ASSESSING POTENTIALLY INAPPROPRIATE MEDICATION USE IN PATIENTS AT RISK FOR ADVERSE DRUG EFFECTS: SPIRONOLACTONE AS A CASE STUDY

Background: Polypharmacy and potentially inappropriate medication (PIM) use are common and associated with considerable morbidity, yet they are often modifiable risk factors. However, some PIM use is a result of limited information on medication safety across patient kidney function. One such medication, spironolactone, an aldosterone antagonist indicated for heart failure, has been demonstrated in clinical trials to reduce morbidity and mortality among individuals with normal renal function, but its safety in those with chronic kidney disease (CKD) is unclear. Methods: We used longitudinal data from the Atherosclerosis Risk in Communities (ARIC) study to quantify PIM use by estimated glomerular filtration rate (eGFR), and to assess the relationship between polypharmacy, PIM use, and subsequent hospitalization and death in older adults. We used commercial claims data from MarketScan and electronic health record data from the Geisinger Health System to identify predictors of spironolactone initiation among patients with heart failure, and used target trial emulation to characterize the risk of hyperkalemia and acute kidney injury (AKI) with spironolactone use among patients using loop diuretics. Results: Participants in ARIC (N=6,392) with CKD reported more medications than those without CKD (p<0.001), and PIM use based on kidney function was prevalent (36%) among those with eGFR <30 ml/min/1.73m2. More concurrent medications were associated with higher risks of hospitalization and death, but PIM use was not, and there were no differences in the relative risks associated with greater numbers of medications by CKD status. Among patients with incident heart failure in MarketScan (N=22,956) and Geisinger (N=16,547), 7.0% and 9.9% initiated spironolactone within two years, respectively. Patients with eGFR <30 were least likely to initiate spironolactone compared to patients with eGFR 60-89 (meta-analyzed hazard ratio [HR]: 0.61, 95% confidence interval [CI]: 0.44-0.83). In Geisinger patients with heart failure using loop diuretics (N=17,110), spironolactone initiation was associated with increases in hyperkalemia and AKI risk compared to use of loop diuretics alone (HR 1.69 [CI: 1.35-2.10], and HR 1.12 [CI: 1.00-1.26], respectively), with no observed differences in the relative risk of either outcome associated with spironolactone by eGFR. Conclusions: Polypharmacy and PIM use were common, with greater numbers of medications associated with greater risk of hospitalization or death. Spironolactone initiation was uncommon within two years of heart failure diagnosis, and least likely among patients with lower kidney function. The addition of spironolactone to loop diuretics increased the risk of hyperkalemia, and more modestly, AKI. Improved data on medication safety in patients with CKD are needed

Analytical Enhancements in Kentucky’s Drug Overdose Mortality Surveillance: Rapid Monitoring of Trends and Decedents’ Recent Controlled Substance Prescription History

Background: Timely drug overdose mortality surveillance is key to informing public health action to reduce overdose-related fatalities. States are increasingly using linked data sources to enhance surveillance activities, yet approaches to their effective utilization and analyses are needed. Objectives: The objective of this study is to describe the development and utilization of analytical tools for rapid, ongoing monitoring of drug overdose trends in Kentucky (KY) and decedents’ exposure to prescribed controlled substances (CS). Methods: KY established a monthly process of linking all-cause death certificate (DC) with prescription drug monitoring program (DC-PDMP) data to enhance mortality surveillance. Using provisional 2018-2020 DC-PDMP data we developed scheduled quarterly analytical reports. Drug overdose deaths are identified based on underlying cause of death (ICD-10 X40-X44, X60-X64, X85, or Y10-Y14); involved drugs/drug classes are identified from multiple cause of death codes (T36 – T50). Common contributing substances are identified from DC cause of death section text fields. Drugs listed on DCs are compared with decedents’ past 90 days CS prescriptions. Results: KY resident drug overdose deaths accounted for 2.8% of all-cause mortality, but among age group 26-40 years, 28.6% of all-cause deaths were due to drug overdose. Drug overdose decedents were disproportionally male (65.4% vs. 51.8% among all-cause deaths). From 2018 to 2020, the number of drug overdose deaths increased 42%. Deaths involving synthetic opioids and psychostimulants increased (56.2%vs 71.7% and 27.3% vs 35.1%, respectively) and deaths involving heroin (10.4% vs 6.0%), benzodiazepines (24.1% vs 15.3%), cocaine (9.6% vs 8.4%) and natural/semi-synthetic opioids (22.7% vs 21.3%) declined. The five substances most frequently listed in the DC in 2020 were fentanyl, methamphetamine, 4-ANPP, gabapentin, and acetyl fentanyl. Sixty-three percent of deaths involving natural/semi- synthetic opioids and 76% of cases involving benzodiazepines had no dispensed prescriptions for those drug classes in the previous 90 days, suggesting possible diversion. A historically high level of drug overdose deaths was observed in the first months of COVID-19 pandemic, with April-June 2020 overdose deaths (n=557), 80%higher than the same period in 2019. Conclusions: The analytical enhancement of KY’s drug overdose surveillance supports rapid assessment to inform public health action and provides a rich dataset for pharmacoepidemiologic studies

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort study

BackgroundAdverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population.MethodsA multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases.FindingsSubstantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism.InterpretationOur findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term.FundingNone

Contextualising adverse events of special interest to characterise the baseline incidence rates in 24 million patients with COVID-19 across 26 databases: a multinational retrospective cohort studyResearch in context

Summary: Background: Adverse events of special interest (AESIs) were pre-specified to be monitored for the COVID-19 vaccines. Some AESIs are not only associated with the vaccines, but with COVID-19. Our aim was to characterise the incidence rates of AESIs following SARS-CoV-2 infection in patients and compare these to historical rates in the general population. Methods: A multi-national cohort study with data from primary care, electronic health records, and insurance claims mapped to a common data model. This study's evidence was collected between Jan 1, 2017 and the conclusion of each database (which ranged from Jul 2020 to May 2022). The 16 pre-specified prevalent AESIs were: acute myocardial infarction, anaphylaxis, appendicitis, Bell's palsy, deep vein thrombosis, disseminated intravascular coagulation, encephalomyelitis, Guillain- Barré syndrome, haemorrhagic stroke, non-haemorrhagic stroke, immune thrombocytopenia, myocarditis/pericarditis, narcolepsy, pulmonary embolism, transverse myelitis, and thrombosis with thrombocytopenia. Age-sex standardised incidence rate ratios (SIR) were estimated to compare post-COVID-19 to pre-pandemic rates in each of the databases. Findings: Substantial heterogeneity by age was seen for AESI rates, with some clearly increasing with age but others following the opposite trend. Similarly, differences were also observed across databases for same health outcome and age-sex strata. All studied AESIs appeared consistently more common in the post-COVID-19 compared to the historical cohorts, with related meta-analytic SIRs ranging from 1.32 (1.05 to 1.66) for narcolepsy to 11.70 (10.10 to 13.70) for pulmonary embolism. Interpretation: Our findings suggest all AESIs are more common after COVID-19 than in the general population. Thromboembolic events were particularly common, and over 10-fold more so. More research is needed to contextualise post-COVID-19 complications in the longer term. Funding: None