Pharmacology

SAN FRANCISCO – Used appropriately, the benefits of benzodiazepines far outweigh the risks in elderly people, according to Carl Salzman, MD, a psychiatry professor at Harvard Medical School, Boston.

M. Alexander Otto/MDedge News

Appropriate use means very low doses – 0.5 mg or less every day or b.i.d. – of short-acting benzodiazepines, either lorazepam, oxazepam, or temazepam. There’s no worry of dose escalation or addiction in the elderly, and since the drugs are not metabolized by the cytochrome P450 system, the risk of drug interactions is very small, except for a compounding effect with alcohol and other sedative hypnotics, such as zolpidem (Ambien). The fall risk is lower than it is with antidepressants and antipsychotics (Psychiatr Serv. 2003 Jul;54[7]:1006-1); (Arch Intern Med. 2009 Nov 23;169[21]:1952-60).

In short, the drugs are “wonderful” for geriatric anxiety and anxiety-related insomnia, Dr. Salzman said at the American Psychiatric Association annual meeting.

Even so, it’s “very hard to get doctors and residents to prescribe them.” It’s like the benzodiazepine scare in the 1980s, about valium. “Newspapers were filled with stories about addicts. I’m having a little bit of déjà vu all over again,” he said.

This time around, the problem is a concern that benzodiazepines cause Alzheimer’s disease, plus collateral damage from the opioid crisis. People with addiction to opioids like benzodiazepines, because they boost the high, so they have significant street value, and drug seekers demand them in the clinic. Some clinicians would rather not deal with the drugs at all.

The Alzheimer’s worry stems largely from a widely reported review that found an association between Alzheimer’s disease and previous benzodiazepine use. The finding was based on public health insurance data from Quebec; no patients were seen (BMJ. 2014 Sep 9;349:g5205).

Among many “very large questions” about the study’s validity, people “may have been on benzos because they already had memory impairment and were anxious about it,” a common occurrence. In that case, “it’s not that benzos caused dementia; it was the other way around.” Also, there was no control for substance and alcohol use, Dr. Salzman said (J Clin Psychopharmacol. 2015 Feb;35[1]:1-3).

A more robust study followed patients 65 years and older for a mean of 7.3 years, comparing benzodiazepine users to nonusers. The team found a slightly higher risk of dementia in people with minimal exposure to benzodiazepines but not with the highest level of exposure, and concluded that the finding did “not support a causal association between benzodiazepine use and dementia” (BMJ. 2016 Feb 2;352:i90).

Meanwhile, a recent review of more than a million patients found either no or a minor increased risk of mortality, another concern with benzodiazepines in the elderly. “If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of” it, the investigators concluded (BMJ. 2017 Jul 6;358:j294).

To be sure, short-term memory loss can occur with benzodiazepines, but patients did not seem to mind in a study Dr. Salzman conducted years ago in an upscale nursing home in Boston. A “dramatic” rebound was reported in short-term recall 2 weeks after volunteers tapered off benzodiazepines, mostly lorazepam, compared with those who stayed on them.

“I sat down to have lunch with the discontinuers, and I said to them, ‘Aren’t you glad that you are not taking these horrible drugs anymore, and your memory is so much better? They said, ‘No, what’s to remember? It was true that when we were taking those drugs, we might not have remembered what we watched on television the night before, but if you give a choice between feeling calm in the days, sleeping at night, and remembering what we watch on television, we’ll take the calm and the sleep every time,’ ” Dr. Salzman said.

He had no disclosures.

aotto@mdedge.com

SAN FRANCISCO – Used appropriately, the benefits of benzodiazepines far outweigh the risks in elderly people, according to Carl Salzman, MD, a psychiatry professor at Harvard Medical School, Boston.

M. Alexander Otto/MDedge News

Appropriate use means very low doses – 0.5 mg or less every day or b.i.d. – of short-acting benzodiazepines, either lorazepam, oxazepam, or temazepam. There’s no worry of dose escalation or addiction in the elderly, and since the drugs are not metabolized by the cytochrome P450 system, the risk of drug interactions is very small, except for a compounding effect with alcohol and other sedative hypnotics, such as zolpidem (Ambien). The fall risk is lower than it is with antidepressants and antipsychotics (Psychiatr Serv. 2003 Jul;54[7]:1006-1); (Arch Intern Med. 2009 Nov 23;169[21]:1952-60).

In short, the drugs are “wonderful” for geriatric anxiety and anxiety-related insomnia, Dr. Salzman said at the American Psychiatric Association annual meeting.

Even so, it’s “very hard to get doctors and residents to prescribe them.” It’s like the benzodiazepine scare in the 1980s, about valium. “Newspapers were filled with stories about addicts. I’m having a little bit of déjà vu all over again,” he said.

This time around, the problem is a concern that benzodiazepines cause Alzheimer’s disease, plus collateral damage from the opioid crisis. People with addiction to opioids like benzodiazepines, because they boost the high, so they have significant street value, and drug seekers demand them in the clinic. Some clinicians would rather not deal with the drugs at all.

The Alzheimer’s worry stems largely from a widely reported review that found an association between Alzheimer’s disease and previous benzodiazepine use. The finding was based on public health insurance data from Quebec; no patients were seen (BMJ. 2014 Sep 9;349:g5205).

Among many “very large questions” about the study’s validity, people “may have been on benzos because they already had memory impairment and were anxious about it,” a common occurrence. In that case, “it’s not that benzos caused dementia; it was the other way around.” Also, there was no control for substance and alcohol use, Dr. Salzman said (J Clin Psychopharmacol. 2015 Feb;35[1]:1-3).

A more robust study followed patients 65 years and older for a mean of 7.3 years, comparing benzodiazepine users to nonusers. The team found a slightly higher risk of dementia in people with minimal exposure to benzodiazepines but not with the highest level of exposure, and concluded that the finding did “not support a causal association between benzodiazepine use and dementia” (BMJ. 2016 Feb 2;352:i90).

