Serious Bleeding in Patients With Atrial Fibrillation Using Diltiazem With Apixaban or Rivaroxaban.

Importance: Diltiazem, a commonly prescribed ventricular rate-control medication for patients with atrial fibrillation, inhibits apixaban and rivaroxaban elimination, possibly causing overanticoagulation. Objective: To compare serious bleeding risk for new users of apixaban or rivaroxaban with atrial fibrillation treated with diltiazem or metoprolol. Design, Setting, and Participants: This retrospective cohort study included Medicare beneficiaries aged 65 years or older with atrial fibrillation who initiated apixaban or rivaroxaban use and also began treatment with diltiazem or metoprolol between January 1, 2012, and November 29, 2020. Patients were followed up to 365 days through November 30, 2020. Data were analyzed from August 2023 to February 2024. Exposures: Diltiazem and metoprolol. Main Outcomes and Measures: The primary outcome was a composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were ischemic stroke or systemic embolism, major ischemic or hemorrhagic events (ischemic stroke, systemic embolism, intracranial or fatal extracranial bleeding, or death with recent evidence of bleeding), and death without recent evidence of bleeding. Hazard ratios (HRs) and rate differences (RDs) were adjusted for covariate differences with overlap weighting. Results: The study included 204 155 US Medicare beneficiaries, of whom 53 275 received diltiazem and 150 880 received metoprolol. Study patients (mean [SD] age, 76.9 [7.0] years; 52.7% female) had 90 927 person-years (PY) of follow-up (median, 120 [IQR, 59-281] days). Patients receiving diltiazem treatment had increased risk for the primary outcome (RD, 10.6 [95% CI, 7.0-14.2] per 1000 PY; HR, 1.21 [95% CI, 1.13-1.29]) and its components of bleeding-related hospitalization (RD, 8.2 [95% CI, 5.1-11.4] per 1000 PY; HR, 1.22 [95% CI, 1.13-1.31]) and death with recent evidence of bleeding (RD, 2.4 [95% CI, 0.6-4.2] per 1000 PY; HR, 1.19 [95% CI, 1.05-1.34]) compared with patients receiving metoprolol. Risk for the primary outcome with initial diltiazem doses exceeding 120 mg/d (RD, 15.1 [95% CI, 10.2-20.1] per 1000 PY; HR, 1.29 [95% CI, 1.19-1.39]) was greater than that for lower doses (RD, 6.7 [95% CI, 2.0-11.4] per 1000 PY; HR, 1.13 [95% CI, 1.04-1.24]). For doses exceeding 120 mg/d, the risk of major ischemic or hemorrhagic events was increased (HR, 1.14 [95% CI, 1.02-1.27]). Neither dose group had significant changes in the risk for ischemic stroke or systemic embolism or death without recent evidence of bleeding. When patients receiving high- and low-dose diltiazem treatment were directly compared, the HR for the primary outcome was 1.14 (95% CI, 1.02-1.26). Conclusions and Relevance: In Medicare patients with atrial fibrillation receiving apixaban or rivaroxaban, diltiazem was associated with greater risk of serious bleeding than metoprolol, particularly for diltiazem doses exceeding 120 mg/d.

Antipsychotic Medications and Mortality in Children and Young Adults.

Importance: Dose-related effects of antipsychotic medications may increase mortality in children and young adults. Objective: To compare mortality for patients aged 5 to 24 years beginning treatment with antipsychotic vs control psychiatric medications. Design, Setting, and Participants: This was a US national retrospective cohort study of Medicaid patients with no severe somatic illness or schizophrenia or related psychoses who initiated study medication treatment. Study data were analyzed from November 2022 to September 2023. Exposures: Current use of second-generation antipsychotic agents in daily doses of less than or equal to 100-mg chlorpromazine equivalents or greater than 100-mg chlorpromazine equivalents vs that for control medications (α agonists, atomoxetine, antidepressants, and mood stabilizers). Main Outcome and Measures: Total mortality, classified by underlying cause of death. Rate differences (RDs) and hazard ratios (HRs) adjusted for potential confounders with propensity score-based overlap weights. Results: The 2 067 507 patients (mean [SD] age, 13.1 [5.3] years; 1 060 194 male [51.3%]) beginning study medication treatment filled 21 749 825 prescriptions during follow-up with 5 415 054 for antipsychotic doses of 100 mg or less, 2 813 796 for doses greater than 100 mg, and 13 520 975 for control medications. Mortality was not associated with antipsychotic doses of 100 mg or less (RD, 3.3; 95% CI, -5.1 to 11.7 per 100 000 person-years; HR, 1.08; 95% CI, 0.89-1.32) but was associated with doses greater than 100 mg (RD, 22.4; 95% CI, 6.6-38.2; HR, 1.37; 95% CI, 1.11-1.70). For higher doses, antipsychotic treatment was significantly associated with overdose deaths (RD, 8.3; 95% CI, 0-16.6; HR, 1.57; 95% CI, 1.02-2.42) and other unintentional injury deaths (RD, 12.3; 95% CI, 2.4-22.2; HR, 1.57; 95% CI, 1.12-2.22) but was not associated with nonoverdose suicide deaths or cardiovascular/metabolic deaths. Mortality for children aged 5 to 17 years was not significantly associated with either antipsychotic dose, whereas young adults aged 18 to 24 years had increased risk for doses greater than 100 mg (RD, 127.5; 95% CI, 44.8-210.2; HR, 1.68; 95% CI, 1.23-2.29). Conclusions and Relevance: In this cohort study of more than 2 million children and young adults without severe somatic disease or diagnosed psychosis, antipsychotic treatment in doses of 100 mg or less of chlorpromazine equivalents or in children aged 5 to 17 years was not associated with increased risk of death. For doses greater than 100 mg, young adults aged 18 to 24 years had significantly increased risk of death, with 127.5 additional deaths per 100 000 person-years.

