Elisabetta Patorno

Anticonvulsant Medications and the Risk of Suicide, Attempted Suicide, or Violent Death

CONTEXTnIn 2008, the US Food and Drug Administration mandated warning labeling for anticonvulsant medications regarding the increased risk of suicidal thoughts and behaviors. The decision was based on a meta-analysis not sufficiently large to investigate individual drugs.nnnOBJECTIVEnTo evaluate the risk of suicidal acts and combined suicidal acts or violent death associated with individual anticonvulsants.nnnDESIGNnA cohort study of the risk of suicidal acts and combined suicidal acts or violent death in patients beginning use of anticonvulsant medications compared with patients initiating a reference anticonvulsant drug.nnnSETTING AND PATIENTSnPatients 15 years and older from the HealthCore Integrated Research Database (HIRD) who began taking an anticonvulsant between July 2001 and December 2006.nnnMAIN OUTCOME MEASURESnCox proportional hazards models and propensity score-matched analyses were used to evaluate risk of attempted or completed suicide and combined suicidal acts or violent death, controlling for psychiatric comorbidities and other risk factors, among individual anticonvulsants compared with topiramate and secondarily carbamazepine.nnnRESULTSnThe study identified 26 completed suicides, 801 attempted suicides, and 41 violent deaths in 297,620 new episodes of treatment with an anticonvulsant (overall median follow-up, 60 days). The incidence of the composite outcomes of completed suicides, attempted suicides, and violent deaths for anticonvulsants used in at least 100 treatment episodes ranged from 6.2 per 1000 person-years for primidone to 34.3 per 1000 person-years for oxcarbazepine. The risk of suicidal acts was increased for gabapentin (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.11-1.80), lamotrigine (HR, 1.84; 95% CI, 1.43-2.37), oxcarbazepine (HR, 2.07; 95% CI, 1.52-2.80), tiagabine (HR, 2.41; 95% CI, 1.65-3.52), and valproate (HR, 1.65; 95% CI, 1.25-2.19), compared with topiramate. The analyses including violent death produced similar results. Gabapentin users had increased risk in subgroups of younger and older patients, patients with mood disorders, and patients with epilepsy or seizure when compared with carbamazepine.nnnCONCLUSIONnThis exploratory analysis suggests that the use of gabapentin, lamotrigine, oxcarbazepine, and tiagabine, compared with the use of topiramate, may be associated with an increased risk of suicidal acts or violent deaths.

Antidepressant Use Late in Pregnancy and Risk of Persistent Pulmonary Hypertension of the Newborn

IMPORTANCEnThe association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of persistent pulmonary hypertension of the newborn (PPHN) has been controversial since the US Food and Drug Administration issued a public health advisory in 2006.nnnOBJECTIVEnTo examine the risk of PPHN associated with exposure to different antidepressant medication classes late in pregnancy.nnnDESIGN AND SETTINGnCohort study nested in the 2000-2010 Medicaid Analytic eXtract for 46 US states and Washington, DC. Last follow-up date was December 31, 2010.nnnPARTICIPANTSnA total of 3,789,330 pregnant women enrolled in Medicaid from 2 months or fewer after the date of last menstrual period through at least 1 month after delivery. The source cohort was restricted to women with a depression diagnosis and logistic regression analysis with propensity score adjustment applied to control for potential confounders. EXPOSURES FOR OBSERVATIONAL STUDIES: SSRI and non-SSRI monotherapy use during the 90 days before delivery vs no use.nnnMAIN OUTCOMES AND MEASURESnRecorded diagnosis of PPHN during the first 30 days after delivery.nnnRESULTSnA total of 128,950 women (3.4%) filled at least 1 prescription for antidepressants late in pregnancy: 102,179 (2.7%) used an SSRI and 26,771 (0.7%) a non-SSRI. Overall, 7630 infants not exposed to antidepressants were diagnosed with PPHN (20.8; 95% CI, 20.4-21.3 per 10,000 births) compared with 322 infants exposed to SSRIs (31.5; 95% CI, 28.3-35.2 per 10,000 births), and 78 infants exposed to non-SSRIs (29.1; 95% CI, 23.3-36.4 per 10,000 births). Associations between antidepressant use and PPHN were attenuated with increasing levels of confounding adjustment. For SSRIs, odds ratios were 1.51 (95% CI, 1.35-1.69) unadjusted and 1.10 (95% CI, 0.94-1.29) after restricting to women with depression and adjusting for the high-dimensional propensity score. For non-SSRIs, the odds ratios were 1.40 (95% CI, 1.12-1.75) and 1.02 (95% CI, 0.77-1.35), respectively. Upon restriction of the outcome to primary PPHN, the adjusted odds ratio for SSRIs was 1.28 (95% CI, 1.01-1.64) and for non-SSRIs 1.14 (95% CI, 0.74-1.74).nnnCONCLUSIONS AND RELEVANCEnEvidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However, the absolute risk was small, and the risk increase appears more modest than suggested in previous studies.

