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- Voight, Benjamin F, et al.
(författare)
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Plasma HDL cholesterol and risk of myocardial infarction : a mendelian randomisation study
- 2012
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Ingår i: The Lancet. - 0140-6736 .- 1474-547X. ; 380:9841, s. 572-580
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.METHODS: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20,913 myocardial infarction cases, 95,407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12,482 cases of myocardial infarction and 41,331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.FINDINGS: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10(-13)) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69-2·69, p=2×10(-10)).INTERPRETATION: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
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| 2. |
- Dal-Re, Rafael, et al.
(författare)
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A limited number of medicines pragmatic trials had potential for waived informed consent following the 2016 CIOMS ethical guidelines
- 2019
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Ingår i: Journal of Clinical Epidemiology. - : ELSEVIER SCIENCE INC. - 0895-4356 .- 1878-5921. ; 114, s. 60-71
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: European regulations do not allow modification or waiver of informed consent for medicines randomized controlled trials (RCTs) where the three 2016 Council for International Organizations of Medical Sciences (CIOMS) provisions are met (consent would be impractical or unfeasible, yet the trial would have high social value and pose no or minimal risk to participants). We aimed to identify whether any such trials of medicines were being conducted in Europe. Study Design and Setting: This is a survey of all phase 4 "ongoing" RCTs on the EU clinical trial register between July 1, 2016 and June 30, 2018, to identify those with potentially high levels of pragmatism. Trials that were excluded were as follows: those conducted on rare diseases; conducted on healthy volunteers (except those assessing vaccines); masked (single-, double-blind) trials; single-center trials; those where one could expect to lead patients to prefer one intervention over the other; and miscellaneous reasons. The degree of pragmatism of the RCTs was self-assessed by trials' investigators by means of the PRECIS-2 tool. Investigators of those trials considered to be highly pragmatic assessed the fulfillment of the three CIOMS provisions. Seven patients assessed the social value of the RCTs. Finally, 33 members of 11 research ethics committees (RECs) assessed the social value of the trials and whether they posed no more than minimal risk to participants. Investigators, patients, and REC members assessed the fulfillment of the CIOMS provisions as "yes," "not sure" or "no." Results: Of the 638 phase 4 trials, 420 were RCTs, and 21 of these (5%) were candidates to be pragmatic. Investigators of 15 of these 21 RCTs self-assessed their trial's degree of pragmatism: 14 were highly pragmatic. Of these 14, eight fulfilled the three CIOMS provisions. Assessments by patients and RECs were inconsistent for several trials. Conclusions: We found few low-risk participant-level pragmatic RCTs that could be suitable for modified or waived participants' informed consent. European regulators should consider amending the current regulation and encouraging the conduct of such trials. (C) 2019 Elsevier Inc. All rights reserved.
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| 5. |
- Makady, Amr, et al.
(författare)
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Social media as a tool for assessing patient perspectives on quality of life in metastatic melanoma : a feasibility study
- 2018
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Ingår i: Health and Quality of Life Outcomes. - : BMC. - 1477-7525 .- 1477-7525. ; 16
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Development of innovative drugs for melanoma is occurring rapidly. Incremental gains in overall survival amongst innovative products may be difficult to measure in clinical trials, and their use may be associated with increased toxicity profiles. Therefore, HTA agencies increasingly require information on HRQoL for the assessment of such drugs. This study explored the feasibility of social media to assess patient perspectives on HRQoL in melanoma, and whether current cancer- and melanoma-specific HRQoL questionnaires represent these perspectives.Methods: A survey was distributed on the social media channels of Melanoma Patient Network Europe to assess melanoma patients' perspectives regarding HRQoL. Two researchers independently conducted content analysis to identify key themes, which were subsequently compared to questions from one current cancer-specific and two melanoma-specific HRQoL questionnaires (i.e. EORTC QLQ-C30, EORTC QLQ-MEL38, FACT-M).Results: In total, 72 patients and 17 carers completed the survey. Patients indicated that family, having a normal life, and enjoying life were the three most important aspects of HRQoL for them. Carers indicated that being capable, having manageable adverse events, and being pain-free were the three most important aspects of HRQoL for patients. Respondents seem to find some questions from HRQoL questionnaires relevant (e.g. Have you felt able to carry on with things as normal?') and others less relevant (e.g. Have you had swelling near your melanoma site?'). Additionally, wording may differ between patients and HRQoL questionnaires, whereby patients generally use a more positive tone.Conclusions: Social media may provide a valuable tool in assessing patient perspectives regarding HRQoL. However, differences seem to emerge between patient and carer perspectives. Additionally, patient perspectives did not seem to fully correlate to questions posed in cancer- (i.e. EORTC QLQ-C30) and melanoma-specific (i.e. EORTC QLQ-MEL38, FACT-M) HRQoL questionnaires examined.
