Pharmacology

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

The monoclonal antibody teplizumab may delay the onset of type 1 diabetes in individuals at high risk, according to research presented at the annual scientific sessions of the American Diabetes Association.

In this study, 76 first-degree relatives of individuals with type 1 diabetes – who did not themselves have the disease but were considered at high risk because of antibodies and abnormal glucose tolerance tests – were randomized to a single two-week outpatient course of intravenous teplizumab or saline placebo. The patients, of whom 72% were 18 years of age or younger, were followed for a median of 745 days and had twice-yearly oral glucose tolerance testing.

Overall, 43% of the 44 patients who received teplizumab were diagnosed with type 1 diabetes during the course of the study, compared with 72% of the 32 who received the placebo. The treatment was associated with a 59% reduction in the hazard ratio for type 1 diabetes, even after adjusting for age, the results of a second oral glucose-tolerance testing before randomization, or the presence of anti-GAD65 antibodies.

The median time to diagnosis was 48.4 months in the teplizumab group and 24.4 months in the placebo group. The greatest effect was seen in the first year after randomization, during which only 7% of the teplizumab group were diagnosed with type 1 diabetes, compared with 44% of the placebo group. The findings were published simultaneously in the New England Journal of Medicine.

“The delay of progression to type 1 diabetes is of clinical importance, particularly for children, in whom the diagnosis is associated with adverse outcomes, and given the challenges of daily management of the condition,” said Dr. Kevan C. Herold, professor of immunobiology and medicine at Yale University, New Haven, Conn., and coauthors.

There were significantly more adverse events in the teplizumab group, compared with placebo, with three-quarters of the 20 grade 3 adverse events being lymphopenia during the first 30 days. In all but one participant, however, the lymphopenia resolved by day 45. Participants receiving teplizumab also reported a higher incidence of dermatologic adverse events, such as a spontaneously-resolving rash that was experienced by just over one-third of the group.

The researchers also looked for evidence of T-cell unresponsiveness, which has been previously seen in patients with new-onset type 1 diabetes who received treatment with teplizumab. They noted an increase in a particular type of CD8+ T cell associated with T-cell unresponsiveness at months 3 and 6 in participants treated with teplizumab.

Teplizumab is an Fc receptor-nonbinding monoclonal antibody that has been shown to reduce the loss of beta-cell function in patients with type 1 diabetes (Diabetes. 2013 Nov;62(11):3766-74).

The study was supported by the National Institutes of Health, the Juvenile Diabetes Research Foundation, and the American Diabetes Association, with the study drug and additional site monitoring provided by MacroGenics. Eight authors declared grants, personal fees, and other support from private industry, with one also declaring income and stock options from MacroGenics.

SOURCE: Herold K et al. NEJM. 2019 Jun 9. doi: 10.1056/NEJMoa1902226*

*Correction, 6/9/2019: An earlier version of this story misstated the doi number for the journal article. The number is 10.1056/NEJMoa1902226.

SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.

Mitchel L. Zoler/MDedge News

The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.

The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.

Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).


To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m².

The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.

In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.

Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.

Dr. Lee had no disclosures.

[email protected]

SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.

SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.

Mitchel L. Zoler/MDedge News

The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.

The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.

Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).


To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m².

The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.

In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.

Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.

Dr. Lee had no disclosures.

[email protected]

SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.

SAN FRANCISCO – The direct-acting anticoagulants, as a class, were more effective and at least as safe as warfarin in low-weight and very-low-weight patients with atrial fibrillation in an adjusted analysis of real-world outcomes data from more than 21,000 Korean patients.

Mitchel L. Zoler/MDedge News

The analysis also showed that the direct-acting oral anticoagulants (DOACs) had the best safety and efficacy on low-weight patients when used at the labeled dosages, with blunted efficacy and safety at dosages that either exceeded or fell short of labeled levels, So-Ryoung Lee, MD, said at the annual scientific sessions of the Heart Rhythm Society.

The overall superiority of DOACs by both efficacy and safety also generally extended to the subgroup of very-low-weight patients, those with weights of less than 50 kg. In this subgroup, which was 28% of the total population studied, the composite adverse event outcome occurred 33% less often among patients treated with a DOAC relative to patients treated with warfarin, a statistically significant difference, said Dr. Lee, a cardiologist at Seoul (South Korea) National University Hospital. Among all patients with weights of 60 kg (132 pounds) or less, the composite outcome occurred 34% less often in the DOAC-treated patients relative to the warfarin-treated patients, also a statistically significant difference.

Dr. Lee and colleagues used a Korean National Health Insurance database that included information on more than 600,000 adults with atrial fibrillation (AFib) as of January 2013. The researchers whittled this down to 21,678 patients who began for the first time treatment with an oral anticoagulant starting during or after January 2014; had no history of a stroke, intracranial hemorrhage, or gastrointestinal bleed; and weighed no more than 60 kg. This cohort included 7,575 (35%) who received warfarin treatment, and 14,103 (65%) who received a DOAC. Within the DOAC-treated group, 42% received rivaroxaban (Xarelto), 26% dabigatran (Pradaxa), 24% apixaban (Eliquis), and 8% edoxaban (Savaysa).


To account for baseline differences in demographics and comorbidities between the patients treated with a DOAC and those who received warfarin, Dr. Lee and her associates did propensity score adjustment, which resulted in similar cohorts of 6,692 patients treated with warfarin and 12,810 patients treated with a DOAC. The average age of these patients was 73 years, a third were men, and the average body mass index was just over 22 kg/m².

The events that the researchers tallied during follow-up through December 2016 included rates of all-cause death, ischemic stroke, intracranial hemorrhage, hospitalization for GI bleeding, hospitalization for major bleeding, and the composite of these five outcomes.

In the propensity-score adjusted full cohort of all patients who weighed 60 kg or less, the rate of each of these five outcomes, as well as the composite outcome, occurred statistically significantly less often among the DOAC-treated patients than in those on warfarin. The reductions ranged from a 41% lower incidence of ischemic stroke on DOAC treatment compared with warfarin treatment, to an 18% reduced rate of hospitalization for a GI bleed, compared with warfarin-treated patients. In the subgroup of patients who weighed less than 50 kg (110 pounds), the reductions ranged from a 41% cut in ischemic stroke on a DOAC compared with warfarin to a 24% relative reduction in the rate of hospitalization for a major bleed, a difference that just reached statistical significance. The outcome of hospitalization for a GI bleed showed no significant between-group difference among very-low-weight patients, but the rates of intracranial hemorrhage and all-cause death also showed statistically significant lower rates among DOAC-treated patients.

