Maarten J. ten Berg

Linking Laboratory and medication data: new opportunities for pharmacoepidemiological research

Abstract Transfer of automated laboratory data collected during routine clinical care from the laboratory information system into a database format that enables linkage to other administrative (e.g., patient characteristics) or clinical (e.g., medication, diagnoses, procedures) data provides a valuable tool for clinical epidemiological research. It allows the investigation of biochemical characteristics of diseases, therapeutic effects and diagnostic and/or prognostic markers for disease with easy access and at relatively low cost. To this end, the Utrecht Patient Oriented Database (UPOD), an infrastructure of relational databases comprising data on patient characteristics, laboratory test results, medication orders, hospital discharge diagnoses and medical procedures for all patients treated at the University Medical Centre Utrecht since January 2004, was established. Current research within UPOD is focused on the innovative linkage of laboratory and medication data, which, for example, makes it possible to assess the quality of pharmacotherapy in clinical practice, to investigate interference between laboratory tests and drugs, to study the risk of adverse drug reactions, and to develop diagnostic and prognostic markers or algorithms for adverse drug reactions. Although recently established, we believe that UPOD broadens the opportunities for clinical pharmacoepidemiological research and can contribute to patient care from a laboratory perspective. Clin Chem Lab Med 2007;45:13–9.

Meta-Analysis of Placebo Rates in Major Depressive Disorder Trials

BACKGROUND: Placebo effects in major depressive disorder (MDD) have received much interest in the medical literature. However, few quantitative analyses have been done in homogeneous populations. OBJECTIVE: To determine efficacy rates for placebo in patients with MDD; to quantify the correlation between efficacy and publication year, as well as between placebo and drug response rates. DESIGN: Searching MEDLINE (1966–December 2000), EMBASE (1998–February 2001), HealthSTAR (1975–December 2000), and Cochrane (1980–December 2000) databases, randomized, placebo-controlled trials were retrieved including patients with MDD as defined by Diagnostic and Statistical Manual of Mental Disorders, 3rd and 4th editions criteria, Hamilton Rating Scale for Depression score ≥18 or Montgomery—Asberg Depression Rating Scale score ≥16, reporting successes as 50% decreases in scores after 6–8 weeks of treatment. Response rates were summarized using a random effects meta-analysis for per protocol (PP) and intent-to-treat (ITT) results. RESULTS: We included 24 of 134 potential studies examining 4459 patients, 1786 on placebo and 2673 on an antidepressant. Placebo response rates were 45.5% (PP) and 26.9% (ITT). Correlations were significant between year and rates (PP rho 0.448, p = 0.042; ITT rho 0.557; p = 0.006), but not for active drugs. Placebo and drug rates were correlated (PP r 0.397, p = 0.020; ITT r 0.539; p = 0.002). CONCLUSIONS: These placebo rates confirm those reported previously, but were from a homogeneous population. Although statistically significant, the correlation between drug and placebo rates was lower than others reported. During the study period, placebo rates increased linearly; active drugs did not. Correlations between placebo and drug response rates reflected moderate to strong effect sizes. We suggest that current methodology has been unsuccessful in achieving unbiased double-blind conditions not influenced by extra-trial factors, including time.

Drug-induced thrombocytopenia: a population study.

AbstractBackground: Drug-induced immune thrombocytopenia, excluding heparin-induced thrombocytopenia, is a rare adverse drug reaction for which the evidence about frequency, relative risk and risk factors mainly originates from case reports and case studies. This study aims to quantify the risk for thrombocytopenia following exposure to drugs that are most often reported to cause thrombocytopenia in the general population. Methods: A retrospective, case-control study was conducted within the PHARMO record linkage system. Cases were defined as patients hospitalised for thrombocytopenia in the period 1 January 1990 to 31 December 2002. For each case, up to four controls were matched based on age, sex and geographical area. Exposure on the index date to anticonvulsants, β-lactam antibacterials, cinchona alkaloids, disease modifying antirheumatic drugs (DMARDs), diuretics, NSAIDs, sulfonamide antibacterials and tuberculostatics was assessed and categorised into mutually exclusive groups of current, recent, past and non-use. The risk was quantified with multivariate conditional logistic regression analysis. Results: The study population comprised 705 cases and 2658 controls. Current use of β-lactam antibacterials was associated with an increased risk for thrombocytopenia (adjusted odds ratio 7.4, 95% CI 1.8, 29.6). Increased risk estimates, although not significant, were found for current exposure to DMARDs and the sulfonamide antibacterial cotrimoxazole (trimethoprim/sulfamethoxazole). No increased risk was found for anticonvulsants, cinchona alkaloids, diuretics, NSAIDs or tuberculostatics. Conclusion: More evidence for an increased risk for thrombocytopenia in current use of β-lactam antibacterials in the general population was provided. The expected increase in risk could not be confirmed for the other drugs investigated, which is possibly a result of the limited statistical power. Future studies including more patients and with laboratory data should confirm our findings before drawing definite conclusions.