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| 7. |
- Marvig, Camilla L., et al.
(författare)
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Quality of life in patients with venous thromboembolism and atrial fibrillation treated with coumarin anticoagulants
- 2015
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 136:1, s. 69-75
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Little is known about the overall quality of life (QOL) in patients newly diagnosed with venous thromboembolism (VTE) and atrial fibrillation (AF). We studied QOL in patients with VTE and AF immediately after the start of anticoagulant therapy, and after three months of treatment. Furthermore we identified whether QOL was affected by age, gender and nationality. Materials and Methods: The European pharmacogenetics of anticoagulant therapy (EU-PACT) study was a multicentre, randomized controlled trial of patients aged > 18 years diagnosed with VTE or AF. QOL was assessed using EuroQol 5 dimensions (EQ-5D) questionnaires. Results: The EQ-5D questionnaires were completed by 187 patients with VTE and 660 patients with AF. The QOL in patients diagnosed with VTE or AF was significantly impaired, however, during a 3 months treatment period, patients experienced an improvement (p < 0.05). The QOL in patients diagnosed with VTE improved with increasing age, with similar effects seen in men and women. Men and women diagnosed with AF differed in QOL (respectively 0.84 and 0.74, p < 0.05), and QOL decreased with age. Comparison between countries showed significant differences in the EQ-Index score at follow-up of patients with VTE, and in both EQ-Index score and EQ-VAS of patients with AF. Conclusions: The QOL in patients with VTE and AF is strongly reduced directly after the start of anticoagulant treatment, but improves within 3 months. Moreover, QOL is influenced by demographic and disease-specific variables. These findings provide useful information for future cost-effectiveness studies.
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| 8. |
- van Schie, Rianne M. F., et al.
(författare)
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Genotype-guided dosing of coumarin derivatives : the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design
- 2009
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Ingår i: Pharmacogenomics (London). - : Future Medicine Ltd. - 1462-2416 .- 1744-8042. ; 10:10, s. 1687-1695
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Tidskriftsartikel (refereegranskat)abstract
- The narrow therapeutic range and wide interpatient variability in dose requirement make anticoagulation response to coumarin derivatives unpredictable. As a result, patients require frequent monitoring to avert adverse effects and maintain therapeutic efficacy. Polymorphisms in VKORC1 and CYP2C9 jointly account for about 40% of the interindividual variability in dose requirements. To date, several pharmacogenetic-guided dosing algorithms for coumarin derivatives, predominately for warfarin, have been developed. However, the potential benefit of these dosing algorithms in terms of their safety and clinical utility has not been adequately investigated in randomized settings. The European Pharmacogenetics of Anticoagulant Therapy (EU-PACT) trial will assess, in a single-blinded and randomized controlled trial with a follow-up period of 3 months, the safety and clinical utility of genotype-guided dosing in daily practice for the three main coumarin derivatives used in Europe. The primary outcome measure is the percentage time in the therapeutic range for international normalized ratio. This report describes the design and protocol for the trial.
