Nested Case Control Analysis Research Articles

Benefits of Repeated Matched-Cohort and Nested Case–Control Analyses with Time-dependent Exposure in Observational Studies

Benefits of Repeated Matched-Cohort and Nested Case–Control Analyses with Time-dependent Exposure in Observational Studies

Glucose-Lowering Drugs and Primary Prevention of Chronic Kidney Disease in Type 2 Diabetes Patients: A Real-World Primary Care Study

Background/Objectives: The burden of chronic kidney disease (CKD) is increasing, as is the prevalence of type 2 diabetes mellitus (T2DM). Post-hoc analyses of clinical trials support that sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptors agonists (GLP-1RAs) prevent CKD in T2DM patients. Methods: We used the Spanish primary care database BIFAP to perform a retrospective cohort study with a nested case-control analysis to assess the incidence, risk factors, and the effect of glucose-lowering drugs (GLDs) on the primary prevention of CKD. Results: From a cohort of 515,701 T2DM subjects (2.75 million person-years), we found 89,075 incident CKD cases, yielding an overall incidence rate (95%CI) of 324.3 (322.1–326.5) per 10,000 person-years. In the nested case–control analysis, gout, hyperuricemia, and hyperkalemia were the factors showing the highest AORs. Long-term users (≥3 years) of GLP1-RAs and SGLT-2i, compared to other GLDs, showed a decreased risk for CKD (AOR = 0.85; 95%CI: 0.73–0.99 and AOR = 0.89; 95%CI: 0.74–1.08, respectively), and for incident CKD at KDIGO stages G3-G5 (AOR = 0.72; 95%CI: 0.56–0.94 and AOR = 0.64; 95%CI: 0.46–0.91, respectively). Conclusions: In a real-world primary care setting, the long-term use of GLP-1RAs and SGLT-2i, but not other GLDs, appeared to decrease the risk of incident CKD in T2DM, supporting a role in primary prevention of CKD.

Uptake, effectiveness and safety of COVID-19 vaccines in individuals at clinical risk due to immunosuppressive drug therapy or transplantation procedures: a population-based cohort study in England

BackgroundImmunocompromised individuals are at increased risk of severe COVID-19 outcomes, underscoring the importance of COVID-19 vaccination in this population. The lack of comprehensive real-world data on vaccine uptake, effectiveness and safety in these individuals presents a critical knowledge gap, highlighting the urgency to better understand and address the unique challenges faced by immunocompromised individuals in the context of COVID-19 vaccination.MethodsWe analysed data from 12,274,946 people in the UK aged > 12 years from 01/12/2020 to 11/04/2022. Of these, 583,541 (4.8%) were immunocompromised due to immunosuppressive drugs, organ transplants, dialysis or chemotherapy. We undertook a cohort analysis to determine COVID-19 vaccine uptake, nested case–control analyses adjusted for comorbidities and sociodemographic characteristics to determine effectiveness of vaccination against COVID-19 hospitalisation, ICU admission and death, and a self-controlled case series assessing vaccine safety for pre-specified adverse events of interest.ResultsOverall, 93.7% of immunocompromised individuals received at least one COVID-19 vaccine dose, with 80.4% having received three or more doses. Uptake reduced with increasing deprivation (hazard ratio [HR] 0.78 [95%CI 0.77–0.79] in the most deprived quintile compared to the least deprived quintile for the first dose). Estimated vaccine effectiveness against COVID-19 hospitalisation 2–6 weeks after the second and third doses compared to unvaccinated was 78% (95%CI 72–83) and 91% (95%CI 88–93) in the immunocompromised population, versus 85% (95%CI 83–86) and 86% (95%CI 85–89), respectively, for the general population. Results showed COVID-19 vaccines were protective against intensive care unit (ICU) admission and death in both populations, with effectiveness of over 92% against COVID-19-related death and up to 95% in reducing ICU admissions for both populations following the third dose. COVID-19 vaccines were generally safe for immunocompromised individuals, though specific doses of ChAdOx1, mRNA-1273 and BNT162b2 raised risks of specific cardiovascular/neurological conditions.ConclusionsCOVID-19 vaccine uptake is high in immunocompromised individuals on immunosuppressive drug therapy or who have undergone transplantation procedures, with documented disparities by deprivation. Findings suggest that COVID-19 vaccines are protective against severe COVID-19 outcomes in this vulnerable population, and show a similar safety profile in immunocompromised individuals and the general population, despite some increased risk of adverse events. These results underscore the importance of ongoing vaccination prioritisation for this clinically at-risk population to maximise protection against severe COVID-19 outcomes.

