Conference Coverage

CHICAGO – Clinicians who prescribe heart failure meds are holding the best hand they’ve ever had, but with so much underuse and suboptimal dosing in actual practice, it seems many may not appreciate the value of their cards. But a major randomized trial that has captured the field’s attention may embolden them to go all in.

Results showed that a strategy of early, rapid up-titration of multiple guideline-directed meds in patients hospitalized with heart failure, compared with a usual-care approach, cut their 6-month risk for death or HF readmission by a steep 34% (P = .002).

The drugs had been started and partly up-titrated in the hospital with the goal of full up-titration within 2 weeks after discharge.

Patients well tolerated the high-intensity approach, researchers said. Their quality-of-life scores improved (P < .0001) compared with the usual-care group, and adverse events were considered few and manageable in the international trial with more than 1,000 patients.

Safety on the high-intensity strategy depended on close patient monitoring at frequently planned clinic visits along with guidance for the up-titrations from clinical signs and natriuretic peptide levels, observed Alexandre Mebazaa, MD, PhD, University of Paris and Public Hospitals of Paris.

Dr. Mebazaa is principal investigator on the trial, called STRONG-HF, which he presented at the American Heart Association scientific sessions, held in Chicago and virtually. He is also lead author on the study’s same-day publication in the Lancet.

The high-intensity strategy’s superiority emerged early in the trial, which was halted early on the data safety monitoring board’s recommendation, with about 90% of follow-ups completed. The board “felt it was unethical to keep patients in usual care,” Dr. Mebazaa said at a press conference.
 

A dramatic change

The next step, he said, will be to educate the heart failure community on the high-intensity care technique so it can swiftly enter clinical practice. Currently in acute heart failure, “very few patients are monitored after discharge and treated with full doses of heart failure therapies.”

Adoption of the strategy “would be a dramatic change from what’s currently being done,” said Martin B. Leon, MD, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, who moderated the press conference.

Only an estimated 5% of patients with HF in the United States receive full guideline-directed medical therapy, Dr. Leon said, “so the generalizability of this strategy, with careful follow-up that has safety involved in it, is absolutely crucial.”

But the potential impact of this high-intensity approach on resource use is unknown, raising questions about how widely and consistently it could be implemented, said Dr. Leon, who is not connected with STRONG-HF.

The trial called for in-hospital initiation of the three distinct drug classes that, at the time, were the core of guideline-directed HF therapy, with up-titration to 50% of recommended dosage by hospital discharge, and then to 100% within 2 weeks later.

The meds included a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system inhibitor (RASI). The latter could be an ACE inhibitor, angiotensin-receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI).
 

How about a fourth drug?

Conspicuously absent from the list, for contemporary practice, was an SGLT2 inhibitor, a class that entered the HF guidelines well after STRONG-HF was designed. They would undoubtedly join the other three agents were the high-intensity strategy to enter practice, potentially changing its complexity and safety profile.

But Dr. Mebazaa and other experts don’t see that as a big challenge and would expect a smooth transition to a high-intensity approach that also includes the SGLT2 inhibitors.

STRONG-HF was necessary in part because many clinicians have been “reluctant” to take full advantage of three agents that had been the basis of guideline-directed therapy, he told this news organization.

That reluctance stemmed from concerns that beta-blockers might worsen the heart failure, ACE inhibitors could hurt the kidneys, or MRAs might cause hyperkalemia, Dr. Mebazaa said. The STRONG-HF high-intensity regimen, therefore, demanded multiple clinic visits for close follow-up.

But the SGLT2 inhibitors “are known to be rather safe drugs, at least much safer than the three others,” he said. So, it seems unlikely that their addition to a beta-blocker, RASI, and MRA in patients with HF would worsen the risk of adverse events.

John G.F. Cleland, MD, PhD, agrees. With addition of the fourth agent, “You may need to be a little bit more careful with renal function, just in that first couple of weeks,” he told this news organization. “But I think it would be easy to add an SGLT2 inhibitor into this regimen. And in general, there’s no titration with an SGLT2 inhibitor, so they’ll all be on full dose predischarge.”

Given the drugs’ diuretic-like action, moreover, some patients might be able to pull back on their loop diuretics, speculated Dr. Cleland, from the University of Glasgow’s School of Health and Wellbeing.

The prospect of a high-intensity strategy’s wide implementation in practice presents both “challenges and opportunities,” Amanda R. Vest, MBBS, MPH, Tufts University, Boston, told this news organization.

“There may be additional challenges in terms of ensuring we avoid hypotension or acute kidney injury in the up-titration phase,” said Dr. Vest, who is medical director of her center’s cardiac transplantation program but not connected with STRONG-HF.

“But it also gives us opportunities,” she added, “because there are some patients, especially in that vulnerable postdischarge phase, who are actually much more able to tolerate introduction of an SGLT2 inhibitor than, for example, an ACE inhibitor, ARB, or ARNI – or maybe a beta-blocker if they’ve been in a low cardiac-output state.” Effective dosing would depend on “the personalization and skill of the clinician in optimizing the medications in their correct sequence,” Dr. Vest said.

“It’s challenging to think that we would ever get to 100% up-titration,” she added, “and even in this excellent study, they didn’t get to 100%.” But as clinicians gain experience with the high-intensity strategy, especially as the SGLT2 inhibitors are included, “I think we can reasonably expect more progress to be made in these up-titration skills.”
 

No restrictions on LVEF

The researchers entered 1,078 patients hospitalized with acute HF in 14 countries across Africa, Europe, the Middle East, and South America, and randomly assigned them to the high-intensity management strategy or usual care.

About 60% of the patients were male and 77% were White. There were no entry restrictions based on left ventricular ejection fraction (LVEF), which exceeded 40% in almost a third of cases.

In the high-intensity care group’s 542 patients, the three agents were up-titrated to 50% of the maximum guideline-recommended dosage prior to hospital discharge, and to 100% within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were monitored closely at four planned clinical visits over the following 6 weeks.

The 536 patients assigned to usual care were discharged and managed according to local standards, with their meds handled by their own primary care doctors or cardiologists, the published report notes. They were reevaluated by STRONG-HF clinicians 90 days after discharge.

The number of clinic visits in the first 90 postdischarge days averaged 4.8 in the high-intensity care group and 1.0 for those receiving usual care. Full up-titration was far more likely in the high-intensity care group: 55% vs. 2% for RASI agents, 49% vs. 4% for beta-blockers, and 84% vs. 46% for MRAs.

They also fared significantly better on all measured parameters associated with decongestion, including weight, prevalence of peripheral edema, jugular venous pressure, NYHA functional class, and natriuretic peptide levels, the researchers said.

The primary endpoint of 180-day death from any cause or HF readmission was met by 15.2% of the high-intensity care group and 23.3% of usual-care patients, for an adjusted risk ratio (RR) of 0.66 (95% CI, 0.50-0.86; P = .0021).

Subgroup analyses saw no significant interactions by age, sex, race, geography, or baseline blood pressure, renal function, or LVEF. Patients with higher vs. lower baseline natriuretic peptide levels trend toward better responses to high-intensity care (P = .08)
 

The COVID effect

The group performed a sensitivity analysis that excluded deaths attributed to COVID-19 in STRONG-HF, which launched prior to the pandemic. The high-intensity strategy’s benefit for the primary endpoint grew, with an adjusted RR of 0.61 (95% CI, 0.46-0.82; P = .0005). There was no corresponding effect on death from any cause (P = .15).

Treatment-related adverse effects in the overall trial were seen in 41.1% of the high-intensity care group and in 29.5% of those assigned to usual care.

The higher rate in the high-intensity care arm “may be related to their higher number of [clinic] visits compared to usual care,” Dr. Mebazaa said. “However, serious adverse events and fatal adverse events were similar in both arms.”

Cardiac failure was the most common adverse event, developing in about 15% in both groups. It was followed by hypotension, hyperkalemia, and renal impairment, according to the published report.

Dr. Cleland cautioned that the risk of adverse events would potentially be higher should the high-intensity strategy become common clinical practice. The median age in STRONG-HF was 63, which is “10-15 years younger, on average, than the population with recently admitted heart failure that we see. There’s no doubt that older people have more multimorbidity.”

STRONG-HF was funded by Roche Diagnostics. Dr. Mebazaa discloses receiving grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck, Sharp & Dohme; and consulting for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and to being a co-inventor on a patent involving combination therapy for patients having acute or persistent dyspnea.

Dr. Vest reports modest relationships with Boehringer Ingelheim, Corvia, and CareDx; and receiving research grants from the American Heart Association and the National Institutes of Health. Dr. Cleland discloses receiving honoraria from Idorsia; and research grants from Vifor Pharma, Medtronic, Bayer, and Bristol-Myers Squibb. Dr. Leon had no disclosures.

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

CHICAGO – Clinicians who prescribe heart failure meds are holding the best hand they’ve ever had, but with so much underuse and suboptimal dosing in actual practice, it seems many may not appreciate the value of their cards. But a major randomized trial that has captured the field’s attention may embolden them to go all in.

Results showed that a strategy of early, rapid up-titration of multiple guideline-directed meds in patients hospitalized with heart failure, compared with a usual-care approach, cut their 6-month risk for death or HF readmission by a steep 34% (P = .002).

The drugs had been started and partly up-titrated in the hospital with the goal of full up-titration within 2 weeks after discharge.

Patients well tolerated the high-intensity approach, researchers said. Their quality-of-life scores improved (P < .0001) compared with the usual-care group, and adverse events were considered few and manageable in the international trial with more than 1,000 patients.

