بسمه تعالی حوزة معاونت پژوهشی دانشگاه علوم پزشكی اصفهان چكيدهاي از طرح تحقيقاتی

Transcription

1 بسمه تعالی حوزة معاونت پژوهشی دانشگاه علوم پزشكی اصفهان چكيدهاي از طرح تحقيقاتی عنوان طرح: Effects of Pentoxifylline on anemia in patients with chronic kidney disease: A systematic review and meta-analysis کلید واژهها: Systematic review, Pentoxifylline, Anemia, Chronic kidney disease مجري اصلي: دکتر شیرین سادات بدری الين تحقیقاتي مجري اصلي: فارماکوتراپی بیماریهای کلیه طرح مصوب مرکز تحقیقات بیماریهای کلیوی دانشگاه علوم پزشکی اصفهان تاريخ تصويب: 3232/50/32 )صدور نامه: 3232/50/53( شماره نامه تصويب: 30/3055 /د

2 مقدمه و ضرورت اجراي طرح )به صورت خالصه( Chronic Kidney Disease (CKD) is a prevalent, worldwide condition, and the number of patients affected continues to increase. Anemia occurs early in development of kidney disease and worsens as kidney function deteriorates. Anemia has been associated with substantial morbidity and mortality. However, with appropriate therapy, anemia can be effectively treated, thereby improving the quality of life in patients with CKD and anemia. Erythropoiesis-stimulating agents (ESAs) and periodic iron supplements are the mainstays of treatment for anemia associated with CKD. However, since ESA started to be used, it has been observed that there is a group of patients with resistance. Besides nonresponsiveness as a major concern, the modest benefits on transfusion rates and some quality of life domains are offset by the risk of major side effects. Pentoxifylline (PTF), derived from methylxanthine, is a nonspecific inhibitor of phosphodiesterase that, besides having rheological properties and being used as a treatment in peripheral vascular disease, has anti-inflammatory activity. The hemorheological properties and the potential to improve circulation and some indices of kidney function led to an interest in the use of PTF as a therapeutic agent in patients with kidney disease. As for the possible benefit of its anti-inflammatory action on anemia in renal patients, some studies show that it increases hemoglobin (Hgb) or hematocrit (Hct) in patients with CKD or patients on a regular hemodialysis program. Pentoxiphylline is a valuable medication in many conditions namely kidney diseases due to its promising clinical characteristics and considerable profile of safety. However, the decision to prescribe pentoxiphylline for anemia in CKD should be based on evidence accrued from randomized controlled trials (RCTs). Yet, substantial heterogeneity exists in RCTs performed to evaluate pentoxiphylline therapy, particularly in relation to classification of patients, the different quality and research design, sample size, baseline Hgb or Hct, target Hgb or Hct, clinical outcome measures, and definitions of endpoints and clinically meaningful improvements. As a result, assessment of pentoxiphylline in treating anemia of CKD by conducting a systematic review and meta-analysis of the published relevant clinical studies seems rational and promising. چكيدهاي از طرح تحقيقاتي صفحة 1

3 اهداف و فرضیات الف. هدف کلي: To document from randomized controlled trials the effect of Pentoxiphylline on anemia in patients with chronic kidney disease, by systematically reviewing the literature and performing meta-analysis ب. اهداف جزئي )اختصاصي(: 1. To determine the effect of Pentoxiphylline therapy on Hemoglobin level in patients with chronic kidney disease 2. To determine the effect of Pentoxiphylline therapy on Hematocrit in patients with chronic kidney disease 3. To determine the effect of Pentoxiphylline on reducing the needed dose of Erythropoietin in patients with chronic kidney disease 4. To assess the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease ج. اهداف فرعي: 1. To determine the effect of administered dose of Pentoxiphylline on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease 2. To determine the effect of duration of treatment with Pentoxiphylline on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease 3. To determine the relationship between stage of CKD and the effect of Pentoxiphylline therapy on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline in patients with chronic kidney disease د. هدف کاربردي: To provide the highest levels of evidence in order to make the decision to prescribe pentoxiphylline for anemia in patients with kidney diseases چكيدهاي از طرح تحقيقاتي صفحة 2

