Methotrexate Polyglutamate Concentrations as a Possible Predictive Marker for Effectiveness of Methotrexate Therapy in Patients with Sarcoidosis: A Pilot Study.

INTRODUCTION: Methotrexate (MTX), a folate antagonist, is often used as second-line treatment in patients with sarcoidosis. Effectiveness of MTX has large inter-patient variability and at present therapeutic drug monitoring (TDM) of MTX is not possible. Upon administration, MTX is actively transported into cells and metabolized to its active forms by adding glutamate residues forming MTXPG(n=1-5) resulting in enhanced cellular retention. In this study we address the question whether different MTXPG(n) concentrations in red blood cells (RBC) of patients with sarcoidosis after 3 months of MTX therapy correlate with response to treatment. METHODS: We retrospectively included patients with sarcoidosis that had started on MTX therapy and from whom blood samples and FDG-PET/CT were available 3 and 6-12 months after MTX initiation, respectively. FDG-uptake was measured by SUVmax in the heart, lungs and thoracic lymph nodes. Changes in SUVmax was used to determine anti-inflammatory response after 6-12 months of MTX therapy. MTXPG(n) concentrations were measured from whole blood RBC using an LC-MS/MS method. Pearson correlation coefficients were calculated to evaluate the relationship between changes in the SUVmax and MTXPG(n) concentrations. RESULTS: We included 42 sarcoidosis patients treated with MTX (15 mg/week); 31 with cardiac sarcoidosis and 11 with pulmonary sarcoidosis. In MTXPG3 and MTXPG4 a significant negative relation between the absolute changes in SUVmax and MTXPG(n) was found r = - 0.312 (n = 42, p = 0.047) for MTXPG3 and r = - 0.336 (n = 42, p = 0.031 for MTXPG4). The other MTXPG(n) did not correlate to changes in SUVmax. CONCLUSION: These results suggest a relation between MTXPG(n) concentrations and the anti-inflammatory effect in patients with sarcoidosis. Further prospective validation is warranted, but if measuring MTXPG concentrations could predict treatment effect of MTX this would be a step in the direction of personalized medicine.

The potential for deprescribing in a palliative oncology patient population: a cross-sectional study.

OBJECTIVES: The use of preventive medication in palliative oncology patients may be inappropriate due to limited life expectancy. Deprescribing tools are available but time-consuming and not always tailored to this specific population. Our primary goal was to identify potentially inappropriate medications (PIMs) in palliative oncology patients with a life expectancy of up to 2 years using an adapted deprescribing tool. Our secondary aim was to identify patient characteristics associated with the presence of PIMs. METHODS: Oncology patients with a life expectancy of up to 2 years were included cross-sectionally. An adapted deprescribing tool was developed to identify PIMs. Logistic regression was used to identify factors associated with having PIMs. RESULTS: A total of 218 patients were included in this study of which 56% had at least one PIM with a population mean of 1.1 PIM per patient. Most frequently defined PIMs were antihypertensive drugs and gastric acid inhibitors. Identification of PIMs by review took an estimated 5-10 min per patient. Polypharmacy, age >65 years and inpatient/outpatient status were found to be associated with having at least one PIM. CONCLUSIONS: Deprescribing is possible in more than half of palliative oncology patients with a life expectancy of up to 2 years. The adapted deprescribing tool used is non-time consuming and suitable for palliative oncology patients, regardless of age.

Switching to an Infliximab Biosimilar Was Safe and Effective in Dutch Sarcoidosis Patients.

The effect of switching from originator infliximab to biosimilar infliximab in patients with sarcoidosis is unknown. The objective of this study is to investigate the effect of switching from Remicade® or Inflectra® to Flixabi® in patients with severe refractory sarcoidosis. This single center retrospective cohort study was performed at St Antonius Hospital Nieuwegein, The Netherlands. All patients diagnosed with severe refractory sarcoidosis receiving Remicade® or Inflectra® switched to Flixabi®. The primary outcome was infliximab discontinuation within 6 months of switching. Secondary endpoints included adverse events and loss of clinical, functional, or inflammatory response. Out of 86 patients who switched to Flixabi®, 79 patients had complete data. None of the 79 patients discontinued infliximab during the first 6 months after switching. Five patients reported an adverse event related to Flixabi® treatment. We found no change from baseline in FVC, FEV1, DLCOc, 6MWT, and infliximab trough levels 26 weeks after switching. An improvement in physical functioning of 7.3 ± 13.4 points (p = 0.002) with RAND/SF36 and in biomarker sIL-2R (-475.58 ± 1452.39; p = 0.005) was observed. Switching from originator infliximab Remicade® or biosimilar infliximab Inflectra® to biosimilar infliximab Flixabi® did not result in treatment discontinuation or loss of clinical/functional/inflammatory remission.