Safety on the high-intensity strategy depended on close patient monitoring at frequently planned clinic visits along with guidance for the up-titrations from clinical signs and natriuretic peptide levels, observed Alexandre Mebazaa, MD, PhD, University of Paris and Public Hospitals of Paris.

Dr. Mebazaa is principal investigator on the trial, called STRONG-HF, which he presented at the American Heart Association scientific sessions, held in Chicago and virtually. He is also lead author on the study’s same-day publication in the Lancet.

The high-intensity strategy’s superiority emerged early in the trial, which was halted early on the data safety monitoring board’s recommendation, with about 90% of follow-ups completed. The board “felt it was unethical to keep patients in usual care,” Dr. Mebazaa said at a press conference.
 

A dramatic change

The next step, he said, will be to educate the heart failure community on the high-intensity care technique so it can swiftly enter clinical practice. Currently in acute heart failure, “very few patients are monitored after discharge and treated with full doses of heart failure therapies.”

Adoption of the strategy “would be a dramatic change from what’s currently being done,” said Martin B. Leon, MD, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, who moderated the press conference.

Only an estimated 5% of patients with HF in the United States receive full guideline-directed medical therapy, Dr. Leon said, “so the generalizability of this strategy, with careful follow-up that has safety involved in it, is absolutely crucial.”

But the potential impact of this high-intensity approach on resource use is unknown, raising questions about how widely and consistently it could be implemented, said Dr. Leon, who is not connected with STRONG-HF.

The trial called for in-hospital initiation of the three distinct drug classes that, at the time, were the core of guideline-directed HF therapy, with up-titration to 50% of recommended dosage by hospital discharge, and then to 100% within 2 weeks later.

The meds included a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system inhibitor (RASI). The latter could be an ACE inhibitor, angiotensin-receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI).
 

How about a fourth drug?

Conspicuously absent from the list, for contemporary practice, was an SGLT2 inhibitor, a class that entered the HF guidelines well after STRONG-HF was designed. They would undoubtedly join the other three agents were the high-intensity strategy to enter practice, potentially changing its complexity and safety profile.

But Dr. Mebazaa and other experts don’t see that as a big challenge and would expect a smooth transition to a high-intensity approach that also includes the SGLT2 inhibitors.

STRONG-HF was necessary in part because many clinicians have been “reluctant” to take full advantage of three agents that had been the basis of guideline-directed therapy, he told this news organization.

That reluctance stemmed from concerns that beta-blockers might worsen the heart failure, ACE inhibitors could hurt the kidneys, or MRAs might cause hyperkalemia, Dr. Mebazaa said. The STRONG-HF high-intensity regimen, therefore, demanded multiple clinic visits for close follow-up.

But the SGLT2 inhibitors “are known to be rather safe drugs, at least much safer than the three others,” he said. So, it seems unlikely that their addition to a beta-blocker, RASI, and MRA in patients with HF would worsen the risk of adverse events.

John G.F. Cleland, MD, PhD, agrees. With addition of the fourth agent, “You may need to be a little bit more careful with renal function, just in that first couple of weeks,” he told this news organization. “But I think it would be easy to add an SGLT2 inhibitor into this regimen. And in general, there’s no titration with an SGLT2 inhibitor, so they’ll all be on full dose predischarge.”

Given the drugs’ diuretic-like action, moreover, some patients might be able to pull back on their loop diuretics, speculated Dr. Cleland, from the University of Glasgow’s School of Health and Wellbeing.

The prospect of a high-intensity strategy’s wide implementation in practice presents both “challenges and opportunities,” Amanda R. Vest, MBBS, MPH, Tufts University, Boston, told this news organization.

“There may be additional challenges in terms of ensuring we avoid hypotension or acute kidney injury in the up-titration phase,” said Dr. Vest, who is medical director of her center’s cardiac transplantation program but not connected with STRONG-HF.

“But it also gives us opportunities,” she added, “because there are some patients, especially in that vulnerable postdischarge phase, who are actually much more able to tolerate introduction of an SGLT2 inhibitor than, for example, an ACE inhibitor, ARB, or ARNI – or maybe a beta-blocker if they’ve been in a low cardiac-output state.” Effective dosing would depend on “the personalization and skill of the clinician in optimizing the medications in their correct sequence,” Dr. Vest said.

“It’s challenging to think that we would ever get to 100% up-titration,” she added, “and even in this excellent study, they didn’t get to 100%.” But as clinicians gain experience with the high-intensity strategy, especially as the SGLT2 inhibitors are included, “I think we can reasonably expect more progress to be made in these up-titration skills.”
 

No restrictions on LVEF

The researchers entered 1,078 patients hospitalized with acute HF in 14 countries across Africa, Europe, the Middle East, and South America, and randomly assigned them to the high-intensity management strategy or usual care.

About 60% of the patients were male and 77% were White. There were no entry restrictions based on left ventricular ejection fraction (LVEF), which exceeded 40% in almost a third of cases.

In the high-intensity care group’s 542 patients, the three agents were up-titrated to 50% of the maximum guideline-recommended dosage prior to hospital discharge, and to 100% within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were monitored closely at four planned clinical visits over the following 6 weeks.

The 536 patients assigned to usual care were discharged and managed according to local standards, with their meds handled by their own primary care doctors or cardiologists, the published report notes. They were reevaluated by STRONG-HF clinicians 90 days after discharge.

The number of clinic visits in the first 90 postdischarge days averaged 4.8 in the high-intensity care group and 1.0 for those receiving usual care. Full up-titration was far more likely in the high-intensity care group: 55% vs. 2% for RASI agents, 49% vs. 4% for beta-blockers, and 84% vs. 46% for MRAs.

They also fared significantly better on all measured parameters associated with decongestion, including weight, prevalence of peripheral edema, jugular venous pressure, NYHA functional class, and natriuretic peptide levels, the researchers said.

The primary endpoint of 180-day death from any cause or HF readmission was met by 15.2% of the high-intensity care group and 23.3% of usual-care patients, for an adjusted risk ratio (RR) of 0.66 (95% CI, 0.50-0.86; P = .0021).

Subgroup analyses saw no significant interactions by age, sex, race, geography, or baseline blood pressure, renal function, or LVEF. Patients with higher vs. lower baseline natriuretic peptide levels trend toward better responses to high-intensity care (P = .08)
 

The COVID effect

The group performed a sensitivity analysis that excluded deaths attributed to COVID-19 in STRONG-HF, which launched prior to the pandemic. The high-intensity strategy’s benefit for the primary endpoint grew, with an adjusted RR of 0.61 (95% CI, 0.46-0.82; P = .0005). There was no corresponding effect on death from any cause (P = .15).

Treatment-related adverse effects in the overall trial were seen in 41.1% of the high-intensity care group and in 29.5% of those assigned to usual care.

The higher rate in the high-intensity care arm “may be related to their higher number of [clinic] visits compared to usual care,” Dr. Mebazaa said. “However, serious adverse events and fatal adverse events were similar in both arms.”

Cardiac failure was the most common adverse event, developing in about 15% in both groups. It was followed by hypotension, hyperkalemia, and renal impairment, according to the published report.

Dr. Cleland cautioned that the risk of adverse events would potentially be higher should the high-intensity strategy become common clinical practice. The median age in STRONG-HF was 63, which is “10-15 years younger, on average, than the population with recently admitted heart failure that we see. There’s no doubt that older people have more multimorbidity.”

STRONG-HF was funded by Roche Diagnostics. Dr. Mebazaa discloses receiving grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck, Sharp & Dohme; and consulting for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and to being a co-inventor on a patent involving combination therapy for patients having acute or persistent dyspnea.

Dr. Vest reports modest relationships with Boehringer Ingelheim, Corvia, and CareDx; and receiving research grants from the American Heart Association and the National Institutes of Health. Dr. Cleland discloses receiving honoraria from Idorsia; and research grants from Vifor Pharma, Medtronic, Bayer, and Bristol-Myers Squibb. Dr. Leon had no disclosures.

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

CHICAGO – Clinicians who prescribe heart failure meds are holding the best hand they’ve ever had, but with so much underuse and suboptimal dosing in actual practice, it seems many may not appreciate the value of their cards. But a major randomized trial that has captured the field’s attention may embolden them to go all in.

Results showed that a strategy of early, rapid up-titration of multiple guideline-directed meds in patients hospitalized with heart failure, compared with a usual-care approach, cut their 6-month risk for death or HF readmission by a steep 34% (P = .002).

The drugs had been started and partly up-titrated in the hospital with the goal of full up-titration within 2 weeks after discharge.

Patients well tolerated the high-intensity approach, researchers said. Their quality-of-life scores improved (P < .0001) compared with the usual-care group, and adverse events were considered few and manageable in the international trial with more than 1,000 patients.

Safety on the high-intensity strategy depended on close patient monitoring at frequently planned clinic visits along with guidance for the up-titrations from clinical signs and natriuretic peptide levels, observed Alexandre Mebazaa, MD, PhD, University of Paris and Public Hospitals of Paris.

Dr. Mebazaa is principal investigator on the trial, called STRONG-HF, which he presented at the American Heart Association scientific sessions, held in Chicago and virtually. He is also lead author on the study’s same-day publication in the Lancet.

The high-intensity strategy’s superiority emerged early in the trial, which was halted early on the data safety monitoring board’s recommendation, with about 90% of follow-ups completed. The board “felt it was unethical to keep patients in usual care,” Dr. Mebazaa said at a press conference.
 

A dramatic change

The next step, he said, will be to educate the heart failure community on the high-intensity care technique so it can swiftly enter clinical practice. Currently in acute heart failure, “very few patients are monitored after discharge and treated with full doses of heart failure therapies.”

Adoption of the strategy “would be a dramatic change from what’s currently being done,” said Martin B. Leon, MD, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, who moderated the press conference.