Nearly two-thirds of the patients on a DOAC received the label-appropriate dose of the drug, but 31% received a dosage that was below the labeled level while 4% received a dosage above the labeled level. An analysis that divided the NOAC patients by the appropriateness of their treatment dosages showed that patients on the correct dosages fared best. For example, in the total cohort of patients who weighed 60 kg or less, those on the correct DOAC dosage had a 9.1% rate of the combined endpoint. Patients on a low DOAC dosage did about as well as did the patients on warfarin, with a combined event rate of 11.6% in each of these subgroups. The worst outcomes occurred among the small number of patients on an inappropriately-high DOAC dosage, with a combined event rate of 15.4%. The researchers found a similar pattern among patients who weighed less than 50 kg.

Dr. Lee had no disclosures.

[email protected]

SOURCE: Lee SR et al. HRS 2019, Abstract S-AB30-05.

Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.¹ In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.¹ According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.^2,3

C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.⁴ Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.^5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.^7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.⁹ The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.

Dosing and Guidelines

Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.^10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.

In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.¹⁴ As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.

Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.

Review of Probiotoc Literature

Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).

In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.¹⁵ The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I² = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I² = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I² = 0%).

Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.

Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.¹⁶ Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).¹⁷ The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).

The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.¹⁸ Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.

In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.¹⁹ The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I² = 0%; P < .001).¹⁹ A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I² = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I² = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.

Trials included in the Cochrane Review used many different probiotic regimens over various durations.¹⁵ All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.^16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.

Probiotic Safety

The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.^21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.^15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.^24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.²⁶ Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.²⁶

CDI Risk Factors

Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.^27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.²⁹ Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.

Conclusion

CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.

The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.

Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.¹ In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.¹ According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.^2,3

C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.⁴ Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.^5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.^7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.⁹ The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.

Dosing and Guidelines

Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.^10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.

In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.¹⁴ As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.

Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.

Review of Probiotoc Literature

Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).

In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.¹⁵ The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I² = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I² = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I² = 0%).

Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.

Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.¹⁶ Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).¹⁷ The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).

The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.¹⁸ Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.

In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.¹⁹ The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I² = 0%; P < .001).¹⁹ A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I² = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I² = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.

Trials included in the Cochrane Review used many different probiotic regimens over various durations.¹⁵ All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.^16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.

Probiotic Safety

The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.^21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.^15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.^24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.²⁶ Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.²⁶

CDI Risk Factors

Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.^27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.²⁹ Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.

Conclusion

CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.

The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.

Clostridium difficile (C difficile) is a gram-positive, toxin-producing bacterium that is of increasing concern among health care providers and patients. Infection with C difficile can have manifestations ranging from mild diarrhea to severe toxic megacolon and can result in prolonged hospitalization with severe cases requiring admission to an intensive care unit.¹ In 2014, the US was estimated to have more than 600,000 cases of C difficile infection (CDI), previously known as C difficile–associated diarrhea, and more than 44,000 associated deaths. The annual economic cost of CDI is thought to exceed $5 billion.¹ According to studies of health care–associated illness, CDI rates are comparable to or have surpassed rates of methicillin-resistant Staphylococcus aureus infection within the US, including at US Department of Veterans Affairs (VA) acute care centers nationwide.^2,3

C difficile has been shown to be the causative agent in 10% to 20% of antibiotic-associated diarrhea episodes.⁴ Colonization of C difficile is uncommon in healthy adults, but colonization rates are as high as 21% in hospitalized patients, with increasing rates proportional to increasing hospital length of stay.^5,6 Although not all colonized patients develop clinically significant CDI, those who do may require multiple treatment courses, over months to years, because of the high risk of disease recurrence. An estimated 25% of patients have a single recurrent episode of CDI within 30 days after treatment completion, and 45% of those patients have additional recurrent infections.^7,8 Although probiotics do not have an approved US Food and Drug Administration (FDA) indication, these supplements are often used to try to prevent CDI from developing during concomitant antibiotic use. Probiotics are microorganisms with potential health benefits, but the mechanisms of these benefits are not fully understood. Proposed mechanisms include reduced growth of pathogenic bacteria, modulation of the immune system, and support of the intestinal wall barrier.⁹ The many probiotic formulations currently marketed include Lactobacillus acidophilus (L acidophilus) capsules and various combinations of L acidophilus, Lactobacillus casei, Bifidobacterium lactis, Bifidobacterium longum, Streptococcus thermophilus, and other bacterial strains.

Dosing and Guidelines

Manufacturers’ suggested dosing for their Lactobacillus capsules, tablets, and packets varies from 1 unit daily to 4 units 4 times daily for dietary supplementation; the products’ labeling does not include any information regarding treatment duration.^10-13 In addition, there are no published recommendations or product labeling guiding the dosing of probiotics or their duration of use in the primary prevention of CDI.

In 2017, the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) updated their CDI treatment guidelines.¹⁴ As these guidelines indicate that the data on probiotic use in CDI are inadequate, IDSA and SHEA make no recommendation for or against probiotic use in primary prevention of the disease. The guidelines point to several limitations in the literature, including variability in probiotic formulations studied, duration of probiotic administration, definitions of CDI, and duration of study follow-up.

Given the lack of consensus guidelines that clinicians can use when deciding which probiotic dosing and duration are appropriate for a patient for primary prevention of CDI, we evaluated the literature on the topic and summarize their findings here.

Review of Probiotoc Literature

Conflicting data exist about probiotics and their effect on CDI prevention. The literature reviewed was selected based on our assessment of its contribution to the topic and its potential utility to clinicians in determining appropriate probiotic therapies and recommendations. Included in our discussion is a large Cochrane Review of probiotic efficacy, 2 trials of probiotic dosing, the PLACIDE trial, and a systematic review of timely probiotic initiation. All of these studies attempted to determine the effect of probiotics on CDI incidence (Table).

In their 2017 Cochrane Review, Goldenberg and colleagues reviewed 39 trials that investigated the efficacy of probiotics in CDI prevention in 9,955 immunocompetent patients receiving antibiotics.¹⁵ The incidence of CDI was significantly lower in patients who received a probiotic than in patients who received placebo or no treatment (1.5% vs 4.0%; relative risk [RR], 0.40; 95% CI, 0.30-0.52; I² = 0%). It is important to note that trials with a control-group CDI incidence of 0% to 2% (baseline CDI risk) found no statistically significant difference in CDI risk between patients using and not using probiotics (RR, 0.77; 95% CI, 0.45-1.32; I² = 0%) and that the preceding statistically significant result may have been driven by the inclusion of trials with high baseline CDI risk (> 5%). Trials that enrolled patients who were at this risk level found a statistically significant 70% reduction in CDI risk in those using probiotics (vs no probiotics) while on concomitant antibiotic therapy (RR, 0.30; 95% CI, 0.21-0.42; I² = 0%).