Real-world outcomes versus clinical trial results of immunotherapy in stage IV non-small cell lung cancer (NSCLC) in the Netherlands.

This study aims to assess how clinical outcomes of immunotherapy in real-world (effectiveness) correspond to outcomes in clinical trials (efficacy) and to look into factors that might explain an efficacy-effectiveness (EE) gap. All patients diagnosed with stage IV non-small cell lung cancer (NSCLC) in 2015-2018 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. Progression-free survival (PFS) and overall survival (OS) from first-line (1L) pembrolizumab and second-line (2L) nivolumab were compared with clinical trial data by calculating hazard ratios (HRs). From 1950 diagnosed patients, 1005 (52%) started with any 1L treatment, of which 83 received pembrolizumab. Nivolumab was started as 2L treatment in 141 patients. For both settings, PFS times were comparable between real-world and trials (HR 1.08 (95% CI 0.75-1.55), and HR 0.91 (95% CI 0.74-1.14), respectively). OS was significantly shorter in real-world for 1L pembrolizumab (HR 1.55; 95% CI 1.07-2.25). Receiving subsequent lines of treatment was less frequent in real-world compared to trials. There is no EE gap for PFS from immunotherapy in patients with stage IV NSCLC. However, there is a gap in OS for 1L pembrolizumab. Fewer patients proceeding to a subsequent line of treatment in real-world could partly explain this.

Evaluation of Serum Biomarker CEA and Ca-125 as Immunotherapy Response Predictors in Metastatic Non-small Cell Lung Cancer.

BACKGROUND/AIM: Treatment options for advanced non-small cell lung cancer (NSCLC) include immunotherapy. Elevated carcinoembryonic antigen (CEA) and cancer antigen 125 (Ca-125) levels are associated with poorer prognoses of resected NSCLC, but currently no predictive biomarkers exist for immunotherapy response. This study evaluated CEA and Ca-125 as predictive biomarkers for immunotherapy efficiency in patients with metastatic NSCLC. PATIENTS AND METHODS: The single-centre observational retrospective study includes NSCLC stage III/IV patients treated with programmed death-ligand 1 (PD-L1) inhibitors nivolumab or pembrolizumab. The primary study endpoint was treatment response assessed by CT-scan following RECIST-criteria 1.1. CEA/Ca-125 serum values were determined at initiation of treatment and repeated every 2 weeks. Values closest to the day of CT-scan were compared to baseline values. RESULTS: A total of 136 patients were treated with mono-immunotherapy. Of these, 73 patients were included in the CEA group and 53 patients were included in the Ca-125 group. Baseline CEA and Ca-125 ranged from 8.14 to 5,909 and 1.1 to 4,238 respectively. The sensitivity for Ca-125 as predictor for tumor response was 62.9% (95% CI=61.8%-63.6%), specificity 61.1% (95% CI=60.2%-62.0%), with a positive predictive value (PPV) of 75.9% (95% CI=75.2%-76.7%). For CEA, the sensitivity was 72.0% (95% CI=71.5%-72.5%), specificity 47.1% (95% CI 46.4%-47.8%), with a PPV of 80.0% (95% CI=79.6%-80.4%). CONCLUSION: Increased serum CEA might predict tumor progression in NSCLC patients treated with PD-L1 inhibitors. Unconfirmed progression accompanied by increased CEA would support discontinuation of the immunotherapy, while continuation would be advised when serum CEA is not increased.

Trends in Drug Costs and Overall Survival in Patients with Metastatic Non-small Cell Lung Cancer in The Netherlands Diagnosed from 2008 Through 2014.