Exposure to prescription opioid analgesics in utero and risk of neonatal abstinence syndrome: population based cohort study

Objective To provide absolute and relative risk estimates of neonatal abstinence syndrome (NAS) based on duration and timing of prescription opioid use during pregnancy in the presence or absence of additional NAS risk factors of history of opioid misuse or dependence, misuse of other substances, non-opioid psychotropic drug use, and smoking. Design Observational cohort study. Setting Medicaid data from 46 US states. Participants Pregnant women filling at least one prescription for an opioid analgesic at any time during pregnancy for whom opioid exposure characteristics including duration of therapy: short term (<30 days) or long term (≥30 days); timing of use: early use (only in the first two trimesters) or late use (extending into the third trimester); and cumulative dose (in morphine equivalent milligrams) were assessed. Main outcome measure Diagnosis of NAS in liveborn infants. Results 1705 cases of NAS were identified among 290u2009605 pregnant women filling opioid prescriptions, corresponding to an absolute risk of 5.9 per 1000 deliveries (95% confidence interval 5.6 to 6.2). Long term opioid use during pregnancy resulted in higher absolute risk of NAS per 1000 deliveries in the presence of additional risk factors of known opioid misuse (220.2 (200.8 to 241.0)), alcohol or other drug misuse (30.8 (26.1 to 36.0)), exposure to other psychotropic medications (13.1 (10.6 to 16.1)), and smoking (6.6 (4.3 to 9.6)) than in the absence of any of these risk factors (4.2 (3.3 to 5.4)). The corresponding risk estimates for short term use were 192.0 (175.8 to 209.3), 7.0 (6.0 to 8.2), 2.0 (1.5 to 2.6), 1.5 (1.0 to 2.0), and 0.7 (0.6 to 0.8) per 1000 deliveries, respectively. In propensity score matched analyses, long term prescription opioid use compared with short term use and late use compared with early use in pregnancy demonstrated greater risk of NAS (risk ratios 2.05 (95% confidence interval 1.81 to 2.33) and 1.24 (1.12 to 1.38), respectively). Conclusions Use of prescription opioids during pregnancy is associated with a low absolute risk of NAS in the absence of additional risk factors. Long term use compared with short term use and late use compared with early use of prescription opioids are associated with increased NAS risk independent of additional risk factors.

Risk of Diabetic Ketoacidosis after Initiation of an SGLT2 Inhibitor

A study that assessed the risk of diabetic ketoacidosis after the initiation of SGLT2 inhibitor therapy showed nearly twice the risk as with a DPP4 inhibitor.

Comparative safety of anesthetic type for hip fracture surgery in adults: retrospective cohort study

Objective To evaluate the effect of anesthesia type on the risk of in-hospital mortality among adults undergoing hip fracture surgery in the United States. Design Retrospective cohort study. Setting Premier research database, United States. Participants 73u2009284 adults undergoing hip fracture surgery on hospital day 2 or greater between 2007 and 2011. Of those, 61u2009554 (84.0%) received general anesthesia, 6939 (9.5%) regional anesthesia, and 4791 (6.5%) combined general and regional anesthesia. Main outcome measure In-hospital all cause mortality. Results In-hospital deaths occurred in 1362 (2.2%) patients receiving general anesthesia, 144 (2.1%) receiving regional anesthesia, and 115 (2.4%) receiving combined anesthesia. In the multivariable adjusted analysis, when compared with general anesthesia the mortality risk did not differ significantly between regional anesthesia (risk ratio 0.93, 95% confidence interval 0.78 to 1.11) or combined anesthesia (1.00, 0.82 to 1.22). A mixed effects analysis accounting for differences between hospitals produced similar results: compared with general anesthesia the risk from regional anesthesia was 0.91 (0.75 to 1.10) and from combined anesthesia was 0.98 (0.79 to 1.21). Findings were also consistent in subgroup analyses. Conclusions In this large nationwide sample of hospital admissions, mortality risk did not differ significantly by anesthesia type among patients undergoing hip fracture surgery. Our results suggest that if the previously posited beneficial effect of regional anesthesia on short term mortality exists, it is likely to be more modest than previously reported.