Meanwhile, a recent review of more than a million patients found either no or a minor increased risk of mortality, another concern with benzodiazepines in the elderly. “If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of” it, the investigators concluded (BMJ. 2017 Jul 6;358:j294).

To be sure, short-term memory loss can occur with benzodiazepines, but patients did not seem to mind in a study Dr. Salzman conducted years ago in an upscale nursing home in Boston. A “dramatic” rebound was reported in short-term recall 2 weeks after volunteers tapered off benzodiazepines, mostly lorazepam, compared with those who stayed on them.

“I sat down to have lunch with the discontinuers, and I said to them, ‘Aren’t you glad that you are not taking these horrible drugs anymore, and your memory is so much better? They said, ‘No, what’s to remember? It was true that when we were taking those drugs, we might not have remembered what we watched on television the night before, but if you give a choice between feeling calm in the days, sleeping at night, and remembering what we watch on television, we’ll take the calm and the sleep every time,’ ” Dr. Salzman said.

He had no disclosures.

aotto@mdedge.com

SAN FRANCISCO – Used appropriately, the benefits of benzodiazepines far outweigh the risks in elderly people, according to Carl Salzman, MD, a psychiatry professor at Harvard Medical School, Boston.

M. Alexander Otto/MDedge News

Appropriate use means very low doses – 0.5 mg or less every day or b.i.d. – of short-acting benzodiazepines, either lorazepam, oxazepam, or temazepam. There’s no worry of dose escalation or addiction in the elderly, and since the drugs are not metabolized by the cytochrome P450 system, the risk of drug interactions is very small, except for a compounding effect with alcohol and other sedative hypnotics, such as zolpidem (Ambien). The fall risk is lower than it is with antidepressants and antipsychotics (Psychiatr Serv. 2003 Jul;54[7]:1006-1); (Arch Intern Med. 2009 Nov 23;169[21]:1952-60).

In short, the drugs are “wonderful” for geriatric anxiety and anxiety-related insomnia, Dr. Salzman said at the American Psychiatric Association annual meeting.

Even so, it’s “very hard to get doctors and residents to prescribe them.” It’s like the benzodiazepine scare in the 1980s, about valium. “Newspapers were filled with stories about addicts. I’m having a little bit of déjà vu all over again,” he said.

This time around, the problem is a concern that benzodiazepines cause Alzheimer’s disease, plus collateral damage from the opioid crisis. People with addiction to opioids like benzodiazepines, because they boost the high, so they have significant street value, and drug seekers demand them in the clinic. Some clinicians would rather not deal with the drugs at all.

The Alzheimer’s worry stems largely from a widely reported review that found an association between Alzheimer’s disease and previous benzodiazepine use. The finding was based on public health insurance data from Quebec; no patients were seen (BMJ. 2014 Sep 9;349:g5205).

Among many “very large questions” about the study’s validity, people “may have been on benzos because they already had memory impairment and were anxious about it,” a common occurrence. In that case, “it’s not that benzos caused dementia; it was the other way around.” Also, there was no control for substance and alcohol use, Dr. Salzman said (J Clin Psychopharmacol. 2015 Feb;35[1]:1-3).

A more robust study followed patients 65 years and older for a mean of 7.3 years, comparing benzodiazepine users to nonusers. The team found a slightly higher risk of dementia in people with minimal exposure to benzodiazepines but not with the highest level of exposure, and concluded that the finding did “not support a causal association between benzodiazepine use and dementia” (BMJ. 2016 Feb 2;352:i90).

Meanwhile, a recent review of more than a million patients found either no or a minor increased risk of mortality, another concern with benzodiazepines in the elderly. “If a detrimental effect exists, it is likely to be much smaller than previously stated and to have uncertain clinical relevance. Residual confounding likely explains at least part of” it, the investigators concluded (BMJ. 2017 Jul 6;358:j294).

To be sure, short-term memory loss can occur with benzodiazepines, but patients did not seem to mind in a study Dr. Salzman conducted years ago in an upscale nursing home in Boston. A “dramatic” rebound was reported in short-term recall 2 weeks after volunteers tapered off benzodiazepines, mostly lorazepam, compared with those who stayed on them.

“I sat down to have lunch with the discontinuers, and I said to them, ‘Aren’t you glad that you are not taking these horrible drugs anymore, and your memory is so much better? They said, ‘No, what’s to remember? It was true that when we were taking those drugs, we might not have remembered what we watched on television the night before, but if you give a choice between feeling calm in the days, sleeping at night, and remembering what we watch on television, we’ll take the calm and the sleep every time,’ ” Dr. Salzman said.

He had no disclosures.

aotto@mdedge.com

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Two doses of recombinant zoster vaccine significantly reduced incidence of herpes zoster in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT), results of a randomized, placebo-controlled trial indicate.

The incidence of herpes zoster was 30 per 1,000 person-years for patients who received the adjuvanted recombinant zoster vaccine (Shingrix) versus 94 per 1,000 person-years for those who received placebo, according to study results.

Recombinant zoster vaccine induced humoral and cellular responses that were strong and occurring at a rate higher than what was seen in the placebo group, said senior author Keith M. Sullivan, MD, of Duke University Medical Center, Durham, N.C., and coauthors, who reported findings on behalf of the Zoster Efficacy Study in Patients Undergoing HSCT (ZOE-HSCT) Study Group.

“The vaccinations were generally well tolerated, and most symptoms were mild and transient and did not substantially deter participants from receiving their second dose,” Dr. Sullivan and colleagues wrote in JAMA.

The risk of herpes zoster is increased for 2-3 years after autologous HSCT because of diminished T-cell immunity, according to the authors.

“Antiviral prophylaxis is commonly administered to patients after HSCT to prevent such complications, but the efficacy depends on adherence to treatment,” they said.