Only an estimated 5% of patients with HF in the United States receive full guideline-directed medical therapy, Dr. Leon said, “so the generalizability of this strategy, with careful follow-up that has safety involved in it, is absolutely crucial.”

But the potential impact of this high-intensity approach on resource use is unknown, raising questions about how widely and consistently it could be implemented, said Dr. Leon, who is not connected with STRONG-HF.

The trial called for in-hospital initiation of the three distinct drug classes that, at the time, were the core of guideline-directed HF therapy, with up-titration to 50% of recommended dosage by hospital discharge, and then to 100% within 2 weeks later.

The meds included a beta-blocker, a mineralocorticoid receptor antagonist (MRA), and a renin-angiotensin system inhibitor (RASI). The latter could be an ACE inhibitor, angiotensin-receptor blocker (ARB), or angiotensin receptor-neprilysin inhibitor (ARNI).
 

How about a fourth drug?

Conspicuously absent from the list, for contemporary practice, was an SGLT2 inhibitor, a class that entered the HF guidelines well after STRONG-HF was designed. They would undoubtedly join the other three agents were the high-intensity strategy to enter practice, potentially changing its complexity and safety profile.

But Dr. Mebazaa and other experts don’t see that as a big challenge and would expect a smooth transition to a high-intensity approach that also includes the SGLT2 inhibitors.

STRONG-HF was necessary in part because many clinicians have been “reluctant” to take full advantage of three agents that had been the basis of guideline-directed therapy, he told this news organization.

That reluctance stemmed from concerns that beta-blockers might worsen the heart failure, ACE inhibitors could hurt the kidneys, or MRAs might cause hyperkalemia, Dr. Mebazaa said. The STRONG-HF high-intensity regimen, therefore, demanded multiple clinic visits for close follow-up.

But the SGLT2 inhibitors “are known to be rather safe drugs, at least much safer than the three others,” he said. So, it seems unlikely that their addition to a beta-blocker, RASI, and MRA in patients with HF would worsen the risk of adverse events.

John G.F. Cleland, MD, PhD, agrees. With addition of the fourth agent, “You may need to be a little bit more careful with renal function, just in that first couple of weeks,” he told this news organization. “But I think it would be easy to add an SGLT2 inhibitor into this regimen. And in general, there’s no titration with an SGLT2 inhibitor, so they’ll all be on full dose predischarge.”

Given the drugs’ diuretic-like action, moreover, some patients might be able to pull back on their loop diuretics, speculated Dr. Cleland, from the University of Glasgow’s School of Health and Wellbeing.

The prospect of a high-intensity strategy’s wide implementation in practice presents both “challenges and opportunities,” Amanda R. Vest, MBBS, MPH, Tufts University, Boston, told this news organization.

“There may be additional challenges in terms of ensuring we avoid hypotension or acute kidney injury in the up-titration phase,” said Dr. Vest, who is medical director of her center’s cardiac transplantation program but not connected with STRONG-HF.

“But it also gives us opportunities,” she added, “because there are some patients, especially in that vulnerable postdischarge phase, who are actually much more able to tolerate introduction of an SGLT2 inhibitor than, for example, an ACE inhibitor, ARB, or ARNI – or maybe a beta-blocker if they’ve been in a low cardiac-output state.” Effective dosing would depend on “the personalization and skill of the clinician in optimizing the medications in their correct sequence,” Dr. Vest said.

“It’s challenging to think that we would ever get to 100% up-titration,” she added, “and even in this excellent study, they didn’t get to 100%.” But as clinicians gain experience with the high-intensity strategy, especially as the SGLT2 inhibitors are included, “I think we can reasonably expect more progress to be made in these up-titration skills.”
 

No restrictions on LVEF

The researchers entered 1,078 patients hospitalized with acute HF in 14 countries across Africa, Europe, the Middle East, and South America, and randomly assigned them to the high-intensity management strategy or usual care.

About 60% of the patients were male and 77% were White. There were no entry restrictions based on left ventricular ejection fraction (LVEF), which exceeded 40% in almost a third of cases.

In the high-intensity care group’s 542 patients, the three agents were up-titrated to 50% of the maximum guideline-recommended dosage prior to hospital discharge, and to 100% within 2 weeks after discharge. Symptoms and laboratory biomarkers, including natriuretic peptides, were monitored closely at four planned clinical visits over the following 6 weeks.

The 536 patients assigned to usual care were discharged and managed according to local standards, with their meds handled by their own primary care doctors or cardiologists, the published report notes. They were reevaluated by STRONG-HF clinicians 90 days after discharge.

The number of clinic visits in the first 90 postdischarge days averaged 4.8 in the high-intensity care group and 1.0 for those receiving usual care. Full up-titration was far more likely in the high-intensity care group: 55% vs. 2% for RASI agents, 49% vs. 4% for beta-blockers, and 84% vs. 46% for MRAs.

They also fared significantly better on all measured parameters associated with decongestion, including weight, prevalence of peripheral edema, jugular venous pressure, NYHA functional class, and natriuretic peptide levels, the researchers said.

The primary endpoint of 180-day death from any cause or HF readmission was met by 15.2% of the high-intensity care group and 23.3% of usual-care patients, for an adjusted risk ratio (RR) of 0.66 (95% CI, 0.50-0.86; P = .0021).

Subgroup analyses saw no significant interactions by age, sex, race, geography, or baseline blood pressure, renal function, or LVEF. Patients with higher vs. lower baseline natriuretic peptide levels trend toward better responses to high-intensity care (P = .08)
 

The COVID effect

The group performed a sensitivity analysis that excluded deaths attributed to COVID-19 in STRONG-HF, which launched prior to the pandemic. The high-intensity strategy’s benefit for the primary endpoint grew, with an adjusted RR of 0.61 (95% CI, 0.46-0.82; P = .0005). There was no corresponding effect on death from any cause (P = .15).

Treatment-related adverse effects in the overall trial were seen in 41.1% of the high-intensity care group and in 29.5% of those assigned to usual care.

The higher rate in the high-intensity care arm “may be related to their higher number of [clinic] visits compared to usual care,” Dr. Mebazaa said. “However, serious adverse events and fatal adverse events were similar in both arms.”

Cardiac failure was the most common adverse event, developing in about 15% in both groups. It was followed by hypotension, hyperkalemia, and renal impairment, according to the published report.

Dr. Cleland cautioned that the risk of adverse events would potentially be higher should the high-intensity strategy become common clinical practice. The median age in STRONG-HF was 63, which is “10-15 years younger, on average, than the population with recently admitted heart failure that we see. There’s no doubt that older people have more multimorbidity.”

STRONG-HF was funded by Roche Diagnostics. Dr. Mebazaa discloses receiving grants from Roche Diagnostics, Abbott Laboratories, 4TEEN4, and Windtree Therapeutics; honoraria for lectures from Roche Diagnostics, Bayer, and Merck, Sharp & Dohme; and consulting for Corteria Pharmaceuticals, S-form Pharma, FIRE-1, Implicity, 4TEEN4, and Adrenomed; and to being a co-inventor on a patent involving combination therapy for patients having acute or persistent dyspnea.

Dr. Vest reports modest relationships with Boehringer Ingelheim, Corvia, and CareDx; and receiving research grants from the American Heart Association and the National Institutes of Health. Dr. Cleland discloses receiving honoraria from Idorsia; and research grants from Vifor Pharma, Medtronic, Bayer, and Bristol-Myers Squibb. Dr. Leon had no disclosures.

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

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

PAU, FRANCE – Postpartum posttraumatic stress disorder tends to get worse over the months following the birth of a child. Therefore, it’s necessary to screen for it as early on as possible and to ensure that women who are affected are given the proper treatment. This was the message delivered during the Infogyn 2022 conference by Ludivine Franchitto, MD, a child psychiatrist at Toulouse University Hospital, France. Because postpartum PTSD is still not fully recognized, treatment remains inadequate and poorly documented.

Impact on the caregivers as well

“The situation is the same as what we saw with postpartum depression. The debate went on for 20 years before its existence was formally declared,” Dr. Franchitto noted. But for her, the important thing is not knowing whether a traumatic stress state may be experienced by the mother who had complications during pregnancy or delivery. Instead, it’s about focusing on the repercussions for the child.

During her presentation, Dr. Franchitto also pointed out that it’s necessary to recognize that caregivers who work in maternity wards may also be negatively impacted, as they routinely see the complications that women have during pregnancy and delivery. These workers may also develop a PTSD state, requiring support so that they can properly carry out their duties.

According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), posttraumatic stress disorder arises after exposure to actual (or threatened) death, serious injury, or sexual violence. Individuals who have witnessed a traumatic event in person or who have experienced repeated (or extreme) exposure to aversive details of traumatic events may also develop PTSD.

Dr. Franchitto mentioned some of the criteria needed to make the diagnosis. “Intrusive distressing memories of the event, recurrent distressing dreams related to the event, persistent avoidance of stimuli associated with the traumatic event, or negative alterations in cognitions and mood associated with the traumatic event. And the duration of the disturbance is more than 1 month.” There may also be marked alterations in arousal and reactivity associated with the traumatic event (for example, irritable behavior, loss of awareness of present surroundings).
 

Prevalent in 18% of women in high-risk groups

According to the studies, there is a wide variability of PTSD rates. If referring only to traumatic symptoms (for example, depressive syndrome, suicidal ideation, hyperreactivity, and persistent avoidance), the rate could reach up to 40%. A 2016 meta-analysis of 59 studies found that the prevalence of childbirth-related PTSD was 5.9%.

