Medication use and kidney cancer survival: A population-based study.

Several studies demonstrate that use of commonly prescribed medications is associated with improved survival in various malignancies. Methods of classifying medication use in many of these studies, however, do not account for intermittent or cumulative use. Moreover, there are limited data in kidney cancer. Therefore, we performed a population-based cohort study utilizing healthcare databases in Ontario, Canada. We identified patients aged ≥65 with an incident diagnosis of kidney cancer between 1997 and 2013 and examined use of nine putative anti-neoplastic medications using prescription claims. Cox proportional hazard models evaluated the association of medication exposure on cancer-specific and overall survival. We conducted three separate analyses: the effect of cumulative duration of exposure to the study medications on outcomes, the effect of current exposure (in a binary nature) and the effect of exposure at diagnosis. During the 16-year study period, we studied 9,124 patients. Increasing cumulative use of angiotensin-converting enzyme inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin reuptake inhibitors were associated with markedly improved cancer-specific survival; increasing use of NSAIDs was associated with markedly improved overall survival. These results were generally discordant with analyses evaluating the effect of current use and exposure at diagnosis. In conclusion, pharmacoepidemiology studies may be sensitive to the method of analysis; cumulative use analyses may be the most robust as it accounts for intermittent use and supports a dose-outcome relationship. Prospective studies are needed to confirm whether patients diagnosed with kidney cancer should be started on an angiotensin-converting enzyme inhibitor, NSAID or selective serotonin reuptake inhibitor to improve survival.

Predictors of Critical Care and Mortality in Bronchiolitis after Emergency Department Discharge.

OBJECTIVES: To identify the epidemiologic predictors and stratify the risk of critical care unit (CCU) admission or death in bronchiolitis following emergency department discharge. This information has not yet been explored. STUDY DESIGN: A population-based cohort study using Ontario-wide demographic and healthcare databases linked at the individual level. We assessed all infants with bronchiolitis discharged home from all emergency departments in Ontario, Canada, 2003-2014. Targeted information included plausible demographic and clinical predictors of CCU admission/death within 14 days of emergency department discharge. Using multivariable logistic regression analyses, we identified independent predictors of this outcome and stratified the outcome risk by the type of multivariable predictor. RESULTS: Of 34 270 study infants, 102 (0.3%) were admitted to CCU or died after discharge. Predictors of CCU admission/death were: comorbidities (OR 5.33; 95% CI 2.82-10.10), younger age [months] (OR 1.47; 95%CI 1.33-1.61), low income (OR 1.53; 95% CI 1.01-2.34), younger gestational age [weeks] (OR 1.14; 95%CI 1.06-1.22), and emergent presentation (Canadian Triage and Acuity Scale 2) at the index visit (OR 1.55, 95% CI 1.03-2.33). The absolute event risk of CCU admission/death in infants with versus without comorbidities were 1.5% versus 0.26%, respectively (P < .001). The odds of these outcomes in infants with comorbidities plus ≥2 other predictors were 25 times higher than in infants without predictors (OR 25.1, 95% CI 11.4-55.3). CONCLUSIONS: Infants with comorbidities plus other predictors discharged from the emergency department with bronchiolitis are at considerable risk of subsequent CCU admission and death. These risk factors should augment current clinical and social considerations determining patient disposition.

A population-based study of the risk of osteoporosis and fracture with dutasteride and finasteride.

