Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Adding a single cycle of rituximab to belimumab (Benlysta) did not improve disease control for patients with systemic lupus erythematosus (SLE) in comparison with belimumab alone in a phase 3, randomized, controlled trial.

Among patients with SLE who were randomly assigned to receive belimumab with either rituximab, placebo, or standard care, there were no statistically significant differences between the rituximab and placebo arms for the primary endpoint of the proportion of patients with disease control at week 52 or in the secondary endpoints of clinical remission at week 64 or disease control at week 104, Cynthia Aranow, MD, reported in a late-breaking poster session presented during the virtual annual meeting of the American College of Rheumatology.

“Using a new, clinically meaningful endpoint underscores the efficacy of belimumab for disease control, with some patients maintaining disease control with considerable reductions in steroids, and no immunosuppressants,” said Dr. Aranow, a rheumatologist specializing in SLE and RA in New York and director of the Clinical Autoimmunity Center of Excellence at Feinstein Institutes for Medical Research, Manhasset, N.Y.

Use of the combination of belimumab and rituximab was, however, associated with significant improvement over belimumab and placebo in several secondary efficacy endpoints.

Investigators in the randomized, controlled trial, dubbed BLISS-BELIEVE, had previously published a rationale for sequential therapy with belimumab, a human monoclonal antibody that binds to soluble B-lymphocyte stimulator, and rituximab, a B-cell–depleting anti-CD20 monoclonal antibody.

“These biologics, which operate through complementary mechanisms, might result in an enhanced depletion of circulating and tissue-resident autoreactive B lymphocytes when administered together. Thus, belimumab and rituximab combination may be a highly effective treatment of SLE,” they wrote in an article published in 2019 in BMJ Open.
 

Three-arm trial

The investigators screened 396 patients, of whom 292 were randomly assigned in a 1:2:1 ratio to receive either subcutaneous belimumab 200 mg/wk plus intravenous placebo at weeks 4 and 6 (BEL/PBO, 72 patients), belimumab plus IV rituximab 1,000 mg at weeks 4 and 6 (BEL/RTX, 144 patients), or open-label belimumab plus standard therapy. Patients were allowed to continue taking antimalarial and nonsteroidal anti-inflammatory drugs throughout the study.

The primary disease-control endpoint was defined as a Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of 2 or less, achieved without other immunosuppression, equivalent to that achieved with prednisone 5 mg/day or less.

As noted before, there were no significant differences between the BEL/RTX and BEL/PBO arms in either disease control at week 52 or in the secondary endpoints of clinical remission at week 64 (SLEDAI-2K score, 0) or in the proportion of patients with disease control at week 104.

However, use of BEL/RTX was associated with a significantly longer duration of disease control through 52 weeks than was BEL/PBO (mean, 105.4 days vs. 60.1 days; P = .0188) and with a large SLEDAI-2K mean change from baseline at week 104 (–7.2 vs 5.1; P = .0033).

In addition, there was a trend toward a shift in proteinuria from baseline high (>0.5 g/24 h) to normal in the BEL/RTX group at week 52 and a significantly greater shift at week 104 (P = .0085).

The overall adverse event profiles were generally consistent with those of the individual agents, although serious infections and infestations occurred more frequently with BEL/RTX than BEL/PBO.
 

Further analyses planned to look for subgroups that benefit

In a poster discussion session, Akshat Khanna, PhD, of Newtown, Pa., a consultant with Effimed Life Sciences Research, asked Dr. Aranow about the rationale for giving rituximab and belimumab concurrently and noted that, in the BEAT-LUPUS and CALIBRATE trials, anti-CD20 agents were given first, followed by belimumab, to prevent activation of humoral immunity.

“The two B-cell agents were given sequentially. Belimumab was given first to maximize the effect of peripheral B-cell depletion and [was] then continued after rituximab to suppress the elevation [of B-lymphocyte stimulator] that occurs after rituximab monotherapy. We used this approach (instead of that used in CALIBRATE and BEAT LUPUS), as we thought this might be more efficacious,” she explained.

When asked whether there were subgroups of patients who might still benefit from the combination, compared with belimumab alone, Dr. Aranow replied: “There may be individual patients in which it might be considered. Further analyses of the data are ongoing/planned.”

The study was supported by GlaxoSmithKline. Dr. Aranow has received grant/research support from GlaxoSmithKline and has consulted for Bristol-Myers Squibb. Dr. Khanna has disclosed no relevant financial relationships.

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

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Breast cancer treatment often results in shoulder and arm problems, such as chronic pain, restricted shoulder movement, or lymphedema in the armpit area, limiting quality of life and delaying recovery. However, according to a U.K. study published by The BMJ on Nov. 10, women who exercised shortly after having nonreconstructive breast cancer surgery experienced less pain and regained better shoulder and arm mobility at 1 year than those who did not exercise.

“Hospitals should consider training physiotherapists in the PROSPER program to offer this structured, prescribed exercise program to women undergoing axillary clearance surgery and those having radiotherapy to the axilla,” said lead author Julie Bruce, PhD, a specialist in surgical epidemiology with the University of Warwick, Coventry, England.

Up to one-third of women experience adverse effects to their lymphatic and musculoskeletal systems after breast cancer surgery and radiotherapy targeting the axilla. A study of 2,411 women in Denmark found that pain remained for up to 7 years after breast cancer treatment. U.K. guidelines for the management of breast cancer recommend referral to physical therapy if such problems develop, but the best timing and intensity along with the safety of postoperative exercise remain uncertain. A review of the literature in 2019 found a lack of adequate evidence to support the use of postoperative exercise after breast cancer surgery. Moreover, concerns with such exercise have been reported, such as increased risks of postoperative wound complications and lymphedema.

“The study was conducted to address uncertainty whether early postoperative exercise after women at high risk of shoulder and arm problems after nonreconstructive surgery was safe, clinically, and cost-effective. Previous studies were small, and no large high-quality randomized controlled trials had been undertaken with this patient population in the U.K.,” Dr. Bruce said.

In UK PROSPER, a multicenter, randomized controlled trial, researchers investigated the effects of an exercise program compared with usual care for 392 women (mean age 58) undergoing breast cancer surgery at 17 National Health Service (NHS) cancer centers. The women were randomly assigned to usual care with structured exercise or usual care alone. Structured exercise, introduced 7-10 days postoperatively, consisted of a physical therapy–led exercise program comprising stretching, strengthening, and physical activity, along with behavioral change techniques to support exercise adherence. Two further appointments were offered 1 and 3 months later. Outcomes included upper limb function, as measured by the Disability of Arm, Hand, and Shoulder (DASH) questionnaire at 12 months, complications, health related quality of life, and cost effectiveness.

At 12 months, women in the exercise group showed improved upper limb function compared with those who received usual care (mean DASH 16.3 for exercise, 23.7 for usual care; adjusted mean difference 7.81, 95% confidence interval, 3.17-12.44; P = .001). Compared with the usual care group, women in the exercise group reported lower pain intensity, fewer arm disability symptoms, and better health related quality of life.

“We found that arm function, measured using the DASH scale, improved over time and found surprisingly, these differences between treatment groups persisted at 12 months,” Dr. Bruce said. “There was no increased risk of neuropathic pain or lymphedema, so we concluded that the structured exercise program introduced from the seventh postoperative day was safe. Strengthening exercises were introduced from 1 month postoperatively.”

While the authors noted that the study was limited as participants and physical therapists knew which treatment they were receiving, they stressed that the study included a larger sample size than that of previous trials, along with a long follow-up period.

“We know that some women develop late lymphedema. Our findings are based on follow-up at 12 months. We hope to undertake longer-term follow up of our patient sample in the future,” Dr. Bruce said.

The authors declared support from the UK National Institute for Health Research (NIHR) Technology Assessment Programme.

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

[email protected]

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

[email protected]

Just over 1.35 million children under age 12 years have received the COVID-19 vaccine since it was approved on Nov. 2, putting them behind the initial pace set by 12- to 15-year-olds in the spring, based on data from the Centers for Disease Control and Prevention.

