Heart Failure

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

Hydroxychloroquine should be initiated with caution in older patients with rheumatoid arthritis who also have heart failure or are at risk for it, say the authors of a study suggesting that the drug could increase their risk for major adverse cardiovascular events (MACE), compared with methotrexate.

A cohort study published online in the Journal of the American College of Cardiology looked at outcomes in 54,462 patients with RA aged 65 years or older and not previously treated with disease-modifying antirheumatic drugs. Half were initiated on methotrexate and half on hydroxychloroquine, making 27,231 propensity-matched pairs.

Across the entire cohort, hydroxychloroquine was not associated with a higher risk for sudden cardiac arrest, ventricular arrhythmia, or MACE, compared with methotrexate. When broken down into individual cardiovascular events, the data suggested a statistically significant 17% increase in the risk for cardiovascular mortality and 10% increase in all-cause mortality with hydroxychloroquine, although there were no differences in the risks for myocardial infarction or stroke.

However, a subgroup analysis revealed a significant 30% increase in the risk for MACE among patients starting hydroxychloroquine who also had a history of heart failure, compared with patients taking methotrexate. The researchers found no difference between the two drugs in patients without a history of heart failure. The study also suggested an overall 41% increase in the risk for hospitalization with heart failure with hydroxychloroquine, regardless of heart failure history.

Hydroxychloroquine was also associated with a 34% increase in the risk for cardiovascular mortality, a 22% increase in the risk for all-cause mortality, and a 74% increase in the risk for MI.

The lead author of the study, Elvira D’Andrea, MD, PhD, of Brigham and Women’s Hospital and Harvard Medical School in Boston, said that hydroxychloroquine is used as a first-line treatment for RA, but there was limited evidence on its cardiovascular risks. The pandemic in particular shined a spotlight on these concerns and prompted the researchers to extend their original prepandemic study to encompass additional cardiovascular outcomes.

“The emerging concerns on its cardiovascular safety in early 2020 has led the rheumatological community, and patients regularly taking hydroxychloroquine for rheumatoid arthritis, to confusion,” Dr. D’Andrea said in an interview.

She advised that clinicians be cautious when initiating hydroxychloroquine in older patients with existing heart failure or who have risk factors for it. “Although heart failure is a known concern for hydroxychloroquine use, these findings helped to clarify the relationship between the use of hydroxychloroquine or methotrexate and heart failure. Clinicians should pay careful attention to clinical manifestations of cardiomyopathy or heart failure in older patients with rheumatoid arthritis treated with hydroxychloroquine.”

Hydroxychloroquine is associated with cardiotoxicity, particularly cardiomyopathy, which may help precipitate MACE or heart failure exacerbations in patients who already have deterioration of their cardiac tissue, the authors suggested.

Short follow-up period leaves risk attribution under question

In an accompanying editorial, Elizabeth Blair Solow, MD, and Bonnie L. Bermas, MD, of the University of Texas Southwestern Medical Center, Dallas, commented that the lack of an increased risk for arrhythmic events or MACE in the overall cohort taking hydroxychloroquine was reassuring. They also suggested the subgroup analysis findings among patients with preexisting heart failure were still “exploratory and hypothesis-generating” and should be interpreted with caution.

They noted that the follow-up time of the study was relatively short – a median of 209 days – given that hydroxychloroquine does not reach a steady-state level for 6 months.

“Evidence to date suggests cardiomyopathy from HCQ [hydroxychloroquine] takes years to develop, many months beyond the exposures described here, bringing into question as to whether HCQ itself increased HF hospitalizations,” the editorialists wrote.

The editorial also raised the question of whether the association observed in the study was related to a possible cardioprotective effect of methotrexate, given that previous studies have suggested this effect in older patients with RA.

The study authors did an exploratory analysis comparing hydroxychloroquine with sulfasalazine, which appeared to support their main findings of a possible cardiovascular effect of hydroxychloroquine. However, they qualified this by pointing out that the analysis involved small numbers of patients.

Senior investigator Seoyoung C. Kim, MD, ScD, of Brigham and Women’s Hospital and Harvard Medical School, both in Boston, also noted that the study only looked at outcomes in patients aged 65 years and older.

“It would be clinically important to further examine the cardiovascular safety of hydroxychloroquine versus methotrexate in a younger population with rheumatic conditions,” she said.

The study was supported by the National Institutes of Health, Brigham and Women’s Hospital, and Harvard Medical School. Four authors declared unrelated research grants from the pharmaceutical sector, with one also declaring stock options and consulting work with the pharmaceutical sector. No other conflicts of interest were declared.

A version of this article first appeared on Medscape.com.

It’s a given that the case of David Bennett, Sr, and his transplanted, genetically modified porcine heart will have a lot to teach, and the peer-reviewed publication this week lends welcome authority to some of its earliest lessons.

Mr. Bennett lived for 2 months after receiving the heart in the pioneering surgery, and the new case report compiles the available clinical, anatomic, and histologic evidence and other potential clues to the underlying cause or causes of death.

It also describes a mystery that came to light at autopsy: a grossly enlarged heart attributable to pervasive interstitial edema, and at the cellular level, a peculiar pattern of myocardial damage that included microvascular deterioration and, potentially as a result, cellular necrosis, according to the new report.

The myocardium itself was described as “thickened and stiff,” consistent with the “diastolic heart failure” that characterized Mr. Bennett’s final 10 days and the likely convergence of several underlying processes. Missing, however, was any conventional sign of graft rejection as it is understood clinically or in animal models, the report states.

If a form of tissue rejection was the cause of graft failure, any implicating cellular evidence may simply have been unrecognizable, given the unprecedented nature of the first pig-to-human heart transplantation, the donor animal’s multiple anti-inflammatory gene deletions, and partly investigational immunosuppression regimen, speculated Bartley P. Griffith, MD, University of Maryland, College Park.

“I’m betting against it being a fulminant rejection,” he told this news organization, “because we saw nothing like the [characteristic] platelet deposition or thrombosis of the capillaries.”

Dr. Griffith, who performed the xenotransplant surgery and led Mr. Bennett’s postoperative care, is lead author on the case report published in the New England Journal of Medicine. “Additional studies are underway to characterize the pathophysiologic mechanisms that resulted in this damage,” the report states.

The report builds on recent meeting presentations on the case, which, as previously reported, gave cursory details regarding the organ damage and other clinical developments during and after the surgery, including evidence that the transplanted heart contained porcine cytomegalovirus (PCMV).

Similar details also appeared in a third-person account based in part on personal communication with Dr. Griffith. The cardiac XTx review that focused on this University of Maryland experience was published June 15 in JACC: Basic to Translational Science, with lead author Jacinthe Boulet, MD, CM, Brigham and Women’s Hospital Heart, Boston.

“The question of how to move XTx forward remains uncertain, and appropriate selection of patients for experimental XTx will be one of the most important challenges to be addressed. The first issue we must contend with is whether we are ready to move to the next XTx in a human. We strongly believe this to be the case,” the review states. “Once early experience is gained, with successive iterations of XTx, the bar for success can be raised with maturation of the technology.”

Evidence has so far not implicated several other potential mechanisms underlying the graft failure that had been the focus of early speculations. For example, the transplanted pig heart was infected with PCMV, as previously reported. Mr. Bennett showed traces of PCMV DNA in his circulation, but no actual virus in his native cells. Still, PCMV remains a suspect.

Mr. Bennett also received intravenous immunoglobulin (IVIG) on several occasions to fight rejection, and also severe infections, including a nasty episode of sepsis. A reaction to the IVIG, derived from pooled donor antibodies, could potentially have caused the unusual myocardial damage seen by the University of Maryland team, Dr. Griffith observed. Alternatively, the damage might have been partly related to the patient’s overall severely diminished condition even before the transplant surgery or his rocky postoperative clinical course.

Indeed, Mr. Bennett’s condition worsened dramatically on postoperative day 50, and echocardiography showed a striking degree of myocardial wall thickening and heart enlargement, determined to be from edema. “The heart got amazingly stiff but maintained a systolic function that wasn›t too terrible, even to the very end. But his heart seemed as though it had swollen overnight,” Dr. Griffith said. “We had never seen that type of process, the suddenness of this swelling, in our nonhuman primate studies.”

The damage to the heart muscle appeared irreversible, based on myocardial biopsy results, so the decision was made to withdraw life support 60 days after the transplant surgery, the report notes.

Among the experience’s apparent lessons for future cardiac xenotransplantation, Dr. Griffith said, would be to select patients for the surgery who are in a bit more robust condition than Mr. Bennett was, who are perhaps ambulatory, not sarcopenic, and not recently on prolonged mechanical circulatory support. “We’re going to try to pick a patient who, on the front end, is less critically ill but who is just as likely not to benefit from continued medical therapy” and who isn’t a candidate for conventional heart transplantation, he said.

Because of universal efforts to manage conditions like diabetes, hypertension, and vascular disease in the population, and “because these conditions cause many of the cases of organ failure and fuel demand for transplantation, one might wonder whether the advances reported by Dr. Griffith and colleagues presage a decreasing demand for organ transplantation,” speculates an accompanying editorialfrom Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, University of Michigan, Ann Arbor.

“We think the answer is no. Since aging is associated with progressive decline in the function of the heart, kidneys, and other organs, advances that extend life expectancy will ultimately increase the prevalence of organ failure and potentially the demand for transplantation.”

