Early Mortality After the First Dose of COVID-19 Vaccination: A Target Trial Emulation.

BACKGROUND: Vaccine hesitancy persists alongside concerns about the safety of coronavirus disease 2019 (COVID-19) vaccines. We aimed to examine the effect of COVID-19 vaccination on risk of death among US veterans. METHODS: We conducted a target trial emulation to estimate and compare risk of death up to 60 days under two COVID-19 vaccination strategies: vaccination within 7 days of enrollment versus no vaccination through follow-up. The study cohort included individuals aged ≥18 years enrolled in the Veterans Health Administration system and eligible to receive a COVID-19 vaccination according to guideline recommendations from 1 March 2021 through 1 July 2021. The outcomes of interest included deaths from any cause and excluding a COVID-19 diagnosis. Observations were cloned to both treatment strategies, censored, and weighted to estimate per-protocol effects. RESULTS: We included 3 158 507 veterans. Under the vaccination strategy, 364 993 received vaccine within 7 days. At 60 days, there were 156 deaths per 100 000 veterans under the vaccination strategy versus 185 deaths under the no vaccination strategy, corresponding to an absolute risk difference of -25.9 (95% confidence limit [CL], -59.5 to 2.7) and relative risk of 0.86 (95% CL, .7 to 1.0). When those with a COVID-19 infection in the first 60 days were censored, the absolute risk difference was -20.6 (95% CL, -53.4 to 16.0) with a relative risk of 0.88 (95% CL, .7 to 1.1). CONCLUSIONS: Vaccination against COVID-19 was associated with a lower but not statistically significantly different risk of death in the first 60 days. These results agree with prior scientific knowledge suggesting vaccination is safe with the potential for substantial health benefits.

Prescription Medications for the Treatment of Insomnia and Risk of Suicide Attempt: a Comparative Safety Study.

IMPORTANCE: Guidelines for the pharmacological treatment of chronic insomnia in adults recognize that trazodone and other off-label medications are commonly prescribed despite poor evidence. The Department of Veterans Health Affairs (VA) fills high volumes of inexpensive, over-the-counter sedating antihistamines and older antidepressants in addition to benzodiazepines and zolpidem. Yet little is known about the comparative safety of these agents with regard to suicidal behavior. OBJECTIVES: To assess the comparative effectiveness of the safety of medications routinely used to treat insomnia in VA. DESIGN: Comparative effectiveness using propensity score-matched samples. SETTING: VA. PARTICIPANTS: VA patients without any history of suicidal ideation or behavior 12 months prior to first exposure. EXPOSURES: VA formularies and data were used to identify prescriptions for insomnia. Agents accounting for at least 1% of total insomnia fill volume were < 200 mg trazodone, hydroxyzine, diphenhydramine, zolpidem, lorazepam, diazepam, and temazepam. Exposure was defined as an incident monotherapy exposure preceded by 12 months without any insomnia medications. Subjects with insomnia polypharmacy or cross-overs in the 12 months following first exposure were excluded. MAIN OUTCOMES AND MEASURES: Suicide attempts within 12 months of first exposure. RESULTS: Three hundred forty-eight thousand four hundred forty-nine subjects met criteria and three well-balanced cohorts by drug class matched to zolpidem were created. After adjusting for days' supply, mental health history, and pain and central nervous system medication history, hazard ratios (compared to zolpidem) were as follows: (< 200 mg) trazodone (HR = 1.61, 95% CI 1.07-2.43); sedating antihistamines (HR = 1.37, 95% CI 0.90-2.07); and benzodiazepines (HR = 1.31, 95% CI 0.85-2.08). CONCLUSIONS AND RELEVANCE: Compared to zolpidem, hazard of suicide attempt was 61% higher with trazodone (< 200 mg). No significant differences in suicide attempt risk were identified between benzodiazepines or sedating antihistamines and zolpidem, respectively. These findings provide the first comparative effectiveness evidence against the use of trazodone for insomnia.

Antidepressant treatment and suicide attempts and self-inflicted injury in children and adolescents.