4 روش اجرا و شیوههاي تجزيه و تحلیل يافتهها )به صورت خالصه( The present systematic review will be done in accordance with the PRISMA guideline for systematic reviews and meta-analysis. Peer-reviewed prospective randomized controlled clinical trials (parallel group or cross-over trials) with at least four weeks of follow-up will be including in the meta-analysis. Participants of any age with chronic kidney disease condition in whom Pentoxiphylline is prescribed for treating anemia, will be including in final analysis. Online databases (PubMed/Medline, ISI Web of Science, EmBase, and Scopus) will be searched from January 1970 to December 2014 using selected MeSH terms and free text terms related to the studied topic, including Pentoxiphylline, [using the set operator] AND Anemia, Hemoglobin, and Hematocrit, limited to studies in humans. We will also review reference lists of the identified publications for additional pertinent studies. No language restrictions will be imposing. Data will be extracted independently by two reviewers using a standard form and then crosschecked. All numeric calculations and extractions from tables, graphs or figures will be confirmed by a second reviewer. In the case of missing information in the included studies, investigators will be contacted (by , letter and/or fax) to obtain the missing information. Overall weighted mean difference (WMD) and 95% CI (confidence interval) will be calculated for the continuous outcomes. If the same continuous outcome is measured differently across studies, an overall standardized mean difference (SMD) and 95% CI will be calculated. Data will be meta-analyzed if possible according to administered dosage of Pentoxiphylline, and duration of therapy. Within and between study heterogeneities will be assessed using Cochran s Q- statistics and the heterogeneity test will be used to assess the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity is quantified using I square which provides a measure of the degree of inconsistency between studies. As we find no evidence of heterogeneity, a fixed effects model will be used; otherwise, random effects approach, Meta-regression or sub-group analysis will be used in the case of statistical heterogeneity. Sensitivity analysis will be conducted to explore the extent to which inferences might depend on a particular study or number of publications. Statistical analyses will be carrying out with Comprehensive Meta-analysis Software, version 2.0 (Englewood, NJ BioStat). P values less than 0.05 will be considered statistically significant. All statistical tests will be two-sided. صفحة 3 چكيدهاي از طرح تحقيقاتي

5 تعريف واژهها Systematic Review: Literature summaries that aim to answer a specific question on the effectiveness of interventions by performing a systematic search in available literature. The term systematic indicates that specific attention is given to formulating the methods of data collection and handling, in order to provide a transparent methodology to the reader who can then make a judgment about the quality of the literature search. This profound method minimizes the risk of bias and results in the best available scientific evidence (14). Pentoxiphylline: Pentoxifylline (PTF) is a methylxanthine phosphodiesterase inhibitor which has been in clinical use since the late 1970s and was used primarily to treat patients with peripheral vascular disease. In addition to its hemorheologic activity, it has been experimentally shown to have potent antiproliferative, antiinflammatory, anti-diabetic, anti cellular damage, and antifibrotic effects. The hemorheological properties and the potential to improve circulation and some indices of kidney function led to an early interest in the use of PTF as a therapeutic agent in patients with kidney disease (15). Anemia: Internationally anemia is defined as a state in which the quality and/or quantity of circulating red blood cells are below normal. Blood hemoglobin (Hgb) concentration serves as the key indicator for anemia because it can be measured directly, has an international standard, and is not influenced by differences in technology (16). The World Health Organization (WHO) defines anemia as a hemoglobin concentration lower than 13.0 g/dl in men and postmenopausal women and lower than 12.0 g/dl in other women (2). Chronic kidney disease: CKD is defined as abnormalities of kidney structure or function, present for more than 3 months, with implications for health (17). The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) defines CKD based on glomerular filtration rate (GFR) and divides the disease into five distinct stages. In Stage 1 CKD, the GFR is 90 ml/min/1.73 m 2. Stages 2, 3, and 4 CKD are defined by a GFR of ml/min/1.73 m 2, ml/min/1.73 m 2, and ml/min/1.73 m 2, respectively. The final stage, Stage 5, occurs when the GFR is < 15 ml/min/1.73 m 2 or when patients require dialysis (1). صفحة 4 چكيدهاي از طرح تحقيقاتي