The donor pig was developed and provided by Revivicor, and the investigational KPL-404 antibody drug used in the experience was provided by Kiniksa. Other disclosures for the case report and editorial from Dr. Platt and Dr. Cascalho are available at NEJM.com. Dr. Boulet reports no relevant relationships; disclosures for the other authors are in their report.

A version of this article first appeared on Medscape.com.

It’s a given that the case of David Bennett, Sr, and his transplanted, genetically modified porcine heart will have a lot to teach, and the peer-reviewed publication this week lends welcome authority to some of its earliest lessons.

Mr. Bennett lived for 2 months after receiving the heart in the pioneering surgery, and the new case report compiles the available clinical, anatomic, and histologic evidence and other potential clues to the underlying cause or causes of death.

It also describes a mystery that came to light at autopsy: a grossly enlarged heart attributable to pervasive interstitial edema, and at the cellular level, a peculiar pattern of myocardial damage that included microvascular deterioration and, potentially as a result, cellular necrosis, according to the new report.

The myocardium itself was described as “thickened and stiff,” consistent with the “diastolic heart failure” that characterized Mr. Bennett’s final 10 days and the likely convergence of several underlying processes. Missing, however, was any conventional sign of graft rejection as it is understood clinically or in animal models, the report states.

If a form of tissue rejection was the cause of graft failure, any implicating cellular evidence may simply have been unrecognizable, given the unprecedented nature of the first pig-to-human heart transplantation, the donor animal’s multiple anti-inflammatory gene deletions, and partly investigational immunosuppression regimen, speculated Bartley P. Griffith, MD, University of Maryland, College Park.

“I’m betting against it being a fulminant rejection,” he told this news organization, “because we saw nothing like the [characteristic] platelet deposition or thrombosis of the capillaries.”

Dr. Griffith, who performed the xenotransplant surgery and led Mr. Bennett’s postoperative care, is lead author on the case report published in the New England Journal of Medicine. “Additional studies are underway to characterize the pathophysiologic mechanisms that resulted in this damage,” the report states.

The report builds on recent meeting presentations on the case, which, as previously reported, gave cursory details regarding the organ damage and other clinical developments during and after the surgery, including evidence that the transplanted heart contained porcine cytomegalovirus (PCMV).

Similar details also appeared in a third-person account based in part on personal communication with Dr. Griffith. The cardiac XTx review that focused on this University of Maryland experience was published June 15 in JACC: Basic to Translational Science, with lead author Jacinthe Boulet, MD, CM, Brigham and Women’s Hospital Heart, Boston.

“The question of how to move XTx forward remains uncertain, and appropriate selection of patients for experimental XTx will be one of the most important challenges to be addressed. The first issue we must contend with is whether we are ready to move to the next XTx in a human. We strongly believe this to be the case,” the review states. “Once early experience is gained, with successive iterations of XTx, the bar for success can be raised with maturation of the technology.”

Evidence has so far not implicated several other potential mechanisms underlying the graft failure that had been the focus of early speculations. For example, the transplanted pig heart was infected with PCMV, as previously reported. Mr. Bennett showed traces of PCMV DNA in his circulation, but no actual virus in his native cells. Still, PCMV remains a suspect.

Mr. Bennett also received intravenous immunoglobulin (IVIG) on several occasions to fight rejection, and also severe infections, including a nasty episode of sepsis. A reaction to the IVIG, derived from pooled donor antibodies, could potentially have caused the unusual myocardial damage seen by the University of Maryland team, Dr. Griffith observed. Alternatively, the damage might have been partly related to the patient’s overall severely diminished condition even before the transplant surgery or his rocky postoperative clinical course.

Indeed, Mr. Bennett’s condition worsened dramatically on postoperative day 50, and echocardiography showed a striking degree of myocardial wall thickening and heart enlargement, determined to be from edema. “The heart got amazingly stiff but maintained a systolic function that wasn›t too terrible, even to the very end. But his heart seemed as though it had swollen overnight,” Dr. Griffith said. “We had never seen that type of process, the suddenness of this swelling, in our nonhuman primate studies.”

The damage to the heart muscle appeared irreversible, based on myocardial biopsy results, so the decision was made to withdraw life support 60 days after the transplant surgery, the report notes.

Among the experience’s apparent lessons for future cardiac xenotransplantation, Dr. Griffith said, would be to select patients for the surgery who are in a bit more robust condition than Mr. Bennett was, who are perhaps ambulatory, not sarcopenic, and not recently on prolonged mechanical circulatory support. “We’re going to try to pick a patient who, on the front end, is less critically ill but who is just as likely not to benefit from continued medical therapy” and who isn’t a candidate for conventional heart transplantation, he said.

Because of universal efforts to manage conditions like diabetes, hypertension, and vascular disease in the population, and “because these conditions cause many of the cases of organ failure and fuel demand for transplantation, one might wonder whether the advances reported by Dr. Griffith and colleagues presage a decreasing demand for organ transplantation,” speculates an accompanying editorialfrom Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, University of Michigan, Ann Arbor.

“We think the answer is no. Since aging is associated with progressive decline in the function of the heart, kidneys, and other organs, advances that extend life expectancy will ultimately increase the prevalence of organ failure and potentially the demand for transplantation.”

The donor pig was developed and provided by Revivicor, and the investigational KPL-404 antibody drug used in the experience was provided by Kiniksa. Other disclosures for the case report and editorial from Dr. Platt and Dr. Cascalho are available at NEJM.com. Dr. Boulet reports no relevant relationships; disclosures for the other authors are in their report.

A version of this article first appeared on Medscape.com.

It’s a given that the case of David Bennett, Sr, and his transplanted, genetically modified porcine heart will have a lot to teach, and the peer-reviewed publication this week lends welcome authority to some of its earliest lessons.

Mr. Bennett lived for 2 months after receiving the heart in the pioneering surgery, and the new case report compiles the available clinical, anatomic, and histologic evidence and other potential clues to the underlying cause or causes of death.

It also describes a mystery that came to light at autopsy: a grossly enlarged heart attributable to pervasive interstitial edema, and at the cellular level, a peculiar pattern of myocardial damage that included microvascular deterioration and, potentially as a result, cellular necrosis, according to the new report.

The myocardium itself was described as “thickened and stiff,” consistent with the “diastolic heart failure” that characterized Mr. Bennett’s final 10 days and the likely convergence of several underlying processes. Missing, however, was any conventional sign of graft rejection as it is understood clinically or in animal models, the report states.

If a form of tissue rejection was the cause of graft failure, any implicating cellular evidence may simply have been unrecognizable, given the unprecedented nature of the first pig-to-human heart transplantation, the donor animal’s multiple anti-inflammatory gene deletions, and partly investigational immunosuppression regimen, speculated Bartley P. Griffith, MD, University of Maryland, College Park.

“I’m betting against it being a fulminant rejection,” he told this news organization, “because we saw nothing like the [characteristic] platelet deposition or thrombosis of the capillaries.”

Dr. Griffith, who performed the xenotransplant surgery and led Mr. Bennett’s postoperative care, is lead author on the case report published in the New England Journal of Medicine. “Additional studies are underway to characterize the pathophysiologic mechanisms that resulted in this damage,” the report states.

The report builds on recent meeting presentations on the case, which, as previously reported, gave cursory details regarding the organ damage and other clinical developments during and after the surgery, including evidence that the transplanted heart contained porcine cytomegalovirus (PCMV).

Similar details also appeared in a third-person account based in part on personal communication with Dr. Griffith. The cardiac XTx review that focused on this University of Maryland experience was published June 15 in JACC: Basic to Translational Science, with lead author Jacinthe Boulet, MD, CM, Brigham and Women’s Hospital Heart, Boston.

“The question of how to move XTx forward remains uncertain, and appropriate selection of patients for experimental XTx will be one of the most important challenges to be addressed. The first issue we must contend with is whether we are ready to move to the next XTx in a human. We strongly believe this to be the case,” the review states. “Once early experience is gained, with successive iterations of XTx, the bar for success can be raised with maturation of the technology.”

Evidence has so far not implicated several other potential mechanisms underlying the graft failure that had been the focus of early speculations. For example, the transplanted pig heart was infected with PCMV, as previously reported. Mr. Bennett showed traces of PCMV DNA in his circulation, but no actual virus in his native cells. Still, PCMV remains a suspect.

Mr. Bennett also received intravenous immunoglobulin (IVIG) on several occasions to fight rejection, and also severe infections, including a nasty episode of sepsis. A reaction to the IVIG, derived from pooled donor antibodies, could potentially have caused the unusual myocardial damage seen by the University of Maryland team, Dr. Griffith observed. Alternatively, the damage might have been partly related to the patient’s overall severely diminished condition even before the transplant surgery or his rocky postoperative clinical course.

Indeed, Mr. Bennett’s condition worsened dramatically on postoperative day 50, and echocardiography showed a striking degree of myocardial wall thickening and heart enlargement, determined to be from edema. “The heart got amazingly stiff but maintained a systolic function that wasn›t too terrible, even to the very end. But his heart seemed as though it had swollen overnight,” Dr. Griffith said. “We had never seen that type of process, the suddenness of this swelling, in our nonhuman primate studies.”

The damage to the heart muscle appeared irreversible, based on myocardial biopsy results, so the decision was made to withdraw life support 60 days after the transplant surgery, the report notes.