Probiotic therapy seems to be effective in reducing CDI risk in immunocompetent patients and may be particularly beneficial in patients at higher CDI risk, though Goldenberg and colleagues did not elaborate on what constitutes higher risk and based their conclusion on their control group’s high CDI incidence (> 5%). The most common adverse events (AEs) attributable to probiotics included abdominal cramping, nausea, fever, soft stools, flatulence, and taste disturbance. The review’s findings are limited in that the inclusion of many small trials with high baseline CDI risk likely contributed to a statistically significant result, and 17 of the review’s 39 trials were industry-sponsored or were conducted by investigators with industry associations; another 12 lacked statements about funding or sponsorship.

Two of the trials in the Cochrane Review investigated whether probiotics have a dose effect on CDI prevention. Gao and colleagues randomly assigned 255 hospitalized Asian patients to 3 groups: those receiving placebo, 1 probiotic capsule daily, and 2 probiotic capsules daily.¹⁶ Each probiotic capsule contained 50 billion colony-forming units (CFUs) of Lactobacillus. Incidence of CDI was lower in patients taking 2 probiotic capsules daily than in those taking 1 probiotic capsule daily (1.2% vs 9.4%; P = .04) or placebo (1.2% vs 23.8%; P = .002). In the other trial, Ouwehand and colleagues randomly assigned 503 hospitalized Asian patients to 3 groups as well: those receiving placebo, low-dose probiotic (4.17 billion CFUs of Lactobacillus and Bifidobacterium), and high-dose probiotic (17 billion CFUs).¹⁷ The incidence of CDI in each probiotic group (low-dose, high-dose) was 1.8%, which was significantly lower than the 4.8% in the placebo group (P = .04).

The Cochrane Review’s largest and most rigorous trial was PLACIDE, a 2013 randomized controlled study of the effect of probiotics on CDI.¹⁸ Allen and colleagues randomly assigned 2,981 inpatients (aged ≥ 65 years; exposed to antibiotics within preceding 7 days) to 2 groups: those receiving either 1 probiotic capsule daily, or 1 placebo capsule daily, for 21 days. Results showed no difference in CDI incidence between the probiotic and placebo groups (0.8% vs 1.2%; RR, 0.71; 95% CI, 0.34-1.47; P = .35). Of note, this trial is free of industry sponsorship, is the largest probiotic trial to date, has a control-group baseline CDI rate consistent with the rate in hospital and ambulatory settings in the US, and found a negative result regarding probiotic use in CDI prevention. Findings are limited in that the study allowed for initiating probiotic therapy up to 7 days after the start of antibiotics, and patients were given 1 relatively low-dose capsule daily, which may have contributed to lack of an effect on CDI prevention. No serious AEs were attributed to probiotic use.

In a 2017 systematic meta-analysis of 19 studies, Shen and colleagues investigated whether timely use of probiotics prevented CDI in 6,261 hospitalized patients receiving antibiotics.¹⁹ The incidence of CDI was significantly lower in patients receiving vs not receiving probiotics (1.6% vs 3.9%; RR, 0.42; 95% CI, 0.30-0.57; I² = 0%; P < .001).¹⁹ A subgroup analysis was performed to compare studies initiating probiotics within 2 days after the start of antibiotics with studies initiating probiotics more than 2 days after the start. CDI risk was reduced by 68% when probiotics were started within 2 days, vs 30% when started after 2 days (RR, 0.32; 95% CI, 0.22-0.48; I² = 0% vs RR, 0.70; 95% CI, 0.40-1.23; I² = 0%; P = .02). Of note, no difference was found in efficacy among the various probiotic formulations, and no significant AEs were noted in any study group.

Trials included in the Cochrane Review used many different probiotic regimens over various durations.¹⁵ All these trials continued probiotics for at least the duration of antibiotic therapy. The 2 trials that evaluated the effect of probiotic therapy over an extended period required probiotics be started within 48 hours after initiation of antibiotic therapy; one trial continued probiotics for 5 days after completion of antibiotics, and the other for 7 days after completion.^16,20 In both trials, CDI was statistically significantly reduced among adults using probiotics compared with adults receiving placebo.

Probiotic Safety

The FDA has not approved probiotics for the prevention or treatment of any health problems. Most probiotics are FDA-regulated as dietary supplements and do not have to meet stringent drug-approval requirements. The FDA has given many strains of common probiotics the Generally Recognized as Safe designation for use in commercially available products and foods.^21-23 Probiotic use has not been associated with significant AEs in clinical trials and generally has been considered safe in immunocompetent and otherwise healthy persons.^15-19 However, clinical trials have been inadequate in reporting or investigating AEs; the alternative for evaluating the risks of probiotic therapy is case reports.^24,25 Theoretical risks associated with probiotics include sepsis, deleterious effects on normal gut digestion, excessive immune stimulation, and possible transfer of antimicrobial resistance genes among microorganisms.²⁶ Boyle and colleagues further described a handful of case reports of sepsis caused by probiotics in immunocompromised individuals; the other theoretical risks have not been reported outside animal studies.²⁶

CDI Risk Factors

Many factors can increase a patient’s CDI risk. Specific antibiotics (eg, ampicillin, amoxicillin, cephalosporins, clindamycin, fluoroquinolones) confer higher risk.^27,28 Other factors include inflammatory bowel disease, organ transplantation, chemotherapy, chronic kidney disease, and immunodeficiency. Advanced age increases CDI risk and can increase the severity of infection. The evidence regarding acid suppression and CDI risk is conflicting, though a recent meta-analysis found that use of proton pump inhibitors is associated with a 2-fold higher risk of developing CDI.²⁹ Patient-specific risk factors should be evaluated when the risk–benefit ratio for probiotic use is being considered.

Conclusion

CDIs are becoming increasingly burdensome to the health care system. More research is needed on the role of probiotics in CDI prevention in patients taking antibiotics. Given the limited risk for AEs when probiotics are used in immunocompetent patients and the relatively low cost of these supplements, the risks likely are outweighed by the postulated benefits, and probiotics may be recommended in select patient populations.