6 قسمت دوم- اطالعات مربوط به طرح پژوهشي عنوان طرح: Effects of Pentoxifylline on anemia in patients with chronic kidney disease: A systematic review and meta-analysis نوع طرح: بنیادی بنیادی- کاربردی کاربردی مقدمه )بیان مسأله مرور متون( Chronic kidney disease (CKD) is a prevalent, worldwide condition, and the number of patients affected continues to increase. In the United States, it is estimated that by 2014, more than 2 million people will be afflicted with CKD (1). In chronic kidney disease, as nephrons are progressively lost, the body attempts to maintain homeostasis via multiple adaptive and maladaptive processes, including a complex range of biochemical and physiologic abnormalities. Almost every organ and system seems to be affected, but the main complications are cardiovascular, neurologic, hematologic, musculoskeletal, and immunologic- and all worsen as kidney function declines (2). Anemia occurs early in the development of kidney disease and worsens with declining kidney function. This complication is very common in patients with chronic kidney disease with an incidence of over 70% in advanced stages of the disease (2). The impact of anemia on patients with CKD is profound. In addition to the well-known symptoms of fatigue, dizziness, and shortness of breath, anemia has been associated with more severe adverse outcomes, such as cardiovascular complications including left ventricular hypertrophy and congestive heart failure (1). Therefore, patients with chronic kidney disease, even those with moderate disease not yet requiring dialysis, need to be periodically monitored for anemia. Although most patients are anemic when they start dialysis, only about a third is receiving treatment for it. Factors likely contributing to anemia in chronic kidney disease include blood loss, shortened red cell life span, vitamin deficiencies, the uremic milieu, erythropoietin (EPO) deficiency, iron deficiency, and inflammation (2). صفحة 5 مقدمه

7 As a result of the potentially severe consequences of anemia in CKD, early recognition and management of anemia are imperative. Correction of anemia has been shown to improve cardiac function possibly by reducing exercise-induced myocardial ischemia. Treatment of anemia associated with CKD has also been shown to result in improvements in exercise capacity, physical performance features such as endurance, energy, and physical mobility (1). Although no randomized trial has fully assessed the consequences of not treating anemia in chronic kidney disease, the consensus is that untreated anemia contributes to the large cardiovascular disease burden in this population (2). Erythropoiesis-stimulating agents (ESAs) and periodic iron supplements are the mainstays of treatment for anemia associated with CKD. Treatment with ESAs has greatly improved the management of anemia in patients with chronic kidney disease, permitting better outcomes and a higher quality of life for most (3). The high rate of response to this treatment has meant that it has been possible not only to avoid red blood cell transfusion in patients on hemodialysis, but also improve their quality of life substantially. However, since EPO started to be used, it has been observed that there is a group of patients with resistance to ESA. In some cases it is attributable to easily treatable factors, such as iron deficiency, severe hyperparathyroidism, ineffective dialysis, blood loss, vitamin deficiencies, etc.; and in others, inflammation has been suggested as a mechanism involved. In fact, all dialysis patients have a certain degree of inflammation that has been related to a greater or lesser extent, to anemia, according to the cases. Inflammation may result in, not only a lower production of EPO, but also a lower response of the erythropoiesis progenitor cell to the aforementioned treatment (4). Recent randomized controlled trials (RCTs) have reported risks and benefits in the correction of anemia using ESAs in patients with pre-dialysis CKD or end-stage renal disease (ESRD). Besides nonresponsiveness as a major concern, the safety of ESAs in treating severe anemia has not been evaluated in large placebo-controlled trials. The modest benefits on transfusion rates and some quality of life domains are offset by the risk of major side effects. Meta-analysis demonstrated that correction of anemia with ESA was associated with a significantly increased risk of hypertension and vascular access clotting and an increased risk of death that approached statistical significance (3). Pentoxifylline (PTF), derived from methylxanthine, is a nonspecific inhibitor of phosphodiesterase that, besides having rheological properties (5) and being used as a treatment in peripheral vascular disease, has anti-inflammatory activity. In fact, it has been described that it reduces levels of interleukin- 6 (IL-6) and other inflammatory parameters in patients on hemodialysis (6). The hemorheological properties and the potential to improve circulation and some indices of kidney function led to an early interest in the use of PTF as a therapeutic agent in patients with kidney disease. As for the possible مقدمه صفحة 6

