Erin M. Macdonald

Co-trimoxazole and sudden death in patients receiving inhibitors of renin-angiotensin system: population based study

Objective To determine whether the prescription of co-trimoxazole with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker is associated with sudden death. Design Population based nested case-control study. Setting Ontario, Canada, from 1 April 1994 to 1 January 2012. Participants Ontario residents aged 66 years or older treated with an angiotensin converting enzyme inhibitor or angiotensin receptor blocker. Cases were those who died suddenly shortly after receiving an outpatient prescription for one of co-trimoxazole, amoxicillin, ciprofloxacin, norfloxacin, or nitrofurantoin. Each case was matched with up to four controls on age, sex, chronic kidney disease, and diabetes. Main outcome measure Odds ratio for the association between sudden death and exposure to each antibiotic relative to amoxicillin, after adjustment for predictors of sudden death according to a disease risk index. Results Of 39 879 sudden deaths, 1027 occurred within seven days of exposure to an antibiotic and were matched to 3733 controls. Relative to amoxicillin, co-trimoxazole was associated with an increased risk of sudden death (adjusted odds ratio 1.38, 95% confidence interval 1.09 to 1.76). The risk was marginally higher at 14 days (adjusted odds ratio 1.54, 1.29 to 1.84). This corresponds to approximately three sudden deaths within 14 days per 1000 co-trimoxazole prescriptions. Ciprofloxacin (a known cause of QT interval prolongation) was also associated with an increased risk of sudden death (adjusted odds ratio 1.29, 1.03 to 1.62), but no such risk was observed with nitrofurantoin or norfloxacin. Conclusions In older patients receiving angiotensin converting enzyme inhibitors or angiotensin receptor blockers, co-trimoxazole is associated with an increased risk of sudden death. Unrecognized severe hyperkalemia may underlie this finding. When appropriate, alternative antibiotics should be considered in such patients.

Risk of suicide following deliberate self-poisoning

IMPORTANCE Suicide is the tenth leading cause of death in the United States, and its rate has risen by 16% in the past decade. Deliberate self-poisoning is the leading method of attempted suicide. Unlike more violent methods, which are almost universally fatal, survival following self-poisoning is common, providing an opportunity for secondary prevention. However, the long-term risk of suicide following a first episode of self-poisoning is unknown. OBJECTIVE To determine the risk of suicide and mortality from other causes following a first self-poisoning episode. DESIGN, SETTING, AND PARTICIPANTS Population-based cohort study using multiple linked health care databases. We identified all individuals with a first self-poisoning episode in Ontario, Canada, from April 1, 2002, through December 31, 2010, and followed up all surviving participants until December 31, 2011, or death, whichever occurred first. For each individual with a deliberate self-poisoning episode, we randomly selected 1 control from the same population with no such history, matched for age (within 3 months), sex, and calendar year. MAIN OUTCOMES AND MEASURES The primary analysis examined the risk of suicide following discharge after self-poisoning. The secondary analyses explored factors associated with suicide and examined the risk of death caused by accidents or any other cause. RESULTS We identified 65 784 patients (18 482 [28.1%] younger than 20 years) who were discharged after a first self-poisoning episode. During a median follow-up of 5.3 years (interquartile range, 3.1-7.6 years), 4176 died, including 976 (23.4%) by suicide. The risk of suicide following self-poisoning was markedly increased relative to controls (hazard ratio, 41.96; 95% CI, 27.75-63.44), corresponding to a suicide rate of 278 vs 7 per 100 000 person-years, respectively. The median time from hospital discharge to completed suicide was 585 days (interquartile range, 147-1301 days). Older age, male sex, multiple intervening self-poisoning episodes, higher socioeconomic status, depression, and recent psychiatric care were strongly associated with suicide. Patients with a self-poisoning episode were also more likely to die because of accidents (hazard ratio, 10.45; 95% CI, 8.10-13.47) and all causes combined (hazard ratio, 5.55; 95% CI, 5.12-6.02). CONCLUSIONS AND RELEVANCE A first self-poisoning episode is a strong predictor of subsequent suicide and premature death. Most suicides occur long after the index poisoning, emphasizing the importance of longitudinal, sustained secondary prevention initiatives.