The PLACIDE trial found no benefit of probiotics in preventing CDI in a population similar to that of a typical US hospital or ambulatory setting, but its intervention allowed late initiation of relatively low doses of probiotics. Therefore, probiotics may be recommended for CDI prevention in patients taking antibiotics, especially patients at high risk for developing CDI. When clinicians recommend probiotic use in this setting, the probiotic should be initiated within 2 days after the start of antibiotics and should be continued for the duration of antibiotic therapy and for up to 7 days after that therapy is completed. Optimal probiotic dosing, likely dependent on the product used, remains unclear. PLACIDE trial results suggest that a dosage of at least 1 probiotic capsule 2 times daily may confer additional efficacy.

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

DALLAS – Warfarin appears to increase the risk of lung transplant or death for patients with fibrotic lung disease who need anticoagulation therapy, Christopher King, MD, said at the American Thoracic Society’s international conference.

Michele G. Sullivan/MDedge News

Compared with direct oral anticoagulation (DOAC), warfarin doubled the risk of those outcomes, even after the researchers controlled for multiple morbidities that accompany the need for anticoagulation, said Dr. King, medical director of the transplant and advanced lung disease critical care program at Inova Fairfax (Va.) Hospital.

“The need for anticoagulation in patients with interstitial lung disease is already associated with an increased risk of death or transplant,” he said. Warfarin – but not oral anticoagulation – seems to increase that risk even more “no matter how you analyze it,” he said.

“We know now that fibrosis and coagulation are entwined, and there’s background epidemiologic data showing an increased incidence of venous thromboembolism and acute coronary syndrome in patients with pulmonary fibrosis. This suggests that a dysregulated coagulation cascade may play a role in the pathogenesis of fibrosis.”

The relationship has been explored for the last decade or so. Two recent meta-analyses came to similar conclusions.

In 2013, a 125-patient retrospective cohort study compared clinical characteristics and survival among patients with idiopathic pulmonary fibrosis (IPF) who received anticoagulant therapy with those who did not (Sarcoidosis Vasc Diffuse Lung Dis. 2013 Aug 1;30[2]:121-7). Those who got the treatment had worse survival outcomes at 1 and 3 years than did those who received no therapy (84% vs. 53% and 89% vs. 64%, respectively).

In 2016, a post hoc analysis of three placebo-controlled studies determined that any anticoagulant use independently increased the risk of death among patients with IPF, compared with nonuse: 15.6% vs 6.3% all-cause mortality (Eur Respir J. 2016. doi: 10.1183/13993003.02087-2015).

But these investigations didn’t parse out the types of anticoagulation. Direct oral anticoagulation (DOAC) is much more common now, however, and Dr. King and colleagues wanted to find out how warfarin and DOAC compared.

They retrospectively analyzed data from the Pulmonary Fibrosis Foundation’s database and compared the risk of lung transplant and death for patients on anticoagulation or no anticoagulation and for those receiving DOACs versus warfarin versus no anticoagulation.

The study comprised 1,918 patients, 91% of whom were not on anticoagulation therapy. The remaining 164 were either taking DOAC (n = 83) or warfarin (n = 81). Both of these groups were significantly older than those not on anticoagulation (70 vs. 67 years). As expected , they were significantly more likely to have cardiac arrhythmias, heart failure, or pulmonary embolism or deep vein thrombosis and significantly more likely to be on immunosuppressant therapy or steroids. Their diffusing capacity of lung for carbon dioxide was also significantly lower.

There were no significant lung disease–related differences in anticoagulation therapy, other than a trend toward more use among those with connective tissue disease–associated interstitial lung disease.

Over 2 years, the entire cohort experienced 110 deaths (5.7%), 52 transplants (2.7%), and 29 withdrawals (1.5%). Among patients with IPF, there were 80 deaths (6.7%), 43 transplants (3.6%) and 20 withdrawals (1.7%).

In an unadjusted analysis, anticoagulation more than doubled the risk of an event, compared with no anticoagulation (hazard ratio, 2.4). This was slightly attenuated, but still significant, in a multivariate model that controlled for age, gender, oxygen use, gastroesophageal reflux disease, obstructive sleep apnea, arrhythmia, cancer, heart failure, obesity, venous thromboembolism, and antifibrotics (HR, 1.88).

A second whole-cohort analysis looked at the survival ratios for both warfarin and DOAC, compared with no treatment. In the fully adjusted model, warfarin was associated with a significantly increased risk HR (2.28) but DOAC was not.

The investigators then examined risk in only patients with lung disease. Among those with IPF, the fully adjusted model showed that warfarin nearly tripled the risk of transplant or death (HR, 2.8), while DOAC had no significant effect.

The reason for this association remains unclear, Dr. King said. “Renal failure may be a big reason patients get warfarin instead of DOAC. It’s difficult to say whether these patients were frail or prone to bleeding. Even something like the care team not being as up to date with treatment could be affecting the numbers. And is it the direct effect of warfarin on fibrotic lung disease? Or maybe DOAC has some beneficial effect on pulmonary fibrosis? We don’t know.

“But what we can take away from this is that warfarin is associated with worse outcomes than DOAC in patients with IPF. It seems reasonable to use DOAC over warfarin if there’s no specific contraindication to DOAC. If you have a patient with pulmonary thrombosis who has indications for anticoagulation I would use DOAC, based on the evidence that we now have available.”

Dr. King had no disclosures.

[email protected]

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

TORONTO – The use of warfarin or related vitamin K antagonists was associated with a more than 100% increased risk of incident or progressive knee or hip osteoarthritis in the Rotterdam Study, Cindy G. Boer reported at the OARSI 2019 World Congress.

A biologically plausible mechanism exists for this relationship, added Ms. Boer, a PhD student with a special interest in the molecular genetics of OA at Erasmus University, Rotterdam, the Netherlands.

Bruce Jancin/MDedge News

About 80% of the OA endpoints in this analysis involved incident OA, defined radiographically as Kellgren-Lawrence grade 2. Progressive OA was defined as going from grade 2 at baseline to grade 3-4 during follow-up.

There was a signal of a treatment duration-related effect, with OA rates trending highest in individuals on warfarin for longer than 365 days, followed by those on the oral anticoagulant for more than 100 days, who in turn had higher rates than those on warfarin for less time.

Ms. Boer said an important next step in this research is to replicate the warfarin/OA association in an independent cohort. Also, she and her coworkers are now gathering OA incidence and progression data in patients on direct oral anticoagulants rather than warfarin to test the hypothesis that they will not have an increased rate of OA, compared with nonusers, since these newer agents don’t affect vitamin K. Of course, if they do turn out to have an elevated risk, it would point to one or more of the conditions for which oral anticoagulants are commonly prescribed as the explanation.

She reported having no financial conflicts regarding her study, sponsored by Erasmus University and the Dutch government.

