CRITICAL APPRAISAL

Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus A pooled meta-analysis of randomized placebo-controlled clinical trials
Prepared 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 Drugs

1. 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 Design

1. 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 <3 months, contraindications to antiplatelet therapy, platelet count<100 g/l, creatinine clearance<25 ml/min, and prior use of glycoprotein IIb/IIIa antagonist, PPI or clopidogrel.
The sample was then randomised 1:1 to omeprazole or pantoprazole with randomisation by sealed envelope.

Is the way the sample was selected and the sample size appropriate? The sample selection method used is consecutive sampling first come first chosen All those who meet the criteria were included. As a type of non-probability sampling does not involve random selection the sample may not reflect general population Practical hard to gather big sample as longer duration is required to recruit enough subjects The sample size is small (n=104) The bigger the sample size = the lesser the error = more precise A sample size of 100 patients was estimated to enable a one-half standard deviation difference (10% difference in PRI VASP between both groups) to be detected, with an 80% statistical power and a 5% alpha risk. Statistical power -the probability that the test will reject the null hypothesis when the null hypothesis is actually false. The higher the %, the less chance of Type II error (false negative). Cohen (1988) suggested 80% as ideal value Alpha Risk risk that a null hypothesis will be rejected when it is actually true. The higher the %, the higher chance of Type I error (false positive). Cohen (1988) suggested 5% as ideal value

5. Are the measurements and/or data collection likely to be reliable and valid? Is (are) the data collection method(s) appropriate given the objectives of the study? Yes. The measurement of Platelet reactivity index (PRI) vasoactive stimulated phosphoprotein (VASP) and adenosine diphosphate (ADP)induced aggregation (ADPAg) can be used to compare the effect of omeprazole and pantoprazole. However, data derived from these biological contents may not translate well into actual clinical effect. Additional clinical studies are required to confirm the clinical effect of these biological interaction. Are there operational definitions for all jet terms? Yes. Clopidogrel response was defined using PRI VASP (lower value = better clopidogrel response, non-responders were defined as PRI VASP >50%) while platelet reactivity was defined by ADP-Ag using PAP4 Aggregometer (high reactivity defined as ADP-Ag >70%) Was a pilot study done to demonstrate the reliability and validity of the data collection tools and process? No. There was no pilot study done to examine the reliability and validity of the PAP4 Aggregometer used for measuring ADP-Ag and standardised flow cytometric assay

6. Is there a description of any statistical methods used? Do the statistics seem appropriate for the measurements of data being collected and the study objectives? Yes. Statistical analysis was performed using the Graphpad Prism Software V4.00 Continuous variables are expressed as meanSD. Categorical variables are expressed as frequencies and percentages.

Comparisons between groups were made with: - Chi-square or Fisher exact test for categorical variables - Mann-Whitney U Test for continuous variables. P <0.05 were considered statistically significant

Do any tables, graphs or diagrams help understanding of the findings? Yes. Figure 2 helps understanding of difference of the results between the study groups in term of clopidogrel response (PRI VASP values) and platelet reactivity (ADP-Ag value) Figure 3 shows the difference of omeprazole and pantoprazole in term of percentage of clopidogrel non-responder.

 Prospective investigation of the factors that may cause a disorder by comparing a cohort of individuals who do not have evidence of an outcome of interest but who are exposed to the putative cause with a concurrent cohort who are also free of the outcome but not exposed to the putative cause. Both cohorts are then followed to compare the incidence of the outcome of interest.

1. Does the title of the study tell you what and who the research is about? Title: Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus A pooled meta-analysis of randomized placebo-controlled clinical trials This meta-analysis study have searched the reference lists of clinical trials using fibrates for prevention of cardiovascular events in patients with diabetes mellitus, both in people without (primary prevention) and with (secondary prevention) known history of cardiovascular disease in the Index Medicus/MEDLINE databases [(1966December 2007) and the Cochrane Collaboration databases for randomized placebo-controlled clinical trials using

2. Is (are) the reason(s) for the study clearly stated?

Rationale of the study The increased cardiovascular risk in diabetes and that associated with the metabolic syndrome and the benefits of fibrates on increasing HDL-C, reducing triglycerides, increasing lipoprotein particle size, improving transaminases and reducingprogression to type 2 diabetes, there was a need for a trial of fibrates in diabetes The study is to define the role of fibrates in the prevention of cardiovascular events in patients with type 2 diabetes mellitus the subpopulation in which fibrates are thought to have the greatest potential.

2. Is (are) the reason(s) for the study clearly stated?

The objectives of the study The objective of the study is to evaluate the role of fibrates in the prevention of cardiovascular events In patients with type 2 diabetes mellitus. It was hypothesized that the potential for fibrates in reducing the cardiovascular risk in patients, including those with features associated with the metabolic syndrome and diabetic dyslipidemia.

3. Is the review of the literature comprehensive?

Literature Riview: The literature identified that the fibrates significantly reduce TG levels and raise HDL-C levels, and have a variable effect on LDL-C levels. They have also been shown to alter the LDL-C subclass distribution towards larger, more buoyant particles, especially in patients with diabetes. These data suggest that fibrates would be ideal agents for the management of dyslipidemia in patients with type 2 diabetes in this study. However, in spite of the plethora of molecular and in vivo data (both in animals and in human studies) suggesting the potential for fibrates in reducing the cardiovascular risk in patients, including those with features associated with themetabolic syndrome and diabetic dyslipidemia, results from large randomized clinical trials have yielded conflicting results. The study was performed in 2008 while most of the references used are published from year 1998-2008, with the oldest reference as old as year 1959.

4. Is the sample appropriate?

Results of the systematic literature search for randomized placebocontrolled clinical trials for meta-analysis.

4. Is the sample appropriate?

All data were abstracted independently by both authors in duplicate using a standardized protocol. When relevant clinical data were not available in the published literature, unpublished data for actual event rates for various cardiovascular outcomes were directly requested from the corresponding authors of selected trials. This study deliberately excluded trials using clofibrate as the study drug, because of the lack of clinical relevance (since clofibrate has long been withdrawn from the market), and also because of major differences in trial design and patient profiles in these older trials. The characteristics of the selected clinical trials were examined, and the final Delphi list was used to assess the quality of the trials and their suitability for inclusion in the pooled meta-analysis.

4. Is the sample appropriate? Salient features of the clinical trials selected for meta-analysis is summarised in Table 1.

5. Are the measurements and/or data collection likely to be reliable and valid?
Conducted a systematic search of the Index Medicus/MEDLINE databases (1966 December 2007) and the Cochrane Collaboration databases for randomized placebocontrolled clinical trials using fibrates for prevention of cardiovascular events in patients with diabetes mellitus, both in people without (primary prevention) and with (secondary prevention) known history of cardiovascular disease. The search was limited to studies published in English language peer-reviewed journals, performed in human subjects, and classified either as randomized controlled trial, clinical trial, clinical trial, phase III, clinical trial, phase IV, controlled clinical trial, or multicenter study. In addition, a manual search of the reference lists of clinical trials using fibrates and pertinent review articles was also performed. The inclusion criteria employed were: 1) randomized placebo-controlled trial design; 2) study sample size of >50 diabetic patients in each arm of the study; 3) mean duration of follow-up >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 <50% or Q-test 2 >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 <0.05 (two-sided alpha error <0.05).

6.Is there a description of any statistical methods use?

The following clinical endpoints were studied: all-cause mortality, cardiac mortality, fatal and non-fatal myocardial infarction, stroke, unstable angina, and the need for invasive coronary revascularization. In addition, the incidence of cancer and cancer-related mortality were also recorded.