Second-Generation Antidepressants and Hyponatremia Risk: A Population-Based Cohort Study of Older Adults.

BACKGROUND: Hyponatremia may occur after initiation of a second-generation antidepressant drug. However, the magnitude of this risk among older adults in routine care is not well characterized. STUDY DESIGN: Retrospective, population-based, matched-cohort study. SETTING & PARTICIPANTS: In Ontario, Canada, 2003 to 2012, we compared older adults with a mood or anxiety disorder who were dispensed 1 of 9 second-generation antidepressant drugs with matched adults with comparable indicators of baseline health who were not dispensed an antidepressant drug (n=138,246 per group). A similar comparison was made in a subpopulation with available laboratory data (n=4,186 per group). PREDICTOR: Second-generation antidepressant prescription versus no antidepressant prescription. OUTCOMES: The primary outcome was hospitalization with hyponatremia. A secondary outcome was hospitalization with both hyponatremia and delirium. MEASUREMENTS: We assessed hospitalization with hyponatremia using a diagnosis code and, in the subpopulation, serum sodium values. We assessed hospitalization with hyponatremia and delirium using a combination of diagnosis codes. RESULTS: Second-generation antidepressant use versus nonuse was associated with higher 30-day risk for hospitalization with hyponatremia (450/138,246 [0.33%] vs 84/138,246 [0.06%]; relative risk [RR], 5.46 [95% CI, 4.32-6.91]). This association was consistent in the subpopulation with serum sodium values (73/4,186 [1.74%] vs 18/4,186 [0.43%]; RR, 4.23 [95% CI, 2.50-7.19]; absolute risk increase, 1.31% [95% CI, 0.87%-1.75%]). Second-generation antidepressant use versus nonuse was also associated with higher 30-day risk for hospitalization with both hyponatremia and delirium (28/138,246 [0.02%] vs 7/138,246 [0.005%]; RR, 4.00 [95% CI, 1.75-9.16]). LIMITATIONS: Measures of serum sodium could be ascertained in only a subpopulation. CONCLUSIONS: Use of a second-generation antidepressant in routine care by older adults is associated with an approximate 5-fold increase in 30-day risk for hospitalization with hyponatremia compared to nonuse. However, the absolute increase in 30-day incidence is low.

Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies.

OBJECTIVE: To examine the 30-day risk of hospitalization with hyponatremia associated with carbamazepine, valproic acid (V), phenytoin (P), or topiramate (T) use compared to nonuse in the outpatient setting among older adults. METHODS: We conducted two population-based, retrospective cohort studies in Ontario, Canada, between 2003 and 2015 using administrative health care databases of older adults. The first study compared carbamazepine users to a propensity-score matched group of antiepileptic drug nonusers, whereas the second compared V-P-T users to a propensity-score matched group of antiepileptic nonusers. The primary outcome was hospitalization with hyponatremia within 30 days of an antiepileptic prescription. RESULTS: The baseline characteristics between matched groups were similar in both cohorts. Carbamazepine use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (82/21,191 [0.39%] versus 30/63,573 [0.05%]; relative risk [RR] 8.20, 95% confidence interval [CI] 5.40-12.46). Similarly, V-P-T use versus nonuse was associated with a higher 30-day risk of hospitalization with hyponatremia (34/20,155 [0.17%] versus 26/40,310 [0.06%]; RR 2.62, 95% CI 1.57-4.36). SIGNIFICANCE: Older adults prescribed carbamazepine and V-P-T have a higher risk of being hospitalized with hyponatremia compared to other adults with similar indicators of baseline health who were not prescribed antiepileptic drugs. Physicians should be mindful of this risk; when a patient presents to a hospital with symptomatic hyponatremia these drugs should be considered as potential causes.

Atypical antipsychotic medications and hyponatremia in older adults: a population-based cohort study.

