Warfarin dose and INR related to genotypes of CYP2C9 and VKORC1 in patients with myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Warfarin treatment has a narrow therapeutic range, requiring meticulous monitoring and dosage titration. Individual dosage requirement has recently partly been explained by genetic variation of the warfarin metabolizing enzyme CYP2C9 and the Vitamin K-activating enzyme VKORC1. In the WARIS-II study, comparing three different antithrombotic regimens after myocardial infarction, warfarin treatment reduced thrombotic events, but was associated with more frequent bleeding than use of acetylsalisylic acid (ASA) alone.</p> <p>Aims</p> <p>The primary aim of the present study was to investigate the relation between genotypes of CYP2C9 and VKORC1 and warfarin maintenance dose in myocardial infarction. The secondary aim was to relate the genotypes to international normalized ratio (INR).</p> <p>Methods</p> <p>Genotyping was performed in 212 myocardial infarction patients from the WARIS-II study by robotic isolation of DNA from EDTA whole blood (MagNa Pure LC) before PCR amplification (LightCycler) and melting point analysis.</p> <p>Results</p> <p>The 420 C>T substitution of CYP2C9*2, the 1075 A>C substitution of CYP2C9*3 and the 1173 C>T substitution of VKORC1 had minor allele frequencies of, 11.3%, 5.7% and 36.6% respectively. Warfarin weekly dose varied between 17 mg and 74 mg among the patients. INR did not vary between genotypes. Warfarin dosage requirement was significantly associated with CYP2C9 and VKORC1 genotypes, treatment group and age. The VKORC1 genotype contributed 24.5% to the interindividual variation in warfarin dosage, whereas the combined CYP2C9 genotypes were only responsible for 7.2% of the dose variation.</p> <p>Conclusion</p> <p>CYP2C9 and VKORC1 genotype frequencies in myocardial infarction patients appear similar to other patient groups and have similar impact on warfarin maintenance dose.</p

Characterization of gastrointestinal adverse effects reported in clinical studies of corticosteroid therapy

Objectives: To examine whether 159 studies included in a previous meta-analysis reported on gastrointestinal bleeding or perforation in accordance with the CONSORT extension for reporting harms outcomes (CONSORT Harms recommendations checklist); whether differences were associated with funding source, journal, or publication year; and whether the CONSORT Harms checklist is a suitable tool for evaluation of adverse effects reporting. Study Design and Setting: Articles were assessed for fulfillment of the CONSORT Harms recommendations, funding source, publication type, and year. Agreement between reviewers was assessed by comparing scores for each study. Results: The mean CONSORT Harms score was 5.25 out of 10 (standard deviation ± 2.09). Most studies included information on participant withdrawals (133 studies, 83.6%), absolute risk of gastrointestinal bleeding or perforation (130 studies, 81.8%), and how harms-related information was collected (118 studies, 74.2%). Reporting of gastrointestinal bleeding or perforation increased with higher scores (odds ratio 1.173, P = 0.042). There was no significant association between CONSORT Harms score achieved and publication year or funding source, but there was a trend toward higher scores in studies published in the major medical journals (score difference 0.78, P = 0.052). Definitions of gastrointestinal bleeding differed between studies. Reviewer agreement was fair to moderate with large variations. Conclusion: Few studies in the systematic review received high scores using the CONSORT Harms criteria. Most studies reported on the most important criteria regarding risk of gastrointestinal bleeding or perforation. Reviewer agreement showed large variations due to imprecise texts and ambiguous criteria. Routine scoring according to fulfillment of the CONSORT Harms recommendations would be inadvisable without qualified judgment

Adverse effects information in clinical guidelines on pharmacological treatment of depression in children and adolescents: a systematic review

Objectives To analyse to what extent clinical practice guidelines on drug treatment of depression in children and adolescents mention the risk of adverse effects, to characterise the citations in the guidelines and to assess to what extent data from a major study (Treatment for Adolescents With Depression Study, TADS) was used as basis for information about adverse effects. Design Systematic review of clinical guidelines and clinical decision support tools. Data sources PubMed, EMBASE, guideline collections, Health libraries. Eligibility criteria We included national guidelines on depression in children and adolescents from European and/or English-speaking countries, published in English, German, French or any Scandinavian language since 2008. We also included well-known, international clinical decision support tools. Data extraction and synthesis Guidelines were examined by all authors to identify and classify information on adverse effects. Citations for statements on adverse effects were extracted and classified by category. The extent of citations about suicidality risk versus other adverse effects was assessed. Results 19 guidelines were assessed. All guidelines discussed risk of suicidal behaviour connected with use of antidepressants. Most guidelines mentioned some other psychiatric adverse effects. Several guidelines did not include information on well-known and common somatic adverse effects. Most references concerned risk of suicidality. Adverse effects identified in underlying studies were not always presented. The TADS study was referred to, directly or indirectly, by 18/19 guidelines, but some only referred to TADS with regard to suicidality without citing the study’s findings of somatic adverse effects. No guideline commented on the lack of long-term adverse effects data from TADS. Conclusions Guidelines for treatment of depression in children and adolescents vary widely regarding information on adverse effects. Many guidelines do not provide information on common somatic adverse effects. There is no consensus as to what extent risks of adverse effects connected with use of antidepressants should be described in guidelines

