Sonja Gandhi

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.

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.

Atypical Antipsychotic Drugs and the Risk for Acute Kidney Injury and Other Adverse Outcomes in Older Adults: A Population-Based Cohort Study

Context Acute kidney injury (AKI) is reportedly associated with atypical antipsychotic drugs, although the risk has not been quantified. Contribution This population-based cohort study found that persons who had received a prescription for any of 3 atypical antipsychotic drugs in the previous 90 days had an elevated risk for hospitalization with AKI. These drugs were also associated with increased risk for hypotension, acute urinary retention, and death. Caution Only older adults and 3 antipsychotic agents were studied. Implication An association with specific adverse events may explain the increased risk for AKI observed with certain atypical antipsychotic drugs. The Editors Each year, millions of older adults worldwide are prescribed atypical antipsychotic drugs (quetiapine, risperidone, and olanzapine). These drugs are frequently used to manage behavioral symptoms of dementia, which is not an approved indication, and such use has raised safety concerns (1, 2). These drugs antagonize -adrenergic, muscarinic, serotonin, and dopamine receptors (3). Acute kidney injury (AKI) (defined as a sudden loss of kidney function) from atypical antipsychotic drugs is described in several case reports (48). Adverse outcomes potentially attributable to these drugs, such as hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis, are known to cause AKI (411). Moreover, pneumonia, acute myocardial infarction, and ventricular arrhythmia have been associated with these drugs in previous population-based studies and AKI may also co-occur with these events (1214). However, no clinical or epidemiologic studies have quantified the risk for AKI from atypical antipsychotic drugs and information on outcomes of hypotension, acute urinary retention, and the neuroleptic malignant syndrome or rhabdomyolysis is limited. Such information would contribute to growing knowledge of potential adverse events from this drug class. The U.S. Food and Drug Administration warns of an increased risk for death in older patients treated with these drugs based on analyses of randomized, placebo-controlled trials (averaging 10 weeks in duration) (1). For these reasons, we did this population-based study of older adults to investigate the 90-day risk for hospitalization with AKI and other adverse outcomes from new use of an oral atypical antipsychotic drug initiated in the nonhospital setting. Methods Design and Setting We conducted this study at the Institute for Clinical Evaluative Sciences according to a prespecified protocol that was approved by the research ethics board at Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. Patient informed consent was not required. We did a population-based, retrospective cohort study of older adults using linked health care databases in Ontario, Canada. Ontario residents have universal access to hospital care and physician services, and those aged 65 years or older have universal prescription drug coverage. The reporting of this study followed guidelines for observational studies (Table 1 of the Supplement) (15). Supplement. Supplementary material Data Sources We ascertained patient characteristics, drug use, covariate information, and outcome data using records from 5 databases. We obtained vital statistics from the Registered Persons Database of Ontario, which contains demographic information on all Ontario residents who have ever been issued a health card. We used the Ontario Drug Benefit database to identify prescription drug use. This database contains highly accurate recordsthe error rate is less than 1%of all outpatient prescriptions dispensed to patients aged 65 years or older (16). We identified diagnostic and procedural information on all hospitalizations from the Canadian Institute for Health Information Discharge Abstract Database. We obtained covariate information from the Ontario Health Insurance Plan database, which includes health claims for inpatient and outpatient physician services. We identified diagnostic information on all admissions to adult mental health beds from the Ontario Mental Health Reporting System. We have used these databases to research adverse drug reactions and health outcomes (including AKI) (1722). The databases were complete for all variables used in this study, except for prescriber information (which was missing for 10.8% of patients in the cohort). Codes from the International Classification of Diseases, Ninth Revision (before 2002), and Tenth Revision (after 2002), were used to assess baseline comorbid conditions in the 5 years before cohort entry (Table 2 of the Supplement). Codes used to ascertain outcomes are detailed in Table 3 of the Supplement, which lists only codes from the Tenth Revision because all events would have occurred after implementation of that coding system. A subpopulation in southwestern Ontario had information on outpatient serum creatinine levels available before cohort entry; this group was in the catchment area of 12 hospitals in which linked laboratory values were also available (23). Patients We established a cohort of older adults with