BACKGROUND: A number of case reports have suggested a possible association between atypical antipsychotic medications and hyponatremia. Currently, there are no reliable estimates of hyponatremia risk from atypical antipsychotic drugs. OBJECTIVE: The objective of this study was to examine the 30-day risk of hospitalization with hyponatremia in older adults dispensed an atypical antipsychotic drug relative to no antipsychotic use. DESIGN: The design of this study was a retrospective, population-based cohort study. SETTING: The setting of this study was in Ontario, Canada, from 2003 to 2012. PATIENTS: Adults 65 years or older with an identified psychiatric condition who were newly dispensed risperidone, olanzapine, or quetiapine in the community setting compared to adults with similar indicators of baseline health who were not dispensed such a prescription. MEASUREMENTS: The primary outcome was the 30-day risk of hospitalization with hyponatremia. The tracer outcome (an outcome that is not expected to be influenced by the study drugs) was the 30-day risk of hospitalization with bowel obstruction. These outcomes were assessed using hospital diagnosis codes. METHODS: Using health administrative data, we applied a propensity score technique to match antipsychotic users 1:1 to non-users of antipsychotic drugs (58,008 patients in each group). We used conditional logistic regression to compare outcomes among the matched users and non-users. RESULTS: A total of 104 baseline characteristics were well-balanced between the two matched groups. Atypical antipsychotic use compared to non-use was associated with an increased risk of hospitalization with hyponatremia within 30 days (86/58,008 (0.15 %) versus 53/58,008 (0.09 %); relative risk 1.62 (95 % confidence interval (CI) 1.15 to 2.29); absolute risk increase 0.06 % (95 % CI 0.02 to 0.10)). The limited number of events precluded some additional analyses to confirm if the association was robust. Atypical antipsychotic use compared to non-use was not associated with hospitalization with bowel obstruction within 30 days (55/58,008 (0.09 %) versus 44/58,008 (0.08 %); relative risk 1.25 (95 % CI 0.84 to 1.86)). LIMITATIONS: We could only study older adults within our data sources. CONCLUSIONS: In this study, the use of an atypical antipsychotic was associated with a modest but statistically significant increase in the 30-day risk of a hospitalization with hyponatremia. The association was less pronounced than that described with other psychotropic drugs.

MISE EN CONTEXTE: De nombreux exposés de cas font état d'une possible corrélation entre la prise de médicaments antipsychotiques atypiques et l'hyponatrémie. Or actuellement, il n'existe aucune évaluation fiable qui vienne corroborer cette association. OBJECTIFS DE L'ÉTUDE: L'étude visait à évaluer le risque, sur une période de 30 jours, d'hospitalisation pour cause d'hyponatrémie chez des patients adultes sous ordonnance d'un antipsychotique atypique, par rapport à un groupe de patients qui n'en consommaient pas. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude de cohorte, représentative de la population et rétrospective, qui s'est tenue en Ontario, au Canada, de 2003 à 2012. PARTICIPANTS: L'étude a porté sur un groupe d'adultes de plus de 65 ans avec un trouble psychiatrique établi et qui débutaient un traitement par risperidone, olanzapine ou quétiapine en milieu communautaire. Ils ont été comparés à un groupe d'individus ayant des indicateurs de santé initiaux équivalents, mais ne prenant pas d'antipsychotiques atypiques. MESURES: Le critère de jugement principal était le risque d'hospitalisation pour cause d'hyponatrémie à l'intérieur d'une période de 30 jours. À titre de traceur (événement sur lequel le médicament administré ne devait avoir aucune influence), on a utilisé le risque d'hospitalisation pour occlusion intestinale. Ces résultats ont été évalués en utilisant les codes de diagnostic des hôpitaux. MÉTHODOLOGIE: À l'aide des données administratives de la santé, la méthode statistique de l'appariement par scores de propension a été utilisée pour jumeler chaque patient sous médication antipsychotique avec un patient n'en consommant pas (58,008 patients dans chacun des groupes). On a eu recours à une régression logistique conditionnelle pour comparer les résultats observés au sein des couples de patients ainsi jumelés. RÉSULTATS: On a identifié 104 caractéristiques initiales bien balancées entre les deux groupes de participants. La prise d'antipsychotiques atypiques a été associée à un risque accru d'hospitalisation pour cause d'hyponatrémie à l'intérieur d'une période de 30 jours, lorsque comparée à la non-consommation (86/58 008 [0,15 %] contre 53/58 008 [0,09 %] ; risque relatif de 1,62 [95 % intervalle de confiance [IC] entre 1,15 et 2,29] ; augmentation absolue du risque à 0,06 % [95 % IC entre 0,02 et 0,10]. Le nombre limité d'événements empêche quelques analyses complémentaires qui permettraient de confirmer la robustesse de l'association entre l'hospitalisation pour hyponatrémie et la médication. Par ailleurs, la prise d'antipsychotiques atypiques n'a pas été associée à une hospitalisation pour obstruction intestinale pour la même période de 30 jours lorsque comparée au groupe de patients n'en consommant pas [55/58 008 [0,09 %] contre 44/58 008 [0,08 %] ; risque relatif de 1,25 [95 % IC entre 0,84 et 1,86]]. LIMITES DE L'ÉTUDE: Les sources de données consultées n'ont permis que d'étudier les cas de patients adultes et âgés. CONCLUSIONS: Dans la présente étude, la consommation d'un médicament antipsychotique atypique a été associée à une légère, quoique significative, augmentation du risque d'être hospitalisé pour cause d'hyponatrémie, à l'intérieur d'une période de 30 jours. Toutefois, l'association s'est avérée moins marquée que pour d'autres médicaments psychotropes.

Kidney function and the use of nitrofurantoin to treat urinary tract infections in older women.