Specific figures for children aged 5-11 years are not yet available, but CDC data show that 1.55 million children under the age of 12 years had received at least one dose of COVID-19 vaccine as of Nov. 15, of whom almost 204,000 already had been vaccinated before Nov. 2. For children aged 12-15, the first 2 weeks after approval on May 12 produced almost 2.1 million vaccine initiations, according to the CDC’s COVID Data Tracker.

That dataset reveals several other noteworthy differences between the two age groups in the 10 days after approval:
 

• There were over 7,000 vaccine initiations on the first day in the 12-15 group; the younger group had 32.
• The older children reached 100,000 per day in 3 days; the younger children took 8 days.
• The older group topped 200,000 vaccinations per day on six different days; the younger group didn’t get above 175,000.

Children under 12 made up 27.5% of vaccine initiations in all age groups during the 2 weeks from Nov. 2 to Nov. 15, versus 3.4% for 12- to 15-year-olds and 1.2% for 16- and 17-year-olds, the CDC said, while also reporting that 3.6% of children under age 12 had received at least one dose of the COVID vaccine, compared with 57.8% of those aged 12-15 and 64.4% of 16- to 17-year-olds.

Meanwhile, the first full week of November marked the second consecutive increase in the number of weekly child COVID cases, with 122,000 reported for Nov. 5-11. The number of new cases has now surpassed 100,000 for 14 consecutive weeks, the American Academy of Pediatrics and the Children’s Hospital Association said in their weekly COVID report. That report, which covers state health departments, has not included current information from Alabama, Nebraska, and Texas since the summer.

Regionally, the increases over the past 2 weeks were spread out among the East, the Midwest, and the West, while the decline that had been going on for several weeks in the South has largely come to a halt. The states with the highest percent increases over those 2 weeks are all in New England: Maine, New Hampshire, and Vermont, the AAP and CHA noted. In a separate report, the AAP said that Vermont has the second-highest child vaccination rate (81%) in the country, just behind Massachusetts (82%).

[email protected]

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

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

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

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

Giving birth may be so arduous for humans in part because the pelvis is optimized for standing upright, a new study suggests.

The study, published in BMC Biology , relies on computer-based simulations of how bone, soft tissue, and skin work in concert as we move. The same approach has been used to identify key elements of a perfect fastball in baseball and the best marathon gait.

In the new analysis, scientists used digital images to examine how bones and muscles around the pelvis move during daily activities and giving birth. Because the shape of the human pelvic canal doesn’t make for a fast or easy birth, the investigators wondered if its dimensions were linked to some other human feature.

In apes, this canal is a simple oval throughout, so labor and delivery might be easier for these species, the scientists note. But the oval in the human canal changes direction through the pelvis, requiring babies to rotate during delivery so that the head and shoulders can pass through.

Computer modeling with digital images suggested that the stress and pressure of being upright on two legs might give the pelvic canal its twist. When the researchers used a consistently oriented oval, like the one that apes have, the pelvis tilted and destabilized the spine, making it harder to balance on two legs.

Our balance might be even better with a widened outlet at the lower portion of the birth canal, the investigators found. But a wider outlet could make childbirth injuries more likely because it would require an even harder twist of the head and shoulders in the canal. The authors say that the shape of the pelvic canal could represent an “evolutionary compromise” between these competing factors.

These findings rely on computer models using digital images and don’t precisely recreate either the evolutionary or birthing process. But they do offer another feature to consider when answering the question of why human labor and delivery are so difficult, compared with our closest living cousins.

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

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

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

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

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

A recent article published in Nature Methods highlights how hierarchical phase-contrast tomography (HiP-CT), an x-ray phase propagation technique that uses spatial coherence to conduct three-dimensional scans of organs ex vivo, may offer clinicians greater insights into disease processes.

“It is not a clinical technique as such,” said Claire Walsh PhD, a biophysicist and senior research fellow at the Center for Advanced Biomedical Imaging, University College London, and one of the authors of the article. She stressed that HiP-CT is used ex vivo.

“This technology uses x-rays from a fourth-generation x-ray source, the European Synchrotron Radiation Facility’s Extremely Brilliant Source. It is an incredibly bright x-ray source,” said Dr. Walsh in an interview. She said synchrotron x-ray tomography provides a much enhanced view of the lungs of persons who had had COVID-19. “We are looking at a different property of the x-ray waves. We are looking at a phase shift. [HiP-CT] is much, much more sensitive to small changes in the tissue than x-ray or CT. Another massive advantage of HiP-CT is the resolution it offers. The resolution goes down to single cells inside an intact human organ,” she said.

The resolution permits researchers to view blood vessels 5 μm in diameter in an intact lung. In comparison, clinical CT images show blood vessels of around 1 mm in diameter – 200 times larger.

“This technique will help us understand the structure of organs at a more fundamental level,” said Dr. Walsh. She noted that the technology has been valuable in allowing greater understanding of COVID-19 disease process. “This is about building an understanding of what the disease is doing in our bodies. If we don’t understand what the disease is changing structurally, it is very hard to understand how to go about developing treatments,” she said.

There are few synchrotron radiation facilities, so this technology is not widely available. Because of the very high radiation dose, the technique will be used ex vivo for the foreseeable future, Dr. Walsh said.

“The x-ray dose is incredibly high; 2-kg normal CT scans are approximately 100 mG [milligauss]. This is 20,000 times more than a medical CT scan,” explained Dr. Walsh. “We don’t really have plans for this to become an in vivo human technique. We are aiming that we will be able to register clinical scans to HiP-CT in a few cases, and so HiP-CT will become a calibration for analyzing clinical techniques.”

Elsie T. Nguyen, MD, FRCPC, vice-president of the Canadian Society of Thoracic Radiology and associate professor of radiology, University of Toronto, noted that the technology will be valuable in pathology and radiology.

“HiP-CT appears to be an exciting new development that can help physicians, including radiologists, understand pathology that was once beyond the spatial resolution of computed tomography scans,” said Dr. Nguyen in an interview. “The fact that vascular abnormalities particularly relating to severe COVID-19 pneumonia can be visualized to the micron level is very novel and exciting. This will help us understand better from a mechanistic point of view what is happening to the blood vessels that contributes to worse outcomes, like shunting of blood or blood clots, and may have applications for prognostication to predict which patients are likely to survive severe COVID-19 pneumonia.”

Dr. Nguyen noted that HiP-CT could help thoracic radiologists better visualize honeycomb cysts associated with fibrotic interstitial lung disease (ILD). It could help to classify the type of fibrotic ILD and inform patient prognosis.

“Currently, we struggle to differentiate early honeycomb cysts, which are a sign of more advanced lung destruction, from traction bronchiolectasis, that is, dilated airways due to surrounding fibrotic lung, on high-resolution computed tomography of the lungs,” said Dr. Nguyen. She said HiP-CT was very promising and had many applications in addition to visualizing the lungs.

The research was funded by the Chan Zuckerberg Initiative, the ESRF, the UK-MRC, and the Royal Academy of Engineering. Dr. Walsh and Dr. Nguyen have disclosed no relevant financial relationships.

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

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

Additional analyses of a postmarketing trial that was required after the Food and Drug Administration’s approval of the Janus kinase inhibitor tofacitinib (Xeljanz, Xeljanz XR) has identified characteristics of older patients with rheumatoid arthritis with at least one cardiovascular risk factor who may be at higher risk for major adverse cardiovascular events (MACE) when taking the drug.

Results from the phase 3b/4 ORAL Surveillance trial presented at the virtual annual meeting of the American College of Rheumatology show that people taking tofacitinib for RA with at least one cardiovascular (CV) risk factor had a nonsignificant higher risk for MACE than did people taking tumor necrosis factor inhibitors (TNFi), with the risk from tofacitinib more pronounced in current smokers, aspirin users, people older than 65 years, and men, compared with women.

