Risk for Recurrent Venous Thromboembolism and Bleeding With Apixaban Compared With Rivaroxaban: An Analysis of Real-World Data.

BACKGROUND: Apixaban and rivaroxaban are replacing vitamin K antagonists for the treatment of venous thromboembolism (VTE) in adults; however, head-to-head comparisons remain limited. OBJECTIVE: To assess the effectiveness and safety of apixaban compared with rivaroxaban in patients with VTE. DESIGN: Retrospective new-user cohort study. SETTING: U.S.-based commercial health care insurance database from 1 January 2015 to 30 June 2020. PARTICIPANTS: Adults with VTE who were newly prescribed apixaban or rivaroxaban. MEASUREMENTS: The primary effectiveness outcome was recurrent VTE, a composite of deep venous thrombosis and pulmonary embolism. The primary safety outcome was a composite of gastrointestinal and intracranial bleeding. RESULTS: Of 49 900 eligible patients with VTE, 18 618 were new users of apixaban and 18 618 were new users of rivaroxaban. Median follow-up was 102 days (25th, 75th percentiles: 30, 128 days) among apixaban and 105 days (25th, 75th percentiles: 30, 140 days) among rivaroxaban users. After propensity score matching, apixaban (vs. rivaroxaban) was associated with a lower rate for recurrent VTE (hazard ratio, 0.77 [95% CI, 0.69 to 0.87]) and bleeding (hazard ratio, 0.60 [CI, 0.53 to 0.69]). The absolute reduction in the probability of recurrent VTE with apixaban versus rivaroxaban was 0.006 (CI, 0.005 to 0.011) within 2 months and 0.011 (CI, 0.011 to 0.013) within 6 months of initiation. The absolute reduction in the probability of gastrointestinal and intracranial bleeding with apixaban versus rivaroxaban was 0.011 (CI, 0.010 to 0.011) within 2 months and 0.015 (CI, 0.013 to 0.015) within 6 months of initiation. LIMITATION: Short follow-up. CONCLUSION: In this population-based cohort study, patients with VTE who were new users of apixaban had lower rates for recurrent VTE and bleeding than new users of rivaroxaban. PRIMARY FUNDING SOURCE: None.

Validity of ICD-10-CM diagnoses to identify hospitalizations for serious infections among patients treated with biologic therapies.

PURPOSE: Identifying hospitalizations for serious infections among patients dispensed biologic therapies within healthcare databases is important for post-marketing surveillance of these drugs. We determined the positive predictive value (PPV) of an ICD-10-CM-based diagnostic coding algorithm to identify hospitalization for serious infection among patients dispensed biologic therapy within the FDA's Sentinel Distributed Database. METHODS: We identified health plan members who met the following algorithm criteria: (1) hospital ICD-10-CM discharge diagnosis of serious infection between July 1, 2016 and August 31, 2018; (2) either outpatient/emergency department infection diagnosis or outpatient antimicrobial treatment within 7 days prior to hospitalization; (3) inflammatory bowel disease, psoriasis, or rheumatological diagnosis within 1 year prior to hospitalization, and (4) were dispensed outpatient biologic therapy within 90 days prior to admission. Medical records were reviewed by infectious disease clinicians to adjudicate hospitalizations for serious infection. The PPV (95% confidence interval [CI]) for confirmed events was determined after further weighting by the prevalence of the type of serious infection in the database. RESULTS: Among 223 selected health plan members who met the algorithm, 209 (93.7% [95% CI, 90.1%-96.9%]) were confirmed to have a hospitalization for serious infection. After weighting by the prevalence of the type of serious infection, the PPV of the ICD-10-CM algorithm identifying a hospitalization for serious infection was 80.2% (95% CI, 75.3%-84.7%). CONCLUSIONS: The ICD-10-CM-based algorithm for hospitalization for serious infection among patients dispensed biologic therapies within the Sentinel Distributed Database had 80% PPV for confirmed events and could be considered for use within pharmacoepidemiologic studies.

Effectiveness and Safety of Direct Oral Anticoagulants Versus Warfarin in Patients With Valvular Atrial Fibrillation : A Population-Based Cohort Study.

BACKGROUND: Direct oral anticoagulants (DOACs) are increasingly used in place of warfarin, but evidence about their effectiveness and safety in patients with valvular atrial fibrillation (AF) remains limited. OBJECTIVE: To assess the effectiveness and safety of DOACs compared with warfarin in patients with valvular AF. DESIGN: New-user retrospective propensity score-matched cohort study. SETTING: U.S.-based commercial health care database from 1 January 2010 to 30 June 2019. PARTICIPANTS: Adults with valvular AF who were newly prescribed DOACs or warfarin. MEASUREMENTS: The primary effectiveness outcome was a composite of ischemic stroke or systemic embolism. The primary safety outcome was a composite of intracranial or gastrointestinal bleeding. RESULTS: Among a total of 56 336 patients with valvular AF matched on propensity score, use of DOACs (vs. warfarin) was associated with lower risk for ischemic stroke or systemic embolism (hazard ratio [HR], 0.64 [95% CI, 0.59 to 0.70]) and major bleeding events (HR, 0.67 [CI, 0.63 to 0.72]). The results for the effectiveness and safety outcomes remained consistent for apixaban (HRs, 0.54 [CI, 0.47 to 0.61] and 0.52 [CI, 0.47 to 0.57], respectively) and rivaroxaban (HRs, 0.74 [CI, 0.64 to 0.86] and 0.87 [CI, 0.79 to 0.96], respectively); with dabigatran, results were consistent for the major bleeding outcome (HR, 0.81 [CI, 0.68 to 0.97]) but not for effectiveness (HR, 1.03 [CI, 0.81 to 1.31]). LIMITATION: Relatively short follow-up; inability to ascertain disease severity. CONCLUSION: In this comparative effectiveness study using practice-based claims data, patients with valvular AF who were new users of DOACs had lower risks for ischemic stroke or systemic embolism and major bleeding than new users of warfarin. These data may be used to guide risk-benefit discussions regarding anticoagulant choices for patients with valvular AF. PRIMARY FUNDING SOURCE: None.