BACKGROUND: The Value-Based Health Care concept defines patient value as patient-relevant outcomes divided by costs. The aim of the present study was to assess the development of systemic treatment costs over the years compared with changes in overall survival (OS) at the level of a diagnosis of stage IV non-small cell lung cancer (NSCLC). METHODS: All patients diagnosed (in 2008-2014) with stage IV NSCLC and treated with systemic treatment in six Dutch large teaching hospitals (Santeon network) were included. We collected data on OS and amounts of drug units (milligrams) for every drug in the applied systemic cancer treatments, until death. These amounts were multiplied by Dutch unit costs (Euros/mg) expressed in 2018 Euros to construct total drug costs per line of treatment per patient. Costs for day care visits were added for drugs requiring parenteral administration. RESULTS: Data were collected from 1214 patients. Median OS and mean total drug costs showed no significant variation over the years (p = 0.437 and p = 0.693, respectively). Mean total drug costs per 1 year of survival ranged from €20,665 to €26,438 during the period under study. Costs for first-line systemic treatment were significantly higher in 2011-2014 compared with 2008-2010. CONCLUSION: This study shows that overall drug costs were stable over the years, despite a relative increase in first-line treatment costs. Median OS remained at around 8 months from year to year. These trend data are very relevant as background for the assessment of costs and achieved outcomes in the more recent years.

Systematic evaluation of the efficacy-effectiveness gap of systemic treatments in extensive disease small cell lung cancer.

PURPOSE: The aim of this study is to assess how clinical outcomes in real-world (effectiveness) correspond to the outcomes in clinical trials (efficacy) of systemic treatments for extensive disease small cell lung cancer (ED SCLC). METHODS: All patients diagnosed with ED SCLC between 2008 and 2014 in six Dutch large teaching hospitals (Santeon network) were identified and followed-up from date of diagnosis until death or end of data collection. For every patient, an efficacy-effectiveness factor (EE factor) was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment. RESULTS: From 792 diagnosed patients, 568 (72%) started with first-line treatment. Overall, the median EE factor was 0.79 (P < .001 from 1.00). Poor performance status (ECOG≥2) and a higher age at diagnosis (age ≥ 65 years) were independent predictors for a lower EE factor. The EE gap was 43% in patients with both age ≥ 65 years and ECOG ≥2 (EE factor 0.57). The mean age and the proportion of patients with ECOG≥2 in real-world were different from those in clinical trials (mean age of 66 versus 62 years, and ECOG≥2 25% versus 17%; both P < .001). CONCLUSION: OS of patients with ED SCLC treated with systemic therapy in real-world practice is 21% shorter than for patients included in trials. Age at diagnosis and performance status partly explain this gap.

Treatment patterns and clinical outcomes of chemotherapy treatment in patients with muscle-invasive or metastatic bladder cancer in the Netherlands.

This retrospective study was performed to evaluate real-world oncological outcomes of patients treated with chemo-based therapy for muscle-invasive or metastatic bladder cancer (MIBC/mBC) and compare results to data from RCTs and other cohorts. Among 1578 patients diagnosed, 470 (30%) had MIBC/mBC. Median overall survival (mOS) for RC alone (47 months), first-line (13 months) and second-line (7 months) chemotherapy, and chemotherapy for recurrent disease (8 months) were similar to literature. Treatment with neoadjuvant and induction chemotherapy (NAIC) was only utilized in 9% of patients, and often in patients with poor disease status, resulting in a lower mOS compared to literature (35 and 20 months, respectively). Patients treated with chemotherapy had many adversities to treatment, with only 50%, 13%, 18% and 7% of patients in NAIC, first-line, salvage after RC, and second-line setting completing the full pre-planned chemotherapy treatment. Real-world data shows NAIC before RC is underutilized. Adversities during chemotherapy treatment are frequent, with many patients requiring dose reduction or early treatment termination, resulting in poor treatment response. Although treatment efficacy between RCTs and real-world patients is quite similar, there are large differences in baseline characteristics and treatment patterns. Possibly, results from retrospective studies on real-world data can deliver missing evidence on efficacy of chemotherapy treatment on older and 'unfit' patients.