“It is the first large, randomized safety study of active RA patients with increased CV risk comparing tofacitinib to TNF inhibition,” study author Christina Charles-Schoeman, MD, said in an interview. “These data emphasize the importance of assessing baseline CV risk when treating patients with RA.” Dr. Charles-Schoeman is chief of rheumatology at the University of California, Los Angeles.

The results shed further light on the trial’s findings, which the FDA used in September 2021 to mandate boxed warnings about the risk of MI or stroke, cancer, venous thromboembolism, and death, as well as updated indications, for tofacitinib and other JAK inhibitors baricitinib (Olumiant) and upadacitinib (Rinvoq). The FDA limited all approved uses of these three medications to patients who have not responded well to TNFi to ensure their benefits outweigh their risks.

Tofacitinib is indicated for RA, psoriatic arthritis, ulcerative colitis, and polyarticular course juvenile idiopathic arthritis. Baricitinib and upadacitinib are approved only for RA.

While the overall results of the trial results show nonsignificant increased incidence rates for MACE in tofacitinib users versus TNFI users, Katherine Liao, MD, a rheumatologist at Brigham and Women’s Hospital in Boston, noted that more information is needed to determine who is at greatest risk. “Another thing to keep in mind is, while there was evidence of an elevated relative risk for MACE, compared to TNFi, the absolute risk, based on the numbers what we know so far, is small,” she said.

The trial compared two different doses of tofacitinib – 5 mg (1,455 patients) and 10 mg (n = 1,456) twice daily – and TNFi (n = 1,451) in people with moderate to severe RA over age 50. Patient characteristics were similar across all three treatment arms, Dr. Charles-Schoeman said. All patients had inadequate response to methotrexate, and about 57% in all three treatment groups were taking corticosteroids. The 10-mg tofacitinib patients switched to the 5-mg dose in February 2019 but represent the 10-mg group in the study analysis.

ORAL Surveillance demonstrated a 24% greater risk of MACE in the 5-mg tofacitinib patients and a 43% heightened risk the 10-mg group, compared with patients who received a TNFi.

The differentiating factor for MACE incidence was MI. The higher- and lower-dose tofacitinib groups had 69% and 80% greater risk for MI. While the risk for fatal MI were similar across all three treatment groups, the risk for nonfatal MI were more than doubled in the respective tofacitinib groups: hazard ratios of 2.32 and 2.08. The incidence of stroke was similar across all three arms, Dr. Charles-Schoeman said.

The study identified a number of baseline characteristics as independent overall risk factors for MACE across all treatment groups. Current smoking and aspirin use more than doubled the risk (HR, 2.18; P < .0001 and HR, 2.11; P = .004, respectively), while age greater than 65 years and male sex approached that level (HR, 1.81; P = .0011 and HR, 1.81; P = .0015) approached that level. Other factors that elevated the risk of MACE to a lesser extent were a history of diabetes, hypertension or coronary artery procedures, and a total cholesterol to HDL ratio greater than4.

Other ORAL Surveillance subanalyses and tofacitinib real-world data reported

This was one of several analyses presented at ACR 2021 that compared adverse event risks for tofacitinib versus TNFi drugs. A separate analysis of claims data from patients with RA in two U.S. insurance databases plus Medicare found a statistically nonsignificant increased risk of adverse CV outcomes (MI or stroke) with tofacitinib, compared with TNFi users, among patients who met the same inclusion and exclusion criteria of the ORAL Surveillance trial but not in a “real-world evidence” cohort of more than 102,000 patients with RA in routine care from the databases.

Two additional ORAL Surveillance analyses presented at ACR 2021 gave details about risk factors for higher rates of malignancies and venous thromboembolic events found in patients taking tofacitinib with at least one CV risk factor. As would be expected, older age (≥65 vs. 50-64 years) and current or past smoking (vs. never smoking) were independent risk factors for higher malignancy rates across all treatment arms. Pulmonary embolism events across treatment groups were independently associated with a history of venous thromboembolism, baseline use of oral contraceptives or hormone replacement therapy, baseline body mass index of at least 30 kg/m², age 65 or older, and history of hypertension.

The ORAL Surveillance findings are worth considering when determining treatments for RA patients with CV risk factors, Dr. Charles-Schoeman said. “Tofacitinib remains an effective RA treatment,” she said. “The choice of specific RA treatment for any patient remains an individual decision between the patient and physician, which is decided based on a number of different factors. This new study provides additional information regarding both tofacitinib as well as traditional CV risk factors for discussion with the patient.”

The ORAL Surveillance results may give rheumatologists reason to rethink use of tofacitinib in some patients with CV risk, said Dr. Liao of Brigham and Women’s Hospital in Boston. “Currently, we have limited data and are still awaiting a report of the full trial results,” she said in an interview. “Based on the data available, I can think of a few patients in my clinic where I would reconsider use of these drugs, i.e., history of heart attack with stable angina, especially if there are other options.” However, she noted that many patients on tofacitinib have already failed on older treatments.

These data emphasize the importance of addressing CV risk with patients, said Brittany N. Weber, MD, PhD, a cardio-rheumatologist at Brigham and Women’s Hospital who works with Dr. Liao. “It is also an opportunity to discuss modification of risk factors and to discuss primary prevention therapies, such as statin therapy, where appropriate,” she added. “Based on the individual’s cardiovascular risk, there may be a role for further risk stratification to further understand an individual’s risk, which can also inform primary prevention cardiovascular therapies and help guide these discussions.” Risk stratification could include cardiac CT for calcium scoring or cardiac coronary CT angiography for determining atherosclerotic burden.

The study was sponsored by Pfizer. Dr. Charles-Schoeman disclosed relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, Pfizer, and Regeneron-Sanofi. Dr. Liao and Dr. Weber have no relevant disclosures.

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]

A regimen of daily, low-dose aspirin failed to produce a significant reduction in the incidence of dementia or cognitive impairment in ASCEND, a randomized, multicenter trial with more than 15,000 people with diabetes followed for an average of more than 9 years, but the results hinted at enough of a benefit to warrant further study, some experts said.

jimdeli/Fotolia

A second metric used a broader outcome definition that tracked EHR entries for not only dementia but also diagnoses of cognitive impairment, delirium, confusion, prescription of dementia medications, and referral to a memory clinic or geriatric psychiatry. The third assessment was a cognitive-function test given to participants at the end of follow-up, but only 58% of enrolled participants completed this part of the study, and it’s also possible that some subjects missed this assessment because of dementia onset. These limitations hamper clear interpretation of this third metric, Dr. Armitage said.

The main findings for the other two, more reliable measures of incident dementia or cognitive deterioration showed a nonsignificant 9% relative risk reduction linked with aspirin use compared with placebo for the more inclusive endpoint, and a nonsignificant 11% relative risk reduction with aspirin using the narrow definition for dementia only, she reported. The third method, a directly administered assessment of dementia and cognition, also showed a small, nonsignificant effect from daily aspirin use relative to placebo.

Results can’t rule out modest aspirin effect

Dr. Armitage highlighted that the two more reliable measures both appeared to rule out risk for neurologic harm from aspirin because the upper limit of the 95% confidence interval for relative effect reached only 1.02 using the broad outcomes, and 1.06 for the narrower endpoint of dementia only. On the other hand, focus on the low end of the 95% confidence interval suggested potentially meaningful benefits, with a possible reduction by aspirin in events relative to placebo of as much as 19% by the broad outcome definition and by 25% with the narrow definition.

“Even if it was only a 15% relative risk reduction, that would be important,” given the high dementia incidence worldwide, Dr. Armitage said during a press briefing. “It’s entirely possible, with our results, that a modest benefit exists.”

This take on the findings won some support. Further studies with more people, longer follow-up, and perhaps enrolling a more selected, higher risk cohort may better address potential neurologic benefit from aspirin, suggested Amytis Towfighi, MD, a stroke neurologist and professor of neurology at the University of Southern California, Los Angeles, and a designated discussant for the report.