Among the experience’s apparent lessons for future cardiac xenotransplantation, Dr. Griffith said, would be to select patients for the surgery who are in a bit more robust condition than Mr. Bennett was, who are perhaps ambulatory, not sarcopenic, and not recently on prolonged mechanical circulatory support. “We’re going to try to pick a patient who, on the front end, is less critically ill but who is just as likely not to benefit from continued medical therapy” and who isn’t a candidate for conventional heart transplantation, he said.

Because of universal efforts to manage conditions like diabetes, hypertension, and vascular disease in the population, and “because these conditions cause many of the cases of organ failure and fuel demand for transplantation, one might wonder whether the advances reported by Dr. Griffith and colleagues presage a decreasing demand for organ transplantation,” speculates an accompanying editorialfrom Jeffrey L. Platt, MD, and Marilia Cascalho, MD, PhD, University of Michigan, Ann Arbor.

“We think the answer is no. Since aging is associated with progressive decline in the function of the heart, kidneys, and other organs, advances that extend life expectancy will ultimately increase the prevalence of organ failure and potentially the demand for transplantation.”

The donor pig was developed and provided by Revivicor, and the investigational KPL-404 antibody drug used in the experience was provided by Kiniksa. Other disclosures for the case report and editorial from Dr. Platt and Dr. Cascalho are available at NEJM.com. Dr. Boulet reports no relevant relationships; disclosures for the other authors are in their report.

A version of this article first appeared on Medscape.com.

Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.

“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.

Medtronic reports one death associated with this recall and two complaints in the affected lot.

Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.

The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.

On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.

It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to rs.cfqfca@medtronic.com.

Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.

The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.

Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.

Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.

Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.

“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.

Medtronic reports one death associated with this recall and two complaints in the affected lot.

Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.

The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.

On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.

It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to rs.cfqfca@medtronic.com.

Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.

The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.

Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.

Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.

Medtronic is recalling a single lot of HeartWare Ventricular Assist Device (HVAD) System batteries because of welding defects that may cause separation of the two cell battery packs used to power the system, according to an alert on the Food and Drug Administration website.

“The welding defect may cause the battery to malfunction and no longer provide power or prevent the battery from holding a full charge or properly recharging,” the FDA said.

Wikimedia Commons/FitzColinGerald/ Creative Commons License

The agency has identified this as a class I recall, the most serious type because of the potential for serious injury or death.

Medtronic reports one death associated with this recall and two complaints in the affected lot.

Back in April, as reported by this news organization, Medtronic alerted providers that patients implanted with the Medtronic HVAD System who develop pump thrombosis could have a welding defect in the internal pump that causes the pump to malfunction.

The batteries from the recalled lot have a model number of 1650DE, were manufactured from April 13 to 19, 2021 and distributed from April 20 to July 19, 2021. The recall affects a total of 429 devices.

On May 5, 2022, Medtronic sent an urgent medical device correction notice to customers asking them to identify and quarantine all affected batteries and notify affected patients. The notice includes a patient template to help communicate directly with patients.

It also includes a customer confirmation form to initiate an exchange. The completed form should be returned to rs.cfqfca@medtronic.com.

Medtronic is replacing the affected batteries with new product and has implemented actions to improve control of the welding process.

The Medtronic HVAD System was approved as a bridge to heart transplantation in 2012. Since then, it’s been fraught with problems.

Earlier in June, the company announced it was stopping all sales of the device and advised physicians to stop implanting it, as reported by this news organization.

Problems related to the Medtronic HVAD System should be reported to the FDA’s MedWatch program.

A version of this article first appeared on Medscape.com.

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

Out-of-pocket (OOP) costs for Medicare enrollees receiving quadruple drug therapy for heart failure with reduced ejection fraction were “substantially higher than regimens limited to generically available medications,” according to a new analysis of prescription drug plans.

“Despite the clinical benefit of quadruple therapy” consisting of beta-blockers, angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors, “coverage was restricted primarily through cost sharing, and estimated annual OOP costs for beneficiaries were [over $2,000] per year under most plans,” wrote Kamil F. Faridi, MD, and associates. The findings were published in the Journal of the American College of Cardiology.

For just 1 month of quadruple drug therapy for heart failure with reduced ejection fraction (HFrEF), the estimated median OOP cost was $94 for individuals covered by a Medicare prescription drug plan during the second quarter of 2020, with the majority coming from the ARNI (median, $47) and the SGLT2 inhibitor (median, $45). Alternative HFrEF regimens were significantly less costly, ranging from $3 to $47 OOP, the investigators reported.

Almost all of the 4,068 plans participating in Medicare at that time covered quadruple therapy for HFrEF, but more than 99% restricted coverage by instituting cost sharing for medications at tier level 3 and above on the drug formularies. Such restrictions for ARNIs and SGLT2 inhibitors “might not be readily apparent to prescribing physicians,” wrote Dr. Faridi of Yale University, New Haven, Conn., and associates.

Other methods of regulating coverage were less common. Prior authorization of ARNIs was invoked by about a quarter of the plans, but none required authorization for any of the other drugs involved, and few plans used step therapy-requirements involving lower-cost alternatives, they noted.

“The use of cost sharing restricts access through high OOP costs for patients. Furthermore, these policies likely disadvantage relatively poorer patients (although the poorest Medicare patients will tend to be dual-enrolled in Medicaid and protected from cost sharing),” Jason H. Wasfy, MD, and Anna C. O’Kelly, MD, said in an accompanying editorial comment .

Since acceptable cost-effectiveness has been demonstrated for dapagliflozin, an SGLT1 inhibitor, and for the ARNIs, and because these medications have no generic equivalents, health plans should “use the discretion they have under Medicare Part D to reduce cost sharing for patients with HFrEF,” Dr. Wasfy and Dr. O’Kelly wrote, adding that the current study “demonstrates that without consensus on cost effectiveness from the societal perspective, costs can be imposed directly on patients in ways that slow uptake of cost-effective drugs.”

Data for all Medicare Advantage plans (n = 3,167) and standalone Part D plans (n = 901) came from the Medicare Prescription Drug Plan Formulary and Pricing Information Files. Annual OOP costs were estimated “using each phase of a 2020 Medicare part D standard benefit,” including deductible, standard coverage, coverage gap, and catastrophic coverage, the investigators explained.

Dr. Faridi and associates did not report any direct funding sources for their study. Dr Faridi received a grant from the National Institutes of Health outside the scope of the present work, and other investigators disclosed ties to the Food and Drug Administration, the Centers for Medicare and Medicaid Services, Johnson & Johnson, AstraZeneca, Boehringer Ingelheim, Amgen, Cytokinetics, and the Institute for Clinical and Economic Review.

Dr. Wasfy is supported by the American Heart Association and has received consulting fees from Pfizer and honoraria from the Institute for Clinical and Economic Review. Dr. O’Kelly has no relevant disclosures.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

ATLANTA – U.S. clinicians caring for people with diabetes should take a more aggressive approach to using combined medical treatments proven to slow the otherwise relentless progression of chronic kidney disease (CKD), according to a new joint statement by the American Diabetes Association and a major international nephrology organization presented during the annual scientific sessions of the American Diabetes Association (ADA).

The statement elevates treatment with an agent from the sodium-glucose cotransporter 2 (SGLT2) inhibitor class to first-line for people with diabetes and laboratory-based evidence of advancing CKD. It also re-emphasizes the key role of concurrent first-line treatment with a renin-angiotensin system inhibitor (an ACE inhibitor or angiotensin-receptor blocker), metformin, and a statin.

The new statement also urges clinicians to rapidly add treatment with the new nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia) for further renal protection in the many patients suitable for treatment with this agent, and it recommends the second-line addition of a glucagon-like peptide-1 (GLP-1) receptor agonist as the best add-on for any patient who needs additional glycemic control on top of metformin and an SGLT2 inhibitor.

The consensus joint statement with these updates came from a nine-member writing group assembled by the ADA and the Kidney Disease: Improving Global Outcomes (KDIGO) organization.

“We’re going to try to make this feasible. We have to; I don’t think we have a choice,” commented Amy K. Mottl, MD, a nephrologist at the University of North Carolina, Chapel Hill. Dr. Mottl was not involved with writing the consensus statement but has been active in the Diabetic Kidney Disease Collaborative of the American Society of Nephrology, another group promoting a more aggressive multidrug-class approach to treating CKD in people with diabetes.
 

Wider use of costly drugs

Adoption of this evidence-based approach by U.S. clinicians will both increase the number of agents that many patients receive and drive a significant uptick in the cost and complexity of patient care, a consequence acknowledged by the authors of the joint statement as well as outside experts.

But they view this as unavoidable given what’s now known about the high incidence of worsening CKD in patients with diabetes and the types of interventions proven to blunt this.

Much of the financial implication stems from the price of agents from the new drug classes now emphasized in the consensus recommendations – SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists. All these drugs currently remain on-patent with relatively expensive retail prices in the range of about $600 to $1,000/month.

Commenting on the cost concerns, Dr. Mottl highlighted that she currently has several patients in her practice on agents from two or more of these newer classes, and she has generally found it possible for patients to get much of their expenses covered by insurers and through drug-company assistance programs.

“The major gap is patients on Medicare,” she noted in an interview, because the Federal health insurance program does not allow beneficiaries to receive rebates for their drug costs. “The Diabetic Kidney Disease Collaborative is currently lobbying members of Congress to lift that barrier,” she emphasized.
 