The authors distinguished two groups of women: those without complications during pregnancy or during delivery and those with severe complications related to the pregnancy, a fear of giving birth, a difficult delivery, an emergency C-section, a baby born prematurely with birth defects, etc. Their analysis showed PTSD rates of 4% and 18.5%, respectively.

Surprisingly, the major risk factor for PTSD turned out to be uncontrollable vomiting during pregnancy (seen in 40% of postpartum PTSD cases). The birth of a baby with birth defects was the second risk factor (35%), and the third, a history of violence in the mother’s childhood (34%). Women who experienced depression during the delivery were also at higher risk.

Other risk factors identified were lack of communication with the health care team, lack of consent, lack of support from the medical staff, and a long labor. Conversely, a sense of control and the support of a partner play a protective role.
 

Early screening

“If the symptoms of posttraumatic stress disorder aren’t treated after delivery, they tend to get worse over the period of 1 to 6 months following the child’s birth,” Dr. Franchitto indicated. This is why it’s necessary to screen for it as early as possible – in particular, by having the women fill out the City Birth Trauma Scale questionnaire – and provide proper treatment accordingly. When seeking to limit the effects of stress, early intervention by a psychologist may be beneficial.

Psychotherapy is the recommended first-line treatment for PTSD, especially cognitive behavioral therapy and Eye Movement Desensitization and Reprocessing therapy. This approach aims to limit the mental and behavioral avoidance that prevents the traumatic memory from being integrated and processed as a regular memory.

The consequences that the mother’s PTSD state has on the child are well documented. “Children whose mothers had PTSD during pregnancy have a lower birth weight and a shorter breast-feeding duration,” Dr. Franchitto reported. With respect to the quality of the mother-child relationship and the long-term development of the child, “the studies have highly conflicting findings.”

At the end of the presentation, Professor Israël Nisand, MD, an ob.gyn. at the American Hospital of Paris and the former president of the National College of French Gynecologists and Obstetricians, made the following comment: “I often think that we underestimate the consequences that the mother’s posttraumatic stress has on the child postpartum.” He added, “Postpartum posttraumatic stress disorder is a reality. Yet it isn’t screened for, let alone treated, even though it has serious consequences for the child.”

Dr. Franchitto also brought up the impact on members of the health care staff, the “second victims” of the traumatic events that occur while caring for the women in the maternity ward. “The estimated prevalence of PTSD symptoms among midwives is 22.9%,” which could lead to “a loss of confidence and a desire to leave the profession.”
 

Providing psychoeducation to health care staff

Dr. Franchitto believes that it’s essential to also protect caregivers who work in maternity wards. “It’s important to have the support of colleagues” – in particular, of team leaders – “and to share one’s experiences,” as long as one knows how to recognize the symptoms of posttraumatic stress through one’s emotions and is able to verbalize them.

She went on to say that providing psychoeducation to health care staff is therefore to be encouraged, as is “simulation-based training, for learning how to manage problematic situations.”

This content was originally published on Medscape French edition. A translated version appeared on Medscape.com.

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – Hydroxychloroquine (HCQ) isn’t any more effective at preventing or delaying the onset of rheumatoid arthritis than placebo, based on interim results of a randomized clinical trial reported at the annual meeting of the American College of Rheumatology. Despite that futility, the percentage of patients who actually went on to develop clinical RA was lower than investigators expected, and the trial supports the use of a key biomarker for identifying RA.

While the StopRA trial was halted early because of futility of the treatment, investigators are continuing to mine the gathered data to deepen their understanding of disease progression and the potential of HCQ to improve symptoms in RA patients, said lead study author Kevin D. Deane, MD, PhD, of the University of Colorado at Denver, Aurora.

Richard Mark Kirkner/MDedge News

Overall, around 35% of the study participants on average developed RA, Dr. Deane said. “We were expecting somewhat more,” he said. “Teasing out who’s really going to progress to RA during a study and who’s not is going to be incredibly important.”

StopRA enrolled 144 adults who had elevated anti–cyclic citrullinated peptide antibodies (CCP3) levels of at least 40 units (about twice the normal level) but no history if inflammatory arthritis, randomizing them on a 1:1 basis to either HCQ (200-400 mg a day based on weight) or placebo for a 1-year treatment regimen.

The study identified participants through rheumatology clinics, testing of first-degree relatives with established RA, health fairs, blood donors, and biobanks. The interim findings are based on 2 years of follow-up after the last dose.

The study focused on HCQ because it has a relatively low risk profile with good safety and tolerability, is easy to administer, and is relatively low cost, Dr. Deane said.

StopRA study failed to meet its primary endpoint: to determine if 1 year of treatment with HCQ reduced the risk of developing inflammatory arthritis and classifiable RA at the end of 3 years in the study population. At the time of the interim analysis, 34% of patients in the HCQ arm and 36% in the placebo arm had developed RA (P = .844), Dr. Deane said. Baseline characteristics were balanced in both treatment arms.

The findings also support the use of CCP3 as a biomarker for RA, Dr. Deane said.

Now that the trial has been terminated, Dr. Deane said investigators are going to review the final data and perform secondary analyses for further clarity on the impact HCQ may have on RA.

“The future analysis should hopefully say if this treatment actually changes symptoms,” he said in an interview. “Because, if somebody felt better on the drug or had a milder form of rheumatoid arthritis once they developed it, that could potentially be a benefit.”

Dr. Deane noted the TREAT EARLIER trial similarly found that a 1-year course of methotrexate didn’t prevent the onset of clinical arthritis, but it did alter the disease course as measured in MRI-detected inflammation, related symptoms, and impairment.

“We’re hoping to look at those things and hopefully look at biologic changes over time,” Dr. Deane said of the extended analysis. “We’re not sure if the drug was associated with changes in biomarkers yet still didn’t halt progression to RA. That might be interesting, because those biomarkers might not be fundamentally related to the disease, but other mechanisms may be. That could give us some insights.”

Richard Mark Kirkner/MDedge News

Session moderator Ted Mikuls, MD, a professor of rheumatology at the University of Nebraska Medical Center, Omaha, said further mining of the study data is warranted.

“It’s common in a study like that, which took a lot of time and investment, to really take a deep dive into the data to make sure there aren’t signals that we’re missing,” he said in an interview.

One of the challenges with the study may have been patient enrollment, Dr. Mikuls noted. “I wonder about the study population in terms of where they recruit patients from. Who’s more likely to get RA? Is it patients who already have symptoms? Is it asymptomatic patients from biobanks? If it’s arthralgia joint pain patients, maybe by the time you have joint and autoantibody positivity it’s too late to have an intervention.”

The National Institute of Allergy and Infectious Diseases sponsored the study. Dr. Deane disclosed a relationship with Werfen. Dr. Mikuls has no relevant disclosures.
 

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

PHILADELPHIA – For patients with rheumatoid arthritis who are already at increased risk for major adverse cardiovascular events (MACE), NSAIDs may be safer than opioids, results of a new-user active comparator study suggest.

Among 6,866 patients with RA who started on opioids and 13,698 patients who started on NSAIDs for pain, the use of both weak and strong opioids was associated with a 33% increase in risk for all-cause mortality and a trend toward higher rates of venous thromboembolism (VTE), compared with NSAID use, reported Gulsen Ozen, MD, of the University of Nebraska Medical Center, Omaha.

Neil Osterweil/MDedge News

“Pain in RA is a very complex process, and we know that it’s not solely dependent on the disease activity, but there is no evidence that opioids have any benefit in long-term pain management, and it can even cause hyperalgesia. And as we show, it’s not safer than NSAIDs,” she said in an oral abstract session at the annual meeting of the American College of Rheumatology.

She stressed that patients should be assessed for non-RA causes of pain and should use nonpharmacologic methods when possible.

“If a pharmacological treatment is needed and NSAIDs are contraindicated, the lowest possible dose of weak opioids can be used for a very limited time for acute pain only,” she said.
 

Pain despite disease control

Even when their disease is well controlled, approximately 60% of patients with RA still report pain. NSAIDs are commonly used to treat pain in patients with RA, but they are associated with modest increases in risk for cardiovascular disease (CVD), gastrointestinal bleeding, renal injury, and hypertension.

Some providers are leery of NSAIDs and will instead prescribe either regular or intermittent opioids for pain control in their patients.

Disease-modifying antirheumatic drugs have only minimal pain-relieving benefits, “and even worse, opioids can delay initiation of DMARDs in RA,” Dr. Ozen said.

Opioids have been shown to increase oxidative stress, platelet aggregation, and myocardial fibrosis, as well as hypogonadism, weight gain, and CVD risk factors.

There is little evidence, however, on whether opioids are associated with cardiovascular events in patients with RA. This dearth of data prompted Dr. Ozen and colleagues to study the relative risks for MACE in patients with RA starting on opioids or NSAIDs for pain.

Matched cohorts

They used data from FORWARD, a joint Canadian and U.S. databank for rheumatic diseases, to conduct a new-user active comparator cohort study. The cohort included adults with RA without cancer who participated in FORWARD for a minimum of 1 year between 1998 and 2021.

The patients were followed either from drug initiation until 3 months after the end of treatment, defined as either discontinuation or a switch to a different analgesic, end of study follow-up, or the development of a MACE outcome.

The investigators used propensity score matching to compare each opioid initiator with two NSAID initiators. The participants were matched by age, sex, body mass index, smoking, alcohol, RA duration, disease activity, Health Assessment Questionnaire, visual analog scale for pain, joint surgeries, prior CVD and VTE, hypertension, diabetes, rheumatic diseases comorbidity index, osteoporosis/fractures, thyroid, chronic liver, kidney, lung and mental health diseases, hospitalizations, 36-Item Short Form Health Survey scores, and sleep scores.

The two groups were well matched, except for a slightly higher incidence of VTE in opioid initiators, although incidence rates were low in both groups (0.9% vs. 0.6% of NSAID initiators).
 

