ABSTRACT
BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) can cause hyperkalemia by reducing renal potassium excretion. We assessed the risk of hyperkalemia after initiating TMP-SMX versus amoxicillin and determined if this risk is modified by a patient's baseline kidney function [estimated glomerular filtration rate (eGFR)]. METHODS: We conducted a population-based cohort study in Ontario, Canada involving adults ≥66 years of age newly treated with TMP-SMX (n = 58 999) matched 1:1 with those newly treated with amoxicillin (2008-2020). The primary outcome was a hospital encounter with hyperkalemia defined by a laboratory serum potassium value ≥5.5 mmol/L within 14 days of antibiotic treatment. Secondary outcomes included a hospital encounter with acute kidney injury (AKI) and all-cause hospitalization. Risk ratios (RRs) were obtained using a modified Poisson regression. RESULTS: A hospital encounter with hyperkalemia occurred in 269/58 999 (0.46%) patients treated with TMP-SMX versus 80/58 999 (0.14%) in those treated with amoxicillin {RR 3.36 [95% confidence interval (CI) 2.62-4.31]}. The absolute risk of hyperkalemia in patients treated with TMP-SMX versus amoxicillin increased progressively with decreasing eGFR (risk difference of 0.12% for an eGFR ≥60 ml/min/1.73 m2, 0.42% for eGFR 45-59, 0.85% for eGFR 30-44 and 1.45% for eGFR <30; additive interaction P < .001). TMP-SMX versus amoxicillin was associated with a higher risk of a hospital encounter with AKI [RR 3.15 (95% CI 2.82-3.51)] and all-cause hospitalization [RR 1.43 (95% CI 1.34-1.53)]. CONCLUSIONS: The 14-day risk of a hospital encounter with hyperkalemia was higher in patients newly treated with TMP-SMX versus amoxicillin and the risk was highest in patients with a low eGFR.
Subject(s)
Acute Kidney Injury , Hyperkalemia , Adult , Humans , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Hyperkalemia/chemically induced , Hyperkalemia/epidemiology , Cohort Studies , Retrospective Studies , Potassium , Acute Kidney Injury/chemically induced , Amoxicillin , Hospitals , Ontario/epidemiologyABSTRACT
BACKGROUND: Malaria morbidity and mortality increase in the Democratic Republic of the Congo (DRC) may be the consequence of the low utilization rate of long-lasting insecticidal nets (LLINs) resulting from poor compliance due to adverse events (AEs). This study aimed at determining the prevalence and predictors of AEs following the mass distribution of LLINs in the Kisantu Health Zone (KHZ), a high malaria-endemic region in the DRC. METHODS: A community-based cross-sectional study embedded was conducted within a randomized controlled trial (RCT) after the mass distribution of LLINs in 30 villages located in DRC KHZ. A three-stage sampling method was used without replacement to select 1790 children. Data was collected on adverse events (AEs) using a reporting form and information on demographics, nutritional status, and house characteristics. This was done using a structured questionnaire administered to household heads. Logistic regression models were used to identify predictors of AEs following the mass distribution of LLINs. RESULT: In a total of 1790 children enrolled, 17.8% (95% CI 16.1-19.7) experienced AEs. The most common AEs were respiratory-related (61%). Around 60% of AEs occurred within 24 h of use, and 51% were resolved without treatment. Sleeping under deltamethrin LLINs (Adjusted OR, 95% CI 5.5 [3.8-8.0]) and zinc roofing (Adjusted OR, 95% CI 1.98 [1.1-3.57]) were associated with the risk of reporting an AE following the mass distribution of LLINs. CONCLUSION: Approximately 1 out of 5 children had an AE within 24 h following LLIN use. These adverse events were often respiratory-related. LLINs and roofing types were associated with a higher risk of reporting AEs. However, further research using a robust study design is needed to confirm these findings. Future studies should design and implement interventions aiming to reduce AEs and improve compliance with LLINs.
Subject(s)
Insecticide-Treated Bednets , Insecticides , Malaria , Child , Humans , Insecticides/adverse effects , Democratic Republic of the Congo/epidemiology , Prevalence , Cross-Sectional Studies , Malaria/prevention & control , Malaria/epidemiology , Mosquito Control/methodsABSTRACT
RATIONALE & OBJECTIVE: Gabapentinoids are opioid substitutes whose elimination by the kidneys is reduced as kidney function declines. To inform their safe prescribing in older adults with chronic kidney disease (CKD), we examined the 30-day risk of serious adverse events according to the prescribed starting dose. STUDY DESIGN: Population-based cohort study. SETTING & PARTICIPANTS: 74,084 older adults (64% women; median age, 79 [interquartile range, 73-85] years) with CKD (defined for this study as an estimated glomerular filtration rate <60 mL/min/1.73 m2 and excluding those receiving dialysis) and a newly prescribed gabapentinoid between 2008 and 2020 in Ontario, Canada. EXPOSURE: Higher-dose gabapentinoids (gabapentin >300 mg/d or pregabalin >75 mg/d) versus lower-dose gabapentinoids (gabapentin ≤300 mg/d or pregabalin ≤75 mg/d). OUTCOMES: The primary composite outcome was the 30-day risk of a hospital visit with encephalopathy, a fall, or a fracture or a hospitalization with respiratory depression. ANALYTICAL APPROACH: Comparison groups were balanced on indicators of baseline health using inverse probability of treatment weighting using propensity score analysis that generated a pseudosample for the reference group with a distribution of measured covariates similar to the exposed group. Weighted risk ratios were estimated using modified Poisson regression, and weighted risk differences were estimated using binomial regression. Prespecified subgroup analyses were conducted by estimated glomerular filtration rate category and type of gabapentinoid. RESULTS: Among 74,084 patients identified with CKD and a new prescription for gabapentin or pregabalin, 41% started at >300 or >75 mg/d, respectively. From this set of patients, a weighted study population with a size of 61,367 was generated. Patients who started at a higher dose had a higher 30-day risk of the primary outcome than patients who started at lower dose. Within the weighted population, the numbers of events for higher versus lower dose were 585 of 30,660 (1.9%) versus 462 of 30,707 (1.5%), respectively. The weighted risk ratio was 1.27 (95% CI, 1.13-1.42), and the weighted risk difference was 0.40% (95% CI, 0.21%-0.60%). In subgroup analyses, neither multiplicative nor additive interactions were statistically significant. LIMITATIONS: Residual confounding. CONCLUSIONS: In this population-based study, starting a gabapentinoid at a higher versus a lower dose was associated with a slightly higher risk of a hospital visit with encephalopathy, a fall, or a fracture or hospitalization with respiratory depression. If verified, these risks should be balanced against the benefits of using a higher-dose gabapentinoid.