Improved alignment

Details of the KDIGO recommendations feature in a guideline from that organization that appeared as a draft document online in March 2022. The ADA’s version recently appeared as an update to its Standards of Medical Care in Diabetes – 2022, as reported by this news organization. A panel of five KDIGO representatives and four members appointed by the ADA produced the harmonization statement.

Recommendations from both organizations were largely in agreement at the outset, but following the panel’s review, the two groups are now “very well-aligned,” said Peter Rossing, MD, DMSc, a diabetologist and professor at the Steno Diabetes Center, Copenhagen, and a KDIGO representative to the writing committee, who presented the joint statement at the ADA meeting.

“These are very important drugs that are vastly underused,” commented Josef Coresh, MD, PhD, an epidemiologist and professor at Johns Hopkins Bloomberg School of Public Health, Baltimore, who specializes in CKD and was not involved with the new statement.

“Coherence and simplicity are what we need so that there are no excuses about moving forward” with the recommended combination treatment, he stressed.

Moving too slow

“No one is resisting using these new medications, but they are just moving too slowly, and data now show that it’s moving more slowly in the United States than elsewhere. That may be partly because U.S. patients are charged much more for these drugs, and partly because U.S. health care is so much more fragmented,” Dr. Coresh said in an interview.

The new joint consensus statement may help, “but the fragmentation of the United States system and COVID-19 are big enemies” for any short-term increased use of the highlighted agents, he added.

Evidence for low U.S. use of SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists is becoming well known.

Dr. Rossing cited a 2019 report from the CURE-CKD registry of more than 600,000 U.S. patients with CKD showing that less than 1% received an SGLT2 inhibitor and less than 1% a GLP-1 receptor agonist. Not all these patients had diabetes, but a subgroup analysis of those with diabetes, prediabetes, or hypertension showed that usage of each of these two classes remained at less than 1% even in this group.

A separate report at the ADA meeting documented that of more than 1.3 million people with type 2 diabetes in the U.S. Veterans Affairs Healthcare System during 2019 and 2020, just 10% received an SGLT2 inhibitor and 7% a GLP-1 receptor agonist. And this is in a setting where drug cost is not a limiting factor.

In addition to focusing on the updated scheme for drug intervention in the consensus statement, Dr. Rossing highlighted several other important points that the writing committee emphasized.

Lifestyle optimization is a core first-line element of managing patients with diabetes and CKD, including a healthy diet, exercise, smoking cessation, and weight control. Other key steps for management include optimization of blood pressure, glucose, and lipids. The statement also calls out a potentially helpful role for continuous glucose monitoring in patients with type 1 or type 2 diabetes and CKD.

The statement notes that patients who also have atherosclerotic cardiovascular disease usually qualify for and could potentially benefit from more intensified lipid management with ezetimibe or a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, as well as a potential role for treatment with antiplatelet agents.
 

‘If you don’t screen, you won’t find it’

Dr. Rossing also stressed the importance of regular screening for the onset of advanced CKD in patients. Patients whose estimated glomerular filtration rate (eGFR) drops below 60 mL/min/1.73m2, as well as those who develop microalbuminuria with a urinary albumin-to-creatinine ratio of at least 30 mg/g (30 mg/mmol), have a stage of CKD that warrants the drug interventions he outlined.

Guidelines from both the ADA and KDIGO were already in place, recommending annual screening of patients with diabetes for both these parameters starting at diagnosis of type 2 diabetes or 5 years following initial diagnosis of type 1 diabetes.

“If you don’t screen, you won’t find it, and you won’t be able to treat,” Dr. Rossing warned. He also highlighted the panel’s recommendation to treat these patients with an SGLT2 inhibitor as long as their eGFR is at least 20 mL/min/1.73m2. Treatment can then continue even when their eGFR drops lower.

Starting treatment with finerenone requires that patients have a normal level of serum potassium, he emphasized.

One reason for developing the new ADA and KDIGO statement is that “discrepancies in clinical practice guideline recommendations from various professional organizations add to confusion that impedes understanding of best practices,” write Katherine R. Tuttle, MD, and associates in a recent commentary.

The goal of the new statement is to harmonize and promote the shared recommendations of the two organizations, added Dr. Tuttle, who is executive director for research at Providence Healthcare, Spokane, Washington, and a KDIGO representative on the statement writing panel.

Dr. Mottl has reported being a consultant to Bayer. Dr. Rossing has reported being a consultant to or speaker on behalf of Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, MSD, Mundipharma, Novo Nordisk, Sanofi Aventis, and Vifor, as well as receiving research grants from AstraZeneca and Novo Nordisk. Dr. Coresh has reported no relevant financial relationships. Dr. Tuttle has reported being a consultant to AstraZeneca, Bayer, Boehringer Ingelheim, Goldfinch Bio, Janssen, Novo Nordisk, and Travere; receiving honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Gilead, Goldfinch Bio, Novo Nordisk, and Travere; and receiving research funding from AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Goldfinch Bio, Novo Nordisk, and Travere.

A version of this article first appeared on Medscape.com.

Ventricular arrhythmias more commonly occur on days when there are higher levels of air pollution, especially with fine particulate matter (PM), a new study suggests.

The investigators studied the relationship between air pollution and ventricular arrhythmias in Piacenza, Italy by examining 5-year data on patients who received an implantable cardioverter defibrillator (ICD).

Thomas321/iStock/Getty Images Plus

They found a significant association between PM2.5 levels and ventricular arrhythmias, especially those treated with direct current shock. Moreover, higher levels of PM2.5 and PM10 were associated with increased risk of all ventricular arrhythmias.

“These data confirm that environmental pollution is not only a climate emergency but also a public health problem,” lead author Alessia Zanni, currently at Maggiore Hospital, Bologna, Italy, and previously at Piacenza Hospital, said in an interview.

“The study suggests that the survival of patients with heart disease is affected not only by pharmacological therapies and advances in cardiology, but also by the air that they breathe,” she said.

The results were presented at European Society of Cardiology Heart Failure 2022.
 

More ED visits

The World Health Organization estimates around 7 million people die every year from exposure to polluted air, “as 91% of the world’s population lives in areas where air contaminants exceed safety levels,” Dr. Zanni said. Furthermore, “air pollution has been defined as the fourth-highest ranking risk factor for mortality – more important than LDL cholesterol, obesity, physical activity, or alcohol use.”

She noted that Piacenza has “historically been very attentive to the issues of early defibrillation and cardiac arrest.” Her group had previously found a correlation between out-of-hospital cardiac arrests and air pollution in the general population.

Moreover, her group recently observed that ED visits for patients with ICDs “tended to cluster; on some special days, many patients with ICDs had cardiac arrhythmias, and during those days, air pollution levels were particularly high.”

Her group therefore decided to compare the concentration of air pollutants on days when patients suffered from an arrhythmia event versus pollution levels on days without an arrhythmia, she said.
 

Further piece in a complex puzzle

The researchers studied 146 patients with ICDs between January 2013 and December 2017, assigning exposures (short, mid, and long term) to these patients based on their residential addresses.

They extracted day-by-day urban PM10, PM2.5, CO, NO₂, and O₃ levels from the Environmental Protection Agency monitoring stations and then, using time-stratified case-crossover analysis methodology, they calculated the association of ventricular arrhythmia onset with 0- to 7-day moving averages of the various air pollutants prior to the event.

Patients had received their ICD to control cardiac dysfunction brought on by previous myocardial infarction (n = 93), genetic or inflammatory conditions (n = 53), secondary prevention after a lethal arrhythmia (n = 67), and primary prevention (n = 79).

Of the 440 ventricular arrhythmias recorded, 322 were treated with antitachycardia pacing, while the remaining 118 were treated with direct current shock.

The researchers found a significant association between PM2.5 levels and ventricular arrhythmia treated with shock, corresponding to a 15% increased risk or every additional 10mg/m³ (P < .019).

They also found that, when PM2.5 concentrations were elevated by 1 mg/m³ for an entire week, compared with average levels, there was a 2.4% higher likelihood of ventricular arrhythmias, regardless of the temperature, and when PM10 was 1 mg/m³ above average for a week, there was a 2.1% increased risk for arrhythmias (odds ratio, 1,024; 95% confidence interval, 1,009-1,040] and OR, 1,021; 95% CI, 1,009-1,033, respectively), Dr. Zanni reported.

“Since the majority of out-of-hospital cardiac arrest causes still remain unclear, our data add a further piece to the complex puzzle of cardiac arrest triggers,” Dr. Zanni commented. “We think that particulate matter can cause acute inflammation of the heart muscle and potentially act as a trigger for lethal cardiac arrhythmias.

“As these toxic particles are emitted from power plants, industries, and cars, we think that cardiovascular research should highlight these new findings to promote green projects among the general population, clarifying the risks to the health of the human being, and we think strategies to prevent air pollutant exposure in high-risk patients [with previous cardiac disease] should be developed,” she added.

Further, “we advise patients at risk, during days with high PM2.5 (> 35 mg/m³) and PM10 (> 50 mg/m³) to use a mask of the N95 type outdoors, to reduce time spent outdoors – particularly in traffic – and to improve home air filtration,” Dr. Zanni said.
 