Higher death rate in opioid users

The incidence rate of MACE among opioid initiators was 20.6% versus18.9% among NSAID initiators, a difference that was not statistically significant. There were also no significant differences in incidence rates of the individual components of the MACE composite outcome: myocardial infarction, stroke, heart failure, CVD death, or VTE.

There were, however, significantly more deaths from any cause among patients in the opioid group, with an incidence rate of 13.5% versus 10.8% in the NSAID group.

An analysis of the associaion of drug type with outcomes, adjusted for propensity score weight and prior VTE showed that patients on opioids had a statistically significant hazard ratio for death from any cause of 1.33 (95% confidence interval, 1.06-1.67).

The increased risk for all-cause mortality occurred both in patients starting on weak opioids (hydrocodone, tramadol, codeine, pentazocine, and propoxyphene) and on strong opioids (hydromorphone, dihydromorphinone, oxymorphone, butorphanol, methadone, morphine, oxycodone, meperidine, and fentanyl).

As noted before, there was a trend toward an increased risk for VTE among opioid initiators, but this was not statistically significant.

The increase in risk was higher among patients on strong versus weak opioids, suggesting a dose-dependent relationship, Dr. Ozen said.

A comparison of opioid-associated risk for all-cause mortality vs. NSAIDs according to type (nonselective or selective) showed that most of the increase in risk was relative to selective cycloxygenase-2 inhibitors.

‘Beautiful’ analysis

“This is a beautiful piece of analysis on a really difficult question to address because the confounding is really hard to unpick,” commented James Galloway, MBBS, deputy head of the center for rheumatic diseases at King’s College London and consulting rheumatologist at King’s College Hospital, also in London.

“The headline message is that there didn’t appear to be a clear signal that NSAIDs were worse, which is what I thought the preexisting view might have been. And so, people may have paradoxically prescribed opioids in favor of NSAIDs in a person with cardiovascular risk,” he said in an interview. Dr. Galloway attended the oral abstract session but was not involved in the study.

The study was supported by a grant to Dr. Ozen from the Rheumatology Research Foundation. Dr. Galloway reported having no relevant disclosures.

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

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

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

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

In most cases, passengers on an airline flight are representative of the general population, which means that anyone could have an emergency at any time.

A study published in the New England Journal of Medicine in 2013 showed that a medical emergency occurred in 1 per 604 flights, as determined on the basis of in-flight medical emergencies that resulted in calls to a physician-directed medical communications center, said Amy Faith Ho, MD, MPH of Integrative Emergency Services, Dallas–Fort Worth, in a presentation at the annual meeting of the American College of Emergency Physicians.

The study authors reviewed records of 11,920 in-flight medical emergencies between Jan. 1, 2008, and Oct. 31, 2010. The data showed that physician passengers provided medical assistance in nearly half of in-flight emergencies (48.1%) and that flights were diverted because of the emergency in 7.3% of cases.

The majority of the in-flight emergencies involved syncope or presyncope (37.4% of cases), followed by respiratory symptoms (12.1%) and nausea or vomiting (9.5%), according to the study.

The in-flight medical bag

Tools in a physician’s in-flight toolbox start with the first-aid kit. Airplanes also have an emergency medical kit (EMK), an oxygen tank, and an AED.

The minimum EMK contents are mandated by the Federal Aviation Administration, said Dr. Ho. The standard equipment includes a stethoscope, a sphygmomanometer, and three sizes of oropharyngeal airways. Other items include self-inflating manual resuscitation devices and CPR masks in thee sizes, alcohol sponges, gloves, adhesive tape, scissors, a tourniquet, as well as saline solution, needles, syringes, and an intravenous administration set consisting of tubing and two Y connectors.

An EMK also should contain the following medications: nonnarcotic analgesic tablets, antihistamine tablets, an injectable antihistamine, atropine, aspirin tablets, a bronchodilator, and epinephrine (both 1:1000; 1 injectable cc and 1:10,000; two injectable cc). Nitroglycerin tablets and 5 cc of 20 mg/mL injectable cardiac lidocaine are part of the mandated kit as well, according to Dr. Ho.

Some airlines carry additional supplies on all their flights, said Dr. Ho. Notably, American Airlines and British Airways carry EpiPens for adults and children, as well as opioid reversal medication (naloxone) and glucose for managing low blood sugar. American Airlines and Delta stock antiemetics, and Delta also carries naloxone. British Airways is unique in stocking additional cardiac medications, both oral and injectable.
 

How to handle an in-flight emergency

Physicians should always carry a copy of their medical license when traveling for documentation by the airline if they assist in a medical emergency during a flight, Dr. Ho emphasized. “Staff” personnel should be used. These include the flight attendants, medical ground control, and other passengers who might have useful skills, such as nursing, the ability to perform CPR, or therapy/counseling to calm a frightened patient. If needed, “crowdsource additional supplies from passengers,” such as a glucometer or pulse oximeter.

Legal lessons

Physicians are not obligated to assist during an in-flight medical emergency, said Dr. Ho. Legal jurisdiction can vary. In the United States, a bystander who assists in an emergency is generally protected by Good Samaritan laws; for international airlines, the laws may vary; those where the airline is based usually apply.

The Aviation Medical Assistance Act, passed in 1998, protects individuals from being sued for negligence while providing medical assistance, “unless the individual, while rendering such assistance, is guilty of gross negligence of willful misconduct,” Dr. Ho noted. The Aviation Medical Assistance Act also protects the airline itself “if the carrier in good faith believes that the passenger is a medically qualified individual.”

Dr. Ho disclosed no relevant financial relationships.

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

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

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

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

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

ORLANDO – Hospitalization rates were higher in patients with advanced chronic kidney disease (CKD) treated with dialysis than those treated with conservative management, among those with an estimated glomerular filtration rate (eGFR) less than 25 mL/min/1.73m² and in most racial/ethnic groups, new research shows.

“Patients mostly start dialysis because of unpleasant symptoms that cause suffering, including high potassium levels and high levels of uremic toxins in the blood,” senior author Kamyar Kalantar-Zadeh, MD, PhD, MPH, told this news organization.

“Conservative management serves to address and manage these symptoms and levels of toxicities without dialysis, so conservative management is an alternative approach, and patients should always be given a choice between [the two],” stressed Dr. Kalantar-Zadeh, professor of medicine at the University of California, Irvine.

The results were presented during the annual meeting of the American Society of Nephrology.

“There has been growing recognition of the importance of conservative nondialytic management as an alternative patient-centered treatment strategy for advanced kidney disease. However, conservative management remains under-utilized in the United States, which may in part be due to uncertainties regarding which patients will most benefit from dialysis versus nondialytic treatment,” said first author Connie Rhee, MD, also of the University of California, Irvine.

“We hope that these findings and further research can help inform treatment options for patients, care partners, and providers in the shared decision-making process of conservative management versus dialysis,” added Dr. Rhee, in a press release from the American Society of Nephrology.

Asked for comment, Sarah Davison, MD, noted that part of the Society’s strategy is, in fact, to promote conservative kidney management (CKM) as a key component of integrated care for patients with kidney failure. Dr. Davison is professor of medicine and chair of the International Society Working Group for Kidney Supportive Care and Conservative Kidney Management.

“We’ve recognized for a long time that there are many patients for whom dialysis provides neither a survival advantage nor a quality of life advantage,” she told this news organization.

“These patients tend to be those who have multiple morbidities, who are more frail, and who tend to be older, and in fact, the patients can live as long, if not longer, with better symptom management and better quality of life by not being on dialysis,” she stressed.
 

Study details

In the study, using data from the Optum Labs Data Warehouse, patients with advanced CKD were categorized according to whether or not they received conservative management, defined as those who did not receive dialysis within 2 years of the index eGFR (first eGFR < 25 mL/min/1.73m²) versus receipt of dialysis parsed as late versus early dialysis transition (eGFR < 15 vs. ≥ 15 mL/min/1.73m² at dialysis initiation).

Hospitalization rates were compared between those treated with conservative management, compared with late or early dialysis.

“Among 309,188 advanced CKD patients who met eligibility [criteria], 55% of patients had greater than or equal to 1 hospitalization(s) within 2 years of the index eGFR,” the authors report. The most common causes of hospitalization among all patients were congestive heart failure, respiratory symptoms, or hypertension.

In most racial groups (non-Hispanic White, non-Hispanic Black, and Hispanic patients), patients on dialysis had higher hospitalization rates than those who received conservative management, and patients who started dialysis early (transitioned to dialysis at higher levels of kidney function) demonstrated the highest rates across all age groups, compared with those who started dialysis late (transitioned to dialysis at lower levels of kidney function) or were treated with conservative management.

Among Asian patients, those on dialysis also had higher hospitalization rates than those receiving conservative management, but patients who started dialysis late had higher rates than those on early dialysis, especially in older age groups, possibly because they were sicker, Dr. Kalantar-Zadeh suggested.
 

Conservative care has pros and cons, but Canada has embraced it

As Dr. Kalantar-Zadeh explained, conservative management has its pros and cons, compared with dialysis. “Conservative management requires that patients work with the multidisciplinary team including nephrologists, nutritionists, and others to try to manage CKD without dialysis, so it requires patient participation.”

On the other hand, dialysis is both easier and more lucrative than conservative management, at least for nephrologists, as they are well-trained in dialysis care, and it can be systematically applied. As to which patients with CKD might be optimal candidates for conservative management, Dr. Kalantar-Zadeh agreed this requires further study.

But he acknowledged that most nephrologists are not hugely supportive of conservative management because they are less well-trained in it, and it is more time-consuming. The one promising change is a new model introduced in 2022, a value-based kidney care model, that, if implemented, will be more incentivizing for nephrologists to offer conservative care more widely.

