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Study challenges everolimus boxed warning
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
Study challenges everolimus boxed warning
Study challenges everolimus boxed warning
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
according to the first phase 3 trial to compare antirejection strategies in the pediatric setting.
Even though MMF and tacrolimus have never been evaluated for pediatric cardiac transplant in a controlled trial, this combination is widely considered a standard based on adult data, said Christopher Almond, MD, a professor of pediatric cardiology at Stanford (Calif.) Medicine.
Everolimus has not been widely used in an antirejection regimen in children following heart transplant in part because of a boxed warning. The warning was added to labeling when this agent was associated with increased infection and increased mortality in adults if given within 3 months of transplant.
In this non-inferiority trial, called TEAMMATE, patients were randomized to the MMF-based or everolimus-based regimen 6 months after transplant.
Everolimus- vs. MMF-based antirejection
The study enrolled 210 children and adolescents 21 years of age or younger. The control arm treatment consisted of MMF (660 mg/m2 every 12 hours) plus standard dose of tacrolimus (initially 7-10 ng/mL followed at 6 months by 5-8 ng/mL).
In the experimental arm, patients received everolimus (3-8 ng/mL) plus a low dose of tacrolimus (initially 3-5 ng/mL followed at 6 months by 2.5-4.5 ng/mL).
The primary endpoint was score on the major adverse transplant event (MATE-6) tool. Based on gradations of severity, this assigns values for cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), acute cellular rejection (ACR), antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder (PTLD).
Thirty months after randomization, the MATE-6 scores were 1.96 in the everolimus group and 2.18 in the MMF group, which conferred the everolimus-based regimen with a numerical but not a significant advantage over the MMF-based regimen. For the goal of noninferiority, the everolimus regimen “met the prespecified safety criterion for success,” Dr. Almond said.
Numerical advantage for everolimus on efficacy
The primary efficacy endpoint was the MATE-3 score, which is limited to CAV, CKD, and ACR. Again, the mean score on this metric (0.93 vs. 1.25) was lower on the everolimus-based regimen but not significantly different.
Looking at specific events in the MATE-6 score, the everolimus-based regimen was associated with lower numerical rates of CAV and CKD, but a higher rate of PTLD, Dr. Almond reported.
On the MATE-3 efficacy analysis, the everolimus-based regimen was again associated with lower numerical rates of CAV and CKD but higher rates of ACR.
In terms of adverse events, including those involving the gastrointestinal tract, blood cells, proteinuria, and interstitial lung disease, most did not differ markedly even if many were numerically more common in the MMF-based arm. The exception was aphthous stomatitis, which was more common on everolimus (32% vs. 7%; P < .001). There were more discontinuations for an adverse event in the MMF arm (21% vs. 12%; P < .001).
Other differences included a lower proportion of patients in the everolimus arm with anti-HLA antibodies (17% vs. 30%; P < .05). Total cholesterol levels at the end of the study were lower but not significantly different in the MMF group, while the higher median glomerular filtration rate was higher on everolimus, and this did reach statistical significance (P < .05).
Infection rates overall were similar, but cytomegalovirus (CMV) infection was more common on the MMF-based regimen. The 30% lower rate of CMV infection in the everolimus proved to be potentially clinically meaningful when it was considered in the context of MATE-3. When these two endpoints were combined (MATE-3 and CMV infection as a prespecified secondary endpoint, the difference was statistically significant (P = .03) in favor of the everolimus-based regimen,
Study supports safety of everolimus regimen
The take-home message is that the everolimus-based regimen, which “is safe in children and young adults when initiated at 6 months after transplant,” can be considered as an alternative to MFF, Dr. Almond concluded.
However, one of the coauthors of the study, Joseph Rossano, MD, chief of the division of cardiology, Children’s Hospital of Philadelphia, suggested a stronger message.
“These data provide compelling reasons to consider initiation of the combination of everolimus and tacrolimus at 6 months post transplant in pediatric heart transplant recipients,” Dr. Rossano said.
Even though the everolimus-based regimen met the terms of noninferiority overall, patients who received this combination rather than the MMF-based regimen “were less likely to have the combined endpoints of vasculopathy, CKD, rejection and CMV infection. Additionally, they were less likely to make donor specific antibodies,” he said.
He also said that this study challenges the current boxed warning for everolimus. He pointed out that the warning, based on early use of everolimus in adults, does not appear to be an issue for children treated at 6 months.
Early mortality based on infection “was not observed in our study,” he said.
The AHA-invited discussant, Antonio G. Cabrera, MD, division chief of pediatric cardiology, University of Utah, Salt Lake City, drew the same conclusions. Based on the study, the everolimus-based regimen can only be described as noninferior to the MMF-based regimen, but Dr. Cabrera listed the same relative advantages as Dr. Rossano, including better kidney function.
Overall, either regimen might be more appealing based on several variables, but Dr. Cabrera said these data suggest everolimus-based treatment “should be considered” as one of two evidence-based options,
Dr. Almond reported no potential financial conflicts of interest. Dr. Rossano reports financial relationships with Abiomed, Bayer, Cytokinetics, Merck, and Myokardia. Dr. Cabrera reported no potential financial conflicts of interest.
FROM AHA 2023