PURPOSE: In the 2004, FDA placed a black box warning on antidepressants for risk of suicidal thoughts and behavior in children and adolescents. The purpose of this paper is to examine the risk of suicide attempt and self-inflicted injury in depressed children ages 5-17 treated with antidepressants in two large observational datasets taking account time-varying confounding. METHODS: We analyzed two large US medical claims databases (MarketScan and LifeLink) containing 221,028 youth (ages 5-17) with new episodes of depression, with and without antidepressant treatment during the period of 2004-2009. Subjects were followed for up to 180 days. Marginal structural models were used to adjust for time-dependent confounding. RESULTS: For both datasets, significantly increased risk of suicide attempts and self-inflicted injury were seen during antidepressant treatment episodes in the unadjusted and simple covariate adjusted analyses. Marginal structural models revealed that the majority of the association is produced by dynamic confounding in the treatment selection process; estimated odds ratios were close to 1.0 consistent with the unadjusted and simple covariate adjusted association being a product of chance alone. CONCLUSIONS: Our analysis suggests antidepressant treatment selection is a product of both static and dynamic patient characteristics. Lack of adjustment for treatment selection based on dynamic patient characteristics can lead to the appearance of an association between antidepressant treatment and suicide attempts and self-inflicted injury among youths in unadjusted and simple covariate adjusted analyses. Marginal structural models can be used to adjust for static and dynamic treatment selection processes such as that likely encountered in observational studies of associations between antidepressant treatment selection, suicide and related behaviors in youth.

Sample size determination for longitudinal designs with binary response.

In this article, we develop appropriate statistical methods for determining the required sample size while comparing the efficacy of an intervention to a control with repeated binary response outcomes. Our proposed methodology incorporates the complexity of the hierarchical nature of underlying designs and provides solutions when varying attrition rates are present over time. We explore how the between-subject variability and attrition rates jointly influence the computation of sample size formula. Our procedure also shows how efficient estimation methods play a crucial role in power analysis. A practical guideline is provided when information regarding individual variance component is unavailable. The validity of our methods is established by extensive simulation studies. Results are illustrated with the help of two randomized clinical trials in the areas of contraception and insomnia.

Risk of suicide attempts and intentional self-harm on alprazolam.

BACKGROUND: From 2000-2021, U.S. suicide deaths have risen 36 %. Identification of pharmacological agents associated with increased suicide risk and safer alternatives may help reduce this trend. METHODS: An exposure-only within-subject time-to-event pharmacoepidemiologic study of the dynamic association between alprazolam treatment and suicide attempts over 2-years. Parallel analyses were conducted for diazepam, lorazepam and buspirone. Data for 2,495,520 patients were obtained from U.S. private insurance medical claims MarketScan from 2010 to 2019. FINDINGS: Alprazolam was associated with over a doubling of risk of suicide attempts (HR=2.21, 95 % CI=2.06,2.38). A duration-response analysis for the modal dose (0.5 mg) revealed a 5 % increase in suicidal events per additional month of treatment (HR=1.05, 95 % CI=1.04,1.07). Parallel analyses with long-acting (diazepam) and short-acting (lorazepam), found similar associations (diazepam HR=2.87, 95 % CI=2.56,3.21; lorazepam HR=1.83, 95 % CI=1.69,2.00), whereas the non-benzodiazepine anxiolytic, buspirone, showed significantly less risk (HR=1.25, 95 % CI=1.13,1.38), and no increased risk in patients with an attempt history (HR=1.05, 95 % CI=0.70,1.59). INTERPRETATION: This study confirmed an earlier signal linking alprazolam to increased suicide attempt risk. The increased risk extends to benzodiazepines in general, regardless of half-life and risk of withdrawal seizure. Buspirone appears to be a safer treatment than benzodiazepines, particularly in patients at increased risk for suicide.

Pallidal versus subthalamic deep-brain stimulation for Parkinson's disease.

BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

Association of perioperative ß-blockade with mortality and cardiovascular morbidity following major noncardiac surgery.

