The REPLENISH trial evaluated the oral 17β-estradiol/progesterone (E2/P4) softgel capsule (TX-001HR; 1 mg E2/100 mg P4) approved by the US Food and Drug Administration in October 2018 as Bijuva (TherapeuticsMD) for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. In separate subanalyses presented at the annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019), researchers examined E2/P4’s ability to address VMS according to age and body mass index (BMI), ability to address sleep, and appropriate dosing in smokers versus nonsmokers.

REPLENISH

The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial evaluating the safety and efficacy of E2/P4 for the treatment of VMS in 1,835 postmenopausal women aged 40 to 65 years with a uterus. Women with moderate to severe VMS (≥7/day or ≥50/week) were randomly assigned to E2/P4 (mg/mg) 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo.¹

E2/P4 and VMS according to age and BMI

Percent changes in the weekly frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12 versus placebo were analyzed by age (<55 and ≥55 years) and BMI in the study participants.¹ The BMI subgroups had similar baseline VMS, but women in the younger age group had higher baseline frequency of moderate to severe VMS than women in the older age group.

Age. The percent changes in VMS frequency from baseline for women treated with E2/P4 were similar at weeks 4 and 12 between age groups. While subgroup analyses were not powered for statistical significance, significant differences were observed between E2/P4 dosages and placebo at week 12. For VMS severity, the percent changes from baseline for women treated with E2/P4 ranged from 16% to 22% at week 4 and 24% to 51% for either age group at week 12.

BMI. When analyzed by BMI, larger percent reductions from baseline in VMS frequency and severity were observed with E2/P4 dosaging versus placebo, with some groups meeting statistical significance at both weeks 4 and 12.

The authors concluded that their subgroup analyses show a consistency of efficacy for VMS frequency and severity among the different age group and BMI populations of women treated with E2/P4.

E2/P4 and sleep outcomes

Participants in the REPLENISH trial took 2 surveys related to sleep—the Medical Outcomes Study (MOS)-Sleep, a 12-item questionnaire measuring 6 sleep dimensions, and the Menopause-specific Quality of Life (MENQOL), which included a “difficulty sleeping” item.² Except for women treated with E2/P4 0.25/50 at week 12, women receiving E2/P4 reported significantly better change in the MOS-Sleep total, as well as better ratings on sleep problems and disturbance subscales, than women treated with placebo at week 12 and months 6 and 12. The incidence of somnolence was low with E2/P4 treatment. In addition, sleep mediation models showed that E2/P4 improved MOS-sleep disturbances indirectly through improvements in VMS. The study authors concluded that women taking E2/P4 for moderate to severe VMS may experience improved sleep.

Smoking and E2/P4 dosage

Among postmenopausal women, smoking has been shown to reduce the efficacy of hormone therapy.³ Researchers found that nonsmokers (never or past smokers) may benefit more from a lower E2/P4 dosage than current smokers (<15 cigarettes per day).⁴ (Women smoking ≥15 cigarettes per day or any e-cigarettes were excluded from REPLENISH). Compared with nonsmokers taking placebo, nonsmokers taking any dosage of E2/P4 had a significant and clinically meaningful reduction in VMS frequency and severity beginning at week 4 and maintained through week 12 (except for the E2/P4 dosage of 0.5/50 at week 4 for severity). By contrast, current smokers in any E2/P4 group had no significant VMS improvements from baseline to weeks 4 and 12 compared with placebo, and proportions of smokers who did measure some response to treatment (at both ≥50% and ≥75% levels) were not different from placebo at weeks 4 and 12. In addition, current smokers had significantly lower median levels of systemic estradiol and estrone concentrations with all E2/P4 treatment groups than did nonsmokers, despite both groups having similar estradiol and estrone concentrations at baseline.

The REPLENISH trial evaluated the oral 17β-estradiol/progesterone (E2/P4) softgel capsule (TX-001HR; 1 mg E2/100 mg P4) approved by the US Food and Drug Administration in October 2018 as Bijuva (TherapeuticsMD) for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. In separate subanalyses presented at the annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019), researchers examined E2/P4’s ability to address VMS according to age and body mass index (BMI), ability to address sleep, and appropriate dosing in smokers versus nonsmokers.

REPLENISH

The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial evaluating the safety and efficacy of E2/P4 for the treatment of VMS in 1,835 postmenopausal women aged 40 to 65 years with a uterus. Women with moderate to severe VMS (≥7/day or ≥50/week) were randomly assigned to E2/P4 (mg/mg) 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo.¹

E2/P4 and VMS according to age and BMI

Percent changes in the weekly frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12 versus placebo were analyzed by age (<55 and ≥55 years) and BMI in the study participants.¹ The BMI subgroups had similar baseline VMS, but women in the younger age group had higher baseline frequency of moderate to severe VMS than women in the older age group.

Age. The percent changes in VMS frequency from baseline for women treated with E2/P4 were similar at weeks 4 and 12 between age groups. While subgroup analyses were not powered for statistical significance, significant differences were observed between E2/P4 dosages and placebo at week 12. For VMS severity, the percent changes from baseline for women treated with E2/P4 ranged from 16% to 22% at week 4 and 24% to 51% for either age group at week 12.

BMI. When analyzed by BMI, larger percent reductions from baseline in VMS frequency and severity were observed with E2/P4 dosaging versus placebo, with some groups meeting statistical significance at both weeks 4 and 12.

The authors concluded that their subgroup analyses show a consistency of efficacy for VMS frequency and severity among the different age group and BMI populations of women treated with E2/P4.

E2/P4 and sleep outcomes

Participants in the REPLENISH trial took 2 surveys related to sleep—the Medical Outcomes Study (MOS)-Sleep, a 12-item questionnaire measuring 6 sleep dimensions, and the Menopause-specific Quality of Life (MENQOL), which included a “difficulty sleeping” item.² Except for women treated with E2/P4 0.25/50 at week 12, women receiving E2/P4 reported significantly better change in the MOS-Sleep total, as well as better ratings on sleep problems and disturbance subscales, than women treated with placebo at week 12 and months 6 and 12. The incidence of somnolence was low with E2/P4 treatment. In addition, sleep mediation models showed that E2/P4 improved MOS-sleep disturbances indirectly through improvements in VMS. The study authors concluded that women taking E2/P4 for moderate to severe VMS may experience improved sleep.

Smoking and E2/P4 dosage

Among postmenopausal women, smoking has been shown to reduce the efficacy of hormone therapy.³ Researchers found that nonsmokers (never or past smokers) may benefit more from a lower E2/P4 dosage than current smokers (<15 cigarettes per day).⁴ (Women smoking ≥15 cigarettes per day or any e-cigarettes were excluded from REPLENISH). Compared with nonsmokers taking placebo, nonsmokers taking any dosage of E2/P4 had a significant and clinically meaningful reduction in VMS frequency and severity beginning at week 4 and maintained through week 12 (except for the E2/P4 dosage of 0.5/50 at week 4 for severity). By contrast, current smokers in any E2/P4 group had no significant VMS improvements from baseline to weeks 4 and 12 compared with placebo, and proportions of smokers who did measure some response to treatment (at both ≥50% and ≥75% levels) were not different from placebo at weeks 4 and 12. In addition, current smokers had significantly lower median levels of systemic estradiol and estrone concentrations with all E2/P4 treatment groups than did nonsmokers, despite both groups having similar estradiol and estrone concentrations at baseline.

The REPLENISH trial evaluated the oral 17β-estradiol/progesterone (E2/P4) softgel capsule (TX-001HR; 1 mg E2/100 mg P4) approved by the US Food and Drug Administration in October 2018 as Bijuva (TherapeuticsMD) for the treatment of moderate to severe vasomotor symptoms (VMS) due to menopause. In separate subanalyses presented at the annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019), researchers examined E2/P4’s ability to address VMS according to age and body mass index (BMI), ability to address sleep, and appropriate dosing in smokers versus nonsmokers.

REPLENISH

The REPLENISH trial was a phase 3, randomized, double-blind, placebo-controlled, multicenter trial evaluating the safety and efficacy of E2/P4 for the treatment of VMS in 1,835 postmenopausal women aged 40 to 65 years with a uterus. Women with moderate to severe VMS (≥7/day or ≥50/week) were randomly assigned to E2/P4 (mg/mg) 1/100, 0.5/100, 0.5/50, 0.25/50, or placebo.¹

E2/P4 and VMS according to age and BMI

Percent changes in the weekly frequency and severity of moderate to severe VMS from baseline to weeks 4 and 12 versus placebo were analyzed by age (<55 and ≥55 years) and BMI in the study participants.¹ The BMI subgroups had similar baseline VMS, but women in the younger age group had higher baseline frequency of moderate to severe VMS than women in the older age group.

Age. The percent changes in VMS frequency from baseline for women treated with E2/P4 were similar at weeks 4 and 12 between age groups. While subgroup analyses were not powered for statistical significance, significant differences were observed between E2/P4 dosages and placebo at week 12. For VMS severity, the percent changes from baseline for women treated with E2/P4 ranged from 16% to 22% at week 4 and 24% to 51% for either age group at week 12.

BMI. When analyzed by BMI, larger percent reductions from baseline in VMS frequency and severity were observed with E2/P4 dosaging versus placebo, with some groups meeting statistical significance at both weeks 4 and 12.

The authors concluded that their subgroup analyses show a consistency of efficacy for VMS frequency and severity among the different age group and BMI populations of women treated with E2/P4.