Seasonal changes in gene expression represent cell-type composition in whole blood

Seasonal patterns in behavior and biological parameters are widespread. Here, we examined seasonal changes in whole blood gene expression profiles of 233 healthy subjects. Using weighted gene co-expression network analysis, we identified three co-expression modules showing circannual patterns. Enrichment analysis suggested that this signal stems primarily from red blood cells and blood platelets. Indeed, a large clinical database with 51 142 observations of blood cell counts over 3 years confirmed a corresponding seasonal pattern of counts of red blood cells, reticulocytes and platelets. We found no direct evidence that these changes are linked to genes known to be key players in regulating immune function or circadian rhythm. It is likely, however, that these seasonal changes in cell counts and gene expression profiles in whole blood represent biological and clinical relevant phenomena. Moreover, our findings highlight possible confounding factors relevant to the study of gene expression profiles in subjects collected at geographical locations with disparaging seasonality patterns.

Thrombocytopenia in adult cancer patients receiving cytotoxic chemotherapy: results from a retrospective hospital-based cohort study.

Background: Data on the frequency and relative risk (RR) of chemotherapy-induced thrombocytopenia (CIT) in patients with solid tumours receiving chemotherapy in clinical practice are limited.Objective: The aim of the study was to estimate the frequency and RR of thrombocytopenia in adult patients with solid tumours receiving chemotherapy treatment.Methods: For this retrospective, hospital-based study, adult patients with solid tumours who received chemotherapy at the University Medical Center Utrecht in the period 2004–6 were identified from the Utrecht Patient Oriented Database. We examined the frequency of (i) overall thrombocytopenia (defined as platelet count <100 × 109/L) with or without other cytopenias; (ii) isolated thrombocytopenia (i.e. without other cytopenias); and (iii) the frequency and RR of overall thrombocytopenia and isolated thrombocytopenia associated with different cytotoxic agents.Results: A total of 614 patients receiving one of 37 different chemotherapy regimens was included. Overall thrombocytopenia frequency was 21.8% and isolated thrombocytopenia frequency was 6.2%. The highest frequencies of thrombocytopenia were observed in patients receiving carboplatin monotherapy (81.8%) and combination therapies that included carboplatin (58.2%), gemcitabine (64.4%) or paclitaxel (59.3%). The highest RRs of thrombocytopenia, compared with cisplatin-based therapy, were observed for combination therapies of carboplatin/gemcitabine (RR 10.1; 95% CI 5.5, 18.5) and carboplatin/paclitaxel/etoposide (RR 11.8; 95% CI 6.7, 20.8). In 54% of cases, the thrombocytopenia was of grade 2–4, which are considered to be the most clinically relevant grades. The highest frequencies of isolated thrombocytopenia were found with combination therapies that included oxaliplatin (28.6%) or gemcitabine (28.9%).Conclusions: The results suggest that CIT is a relevant problem in clinical practice. Further research is necessary to investigate the clinical consequences of thrombocytopenia. The observed frequencies of thrombocytopenia were lower than those observed in older studies, but comparable with that observed in a recent US-based study. The observed increased risks for possible immune-mediated thrombocytopenia associated with exposure to oxaliplatin and gemcitabine contribute to the suspicion that these drugs can cause immune-mediated thrombocytopenia, and warrant further investigation. For clinicians, the mechanism has important consequences because in immune-mediated thrombocytopenia the drug must be avoided, while in dose-dependent thrombocytopenia a dose reduction may be sufficient.