IMPORTANCE: The effectiveness of perioperative ß-blockade in patients undergoing noncardiac surgery remains controversial. OBJECTIVE: To determine the associations of early perioperative exposure to ß-blockers with 30-day postoperative outcome in patients undergoing noncardiac surgery. DESIGN, SETTING, AND PATIENTS: A retrospective cohort analysis evaluating exposure to ß-blockers on the day of or following major noncardiac surgery among a population-based sample of 136,745 patients who were 1:1 matched on propensity scores (37,805 matched pairs) treated at 104 VA medical centers from January 2005 through August 2010. MAIN OUTCOMES AND MEASURES: All cause 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction). RESULTS: Overall 55,138 patients (40.3%) were exposed to ß-blockers. Exposure was higher in the 66.7% of 13,863 patients undergoing vascular surgery (95% CI, 65.9%-67.5%) than in the 37.4% of 122,882 patients undergoing nonvascular surgery (95% CI, 37.1%-37.6%; P < .001). Exposure increased as Revised Cardiac Risk Index factors increased, with 25.3% (95% CI, 24.9%-25.6%) of those with no risk vs 71.3% (95% CI, 69.5%-73.2%) of those with 4 risk factors or more exposed to ß-blockers (P < .001). Death occurred among 1.1% (95% CI, 1.1%-1.2%) and cardiac morbidity occurred among 0.9% (95% CI, 0.8%-0.9%) of patients. In the propensity matched cohort, exposure was associated with lower mortality (relative risk [RR], 0.73; 95% CI, 0.65-0.83; P < .001; number need to treat [NNT], 241; 95% CI, 173-397). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, ß-blocker exposure was associated with significantly lower mortality among patients with 2 factors (RR, 0.63 [95% CI, 0.50-0.80]; P < .001; NNT, 105 [95% CI, 69-212]), 3 factors (RR, 0.54 [95% CI, 0.39-0.73]; P < .001; NNT, 41 [95% CI, 28-80]), or 4 factors or more (RR, 0.40 [95% CI, 0.25-0.73]; P < .001; NNT, 18 [95% CI, 12-34]). This association was limited to patients undergoing nonvascular surgery. ß-Blocker exposure was also associated with a lower rate of nonfatal Q-wave infarction or cardiac arrest (RR, 0.67 [95% CI, 0.57-0.79]; P < .001; NNT, 339 [95% CI, 240-582]), again limited to patients undergoing nonvascular surgery. CONCLUSIONS AND RELEVANCE: Among propensity-matched patients undergoing noncardiac, nonvascular surgery, perioperative ß-blocker exposure was associated with lower rates of 30-day all-cause mortality in patients with 2 or more Revised Cardiac Risk Index factors. Our findings support use of a cumulative number of Revised Cardiac Risk Index predictors in decision making regarding institution and continuation of perioperative ß-blockade. A multicenter randomized trial involving patients at a low to intermediate risk by these factors would be of interest to validate these observational findings.

Not just a walk in the park: efficacy to effectiveness for after school programs in communities of concentrated urban poverty.

This study examined a model for mental health consultation, training and support designed to enhance the benefits of publicly-funded recreational after-school programs in communities of concentrated urban poverty for children's academic, social, and behavioral functioning. We assessed children's mental health needs and examined the feasibility and impact of intervention on program quality and children's psychosocial outcomes in three after-school sites (n = 15 staff, 89 children), compared to three demographically-matched sites that received no intervention (n = 12 staff, 38 children). Findings revealed high staff satisfaction and feasibility of intervention, and modest improvements in observed program quality and staff-reported children's outcomes. Data are considered with a public health lens of mental health promotion for children in urban poverty.

Folic acid prescription and suicide attempt prevention: effect of past suicidal behaviour, psychiatric diagnosis and psychotropic medication.

We previously showed that folic acid prescriptions for any indication were associated with lower rates of suicidal behaviour. Given that future randomised clinical trials are likely to focus on psychiatric disorders carrying elevated risk for suicide, we now report on the moderating effects of prior suicidal behaviour, psychiatric diagnoses and psychotropic medications on potential antisuicidal effects of folic acid. Data were obtained from the MarketScan Commercial Claims and Encounters databases that cover 164 million insured persons from 2005-2017, from which a cohort of 866 586 patients was derived. Analysis revealed no significant moderation effects on the antisuicidal effect of folic acid. These findings indicate that the potential benefit of folic acid for preventing suicidal behaviour is comparable in psychiatric populations at higher risk of suicide and that it may be additive to any benefit from psychotropic medications.