Antipsychotic Use in Pregnancy and the Risk for Congenital Malformations

IMPORTANCEnThe frequency of antipsychotic (AP) use during pregnancy has approximately doubled during the last decade. However, little is known about their safety for the developing fetus, and concerns have been raised about a potential association with congenital malformations.nnnOBJECTIVEnTo examine the risk for congenital malformations overall and cardiac malformations associated with first-trimester exposure to APs.nnnDESIGN, SETTING, AND PARTICIPANTSnThis nationwide sample of 1u202f360u202f101 pregnant women enrolled in Medicaid with a live-born infant constituted the pregnancy cohort nested in the Medicaid Analytic Extract database, which included data from January 1, 2000, to December 31, 2010. Participants were enrolled in Medicaid from 3 months before their last menstrual period through at least 1 month after delivery. Relative risks (RRs) were estimated using generalized linear models with fine stratification on the propensity score to control for the underlying psychiatric disorders and other potential confounders. Data were analyzed during 2015.nnnEXPOSURESnUse of APs during the first trimester, the etiologically relevant period for organogenesis.nnnMAIN OUTCOMES AND MEASURESnMajor congenital malformations overall and cardiac malformations identified during the first 90 days after delivery.nnnRESULTSnOf the 1u202f341u202f715 pregnancies that met inclusion criteria (mean [SD] age of women, 24.02 [5.77] years), 9258 (0.69%) filled at least 1 prescription for an atypical AP and 733 (0.05%) filled at least 1 prescription for a typical AP during the first trimester. Overall, 32.7 (95% CI, 32.4-33.0) per 1000 births not exposed to APs were diagnosed with congenital malformations compared with 44.5 (95% CI, 40.5-48.9) per 1000 births exposed to atypical and 38.2 (95% CI, 26.6-54.7) per 1000 births exposed to typical APs. Unadjusted analyses suggested an increased risk for malformations overall for atypical APs (RR, 1.36; 95% CI, 1.24-1.50) but not for typical APs (RR, 1.17; 95% CI, 0.81-1.68). After confounding adjustment, the RR was reduced to 1.05 (95% CI, 0.96-1.16) for atypical APs and 0.90 (95% CI, 0.62-1.31) for typical APs. The findings for cardiac malformations were similar. For the individual agents examined, a small increased risk in overall malformations (RR, 1.26; 95% CI, 1.02-1.56) and cardiac malformations (RR, 1.26; 95% CI, 0.88-1.81) was found for risperidone that was independent of measured confounders.nnnCONCLUSIONS AND RELEVANCEnEvidence from this large study suggests that use of APs early in pregnancy generally does not meaningfully increase the risk for congenital malformations overall or cardiac malformations in particular. The small increase in the risk for malformations observed with risperidone requires additional study.

Perioperative factors associated with prolonged mechanical ventilation after complex congenital heart surgery.

Objective: To evaluate perioperative factors associated with prolonged mechanical ventilation in children undergoing complex cardiac surgery for congenital heart disease. Design: Retrospective chart review. Setting: A tertiary care pediatric cardiac intensive care. Interventions: None. Measurements and Main Results: This retrospective cohort study included all patients undergoing complex cardiac surgical procedures (Risk Adjustment in Congenital Heart Surgery-1 category ≥3) at our institution during 2003. We defined prolonged mechanical ventilation as need for mechanical ventilation for ≥7 days (90th percentile of duration of mechanical ventilation for the whole cohort). Multivariate logistic regression analyses were used to determine independent relationships between perioperative factors and prolonged mechanical ventilation. A total of 362 patients were admitted to the cardiac intensive care unit after a cardiac surgical procedure of Risk Adjustment in Congenital Heart Surgery-1 ≥3 level of complexity and survived to hospital discharge. Median age was 242 days (range, 4 days−14.4 yrs), the median duration of mechanical ventilation was 1.5 days (range, 0–7 days), and 41 patients (11%) were ventilated for ≥7 days. Age of <30 days at surgery, higher Pediatric Risk of Mortality III score at the time of cardiac intensive care unit admission, the presence of major noncardiac structural anomalies, healthcare-associated infections, noninfectious pulmonary complications (pleural effusions and pneumothorax), and the need for reintervention were all independently associated with prolonged mechanical ventilation. Conclusions: Younger age, greater severity of illness at postoperative admission, healthcare-associated infections, noninfectious pulmonary complications, and the need for reintervention are associated with prolonged mechanical ventilation after complex cardiac surgery. Future studies and quality improvement initiatives should focus on those risk factors that are modifiable to promote early extubation in children recovering from complex congenital heart surgery.

Studies with many covariates and few outcomes: selecting covariates and implementing propensity-score-based confounding adjustments.