While vaccines could provide long-term protection, immunocompromised individuals receiving live attenuated vaccine would be at increased risk of varicella caused by spread of the vaccine strain, they added.

There have been a few encouraging recent studies of non-live vaccines in this setting, including one large phase 3 trial of a heat-inactivated varicella-zoster virus vaccine that showed patients undergoing autologous HSCT had a 63.8% estimated efficacy in preventing herpes zoster, investigators from that study said in The Lancet (2018 May 26;391[10135]:2116-27).

A phase 1/2a study of the adjuvanted recombinant zoster vaccine in patients undergoing HSCT demonstrated strong humoral and cell-mediated immunity responses, which provided the rationale for studying the vaccine further in the randomized ZOE-HSCT study, according to Dr. Sullivan and coauthors.

Their study included a total of 1,846 adults who had undergone autologous HSCT. They were randomized to receive two doses of the recombinant zoster vaccine, the first at 50-70 days after the procedure and the second 1-2 months later.

Herpes zoster cases were seen in 49 and 136 individuals in the vaccine and placebo groups, respectively, which resulted in overall incidences of 30 and 94 per 1,000 person-years.

The incidence rate ratio of a first episode of herpes zoster was 0.36 for individuals receiving at least one dose, which authors said was equivalent to a vaccine efficacy of 63.7%.

That efficacy rate is “very similar” to the estimated efficacy reported for the heat-inactivated varicella-zoster virus vaccine reported in The Lancet, said Dr. Sullivan and coauthors.

However, the heat-inactivated vaccine achieved that level of protection with a four-dose schedule, including one dose given prior to autologous HSCT.

“An advantage of the short 2-dose posttransplantation schedule is that more patients might complete the vaccination program,” they said in a discussion of the results, noting that 94.7% of the recombinant zoster vaccine recipients completed two doses, compared with 81.9% of recipients who received the heat-inactivated herpes zoster vaccine in the previous report.

The study was funded and sponsored by GlaxoSmithKline Biologicals SA. Dr. Sullivan reported disclosures related to GlaxoSmithKline (GSK), Kiadis Pharmaceutical, Roche Genentech, and the National Institute of Allergy and Infectious Diseases. Coauthors provided disclosures related to GSK, AbbVie, Roche, Gilead, Janssen, Pharmacyclics, Morphosys, Helsinn, Celgene, and others.

SOURCE: Bastidas A et al. JAMA. 2019 July 9. doi: 10.1001/jama.2019.9053.

Black individuals who develop type 2 diabetes are more likely than their white counterparts to develop dementia. Now, findings from a new study point to a possible preventive strategy: Putting older patients on metformin when they are diagnosed could reduce their risk for dementia by as much as 40%, whereas sulfonylureas do not seem to have such an effect.

The researchers did not examine cause and effect, so their findings are not conclusive, and very few women were included in the study. Still, the authors said that their data showing a 29% lower risk of dementia associated with metformin use in black patients aged 65-74 years, and a 40% lower risk in those aged 50-64 years, suggested that “this inexpensive, widely available treatment could be broadly prescribed to substantially reduce the risk of dementia in younger [black] patients with [type 2 diabetes]” (Ann Fam Med. 2019;17:352-62).

Previous findings have suggested that black patients with type 2 diabetes face a 10%-18% higher risk of dementia, compared with white patients (Diabetes Care. 2014; 37[4]:1009-15). Another study linked type 2 diabetes in middle-aged black patients to a 41% decrease in cognition per test results over 14 years. There was no such decrease in white patients (Neuroepidemiology. 2014;43[3-4]: 220-7).

For the new study, researchers led by Jeffrey F. Scherrer, PhD, of Saint Louis University tracked 73,761 patients aged 50 years or older from 2000-2001 (when they were free of dementia and not taking diabetes) to 2015. Among the patients, 86% were white and 14% were black. In the white and black groups, 97% and 95% were men, respectively, and 61% and 55% were obese, respectively.

All participants began metformin (76%) or sulfonylurea (24%) monotherapy after the baseline period. Guidelines recommend metformin as a first-line treatment for type 2 diabetes, whereas sulfonylureas are considered second-line drugs that should be added to metformin.

After adjustment for confounders such as socioeconomic status and other medical conditions, the researchers found a significantly lower risk of dementia in black patients who took metformin, compared with those taking a sulfonylurea (hazard ratio, 0.73; 95% confidence interval, 0.6-0.89). There was no difference between the drugs among white patients (HR, 0.96; 95% CI, 0.9-1.03, both P = .008)

The results were not statistically significant among age groups, but there were trends. In black patients, the dementia-lowering benefit was largest among those aged 50-64 years (HR, 0.6; 95% CI, 0.45-0.81), followed by those aged 65-74 years (HR, 0.71; 95% CI, 0.53-0.94), and there was no benefit among those aged at least 75 (HR, 1.17; 95% CI, 0.73-1.85) all P = .055. There was a slight benefit among white patients in one of the age groups – 65-74 years (HR, 0.9; 95% CI, 0.82-0.99; P = .315).

The authors suggested that the findings could have been the result of an effect of metformin to reduce vascular disease and chronic inflammation in black patients.

They also noted that further research is needed to identify the demographic and clinical subgroups in which metformin is most strongly associated with a reduction in the risk of dementia. In addition, they emphasized that clinical trials are needed to confirm the study findings.

The National Institutes of Health funded the study. The authors report no relevant disclosures.

SOURCE: Scherrer JF et al. Ann Fam Med. 2019;17:352-62.

Black individuals who develop type 2 diabetes are more likely than their white counterparts to develop dementia. Now, findings from a new study point to a possible preventive strategy: Putting older patients on metformin when they are diagnosed could reduce their risk for dementia by as much as 40%, whereas sulfonylureas do not seem to have such an effect.

