CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

CHICAGO – Treatment with the “twincretin” tirzepatide led to significant and potentially clinically meaningful cuts in 24-hour ambulatory blood pressure, compared with placebo, while causing modest increases in heart rate, in a prespecified substudy of the SURMOUNT-1 trial.

“The large effects on ambulatory 24-hour blood pressure raise the possibility that there may be important long-term benefits of [tirzepatide] on the complications of obesity,” said James A. de Lemos, MD, during a presentation at the American Heart Association scientific sessions.

Mitchel L. Zoler/MDedge News

“The findings are concordant with the [previously reported] office-based measurements, and the blood pressure reductions provide further evidence for the potential benefits of tirzepatide on cardiovascular health and outcomes,” said Dr. de Lemos, a cardiologist and professor at the University of Texas Southwestern Medical Center, Dallas.

The substudy included 600 of the 2,539 people enrolled in SURMOUNT-1, the first of two pivotal trials for tirzepatide (Mounjaro) in people without diabetes but with obesity or overweight (body mass index of 27-29 kg/m²) plus at least one weight-related complication. The primary endpoints of SURMOUNT-1 were the percent change in weight from baseline to 72 weeks on treatment with either of three different weekly injected doses of tirzepatide, compared with control subjects who received placebo, and the percentage of enrolled subjects achieving at least 5% loss in baseline weight, compared with the controls.

Tirzepatide treatment led to significant increases in both results, compared with controls, with the highest dose tested, 15 mg/week, resulting in an average 20.9% drop in weight from baseline after 72 weeks of treatment, and 91% of enrolled subjects on that dose achieving the 5% weight-loss threshold during the same time frame, in results published in 2022 in the New England Journal of Medicine.
 

24-hour ambulatory pressures from 494 people

The substudy enrolled 600 of the SURMOUNT-1 participants and involved 24-hour ambulatory BP and heart rate measurements at entry and after 36 weeks on treatment. Full results were available for 494 of these people. The substudy included only study participants who entered with a BP of less than 140/90 mm Hg. Enrollment in SURMOUNT-1 overall excluded people with a BP of 160/100 mm Hg or higher. The average BP among all enrolled participants was about 123/80 mm Hg, while heart rates averaged about 73 beats per minute.

Systolic BP measured with the ambulatory monitor fell from baseline by an average of 5.6, 8.8, and 6.2 mm Hg in the people who received tirzepatide in weekly doses of 5, 10, or 15 mg, respectively, and rose by an average 1.8 mm Hg among the controls, Dr. de Lemos reported. Diastolic BP dropped among the tirzepatide recipients by an average of 1.5, 2.4, and 0.0 mm Hg in the three ascending tirzepatide treatment arms, and rose by an average 0.5 mm Hg among the controls. All of the differences between the intervention groups and the controls were significant except for the change in diastolic BP among participants who received 15 mg of tirzepatide weekly.

The results showed that 36 weeks on tirzepatide treatment was associated with “arguably clinically meaningful” reductions in systolic and diastolic BPs, Dr. de Lemos said. “There is a lot of optimism that this will translate into clinical benefits.” He also noted that, “within the limits of cross-study comparisons, the blood pressure changes look favorable, compared with the single-incretin mechanism GLP-1 [glucagonlike peptide–1] receptor agonists.”

Heart rate fell by an average 1.8 bpm in the controls, and rose by an average 0.3, 0.5, and 3.6 bpm among the three groups receiving ascending weekly tirzepatide doses, effects that were “consistent with what’s been seen with the GLP-1 receptor agonists,” noted Dr. de Lemos.

Tirzepatide is known as a “twincretin” because it shares this GLP-1 receptor agonism and also has a second incretin agonist activity, to the receptor for the glucose-dependent insulinotropic polypeptide.

Lowering of blood pressure plateaus

Changes in BP over time during the 72 weeks on treatment, data first presented in the original report, showed that average systolic pressure in the people who received tirzepatide fell sharply during the first 24 weeks on treatment, and then leveled out with little further change over time. Furthermore, all three tirzepatide doses produced roughly similar systolic BP reductions. Changes in diastolic pressure over time showed a mostly similar pattern of reduction, although a modest ongoing decrease in average diastolic pressure continued beyond 24 weeks.

Mitchel L. Zoler/MDedge News

This pattern of a plateau in BP reduction has been seen before in studies using other treatments to produce weight loss, including bariatric surgery, said Naveed Sattar, MBChB, PhD, professor of metabolic medicine at the University of Glasgow, who was not involved in SURMOUNT-1. He attributed the plateau in BP reduction among tirzepatide-treated people to them hitting a wall in their BP nadir based on homeostatic limits. Dr. Sattar noted that most enrolled participants had normal BPs at entry based on the reported study averages.

“It’s hard to go lower, but the blood pressure reduction may be larger in people who start at higher pressure levels,” Dr. Sattar said in an interview.

Mitchel L. Zoler/MDedge News

Another inferred cap on BP reductions in the trial hypothesizes that the individual clinicians who managed the enrolled patients may have cut back on other BP-lowering agents as the pressures of the tirzepatide recipients fell to relatively low levels, suggested Darren McGuire, MD, a cardiologist and professor at UT Southwestern Medical Center, who also was not involved in the SURMOUNT-1 study.
 

Incretin agonists as antihypertensive drugs

The substantial BP-lowering seen with tirzepatide, as well as with other incretin agonist agents, suggests a new way to think about BP control in people with overweight or obesity, Dr. Sattar said.

“Until now, we haven’t had tools where people lose so much weight. Now that we have these tools [incretin agonists as well as bariatric surgery], we see substantial blood pressure reductions. It makes you think we should use weight-loss agents to lower blood pressure rather than a beta-blocker or angiotensin-converting enzyme inhibitor; then we’d also produce all the other benefits from weight loss,” Dr. Sattar suggested.

Dr. de Lemos said he sees signals that the BP reductions caused by tirzepatide and the GLP-1 receptor agonists may go beyond just weight-loss effects.

“There appears to be a larger blood pressure reduction than anticipated based on the change in weight,” he said during his presentation. “GLP-1 is active in most vascular tissues, so these [receptor agonist] agents likely have vascular or cardiac effects, or even effects on other tissues that may affect blood pressure.”
 

Heart rate increases were usually modest

The experiences with GLP-1 receptor agonists also suggest that the heart rate increases seen with tirzepatide treatment in SURMOUNT-1 will not have long-term effects. “The [Food and Drug Administration] mandated this heart rate substudy to make sure that the increase in heart rate was not larger than what would be anticipated” with a GLP-1 receptor agonist, Dr. de Lemos explained.

SURMOUNT-1 had a treatment-stopping rule to prevent a person’s heart rate from rising beyond 10 bpm from baseline. “Trivial numbers” of patients experienced a heart rate increase of this magnitude, he said. If used in routine practice, Dr. de Lemos said that he would closely investigate a patient with a heart rate increase greater than 10 mm Hg. The average increase seen with the highest dose, about 4 bpm above baseline, would generally not be concerning.

Tirzepatide received U.S. marketing approval from the FDA in May 2022 for treating people with type 2 diabetes. In October 2022, the FDA gave tirzepatide “Fast Track” designation for the pending application for approval of an indication to treat people with overweight or obesity who match the entry criteria for SURMOUNT-1 and for the second pivotal trial for this indication, SURMOUNT-2. According to a statement from Eli Lilly, the company that is developing and markets tirzepatide (Mounjaro), the FDA’s decision on the obesity indication will remain pending until the SURMOUNT-2 results are available, which the company expects will occur in 2023.

SURMOUNT-1 and SURMOUNT-2 were sponsored by Lilly, the company that markets tirzepatide. Dr. de Lemos has been a consultant to Lilly as well as to Amgen, AstraZeneca, Janssen, Novo Nordisk, Ortho, Quidel Cardiovascular, and Regeneron. Dr. Sattar has financial ties to Lilly, Afimmune, Amgen, AstraZeneca, Boehringer Ingelheim, Hammi, Merck Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Roche, and Sanofi-Aventis. Dr. McGuire has ties to Lilly as well as to Altimmune, Applied Therapeutics, Bayer, Boehringer Ingelheim, CSL Behring, Lexicon, Merck, Metavant, Novo Nordisk, and Sanofi.

Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live. The nod from the FDA on Oct. 25 for teclistamab, the first bispecific B-cell maturation antigen–directed CD3 T-cell engager to be approved, was based on data from a phase 1/2 study called MagesTEC-1 (NCT03145181; NCT04557098). Patients in the study showed an overall response rate of 61.8%, and 26.7% of people in the study had no detectable disease.

This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”

The first cut of the data appeared in the New England Journal of Medicine.

At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.

Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”

Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.

He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.

Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”

However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?

Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.

When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”

He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”

Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”

For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.

In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”

In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.

Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.

A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”

Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.

“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”

Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.

“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”

The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.

Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.

Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.

Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.

Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.

The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.

To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.

Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.

Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.

Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live. The nod from the FDA on Oct. 25 for teclistamab, the first bispecific B-cell maturation antigen–directed CD3 T-cell engager to be approved, was based on data from a phase 1/2 study called MagesTEC-1 (NCT03145181; NCT04557098). Patients in the study showed an overall response rate of 61.8%, and 26.7% of people in the study had no detectable disease.

This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”

The first cut of the data appeared in the New England Journal of Medicine.

At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.

Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”

Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.

He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.

Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”

However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?

Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.

When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”

He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”

Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”

For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.

In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”

In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.

Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.

A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”

Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.

“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”

Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.

“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”

The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.

Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.

Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.

Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.

Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.

The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.

To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.

Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.

Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.

Following “unprecedented” results in a phase 1/2 study, teclistamab (Tecvayli, Janssen Biotech) received accelerated approval from the Food and Drug Administration for adults with relapsed/refractory multiple myeloma who had received at least four lines of therapy. Typically, patients in this situation have just a few weeks to live. The nod from the FDA on Oct. 25 for teclistamab, the first bispecific B-cell maturation antigen–directed CD3 T-cell engager to be approved, was based on data from a phase 1/2 study called MagesTEC-1 (NCT03145181; NCT04557098). Patients in the study showed an overall response rate of 61.8%, and 26.7% of people in the study had no detectable disease.

This is “unprecedented” said Nikhil Munshi, MD, professor of medicine at Harvard Medical School, Boston, who was not involved with the study. “Pomalidomide got approved with 30% response rate, carfilzomib got approved with 29% response rate, selinexor got approved with 31% response rate and so on and on. ... So here is teclistamab with [this] response rate in patients having five, six lines of treatment. ...[It’s] going to be so much in demand because it’s a great drug.”

The first cut of the data appeared in the New England Journal of Medicine.

At the 6-month mark, 90.6% of patients who responded had no progression of their disease, and at 9 months, 66.5% of patients were still holding steady.

Senior investigator in the trial, Saad Usmani, MD, of Memorial Sloan Kettering Cancer Center, New York, said: “What was most striking was the high response rates and the durability of response.”

Dr. Usmani said ease of administration was the other aspect of teclistamab that impressed him. The drug is given by subcutaneous injection weekly after a short ramp-up period.

He contrasted this regimen with that of chimeric antigen receptor (CAR) T-cell therapy, the only alternative with similar efficacy in such sick patients: “I can prescribe [teclistamab] today, and my patient gets it tomorrow,” Dr. Usmani said. “With CAR T, I prescribe today and it will take 4-6 weeks for us to collect T cells and another 6-7 weeks for the product to come back.” Dr. Usmani said many patients die before CAR T reaches them.