BACKGROUND: Dutasteride is a potent inhibitor of 5-alpha reductase enzymes that reduces concentrations of dihydrotestosterone to a greater extent than finasteride. Whether this has adverse implications for bone health is unknown. We compared the risk of osteoporosis and fractures in older men treated with dutasteride or finasteride. METHODS: We conducted a population-based retrospective cohort study with high-dimensional propensity score matching of Ontario men aged 66 years or older who started treatment with dutasteride or finasteride between January 1, 2006 and December 31, 2012. The primary outcome was a diagnosis of osteoporosis within 2 years of treatment initiation. A secondary outcome was osteoporotic or fragility fractures. RESULTS: We studied 31,615 men treated with dutasteride and an equal number of men treated with finasteride. Dutasteride-treated patients had a lower incidence of osteoporosis than those receiving finasteride [2.2 versus 2.6 per 100 person years; hazard ratio (HR) 0.82; 95% confidence interval (CI) 0.72 to 0.93]. This effect was no longer statistically significant following adjustment for specialty of prescribing physician (HR 0.90; 95% CI 0.78 to 1.02)]. There was no differential risk of fractures with dutasteride (HR 1.04; 95% 0.86 to 1.25). CONCLUSIONS: Despite differential effects on 5-alpha reductase, dutasteride is not associated with an increased risk of osteoporosis or fractures in older men relative to finasteride. These findings suggest that dutasteride does not adversely affect bone health.

The Cardiovascular Safety of Dutasteride.

PURPOSE: Randomized controlled trials suggest an increased risk of heart failure with dutasteride, which inhibits both the type 1 and type 2 isoforms of 5α-reductase. In contrast, no such association has been suggested for finasteride, which selectively inhibits the type 2 isoform. We investigated the risk of cardiovascular events among patients receiving dutasteride relative to finasteride. MATERIALS AND METHODS: We performed a population based cohort study of Ontario men 66 years old or older who commenced treatment with dutasteride or finasteride between October 1, 2005 and March 31, 2015. For each individual treated with dutasteride, we identified 1 treated with finasteride, matching on a propensity score and calendar quarter of treatment initiation to account for temporal changes in prescribing. The primary outcome was hospitalization for heart failure. Secondary analyses were done to examine acute myocardial infarction and stroke. Cox proportional hazards regression was used to adjust for differences between groups. RESULTS: We studied 36,311 men who commenced dutasteride and 36,311 treated with finasteride. In the primary analysis, we found no difference in the risk of heart failure among patients receiving dutasteride relative to those receiving finasteride (adjusted HR 0.98, 95% CI 0.88-1.08). Similarly, we found no difference in the risk of acute myocardial infarction (HR 0.94, 95% CI 0.82-1.08) or stroke (HR 1.03, 95% CI 0.88-1.20). CONCLUSIONS: In this population based cohort study of more than 72,000 older men, dutasteride was not associated with an increased risk of cardiovascular events relative to finasteride.

Association between statin use and ischemic stroke or major hemorrhage in patients taking dabigatran for atrial fibrillation.

BACKGROUND: Dabigatran etexilate is a prodrug whose absorption is opposed by intestinal P-glycoprotein and which is converted by carboxylesterase to its active form, dabigatran. Unlike other statins, simvastatin and lovastatin are potent inhibitors of P-glycoprotein and carboxylesterase, and might either increase the risk of hemorrhage with dabigatran etexilate or decrease its effectiveness. METHODS: We conducted 2 population-based, nested case-control studies involving Ontario residents 66 years of age and older who started dabigatran etexilate between May 1, 2012, and Mar. 31, 2014. In the first study, cases were patients with ischemic stroke; in the second, cases were patients with major hemorrhage. Each case was matched with up to 4 controls by age and sex. All cases and controls received a single statin in the 60 days preceding the index date. We determined the association between each outcome and the use of simvastatin or lovastatin, relative to other statins. RESULTS: Among 45 991 patients taking dabigatran etexilate, we identified 397 cases with ischemic stroke and 1117 cases with major hemorrhage. After multivariable adjustment, use of simvastatin or lovastatin was not associated with an increased risk of stroke (adjusted odds ratio [OR] 1.33, 95% confidence interval [CI] 0.88 to 2.01). In contrast, use of simvastatin and lovastatin were associated with a higher risk of major hemorrhage (adjusted OR 1.46, 95% CI 1.17 to 1.82). INTERPRETATION: In patients receiving dabigatran etexilate, simvastatin and lovastatin were associated with a higher risk of major hemorrhage relative to other statins. Preferential use of the other statins should be considered in these patients.