The researchers did not examine cause and effect, so their findings are not conclusive, and very few women were included in the study. Still, the authors said that their data showing a 29% lower risk of dementia associated with metformin use in black patients aged 65-74 years, and a 40% lower risk in those aged 50-64 years, suggested that “this inexpensive, widely available treatment could be broadly prescribed to substantially reduce the risk of dementia in younger [black] patients with [type 2 diabetes]” (Ann Fam Med. 2019;17:352-62).

Previous findings have suggested that black patients with type 2 diabetes face a 10%-18% higher risk of dementia, compared with white patients (Diabetes Care. 2014; 37[4]:1009-15). Another study linked type 2 diabetes in middle-aged black patients to a 41% decrease in cognition per test results over 14 years. There was no such decrease in white patients (Neuroepidemiology. 2014;43[3-4]: 220-7).

For the new study, researchers led by Jeffrey F. Scherrer, PhD, of Saint Louis University tracked 73,761 patients aged 50 years or older from 2000-2001 (when they were free of dementia and not taking diabetes) to 2015. Among the patients, 86% were white and 14% were black. In the white and black groups, 97% and 95% were men, respectively, and 61% and 55% were obese, respectively.

All participants began metformin (76%) or sulfonylurea (24%) monotherapy after the baseline period. Guidelines recommend metformin as a first-line treatment for type 2 diabetes, whereas sulfonylureas are considered second-line drugs that should be added to metformin.

After adjustment for confounders such as socioeconomic status and other medical conditions, the researchers found a significantly lower risk of dementia in black patients who took metformin, compared with those taking a sulfonylurea (hazard ratio, 0.73; 95% confidence interval, 0.6-0.89). There was no difference between the drugs among white patients (HR, 0.96; 95% CI, 0.9-1.03, both P = .008)

The results were not statistically significant among age groups, but there were trends. In black patients, the dementia-lowering benefit was largest among those aged 50-64 years (HR, 0.6; 95% CI, 0.45-0.81), followed by those aged 65-74 years (HR, 0.71; 95% CI, 0.53-0.94), and there was no benefit among those aged at least 75 (HR, 1.17; 95% CI, 0.73-1.85) all P = .055. There was a slight benefit among white patients in one of the age groups – 65-74 years (HR, 0.9; 95% CI, 0.82-0.99; P = .315).

The authors suggested that the findings could have been the result of an effect of metformin to reduce vascular disease and chronic inflammation in black patients.

They also noted that further research is needed to identify the demographic and clinical subgroups in which metformin is most strongly associated with a reduction in the risk of dementia. In addition, they emphasized that clinical trials are needed to confirm the study findings.

The National Institutes of Health funded the study. The authors report no relevant disclosures.

SOURCE: Scherrer JF et al. Ann Fam Med. 2019;17:352-62.

Black individuals who develop type 2 diabetes are more likely than their white counterparts to develop dementia. Now, findings from a new study point to a possible preventive strategy: Putting older patients on metformin when they are diagnosed could reduce their risk for dementia by as much as 40%, whereas sulfonylureas do not seem to have such an effect.

The researchers did not examine cause and effect, so their findings are not conclusive, and very few women were included in the study. Still, the authors said that their data showing a 29% lower risk of dementia associated with metformin use in black patients aged 65-74 years, and a 40% lower risk in those aged 50-64 years, suggested that “this inexpensive, widely available treatment could be broadly prescribed to substantially reduce the risk of dementia in younger [black] patients with [type 2 diabetes]” (Ann Fam Med. 2019;17:352-62).

Previous findings have suggested that black patients with type 2 diabetes face a 10%-18% higher risk of dementia, compared with white patients (Diabetes Care. 2014; 37[4]:1009-15). Another study linked type 2 diabetes in middle-aged black patients to a 41% decrease in cognition per test results over 14 years. There was no such decrease in white patients (Neuroepidemiology. 2014;43[3-4]: 220-7).

For the new study, researchers led by Jeffrey F. Scherrer, PhD, of Saint Louis University tracked 73,761 patients aged 50 years or older from 2000-2001 (when they were free of dementia and not taking diabetes) to 2015. Among the patients, 86% were white and 14% were black. In the white and black groups, 97% and 95% were men, respectively, and 61% and 55% were obese, respectively.

All participants began metformin (76%) or sulfonylurea (24%) monotherapy after the baseline period. Guidelines recommend metformin as a first-line treatment for type 2 diabetes, whereas sulfonylureas are considered second-line drugs that should be added to metformin.

After adjustment for confounders such as socioeconomic status and other medical conditions, the researchers found a significantly lower risk of dementia in black patients who took metformin, compared with those taking a sulfonylurea (hazard ratio, 0.73; 95% confidence interval, 0.6-0.89). There was no difference between the drugs among white patients (HR, 0.96; 95% CI, 0.9-1.03, both P = .008)

The results were not statistically significant among age groups, but there were trends. In black patients, the dementia-lowering benefit was largest among those aged 50-64 years (HR, 0.6; 95% CI, 0.45-0.81), followed by those aged 65-74 years (HR, 0.71; 95% CI, 0.53-0.94), and there was no benefit among those aged at least 75 (HR, 1.17; 95% CI, 0.73-1.85) all P = .055. There was a slight benefit among white patients in one of the age groups – 65-74 years (HR, 0.9; 95% CI, 0.82-0.99; P = .315).

The authors suggested that the findings could have been the result of an effect of metformin to reduce vascular disease and chronic inflammation in black patients.

They also noted that further research is needed to identify the demographic and clinical subgroups in which metformin is most strongly associated with a reduction in the risk of dementia. In addition, they emphasized that clinical trials are needed to confirm the study findings.

The National Institutes of Health funded the study. The authors report no relevant disclosures.

SOURCE: Scherrer JF et al. Ann Fam Med. 2019;17:352-62.

Incarceration versus treatment takes center stage in a new analysis of U.S. data from researchers in the United Kingdom.