Description of maternal and neonatal adverse events in pregnant people immunised with COVID-19 vaccines during pregnancy in the CLAP NETWORK of sentinel sites: nested case–control analysis of the immunization-associated risk – a study protocol

IntroductionCOVID-19 is associated with higher morbimortality in pregnant people compared with non-pregnant people. At present, the benefits of maternal immunisation are considered to outweigh the risks, and therefore, vaccination is...

Impact of thyroid hormone replacement on the risk of second cancer after thyroidectomy: a Korean National Cohort Study

We aimed to investigate the effect of thyroid hormone administration on the risk of second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer. Data were extracted from the medical billing data of the Health Insurance Review and Assessment Service in South Korea. Patients between 19 and 80 years old who underwent thyroid surgery at least once between January 2009 and June 2020 were included. Data of patients with second primary cancer and control patients with matched age, sex, operation date, and follow-up duration were extracted at a ratio of 1:4. A nested case–control analysis was performed to exclude length bias to confirm the correlation between the duration of thyroid hormone administration, dose, and incidence of second primary cancer. Of the 261,598 patients who underwent surgery for thyroid cancer included in the study, 11,790 with second primary cancer and 47,160 without second primary cancer were matched. The average dose of thyroid hormone increased the adjusted odds ratio (OR) for both low (≤ 50 μg, OR 1.29, confidence interval (CI) 1.12–1.48) and high (< 100 μg, OR 1.24, CI 1.12–1.37) doses. Analyzing over time, the adjusted OR of second primary cancer increased, especially in short (≤ 1 year) (OR 1.19; CI 1.06–1.34) and long (> 5 years) duration (OR 1.25; CI 1.10–1.41). In conclusion, insufficient and excessive thyroid hormone replacement might be linked to increased second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer.

Staphylococcus aureus surgical site infection rates in 5 European countries

ObjectiveTo determine the overall and procedure-specific incidence of surgical site infections (SSI) caused by Staphylococcus aureus (S. aureus) as well as risk factors for such across all surgical disciplines in Europe.MethodsThis is a retrospective cohort of patients with surgical procedures performed at 14 European centres in 2016, with a nested case–control analysis. S. aureus SSI were identified by a semi-automated crossmatching bacteriological and electronic health record data. Within each surgical procedure, cases and controls were matched using optimal propensity score matching.ResultsA total of 764 of 178 902 patients had S. aureus SSI (0.4%), with 86.0% of these caused by methicillin susceptible and 14% by resistant pathogens. Mean S. aureus SSI incidence was similar for all surgical specialties, while varying by procedure.ConclusionsThis large procedure-independent study of S. aureus SSI proves a low overall infection rate of 0.4% in this cohort. It provides proof of principle for a semi-automated approach to utilize big data in epidemiological studies of healthcare-associated infections.Trials registration The study was registered at clinicaltrials.gov under NCT03353532 (11/2017).