Subject(s)
Brain Diseases , Renal Insufficiency, Chronic , Respiratory Insufficiency , Aged , Aged, 80 and over , Cohort Studies , Female , Gabapentin/adverse effects , Humans , Male , Ontario/epidemiology , Pregabalin/adverse effects , Respiratory Insufficiency/chemically inducedABSTRACT
RATIONALE & OBJECTIVE: Allopurinol should be started at lower doses in patients with chronic kidney disease (CKD) to avoid adverse effects. We examined the risk of severe cutaneous reactions in older adults with CKD who were newly prescribed allopurinol at varied doses. STUDY DESIGN: Population-based cohort study using linked health care databases. SETTING & PARTICIPANTS: Patients in Ontario, Canada (2008-2019) aged ≥66 years, with an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, and who were new users of allopurinol. EXPOSURE: A new prescription for allopurinol >100 mg/d versus a dose ≤100 mg/d. OUTCOME: The primary outcome was a hospital visit with a severe cutaneous reaction within 180 days of starting allopurinol. Secondary outcomes included all-cause hospitalization and all-cause mortality. ANALYTICAL APPROACH: The exposure and referent groups were balanced on indicators of baseline health using inverse probability of treatment weighting on the propensity score. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. RESULTS: Of 47,315 patients (median age, 76 years; median eGFR, 45 mL/min/1.73 m2), 55% started allopurinol at >100 mg/d. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of a severe cutaneous reaction: number of events (weighted), 103 of 25,802 (0.40%) versus 46 of 25,816 (0.18%), respectively (weighted RR, 2.25 [95% CI, 1.50-3.37]; weighted RD, 0.22% [95% CI, 0.12%-0.32%]. Starting allopurinol at >100 versus ≤100 mg/d was associated with an increased risk of all-cause hospitalization but not with all-cause mortality. LIMITATIONS: This study was underpowered to detect risk differences in the association of allopurinol dose with outcomes across eGFR categories (ie, 45-59, 30-44, and <30 mL/min/1.73 m2). CONCLUSIONS: Older patients with CKD who started allopurinol at >100 mg/d versus ≤100 mg/d were twice as likely to visit a hospital with a severe cutaneous reaction in the next 180 days.
Subject(s)
Allopurinol , Renal Insufficiency, Chronic , Humans , Aged , Allopurinol/adverse effects , Gout Suppressants/adverse effects , Cohort Studies , Renal Insufficiency, Chronic/drug therapy , Ontario/epidemiologyABSTRACT
At least 23 case reports link the muscle relaxant baclofen to encephalopathy in patients receiving dialysis. To explore this issue, we conducted a study to quantify the risk of encephalopathy from baclofen in patients receiving dialysis. Linked healthcare databases were used to conduct a population-based cohort study of older adults receiving maintenance dialysis in Ontario, Canada (1997-2018) to compare new users of baclofen to non-users. The primary outcome was the 30-day risk of hospitalization with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, or transient cerebral ischemic attack. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. We studied 360 new baclofen users and 6109 non-users (2638 [41%] women; median age 75). The median baclofen dose was 20 mg/day. Hospitalization with encephalopathy occurred in 26 of 360 baclofen users (7.2%) and in under six of 6109 non-users (under 0.1%); weighted risk ratios, 78.3 (95% confidence interval 27.9 to 219.2); weighted risk differences, 7.1% (4.5% to 9.8%). The median time from baclofen dispensing to hospitalization with encephalopathy was three days. Among patients receiving dialysis, approximately one in 14 were hospitalized with encephalopathy shortly after starting baclofen. Thus, baclofen should be avoided in older adults receiving dialysis, and other muscle relaxants considered in its place. Hence, if baclofen must be used, a low dose should be prescribed, and older adults should be carefully monitored for signs of encephalopathy.