Critical appraisal of adverse effects reporting in the 'Treatment for Adolescents With Depression Study (TADS)'

To identify all publications from the ‘Treatment for Adolescents With Depression Study (TADS)’ and assess the findings regarding occurrence of any adverse effects in the treatment groups both for the short-term and long-term study stages.Descriptive analysis of TADS publications with any information on adverse effects.We identified 48 publications describing various aspects of the TADS, in which 439 adolescent patients received treatment with fluoxetine, cognitive–behavioural therapy, cognitive–behavioural therapy plus fluoxetine or placebo. Eight publications were assessed as providing some data on adverse effects. Risk of suicidal behaviour was the only adverse effect that was addressed in all publications. Several psychiatric and physical adverse effects were reported during the first 12 weeks, but not mentioned in reports from later study stages. Common adverse effects of fluoxetine, such as weight changes or sexual problems, were not identified or mentioned in the publications.The TADS publications do not present a comprehensive assessment of treatment risk with fluoxetine in adolescents, especially for more than 12 weeks of treatment. Risk of suicidality was the only adverse effect that was reported over time. Reporting of adverse effects was incomplete with regard to the long-term safety profile of fluoxetine

Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis

Objective To assess whether corticosteroids are associated with increased risk of gastrointestinal bleeding or perforation. Design Systematic review and meta-analysis of randomised, double-blind, controlled trials comparing a corticosteroid to placebo for any medical condition or in healthy participants. Studies with steroids given either locally, as a single dose, or in crossover studies were excluded. Data sources Literature search using MEDLINE, EMBASE and Cochrane Database of Systematic Reviews between 1983 and 22 May 2013. Outcome measure Outcome measures were the occurrence of gastrointestinal bleeding or perforation. Predefined subgroup analyses were carried out for disease severity, use of non-steroidal anti-inflammatory drugs (NSAIDs) or gastroprotective drugs, and history of peptic ulcer. Results 159 studies (N=33 253) were included. In total, 804 (2.4%) patients had a gastrointestinal bleeding or perforation (2.9% and 2.0% for corticosteroids and placebo). Corticosteroids increased the risk of gastrointestinal bleeding or perforation by 40% (OR 1.43, 95% CI 1.22 to 1.66). The risk was increased for hospitalised patients (OR 1.42, 95% CI 1.22 to 1.66). For patients in ambulatory care, the increased risk was not statistically significant (OR 1.63, 95% CI 0.42 to 6.34). Only 11 gastrointestinal bleeds or perforations occurred among 8651 patients in ambulatory care (0.13%). Increased risk was still present in subgroup analyses (studies with NSAID use excluded; OR 1.44, 95% CI 1.20 to 1.71, peptic ulcer as an exclusion criterion excluded; OR 1.47, 95% CI 1.21 to 1.78, and use of gastroprotective drugs excluded; OR 1.42, 95% CI 1.21 to 1.67). Conclusions Corticosteroid use was associated with increased risk of gastrointestinal bleeding and perforation. The increased risk was statistically significant for hospitalised patients only. For patients in ambulatory care, the total occurrence of bleeding or perforation was very low, and the increased risk was not statistically significant

Mortality among head trauma patients taking preinjury antithrombotic agents: a retrospective cohort analysis from a Level 1 trauma centre

Background Bleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma. Methods A retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use. Results Of the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients’ arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality. Conclusions The use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department

Genetic Variation of VKORC1 and CYP4F2 Genes Related to Warfarin Maintenance Dose in Patients with Myocardial Infarction

The aim of this study was to investigate whether the VKORC1*3 (rs7294/9041 G > A), VKORC1*4 (rs17708472/6009 C > T), and CYP4F2 (rs2108622/1347 C > T) polymorphisms were associated with elevated warfarin maintenance dose requirements in patients with myocardial infarction (n=105) from the Warfarin Aspirin Reinfarction Study (WARIS-II). We found significant associations between elevated warfarin dose requirements and VKORC1*3 and VKORC1*4 polymorphisms (P=.001 and P=.004, resp.), whereas CYP4F2 (1347 C > T) showed a weak association on higher warfarin dose requirements (P=.09). However, analysing these variant alleles in a regression analysis together with our previously reported data on VKORC1*2, CYP2C9*2 and CYP2C9*3 polymorphisms, gave no significant associations for neither VKORC1*3, VKORC1*4 nor CYP4F2 (1347 C > T). In conclusion, in patients with myocardial infarction, the individual contribution to warfarin dose requirements from VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms was negligible. Our results indicate that pharmacogenetic testing for VKORC1*2, CYP2C9*2 and CYP2C9*3 is more informative regarding warfarin dose requirements than testing for VKORC1*3, VKORC1*4, and CYP4F2 (1347 C > T) polymorphisms