Screening to identify signals of opioid drug interactions leading to unintentional traumatic injury.

BACKGROUND: Efforts to minimize harms from opioid drug interactions may be hampered by limited evidence on which drugs, when taken concomitantly with opioids, result in adverse clinical outcomes. OBJECTIVE: To identify signals of opioid drug interactions by identifying concomitant medications (precipitant drugs) taken with individual opioids (object drugs) that are associated with unintentional traumatic injury DESIGN: We conducted pharmacoepidemiologic screening of Optum Clinformatics Data Mart, identifying drug interaction signals by performing confounder-adjusted self-controlled case series studies for opioid + precipitant pairs and injury. SETTING: Beneficiaries of a major United States-based commercial health insurer during 2000-2015 PATIENTS: Persons aged 16-90 years co-dispensed an opioid and ≥1 precipitant drug(s), with an unintentional traumatic injury event during opioid therapy, as dictated by the case-only design EXPOSURE: Precipitant-exposed (vs. precipitant-unexposed) person-days during opioid therapy. OUTCOME: Emergency department or inpatient International Classification of Diseases discharge diagnosis for unintentional traumatic injury. We used conditional Poisson regression to generate confounder adjusted rate ratios. We accounted for multiple estimation via semi-Bayes shrinkage. RESULTS: We identified 25,019, 12,650, and 10,826 new users of hydrocodone, tramadol, and oxycodone who experienced an unintentional traumatic injury. Among 464, 376, and 389 hydrocodone-, tramadol-, and oxycodone-precipitant pairs examined, 20, 17, and 16 (i.e., 53 pairs, 34 unique precipitants) were positively associated with unintentional traumatic injury and deemed potential drug interaction signals. Adjusted rate ratios ranged from 1.23 (95 % confidence interval: 1.05-1.44) for hydrocodone + amoxicillin-clavulanate to 4.21 (1.88-9.42) for oxycodone + telmisartan. Twenty (37.7 %) of 53 signals are currently reported in a major drug interaction knowledgebase. LIMITATIONS: Potential for reverse causation, confounding by indication, and chance CONCLUSIONS: We identified previously undescribed and/or unappreciated signals of opioid drug interactions associated with unintentional traumatic injury. Subsequent etiologic studies should confirm (or refute) and elucidate these potential drug interactions.

Outdoor temperature and survival benefit of empiric potassium in users of furosemide in US Medicaid enrollees: a cohort study.

OBJECTIVE: Heat is associated with elevated all-cause mortality, and furosemide-induced potassium depletion might be worsened by heat-induced sweating. Because empiric potassium is associated with a marked survival benefit in users of furosemide at a dose of ≥40 mg/day, we hypothesised that this empiric potassium's survival benefit would increase with higher temperature (≥24°C). DESIGN: Cohort study. SETTING: Outpatient setting, captured by Medicaid claims, supplemented with Medicare claims for dual enrollees, from 5 US states from 1999 to 2010, linked to meteorological data. POPULATION/PARTICIPANTS: Furosemide (≥40 mg/day) initiators among adults continuously enrolled in Medicaid for at least 1 year prior to cohort entry (defined as the day following the dispensing day of each individual's first observed furosemide prescription). EXPOSURE: Interaction between: (1) empiric potassium, dispensed the day of or the day following the dispensing of the initial furosemide prescription, and (2) daily average temperature and daily maximum temperature, examined separately. OUTCOME: All-cause mortality. RESULTS: In 1:1 propensity score matched cohorts (total n=211 878) that included 89 335 person-years and 9007 deaths, all-cause mortality rates per 1000 person-years were 96.0 (95% CI 93.2 to 98.9) and 105.8 (95% CI 102.8 to 108.9) for potassium users and non-users, respectively. The adjusted OR of all-cause mortality for potassium use declined (ie, its apparent protective effect increased) as temperature increased, from a daily average temperature of about 28°C and a daily maximum temperature of about 31°C. This relationship was not statistically significant with daily average temperature, but was statistically significant with daily maximum temperature (p values for the interaction of potassium with daily maximum temperature and daily maximum temperature squared were 0.031 and 0.028, respectively). CONCLUSIONS: The results suggest that empiric potassium's survival benefit among furosemide (≥40 mg/day) initiators may increase as daily maximum temperature increases. If this relationship is real, use of empiric potassium in Medicaid enrollees initiating furosemide might be particularly important on hot days.

