Transfusion trigger after operations in high cardiac risk patients (TOP) trial protocol. Protocol for a multicenter randomized controlled transfusion strategy trial.

BACKGROUND: There is substantial uncertainty regarding the effects of restrictive postoperative transfusion among patients who have underlying cardiovascular disease. The TOP Trial's objective is to compare adverse outcomes between liberal and restrictive transfusion strategies in patients undergoing vascular and general surgery operations, and with a high risk of postoperative cardiac events. METHODS: A two-arm, single-blinded, randomized controlled superiority trial will be used across 15 Veterans Affairs hospitals with expected enrollment of 1520 participants. Postoperative transfusions in the liberal arm commence when Hb is <10 g/ dL and continue until Hb is greater than or equal to 10 g/dL. In the restrictive arm, transfusions begin when Hb is <7 g/dL and continue until Hb is greater than or equal to 7 g/dL. Study duration is estimated to be 5 years including a 3-month start-up period and 4 years of recruitment. Each randomized participant will be followed for 90 days after randomization with a mortality assessment at 1 year. RESULTS: The primary outcome is a composite endpoint of all-cause mortality, myocardial infarction (MI), coronary revascularization, acute renal failure, or stroke occurring up to 90-days after randomization. Events rates will be compared between restrictive and liberal transfusion groups. CONCLUSIONS: The TOP Trial is uniquely positioned to provide high quality evidence comparing transfusion strategies among patients with high cardiac risk. Results will clarify the effect of postoperative transfusion strategies on adverse outcomes and inform postoperative management algorithms. TRIAL REGISTRATION: http://clinicaltrials.gov identifier: NCT03229941.

Defining optimal treatment for recurrent Clostridioides difficile infection (OpTION study): A randomized, double-blind comparison of three antibiotic regimens for patients with a first or second recurrence.

BACKGROUND: Although many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI. METHODS: VA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59. DISCUSSION: CSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic. TRIAL REGISTRATION: This study is registered with clinicaltrials.gov (Identifier: NCT02667418).

Lateralized abnormalities in auditory M50 sensory gating and cortical thickness of the superior temporal gyrus in post-traumatic stress disorder: preliminary results.

Auditory sensory gating deficits have been reported in subjects with post-traumatic stress disorder (PTSD), but the hemispheric and neuronal origins of this deficit are not well understood. The objectives of this study were to: (1) investigate auditory sensory gating of the 50-ms response (M50) in patients diagnosed with PTSD by utilizing magnetoencephalography (MEG); (2) explore the relationship between M50 sensory gating and cortical thickness of the superior temporal gyrus (STG) measured with structural magnetic resonance imaging (MRI); and (3) examine the association between PTSD symptomatology and bilateral sensory gating. Seven participants with combat-related PTSD and eleven controls underwent the paired-click sensory gating paradigm. MEG localized M50 neuronal generators to the STG in both groups. The PTSD group displayed impaired M50 gating in the right hemisphere. Thinner right STG cortical thickness was associated with worse right sensory gating in the PTSD group. The right S1 M50 source strength and gating ratio were correlated with PTSD symptomatology. These findings suggest that the structural integrity of right hemisphere STG cortices play an important role in auditory sensory gating deficits in PTSD.

Efficacy of Quetiapine Monotherapy in Posttraumatic Stress Disorder: A Randomized, Placebo-Controlled Trial.

OBJECTIVE: This was a 12-week randomized, placebo-controlled trial to assess the efficacy of quetiapine monotherapy in the treatment of posttraumatic stress disorder (PTSD). METHOD: Eighty patients were randomly assigned to treatment with either quetiapine or placebo. The primary outcome measure was the Clinician-Administered PTSD Scale (CAPS). Secondary efficacy measures included the CAPS subscales, the Davidson Trauma Scale, the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impressions (CGI) scales for severity of Illness and improvement, the Hamilton Depression Rating Scale (HAM-D), and the Hamilton Anxiety Rating Scale (HAM-A). Safety measurements included adverse events, vital signs, the Abnormal Involuntary Movement Scale, the Barnes Akathisia Scale, the Simpson-Angus Scale, and the Arizona Sexual Experiences Scale. RESULTS: After a 1-week placebo run-in, quetiapine was started at a daily dosage of 25 mg and increased to a maximum of 800 mg; the average was 258 mg (range, 50-800 mg). Reductions in CAPS total, re-experiencing, and hyperarousal scores were significantly greater for the quetiapine group than for the placebo group. Greater improvements were also observed for quetiapine in scores on the Davidson Trauma Scale, CGI severity and improvement ratings, PANSS positive symptom and general psychopathology subscales, HAM-A, and HAM-D than for placebo. Adverse events were generally mild and expected based on prior studies of quetiapine in this and other patient population. There were no differences in safety measures between groups. CONCLUSION: Quetiapine monotherapy was efficacious in the treatment of PTSD. These findings suggest quetiapine as a single agent is effective in treating military PTSD.