The incidence, risk factors and outcomes of wound complications after preoperative radiotherapy and surgery for high grade extremity soft tissue sarcomas: A 14-year retrospective study

ObjectiveThe aim of this study was to analyze the wound complication (WC) rate and to determine the risk factors for WC in patients with soft tissue sarcoma treated with preoperative radiotherapy followed by surgical resection. MethodsUsing the database of Oxford University Hospital (OUH) we retrospectively studied 126 cases of soft tissue sarcomas treated with preoperative radiotherapy and surgery between 2007 and 2021. WC were defined as minor wound complication (MiWC) not requiring surgical intervention or major wound complication (MaWC) if they received a secondary surgical intervention. Univariate and multiple regression analyses were performed using frequency of WC and MaWC as a dependent variable. ResultsThe incidence of WC and MaWC was 43.7% (55/126) and 19% (24/126). Age (OR:1.03, 95%CI: 1.00–1.06, p = 0.016), tumor size (OR:1.11, 95%CI:1.01–1.21, p = 0.027) and tumor site namely proximal lower limb vs upper limb (OR:10.87, 95%CI 1.15–103.03, p = 0.038) were risk factors on multivariate analysis. In nested case control analysis, the incidence of MaWC was 43.6% (24/55), the mean recovery time is 143 days in patients with MaWC. Smoking increases the risk for MaWC (OR:8.32, 95%CI:1.36–49.99, p = 0.022). The time interval between surgery and wound complication reduces the risk for MaWC (OR:0.91, 95%CI:0.84–0.99, p = 0.028) in multivariate analysis. ConclusionsAge, tumor site and size are risk factors for WC requiring preoperative radiotherapy. Smoking and the time interval between surgery and wound complication are risk factors for MaWC as compared with MiWC. MaWC rate (19%) are comparable to those in postoperative radiotherapy and surgery alone.

Statin Treatment on Cardiovascular Risk After Retinal Artery Occlusion: A Historical Cohort Study

IntroductionRetinal artery occlusion (RAO) is a major cause of acute visual loss and patients with RAO have an increased risk for subsequent cardiovascular events. However, there is little evidence of whether the use of statins is associated with the prevention of cardiovascular events in patients with RAO. We investigated whether statin treatment in patients with RAO is associated with a lower risk of cardiovascular events.MethodsThis study was a historical cohort study with nested case–control analysis. Using the nationwide health insurance claims database in Korea, we retrospectively established a cohort of newly diagnosed RAO patients without prior cardiovascular events between January 2008 and March 2020. We defined the case group as those who had cardiovascular events (stroke or myocardial infarction) and the control group as RAO patients without primary outcome matched by sex, age, comorbidities, and duration of follow-up (1:2 incidence density sampling). Conditional logistic regression was performed.ResultsAmong 13,843 patients newly diagnosed with RAO, 1030 patients had cardiovascular events (mean follow-up period of 6.4 ± 3.7 years). A total of 957 cases were matched to 1914 controls. Throughout the study period, the proportion of patients taking statin was less than half. Statin treatment after RAO was associated with a low risk of cardiovascular events (adjusted OR, 0.637; 95% CI 0.520–0.780; P < 0.001). A longer duration of statin exposure was associated with a lower cardiovascular risk.ConclusionsIn patients with newly diagnosed RAO, treatment with statins, particularly long-term use, was associated with a low risk of future cardiovascular events.

Influence of extent of surgical resection on post-hepatectomy shoulder pain: an observational study

Shoulder pain frequently follows hepatectomy. However, the influence of surgical procedures on shoulder pain is unclear. In this observational study, patients who underwent hepatectomy were enrolled in Shanghai Cancer Center. Shoulder pain and surgical pain were assessed using the numeric rating scale 2 days after surgery. The incidence of shoulder pain was the outcome of the cohort study. Nested case–control analyses were further applied. Three hundred and twelve patients were finally enrolled in this study. Nested case–control analysis showed that there were no significant differences in the number of surgical segments between the two groups (P = 0.09). In addition, minor hepatectomy did not reduce the incidence of shoulder pain compared with major hepatectomy (P = 0.37). The drainage volume within 2 days after surgery was significantly more in those patients with shoulder pain (P = 0.017). In open surgery, surgical sites involving the right anterior lobe (OR (95% CI) 2.021 (1.075, 3.802), P = 0.029) and right posterior lobe (OR (95% CI) 2.322 (1.193, 4.522), P = 0.013) were both independent risk factors for shoulder pain. Left shoulder pain also occurred in patients who did not receive left lateral hepatectomy. The preventive phrenic nerve block was not suitable for post-hepatectomy shoulder pain. Stronger preventative intervention should be used in those high-risk patients.