BACKGROUND: The antibiotic nitrofurantoin is commonly used to treat uncomplicated urinary tract infections. However, when this drug is used by patients with reduced kidney function, its urine concentration may be subtherapeutic. METHODS: We conducted a population-based study of older women (mean age 79 years) in Ontario, Canada, whose estimated glomerular filtration rate was relatively low (median 38 mL/min per 1.73 m(2)) and for whom 1 of 4 antibiotics had been prescribed for urinary tract infection: nitrofurantoin, ciprofloxacin, norfloxacin or trimethoprim-sulfamethoxazole. We assessed 2 measures of treatment failure in the subsequent 14 days: receipt of a second antibiotic indicated for urinary tract infection and hospital encounter (emergency department visit or hospital admission) with a urinary tract infection. We repeated the analysis for older women with relatively high estimated glomerular filtration rate (median 69 mL/min per 1.73 m(2)). RESULTS: The baseline characteristics of the 4 antibiotic groups were similar. Relative to nitrofurantoin, the other antibiotics (including ciprofloxacin) were associated with a lower rate of treatment failure among women with relatively low estimated glomerular filtration rate (for ciprofloxacin v. nitrofurantoin: second antibiotic prescription, 130/1989 [6.5%] v. 516/3739 [13.8%], odds ratio [OR] 0.44, 95% confidence interval [CI] 0.36-0.53; hospital encounter, 21/1989 [1.1%] v. 95/3739 [2.5%], OR 0.41, 95% CI 0.25-0.66). However, a similar risk of treatment failure with nitrofurantoin was also observed among women with relatively high estimated glomerular filtration rate. The results were consistent in multiple additional analyses. INTERPRETATION: In this study, the presence of mild or moderate reductions in estimated glomerular filtration rate did not justify avoidance of nitrofurantoin.

Risk of adverse events among older adults following co-prescription of clarithromycin and statins not metabolized by cytochrome P450 3A4.

BACKGROUND: The cytochrome P450 3A4 (CYP3A4) inhibitor clarithromycin may also inhibit liver-specific organic anion-transporting polypeptides (OATP1B1 and OATP1B3). We studied whether concurrent use of clarithromycin and a statin not metabolized by CYP3A4 was associated with an increased frequency of serious adverse events. METHODS: Using large health care databases, we studied a population-based cohort of older adults (mean age 74 years) who were taking a statin not metabolized by CYP3A4 (rosuvastatin [76% of prescriptions], pravastatin [21%] or fluvastatin [3%]) between 2002 and 2013 and were newly prescribed clarithromycin (n=51,523) or azithromycin (n=52,518), the latter an antibiotic that inhibits neither CYP3A4 nor OATP1B1 and OATP1B3. Outcomes were hospital admission with a diagnostic code for rhabdomyolysis, acute kidney injury or hyperkalemia, and all-cause mortality. All outcomes were assessed within 30 days after co-prescription. RESULTS: Compared with the control group, patients co-prescribed clarithromycin and a statin not metabolized by CYP3A4 were at increased risk of hospital admission with acute kidney injury (adjusted relative risk [RR] 1.65, 95% confidence interval [CI] 1.31 to 2.09), admission with hyperkalemia (adjusted RR 2.17, 95% CI 1.22 to 3.86) and all-cause mortality (adjusted RR 1.43, 95% CI 1.15 to 1.76). The adjusted RR for admission with rhabdomyolysis was 2.27 (95% CI 0.86 to 5.96). The absolute increase in risk for each outcome was small and likely below 1%, even after we considered the insensitivity of some hospital database codes. INTERPRETATION: Among older adults taking a statin not metabolized by CYP3A4, co-prescription of clarithromycin versus azithromycin was associated with a modest but statistically significant increase in the 30-day absolute risk of adverse outcomes.

Atypical antipsychotic drugs and the risk for acute kidney injury and other adverse outcomes in older adults: a population-based cohort study.

BACKGROUND: Several adverse outcomes attributed to atypical antipsychotic drugs, specifically quetiapine, risperidone, and olanzapine, are known to cause acute kidney injury (AKI). Such outcomes include hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis. OBJECTIVE: To investigate the risk for AKI and other adverse outcomes associated with use of atypical antipsychotic drugs versus nonuse. DESIGN: Population-based cohort study. SETTING: Ontario, Canada, from 2003 to 2012. PATIENTS: Adults aged 65 years or older who received a new outpatient prescription for an oral atypical antipsychotic drug (n=97,777) matched 1:1 with those who did not receive such a prescription. MEASUREMENTS: The primary outcome was hospitalization with AKI (assessed by using a hospital diagnosis code and, in a subpopulation, serum creatinine levels) within 90 days of prescription for atypical antipsychotic drugs. RESULTS: Atypical antipsychotic drug use versus nonuse was associated with a higher risk for hospitalization with AKI (relative risk [RR], 1.73 [95% CI, 1.55 to 1.92]). This association was consistent when AKI was assessed in a subpopulation for which information on serum creatinine levels was available (5.46% vs. 3.34%; RR, 1.70 [CI, 1.22 to 2.38]; absolute risk increase, 2.12% [CI, 0.80% to 3.43%]). Drug use was also associated with hypotension (RR, 1.91 [CI, 1.60 to 2.28]), acute urinary retention (RR, 1.98 [CI, 1.63 to 2.40]), and all-cause mortality (RR, 2.39 [CI, 2.28 to 2.50]). LIMITATION: Only older adults were included in the study. CONCLUSION: Atypical antipsychotic drug use is associated with an increased risk for AKI and other adverse outcomes that may explain the observed association with AKI. The findings support current safety concerns about the use of these drugs in older adults. PRIMARY FUNDING SOURCE: Academic Medical Organization of Southwestern Ontario.