Subject(s)
Baclofen , Brain Diseases , Aged , Baclofen/adverse effects , Brain Diseases/chemically induced , Brain Diseases/epidemiology , Cohort Studies , Female , Hospitalization , Humans , Ontario/epidemiology , Renal Dialysis/adverse effects , Retrospective StudiesABSTRACT
IMPORTANCE: At least 30 case reports have linked the muscle relaxant baclofen to encephalopathy in patients with chronic kidney disease (CKD). OBJECTIVE: To compare the 30-day risk of encephalopathy in patients with CKD and newly prescribed baclofen at greater than or equal to 20 mg per day vs less than 20 mg per day. The secondary objective was to compare the risk of encephalopathy in baclofen users vs nonusers. DESIGN, SETTING, AND PARTICIPANTS: Retrospective population-based cohort study in Ontario, Canada (2007-2018) using linked health care data. Participants comprised 15â¯942 older adults (aged 66 years or older) with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis). The primary cohort was restricted to patients who were newly prescribed baclofen; participants in the secondary cohort were new users and nonusers. EXPOSURES: Prescription for oral baclofen greater than or equal to 20 mg per day vs less than 20 mg per day. MAIN OUTCOMES AND MEASURES: Hospital admission with encephalopathy, defined as a main diagnosis of delirium, disorientation, transient alteration of awareness, transient cerebral ischemic attack, or unspecified dementia within 30 days of starting baclofen. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RRs) were obtained using modified Poisson regression and weighted risk differences (RDs) using binomial regression. Prespecified subgroup analyses were conducted by eGFR category. RESULTS: The primary cohort comprised 15â¯942 patients with CKD (9699 [61%] women; median age, 77 years [interquartile range, 71-82]; 9707 [61%] patients started baclofen at ≥20 mg/d and 6235 [39%] at <20 mg/d). The primary outcome, hospitalization with encephalopathy, occurred in 108/9707 (1.11%) patients who started baclofen at greater than or equal to 20 mg per day and in 26/6235 (0.42%) who started baclofen at less than 20 mg per day; weighted RR, 3.54 (95% CI, 2.24 to 5.59); weighted RD, 0.80% (95% CI, 0.55% to 1.04%). In subgroup analysis, the absolute risk increased progressively at lower eGFR (weighted RD eGFR 45-59, 0.42% [95% CI, 0.19%-0.64%]; eGFR 30-44, 1.23% [95% CI, 0.62%-1.84%]; eGFR <30, 2.90% [95% CI, 1.30%-4.49%]; P for interaction, <.001]). In the secondary comparison with 284â¯263 nonusers, both groups of baclofen users had a higher risk of encephalopathy (<20 mg/d weighted RR, 5.90 [95% CI, 3.59 to 9.70] and ≥20 mg/d weighted RR, 19.8 [95% CI, 14.0 to 28.0]). CONCLUSIONS AND RELEVANCE: Among older patients with CKD who were newly prescribed baclofen, the 30-day incidence of encephalopathy was increased among those prescribed higher doses compared with lower doses. If verified, these risks should be balanced against the benefits of baclofen use.
ABSTRACT
AIMS: Data available on the fetal safety of trimethoprim-sulfamethoxazole (TMP-SMX) exposure during pregnancy remains scarce and inconclusive. A previous study assessing the link between TMP-SMX exposure during pregnancy and the risk of spontaneous abortion (SA) did not control for protopathic bias and indication bias. METHODS: We conducted a nested control study (n = 77 429 pregnancies including 7039 cases of SA and 70 390 controls) within the Quebec Pregnancy Cohort. For each case of SA, we selected 10 controls at the index date that were matched on gestational age and year of pregnancy. TMP-SMX exposure was defined as either having filled at least one prescription between the first day of gestation (1DG) and the index date, or as having filled a prescription before pregnancy but with a duration overlapping the 1DG (102 pregnancies exposed to TMP-SMX, including 25 cases of SA and 77 controls). RESULTS: Adjusting for potential confounders, TMP-SMX exposure was associated with an increased risk of SA (AOR 2.94, 95% C 1.89-4.57, 25 exposed cases). Similar results were found after controlling for indication bias and protopathic bias. CONCLUSION: Given that this drug is widely use in HIV patients to prevent opportunistic infections and malaria, there is an urgent need to identify potential data sources in Africa for analysis of early pregnancy exposure to TMP-SMX.
Subject(s)
Abortion, Spontaneous/chemically induced , Anti-Bacterial Agents/adverse effects , Pregnancy Complications, Infectious/drug therapy , Sulfadoxine/adverse effects , Trimethoprim/adverse effects , Adolescent , Adult , Anti-Bacterial Agents/administration & dosage , Case-Control Studies , Drug Combinations , Female , Gestational Age , Humans , Middle Aged , Pregnancy , Pregnancy Complications, Infectious/diagnosis , Pregnancy Complications, Infectious/microbiology , Quebec , Risk Assessment , Risk Factors , Sulfadoxine/administration & dosage , Treatment Outcome , Trimethoprim/administration & dosage , Young AdultABSTRACT
AIMS: Few studies have investigated the link between individual antibiotics and major congenital malformations (MCMs) including specific malformations owing to small sample size. We aimed to quantify the association between exposure to gestational antibiotic and the risk of MCMs. METHODS: Using the Quebec pregnancy cohort (1998-2008), we included a total of 139 938 liveborn singleton alive whose mothers were covered by the "Régie de l'assurance maladie du Québec" drug plan for at least 12 months before and during pregnancy. Antibiotic exposure was assessed in the first trimester and MCMs were identified within the first year of life. RESULTS: After adjusting for potential confounders, clindamycin exposure was associated with an increased risk of MCMs (aOR 1.34, 95% CI 1.02-1.77, 60 exposed cases), musculoskeletal system malformations (aOR 1.67, 95% CI 1.12-2.48, 29 exposed cases) and ventricular/atrial septal defect (aOR 1.81, 95% CI 1.04-3.16, 13 exposed cases). Doxycycline exposure increased the risk of circulatory system malformation, cardiac malformations and ventricular/atrial septal defect (aOR 2.38, 95% CI 1.21-4.67, 9 exposed cases; aOR 2.46, 95% CI 1.21-4.99, 8 exposed cases; aOR 3.19, 95% CI 1.57-6.48, 8 exposed cases, respectively). Additional associations were seen with quinolone (1 defect), moxifloxacin (1 defect), ofloxacin (1 defect), macrolide (1 defect), erythromycin (1 defect) and phenoxymethylpenicillin (1 defect). No link was observed with amoxicillin, cephalosporins and nitrofurantoin. Similar results were found when penicillins were used as the comparator group. CONCLUSIONS: Clindamycin, doxycycline, quinolones, macrolides and phenoxymethylpenicillin in utero exposure were linked to organ-specific malformations. Amoxicillin, cephalosporins and nitrofurantoin were not associated with MCMs.