Background: Propensity scores are useful for confounding adjustment in the commonly observed setting of many potential confounders, frequent exposure, and rare events. However, with few exposed outcomes to inform covariate selection and many candidate confounders, optimal approaches to construct and implement propensity-score–based confounding adjustment remain unclear. Methods: In a cohort study on the effect of anticonvulsant drugs on cardiovascular risk among adult patients from the HealthCore Integrated Research Database, we compared the performance for confounding control of various covariate-selection strategies for propensity-score estimation (expert knowledge only, expert knowledge informed by empirical covariate selection via high-dimensional propensity-score, and high-dimensional propensity-score empirical specification only) and propensity-score–based adjustment methods (propensity-score-matching and propensity-score-decile stratification). This article focuses on the first 90 days of follow-up because any treatment effect identified in this temporal window almost certainty originates from residual confounding rather than pharmacologic action. Results: We identified 166,031 new users and 564 ischemic cardiovascular events. Among those, 12,580 patients initiated anticonvulsants that strongly induce cytochrome P450 enzymes and experienced 68 events. The unadjusted hazard ratio was 1.72 (95% confidence interval = 1.34–2.22). Adjustment for investigator-identified covariates led to 41% to 59% reductions in the hazard ratio; adjustment for both investigator-identified and high-dimensional propensity-score empirically identified covariates led to larger reductions (54% to 72%). A selection strategy based on high-dimensional propensity-score empirical specification alone produced less-attenuated and more-volatile hazard ratio estimates. This volatility seemed to be slightly attenuated in a trimmed propensity-score–stratified analysis. Conclusions: The high-dimensional propensity-score algorithm complements expert knowledge for confounding adjustment, but in settings with few exposed outcomes, its performance without investigator-specified covariates is less clear and may be associated with an increased likelihood of bias. In our example, investigator specification of variables combined with high-dimensional propensity-score empirical selection and the use of trimmed propensity-score–stratified analysis seem to improve effect estimation. Plotting the relation of effect estimates to the increasing number of empirical covariates is a useful diagnostic.

Variations in the Use of Perioperative Multimodal Analgesic Therapy

Background:Practice guidelines for perioperative pain management recommend that multimodal analgesic therapy should be used for all postsurgical patients. However, the proportion of patients who actually receive this evidence-based approach is unknown. The objective of this study was to describe hospital-level patterns in the utilization of perioperative multimodal analgesia. Methods:Data for the study were obtained from the Premier Research Database. Patients undergoing below-knee amputation, open lobectomy, total knee arthroplasty, and open colectomy between 2007 and 2014 were included in the analysis. Patients were considered to have multimodal therapy if they received one or more nonopioid analgesic therapies. Mixed-effects logistic regression models were used to estimate the hospital-specific frequency of multimodal therapy use while adjusting for the case mix of patients and hospital characteristics and accounting for random variation. Results:The cohort consisted of 799,449 patients who underwent a procedure at 1 of 315 hospitals. The mean probability of receiving multimodal therapy was 90.4%, with 95% of the hospitals having a predicted probability between 42.6 and 99.2%. A secondary analysis examined whether patients received two or more nonopioid analgesics, which gave an average predicted probability of 54.2%, with 95% of the hospitals having a predicted probability between 9.3 and 93.2%. Conclusions:In this large nationwide sample of surgical admissions in the United States, the authors observed tremendous variation in the utilization of multimodal therapy not accounted for by patient or hospital characteristics. Efforts should be made to identify why there are variations in the use of multimodal analgesic therapy and to promote its adoption in appropriate patients.

Observational studies of the association between glucose-lowering medications and cardiovascular outcomes: addressing methodological limitations

BackgroundRecent years have witnessed a growing body of observational literature on the association between glucose-lowering treatments and cardiovascular disease. However, many of the studies are based on designs or analyses that inadequately address the methodological challenges involved.MethodsWe reviewed recent observational literature on the association between glucose-lowering medications and cardiovascular outcomes and assessed the design and analysis methods used, with a focus on their ability to address specific methodological challenges. We describe and illustrate these methodological issues and their impact on observed associations, providing examples from the reviewed literature. We suggest approaches that may be employed to manage these methodological challenges.ResultsFrom the evaluation of 81 publications of observational investigations assessing the association between glucose-lowering treatments and cardiovascular outcomes, we identified the following methodological challenges: 1) handling of temporality in administrative databases; 2) handling of risks that vary with time and treatment duration; 3) definitions of the exposure risk window; 4) handling of exposures that change over time; and 5) handling of confounding by indication. Most of these methodological challenges may be suitably addressed through application of appropriate methods.Conclusions/interpretationObservational research plays an increasingly important role in the evaluation of the clinical effects of diabetes treatment. Implementation of appropriate research methods holds the promise of reducing the potential for spurious findings and the risk that the spurious findings will mislead the medical community about risks and benefits of diabetes medications.