Concurrent Gabapentin and Opioid Use and Risk of Mortality in Medicare Recipients with Non-Cancer Pain.

Gabapentin is prescribed for pain and is perceived as safe generally. However, gabapentin can cause respiratory depression, exacerbated by concomitant central nervous system depressants (e.g., opioids), a concern for vulnerable populations. We compared mortality rates among new users of either gabapentin or duloxetine with or without concurrent opioids in the 20% Medicare sample. We conducted a new-user design retrospective cohort study, in Medicare enrollees ages 65-89 years with noncancer chronic pain and no severe illness who filled prescriptions between 2015 and 2018 for gabapentin (n = 233,060) or duloxetine (n = 34,009). Daily opioid doses, estimated in morphine milligram equivalents (MMEs), were classified into none, low (0 < MME < 50), and high (≥ 50 MME), based on Centers for Disease Control and Prevention (CDC) recommendations. The outcomes were all-cause mortality (primary) and out-of-hospital mortality (secondary). We used inverse probability of treatment weighting to adjust for differences between gabapentin and duloxetine users. During 116,707 person-years of follow-up, 1,379 patients died. All-cause mortality rate in gabapentin users was 12.16 per 1,000 person-years vs. 9.94 per 1,000 in duloxetine users. Risks were similar for users with no concurrent opioids (adjusted hazard ratio (aHR) = 1.03, 95% confidence interval (CI): 0.80-1.31) or low-dose daily opioids (aHR = 1.06, 95% CI: 0.63-1.76). However, gabapentin users receiving concurrent high-dose daily opioids had an increased rate of all-cause mortality compared with duloxetine users on high-dose opioids (aHR = 2.03, 95% CI: 1.19-3.46). Out-of-hospital mortality yielded similar results. In this retrospective cohort study of Medicare beneficiaries, concurrent use of high-dose opioids and gabapentin was associated with a higher all-cause mortality risk than that for concurrent use of high-dose opioids and duloxetine.

Risk for Bleeding-Related Hospitalizations During Use of Amiodarone With Apixaban or Rivaroxaban in Patients With Atrial Fibrillation : A Retrospective Cohort Study.

BACKGROUND: Amiodarone, the most effective antiarrhythmic drug in atrial fibrillation, inhibits apixaban and rivaroxaban elimination, thus possibly increasing anticoagulant-related risk for bleeding. OBJECTIVE: For patients receiving apixaban or rivaroxaban, to compare risk for bleeding-related hospitalizations during treatment with amiodarone versus flecainide or sotalol, antiarrhythmic drugs that do not inhibit these anticoagulants' elimination. DESIGN: Retrospective cohort study. SETTING: U.S. Medicare beneficiaries aged 65 years or older. PATIENTS: Patients with atrial fibrillation began anticoagulant use between 1 January 2012 and 30 November 2018 and subsequently initiated treatment with study antiarrhythmic drugs. MEASUREMENTS: Time to event for bleeding-related hospitalizations (primary outcome) and ischemic stroke, systemic embolism, and death with or without recent (past 30 days) evidence of bleeding (secondary outcomes), adjusted with propensity score overlap weighting. RESULTS: There were 91 590 patients (mean age, 76.3 years; 52.5% female) initiating use of study anticoagulants and antiarrhythmic drugs, 54 977 with amiodarone and 36 613 with flecainide or sotalol. Risk for bleeding-related hospitalizations increased with amiodarone use (rate difference [RD], 17.5 events [95% CI, 12.0 to 23.0 events] per 1000 person-years; hazard ratio [HR], 1.44 [CI, 1.27 to 1.63]). Incidence of ischemic stroke or systemic embolism did not increase (RD, -2.1 events [CI, -4.7 to 0.4 events] per 1000 person-years; HR, 0.80 [CI, 0.62 to 1.03]). The risk for death with recent evidence of bleeding (RD, 9.1 events [CI, 5.8 to 12.3 events] per 1000 person-years; HR, 1.66 [CI, 1.35 to 2.03]) was greater than that for other deaths (RD, 5.6 events [CI, 0.5 to 10.6 events] per 1000 person-years; HR, 1.15 [CI, 1.00 to 1.31]) (HR comparison: P = 0.003). The increased incidence of bleeding-related hospitalizations for rivaroxaban (RD, 28.0 events [CI, 18.4 to 37.6 events] per 1000 person-years) was greater than that for apixaban (RD, 9.1 events [CI, 2.8 to 15.3 events] per 1000 person-years) (P = 0.001). LIMITATION: Possible residual confounding. CONCLUSION: In this retrospective cohort study, patients aged 65 years or older with atrial fibrillation treated with amiodarone during apixaban or rivaroxaban use had greater risk for bleeding-related hospitalizations than those treated with flecainide or sotalol. PRIMARY FUNDING SOURCE: National Heart, Lung, and Blood Institute.

Duloxetine, Gabapentin, and the Risk for Acute Myocardial Infarction, Stroke, and Out-of-Hospital Death in Medicare Beneficiaries With Non-Cancer Pain.