Subject(s)
Abnormalities, Drug-Induced/epidemiology , Anti-Bacterial Agents/adverse effects , Pharmacoepidemiology/statistics & numerical data , Pregnancy Trimester, First/drug effects , Abnormalities, Drug-Induced/etiology , Adult , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Pregnancy , Quebec/epidemiology , Risk Factors , Young AdultABSTRACT
BACKGROUND: Although antibiotics are widely used during pregnancy, evidence regarding their fetal safety remains limited. Our aim was to quantify the association between antibiotic exposure during pregnancy and risk of spontaneous abortion. METHODS: We conducted a nested case-control study within the Quebec Pregnancy Cohort (1998-2009). We excluded planned abortions and pregnancies exposed to fetotoxic drugs. Spontaneous abortion was defined as having a diagnosis or procedure related to spontaneous abortion before the 20th week of pregnancy. The index date was defined as the calendar date of the spontaneous abortion. Ten controls per case were randomly selected and matched by gestational age and year of pregnancy. Use of antibiotics was defined by filled prescriptions between the first day of gestation and the index date and was compared with (a) non-exposure and (b) exposure to penicillins or cephalosporins. We studied type of antibiotics separately using the same comparator groups. RESULTS: After adjustment for potential confounders, use of azithromycin (adjusted odds ratio [OR] 1.65, 95% confidence interval [CI] 1.34-2.02; 110 exposed cases), clarithromycin (adjusted OR 2.35, 95% CI 1.90-2.91; 111 exposed cases), metronidazole (adjusted OR 1.70, 95% CI 1.27-2.26; 53 exposed cases), sulfonamides (adjusted OR 2.01, 95% CI 1.36-2.97; 30 exposed cases), tetracyclines (adjusted OR 2.59, 95% CI 1.97-3.41; 67 exposed cases) and quinolones (adjusted OR 2.72, 95% CI 2.27-3.27; 160 exposed cases) was associated with an increased risk of spontaneous abortion. Similar results were found when we used penicillins or cephalosporins as the comparator group. INTERPRETATION: After adjustment for potential confounders, use of macro-lides (excluding erythromycin), quinolones, tetracyclines, sulfonamides and metronidazole during early pregnancy was associated with an increased risk of spontaneous abortion. Our findings may be of use to policy-makers to update guidelines for the treatment of infections during pregnancy.
Subject(s)
Abortion, Spontaneous/epidemiology , Anti-Bacterial Agents/adverse effects , Maternal Exposure/adverse effects , Pregnancy Complications, Infectious/drug therapy , Abortion, Spontaneous/chemically induced , Adolescent , Adult , Case-Control Studies , Cohort Studies , Databases, Factual , Female , Gestational Age , Humans , Macrolides/adverse effects , Metronidazole/adverse effects , Odds Ratio , Pregnancy , Quebec , Quinolones/adverse effects , Risk Assessment , Risk Factors , Sulfonamides/adverse effects , Tetracyclines/adverse effects , Young AdultSubject(s)
Accidental Falls/prevention & control , Baclofen/therapeutic use , Fractures, Bone/prevention & control , Accidental Falls/statistics & numerical data , Aged , Fractures, Bone/epidemiology , Fractures, Bone/etiology , GABA-B Receptor Agonists/therapeutic use , Global Health , Humans , Incidence , Renal Insufficiency, Chronic/complications , Risk FactorsABSTRACT
AIM: To describe biases in antimalarial randomized controlled trials (RCTs) during pregnancy and their influence on antimalarial drug efficacy to reduce the risk of low birth weight (LBW). METHODS: RCT characteristics and results were retrieved from a previous systematic review on the efficacy of antimalarials. The Cochrane risk of bias assessment was used to investigate source of biases in each RCT. The quality of RCT reporting published after the introduction of the CONSORT statement in medical literature in 1996 were compared to those published before 1996. A meta-regression analysis was performed to examine the impact of bias on the efficacy of antimalarials to reduce LBW after controlling for the time period prior to 1996. RESULTS: Twenty out of 25 RCTs (80%) had a high risk of bias. The proportion of RCTs having a low risk of bias was higher in manuscripts published after the introduction of CONSORT compared to those published before 1996 for sequence generation (P = 0.04) and allocation concealment (P = 0.04). Heterogeneity between RCTs was associated with an overestimation of the efficacy of antimalarial drugs in reducing LBW in RCTs with inadequate methods for randomization, allocation concealment or not being free of other bias. CONCLUSION: Antimalarial RCTs during pregnancy are poorly reported but may be improved by using the CONSORT statement. After taking into account the time period before 1996, we found that biases had an impact on the efficacy of antimalarials to reduce the risk of LBW.