Pregabalin and heart failure: A population-based study.

PURPOSE: The anticonvulsant pregabalin is increasingly prescribed for pain, seizures, and psychiatric disorders. Although evidence suggests pregabalin can cause edema and heart failure, its cardiac safety profile in clinical practice is unknown. We sought to examine the risk of heart failure among older patients receiving pregabalin compared to those receiving gabapentin. METHODS: We conducted a population-based cohort study of Ontarians aged 66 and older with a history of seizure who received pregabalin or gabapentin between April 2013 and March 2014. We used propensity scores to match patients commencing pregabalin to those commencing gabapentin. The primary outcome was an emergency department visit or hospitalization for heart failure within 90 days. RESULTS: We studied 9855 patients who initiated pregabalin and an equal number treated with gabapentin. In the primary analysis, we found no difference in the risk of heart failure with pregabalin compared to gabapentin (1.2% versus 1.3%, hazard ratio of 0.77; 95% CI 0.58-1.03). Secondary analyses stratified for baseline history of heart failure yielded similar findings. CONCLUSION: In a large cohort of older patients with a seizure disorder, pregabalin was not associated with an increased risk of heart failure relative to gabapentin.

Concomitant pulmonologist and primary care for chronic obstructive pulmonary disease: a population study.

Background: Pulmonologists provide quality care, however, their number is not adequate to take care of all the chronic obstructive pulmonary disease (COPD) needs of the population and their services come with a cost. Their optimal role should be defined, ideally based on evidence, to ensure that their abilities are applied most efficiently where needed. Objective: To determine if concomitant pulmonologist and primary care physician care after COPD hospital or emergency department discharge was associated with better health outcomes than primary care services alone. Methods: A population cohort study was conducted in Ontario, Canada from 2004 to 2011. All individuals with a COPD hospital or emergency department discharge were included. Patients who visited both a pulmonologist and a primary care physician within 30 days of the index discharge were matched to patients who had visited a primary care physician alone using propensity scores. The composite outcome of death, COPD hospitalization or COPD emergency department visit was compared using proportional hazards regression. Results: In the propensity score matched sample, 39.7% of patients who received concomitant care and 38.9% who received primary care only died or visited the emergency department visit or hospital for COPD within 1 year (adjusted hazard ratio 1.08, 95% confidence interval 1.00-1.17). The former, however, were more likely to receive diagnostic testing and medications. Conclusion: Patients who received concomitant care after COPD emergency department or hospital discharge did not have better outcomes than those who received primary care alone, however, they did receive more testing and medical management.

Medication use and survival in diabetic patients with kidney cancer: A population-based cohort study.

Survival rates in kidney cancer have improved little over time, and diabetes may be an independent risk factor for poor survival in kidney cancer. We sought to determine whether medications with putative anti-neoplastic properties (statins, metformin and non-steroidal anti-inflammatory drugs (NSAIDs)) are associated with survival in diabetics with kidney cancer. We conducted a population-based cohort study utilizing linked healthcare databases in Ontario, Canada. Patients were aged 66 or older with newly diagnosed diabetes and a subsequent diagnosis of incident kidney cancer. Receipt of metformin, statins or NSAIDs was defined using prescription claims. The primary outcome was all-cause mortality and the secondary outcome was cancer-specific mortality. We used multivariable Cox proportional hazard regression, with medication use modeled with time-varying and cumulative exposure analyses to account for intermittent use. During the 14-year study period, we studied 613 patients. Current statin use was associated with a markedly reduced risk of death from any cause (adjusted hazard ratio 0.74; 95% CI 0.59-0.91) and death due to kidney cancer (adjusted hazard ratio 0.71; 95% CI 0.51-0.97). However, survival was not associated with current use of metformin or NSAIDs, or cumulative exposure to any of the medications studied. Among diabetic patients with kidney cancer, survival outcomes are associated with active statin use, rather than total cumulative use. These findings support the use of randomized trials to confirm whether diabetics with kidney cancer should be started on a statin at the time of cancer diagnosis to improve survival outcomes.