Community oncology will benefit greatly from teclistamab, especially patients for whom CAR T isn’t feasible, said Kashyap Patel, MD, president of the Community Oncology Alliance. “My patients are most of them underserved minority-class populations with myeloma, and they cannot travel many miles to go to a CAR T center. With sub[cutaneous] injection, the patient can have [teclistamab] administered in their doctor’s office and continue to live their normal life.”

However, how should the wider oncology community make sense of a drug approval based solely on response in a single-arm, phase 1/2 study, with no survival data?

Dr. Patel said, “Phase 1 plus phase 2 data is probably a little bit quick, but time will tell eventually.” He cited melflufen as a cautionary tale: a product given accelerated approval for multiple myeloma, then withdrawn when new data showed that it increased the risk of death.

When Dr. Munshi was asked about trial design for accelerated approvals, he responded, “you are touching a topic very close to my heart, a topic of great significance currently.”

He went on to say that overall survival (OS) is no longer a viable trial endpoint in diseases like multiple myeloma for several reasons. Most significantly, he noted: “Survival has gone up to 10 or 15 years [so] today, if you randomize between one [drug] versus another, there are going to be seven or eight more treatments before the patient dies.”

Similarly, progression-free survival (PFS) in multiple myeloma is now as much as 5 years, Dr. Munshi said. “Do we want a patient to wait 5 years to get a very good new drug?”

For these reasons and others, Dr, Munshi observed, myeloma researchers are increasingly relying on a surrogate called “negative minimal residual disease” (negative MRD) – in other words, a situation in which myeloma cells can no longer be detected in the bone marrow. MRD is hunted out using next-generation flow or next-generation sequencing of myeloma-cell DNA from bone-marrow aspirate to levels as low as 1 in 100,000 or 1,000,000 cells.

In 2020, Dr. Munshi and colleagues published a large meta-analysis showing that a negative MRD in a patient with multiple myeloma was significantly prognostic for both progression-free survival (hazard ratio, 0.33; P < .001) and overall survival (HR, 0.45; P < .001). The team concluded: “MRD can fulfill all the prerequisites to be a clinically valid surrogate biomarker for PFS and OS in [multiple myeloma].”

In MajesTEC-1 overall, 26.7% of patients on teclistamab had no signs of residual disease at a threshold of 1 in 100,000. Among patients who showed a “complete response” by International Myeloma Working Group criteria, 46% had no residual disease.

Dr. Munshi stressed that such patients are not necessarily “cured.” It will take a few more years to prove that. He noted: “Simply, physiologically, [negative MRD] means that if a patient has one [myeloma] cell in a million, that cell is going to take a much longer time to grow up to be myeloma.”

On Nov. 8 and 9, the FDA and the International Myeloma Society held a workshop to discuss the vexed question of surrogate endpoints and single-arm studies for drug approvals entitled the “Future of Drug Development in Multiple Myeloma.” Dr. Munshi was cochair.

A panelist at the meeting who was a senior investigator in the MajesTEC-1 trial, Ajai Chari, MD, professor of medicine at the Icahn School of Medicine at Mount Sinai, New York, summed up the dilemma: “No one disagrees that randomized studies are the best way of doing things. The question is, if you’re a patient who’s exhausted all available therapies, do you have that time to wait? ... The role of accelerated approval is to get the drug to the patient faster. But what does it not pick up? How do we make these accelerated approvals more meaningful and not have to retract for safety?”

Jonathon Vallejo, also on the panel, agreed that safety was the key worry. The ideal scenario for accelerated approval would be a drug that was better than available therapy, and “in some sense, it’s much safer.” However, such situations are rare.

“Most of the time, we don’t have these products that come in that have no toxicity signals,” he said. “So one thing we have to think carefully about in the single-arm trial setting is, what are the toxicities? How do they stack up?”

Dr. Chari said that, for his part, he wanted to see more transparency around “cause of death” in all studies that lead to accelerated approvals. He said he was “tired” of seeing a death labeled as “not attributed” to the drug by the investigator or the drug company.

“Let me decide. Show me the deaths, and show me the myeloma status at that point,” Dr. Chari said. “That’s a signal – if you’re a responding patient and dying, then the FDA should be a little bit more cautious.”

The FDA has added a boxed warning to the teclistamab product information concerning cytokine-release syndrome and neurologic toxicity.

Cytokine-release syndrome, the most common side effect overall, showed up in 72% of patients, typically 2 days after the first step-up dose.

Neurologic toxicity occurred in 57% of patients, including headache (25%), motor dysfunction (16%), sensory neuropathy (15%) and encephalopathy (13%). About 6%of patients developed a serious, life-threatening neurologic condition called immune effector cell–associated neurotoxicity syndrome.

Overall, serious adverse reactions occurred in 54% of participants in MajesTEC-1, and 5% of people in the trial died from adverse reactions during the study, most commonly infections.

Because of its safety profile, teclistamab is available only through a restricted program called TECVAYLI Risk Evaluation and Mitigation Strategy.

The continued approval of teclistamab for this indication “may be contingent upon verification and description of clinical benefit in confirmatory trials,” according to the FDA.

To that end, eight more studies of teclistamab are underway, aiming for approximately 1,300 multiple myeloma patients around the world. Three of these trials are in newly diagnosed patients. Four more studies are planned to come online in the next 3 months, raising the final tally of patients testing out teclistamab to approximately 4,700. The trials will look at teclistamab in sequence or in combination with standards such as bortezomib and pomalidomide. All studies are open label.

Dr. Patel believes that, until these trials say otherwise, the benefits of teclistamab outweigh the risks. “I’m very happy we have one more option in this space, particularly the fourth or fifth line for patients who want to continue to fight the disease,” Dr. Patel concluded.

Dr. Munshi disclosed advisory board/consultant work for Adaptive, Abbvie, Amgen, Bristol-Myers Squibb, Celgene, Janssen, Karyopharm, Legend, Millennium, Novartis, Oncopep, and Pfizer and is the scientific founder of Oncopep and DCT. The 2020 meta-analysis by Dr. Munshi and colleagues was funded by Janssen-Cilag. Dr. Patel declared funding from Janssen for a diversity-equity initiative and membership of the South Carolina Medicaid P & T Committee. Dr. Usmani declared conflicts of interest with Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, Abbvie, Genentech, Gilead, Sanofi, Seattle Genetics, SecuraBio, SkylineDX, Takeda, and TeneoBio.

There has been a steady decline in Medicare reimbursement for common gastrointestinal (GI) services and patient office visits over the past 15 years, which could have a direct impact on patients.

“When Medicare reimbursements decrease, health outcomes, health care access, and patient satisfaction may be affected, particularly in light of high inflation and increased costs due to staffing shortages, increased staffing salaries, and additional equipment necessary for COVID-19 safety,” researchers wrote in The American Journal of Gastroenterology.

Samir A. Shah, MD, of Brown University, Providence, R.I., and colleagues evaluated trends from 2007 to 2022 in Medicare reimbursement for the top 10 common GI procedures.

These procedures, which included colonoscopies, endoscopies, and gastrostomy tube placement, were identified through a joint list published by the American College of Gastroenterology, the American Society of Gastrointestinal Endoscopy, and the American Gastroenterological Association (AGA).

From 2007 to 2022, unadjusted and adjusted reimbursement for GI procedures declined by 7% and 33%, respectively, on average.

The adjusted change in physician reimbursement ranged from a decrease of roughly 29% for esophagus endoscopy to 38% for colonoscopy and biopsy, the study team found.

They found that the decline in reimbursement of GI procedures was significantly larger after 2015 (P < .001).

From 2007 to 2014, the mean decrease in physician reimbursement for GI services was 6.7%, and the annual growth rate in reimbursement was –1.0%.

In comparison, from 2015 to 2022, the mean decrease in physician reimbursement was 28.2%, and the mean annual growth rate in reimbursement was –4.7%.

To examine trends in reimbursement for office and inpatient visits from 2007 to 2022, the researchers identified the top five current procedural terminology (CPT) codes from outpatient office and inpatient consult visits provided to Medicare Part B beneficiaries by gastroenterologists.

In contrast to the reimbursement trends for GI procedures, the unadjusted physician reimbursement for inpatient and outpatient visits showed an average increase of 32%.

However, after adjustment for inflation, physician reimbursement for patient visits showed an average decline of 4.9%.

Overall, reimbursement for outpatient visits increased by 4.3%, while reimbursement for inpatient visits decreased by 18.8%.

Dr. Shah and colleagues said their findings are important, given that Medicare patients make up a substantial and growing proportion of patients with GI problems and because fewer than 1% of gastroenterologists have opted out of Medicare.

They noted that the trends in GI reimbursement they observed mirror trends in other specialties, which have also noted a decrease in adjusted reimbursement for care.

Physicians are once again facing cuts of at least 4.5% on Jan. 1, 2023, unless Congress acts. AGA and the entire medical community continue to call on Congress to make statutory changes to the Medicare payment system to address these payment challenges. Specifically, AGA and the physician community have recommended that payment rates include an inflationary adjustment similar to what other providers, such as hospitals, nursing homes, and ambulatory surgery centers, receive to account for practice, equipment, labor, and other costs associated with running a clinical practice.

AGA continues to urge physicians to write federal lawmakers to educate Congress about the detrimental effects of payment cuts, noting that the cuts, when coupled with rising inflation, increased administrative burdens, and staffing shortages, will negatively impact patients’ access to care.

The study had no financial support. The authors have disclosed no relevant financial relationships.

--From Staff Reports

There has been a steady decline in Medicare reimbursement for common gastrointestinal (GI) services and patient office visits over the past 15 years, which could have a direct impact on patients.

“When Medicare reimbursements decrease, health outcomes, health care access, and patient satisfaction may be affected, particularly in light of high inflation and increased costs due to staffing shortages, increased staffing salaries, and additional equipment necessary for COVID-19 safety,” researchers wrote in The American Journal of Gastroenterology.

Samir A. Shah, MD, of Brown University, Providence, R.I., and colleagues evaluated trends from 2007 to 2022 in Medicare reimbursement for the top 10 common GI procedures.

These procedures, which included colonoscopies, endoscopies, and gastrostomy tube placement, were identified through a joint list published by the American College of Gastroenterology, the American Society of Gastrointestinal Endoscopy, and the American Gastroenterological Association (AGA).

From 2007 to 2022, unadjusted and adjusted reimbursement for GI procedures declined by 7% and 33%, respectively, on average.

The adjusted change in physician reimbursement ranged from a decrease of roughly 29% for esophagus endoscopy to 38% for colonoscopy and biopsy, the study team found.

They found that the decline in reimbursement of GI procedures was significantly larger after 2015 (P < .001).

From 2007 to 2014, the mean decrease in physician reimbursement for GI services was 6.7%, and the annual growth rate in reimbursement was –1.0%.

In comparison, from 2015 to 2022, the mean decrease in physician reimbursement was 28.2%, and the mean annual growth rate in reimbursement was –4.7%.

To examine trends in reimbursement for office and inpatient visits from 2007 to 2022, the researchers identified the top five current procedural terminology (CPT) codes from outpatient office and inpatient consult visits provided to Medicare Part B beneficiaries by gastroenterologists.

In contrast to the reimbursement trends for GI procedures, the unadjusted physician reimbursement for inpatient and outpatient visits showed an average increase of 32%.

However, after adjustment for inflation, physician reimbursement for patient visits showed an average decline of 4.9%.

Overall, reimbursement for outpatient visits increased by 4.3%, while reimbursement for inpatient visits decreased by 18.8%.