Subject(s)
Antimalarials/therapeutic use , Infant, Low Birth Weight , Randomized Controlled Trials as Topic/standards , Bias , Female , Humans , Pregnancy , Research DesignABSTRACT
AIMS: The aim of this study was to perform an up-to-date meta-analysis on the risk of cardiac malformations associated with gestational exposure to paroxetine, taking into account indication, study design and reference category. METHOD: A systematic review of studies published between 1966 and November 2015 was conducted using embase and MEDLINE. Studies reporting major malformations with first trimester exposure to paroxetine were included. Potentially relevant articles were assessed and relevant data extracted to calculate risk estimates. Outcomes included any major malformations and major cardiac malformations. Pooled odds ratios and 95% confidence intervals were calculated using random-effects models. RESULTS: Twenty-three studies were included. Compared with non-exposure to paroxetine, first trimester use of paroxetine was associated with an increased risk of any major congenital malformations combined (pooled OR 1.23, 95% CI 1.10, 1.38; n = 15 studies), major cardiac malformations (pooled OR 1.28, 95% CI 1.11, 1.47; n = 18 studies), specifically bulbus cordis anomalies and anomalies of cardiac septal closure (pooled OR 1.42, 95% CI 1.07, 1.89; n = 8 studies), atrial septal defects (pooled OR 2.38, 95% CI 1.14, 4.97; n = 4 studies) and right ventricular outflow track defect (pooled OR 2.29, 95% CI 1.06, 4.93; n = 4 studies). Although the estimates varied depending on the comparator group, study design and malformation detection period, a trend towards increased risk was observed. CONCLUSIONS: Paroxetine use during the first trimester of pregnancy is associated with an increased risk of any major congenital malformations and cardiac malformations. The increase in risk is not dependent on the study method or population.
Subject(s)
Abnormalities, Drug-Induced/etiology , Heart Defects, Congenital/chemically induced , Maternal Exposure/adverse effects , Paroxetine/adverse effects , Selective Serotonin Reuptake Inhibitors/adverse effects , Female , Humans , Paroxetine/administration & dosage , Paroxetine/therapeutic use , Pregnancy , Pregnancy Trimester, First , Risk Assessment , Selective Serotonin Reuptake Inhibitors/administration & dosage , Selective Serotonin Reuptake Inhibitors/therapeutic useABSTRACT
Background: In some jurisdictions, individuals become eligible or recommended for referral for different types of kidney care using criteria based on their estimated glomerular filtration rate (eGFR). Historically, GFR was estimated with an equation developed in 2009, which included a Black race term. An updated, race-free equation was developed in 2021. It is unclear how adoption of the 2021 equation will influence the number of individuals meeting referral criteria to receive different types of kidney care. Objective: To develop population-based estimates on how the number of individuals meeting the eGFR-based referral criteria to receive three different types of kidney care (nephrologist consultation, care in a multi-care specialty clinic, kidney transplant evaluation) changes when the 2021 versus 2009 equation is used to calculate eGFR. Design: Population-based, cross-sectional study. Setting: Ontario, Canada's most populous province with 14.2 million residents as of 2021. Less than 5% of Ontario's residents self-identify as being of Black race. Patients: Adults with at least one outpatient serum creatinine measurement in the 2 years prior to December 31, 2021. Measurements: Referral criteria to 3 different types of kidney care: nephrologist consultation, multi-care specialty clinic, and evaluation for a kidney transplant. The eGFR thresholds used to define referral eligibility or recommendation for these kidney health services were based on guidelines from Ontario's provincial renal agency. Methods: The number of individuals meeting referral criteria for the 3 different healthcare services was compared between the 2009 and 2021 equations, restricted to individuals not yet receiving that level of care. As individual-level race data were not available, estimates were repeated, randomly assigning a Black race status to 1%, 5%, and 10% of the population. Results: We had an outpatient serum creatinine measurement available for 1 048 110 adults. Using the 2009 equation, 37 345 individuals met the criteria to be referred to a nephrologist, 10 019 met the criteria to receive care in a multi-care specialty clinic, and 10 178 met the criteria to be referred for kidney transplant evaluation. Corresponding numbers with the 2021 equation (and the percent relative to the 2009 equation) were 26 645 (71.3%), 9009 (89.9%), and 8615 (84.6%) individuals, respectively. These numbers were largely unchanged when Black race was assumed in up to 10% of the population. Limitations: Referral criteria based solely on urine albumin-to-creatinine ratio were not assessed. Self-reported race data were unavailable. Conclusions: For healthcare planning, in regions where a minority of the population is Black, a substantial number of individuals may no longer meet referral criteria for different types of kidney healthcare following adoption of the new 2021 eGFR equation.