Benztropine and suicide attempts and intentional self-harm.

BACKGROUND: This large-scale pharmacoepidemiologic study was conducted to confirm a previous signal for decreased risk of suicide attempt following prescription fills for benztropine. METHODS: We used a within-person exposure-only cohort design to study the dynamic association between benztropine prescription fills over a 12-month period and suicidal events (suicide attempts and intentional self-harm) in 62,493 patients with private health insurance (MarketScan - MS) who filled a new benztropine prescription between 2011 and 2019. A discrete-time survival analysis was used to analyze the data, adjusting for age, sex, diagnoses related to suicidal behavior, Parkinson's disease, medical comorbidities, history of suicide attempts, concomitant CNS medications, and time-varying antipsychotic use. RESULTS: Overall, there were 486 suicidal events (0.8%) following the index end-date of the one-year baseline period. Benztropine use was associated with fewer suicidal events (HR=0.63, 95% CI = 0.50, 0.80). Patients treated with antipsychotics and benztropine had a similar reduction in suicidal events as patients treated with benztropine alone in both within-subject and between-subject analyses. Similar associations were found for patients with bipolar disorder or schizophrenia, and those treated with newer versus older generation antipsychotics. Dose-response and duration response relationships were found, with an overall 6% reduction in suicidal events per 1 mg equivalent dosage per month, that was similar in those treated and those not treated with antipsychotics. INTERPRETATIONS: Benztropine was found to lower suicidal event rates, comparably in those receiving or not receiving antipsychotic medications, regardless of the presence of major psychiatric disorders. This observation warrants testing in a randomized clinical trial. FUNDING: No funding sources were utilized for this manuscript.

Associations between insomnia medications and risk of death by suicide.

PURPOSE: Insomnia is a modifiable risk factor for suicide often treated with medications. However, little is known about the associations between insomnia medications and risk of death by suicide. The purpose of this study is to model the comparative risk of suicide by each insomnia medication compared to zolpidem, a sedative-hypnotic approved for insomnia. METHODS: First prescription fills of medications commonly used to treat insomnia were identified in electronic medical records. Date and cause of death were identified in death certificates. Cox proportional hazards models were used to analyze time from insomnia prescription to suicide. RESULTS: More than 2 million patients filled a new insomnia prescription between 2005 and 2015, and 518 of them died by suicide within 12 months. Compared to zolpidem, the tricyclic antidepressants (amitriptyline, doxepin) were associated with a 64% lower risk of suicide (HR 0.36 (95% CI 0.22-0.66) and the sedating antihistamines (hydroxyzine, diphenhydramine) a 40% lower risk of suicide (HR 0.60 (0.41-0.89)). In contrast, the tetracyclic antidepressant (mirtazapine) was associated with a 62% higher risk of suicide (HR 1.62 (95% CI 1.10-2.38) compared to zolpidem. CONCLUSION: Insomnia is a modifiable risk factor for suicide, yet many medications used to treat insomnia have never been tested for the indication in clinical trials. To define efficacy in the prevention of suicide, trials are warranted.

Incidence Rates and Clinical Characteristics of Patients With Confirmed Myocarditis or Pericarditis Following COVID-19 mRNA Vaccination: Experience of the Veterans Health Administration Through 9 October 2022.