Dr. Shah and colleagues said their findings are important, given that Medicare patients make up a substantial and growing proportion of patients with GI problems and because fewer than 1% of gastroenterologists have opted out of Medicare.

They noted that the trends in GI reimbursement they observed mirror trends in other specialties, which have also noted a decrease in adjusted reimbursement for care.

Physicians are once again facing cuts of at least 4.5% on Jan. 1, 2023, unless Congress acts. AGA and the entire medical community continue to call on Congress to make statutory changes to the Medicare payment system to address these payment challenges. Specifically, AGA and the physician community have recommended that payment rates include an inflationary adjustment similar to what other providers, such as hospitals, nursing homes, and ambulatory surgery centers, receive to account for practice, equipment, labor, and other costs associated with running a clinical practice.

AGA continues to urge physicians to write federal lawmakers to educate Congress about the detrimental effects of payment cuts, noting that the cuts, when coupled with rising inflation, increased administrative burdens, and staffing shortages, will negatively impact patients’ access to care.

The study had no financial support. The authors have disclosed no relevant financial relationships.

--From Staff Reports

There has been a steady decline in Medicare reimbursement for common gastrointestinal (GI) services and patient office visits over the past 15 years, which could have a direct impact on patients.

“When Medicare reimbursements decrease, health outcomes, health care access, and patient satisfaction may be affected, particularly in light of high inflation and increased costs due to staffing shortages, increased staffing salaries, and additional equipment necessary for COVID-19 safety,” researchers wrote in The American Journal of Gastroenterology.

Samir A. Shah, MD, of Brown University, Providence, R.I., and colleagues evaluated trends from 2007 to 2022 in Medicare reimbursement for the top 10 common GI procedures.

These procedures, which included colonoscopies, endoscopies, and gastrostomy tube placement, were identified through a joint list published by the American College of Gastroenterology, the American Society of Gastrointestinal Endoscopy, and the American Gastroenterological Association (AGA).

From 2007 to 2022, unadjusted and adjusted reimbursement for GI procedures declined by 7% and 33%, respectively, on average.

The adjusted change in physician reimbursement ranged from a decrease of roughly 29% for esophagus endoscopy to 38% for colonoscopy and biopsy, the study team found.

They found that the decline in reimbursement of GI procedures was significantly larger after 2015 (P < .001).

From 2007 to 2014, the mean decrease in physician reimbursement for GI services was 6.7%, and the annual growth rate in reimbursement was –1.0%.

In comparison, from 2015 to 2022, the mean decrease in physician reimbursement was 28.2%, and the mean annual growth rate in reimbursement was –4.7%.

To examine trends in reimbursement for office and inpatient visits from 2007 to 2022, the researchers identified the top five current procedural terminology (CPT) codes from outpatient office and inpatient consult visits provided to Medicare Part B beneficiaries by gastroenterologists.

In contrast to the reimbursement trends for GI procedures, the unadjusted physician reimbursement for inpatient and outpatient visits showed an average increase of 32%.

However, after adjustment for inflation, physician reimbursement for patient visits showed an average decline of 4.9%.

Overall, reimbursement for outpatient visits increased by 4.3%, while reimbursement for inpatient visits decreased by 18.8%.

Dr. Shah and colleagues said their findings are important, given that Medicare patients make up a substantial and growing proportion of patients with GI problems and because fewer than 1% of gastroenterologists have opted out of Medicare.

They noted that the trends in GI reimbursement they observed mirror trends in other specialties, which have also noted a decrease in adjusted reimbursement for care.

Physicians are once again facing cuts of at least 4.5% on Jan. 1, 2023, unless Congress acts. AGA and the entire medical community continue to call on Congress to make statutory changes to the Medicare payment system to address these payment challenges. Specifically, AGA and the physician community have recommended that payment rates include an inflationary adjustment similar to what other providers, such as hospitals, nursing homes, and ambulatory surgery centers, receive to account for practice, equipment, labor, and other costs associated with running a clinical practice.

AGA continues to urge physicians to write federal lawmakers to educate Congress about the detrimental effects of payment cuts, noting that the cuts, when coupled with rising inflation, increased administrative burdens, and staffing shortages, will negatively impact patients’ access to care.

The study had no financial support. The authors have disclosed no relevant financial relationships.

--From Staff Reports

PHILADELPHIA – Patients with systemic lupus erythematosus treated with lower doses of hydroxychloroquine (HCQ) had an increased risk for hospitalization for flares, according to study results presented during a press conference at the annual meeting of the American College of Rheumatology.

Doses decreased with changing guidelines

Guidelines over the years have recommended decreasing doses of HCQ. In 2011, ophthalmology guidelines recommended limiting HCQ dosing to 6.5 mg/kg per day or less of ideal body weight to reduce the chance of retinopathy. For many patients, this required a dose lower than 400 mg/day, an amount frequently used to treat lupus.

In 2016, updated guidelines further lowered the dosage of HCQ, recommending 5 mg/kg or less of patient’s actual body weight.

The effects that lower dosing has had on SLE-associated hospitalizations was unknown, which inspired Dr. Nestor’s research.

The team conducted a case-crossover study within the Mass General Brigham SLE cohort.

Hospitalizations studied over a decade

Dr. Nestor and colleagues identified patients with SLE (via electronic health records) who had at least one visit for SLE and were prescribed HCQ between January 2011 and December 2021, the period over which the recommendations were made.

They identified patients who had been hospitalized during that decade with SLE as the primary discharge diagnosis.

Patients were excluded if they had non-SLE indications, such as kidney transplant or infection without a concomitant SLE flare.

Of 2,971 patients with SLE who used HCQ, 576 had at least one hospitalization with primary discharge diagnosis of SLE.

Of these, 108 were hospitalized for an SLE flare and had used HCQ prior to that hospitalization and had at least one control period with HCQ use during the study period.

All of the patients in the study had to have a case period and a control period, Dr. Nestor explained. The case period was 6 months on HCQ ending in hospitalization for lupus and the control period was 6 months on HCQ that did not end in hospitalization for lupus.
 

Significantly increased hospitalizations

Low-dose HCQ by weight-based dose (≤ 5 vs. > 5 mg/kg per day) and by non–weight-based dose (< 400 vs. 400 mg per day) were both associated with significantly increased hospitalizations for SLE (adjusted odds ratio, 4.41; 95% confidence interval, 1.50-12.98; and AOR, 3.48; 95% CI, 1.33-9.13, respectively).

The average age of the hospitalized group was 36 years. Most patients (92%) were female, 43.5% were White, and 32.4% were Black.

In calling for reassessment of the dosing, Dr. Nestor said, “We are protecting our patients against a very long-term side effect of hydroxychloroquine retinopathy. [It] typically takes 10-20 years to develop in our patients. But by doing that, we’re missing many of the short-term benefits from hydroxychloroquine in our patients, leading to more lupus flares, which leads to more end-organ damage.”

She said patients taking HCQ for lupus are asked to see an ophthalmologist once a year to monitor for the side effect, adding that rheumatologists and ophthalmologists could work together to adjust the guidelines.

Dr. Nestor suggested it’s possible that patients need higher doses of HCQ earlier in their disease and lower doses later. “Perhaps it’s just the patients who are particularly active who need the higher doses,” she said.

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

PHILADELPHIA – Patients with systemic lupus erythematosus treated with lower doses of hydroxychloroquine (HCQ) had an increased risk for hospitalization for flares, according to study results presented during a press conference at the annual meeting of the American College of Rheumatology.

Doses decreased with changing guidelines

Guidelines over the years have recommended decreasing doses of HCQ. In 2011, ophthalmology guidelines recommended limiting HCQ dosing to 6.5 mg/kg per day or less of ideal body weight to reduce the chance of retinopathy. For many patients, this required a dose lower than 400 mg/day, an amount frequently used to treat lupus.

In 2016, updated guidelines further lowered the dosage of HCQ, recommending 5 mg/kg or less of patient’s actual body weight.

The effects that lower dosing has had on SLE-associated hospitalizations was unknown, which inspired Dr. Nestor’s research.

The team conducted a case-crossover study within the Mass General Brigham SLE cohort.

Hospitalizations studied over a decade

Dr. Nestor and colleagues identified patients with SLE (via electronic health records) who had at least one visit for SLE and were prescribed HCQ between January 2011 and December 2021, the period over which the recommendations were made.

They identified patients who had been hospitalized during that decade with SLE as the primary discharge diagnosis.

Patients were excluded if they had non-SLE indications, such as kidney transplant or infection without a concomitant SLE flare.

Of 2,971 patients with SLE who used HCQ, 576 had at least one hospitalization with primary discharge diagnosis of SLE.

Of these, 108 were hospitalized for an SLE flare and had used HCQ prior to that hospitalization and had at least one control period with HCQ use during the study period.

All of the patients in the study had to have a case period and a control period, Dr. Nestor explained. The case period was 6 months on HCQ ending in hospitalization for lupus and the control period was 6 months on HCQ that did not end in hospitalization for lupus.
 

Significantly increased hospitalizations

Low-dose HCQ by weight-based dose (≤ 5 vs. > 5 mg/kg per day) and by non–weight-based dose (< 400 vs. 400 mg per day) were both associated with significantly increased hospitalizations for SLE (adjusted odds ratio, 4.41; 95% confidence interval, 1.50-12.98; and AOR, 3.48; 95% CI, 1.33-9.13, respectively).

The average age of the hospitalized group was 36 years. Most patients (92%) were female, 43.5% were White, and 32.4% were Black.

In calling for reassessment of the dosing, Dr. Nestor said, “We are protecting our patients against a very long-term side effect of hydroxychloroquine retinopathy. [It] typically takes 10-20 years to develop in our patients. But by doing that, we’re missing many of the short-term benefits from hydroxychloroquine in our patients, leading to more lupus flares, which leads to more end-organ damage.”

She said patients taking HCQ for lupus are asked to see an ophthalmologist once a year to monitor for the side effect, adding that rheumatologists and ophthalmologists could work together to adjust the guidelines.

Dr. Nestor suggested it’s possible that patients need higher doses of HCQ earlier in their disease and lower doses later. “Perhaps it’s just the patients who are particularly active who need the higher doses,” she said.

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

PHILADELPHIA – Patients with systemic lupus erythematosus treated with lower doses of hydroxychloroquine (HCQ) had an increased risk for hospitalization for flares, according to study results presented during a press conference at the annual meeting of the American College of Rheumatology.

Doses decreased with changing guidelines

Guidelines over the years have recommended decreasing doses of HCQ. In 2011, ophthalmology guidelines recommended limiting HCQ dosing to 6.5 mg/kg per day or less of ideal body weight to reduce the chance of retinopathy. For many patients, this required a dose lower than 400 mg/day, an amount frequently used to treat lupus.

In 2016, updated guidelines further lowered the dosage of HCQ, recommending 5 mg/kg or less of patient’s actual body weight.

The effects that lower dosing has had on SLE-associated hospitalizations was unknown, which inspired Dr. Nestor’s research.

The team conducted a case-crossover study within the Mass General Brigham SLE cohort.

Hospitalizations studied over a decade

Dr. Nestor and colleagues identified patients with SLE (via electronic health records) who had at least one visit for SLE and were prescribed HCQ between January 2011 and December 2021, the period over which the recommendations were made.

They identified patients who had been hospitalized during that decade with SLE as the primary discharge diagnosis.

Patients were excluded if they had non-SLE indications, such as kidney transplant or infection without a concomitant SLE flare.

Of 2,971 patients with SLE who used HCQ, 576 had at least one hospitalization with primary discharge diagnosis of SLE.