8 benefit of its anti-inflammatory action on anemia in renal patients, some studies show that it increases hemoglobin (Hgb) in patients with CKD or patients on a regular hemodialysis program (4, 7-12). Systematic Review The average physician is faced with increasingly large amounts of new information about medical conditions. This ranges from the latest findings of complex molecular studies to results from randomized controlled trials (RCTs) to case reports of possible therapies for very rare conditions. With this vast amount of information being produced in published journals, presentations at conferences, and now increasingly online, it is virtually impossible for physicians to keep up to date without many hours being spent searching and reading articles. Review articles traditionally provide an overview of a topic and summarize the latest evidence, thus reducing the time clinicians would need to spend performing literature searches and interpreting the primary data. These review articles, known as narrative reviews, typically address a broad number of issues related to a topic. Narrative reviews do not describe the process of searching the literature, article selection, or study quality assessment. The data are usually summarized but not statistically combined (qualitative summary), and key studies are highlighted. The inferences made from narrative reviews may be, but are not necessarily, evidence based. Narrative reviews are useful for obtaining a broad overview of a topic, usually from acknowledged experts. However, narrative reviews are susceptible to bias if a comprehensive literature search is not performed, or if only selected data are presented which conveys the author s views on a particular topic. Systemic reviews aim to reduce bias with the use of explicit methods to perform a comprehensive literature search and critical appraisal of the individual studies. Thus, in contrast to narrative reviews, systematic reviews pose a defined clinical question. The process of performing the literature search and the specific inclusion and exclusion criteria used for study selection are described. The quality of the included studies is formally appraised. The data are summarized, and, if the data are statistically combined (quantitative summary), the systematic review is referred to as a meta-analysis. The inferences made from systematic reviews are usually evidence based. Furthermore, systematic reviews also attempt to identify if certain subtypes of evidence (eg, small negative studies) are absent from the literature; this so-called publication bias is an صفحة 7 مقدمه

9 important cause of incorrect conclusions in narrative reviews. Systematic reviews frequently, but not necessarily, use statistical methods and meta-analysis to combine the data from the literature search to produce a single estimate of effect (13). ضرورت اجراي طرح: Pentoxiphylline is a valuable medication in many conditions namely kidney diseases due to its promising clinical characteristics and considerable profile of safety. Furthermore, thanks to its antiinflammatory properties, it includes substantial beneficial therapeutic effects in different aspects of kidney disease complications such as proteinuria, makes it a notable choice in this vulnerable population. However, the decision to prescribe pentoxiphylline for anemia in CKD should be based on evidence accrued from randomized controlled trials (RCTs). Yet, substantial heterogeneity exists in RCTs performed to evaluate pentoxiphylline therapy, particularly in relation to classification of patients, the different quality and research design, sample size, baseline Hgb or Hct, target Hgb or Hct, clinical outcome measures, and definitions of endpoints and clinically meaningful improvements. As a result, assessment of pentoxiphylline in treating anemia of CKD by conducting a systematic review and metaanalysis of the published relevant clinical studies seems rational and promising. صفحة 8 مقدمه

10 اهداف و فرضیات الف. هدف کلي: To document from randomized controlled trials the effect of Pentoxiphylline on anemia in patients with chronic kidney disease, by systematically reviewing the literature and performing meta-analysis ب. اهداف جزئي )اختصاصي(: 1. To determine the effect of Pentoxiphylline therapy on Hemoglobin level in patients with chronic kidney disease 2. To determine the effect of Pentoxiphylline therapy on Hematocrit in patients with chronic kidney disease 3. To determine the effect of Pentoxiphylline on reducing the needed dose of Erythropoietin in patients with chronic kidney disease 4. To assess the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease ج. اهداف فرعي: 1. To determine the effect of administered dose of Pentoxiphylline on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease 2. To determine the effect of duration of treatment with Pentoxiphylline on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline therapy in patients with chronic kidney disease 3. To determine the relationship between stage of CKD and the effect of Pentoxiphylline therapy on Hemoglobin level, Hematocrit, reducing the needed dose of Erythropoietin, and emerging the possible adverse reactions of Pentoxiphylline in patients with chronic kidney disease د. هدف کاربردي: To provide the highest levels of evidence in order to make the decision to prescribe pentoxiphylline for anemia in patients with kidney diseases اهداف و فرضيات صفحة 9