E2/P4 and sleep outcomes

Participants in the REPLENISH trial took 2 surveys related to sleep—the Medical Outcomes Study (MOS)-Sleep, a 12-item questionnaire measuring 6 sleep dimensions, and the Menopause-specific Quality of Life (MENQOL), which included a “difficulty sleeping” item.² Except for women treated with E2/P4 0.25/50 at week 12, women receiving E2/P4 reported significantly better change in the MOS-Sleep total, as well as better ratings on sleep problems and disturbance subscales, than women treated with placebo at week 12 and months 6 and 12. The incidence of somnolence was low with E2/P4 treatment. In addition, sleep mediation models showed that E2/P4 improved MOS-sleep disturbances indirectly through improvements in VMS. The study authors concluded that women taking E2/P4 for moderate to severe VMS may experience improved sleep.

Smoking and E2/P4 dosage

Among postmenopausal women, smoking has been shown to reduce the efficacy of hormone therapy.³ Researchers found that nonsmokers (never or past smokers) may benefit more from a lower E2/P4 dosage than current smokers (<15 cigarettes per day).⁴ (Women smoking ≥15 cigarettes per day or any e-cigarettes were excluded from REPLENISH). Compared with nonsmokers taking placebo, nonsmokers taking any dosage of E2/P4 had a significant and clinically meaningful reduction in VMS frequency and severity beginning at week 4 and maintained through week 12 (except for the E2/P4 dosage of 0.5/50 at week 4 for severity). By contrast, current smokers in any E2/P4 group had no significant VMS improvements from baseline to weeks 4 and 12 compared with placebo, and proportions of smokers who did measure some response to treatment (at both ≥50% and ≥75% levels) were not different from placebo at weeks 4 and 12. In addition, current smokers had significantly lower median levels of systemic estradiol and estrone concentrations with all E2/P4 treatment groups than did nonsmokers, despite both groups having similar estradiol and estrone concentrations at baseline.

Researchers from Kaiser Permanente Northwest and Oregon Health & Science University, both in Portland, performed a secondary analysis of a survey of postmenopausal women conducted to assess the impact of a health system intervention on genitourinary syndrome of menopause (GSM). They presented their results at the recent annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019). The intervention included clinician education and computer support tools and was assessed in a clinic-based, cluster-randomized trial in which primary care and gynecology clinics either received the intervention or did not. Women received follow-up 2 weeks after a well-woman visit with a survey that elicited vulvovaginal, sexual, and urinary symptoms with bother.

About 45% of those responding to the survey (N = 1,533) reported 1 or more vulvovaginal atrophy (VVA) symptoms—on average described as somewhat or moderately bothersome—but less than half of those women (39%) discussed their symptom(s) at their well-woman visit. Typically it was the woman, rather than the clinician, who initiated the discussion of the VVA symptom(s) (59% vs 22%, respectively). About 16% of women reported that both parties brought up the symptom(s). Most women (83%) were satisfied with the VVA symptom discussion. Of the women not having such a discussion, 18% wished that one had occurred. A VVA symptom discussion was positively associated with clinicians providing written materials, suggesting lubricants or vaginal estrogen, and providing a referral. Therefore, there is a greater role for clinician-initiated screening for GSM, the study authors concluded.
 

Researchers from Kaiser Permanente Northwest and Oregon Health & Science University, both in Portland, performed a secondary analysis of a survey of postmenopausal women conducted to assess the impact of a health system intervention on genitourinary syndrome of menopause (GSM). They presented their results at the recent annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019). The intervention included clinician education and computer support tools and was assessed in a clinic-based, cluster-randomized trial in which primary care and gynecology clinics either received the intervention or did not. Women received follow-up 2 weeks after a well-woman visit with a survey that elicited vulvovaginal, sexual, and urinary symptoms with bother.

About 45% of those responding to the survey (N = 1,533) reported 1 or more vulvovaginal atrophy (VVA) symptoms—on average described as somewhat or moderately bothersome—but less than half of those women (39%) discussed their symptom(s) at their well-woman visit. Typically it was the woman, rather than the clinician, who initiated the discussion of the VVA symptom(s) (59% vs 22%, respectively). About 16% of women reported that both parties brought up the symptom(s). Most women (83%) were satisfied with the VVA symptom discussion. Of the women not having such a discussion, 18% wished that one had occurred. A VVA symptom discussion was positively associated with clinicians providing written materials, suggesting lubricants or vaginal estrogen, and providing a referral. Therefore, there is a greater role for clinician-initiated screening for GSM, the study authors concluded.
 

Researchers from Kaiser Permanente Northwest and Oregon Health & Science University, both in Portland, performed a secondary analysis of a survey of postmenopausal women conducted to assess the impact of a health system intervention on genitourinary syndrome of menopause (GSM). They presented their results at the recent annual Scientific Meeting of the North American Menopause Society in Chicago, Illinois (September 25-28, 2019). The intervention included clinician education and computer support tools and was assessed in a clinic-based, cluster-randomized trial in which primary care and gynecology clinics either received the intervention or did not. Women received follow-up 2 weeks after a well-woman visit with a survey that elicited vulvovaginal, sexual, and urinary symptoms with bother.

About 45% of those responding to the survey (N = 1,533) reported 1 or more vulvovaginal atrophy (VVA) symptoms—on average described as somewhat or moderately bothersome—but less than half of those women (39%) discussed their symptom(s) at their well-woman visit. Typically it was the woman, rather than the clinician, who initiated the discussion of the VVA symptom(s) (59% vs 22%, respectively). About 16% of women reported that both parties brought up the symptom(s). Most women (83%) were satisfied with the VVA symptom discussion. Of the women not having such a discussion, 18% wished that one had occurred. A VVA symptom discussion was positively associated with clinicians providing written materials, suggesting lubricants or vaginal estrogen, and providing a referral. Therefore, there is a greater role for clinician-initiated screening for GSM, the study authors concluded.
 

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

SAN DIEGO – The Food and Drug Administration has not approved a drug to treat agitation in dementia, and the absence of medication candidates is only part of the picture. As a geriatric psychiatrist explained to colleagues, the FDA has not taken the step of recognizing that the condition exists. But there are still options to treat this dangerous disorder – although none is ideal.

Research into efficacy of potential treatments for agitation is limited, variable, and “have high placebo effects,” said Marc E. Agronin, MD, of the MIND Institute and Miami Jewish Health, at the annual Psych Congress. “There is no one single magic bullet, especially since there are so many manifestations of agitation, and there are side effects of medication. This is a tough area to focus on.”

What can clinicians do? Dr. Agronin recommended starting with the steps in the DICE algorithm.

• Describe: Learn about the aspects of agitation by talking to caregivers and understanding the circumstances when symptoms develop.
• Investigate: Identify contributing factors, such as those related to illness, medication, and the environment.
• Create: Come up with a team strategy to address the contributing factors. Address the most urgent risks first, such as danger to self or others, which can require quick action – such as medication adjustment, an ED visit, or psychiatric hospitalization. Delirium is especially dangerous since it can lead to injury and subacute cognitive decline. And keep in mind, Dr. Agorin said, that it may be risky to do nothing or undertreat.
• Evaluate: Track the results of the strategy while realizing that there’s “not always a quick fix.” Research suggests that therapeutic approaches such as music, aromatherapy, exercise, group activities, hand massage, and thermal baths can be helpful, Dr. Agronin said.

As for medications, he advised starting with lower doses, perhaps 50%, because older people are less tolerant of medication. And beware of oversedation, dizziness, and lowered blood pressure, which can lead to falls. A hip fracture can “spiral down to someone’s demise very quickly,” he said.

Here’s a closer look at Dr. Agronin’s comments regarding specific medications.

• Antipsychotics: “Every antipsychotic has been used for agitation,” he said, “and they probably have the best efficacy,” compared with other drugs. But the risk of side effects is moderate to high, and atypical antipsychotics have a black-box warning about their use in dementia-related psychosis in elderly patients. Also, discontinuation of antipsychotics can trigger worsening symptoms in some patients. There has been tremendous controversy in recent years over the use of antipsychotics in older patients, but other drugs might be less effective than antipsychotics while still having similar side effect profiles, he said. And clinicians might be too cautious about doses even when they do use these drugs.
• Benzodiazepines: They can work quickly but come with a risk of sedation. Trazodone is an “excellent” alternative to reduce agitation in the short-term, he said.
• Antidepressants: These drugs can address underlying depression. Study results have been mixed.
• Mood stabilizers: Study results are mixed. “Unfortunately, in many situations [clinicians] get scared away from antipsychotics and use mood stabilizers, but there is less data for them in terms of efficacy, and there are a lot of side effects that have to be monitored,” he said.

Dr. Agronin is the author of “How We Age” (Da Capo Lifelong Books, 2012) and “The End of Old Age” (Da Capo Lifelong Books, 2018). He has no relevant disclosures.

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

sworcester@mdedge.com

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

sworcester@mdedge.com

EDINBURGH – Routine empiric prophylaxis against pneumocystis jiroveci pneumonia (PJP) may be unwarranted in chronic lymphocytic leukemia patients initiating Bruton tyrosine kinase (BTK) inhibitor therapy, a retrospective chart review suggests.

Among 212 patients with chronic lymphocytic leukemia (CLL) who were treated with ibrutinib or acalabrutinib either as monotherapy or as part of a combination regimen for at least 30 days between Jan. 1, 2010, and Feb. 1, 2019, at Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston, 125 (59%) received PJP prophylaxis, including either trimethoprim-sulfamethoxazole (74%) or atovaquone (26%), Christine Ryan, MD, reported at the International Workshop on CLL.

Two PJP cases occurred in the 120 patients on single-agent ibrutinib, including one in a previously untreated patient and one in a patient with relapsed/refractory CLL. Neither patient had received PJP prophylaxis, said Dr. Ryan, a senior resident at Brigham and Women’s Hospital.