The result “was rather encouraging. I was a little surprised” by the findings, commented Chrystie M. Ballantyne, MD, professor and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine, Houston, also a discussant.

The results “don’t mean that no one benefits from aspirin. Perhaps certain people at risk would benefit from dementia protection. It’s an open question,” commented Erin D. Michos, MD, director of Women’s Cardiovascular Health at Johns Hopkins Medicine, Baltimore.

Evidence against routine, widespread primary prevention with aspirin

ASCEND had the primary goal of assessing a daily, 100-mg aspirin dose for its safety and efficacy for preventing vascular events such as MIs and ischemic strokes in 15,480 people with diabetes who were at least 40 years old at enrollment and had no history of cardiovascular disease. The main results came out in 2018 and showed that while aspirin produced a significant benefit by reducing thrombotic events, it also resulted in significantly more major bleeding events compared with placebo, and overall the magnitude of benefit roughly matched magnitude of risk.

These findings, along with similar results from two other high-profile aspirin studies reported at about the same time (ASPREE, and ARRIVE), led to recommendations from groups like the U.S. Preventive Services Task Force and from the American College of Cardiology and American Heart Association that caution against widespread, routine aspirin use for primary prevention of atherosclerotic cardiovascular disease events in most adults.

The groups instead endorsed a tailored strategy of targeting aspirin to people with a higher than average risk for ischemic thrombotic events and a lower than average bleeding risk. (The most recent aspirin recommendations from the USPSTF, currently in draft form, substantially curtail aspirin’s appropriate use, eliminating it in those over age 60 years.)

However, experts and prevailing practice recommendations continue to endorse routine aspirin use for secondary prevention in patients with an established history of cardiovascular disease.

The new findings reported by Dr. Armitage came from additional analyses of dementia and cognitive impairment overlaid on the main ASCEND outcome analyses. ASCEND actively treated and followed study participants for an average of 7.4 years, then researchers tracked further dementia outcomes based on medical-record entries for an average of another 1.8 years.

ASCEND received partial funding or support from Abbott, Bayer, Mylan, and Solvay. Dr. Armitage had no disclosures. Dr. Towfighi, Dr. Khera, and Dr. Michos had no disclosures. Dr. Ballantyne has had financial relationships with numerous companies.

[email protected]

If you are a psychiatrist who has done a public lecture in the past year, you likely encountered the question, “What about Britney’s conservatorship?” Many psychiatrists are far removed from conservatorship evaluations, doing the different yet still important work of alleviating mental suffering without paddling in the controversial waters of involuntary treatment. Others judiciously hide behind the veil of the prudent Goldwater Rule in avoiding such discussions altogether. Regardless of whether psychiatry attempts to stay out of such affairs publicly, our field remains intimately involved in the process itself. This can lead to negative views of psychiatry among the public – that of a medical specialty with ulterior motives operating at the behest of the state.

Some psychiatrists simplistically advocate against any form of involuntary treatment.¹ In many ways, this may appear noble. However, the reality of mental illness, with its potential harm to self and others, introduces the potential for dire consequences of such a position. If society is unwilling to accept behavior that may lead to harm, but psychiatry is unwilling to intervene, then other avenues of restricting such behavior will emerge. Those avenues traditionally have included conscription of law enforcement and the incarceration of patients with mental illness.

Yet, therein lies the conundrum of Ms. Spears and other celebrities on conservatorship. At face value, they do not appear to require conservatorship. We do not think it violates the Goldwater Rule to render this observation. In fact, it may reassure the public if the American Psychiatric Association, as well as individual psychiatrists, were more open about the goal, intent, and limitations of conservatorships.

The process of establishing conservatorships is not driven solely by mental health professionals. Rather, conservatorship laws permit society to enact, through psychiatrists, its desire to alleviate behaviors considered unacceptable in the context of mental illness.

In California, it has resulted in our famous or infamous “5150,” which asks psychiatrists to comment on the danger to self, danger to others, and grave disability of our patients. It can be helpful to frame these criteria regarding the relationship between society and our patients. The criteria of danger to self represents society’s wish to intervene in cases of patients with imminent intent of self-harm, operating under the presumption that a suicide can be prevented. Danger to others represents the societal angst, at times exaggerated,² about people with mental illness perpetuating homicides, especially when off their medication. Grave disability represents public shame at the thought of persons so lost to mental illness they are unable to provide for themselves or even accept food, clothing, and shelter.

While an involuntary hold is necessary at times, working against our patients engenders revolting feelings. We often rationalize involuntary holds as illustrative of sincere compassion for our patients’ suffering and an attempt to lift them out of such tragic conditions. Our patients regularly do not feel our compassion when we are making an argument in a hearing for the restriction of their rights. They see our efforts as an attempt to lock them away “for their own good” because of society’s discomfort with homelessness. As such, we wonder whether our role becomes one of doctors for society, prescribing a treatment for the emotional distress of the community, and at times for ourselves, rather than that of the patient.

One may be perplexed as to how a celebrity could be considered gravely disabled. Celebrities generally have enough income to afford food, clothing, and shelter. One could justifiably ask why an individual with no history of violence would be considered a danger to others. Similarly, one may wonder how, in the absence of any reported attempts to engage in self-harm, with no visible marks of self-harm, someone is determined to be a danger to himself or herself. The bafflement on the part of one on the outside of these determinations can be sharply contrasted by the desperation felt by family members whose loved ones with mental illness appear to meet those criteria yet are consistently turned away by mental health programs and hospitals.

Not uncommonly, it is families advocating for involuntary hospitalization – while lamenting our strict criteria – that prevent doctors from intervening until some tragic fate befalls their loved ones. They criticize what they consider to be too-stringent mental health laws and are infuriated by seemingly obtuse insurance policies limiting care to patients. Most of our colleagues working with those who have severe mental illness share the frustration of these families over the scarcity of psychiatry beds. Therefore, it is particularly shocking when the most mediatized story about conservatorship is not about how hard it is to obtain. The story is about a singer who was seemingly safe, caring for herself, and yet still ended up on a conservatorship.

We wonder whether there is a question of magnitude. Are homeless patients more difficult to place on conservatorship because society sees a lesser stake? One could argue that Ms. Spears and other celebrities would have so much to lose in a single episode of mental illness. A week with mania or psychosis could cause irreparable damage to their persona, opportunity for employment, and their fortune. On the contrary, many of our patients on conservatorship have little to their names, and no one keeping up on their reputation. Triers of facts should ask themselves about the nature of their motivations. Envy, a desire to live vicariously through celebrities, or even less ethical motivations – such as a desire to control and exert authority over those individuals – can influence our decisions.

Throughout the past year, when asked about Ms. Spears, we have pointed out the obvious – she seemingly has a life incompatible with meeting criteria for a psychiatric conservatorship. We have outlined the role, history, and limitations of psychiatric conservatorship. We have shared how such cases are often approached, when required for our own patients or when asked by the court to do so. We have discussed the significant oversight of the system, including the public conservator’s office, which frequently refuses petitions outright. There are hearing officers, who, in the early stages of this process, weigh our case against that of the patients, aided by passionately driven patient advocates. There is the public defender’s office, which, at least in San Diego, vigorously defends the rights of those with mental illness. Most importantly, there are judges who adjudicate those cases with diligence and humility.

As the story has continued to be in the news, we have had numerous conversations about Ms. Spears’ conservatorship with colleagues sharing strong opinions on her case. Many of these colleagues do not have forensic practices and we inevitably find ourselves responding along the lines of, “It is easy to say this, but quite a different thing to prove it in court.” It is hard not to imagine testifying in such a high-profile conservatorship case; testifying, in front of jurors, about a celebrity who may have engaged in what some considered to be unusual behavior.