[email protected]

Among adults aged over age 65 years, taking a statin within 90 days after a concussion was associated with a 13% reduced risk of developing dementia in the subsequent 5 years, compared with similar adults not taking statins.

The findings come from a population-based double cohort study of 28,815 patients in the Ontario Health Insurance Plan. Study patients were enrolled over 20 years, and had a minimum follow-up of 3 years. The study excluded patients hospitalized caused by a severe concussion, those previously diagnosed with delirium or dementia, and those who died within 90 days of their concussions.

Concussions are a common injury in older adults and dementia may be a frequent outcome years afterward, Donald A. Redelmeier, MD, of the University of Toronto and colleagues wrote in a study published in JAMA Neurology. A concussion should not be interpreted as a reason to stop statins, and a potential neuroprotective benefit may encourage medication adherence among patients who are already prescribed a statin.

Of the 28,815 patients studied, 4,727 patients (1 case per 6 patients) developed dementia over the mean follow-up period of 3.9 years. The 7,058 patients who received a statin had a 13% reduced risk of developing dementia, compared with the 21,757 patients who did not (relative risk, 0.87; 95% confidence interval, 0.81-0.93; P less than .001).

Even though statin use was associated with a lower risk, the subsequent incidence of dementia was still twice the population norm in statin users who had concussions, the researchers wrote. The findings indicate concussions are a common injury in older adults and dementia may be a frequent outcome years after concussions.

Statin users who had concussions continued to have a reduced risk of developing dementia after adjustment for patient characteristics, use of other cardiovascular medications, dosage, and depression risk. The statin associated with the greatest risk reduction was rosuvastatin; simvastatin was associated with the least risk reduction. With the possible exception of angiotensin II receptor blockers, no other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion, the researchers wrote.

They also examined data for elderly patients using statins after an ankle sprain and found the risk of dementia was similar for those who did and did not receive statins after the injury.

Factors such as smoking status, exercise, drug adherence, and other unknown aspects of patient health might have influenced the results of the study, the researchers acknowledged. Additionally, a secondary analysis was not statistically powered to distinguish the relative efficacy of statin use before a concussion.

This study was funded in part by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto. The authors reported no relevant conflicts of interest.

SOURCE: Redelmeier DA et al. JAMA Neurol. 2019 May 20. doi: 10.1001/jamaneurol.2019.1148.

Among adults aged over age 65 years, taking a statin within 90 days after a concussion was associated with a 13% reduced risk of developing dementia in the subsequent 5 years, compared with similar adults not taking statins.

The findings come from a population-based double cohort study of 28,815 patients in the Ontario Health Insurance Plan. Study patients were enrolled over 20 years, and had a minimum follow-up of 3 years. The study excluded patients hospitalized caused by a severe concussion, those previously diagnosed with delirium or dementia, and those who died within 90 days of their concussions.

Concussions are a common injury in older adults and dementia may be a frequent outcome years afterward, Donald A. Redelmeier, MD, of the University of Toronto and colleagues wrote in a study published in JAMA Neurology. A concussion should not be interpreted as a reason to stop statins, and a potential neuroprotective benefit may encourage medication adherence among patients who are already prescribed a statin.

Of the 28,815 patients studied, 4,727 patients (1 case per 6 patients) developed dementia over the mean follow-up period of 3.9 years. The 7,058 patients who received a statin had a 13% reduced risk of developing dementia, compared with the 21,757 patients who did not (relative risk, 0.87; 95% confidence interval, 0.81-0.93; P less than .001).

Even though statin use was associated with a lower risk, the subsequent incidence of dementia was still twice the population norm in statin users who had concussions, the researchers wrote. The findings indicate concussions are a common injury in older adults and dementia may be a frequent outcome years after concussions.

Statin users who had concussions continued to have a reduced risk of developing dementia after adjustment for patient characteristics, use of other cardiovascular medications, dosage, and depression risk. The statin associated with the greatest risk reduction was rosuvastatin; simvastatin was associated with the least risk reduction. With the possible exception of angiotensin II receptor blockers, no other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion, the researchers wrote.

They also examined data for elderly patients using statins after an ankle sprain and found the risk of dementia was similar for those who did and did not receive statins after the injury.

Factors such as smoking status, exercise, drug adherence, and other unknown aspects of patient health might have influenced the results of the study, the researchers acknowledged. Additionally, a secondary analysis was not statistically powered to distinguish the relative efficacy of statin use before a concussion.

This study was funded in part by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto. The authors reported no relevant conflicts of interest.

SOURCE: Redelmeier DA et al. JAMA Neurol. 2019 May 20. doi: 10.1001/jamaneurol.2019.1148.

Among adults aged over age 65 years, taking a statin within 90 days after a concussion was associated with a 13% reduced risk of developing dementia in the subsequent 5 years, compared with similar adults not taking statins.

The findings come from a population-based double cohort study of 28,815 patients in the Ontario Health Insurance Plan. Study patients were enrolled over 20 years, and had a minimum follow-up of 3 years. The study excluded patients hospitalized caused by a severe concussion, those previously diagnosed with delirium or dementia, and those who died within 90 days of their concussions.

Concussions are a common injury in older adults and dementia may be a frequent outcome years afterward, Donald A. Redelmeier, MD, of the University of Toronto and colleagues wrote in a study published in JAMA Neurology. A concussion should not be interpreted as a reason to stop statins, and a potential neuroprotective benefit may encourage medication adherence among patients who are already prescribed a statin.

Of the 28,815 patients studied, 4,727 patients (1 case per 6 patients) developed dementia over the mean follow-up period of 3.9 years. The 7,058 patients who received a statin had a 13% reduced risk of developing dementia, compared with the 21,757 patients who did not (relative risk, 0.87; 95% confidence interval, 0.81-0.93; P less than .001).

Even though statin use was associated with a lower risk, the subsequent incidence of dementia was still twice the population norm in statin users who had concussions, the researchers wrote. The findings indicate concussions are a common injury in older adults and dementia may be a frequent outcome years after concussions.

Statin users who had concussions continued to have a reduced risk of developing dementia after adjustment for patient characteristics, use of other cardiovascular medications, dosage, and depression risk. The statin associated with the greatest risk reduction was rosuvastatin; simvastatin was associated with the least risk reduction. With the possible exception of angiotensin II receptor blockers, no other cardiovascular or noncardiovascular medications were associated with a decreased risk of dementia after a concussion, the researchers wrote.

They also examined data for elderly patients using statins after an ankle sprain and found the risk of dementia was similar for those who did and did not receive statins after the injury.