The relationship between neuron-specific enolase, high sensitivity C reactive protein, and diabetic peripheral neuropathy in Chinese patients with type 2 diabetes: A prospective nested case–control analysis

BackgroundDiabetic peripheral neuropathy (DPN) involves a very complex pathogenesis, and there is no neuro-specific marker for risk prediction. Neuron-specific enolase (NSE), a key enzyme in glycolysis, has a broad spectrum neurotrophic and neuroprotective effect on neurons, and also cause injury and inflammatory response of peripheral nerves. The relationship between neuron-specific enolase, highly sensitive c-reactive protein (hsCRP), and diabetic peripheral neuropathy remains unclear. We aimed to investigate whether elevated serum NSE and hsCRP levels increased the risk of DPN in patients with type 2 diabetes.Materials and methodsIn this prospective nested case–control study, a total of 1072 eligible subjects with type 2 diabetes constituted the follow-up cohort. Demographic data and parameters including serum NSE and hsCRP were collected at baseline. Two neuropathy screening scales (MNSI and MDNS) were used to assess DPN during follow-up period. Nerve conduction studies were performed at the end of follow-up. Conditional logistic regression was used to inspect the risk factors of the incidence of DPN.ResultsDuring an average follow-up period of 5.1 years, 176 subjects developed DPN. Serum NSE and hsCRP levels at baseline were significantly higher in DPN group than in matched non-DPN groups (p < 0.001). NSE was positively correlated with age and hsCRP (p < 0.001). The amplitude of sensory nerve action potential and compound muscle action potential of the lower extremity nerves were significantly decreased in the high tertile of NSE. After adjustment for matching and confusing factor, conditional logistic regression showed the risk of DPN in the high tertile of NSE level was still 3.176 times higher than that in the low tertile of NSE level (p < 0.001).ConclusionElevated serum NSE levels predicted the high incidence of DPN in Chinese patients with type 2 diabetes for an average of 5.1 years, which may be associated with increased neuroinflammatory response caused by high NSE levels, but further studies are needed.

Safety and effectiveness of rivaroxaban for prevention of stroke in patients with nonvalvular atrial fibrillation: analysis of routine clinical data from four countries

ABSTRACT Background The safety and effectiveness of rivaroxaban versus vitamin K antagonists (standard of care [SOC]) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) was evaluated in Europe. Research design and methods Observational studies were conducted in the UK, the Netherlands, Germany, and Sweden. Primary safety outcomes were hospitalization for intracranial hemorrhage, gastrointestinal bleeding, or urogenital bleeding among new users of rivaroxaban and SOC with NVAF; outcomes were analyzed using cohort (rivaroxaban or SOC use) and nested case–control designs (current vs nonuse). Statistical analyses comparing rivaroxaban and SOC cohorts were not performed. Results Overall, 162,919 rivaroxaban users and 177,758 SOC users were identified. In the cohort analysis, incidence ranges for rivaroxaban users were 0.25–0.63 events per 100 person-years for intracranial bleeding, 0.49–1.72 for gastrointestinal bleeding, and 0.27–0.54 for urogenital bleeding. Corresponding ranges for SOC users were 0.30–0.80, 0.30–1.42, and 0.24–0.42, respectively. In the nested case–control analysis, current SOC use generally presented a greater risk of bleeding outcomes than nonuse. Rivaroxaban use (vs nonuse) was associated with a higher risk of gastrointestinal bleeding, but a similar risk of intracranial or urogenital bleeding, in most countries. Ischemic stroke incidence ranged from 0.31 to 1.52 events per 100 person-years for rivaroxaban users. Conclusions Incidences of intracranial bleeding were generally lower with rivaroxaban than with SOC, whereas incidences of gastrointestinal and urogenital bleeding were generally higher. The safety profile of rivaroxaban for NVAF in routine practice is consistent with findings from randomized controlled trials and other studies.