No PJP cases occurred in the 21 patients who received acalabrutinib monotherapy or in the 14 patients who received acalabrutinib combination therapy, and 1 occurred in a trial cohort of 57 patients receiving frontline ibrutinib plus fludarabine-based chemotherapy (FCR). The latter had been prescribed PJP prophylaxis, but “unfortunately self-discontinued the prophylaxis” 2 months prior to the infection, Dr. Ryan said.

“The overall prevalence of PJP in patients not on prophylaxis was 3.4%, there were no cases of PJP in patients on prophylaxis, and the incidence rate in patients not on prophylaxis was 1.9 per 100 person-years, with a number needed to treat to prevent 1 case of PJP calculated to be 42 patients,” she said.

In addition to PJP, three cases of proven or probable invasive fungal infections (IFI) occurred, including one case of pulmonary histoplasmosis in the ibrutinib plus FCR trial cohort and two cases of aspergillosis, including a pulmonary case and a brain abscess, in an ibrutinib plus umbralisib trial cohort.

“The overall prevalence of aspergillosis or histoplasmosis in our entire cohort was 1.4%, and notably there were no cases of IFI in the single-agent therapy cohort, but the prevalence in the ibrutinib-combination therapy patients was 4.2%,” Dr. Ryan said.

Patients included in the review were adults with a median age of 64.8 years, and 64% were men. The median duration of BTK inhibitor therapy was 23.2 months.

“We know that CLL patients treated with fludarabine have an increased risk of PJP,” she said. “As such, it is routinely recommended that patients receiving fludarabine-containing chemotherapy regimens are prescribed PJP prophylaxis.”

Additionally, the increasing use of oral BTK inhibitors has raised concerns about the potential risk of PJP or other IFIs in patients on those agents, Dr. Ryan explained, noting that existing case reports and case series looking at PJP have shown varying prevalence rates, and little is known about the effects of prophylaxis.

“At present, there are no international guidelines regarding the use of antimicrobial prophylaxis in CLL patients treated with BTK inhibitors, and prophylaxis practices vary widely across countries and institutions,” she said.

The findings of the current study demonstrate that such variation exists “even within our own institution,” Dr. Ryan added.

The findings also show an overall low PJP prevalence of 3.4% in patients not receiving prophylaxis, which falls below the “commonly accepted threshold of 5%, above which routine prophylaxis becomes recommended,” she said.

“Overall, our data suggest that routine PJP or IFI prophylaxis in patients receiving BTK inhibitors may not be needed, but this is definitely an area that requires further study, ideally with a prospective trial with a larger sample size and multiple institutions, to support the development of consensus guidelines on this issue,” she said.

Dr. Ryan reported having no financial disclosures.

sworcester@mdedge.com

It is well established, both in research and everyday real-world experience, that posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) independently can have a huge impact on physical health. There is evidence, for instance, that both are independent “robust risk factors” for the onset of chronic physical illnesses, including musculoskeletal, digestive, and circulatory, say researchers from VA San Diego; University of California, San Diego; VA Center of Excellence for Stress and Mental Health, San Diego; National Center for PTSD, Vermont;  VA Connecticut Health Care System, and Yale. However, less is known about how the 2 conditions might synergistically affect physical health and well-being.

In this, the first population-based study of the burden of medical illness associated with PTSD, MDD, and their comorbidity, the researchers examined data from 2,732 participants in the National Health and Resilience in Veterans Study.

Of the participants, 40 had PTSD only, 141 had MDD only, and 60 had both. Among veterans who screened positive for probable PTSD, 47% also screened positive for probable MDD. Among veterans who screened positive for probable MDD, 83% screened positive for probable PTSD.

The participants with PTSD, MDD, or both had substantially greater burden of medical illness compared with that of those participants who had no lifetime history of either condition. Consistent with findings from previous studies, each group had a greater prevalence of a broad range of medical conditions, including cardiovascular, respiratory, neurologic, and chronic pain-related diseases.

However, the study results indicated that comorbid PTSD/MDD was associated with substantially greater medical comorbidity compared with either disorder alone. Veterans with co-occurring PTSD and MDD had higher odds of being diagnosed with migraine, fibromyalgia, and rheumatoid arthritis, for instance, relative to those with MDD alone.

Co-occurring PTSD/MDD was also associated with “markedly worse” cardiovascular health compared with either condition alone. Veterans with PTSD/MDD had more than twice the likelihood of being diagnosed with hypercholesterolemia and hypertension compared with those who had PTSD alone. They had more than double the odds of being diagnosed with heart disease compared with those who had only MDD.

Several factors may account for why PTSD seems to compound risk for pain-related conditions, the researchers say. People with PTSD may have increased attentional bias toward threatening internal stimuli (above and beyond MDD), which may heighten appraisal of pain; they also tend to have higher levels of anxiety sensitivity, which may amplify fear reactivity to pain. Some evidence suggests that the brain region involved in processing the affective component of pain is dysfunctional in PTSD, leading to an exaggerated response.

The associations between PTSD and pain, and PTSD/MDD and cardiovascular risks were noteworthy, the researchers say, because they were found even after “stringently controlling” for relevant covariates, including lifetime trauma exposure; combat veteran status; and alcohol, drug, and nicotine use disorder.

The finding that PTSD/MDD and PTSD were associated with higher levels of somatization is consistent with other research, the researchers note. But they say more research is needed to examine whether somatization increases vulnerability to the development of PTSD and MDD, or whether symptoms arise as a consequence of the disorders.

Further, they underscore the importance of integrating mental health services in primary care settings. Previous research has shown that older veterans tend to report mental health concerns to their primary care provider rather than seek specialty mental health treatment; they also underreport symptoms related to emotional difficulties and overreport somatic complaints.

Perhaps most important from a public health perspective, the researchers say, is that current findings suggest that veterans with co-occurring PTSD/MDD represent a “particularly high-risk group” for cardiovascular problems. The issue, they emphasize, “deserves careful attention” from the VA and other health care systems.

It is well established, both in research and everyday real-world experience, that posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) independently can have a huge impact on physical health. There is evidence, for instance, that both are independent “robust risk factors” for the onset of chronic physical illnesses, including musculoskeletal, digestive, and circulatory, say researchers from VA San Diego; University of California, San Diego; VA Center of Excellence for Stress and Mental Health, San Diego; National Center for PTSD, Vermont;  VA Connecticut Health Care System, and Yale. However, less is known about how the 2 conditions might synergistically affect physical health and well-being.

In this, the first population-based study of the burden of medical illness associated with PTSD, MDD, and their comorbidity, the researchers examined data from 2,732 participants in the National Health and Resilience in Veterans Study.

Of the participants, 40 had PTSD only, 141 had MDD only, and 60 had both. Among veterans who screened positive for probable PTSD, 47% also screened positive for probable MDD. Among veterans who screened positive for probable MDD, 83% screened positive for probable PTSD.

The participants with PTSD, MDD, or both had substantially greater burden of medical illness compared with that of those participants who had no lifetime history of either condition. Consistent with findings from previous studies, each group had a greater prevalence of a broad range of medical conditions, including cardiovascular, respiratory, neurologic, and chronic pain-related diseases.

However, the study results indicated that comorbid PTSD/MDD was associated with substantially greater medical comorbidity compared with either disorder alone. Veterans with co-occurring PTSD and MDD had higher odds of being diagnosed with migraine, fibromyalgia, and rheumatoid arthritis, for instance, relative to those with MDD alone.

Co-occurring PTSD/MDD was also associated with “markedly worse” cardiovascular health compared with either condition alone. Veterans with PTSD/MDD had more than twice the likelihood of being diagnosed with hypercholesterolemia and hypertension compared with those who had PTSD alone. They had more than double the odds of being diagnosed with heart disease compared with those who had only MDD.

Several factors may account for why PTSD seems to compound risk for pain-related conditions, the researchers say. People with PTSD may have increased attentional bias toward threatening internal stimuli (above and beyond MDD), which may heighten appraisal of pain; they also tend to have higher levels of anxiety sensitivity, which may amplify fear reactivity to pain. Some evidence suggests that the brain region involved in processing the affective component of pain is dysfunctional in PTSD, leading to an exaggerated response.

The associations between PTSD and pain, and PTSD/MDD and cardiovascular risks were noteworthy, the researchers say, because they were found even after “stringently controlling” for relevant covariates, including lifetime trauma exposure; combat veteran status; and alcohol, drug, and nicotine use disorder.

The finding that PTSD/MDD and PTSD were associated with higher levels of somatization is consistent with other research, the researchers note. But they say more research is needed to examine whether somatization increases vulnerability to the development of PTSD and MDD, or whether symptoms arise as a consequence of the disorders.

Further, they underscore the importance of integrating mental health services in primary care settings. Previous research has shown that older veterans tend to report mental health concerns to their primary care provider rather than seek specialty mental health treatment; they also underreport symptoms related to emotional difficulties and overreport somatic complaints.

Perhaps most important from a public health perspective, the researchers say, is that current findings suggest that veterans with co-occurring PTSD/MDD represent a “particularly high-risk group” for cardiovascular problems. The issue, they emphasize, “deserves careful attention” from the VA and other health care systems.

It is well established, both in research and everyday real-world experience, that posttraumatic stress disorder (PTSD) and major depressive disorder (MDD) independently can have a huge impact on physical health. There is evidence, for instance, that both are independent “robust risk factors” for the onset of chronic physical illnesses, including musculoskeletal, digestive, and circulatory, say researchers from VA San Diego; University of California, San Diego; VA Center of Excellence for Stress and Mental Health, San Diego; National Center for PTSD, Vermont;  VA Connecticut Health Care System, and Yale. However, less is known about how the 2 conditions might synergistically affect physical health and well-being.

In this, the first population-based study of the burden of medical illness associated with PTSD, MDD, and their comorbidity, the researchers examined data from 2,732 participants in the National Health and Resilience in Veterans Study.