Entering the mainstream

In a comment, Joel Kaufman, MD, MPH, professor of internal medicine and environmental health, University of Washington, Seattle, said the study “adds to a fairly substantial literature already on this topic of short-term exposure to air pollution.”

The evidence that air pollutants “can be a trigger of worsening of cardiovascular disease is fairly consistent at this time, and although the effect sizes are small, they are consistent,” said Dr. Kaufman, who was the chair of the writing group for the American Heart Association’s 2020 policy statement, “Guidance to Reduce Cardiovascular Burden of Ambient Air Pollutants.”

“The research into this issue has become clearer during the past 10 years but still is not in the mainstream of most cardiologists’ awareness. They tend to focus more on controlling cholesterol and performing procedures, etc., but there are modifiable risk factors like air pollution that are increasingly recognized as being part of the picture,” said Dr. Kaufman, who was not involved with the current study.

Dr. Zanni added: “It is important that politics work hand in hand with the scientific community in order to win the battle against global warming, which will reduce the number of cardiovascular deaths – the leading cause of death worldwide – as well as environmental integrity.”

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Dr. Zanni and coauthors and Dr. Kaufman reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Ventricular arrhythmias more commonly occur on days when there are higher levels of air pollution, especially with fine particulate matter (PM), a new study suggests.

The investigators studied the relationship between air pollution and ventricular arrhythmias in Piacenza, Italy by examining 5-year data on patients who received an implantable cardioverter defibrillator (ICD).

Thomas321/iStock/Getty Images Plus

They found a significant association between PM2.5 levels and ventricular arrhythmias, especially those treated with direct current shock. Moreover, higher levels of PM2.5 and PM10 were associated with increased risk of all ventricular arrhythmias.

“These data confirm that environmental pollution is not only a climate emergency but also a public health problem,” lead author Alessia Zanni, currently at Maggiore Hospital, Bologna, Italy, and previously at Piacenza Hospital, said in an interview.

“The study suggests that the survival of patients with heart disease is affected not only by pharmacological therapies and advances in cardiology, but also by the air that they breathe,” she said.

The results were presented at European Society of Cardiology Heart Failure 2022.
 

More ED visits

The World Health Organization estimates around 7 million people die every year from exposure to polluted air, “as 91% of the world’s population lives in areas where air contaminants exceed safety levels,” Dr. Zanni said. Furthermore, “air pollution has been defined as the fourth-highest ranking risk factor for mortality – more important than LDL cholesterol, obesity, physical activity, or alcohol use.”

She noted that Piacenza has “historically been very attentive to the issues of early defibrillation and cardiac arrest.” Her group had previously found a correlation between out-of-hospital cardiac arrests and air pollution in the general population.

Moreover, her group recently observed that ED visits for patients with ICDs “tended to cluster; on some special days, many patients with ICDs had cardiac arrhythmias, and during those days, air pollution levels were particularly high.”

Her group therefore decided to compare the concentration of air pollutants on days when patients suffered from an arrhythmia event versus pollution levels on days without an arrhythmia, she said.
 

Further piece in a complex puzzle

The researchers studied 146 patients with ICDs between January 2013 and December 2017, assigning exposures (short, mid, and long term) to these patients based on their residential addresses.

They extracted day-by-day urban PM10, PM2.5, CO, NO₂, and O₃ levels from the Environmental Protection Agency monitoring stations and then, using time-stratified case-crossover analysis methodology, they calculated the association of ventricular arrhythmia onset with 0- to 7-day moving averages of the various air pollutants prior to the event.

Patients had received their ICD to control cardiac dysfunction brought on by previous myocardial infarction (n = 93), genetic or inflammatory conditions (n = 53), secondary prevention after a lethal arrhythmia (n = 67), and primary prevention (n = 79).

Of the 440 ventricular arrhythmias recorded, 322 were treated with antitachycardia pacing, while the remaining 118 were treated with direct current shock.

The researchers found a significant association between PM2.5 levels and ventricular arrhythmia treated with shock, corresponding to a 15% increased risk or every additional 10mg/m³ (P < .019).

They also found that, when PM2.5 concentrations were elevated by 1 mg/m³ for an entire week, compared with average levels, there was a 2.4% higher likelihood of ventricular arrhythmias, regardless of the temperature, and when PM10 was 1 mg/m³ above average for a week, there was a 2.1% increased risk for arrhythmias (odds ratio, 1,024; 95% confidence interval, 1,009-1,040] and OR, 1,021; 95% CI, 1,009-1,033, respectively), Dr. Zanni reported.

“Since the majority of out-of-hospital cardiac arrest causes still remain unclear, our data add a further piece to the complex puzzle of cardiac arrest triggers,” Dr. Zanni commented. “We think that particulate matter can cause acute inflammation of the heart muscle and potentially act as a trigger for lethal cardiac arrhythmias.

“As these toxic particles are emitted from power plants, industries, and cars, we think that cardiovascular research should highlight these new findings to promote green projects among the general population, clarifying the risks to the health of the human being, and we think strategies to prevent air pollutant exposure in high-risk patients [with previous cardiac disease] should be developed,” she added.

Further, “we advise patients at risk, during days with high PM2.5 (> 35 mg/m³) and PM10 (> 50 mg/m³) to use a mask of the N95 type outdoors, to reduce time spent outdoors – particularly in traffic – and to improve home air filtration,” Dr. Zanni said.
 

Entering the mainstream

In a comment, Joel Kaufman, MD, MPH, professor of internal medicine and environmental health, University of Washington, Seattle, said the study “adds to a fairly substantial literature already on this topic of short-term exposure to air pollution.”

The evidence that air pollutants “can be a trigger of worsening of cardiovascular disease is fairly consistent at this time, and although the effect sizes are small, they are consistent,” said Dr. Kaufman, who was the chair of the writing group for the American Heart Association’s 2020 policy statement, “Guidance to Reduce Cardiovascular Burden of Ambient Air Pollutants.”

“The research into this issue has become clearer during the past 10 years but still is not in the mainstream of most cardiologists’ awareness. They tend to focus more on controlling cholesterol and performing procedures, etc., but there are modifiable risk factors like air pollution that are increasingly recognized as being part of the picture,” said Dr. Kaufman, who was not involved with the current study.

Dr. Zanni added: “It is important that politics work hand in hand with the scientific community in order to win the battle against global warming, which will reduce the number of cardiovascular deaths – the leading cause of death worldwide – as well as environmental integrity.”

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Dr. Zanni and coauthors and Dr. Kaufman reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Ventricular arrhythmias more commonly occur on days when there are higher levels of air pollution, especially with fine particulate matter (PM), a new study suggests.

The investigators studied the relationship between air pollution and ventricular arrhythmias in Piacenza, Italy by examining 5-year data on patients who received an implantable cardioverter defibrillator (ICD).

Thomas321/iStock/Getty Images Plus

They found a significant association between PM2.5 levels and ventricular arrhythmias, especially those treated with direct current shock. Moreover, higher levels of PM2.5 and PM10 were associated with increased risk of all ventricular arrhythmias.

“These data confirm that environmental pollution is not only a climate emergency but also a public health problem,” lead author Alessia Zanni, currently at Maggiore Hospital, Bologna, Italy, and previously at Piacenza Hospital, said in an interview.

“The study suggests that the survival of patients with heart disease is affected not only by pharmacological therapies and advances in cardiology, but also by the air that they breathe,” she said.

The results were presented at European Society of Cardiology Heart Failure 2022.
 

More ED visits

The World Health Organization estimates around 7 million people die every year from exposure to polluted air, “as 91% of the world’s population lives in areas where air contaminants exceed safety levels,” Dr. Zanni said. Furthermore, “air pollution has been defined as the fourth-highest ranking risk factor for mortality – more important than LDL cholesterol, obesity, physical activity, or alcohol use.”

She noted that Piacenza has “historically been very attentive to the issues of early defibrillation and cardiac arrest.” Her group had previously found a correlation between out-of-hospital cardiac arrests and air pollution in the general population.

Moreover, her group recently observed that ED visits for patients with ICDs “tended to cluster; on some special days, many patients with ICDs had cardiac arrhythmias, and during those days, air pollution levels were particularly high.”

Her group therefore decided to compare the concentration of air pollutants on days when patients suffered from an arrhythmia event versus pollution levels on days without an arrhythmia, she said.
 

Further piece in a complex puzzle

The researchers studied 146 patients with ICDs between January 2013 and December 2017, assigning exposures (short, mid, and long term) to these patients based on their residential addresses.

They extracted day-by-day urban PM10, PM2.5, CO, NO₂, and O₃ levels from the Environmental Protection Agency monitoring stations and then, using time-stratified case-crossover analysis methodology, they calculated the association of ventricular arrhythmia onset with 0- to 7-day moving averages of the various air pollutants prior to the event.

Patients had received their ICD to control cardiac dysfunction brought on by previous myocardial infarction (n = 93), genetic or inflammatory conditions (n = 53), secondary prevention after a lethal arrhythmia (n = 67), and primary prevention (n = 79).

Of the 440 ventricular arrhythmias recorded, 322 were treated with antitachycardia pacing, while the remaining 118 were treated with direct current shock.

The researchers found a significant association between PM2.5 levels and ventricular arrhythmia treated with shock, corresponding to a 15% increased risk or every additional 10mg/m³ (P < .019).