Association between COVID-19 and consistent mask wearing during contact with others outside the household-A nested case-control analysis, November 2020-October 2021.

Face masks have been recommended to reduce SARS-CoV-2 transmission. However, evidence of the individual benefit of face masks remains limited, including by vaccination status. As part of the COVID-19 Community Research Partnership cohort study, we performed a nested case-control analysis to assess the association between self-reported consistent mask use during contact with others outside the household and subsequent odds of symptomatic SARS-CoV-2 infection (COVID-19) during November 2020-October 2021. Using conditional logistic regression, we compared 359 case-participants to 3544 control-participants who were matched by date, adjusting for enrollment site, age group, sex, race/ethnicity, urban/rural county classification, and healthcare worker occupation. COVID-19 was associated with not consistently wearing a mask (adjusted odds ratio [aOR] 1.49; 95% confidence interval [CI] [1.14, 1.95]). Compared with persons ≥14 days after mRNA vaccination who also reported always wearing a mask, COVID-19 was associated with being unvaccinated (aOR 5.94; 95% CI [3.04, 11.62]), not wearing a mask (aOR 1.62; 95% CI [1.07, 2.47]), or both unvaccinated and not wearing a mask (aOR 9.07; 95% CI [4.81, 17.09]). Our findings indicate that consistent mask wearing can complement vaccination to reduce the risk of COVID-19.

Risk factors for community-acquired bacterial infection among young infants in South Asia: a longitudinal cohort study with nested case–control analysis

ObjectiveRisk factors predisposing infants to community-acquired bacterial infections during the first 2 months of life are poorly understood in South Asia. Identifying risk factors for infection could lead to improved...

Antiretroviral therapy adherence patterns, virological suppression, and emergence of drug resistance: A nested case-control study from Uganda and South Africa.

Relationships between distinct antiretroviral therapy (ART) adherence patterns and risk of drug resistance are not well understood. We conducted a nested case-control analysis within a longitudinal cohort study of individuals initiating efavirenz-based ART. Primary outcomes of interest, measured at 6 and 12months after treatment initiation, were: 1) virologic suppression, 2) virologic failure with resistance, and 3) virologic failure without resistance. Our primary exposure of interest was ART adherence, measured over the 6months before each visit with electronic pill monitors, and categorized in three ways: 1) 6months average adherence; 2) running adherence, defined as the proportion of days with average adherence over 9days of less than or equal to 10%, 20%, and 30%; and 3) number of 3-, 7-, and 28-day treatment gaps in the prior 6months. We analyzed data from 166 individuals (107 had virologic failure during observation and 59 had virologic suppression at 6 and 12months). Average adherence was higher among those with virologic suppression (median 83%, IQR 58-96%) versus those with virologic failure with resistance (median 35%, IQR 20-77%, pairwise P < 0.01) and those with virologic failure without resistance (median 21%, IQR 2-54%, pairwise P < 0.01). Although treatment gaps generally predicted virologic failure (P < 0.01), they did not differentiate failure with and without drug resistance (P > 0.6). Average adherence patterns, but not the assessed frequency of treatment gaps, differentiated failure with versus without drug resistance among individuals initiating efavirenz-based ART. Future work should explore adherence-resistance relationships for integrase inhibitor-based regimens.

Use of combined oral contraceptives and risk of venous thromboembolism in young women: a nested case-control analysis using German claims data.