Altered mental status in older adults with histamine2-receptor antagonists: a population-based study.

BACKGROUND: Standard doses of histamine2-receptor antagonists (H2RAs) may induce altered mental status in older adults, especially in those with chronic kidney disease (CKD). METHODS: Population-based cohort study of older adults who started a new H2RA between 2002 and 2011 was conducted. Ninety percent received the current standard H2RA dose in routine care. There was no significant difference in 27 baseline patient characteristics. The primary outcome was hospitalization with an urgent head computed tomography (CT) scan (proxy for altered mental status), and the secondary outcome was all-cause mortality also within 30days of a new H2RA prescription. RESULTS: Standard vs. low H2RA dose was associated with a higher risk of hospitalization with an urgent head CT scan (0.98% vs. 0.74%, absolute risk difference 0.24% [95% CI 0.11% to 0.36%], relative risk 1.33 [95% CI 1.12 to 1.58]). This risk was not modified by the presence of CKD (interaction P value=0.71). Standard vs. low H2RA dose was associated with a higher risk of mortality (1.07% vs.0.74%; absolute risk difference 0.34% [95% CI 0.20% to 0.46%], relative risk 1.46 [95% CI 1.23 to 1.73]). INTERPRETATION: Compared to a lower dose, initiation of the current standard dose of H2RA in older adults is associated with a small absolute increase in the 30-day risk of altered mental status (using neuroimaging as a proxy), even in the absence of CKD. This risk may be avoided by initiating older adults on low doses of H2RAs for gastroesophogeal reflux disease, and increasing dosing as necessary for symptom control.

Higher anti-depressant dose and major adverse outcomes in moderate chronic kidney disease: a retrospective population-based study.

BACKGROUND: Many older patients have chronic kidney disease (CKD), and a lower dose of anti-depressants paroxetine, mirtazapine and venlafaxine is recommended in patients with CKD to prevent drug accumulation from reduced elimination. Using information available in large population-based healthcare administrative databases, we conducted this study to determine if ignoring the recommendation and prescribing a higher versus lower dose of anti-depressants associates with a higher risk of adverse events. METHODS: We conducted a population-based cohort study to describe the 30-day risk of delirium in older adults who initiated a higher vs. lower dose of these three anti-depressants in routine care. We defined delirium using the best proxy available in our data sources - hospitalization with an urgent head computed tomography (CT) scan. We determined if CKD status modified the association between anti-depressant dose and outcome, and examined the secondary outcome of 30 day all-cause mortality. We used multivariable logistic regression analyses to estimate adjusted odds ratios (relative risk (RR)) and 95% confidence intervals. RESULTS: We identified adults (mean age 75) in Ontario who started a new study anti-depressant at a higher dose (n=36,651; 31%) or lower dose (n=81,160; 69%). Initiating a higher vs. lower dose was not associated with an increased risk of hospitalization with head CT (1.09% vs. 1.27% (adjusted RR 0.90; 95% CI, 0.80 to 1.02), but was associated with a lower risk of all-cause mortality (0.76% vs. 0.97% RR 0.82; 95% CI, 0.71 to 0.95). Neither of these relative risks were modified by the presence of CKD (p=0.16, 0.68, respectively). CONCLUSIONS: We did not observe an increase in two adverse outcomes when study anti-depressants were initiated at a higher dose in elderly patients with moderate CKD. Contrary to our hypothesis, the 30-day risk of mortality was lower when a higher versus lower dose of anti-depressant was initiated in these patients, a finding which requires corroboration and further study.

Hyponatremia and sodium picosulfate bowel preparations in older adults.