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| 9. |
- van Schie, Rianne M F, et al.
(författare)
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Loading and maintenance dose algorithms for phenprocoumon and acenocoumarol using patient characteristics and pharmacogenetic data
- 2011
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Ingår i: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 32:15, s. 1909-1917
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Polymorphisms in CYP2C9 and VKORC1 influence patients' phenprocoumon (PHE) and acenocoumarol (ACE) dose requirements. To provide physicians with tools to estimate the patient's individual dose, we aimed to develop algorithms for PHE and ACE. METHODS AND RESULTS: In two Dutch anticoagulation clinics, data on age, sex, height, weight, co-medication, coumarin derivative doses, and international normalized ratio values were obtained from 624 patients taking PHE and 471 taking ACE. Single nucleotide polymorphisms relevant to coumarin derivative dosing on the CYP2C9 and VKORC1 genes were determined. Using multiple linear regression, we developed genotype-guided and non-genotype-guided algorithms to predict the maintenance dose with patient characteristics and genetic information. In addition, loading doses were derived from the calculated maintenance doses. We performed external validation in an independent data set with 229 PHE and 168 ACE users. CYP2C9 and VKORC1 genotype, weight, height, sex, age, and amiodarone use contributed to the maintenance dose of PHE and ACE. The genotype-guided algorithms explained 55.9% (PHE) and 52.6% (ACE) of the variance of the maintenance dose, the non-genetic algorithms 17.3% (PHE) and 23.7% (ACE). Validation in an independent data set resulted in an explained variation of 59.4% (PHE) and 49.0% (ACE) for the genotype-guided algorithms and for 23.5% (PHE) and 17.8% (ACE) for the non-genotype-guided algorithms, without height and weight as parameters. CONCLUSION: To our knowledge, these are the first genotype-guided loading and maintenance dose algorithms for PHE and ACE using large cohorts. The utility of these algorithms will be tested in randomized controlled trials.
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| 10. |
- Verhoef, Talitha I., et al.
(författare)
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A Randomized Trial of Genotype-Guided Dosing of Acenocoumarol and Phenprocoumon
- 2013
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Ingår i: New England Journal of Medicine. - 0028-4793 .- 1533-4406. ; 369:24, s. 2304-2312
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Tidskriftsartikel (refereegranskat)abstract
- Background: Observational evidence suggests that the use of a genotype-guided dosing algorithm may increase the effectiveness and safety of acenocoumarol and phenprocoumon therapy.Methods: We conducted two single-blind, randomized trials comparing a genotype-guided dosing algorithm that included clinical variables and genotyping for CYP2C9 and VKORC1 with a dosing algorithm that included only clinical variables, for the initiation of acenocoumarol or phenprocoumon treatment in patients with atrial fibrillation or venous thromboembolism. The primary outcome was the percentage of time in the target range for the international normalized ratio (INR; target range, 2.0 to 3.0) in the 12-week period after the initiation of therapy. Owing to low enrollment, the two trials were combined for analysis. The primary outcome was assessed in patients who remained in the trial for at least 10 weeks.Results: A total of 548 patients were enrolled (273 patients in the genotype-guided group and 275 in the control group). The follow-up was at least 10 weeks for 239 patients in the genotype-guided group and 245 in the control group. The percentage of time in the therapeutic INR range was 61.6% for patients receiving genotype-guided dosing and 60.2% for those receiving clinically guided dosing (P=0.52). There were no significant differences between the two groups for several secondary outcomes. The percentage of time in the therapeutic range during the first 4 weeks after the initiation of treatment in the two groups was 52.8% and 47.5% (P=0.02), respectively. There were no significant differences with respect to the incidence of bleeding or thromboembolic events.Conclusions: Genotype-guided dosing of acenocoumarol or phenprocoumon did not improve the percentage of time in the therapeutic INR range during the 12 weeks after the initiation of therapy.
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