Factors such as smoking status, exercise, drug adherence, and other unknown aspects of patient health might have influenced the results of the study, the researchers acknowledged. Additionally, a secondary analysis was not statistically powered to distinguish the relative efficacy of statin use before a concussion.

This study was funded in part by a Canada Research Chair in Medical Decision Sciences, the Canadian Institutes of Health Research, the BrightFocus Foundation, and the Comprehensive Research Experience for Medical Students at the University of Toronto. The authors reported no relevant conflicts of interest.

SOURCE: Redelmeier DA et al. JAMA Neurol. 2019 May 20. doi: 10.1001/jamaneurol.2019.1148.

Early-pregnancy spontaneous abortion was almost twice as common among women who used benzodiazepines, according to 17 years’ worth of data from the Quebec Pregnancy Cohort, which prospectively collects data on all pregnancies of women covered by the Quebec Public Prescription Drug Insurance Plan.

The findings suggest the need for caution before prescribing benzodiazepines to treat insomnia and mood or anxiety disorders in early pregnancy. “Alternative nonpharmacologic treatments exist and are recommended, but if benzodiazepines are needed, they should be prescribed for short durations,” wrote Odile Sheehy, MSc, of the Research Center at Centre Hospitalier Universitaire Sainte-Justine, Montreal, and colleagues, in a study published in JAMA Psychiatry.

The researchers evaluated data from 27,149 study-eligible women who had a spontaneous abortion after 6 weeks’ gestation and before 20 weeks’ gestation between Jan. 1, 1998, and Dec. 31, 2015. Among filled prescriptions, at least one benzodiazepine was used by 375 (1.4%) of the women. These women were matched with five randomly selected control pregnancies per case. The data were adjusted for diagnoses of mood and anxiety disorders and insomnia as well as for several documented proxies of these diseases, such as concomitant exposure to antidepressants or antipsychotics, visits to a psychiatrist, comorbidities, and hospitalizations.

The investigators found an adjusted odds ratio (aOR) of 1.85 (95% confidence interval, 1.61-2.12) for benzodiazepine use. The odds of spontaneous abortion was increased with use of all types of benzodiazepines evaluated in the study, with aORs as low as 1.13 and as high as 3.43, as well as similar aORs between long-acting and short-acting benzodiazepines (1.81 vs. 1.73, respectively).

While the information is accurate regarding filled prescriptions, the findings might not apply to women with private drug insurance as the study included only women in a prescription drug program, the researchers said. They noted, however, that pregnant women receiving medication insurance from Quebec’s public system have characteristics and comorbidities similar to those of women who are covered by private medication insurance.

One author reported being a consultant for plaintiffs in litigations involving antidepressants and birth defects. No other disclosures were reported.

[email protected]

SOURCE: Sheehy O et al. JAMA Psychiatry. 2019 May 15. doi: 10.1001/jamapsychiatry.2019.0963.

Early-pregnancy spontaneous abortion was almost twice as common among women who used benzodiazepines, according to 17 years’ worth of data from the Quebec Pregnancy Cohort, which prospectively collects data on all pregnancies of women covered by the Quebec Public Prescription Drug Insurance Plan.

The findings suggest the need for caution before prescribing benzodiazepines to treat insomnia and mood or anxiety disorders in early pregnancy. “Alternative nonpharmacologic treatments exist and are recommended, but if benzodiazepines are needed, they should be prescribed for short durations,” wrote Odile Sheehy, MSc, of the Research Center at Centre Hospitalier Universitaire Sainte-Justine, Montreal, and colleagues, in a study published in JAMA Psychiatry.

The researchers evaluated data from 27,149 study-eligible women who had a spontaneous abortion after 6 weeks’ gestation and before 20 weeks’ gestation between Jan. 1, 1998, and Dec. 31, 2015. Among filled prescriptions, at least one benzodiazepine was used by 375 (1.4%) of the women. These women were matched with five randomly selected control pregnancies per case. The data were adjusted for diagnoses of mood and anxiety disorders and insomnia as well as for several documented proxies of these diseases, such as concomitant exposure to antidepressants or antipsychotics, visits to a psychiatrist, comorbidities, and hospitalizations.

The investigators found an adjusted odds ratio (aOR) of 1.85 (95% confidence interval, 1.61-2.12) for benzodiazepine use. The odds of spontaneous abortion was increased with use of all types of benzodiazepines evaluated in the study, with aORs as low as 1.13 and as high as 3.43, as well as similar aORs between long-acting and short-acting benzodiazepines (1.81 vs. 1.73, respectively).

While the information is accurate regarding filled prescriptions, the findings might not apply to women with private drug insurance as the study included only women in a prescription drug program, the researchers said. They noted, however, that pregnant women receiving medication insurance from Quebec’s public system have characteristics and comorbidities similar to those of women who are covered by private medication insurance.

One author reported being a consultant for plaintiffs in litigations involving antidepressants and birth defects. No other disclosures were reported.

[email protected]

SOURCE: Sheehy O et al. JAMA Psychiatry. 2019 May 15. doi: 10.1001/jamapsychiatry.2019.0963.

Early-pregnancy spontaneous abortion was almost twice as common among women who used benzodiazepines, according to 17 years’ worth of data from the Quebec Pregnancy Cohort, which prospectively collects data on all pregnancies of women covered by the Quebec Public Prescription Drug Insurance Plan.

The findings suggest the need for caution before prescribing benzodiazepines to treat insomnia and mood or anxiety disorders in early pregnancy. “Alternative nonpharmacologic treatments exist and are recommended, but if benzodiazepines are needed, they should be prescribed for short durations,” wrote Odile Sheehy, MSc, of the Research Center at Centre Hospitalier Universitaire Sainte-Justine, Montreal, and colleagues, in a study published in JAMA Psychiatry.

The researchers evaluated data from 27,149 study-eligible women who had a spontaneous abortion after 6 weeks’ gestation and before 20 weeks’ gestation between Jan. 1, 1998, and Dec. 31, 2015. Among filled prescriptions, at least one benzodiazepine was used by 375 (1.4%) of the women. These women were matched with five randomly selected control pregnancies per case. The data were adjusted for diagnoses of mood and anxiety disorders and insomnia as well as for several documented proxies of these diseases, such as concomitant exposure to antidepressants or antipsychotics, visits to a psychiatrist, comorbidities, and hospitalizations.

The investigators found an adjusted odds ratio (aOR) of 1.85 (95% confidence interval, 1.61-2.12) for benzodiazepine use. The odds of spontaneous abortion was increased with use of all types of benzodiazepines evaluated in the study, with aORs as low as 1.13 and as high as 3.43, as well as similar aORs between long-acting and short-acting benzodiazepines (1.81 vs. 1.73, respectively).