To compare the risk of venous thromboembolism (VTE) among young women for nine combined oral contraceptives (COCs), including progestogens with an as yet unclear risk of VTE such as chlormadinone and nomegestrol, using COCs containing levonorgestrel with low ethinylestradiol (<50 μg) as a reference. Case-control study nested in a cohort of new users of COCs. German claims data. A total of 1166 cases of VTE matched to 11 660 controls nested in a cohort of 677 331 girls and young women aged 10-19 years with one or more COCs dispensed between 2005 and 2017 after a 1-year period without any COCs. Confounder-adjusted odds ratios (aORs) of VTE associated with current use of the respective COCs were calculated using conditional logistic regression. Venous thromboembolism (VTE), defined as a diagnosis of pulmonary embolism or deep vein thrombosis. Compared with levonorgestrel with low ethinylestradiol (<50 μg), the risk of VTE was increased two-fold for COCs containing dienogest (aOR2.23, 95%CI 1.77-2.80), cyproterone (aOR2.15, 95%CI 1.43-3.25), chlormadinone (aOR2.06, 95% CI 1.58-2.68), desogestrel (aOR1.93, 95%CI 1.44-2.61) and drospirenone (aOR1.89, 95% CI1.41-2.55), and increased five-fold for gestodene (aOR 5.05, 95% CI 1.23-20.74). For norgestimate and nomegestrol, the point estimates suggest a two-fold increased risk (aOR1.90, 95%CI 0.62-5.81) and 40% increased risk (aOR1.41, 95%CI 0.52-3.81), respectively. Our study confirms that levonorgestrel with low ethinylestradiol (<50 μg) is the COC associated with the lowest risk of VTE and suggests that for chlormadinone the risk of VTE is two times higher, and thus in the same range as for desogestrel and drospirenone.

Increased Mild Vaccine-Related Side Effects and Higher Specific Antibody Titers in Health Care Workers with Previous SARS-CoV-2 Infection after the mRNA BNT162b2 Vaccine.

Background: to evaluate whether prior SARS-CoV-2 infection affects side effects and specific antibody production after vaccination with BNT162b2. Methods: We included 1106 health care workers vaccinated with BNT162b2. We assessed whether prior SARS-CoV-2 infection affects the number and type of side effects and performed a nested case–control analysis comparing plasma levels of specific IgG titers between SARS-CoV-2-naïve and previously infected subjects after the first and the second vaccine doses. Results: After the first dose, SARS-CoV-2-naïve subjects experienced side effects more often than SARS-CoV-2 naïve subjects. Individuals with prior SARS-CoV-2 infection more often reported pain at the injection site, weakness, and fever than SARS-CoV-2-naïve subjects. After the second dose, the frequency of side effects was similar in the two groups. All subjects with prior SARS-CoV-2 infection developed either a high (>100 AU/mL) or intermediate (10–100 AU/mL) antibody titer. Among SARS-CoV-2-naïve subjects, the majority developed an intermediate titer. After the second dose, a high (>2000 AU/mL) antibody titer was more common among subjects with prior SARS-CoV-2 infection. Conclusions: vaccine-related side effects and a higher anti-SARS-CoV-2-RBD IgG titer were more common in subjects with previous infection than in SARS-CoV-2-naïve after the first, but not after the second dose of the BNT162b2 vaccine.

Safety and effectiveness of appropriately and inappropriately dosed rivaroxaban or apixaban versus warfarin in patients with atrial fibrillation: a cohort study with nested case–control analyses from UK primary care

ObjectivesTo investigate effects of appropriately and inappropriately dosed apixaban/rivaroxaban versus warfarin on effectiveness and safety outcomes in patients with non-valvular atrial fibrillation (NVAF).DesignCohort study with nested case–control analyses using primary...

Serum metabolomic signatures of gestational diabetes in South Asian and white European women

IntroductionThis study aimed to identify serum metabolomic signatures associated with gestational diabetes mellitus (GDM), and to examine if ethnic-specific differences exist between South Asian and white European women.Research design and...