A 1980 Letter on the Risk of Opioid Addiction

A five-sentence letter published in the Journal in 1980 has been heavily cited as evidence that long-term opioid therapy has seldom been associated with addiction. Of the 608 citations, 72.2% used the letter uncritically as evidence that such addiction was rare.

Recurrence and Mortality Following Severe Cutaneous Adverse Reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions. Both primarily develop as idiosyncratic responses to drugs,1 resulting in extensive epidermal detachment. Recurrence has been reported in isolated cases, and the overall risk of recurrence is unknown. Given the rarity of SJS and TEN, valid inferences about recurrence rates require the study of large populations over an extended period. We examined the long-term risk of recurrence following a first SJS or TEN episode.

Proton Pump Inhibitors and the Risk of Adverse Cardiac Events

Background Recent evidence suggests that proton pump inhibitors (PPIs) might be linked with adverse cardiac events, but a causal relationship is unproven. Methods We applied the self-matched case series method to two studies using population-based health care data from Ontario, Canada between 1996 and 2008. The first included subjects aged 66 years or older hospitalized for acute myocardial infarction within 12 weeks following initiation of PPI, while the second included subjects hospitalized for heart failure. In both studies we designated the primary risk interval as the initial 4 weeks of therapy and the control interval as the final 4 weeks. To test the specificity of our findings we examined use of histamine H2 receptor antagonists and benzodiazepines, drugs with no plausible causal link to adverse cardiac events. Results During the 13-year study period, we identified 5550 hospital admissions for acute myocardial infarction and 6003 admissions for heart failure within 12 weeks of commencing PPI therapy. In the main analyses, we found that initiation of a PPI was associated with a higher risk of acute myocardial infarction (odds ratio 1.8; 95% confidence interval 1.7 to 1.9) and heart failure (odds ratio 1.8; 95% confidence interval 1.7 to 1.9). However, secondary analyses revealed similar risk estimates histamine H2 receptor antagonists and benzodiazepines, drugs with no known or suspected association with adverse cardiac events. Conclusion PPIs are associated with a short-term risk of adverse cardiac events, but similar associations are seen with other drugs exhibiting no known cardiac toxicity. Collectively these observations suggest that the association between PPIs and adverse cardiac events does not represent reflect cause-and-effect.

Long-term outcomes following self-poisoning in adolescents: a population-based cohort study

BACKGROUND Suicide is the third most common cause of death among adolescents worldwide, and poisoning is the leading method of attempted suicide. Unlike more violent methods, survival after self-poisoning is common, providing an opportunity for secondary prevention. We determined the risk and time course of completed suicide after adolescent self-poisoning, and explored potential risk factors. METHODS We did a population-based cohort study using multiple linked health-care databases in Ontario, Canada, from Jan 1, 2001, to Dec 31, 2012. We identified all adolescents aged 10-19 years presenting to hospital after a first self-poisoning episode. Each was matched with 50 population-based reference individuals with no such history, matching on age, sex, and year of cohort entry. The primary outcome was the risk of suicide after a first self-poisoning episode. Secondary analyses explored factors associated with suicide and self-poisoning repetition. FINDINGS We identified 20,471 adolescents discharged from hospital after a first self-poisoning episode and 1,023,487 matched reference individuals. Over a median follow-up of 7·2 years (IQR 4·2-9·7), 248 (1%) adolescents discharged after self-poisoning died, 126 (51%) of whom died by suicide. The risk of suicide at 1 year after self-poisoning was greatly increased relative to reference individuals (hazard ratio [HR] 32·1, 95% CI 23·6-43·6), corresponding to a suicide rate of 89·6 (95% CI 75·2-106·7) per 100,000 person-years over the course of follow-up. The median time from hospital discharge to suicide was 3·0 years (IQR 1·1-5·3). Factors associated with suicide included recurrent self-poisoning (adjusted HR 3·5, 95% CI 2·4-5·0), male sex (2·5, 1·8-3·6) and psychiatric care in the preceding year (1·7, 1·1-2·5). Adolescents admitted to hospital for self-poisoning were also more likely to die from accidents (5·2, 4·1-6·6) and from all causes (3·9, 2·8-5·4) during follow-up. INTERPRETATION Self-poisoning in adolescence is a strong predictor of suicide and premature death in the ensuing decade, and identifies a high-risk group for targeted secondary prevention. Suicide risk is increased for many years after the index hospital admission, emphasising the importance of sustained prevention efforts. FUNDING The Canadian Drug Safety and Effectiveness Research Network, Ontario Ministry of Health and Long-Term Care, Paediatric Consultants Partnership.