Of the participants, 40 had PTSD only, 141 had MDD only, and 60 had both. Among veterans who screened positive for probable PTSD, 47% also screened positive for probable MDD. Among veterans who screened positive for probable MDD, 83% screened positive for probable PTSD.

The participants with PTSD, MDD, or both had substantially greater burden of medical illness compared with that of those participants who had no lifetime history of either condition. Consistent with findings from previous studies, each group had a greater prevalence of a broad range of medical conditions, including cardiovascular, respiratory, neurologic, and chronic pain-related diseases.

However, the study results indicated that comorbid PTSD/MDD was associated with substantially greater medical comorbidity compared with either disorder alone. Veterans with co-occurring PTSD and MDD had higher odds of being diagnosed with migraine, fibromyalgia, and rheumatoid arthritis, for instance, relative to those with MDD alone.

Co-occurring PTSD/MDD was also associated with “markedly worse” cardiovascular health compared with either condition alone. Veterans with PTSD/MDD had more than twice the likelihood of being diagnosed with hypercholesterolemia and hypertension compared with those who had PTSD alone. They had more than double the odds of being diagnosed with heart disease compared with those who had only MDD.

Several factors may account for why PTSD seems to compound risk for pain-related conditions, the researchers say. People with PTSD may have increased attentional bias toward threatening internal stimuli (above and beyond MDD), which may heighten appraisal of pain; they also tend to have higher levels of anxiety sensitivity, which may amplify fear reactivity to pain. Some evidence suggests that the brain region involved in processing the affective component of pain is dysfunctional in PTSD, leading to an exaggerated response.

The associations between PTSD and pain, and PTSD/MDD and cardiovascular risks were noteworthy, the researchers say, because they were found even after “stringently controlling” for relevant covariates, including lifetime trauma exposure; combat veteran status; and alcohol, drug, and nicotine use disorder.

The finding that PTSD/MDD and PTSD were associated with higher levels of somatization is consistent with other research, the researchers note. But they say more research is needed to examine whether somatization increases vulnerability to the development of PTSD and MDD, or whether symptoms arise as a consequence of the disorders.

Further, they underscore the importance of integrating mental health services in primary care settings. Previous research has shown that older veterans tend to report mental health concerns to their primary care provider rather than seek specialty mental health treatment; they also underreport symptoms related to emotional difficulties and overreport somatic complaints.

Perhaps most important from a public health perspective, the researchers say, is that current findings suggest that veterans with co-occurring PTSD/MDD represent a “particularly high-risk group” for cardiovascular problems. The issue, they emphasize, “deserves careful attention” from the VA and other health care systems.

SAN FRANCISCO – Among patients with left main coronary artery disease and low or intermediate coronary disease complexity, no significant differences were observed between percutaneous coronary intervention and coronary artery bypass graft surgery with respect to the composite rate of death, stroke, or myocardial infarction at 5 years.

Doug Brunk/MDedge News

The findings come from an analysis of data from the EXCEL trial, which lead investigator Gregg W. Stone, MD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

“PCI may be considered an acceptable revascularization modality for selected patients with left main coronary artery disease, a decision which should be made after heart team discussion, taking into account each patient’s individual risk factors and preferences,” said Dr. Stone, professor of medicine and professor of population health sciences and policy at the Icahn School of Medicine at Mount Sinai, New York.

Between September 2010 and March 2014, Dr. Stone and his colleagues at 126 sites in 17 countries enrolled 1,905 patients with left main CAD and site-assessed low or intermediate CAD complexity (SYNTAX score of up to 32) for randomization into one of two arms: 948 to revascularization with the Xience everolimus-eluting stent and 957 to coronary artery bypass graft surgery (CABG). The primary outcome was the composite of death, stroke, or myocardial infarction at 5 years. Long-term additional secondary outcomes included their components at 5 years, as well as therapy failure (definite stent thrombosis or symptomatic graft stenosis or occlusion), all revascularizations, and all cerebrovascular events (stroke or transient ischemic attack).

Dr. Stone reported that at 5 years, the primary composite of death, stroke, or MI occurred in 22.0% of patients in the PCI group and 19.2% of patients in the CABG group, a nonsignificant difference at P = 0.13).

However, when the researchers broke the results into three distinct risk periods within the 5-year time frame, they found that, with longer follow-up, came more of an advantage for CABG. The relative risk of PCI vs. CABG for the primary outcome favored PCI over CABG in the first 30 days (4.9% vs. 8%; hazard ratio, 0.61; P = .008), was neutral at 30 days to 1 year (4.1 vs. 3.8%; HR, 1.07; P = .76), and reversed at 1-5 years (15.1% vs. 9.7%; HR, 1.61; P less than .001). Using restricted mean survival time analysis, Dr. Stone and his colleagues found that, at the end of the 5-year follow-up period, event-free survival time was 5.2 days longer after PCI, compared with CABG. This translates into “a very similar event-free survival of a burden of disease from these two therapies at the end of 5 years,” he said.

In their analysis of secondary endpoints, some differences were noted, including an elevated risk of all-cause mortality in the PCI group, compared with the CABG group (13% vs. 9.9%, respectively; odds ratio, 1.38), yet no differences in definite cardiovascular mortality (5% vs. 4.5%; OR, 1.13) or in MI (10.6% vs. 9.1%; OR 1.14). In addition, there were fewer cerebrovascular events in the PCI vs. CABG groups (3.3% vs. 5.2%; OR, 0.61). “Overall, all of these differences were relatively small given the 5-year perspective,” Dr. Stone said at the meeting sponsored by the Cardiovascular Research Foundation. He concluded that the early benefits of PCI attributable to reduced periprocedural risk “were attenuated by the greater number of events occurring during follow-up with CABG, such that at 5 years the cumulative mean time free from adverse events was similar with both treatments.” He noted that a 10-year or longer follow-up is required to characterize the very late safety profile of PCI and CABG as both stents and bypass grafts progressively fail over time.

Discussant Dharam Kumbhani, MD, an interventional cardiologist at UT Southwestern Medical Center, Dallas, said that the findings from EXCEL “help us move the field forward and help us understand this concept of risk with PCI versus CABG. It really does help inform shared decision-making with patients.”

Results of the study were published online at the time of presentation (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406). The EXCEL trial was funded by Abbott Vascular. Dr. Stone disclosed having relationships with numerous device and pharmaceutical companies but had no relevant disclosures for this study.

dbrunk@mdedge.com

SOURCE: Stone G et al. TCT 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406.
 

SAN FRANCISCO – Among patients with left main coronary artery disease and low or intermediate coronary disease complexity, no significant differences were observed between percutaneous coronary intervention and coronary artery bypass graft surgery with respect to the composite rate of death, stroke, or myocardial infarction at 5 years.

Doug Brunk/MDedge News

The findings come from an analysis of data from the EXCEL trial, which lead investigator Gregg W. Stone, MD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

“PCI may be considered an acceptable revascularization modality for selected patients with left main coronary artery disease, a decision which should be made after heart team discussion, taking into account each patient’s individual risk factors and preferences,” said Dr. Stone, professor of medicine and professor of population health sciences and policy at the Icahn School of Medicine at Mount Sinai, New York.

Between September 2010 and March 2014, Dr. Stone and his colleagues at 126 sites in 17 countries enrolled 1,905 patients with left main CAD and site-assessed low or intermediate CAD complexity (SYNTAX score of up to 32) for randomization into one of two arms: 948 to revascularization with the Xience everolimus-eluting stent and 957 to coronary artery bypass graft surgery (CABG). The primary outcome was the composite of death, stroke, or myocardial infarction at 5 years. Long-term additional secondary outcomes included their components at 5 years, as well as therapy failure (definite stent thrombosis or symptomatic graft stenosis or occlusion), all revascularizations, and all cerebrovascular events (stroke or transient ischemic attack).

Dr. Stone reported that at 5 years, the primary composite of death, stroke, or MI occurred in 22.0% of patients in the PCI group and 19.2% of patients in the CABG group, a nonsignificant difference at P = 0.13).

However, when the researchers broke the results into three distinct risk periods within the 5-year time frame, they found that, with longer follow-up, came more of an advantage for CABG. The relative risk of PCI vs. CABG for the primary outcome favored PCI over CABG in the first 30 days (4.9% vs. 8%; hazard ratio, 0.61; P = .008), was neutral at 30 days to 1 year (4.1 vs. 3.8%; HR, 1.07; P = .76), and reversed at 1-5 years (15.1% vs. 9.7%; HR, 1.61; P less than .001). Using restricted mean survival time analysis, Dr. Stone and his colleagues found that, at the end of the 5-year follow-up period, event-free survival time was 5.2 days longer after PCI, compared with CABG. This translates into “a very similar event-free survival of a burden of disease from these two therapies at the end of 5 years,” he said.

In their analysis of secondary endpoints, some differences were noted, including an elevated risk of all-cause mortality in the PCI group, compared with the CABG group (13% vs. 9.9%, respectively; odds ratio, 1.38), yet no differences in definite cardiovascular mortality (5% vs. 4.5%; OR, 1.13) or in MI (10.6% vs. 9.1%; OR 1.14). In addition, there were fewer cerebrovascular events in the PCI vs. CABG groups (3.3% vs. 5.2%; OR, 0.61). “Overall, all of these differences were relatively small given the 5-year perspective,” Dr. Stone said at the meeting sponsored by the Cardiovascular Research Foundation. He concluded that the early benefits of PCI attributable to reduced periprocedural risk “were attenuated by the greater number of events occurring during follow-up with CABG, such that at 5 years the cumulative mean time free from adverse events was similar with both treatments.” He noted that a 10-year or longer follow-up is required to characterize the very late safety profile of PCI and CABG as both stents and bypass grafts progressively fail over time.