While the information is accurate regarding filled prescriptions, the findings might not apply to women with private drug insurance as the study included only women in a prescription drug program, the researchers said. They noted, however, that pregnant women receiving medication insurance from Quebec’s public system have characteristics and comorbidities similar to those of women who are covered by private medication insurance.

One author reported being a consultant for plaintiffs in litigations involving antidepressants and birth defects. No other disclosures were reported.

[email protected]

SOURCE: Sheehy O et al. JAMA Psychiatry. 2019 May 15. doi: 10.1001/jamapsychiatry.2019.0963.

Lenalidomide can reduce the risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM), according to a phase 2/3 trial.

At 3 years, the rate of progression-free survival (PFS) was 91% in SMM patients randomized to lenalidomide and 66% in those randomized to observation.

However, more than half of patients randomized to lenalidomide discontinued treatment because of toxicity.

These results are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, discussed the results in a press briefing in advance of the meeting.

A prior trial suggested that lenalidomide plus dexamethasone can improve time to MM development and overall survival in patients with high-risk SMM (Mateos MV et al. NEJM 2013). However, inferior imaging was used in this trial, and the addition of dexamethasone hindered researchers’ ability to isolate the effects of lenalidomide, Dr. Lonial said.

With their trial (NCT01169337), Dr. Lonial and colleagues tested lenalidomide alone and screened patients using magnetic resonance imaging.

The trial enrolled patients with intermediate or high-risk SMM in two phases. In phase 2, all 44 patients received lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle. They also received aspirin at 325 mg on days 1-28.

In the phase 3 portion of the trial, 182 patients were randomized to observation or lenalidomide and aspirin at the aforementioned dose and schedule. Patients were stratified according to time since SMM diagnosis – 1 year or less vs. more than 1 year.

Safety

Dr. Lonial said, in general, lenalidomide was “very well tolerated.” However, 80% of patients in phase 2 and 51% in phase 3 discontinued lenalidomide due to toxicity.

The rates of treatment-related adverse events (AEs) in the phase 2 portion were 34.1% for grade 3 AEs, 11.4% for grade 4, and 4.5% for grade 5. In the phase 3 portion, 35.2% of patients had grade 3 treatment-related AEs, and 5.7% had grade 4 treatment-related AEs.

Common AEs in phase 3 were grade 4 neutrophil count decrease (4.5%) and grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin AEs (5.7%), dyspnea (5.7%), and hypokalemia (3.4%).
 

Efficacy

“It is worth noting that about 50% of patients had an objective response to lenalidomide in both the phase 2 and the phase 3 trial,” Dr. Lonial said. “I think it’s also important to realize that, in the phase 2 portion of this study, of the 44 patients enrolled, 78% of them did not progress to myeloma with a median follow-up of over 5 years.”

In phase 2, PFS was 98% at 1 year, 87% at 3 years, and 78% at 5 years.

In phase 3, PFS was 98% in the lenalidomide arm and 89% in the observation arm at 1 year. At 2 years, PFS was 93% in the lenalidomide arm and 76% in the observation arm. At 3 years, PFS was 91% in the lenalidomide arm and 66% in the observation arm.

“What’s really quite interesting is that each [risk] group appeared to benefit almost equally from the early intervention of lenalidomide as a single agent,” Dr. Lonial said. “[W]hile the high-risk group may be the target now, this may be a fertile area for investigation in the intermediate-risk group as well.”

Dr. Lonial has relationships with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis, and Takeda. The trial was funded by the National Institutes of Health.

[email protected]

SOURCE: Lonial S et al. ASCO 2019. Abstract 8001.

Lenalidomide can reduce the risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM), according to a phase 2/3 trial.

At 3 years, the rate of progression-free survival (PFS) was 91% in SMM patients randomized to lenalidomide and 66% in those randomized to observation.

However, more than half of patients randomized to lenalidomide discontinued treatment because of toxicity.

These results are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, discussed the results in a press briefing in advance of the meeting.

A prior trial suggested that lenalidomide plus dexamethasone can improve time to MM development and overall survival in patients with high-risk SMM (Mateos MV et al. NEJM 2013). However, inferior imaging was used in this trial, and the addition of dexamethasone hindered researchers’ ability to isolate the effects of lenalidomide, Dr. Lonial said.

With their trial (NCT01169337), Dr. Lonial and colleagues tested lenalidomide alone and screened patients using magnetic resonance imaging.

The trial enrolled patients with intermediate or high-risk SMM in two phases. In phase 2, all 44 patients received lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle. They also received aspirin at 325 mg on days 1-28.

In the phase 3 portion of the trial, 182 patients were randomized to observation or lenalidomide and aspirin at the aforementioned dose and schedule. Patients were stratified according to time since SMM diagnosis – 1 year or less vs. more than 1 year.

Safety

Dr. Lonial said, in general, lenalidomide was “very well tolerated.” However, 80% of patients in phase 2 and 51% in phase 3 discontinued lenalidomide due to toxicity.

The rates of treatment-related adverse events (AEs) in the phase 2 portion were 34.1% for grade 3 AEs, 11.4% for grade 4, and 4.5% for grade 5. In the phase 3 portion, 35.2% of patients had grade 3 treatment-related AEs, and 5.7% had grade 4 treatment-related AEs.

Common AEs in phase 3 were grade 4 neutrophil count decrease (4.5%) and grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin AEs (5.7%), dyspnea (5.7%), and hypokalemia (3.4%).
 

Efficacy

“It is worth noting that about 50% of patients had an objective response to lenalidomide in both the phase 2 and the phase 3 trial,” Dr. Lonial said. “I think it’s also important to realize that, in the phase 2 portion of this study, of the 44 patients enrolled, 78% of them did not progress to myeloma with a median follow-up of over 5 years.”

In phase 2, PFS was 98% at 1 year, 87% at 3 years, and 78% at 5 years.

In phase 3, PFS was 98% in the lenalidomide arm and 89% in the observation arm at 1 year. At 2 years, PFS was 93% in the lenalidomide arm and 76% in the observation arm. At 3 years, PFS was 91% in the lenalidomide arm and 66% in the observation arm.

“What’s really quite interesting is that each [risk] group appeared to benefit almost equally from the early intervention of lenalidomide as a single agent,” Dr. Lonial said. “[W]hile the high-risk group may be the target now, this may be a fertile area for investigation in the intermediate-risk group as well.”