OBJECTIVE: Duloxetine is a serotonin-norepinephrine reuptake inhibitor prescribed for musculoskeletal and other forms of chronic pain. Its dual pharmacologic properties have the potential to either raise or lower cardiovascular risk: adrenergic activity may increase the risk for acute myocardial infarction (AMI) and stroke, but antiplatelet activity may decrease risk. Gabapentin is another nonopioid medication used to treat pain, which is not thought to have adrenergic/antiplatelet effects. With the current emphasis on the use of nonopioid medications to treat patients with chronic pain, assessing cardiovascular risks associated with these medications among high-risk patients is important. MATERIALS AND METHODS: We conducted a retrospective cohort study among a 20% sample of Medicare enrollees, aged 65 to 89, with chronic pain who were new users between 2015 and 2018 of either duloxetine (n = 34,009) or gabapentin (n = 233,060). We excluded individuals with cancer or other life-threatening conditions at study drug initiation. The primary outcome was a composite of AMI, stroke, and out-of-hospital mortality. We adjusted for comorbidity differences with time-dependent inverse probability of treatment weighting. RESULTS: During 115,668 person-years of follow-up, 2361 patients had the composite primary outcome; the rate among new users of duloxetine was 16.7/1000 person-years compared with new users of gabapentin (21.1/1000 person-years), adjusted hazard ratio = 0.98 (95% CI: 0.83, 1.16). Results were similar for the individual components of the composite outcome as well as in analyses stratified by demographic and clinical characteristics. DISCUSSION: In summary, cohort Medicare patients with non-cancer pain beginning treatment with duloxetine had rates of AMI, stroke, and out-of-hospital mortality comparable to those who initiated gabapentin.

Association of Rivaroxaban vs Apixaban With Major Ischemic or Hemorrhagic Events in Patients With Atrial Fibrillation.

Importance: The comparative effectiveness of rivaroxaban and apixaban, the most frequently prescribed oral anticoagulants for ischemic stroke prevention in patients with atrial fibrillation, is uncertain. Objective: To compare major ischemic and hemorrhagic outcomes in patients with atrial fibrillation treated with rivaroxaban or apixaban. Design, Setting, and Participants: Retrospective cohort study using computerized enrollment and claims files for US Medicare beneficiaries 65 years or older. Between January 1, 2013, and November 30, 2018, a total of 581 451 patients with atrial fibrillation began rivaroxaban or apixaban treatment and were followed up for 4 years, through November 30, 2018. Exposures: Rivaroxaban (n = 227 572) and apixaban (n = 353 879), either standard or reduced dose. Main Outcomes and Measures: The primary outcome was a composite of major ischemic (stroke/systemic embolism) and hemorrhagic (intracerebral hemorrhage/other intracranial bleeding/fatal extracranial bleeding) events. Secondary outcomes were nonfatal extracranial bleeding and total mortality (fatal ischemic/hemorrhagic event or other death during follow-up). Rates, hazard ratios (HRs), and rate differences (RDs) were adjusted for baseline differences in comorbidity with inverse probability of treatment weighting. Results: Study patients (mean age, 77.0 years; 291 966 [50.2%] women; 134 393 [23.1%] receiving reduced dose) had 474 605 person-years of follow-up (median [IQR] of 174 [62-397] days). The adjusted primary outcome rate for rivaroxaban was 16.1 per 1000 person-years vs 13.4 per 1000 person-years for apixaban (RD, 2.7 [95% CI, 1.9-3.5]; HR, 1.18 [95% CI, 1.12-1.24]). The rivaroxaban group had increased risk for both major ischemic events (8.6 vs 7.6 per 1000 person-years; RD, 1.1 [95% CI, 0.5-1.7]; HR, 1.12 [95% CI, 1.04-1.20]) and hemorrhagic events (7.5 vs 5.9 per 1000 person-years; RD, 1.6 [95% CI, 1.1-2.1]; HR, 1.26 [95% CI, 1.16-1.36]), including fatal extracranial bleeding (1.4 vs 1.0 per 1000 person-years; RD, 0.4 [95% CI, 0.2-0.7]; HR, 1.41 [95% CI, 1.18-1.70]). Patients receiving rivaroxaban had increased risk of nonfatal extracranial bleeding (39.7 vs 18.5 per 1000 person-years; RD, 21.1 [95% CI, 20.0-22.3]; HR, 2.07 [95% CI, 1.99-2.15]), fatal ischemic/hemorrhagic events (4.5 vs 3.3 per 1000 person-years; RD, 1.2 [95% CI, 0.8-1.6]; HR, 1.34 [95% CI, 1.21-1.48]), and total mortality (44.2 vs 41.0 per 1000 person-years; RD, 3.1 [95% CI, 1.8-4.5]; HR, 1.06 [95% CI, 1.02-1.09]). The risk of the primary outcome was increased for rivaroxaban in both those receiving the reduced dose (27.4 vs 21.0 per 1000 person-years; RD, 6.4 [95% CI, 4.1-8.7]; HR, 1.28 [95% CI, 1.16-1.40]) and the standard dose (13.2 vs 11.4 per 1000 person-years; RD, 1.8 [95% CI, 1.0-2.6]; HR, 1.13 [95% CI, 1.06-1.21]) groups. Conclusions and Relevance: Among Medicare beneficiaries 65 years or older with atrial fibrillation, treatment with rivaroxaban compared with apixaban was associated with a significantly increased risk of major ischemic or hemorrhagic events.

Mortality and concurrent use of opioids and hypnotics in older patients: A retrospective cohort study.