OBJECTIVES: Bowel preparations are commonly prescribed drugs. Case reports and our clinical experience suggest that sodium picosulfate bowel preparations can precipitate severe hyponatremia in some older adults. At present, this risk is poorly quantified. We investigated the association between sodium picosulfate use and the risk of hyponatremia in older adults. METHODS: We conducted a population-based retrospective cohort study using six linked administrative databases in Ontario, Canada. All Ontario residents over the age of 65 years who filled an outpatient bowel preparation prescription before colonoscopy were eligible. We enrolled new users of either sodium picosulfate (n=99,237) or polyethylene glycol (n=48,595). The primary outcome was hospitalization with hyponatremia within 30 days of the bowel preparation assessed by database codes. The secondary outcomes were hospitalization with urgent head computed tomography (CT) (a proxy for acute central nervous system disturbance) and all-cause mortality. RESULTS: The baseline characteristics of the two groups, including patient demographics, comorbid conditions, and concomitant medications, were nearly identical. Compared with polyethylene glycol, sodium picosulfate was associated with a higher risk of hospitalization with hyponatremia (absolute risk increase: 0.05%, 95% confidence interval (CI): 0.04-0.06%, relative risk (RR): 2.4, 95% CI: 1.5-3.9), but not hospitalization with urgent CT head (RR: 1.1, 95% CI: 0.7-1.4) or mortality (RR: 0.9, 95% CI: 0.7-1.3). CONCLUSIONS: Sodium picosulfate bowel preparations lead to more hyponatremia than polyethylene glycol. There was no evidence of increased risk of acute neurologic symptoms or mortality. The absolute increase in risk of hospitalization with hyponatremia remains low but may be avoidable through appropriate fluid intake or preferential use of polyethylene glycol in some older adults.

Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury.

IMPORTANCE: Calcium-channel blockers are metabolized by the cytochrome P450 3A4 (CYP3A4; EC 1.14.13.97) enzyme. Blood concentrations of these drugs may rise to harmful levels when CYP3A4 activity is inhibited. Clarithromycin is an inhibitor of CYP3A4 and azithromycin is not, which makes comparisons between these 2 macrolide antibiotics useful in assessing clinically important drug interactions. OBJECTIVE: To characterize the risk of acute adverse events following coprescription of clarithromycin compared with azithromycin in older adults taking a calcium-channel blocker. DESIGN, SETTING, AND PARTICIPANTS: Population-based retrospective cohort study in Ontario, Canada, from 2003 through 2012 of older adults (mean age, 76 years) who were newly coprescribed clarithromycin (n = 96,226) or azithromycin (n = 94,083) while taking a calcium-channel blocker (amlodipine, felodipine, nifedipine, diltiazem, or verapamil). MAIN OUTCOMES AND MEASURES: Hospitalization with acute kidney injury (primary outcome) and hospitalization with hypotension and all-cause mortality (secondary outcomes examined separately). Outcomes were assessed within 30 days of a new coprescription. RESULTS: There were no differences in measured baseline characteristics between the clarithromycin and azithromycin groups. Amlodipine was the most commonly prescribed calcium-channel blocker (more than 50% of patients). Coprescribing clarithromycin vs azithromycin with a calcium-channel blocker was associated with a higher risk of hospitalization with acute kidney injury (420 patients of 96,226 taking clarithromycin [0.44%] vs 208 patients of 94,083 taking azithromycin [0.22%]; absolute risk increase, 0.22% [95% CI, 0.16%-0.27%]; odds ratio [OR], 1.98 [95% CI, 1.68-2.34]). In a subgroup analysis, the risk was highest with dihydropyridines, particularly nifedipine (OR, 5.33 [95% CI, 3.39-8.38]; absolute risk increase, 0.63% [95% CI, 0.49%-0.78%]). Coprescription with clarithromycin was also associated with a higher risk of hospitalization with hypotension (111 patients of 96,226 taking clarithromycin [0.12%] vs 68 patients of 94,083 taking azithromycin [0.07%]; absolute risk increase, 0.04% [95% CI, 0.02%-0.07%]; OR, 1.60 [95% CI, 1.18-2.16]) and all-cause mortality (984 patients of 96,226 taking clarithromycin [1.02%] vs 555 patients of 94,083 taking azithromycin [0.59%]; absolute risk increase, 0.43% [95% CI, 0.35%-0.51%]; OR, 1.74 [95% CI, 1.57-1.93]). CONCLUSIONS AND RELEVANCE: Among older adults taking a calcium-channel blocker, concurrent use of clarithromycin compared with azithromycin was associated with a small but statistically significant greater 30-day risk of hospitalization with acute kidney injury. These findings support current safety warnings regarding concurrent use of CYP3A4 inhibitors and calcium-channel blockers.

Comparing two types of macrolide antibiotics for the purpose of assessing population-based drug interactions.