Dr. Lonial has relationships with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis, and Takeda. The trial was funded by the National Institutes of Health.

[email protected]

SOURCE: Lonial S et al. ASCO 2019. Abstract 8001.

Lenalidomide can reduce the risk of progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM), according to a phase 2/3 trial.

At 3 years, the rate of progression-free survival (PFS) was 91% in SMM patients randomized to lenalidomide and 66% in those randomized to observation.

However, more than half of patients randomized to lenalidomide discontinued treatment because of toxicity.

These results are scheduled to be presented at the annual meeting of the American Society of Clinical Oncology.

Sagar Lonial, MD, of Winship Cancer Institute, Emory University, Atlanta, discussed the results in a press briefing in advance of the meeting.

A prior trial suggested that lenalidomide plus dexamethasone can improve time to MM development and overall survival in patients with high-risk SMM (Mateos MV et al. NEJM 2013). However, inferior imaging was used in this trial, and the addition of dexamethasone hindered researchers’ ability to isolate the effects of lenalidomide, Dr. Lonial said.

With their trial (NCT01169337), Dr. Lonial and colleagues tested lenalidomide alone and screened patients using magnetic resonance imaging.

The trial enrolled patients with intermediate or high-risk SMM in two phases. In phase 2, all 44 patients received lenalidomide at 25 mg daily on days 1-21 of a 28-day cycle. They also received aspirin at 325 mg on days 1-28.

In the phase 3 portion of the trial, 182 patients were randomized to observation or lenalidomide and aspirin at the aforementioned dose and schedule. Patients were stratified according to time since SMM diagnosis – 1 year or less vs. more than 1 year.

Safety

Dr. Lonial said, in general, lenalidomide was “very well tolerated.” However, 80% of patients in phase 2 and 51% in phase 3 discontinued lenalidomide due to toxicity.

The rates of treatment-related adverse events (AEs) in the phase 2 portion were 34.1% for grade 3 AEs, 11.4% for grade 4, and 4.5% for grade 5. In the phase 3 portion, 35.2% of patients had grade 3 treatment-related AEs, and 5.7% had grade 4 treatment-related AEs.

Common AEs in phase 3 were grade 4 neutrophil count decrease (4.5%) and grade 3 infections (20.5%), hypertension (9.1%), fatigue (6.8%), skin AEs (5.7%), dyspnea (5.7%), and hypokalemia (3.4%).
 

Efficacy

“It is worth noting that about 50% of patients had an objective response to lenalidomide in both the phase 2 and the phase 3 trial,” Dr. Lonial said. “I think it’s also important to realize that, in the phase 2 portion of this study, of the 44 patients enrolled, 78% of them did not progress to myeloma with a median follow-up of over 5 years.”

In phase 2, PFS was 98% at 1 year, 87% at 3 years, and 78% at 5 years.

In phase 3, PFS was 98% in the lenalidomide arm and 89% in the observation arm at 1 year. At 2 years, PFS was 93% in the lenalidomide arm and 76% in the observation arm. At 3 years, PFS was 91% in the lenalidomide arm and 66% in the observation arm.

“What’s really quite interesting is that each [risk] group appeared to benefit almost equally from the early intervention of lenalidomide as a single agent,” Dr. Lonial said. “[W]hile the high-risk group may be the target now, this may be a fertile area for investigation in the intermediate-risk group as well.”

Dr. Lonial has relationships with AbbVie, Amgen, Bristol-Myers Squibb, Celgene, GlaxoSmithKline, Janssen Oncology, Juno Therapeutics, Merck, Novartis, and Takeda. The trial was funded by the National Institutes of Health.

[email protected]

SOURCE: Lonial S et al. ASCO 2019. Abstract 8001.

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

MADISON, WISC. – Only half of United States veterans with inflammatory arthritis received disease-modifying medication within 90 days of diagnosis if they received care within the Veterans Health Administration, according to a study presented at the annual meeting of the Spondyloarthritis Research and Treatment Network (SPARTAN).

Over the study period, 58.2% of all inflammatory arthritis patients began a disease-modifying antirheumatic drug (DMARD) within 12 months of diagnosis. Rates of DMARD initiation were similar for patients with rheumatoid arthritis (RA, 57.7%) and psoriatic arthritis (PsA, 64.3%), said the first author of the poster presentation, Sogol S. Amjadi, DO, a resident physician at Bingham Memorial Hospital, Blackfoot, Idaho.

However, at 12 months after diagnosis, only 29.6% of ankylosing spondylitis (AS) patients had not been started on a DMARD. “The ankylosing spondylitis group really had the lowest DMARD initiation over time,” said Dr. Amjadi in an interview.

The study used diagnosis codes and natural language processing to look for incident cases of the three inflammatory arthritides (IAs) among patients receiving care within the Veterans Health Administration from 2007 through 2015.

In all, 12,118 patients with incident IA were identified. Of these, 9,711 had RA, 1,472 had PsA, and 935 had AS. Patients were mostly (91.3%) male, with a mean age of 63.7 years.

Over the study period, 41.2% of IA patients were dispensed a DMARD within 30 days of diagnosis, and 50% received a DMARD within 90 days of diagnosis. Patients with PsA or RA had similar rates of DMARD prescription within 30 days of diagnosis (about 42% and 43%, respectively).

The investigators discovered in their analysis that another factor in prompt treatment was access to specialty care.“Timely access to a rheumatology provider is likely important for early DMARD treatment,” wrote Dr. Amjadi and her coauthors in the poster accompanying the presentation. Of patients who did receive a DMARD, 82.7% had received rheumatology specialty care before nonbiologic DMARD dispensing, as had 90.0% of patients receiving biologic DMARDs. Over the entire study period, about 10% of all IA patients had biologic DMARD exposure.

There was a trend over time for increased DMARD dispensing, said the investigators. “The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015.”

For AS patients, early DMARD prescribing rates rose from about 20% in 2007 to nearly 30% in 2015. “DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but nontreatment remained common, particularly in patients with AS,” wrote the investigators. “Delays in treatment for inflammatory arthritis are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability.”

The authors reported no conflicts of interest and no outside sources of funding.

[email protected]

The Food and Drug Administration will now require that certain medications prescribed for insomnia carry a boxed warning because of associated complex sleep behaviors.

[email protected]

The Food and Drug Administration will now require that certain medications prescribed for insomnia carry a boxed warning because of associated complex sleep behaviors.

[email protected]

The Food and Drug Administration will now require that certain medications prescribed for insomnia carry a boxed warning because of associated complex sleep behaviors.

[email protected]