Contexte: Dans certaines régions, les individus sont dirigés vers différents types de soins rénaux, ou y deviennent admissibles, selon des critères fondés sur le débit de filtration glomérulaire estimé (DFGe). Historiquement, le DFG était estimé avec une équation développée en 2009 comportant un terme qui tenait compte du fait d'être une personne de race noire. Une nouvelle équation sans mention de la race a été développée en 2021. Il est difficile de savoir comment l'adoption de l'équation de 2021 influencera le nombre de personnes qui répondront aux critères pour recevoir divers types de soins rénaux. Objectifs: Établir des estimations populationnelles de la variation du nombre de personnes qui répondent aux critères d'orientation fondés sur le DFGe pour recevoir trois différents types de soins rénaux (consultation avec un néphrologue, soins dans une clinique multidisciplinaire spécialisée, évaluation pour une transplantation rénale) selon que le DFGe est calculé avec l'équation de 2021 ou de 2009. Conception: Étude populationnelle transversale rétrospective. Cadre: L'Ontario, la province la plus peuplée du Canada avec 14,2 millions d'habitants en 2021. Moins de 5 % des résidents de l'Ontario s'identifient comme étant de race noire. Sujets: Des adultes avec au moins une mesure de la créatinine sérique en ambulatoire au cours des deux ans précédant le 31 décembre 2021. Mesures: Les critères d'orientation vers trois différents types de soins rénaux : consultation avec un néphrologue, soins en clinique multidisciplinaire spécialisée et évaluation pour une transplantation rénale. Les seuils de DFGe utilisés pour définir l'admissibilité à ou l'orientation vers ces services de santé rénale étaient fondés sur les lignes directrices de l'agence provinciale de soins rénaux de l'Ontario. Méthodologie: On a comparé les nombres d'individus répondant aux critères d'orientation pour les trois différents services de santé, calculés avec les équations de 2009 et de 2021, en se limitant aux personnes qui ne recevaient pas encore de tels soins. Les données individuelles sur la race n'étant pas disponibles, les estimations ont été répétées en attribuant aléatoirement un statut de race noire à 1 %, à 5 % et à 10 % de la population étudiée. Résultats: Une mesure de la créatinine sérique en ambulatoire était disponible pour un total de 1 048 110 adultes. Avec l'équation de 2009, 37 345 personnes répondaient aux critères pour être dirigées vers un néphrologue, 10 019 répondaient aux critères pour recevoir des soins dans une clinique multidisciplinaire spécialisée et 10 178 répondaient aux critères pour être évaluées pour une transplantation rénale. Avec l'équation de 2021, ces mêmes nombres de personnes (pourcentage par rapport à l'équation de 2009) étaient respectivement 26 645 (71,3 %), 9 009 (89,9 %) et 8 615 (84,6 %). Des chiffres qui sont demeurés majoritairement inchangés même en assumant une proportion de jusqu'à 10 % de personnes de race noire dans la population. Limites: Les critères d'orientation fondés uniquement sur le rapport albumine/créatinine urinaire n'ont pas été évalués. Les données autodéclarées sur la race n'étaient pas disponibles. Conclusion: Pour la planification des soins de santé, dans les régions où une minorité de la population est noire, un nombre important de personnes pourraient ne plus répondre aux critères d'orientation vers différents types de soins rénaux après l'adoption de l'équation de 2021 pour le calcul du DFGe.
ABSTRACT
Background: Safety issues are detected in about one third of prescription drugs in the years following regulatory agency approval. Older adults, especially those with chronic kidney disease, are at particular risk of adverse reactions to prescription drugs. This protocol describes a new approach that may identify credible drug-safety signals more efficiently using administrative health care data. Objective: To use high-throughput computing and automation to conduct 700+ drug-safety cohort studies in older adults in Ontario, Canada. Each study will compare 74 acute (30-day) outcomes in patients who start a new prescription drug (new users) to a group of nonusers with similar baseline health characteristics. Risks will be assessed within strata of baseline kidney function. Design and setting: The studies will be population-based, new-user cohort studies conducted using linked administrative health care databases in Ontario, Canada (January 1, 2008, to March 1, 2020). The source population for these studies will be residents of Ontario aged 66 years or older who filled at least one outpatient prescription through the Ontario Drug Benefit (ODB) program during the study period (all residents have universal health care, and those aged 65+ have universal prescription drug coverage through the ODB). Patients: We identified 3.2 million older adults in the source population during the study period and built 700+ initial medication cohorts, each containing mutually exclusive groups of new users and nonusers. Nonusers were randomly assigned cohort entry dates that followed the same distribution of prescription start dates as new users. Eligibility criteria included a baseline estimated glomerular filtration rate (eGFR) measurement within 12 months before the cohort entry date (median time was 71 days before cohort entry in the new user group), no prior receipt of maintenance dialysis or a kidney transplant, and no prior prescriptions for drugs in the same subclass as the study drug. New users and nonusers will be balanced on ~400 baseline health characteristics using inverse probability of treatment weighting on propensity scores within 3 strata of baseline eGFR: ≥60, 45 to <60, <45 mL/min per 1.73 m2. Outcomes: We will compare new user and nonuser groups on 74 clinically relevant outcomes (17 composites and 57 individual outcomes) in the 30 days after cohort entry. We used a prespecified approach to identify these 74 outcomes. Statistical analysis plan: In each cohort, we will obtain eGFR-stratum-specific weighted risk ratios and risk differences using modified Poisson regression and binomial regression, respectively. Additive and multiplicative interaction by eGFR category will be examined. Drug-outcome associations that meet prespecified criteria (identified signals) will be further examined in additional analyses (including survival, negative-control exposure, and E-value analyses) and visualizations. Results: The initial medication cohorts had a median of 6120 new users per cohort (interquartile range: 1469-38 839) and a median of 1 088 301 nonusers (interquartile range: 751 697-1 267 009). Medications with the largest number of new users were amoxicillin trihydrate (n = 1 000 032), cephalexin (n = 571 566), prescription acetaminophen (n = 571 563), and ciprofloxacin (n = 504,374); 19% to 29% of new users in these cohorts had an eGFR <60 mL/min per 1.73 m2. Limitations: Despite our use of robust techniques to balance baseline indicators and to control for confounding by indication, residual confounding will remain a possibility. Only acute (30-day) outcomes will be examined. Our data sources do not include nonprescription (over-the-counter) drugs or drugs prescribed in hospitals and do not include outpatient prescription drug use in children or adults <65 years. Conclusion: This accelerated approach to conducting postmarket drug-safety studies has the potential to more efficiently detect drug-safety signals in a vulnerable population. The results of this protocol may ultimately help improve medication safety.