evidence of a new outpatient prescription for an oral atypical antipsychotic drug (quetiapine, risperidone, or olanzapine) between June 2003 and December 2011. The date of this prescription served as the index date (cohort entry date) for the drug recipients. We matched a group of drug nonrecipients similar in health status to the recipients. We randomly assigned an index date to the entire Ontario population according to the index date of the drug recipients. For example, if more recipients had an index date between 2003 and 2005, a greater proportion of the population would have been randomly assigned an index date between 2003 and 2005. From these adults, after applying our exclusions to both groups, we matched a drug nonrecipient to each recipient on the following 11 characteristics: age (within 2 years); sex; residential status (community-dwelling or long-term care); evidence of comorbid conditions (dementia, schizophrenia or other psychotic disorder, bipolar disorder, major depression or anxiety disorder, Parkinson disease, and chronic kidney disease); constituency in the subpopulation with available information on serum creatinine levels; and the logit of the propensity score for the predicted probability of newly receiving an atypical antipsychotic drug (within a caliper of 0.2 SDs). We derived this propensity score from a logistic regression model and selected 91 variables for inclusion in the score on the basis of their potential association with the study outcomes or atypical antipsychotic drug initiation (variables listed in Table 4 of the Supplement) (24). One of the variables was the Johns Hopkins Adjusted Clinical Group Aggregated Diagnosis Groups (a validated measure of the complexity of comorbid conditions based on groups of diagnoses) (25, 26). Before matching, we excluded the following patients from both groups: those with prescriptions for any antipsychotic drug in the 180 days before their index date to ensure that the drug was newly prescribed (or had the potential to be newly prescribed in the case of the nonrecipients); those who were discharged from a hospital in the 2 days before their index date to ensure that drug use was newly initiated in the nonhospitalized setting (as in Ontario, patients continuing atypical antipsychotic drug treatment initiated in a hospital would have their oral outpatient prescription dispensed the day of or the day after hospital discharge); and those with evidence of end-stage renal disease before their index date (because the development of AKI is no longer relevant). Among the drug recipients, those who received a prescription for more than 1 type of antipsychotic drug (for example, a prescription for quetiapine and olanzapine) on their index date were excluded to compare mutually exclusive groups in subgroup analyses. Among the nonrecipients, those who did not have at least 1 outpatient medication dispensed in the 90 days before their index date were excluded to ensure that such persons were able to receive a prescription. Each drug recipient and nonrecipient could be selected only once for cohort entry. Outcomes We followed patients for 90 days after the index date to assess the prespecified outcomes. We chose 90 days to focus on acute adverse events, avoid potential crossovers between the 2 groups that might occur with longer follow-up, and mimic the duration of follow-up described in clinical trials of atypical antipsychotic drugs in older patients (1, 2, 27). The primary outcome was hospitalization with AKI. The secondary adverse outcomes were known causes of AKI (hospitalization with hypotension, acute urinary retention, the neuroleptic malignant syndrome or rhabdomyolysis, pneumonia, acute myocardial infarction, and ventricular arrhythmia) and all-cause mortality. The diagnosis codes used to identify the outcomes and information on their accuracy are presented in Table 3 of the Supplement (2830). For hospitalization records, up to 25 diagnosis codes can be assigned per hospitalization (for example, codes for AKI or rhabdomyolysis). Therefore, patients with codes for multiple study outcomes were accounted for in the assessment of each outcome. We previously examined the validity of the database code for hospitalization with AKI used in the current study. In this previous validation study (30), the database code for AKI identified a median increase in serum creatinine level of 98 mol/L (1.11 mg/dL) (interquartile range [IQR], 43 to 200 mol/L [0.49 to 2.26 mg/dL]) at the time of hospital presentation from the most recent value before hospitalization. The absence of such a code represented no statistically significant change in serum creatinine level (6 mol/L [0.07 mg/dL]; IQR, 4 to 20 mol/L [0.05 to 0.23 mg/dL]) (30). Although specificity was greater than 95%, the sensitivity of the hospital diagnosis was

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.

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.

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.

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.

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 m2) 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 m2). 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.

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.

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.