Serious Hypoglycemia and Use of Warfarin in Combination With Sulfonylureas or Metformin.

Prior research suggests that warfarin, when given concomitantly with some sulfonylureas, may increase the risk of serious hypoglycemia. However, the clinical significance remains unclear. We examined rate ratios (RRs) for the association between serious hypoglycemia and concomitant use of warfarin with either sulfonylureas or metformin using a self-controlled case series design and US Medicaid claims (supplemented with Medicare claims) from 1999 to 2011. Across all risk windows combined, warfarin was associated with an elevated rate of serious hypoglycemia when given concomitantly with glimepiride (RR, 1.47; 95% confidence interval (CI), 1.07-2.02) and metformin (RR, 1.73; 95% CI, 1.38-2.16). Particularly in the late risk window (>120 days since beginning concomitancy), most of the RRs for warfarin were elevated: glipizide (RR, 1.72; 95% CI, 1.29-2.29), glyburide (RR, 1.57; 95% CI, 1.15-2.15), metformin (RR, 2.26; 95% CI, 1.67-3.05), and glimepiride (RR, 1.56; 95% CI, 0.97-2.50). These results are consistent with a previously hypothesized hypoglycemic effect of warfarin in patients with type 2 diabetes through inhibition of the carboxylation of osteocalcin.

Empiric potassium supplementation and increased survival in users of loop diuretics.

BACKGROUND: The effectiveness of the clinical strategy of empiric potassium supplementation in reducing the frequency of adverse clinical outcomes in patients receiving loop diuretics is unknown. We sought to examine the association between empiric potassium supplementation and 1) all-cause death and 2) outpatient-originating sudden cardiac death (SD) and ventricular arrhythmia (VA) among new starters of loop diuretics, stratified on initial loop diuretic dose. METHODS: We conducted a one-to-one propensity score-matched cohort study using 1999-2007 US Medicaid claims from five states. Empiric potassium supplementation was defined as a potassium prescription on the day of or the day after the initial loop diuretic prescription. Death, the primary outcome, was ascertained from the Social Security Administration Death Master File; SD/VA, the secondary outcome, from incident, first-listed emergency department or principal inpatient SD/VA discharge diagnoses (positive predictive value = 85%). RESULTS: We identified 654,060 persons who met eligibility criteria and initiated therapy with a loop diuretic, 27% of whom received empiric potassium supplementation (N = 179,436) and 73% of whom did not (N = 474,624). The matched hazard ratio for empiric potassium supplementation was 0.93 (95% confidence interval, 0.89-0.98, p = 0.003) for all-cause death. Stratifying on initial furosemide dose, hazard ratios for empiric potassium supplementation with furosemide < 40 and ≥ 40 milligrams/day were 0.93 (0.86-1.00, p = 0.050) and 0.84 (0.79-0.89, p < 0.0001). The matched hazard ratio for empiric potassium supplementation was 1.02 (0.83-1.24, p = 0.879) for SD/VA. CONCLUSIONS: Empiric potassium supplementation upon initiation of a loop diuretic appears to be associated with improved survival, with a greater apparent benefit seen with higher diuretic dose. If confirmed, these findings support the use of empiric potassium supplementation upon initiation of a loop diuretic.

Natural supplements for H1N1 influenza: retrospective observational infodemiology study of information and search activity on the Internet.

BACKGROUND: As the incidence of H1N1 increases, the lay public may turn to the Internet for information about natural supplements for prevention and treatment. OBJECTIVE: Our objective was to identify and characterize websites that provide information about herbal and natural supplements with information about H1N1 and to examine trends in the public's behavior in searching for information about supplement use in preventing or treating H1N1. METHODS: This was a retrospective observational infodemiology study of indexed websites and Internet search activity over the period January 1, 2009, through November 15, 2009. The setting is the Internet as indexed by Google with aggregated Internet user data. The main outcome measures were the frequency of "hits" or webpages containing terms relating to natural supplements co-occurring with H1N1/swine flu, terms relating to natural supplements co-occurring with H1N1/swine flu proportional to all terms relating to natural supplements, webpage rank, webpage entropy, and temporal trend in search activity. RESULTS: A large number of websites support information about supplements and H1N1. The supplement with the highest proportion of H1N1/swine flu information was a homeopathic remedy known as Oscillococcinum that has no known side effects; supplements with the next highest proportions have known side effects and interactions. Webpages with both supplement and H1N1/swine flu information were less likely to be medically curated or authoritative. Search activity for supplements was temporally related to H1N1/swine flu-related news reports and events. CONCLUSIONS: The prevalence of nonauthoritative webpages with information about supplements in the context of H1N1/swine flu and the increasing number of searches for these pages suggest that the public is interested in alternatives to traditional prevention and treatment of H1N1. The quality of this information is often questionable and clinicians should be cognizant that patients may be at risk of adverse events associated with the use of supplements for H1N1.