Treatment of oncogene-driven non-small cell lung cancer.

PURPOSE OF REVIEW: With the development of targeted therapies, the treatment strategy of patients with advanced or metastatic non-small cell lung cancer (NSCLC) has changed tremendously. In this review, we focus on the different aspects of the treatment of oncogene-driven NSCLC. RECENT FINDINGS: Patients with an EGFR or ALK alteration show a better clinical outcome with tyrosine kinase inhibitor (TKI) treatment compared to chemotherapy.Patients with a ROS1 rearrangement or a BRAF V600E mutation show favorable clinical outcome with TKI treatment compared to chemotherapy, although randomized trials are not available.Patients on TKIs will eventually develop disease progression because of acquired resistance.The treatment with immunotherapy in EGFR and ALK-positive NSCLC patients did not improve overall survival over that of chemotherapy.Blood-based genetic analysis provides the opportunity to noninvasively screen patients for the presence of oncogenic drivers and to monitor resistance during TKI treatment. SUMMARY: Targeted molecular therapies are now standard of care for patients with oncogene-driven NSCLC with a good clinical benefit and minimal toxicity. The role of immunotherapy in patients with molecular alterations is still unclear. Blood-based genotyping has gained interest in the diagnostic and resistance monitoring setting for patients with NSCLC.

Recurrent Episodes of Nivolumab-Induced Pneumonitis after Nivolumab Discontinuation and the Time Course of Carcinoembryonic Antigen Levels: A Case of a 58-Year-Old Woman with Non-Small Cell Lung Cancer.

INTRODUCTION: The introduction of immune checkpoint inhibitors heralded a new era in the treatment of non-small cell lung cancer. However, nivolumab, an anti-PD-1 antibody, can cause serious adverse events that are mostly autoimmune related. CASE PRESENTATION: A 58-year-old woman was treated with nivolumab as second-line therapy for stage IV adenocarcinoma. The patient developed a nivolumab-induced recurrent pneumonitis preceding durable clinical remission after seven cycles of nivolumab. Although high-dose glucocorticosteroids were tapered to conform to contemporary guidelines, recurring episodes of pneumonitis occurred without nivolumab rechallenge. In addition, carcinoembryonic antigen (CEA) serum levels were associated with treatment response, since CEA decline correlated with a near complete radiological response and, conversely, elevated CEA serum levels were associated with progressive disease. CONCLUSIONS: In this case, we described recurrence of nivolumab-induced pneumonitis as a serious adverse event in immune checkpoint inhibitors. Our case illustrates that immune-related adverse events may correlate with antitumour activity, even after treatment discontinuation. In addition, this case suggests the possible clinical utility of CEA serum levels for the assessment of (durable) effects of immunotherapy.

Systematic evaluation of the efficacy-effectiveness gap of systemic treatments in metastatic nonsmall cell lung cancer.

The divergence between clinical trial results and real-world outcomes is largely unknown for many cancer types. The present study aims overall to assess the efficacy-effectiveness gap (difference between outcomes in clinical trials and the real world) in systemic treatment for metastatic nonsmall cell lung cancer (NSCLC).All patients diagnosed with stage IV NSCLC between 2008 and 2014 within a network of seven Dutch large teaching hospitals (Santeon) were studied. For every patient, an efficacy-effectiveness (EE) factor was calculated by dividing individual patients' overall survival (OS) by the pooled median OS assessed from clinical trials with the respective treatment.From 2989 diagnosed patients, 1214 (41%) started with first-line treatment. For all studied regimens, real-world OS was shorter than OS reported in clinical trials. Overall, the EE factor was 0.77 (95% CI 0.70-0.85; p<0.001). Real-world patients completed their treatment plan less often and proceeded less frequently to further lines of treatment. These parameters together with Eastern Cooperative Oncology Group performance status explained 35% of the variation in EE factor.Survival of patients with metastatic NSCLC treated with chemotherapy or targeted therapy in real-world practice is nearly one-quarter shorter than for patients included in trials. Patients' performance status, earlier discontinuation and fewer subsequent lines of treatment partly explained this difference.