Contexte: Des problèmes d'innocuité sont détectés dans environ un tiers des médicaments d'ordonnance au cours des années qui suivent leur approbation par l'organisme de réglementation. Les personnes âgées, en particulier celles qui sont atteintes d'insuffisance rénale chronique, sont particulièrement exposées aux effets indésirables des médicaments d'ordonnance. Ce protocole décrit une nouvelle approche qui, à partir des données administratives du système de santé, pourrait permettre d'identifier plus efficacement les signaux crédibles sur la sécurité des médicaments. Objectif: Utiliser l'informatique à haut débit et l'automatisation pour mener plus de 700 études de cohorte sur l'innocuité des médicaments chez les adultes âgés résidant en Ontario (Canada). Chaque étude comparera 74 résultats aigus (30 jours) chez des patients qui commencent un nouveau médicament sur ordonnance (nouveaux utilisateurs) à ceux d'un groupe de non-utilisateurs avec des caractéristiques de santé initiales similaires. Les risques seront évalués par strates de la fonction rénale initiale. Cadre et type d'étude: Études populationnelles de cohortes de nouveaux utilisateurs de médicaments menées à l'aide des bases de données administratives couplées du système de santé ontarien (Canada). Période étudiée: du 1er janvier 2008 au 1er mars 2020. Population source: les Ontariens de 66 ans ou plus ayant rempli au moins une ordonnance pour patient non hospitalisé par l'entremise du Program de médicaments de l'Ontario (PMO) pendant la période de l'étude (tous les résidents de la province bénéficient d'un système de soins de santé universel; les personnes âgées de 65 ans et plus bénéficient d'une couverture universelle des médicaments d'ordonnance par l'intermédiaire du PMO). Sujets: Nous avons identifié 3,2 millions d'adultes âgés dans la population source au cours de la période d'étude et constitué plus de 700 cohortes de médicaments, chacune contenant des groupes mutuellement exclusifs de nouveaux utilisateurs et de non-utilisateurs. Les non-utilisateurs se sont vu attribuer au hasard des dates d'entrée dans la cohorte qui suivaient les dates de début d'ordonnance des nouveaux utilisateurs. Les critères d'admissibilité étaient d'avoir une mesure initiale du débit de filtration glomérulaire estimé [DFGe] dans les 12 mois précédant la date d'entrée dans la cohorte (dans le groupe des nouveaux utilisateurs, le délai médian était de 71 jours avant l'entrée dans la cohorte), ne pas suivre de dialyze chronique, ne pas avoir eu de greffe rénale et n'avoir jamais eu de prescription d'un médicament de la même sous-classe que le médicament à l'étude. Les nouveaux utilisateurs et les non-utilisateurs seront jumelés selon environ 400 caractéristiques de santé initiales à l'aide de la probabilité inverse de traitement pondérée selon les scores de propension dans les trois strates de mesure du DFGe initial: ≥60 ml/min/1,73 m2; 45 à <60 ml/min/1,73 m2 et <45 ml/min/1,73 m2. Résultats: Nous comparerons les groupes de nouveaux utilisateurs et de non-utilisateurs selon 74 critères de jugement cliniquement pertinents (17 critères composites et 57 critères individuels) pendant les 30 jours suivant l'entrée dans la cohorte. Une approche prédéfinie a permis de déterminer ces 74 résultats. Plan d'analyze statistique: Dans chaque cohorte, nous calculerons les différences de risque (par régression de Poisson) et les rapports de risque (par régression binomiale) pondérés pour chaque strate de DFGe. Les interactions additives et multiplicatives par catégorie de DFGe seront examinées. Les associations médicaments-résultats répondant à des critères prédéfinis (signaux identifiés) seront examinées plus avant dans des analyses supplémentaires (survie, exposition à des témoins négatifs, analyses de la valeur E, etc.) et des visualizations. Résultats: Dans les cohortes initiales de médicaments, les médianes sont de 6 120 nouveaux utilisateurs (intervalle interquartile de 1 469 à 38 839) et de 1 088 301 non-utilisateurs (intervalle interquartile de 751 697 à 1 267 009). Les médicaments comptant le plus grand nombre de nouveaux utilisateurs sont le trihydrate d'amoxicilline (n = 1 000 032), la céfalexine (n = 571 566), l'acétaminophène sur ordonnance (n = 571 563) et la ciprofloxacine (n = 504 374). De 19 à 29 % des nouveaux utilisateurs dans ces cohortes présentaient un DFGe < 60 ml/min/1.73 m2. Limites: Malgré l'utilization de techniques robustes pour équilibrer les indicateurs de base et pour contrôler le risque de confusion par indication, il pourrait subsister des facteurs de confusion résiduels. Seuls les résultats aigus (30 jours) seront examinés. Nos sources de données ne comprennent pas les médicaments sans ordonnance (en vente libre) ni les médicaments prescrits dans les hôpitaux, et n'incluent pas l'utilization de médicaments sur ordonnance en ambulatoire chez les enfants ou les adultes de moins de 65 ans. Conclusion: Cette approche accélérée pour la réalisation d'études d'innocuité des médicaments après leur mise en marché a le potentiel de détecter efficacement les effets indésirables de ces médicaments dans une population vulnérable. Les résultats de ce protocole serviront à améliorer l'innocuité des médicaments.