Dr. Davison meanwhile believes the “vast majority” of nephrologists based in Canada – as she is – are “highly supportive” of CKM as an important modality.

“The challenge, however, is that many nephrologists remain unsure as to how to best deliver or optimize all aspects of CKM, whether that is symptom management, advanced care planning, or how they must manage symptoms to align with a patient’s goals,” Dr. Davison explained.

“But it’s not that they do not believe in the value of CKM.”

Indeed, in her province, Alberta, nephrologists have been offering CKM for decades, and while they are currently standardizing care to make it easier to deliver, there is no financial incentive to offer dialysis over CKM.

“We are now seeing those elements of kidney supportive care as part of core competencies to manage any person with chronic illness, including CKD,” Dr. Davison said.

“So it’s absolutely doable, and contrary to one of the myths about CKM, it is not more time-consuming than dialysis – not when you know how to do it. You are just shifting your focus,” she emphasized.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases. Dr. Kalantar-Zadeh has reported receiving honoraria and medical directorship fees from Fresenius and DaVita. Dr. Davison has reported no relevant financial relationships.

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

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

PHILADELPHIA – Prednisone appears to have the edge over colchicine for control of pain in patients with acute calcium pyrophosphate (CPP) crystal arthritis, an intensely painful rheumatic disease primarily affecting older patients.

Among 111 patients with acute CPP crystal arthritis randomized to receive either prednisone or colchicine for control of acute pain in a multicenter study, 2 days of therapy with the oral agents provided equivalent pain relief on the second day, and patients generally tolerated each agent well, reported Tristan Pascart, MD, from the Groupement Hospitalier de l’Institut Catholique de Lille (France).

Neil Osterweil/MDedge News

“Almost three-fourths of patients are considered to be good responders to both drugs on day 3, and, maybe, safety is the key issue distinguishing the two treatments: Colchicine was generally well tolerated, but even with this very short time frame of treatment, one patient out of five had diarrhea, which is more of a concern in this elderly population at risk of dehydration,” he said in an oral abstract session at the annual meeting of the American College of Rheumatology.

In contrast, only about 6% of patients assigned to prednisone had diarrhea, and other adverse events that occurred more frequently with the corticosteroid, including hypertension, hyperglycemia, and insomnia all resolved after the therapy was stopped.
 

Common and acutely painful

Acute CPP crystal arthritis is a common complication that often occurs during hospitalization for primarily nonrheumatologic causes, Dr. Pascart said, and “in the absence of clinical trials, the management relies on expert opinion, which stems from extrapolated data from gap studies” primarily with prednisone or colchicine, Dr. Pascart said.

To fill in the knowledge gap, Dr. Pascart and colleagues conducted the COLCHICORT study to evaluate whether the two drugs were comparable in efficacy and safety for control of acute pain in a vulnerable population.

The multicenter, open-label trial included patients older than age 65 years with an estimated glomerular filtration rate above 30 mL/min per 1.73 m² who presented with acute CPP deposition arthritis with symptoms occurring within the previous 36 hours. CPP arthritis was defined by the identification of CPP crystals on synovial fluid analysis or typical clinical presentation with evidence of chondrocalcinosis on x-rays or ultrasound.

Patients with a history of gout, cognitive decline that could impair pain assessment, or contraindications to either of the study drugs were excluded.

The participants were randomized to receive either colchicine 1.5 mg (1 mg to start, then 0.5 mg one hour later) at baseline and then 1 mg on day 1, or oral prednisone 30 mg at baseline and on day 1. The patients also received 1 g of systemic acetaminophen, and three 50-mg doses of tramadol during the first 24 hours.

Of the 111 patients randomized, 54 were assigned to receive prednisone, and 57 were assigned to receive colchicine. Baseline characteristics were similar between the groups, with a mean age of about 86 years, body mass index of around 25 kg/m², and blood pressure in the range of 130/69 mm Hg.

For nearly half of all patients in study each arm the most painful joint was the knee, followed by wrists and ankles.

There was no difference between the groups in the primary efficacy outcome of a change at 24 hours over baseline in visual analog scale (VAS) (0-100 mm) scores, either in a per-protocol analysis or modified intention-to-treat analysis. The mean change in VAS at 24 hours in the colchicine group was –36.6 mm, compared with –37.7 mm in the prednisone group. The investigators had previously determined that any difference between the two drugs of less than 13 mm on pain VAS at 24 hours would meet the definition for equivalent efficacy.

In both groups, a majority of patients had either an improvement greater than 50% in pain VAS scores and/or a pain VAS score less than 40 mm at both 24 and 48 hours.

At 7 days of follow-up, 21.8% of patients assigned to colchicine had diarrhea, compared with 5.6% of those assigned to prednisone. Adverse events occurring more frequently with prednisone included hyperglycemia, hypertension, and insomnia.

Patients who received colchicine and were also on statins had a trend toward a higher risk for diarrhea, but the study was not adequately powered to detect an association, and the trend was not statistically significant, Dr. Pascart said.

“Taken together, safety issues suggest that prednisone should be considered as the first-line therapy in acute CPP crystal arthritis. Future research is warranted to determine factors increasing the risk of colchicine-induced diarrhea,” he concluded.
 

Both drugs are used

Sara K. Tedeschi, MD, from Brigham & Women’s Hospital in Boston, who attended the session where the data were presented, has a special clinical interest in CPP deposition disease. She applauded Dr. Pascart and colleagues for conducting a rare clinical trial in CPP crystal arthritis.

In an interview, she said that the study suggests “we can keep in mind shorter courses of treatment for acute CPP crystal arthritis; I think that’s one big takeaway from this study.”

Asked whether she would change her practice based on the findings, Dr. Tedeschi replied: “I personally am not sure that I would be moved to use prednisone more than colchicine; I actually take away from this that colchicine is equivalent to prednisone for short-term use for CPP arthritis, but I think it’s also really important to note that this is in the context of quite a lot of acetaminophen and quite a lot of tramadol, and frankly I don’t usually use tramadol with my patients, but I might consider doing that, especially as there were no delirium events in this population.”

Dr. Tedeschi was not involved in the study.

Asked the same question, Michael Toprover, MD, from New York University Langone Medical Center, a moderator of the session who was not involved in the study, said: “I usually use a combination of medications. I generally, in someone who is hospitalized in particular and is in such severe pain, use a combination of colchicine and prednisone, unless I’m worried about infection, in which case I’ll start colchicine until we’ve proven that it’s CPPD, and then I’ll add prednisone.”

The study was funded by PHRC-1 GIRCI Nord Ouest, a clinical research program funded by the Ministry of Health in France. Dr. Pascart, Dr. Tedeschi, and Dr. Toprover all reported having no relevant conflicts of interest.

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

CHICAGO – Renal denervation, relative to a sham procedure, was linked with statistically significant reductions in blood pressure in the newly completed SPYRAL HTN–ON MED trial, but several factors are likely to have worked in concert to prevent the study from meeting its primary endpoint.

Of these differences, probably none was more important than the substantially higher proportion of patients in the sham group that received additional BP-lowering medications over the course of the study, David E. Kandzari, MD, reported at the American Heart Association scientific sessions.

Ted Bosworth/MDedge News

The SPYRAL HTN–ON MED pivotal trial followed the previously completed SPYRAL HTN–ON MED pilot study, which did show a significant BP-lowering effect on antihypertensive medications followed radiofrequency denervation. In a recent update of the pilot study, the effect was persistent out to 3 years.

In the SPYRAL HTN–ON MED program, patients on their second screening visit were required to have a systolic pressure of between 140 and 170 mm Hg on 24-hour ambulatory BP monitoring (ABPM) while taking up to three antihypertensive medications. Patients who entered the study were randomized to renal denervation or sham control while maintaining their baseline antihypertensive therapies.

The previously reported pilot study comprised 80 patients. The expansion pivotal trial added 257 more patients for a total cohort of 337 patients. The primary efficacy endpoint was based on a Bayesian analysis of change in 24-hour systolic ABPM at 6 months for those in the experimental arm versus those on medications alone. Participants from both the pilot and pivotal trials were included.

The prespecified definition of success for renal denervation was a 97.5% threshold for probability of superiority on the basis of this Bayesian analysis. However, the Bayesian analysis was distorted by differences in the pilot and expansion cohorts, which complicated the superiority calculation. As a result, the analysis only yielded a 51% probability of superiority, a level substantially below the predefined threshold.

Despite differences seen in BP control in favor of renal denervation, several factors were identified that likely contributed to the missed primary endpoint. One stood out.

“Significant differences in medication prescriptions were disproportionate in favor of the sham group,” reported Dr. Kandzari, chief of Piedmont Heart Institute, Atlanta. He said these differences, which were a violation of the protocol mandate, led to a “bias toward the null” for the primary outcome.

The failure to meet the primary outcome was particularly disappointing in the wake of the favorable pilot study and the SPYRAL HTN–OFF MED pivotal trial, which were both positive.

In the pilot study, which did not have a medication imbalance, a 7.3–mm Hg reduction (P = .004) in 24-hour ABPM was seen at 6 months. Relative reductions in office-based systolic pressure reductions for renal denervation versus sham were 6.6 mm Hg (P = .03) and 4.0 mm Hg (P = .03) for the pilot and expansions groups, respectively.

On the basis of a Win ratio derived from a hierarchical analysis of ABMP and medication burden reduction, the 1.50 advantage (P = .005) for the renal denervation arm in the newly completed SPYRAL HTN–ON MED trial was also compelling.