Discussant Dharam Kumbhani, MD, an interventional cardiologist at UT Southwestern Medical Center, Dallas, said that the findings from EXCEL “help us move the field forward and help us understand this concept of risk with PCI versus CABG. It really does help inform shared decision-making with patients.”

Results of the study were published online at the time of presentation (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406). The EXCEL trial was funded by Abbott Vascular. Dr. Stone disclosed having relationships with numerous device and pharmaceutical companies but had no relevant disclosures for this study.

dbrunk@mdedge.com

SOURCE: Stone G et al. TCT 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406.
 

SAN FRANCISCO – Among patients with left main coronary artery disease and low or intermediate coronary disease complexity, no significant differences were observed between percutaneous coronary intervention and coronary artery bypass graft surgery with respect to the composite rate of death, stroke, or myocardial infarction at 5 years.

Doug Brunk/MDedge News

The findings come from an analysis of data from the EXCEL trial, which lead investigator Gregg W. Stone, MD, presented at the Transcatheter Cardiovascular Therapeutics annual meeting.

“PCI may be considered an acceptable revascularization modality for selected patients with left main coronary artery disease, a decision which should be made after heart team discussion, taking into account each patient’s individual risk factors and preferences,” said Dr. Stone, professor of medicine and professor of population health sciences and policy at the Icahn School of Medicine at Mount Sinai, New York.

Between September 2010 and March 2014, Dr. Stone and his colleagues at 126 sites in 17 countries enrolled 1,905 patients with left main CAD and site-assessed low or intermediate CAD complexity (SYNTAX score of up to 32) for randomization into one of two arms: 948 to revascularization with the Xience everolimus-eluting stent and 957 to coronary artery bypass graft surgery (CABG). The primary outcome was the composite of death, stroke, or myocardial infarction at 5 years. Long-term additional secondary outcomes included their components at 5 years, as well as therapy failure (definite stent thrombosis or symptomatic graft stenosis or occlusion), all revascularizations, and all cerebrovascular events (stroke or transient ischemic attack).

Dr. Stone reported that at 5 years, the primary composite of death, stroke, or MI occurred in 22.0% of patients in the PCI group and 19.2% of patients in the CABG group, a nonsignificant difference at P = 0.13).

However, when the researchers broke the results into three distinct risk periods within the 5-year time frame, they found that, with longer follow-up, came more of an advantage for CABG. The relative risk of PCI vs. CABG for the primary outcome favored PCI over CABG in the first 30 days (4.9% vs. 8%; hazard ratio, 0.61; P = .008), was neutral at 30 days to 1 year (4.1 vs. 3.8%; HR, 1.07; P = .76), and reversed at 1-5 years (15.1% vs. 9.7%; HR, 1.61; P less than .001). Using restricted mean survival time analysis, Dr. Stone and his colleagues found that, at the end of the 5-year follow-up period, event-free survival time was 5.2 days longer after PCI, compared with CABG. This translates into “a very similar event-free survival of a burden of disease from these two therapies at the end of 5 years,” he said.

In their analysis of secondary endpoints, some differences were noted, including an elevated risk of all-cause mortality in the PCI group, compared with the CABG group (13% vs. 9.9%, respectively; odds ratio, 1.38), yet no differences in definite cardiovascular mortality (5% vs. 4.5%; OR, 1.13) or in MI (10.6% vs. 9.1%; OR 1.14). In addition, there were fewer cerebrovascular events in the PCI vs. CABG groups (3.3% vs. 5.2%; OR, 0.61). “Overall, all of these differences were relatively small given the 5-year perspective,” Dr. Stone said at the meeting sponsored by the Cardiovascular Research Foundation. He concluded that the early benefits of PCI attributable to reduced periprocedural risk “were attenuated by the greater number of events occurring during follow-up with CABG, such that at 5 years the cumulative mean time free from adverse events was similar with both treatments.” He noted that a 10-year or longer follow-up is required to characterize the very late safety profile of PCI and CABG as both stents and bypass grafts progressively fail over time.

Discussant Dharam Kumbhani, MD, an interventional cardiologist at UT Southwestern Medical Center, Dallas, said that the findings from EXCEL “help us move the field forward and help us understand this concept of risk with PCI versus CABG. It really does help inform shared decision-making with patients.”

Results of the study were published online at the time of presentation (N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406). The EXCEL trial was funded by Abbott Vascular. Dr. Stone disclosed having relationships with numerous device and pharmaceutical companies but had no relevant disclosures for this study.

dbrunk@mdedge.com

SOURCE: Stone G et al. TCT 2019. N Engl J Med. 2019 Sep 28. doi: 10.1056/NEJMoa1909406.
 

The Food and Drug Administration has approved a transdermal asenapine delivery system (Secuado) for treatment of schizophrenia in adults, according to a release from Noven Pharmaceuticals.

Olivier Le Moal/Getty Images

The patch formulation is designed to deliver sustained concentrations of asenapine over 24-hour periods, so the system is a once-daily treatment. The efficacy and safety profile for children younger than 18 years is unknown.

The approval is based on an international, phase 3, double-blind, placebo-controlled study that included 616 adults with schizophrenia. The transdermal system achieved the study’s primary endpoint of statistically significant improvement at week 6 in the Positive and Negative Syndrome Scale, compared with placebo.

The safety profile of the system was consistent with the known profile of sublingual asenapine, and the most commonly observed adverse reactions were extrapyramidal disorder, application site reaction, and weight gain. The full prescribing information includes a boxed warning explaining that antipsychotics, such as asenapine, are associated with increased risk of death among elderly patients with dementia-related psychosis, an indication not approved for this transdermal asenapine-delivery system. Other warnings described in the prescribing information include neuroleptic malignant syndrome, tardive dyskinesia, and metabolic changes.

“In addition to offering a new delivery option, transdermal patches can also provide caretakers and health care providers with a nonintrustive, visual confirmation that a treatment is being utilized,” noted Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, in the release.

Noven is a subsidiary of Hisamitsu Pharmaceutical.

cpalmer@mdedge.com

The Food and Drug Administration has approved a transdermal asenapine delivery system (Secuado) for treatment of schizophrenia in adults, according to a release from Noven Pharmaceuticals.

Olivier Le Moal/Getty Images

The patch formulation is designed to deliver sustained concentrations of asenapine over 24-hour periods, so the system is a once-daily treatment. The efficacy and safety profile for children younger than 18 years is unknown.

The approval is based on an international, phase 3, double-blind, placebo-controlled study that included 616 adults with schizophrenia. The transdermal system achieved the study’s primary endpoint of statistically significant improvement at week 6 in the Positive and Negative Syndrome Scale, compared with placebo.

The safety profile of the system was consistent with the known profile of sublingual asenapine, and the most commonly observed adverse reactions were extrapyramidal disorder, application site reaction, and weight gain. The full prescribing information includes a boxed warning explaining that antipsychotics, such as asenapine, are associated with increased risk of death among elderly patients with dementia-related psychosis, an indication not approved for this transdermal asenapine-delivery system. Other warnings described in the prescribing information include neuroleptic malignant syndrome, tardive dyskinesia, and metabolic changes.

“In addition to offering a new delivery option, transdermal patches can also provide caretakers and health care providers with a nonintrustive, visual confirmation that a treatment is being utilized,” noted Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, in the release.

Noven is a subsidiary of Hisamitsu Pharmaceutical.

cpalmer@mdedge.com

The Food and Drug Administration has approved a transdermal asenapine delivery system (Secuado) for treatment of schizophrenia in adults, according to a release from Noven Pharmaceuticals.

Olivier Le Moal/Getty Images

The patch formulation is designed to deliver sustained concentrations of asenapine over 24-hour periods, so the system is a once-daily treatment. The efficacy and safety profile for children younger than 18 years is unknown.

The approval is based on an international, phase 3, double-blind, placebo-controlled study that included 616 adults with schizophrenia. The transdermal system achieved the study’s primary endpoint of statistically significant improvement at week 6 in the Positive and Negative Syndrome Scale, compared with placebo.

The safety profile of the system was consistent with the known profile of sublingual asenapine, and the most commonly observed adverse reactions were extrapyramidal disorder, application site reaction, and weight gain. The full prescribing information includes a boxed warning explaining that antipsychotics, such as asenapine, are associated with increased risk of death among elderly patients with dementia-related psychosis, an indication not approved for this transdermal asenapine-delivery system. Other warnings described in the prescribing information include neuroleptic malignant syndrome, tardive dyskinesia, and metabolic changes.

“In addition to offering a new delivery option, transdermal patches can also provide caretakers and health care providers with a nonintrustive, visual confirmation that a treatment is being utilized,” noted Leslie Citrome, MD, MPH, clinical professor of psychiatry and behavioral sciences at New York Medical College, in the release.

Noven is a subsidiary of Hisamitsu Pharmaceutical.

cpalmer@mdedge.com

Individuals with schizophrenia had elevated levels of one Epstein-Barr virus (EBV) antibody but atypically low levels of another, which investigators deemed an “aberrant immune response.”

Faith Dickerson, PhD, MPH, Lorraine Jones-Brando, PhD,and colleagues investigated the IgG antibodies and genetics of 432 individuals with schizophrenia and 311 without. The investigators used solid-phase immunoassays to measure antibodies, and they measured titers of antibodies not just for EBV but also for related viruses. The group with schizophrenia was slightly older, with a mean age of 38.2 years, compared with a mean age of 32.03 years in the group without schizophrenia. Also, 65.7% of the study participants in the schizophrenia group were male, compared with 39.2% of those in the group without schizophrenia. More than 60% of participants in the schizophrenia group were cigarette smokers, compared with 14.8% of the controls. The study was published in Schizophrenia Bulletin.