They also found that, when PM2.5 concentrations were elevated by 1 mg/m³ for an entire week, compared with average levels, there was a 2.4% higher likelihood of ventricular arrhythmias, regardless of the temperature, and when PM10 was 1 mg/m³ above average for a week, there was a 2.1% increased risk for arrhythmias (odds ratio, 1,024; 95% confidence interval, 1,009-1,040] and OR, 1,021; 95% CI, 1,009-1,033, respectively), Dr. Zanni reported.

“Since the majority of out-of-hospital cardiac arrest causes still remain unclear, our data add a further piece to the complex puzzle of cardiac arrest triggers,” Dr. Zanni commented. “We think that particulate matter can cause acute inflammation of the heart muscle and potentially act as a trigger for lethal cardiac arrhythmias.

“As these toxic particles are emitted from power plants, industries, and cars, we think that cardiovascular research should highlight these new findings to promote green projects among the general population, clarifying the risks to the health of the human being, and we think strategies to prevent air pollutant exposure in high-risk patients [with previous cardiac disease] should be developed,” she added.

Further, “we advise patients at risk, during days with high PM2.5 (> 35 mg/m³) and PM10 (> 50 mg/m³) to use a mask of the N95 type outdoors, to reduce time spent outdoors – particularly in traffic – and to improve home air filtration,” Dr. Zanni said.
 

Entering the mainstream

In a comment, Joel Kaufman, MD, MPH, professor of internal medicine and environmental health, University of Washington, Seattle, said the study “adds to a fairly substantial literature already on this topic of short-term exposure to air pollution.”

The evidence that air pollutants “can be a trigger of worsening of cardiovascular disease is fairly consistent at this time, and although the effect sizes are small, they are consistent,” said Dr. Kaufman, who was the chair of the writing group for the American Heart Association’s 2020 policy statement, “Guidance to Reduce Cardiovascular Burden of Ambient Air Pollutants.”

“The research into this issue has become clearer during the past 10 years but still is not in the mainstream of most cardiologists’ awareness. They tend to focus more on controlling cholesterol and performing procedures, etc., but there are modifiable risk factors like air pollution that are increasingly recognized as being part of the picture,” said Dr. Kaufman, who was not involved with the current study.

Dr. Zanni added: “It is important that politics work hand in hand with the scientific community in order to win the battle against global warming, which will reduce the number of cardiovascular deaths – the leading cause of death worldwide – as well as environmental integrity.”

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Dr. Zanni and coauthors and Dr. Kaufman reported no relevant financial relationships.

A version of this article first appeared on Medscape.com.

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

A version of this article first appeared on Medscape.com.

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

A version of this article first appeared on Medscape.com.

The underlying cause of David Bennett’s death on March 8, two months after he received the heart of a genetically altered pig, remains unknown and is only slightly less mysterious for what can likely be ruled out, suggests a progress report on the case from the director of the cardiac xenotransplantation program where the pioneering surgery took place.

Mr. Bennett died in “diastolic heart failure,” reported Muhammad M. Mohiuddin, MBBS, University of Maryland School of Medicine, Baltimore, “but the mechanism is still under investigation.”

University of Maryland Medical Center

Rocky clinical course

Early characterizations of the patient’s death focused more on his diminished, end-stage clinical condition at the time of the surgery than on immune rejection or other direct effects of the xenograft or on the first-of-its-kind procedure itself.

The 57-year-old Mr. Bennett had presented to the University of Maryland team with nonischemic cardiomyopathy, on multiple inotropes, and requiring an intra-aortic balloon pump, Dr. Mohiuddin said in his ATC presentation. The patient had suffered multiple arrests and resuscitations, and by the time of surgery had been hospitalized for almost 2 months, including 40 days on veno-arterial extracorporeal membrane oxygenation (ECMO).

The transplant procedure itself went as planned until removal of the aortic cross clamp, which triggered a type-A aortic dissection. “We put a graft in the ascending aorta and a stent in the descending aorta. Even after 2 days, we found the dissection extending to the renal artery, so we had to go back and also put a stent in the renal artery,” Dr. Mohiuddin said.

Mr. Bennett also underwent two exploratory laparotomies in the first 10 days after transplantation, after CT imaging revealed signs of possible bowel inflammation and ischemia.

Further, he had to fight back a series of infections that led to major changes to his experimental drug regimen, which included immunosuppressants methylprednisolone and mycophenolate mofetil (MMF), the investigational anti-CD40 antibody KPL-404 (Kiniksa Pharmaceuticals), and the anti-inflammatories etanercept (Enbrel) and tocilizumab (Actemra).

One episode of sepsis, in particular, forced temporary withdrawal of MMF and a reduction in methylprednisolone dosage. It’s unknown whether the 30-day MMF suspension played a role in Mr. Bennett’s ultimate clinical deterioration and death, but it’s “highly possible,” Dr. Mohiuddin said in an interview.

Realistically, Mr. Bennett’s death was likely “multifactorial,” Dr. Mohiuddin said. He was in such poor clinical condition going into the procedure, and afterward confronted so many clinical challenges, that “it’s very difficult to say that one thing caused it.”

That hasn’t lessened speculation that the patient’s heart failed secondary to immunologic rejection or PCMV infection, either in Mr. Bennett or the donor pig.
 

A role for PCMV?

Weeks after Mr. Bennett’s death, as previously reported, his surgeon announced at a public forum that PCMV had been identified in the transplanted heart and in tissues of the donor pig. Mr. Bennett’s circulation showed traces of the viral DNA but not of the virus itself.

The presence of PCMV in transplanted porcine hearts is a well-recognized potential hazard in animal models but is considered avoidable with proper screening. In Mr. Bennett’s case, preoperative screening of the pig donor missed signs of the virus.  

Still, PCMV could potentially have contributed to Mr. Bennett’s death, acknowledged Bartley P. Griffith, MD, University of Maryland School of Medicine, who had announced the PCMV finding in an AST-sponsored April 20 webcast.

Preclinical evidence does suggest that PCMV can harm a xenograft organ, observed David H. Sachs, MD, Columbia University Medical Center, New York, from the audience during the comment period after Dr. Mohiuddin’s presentation.

“Each species has a CMV, and they’re quite species-specific,” observed the renowned surgeon and xenotransplantation immunologist. “We showed almost 10 years ago that if PCMV was in a pig kidney, it led to a much shortened survival of the pig kidney in a baboon. There was never any evidence, however, that the CMV infected the baboon or any baboon cells.”

Dr. Sachs asked Dr. Mohiuddin for confirmation that Mr. Bennett displayed no more than DNAemia, circulating cell-free PCMV DNA presumably shed from the porcine heart, but no sign of the virus itself outside of the heart’s porcine cells.

Cell-free DNA had shown up in Mr. Bennett’s circulation about 20 days after the surgery, with concentrations rising until at least day 50. Post-hoc polymerase chain reaction (PCR) testing disclosed PCMV only in the pig’s spleen and porcine cells of the transplanted heart, Dr. Mohiuddin noted.

“We have not found any evidence that the patient was infected by PCMV,” nor was there evidence of any disease related to PCMV, Dr. Mohiuddin replied.

Nor of ongoing rejection

Mr. Bennett’s new heart passed a critical test in the first post-implantation hours by avoiding acute rejection, a potentially disastrous outcome that three of the pig’s 10 gene edits had been designed to prevent.

Although chronic immune rejection was always a concern despite Mr. Bennett’s novel immunosuppressant regimen, myocardial biopsy on postoperative days 34, 50, and 56 and necropsy showed “no signs of typical xenograft rejection,” Dr. Mohiuddin said at the ATC presentation. But “there’s a chance of atypical rejection which we were not accustomed to.”

By day 50, his diastolic function showed echocardiographic signs of deterioration, and “we started seeing interstitial edema with some extravasation of red blood cells, which we thought would resolve over a period of time,” he said. Eventually, however, “we saw that turn into fibroblasts and scar tissue.”

Mr. Bennett once again went on veno-arterial ECMO but died 10 days later. Once they had seen histologic evidence of fibrosis, Dr. Mohiuddin told this news organization, the team believed the myocardial injury was irreversible. “That was the reason we gave up on recovery.”

Mr. Bennett’s xenotransplantation journey has taught the field a lot, he said. “By no means was this a failure; we consider this a huge success. You can do all the experiments in animal models, but you won’t find out the true mechanism of rejection unless you do these kinds of human experiments.”
 

Looking ahead to clinical trials

Research involving humans is always subject to vagaries of human nature, including degree of adherence to prescribed therapy and – in xenotransplantation – precautions in place to mitigate any risks to public health. Such risks theoretically include transfer of porcine viruses or other pathogens to the patient and subsequent release into the general population.

Looking ahead to the possibility of clinical trials after this successful xenotransplantation experience, transplant nephrologist and epidemiologist Peter P. Reese, MD, PhD, University of Pennsylvania, Philadelphia, raised the potentially controversial issue in discussion following Dr. Mohiuddin’s presentation.

It’s known that Mr. Bennett had been repeatedly turned down for a conventional allograft transplant primarily because of his history of treatment noncompliance. Should such a record, Dr. Reese asked, be a relative contraindication to enrollment in any future xenotransplantation trials? Or does the field need a standardized gauge of a patient’s readiness, once discharged, to adhere not only to all medications – including those that fight infection – but also with rules established for public safety, such as routine contact reporting?