At study entry, the median number of medications was 1.9 in both the renal denervation and sham arms. At the end of 6 months, the median number of medications was unchanged in the experimental arm but rose to 2.1 (P = .01) in the sham group. Similarly, there was little change in the medication burden from the start to the end of the trial in the denervation group (2.8 vs. 3.0), but a statistically significant change in the sham group (2.9 vs. 3.5; P = .04).

Furthermore, the net percentage change of patients receiving medications favoring BP reduction over the course of the study did not differ between the experimental and control arms of the pilot cohort, but was more than 10 times higher among controls in the expansion group (1.9% vs. 21.8%; P < .0001).

Medication changes over the course of the SPYRAL HTN–ON MED trial were even greater in some specific subgroups. Among Black participants, for example, 14.2% of those randomized to renal denervation and 54.6% of those randomized to the sham group increased their antihypertensive therapies over the course of the study.

The COVID-19 epidemic is suspected of playing another role in the negative results, according to Dr. Kandzari. After a brief pause in enrollment, the SPYRAL HTN–ON MED trial was resumed, but approximately 80% of the expansion cohort data were collected during this period. When compared, variances in office and 24-hour ABPM were observed for participants who were or were not evaluated during COVID.

“Significant differences in 24-hour ABPM patterns pre- and during COVID may reflect changes in patient behavior and lifestyle,” Dr. Kandzari speculated.

The data from this study differ from essentially all of the other studies in the SPYRAL HTN program as well as several other sham-controlled studies with renal denervation, according to Dr. Kandzari.

Ted Bosworth/MDedge News

The AHA-invited discussant, Ajay J. Kirtane, MD, director of the Cardiac Catheterization Laboratories at Columbia University, New York, largely agreed that several variables appeared to conspire against a positive result in this trial, but he zeroed in on the imbalance of antihypertensive medications.

“Any trial that attempts to show a difference between renal denervation and a sham procedure must insure that antihypertensive medications are the same in the two arms. They cannot be different,” he said.

As an active investigator in the field of renal denervation, Dr. Kirtane thinks the evidence does support a benefit from renal denervation, but he believes data are still needed to determine which patients are candidates.

“Renal denervation is not going to be a replacement for previous established therapies, but it will be an adjunct,” he predicted. The preponderance of evidence supports clinically meaningful reductions in BP with this approach, “but we need to determine who to consider [for this therapy] and to have realistic expectations about the degree of benefit.”

Dr. Kandzari reported financial relationships with Abbott Vascular, Ablative Solutions, Biotronik, Boston Scientific, CSI, Medtronic Cardiovascular, OrbusNeich, and Teleflex. Dr. Kirtane reported financial relationships with Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems, Cathworks, Chiesi, Medtronic, Opens, Philipps, Regeneron, ReCor Medical, Siemens, Spectranetics, and Zoll.
 

PHILADELPHIA – Women with spondyloarthritis (SpA) who are desiring pregnancy may want to consider decreasing use or discontinuing use (with supervision) of nonsteroidal anti-inflammatory drugs before conception, new data suggest.

Researchers have found a connection between NSAID use and age and a significantly longer time to conception among women with spondyloarthritis. Sabrina Hamroun, MMed, with the rheumatology department at the University Hospital Cochin, Paris, presented the findings during a press conference at the annual meeting of the American College of Rheumatology.

Subfertility group took an average of 16 months to get pregnant

Subfertility was observed in 40 (45.4%) of the women, with an average time to conception of 16.1 months. A woman was considered subfertile if her time to conception was more than 12 months or if she did not become pregnant.

The average preconception Bath Ankylosing Spondylitis Disease Activity Index score was 2.9 (+/- 2.1), the authors noted. The average age of the participants was 32 years.

Twenty-three patients were treated with NSAIDs, eight with corticosteroids, 12 with conventional synthetic disease-modifying antirheumatic drugs, and 61 with biologics.

Researchers adjusted for factors including age, body mass index, disease duration and severity, smoking, form of SpA (axial, peripheral, or both), and medication in the preconception period.

They found significant associations between longer time to conception and age (hazard ratio, 1.22; 95% confidence interval, 1.08-1.40; P < .001), and a much higher hazard ratio with the use of NSAIDs during preconception (HR, 3.01; 95% CI, 2.15-3.85; P = .01).

Some data unavailable

Ms. Hamroun acknowledged that no data were available on the frequency of sexual intercourse or quality of life, factors that could affect time to conception. Women were asked when they discontinued contraceptive use and actively began trying to become pregnant.

She stated that information on the dose of NSAIDs used by the patients was incomplete, noting, “We were therefore unable to adjust the results of our statistical analyses on the dose used by patients.”

Additionally, because the study participants were patients at tertiary centers in France and had more severe disease, the results may not be generalizable to all women of childbearing age. Patients with less severe SpA are often managed in outpatient settings in France, she said.

When asked about alternatives to NSAIDs, Ms. Hamroun said that anti–tumor necrosis factor agents with low placental passage may be a good alternative “if a woman with long-standing difficulties to conceive needs a regular use of NSAIDs to control disease activity, in the absence of any other cause of subfertility.”

The patient’s age must also be considered, she noted.

“A therapeutic switch may be favored in a woman over 35 years of age, for example, whose fertility is already impaired by age,” Ms. Hamroun said.

As for the mechanism that might explain the effects of NSAIDs on conception, Ms. Hamroun said that prostaglandins are essential to ovulation and embryo implantation and explained that NSAIDs may work against ovulation and result in poor implantation (miscarriage) by blocking prostaglandins.

She pointed out that her results are in line with the ACR’s recommendation to discontinue NSAID use during the preconception period in women with SpA who are having difficulty conceiving.
 

Control before conception is important

Sinead Maguire, MD, a clinical and research fellow in the Spondylitis Program at Toronto (Ont.) Western Hospital who was not part of the study, said the study highlights the importance of optimizing disease control before conception.

“There are a number of things rheumatologists can do to support our SpA patients when they are trying to conceive,” she told this news organization. “One of the most important issues to address is ensuring their SpA is in remission and continues to remain so. For that reason, if a woman is requiring regular NSAIDs for symptom control, the results of this study might encourage me to consider a biologic agent sooner to ensure remission.”

She urged women who want to become pregnant to discuss medications with their rheumatologist before trying to conceive.

“It is very exciting to see studies such as this so that rheumatologists can provide answers to our patients’ questions with evidence-based advice,” she said.

Ms. Hamroun and several coauthors had no disclosures. Other coauthors disclosed relationships with companies including Merck/MSD, Novartis, Janssen, AbbVie/Abbott, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, Eli Lilly, Novartis, and/or UCB. Dr. Maguire reports no relevant financial relationships.

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

PHILADELPHIA – Women with spondyloarthritis (SpA) who are desiring pregnancy may want to consider decreasing use or discontinuing use (with supervision) of nonsteroidal anti-inflammatory drugs before conception, new data suggest.

Researchers have found a connection between NSAID use and age and a significantly longer time to conception among women with spondyloarthritis. Sabrina Hamroun, MMed, with the rheumatology department at the University Hospital Cochin, Paris, presented the findings during a press conference at the annual meeting of the American College of Rheumatology.

Subfertility group took an average of 16 months to get pregnant

Subfertility was observed in 40 (45.4%) of the women, with an average time to conception of 16.1 months. A woman was considered subfertile if her time to conception was more than 12 months or if she did not become pregnant.

The average preconception Bath Ankylosing Spondylitis Disease Activity Index score was 2.9 (+/- 2.1), the authors noted. The average age of the participants was 32 years.

Twenty-three patients were treated with NSAIDs, eight with corticosteroids, 12 with conventional synthetic disease-modifying antirheumatic drugs, and 61 with biologics.

Researchers adjusted for factors including age, body mass index, disease duration and severity, smoking, form of SpA (axial, peripheral, or both), and medication in the preconception period.

They found significant associations between longer time to conception and age (hazard ratio, 1.22; 95% confidence interval, 1.08-1.40; P < .001), and a much higher hazard ratio with the use of NSAIDs during preconception (HR, 3.01; 95% CI, 2.15-3.85; P = .01).

Some data unavailable

Ms. Hamroun acknowledged that no data were available on the frequency of sexual intercourse or quality of life, factors that could affect time to conception. Women were asked when they discontinued contraceptive use and actively began trying to become pregnant.

She stated that information on the dose of NSAIDs used by the patients was incomplete, noting, “We were therefore unable to adjust the results of our statistical analyses on the dose used by patients.”

Additionally, because the study participants were patients at tertiary centers in France and had more severe disease, the results may not be generalizable to all women of childbearing age. Patients with less severe SpA are often managed in outpatient settings in France, she said.

When asked about alternatives to NSAIDs, Ms. Hamroun said that anti–tumor necrosis factor agents with low placental passage may be a good alternative “if a woman with long-standing difficulties to conceive needs a regular use of NSAIDs to control disease activity, in the absence of any other cause of subfertility.”

The patient’s age must also be considered, she noted.

“A therapeutic switch may be favored in a woman over 35 years of age, for example, whose fertility is already impaired by age,” Ms. Hamroun said.

As for the mechanism that might explain the effects of NSAIDs on conception, Ms. Hamroun said that prostaglandins are essential to ovulation and embryo implantation and explained that NSAIDs may work against ovulation and result in poor implantation (miscarriage) by blocking prostaglandins.

She pointed out that her results are in line with the ACR’s recommendation to discontinue NSAID use during the preconception period in women with SpA who are having difficulty conceiving.
 

Control before conception is important

Sinead Maguire, MD, a clinical and research fellow in the Spondylitis Program at Toronto (Ont.) Western Hospital who was not part of the study, said the study highlights the importance of optimizing disease control before conception.