The researchers performed an observational study looking at rates of incarceration, income, and drug-related deaths from 1983 to 2014 in the United States. They found a strong association between incarceration rates and drug-related deaths. Also, a very strong association was found between lower household income and drug-related deaths. Strikingly, in the counties with the highest incarceration rates, there was a 50% higher rate of drug deaths, reported Elias Nosrati, PhD, and associates (Lancet Public Health. 2019 Jul 3;4:e326-33). It is clearer every day that our opioid epidemic was in part wrought by a zealous push to change protocols on treating chronic pain. The epidemic also appears tied to well-meaning but overprescribing doctors and allegedly unscrupulous pharmaceutical companies and distributors. What we are learning through this most recent study is that another factor tied to the opioid and overdose epidemic could be incarceration.

According to the study, an increase in crime rates combined with sentencing reforms led the number of people incarcerated in state and federal prisons to soar from less than 200,000 in 1970 to almost 1 million in 1995. Furthermore, Dr. Nosrati and associates wrote, “Incarceration is directly associated with stigma, discrimination, poor mental health, and chronic economic hardship, all of which are linked to drug use disorders.”

Treatment for drug addiction in prison systems is rare, as is adequate mental health treatment. However, treatment for this population would likely help reduce drug overdose deaths and improve the quality of life for people who are incarcerated and their families. In the Philadelphia prison system, for example, treatment for inmates is available for opioid addiction, both with methadone and now more recently with buprenorphine (Suboxone). The Philadelphia Department of Prisons also provides cognitive-behavioral therapy. In Florida, Chapter 397 of the Florida statutes – known as the Marchman Act – provides for the involuntary (and voluntary) treatment of individuals with substance abuse problems.

The court systems in South Florida have a robust drug-diversion program, aimed at directing people facing incarceration for drug offenses into treatment instead. North Carolina has studied this issue specifically and found through a model simulation that diverting 10% of drug-abusing offenders out of incarceration into treatment would save $4.8 billion in legal costs for North Carolina counties and state legal systems. Diverting 40% of individuals would close to triple that savings.

There are striking data from programs treating individuals who are leveraged into treatment in order to maintain professional licenses. These such individuals, many of whom are physicians, airline pilots, and nurses, have a rate of sobriety of 90% or greater after 5 years. This data show that leveraged treatment has teeth and that those success rates are close to double the rates found within the general population.

In addition to the potential reduction in morbidity and mortality as well as the financial savings, why is treatment important? Because of societal costs. When parents or family members are put in jail for a drug charge or other charge, they leave behind a community, family, and very often children who are affected economically, emotionally, and socially. Those children in particular have higher risks of depression and PTSD. Diverting an offender into treatment or treating an incarcerated person for drug and mental health problems can change the life of a child or family member, and ultimately can change society.

Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.

Incarceration versus treatment takes center stage in a new analysis of U.S. data from researchers in the United Kingdom.

The researchers performed an observational study looking at rates of incarceration, income, and drug-related deaths from 1983 to 2014 in the United States. They found a strong association between incarceration rates and drug-related deaths. Also, a very strong association was found between lower household income and drug-related deaths. Strikingly, in the counties with the highest incarceration rates, there was a 50% higher rate of drug deaths, reported Elias Nosrati, PhD, and associates (Lancet Public Health. 2019 Jul 3;4:e326-33). It is clearer every day that our opioid epidemic was in part wrought by a zealous push to change protocols on treating chronic pain. The epidemic also appears tied to well-meaning but overprescribing doctors and allegedly unscrupulous pharmaceutical companies and distributors. What we are learning through this most recent study is that another factor tied to the opioid and overdose epidemic could be incarceration.

According to the study, an increase in crime rates combined with sentencing reforms led the number of people incarcerated in state and federal prisons to soar from less than 200,000 in 1970 to almost 1 million in 1995. Furthermore, Dr. Nosrati and associates wrote, “Incarceration is directly associated with stigma, discrimination, poor mental health, and chronic economic hardship, all of which are linked to drug use disorders.”

Treatment for drug addiction in prison systems is rare, as is adequate mental health treatment. However, treatment for this population would likely help reduce drug overdose deaths and improve the quality of life for people who are incarcerated and their families. In the Philadelphia prison system, for example, treatment for inmates is available for opioid addiction, both with methadone and now more recently with buprenorphine (Suboxone). The Philadelphia Department of Prisons also provides cognitive-behavioral therapy. In Florida, Chapter 397 of the Florida statutes – known as the Marchman Act – provides for the involuntary (and voluntary) treatment of individuals with substance abuse problems.

The court systems in South Florida have a robust drug-diversion program, aimed at directing people facing incarceration for drug offenses into treatment instead. North Carolina has studied this issue specifically and found through a model simulation that diverting 10% of drug-abusing offenders out of incarceration into treatment would save $4.8 billion in legal costs for North Carolina counties and state legal systems. Diverting 40% of individuals would close to triple that savings.

There are striking data from programs treating individuals who are leveraged into treatment in order to maintain professional licenses. These such individuals, many of whom are physicians, airline pilots, and nurses, have a rate of sobriety of 90% or greater after 5 years. This data show that leveraged treatment has teeth and that those success rates are close to double the rates found within the general population.

In addition to the potential reduction in morbidity and mortality as well as the financial savings, why is treatment important? Because of societal costs. When parents or family members are put in jail for a drug charge or other charge, they leave behind a community, family, and very often children who are affected economically, emotionally, and socially. Those children in particular have higher risks of depression and PTSD. Diverting an offender into treatment or treating an incarcerated person for drug and mental health problems can change the life of a child or family member, and ultimately can change society.

Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.

Incarceration versus treatment takes center stage in a new analysis of U.S. data from researchers in the United Kingdom.