“It makes me wonder about choosing a noncompliant patient for these trials,” Dr. Reese said. “If we discharge a patient from the hospital who is at risk for a zoonotic infection that could spread if they basically refuse to cooperate with us or with public health authorities, it really could have negative consequences for the reputation of the field.”

Dr. Mohiuddin agreed such concerns are valid. Mr. Bennett “and all his immediate contacts” signed consent forms acknowledging their willingness to be followed should he be discharged. Mr. Bennett himself “signed a consent to inform us if he has any other intimate contact with someone,” he said in an interview.

“But those are only on paper.” Had Mr. Bennett survived to be discharged, Dr. Mohuiddin said, “no one knows how he would have behaved.”

Dr. Mohiuddin said the research staff had prepared to monitor Mr. Bennett at his home if that’s what it took. “We were ready to follow him as long as we could. There was a surveillance plan in place.”

A version of this article first appeared on Medscape.com.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

NEW ORLEANS – The case continues to grow for prioritizing a sodium-glucose transporter 2 (SGLT2) inhibitor in patients with type 2 diabetes, as real-world evidence of benefit and safety accumulates on top of the data from randomized trials that first established this class as a management pillar.

Another important effect of these agents gaining increasing currency, on top of their well-established benefits in patients with type 2 diabetes for preventing acute heart failure exacerbations and slowing progression of diabetic kidney disease, is that they cut the incidence of new-onset atrial fibrillation (AFib). That effect was confirmed in an analysis of data from about 300,000 U.S. patients included in recent Medicare records, Elisabetta Patorno, MD, reported at the annual scientific sessions of the American Diabetes Association.

Mitchel L. Zoler/MDedge News

But despite documentation like this, real-world evidence also continues to show limited uptake of SGLT2 inhibitors in U.S. patients with type 2 diabetes. Records from more than 1.3 million patients with type 2 diabetes managed in the Veterans Affairs Healthcare System during 2019 or 2022 documented that just 10% of these patients received an agent from this class, even though all were eligible to receive it, according to findings in a separate report at the meeting.

The AFib analysis analyzed two sets of propensity score–matched Medicare patients during 2013-2018 aged 65 years or older with type 2 diabetes and no history of AFib. One analysis focused on 80,475 matched patients who started on treatment with either an SGLT2 inhibitor or a glucagonlike peptide–1 (GLP-1) receptor agonist, and a second on 74,868 matched patients who began either an SGTL2 inhibitor or a dipeptidyl peptidase–4 (DPP4) inhibitor. In both analyses, matching involved more than 130 variables. In both pair sets, patients at baseline averaged about 72 years old, nearly two-thirds were women, about 8%-9% had heart failure, 77%-80% were on metformin, and 20%-25% were using insulin.

The study’s primary endpoint was the incidence of hospitalization for AFib, which occurred a significant 18% less often in the patients who started on an SGLT2, compared with those who started a DPP4 inhibitor during median follow-up of 6.7 months, and a significant 10% less often, compared with those starting a GLP-1 receptor agonist during a median follow-up of 6.0 months, Elisabetta Patorno, MD, DrPH, reported at the meeting. This worked out to 3.7 fewer hospitalizations for AFib per 1,000 patient-years of follow-up among the people who received an SGLT2 inhibitor, compared with a DPP4 inhibitor, and a decrease of 1.8 hospitalizations/1,000 patient-years when compared against patients in a GLP-1 receptor agonist.

Two secondary outcomes showed significantly fewer episodes of newly diagnosed AFib, and significantly fewer patients initiating AFib treatment among those who received an SGLT2 inhibitor relative to the comparator groups. In addition, these associations were consistent across subgroup analyses that divided patients by their age, sex, history of heart failure, and history of atherosclerotic cardiovascular disease.
 

AFib effects add to benefits

The findings “suggest that initiation of an SGLT2 inhibitor may be beneficial in older adults with type 2 diabetes who are at risk for AFib,” said Dr. Patorno, a researcher in the division of pharmacoepidemiology and pharmacoeconomics at Brigham and Women’s Hospital, Boston. “These new findings on AFib may be helpful when weighing the potential risks and benefits of various glucose-lowering drugs in older patients with type 2 diabetes.”

This new evidence follows several prior reports from other research groups of data supporting an AFib benefit from SGLT2 inhibitors. The earlier reports include a post hoc analysis of more than 17,000 patients enrolled in the DECLARE-TIMI 58 cardiovascular outcome trial of dapagliflozin (Farxiga), which showed a 19% relative decrease in the rate of incident AFib or atrial flutter events during a median 4.2 year follow-up.

Other prior reports that found a reduced incidence of AFib events linked with SGLT2 inhibitor treatment include a 2020 meta-analysis based on data from more than 38,000 patients with type 2 diabetes enrolled in any of 16 randomized, controlled trials, which found a 24% relative risk reduction. And an as-yet unpublished report from researchers at the University of Rochester (N.Y.) and their associates presented in November 2021 at the annual scientific sessions of the American Heart Association that documented a significant 24% relative risk reduction in incident AFib events linked to SGLT2 inhibitor treatment in a prospective study of 13,890 patients at several hospitals in Israel or the United States.
 

Evidence ‘convincing’ in totality

The accumulated evidence for a reduced incidence of AFib when patients were on treatment with an SGLT2 inhibitor are “convincing because it’s real world data that complements what we know from clinical trials,” commented Silvio E. Inzucchi, MD, professor of medicine at Yale University and director of the Yale Medicine Diabetes Center in New Haven, Conn., who was not involved with the study.

“If these drugs reduce heart failure, they may also reduce AFib. Heart failure patients easily slip into AFib,” he noted in an interview, but added that “I don’t think this explains all cases” of the reduced AFib incidence.

Dr. Patorno offered a few other possible mechanisms for the observed effect. The class may work by reducing blood pressure, weight, inflammation, and oxidative stress, mitochondrial dysfunction, atrial remodeling, and AFib susceptibility. These agents are also known to cause natriuresis and diuresis, which could reduce atrial dilation, a mechanism that again relates the AFib effect to the better documented reduction in acute heart failure exacerbations.

“With the diuretic effect, we’d expect less overload at the atrium and less dilation, and the same mechanism would reduce heart failure,” she said in an interview.

“If you reduce preload and afterload you may reduce stress on the ventricle and reduce atrial stretch, and that might have a significant effect on atrial arrhythmia,” agreed Dr. Inzucchi.
 

EMPRISE produces more real-world evidence

A pair of additional reports at the meeting that Dr. Patorno coauthored provided real-world evidence supporting the dramatic heart failure benefit of the SGLT2 inhibitor empagliflozin (Jardiance) in U.S. patients with type 2 diabetes, compared with alternative drug classes. The EMPRISE study used data from the Medicare, Optum Clinformatics, and MarketScan databases during the period from August 2014, when empagliflozin became available, to September 2019. The study used more than 140 variables to match patients treated with either empagliflozin or a comparator agent.

The results showed that, in an analysis of more than 130,000 matched pairs, treatment with empagliflozin was linked to a significant 30% reduction in the incidence of hospitalization for heart failure, compared with patients treated with a GLP-1 receptor agonist. Analysis of more than 116,000 matched pairs of patients showed that treatment with empagliflozin linked with a significant 29%-50% reduced rate of hospitalization for heart failure, compared with matched patients treated with a DPP4 inhibitor.

These findings “add to the pool of information” on the efficacy of agents from the SGLT2 inhibitor class, Dr. Patorno said in an interview. “We wanted to look at the full range of patients with type 2 diabetes who we see in practice,” rather than the more selected group of patients enrolled in randomized trials.

SGLT2 inhibitor use lags even when cost isn’t an issue

Despite all the accumulated evidence for efficacy and safety of the class, usage remains low, Julio A. Lamprea-Montealegre, MD, PhD, a cardiologist at the University of California, San Francisco, reported in a separate talk at the meeting. The study he presented examined records for 1,319,500 adults with type 2 diabetes managed in the VA Healthcare System during 2019 and 2020. Despite being in a system that “removes the influence of cost,” just 10% of these patients received treatment with an SGLT2 inhibitor, and 7% received treatment with a GLP-1 receptor agonist.

Notably, his analysis further showed that treatment with an SGLT2 inhibitor was especially depressed among patients with an estimated glomerular filtration rate (eGFR) of 30-44 mL/min per 1.73m². In this subgroup, usage of a drug from this class was at two-thirds of the rate, compared with patients with an eGFR of at least 90 mL/min per 1.73m2. His findings also documented lower rates of use in patients with higher risk for atherosclerotic cardiovascular disease. Dr. Lamprea-Montealegre called this a “treatment paradox,” in which patients likely to get the most benefit from an SGLT2 inhibitor were also less likely to actually receive it.

While his findings from the VA System suggest that drug cost is not the only factor driving underuse, the high price set for the SGLT2 inhibitor drugs that all currently remain on U.S. patents is widely considered an important factor.

“There is a big problem of affordability,” said Dr. Patorno.

“SGLT2 inhibitors should probably be first-line therapy” for many patients with type 2 diabetes, said Dr. Inzucchi. “The only thing holding it back is cost,” a situation that he hopes will dramatically shift once agents from this class become generic and have substantially lower price tags.

The EMPRISE study received funding from Boehringer Ingelheim, the company that markets empagliflozin (Jardiance). Dr. Patorno had no relevant commercial disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk. Dr. Lamprea-Montealegre had received research funding from Bayer.

