety concerns specific to transplant recipients, but early studies suggest that vaccine side effects and safety are similar among transplant recipients and the general population.