ABSTRACT
IMPORTANCE: Trimethoprim-sulfamethoxazole (TMP-SMX) may increase digoxin concentration, a medication with a narrow therapeutic index. Small changes in digoxin concentration could predispose individuals to the risk of toxicity. OBJECTIVE: To characterize the risk of digoxin toxicity in older adults taking digoxin following co-prescription of TMP-SMX compared with co-prescription of amoxicillin. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective population-based cohort study in Ontario, Canada (2002-2020) using linked health care data. Participants comprised 47,961 older adults taking digoxin (58% women; median age 80 years [interquartile range 74-86]) who were newly treated with TMP-SMX (n = 10,273) compared with those newly treated with amoxicillin (n = 37,688). EXPOSURE: Co-prescription of TMP-SMX versus amoxicillin in older adults concurrently taking digoxin. MAIN OUTCOME AND MEASURE: The primary outcome was a hospital encounter (i.e., hospital admission or emergency department visit) with digoxin toxicity within 30 days of the antibiotic prescription. Inverse probability of treatment weighting on the propensity score was used to balance comparison groups on indicators of baseline health. Weighted risk ratios (RR) were obtained using modified Poisson regression and weighted risk differences (RD) using binomial regression. The number needed to harm (NNH) was calculated as 1/RD. RESULTS: A hospital encounter with digoxin toxicity occurred in 49/10,273 (0.48%) patients treated with TMP-SMX versus 32/37,688 (0.08%) in those treated with amoxicillin (weighted RR, 5.71 [95% confidence interval (CI), 3.19 to 10.24]; weighted RD, 0.39% [95% CI, 0.25% to 0.53%]; NNH 256 [95% CI, 233 to 400]). CONCLUSION AND RELEVANCE: In older adults taking digoxin, the 30-day risk of a hospital encounter with digoxin toxicity was nearly 6 times higher in those co-prescribed TMP-SMX versus amoxicillin, although the absolute risk difference was low (0.4%). Physicians should prescribe an alternative antibiotic when clinically appropriate. If TMP-SMX must be co-prescribed with digoxin (if the benefit is believed to outweigh the risk), digoxin should be dose-reduced on an individual basis.
Subject(s)
Amoxicillin , Anti-Bacterial Agents , Digoxin , Trimethoprim, Sulfamethoxazole Drug Combination , Humans , Digoxin/adverse effects , Digoxin/administration & dosage , Aged , Female , Male , Aged, 80 and over , Retrospective Studies , Amoxicillin/adverse effects , Amoxicillin/administration & dosage , Trimethoprim, Sulfamethoxazole Drug Combination/adverse effects , Trimethoprim, Sulfamethoxazole Drug Combination/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/administration & dosage , Cohort Studies , Drug Interactions , Ontario/epidemiology , Cardiotonic Agents/adverse effects , Cardiotonic Agents/therapeutic use , Cardiotonic Agents/administration & dosageABSTRACT
Importance: Low-dose methotrexate is used to treat rheumatoid arthritis and psoriasis. Due to its kidney elimination, better evidence is needed to inform its safety in adults with chronic kidney disease (CKD). Objectives: To compare the 90-day risk of serious adverse events among adults with CKD who started low-dose methotrexate vs those who started hydroxychloroquine and to compare the risk of serious adverse events among adults with CKD starting 2 distinct doses of methotrexate vs those starting hydroxychloroquine. Design, Setting, and Participants: This retrospective, population-based, new-user cohort study was conducted in Ontario, Canada (2008-2021) using linked administrative health care data. Adults aged 66 years or older with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2 but not receiving dialysis) who started low-dose methotrexate (n = 2309) were matched 1:1 with those who started hydroxychloroquine. Exposure: Low-dose methotrexate (5-35 mg/wk) vs hydroxychloroquine (200-400 mg/d). Main Outcome and Measure: The primary outcome was a composite of serious adverse events: a hospital visit with myelosuppression, sepsis, pneumotoxic effects, or hepatotoxic effects within 90 days of starting the study drug. Prespecified subgroup analyses were conducted by eGFR category. Propensity score matching was used to balance comparison groups on indicators of baseline health. Risk ratios (RRs) were obtained using modified Poisson regression, and risk differences (RDs) using binomial regression. Results: In a propensity score-matched cohort of 4618 adults with CKD (3192 [69%] women; median [IQR] age, 76 [71-82] years), the primary outcome was higher in patients who started low-dose methotrexate vs those who started hydroxychloroquine (82 of 2309 [3.55%] vs 40 of 2309 [1.73%]; RR, 2.05 (95% CI, 1.42-2.96); RD, 1.82% [95% CI, 0.91%-2.73%]). In subgroup analysis, the risks increased progressively at lower eGFR (eg, eGFR <45 mL/min/1.73 m2: RR, 2.79 [95% CI, 1.51-5.13]). In the secondary comparison with hydroxychloroquine, methotrexate users at 15 to 35 mg/wk had a higher risk of the primary outcome. Conclusions and Relevance: In this cohort of 4618 older patients with CKD, the 90-day risk of serious adverse events was higher among those who started low-dose methotrexate than those who started hydroxychloroquine. If verified, these risks should be balanced against the benefits of low-dose methotrexate use.