Rituximab-induced thrombocytopenia: A cohort study

The combined information of drug exposure and laboratory test results on an individual patient level obtained in daily clinical practice can add important information about the safety of a drug. Thrombocytopenia is a known adverse drug reaction of rituximab, which has already been identified during the preregistration trials, but knowledge on incidence and risk factors in clinical practice is limited. We, therefore, aimed to estimate the incidence and explore the risk factors for the development of rituximab‐induced thrombocytopenia (a platelet count, <100 × 109 platelets/L) in clinical practice. Ninety patients were eligible for inclusion of which 27 developed thrombocytopenia (cumulative incidence, 30%) within 30 days after administration of rituximab and 18 patients developed grade 3/4 thrombocytopenia (cumulative incidence, 20%). Patients with and without thrombocytopenia were compared to explore risk factors. Patients with a relatively low platelet count (217 vs. 324 × 109/L, P = 0.011) before administration of rituximab had a higher risk for the development of thrombocytopenia, and although not statistically significant, patients treated with rituximab within the oncology setting (OR, 4.7; 95% CI, 1.0–23.3), independent of concomitant use of cytostatics, as compared to the autoimmune diseases and patients with a high platelet distribution width (PDW) (16.1 vs. 15.8, P = 0.051). In conclusion, the incidence of rituximab‐induced thrombocytopenia was higher than that identified during the clinical trials. Healthcare professionals should consider thrombocytopenia as a relevant reaction during treatment with rituximab. More frequent monitoring of the platelet count is especially advised in patients treated in the oncology indication and/or with a low platelet count and high PDW.

Compliance with Platelet Count Monitoring Recommendations and Management of Possible Heparin-Induced Thrombocytopenia in Hospitalized Patients Receiving Low-Molecular-Weight Heparin

Background: Summaries of product characteristics (SPCs) and clinical guideline recommendations are available for monitoring the platelet count for heparin-induced thrombocytopenia (HIT) in patients receiving low-molecular-weight heparin (LMWH). Testing for the presence of heparin-platelet factor 4 antibodies (HPF4-Ab) and starting alternative anticoagulation is recommended when HIT is suspected. Objective: To investigate the frequency of compliance with recommendations for platelet count monitoring and management of possible HIT in hospitalized patients receiving prophylaxis and treatment dosing of LMWH for at least 5 consecutive days. Methods: A retrospective cohort study within the Utrecht Patient Oriented Database (UPOD) was conducted. For all inpatients, all episodes of exposure to dalteparin or nadroparin for at least 5 consecutive days in 2004–2005 were selected. In 4 different nonexclusive groups of patients (all pts. receiving dalteparin, all pts. receiving nadroparin, surgical pts. with a prophylactic dose of either dalteparin or nadroparin, and pts. exposed to unfractionated heparin [UFH] within 100 days before receiving either dalteparin or nadroparin), compliance with recommendations for platelet count monitoring from SPCs and a clinical guideline was studied. The frequency of compliance with these recommendations was determined. In addition, it was determined whether patient and treatment characteristics were associated with regular platelet count monitoring. Finally, the frequency of testing for HPF4-Ab and the initiation of danaparoid treatment in patients with a drop of at least 50% in platelet count were investigated. Results: A total of 6804 patients, with 7770 episodes of LMWH treatment, were included in the analysis. The frequency of compliance with platelet count monitoring recommendations was 26.3% for all patients receiving dalteparin, 35.6% for all patients receiving nadroparin, 23.0% for surgical patients receiving prophylactic dosing of either dalteparin or nadroparin, and 41.5% for patients exposed to UFH within 100 days before the start of either dalteparin or nadroparin treatment. Regular platelet count monitoring was strongly positively associated with medical patients (relative risk [RR] 2.33), surgical patients (RR 2.03), critically ill patients (RR 2.60), and those with recent exposure to UFH (RR 2.19). The frequency of testing for HPF4-Ab was 5.4% and the initiation of alternative anticoagulation with danaparoid in patients with a 50% drop in platelet count was 0%. Conclusions: The results suggest that compliance with recommendations for platelet count monitoring and management of possible HIT is low at our institution. Policies and tools to improve compliance with recommended laboratory monitoring should be developed to secure the safe use of LMWH and other medications.