Compared with the controls, individuals with schizophrenia had elevated levels of EBV viral capsid antibody (EBV-VCA) with a mean effect size of 0.356 (P less than .002); however, the levels of EBV nuclear antigen-1 (EBNA-1) were not significantly different from those seen in individuals without schizophrenia, reported Dr. Dickerson of the Stanley Research Program at Sheppard Pratt, and Dr. Jones-Brando of Johns Hopkins University, both in Baltimore.

The investigators also examined adjusted odds ratios for individuals with schizophrenia having levels of antibodies higher than percentile cutoffs of the controls; for example, the aOR for those individuals having EBV VCA levels at the 90th percentile of controls was 2.03 (95% confidence interval, 1.23-3.37; P = .007). The aORs for EBNA-1 were not significant.

Those results suggest an aberrant immune response to EBV because, in most cases, EBV VCA and EBNA-1 are expressed at roughly equal levels, the investigators said.

“There are a number of therapeutic interventions available for the modulation of EBV infection including antiviral medications and pharmacological compounds which can modulate the immune response,” they wrote.

“An increased understanding of the role of EBV infection might thus lead to novel methods for the prevention and treatment of schizophrenia.”

The study was funded by the Silvio O. Conte Center at Johns Hopkins University in Baltimore, and the Stanley Medical Research Institute, Chevy Chase, Md. Dr. Dickerson, Dr. Jones-Brando, and colleagues reported having no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Dickerson F et al. Schizophr Bull. 2019 Sep 11;45(5):1112-9.

Individuals with schizophrenia had elevated levels of one Epstein-Barr virus (EBV) antibody but atypically low levels of another, which investigators deemed an “aberrant immune response.”

Faith Dickerson, PhD, MPH, Lorraine Jones-Brando, PhD,and colleagues investigated the IgG antibodies and genetics of 432 individuals with schizophrenia and 311 without. The investigators used solid-phase immunoassays to measure antibodies, and they measured titers of antibodies not just for EBV but also for related viruses. The group with schizophrenia was slightly older, with a mean age of 38.2 years, compared with a mean age of 32.03 years in the group without schizophrenia. Also, 65.7% of the study participants in the schizophrenia group were male, compared with 39.2% of those in the group without schizophrenia. More than 60% of participants in the schizophrenia group were cigarette smokers, compared with 14.8% of the controls. The study was published in Schizophrenia Bulletin.

Compared with the controls, individuals with schizophrenia had elevated levels of EBV viral capsid antibody (EBV-VCA) with a mean effect size of 0.356 (P less than .002); however, the levels of EBV nuclear antigen-1 (EBNA-1) were not significantly different from those seen in individuals without schizophrenia, reported Dr. Dickerson of the Stanley Research Program at Sheppard Pratt, and Dr. Jones-Brando of Johns Hopkins University, both in Baltimore.

The investigators also examined adjusted odds ratios for individuals with schizophrenia having levels of antibodies higher than percentile cutoffs of the controls; for example, the aOR for those individuals having EBV VCA levels at the 90th percentile of controls was 2.03 (95% confidence interval, 1.23-3.37; P = .007). The aORs for EBNA-1 were not significant.

Those results suggest an aberrant immune response to EBV because, in most cases, EBV VCA and EBNA-1 are expressed at roughly equal levels, the investigators said.

“There are a number of therapeutic interventions available for the modulation of EBV infection including antiviral medications and pharmacological compounds which can modulate the immune response,” they wrote.

“An increased understanding of the role of EBV infection might thus lead to novel methods for the prevention and treatment of schizophrenia.”

The study was funded by the Silvio O. Conte Center at Johns Hopkins University in Baltimore, and the Stanley Medical Research Institute, Chevy Chase, Md. Dr. Dickerson, Dr. Jones-Brando, and colleagues reported having no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Dickerson F et al. Schizophr Bull. 2019 Sep 11;45(5):1112-9.

Individuals with schizophrenia had elevated levels of one Epstein-Barr virus (EBV) antibody but atypically low levels of another, which investigators deemed an “aberrant immune response.”

Faith Dickerson, PhD, MPH, Lorraine Jones-Brando, PhD,and colleagues investigated the IgG antibodies and genetics of 432 individuals with schizophrenia and 311 without. The investigators used solid-phase immunoassays to measure antibodies, and they measured titers of antibodies not just for EBV but also for related viruses. The group with schizophrenia was slightly older, with a mean age of 38.2 years, compared with a mean age of 32.03 years in the group without schizophrenia. Also, 65.7% of the study participants in the schizophrenia group were male, compared with 39.2% of those in the group without schizophrenia. More than 60% of participants in the schizophrenia group were cigarette smokers, compared with 14.8% of the controls. The study was published in Schizophrenia Bulletin.

Compared with the controls, individuals with schizophrenia had elevated levels of EBV viral capsid antibody (EBV-VCA) with a mean effect size of 0.356 (P less than .002); however, the levels of EBV nuclear antigen-1 (EBNA-1) were not significantly different from those seen in individuals without schizophrenia, reported Dr. Dickerson of the Stanley Research Program at Sheppard Pratt, and Dr. Jones-Brando of Johns Hopkins University, both in Baltimore.

The investigators also examined adjusted odds ratios for individuals with schizophrenia having levels of antibodies higher than percentile cutoffs of the controls; for example, the aOR for those individuals having EBV VCA levels at the 90th percentile of controls was 2.03 (95% confidence interval, 1.23-3.37; P = .007). The aORs for EBNA-1 were not significant.

Those results suggest an aberrant immune response to EBV because, in most cases, EBV VCA and EBNA-1 are expressed at roughly equal levels, the investigators said.

“There are a number of therapeutic interventions available for the modulation of EBV infection including antiviral medications and pharmacological compounds which can modulate the immune response,” they wrote.

“An increased understanding of the role of EBV infection might thus lead to novel methods for the prevention and treatment of schizophrenia.”

The study was funded by the Silvio O. Conte Center at Johns Hopkins University in Baltimore, and the Stanley Medical Research Institute, Chevy Chase, Md. Dr. Dickerson, Dr. Jones-Brando, and colleagues reported having no conflicts of interest.

cpalmer@mdedge.com

SOURCE: Dickerson F et al. Schizophr Bull. 2019 Sep 11;45(5):1112-9.

SAN DIEGO – Its toll is obscured by the opioid crisis, but methamphetamine use is on the rise in the United States. There are no approved treatments for methamphetamine use, but a psychiatrist told colleagues that several off-label medications might prove helpful.

However, the evidence supporting the use of these medications for patients taking methamphetamine is not robust, “and none are even close to [Food and Drug Administration] approval,” said Larissa J. Mooney, MD, of the University of California, Los Angeles, and the VA Greater Los Angeles Healthcare System. “But if I use something that’s approved for depression or might be helpful for anxiety symptoms, maybe it would also help reduce their likelihood of relapse in conjunction with an evidence-based behavioral program or treatment with a therapist.”

Dr. Mooney, who spoke at the annual Psych Congress, highlighted a federal report estimating that 0.4% of people aged 18-25 in 2017 used the drug within the past month, compared with 0.3% of those aged 26 and higher.

There were about 758,000 current adult users of methamphetamine in 2017, the report found.

Meanwhile, concurrent use of methamphetamine among patients who use opioids chronically has almost doubled, to 34% in 2017, from 19% in 2011 (Drug Alcohol Depend. 2018 Dec 1;193:14-20). And, Dr. Mooney said, deaths from stimulants are rising, even independent of opioid deaths.

Stimulant users typically have other psychiatric conditions, such as depression, anxiety, and concentration problems, Dr. Mooney said. In those cases, she said, treating those conditions might help with the substance use, too.

For methamphetamine use disorder, she highlighted some medications that might be helpful, although, again, she cautioned that evidence is not strong:

• Bupropion (Wellbutrin). Research suggests that this drug is more effective in patients with less severe methamphetamine use disorder, Dr. Mooney said. “It’s a more stimulating antidepressant, and can be helpful with concentration and attention.”
• Mirtazapine (Remeron). “I keep it in my list of options for some [who are] really anxious and not sleeping well,” she said. “It might be beneficial.”
• Naltrexone (ReVia, Depade, Vivitrol). “There are some early signs of efficacy,” she said, and a randomized, controlled trial is in progress.
• Methylphenidate (Ritalin, Concerta) and topiramate (Topamax). There’s “low-strength” evidence that the drugs can be helpful and lower use of methamphetamine, she said. However, methylphenidate is a stimulant. There’s controversy over the use of stimulants to treat patients with substance use disorders, Dr. Mooney said, and she tends to be conservative about their use in this population.

Why not use them to treat methamphetamine users in the same way that opioids such as methadone are used to treat opioid use addiction? “We don’t have an equivalent stimulant that works in the same way,” she said. “They don’t stay in the system for 24 hours. If you take a prescription stimulant, by the end of the day it wears off. It won’t stay in the same way as agonist treatments for opioid disorder.”

Even so, she said, “it makes sense that stimulants might be helpful.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Its toll is obscured by the opioid crisis, but methamphetamine use is on the rise in the United States. There are no approved treatments for methamphetamine use, but a psychiatrist told colleagues that several off-label medications might prove helpful.

However, the evidence supporting the use of these medications for patients taking methamphetamine is not robust, “and none are even close to [Food and Drug Administration] approval,” said Larissa J. Mooney, MD, of the University of California, Los Angeles, and the VA Greater Los Angeles Healthcare System. “But if I use something that’s approved for depression or might be helpful for anxiety symptoms, maybe it would also help reduce their likelihood of relapse in conjunction with an evidence-based behavioral program or treatment with a therapist.”

Dr. Mooney, who spoke at the annual Psych Congress, highlighted a federal report estimating that 0.4% of people aged 18-25 in 2017 used the drug within the past month, compared with 0.3% of those aged 26 and higher.