Conservatorship laws are not about the minutia or criteria of a specific mental health disorder. Patients do not meet criteria for conservatorship by having a certain number of delusional thoughts or a specific type of hallucination. Patients meet criteria for conservatorship because of state-enacted laws based on social factors – such as danger and self-care – the population wishes to treat, even if against the will of those treated. Under this light, one must recognize that a conservatorship trial is not just about mental illness but about how society wants to care for human beings. Psychiatric illness itself is not grounds for conservatorship. Oftentimes, severely ill patients win a hearing for grave disability by simply accepting a referral for housing, showing up to court clothed, and eating the meals provided at the hospital.

With understanding that these laws pertain specifically to behaviors resulting from mental illness that society finds unacceptable, the narrative of a celebrity conservatorship can be considered differently. The stories of celebrities being used and abused by deleterious beings and deleterious conditions have become a genre. Paul Prenter’s treatment of Freddie Mercury documented in the 2018 movie “Bohemian Rhapsody” and John Reid’s alleged betrayal of Elton John, who was suffering from a substance use disorder, documented in the 2019 movie “Rocketman,” are recent examples, among many.

Imagine yourself, as a juror, deciding on the fate of a celebrity. Would you require them to have lost all property, including the clothing on their backs, before intervening? Consider the next time you hear of a celebrity swindled from his or her fortune in a time of crisis and whether it would have been righteous to prevent it. We personally have, at times, argued for restraint in psychiatry’s desire to have more power. This concern extends not only to our ability to control people, but also our ability to force them into being subjected to psychotropic medications with well-known side effects.

At the same time, we remain cognizant of the magnified impact of adverse outcomes on public figures. John Hinckley Jr. did not attempt to murder a bystander; he attempted to kill the president of the United States when he shot at President Ronald Reagan in 1981. That incident led to considerable changes in our laws about insanity. More recently, society was particularly affected by Tom Hanks’ COVID-19 diagnosis. Mr. Hanks’ illness led to scientifically measurable changes in the public’s beliefs regarding the pandemic.³

On the other hand, and of equal importance to the desire to protect public figures from adverse events, is the risk that those same laws intended to protect will harm. From unsanitary asylums to disproportionate placements of minorities on psychiatric holds, we are concerned with unbridled control in the hands of those meant to cure and care. Sadly, there is also a cinematic genre of unprincipled and detrimental mental health treatment, from Brian Wilson’s treatment by his psychologist documented in “Love & Mercy,” to the upcoming “The Shrink Next Door,” featuring a psychiatrist swindling his patient.

With this additional understanding and analysis, we now ask our colleagues what it would take for them to intervene. Would a celebrity losing $100,000,000 because of mental illness constitute a form of grave disability despite remaining dressed? Would a celebrity engaging in significant drug use constitute a form of self-harm despite still recording albums? Would a celebrity failing to fulfill a social commitment to others, including children, constitute a form of harm to others? Those are not trivial questions to answer, and we are glad the Goldwater Rule reminds us of the limitations of speculating on people we do not know.

Nonetheless, the question of conservatorship is more complex than simply saying: “They make money; they have clothes on; this is absurd.” While this may be a catchy, compelling, and relevant argument, when confronted with a more complete narrative, triers of facts may feel compelled to intervene because, in the end, conservatorship laws are about what society is willing to accept rather than an enumeration of psychiatric symptoms.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research.

References

1. Badre N et al. “Coercion and the critical psychiatrist.” In Critical Psychiatry. Springer, Cham, 2019. doi: 10.1007/97-3-030-02732-2_7.

2. Barnes SS and Badre N. Psychiatr Serv. 2016 Jul 1;67(7)784-6.

3. Myrick JG and Willoughby JF. Health Commun. 2021 Jan 14;1-9.

If you are a psychiatrist who has done a public lecture in the past year, you likely encountered the question, “What about Britney’s conservatorship?” Many psychiatrists are far removed from conservatorship evaluations, doing the different yet still important work of alleviating mental suffering without paddling in the controversial waters of involuntary treatment. Others judiciously hide behind the veil of the prudent Goldwater Rule in avoiding such discussions altogether. Regardless of whether psychiatry attempts to stay out of such affairs publicly, our field remains intimately involved in the process itself. This can lead to negative views of psychiatry among the public – that of a medical specialty with ulterior motives operating at the behest of the state.

Some psychiatrists simplistically advocate against any form of involuntary treatment.¹ In many ways, this may appear noble. However, the reality of mental illness, with its potential harm to self and others, introduces the potential for dire consequences of such a position. If society is unwilling to accept behavior that may lead to harm, but psychiatry is unwilling to intervene, then other avenues of restricting such behavior will emerge. Those avenues traditionally have included conscription of law enforcement and the incarceration of patients with mental illness.

Yet, therein lies the conundrum of Ms. Spears and other celebrities on conservatorship. At face value, they do not appear to require conservatorship. We do not think it violates the Goldwater Rule to render this observation. In fact, it may reassure the public if the American Psychiatric Association, as well as individual psychiatrists, were more open about the goal, intent, and limitations of conservatorships.

The process of establishing conservatorships is not driven solely by mental health professionals. Rather, conservatorship laws permit society to enact, through psychiatrists, its desire to alleviate behaviors considered unacceptable in the context of mental illness.

In California, it has resulted in our famous or infamous “5150,” which asks psychiatrists to comment on the danger to self, danger to others, and grave disability of our patients. It can be helpful to frame these criteria regarding the relationship between society and our patients. The criteria of danger to self represents society’s wish to intervene in cases of patients with imminent intent of self-harm, operating under the presumption that a suicide can be prevented. Danger to others represents the societal angst, at times exaggerated,² about people with mental illness perpetuating homicides, especially when off their medication. Grave disability represents public shame at the thought of persons so lost to mental illness they are unable to provide for themselves or even accept food, clothing, and shelter.

While an involuntary hold is necessary at times, working against our patients engenders revolting feelings. We often rationalize involuntary holds as illustrative of sincere compassion for our patients’ suffering and an attempt to lift them out of such tragic conditions. Our patients regularly do not feel our compassion when we are making an argument in a hearing for the restriction of their rights. They see our efforts as an attempt to lock them away “for their own good” because of society’s discomfort with homelessness. As such, we wonder whether our role becomes one of doctors for society, prescribing a treatment for the emotional distress of the community, and at times for ourselves, rather than that of the patient.

One may be perplexed as to how a celebrity could be considered gravely disabled. Celebrities generally have enough income to afford food, clothing, and shelter. One could justifiably ask why an individual with no history of violence would be considered a danger to others. Similarly, one may wonder how, in the absence of any reported attempts to engage in self-harm, with no visible marks of self-harm, someone is determined to be a danger to himself or herself. The bafflement on the part of one on the outside of these determinations can be sharply contrasted by the desperation felt by family members whose loved ones with mental illness appear to meet those criteria yet are consistently turned away by mental health programs and hospitals.

Not uncommonly, it is families advocating for involuntary hospitalization – while lamenting our strict criteria – that prevent doctors from intervening until some tragic fate befalls their loved ones. They criticize what they consider to be too-stringent mental health laws and are infuriated by seemingly obtuse insurance policies limiting care to patients. Most of our colleagues working with those who have severe mental illness share the frustration of these families over the scarcity of psychiatry beds. Therefore, it is particularly shocking when the most mediatized story about conservatorship is not about how hard it is to obtain. The story is about a singer who was seemingly safe, caring for herself, and yet still ended up on a conservatorship.

We wonder whether there is a question of magnitude. Are homeless patients more difficult to place on conservatorship because society sees a lesser stake? One could argue that Ms. Spears and other celebrities would have so much to lose in a single episode of mental illness. A week with mania or psychosis could cause irreparable damage to their persona, opportunity for employment, and their fortune. On the contrary, many of our patients on conservatorship have little to their names, and no one keeping up on their reputation. Triers of facts should ask themselves about the nature of their motivations. Envy, a desire to live vicariously through celebrities, or even less ethical motivations – such as a desire to control and exert authority over those individuals – can influence our decisions.