Utilization of Molecular Testing and Survival Outcomes of Treatment with First- or Second-line Tyrosine Kinase Inhibitors in Advanced Non-small Cell Lung Cancer in a Dutch Population.

BACKGROUND/AIM: Epidermal growth factor receptor (EGFR) mutation testing is standard-of-care for advanced non-small cell lung cancer (NSCLC). Outcomes of second-/third-line compared to first-line tyrosine kinase inhibitors (TKIs) have shown conflicting results. We investigated utilization of molecular diagnostics and the outcomes of treatment with first-/second-line TKIs in patients with advanced NSCLC. MATERIALS AND METHODS: Retrospective analysis was carried out of 2,206 patients with stage IIIb/IV NSCLC treated between 2008 and 2014 in four hospitals in the Netherlands. RESULTS: The rate of performing molecular diagnostics increased from 20.8% to 74.4% in the study period. The median overall survival of EGFR mutation-positive patients treated with TKIs was superior compared to EGFR mutation-negative patients treated with chemotherapy (720 vs. 274 days, p<0.0001). No difference in overall survival was found between EGFR mutation-positive patients treated only with TKIs compared to those treated with chemotherapy prior to TKIs, or upon progression under TKIs. CONCLUSION: The rate of EGFR testing has improved, increasing the number of patients eligible for targeted therapy. Chemotherapy, prior or subsequent to TKIs, for the treatment of EGFR mutation-positive patients, did not result in significantly better overall survival compared to that achieved with TKIs alone.

Trends in prescribing systemic treatment and overall survival for non-small cell lung cancer stage IIIB/IV in the Netherlands: 2008-2012.

BACKGROUND: The present study aims to give a detailed overview of day-to-day practice in the systemic treatment of NSCLC stage IIIB/IV and its clinical outcomes in six large teaching hospitals in the Netherlands in the period 2008-2012. METHODS: A retrospective observational cohort study was conducted in the Care for Outcome registry. Patients diagnosed with stage IIIB/IV NSCLC were included and drug data were collected. Outcomes included percentage of patients treated with systemic treatment, percentage of different first line treatment options, survival, and number and percentage of switches, dose reductions (<80% of the initial dose), and early discontinuation (<4 cycles). Descriptive analyses were conducted per hospital, year of diagnosis and several patient characteristics. Predictors for early discontinuation were explored in a logistic regression model. RESULTS: Overall, 47,9% of 2158 patients that were included received systemic treatment and 33,7% of those received second line treatment. Treatment frequencies were different between age categories, disease stage, PS and hospital (p<0.001). Half of the patients received <4 cycles and dose reductions were found for 20% of all patients. Interhospital differences were observed for early discontinuation and the number of switches. PS2-3 was associated with early discontinuation (OR 1.97 (p=0,007). Median survival was not different between hospitals and years of diagnosis. DISCUSSION: We provided detailed overview of day-to-day systemic treatment of NSCLC for six hospitals that (a) can fuel interhospital discussion to streamline treatment towards best practice and (b) can serve as reference data for follow-up of the adoption of novel systemic treatment options for advanced lung cancer.

Quantitative and qualitative assessment of real world data comparative effectiveness research of systemic therapies in lung oncology: A systematic review.

INTRODUCTION: The growing interest in comparative effectiveness research (CER) based on data from routine clinical practice also extends towards lung oncology. Although CER studies using real world data (RWD) have the potential to assist clinical decision-making, concerns about the quality and validity of studies with observational data subsist. The primary objective of the present study is to assess the current status of observational CER in the field of lung oncology, both quantitatively as qualitatively. METHODS: We performed a systematic electronic literature database search in MEDLINE and EMBASE (up to 1 July 2015). The quality of all selected studies was assessed according to the Good ReseArch for Comparative Effectiveness (GRACE) checklist. RESULTS: The first selection included 657 publications. After screening the corresponding abstracts and full-text papers, 38 studies remained. A total of 36 studies included patients with advanced NSCLC. The comparison of the effectiveness of gefitinib versus erlotinib was the main objective in 22% of the studies. The median number of patients per study was 202 (range 21-10064). The number of publications increased over the years whereas the quality score remained stable over the years with several common shortcomings (checklist items M5, D1, D4, D6). DISCUSSION: The growing interest in clinical oncology CER studies using RWD is reflected in an increasing number of publications in the recent years. The studies have several common methodological shortcomings possibly limiting their applicability in clinical decision-making. To fulfil the promise of RWD CER in lung oncology effort should be continued to overcome these shortcomings.