There were about 758,000 current adult users of methamphetamine in 2017, the report found.

Meanwhile, concurrent use of methamphetamine among patients who use opioids chronically has almost doubled, to 34% in 2017, from 19% in 2011 (Drug Alcohol Depend. 2018 Dec 1;193:14-20). And, Dr. Mooney said, deaths from stimulants are rising, even independent of opioid deaths.

Stimulant users typically have other psychiatric conditions, such as depression, anxiety, and concentration problems, Dr. Mooney said. In those cases, she said, treating those conditions might help with the substance use, too.

For methamphetamine use disorder, she highlighted some medications that might be helpful, although, again, she cautioned that evidence is not strong:

• Bupropion (Wellbutrin). Research suggests that this drug is more effective in patients with less severe methamphetamine use disorder, Dr. Mooney said. “It’s a more stimulating antidepressant, and can be helpful with concentration and attention.”
• Mirtazapine (Remeron). “I keep it in my list of options for some [who are] really anxious and not sleeping well,” she said. “It might be beneficial.”
• Naltrexone (ReVia, Depade, Vivitrol). “There are some early signs of efficacy,” she said, and a randomized, controlled trial is in progress.
• Methylphenidate (Ritalin, Concerta) and topiramate (Topamax). There’s “low-strength” evidence that the drugs can be helpful and lower use of methamphetamine, she said. However, methylphenidate is a stimulant. There’s controversy over the use of stimulants to treat patients with substance use disorders, Dr. Mooney said, and she tends to be conservative about their use in this population.

Why not use them to treat methamphetamine users in the same way that opioids such as methadone are used to treat opioid use addiction? “We don’t have an equivalent stimulant that works in the same way,” she said. “They don’t stay in the system for 24 hours. If you take a prescription stimulant, by the end of the day it wears off. It won’t stay in the same way as agonist treatments for opioid disorder.”

Even so, she said, “it makes sense that stimulants might be helpful.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

SAN DIEGO – Its toll is obscured by the opioid crisis, but methamphetamine use is on the rise in the United States. There are no approved treatments for methamphetamine use, but a psychiatrist told colleagues that several off-label medications might prove helpful.

However, the evidence supporting the use of these medications for patients taking methamphetamine is not robust, “and none are even close to [Food and Drug Administration] approval,” said Larissa J. Mooney, MD, of the University of California, Los Angeles, and the VA Greater Los Angeles Healthcare System. “But if I use something that’s approved for depression or might be helpful for anxiety symptoms, maybe it would also help reduce their likelihood of relapse in conjunction with an evidence-based behavioral program or treatment with a therapist.”

Dr. Mooney, who spoke at the annual Psych Congress, highlighted a federal report estimating that 0.4% of people aged 18-25 in 2017 used the drug within the past month, compared with 0.3% of those aged 26 and higher.

There were about 758,000 current adult users of methamphetamine in 2017, the report found.

Meanwhile, concurrent use of methamphetamine among patients who use opioids chronically has almost doubled, to 34% in 2017, from 19% in 2011 (Drug Alcohol Depend. 2018 Dec 1;193:14-20). And, Dr. Mooney said, deaths from stimulants are rising, even independent of opioid deaths.

Stimulant users typically have other psychiatric conditions, such as depression, anxiety, and concentration problems, Dr. Mooney said. In those cases, she said, treating those conditions might help with the substance use, too.

For methamphetamine use disorder, she highlighted some medications that might be helpful, although, again, she cautioned that evidence is not strong:

• Bupropion (Wellbutrin). Research suggests that this drug is more effective in patients with less severe methamphetamine use disorder, Dr. Mooney said. “It’s a more stimulating antidepressant, and can be helpful with concentration and attention.”
• Mirtazapine (Remeron). “I keep it in my list of options for some [who are] really anxious and not sleeping well,” she said. “It might be beneficial.”
• Naltrexone (ReVia, Depade, Vivitrol). “There are some early signs of efficacy,” she said, and a randomized, controlled trial is in progress.
• Methylphenidate (Ritalin, Concerta) and topiramate (Topamax). There’s “low-strength” evidence that the drugs can be helpful and lower use of methamphetamine, she said. However, methylphenidate is a stimulant. There’s controversy over the use of stimulants to treat patients with substance use disorders, Dr. Mooney said, and she tends to be conservative about their use in this population.

Why not use them to treat methamphetamine users in the same way that opioids such as methadone are used to treat opioid use addiction? “We don’t have an equivalent stimulant that works in the same way,” she said. “They don’t stay in the system for 24 hours. If you take a prescription stimulant, by the end of the day it wears off. It won’t stay in the same way as agonist treatments for opioid disorder.”

Even so, she said, “it makes sense that stimulants might be helpful.”

Dr. Mooney disclosed an advisory board relationship with Alkermes and grant/research support from the National Institute on Drug Abuse.

Maternal weight gains at either end of the weight spectrum may influence the risk of poor neonatal outcomes for twins, Lisa M. Bodnar, PhD, and colleagues determined.

anopdesignstock/Thinkstock

The risks of cesarean section and neonatal death were elevated for those mothers who were overweight before pregnancy and then gained too much. But infants of underweight women who didn’t gain enough faced risks as well, wrote Dr. Bodnar of the University of Pittsburgh and associates in Obstetrics & Gynecology.

Among the most severely overweight women (obesity grade 2 or 3) who gained the most weight (43 kg) at 37 weeks’ gestation, there were 6 fewer small-for-gestational-age (SGA) infants per 100 births, but 14 more large-for-gestational-age (LGA) infants, 4 more cesarean deliveries, and 2 more neonatal deaths per 100 births. By contrast, among the most severely underweight women who gained the least amount of weight (9 kg), there were 18 more SGA infants, 3 fewer LGA infants, and 11 fewer cesareans, but 6 more preterm births before 32 weeks’ gestation.

The same U-shaped pattern also occurred within the individual weight categories. For example, compared with the outcomes among the most underweight women who gained least, among underweight women who gained the most (37 kg), there were eight fewer SGA infants, but four more LGA infants, 16 excess preterm births, and 9 excess infant deaths.

“If the associations we observed are even partially reflective of causality, targeted modification of pregnancy weight gain in women carrying twins might improve pregnancy outcomes,” wrote Dr. Bodnar and her team. “Data on a wide range of short- and long-term outcomes and information on the relative seriousness of these outcomes are needed to determine optimal gestational weight gain ranges for twin pregnancies.”

The cohort comprised 54,836 live-born twins from 27,723 twin pregnancies who were included in the MOMs database maintained by the University of Pennsylvania, Philadelphia. The population-based study tracks maternal obesity, gestational weight gain, and adverse birth outcomes. The information came from infant birth and death vital statistics records from 2003 to 2013.

However, this very source puts the findings in some degree of uncertainty, Ozhan Turan, MD, said in an interview.

“It’s a very nice study, and the statistics are very well done,” said Dr. Turan, who is the director of fetal therapy and complex obstetric surgery at the University of Maryland School of Medicine. “But that kind of data has pitfalls that are unavoidable. For example, they don’t have access to maternal medical comorbidities which are mostly related to the outcome, particularly gestational diabetes and preeclampsia. They also don’t have the information on chorionicity – and we know that monochorionic twins face much greater risk for these outcomes than dichorionic twins.”

The investigators calculated total gestational weight gain by subtracting prepregnancy weight from maternal weight at delivery. The analysis controlled for race and ethnicity, education, neonatal care, level of birth facility, parity, payment at delivery, smoking during pregnancy, marital status, year of birth, height, maternal age, preexisting diabetes or hypertension, infertility treatment, neonatal sex, and racial composition of neighborhood, as a proxy of neighborhood-level socioeconomic status. Approximately 16% of mothers received infertility treatment.

Of the cohort, 3% were underweight, 48% were normal weight, 24% were overweight, 13% were grade 1 obese, 7% grade 2 obese, and 5% grade 3 obese.

“Pregnancy weight gain was negatively associated with SGA and positively associated with LGA and cesarean delivery in all [body mass index] groups. For example, among normal-weight women, compared with a pregnancy weight gain equivalent to 20 kg at 37 weeks’ of gestation, a weight gain of 27 kg at 37 weeks’ of gestation was associated with 2.2 fewer cases of SGA but 2.9 more cases of LGA and 3.7 more cases of cesarean delivery,” Dr. Bodnar and associates wrote.

The investigators found that “weight gains well above or well below the [Institute of Medicine] provisional guidelines (less than 14 kg or more than 27 kg in underweight or normal-weight women, less than 11 kg or more than 28 kg in overweight women, and less than 6.4 kg or more than 26 kg in women with obesity) were associated with the highest risk of adverse outcomes.”

“I would not say this is practice-changing information,” said Dr. Turan. “We already know all this. What would be very helpful is an algorithm to tell us, if a patient is pregnant with twins, this is the amount of weight you have to gain.”

For overweight patients, Dr. Turan tries to impart the key message of moderate or slight weight gain, according to prepregnancy body mass index. For underweight patients, the picture is a bit more complex.

“There are not that many who are underweight before pregnancy, so first thing I look for is the reason a woman is underweight. Is she just not eating properly? Is there a drug dependence issue, alcohol dependence, HIV? Is there smoking? A gut problem that causes malnutrition. You can’t just say ‘eat more.’ That does not solve the problem. We need to find out why she is underweight and fix that first,” said Dr. Turan.

Neither Dr. Bodnar nor Dr. Turan had any relevant financial disclosures. One coauthor disclosed her institution received funds from the University of Pittsburgh. The study was funded by National Institutes of Health grants.
 

SOURCE: Bodnar LM et al. Obstet Gynecol. 2019;134:1075-86.