BACKGROUND: Benzodiazepine hypnotics and the related nonbenzodiazepine hypnotics (z-drugs) are among the most frequently prescribed medications for older adults. Both can depress respiration, which could have fatal cardiorespiratory effects, particularly among patients with concurrent opioid use. Trazodone, frequently prescribed in low doses for insomnia, has minimal respiratory effects, and, consequently, may be a safer hypnotic for older patients. Thus, for patients beginning treatment with benzodiazepine hypnotics or z-drugs, we compared deaths during periods of current hypnotic use, without or with concurrent opioids, to those for comparable patients receiving trazodone in doses up to 100 mg. METHODS AND FINDINGS: The retrospective cohort study in the United States included 400,924 Medicare beneficiaries 65 years of age or older without severe illness or evidence of substance use disorder initiating study hypnotic therapy from January 2014 through September 2015. Study endpoints were out-of-hospital (primary) and total mortality. Hazard ratios (HRs) were adjusted for demographic characteristics, psychiatric and neurologic disorders, cardiovascular and renal conditions, respiratory diseases, pain-related diagnoses and medications, measures of frailty, and medical care utilization in a time-dependent propensity score-stratified analysis. Patients without concurrent opioids had 32,388 person-years of current use, 260 (8.0/1,000 person-years) out-of-hospital and 418 (12.9/1,000) total deaths for benzodiazepines; 26,497 person-years,150 (5.7/1,000) out-of-hospital and 227 (8.6/1,000) total deaths for z-drugs; and 16,177 person-years,156 (9.6/1,000) out-of-hospital and 256 (15.8/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (respective HRs: 0.99 [95% confidence interval, 0.81 to 1.22, p = 0.954] and 0.95 [0.82 to 1.14, p = 0.513] and z-drugs (HRs: 0.96 [0.76 to 1.23], p = 0.767 and 0.87 [0.72 to 1.05], p = 0.153) did not differ significantly from that for trazodone. Patients with concurrent opioids had 4,278 person-years of current use, 90 (21.0/1,000) out-of-hospital and 127 (29.7/1,000) total deaths for benzodiazepines; 3,541 person-years, 40 (11.3/1,000) out-of-hospital and 64 (18.1/1,000) total deaths for z-drugs; and 2,347 person-years, 19 (8.1/1,000) out-of-hospital and 36 (15.3/1,000) total deaths for trazodone. Out-of-hospital and total mortality for benzodiazepines (HRs: 3.02 [1.83 to 4.97], p < 0.001 and 2.21 [1.52 to 3.20], p < 0.001) and z-drugs (HRs: 1.98 [1.14 to 3.44], p = 0.015 and 1.65 [1.09 to 2.49], p = 0.018) were significantly increased relative to trazodone; findings were similar with exclusion of overdose deaths or restriction to those with cardiovascular causes. Limitations included composition of the study cohort and potential confounding by unmeasured variables. CONCLUSIONS: In US Medicare beneficiaries 65 years of age or older without concurrent opioids who initiated treatment with benzodiazepine hypnotics, z-drugs, or low-dose trazodone, study hypnotics were not associated with mortality. With concurrent opioids, benzodiazepines and z-drugs were associated with increased out-of-hospital and total mortality. These findings indicate that the dangers of benzodiazepine-opioid coadministration go beyond the documented association with overdose death and suggest that in combination with opioids, the z-drugs may be more hazardous than previously thought.

Individual short-acting opioids and the risk of opioid-related adverse events in adolescents.

PURPOSE: Hydrocodone, codeine, oxycodone, and tramadol are frequently prescribed to adolescents for moderate pain related to minor trauma or dental, surgical, or medical procedures. Pharmacokinetic and pharmacodynamic differences between these opioids could affect their relative safety. We aimed to compare occurrence of opioid-related adverse events in adolescents without cancer or other severe conditions taking hydrocodone, codeine, oxycodone, and tramadol. METHODS: Retrospective cohort study of 201 940 Tennessee Medicaid enrollees 12 to 17 years of age without cancer, other severe conditions, or evidence of substance abuse with 529 731 filled prescriptions for study opioids. Adverse events were defined as an emergency department visit, hospital admission, or death related to opioid use, confirmed by medical record review. Serious events had opioid-related escalation of care, hospitalization, or death. Propensity-score adjusted hazard ratios (HRs) were calculated with hydrocodone as the reference category. RESULTS: The incidence of opioid-related adverse events per 10 000 person-years of opioid exposure was 97.5 for hydrocodone (127 events/13 026 person-years), 91.2 for codeine (58/6,359), 229.7 for oxycodone (43/1,872), and 317.7 for tramadol (47/1479). The HRs for tramadol in comparison with hydrocodone for all and serious events were 2.98 (2.03-4.39) and 2.94 (1.81-4.75), respectively. Increased risk for tramadol was consistently present when the adverse events were restricted to those with neurologic-respiratory depression/other symptoms of possible overdose. CONCLUSION: In adolescents without cancer or other severe conditions prescribed short-acting opioids, the incidence of both all opioid-related adverse events and more serious events with opioid-related escalation of care, hospitalization, or death was consistently greater for tramadol than for hydrocodone.

Comparative out-of-hospital mortality of long-acting opioids prescribed for non-cancer pain: A retrospective cohort study.