Of these, 108 were hospitalized for an SLE flare and had used HCQ prior to that hospitalization and had at least one control period with HCQ use during the study period.

All of the patients in the study had to have a case period and a control period, Dr. Nestor explained. The case period was 6 months on HCQ ending in hospitalization for lupus and the control period was 6 months on HCQ that did not end in hospitalization for lupus.
 

Significantly increased hospitalizations

Low-dose HCQ by weight-based dose (≤ 5 vs. > 5 mg/kg per day) and by non–weight-based dose (< 400 vs. 400 mg per day) were both associated with significantly increased hospitalizations for SLE (adjusted odds ratio, 4.41; 95% confidence interval, 1.50-12.98; and AOR, 3.48; 95% CI, 1.33-9.13, respectively).

The average age of the hospitalized group was 36 years. Most patients (92%) were female, 43.5% were White, and 32.4% were Black.

In calling for reassessment of the dosing, Dr. Nestor said, “We are protecting our patients against a very long-term side effect of hydroxychloroquine retinopathy. [It] typically takes 10-20 years to develop in our patients. But by doing that, we’re missing many of the short-term benefits from hydroxychloroquine in our patients, leading to more lupus flares, which leads to more end-organ damage.”

She said patients taking HCQ for lupus are asked to see an ophthalmologist once a year to monitor for the side effect, adding that rheumatologists and ophthalmologists could work together to adjust the guidelines.

Dr. Nestor suggested it’s possible that patients need higher doses of HCQ earlier in their disease and lower doses later. “Perhaps it’s just the patients who are particularly active who need the higher doses,” she said.

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

Adults who underwent either total ankle replacement or ankle fusion for end-stage ankle osteoarthritis showed similar clinical scores and adverse event numbers, in a randomized controlled trial of approximately 300 patients.

Ankle osteoarthritis remains a cause of severe pain and disability. Patients are treated nonoperatively if possible, but surgery is often needed for individuals with end-stage disease, wrote Andrew Goldberg, MBBS, of University College London and colleagues in the Annals of Internal Medicine.

“Most patients with ankle arthritis respond to nonoperative treatments, such as weight loss, activity modification, support braces, and analgesia, [but] once the disease has progressed to end-stage osteoarthritis, the main surgical treatments are total ankle re-placement or ankle arthrodesis,” Dr. Goldberg said, in an interview.

In the new study, patients were randomized to receive either a total ankle replacement (TAR) or ankle fusion (AF).

“We showed that, in both treatment groups the clinical scores improved hugely, by more than three times the minimal clinically important difference,” Dr. Goldberg said in an interview.

“Although the ankle replacement arm improved, on average, by more than an extra 4 points over ankle fusion, this was not considered clinically or statistically significant,” he said.

The study is the first randomized trial to show high-quality and robust results, he noted, and findings support data from previous studies.

“Although both TAR and ankle fusion have been shown to be effective, they are very different treatments, with one fusing the bones so that there is no ankle joint movement, and the other replacing the joint with the aim of retaining ankle joint movement. It is difficult for a patient to know which treatment is more suitable for them, with most seeking guidance from their surgeon,” he said.

Generating high-quality evidence

The study, a randomized, multicenter, open-label trial known as TARVA (Total Ankle Replacement Versus Ankle Arthrodesis), aimed to compare the clinical effectiveness of the two existing publicly funded U.K. treatment options, the authors wrote.

Patients were recruited at 17 U.K. centers between March 6, 2015, and Jan. 10, 2019. The study enrolled 303 adults aged 50-85 years with end-stage ankle osteoarthritis. The mean age of the participants was 68 years; 71% were men. A total of 137 TAR patients and 144 ankle fusion patients completed their surgeries with clinical scores available for analysis. Baseline characteristics were mainly similar between the groups.

Blinding was not possible because of the nature of the procedures, but the surgeons who screened the patients were not aware of the randomization allocations, the researchers noted. A total of 33 surgeons participated in the trial, with a median number of seven patients per surgeon during the study period.

For TAR, U.K. surgeons use both two-component, fixed-bearing and three-component, mobile-bearing implants, the authors write. Ankle fusion was done using the surgeon’s usual technique of either arthroscopic-assisted or open ankle fusion.

The primary outcome was the change in the Manchester–Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores from baseline to 52 weeks after surgery. The MOXFQ-W/S uses a scale of 0-100, with lower scores representing better outcomes. Secondary outcomes included change in the MOXFQ-W/S scores at 26 weeks after surgery, as well as measures of patient quality of life.

No statistically significant difference

Overall, the mean MOXFQ-W/S scores improved significantly from baseline to 52 weeks for both groups, with average improvements of 49.9 in the TAR group and 44.4 points in the AF group. The average scores at 52 weeks were 31.4 in the TAR group and 36.8 in the AF group.

The adjusted difference in score change from baseline was –5.56, showing a slightly greater degree of improvement with TAR, but this difference was not clinically or statistically significant, the researchers noted.

Adverse event numbers were similar for both procedures, with 54% of TAR patients and 53% of AF patients experiencing at least 1 adverse event during the study period. Of those, 18% of TAR patients and 24% of AF patients experienced at least 1 serious adverse event.

However, the TAR patients experienced a higher rate of wound healing complications and nerve injuries, while thromboembolism was higher in the AF patients, the researchers noted.

A prespecified subgroup analysis of patients with osteoarthritis in adjacent joints suggested a greater improvement in TAR, compared with AF, a difference that increased when fixed-bearing TAR was compared with AF, the authors wrote.

“This reinforces previous reports that suggest that the presence of adjacent joint arthritis may be an indication for ankle replacement over AF,” the authors wrote in their discussion.

“Many of these patients did not have any symptoms in the adjacent joints,” they noted.

“The presence of adjacent joint arthritis, meaning the wear and tear of the joints around the ankle joint, seemed to favor ankle replacement,” Dr. Goldberg said. Approximately 30 joints in the foot continue to move after the ankle is fused, and if these adjacent joints are not healthy before surgery [as was the case in 42% of the study patients], the results of fusion were less successful, he explained.

A post hoc analysis between TAR subtypes showed that patients who had fixed-bearing TAR had significantly greater improvements, compared with AF patients, but this difference was not observed in patients who had mobile-bearing TAR, the researchers noted.

Dr. Goldberg said it was surprising “that, in a separate analysis, we found that the fixed-bearing ankle replacement patients [who accounted for half of the implants used] improved by a much greater difference when compared to ankle fusion.”

The study findings were limited by several factors including the short follow-up and study design that allowed surgeons to choose any implant and technique, the researchers noted.

Other limitations include a lack of data on cost-effectiveness and the impact of comorbidities on outcomes, they wrote. However, the study is the first completed multicenter randomized controlled trial to compare TAR and AF procedures for end-stage ankle osteoarthritis and shows that both yield similar clinical improvements, they concluded.

Data can inform treatment discussion

The take-home messages for clinicians are that both ankle replacement and ankle fusion are effective treatments that improve patients’ quality of life, and it is important to establish the health of adjacent joints before making treatment recommendations, Dr. Goldberg said.

“Careful counseling on the relative risks of each procedure should be part of the informed consent process,” he added. Ideally, all patients seeking surgical care for ankle arthritis should have a choice between ankle replacement and ankle fusion, but sometimes there is inequity of provision of the two treatments, he noted.

“We now encourage all surgeons to work in ankle arthritis networks so that every patient, no matter where they live, can have choice about the best treatment for them,” he said.

Researchers met the challenge of surgical RCT

Randomized trials of surgical interventions are challenging to conduct, and therefore limited, wrote Bruce Sangeorzan, MD, of the University of Washington, Seattle, and colleagues in an accompanying editorial. However, the new study was strengthened by the inclusion of 17 centers for heterogeneity of implant type and surgeon experience level, the editorialists said in the Annals of Internal Medicine.

The study is especially important, because ankle arthritis treatment is very understudied, compared with hip and knee arthritis, but it has a similar impact on activity, editorial coauthor Dr. Sangeorzan said in an interview.

“Randomized controlled trials are the gold standard for comparing medical therapies,” he said, “but they are very difficult to do in surgical treatments, particularly when the two treatments can be differentiated, in this case by movement of the ankle.”

In addition, there is a strong placebo effect attached to interventions, Dr. Sangeorzan noted. “Determining best-case treatment relies on prospective research, preferably randomized. Since both ankle fusion and ankle replacement are effective therapies, a prospective randomized trial is the best way to help make treatment decisions,” he said.

The current study findings are not surprising, but they are preliminary, and 1 year of follow-up is not enough to determine effectiveness, Dr. Sangeorzan emphasized. However, “the authors have done the hard work of randomizing the patients and collecting the data, and the patients can now be followed for a longer time,” he said.

“In addition, the trial was designed with multiple secondary outcome measures, so the data can be matched up with larger trials that were not randomized to identify key elements of success for each procedure,” he noted.

The key message for clinicians is that ankle arthritis has a significant impact on patients’ lives, but there are two effective treatments that can reduce the impact of the disease, said Dr. Sangeorzan. “The data suggest that there are differences in implant design and differences in comorbidities that should influence decision-making,” he added.

Additional research is needed in the form of a longer study duration with larger cohorts, said Dr. Sangeorzan. In particular, researchers need to determine what comorbidities might drive patients to one type of care vs. another, he said. “The suggestion that [patients receiving implants with two motion segments have better outcomes than those receiving implants with a one-motion segment] also deserves further study,” he added.

The research was supported by the UK National Institute for Health and Care Research Health Technology Assessment Programme. The trial was sponsored by University College London. Dr. Goldberg disclosed grant support from NIHR HTA, as well as financial relationships with companies including Stryker, Paragon 28, and stock options with Standing CT Company, Elstree Waterfront Outpatients, and X Bolt Orthopedics.

The editorialists had no financial conflicts to disclose.

Adults who underwent either total ankle replacement or ankle fusion for end-stage ankle osteoarthritis showed similar clinical scores and adverse event numbers, in a randomized controlled trial of approximately 300 patients.

Ankle osteoarthritis remains a cause of severe pain and disability. Patients are treated nonoperatively if possible, but surgery is often needed for individuals with end-stage disease, wrote Andrew Goldberg, MBBS, of University College London and colleagues in the Annals of Internal Medicine.

“Most patients with ankle arthritis respond to nonoperative treatments, such as weight loss, activity modification, support braces, and analgesia, [but] once the disease has progressed to end-stage osteoarthritis, the main surgical treatments are total ankle re-placement or ankle arthrodesis,” Dr. Goldberg said, in an interview.

In the new study, patients were randomized to receive either a total ankle replacement (TAR) or ankle fusion (AF).

“We showed that, in both treatment groups the clinical scores improved hugely, by more than three times the minimal clinically important difference,” Dr. Goldberg said in an interview.

“Although the ankle replacement arm improved, on average, by more than an extra 4 points over ankle fusion, this was not considered clinically or statistically significant,” he said.

The study is the first randomized trial to show high-quality and robust results, he noted, and findings support data from previous studies.

“Although both TAR and ankle fusion have been shown to be effective, they are very different treatments, with one fusing the bones so that there is no ankle joint movement, and the other replacing the joint with the aim of retaining ankle joint movement. It is difficult for a patient to know which treatment is more suitable for them, with most seeking guidance from their surgeon,” he said.

Generating high-quality evidence

The study, a randomized, multicenter, open-label trial known as TARVA (Total Ankle Replacement Versus Ankle Arthrodesis), aimed to compare the clinical effectiveness of the two existing publicly funded U.K. treatment options, the authors wrote.

