CRITICAL APPRAISALFibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus A pooled meta-analysis of randomized placebo-controlled clinical trialsPrepared by: Ebson Anak Ngumbang Kevin Lau
Introduction Fibrates: a class of lipid-lowering medication primarily used as second-line agents behind statins. Fibrates were shown to increase HDL-C, reduce triglycerides and increase particle sizes of both LDL and HDL particles. Dosage - Adults: Gemfibrozil : 600 BD (avoid concomitant use with statiins: high risk of rhabdomyolysis) Fenofibrate :160mg OD (This dosage form is not suitable for patients with renal impairment) Clofibrate : 100mg OD (Contra-indicated in severe renal failure) Side-effect profile of fibrates includes gastrointestinal symptoms, increased liver function tests, a reversible rise in creatinine and myositis, in general, fibrates seem to be safe to use in combination with other lipid lowering medications.
Introduction Fibrates are widely prescribed lipid-lowering drug in the treatment of dyslipidemia. Their main clinical effects, mediated by peroxisome proliferative activated receptor (PPAR) alpha activation, are a moderate reduction in total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels, a marked reduction in triglycerides (TG) and an increase in high-density lipoprotein cholesterol (HDL-C), usually dependent of their baseline levels and dyslipidemia type. The abnormalities of lipid metabolism observed in type 2 diabetes are among the major factors contributing to vascular risk Thus, they appear to be appropriate drugs to treat diabetic dyslipidaemia and potentially to reduce cardiovascular risk in patients with type 2 diabetes.
Strategy For Lipid Lowering Drugs1. Inhibition of Cholesterol Synthesis (HMG-CoA ReductaseInhibitors, e.g. Statins) 2. Prevention of Cholesterol
Reabsorption (e.g. Resins)3. Reduction of VLDL Secretion (e.g. Niacin) 4. Increased Synthesis of Lipoprotein Lipase (e.g. Fibrates)
Critical Appraisal of a Research Design1. Does the title of the study tell you what and who the research is about?
Is the subject of the research in the title? Yes. Comparison of Omeprazole and Pantoprazole Influence on a High 150-mg Clopidogrel Maintenance Dose Is the type of people the research is about (i.e. the population) referred to in the title? Research is about patient taking High 150-mg Clopidogrel Maintenance Dose Is the approach to the research referred to in the title? Yes. The PACA (Proton Pump Inhibitors And Clopidogrel Association) Prospective Randomized Study
2. Is (are) the reason(s) for the study clearly stated? Is it clear what the study is about? Yes. Its about a randomised prospective study on comparison of effect of omeprazole & pantoprazole on patient taking 150mg clopidogrel daily Is the rationale for doing the study stated? Yes. A low response to clopidogrel has been associated with an increased risk of ischemic events and worse clinical outcome, thus is a medical concern. Different PPIs was shown to be metabolised to a varying degree by CYP2C19 which plays a major role in clopidogrel metabolism, and its activity dramatically influences the antiplatelet effect of clopidogrel. The rationale behind this study is to determine if pantoprazole is the preferred PPI over omeprazole for prophylaxis of GI bleeding in patient taking clopidogrel. Are the objectives of the research questions and/or hypotheses stated clearly? Yes. The objective of the study is to compare the effect of 2 PPIs on platelet response to clopidogrel after coronary stenting for nonST-segment elevation acute coronary syndrome (NSTE ACS). It was hypothesized that the reported negative omeprazoleclopidogrel drug interaction may not be caused by a class effect i.e. Pantoprazole does not affect clopidogrel antiplatelet effect negatively
4. Is the sample appropriate? Is the type of people the research is about, i.e. the population, adequately described? Yes. The study population is briefly described with their baseline characteristic presented in Table 1.
If a sample is used, is there a description of how the sample was selected? The sample selection method was described: All subjects selected were consecutive patients admitted for NSTE ACS and subsequently undergone successful coronary stenting. NSTE ACS was defined as clinical symptoms compatible with acute myocardial ischemia within 12 h before admission and at least 1 of the following: a new finding of ST-segment changes in at least 2 leads, elevated levels of cardiac markers, or coronary artery disease as documented by a history of revascularization or MI. The exclusion criteria were history of bleeding tendency, persistent STsegment elevation ACS, New York Heart Association functional class IV, percutaneous intervention or coronary artery bypass grafting 1 year (long-term); 4) clinical endpoints were pre-defined and recorded for patients enrolled in the study.
5. Are the measurements and/or data collection likely to be reliable and valid? The Quality of Reporting of Meta-analyses (QUOROM) guidelines for the reporting of meta analyses were used in formulating this meta-analysis and review Abbreviations: QUOROM, QUality Of Reporting Of Meta-analysis statement; HHS, Helsinki Heart Study; VA-HIT, Department of Veterans' Affairs High-density lipoprotein Intervention Trial; BIP, Bezafibrate Infarction Prevention study; SENDCAP, St. Mary's, Ealing, Northwick Park Diabetes Cardiovascular Disease Prevention Study; DAIS, Diabetes Atherosclerosis Intervention Study; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes study; NNT, Number needed to treat; MI, myocardial infarction; CHD, coronary heart disease; ACCORD, Action to Control Cardiovascular Risk in Diabetes.
6.Is there a description of any statistical methods use? Measuring the inconsistency of studies results Heterogeneity in meta-analysis refers to the variation in study outcomes between studies. Heterogeneity between the trials: Cochran's Q-test &I2 test. Result: no significant heterogeneity (I2 N0.05) between the selected trials In the presence of significant heterogeneity between trials: The random effects model of DerSimonian & Laird was used The random-effects method (DerSimonian 1986) incorporates an assumption that the different studies are estimating different, yet related, intervention effects. Meta-analysis Meta-analysis is used to investigate the combination or interaction of a group of independent studies MantelHaenszel fixed effects model
6.Is there a description of any statistical methods use? Relative risks were calculated using the pooled data and the zstatistic was computed for each clinical outcome to determine statistical significance. Results were considered statistically significant at a p-value of