PURPOSE: Despite significant growth of opioid prescriptions, only limited data are available regarding the comparative safety of long-acting opioids for chronic non-cancer pain. Recent data suggest that transdermal fentanyl and oxycodone CR may have greater toxicity than morphine SR in patients with non-cancer pain. Thus, we compared the risk of out-of-hospital deaths in patients with non-cancer pain filling prescriptions for transdermal fentanyl or oxycodone CR with that for morphine SR. METHODS: We conducted a retrospective cohort study in 50 658 patients enrolled in Tennessee Medicaid who filled prescriptions for transdermal fentanyl (n = 8717), oxycodone CR (n = 14 118), or morphine SR (n = 27 823) between 1999 and 2011. We excluded individuals with cancer or other life-threatening diagnoses and used propensity scores to adjust for multiple potential confounders. The primary outcome was out-of-hospital mortality. RESULTS: During 44 385 person-years of follow-up, 689 patients died. The out-of-hospital mortality rate among all study subjects was 155/10 000 patient-years. Contrary to earlier data suggesting greater risk, mortality was not significantly different in patients filling prescriptions for transdermal fentanyl compared with morphine SR (adjusted HR = 0.96, 95% C.I.: 0.77-1.21); moreover, patients filling prescriptions for oxycodone CR had lower mortality risk compared with those filling prescriptions for morphine SR (adjusted HR = 0.79, 95% C.I. 0.66-0.95). CONCLUSION: In the study population, long-acting opioids for non-cancer pain were associated with high out-of-hospital mortality rates. We found comparable out-of-hospital mortality risks associated with transdermal fentanyl and morphine SR. The risk of out-of-hospital death for oxycodone CR was lower than that for morphine SR.

Association of Antipsychotic Treatment With Risk of Unexpected Death Among Children and Youths.

Importance: Children and youths who are prescribed antipsychotic medications have multiple, potentially fatal, dose-related cardiovascular, metabolic, and other adverse events, but whether or not these medications are associated with an increased risk of death is unknown. Objective: To compare the risk of unexpected death among children and youths who are beginning treatment with antipsychotic or control medications. Design, Setting, and Participants: This retrospective cohort study was conducted from 1999 through 2014 and included Medicaid enrollees aged 5 to 24 years in Tennessee who had no diagnosis of severe somatic illness, schizophrenia or related psychoses, or Tourette syndrome or chronic tic disorder. Data analysis was performed from January 1, 2017, to August 15, 2018. Exposures: Current, new antipsychotic medication use at doses higher than 50 mg (higher-dose group) or 50 mg or lower chlorpromazine equivalents (lower-dose group) as well as control medications (ie, attention-deficit/hyperactivity disorder medications, antidepressants, or mood stabilizers) (control group). Main Outcomes and Measures: Deaths during study follow-up while out of hospital or within 7 days after hospital admission, classified as either deaths due to injury or suicide or unexpected deaths. Secondary outcomes were unexpected deaths not due to overdose and death due to cardiovascular or metabolic causes. Results: This study included 189 361 children and youths in the control group (mean [SD] age, 12.0 [5.1] years; 43.4% female), 28 377 in the lower-dose group (mean [SD] age, 11.7 [4.4] years; 32.3% female), and 30 120 in the higher-dose group (mean [SD] age, 14.5 [4.8] years; 39.2% female). The unadjusted incidence of death in the higher-dose group was 146.2 per 100 000 person-years (40 deaths per 27 354 person-years), which was significantly greater than that in the control group (54.5 per 100 000 population; 67 deaths per 123 005 person-years) (P < .001). The difference was primarily attributable to the increased incidence of unexpected deaths in the higher-dose group (21 deaths; 76.8 per 100 000 population) compared with the control group (22 deaths; 17.9 per 100 000 population). The propensity score-adjusted hazard ratios were as follows: all deaths (1.80; 95% CI, 1.06-3.07), deaths due to unintentional injury or suicide (1.03; 95% CI, 0.53-2.01), and unexpected deaths (3.51; 95% CI, 1.54-7.96). The hazard ratio was 3.50 (95% CI, 1.35-9.11) for unexpected deaths not due to overdose and 4.29 (95% CI, 1.33-13.89) for deaths due to cardiovascular or metabolic causes. Neither the unadjusted nor adjusted incidence of death in the lower-dose group differed significantly from that in the control group. Conclusions and Relevance: The findings suggest that antipsychotic use is associated with increased risk of unexpected death and appear to reinforce recommendations for careful prescribing and monitoring of antipsychotic treatment for children and youths and to underscore the need for larger antipsychotic treatment safety studies in this population.

Association of Oral Anticoagulants and Proton Pump Inhibitor Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding.