Hematological Parameters Improve Prediction of Mortality and Secondary Adverse Events in Coronary Angiography Patients : A Longitudinal Cohort Study

AbstractPrediction of primary cardiovascular events has been thoroughly investigated since the landmark Framingham risk score was introduced. However, prediction of secondary events after initial events of coronary artery disease (CAD) poses a new challenge.In a cohort of coronary angiography patients (n = 1760), we examined readily available hematological parameters from the UPOD (Utrecht Patient Oriented Database) and their addition to prediction of secondary cardiovascular events. Backward stepwise multivariable Cox regression analysis was used to test their ability to predict death and major adverse cardiovascular events (MACE). Continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI) measures were calculated for the hematological parameters on top of traditional risk factors to assess prediction improvement.Panels of 3 to 8 hematological parameters significantly improved prediction of death and adverse events. The IDIs ranged from 0.02 to 0.07 (all P < 0.001) among outcome measures and the cNRIs from 0.11 to 0.40 (P < 0.001 in 5 of 6 outcome measures). In the hematological panels red cell distribution width (RDW) appeared most often. The multivariable adjusted hazard ratio of RDW per 1 standard deviation (SD) increase for MACE was 1.19 [1.08–1.32], P < 0.001.Routinely measured hematological parameters significantly improved prediction of mortality and adverse events in coronary angiography patients. Accurately indicating high-risk patients is of paramount importance in clinical decision-making.

Routinely analyzed leukocyte characteristics improve prediction of mortality after coronary angiography

Background Inflammation and leukocyte infiltration are hallmarks of atherosclerosis. Clinically routine hematology analyzers mostly perform an entire differential blood count by default, irrespective of the requested parameter. We hypothesize that these normally unreported leukocyte characteristics associate with coronary artery disease (CAD) severity and can improve prediction of mortality in coronary angiography patients. Methods We studied coronary angiography patients suspected of CAD (n = 1015) from the Utrecht Coronary Biobank cohort. Leukocyte characteristics were routinely assessed in blood drawn directly prior to angiography using an automated hematology analyzer and extracted from the Utrecht patient oriented database (UPOD) database. Patients were followed up for a median duration of 805 days, during which 65 patients died. We evaluated the association of leukocyte characteristics with synergy between PCI with taxus and cardiac surgery (SYNTAX) score as a measure of CAD severity, all-cause and cardiovascular mortality and major adverse cardiovascular events (MACEs). In order to determine the improvement of risk prediction, we calculated continuous net reclassification improvement (cNRI) and integrated discrimination improvement (IDI). Results Monocyte percentage showed strong independent predictive value for all-cause mortality (hazard ratio (HR) 1.44 (1.19–1.74), p < 0.001), and the monocyte-to-lymphocyte ratio performed best for cardiovascular mortality (HR 1.42 (1.11–1.81), p = 0.005). The cNRIs and IDIs of leukocyte characteristics for all-cause mortality confirmed the improvement in mortality risk prediction. No significantly predictive leukocyte characteristics were found for MACEs. Conclusion Readily available yet unreported leukocyte characteristics from routine hematology analyzers significantly improved prediction of mortality in coronary angiography patients on top of clinical characteristics.

Discriminative value of platelet size indices for the identification of the mechanism of chemotherapy-induced thrombocytopenia

Context: A biomarker for discriminating mechanisms of chemotherapy-induced thrombocytopenia (CIT) (i.e. increased platelet destruction and decreased platelet production) would be valuable in managing treatment. Objective: We explored the discriminating value of platelet size indices for this purpose in a population of adult oncology patients. Materials and methods: Mean platelet volume (MPV) and platelet distribution width (PDW) were compared between patients with (i) thrombocytopenia possibly due to increased platelet destruction; (ii) thrombocytopenia possibly due to decreased platelet destruction; and (iii) no thrombocytopenia. Results and conclusions: We obtained negative results, suggesting that these indices are not useful for discriminating different CIT mechanisms.