Background: Although the benefits outweigh the risks, COVID-19 vaccines have been associated with an increased risk of myocarditis and pericarditis. This report is based on a national US veteran population with confirmed myocarditis/pericarditis following mRNA COVID-19 vaccines according to the near real-time active surveillance program of Veterans Affairs. Methods: This study is based on a cohort evaluation of all adults administered ≥1 mRNA COVID-19 vaccine, including boosters, in the Veterans Health Administration between 14 December 2020 and 9 October 2022. ICD-10-CM diagnosis codes were used to identify potential safety signals in near real time through a database analysis. All potential cases of myocarditis/pericarditis identified in the database analysis underwent in-depth chart review and case validation by a team of pharmacists and expert clinicians. Our main outcome was the incidence rate of confirmed myocarditis/pericarditis among vaccine recipients (overall and those aged 18-39 years) within 21 days of a first, second, or booster dose of a mRNA COVID-19 vaccine. We calculated the ratio of observed events among COVID-19 vaccine recipients over expected events from historical vaccine recipient controls (2015-2020) in the Veterans Health Administration. We used confirmed cases to calculate incidence rates and 95% CIs. Results: Through 9 October 2022, 3 877 453 doses of BNT162b2 (Pfizer-BioNTech) and 4 221 397 doses of mRNA-1273 (Moderna) were administered as first or second dose across Veterans Affairs, and 1 012 561 BNT162b2 and 1 156 160 mRNA-1273 booster doses were administered. Among all doses, the rapid cycle analysis identified 178 potential cases of myocarditis/pericarditis among vaccinees of any age and 22 potential cases among those aged 18-39 years. Of these, 33 cases, including 6 among those 18-39 years old, were confirmed after in-depth chart review and validation, corresponding with an overall incidence rate per million ranging from 0.46 (95% CI, .01-2.55) for Moderna dose 1 to 6.91 (95% CI, 2.78-14.24) for Pfizer booster. Among those aged 18-39, incidence rates ranged from 7.1 (95% CI, .18-39.56) for Moderna dose 2 to 19.76 (95% CI, 5.38-50.58) for Pfizer dose 2. Patients with confirmed cases were hospitalized for a mean 4.1 days (range, 1-15). The final disposition for 32 (97%) of 33 cases was discharge to home. Conclusions: This report is a real-world demonstration of the Veterans Affairs' active surveillance system for vaccines. Although the rapid cycle analysis initially identified 178 potential cases of myocarditis/pericarditis, only 1 of 5 cases was confirmed to be related to a COVID-19 vaccine after chart review. These findings highlight the paramount importance of active surveillance and chart validation for rare but serious adverse events related to COVID-19 vaccines.

Association Between Folic Acid Prescription Fills and Suicide Attempts and Intentional Self-harm Among Privately Insured US Adults.

Importance: Suicide is a leading cause of death in the United States, having increased more than 30% from 2000 to 2018. An inexpensive, safe, widely available treatment for preventing suicidal behavior could reverse this trend. Objective: To confirm a previous signal for decreased risk of suicide attempt following prescription fills for folic acid in a national pharmacoepidemiologic study of patients treated with folic acid. Design, Setting, and Participants: A within-person exposure-only cohort design was used to study the dynamic association between folic acid (vitamin B9) prescription fills over a 24-month period and suicide attempts and intentional self-harm. Data were collected from a pharmacoepidemiologic database of US medical claims (MarketScan) for patients with private health insurance who filled a folic acid prescription between 2012 and 2017. The same analysis was repeated with a control supplement (cyanocobalamin, vitamin B12). Data were analyzed from August 2021 to June 2022. Exposure: Folic acid prescription fills. Main Outcome and Measure: Suicide attempt or intentional self-harm resulting in an outpatient visit or inpatient admission as identified by codes from the International Statistical Classification of Diseases, Ninth and Tenth Revisions, Clinical Modification. Results: Data on 866 586 patients were collected; 704 514 (81.30%) were female, and 90 296 (10.42%) were 60 years and older. Overall, there were 261 suicidal events during months covered by a folic acid prescription (5 521 597 person-months) for a rate of 4.73 per 100 000 person-months, compared with 895 suicidal events during months without folic acid (8 432 340) for a rate of 10.61 per 100 000 person-months. Adjusting for age and sex, diagnoses related to suicidal behavior, diagnoses related to folic acid deficiency, folate-reducing medications, history of folate-reducing medications, and history of suicidal events, the hazard ratio (HR) for folic acid for suicide events was 0.56 (95% CI, 0.48-0.65), with similar results for the modal dosage of 1 mg of folic acid per day (HR, 0.57; 95% CI, 0.48-0.69) and women of childbearing age (HR, 0.60; 95% CI, 0.50-0.73). A duration-response analysis (1-mg dosage) revealed a 5% decrease in suicidal events per month of additional treatment (HR, 0.95; 95% CI, 0.93-0.97). The same analysis for the negative control, cyanocobalamin, found no association with suicide attempt (HR, 1.01; 95% CI, 0.80-1.27). Conclusions and Relevance: This large-scale pharmacoepidemiologic study of folic acid found a beneficial association in terms of lower rates of suicide attempts. The results warrant the conduct of a randomized clinical trial with suicidal ideation and behavior as outcomes of interest. If confirmed, folic acid may be a safe, inexpensive, and widely available treatment for suicidal ideation and behavior.