The researchers performed an observational study looking at rates of incarceration, income, and drug-related deaths from 1983 to 2014 in the United States. They found a strong association between incarceration rates and drug-related deaths. Also, a very strong association was found between lower household income and drug-related deaths. Strikingly, in the counties with the highest incarceration rates, there was a 50% higher rate of drug deaths, reported Elias Nosrati, PhD, and associates (Lancet Public Health. 2019 Jul 3;4:e326-33). It is clearer every day that our opioid epidemic was in part wrought by a zealous push to change protocols on treating chronic pain. The epidemic also appears tied to well-meaning but overprescribing doctors and allegedly unscrupulous pharmaceutical companies and distributors. What we are learning through this most recent study is that another factor tied to the opioid and overdose epidemic could be incarceration.

According to the study, an increase in crime rates combined with sentencing reforms led the number of people incarcerated in state and federal prisons to soar from less than 200,000 in 1970 to almost 1 million in 1995. Furthermore, Dr. Nosrati and associates wrote, “Incarceration is directly associated with stigma, discrimination, poor mental health, and chronic economic hardship, all of which are linked to drug use disorders.”

Treatment for drug addiction in prison systems is rare, as is adequate mental health treatment. However, treatment for this population would likely help reduce drug overdose deaths and improve the quality of life for people who are incarcerated and their families. In the Philadelphia prison system, for example, treatment for inmates is available for opioid addiction, both with methadone and now more recently with buprenorphine (Suboxone). The Philadelphia Department of Prisons also provides cognitive-behavioral therapy. In Florida, Chapter 397 of the Florida statutes – known as the Marchman Act – provides for the involuntary (and voluntary) treatment of individuals with substance abuse problems.

The court systems in South Florida have a robust drug-diversion program, aimed at directing people facing incarceration for drug offenses into treatment instead. North Carolina has studied this issue specifically and found through a model simulation that diverting 10% of drug-abusing offenders out of incarceration into treatment would save $4.8 billion in legal costs for North Carolina counties and state legal systems. Diverting 40% of individuals would close to triple that savings.

There are striking data from programs treating individuals who are leveraged into treatment in order to maintain professional licenses. These such individuals, many of whom are physicians, airline pilots, and nurses, have a rate of sobriety of 90% or greater after 5 years. This data show that leveraged treatment has teeth and that those success rates are close to double the rates found within the general population.

In addition to the potential reduction in morbidity and mortality as well as the financial savings, why is treatment important? Because of societal costs. When parents or family members are put in jail for a drug charge or other charge, they leave behind a community, family, and very often children who are affected economically, emotionally, and socially. Those children in particular have higher risks of depression and PTSD. Diverting an offender into treatment or treating an incarcerated person for drug and mental health problems can change the life of a child or family member, and ultimately can change society.

Dr. Jorandby is chief medical officer of Lakeview Health in Jacksonville, Fla. She trained in addiction psychiatry at Yale University, New Haven, Conn.

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Selinexor (Xpovio) has been approved for use in combination with dexamethasone for the treatment of select adult patients with relapsed refractory multiple myeloma (RRMM), the Food and Drug Administration announced in a statement.

The oral therapy was approved for patients who have received at least four prior therapies and whose disease is resistant to several other forms of treatment, including at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody, according to the FDA.

The approval provides a “treatment option for patients with multiple myeloma with no (other) available therapy,” said Richard Pazdur, MD, director of the FDA Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA Center for Drug Evaluation and Research.

The approval was based on a study that included 83 patients with RRMM who had an overall response rate of 25.3% to Xpovio in combination with dexamethasone.

“The median time to first response was 4 weeks, with a range of 1-10 weeks. The median duration of response was 3.8 months. The efficacy evaluation was supported by additional information from an ongoing, randomized trial in patients with multiple myeloma,” according to the statement.

Common side effects seen in patients taking Xpovio in combination with dexamethasone include leukopenia, neutropenia, thrombocytopenia, and anemia. Patients also reported vomiting, nausea, fatigue, diarrhea, fever, decreased appetite and weight, constipation, upper respiratory tract infections, and hyponatremia.

Patients taking Xpovio should be monitored for low blood counts, platelets, and sodium levels, and should avoid other medications that may cause dizziness or confusion. Patients’ hydration status, blood counts, and other medications should be optimized to avoid dizziness or confusion. Females of reproductive age and males with a female partner of reproductive potential must use effective contraception during treatment with Xpovio. Women who are pregnant or breastfeeding should not take Xpovio.

Xpovio must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks.

Xpovio in combination with dexamethasone was granted accelerated approval, and further clinical trials are required to verify and describe the drug’s clinical benefit.

The FDA granted the approval of Xpovio to Karyopharm Therapeutics.

mdales@mdedge.com

Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.

Ocskaymark/Thinkstock

“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.

The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.

Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.

“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.

After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.

“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.

However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.

One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.

The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.

One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).

While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.

However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.

The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.

SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677

Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.

Ocskaymark/Thinkstock

“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.

The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.

Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.

“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.

After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.

“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.

However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.

One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.

The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.

One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).

While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.

However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.

The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.

SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677

Exposures to various types of anticholinergic medications were associated with a significantly increased risk of dementia in people aged 55 years or older in a large pharmacoepidemiologic study.

Ocskaymark/Thinkstock

“This study was designed to assess the association between cumulative anticholinergic drug use and risk of dementia in a large, representative British population,” wrote Carol A. C. Coupland, PhD, of the division of primary care at the University of Nottingham (England), and colleagues. The findings were published in JAMA Internal Medicine.

The researchers conducted a large nested case-control study that included 58,769 patients with dementia and 225,574 matched controls from the QResearch database in England. Each study participant was matched to five controls based on various characteristics, including sex, age, and calendar time, among others.

Prescription data related to 56 different drugs with strong anticholinergic properties, including antipsychotics, bladder antimuscarinics, antiepileptics, antiparkinson agents, and antidepressants were used to measure drug exposure. The study data were analyzed from 2016 to 2018.