OBJECTIVE: Clarithromycin strongly inhibits enzyme cytochrome P450 3A4, preventing the metabolism of some other drugs, while azithromycin is a weak inhibitor. Accordingly, blood concentrations of other drugs increase with clarithromycin coprescription leading to adverse events. These macrolide antibiotics also differ on other properties that may impact outcomes. In this study, we compared outcomes in two groups of macrolide antibiotic users in the absence of potentially interacting drugs. DESIGN: Population-based retrospective cohort study. SETTING: Ontario, Canada, from 2003 to 2010. PATIENTS: Patients (mean 74 years) prescribed clarithromycin (n=52 251) or azithromycin (referent group, n=46 618). MAIN OUTCOMES: The primary outcomes were hospital admission within 30 days of a new antibiotic prescription with any of the 12 conditions examined separately (acute kidney injury, acute myocardial infarction, neuroimaging (proxy for delirium), hypotension, syncope, hyperkalaemia, hyponatraemia, hyperglycaemia, arrhythmia, ischaemic stroke, gastrointestinal bleeding and sepsis). The secondary outcome was mortality. RESULTS: The baseline characteristics of the two groups, including patient demographics, comorbid conditions, infection type and prescribing physician specialty, were nearly identical. The median daily dose was 1000 mg for clarithromycin and 300 mg for azithromycin and the median duration of dispensing antibiotics was 10 and 5 days, respectively. There was no difference between the groups in the risk of hospitalisation for any condition studied (relative risk ranged from 0.67 to 1.23). Compared with azithromycin, clarithromycin was associated with a slightly higher risk of all-cause mortality (0.46% vs 0.37%, relative risk 1.25, 95% CI 1.03 to 1.52). CONCLUSIONS: Clarithromycin can be used to assess drug interactions in population-based studies with azithromycin serving as a control group. However, any differences in mortality observed between the two antibiotic groups in the setting of other drug use may be partially attributable to factors beyond the inhibition of drug metabolising enzymes and transporters, as the difference for this outcome was significant.

Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study.

BACKGROUND: Clarithromycin and erythromycin, but not azithromycin, inhibit cytochrome P450 isoenzyme 3A4 (CYP3A4), and inhibition increases blood concentrations of statins that are metabolized by CYP3A4. OBJECTIVE: To measure the frequency of statin toxicity after coprescription of a statin with clarithromycin or erythromycin. DESIGN: Population-based cohort study. SETTING: Ontario, Canada, from 2003 to 2010. PATIENTS: Continuous statin users older than 65 years who were prescribed clarithromycin (n = 72,591) or erythromycin (n = 3267) compared with those prescribed azithromycin (n = 68,478). MEASUREMENTS: The primary outcome was hospitalization with rhabdomyolysis within 30 days of the antibiotic prescription. RESULTS: Atorvastatin was the most commonly prescribed statin (73%) followed by simvastatin and lovastatin. Compared with azithromycin, coprescription of a statin with clarithromycin or erythromycin was associated with a higher risk for hospitalization with rhabdomyolysis (absolute risk increase, 0.02% [95% CI, 0.01% to 0.03%]; relative risk [RR], 2.17 [CI, 1.04 to 4.53]) or with acute kidney injury (absolute risk increase, 1.26% [CI, 0.58% to 1.95%]; RR, 1.78 [CI, 1.49 to 2.14]) and for all-cause mortality (absolute risk increase, 0.25% [CI, 0.17% to 0.33%]; RR, 1.56 [CI, 1.36 to 1.80]). LIMITATIONS: Only older adults were included in the study. The absolute risk increase for rhabdomyolysis may be underestimated because the codes used to identify it were insensitive. CONCLUSION: In older adults, coprescription of clarithromycin or erythromycin with a statin that is metabolized by CYP3A4 increases the risk for statin toxicity. PRIMARY FUNDING SOURCE: Academic Medical Organization of Southwestern Ontario.

Risk of acute kidney injury from oral acyclovir: a population-based study.

BACKGROUND: Intravenous acyclovir-induced acute kidney injury (AKI) from drug crystallization in the renal tubules is described in case reports, review articles, and drug prescribing manuals. Similarly, AKI from oral acyclovir is described in case reports, but the risk in routine practice is unknown. STUDY DESIGN: Retrospective population-based cohort study. SETTING & PARTICIPANTS: We studied a large cohort of older patients in Ontario, Canada, receiving new outpatient prescriptions from 1997 to 2011 for oral acyclovir or valacyclovir (which is metabolized to acyclovir). The comparison drug was famciclovir, an antiviral used for indications similar to acyclovir, but with no known renal toxicity. PREDICTOR: Outpatient prescription for oral acyclovir, valacyclovir, or famciclovir. OUTCOMES: The primary outcome was hospital admission with AKI in the 30 days after the initial prescription. MEASUREMENTS: We assessed the primary outcome with health care diagnostic codes. In a subpopulation, we assessed AKI using available laboratory serum creatinine measurements. RESULTS: 76,269 patients received acyclovir or valacyclovir and 84,646 received famciclovir. On average, patients were aged 76 [IQR, 71-81] years and prescription duration was 7 days. Acyclovir or valacyclovir use was not associated with a higher risk of hospital admission with AKI (209 [0.27%] events with acyclovir or valacyclovir vs 238 [0.28%] events with famciclovir [relative risk, 0.97; 95% CI, 0.81-1.17]). Results were consistent in adjusted analyses, in all subgroups, and in the subpopulation with laboratory measurements. LIMITATIONS: Diagnostic codes had high specificity but low sensitivity and underestimated the incidence of AKI. Only a limited number of patients (n = 2,729) had serum creatinine values available. CONCLUSIONS: In this population-based study of older adults, oral acyclovir use was not associated with a higher risk of AKI compared to famciclovir.