Concomitant opioid and benzodiazepine use and risk of suicide attempt and intentional self-harm: Pharmacoepidemiologic study.

BACKGROUND: Overdose due to concomitant use of opioids and benzodiazepines has been raised as a major public health concern, although little research has examined whether this risk extends to intentional overdose or other self-harm. This study examined whether prescription opioids and benzodiazepines interact to increase the rate of suicide attempt and intentional self-harm. METHODS: The study analyzed 4,762,438 users of opioids, benzodiazepines, both drugs concomitantly, or neither drug from the MarketScan Commercial Claims and Encounters databases (2014-2016). The four groups were matched using inverse probability of treatment weighting and a difference in difference design was used to examine associations with risk of suicide attempt, intentional self-harm and drug overdose, including suicide death resulting in a medical claim. RESULTS: There was a small association for opioids (HR=1.23; 95% CI 1.06-1.43) but a larger association for benzodiazepines (HR=2.55; 95% CI 2.12-3.05) with suicide attempt, intentional self-harm, and drug overdose. The medication interaction was opposite to the expected direction (HR=0.70; 95% CI 0.55-0.89), indicating that risk associated with concomitant use was lower than would be expected on an additive basis. Sensitivity analyses found no evidence of increased risk due to interaction between the two drug classes. CONCLUSIONS: Increased risk of suicide attempt, intentional self-harm and drug overdose for concomitant use of opioids and benzodiazepines is in large part attributable to benzodiazepine use alone. In typically prescribed quantities, opioids and benzodiazepines may not represent a drug interaction in terms of yielding increased risk of suicide attempt and intentional self-harm resulting in medical care.

Post-approval drug safety surveillance.

Following the drug-approval process, concerns remain regarding the safety of new drugs that are introduced into the marketplace. In the case of rare adverse events, the number of subjects that are treated in randomized controlled trials is invariably inadequate to determine the safety of the new pharmaceutical. Identifying safety signals for new and/or existing drugs is a major priority in the protection of public health. Unfortunately, design, analysis, and available data are often quite limited for detecting in a timely fashion any potentially harmful effects of drugs. In this review, we examine a variety of approaches for determining the possibility of adverse drug reactions. Our review includes spontaneous reports, meta-analysis of randomized controlled clinical trials, ecological studies, and analysis of medical claims data. We consider both experimental design and analytic problems as well as potential solutions. Many of these methodologies are then illustrated through application to data on the possible relationship between taking antidepressants and increased risk of suicidality.

Gabapentin and suicide attempts.

PURPOSE: On 16 December 2008, FDA issued a class warning for antiepileptic drugs and suicidal thoughts and behavior. The purpose of this study was to determine if the antiepileptic drug gabapentin increases risk of suicide attempt in patients to which it was prescribed for various indications. METHODS: We conducted a pharmacoepidemiologic study in which suicide attempt rates were compared before and after gabapentin was prescribed. We used the PharMetrics medical claims database to study the relationship between gabapentin and suicide attempts in a cohort of 131,178 patients with a 1-year window of information before and after initial prescription. Patients had diagnoses of epilepsy, pain disorders, bipolar illness, major depressive disorder, schizophrenia, and other psychiatric disorders. RESULTS: Overall, there was no significant difference in suicide attempt rates before (3.48/1000 patient years--PY) versus after (3.45/1000 PY) gabapentin prescription. Pre-prescription suicide attempt rates were five times higher in psychiatric populations compared with non-psychiatric populations leading us to analyze the two groups separately. No drug effect was detected in the non-psychiatric populations. Significant reductions in suicide attempt rates were seen for bipolar disorder (47.85/1000 PY versus 31.46/1000 PY), major depressive disorder (17.30/1000 PY versus 12.66/1000 PY), and other psychiatric disorders (12.84/1000 PY versus 10.14/1000 PY). Person-time analysis revealed an overall significant reduction in suicide attempt rates (2.01/1000 PY on drug versus 2.30/1000 PY off drug). CONCLUSIONS: This study finds that gabapentin does not increase risk of suicide attempts in non-psychiatric populations and is associated with a reduction in suicide attempt risk in patients with psychiatric disorders.