“The primary exposure was the total standardized daily doses (TSDDs) of anticholinergic drugs prescribed in the 1 to 11 years prior to the date of diagnosis of dementia or equivalent date in matched controls,” Dr. Coupland and colleagues wrote.

After analysis, the researchers found that exposure to antipsychotics (adjusted odds ratio, 1.70), bladder antimuscarinics (aOR, 1.65), antiepileptics (aOR, 1.39), antiparkinson agents (aOR, 1.52), and anticholinergic antidepressants (aOR, 1.29) was associated with an increased risk of dementia after adjustment for confounding factors.

“Associations were stronger in [dementia] cases diagnosed before the age of 80 years,” the researchers noted.

However, antihistamine, antivertigo/antiemetic, skeletal muscle relaxant, gastrointestinal antispasmodic, antiarrhythmic, and antimuscarinic bronchodilator anticholinergic agents were not associated with any increased risk of dementia.

One key limitation of the study was the absence of medication compliance assessment, which could result in exposure misclassification. Dr. Coupland and colleagues acknowledged this could underestimate some associations with medication exposure.

The stronger risk of dementia found among people who had dementia before age 80 “indicates that anticholinergic drugs should be prescribed with caution in middle-aged and older people,” they concluded.

One question that remains from the current study is whether anticholinergic drugs are a definite modifiable risk factor for Alzheimer’s disease and related dementias, Noll L. Campbell, PharmD, of Purdue University, West Lafayette, Ind., and colleagues wrote in an editorial accompanying the study by Dr. Coupland and associates (JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0676).

While a pharmacologic basis for this association has been proposed, causation has yet to be established by means of prospective randomized studies. The current supposition is that deprescribing anticholinergic medications has the potential to positively effect cholinergic neurotransmission in certain regions of the brain, which could lead to improved cognitive functioning, and lower the likelihood of developing Alzheimer’s disease and related dementias, they wrote in the editorial.

However, the discontinuation of some anticholinergic agents may pose other risks, such as worsening pain or depressive symptoms, in addition to increasing the utilization of acute care facilities. As a result, high-quality, well-designed, randomized trials are needed to better understand the long-term effects of deprescribing anticholinergic medications. These trials would help inform clinicians, patients, and policymakers about the risks and benefits of deprescribing interventions, Dr. Campbell and coauthors said.

The study was supported by the National Institute for Health Research and the University of Nottingham. The authors reported financial affiliations with ClinRisk Ltd. The authors of the editorial reported receiving support from the National Institute on Aging and the Agency for Healthcare Research and Quality. Dr. Campbell reported receiving personal fees from Astellas Pharma US.

SOURCE: Coupland C et al. JAMA Intern Med. 2019 Jun 24. doi: 10.1001/jamainternmed.2019.0677

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

tborden@mdedge.com

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

tborden@mdedge.com

The Food and Drug Administration has approved bremelanotide (Vyleesi) to treat acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women.

“There are women who, for no known reason, have reduced sexual desire that causes marked distress, and who can benefit from safe and effective pharmacologic treatment,” Hylton V. Joffe, MD, director of the Center for Drug Evaluation and Research’s Division of Bone, Reproductive, and Urologic Products, stated in a press release. “Today’s approval provides women with another treatment option for this condition.”

HSDD is characterized by low sexual desire that causes marked distress or interpersonal difficulty and is not caused by a medical or psychiatric condition. Acquired HSDD develops in a patient who previously experienced no problems with sexual desire, and generalized HSDD is a lack of desire that occurs regardless of the type of sexual activity, situation, or partner.

Vyleesi was studied in two 24-week, randomized, double-blind, placebo-controlled trials in 1,247 premenopausal women with acquired, generalized HSDD. The women used Vyleesi two or three times per month and no more than once a week. About one-quarter of patients treated with Vyleesi had an increase of 1.2 or more in their sexual desire score (scored on a range of 1.2 to 6.0, with higher scores indicating greater sexual desire), compared with about 17% of those who took placebo. About 35% of the patients treated with Vyleesi had a decrease of one or more in their distress score (scored on a range of 0-4, with higher scores indicating greater distress from low sexual desire) compared with about 31% of those who took placebo.

The drug is injected under the skin of the abdomen or thigh at least 45 minutes before anticipated sexual activity. Patients may decide the optimal time to use Vyleesi based on the duration of benefit and any side effects, such as nausea. Patients should not take more than one dose of Vyleesi within 24 hours, or more than eight doses per month. Patients should discontinue treatment after 8 weeks if they do not report an improvement in sexual desire and associated distress.

Vyleesi works by activating melanocortin receptors but the exact mechanism for improving sexual desire is unknown. Some side effects were reported. “The most common side effects of Vyleesi are nausea and vomiting, flushing, injection site reactions, and headache. About 40% of patients in the clinical trials experienced nausea, most commonly with the first Vyleesi injection, and 13% needed medications for the treatment of nausea. About 1% of patients treated with Vyleesi in the clinical trials reported darkening of the gums and parts of the skin, including the face and breasts, which did not go away in about half the patients after stopping treatment. Patients with dark skin were more likely to develop this side effect,” according to the press release.

A temporary increase in blood pressure in patients after dosing with Vyleesi was observed during the clinical trials and therefore the drug is not recommended in patients at high risk for cardiovascular disease. In addition, patients who take a naltrexone-containing medication by mouth to treat alcohol or opioid dependence should not use Vyleesi because it may significantly decrease the levels of naltrexone in the blood and could lead to naltrexone treatment failure.

The full press release can be found on the FDA website.

tborden@mdedge.com

Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from ­–21% to +23%.

“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.

To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”

“The nonrobustness of the earlier findings also highlights the challenges of controlling scientific messages in controversial policy areas. Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.

Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.

lfranki@mdedge.com

SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.

Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from ­–21% to +23%.

“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.