Socioeconomic status and risk of hemorrhage during warfarin therapy for atrial fibrillation: A population-based study.

BACKGROUND: Among patients taking warfarin, lower socioeconomic status is associated with poorer control of anticoagulation. However, the extent to which socioeconomic status influences the risk of hemorrhage is unknown. We examined the extent to which socioeconomic status influences the risk of hemorrhage in older individuals newly commencing warfarin therapy for atrial fibrillation. METHODS: We conducted a population-based cohort study of individuals 66 years or older with atrial fibrillation who commenced warfarin therapy between April 1, 1997, and November 30th 2011, in Ontario, Canada. We used neighborhood-level income quintiles as a measure of socioeconomic status. The primary outcome was an emergency department visit or hospitalization for hemorrhage, and the secondary outcome was fatal hemorrhage. RESULTS: We studied 166,742 older patients with atrial fibrillation who commenced warfarin therapy. Of these, 16,371 (9.8%) were hospitalized for hemorrhage during a median follow-up of 369 (interquartile range 102-865) days. After multivariable adjustment using Cox proportional hazards regression, we found that those in the lowest-income quintile faced an increased risk of hospitalization for hemorrhage relative to those in the highest quintile (adjusted hazard ratio 1.18, 95% CI 1.12-1.23). Similarly, the risk of fatal hemorrhage (n = 1,802) was increased in the lowest-income relative to the highest-income quintile (adjusted hazard ratio 1.28, 95% CI 1.11-1.48). CONCLUSIONS: Among older individuals receiving warfarin therapy for atrial fibrillation, lower socioeconomic status is a risk factor for hemorrhage and hemorrhage-related mortality. This factor should be carefully considered when initiating and monitoring warfarin therapy.

Prescription Stimulant Use and Hospitalization for Psychosis or Mania: A Population-Based Study.

Small studies suggest that prescription stimulants can precipitate psychosis and mania. We conducted a population-based case-crossover study to examine whether hospitalization for psychosis or mania was associated with initiation of stimulant therapy. Between October 1, 1999 and March 31, 2013, we studied 12,856 young people who received a stimulant prescription and were subsequently hospitalized for psychosis or mania. Of these, 183 commenced treatment during 1 of 2 prespecified 60-day intervals (defined as the "risk interval" and "control interval," respectively) prior to admission. We found that stimulant initiation was associated with an increased risk of hospitalization for psychosis or mania in the subsequent 60 days (odds ratio, 1.86; 95% confidence interval, 1.39-2.56). The risk was marginally higher in patients treated with antipsychotic drugs (odds ratio, 2.06; 95% confidence interval, 1.38-3.28), but remained in patients with no such history (odds ratio, 1.66; 95% confidence interval, 1.09-2.66). One third of subjects received another stimulant prescription after hospital discharge. Of these, 45% were readmitted with psychosis or mania shortly thereafter. We conclude that initiation of prescription stimulants is associated with an increased risk of hospitalization for psychosis or mania. Resumption of therapy is common, which may reflect a lack of awareness of the potential causative role of these drugs.

A population-based study of the drug interaction between clopidogrel and angiotensin converting enzyme inhibitors.