Throughout the past year, when asked about Ms. Spears, we have pointed out the obvious – she seemingly has a life incompatible with meeting criteria for a psychiatric conservatorship. We have outlined the role, history, and limitations of psychiatric conservatorship. We have shared how such cases are often approached, when required for our own patients or when asked by the court to do so. We have discussed the significant oversight of the system, including the public conservator’s office, which frequently refuses petitions outright. There are hearing officers, who, in the early stages of this process, weigh our case against that of the patients, aided by passionately driven patient advocates. There is the public defender’s office, which, at least in San Diego, vigorously defends the rights of those with mental illness. Most importantly, there are judges who adjudicate those cases with diligence and humility.

As the story has continued to be in the news, we have had numerous conversations about Ms. Spears’ conservatorship with colleagues sharing strong opinions on her case. Many of these colleagues do not have forensic practices and we inevitably find ourselves responding along the lines of, “It is easy to say this, but quite a different thing to prove it in court.” It is hard not to imagine testifying in such a high-profile conservatorship case; testifying, in front of jurors, about a celebrity who may have engaged in what some considered to be unusual behavior.

Conservatorship laws are not about the minutia or criteria of a specific mental health disorder. Patients do not meet criteria for conservatorship by having a certain number of delusional thoughts or a specific type of hallucination. Patients meet criteria for conservatorship because of state-enacted laws based on social factors – such as danger and self-care – the population wishes to treat, even if against the will of those treated. Under this light, one must recognize that a conservatorship trial is not just about mental illness but about how society wants to care for human beings. Psychiatric illness itself is not grounds for conservatorship. Oftentimes, severely ill patients win a hearing for grave disability by simply accepting a referral for housing, showing up to court clothed, and eating the meals provided at the hospital.

With understanding that these laws pertain specifically to behaviors resulting from mental illness that society finds unacceptable, the narrative of a celebrity conservatorship can be considered differently. The stories of celebrities being used and abused by deleterious beings and deleterious conditions have become a genre. Paul Prenter’s treatment of Freddie Mercury documented in the 2018 movie “Bohemian Rhapsody” and John Reid’s alleged betrayal of Elton John, who was suffering from a substance use disorder, documented in the 2019 movie “Rocketman,” are recent examples, among many.

Imagine yourself, as a juror, deciding on the fate of a celebrity. Would you require them to have lost all property, including the clothing on their backs, before intervening? Consider the next time you hear of a celebrity swindled from his or her fortune in a time of crisis and whether it would have been righteous to prevent it. We personally have, at times, argued for restraint in psychiatry’s desire to have more power. This concern extends not only to our ability to control people, but also our ability to force them into being subjected to psychotropic medications with well-known side effects.

At the same time, we remain cognizant of the magnified impact of adverse outcomes on public figures. John Hinckley Jr. did not attempt to murder a bystander; he attempted to kill the president of the United States when he shot at President Ronald Reagan in 1981. That incident led to considerable changes in our laws about insanity. More recently, society was particularly affected by Tom Hanks’ COVID-19 diagnosis. Mr. Hanks’ illness led to scientifically measurable changes in the public’s beliefs regarding the pandemic.³

On the other hand, and of equal importance to the desire to protect public figures from adverse events, is the risk that those same laws intended to protect will harm. From unsanitary asylums to disproportionate placements of minorities on psychiatric holds, we are concerned with unbridled control in the hands of those meant to cure and care. Sadly, there is also a cinematic genre of unprincipled and detrimental mental health treatment, from Brian Wilson’s treatment by his psychologist documented in “Love & Mercy,” to the upcoming “The Shrink Next Door,” featuring a psychiatrist swindling his patient.

With this additional understanding and analysis, we now ask our colleagues what it would take for them to intervene. Would a celebrity losing $100,000,000 because of mental illness constitute a form of grave disability despite remaining dressed? Would a celebrity engaging in significant drug use constitute a form of self-harm despite still recording albums? Would a celebrity failing to fulfill a social commitment to others, including children, constitute a form of harm to others? Those are not trivial questions to answer, and we are glad the Goldwater Rule reminds us of the limitations of speculating on people we do not know.

Nonetheless, the question of conservatorship is more complex than simply saying: “They make money; they have clothes on; this is absurd.” While this may be a catchy, compelling, and relevant argument, when confronted with a more complete narrative, triers of facts may feel compelled to intervene because, in the end, conservatorship laws are about what society is willing to accept rather than an enumeration of psychiatric symptoms.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research.

References

1. Badre N et al. “Coercion and the critical psychiatrist.” In Critical Psychiatry. Springer, Cham, 2019. doi: 10.1007/97-3-030-02732-2_7.

2. Barnes SS and Badre N. Psychiatr Serv. 2016 Jul 1;67(7)784-6.

3. Myrick JG and Willoughby JF. Health Commun. 2021 Jan 14;1-9.

If you are a psychiatrist who has done a public lecture in the past year, you likely encountered the question, “What about Britney’s conservatorship?” Many psychiatrists are far removed from conservatorship evaluations, doing the different yet still important work of alleviating mental suffering without paddling in the controversial waters of involuntary treatment. Others judiciously hide behind the veil of the prudent Goldwater Rule in avoiding such discussions altogether. Regardless of whether psychiatry attempts to stay out of such affairs publicly, our field remains intimately involved in the process itself. This can lead to negative views of psychiatry among the public – that of a medical specialty with ulterior motives operating at the behest of the state.

Some psychiatrists simplistically advocate against any form of involuntary treatment.¹ In many ways, this may appear noble. However, the reality of mental illness, with its potential harm to self and others, introduces the potential for dire consequences of such a position. If society is unwilling to accept behavior that may lead to harm, but psychiatry is unwilling to intervene, then other avenues of restricting such behavior will emerge. Those avenues traditionally have included conscription of law enforcement and the incarceration of patients with mental illness.

Yet, therein lies the conundrum of Ms. Spears and other celebrities on conservatorship. At face value, they do not appear to require conservatorship. We do not think it violates the Goldwater Rule to render this observation. In fact, it may reassure the public if the American Psychiatric Association, as well as individual psychiatrists, were more open about the goal, intent, and limitations of conservatorships.

The process of establishing conservatorships is not driven solely by mental health professionals. Rather, conservatorship laws permit society to enact, through psychiatrists, its desire to alleviate behaviors considered unacceptable in the context of mental illness.

In California, it has resulted in our famous or infamous “5150,” which asks psychiatrists to comment on the danger to self, danger to others, and grave disability of our patients. It can be helpful to frame these criteria regarding the relationship between society and our patients. The criteria of danger to self represents society’s wish to intervene in cases of patients with imminent intent of self-harm, operating under the presumption that a suicide can be prevented. Danger to others represents the societal angst, at times exaggerated,² about people with mental illness perpetuating homicides, especially when off their medication. Grave disability represents public shame at the thought of persons so lost to mental illness they are unable to provide for themselves or even accept food, clothing, and shelter.

While an involuntary hold is necessary at times, working against our patients engenders revolting feelings. We often rationalize involuntary holds as illustrative of sincere compassion for our patients’ suffering and an attempt to lift them out of such tragic conditions. Our patients regularly do not feel our compassion when we are making an argument in a hearing for the restriction of their rights. They see our efforts as an attempt to lock them away “for their own good” because of society’s discomfort with homelessness. As such, we wonder whether our role becomes one of doctors for society, prescribing a treatment for the emotional distress of the community, and at times for ourselves, rather than that of the patient.

One may be perplexed as to how a celebrity could be considered gravely disabled. Celebrities generally have enough income to afford food, clothing, and shelter. One could justifiably ask why an individual with no history of violence would be considered a danger to others. Similarly, one may wonder how, in the absence of any reported attempts to engage in self-harm, with no visible marks of self-harm, someone is determined to be a danger to himself or herself. The bafflement on the part of one on the outside of these determinations can be sharply contrasted by the desperation felt by family members whose loved ones with mental illness appear to meet those criteria yet are consistently turned away by mental health programs and hospitals.