Identifying geographical regions serviced by hospitals to assess laboratory-based outcomes.

OBJECTIVE: To define geographical regions (forward sortation areas; FSAs) in Southwestern Ontario, Canada from which patients would reliably present to a hospital with linked laboratory data if they developed adverse events related to medications dispensed in outpatient pharmacies. DESIGN: Descriptive research. SETTING: Forty-five hospitals in Southwestern Ontario, Canada, from 2003 to 2009. PARTICIPANTS: Patients aged 66 years and older who received an outpatient prescription for any drug and presented to the emergency department in the subsequent 120 days. MAIN OUTCOME MEASURE: The proportion of patients in a given FSA presenting to an emergency department at a hospital with linked laboratory data versus a hospital without linked laboratory data. To be included in the catchment area at least 90% of emergency department visits in an FSA must have occurred at laboratory-linked hospitals in a given year. RESULTS: Over the study period, there were 649 713 emergency department visits by patients with recent prescription claims from pharmacies in 1 of 118 FSAs. In total, 141 302 of these patients presented to an emergency department at a laboratory-linked hospital. For the year 2003, 12 FSAs met our criteria to be in the catchment area and this number grew to 25 FSAs by the year 2009. CONCLUSIONS: The relevant geographical regions for hospitals with linked laboratory data have been successfully identified. Studies can now be conducted using these well-defined areas to obtain reliable information on the incidence and absolute risk of presenting to hospital with laboratory abnormalities in older adults dispensed commonly prescribed medications in outpatient pharmacies.

Validity of the International Classification of Diseases, Tenth Revision code for acute kidney injury in elderly patients at presentation to the emergency department and at hospital admission.

OBJECTIVE: To evaluate the validity of the International Classification of Diseases, Tenth Revision (ICD-10) code N17x for acute kidney injury (AKI) in elderly patients in two settings: at presentation to the emergency department and at hospital admission. DESIGN: A population-based retrospective validation study. SETTING: Southwestern Ontario, Canada, from 2003 to 2010. PARTICIPANTS: Elderly patients with serum creatinine measurements at presentation to the emergency department (n=36 049) or hospital admission (n=38 566). The baseline serum creatinine measurement was a median of 102 and 39 days prior to presentation to the emergency department and hospital admission, respectively. MAIN OUTCOME MEASURES: Sensitivity, specificity and positive and negative predictive values of ICD-10 diagnostic coding algorithms for AKI using a reference standard based on changes in serum creatinine from the baseline value. Median changes in serum creatinine of patients who were code positive and code negative for AKI. RESULTS: The sensitivity of the best-performing coding algorithm for AKI (defined as a ≥2-fold increase in serum creatinine concentration) was 37.4% (95% CI 32.1% to 43.1%) at presentation to the emergency department and 61.6% (95% CI 57.5% to 65.5%) at hospital admission. The specificity was greater than 95% in both settings. In patients who were code positive for AKI, the median (IQR) increase in serum creatinine from the baseline was 133 (62 to 288) µmol/l at presentation to the emergency department and 98 (43 to 200) µmol/l at hospital admission. In those who were code negative, the increase in serum creatinine was 2 (-8 to 14) and 6 (-4 to 20) µmol/l, respectively. CONCLUSIONS: The presence or absence of ICD-10 code N17× differentiates two groups of patients with distinct changes in serum creatinine at the time of a hospital encounter. However, the code underestimates the true incidence of AKI due to a limited sensitivity.

Availability of renal literature in six bibliographic databases.

BACKGROUND: When searching for renal literature, nephrologists must choose between several different bibliographic databases. We compared the availability of renal clinical studies in six major bibliographic databases. METHODS: We gathered 151 renal systematic reviews, which collectively contained 2195 unique citations referencing primary studies in the form of journal articles, meeting articles or meeting abstracts published between 1963 and 2008. We searched for each citation in three subscription-free bibliographic databases (PubMed, Google Scholar and Scirus) and three subscription-based databases (EMBASE, Ovid-MEDLINE and ISI Web of Knowledge). For the subscription-free databases, we determined which full-text journal articles were available free of charge via links to the article source. RESULTS: The proportion of journal articles contained within each of the six databases ranged from 96 to 97%; results were similar for meeting articles. Availability of meeting abstracts was poor, ranging from 0 to 37% (P < 0.01) with ISI Web of Knowledge containing the largest proportion [37%, 95% confidence interval (95% CI) 32-43%]. Among the subscription-free databases, free access to full-text articles was highest in Google Scholar (38% free, 95% CI 36-41%), and was only marginally higher (39%) when all subscription-free databases were searched. After 2000, free access to full-text articles increased to 49%. CONCLUSIONS: Over 99% of renal clinical journal articles are available in at least one major bibliographic database. Subscription-free databases provide free full-text access to almost half of the articles published after the year 2000, which may be of particular interest to clinicians in settings with limited access to subscription-based resources.