Importance: Anticoagulant choice and proton pump inhibitor (PPI) cotherapy could affect the risk of upper gastrointestinal tract bleeding, a frequent and potentially serious complication of oral anticoagulant treatment. Objectives: To compare the incidence of hospitalization for upper gastrointestinal tract bleeding in patients using individual anticoagulants with and without PPI cotherapy, and to determine variation according to underlying gastrointestinal bleeding risk. Design, Setting, and Participants: Retrospective cohort study in Medicare beneficiaries between January 1, 2011, and September 30, 2015. Exposures: Apixaban, dabigatran, rivaroxaban, or warfarin with or without PPI cotherapy. Main Outcomes and Measures: Hospitalizations for upper gastrointestinal tract bleeding: adjusted incidence and risk difference (RD) per 10 000 person-years of anticoagulant treatment, incidence rate ratios (IRRs). Results: There were 1 643 123 patients with 1 713 183 new episodes of oral anticoagulant treatment included in the cohort (mean [SD] age, 76.4 [2.4] years, 651 427 person-years of follow-up [56.1%] were for women, and the indication was atrial fibrillation for 870 330 person-years [74.9%]). During 754 389 treatment person-years without PPI cotherapy, the adjusted incidence of hospitalization for upper gastrointestinal tract bleeding (n = 7119) was 115 per 10 000 person-years (95% CI, 112-118). The incidence for rivaroxaban (n = 1278) was 144 per 10 000 person-years (95% CI, 136-152), which was significantly greater than the incidence of hospitalizations for apixaban (n = 279; 73 per 10 000 person-years; IRR, 1.97 [95% CI, 1.73-2.25]; RD, 70.9 [95% CI, 59.1-82.7]), dabigatran (n = 629; 120 per 10 000 person-years; IRR, 1.19 [95% CI, 1.08-1.32]; RD, 23.4 [95% CI, 10.6-36.2]), and warfarin (n = 4933; 113 per 10 000 person-years; IRR, 1.27 [95% CI, 1.19-1.35]; RD, 30.4 [95% CI, 20.3-40.6]). The incidence for apixaban was significantly lower than that for dabigatran (IRR, 0.61 [95% CI, 0.52-0.70]; RD, -47.5 [95% CI,-60.6 to -34.3]) and warfarin (IRR, 0.64 [95% CI, 0.57-0.73]; RD, -40.5 [95% CI, -50.0 to -31.0]). When anticoagulant treatment with PPI cotherapy (264 447 person-years; 76 per 10 000 person-years) was compared with treatment without PPI cotherapy, risk of upper gastrointestinal tract bleeding hospitalizations (n = 2245) was lower overall (IRR, 0.66 [95% CI, 0.62-0.69]) and for apixaban (IRR, 0.66 [95% CI, 0.52-0.85]; RD, -24 [95% CI, -38 to -11]), dabigatran (IRR, 0.49 [95% CI, 0.41-0.59]; RD, -61.1 [95% CI, -74.8 to -47.4]), rivaroxaban (IRR, 0.75 [95% CI, 0.68-0.84]; RD, -35.5 [95% CI, -48.6 to -22.4]), and warfarin (IRR, 0.65 [95% CI, 0.62-0.69]; RD, -39.3 [95% CI, -44.5 to -34.2]). Conclusions and Relevance: Among patients initiating oral anticoagulant treatment, incidence of hospitalization for upper gastrointestinal tract bleeding was the highest in patients prescribed rivaroxaban, and the lowest for patients prescribed apixaban. For each anticoagulant, the incidence of hospitalization for upper gastrointestinal tract bleeding was lower among patients who were receiving PPI cotherapy. These findings may inform assessment of risks and benefits when choosing anticoagulant agents.

Outpatient Opioid Prescriptions for Children and Opioid-Related Adverse Events.

BACKGROUND AND OBJECTIVES: Little is known about opioid prescribing for children without severe conditions. We studied the prevalence of and indications for outpatient opioid prescriptions and the incidence of opioid-related adverse events in this population. METHODS: This retrospective cohort study between 1999 and 2014 included Tennessee Medicaid children and adolescents aged 2 to 17 without major chronic diseases, prolonged hospitalization, institutional residence, or evidence of a substance use disorder. We estimated the annual prevalence of outpatient opioid prescriptions and incidence of opioid-related adverse events, defined as an emergency department visit, hospitalization, or death related to an opioid adverse effect. RESULTS: There were 1 362 503 outpatient opioid prescriptions; the annual mean prevalence of opioid prescriptions was 15.0%. The most common opioid indications were dental procedures (31.1% prescriptions), outpatient procedure and/or surgery (25.1%), trauma (18.1%), and infections (16.5%). There were 437 cases of opioid-related adverse events confirmed by medical record review; 88.6% were related to the child's prescription and 71.2% had no recorded evidence of deviation from the prescribed regimen. The cumulative incidence of opioid-related adverse events was 38.3 of 100 000 prescriptions. Adverse events increased with age (incidence rate ratio = 2.22; 95% confidence interval, 1.67-2.96; 12-17 vs 2-5 years of age) and higher opioid doses (incidence rate ratio = 1.86 [1.45-2.39]; upper versus lower dose tertiles). CONCLUSIONS: Children without severe conditions enrolled in Tennessee Medicaid frequently filled outpatient opioid prescriptions for acute, self-limited conditions. One of every 2611 study opioid prescriptions was followed by an opioid-related adverse event (71.2% of which were related to therapeutic use of the prescribed opioid).

High-Dose Citalopram and Escitalopram and the Risk of Out-of-Hospital Death.

OBJECTIVE: Studies demonstrating that higher doses of citalopram (> 40 mg) and escitalopram (> 20 mg) prolong the corrected QT interval prompted regulatory agency warnings, which are controversial, given the absence of confirmatory clinical outcome studies. We compared the risk of potential arrhythmia-related deaths for high doses of these selective serotonin reuptake inhibitors (SSRIs) to that for equivalent doses of fluoxetine, paroxetine, and sertraline. METHODS: The Tennessee Medicaid retrospective cohort study included 54,220 persons 30-74 years of age without cancer or other life-threatening illness who were prescribed high-dose SSRIs from 1998 through 2011. The mean age was 47 years, and 76% were female. Demographic characteristics and comorbidity for individual SSRIs were comparable. Because arrhythmia-related deaths are typically sudden and occur outside the hospital, we analyzed out-of-hospital sudden unexpected death as well as sudden cardiac deaths, a more specific indicator of proarrhythmic effects. RESULTS: The adjusted risk of sudden unexpected death for citalopram did not differ significantly from that for the other SSRIs. The respective hazard ratios (HRs) for citalopram versus escitalopram, fluoxetine, paroxetine, and sertraline were 0.84 (95% CI, 0.40-1.75), 1.24 (95% CI, 0.75-2.05), 0.75 (95% CI, 0.45-1.24), and 1.53 (95% CI, 0.91-2.55). There were no significant differences for sudden cardiac death or all study deaths, nor were there significant differences among high-risk patients (≥ 60 years of age, upper quartile baseline cardiovascular risk). Escitalopram users had no significantly increased risk for any study end point. CONCLUSIONS: We found no evidence that risk of sudden unexpected death, sudden cardiac death, or total mortality for high-dose citalopram and escitalopram differed significantly from that for comparable doses of fluoxetine, paroxetine, and sertraline.