Patients were recruited at 17 U.K. centers between March 6, 2015, and Jan. 10, 2019. The study enrolled 303 adults aged 50-85 years with end-stage ankle osteoarthritis. The mean age of the participants was 68 years; 71% were men. A total of 137 TAR patients and 144 ankle fusion patients completed their surgeries with clinical scores available for analysis. Baseline characteristics were mainly similar between the groups.

Blinding was not possible because of the nature of the procedures, but the surgeons who screened the patients were not aware of the randomization allocations, the researchers noted. A total of 33 surgeons participated in the trial, with a median number of seven patients per surgeon during the study period.

For TAR, U.K. surgeons use both two-component, fixed-bearing and three-component, mobile-bearing implants, the authors write. Ankle fusion was done using the surgeon’s usual technique of either arthroscopic-assisted or open ankle fusion.

The primary outcome was the change in the Manchester–Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores from baseline to 52 weeks after surgery. The MOXFQ-W/S uses a scale of 0-100, with lower scores representing better outcomes. Secondary outcomes included change in the MOXFQ-W/S scores at 26 weeks after surgery, as well as measures of patient quality of life.

No statistically significant difference

Overall, the mean MOXFQ-W/S scores improved significantly from baseline to 52 weeks for both groups, with average improvements of 49.9 in the TAR group and 44.4 points in the AF group. The average scores at 52 weeks were 31.4 in the TAR group and 36.8 in the AF group.

The adjusted difference in score change from baseline was –5.56, showing a slightly greater degree of improvement with TAR, but this difference was not clinically or statistically significant, the researchers noted.

Adverse event numbers were similar for both procedures, with 54% of TAR patients and 53% of AF patients experiencing at least 1 adverse event during the study period. Of those, 18% of TAR patients and 24% of AF patients experienced at least 1 serious adverse event.

However, the TAR patients experienced a higher rate of wound healing complications and nerve injuries, while thromboembolism was higher in the AF patients, the researchers noted.

A prespecified subgroup analysis of patients with osteoarthritis in adjacent joints suggested a greater improvement in TAR, compared with AF, a difference that increased when fixed-bearing TAR was compared with AF, the authors wrote.

“This reinforces previous reports that suggest that the presence of adjacent joint arthritis may be an indication for ankle replacement over AF,” the authors wrote in their discussion.

“Many of these patients did not have any symptoms in the adjacent joints,” they noted.

“The presence of adjacent joint arthritis, meaning the wear and tear of the joints around the ankle joint, seemed to favor ankle replacement,” Dr. Goldberg said. Approximately 30 joints in the foot continue to move after the ankle is fused, and if these adjacent joints are not healthy before surgery [as was the case in 42% of the study patients], the results of fusion were less successful, he explained.

A post hoc analysis between TAR subtypes showed that patients who had fixed-bearing TAR had significantly greater improvements, compared with AF patients, but this difference was not observed in patients who had mobile-bearing TAR, the researchers noted.

Dr. Goldberg said it was surprising “that, in a separate analysis, we found that the fixed-bearing ankle replacement patients [who accounted for half of the implants used] improved by a much greater difference when compared to ankle fusion.”

The study findings were limited by several factors including the short follow-up and study design that allowed surgeons to choose any implant and technique, the researchers noted.

Other limitations include a lack of data on cost-effectiveness and the impact of comorbidities on outcomes, they wrote. However, the study is the first completed multicenter randomized controlled trial to compare TAR and AF procedures for end-stage ankle osteoarthritis and shows that both yield similar clinical improvements, they concluded.

Data can inform treatment discussion

The take-home messages for clinicians are that both ankle replacement and ankle fusion are effective treatments that improve patients’ quality of life, and it is important to establish the health of adjacent joints before making treatment recommendations, Dr. Goldberg said.

“Careful counseling on the relative risks of each procedure should be part of the informed consent process,” he added. Ideally, all patients seeking surgical care for ankle arthritis should have a choice between ankle replacement and ankle fusion, but sometimes there is inequity of provision of the two treatments, he noted.

“We now encourage all surgeons to work in ankle arthritis networks so that every patient, no matter where they live, can have choice about the best treatment for them,” he said.

Researchers met the challenge of surgical RCT

Randomized trials of surgical interventions are challenging to conduct, and therefore limited, wrote Bruce Sangeorzan, MD, of the University of Washington, Seattle, and colleagues in an accompanying editorial. However, the new study was strengthened by the inclusion of 17 centers for heterogeneity of implant type and surgeon experience level, the editorialists said in the Annals of Internal Medicine.

The study is especially important, because ankle arthritis treatment is very understudied, compared with hip and knee arthritis, but it has a similar impact on activity, editorial coauthor Dr. Sangeorzan said in an interview.

“Randomized controlled trials are the gold standard for comparing medical therapies,” he said, “but they are very difficult to do in surgical treatments, particularly when the two treatments can be differentiated, in this case by movement of the ankle.”

In addition, there is a strong placebo effect attached to interventions, Dr. Sangeorzan noted. “Determining best-case treatment relies on prospective research, preferably randomized. Since both ankle fusion and ankle replacement are effective therapies, a prospective randomized trial is the best way to help make treatment decisions,” he said.

The current study findings are not surprising, but they are preliminary, and 1 year of follow-up is not enough to determine effectiveness, Dr. Sangeorzan emphasized. However, “the authors have done the hard work of randomizing the patients and collecting the data, and the patients can now be followed for a longer time,” he said.

“In addition, the trial was designed with multiple secondary outcome measures, so the data can be matched up with larger trials that were not randomized to identify key elements of success for each procedure,” he noted.

The key message for clinicians is that ankle arthritis has a significant impact on patients’ lives, but there are two effective treatments that can reduce the impact of the disease, said Dr. Sangeorzan. “The data suggest that there are differences in implant design and differences in comorbidities that should influence decision-making,” he added.

Additional research is needed in the form of a longer study duration with larger cohorts, said Dr. Sangeorzan. In particular, researchers need to determine what comorbidities might drive patients to one type of care vs. another, he said. “The suggestion that [patients receiving implants with two motion segments have better outcomes than those receiving implants with a one-motion segment] also deserves further study,” he added.

The research was supported by the UK National Institute for Health and Care Research Health Technology Assessment Programme. The trial was sponsored by University College London. Dr. Goldberg disclosed grant support from NIHR HTA, as well as financial relationships with companies including Stryker, Paragon 28, and stock options with Standing CT Company, Elstree Waterfront Outpatients, and X Bolt Orthopedics.

The editorialists had no financial conflicts to disclose.

Adults who underwent either total ankle replacement or ankle fusion for end-stage ankle osteoarthritis showed similar clinical scores and adverse event numbers, in a randomized controlled trial of approximately 300 patients.

Ankle osteoarthritis remains a cause of severe pain and disability. Patients are treated nonoperatively if possible, but surgery is often needed for individuals with end-stage disease, wrote Andrew Goldberg, MBBS, of University College London and colleagues in the Annals of Internal Medicine.

“Most patients with ankle arthritis respond to nonoperative treatments, such as weight loss, activity modification, support braces, and analgesia, [but] once the disease has progressed to end-stage osteoarthritis, the main surgical treatments are total ankle re-placement or ankle arthrodesis,” Dr. Goldberg said, in an interview.

In the new study, patients were randomized to receive either a total ankle replacement (TAR) or ankle fusion (AF).

“We showed that, in both treatment groups the clinical scores improved hugely, by more than three times the minimal clinically important difference,” Dr. Goldberg said in an interview.

“Although the ankle replacement arm improved, on average, by more than an extra 4 points over ankle fusion, this was not considered clinically or statistically significant,” he said.

The study is the first randomized trial to show high-quality and robust results, he noted, and findings support data from previous studies.

“Although both TAR and ankle fusion have been shown to be effective, they are very different treatments, with one fusing the bones so that there is no ankle joint movement, and the other replacing the joint with the aim of retaining ankle joint movement. It is difficult for a patient to know which treatment is more suitable for them, with most seeking guidance from their surgeon,” he said.

Generating high-quality evidence

The study, a randomized, multicenter, open-label trial known as TARVA (Total Ankle Replacement Versus Ankle Arthrodesis), aimed to compare the clinical effectiveness of the two existing publicly funded U.K. treatment options, the authors wrote.

Patients were recruited at 17 U.K. centers between March 6, 2015, and Jan. 10, 2019. The study enrolled 303 adults aged 50-85 years with end-stage ankle osteoarthritis. The mean age of the participants was 68 years; 71% were men. A total of 137 TAR patients and 144 ankle fusion patients completed their surgeries with clinical scores available for analysis. Baseline characteristics were mainly similar between the groups.

Blinding was not possible because of the nature of the procedures, but the surgeons who screened the patients were not aware of the randomization allocations, the researchers noted. A total of 33 surgeons participated in the trial, with a median number of seven patients per surgeon during the study period.

For TAR, U.K. surgeons use both two-component, fixed-bearing and three-component, mobile-bearing implants, the authors write. Ankle fusion was done using the surgeon’s usual technique of either arthroscopic-assisted or open ankle fusion.

The primary outcome was the change in the Manchester–Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores from baseline to 52 weeks after surgery. The MOXFQ-W/S uses a scale of 0-100, with lower scores representing better outcomes. Secondary outcomes included change in the MOXFQ-W/S scores at 26 weeks after surgery, as well as measures of patient quality of life.

No statistically significant difference

Overall, the mean MOXFQ-W/S scores improved significantly from baseline to 52 weeks for both groups, with average improvements of 49.9 in the TAR group and 44.4 points in the AF group. The average scores at 52 weeks were 31.4 in the TAR group and 36.8 in the AF group.

The adjusted difference in score change from baseline was –5.56, showing a slightly greater degree of improvement with TAR, but this difference was not clinically or statistically significant, the researchers noted.

Adverse event numbers were similar for both procedures, with 54% of TAR patients and 53% of AF patients experiencing at least 1 adverse event during the study period. Of those, 18% of TAR patients and 24% of AF patients experienced at least 1 serious adverse event.

However, the TAR patients experienced a higher rate of wound healing complications and nerve injuries, while thromboembolism was higher in the AF patients, the researchers noted.

A prespecified subgroup analysis of patients with osteoarthritis in adjacent joints suggested a greater improvement in TAR, compared with AF, a difference that increased when fixed-bearing TAR was compared with AF, the authors wrote.

“This reinforces previous reports that suggest that the presence of adjacent joint arthritis may be an indication for ankle replacement over AF,” the authors wrote in their discussion.

“Many of these patients did not have any symptoms in the adjacent joints,” they noted.

“The presence of adjacent joint arthritis, meaning the wear and tear of the joints around the ankle joint, seemed to favor ankle replacement,” Dr. Goldberg said. Approximately 30 joints in the foot continue to move after the ankle is fused, and if these adjacent joints are not healthy before surgery [as was the case in 42% of the study patients], the results of fusion were less successful, he explained.

A post hoc analysis between TAR subtypes showed that patients who had fixed-bearing TAR had significantly greater improvements, compared with AF patients, but this difference was not observed in patients who had mobile-bearing TAR, the researchers noted.

Dr. Goldberg said it was surprising “that, in a separate analysis, we found that the fixed-bearing ankle replacement patients [who accounted for half of the implants used] improved by a much greater difference when compared to ankle fusion.”

The study findings were limited by several factors including the short follow-up and study design that allowed surgeons to choose any implant and technique, the researchers noted.

Other limitations include a lack of data on cost-effectiveness and the impact of comorbidities on outcomes, they wrote. However, the study is the first completed multicenter randomized controlled trial to compare TAR and AF procedures for end-stage ankle osteoarthritis and shows that both yield similar clinical improvements, they concluded.