Not uncommonly, it is families advocating for involuntary hospitalization – while lamenting our strict criteria – that prevent doctors from intervening until some tragic fate befalls their loved ones. They criticize what they consider to be too-stringent mental health laws and are infuriated by seemingly obtuse insurance policies limiting care to patients. Most of our colleagues working with those who have severe mental illness share the frustration of these families over the scarcity of psychiatry beds. Therefore, it is particularly shocking when the most mediatized story about conservatorship is not about how hard it is to obtain. The story is about a singer who was seemingly safe, caring for herself, and yet still ended up on a conservatorship.

We wonder whether there is a question of magnitude. Are homeless patients more difficult to place on conservatorship because society sees a lesser stake? One could argue that Ms. Spears and other celebrities would have so much to lose in a single episode of mental illness. A week with mania or psychosis could cause irreparable damage to their persona, opportunity for employment, and their fortune. On the contrary, many of our patients on conservatorship have little to their names, and no one keeping up on their reputation. Triers of facts should ask themselves about the nature of their motivations. Envy, a desire to live vicariously through celebrities, or even less ethical motivations – such as a desire to control and exert authority over those individuals – can influence our decisions.

Throughout the past year, when asked about Ms. Spears, we have pointed out the obvious – she seemingly has a life incompatible with meeting criteria for a psychiatric conservatorship. We have outlined the role, history, and limitations of psychiatric conservatorship. We have shared how such cases are often approached, when required for our own patients or when asked by the court to do so. We have discussed the significant oversight of the system, including the public conservator’s office, which frequently refuses petitions outright. There are hearing officers, who, in the early stages of this process, weigh our case against that of the patients, aided by passionately driven patient advocates. There is the public defender’s office, which, at least in San Diego, vigorously defends the rights of those with mental illness. Most importantly, there are judges who adjudicate those cases with diligence and humility.

As the story has continued to be in the news, we have had numerous conversations about Ms. Spears’ conservatorship with colleagues sharing strong opinions on her case. Many of these colleagues do not have forensic practices and we inevitably find ourselves responding along the lines of, “It is easy to say this, but quite a different thing to prove it in court.” It is hard not to imagine testifying in such a high-profile conservatorship case; testifying, in front of jurors, about a celebrity who may have engaged in what some considered to be unusual behavior.

Conservatorship laws are not about the minutia or criteria of a specific mental health disorder. Patients do not meet criteria for conservatorship by having a certain number of delusional thoughts or a specific type of hallucination. Patients meet criteria for conservatorship because of state-enacted laws based on social factors – such as danger and self-care – the population wishes to treat, even if against the will of those treated. Under this light, one must recognize that a conservatorship trial is not just about mental illness but about how society wants to care for human beings. Psychiatric illness itself is not grounds for conservatorship. Oftentimes, severely ill patients win a hearing for grave disability by simply accepting a referral for housing, showing up to court clothed, and eating the meals provided at the hospital.

With understanding that these laws pertain specifically to behaviors resulting from mental illness that society finds unacceptable, the narrative of a celebrity conservatorship can be considered differently. The stories of celebrities being used and abused by deleterious beings and deleterious conditions have become a genre. Paul Prenter’s treatment of Freddie Mercury documented in the 2018 movie “Bohemian Rhapsody” and John Reid’s alleged betrayal of Elton John, who was suffering from a substance use disorder, documented in the 2019 movie “Rocketman,” are recent examples, among many.

Imagine yourself, as a juror, deciding on the fate of a celebrity. Would you require them to have lost all property, including the clothing on their backs, before intervening? Consider the next time you hear of a celebrity swindled from his or her fortune in a time of crisis and whether it would have been righteous to prevent it. We personally have, at times, argued for restraint in psychiatry’s desire to have more power. This concern extends not only to our ability to control people, but also our ability to force them into being subjected to psychotropic medications with well-known side effects.

At the same time, we remain cognizant of the magnified impact of adverse outcomes on public figures. John Hinckley Jr. did not attempt to murder a bystander; he attempted to kill the president of the United States when he shot at President Ronald Reagan in 1981. That incident led to considerable changes in our laws about insanity. More recently, society was particularly affected by Tom Hanks’ COVID-19 diagnosis. Mr. Hanks’ illness led to scientifically measurable changes in the public’s beliefs regarding the pandemic.³

On the other hand, and of equal importance to the desire to protect public figures from adverse events, is the risk that those same laws intended to protect will harm. From unsanitary asylums to disproportionate placements of minorities on psychiatric holds, we are concerned with unbridled control in the hands of those meant to cure and care. Sadly, there is also a cinematic genre of unprincipled and detrimental mental health treatment, from Brian Wilson’s treatment by his psychologist documented in “Love & Mercy,” to the upcoming “The Shrink Next Door,” featuring a psychiatrist swindling his patient.

With this additional understanding and analysis, we now ask our colleagues what it would take for them to intervene. Would a celebrity losing $100,000,000 because of mental illness constitute a form of grave disability despite remaining dressed? Would a celebrity engaging in significant drug use constitute a form of self-harm despite still recording albums? Would a celebrity failing to fulfill a social commitment to others, including children, constitute a form of harm to others? Those are not trivial questions to answer, and we are glad the Goldwater Rule reminds us of the limitations of speculating on people we do not know.

Nonetheless, the question of conservatorship is more complex than simply saying: “They make money; they have clothes on; this is absurd.” While this may be a catchy, compelling, and relevant argument, when confronted with a more complete narrative, triers of facts may feel compelled to intervene because, in the end, conservatorship laws are about what society is willing to accept rather than an enumeration of psychiatric symptoms.

Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research.

References

1. Badre N et al. “Coercion and the critical psychiatrist.” In Critical Psychiatry. Springer, Cham, 2019. doi: 10.1007/97-3-030-02732-2_7.

2. Barnes SS and Badre N. Psychiatr Serv. 2016 Jul 1;67(7)784-6.

3. Myrick JG and Willoughby JF. Health Commun. 2021 Jan 14;1-9.

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

In November, the office manager of a San Antonio dermatology practice was sentenced to 46 months in prison for defrauding the practice of nearly $350,000 from patient billings and employee profit sharing accounts.

Per the indictment, the practice conducted a nonprofit educational symposium in 2012. A bank account was established to collect contributions for that event, which was supposed to be closed at its conclusion; but the office manager kept it open, and deposited practice receipts into it. She then used the account as her slush fund for travel, property payments, meal purchases, and other personal expenses on credit cards she fraudulently opened in the practice’s name. This continued for several years.

Because this case has received national attention, I am republishing my column on embezzlement, which includes recommendations that could prevent such unfortunate situations from occurring.

Few crimes are more easily overlooked than theft from within. Embezzlement remains far more common in medical offices than generally assumed – and it often occurs in full view of physicians who think everything is fine. Most embezzlers are not skillful or discreet; but their transgressions may go undetected for years, simply because no one suspects it is happening.

Detecting fraud is an inexact science. There is no textbook approach that one can follow, but a few simple measures will prevent or expose the most common forms:

Make it more difficult. Theft and embezzlement are usually products of opportunity, so minimize those opportunities. No one person should be in charge of the entire bookkeeping process: the person who enters charges should be different from the one who enters payments. The one who writes checks or makes electronic fund transfers should not balance the books, and so on. Internal audits should be done on a regular basis, and all employees should know that. Your accountant can help.

Reconcile cash receipts daily. Embezzlement does not require sophisticated technology; the most common form is simply taking cash out of the till. In a typical scenario, a patient pays a copay of $15 in cash; the receptionist records the payment as $5, and pockets the rest. Make sure a receipt is generated for every cash transaction, and that someone other than the person accepting cash reconciles the charges, receipts, and cash totals daily.