AIMS: Clopidogrel and angiotensin converting enzyme (ACE) inhibitors are commonly co-prescribed drugs. Clopidogrel inhibits carboxylesterase 1 (CES1), the enzyme responsible for converting prodrug ACE inhibitors (such as ramipril and perindopril) to their active metabolites. The clinical implications of this potential drug interaction are unknown. The clinical consequences of the potential drug interaction between clopidogrel and prodrug ACE inhibitors were examined. METHODS: We conducted a nested case-control study of Ontarians aged 66 years and older treated with clopidogrel between September 1 2003 and March 31 2013 following acute myocardial infarction. Cases were subjects who died or were hospitalized for reinfarction or heart failure in the subsequent year, and each was matched with up to four controls. The primary outcome was a composite of reinfarction, heart failure or death. The primary analysis examined whether use of the prodrug ACE inhibitors ramipril or perindopril was more common among cases than use of lisinopril, an active ACE inhibitor. RESULTS: Among 45 918 patients treated with clopidogrel following myocardial infarction, we identified 4203 cases and 14 964 controls. After adjustment, we found no association between the composite outcome and use of perindopril (adjusted odds ratio (aOR) 0.94, 95% confidence interval (CI) 0.76, 1.16) or ramipril (aOR 0.97, 95% CI 0.80, 1.18), relative to lisinopril. Secondary analyses of each element of the composite outcome yielded similar findings. CONCLUSIONS: Following myocardial infarction, use of clopidogrel with ACE inhibitors activated by CES1 is not associated with an increased risk of adverse cardiovascular outcomes relative to lisinopril. These findings suggest that the recently described drug interaction between clopidogrel and prodrug ACE inhibitors is of little clinical relevance.

Trimethoprim-sulfamethoxazole and risk of sudden death among patients taking spironolactone.

BACKGROUND: Trimethoprim-sulfamethoxazole increases the risk of hyperkalemia when used with spironolactone. We examined whether this drug combination is associated with an increased risk of sudden death, a consequence of severe hyperkalemia. METHODS: We conducted a population-based nested case-control study involving Ontario residents aged 66 years or older who received spironolactone between Apr. 1, 1994, and Dec. 31, 2011. Within this group, we identified cases as patients who died of sudden death within 14 days after receiving a prescription for trimethoprim-sulfamethoxazole or one of the other study antibiotics (amoxicillin, ciprofloxacin, norfloxacin or nitrofurantoin). For each case, we identified up to 4 controls matched by age and sex. We determined the odds ratio (OR) for the association between sudden death and exposure to each antibiotic relative to amoxicillin, adjusted for predictors of sudden death using a disease risk index. RESULTS: Of the 11,968 patients who died of sudden death while receiving spironolactone, we identified 328 whose death occurred within 14 days after antibiotic exposure. Compared with amoxicillin, trimethoprim-sulfamethoxazole was associated with a more than twofold increase in the risk of sudden death (adjusted OR 2.46, 95% confidence interval [CI] 1.55-3.90). Ciprofloxacin (adjusted OR 1.55, 95% CI 1.02-2.38) and nitrofurantoin (adjusted OR 1.70, 95% CI 1.03-2.79) were also associated with an increased risk of sudden death, although the risk with nitrofurantoin was not apparent in a sensitivity analysis. INTERPRETATION: The antibiotic trimethoprim-sulfamethoxazole was associated with an increased risk of sudden death among older patients taking spironolactone. When clinically appropriate, alternative antibiotics should be considered in these patients.

Rates of Anomalous Bupropion Prescriptions in Ontario, Canada.

PURPOSE: Reports of bupropion misuse have increased since it was first reported in 2002. The purpose of this study was to explore trends in bupropion prescribing suggestive of misuse or diversion in Ontario, Canada. METHODS: A serial cross-sectional study was conducted of Ontarians aged younger than 65 years who received prescriptions under Ontario's public drug program from April 1, 2000, to March 31, 2013. We determined the number of potentially inappropriate prescriptions in each quarter, defined as early refills dispensed within 50% of the duration of the preceding prescription, as well as potentially duplicitous prescriptions, defined as similarly early refills originating from a different prescriber and different pharmacy. We replicated these analyses for citalopram and sertraline, antidepressants not known to be prone to abuse. RESULTS: We identified 1,780,802 prescriptions for bupropion, 3,402,462 for citalopram, and 1,775,285 for sertraline. Rates of early refills for bupropion declined during the study from 4.8% to 3.1%. In the final quarter, rates of early refills for bupropion were more common than for citalopram (3.1% vs 2.2%) (P <.001) but not for sertraline (3.1% vs 2.9%) (P =.16). Potentially duplicitous prescriptions for bupropion increased dramatically, from <0.05% of all prescriptions in early 2000 to 0.47% in early 2013 and by the final quarter were more common than both citalopram (0.11%) and sertraline (0.12%) (P <.001). CONCLUSIONS: Although no marked differences were seen for early refills of bupropion relative to its comparators, potentially duplicitous prescriptions have increased dramatically in Ontario, suggesting growing misuse of the drug.