The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.

“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

courtesy University of California, Los Angeles

“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.

The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.

At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.  

Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:

• One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
• Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
• Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.

Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.

Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.

Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.

The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”

These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.

Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
 

The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.

“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

courtesy University of California, Los Angeles

“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.

The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.

At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.  

Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:

• One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
• Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
• Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.

Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.

Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.

Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.

The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”

These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.

Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
 

The 1-year results of the Harmony transcatheter pulmonary valve to treat severe pulmonary regurgitation have shown a high rate of eliminating or reducing the degree of symptoms as well as freedom from endocarditis, sustained ventricular tachycardia, and the need for further interventions.

“Simply put, the good news is no endocarditis,” said Daniel S. Levi, MD, in presenting results from three different studies with 108 patients who received three different iterations of the device at the Society for Cardiovascular Angiography & Interventions annual scientific sessions.

courtesy University of California, Los Angeles

“Endocarditis has been an issue for us in the pulmonary position; we have yet to have an endocarditis in these patients in 1 year,” he stressed.

The studies evaluated three different versions of the Harmony valve: TPV22 (42 patients), the first version with a 22-mm diameter; the Clinical TPV25 (17 patients), the first iteration of a 25 mm–wide device that has since been discontinued; and the modified TPV25 (45 patients), the second version of the 25-mm valve. The three studies are the early feasibility study of the TPV22, the continued-access study of the TPV22 and the mTPV25, and the pivotal study that included all three versions.

At baseline, 89% of patients had severe and 11% had moderate pulmonary regurgitation (PR). At 1 year, 92% had none or trace PR, 3% had mild PR, and 4% moderate disease.  

Dr. Levi said the device “speaks for itself” in the results he presented. They include no deaths, no heart attacks, and no pulmonary thromboembolism. Other key outcomes include:

• One major stent fracture in one of the early feasibility study patients at 1-month follow-up.
• Four explants, with two in the discontinued cTPV25 and two with the TPV22 in the early-feasibility study.
• Four reinterventions, two with the discontinued cTPV25 and two valve-in-valve procedures with the mTPV25 in the continued-access study, one with stent placement in the right ventricular outflow tract.

Dr. Levi and coinvestigators also performed a breakdown of 1-year outcomes – freedom from PR, stenosis, and interventions – by device: 95.1% for TPV22; 89.7% for mTPV25; and 73.3% for the discontinued cTPV25.

Although the valve is indicated for adolescents and adults, most of the patients in the three studies were adults, with an average weight of 165 pounds (75 kg) who have had PR for decades, said Dr. Levi, an interventional pediatric cardiologist at the University of California, Los Angeles. “With a device like this we are hopefully shifting to treating that a little bit earlier, but fortunately we don’t usually need to treat it before puberty.” The 25-mm TPV gives “a really nice landing zone” for future valve placement. “The goal is to keep patients out of the operating room for at least a few decades if not their whole lives,” he said.

Dr. Levi said the Harmony investigators will follow outcomes with the 22- and modified 25-mm Harmony valves, both of which remain commercially available, out to 10 years.

The study represents the first collective cohort evaluating the Harmony device across the early feasibility, continued access and pivotal studies, said Brian Morray, MD. “It’s important that people understand that evolution and how that impacts the way we look at outcomes, because when you aggregate the data, particularly for the TPV25, some of the procedural outcomes and the adverse events are no longer really reflective in the current time frame.”

These Harmony results “represent another big step in the evolution of interventional cardiology and will be up there with development of the Melody valve and the utility and the use of the Sapien valve in the pulmonary position,” said Dr. Morray, an associate professor of pediatrics at the University of Washington, Seattle, and an interventional cardiologist at Seattle Children’s Hospital.

Dr. Levi disclosed he is a consultant to Medtronic and Edwards Lifesciences. Dr. Morray disclosed he is a clinical proctor for Abbott and a consultant to Medtronic, but not for the Harmony device.
 

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.

NEW ORLEANS – High out-of-pocket costs for medications used by patients with diabetes are tied to reduced use of these drugs and ultimately worse clinical outcomes, according to findings from two separate studies.

One study looked at the insurance records of more than 70,000 U.S. patients with type 2 diabetes and established cardiovascular disease who were already on metformin. The findings showed that, after adjustment for confounders, the quartile of patients with the highest out-of-pocket cost for an agent from the sodium-glucose cotransporter 2 (SGLT2)–inhibitor class filled a prescription for one of these drugs a significant 21% less often than did patients from the quartile with the lowest personal expense, after adjustment for a variety of potential confounding factors, reported Jing Luo, MD, at the annual scientific sessions of the American Diabetes Association.

A similar analysis run by Dr. Luo and his associates looking at glucagonlike peptide-1 (GLP-1) receptor agonists showed that the quartile of patients who had to pay the most for one of those drugs had an adjusted 12% lower rate of filling a prescription, compared with those with the lowest out-of-pocket expense, a difference that fell just short of significance.

“If we consistently see that high drug costs affect use of highly effective medications in patients with type 2 diabetes and risk factors, it’s quite problematic because it’s not just a matter of money, but it also makes a difference in the patient’s quality of care,” Dr. Luo said in an interview.

Prevention drug lists can help

Consistency turned up in a second report at the same ADA session that retrospectively reviewed data collected during 2004-2017 by a single large U.S. health insurer to identify 3,315 matched pairs of children and adults with diabetes who all had high-deductible health plans for their medical insurance, along with an associated health savings account.

One set of patients in each matched pair began to receive, at some point during follow-up, coverage with a prevention drug list (PDL; also called a formulary) that provided them with a variety of specified agents at no charge. They included oral antidiabetes agents, insulin, antihypertensives, and lipid-lowering drugs. The other half of the matched pairs of patients received no PDL coverage and had copays for their antidiabetes medications.

The findings showed that the rates of out-of-pocket costs for antidiabetes drugs, antidiabetic medications used, and acute diabetes complications all tracked extremely closely between the matched pairs before half of them started to receive their PDL coverage. However, after PDL coverage kicked in, out of pocket costs dropped by 32% for the people with PDL coverage, compared with those who did not receive this coverage. Oral antidiabetes medication use rose modestly, but acute diabetes complications “declined substantially,” with a 14% relative reduction overall in those with PDL coverage, compared with those without, reported J. Franklin Wharam, MBBCh, a professor and health policy researcher at Duke University in Durham, N.C. In the roughly half of the study cohort who fell into a low-income category based on where they lived, the rate of excess acute diabetes complications was 23% higher for those without a PDL, compared with those who had that coverage.

PDL coverage linked with “large reductions in acute, preventable diabetes complications,” concluded Dr. Wharam. “Policy makers and employers should incentivize PDL uptake among low-income patients with diabetes.”

Newer, more effective drugs cost a lot

“The more comorbidities that patients have, the greater is the strength of the evidence for using newer antidiabetes drugs that are more expensive,” but that would mean spending much more on this part of patient care, noted Dr. Luo, an internal medicine physician and researcher at the University of Pittsburgh. “It will cost a lot of money, and I’m not sure what the solution is. It’s a huge conundrum.”

About 30 million Americans have type 2 diabetes. If every one of them went on an SGLT2 inhibitor, or went on an SGLT2 inhibitor plus a GLP-1 receptor agonist, “it would bankrupt the U.S. health care system, so we can’t do that,” commented Sylvio E. Inzucchi, MD, in an interview. “The only thing holding this back is cost. We target these drugs to the patients most apt to benefit from them. If they were generic they would be used much more widely,” noted Dr. Inzucchi, professor and clinical chief of endocrinology at Yale University in New Haven, Conn.

The study run by Dr. Luo and his associates retrospectively reviewed data from 72,743 U.S. adults included in the Optum Clinformatics database during December 2017–December 2019. All included patients had type 2 diabetes, received metformin monotherapy, and had established atherosclerotic cardiovascular disease. They averaged 72 years of age, 56% were men, and 88% were on a Medicare Advantage plan, while the remainder had commercial insurance. Their average hemoglobin A1c level was 6.8%.

People in the quartile with the lowest copays spent an average of about $20/month for either an SGLT2 inhibitor or a GLP-1 receptor agonist. Those in the quartile with the highest copays spent roughly $100/month for agents from each of these two classes. The analysis followed patients for a median of 914 days.

In addition to finding disparate rates of drug use between these two quartiles, the analysis also showed that higher copays linked with longer times to initially fill prescriptions for these drugs. But while those with higher copays took longer to start both classes than did those with the smallest copays, even those with the lowest out-of-pocket costs averaged about a year to initiate treatment.

Dr. Luo attributed this delay to other factors besides costs to patients, such as clinicians prescribing other classes of second-line oral antidiabetes agents, clinical inertia, and lack of awareness by clinicians of the special benefits of SGLT2 inhibitors and GLP-1 receptor antagonists for patients with type 2 diabetes and cardiovascular disease.

“A lot of clinical and social factors drive medication use,” not just out-of-pocket cost, he explained.

Dr. Luo is a consultant to Alosa Health. Dr. Wharam had no disclosures. Dr. Inzucchi is an adviser to Abbott Diagnostics, Esperion Therapeutics, and vTv Therapeutics, a consultant to Merck and Pfizer, and has other relationships with AstraZeneca, Boehringer Ingelheim, Lexicon, and Novo Nordisk.