Inventory your stock. Cash isn’t the only susceptible commodity. If you sell cosmetics or other products, inventory your stock frequently. And office personnel are not the only potential thieves: Over a year ago, a locum tenens physician down the street conspired with a receptionist to take cash transactions for cosmetic neurotoxins and fillers “off the books” and split the spoils. That office was being ripped off twice; first for the neurotoxin and filler materials themselves, and then for the cash proceeds.

Separate all accounting duties. Another popular ploy is false invoicing for imaginary supplies. A friend’s experience provides a good example (retold with his permission): His bookkeeper wrote sizable checks to herself, disguising them in the ledger as payments to vendors commonly used by his practice. Since the same employee also balanced the checkbook, she got away with it for years. “It wasn’t at all clever,” he told me, “and I’m embarrassed to admit that it happened to me.”

Once again, separation of duties is the key to prevention. One employee should enter invoices into the data system, another should issue the check or make the electronic transfer, and a third should match invoices to goods and services received.

Verify expense reports. False expense reporting is a subset of the fake invoice scam. When an employee asks for reimbursement of expenses, make sure those expenses are real.

Ask about computer safeguards. Computers facilitate a lot of financial chores, but they also consolidate financial data in one place, where it is potentially accessible to anybody, anywhere. Your computer vendor should be aware of this, and should have safeguards built into your system. Ask about them. If they aren’t there, ask why.

Hire honest employees. All applicants look great on paper, so check their references; and with their permission, you can run background checks for a few dollars on any of several public information websites. (See my previous columns on hiring at http://www.mdedge.com/dermatology/managing-your-practice.)

Look for “red flags.” Examples are employees who refuse to take vacations, because someone else will have do their work; or who insist on posting expenses that are a coworker’s responsibility, “just to be nice.” Anyone obviously living beyond his or her means merits suspicion as well.

Consider bonding your employees. Dishonesty bonds are relatively inexpensive, and you will be assured of some measure of recovery should your safeguards fail. In addition, the mere knowledge that your staff is bonded will frighten off most dishonest applicants. One effective screen is a question on your employment application: “Would you object to being bonded?”

Dr. Eastern practices dermatology and dermatologic surgery in Belleville, N.J. He is the author of numerous articles and textbook chapters, and is a longtime monthly columnist for Dermatology News. Write to him at [email protected].

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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

A high dose of the purified form of eicosapentaenoic acid, icosapent ethyl (Vascepa, Amarin), failed to significantly reduce hospitalizations or death in patients infected with COVID-19 in the PREPARE-IT 2 study.

The study did, however, show a favorable trend, with a 16% reduction in the primary endpoint of death or an indication for hospitalization. All secondary endpoints were also numerically reduced, but none reached statistical significance.

The product was also well tolerated over the 28 days of the study period, even though a new high-loading dose was used, with no increase in atrial fibrillation or bleeding or other adverse events versus placebo, although there was a slightly higher rate of discontinuation.

The trial was presented at the American Heart Association scientific sessions on Nov. 15 by Rafael Díaz, MD, director of Estudios Clínicos Latinoamérica in Rosario, Argentina.

“Larger, randomized trials powered for a relative risk reduction of around 15% with icosapent ethyl are needed to establish whether or not this product may have a role in the management of COVID-positive outpatients,” Dr. Diaz concluded.
 

‘Intriguing signals’

Commenting on the study, Manesh Patel, MD, chief of the division of cardiology and codirector of the Heart Center at Duke University, Durham, N.C., and chair of the Scientific Sessions scientific program, said that: “Certainly there are some intriguing signals.”

“I think the trend is valuable, but do we need a larger trial to confirm a benefit? I will leave that to the clinical community to decide,” Dr. Patel added. “But it is hard to power a trial to get that answer, and the world of COVID has changed since this trial started with vaccines now available and new therapeutics coming. So, there’s going to be a competing landscape.”

Discussing the trial at an AHA news briefing, Erin Michos, MD, associate professor of medicine within the division of cardiology at Johns Hopkins University, Baltimore, said: “Results showed that everything trended in the right direction, but did not reach statistical significance largely because there were fewer events than anticipated. COVID hospitalizations are going down because of the broad adoption of vaccines, which meant that this study didn’t quite meet its endpoint.”

But, she added: “Reassuringly, even with the higher loading dose, there was no increased risk of [atrial fibrillation] when used for just 28 days, and no increased risk in bleeding, so there was very good safety.”

“We need a larger trial to really definitely show whether icosapent ethyl can or cannot help COVID-positive outpatients, but I think a better prevention strategy would be the broad adoption of vaccinations globally,” Dr. Michos concluded.
 

‘A pretty big ask’

Donald Lloyd-Jones, MD, AHA president and designated discussant at the late-breaking science session, congratulated the investigators on conducting “a very nice pragmatic trial in the midst of the COVID pandemic.”

Dr. Lloyd-Jones concluded that the broad range of potentially beneficial actions of icosapent ethyl – including antitriglyceride, anti-inflammatory, antioxidant, and antithrombotic effects – leads to the possibility of it helping in COVID, but he added that “this is a pretty big ask for a fish oil supplement given short term.”

Presenting the study, Dr. Diaz noted that there are limited options for the outpatient treatment of patients with COVID-19 infection, and it is believed that inflammation plays a major role in worsening the severity of the infection.

He pointed out that previous data support a potential role of omega-3 fatty acids in reducing inflammation and infection, and that icosapent ethyl has shown a reduction in major cardiovascular events in the REDUCE-IT trial, with the mechanism thought to involve anti-inflammatory effects.

In the first trial to investigate the role of icosapent ethyl in COVID-19, PREPARE-IT, the product did not prevent uninfected individuals at risk from COVID from becoming infected with the virus, but there was no increase in side effects versus placebo with use over a 60-day period.

A small study last year in 100 COVID-positive patients showed icosapent ethyl reduced C-reactive protein, an inflammatory marker, and also improved symptoms.

PREPARE-IT 2, a pragmatic web-based trial, was conducted to investigate whether icosapent ethyl in nonhospitalized patients with a positive diagnosis of COVID-19 could reduce hospitalization rates and complications.

The trial enrolled 2,052 patients (mean age, 50 years), of whom 1,010 were allocated to the active group and 1,042 to the placebo group. Inclusion criteria included individuals aged 40 years or older with a confirmed COVID-19 diagnosis and no more than 7 days from the onset of symptoms and without a clear indication for hospitalization.

Patients who were allocated to the active arm received icosapent ethyl at a dose of 8 g (four capsules every 12 hours, morning and evening) for the first 3 days, followed by 4 g (two capsules every 12 hours) thereafter (days 4-28).

The primary outcome, COVID-19–related hospitalization (indication for hospitalization or hospitalization) or death at 28 days, occurred in 11.16% of the active group and 13.69% of the placebo group, giving a hazard ratio of 0.84 (95% confidence interval, 0.65-1.08; P = .166)

Secondary outcomes showed similar positive trends, but none were significant. These included: death or still hospitalized at 28 days (HR, 0.74), major events (MI, stroke, death; HR, 0.38), and total mortality (HR, 0.52).

In terms of safety, there was no significant difference in total adverse events between the two groups (16.5% in the active group vs. 14.8% in the placebo group). The most common adverse effects were constipation (2.7%), diarrhea (7.2%), and nausea (4%), but these were not significantly different from placebo. There were, however, more discontinuations in the active group (7% vs. 4%).

Dr. Diaz pointed out that the PREPARE-IT 2 trial was started in May 2020, when there wasn’t much known about the COVID-19 condition, and there were no vaccines or treatments, so hospitalization rates were high.

“We were hoping to see a 25%-30% reduction in hospitalizations with icosapent ethyl, and the trial was powered for that sort of reduction, but today we know we can expect a more modest reduction of about 15%,” Dr. Diaz concluded. “But to show that, we need a much larger trial with 8,000 or 9,000 patients, and that will be much more difficult to conduct.”

The PREPARE-IT 2 study was funded by Amarin. Dr. Diaz has received grants from Dalcor, Amarin, PHRI, and Lepetit.

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