Data can inform treatment discussion

The take-home messages for clinicians are that both ankle replacement and ankle fusion are effective treatments that improve patients’ quality of life, and it is important to establish the health of adjacent joints before making treatment recommendations, Dr. Goldberg said.

“Careful counseling on the relative risks of each procedure should be part of the informed consent process,” he added. Ideally, all patients seeking surgical care for ankle arthritis should have a choice between ankle replacement and ankle fusion, but sometimes there is inequity of provision of the two treatments, he noted.

“We now encourage all surgeons to work in ankle arthritis networks so that every patient, no matter where they live, can have choice about the best treatment for them,” he said.

Researchers met the challenge of surgical RCT

Randomized trials of surgical interventions are challenging to conduct, and therefore limited, wrote Bruce Sangeorzan, MD, of the University of Washington, Seattle, and colleagues in an accompanying editorial. However, the new study was strengthened by the inclusion of 17 centers for heterogeneity of implant type and surgeon experience level, the editorialists said in the Annals of Internal Medicine.

The study is especially important, because ankle arthritis treatment is very understudied, compared with hip and knee arthritis, but it has a similar impact on activity, editorial coauthor Dr. Sangeorzan said in an interview.

“Randomized controlled trials are the gold standard for comparing medical therapies,” he said, “but they are very difficult to do in surgical treatments, particularly when the two treatments can be differentiated, in this case by movement of the ankle.”

In addition, there is a strong placebo effect attached to interventions, Dr. Sangeorzan noted. “Determining best-case treatment relies on prospective research, preferably randomized. Since both ankle fusion and ankle replacement are effective therapies, a prospective randomized trial is the best way to help make treatment decisions,” he said.

The current study findings are not surprising, but they are preliminary, and 1 year of follow-up is not enough to determine effectiveness, Dr. Sangeorzan emphasized. However, “the authors have done the hard work of randomizing the patients and collecting the data, and the patients can now be followed for a longer time,” he said.

“In addition, the trial was designed with multiple secondary outcome measures, so the data can be matched up with larger trials that were not randomized to identify key elements of success for each procedure,” he noted.

The key message for clinicians is that ankle arthritis has a significant impact on patients’ lives, but there are two effective treatments that can reduce the impact of the disease, said Dr. Sangeorzan. “The data suggest that there are differences in implant design and differences in comorbidities that should influence decision-making,” he added.

Additional research is needed in the form of a longer study duration with larger cohorts, said Dr. Sangeorzan. In particular, researchers need to determine what comorbidities might drive patients to one type of care vs. another, he said. “The suggestion that [patients receiving implants with two motion segments have better outcomes than those receiving implants with a one-motion segment] also deserves further study,” he added.

The research was supported by the UK National Institute for Health and Care Research Health Technology Assessment Programme. The trial was sponsored by University College London. Dr. Goldberg disclosed grant support from NIHR HTA, as well as financial relationships with companies including Stryker, Paragon 28, and stock options with Standing CT Company, Elstree Waterfront Outpatients, and X Bolt Orthopedics.

The editorialists had no financial conflicts to disclose.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

CHICAGO – A new, expanded meta-analysis confirmed the long-known effect that statin treatment has on raising blood glucose levels and causing incident diabetes, but it also documented that these effects are small and any risk they pose to statin users is dwarfed by the cholesterol-lowering effect of statins and their ability to reduce risk for atherosclerotic cardiovascular disease (ASCVD).

Mitchel L. Zoler/MDedge

This meta-analysis of 23 trials with a total of more than 150,000 participants showed that statin therapy significantly increased the risk for new-onset diabetes and worsening glycemia, driven by a “very small but generalized increase in glucose,” with a greater effect from high-intensity statin regimens and a similar but somewhat more muted effect from low- and moderate-intensity statin treatment, David Preiss, MBChB, PhD, reported at the American Heart Association scientific sessions.

Dr. Preiss also stressed that despite this, “the cardiovascular benefits of statin therapy remain substantial and profound” in people regardless of whether they have diabetes, prediabetes, or normoglycemia when they start statin treatment, noting that the impact of even high-intensity statin treatment is “absolutely tiny” increases in hemoglobin A1c and blood glucose.

“This does not detract from the substantial benefit of statin treatment,” declared Dr. Preiss, a metabolic medicine specialist and endocrinologist at Oxford (England) University.
 

Small glycemia increases ‘nudge’ some into diabetes

The data Dr. Preiss reported showed that high-intensity statin treatment (atorvastatin at a daily dose of at least 40 mg, or rosuvastatin at a daily dose of at least 20 mg) led to an average increase in A1c levels of 0.08 percentage points among people without diabetes when their treatment began and 0.24 percentage points among people already diagnosed with diabetes. Blood glucose levels rose by an average of 0.04 mmol/L (less than 1 mg/d) in those without diabetes, and by an average 0.22 mmol/L (about 4 mg/dL) in those with diabetes. People who received low- or moderate-intensity statin regimens had significant but smaller increases.

“We’re not talking about people going from no diabetes to frank diabetes. We’re talking about [statins] nudging a very small number of people across a diabetes threshold,” an A1c of 6.5% that is set somewhat arbitrarily based on an increased risk for developing retinopathy, Dr. Preiss said. ”A person just needs to lose a [daily] can of Coke’s worth of weight to eliminate any apparent diabetes risk,” he noted.
 

Benefit outweighs risks by three- to sevenfold

Dr. Preiss presented two other examples of what his findings showed to illustrate the relatively small risk posed by statin therapy compared with its potential benefits. Treating 10,000 people for 5 years with a high-intensity statin regimen in those with established ASCVD (secondary prevention) would result in an increment of 150 extra people developing diabetes because of the hyperglycemic effect of statins, compared with an expected prevention of 1,000 ASCVD events. Among 10,000 people at high ASCVD risk and taking a high-intensity statin regimen for primary prevention 5 years of treatment would result in roughly 130 extra cases of incident diabetes while preventing about 500 ASCVD events.

In addition, applying the new risk estimates to the people included in the UK Biobank database, whose median A1c is 5.5%, showed that a high-intensity statin regimen could be expected to raise the prevalence of those with an A1c of 6.5% or greater from 4.5% to 5.7%.

Several preventive cardiologists who heard the report and were not involved with the analysis agreed with Dr. Preiss that the benefits of statin treatment substantially offset this confirmed hyperglycemic effect.
 

Risk ‘more than counterbalanced by benefit’

“He clearly showed that the small hyperglycemia risk posed by statin use is more than counterbalanced by its benefit for reducing ASCVD events,” commented Neil J. Stone, MD, a cardiologist and professor of medicine at Northwestern University, Chicago. “I agree that, for those with prediabetes who are on the road to diabetes with or without a statin, the small increase in glucose with a statin should not dissuade statin usage because the benefit is so large. Rather, it should focus efforts to improve diet, increase physical activity, and keep weight controlled.”

Dr. Stone also noted in an interview that in the JUPITER trial, which examined the effects of a daily 20-mg dose of rosuvastatin (Crestor), a high-intensity regimen, study participants with diabetes risk factors who were assigned to rosuvastatin had an onset of diabetes that was earlier than people assigned to placebo by only about 5.4 weeks, yet this group had evidence of significant benefit.

Mitchel L. Zoler/MDedge News

“I agree with Dr. Preiss that the benefits of statins in reducing heart attack, stroke, and cardiovascular death far outweigh their modest effects on glycemia,” commented Brendan M. Everett, MD, a cardiologist and preventive medicine specialist at Brigham and Women’s Hospital in Boston. “This is particularly true for those with preexisting prediabetes or diabetes, who have an elevated risk of atherosclerotic events and thus stand to derive more significant benefit from statins. The benefits of lowering LDL cholesterol with a statin for preventing seriously morbid, and potentially fatal, cardiovascular events far outweigh the extremely modest, or even negligible, increases in the risk of diabetes that could be seen with the extremely small increases in A1c,” Dr. Everett said in an interview.

The new findings “reaffirm that there is a increased risk [from statins] but the most important point is that it is a very, very tiny difference in A1c,” commented Marc S. Sabatine, MD, a cardiologist and professor at Harvard Medical School, Boston. “These data have been known for quite some time, but this analysis was done in a more rigorous way.” The finding of “a small increase in risk for diabetes is really because diabetes has a biochemical threshold and statin treatment nudges some people a little past a line that is semi-arbitrary. It’s important to be cognizant of this, but it in no way dissuades me from treating patients aggressively with statins to reduce their ASCVD risk. I would monitor their A1c levels, and if they go higher and can’t be controlled with lifestyle we have plenty of medications that can control it,” he said in an interview.
 

No difference by statin type

The meta-analysis used data from 13 placebo-controlled statin trials that together involved 123,940 participants and had an average 4.3 years of follow-up, and four trials that compared one statin with another and collectively involved 30,734 participants with an average 4.9 years of follow-up.

The analyses showed that high-intensity statin treatment increased the rate of incident diabetes by a significant 36% relative to controls and increased the rate of worsening glycemia by a significant 24% compared with controls. Low- or moderate-intensity statin regimens increased incident diabetes by a significant 10% and raised the incidence of worsening glycemia by a significant 10% compared with controls, Dr. Preiss reported.

These effects did not significantly differ by type of statin (the study included people treated with atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin), nor across a variety of subgroups based on age, sex, race, body mass index, diabetes risk, renal function, cholesterol levels, or cardiovascular disease. The effect was also consistent regardless of the duration of treatment.

Dr. Preiss also downplayed the magnitude of the apparent difference in risk posed by high-intensity and less intense statin regimens. “I suspect the apparent heterogeneity is true, but not quite as big as what we see,” he said.

The mechanisms by which statins have this effect remain unclear, but evidence suggests that it may be a direct effect of the main action of statins, inhibition of the HMG-CoA reductase enzyme.

The study received no commercial funding. Dr. Preiss and Dr. Stone had no disclosures. Dr. Everett has been a consultant to Eli Lilly, Gilead, Ipsen, Janssen, and Provention. Dr. Sabatine has been a consultant to Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics.

Adding granulocyte-colony stimulating factor (G-CSF) to steroid therapy can improve 90-day survival for patients with severe alcoholic hepatitis (SAH), researchers from India reported.

Among patients with SAH, the combination of G-CSF and prednisolone was associated with a 90-day survival rate of 88.1%, compared with 78.6% for patients assigned to G-CSF alone, and 64.3% for patients assigned to prednisolone alone (P = .03).

The G-CSF/prednisolone combination was also associated with significantly better steroid responsiveness, as determined by the Lille Model for Alcoholic Hepatitis, reported Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences, New Delhi.

The drug combo in steroid-eligible patients also “reduces morbidity related to infections, rehospitalizations, and hepatic encephalopathy [and] reduces infection rates,” Dr. Sarin said at the annual meeting of the American Association for the Study of Liver Diseases. He did caution that the treatment requires close monitoring.
 

Prednisolone-only drawbacks

For patients with SAH, 30-day mortality ranges from 20%-50%. While some patients respond to treatment with corticosteroids, the response is often modest and limited in duration, Dr. Sarin said.

The STOPAH trial found that 15% of patients with SAH treated with prednisolone developed serious infections, compared with 8% of patients on placebo (P = .002), he noted.

Dr. Sarin also pointed to a recent worldwide study attempting to identify the optimal therapeutic window for steroid use in patients with alcoholic hepatitis. The investigators found that corticosteroids reduced 30-day mortality by 41% but only among patients with SAH, especially those with Model for End-Stage Liver Disease (MELD) scores between 25 and 39.