Assessment of Use and Safety of Edaravone for Amyotrophic Lateral Sclerosis in the Veterans Affairs Health Care System.

Importance: Using real-world data, the US Department of Veterans Affairs (VA) initiated a surveillance evaluation of edaravone after its approval for amyotrophic lateral sclerosis (ALS) in 2017. The use and safety of edaravone for patients with ALS in the VA health care system remain to be assessed. Objective: To describe a pharmacovigilance surveillance initiative with edaravone to monitor patient characteristics, utilization (edaravone cycles and riluzole use), and safety and to evaluate safety/effectiveness. Design, Setting, and Participants: This propensity score-matched cohort study used data on 369 patients with documented definite or probable ALS in the Veterans Health Administration (VHA) with at least 1 prescription for edaravone between August 1, 2017, and September 30, 2019. The analysis compared edaravone (alone or with riluzole) with riluzole only. For chronic users (≥6 months of drug), a time-to-event model evaluated ALS-related outcomes, with censoring at outcome, death, or end of evaluation. Patients with Parkinson disease, dementia, schizophrenia, or significant respiratory insufficiency per diagnosis codes within 2 years before prescription initiation were excluded. In overall matched cohorts, 223 patients treated with edaravone were 1:3 propensity score matched based on predefined confounders. For the chronic user subgroup analysis, 96 patients receiving edaravone and 424 patients receiving riluzole only were included. Exposures: Edaravone (alone or with riluzole) vs riluzole only. Main Outcomes and Measures: Patient characteristics, ALS drug use, and mortality. Acute outcomes (within 6 months of index) included proportion and mean time to event for death, discontinuation, or all-cause hospitalization, and outcomes for chronic users (receiving >6 months of treatment) included hazard ratios of outcomes related to disease-state progression. Results: Of 369 patients who received edaravone, most were older (mean [SD] age, 64.6 [11.3] years), male (346 [93.8%]), and White (261 [70.7%]). As of September 2019, 59.9% of edaravone patients had discontinued treatment; of those, 49.5% (108 of 218) received only 1 to 3 treatment cycles. Approximately 30% (110 patients) died. In a matched evaluation, significantly more acute all-cause hospitalization events occurred with edaravone (35.4% vs 22.0% for riluzole only); 72.6% of the edaravone cohort received edaravone with riluzole. Among chronic users, edaravone patients (70.8% edaravone with riluzole) had an increased hazard ratio of ALS-associated hospitalization (2.51; 95% CI, 1.18-8.16). The death rate was lower with edaravone but the difference was not statistically significant. Conclusions and Relevance: Early edaravone discontinuation was common in the VA. Although outcomes favored use of riluzole only in the matched analysis, results should be interpreted with caution, as unmeasured bias in observational data is likely.

Medication for Attention-Deficit/Hyperactivity Disorder and Risk for Suicide Attempts.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is a risk factor for suicidal behavior, but the effect of ADHD medication on suicidal behavior remains unclear. This study aimed to examine the associations between medication treatment for ADHD and risk of suicide attempts. METHODS: We identified a large cohort of patients with ADHD (N = 3,874,728, 47.8% female patients) using data from commercial health care claims from 2005 to 2014 in the United States. We used population-level and within-individual analyses to compare risk of suicide attempts during months when individuals received prescribed stimulant or nonstimulant medication relative to months when they did not receive medication. RESULTS: In both population-level and within-individual analyses, ADHD medication was associated with lower odds of suicide attempts (odds ratio [OR], 0.69; 95% confidence interval [CI], 0.66-0.73; and OR, 0.61; 95% CI, 0.57-0.66, respectively). Similar reductions were found in children to middle-aged adults and in clinically relevant subgroups, including patients with ADHD with preexisting depression or substance use disorder. The reduction was mainly seen for stimulant medication (OR, 0.72; 95% CI, 0.66-0.77); nonstimulant medication was not associated with statistically significant changes in risk of suicide attempts (OR, 0.94; 95% CI, 0.74-1.19). Sensitivity analyses assessing the influence of different exposure definitions, different outcome definitions, subsets of the cohort, and different analytic approaches provided comparable results. CONCLUSIONS: Stimulant medication was associated with a reduced risk of suicide attempts in patients with ADHD, and nonstimulant medication is unlikely to increase the risk of suicide attempts.