“There are a number of things rheumatologists can do to support our SpA patients when they are trying to conceive,” she told this news organization. “One of the most important issues to address is ensuring their SpA is in remission and continues to remain so. For that reason, if a woman is requiring regular NSAIDs for symptom control, the results of this study might encourage me to consider a biologic agent sooner to ensure remission.”

She urged women who want to become pregnant to discuss medications with their rheumatologist before trying to conceive.

“It is very exciting to see studies such as this so that rheumatologists can provide answers to our patients’ questions with evidence-based advice,” she said.

Ms. Hamroun and several coauthors had no disclosures. Other coauthors disclosed relationships with companies including Merck/MSD, Novartis, Janssen, AbbVie/Abbott, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, Eli Lilly, Novartis, and/or UCB. Dr. Maguire reports no relevant financial relationships.

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

PHILADELPHIA – Women with spondyloarthritis (SpA) who are desiring pregnancy may want to consider decreasing use or discontinuing use (with supervision) of nonsteroidal anti-inflammatory drugs before conception, new data suggest.

Researchers have found a connection between NSAID use and age and a significantly longer time to conception among women with spondyloarthritis. Sabrina Hamroun, MMed, with the rheumatology department at the University Hospital Cochin, Paris, presented the findings during a press conference at the annual meeting of the American College of Rheumatology.

Subfertility group took an average of 16 months to get pregnant

Subfertility was observed in 40 (45.4%) of the women, with an average time to conception of 16.1 months. A woman was considered subfertile if her time to conception was more than 12 months or if she did not become pregnant.

The average preconception Bath Ankylosing Spondylitis Disease Activity Index score was 2.9 (+/- 2.1), the authors noted. The average age of the participants was 32 years.

Twenty-three patients were treated with NSAIDs, eight with corticosteroids, 12 with conventional synthetic disease-modifying antirheumatic drugs, and 61 with biologics.

Researchers adjusted for factors including age, body mass index, disease duration and severity, smoking, form of SpA (axial, peripheral, or both), and medication in the preconception period.

They found significant associations between longer time to conception and age (hazard ratio, 1.22; 95% confidence interval, 1.08-1.40; P < .001), and a much higher hazard ratio with the use of NSAIDs during preconception (HR, 3.01; 95% CI, 2.15-3.85; P = .01).

Some data unavailable

Ms. Hamroun acknowledged that no data were available on the frequency of sexual intercourse or quality of life, factors that could affect time to conception. Women were asked when they discontinued contraceptive use and actively began trying to become pregnant.

She stated that information on the dose of NSAIDs used by the patients was incomplete, noting, “We were therefore unable to adjust the results of our statistical analyses on the dose used by patients.”

Additionally, because the study participants were patients at tertiary centers in France and had more severe disease, the results may not be generalizable to all women of childbearing age. Patients with less severe SpA are often managed in outpatient settings in France, she said.

When asked about alternatives to NSAIDs, Ms. Hamroun said that anti–tumor necrosis factor agents with low placental passage may be a good alternative “if a woman with long-standing difficulties to conceive needs a regular use of NSAIDs to control disease activity, in the absence of any other cause of subfertility.”

The patient’s age must also be considered, she noted.

“A therapeutic switch may be favored in a woman over 35 years of age, for example, whose fertility is already impaired by age,” Ms. Hamroun said.

As for the mechanism that might explain the effects of NSAIDs on conception, Ms. Hamroun said that prostaglandins are essential to ovulation and embryo implantation and explained that NSAIDs may work against ovulation and result in poor implantation (miscarriage) by blocking prostaglandins.

She pointed out that her results are in line with the ACR’s recommendation to discontinue NSAID use during the preconception period in women with SpA who are having difficulty conceiving.
 

Control before conception is important

Sinead Maguire, MD, a clinical and research fellow in the Spondylitis Program at Toronto (Ont.) Western Hospital who was not part of the study, said the study highlights the importance of optimizing disease control before conception.

“There are a number of things rheumatologists can do to support our SpA patients when they are trying to conceive,” she told this news organization. “One of the most important issues to address is ensuring their SpA is in remission and continues to remain so. For that reason, if a woman is requiring regular NSAIDs for symptom control, the results of this study might encourage me to consider a biologic agent sooner to ensure remission.”

She urged women who want to become pregnant to discuss medications with their rheumatologist before trying to conceive.

“It is very exciting to see studies such as this so that rheumatologists can provide answers to our patients’ questions with evidence-based advice,” she said.

Ms. Hamroun and several coauthors had no disclosures. Other coauthors disclosed relationships with companies including Merck/MSD, Novartis, Janssen, AbbVie/Abbott, Amgen, AstraZeneca, Biogen, Bristol-Myers Squibb, Galapagos, Eli Lilly, Novartis, and/or UCB. Dr. Maguire reports no relevant financial relationships.

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

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.

PHILADELPHIA – Combining the immunomodulatory agent mycophenolate with the antifibrotic pirfenidone led to more rapid improvement and showed a trend to be more effective than mycophenolate mofetil alone for treating the signs and symptoms of scleroderma-related interstitial lung disease, but the combination therapy came with an increase in side effects, according to results from the Scleroderma Lung Study III.

Dinesh Khanna, MBBS, MSc, of the University of Michigan, Ann Arbor, presented the results at the annual meeting of the American College of Rheumatology. He noted some problems with the study – namely its small size, enrolling only 51 patients, about one-third of its original goal. But he also said it showed a potential signal for efficacy and that the study itself could serve as a “template” for future studies of combination mycophenolate mofetil (MMF) plus pirfenidone therapy for scleroderma-related interstitial lung disease (SSc-ILD).

“The pirfenidone patients had quite a bit more GI side effects and photosensitivity, and those are known side effects,” Dr. Khanna said in an interview. “So the combination therapy had more side effects but trends to higher efficacy.”

The design of SLS-III, a phase 2 clinical trial, was a challenge, Dr. Khanna explained. The goal was to enroll 150 SSc-ILD patients who hadn’t had any previous treatment for their disease. Finding those patients proved difficult. “In fact, if you look at the recent history, 70% of the patients with early diffuse scleroderma are on MMF,” he said in his presentation. Compounding low study enrollment was the intervening COVID-19 pandemic, he added.
 

Testing a faster-acting combination

Nonetheless, the trial managed to enroll 27 patients in the combination therapy group and 24 in the MMF-plus-placebo group and compared their outcomes over 18 months. Study dosing was 1,500 mg MMF twice daily and pirfenidone 801 mg three times daily, titrated to the tolerable dose.

Despite the study’s being underpowered, Dr. Khanna said, it still reported some notable outcomes that merit further investigation. “I think what was intriguing in the study was the long-term benefit in the patient-reported outcomes and the structural changes,” he said in the interview.

Among those notable outcomes was a clinically significant change in forced vital capacity (FVC) percentage for the combination vs. the placebo groups: 2.24% vs. 2.09%. He also noted that the combination group saw a somewhat more robust improvement in FVC at six months: 2.59% (± 0.98%) vs. 0.92% (± 1.1%) in the placebo group.

The combination group showed greater improvements in high-resolution computed tomography-evaluated lung involvement and lung fibrosis and patient-reported outcomes, including a statistically significant 3.67-point greater improvement in PROMIS-29 physical function score (4.42 vs. 0.75).

The patients on combination therapy had higher rates of serious adverse events (SAEs), and seven discontinued one or both study drugs early, all in the combined arm. Four combination therapy patients had six SAEs, compared to two placebo patients with three SAEs. In the combination group, SAEs included chest pain, herpes zoster ophthalmicus, nodular basal cell cancer, marginal zone B cell lymphoma, renal crisis, and dyspnea. SAEs in the placebo group were colitis, COVID-19 and hypoxic respiratory failure.

Study design challenges

Nonetheless, Dr. Khanna said the SLS-III data are consistent with the SLS-II findings, with mean improvements in FVC of 2.24% and 2.1%, respectively.

“The next study may be able to replicate what we tried to do, keeping in mind that there are really no MMF-naive patients who are walking around,” Dr. Khanna said. “So the challenge is about the feasibility of recruiting within a trial vs. trying to show a statistical difference between the drug and placebo.”

This study could serve as a foundation for future studies of MMF in patients with SSc-ILD, Robert Spiera, MD, of the Hospital for Special Surgery in New York, said in an interview. “There are lessons to be learned both from the study but also from prior studies looking at MMF use in the background in patients treated with other drugs in clinical trials,” he said.

Dr. Spiera noted that the study had other challenges besides the difficulty in recruiting patients who hadn’t been on MMF therapy. “A great challenge is that the benefit with regard to the impact on the lungs from MMF seems most prominent in the first 6 months to a year to even 2 years that somebody is on the drug,” he said.

The other challenge with this study is that a large proportion of patients had limited systemic disease and relatively lower levels of skin disease compared with other studies of patients on MMF, Dr. Spiera said.

“The optimal treatment of scleroderma-associated lung disease remains a very important and not-adequately met need,” he said. “Particularly, we’re looking for drugs that are tolerable in a patient population that are very prone to GI side effects in general. This study and others have taught us a lot about trial design, and I think more globally this will allow us to move this field forward.”

Dr. Khanna disclosed relationships with Actelion, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Horizon Therapeutics USA, Janssen Global Services, Prometheus Biosciences, Mitsubishi Tanabe Pharma Corp., Genentech/Roche, Theraly, and Pfizer. Genentech provided funding for the study and pirfenidone and placebo drugs at no cost.

Dr. Spiera disclosed relationships with GlaxoSmithKline, Boehringer-Ingelheim, Corbus Pharmaceutical, InflaRx, AbbVie/Abbott, Sanofi, Novartis, Chemocentryx, Roche and Vera.