In previous studies, G-CSF has been shown to improve survival in patients with acute-on-chronic liver failure, including patients with SAH; in patients with SAH alone; and in steroid nonresponders, Dr. Sarin said.
 

Regenerative properties

In an interview with this news organization, Dr. Sarin said that although the use of G-CSF for patients with severe SAH is still under investigation at his center, “we are using G-CSF routinely for decompensated cirrhosis, where it is like an in vivo extension of regenerative stem cells. G-CSF recruits from bone marrow a lot of hematopoietic stem cells and mesenchymal stem cells.”

Dr. Sarin and colleagues hypothesized that G-CSF, with its immunomodulatory and regenerative properties, would be effective either alone or in combination with steroids in steroid-eligible patients with SAH.

To test this idea, they enrolled 126 patients ages 18-65 with SAH, defined as a Maddrey’s Discriminant Function (mDF) score greater than 32. They excluded patients with active infections, acute gastrointestinal bleeding, hepatorenal syndrome, an mDF score greater than 90, autoimmune hepatitis, hepatitis B or C, HIV, pregnancy, hemophagocytic lymphohistiocytosis, and those with hemoglobin below 8 and baseline white blood cell count over 25,000.

The patients were randomly assigned, 42 in each group, to receive one of the following:

• Prednisolone monotherapy 40 mg/day for 7 days, with the drug stopped at 7 days for patients with Lille scores above 0.45 or continued for up to 21 days for those with Lille scores below 0.45;
• Prednisolone plus G-CSF 300 mcg/day for 7 days, with those who achieve a Lille score above 0.45 stopping the steroid but continuing G-CSF, while those with Lille scores below 0.45 continuing on prednisolone for 21 days, plus G-CSF once every 3 days for 5 additional doses; or
• G-CSF monotherapy at a dose of 150-300 mcg/day for 7 days, then every 3 days for 28 days up to a total of 12 doses.

Improved response

In addition to its superior results on the primary endpoint of 90-day survival, combination therapy was associated with significantly better response to therapy. The mean Lille score at day 7 was 0.14 for the combination, compared with 0.21 for prednisolone alone and 0.28 for G-CSF alone (P = .002).

There were also significantly fewer nonresponders in the combination arm than either of the monotherapy groups (P = .03).

At 90 days, the rate of new infections was significantly higher among patients treated with prednisolone alone, at 35.7%, compared with 19% in the combination arm and 7.1% in the G-CSF alone group (P = .02). There were also significantly fewer skin and mucosal bleeding episodes with the combination (19% vs, 25% and 35.7% with prednisolone and G-CSF monotherapies, respectively, P = .03), as well as lower rates of hepatic encephalopathy (9.5% vs. 47.5% and 25%, respectively, P < .01).

No differences in alcohol relapse rates were found among the three groups.
 

Patient selection important

“I know a lot of the G-CSF studies that have been conducted in the U.S. and Europe have all been negative,” said David Goldberg, MD, from the University of Miami, during the session. “Do you think there’s something unique in your patients, the microbiome or maybe genetics, that leads to such different results?” he asked Dr. Sarin.

European studies included patients with infections, acute kidney injury (AKI), or other comorbidities that were exclusion criteria in his study, Dr. Sarin noted.

“If you already have an infection, you already have an AKI, then it’s not a good patient for treatment, so I think the choice of patient is important,” he said.

The study was internally supported. Dr. Sarin and Dr. Goldberg report no relevant financial relationships.

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

Adding granulocyte-colony stimulating factor (G-CSF) to steroid therapy can improve 90-day survival for patients with severe alcoholic hepatitis (SAH), researchers from India reported.

Among patients with SAH, the combination of G-CSF and prednisolone was associated with a 90-day survival rate of 88.1%, compared with 78.6% for patients assigned to G-CSF alone, and 64.3% for patients assigned to prednisolone alone (P = .03).

The G-CSF/prednisolone combination was also associated with significantly better steroid responsiveness, as determined by the Lille Model for Alcoholic Hepatitis, reported Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences, New Delhi.

The drug combo in steroid-eligible patients also “reduces morbidity related to infections, rehospitalizations, and hepatic encephalopathy [and] reduces infection rates,” Dr. Sarin said at the annual meeting of the American Association for the Study of Liver Diseases. He did caution that the treatment requires close monitoring.
 

Prednisolone-only drawbacks

For patients with SAH, 30-day mortality ranges from 20%-50%. While some patients respond to treatment with corticosteroids, the response is often modest and limited in duration, Dr. Sarin said.

The STOPAH trial found that 15% of patients with SAH treated with prednisolone developed serious infections, compared with 8% of patients on placebo (P = .002), he noted.

Dr. Sarin also pointed to a recent worldwide study attempting to identify the optimal therapeutic window for steroid use in patients with alcoholic hepatitis. The investigators found that corticosteroids reduced 30-day mortality by 41% but only among patients with SAH, especially those with Model for End-Stage Liver Disease (MELD) scores between 25 and 39.

In previous studies, G-CSF has been shown to improve survival in patients with acute-on-chronic liver failure, including patients with SAH; in patients with SAH alone; and in steroid nonresponders, Dr. Sarin said.
 

Regenerative properties

In an interview with this news organization, Dr. Sarin said that although the use of G-CSF for patients with severe SAH is still under investigation at his center, “we are using G-CSF routinely for decompensated cirrhosis, where it is like an in vivo extension of regenerative stem cells. G-CSF recruits from bone marrow a lot of hematopoietic stem cells and mesenchymal stem cells.”

Dr. Sarin and colleagues hypothesized that G-CSF, with its immunomodulatory and regenerative properties, would be effective either alone or in combination with steroids in steroid-eligible patients with SAH.

To test this idea, they enrolled 126 patients ages 18-65 with SAH, defined as a Maddrey’s Discriminant Function (mDF) score greater than 32. They excluded patients with active infections, acute gastrointestinal bleeding, hepatorenal syndrome, an mDF score greater than 90, autoimmune hepatitis, hepatitis B or C, HIV, pregnancy, hemophagocytic lymphohistiocytosis, and those with hemoglobin below 8 and baseline white blood cell count over 25,000.

The patients were randomly assigned, 42 in each group, to receive one of the following:

• Prednisolone monotherapy 40 mg/day for 7 days, with the drug stopped at 7 days for patients with Lille scores above 0.45 or continued for up to 21 days for those with Lille scores below 0.45;
• Prednisolone plus G-CSF 300 mcg/day for 7 days, with those who achieve a Lille score above 0.45 stopping the steroid but continuing G-CSF, while those with Lille scores below 0.45 continuing on prednisolone for 21 days, plus G-CSF once every 3 days for 5 additional doses; or
• G-CSF monotherapy at a dose of 150-300 mcg/day for 7 days, then every 3 days for 28 days up to a total of 12 doses.

Improved response

In addition to its superior results on the primary endpoint of 90-day survival, combination therapy was associated with significantly better response to therapy. The mean Lille score at day 7 was 0.14 for the combination, compared with 0.21 for prednisolone alone and 0.28 for G-CSF alone (P = .002).

There were also significantly fewer nonresponders in the combination arm than either of the monotherapy groups (P = .03).

At 90 days, the rate of new infections was significantly higher among patients treated with prednisolone alone, at 35.7%, compared with 19% in the combination arm and 7.1% in the G-CSF alone group (P = .02). There were also significantly fewer skin and mucosal bleeding episodes with the combination (19% vs, 25% and 35.7% with prednisolone and G-CSF monotherapies, respectively, P = .03), as well as lower rates of hepatic encephalopathy (9.5% vs. 47.5% and 25%, respectively, P < .01).

No differences in alcohol relapse rates were found among the three groups.
 

Patient selection important

“I know a lot of the G-CSF studies that have been conducted in the U.S. and Europe have all been negative,” said David Goldberg, MD, from the University of Miami, during the session. “Do you think there’s something unique in your patients, the microbiome or maybe genetics, that leads to such different results?” he asked Dr. Sarin.

European studies included patients with infections, acute kidney injury (AKI), or other comorbidities that were exclusion criteria in his study, Dr. Sarin noted.

“If you already have an infection, you already have an AKI, then it’s not a good patient for treatment, so I think the choice of patient is important,” he said.

The study was internally supported. Dr. Sarin and Dr. Goldberg report no relevant financial relationships.

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

Adding granulocyte-colony stimulating factor (G-CSF) to steroid therapy can improve 90-day survival for patients with severe alcoholic hepatitis (SAH), researchers from India reported.

Among patients with SAH, the combination of G-CSF and prednisolone was associated with a 90-day survival rate of 88.1%, compared with 78.6% for patients assigned to G-CSF alone, and 64.3% for patients assigned to prednisolone alone (P = .03).

The G-CSF/prednisolone combination was also associated with significantly better steroid responsiveness, as determined by the Lille Model for Alcoholic Hepatitis, reported Shiv K. Sarin, MD, from the Institute of Liver and Biliary Sciences, New Delhi.

The drug combo in steroid-eligible patients also “reduces morbidity related to infections, rehospitalizations, and hepatic encephalopathy [and] reduces infection rates,” Dr. Sarin said at the annual meeting of the American Association for the Study of Liver Diseases. He did caution that the treatment requires close monitoring.
 

Prednisolone-only drawbacks

For patients with SAH, 30-day mortality ranges from 20%-50%. While some patients respond to treatment with corticosteroids, the response is often modest and limited in duration, Dr. Sarin said.

The STOPAH trial found that 15% of patients with SAH treated with prednisolone developed serious infections, compared with 8% of patients on placebo (P = .002), he noted.

Dr. Sarin also pointed to a recent worldwide study attempting to identify the optimal therapeutic window for steroid use in patients with alcoholic hepatitis. The investigators found that corticosteroids reduced 30-day mortality by 41% but only among patients with SAH, especially those with Model for End-Stage Liver Disease (MELD) scores between 25 and 39.

In previous studies, G-CSF has been shown to improve survival in patients with acute-on-chronic liver failure, including patients with SAH; in patients with SAH alone; and in steroid nonresponders, Dr. Sarin said.
 

Regenerative properties

In an interview with this news organization, Dr. Sarin said that although the use of G-CSF for patients with severe SAH is still under investigation at his center, “we are using G-CSF routinely for decompensated cirrhosis, where it is like an in vivo extension of regenerative stem cells. G-CSF recruits from bone marrow a lot of hematopoietic stem cells and mesenchymal stem cells.”

Dr. Sarin and colleagues hypothesized that G-CSF, with its immunomodulatory and regenerative properties, would be effective either alone or in combination with steroids in steroid-eligible patients with SAH.

To test this idea, they enrolled 126 patients ages 18-65 with SAH, defined as a Maddrey’s Discriminant Function (mDF) score greater than 32. They excluded patients with active infections, acute gastrointestinal bleeding, hepatorenal syndrome, an mDF score greater than 90, autoimmune hepatitis, hepatitis B or C, HIV, pregnancy, hemophagocytic lymphohistiocytosis, and those with hemoglobin below 8 and baseline white blood cell count over 25,000.

The patients were randomly assigned, 42 in each group, to receive one of the following:

• Prednisolone monotherapy 40 mg/day for 7 days, with the drug stopped at 7 days for patients with Lille scores above 0.45 or continued for up to 21 days for those with Lille scores below 0.45;
• Prednisolone plus G-CSF 300 mcg/day for 7 days, with those who achieve a Lille score above 0.45 stopping the steroid but continuing G-CSF, while those with Lille scores below 0.45 continuing on prednisolone for 21 days, plus G-CSF once every 3 days for 5 additional doses; or
• G-CSF monotherapy at a dose of 150-300 mcg/day for 7 days, then every 3 days for 28 days up to a total of 12 doses.