Attention-Deficit/Hyperactivity Disorder Medication and Unintentional Injuries in Children and Adolescents.

OBJECTIVE: Our objective was to determine whether attention-deficit/hyperactivity disorder (ADHD) medication is associated with a decreased risk of unintentional injuries in children and adolescents in the United States across sexes, age groups and injury types. METHOD: We used de-identified inpatient, outpatient, and filled prescription claims data from the Truven Health MarketScan Research Databases. Individuals were followed from January 1, 2005, date of first ADHD diagnosis, or medication prescription, or age 6 years, whichever occurred last, until December 31, 2014, first healthcare insurance disenrollment, or the first year at which their age was recorded as 19 years, whichever occurred first. A person was considered on ADHD medication during a given month if a prescription was filled in that month. The outcome was defined as emergency department visits for injuries, including traumatic brain injuries, with unintentional causes. Odds of having the outcome were compared between medicated and unmedicated months at the population-level and in within-individual analyses using logistic regression. RESULTS: Among 1,968,146 individuals diagnosed with ADHD or receiving ADHD medication, 87,154 had at least one event. At the population level, medication use was associated with a lower risk of injuries, both in boys (odds ratio [OR] = 0.85; 95% CI = 0.84-0.86) and girls (OR = 0.87; 95% CI = 0.85-0.89). Similar results were obtained from within-individual analysis among male (OR = 0.72; 95% CI = 0.70-0.74) and female (OR = 0.72; 95% CI = 0.69-0.75) children, and among male (OR = 0.64; 95% CI = 0.60-0.67) and female (OR = 0.65; 95% CI = 0.60-0.71) adolescents. Similar results were found for traumatic brain injuries. CONCLUSION: ADHD medication use was associated with a reduction of different types of unintentional injuries in children and adolescents of both sexes.

Does the type of ventricular assisted device influence survival, infection, and rejection rates following heart transplantation?

OBJECTIVE: To determine the influence of the type of left ventricular assisted device (LVAD) as predictor of survival, hospitalizations due to infection, and rejection following heart transplantation and to delineate any further predictors of such outcomes. METHODS: Patients who received a left ventricular assist device (HeartMate [Thoratec Corp., Pleasanton, CA, USA] or Novacor [World Heart Corporation, Ottawa, Canada]) as a bridge to heart transplantation between October 1991 and June 2004 using the United Network for Organ Sharing (UNOS) Thoracic Registry database were evaluated. Comparison of survival curves between HeartMate and Novacor was performed using Kaplan-Meier survival method and Cox proportional hazard model adjusting for patient demographics and co-morbidities. Infection and rejection rates between the two devices were analyzed using multivariable logistic regression model. RESULTS: The UNOS database provided 1255 patients with HeartMate and 154 patients with Novacor between 1991 and 2004. Unadjusted one- and five-year survivals for HeartMate and Novacor were 0.84 and 0.80 and 0.72 and 0.56, respectively, following heart transplantation. Adjusting for patient demographics and co-morbidities, no statistical significant difference in one-year survival was observed between those who received HeartMate and Novacor (HR = 1.49, p = 0.127). At five years, however, the HeartMate group had higher survival than Novacor (HR = 1.53, p = 0.043). All-time posttransplant hospitalizations due to infection and rejection were similar between HeartMate and Novacor recipients after adjusting for patient case mix. CONCLUSION: Controlling for patient case mix, there was no survival difference at one year between those who received Novacor versus HeartMate LVAD. At five years, a Novacor bridge to transplant patient on average had statistically significantly lower survival than HeartMate recipients. No difference in infection and rejection were observed.