Maternal weight gains at either end of the weight spectrum may influence the risk of poor neonatal outcomes for twins, Lisa M. Bodnar, PhD, and colleagues determined.

anopdesignstock/Thinkstock

The risks of cesarean section and neonatal death were elevated for those mothers who were overweight before pregnancy and then gained too much. But infants of underweight women who didn’t gain enough faced risks as well, wrote Dr. Bodnar of the University of Pittsburgh and associates in Obstetrics & Gynecology.

Among the most severely overweight women (obesity grade 2 or 3) who gained the most weight (43 kg) at 37 weeks’ gestation, there were 6 fewer small-for-gestational-age (SGA) infants per 100 births, but 14 more large-for-gestational-age (LGA) infants, 4 more cesarean deliveries, and 2 more neonatal deaths per 100 births. By contrast, among the most severely underweight women who gained the least amount of weight (9 kg), there were 18 more SGA infants, 3 fewer LGA infants, and 11 fewer cesareans, but 6 more preterm births before 32 weeks’ gestation.

The same U-shaped pattern also occurred within the individual weight categories. For example, compared with the outcomes among the most underweight women who gained least, among underweight women who gained the most (37 kg), there were eight fewer SGA infants, but four more LGA infants, 16 excess preterm births, and 9 excess infant deaths.

“If the associations we observed are even partially reflective of causality, targeted modification of pregnancy weight gain in women carrying twins might improve pregnancy outcomes,” wrote Dr. Bodnar and her team. “Data on a wide range of short- and long-term outcomes and information on the relative seriousness of these outcomes are needed to determine optimal gestational weight gain ranges for twin pregnancies.”

The cohort comprised 54,836 live-born twins from 27,723 twin pregnancies who were included in the MOMs database maintained by the University of Pennsylvania, Philadelphia. The population-based study tracks maternal obesity, gestational weight gain, and adverse birth outcomes. The information came from infant birth and death vital statistics records from 2003 to 2013.

However, this very source puts the findings in some degree of uncertainty, Ozhan Turan, MD, said in an interview.

“It’s a very nice study, and the statistics are very well done,” said Dr. Turan, who is the director of fetal therapy and complex obstetric surgery at the University of Maryland School of Medicine. “But that kind of data has pitfalls that are unavoidable. For example, they don’t have access to maternal medical comorbidities which are mostly related to the outcome, particularly gestational diabetes and preeclampsia. They also don’t have the information on chorionicity – and we know that monochorionic twins face much greater risk for these outcomes than dichorionic twins.”

The investigators calculated total gestational weight gain by subtracting prepregnancy weight from maternal weight at delivery. The analysis controlled for race and ethnicity, education, neonatal care, level of birth facility, parity, payment at delivery, smoking during pregnancy, marital status, year of birth, height, maternal age, preexisting diabetes or hypertension, infertility treatment, neonatal sex, and racial composition of neighborhood, as a proxy of neighborhood-level socioeconomic status. Approximately 16% of mothers received infertility treatment.

Of the cohort, 3% were underweight, 48% were normal weight, 24% were overweight, 13% were grade 1 obese, 7% grade 2 obese, and 5% grade 3 obese.

“Pregnancy weight gain was negatively associated with SGA and positively associated with LGA and cesarean delivery in all [body mass index] groups. For example, among normal-weight women, compared with a pregnancy weight gain equivalent to 20 kg at 37 weeks’ of gestation, a weight gain of 27 kg at 37 weeks’ of gestation was associated with 2.2 fewer cases of SGA but 2.9 more cases of LGA and 3.7 more cases of cesarean delivery,” Dr. Bodnar and associates wrote.

The investigators found that “weight gains well above or well below the [Institute of Medicine] provisional guidelines (less than 14 kg or more than 27 kg in underweight or normal-weight women, less than 11 kg or more than 28 kg in overweight women, and less than 6.4 kg or more than 26 kg in women with obesity) were associated with the highest risk of adverse outcomes.”

“I would not say this is practice-changing information,” said Dr. Turan. “We already know all this. What would be very helpful is an algorithm to tell us, if a patient is pregnant with twins, this is the amount of weight you have to gain.”

For overweight patients, Dr. Turan tries to impart the key message of moderate or slight weight gain, according to prepregnancy body mass index. For underweight patients, the picture is a bit more complex.

“There are not that many who are underweight before pregnancy, so first thing I look for is the reason a woman is underweight. Is she just not eating properly? Is there a drug dependence issue, alcohol dependence, HIV? Is there smoking? A gut problem that causes malnutrition. You can’t just say ‘eat more.’ That does not solve the problem. We need to find out why she is underweight and fix that first,” said Dr. Turan.

Neither Dr. Bodnar nor Dr. Turan had any relevant financial disclosures. One coauthor disclosed her institution received funds from the University of Pittsburgh. The study was funded by National Institutes of Health grants.
 

SOURCE: Bodnar LM et al. Obstet Gynecol. 2019;134:1075-86.

Maternal weight gains at either end of the weight spectrum may influence the risk of poor neonatal outcomes for twins, Lisa M. Bodnar, PhD, and colleagues determined.

anopdesignstock/Thinkstock

The risks of cesarean section and neonatal death were elevated for those mothers who were overweight before pregnancy and then gained too much. But infants of underweight women who didn’t gain enough faced risks as well, wrote Dr. Bodnar of the University of Pittsburgh and associates in Obstetrics & Gynecology.

Among the most severely overweight women (obesity grade 2 or 3) who gained the most weight (43 kg) at 37 weeks’ gestation, there were 6 fewer small-for-gestational-age (SGA) infants per 100 births, but 14 more large-for-gestational-age (LGA) infants, 4 more cesarean deliveries, and 2 more neonatal deaths per 100 births. By contrast, among the most severely underweight women who gained the least amount of weight (9 kg), there were 18 more SGA infants, 3 fewer LGA infants, and 11 fewer cesareans, but 6 more preterm births before 32 weeks’ gestation.

The same U-shaped pattern also occurred within the individual weight categories. For example, compared with the outcomes among the most underweight women who gained least, among underweight women who gained the most (37 kg), there were eight fewer SGA infants, but four more LGA infants, 16 excess preterm births, and 9 excess infant deaths.

“If the associations we observed are even partially reflective of causality, targeted modification of pregnancy weight gain in women carrying twins might improve pregnancy outcomes,” wrote Dr. Bodnar and her team. “Data on a wide range of short- and long-term outcomes and information on the relative seriousness of these outcomes are needed to determine optimal gestational weight gain ranges for twin pregnancies.”

The cohort comprised 54,836 live-born twins from 27,723 twin pregnancies who were included in the MOMs database maintained by the University of Pennsylvania, Philadelphia. The population-based study tracks maternal obesity, gestational weight gain, and adverse birth outcomes. The information came from infant birth and death vital statistics records from 2003 to 2013.

However, this very source puts the findings in some degree of uncertainty, Ozhan Turan, MD, said in an interview.

“It’s a very nice study, and the statistics are very well done,” said Dr. Turan, who is the director of fetal therapy and complex obstetric surgery at the University of Maryland School of Medicine. “But that kind of data has pitfalls that are unavoidable. For example, they don’t have access to maternal medical comorbidities which are mostly related to the outcome, particularly gestational diabetes and preeclampsia. They also don’t have the information on chorionicity – and we know that monochorionic twins face much greater risk for these outcomes than dichorionic twins.”

The investigators calculated total gestational weight gain by subtracting prepregnancy weight from maternal weight at delivery. The analysis controlled for race and ethnicity, education, neonatal care, level of birth facility, parity, payment at delivery, smoking during pregnancy, marital status, year of birth, height, maternal age, preexisting diabetes or hypertension, infertility treatment, neonatal sex, and racial composition of neighborhood, as a proxy of neighborhood-level socioeconomic status. Approximately 16% of mothers received infertility treatment.

Of the cohort, 3% were underweight, 48% were normal weight, 24% were overweight, 13% were grade 1 obese, 7% grade 2 obese, and 5% grade 3 obese.

“Pregnancy weight gain was negatively associated with SGA and positively associated with LGA and cesarean delivery in all [body mass index] groups. For example, among normal-weight women, compared with a pregnancy weight gain equivalent to 20 kg at 37 weeks’ of gestation, a weight gain of 27 kg at 37 weeks’ of gestation was associated with 2.2 fewer cases of SGA but 2.9 more cases of LGA and 3.7 more cases of cesarean delivery,” Dr. Bodnar and associates wrote.

The investigators found that “weight gains well above or well below the [Institute of Medicine] provisional guidelines (less than 14 kg or more than 27 kg in underweight or normal-weight women, less than 11 kg or more than 28 kg in overweight women, and less than 6.4 kg or more than 26 kg in women with obesity) were associated with the highest risk of adverse outcomes.”

“I would not say this is practice-changing information,” said Dr. Turan. “We already know all this. What would be very helpful is an algorithm to tell us, if a patient is pregnant with twins, this is the amount of weight you have to gain.”

For overweight patients, Dr. Turan tries to impart the key message of moderate or slight weight gain, according to prepregnancy body mass index. For underweight patients, the picture is a bit more complex.

“There are not that many who are underweight before pregnancy, so first thing I look for is the reason a woman is underweight. Is she just not eating properly? Is there a drug dependence issue, alcohol dependence, HIV? Is there smoking? A gut problem that causes malnutrition. You can’t just say ‘eat more.’ That does not solve the problem. We need to find out why she is underweight and fix that first,” said Dr. Turan.

Neither Dr. Bodnar nor Dr. Turan had any relevant financial disclosures. One coauthor disclosed her institution received funds from the University of Pittsburgh. The study was funded by National Institutes of Health grants.
 

SOURCE: Bodnar LM et al. Obstet Gynecol. 2019;134:1075-86.