Validity of the International Classification of Diseases 10th revision code for hospitalisation with hyponatraemia in elderly patients.

OBJECTIVE: To evaluate the validity of the International Classification of Diseases, 10th Revision (ICD-10) diagnosis code for hyponatraemia (E87.1) in two settings: at presentation to the emergency department and at hospital admission. DESIGN: Population-based retrospective validation study. SETTING: Twelve hospitals in Southwestern Ontario, Canada, from 2003 to 2010. PARTICIPANTS: Patients aged 66 years and older with serum sodium laboratory measurements at presentation to the emergency department (n=64 581) and at hospital admission (n=64 499). MAIN OUTCOME MEASURES: Sensitivity, specificity, positive predictive value and negative predictive value comparing various ICD-10 diagnostic coding algorithms for hyponatraemia to serum sodium laboratory measurements (reference standard). Median serum sodium values comparing patients who were code positive and code negative for hyponatraemia. RESULTS: The sensitivity of hyponatraemia (defined by a serum sodium ≤132 mmol/l) for the best-performing ICD-10 coding algorithm was 7.5% at presentation to the emergency department (95% CI 7.0% to 8.2%) and 10.6% at hospital admission (95% CI 9.9% to 11.2%). Both specificities were greater than 99%. In the two settings, the positive predictive values were 96.4% (95% CI 94.6% to 97.6%) and 82.3% (95% CI 80.0% to 84.4%), while the negative predictive values were 89.2% (95% CI 89.0% to 89.5%) and 87.1% (95% CI 86.8% to 87.4%). In patients who were code positive for hyponatraemia, the median (IQR) serum sodium measurements were 123 (119-126) mmol/l and 125 (120-130) mmol/l in the two settings. In code negative patients, the measurements were 138 (136-140) mmol/l and 137 (135-139) mmol/l. CONCLUSIONS: The ICD-10 diagnostic code for hyponatraemia differentiates between two groups of patients with distinct serum sodium measurements at both presentation to the emergency department and at hospital admission. However, these codes underestimate the true incidence of hyponatraemia due to low sensitivity.

Validity of the International Classification of Diseases 10th revision code for hyperkalaemia in elderly patients at presentation to an emergency department and at hospital admission.

OBJECTIVES: Evaluate the validity of the International Classification of Diseases, 10th revision (ICD-10) code for hyperkalaemia (E87.5) in two settings: at presentation to an emergency department and at hospital admission. DESIGN: Population-based validation study. SETTING: 12 hospitals in Southwestern Ontario, Canada, from 2003 to 2010. PARTICIPANTS: Elderly patients with serum potassium values at presentation to an emergency department (n=64 579) and at hospital admission (n=64 497). PRIMARY OUTCOME: Sensitivity, specificity, positive-predictive value and negative-predictive value. Serum potassium values in patients with and without a hyperkalaemia code (code positive and code negative, respectively). RESULTS: The sensitivity of the best-performing ICD-10 coding algorithm for hyperkalaemia (defined by serum potassium >5.5 mmol/l) was 14.1% (95% CI 12.5% to 15.9%) at presentation to an emergency department and 14.6% (95% CI 13.3% to 16.1%) at hospital admission. Both specificities were greater than 99%. In the two settings, the positive-predictive values were 83.2% (95% CI 78.4% to 87.1%) and 62.0% (95% CI 57.9% to 66.0%), while the negative-predictive values were 97.8% (95% CI 97.6% to 97.9%) and 96.9% (95% CI 96.8% to 97.1%). In patients who were code positive for hyperkalaemia, median (IQR) serum potassium values were 6.1 (5.7 to 6.8) mmol/l at presentation to an emergency department and 6.0 (5.1 to 6.7) mmol/l at hospital admission. For code-negative patients median (IQR) serum potassium values were 4.0 (3.7 to 4.4) mmol/l and 4.1 (3.8 to 4.5) mmol/l in each of the two settings, respectively. CONCLUSIONS: Patients with hospital encounters who were ICD-10 E87.5 hyperkalaemia code positive and negative had distinct higher and lower serum potassium values, respectively. However, due to very low sensitivity, the incidence of hyperkalaemia is underestimated.