Association of Proton Pump Inhibitors With Reduced Risk of Warfarin-Related Serious Upper Gastrointestinal Bleeding.

BACKGROUND & AIMS: Proton pump inhibitors (PPIs) might reduce the risk of serious warfarin-related upper gastrointestinal bleeding, but the evidence of their efficacy for this indication is limited. A gastroprotective effect of PPIs would be particularly important for patients who take warfarin with antiplatelet drugs or nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), which further increase the risk of gastrointestinal bleeding. METHODS: This retrospective cohort study of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample identified 97,430 new episodes of warfarin treatment with 75,720 person-years of follow-up. The study end points were hospitalizations for upper gastrointestinal bleeding potentially preventable by PPIs and for bleeding at other sites. RESULTS: Patients who took warfarin without PPI co-therapy had 119 hospitalizations for upper gastrointestinal bleeding per 10,000 person-years of treatment. The risk decreased by 24% among patients who received PPI co-therapy (adjusted hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.63-0.91). There was no significant reduction in the risk of other gastrointestinal bleeding hospitalizations (HR, 1.07; 95% CI, 0.94-1.22) or non-gastrointestinal bleeding hospitalizations (HR, 0.98; 95% CI, 0.84-1.15) in this group. Among patients concurrently using antiplatelet drugs or NSAIDs, those without PPI co-therapy had 284 upper gastrointestinal bleeding hospitalizations per 10,000 person-years of warfarin treatment. The risk decreased by 45% (HR, 0.55; 95% CI, 0.39-0.77) with PPI co-therapy. PPI co-therapy had no significant protective effect for warfarin patients not using antiplatelet drugs or NSAIDs (HR, 0.86; 95% CI, 0.70-1.06). Findings were similar in both study populations. CONCLUSIONS: In an analysis of patients beginning warfarin treatment in Tennessee Medicaid and the 5% National Medicare Sample, PPI co-therapy was associated with reduced risk of warfarin-related upper gastrointestinal bleeding; the greatest reduction occurred in patients also taking antiplatelet drugs or NSAIDs.

Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain.

IMPORTANCE: Long-acting opioids increase the risk of unintentional overdose deaths but also may increase mortality from cardiorespiratory and other causes. OBJECTIVE: To compare all-cause mortality for patients with chronic noncancer pain who were prescribed either long-acting opioids or alternative medications for moderate to severe chronic pain. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study between 1999 and 2012 of Tennessee Medicaid patients with chronic noncancer pain and no evidence of palliative or end-of-life care. EXPOSURES: Propensity score-matched new episodes of prescribed therapy for long-acting opioids or either analgesic anticonvulsants or low-dose cyclic antidepressants (control medications). MAIN OUTCOMES AND MEASURES: Total and cause-specific mortality as determined from death certificates. Adjusted hazard ratios (HRs) and risk differences (difference in incidence of death) were calculated for long-acting opioid therapy vs control medication. RESULTS: There were 22,912 new episodes of prescribed therapy for both long-acting opioids and control medications (mean [SD] age, 48 [11] years; 60% women). The long-acting opioid group was followed up for a mean 176 days and had 185 deaths and the control treatment group was followed up for a mean 128 days and had 87 deaths. The HR for total mortality was 1.64 (95% CI, 1.26-2.12) with a risk difference of 68.5 excess deaths (95% CI, 28.2-120.7) per 10,000 person-years. Increased risk was due to out-of-hospital deaths (154 long-acting opioid, 60 control deaths; HR, 1.90; 95% CI, 1.40-2.58; risk difference, 67.1; 95% CI, 30.1-117.3) excess deaths per 10,000 person-years. For out-of-hospital deaths other than unintentional overdose (120 long-acting opioid, 53 control deaths), the HR was 1.72 (95% CI, 1.24-2.39) with a risk difference of 47.4 excess deaths (95% CI, 15.7-91.4) per 10,000 person-years. The HR for cardiovascular deaths (79 long-acting opioid, 36 control deaths) was 1.65 (95% CI, 1.10-2.46) with a risk difference of 28.9 excess deaths (95% CI, 4.6-65.3) per 10,000 person-years. The HR during the first 30 days of therapy (53 long-acting opioid, 13 control deaths) was 4.16 (95% CI, 2.27-7.63) with a risk difference of 200 excess deaths (95% CI, 80-420) per 10,000 person-years. CONCLUSIONS AND RELEVANCE: Prescription of long-acting opioids for chronic noncancer pain, compared with anticonvulsants or cyclic antidepressants, was associated with a significantly increased risk of all-cause mortality, including deaths from causes other than overdose, with a modest absolute risk difference. These findings should be considered when evaluating harms and benefits of treatment.

Development of an algorithm to identify serious opioid toxicity in children.