The SLCO1B1 c.521T>C polymorphism is associated with dose decrease or switching during statin therapy in the Rotterdam Study.

OBJECTIVE: The SLCO1B1 c.521T>C polymorphism is associated with statin plasma levels and simvastatin-induced adverse drug reactions. We studied whether the c.521T>C polymorphism is associated with dose decreases or switches to other cholesterol-lowering drugs during simvastatin and atorvastatin therapy, because these events are indicators of adverse drug reactions. MATERIALS AND METHODS: We identified 1939 incident simvastatin and atorvastatin users in the Rotterdam Study, a population-based cohort study. Associations were studied using Cox proportional hazards analysis. Meta-analysis was performed with data from the Utrecht Cardiovascular Pharmacogenetics study. RESULTS: Simvastatin users with the c.521 CC genotype had a significantly higher risk of a dose decrease or switch than users with the TT genotype [hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.05-2.88]. Female sex, age below 70 years, and low starting dose were risk factors. In atorvastatin users with starting dose of more than 20 mg, the risk of a dose decrease or switch was higher in users carrying a C allele than in users with the TT genotype (HR 3.26, 95% CI 1.47-7.25). In the meta-analysis the association in simvastatin users remained, with a significantly higher risk of a dose decrease or switch in simvastatin users with two minor alleles (HR 1.69, 95% CI 1.05-2.73). For atorvastatin users no significant association was found. CONCLUSION: In simvastatin users in the Rotterdam Study, we demonstrated an association between the c.521T>C polymorphism and dose decrease or switching, as indicators of adverse drug reactions, and provided risk factors for this association. For atorvastatin, an association was found in users with a starting dose of more than 20 mg.

Validation of an automated method for compounding monoclonal antibody patient doses: case studies of Avastin (bevacizumab), Remicade (infliximab) and Herceptin (trastuzumab).

Automation robots have recently come to the market as an alternative for manual compounding of drugs for intravenous administration. Our aim was to assess whether robotic compounding can be performed with monoclonal antibodies (mAbs) without influencing the aggregation state of the proteins. Three frequently used mAbs were studied: infliximab (Remicade, Janssen Biotech) and trastuzumab (Herceptin, Roche) in lyophilised form, and bevacizumab (Avastin, Roche) as a liquid formulation stored at 2°C to 8°C. The effects of different procedures to prepare the patient doses on antibody aggregation were evaluated. Remicade and Herceptin were reconstituted both manually and by a robotic arm (i.v.STATION, Health Robotics). Additionally, the influence of vigorous shaking during reconstitution was investigated. The effects of rapid aspiration and dispensing on antibody aggregation were investigated for all three mAbs. Aggregation state was assessed by UV-Vis absorbance, 90° light scatter, fluorescence spectroscopy, Nile red fluorescence microscopy, and field flow fractionation without cross and focus flow. Robotic reconstituted samples showed similar findings compared with manual reconstitution if performed exactly according to the summary of product characteristics (SPC). Vials that were vigorously shaken showed a significant increase in aggregates. Similarly, rapid aspiration/dispense cycles resulted in a strong increase in the number and sizes of aggregates for all three mAbs; this result was observed after just one rapid aspiration/dispense cycle. Our study showed that robotic compounding of mAbs is feasible if the robot is exactly programmed according to the SPC, indicating that robotic compounding can be used to achieve reproducible high-quality compounding for delicate formulations.

Genetic variability within the cholesterol lowering pathway and the effectiveness of statins in reducing the risk of MI.