Duloxetine in military posttraumatic stress disorder.

The objective of this prospective study was to assess the efficacy and tolerability of duloxetine in the treatment of in military veterans with posttraumatic stress disorder (PTSD).Twenty subjects were enrolled in this 12-week, open-label trial. Diagnosis and symptom severity were assessed with the Clinician Administered PTSD Scale (CAPS). Depressive symptoms were assessed the Hamilton Depression Rating Scale. All subjects had a CAPS score of at least 60 at baseline. Subjects with lifetime history of psychotic disorders or bipolar illness were excluded. Fifteen participants completed 12 weeks of treatment, five dropped-out from the trial, 3 due to side effects. For patients who discontinued, missing values were estimated using "the last observation carried forward" method. Significant improvements were seen on: CAPS total and all subscales, depression and sleep measures. Most of the improvement was observed by week 2 of treatment. Nine participants (45%) were classified as responders, defined by 20% or greater improvement on CAPS total score. The mean daily dose of duloxetine was 81 mg. The most common side effects were constipation (20%) diarrhea (25%) and nausea (20%). Two subjects developed tachycardia, one withdrew from the trial due to this problem. Duloxetine had a fast onset of action and was effective in about half of the subjects, it was well tolerated in most subjects. These preliminary results in a difficult to treat population warrant the conduction of a double blind, placebo-controlled study of duloxetine in PTSD.

Prospective study to evaluate the efficacy of aripiprazole as a monotherapy in patients with severe chronic posttraumatic stress disorder: an open trial.

The objective of the study was to assess the efficacy and safety of aripiprazole in outpatients with posttraumatic stress disorder (PTSD) on a 12-week, open-label trial. Twenty-two subjects with DSM-IV diagnosis of PTSD participated; 16 were combat veterans. The primary outcome measure was PTSD symptom severity assessed with the Clinician Administered PTSD Scale (CAPS). Secondary outcome measures included the Positive and Negative Symptoms Scale and the Hamilton Depression and Anxiety Scales. All subjects had a CAPS score of > or = 60 at baseline. Lifetime history of psychotic disorders or bipolar illness was exclusionary. The overall analysis across time was Repeated Measures ANOVA, using Bonferroni corrections. Fourteen subjects completed 12 weeks of treatment. Eight subjects dropped-out due to side effects. For patients who discontinued, missing values were estimated using "the last observation carried forward" method. Significant improvements were seen on: CAPS total, all its subscales, positive symptoms, anxiety and depression scores. Fourteen participants were classified as responders, defined by 20% or greater improvement on CAPS total score. Of the 13 subjects who completed final ratings, CAPS total scores improved significantly (P = .011). Two subjects attained remission of PTSD (CAPS < 20), and three had a final CAPS < or = 26. The mean daily dose of aripiprazole was 12.95 mg. The most common side effects were somnolence (54.5%), restlessness (50%), insomnia (36.4%), and asthenia (31.8%). These results indicate that aripiprazole was effective in about two thirds of subjects that tolerated this medication. The initially high dropout rate may be related to intolerability due to a high starting dose (10 mg), suggesting beginning treatment at lower doses. These preliminary results are encouraging; a double blind study seems warranted.

Fluvoxamine treatment in veterans with combat-related post-traumatic stress disorder.

This study was designed to investigate the efficacy of the antidepressant fluvoxamine in the treatment of combat-related post-traumatic stress disorder (PTSD). Fifteen veterans with combat-related PTSD and no other psychiatric diagnosis except depression were recruited to participate in a 14-week open-label study of fluvoxamine. Patients underwent a 30-day washout period and were rated with the Clinician Administered PTSD Scale (CAPS), Mississippi Scale, Beck Depression Inventory (BDI), Hamilton Rating Scale for Depression (HAM-D) and Hamilton Rating Scale for Anxiety (HAM-A) at baseline, and every 2 weeks until week 14. Three patients stopped fluvoxamine prematurely due to side effects and 7 withdrew consent before completing the 14-week trial. Eight patients completed at least 8 weeks of treatment. The total daily dose of fluvoxamine ranged from 100 to 300 mg with a mean daily dose of 150 mg at week 14. Intent-to-treat analysis revealed a significant improvement in total CAPS scores, and in the intrusion and the avoidance/numbing subscales. The CAPS hyper-arousal scores did not change significantly. HAM-A score also improved significantly. No significant changes were seen on the Mississippi scale, HAM-D, or Beck Depression Inventory in the intent-to-treat analysis. In summary, our study shows that fluvoxamine appears to improve combat-related PTSD symptoms but not depressive symptoms. The high attrition rate and lack of a placebo group limits the conclusions of our study. Controlled studies of fluvoxamine in the treatment of PTSD are warranted.