Improved response

In addition to its superior results on the primary endpoint of 90-day survival, combination therapy was associated with significantly better response to therapy. The mean Lille score at day 7 was 0.14 for the combination, compared with 0.21 for prednisolone alone and 0.28 for G-CSF alone (P = .002).

There were also significantly fewer nonresponders in the combination arm than either of the monotherapy groups (P = .03).

At 90 days, the rate of new infections was significantly higher among patients treated with prednisolone alone, at 35.7%, compared with 19% in the combination arm and 7.1% in the G-CSF alone group (P = .02). There were also significantly fewer skin and mucosal bleeding episodes with the combination (19% vs, 25% and 35.7% with prednisolone and G-CSF monotherapies, respectively, P = .03), as well as lower rates of hepatic encephalopathy (9.5% vs. 47.5% and 25%, respectively, P < .01).

No differences in alcohol relapse rates were found among the three groups.
 

Patient selection important

“I know a lot of the G-CSF studies that have been conducted in the U.S. and Europe have all been negative,” said David Goldberg, MD, from the University of Miami, during the session. “Do you think there’s something unique in your patients, the microbiome or maybe genetics, that leads to such different results?” he asked Dr. Sarin.

European studies included patients with infections, acute kidney injury (AKI), or other comorbidities that were exclusion criteria in his study, Dr. Sarin noted.

“If you already have an infection, you already have an AKI, then it’s not a good patient for treatment, so I think the choice of patient is important,” he said.

The study was internally supported. Dr. Sarin and Dr. Goldberg report no relevant financial relationships.

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

Among older adults who use the U.S. Supplemental Nutrition Assistance Program (SNAP), rates of memory decline appear to be slower than among those who don’t use the program, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.

Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.

Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.

She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.

Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.

The study was published online in Neurology.
 

Memory preservation

Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.

At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.

Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.

The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.

One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.

While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.

Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.

The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.

“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
 

An underutilized program

In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.

Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.

“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.

The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.

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

Among older adults who use the U.S. Supplemental Nutrition Assistance Program (SNAP), rates of memory decline appear to be slower than among those who don’t use the program, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.

Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.

Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.

She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.

Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.

The study was published online in Neurology.
 

Memory preservation

Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.

At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.

Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.

The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.

One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.

While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.

Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.

The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.

“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
 

An underutilized program

In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.

Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.

“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.

The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.

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

Among older adults who use the U.S. Supplemental Nutrition Assistance Program (SNAP), rates of memory decline appear to be slower than among those who don’t use the program, new research shows. Researchers assessed the memory function of more than 3,500 persons who used SNAP or did not use SNAP over a period of 20 years. They found that those who didn’t use the food benefits program experienced 2 more years of cognitive aging compared with program users.

Of the 3,555 individuals included in the study, all were eligible to use the benefits, but only 559 did, leaving 2,996 participants who did not take advantage of the program.

Low program participation levels translate into a missed opportunity to prevent dementia, said study investigator Adina Zeki Al Hazzouri, PhD, assistant professor of epidemiology at the Columbia Aging Center at Columbia University Mailman School of Public Health in New York.

She said that prior research has shown that stigma may prevent older Americans from using SNAP. “Educational programs are needed to reduce the stigma that the public holds towards SNAP use,” she said.

Policy change could increase usage among older individuals, Dr. Zeki Al Hazzouri noted. Such changes could include simplifying enrollment and reporting procedures, shortening recertification periods, and increasing benefit levels.

The study was published online in Neurology.
 

Memory preservation

Dr. Zeki Al Hazzouri and her team assessed respondents from the Health and Retirement Study (HRS), a representative sample of Americans aged 50 and older. All respondents who were eligible to participate in SNAP in 1996 were followed every 2 years until 2016.

At each assessment, HRS respondents completed memory tests, including immediate and delayed word recall. For those who were too impaired to complete the interview, proxy informants – typically, their spouses or family members – assessed the memory and cognition of their family members using validated instruments, such as the 16-item Informant Questionnaire for Cognitive Decline.

Investigators used a validated memory function composite score, which is benchmarked against the memory assessments and evaluations of the Aging, Demographics, and Memory Study (ADAMS) cohort.

The team found that compared with nonusers, SNAP users were more likely to be women, Black, and born in the southern United States. They were less likely to be married and had more chronic conditions, such as high blood pressure, diabetes, cancer, heart problems, psychiatric problems, and arthritis.

One important study limitation was that SNAP use was measured only once during the study, the investigators noted. Ideally, Dr. Zeki Al Hazzouri said, future research would examine cumulative SNAP use history and explore the pathways that might account for the association between SNAP use and memory decline.

While findings suggest that there were no significant differences in baseline memory function between SNAP users and nonusers, users experienced approximately 2 fewer years of cognitive aging over a 10-year period than those who didn’t use the program.

Dr. Zeki Al Hazzouri speculated that SNAP benefits may slow cognitive aging by contributing to overall brain health and that, in comparison with nonusers, SNAP users absorb more nutrients, which promote neuronal integrity.

The investigators theorized that SNAP benefits may reduce stress from financial hardship, which has been linked to premature cognitive aging in other research.

“SNAP may also increase the purchasing power and investment in other health preserving behaviors, but also resulting in better access to care, which may in turn result in better disease management and management of risk factors for cognitive function,” the investigators wrote.
 

An underutilized program

In an accompanying editorial, Steven Albert, PhD, Philip B. Hallen Endowed Chair in Community Health and Social Justice at the University of Pittsburgh, noted that in 2020, among households with people aged 50 and older in the United States, more than 9 million Americans experienced food insecurity.

Furthermore, he pointed out, research from 2018 showed that 71% of people aged 60 and older who met income eligibility for SNAP did not participate in the program. “SNAP is an underutilized food security program involving substantial income supplements for older people with low incomes.

“Against the backdrop of so many failures of pharmacotherapy for dementia and the so far inexorable increase in the prevalence of dementia due to population aging, are we missing an opportunity to support cognitive health by failing to enroll the 14 million Americans who are over age 60 and eligible for SNAP but who do not participate?” Dr. Albert asked. He suggested that it would be helpful to determine this through a randomized promotion trial.

The study was funded by the National Institute on Aging. The authors reported no relevant financial relationships.

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

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Dear Colleagues,

We have a mismatch. The evidence supporting treatment for Paxlovid is compelling for people aged 60 or over, but the older patients in the United States are much less likely to be treated. Not only was there a randomized, placebo-controlled trial of high-risk patients which showed 89% reduction of hospitalizations and deaths (median age, 45), but there have been multiple real-world effectiveness studies subsequently published that have partitioned the benefit for age 65 or older, such as the ones from Israel and Hong Kong (age 60+). Overall, the real-world effectiveness in the first month after treatment is at least as good, if not better, than in the high-risk randomized trial.

But it’s more likely in the United States for a person age 45-50 to get Paxlovid over people age 80 or older. Why? We’re doing the current survey to find out, but the most likely reasons include (1) lack of confidence of benefit; (2) medication interactions; and (3) concerns over rebound.

Let me address each of these briefly. The lack of confidence in benefit stems from the fact that the initial high-risk trial was in unvaccinated individuals. That concern can now be put aside because all of the several real-world studies confirming the protective benefit against hospitalizations and deaths are in people who have been vaccinated, and a significant proportion received booster shots.

The potential medication interactions due to the ritonavir component of the Paxlovid drug combination, attributable to its cytochrome P450 3A4 inhibition, have been unduly emphasized. There are many drug-interaction checkers for Paxlovid, but this one from the University of Liverpool is user friendly, color- and icon-coded, and shows that the vast majority of interactions can be sidestepped by discontinuing the medication of concern for the length of the Paxlovid treatment, 5 days. The simple chart is provided in my recent substack newsletter.

As far as rebound, this problem has unfortunately been exaggerated because of lack of prospective systematic studies and appreciation that a positive test of clinical symptom rebound can occur without Paxlovid. There are soon to be multiple reports that the incidence of Paxlovid rebound is fairly low, in the range of 10%. That concern should not be a reason to withhold treatment.

Now the plot thickens. A new preprint report from the Veterans Health Administration, the largest health care system in the United States, looks at 90-day outcomes of about 9,000 Paxlovid-treated patients and approximately 47,000 controls. Not only was there a 26% reduction in long COVID, but of the breakdown of 12 organs/systems and symptoms, 10 of 12 were significantly reduced with Paxlovid, including pulmonary embolism, deep vein thrombosis, and neurocognitive impairment. There was also a 48% reduction in death and a 30% reduction in hospitalizations after the first 30 days. I have reviewed all of these data and put them in context in a recent newsletter. A key point is that the magnitude of benefit was unaffected by vaccination or booster status, or prior COVID infections, or unvaccinated status. Also, it was the same for men and women, as well as for age > 70 and age < 60. These findings all emphasize a new reason to be using Paxlovid therapy, and if replicated, Paxlovid may even be indicated for younger patients (who are at low risk for hospitalizations and deaths but at increased risk for long COVID).

In summary, for older patients, we should be thinking of why we should be using Paxlovid rather than the reason not to treat. We’ll be interested in the survey results to understand the mismatch better, and we look forward to your ideas and feedback to make better use of this treatment for the people who need it the most.

Sincerely yours, Eric J. Topol, MD

Dr. Topol reports no conflicts of interest with Pfizer; he receives no honoraria or speaker fees, does not serve in an advisory role, and has no financial association with the company.

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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

Getting COVID-19 a second time doubles a person’s chance of dying and triples the likelihood of being hospitalized in the next 6 months, a new study found.

Vaccination and booster status did not improve survival or hospitalization rates among people who were infected more than once.

“Reinfection with COVID-19 increases the risk of both acute outcomes and long COVID,” study author Ziyad Al-Aly, MD, told Reuters. “This was evident in unvaccinated, vaccinated and boosted people.”

The study was published in the journal Nature Medicine.

Researchers analyzed U.S. Department of Veterans Affairs data, including 443,588 people with a first infection of SARS-CoV-2, 40,947 people who were infected two or more times, and 5.3 million people who had not been infected with coronavirus, whose data served as the control group.

“During the past few months, there’s been an air of invincibility among people who have had COVID-19 or their vaccinations and boosters, and especially among people who have had an infection and also received vaccines; some people started to [refer] to these individuals as having a sort of superimmunity to the virus,” Dr. Al-Aly said in a press release from Washington University in St. Louis. “Without ambiguity, our research showed that getting an infection a second, third or fourth time contributes to additional health risks in the acute phase, meaning the first 30 days after infection, and in the months beyond, meaning the long COVID phase.”

Being infected with COVID-19 more than once also dramatically increased the risk of developing lung problems, heart conditions, or brain conditions. The heightened risks persisted for 6 months.

Researchers said a limitation of their study was that data primarily came from White males.

An expert not involved in the study told Reuters that the Veterans Affairs population does not reflect the general population. Patients at VA health facilities are generally older with more than normal health complications, said John Moore, PhD, a professor of microbiology and immunology at Weill Cornell Medicine, New York.

Dr. Al-Aly encouraged people to be vigilant as they plan for the holiday season, Reuters reported.

“We had started seeing a lot of patients coming to the clinic with an air of invincibility,” he told Reuters. “They wondered, ‘Does getting a reinfection really matter?’ The answer is yes, it absolutely does.”

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