Genetic variability has been shown to affect statin responsiveness. Participants from the Utrecht Cardiovascular Pharmacogenetics (UCP) studies were enrolled from a population-based registry of pharmacy records linked to hospital discharge records (PHARMO) to investigate tagging SNPs within candidate genes involved in the cholesterol lowering pathway for modification of the effectiveness of statins in reducing the risk of myocardial infarction (MI). Patients who received a prescription for an antihypertensive drug and/or had hypercholesterolemia were selected from the PHARMO database. We designed a nested case-control study in which cases were hospitalized for MI and controls were not. Patients were contacted through their community pharmacies. For this study, only hypercholesterolemic participants were selected. Logistic regression analysis was used to investigate pharmacogenetic interactions. The Heart and Vascular Health Study (HVH) was used to replicate findings from UCP. The study population included 668 cases and 1217 controls. We selected 231 SNPs of which 209 SNPs in 27 genes passed quality control. Ten SNPs in eight genes were found to influence the effectiveness of statins in UCP, of which the most significant interaction was found with SCARB1 rs4765615. Other genes that reached statistical significance (p<0.05) included two SNPs in PCSK9 (rs10888896 and rs505151 (E670G)), two SNPs in ABCG5 (rs4245786 and rs1864815), LIPC rs16940379, ABCA1 rs4149264, PPARG rs2972164, LRP1 rs715948, and SOAT1 rs2493121. None of the total of 5 SNPs that were available for replication in HVH reached statistical significance. In conclusion, ten SNPs were found to modify the effectiveness of statins in reducing the risk of MI in the UCP study. Five were also tested in the HVH study, but no interactions reached statistical significance.

Variants of ADAMTS1 modify the effectiveness of statins in reducing the risk of myocardial infarction.

OBJECTIVE: To investigate the influence of tagging single-nucleotide polymorphisms (SNPs) within candidate genes involved in the putative anti-inflammatory effects of statins on the effectiveness of statins in reducing the risk of myocardial infarction (MI). METHODS: We conducted a case-control study in a population-based registry of pharmacy records linked to hospital discharge records (PHARMO). Cases and controls were selected from within a hypercholesterolemic cohort. Cases were hospitalized for MI, whereas controls were not. Logistic regression analysis was used to investigate pharmacogenetic interactions. RESULTS: The study population comprised 668 cases and 1217 controls. We genotyped 84 SNPs in 24 genes. The effectiveness of statins was found to be modified by seven SNPs in three genes. Five out of six SNPs that were selected in the A disintegrin and metallopeptidase with thrombospondin motif type I (ADAMTS1) gene were associated with a modified response to statins, three of which were in strong linkage disequilibrium. The strongest interaction was found for ADAMTS1 rs402007. Homozygous carriers of the variant allele had the most benefit from statins [adjusted odds ratio (OR): 0.10, 95% confidence interval (CI): 0.03-0.35], compared with heterozygous (OR: 0.43, 95% CI: 0.24-0.51) and homozygous wildtype carriers (OR: 0.49, 95% CI: 0.32-0.57). CONCLUSION: Consistent with earlier findings, polymorphisms within the ADAMTS1 gene influenced the effectiveness of statins in reducing the risk of MI. Other pharmacogenetic interactions with SNPs in the TNFRSF1A and ITGB2 genes were established and the confirmation will be pursued in future studies.

Pharmacogenetic interactions between ABCB1 and SLCO1B1 tagging SNPs and the effectiveness of statins in the prevention of myocardial infarction.

AIMS: Genetic variability within the SLCO1B1 and ABCB1 transporter genes has been associated with modification of statin effectiveness in cholesterol management. MATERIALS & METHODS: We conducted a case-control study using a population-based registry of pharmacy records linked to the hospital discharge records. Within a hypercholesterolemic cohort, we included 668 myocardial infarction cases and 1217 controls. RESULTS: We tested 24 tagging SNPs and found two SNPs within ABCB1 (rs3789244, p = 0.01; rs1922242, p = 0.01) to interact with statin treatment. In addition, we found a nonsignificant haplotype-treatment interaction (p = 0.054). The odds ratio for subjects homozygous for SLCO1B1*1A was 0.49 (95% CI: 0.34-0.71) compared with 0.31 (95% CI: 0.24-0.41) for heterozygous or noncarriers of the *1A allele. CONCLUSION: This is the first study to demonstrate that common genetic variability within the SLCO1B1 and ABCB1 genes is associated with the modification of the effectiveness of statins in the prevention of the clinical outcome, myocardial infarction.