To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”

“The nonrobustness of the earlier findings also highlights the challenges of controlling scientific messages in controversial policy areas. Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.

Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.

lfranki@mdedge.com

SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.

Contrary to previous research indicating that medical cannabis laws reduced opioid overdose mortality, the association between these two has reversed, with opioid overdose mortality increased in states with comprehensive medical cannabis laws, according to Chelsea L. Shover, PhD, and associates.

Courtesy Wikimedia Commons/Coaster420/Creative Commons License

The original research by Marcus A. Bachhuber, MD, and associates showed that the introduction of state medical cannabis laws was associated with a 24.8% reduction in opioid overdose deaths per 100,000 population between 1999 and 2010. In contrast, the new research – which looked at a longer time period than the original research did – found that the association between state medical cannabis laws and opioid overdose mortality reversed direction, from ­–21% to +23%.

“We find it unlikely that medical cannabis – used by about 2.5% of the U.S. population – has exerted large conflicting effects on opioid overdose mortality,” wrote Dr. Shover, of the department of psychiatry and behavioral sciences at Stanford (Calif.) University, and associates. “A more plausible interpretation is that this association is spurious.” Their study was published in the Proceedings of the National Academy of Sciences.

To conduct their analysis, Dr. Shover and associates extended the timeline reviewed by Dr. Bachhuber and associates to 2017. During 2010-2017, 32 states enacted medical cannabis laws, including 17 allowing only medical cannabis with low levels of tetrahydrocannabinol (THC), and 8 legalized recreational marijuana. In the expanded timeline during 1999-2017, states possessing a comprehensive medical marijuana law saw an increase in opioid overdose mortality of 28.2%. Meanwhile, states with recreational marijuana laws saw a decrease of 14.7% in opioid overdose mortality, and states with low-THC medical cannabis laws saw a decrease of 7.1%. However, the investigators noted that those values had wide confidence intervals, which indicates “compatibility with large range of true associations.”

“The nonrobustness of the earlier findings also highlights the challenges of controlling scientific messages in controversial policy areas. Corporate actors with deep pockets have substantial ability to promote congenial results, and suffering people are desperate for effective solutions. Cannabinoids have demonstrated therapeutic benefits, but reducing population-level opioid overdose mortality does not appear to be among them,” Dr. Shover and associates noted.

Dr. Shover reported receiving support from National Institute on Drug Abuse and the Wu Tsai Neurosciences Institute. Another coauthor received support from the Veterans Health Administration, Wu Tsai Neurosciences Institute, and the Esther Ting Memorial Professorship at Stanford.

lfranki@mdedge.com

SOURCE: Shover CL et al. Proc Natl Acad Sci U S A. 2019 Jun 10. doi: 10.1073/pnas.1903434116.

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

dbrunk@mdedge.com

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.

MILAN – Patients on checkpoint inhibitors who experience both dermatologic and gastrointestinal side effects may be at increased risk of further immune-related adverse events, even though they may have better odds of a favorable outcome on the cancer treatment, results of a study presented at the World Congress of Dermatology suggest.

Andrew Bowser/MDedge News

The co-occurrence of dermatologic and gastrointestinal immune-related adverse events (irAEs), which was usually seen early in the course of treatment, was independently associated with favorable progression-free and overall survival in this study, said Gabriel E. Molina, a medical student at Harvard Medical School, Boston.

Compared with patients with colitis alone, those patients who had both immune checkpoint inhibitor-induced rash and colitis were at significantly increased risk of additional irAEs affecting other organ systems, according to Mr. Molina. As a result, patients with both dermatologic and gastrointestinal irAEs may warrant earlier or closer monitoring, and need prompt referral to specialty care at first sign of emerging toxicity.

“We are really excited by the possibility that this co-occurrence of rash and colitis may be a unique and early clinical marker of both high-risk irAE patients and favorable treatment response,” Mr. Molina said.

The single-center, retrospective cohort study reported by Mr. Molina included 67 patients treated with immune checkpoint inhibitors who subsequently developed colitis. Of that group, 28 (or about 42%) also had a rash induced by that treatment.

The median time from starting treatment to onset of rash was 32.5 days, according to this report. Median onset of gastrointestinal toxicity was roughly similar between the patients who also had rash, at 73 days, as compared with patients who did not have rash, at 64 days. Most rashes were grade 1-2 in severity, and were treated with topical corticosteroids in 50% of cases or with nothing at all in 43%, according to the report.

The odds of developing an additional irAE such as hepatitis or hypophysitis was 18.5 times higher in the patients who had rash and colitis as compared with those with colitis only, the researchers also found.

In multivariate analysis, the patients with both rash and colitis had longer progression-free survival (hazard ratio, 0.37; 95% confidence interval, 0.17-0.80; P = .012) and overall survival (HR, 0.20; 95% CI, 0.05-0.83; P = .026), as compared with those with just colitis, Mr. Molina reported.

This isn’t the first study to show that the occurrence of an irAE foreshadows a better prognosis. “One promising observation that has consistently emerged in the literature is that cancer patients who develop these toxicities may actually have better oncologic outcomes than those who don’t,” Mr. Molina said.

Harvard now has a multidisciplinary group, including a dermatologist, dedicated to evaluating irAEs, he said. To date, however, a minority of patients are being referred, at which point, the dermatologic toxicity may be quite severe. “There’s this belief – which is generally true – that the rashes are mild and can be treated with topical steroids. So there’s often a delay before they see us.”

While larger studies are needed to validate the findings, just tallying up toxicities isn’t going far enough, according to the investigator.

“Our ultimate goal is to bridge the translational research gap, and to use thoughtful specimen collection to one day identify, ideally at the individualized level, the irAE risk level of the patient as soon as they start their immune checkpoint inhibitor, and then reprognosticate them each time they present with a new toxicity,” Mr. Molina said.

Mr. Molina reported no conflicts of interest.