Predictors of Opioid-Related Death During Methadone Therapy.

We aimed to examine pharmacologic, demographic and medical comorbidity risk factors for opioid-related mortality among patients currently receiving methadone for an opioid use disorder. We conducted a population-based, nested case-control study linking healthcare and coroners records in Ontario, Canada, from January 31, 1994 to December 31, 2010. We included social assistance recipients receiving methadone for an opioid use disorder. Within this group, cases were those who died of opioid-related causes. For each case, we identified up to 5 controls matched on calendar quarter. The primary analysis examined the association between use of psychotropic drugs (benzodiazepines, antidepressants or antipsychotics) and opioid-related mortality. Secondary analyses examined the associations between baseline characteristics, health service utilization, comorbidities and opioid-related mortality. Among 43,545 patients receiving methadone for an opioid use disorder, we identified 175 (0.4%) opioid-related deaths, along with 873 matched controls. Psychotropic drug use was associated with a two fold increased risk of opioid-related death (adjusted odds ratio (OR) 2.0; 95% confidence interval (CI) 1.2 to 3.5). Specifically, benzodiazepines (adjusted OR 1.6; 95% CI 1.1 to 2.5) and antipsychotics (adjusted OR 2.3; 95% CI 1.5 to 3.5) were independently associated with opioid-related death. Other associated factors included chronic lung disease (adjusted OR 1.7; 95% CI 1.2 to 2.6), an alcohol use disorder (adjusted OR 1.9; 95% CI 1.2 to 3.2), mood disorders (adjusted OR 1.8; 95% CI 1.0 to 3.2), and a history of heart disease (adjusted OR 5.3; 95% CI 2.0 to 14.0). Psychotropic drug use is associated with opioid-related death in patients receiving methadone. Mindfulness of these factors may reduce the risk of death among methadone recipients.

Trimethoprim–sulfamethoxazole and risk of sudden death among patients taking spironolactone

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

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

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

Repetition of intentional drug overdose: a population-based study

Abstract Context: Intentional overdose is a leading method of self-harm and suicide, and repeat attempts strongly predict eventual death by suicide. Objectives: To determine the risk of recurrence after a first intentional overdose. Secondary objectives included characterization of the temporal course and potential predictors of repeat overdose, a strong risk factor for death from suicide. Methods: Design: Population-based cohort study. Setting: Ontario, Canada, from 1 April 2002 to 31 March 2013. Participants: All Ontario residents presenting to an emergency department after a first intentional overdose. Main outcome measures: The incidence and timing of recurrent overdose. Results: We followed 81,675 patients discharged from hospital after a first intentional overdose. Overall, 13,903 (17.0%) returned with a repeat overdose after a median interval of 288 (inter-quartile range: 62 to 834) days. Of these, 4493 (5.5%) had multiple repeat episodes. Factors associated with repeat self-poisoning included psychiatric care in the preceding year (adjusted hazard ratio [aHR] 1.55; 95% confidence interval [CI] 1.50 to 1.61), alcohol dependence (aHR 1.41; 95% CI 1.35 to 1.46) and documented depression (aHR 1.39; 95% CI 1.34 to 1.44). Female sex, rural residence, lower socioeconomic status, ingestion of psychoactive drugs and younger age were also weakly associated with repeat overdose. Discussion: Hospital presentation for repetition of intentional overdose is common, with recurrent episodes often far removed from the first. While several factors predict overdose repetition, none is particularly strong. Conclusion: Secondary prevention initiatives should be implemented for all individuals who present to the emergency department and survive intentional overdose.