Adequacy of prenatal care among women living with human immunodeficiency virus: a population-based study.

BACKGROUND: Prenatal care reduces perinatal morbidity. However, there are no population-based studies examining the adequacy of prenatal care among women living with HIV. Accordingly, we compared the prevalence of adequate prenatal care among women living with and without HIV infection in Ontario, Canada. METHODS: Using administrative data in a universal single-payer setting, we determined the proportions of women initiating care in the first trimester and receiving adequate prenatal care according to the Revised-Graduated Prenatal Care Utilization Index . We also determined the proportion of women with HIV receiving adequate prenatal care by immigration status. We used generalized estimating equations with a logit link function to derive adjusted odds ratios (aORs) and 95% confidence intervals (CI) for all analyses. RESULTS: Between April 1, 2002 and March 31, 2011, a total of 1,132,135 pregnancies were available for analysis, of which 634 (0.06%) were among women living with HIV. Following multivariable adjustment, women living with HIV were less likely to receive adequate prenatal care (36.1% versus 43.3%; aOR 0.74, 95% CI 0.62 to 0.88) or initiate prenatal care in the first trimester (50.8% versus 70.0%; aOR 0.51, 95% CI 0.43 to 0.60) than women without HIV. Among women with HIV, recent (i.e. ≤ 5 years) immigrants from Africa and the Caribbean were less likely to receive adequate prenatal care (25.5% versus 38.5%; adjusted odds ratio 0.51; 95% CI, 0.32 to 0.81) than Canadian-born women. CONCLUSION: Despite universal health care, disparities exist in the receipt of adequate prenatal care between women living with and without HIV. Interventions are required to ensure that women with HIV receive timely and adequate prenatal care.

Adverse Neonatal Outcomes Among Women Living With HIV: A Population-Based Study.

BACKGROUND: There have been few population-based studies describing the risk of adverse neonatal outcomes among women living with HIV in Canada. Accordingly, we compared the risk of preterm birth (PTB), low birth weight (LBW) and small for gestational age births among Ontario women aged 18 to 49 years living with and without HIV infection. METHODS: We conducted a population-based study using Ontario health administrative data. Generalized estimating equations with a logit link function were used to derive adjusted odds ratios (aORs) and 95% confidence intervals for the association of HIV infection with adverse neonatal outcomes. RESULTS: Between 2002-2003 and 2010-2011, a total of 1 113 874 singleton live births were available for analysis, of which 615 (0.06%) were to women living with HIV. The proportion of singleton births that were SGA (14.6% vs. 10.3%; P < 0.001), PTB (14.6% vs. 6.3%; P < 0.001), and LBW (12.5% vs. 4.6%; P < 0.001) were higher among women living with HIV than among women without HIV. Following multivariable adjustment, the risks of PTB (aOR 1.76; 95% CI 1.38 to 2.24), SGA (aOR 1.43; 95% CI 1.12 to 1.81), and LBW (aOR 1.90; 95% CI 1.47 to 2.45) were higher for women living with HIV than for women without HIV. CONCLUSION: Women with HIV are at higher risk of adverse neonatal outcomes than HIV-negative women. Further research is required to develop preconception and prenatal interventions that could reduce the excess burden of poor pregnancy outcomes among women living with HIV.