BACKGROUND: The use of opioids is increasing in children; therefore, opioid toxicity could be a public health problem in this vulnerable population. However, we are not aware of a published algorithm to identify cases of opioid toxicity in children using administrative databases. We sought to develop an algorithm to identify them. After review of literature and de-identified computer profiles, a broad set of ICD-9 CM codes consistent with serious opioid toxicity was selected. Based on these codes, we identified 195 potential cases of opioid toxicity in children enrolled in Tennessee Medicaid. Medical records were independently reviewed by two physicians; episodes considered equivocal were reviewed by an adjudication committee. Cases were adjudicated as Group 1 (definite/probable), Group 2 (possible), or Group 3 (excluded). RESULTS: Of the 195 potential cases, 168 (86.2%) had complete records for review and 85 were confirmed cases. The overall positive predictive value (PPV) for all codes was 50.6%. The PPV for codes indicating: unintentional opioid overdose (25/31) was 80.7%; intentional opioid overdose (15/30) was 50.0%, adverse events (33/58) was 56.9%, the presence of signs or symptoms compatible with opioid toxicity (12/47) was 25.5%, and no cases were confirmed in records from the two deaths. Of the confirmed cases, 65.8% were related to therapeutic opioid use. CONCLUSION: For studies utilizing administrative claims to quantify incidence of opioid toxicity in children, our findings suggest that use of a broad set of screening codes coupled with medical record review is important to increase the completeness of case ascertainment.

Out-of-hospital mortality among patients receiving methadone for noncancer pain.

IMPORTANCE: Growing methadone use in pain management has raised concerns regarding its safety relative to other long-acting opioids. Methadone hydrochloride may increase the risk for lethal respiratory depression related to accidental overdose and life-threatening ventricular arrhythmias. OBJECTIVE: To compare the risk of out-of-hospital death in patients receiving methadone for noncancer pain with that in comparable patients receiving sustained-release (SR) morphine sulfate. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted using Tennessee Medicaid records from 1997 through 2009. The cohort included patients receiving morphine SR or methadone who were aged 30 to 74 years, did not have cancer or another life-threatening illness, and were not in a hospital or nursing home. At cohort entry, 32 742 and 6014 patients had filled a prescription for morphine SR or methadone, respectively. The patients' median age was 48 years, 57.9% were female, and comparable proportions had received cardiovascular, psychotropic, and other musculoskeletal medications. Nearly 90% of the patients received the opioid for back pain or other musculoskeletal pain. The median doses prescribed for morphine SR and methadone were 90 mg/d and 40 mg/d, respectively. MAIN OUTCOMES AND MEASURES: The primary study end point was out-of-hospital mortality, given that opioid-related deaths typically occur outside the hospital. RESULTS: There were 477 deaths during 28 699 person-years of follow-up (ie, 166 deaths per 10 000 person-years). After control for study covariates, patients receiving methadone had a 46% increased risk of death during the follow-up period, with an adjusted hazard ratio (HR) of 1.46 (95% CI, 1.17-1.83; P < .001), resulting in 72 (95% CI, 27-130) excess deaths per 10 000 person-years of follow-up. Methadone doses of 20 mg/d or less, the lowest dose quartile, were associated with an increased risk of death (HR, 1.59; 95% CI, 1.01-2.51, P = .046) relative to a comparable dose of morphine SR (<60 mg/d). CONCLUSIONS AND RELEVANCE: The increased risk of death observed for patients receiving methadone in this retrospective cohort study, even for low doses, supports recommendations that it should not be a drug of first choice for noncancer pain.

Performance of time-dependent propensity scores: a pharmacoepidemiology case study.

PURPOSE: Pharmacoepidemiologic studies of acute effects of episodic exposures often must control for many time-dependent confounders. Marginal structural models permit this and provide unbiased estimates when confounders are on the causal pathway. However, if causal pathway confounding is minimal, analyses with time-dependent propensity scores, calculated for time periods defined by individual drug prescriptions, may have better efficiency. We justify time-dependent propensity scores and compare the performance of these methods in a case study from a previous investigation of the risk of medication toxicity death in current users of propoxyphene and hydrocodone, with both substantial time-dependent confounding and a large number of covariates. METHODS: The cohort included Tennessee Medicaid enrollees who filled a qualifying study opioid prescription between 1992 and 2007. We identified 22 time-dependent covariates that accounted for most of the confounding in the original study. We compared analyses with all covariates in the regression model with those based on time-dependent propensity scores and those from marginal structural models. RESULTS: We identified 489,008 persons with 1,771,295 propoxyphene and 4,088,754 hydrocodone prescriptions. The unadjusted hazard ratio (propoxyphene : hydrocodone) was 0.70 (95%CI, 0.46-1.07). Estimates from inclusion of all covariates in the model, time-dependent propensity score analysis with inverse probability of treatment weighting, and marginal structural models were 1.63 (1.04-2.57), 1.65 (1.01-2.72), and 1.64 (0.83-3.27), respectively. Findings varied little with use of alternative propensity score methods, time origin, or techniques for marginal structural model estimation. CONCLUSIONS: Time-dependent propensity scores may be useful for pharmacoepidemiologic studies with time-varying exposures when causal pathway confounding is limited.

Genotype and risk of major bleeding during warfarin treatment.

AIM: To determine whether genetic variants associated with warfarin dose variability were associated with increased risk of major bleeding during warfarin therapy. MATERIALS & METHODS: Using Vanderbilt's DNA biobank we compared the prevalence of CYP2C9, VKORC1 and CYP4F2 variants in 250 cases with major bleeding and 259 controls during warfarin therapy. RESULTS: CYP2C9*3 was the only allele that differed significantly among cases (14.2%) and controls (7.8%; p = 0.022). In the 214 (85.6%) cases with a major bleed 30 or more days after warfarin initiation, CYP2C9*3 was the only variant associated with bleeding (adjusted odds ratio: 2.05; 95% CI: 1.04, 4.04). CONCLUSION: The CYP2C9*3 allele may double the risk of major bleeding among patients taking warfarin for 30 or more days.