An Observational Study to Assess the Effectiveness of 4CMenB against Meningococcal Disease and Carriage and Gonorrhea in Adolescents in the Northern Territory, Australia-Study Protocol.

Invasive meningococcal disease (IMD) causes significant morbidity and mortality worldwide with serogroup B being the predominant serogroup in Australia and other countries for the past few decades. The licensed 4CMenB vaccine is effective in preventing meningococcal B disease. Emerging evidence suggests that although 4CMenB impact on carriage is limited, it may be effective against gonorrhoea due to genetic similarities between Neisseria meningitidis and Neisseria gonorrhoeae. This study protocol describes an observational study that will assess the effect of the 4CMenB vaccine against meningococcal carriage, IMD and gonorrhoea among adolescents in the Northern Territory (NT). All 14–19-year-olds residing in the NT with no contraindication for 4CMenB vaccine will be eligible to participate in this cohort study. Following consent, two doses of 4CMenB vaccine will be administered two months apart. An oropharyngeal swab will be collected at baseline and 12 months to detect pharyngeal carriage of Neisseria meningitidis by PCR. The main methodological approaches to assess the effect of 4CMenB involve a nested case control analysis and screening method to assess vaccine effectiveness and an Interrupted Time Series regression analysis to assess vaccine impact. Research ethics approvals have been obtained from Menzies and Central Australian Human Research Ethics Committees and the Western Australian Aboriginal Health Ethics Committee. Results will be provided in culturally appropriate formats for NT remote and regional communities and published in international peer reviewed journals. ClinicalTrials.gov Identifier: NCT04398849.

Culprit Medications and Risk Factors Associated with Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis: Population-Based Nested Case-Control Study.

ObjectiveOur objective was to describe the incidence of Stevens–Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in a large unselected cohort, to validate the culprit drugs involved and the frequency of SJS/TEN for each drug, and to analyze the clinical risk factors for SJS/TEN.MethodsUsing the computerized database of Clalit Health Services, we identified all adult patients with a new SJS/TEN diagnosis between 1 January, 2008 and 30 June, 2019 and validated each case. Cumulative incidence of SJS/TEN for each culprit drug was calculated by dividing the number of valid cases by the total number of new users of the drug in the study period. Using risk-set sampling, 20 controls were matched to each case by sex and age on the index date for a nested case–control analysis. Multivariable conditional logistic regression was used to estimate the odds ratio and 95% confidence interval for the association of incident SJS/TEN with chronic diseases.ResultsWe identified 87 adult cases of true/probable SJS/TEN between 1 January, 2008 and 30 June, 2019. Culprit drugs [with ALDEN scores ascertained as at least probable (≥ 4)] associated with the highest absolute risks were phenytoin, lamotrigine, and allopurinol with 3.56, 2.82, and 1.10 SJS/TEN cases/10,000 new users, respectively. Additional drugs with mean ALDEN scores ≥ 4 were sunitinib, sulfasalazine, carbamazepine, etoricoxib, etodolac, and cefuroxime, cumulative incidence: 13.57, 0.72, 0.32, 0.05, 0.02, and 0.02/10,000 new users, respectively. Previous diagnosis of systemic lupus erythematosus, psoriasis, previous drug allergies, epilepsy, malignancy, history of cerebrovascular accident, and history of diabetes mellitus were associated with an increased risk for SJS/TEN, odds ratios (95% confidence interval):17.41 (1.31–230.72), 10.28 (3.61–29.31), 5.21 (2.95–9.19), 4.92 (1.88–12.85), 3.17 (1.77–5.66), 2.61 (1.26–5.41), and 1.98 (1.12–3.53), respectively.ConclusionsAttention should be drawn to drugs assessed by high ALDEN scores that were associated with high absolute risks for SJS/TEN. Psoriasis, former drug allergies, in addition to systemic lupus erythematosus, malignancy, history of cerebrovascular accident, and diabetes mellitus were associated with increased SJS/TEN risk in our analysis.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40257-021-00661-0.