Purpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in... Show morePurpose: Sepsis is one of the leading causes of morbidity and mortality worldwide with approximately 50 million annual cases. There is ongoing debate on the clinical benefit of hydrocortisone in the prevention of death in septic patients. Here we evaluated the association between hydrocortisone treatment and mortality in patients diagnosed with sepsis in a large-scale clinical dataset.Methods: Data from patients between 2008 and 2019 were extracted from the retrospective Medical Information Mart for Intensive Care IV (MIMIC-IV) database. Patients who received hydrocortisone after diagnosis were matched using propensity-score matching with patients who did not, to balance confounding (by indication and contraindication) factors between the groups. 90-day mortality and survivors' length of hospital stay was compared between patients who did or did not receive hydrocortisone.Results: A total of 31,749 septic patients were included in the study (mean age: 67, men: 57.3%, in-hospital mortality: 15.6%). 90-day mortality was higher among the 1802 patients receiving hydrocortisone when compared with the 6348 matched non-users (hazard ratio: 1.35, 95% CI: 1.24-1.47). Hydrocortisone treatment was also associated with increased in-hospital mortality (40.9% vs. 27.6%, p < 0.0001) and prolonged hospital stay in those who survived until discharge (median 12.6 days vs. 10.8 days, p < 0.0001). Stratification for age, gender, ethnicity, occurrence of septic shock, and the need for vasopressor drug administration such as (nor) epinephrine did not reveal sub-population(s) benefiting of hydrocortisone use.Conclusion: Hydrocortisone treatment is associated with increased risk of death as well as prolonged hospital stay in septic patients. Although residual confounding (by indication) cannot be ruled out completely due to the observational nature of the study, the present study suggests clinical implication of hydrocortisone use in patients with sepsis. Show less
PHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a... Show morePHARMACOM-EPI is a novel framework to predict plasma concentrations of drugs at the time of occurrence of clinical outcomes. In early 2021, the U.S. Food and Drug Administration (FDA) issued a warning on the anti-seizure drug lamotrigine claiming that it has the potential to increase the risk of arrhythmias and related sudden cardiac death due to a pharmacological sodium channel-blocking effect. We hypothesized that the risk of ar-rhythmias and related death is due to toxicity. We used the PHARMACOM-EPI framework to investigate the relationship between lamotrigine's plasma concentrations and the risk of death in older patients using real-world data. Danish nationwide administrative and healthcare registers were used as data sources and individuals aged 65 years or older during the period 1996 - 2018 were included in the study. According to the PHARMACOM-EPI framework, plasma concentrations of lamotrigine were predicted at the time of death and patients were cate-gorized into non-toxic and toxic groups based on the therapeutic range of lamotrigine (3-15 mg/L). Over 1 year of treatment, the incidence rate ratio (IRR) of all-cause mortality was calculated between the propensities score matched toxic and non-toxic groups. In total, 7286 individuals were diagnosed with epilepsy and were exposed to lamotrigine, 432 of which had at least one plasma concentration measurement The pharmacometric model by Chavez et al. was used to predict lamotrigine's plasma concentrations considering the lowest absolute percentage error among identified models (14.25 %, 95 % CI: 11.68-16.23). The majority of lamotrigine associated deaths were cardiovascular-related and occurred among individuals with plasma concentrations in the toxic range. The IRR of mortality between the toxic group and non-toxic group was 3.37 [95 % CI: 1.44-8.32] and the cumulative incidence of all-cause mortality exponentially increased in the toxic range. Application of our novel framework PHARMACOM-EPI provided strong evidence to support our hypothesis that the increased risk of all-cause and cardiovascular death was associated with a toxic plasma concentration level of lamotrigine among older lamo-trigine users. Show less
This dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This... Show moreThis dissertation focuses on developing new mathematical and statistical methods to properly represent time-varying covariates and model them within the context of time-to-event analysis. This research topic is motivated by specific clinical questions aimed at gaining insights into personalised treatments for cardiological and oncological patients. The main purpose is to enrich the knowledge available for modelling patients’ survival with relevant features related to the time-varying processes of interest.The efforts of this work address the complexities of both (i) developing adequate dynamic characterizations of the processes under study (i.e., representation problem) and (ii) identifying and quantifying the association between time-varying processes and patient survival (i.e., time-to-event modelling problem). In both cases, the main issue is dealing with complex data sources while taking into account the nature of the processes and managing the complex trade-off between clinical interpretability and mathematical formulation.By solving the aforementioned statistical complexities, this work is not only impacting the community of researchers in mathematics and statistics. The development of these novel methodologies may represent a significant step forward in the definition of customized and flexible monitoring tools to support doctors and clinicians in their work.*********This doctoral dissertation was part of a cotutelle agreement between the Politecnico di Milano and Leiden University Show less
This thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to... Show moreThis thesis investigates the effectiveness and safety of treatments in patients with cardiovascular and kidney disease. Routinely collected healthcare data provide an immense opportunity to investigate such questions in populations underrepresented in clinical trials, such as patients with advanced chronic kidney disease (CKD).The first part of this thesis deals with how to appropriately use routinely collected data to answer causal questions. It illustrates what study designs eliminate commonly occurring biases, namely immortal time and prevalent user bias, and how to use propensity scores to correctly adjust for confounding in the setting of time-fixed and time-varying treatments.The second part investigates the effectiveness and safety of various treatments. For instance, the effectiveness of beta-blockers in patients with heart failure and advanced CKD is investigated. Renin-angiotensin system inhibitors (RASi) are an especially widely used medication class in CKD patients. The relationship between the magnitude of renal function decline - which is commonly observed after initiation of these drugs - with mortality and cardiorenal outcomes is investigated. In addition, comparative effectiveness study of RASi and calcium channel blockers among patients with advanced CKD is performed. In the last two chapters, a target trial is explicitly emulated to investigate the effect of stopping or continuing RASi and the optimal timing to start dialysis in patients with advanced chronic kidney disease. Show less
Hendriksen, L.C.; Linden, P.D. van der; Lagro-Janssen, A.L.M.; Bemt, P.M.L.A. van den; Siiskonen, S.J.; Teichert, M.; ... ; Visser, L.E. 2021
Background Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more... Show moreBackground Adverse drug events, including adverse drug reactions (ADRs), are responsible for approximately 5% of unplanned hospital admissions: a major health concern. Women are 1.5-1.7 times more likely to develop ADRs. The main objective was to identify sex differences in the types and number of ADRs leading to hospital admission. Methods ADR-related hospital admissions between 2005 and 2017 were identified from the PHARMO Database Network using hospital discharge diagnoses. Patients aged >= 16 years with a drug possibly responsible for the ADR and dispensed within 3 months before admission were included. Age-adjusted odds ratios (OR) with 95% CIs for drug-ADR combinations for women versus men were calculated. Results A total of 18,469 ADR-related hospital admissions involving women (0.35% of all women admitted) and 14,678 admissions involving men (0.35% of all men admitted) were included. Most substantial differences were seen in ADRs due to anticoagulants and diuretics. Anticoagulants showed a lower risk of admission with persistent haematuria (ORadj 0.31; 95%CI 0.21, 0.45) haemoptysis (ORadj 0.47, 95%CI 0.30,0.74) and subdural haemorrhage (ORadj 0.61; 95%CI 0.42,0.88) in women than in men and a higher risk of rectal bleeding in women (ORadj 1.48; 95%CI 1.04,2.11). Also, there was a higher risk of admission in women using thiazide diuretics causing hypokalaemia (ORadj 3.03; 95%CI 1.58, 5.79) and hyponatraemia (ORadj 3.33, 95%CI 2.31, 4.81) than in men. Conclusions There are sex-related differences in the risk of hospital admission in specific drug-ADR combinations. The most substantial differences were due to anticoagulants and diuretics. Show less
Purpose: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all... Show morePurpose: Potential drug-drug interactions (pDDIs) may harm patients admitted to the Intensive Care Unit (ICU). Due to the patient's critical condition and continuous monitoring on the ICU, not all pDDIs are clinically relevant. Clinical decision support systems (CDSSs) warning for irrelevant pDDIs could result in alert fatigue and overlooking important signals. Therefore, our aim was to describe the frequency of clinically relevant pDDIs (crpDDIs) to enable tailoring of CDSSs to the ICU setting. Materials & methods: In this multicenter retrospective observational study, we used medication administration data to identify pDDIs in ICU admissions from 13 ICUs. Clinical relevance was based on a Delphi study in which intensivists and hospital pharmacists assessed the clinical relevance of pDDIs for the ICU setting. Results: The mean number of pDDIs per 1000 medication administrations was 70.1, dropping to 31.0 when con -sidering only crpDDIs. Of 103,871 ICU patients, 38% was exposed to a crpDDI. The most frequently occurring crpDDIs involve QT-prolonging agents, digoxin, or NSAIDs. Conclusions: Considering clinical relevance of pDDIs in the ICU setting is important, as only half of the detected pDDIs were crpDDIs. Therefore, tailoring CDSSs to the ICU may reduce alert fatigue and improve medication safety in ICU patients. ? 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/). Show less
Klatte, D.C.F.; Gasparini, A.; Xu, H.; Deco, P. de; Trevisan, M.; Johansson, A.L.V.; ... ; Carrero, J.J. 2017
Cutaneous melanoma is the most aggressive form of skin cancer and its incidence among Caucasian populations has increased whereas mortality rates are stabilizing or decreasing. The total burden of... Show moreCutaneous melanoma is the most aggressive form of skin cancer and its incidence among Caucasian populations has increased whereas mortality rates are stabilizing or decreasing. The total burden of melanoma is expected to be increasing. As effective treatment options for advanced melanoma are lacking, melanoma prevention may be the key issue in melanoma disease control. Although sun protection programs have increased awareness, they have not resulted in a decreased melanoma incidence. In addition, most melanoma risk factors are not amenable. Alternative approaches such as cancer chemoprevention are, therefore, important research topics. Several agents, such as statins, non-steroidal anti-inflammatory drugs, and angiotensin-converting enzyme inhibitors, have been claimed to have chemopreventive properties. However, it is unknown which of these have the best potential to be useful. This thesis presents: - epidemiologic cancer registry-based studies from The Netherlands on the epidemiology of extracutaneous melanoma and on the burden of disease due to cutaneous melanoma - a qualitative review discussing candidate drugs for melanoma chemoprevention, their possible mechanisms of action, and evidence for their chemopreventive efficacy, safety and tolerability - pharmacoepidemiological studies testing hypotheses on chemopreventive activityof several drugs on melanoma - pharmacoepidemiological studies on the association between estrogen use and melanoma. Show less