Contexte : Peu d'études en population générale ont décrit le risque d'issues néonatales indésirables chez les femmes vivant avec le VIH au Canada. Par conséquent, nous avons comparé les risques d'accouchement préterme (APT), de faible poids de naissance (FPN) et d'hypotrophie fœtale (HF) chez des Ontariennes de 18-49 ans vivant ou non avec le VIH. Méthodes : Nous avons mené une étude en population générale au moyen de données administratives sur la santé en Ontario. Des équations d'estimation généralisées comptant une fonction Logit ont été utilisées pour en venir à des rapports de cotes corrigés (RCc) et à des intervalles de confiance à 95 % en ce qui concerne l'association entre l'infection au VIH et des issues néonatales indésirables. Résultats : Entre 2002­2003 et 2010­2011, 1 113 874 naissances vivantes issues de grossesses monofœtales étaient disponibles aux fins de l'analyse, 615 (0,06 %) desquelles mettaient en jeu des femmes vivant avec le VIH. La proportion de naissances issues de grossesses monofœtales qui présentaient une HF (14,6 % vs 10,3 %; P < 0,001), un APT (14,6 % vs 6,3 %; P < 0,001) et un FPN (12,5 % vs 4,6 %; P < 0,001) était plus élevée chez les femmes vivant avec le VIH que chez les femmes n'étant pas infectées par ce dernier. À la suite d'une correction multivariée, les risques d'APT (RCc, 1,76; IC à 95 %, 1,38 - 2,24), d'HF (RCc, 1,43; IC à 95 %, 1,12 - 1,81) et de FPN (RCc, 1,90; IC à 95 %, 1,47 - 2,45) étaient plus élevés chez les femmes vivant avec le VIH que chez les femmes n'étant pas infectées par ce dernier. Conclusion : Les femmes vivant avec le VIH sont exposées à des risques d'issues néonatales indésirables plus élevés que les femmes séronégatives pour le VIH. La tenue d'autres recherches s'avère requise pour que l'on puisse élaborer des interventions préconceptionnelles et prénatales qui pourraient atténuer le fardeau supplémentaire que doivent assumer les femmes vivant avec le VIH en matière de piètres issues de grossesse.

Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study.

BACKGROUND: Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. METHODS AND FINDINGS: We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06-1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11-2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81-1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54-2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of hypomagnesemia, and generalizability of our findings to younger patients. CONCLUSIONS: PPIs are associated with a small increased risk of hospitalization with hypomagnesemia among patients also receiving diuretics. Physicians should be aware of this association, particularly for patients with hypomagnesemia. Please see later in the article for the Editors' Summary.

Oxycodone, Hydromorphone, and the Risk of Suicide: A Retrospective Population-Based Case-Control Study.

INTRODUCTION: Opioids have been increasingly associated with suicide, but whether they are independent contributors is unclear. Oxycodone and hydromorphone are commonly prescribed high-potency opioids that can differentially affect mood. OBJECTIVE: The objective of this study was to explore whether oxycodone and hydromorphone are differentially associated with suicide. METHODS: We conducted a retrospective population-based case-control study in Ontario, Canada, from 1992 to 2014. Using coronial data, we defined case subjects as individuals who died by suicide involving an opioid overdose. Each of these was matched with up to four controls who died of accidental opioid overdose. We ascertained exposure to oxycodone, hydromorphone, and other opioids from postmortem toxicology testing. We used odds ratios and 95% confidence intervals to examine whether opioid-related suicide was disproportionately associated with oxycodone relative to hydromorphone. RESULTS: We identified 438 suicides and 1212 accidental deaths, each of which involved either oxycodone or hydromorphone but not both. The median age at death was 49 years and 51% were men. After adjusting for a history of self-harm, psychiatric illness, and exposure to other opioids, we found that oxycodone was more strongly associated with suicide than hydromorphone (adjusted odds ratio 1.59; 95% confidence interval 1.20-2.11). In a secondary analysis, we observed a trend of similar magnitude in which combined exposure to oxycodone and hydromorphone was more strongly associated with suicide than hydromorphone alone (adjusted odds ratio 1.68; 95% confidence interval 0.92-3.09). CONCLUSIONS: While preliminary, these findings support the possibility that some high-potency opioids might independently influence the risk of suicide in susceptible individuals.