11 فهرست منابع مورد استفاده در اين طرح 1. O Mara NB. Anemia in patients with chronic kidney disease. Diabetes Spectrum 2008; 21(1): Nurko S. Anemia in chronic kidney disease: Causes, diagnosis, treatment. Cleveland Clinic Journal of Medicine 2006; 73(3): Parfrey PS. Critical appraisal of randomized controlled trials of anemia correction in patients with renal failure. Current Opinion in Nephrology and Hypertension 2011; 20: Mora-Gutiérrez JM, Ferrer-Nadal A, García-Fernández N. Effect of pentoxifylline on anemia control in hemodialysis patients: retrospective observational case-control study. Nefrologia 2013; 33(4): Aviado DM, Porter JM. Pentoxifylline: a new drug for the treatment of intermittent claudication. Mechanism of action, pharmacokinetics, clinical efficacy and adverse effects. Pharmacotherapy 1984; 4: González-Espinoza L, Rojas-Campos E, Medina-Pérez M, Peña-Quintero P, Gómez-Navarro B, Alfonso M, et al. Pentoxifylline decreases serum levels of tumor necrosis factor alpha, interleukin 6 and C-reactive protein in hemodialysis patients: results of a randomized double-blind, controlled clinical trial. Nephrol Dial Transplant 2012; 27: Navarro JF, Mora C, Garcı a J, Rivero A, Macı a M, Gallego E, et al. Effects of Pentoxifylline on the hematologic status in anemic patients with advanced renal failure. Scand J Urol Nephrol 1999; 33: Mohammadpour AH, Nazemian F, Hassanzade Khaiat M, Tafaghodi M, Salari P, Charkazi S, et al. Evaluation of the effect of Pentoxifylline on erythropoietin-resistant anemia in hemodialysis patients. Saudi J Kidney Dis Transpl 2014; 25(1): Mortazavi M, Seirafian S, Taheri S, Nasiri R, Dolatkhah S, Emami Naini A, et al. Role of Pentoxifylline in treatment of anemic patients suffering chronic hemodialysis: a randomized clinical trial. Med Arh. 2012; 66(2): Mortazavi M, Seirafian S, Taheri S, Emami A, Samiminia F, Moinzadeh F, et al. The effect of Pentoxyfiline on hemoglobin and the dose of erythropoietin in anemic peritoneal dialysis patients. Journal of Isfahan Medical School 2011; 28(115): فهرست منابع صفحة 11

12 11. Ferrari P, Mallon D, Trinder D, Olynyk JK. Pentoxifylline improves hemoglobin and interleukin- 6 levels in chronic kidney disease. Nephrology (Carlton) 2010; 15(3): Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Pentoxiphylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol 2004; 15(7): Crowther M, Lim W, Crowther MA. Systematic review and meta-analysis methodology. Blood 2010; 116(17): Centre of Evidence-Based Practice (CEBaP) of the Belgian Red Cross-Flanders. Development of evidence-based practice guidelines and development of a systematic review. Belgian Red Cross- Flanders 2013; Badri S, Dashti-Khavidaki S, Lessan-Pezeshki M, Abdollahi M; A review of the potential benefits of pentoxifylline in diabetic and non-diabetic proteinuria. Journal of Pharmacy and Pharmaceutical Sciences 2011; 14(1): NICE clinical guideline 114. Anemia management in people with chronic kidney disease. National Institute for Health and Care Excellence (NICE) 2011; Available at: nice.org.uk/guidance/cg114. Last accessed: August KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International Supplement 2013; 3(1): Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6 (6): e The transparent reporting of systematic reviews and meta-analysis. Available at: Last accessed: August Standards for systematic reviews. In: Finding what works in health care. Institute of Medicine of the National Academies Available at: Last accessed: August Pai M, McCulloch M, Gorman JD, Pai N, Enanoria W, Kennedy G, et al. Systematic reviews and meta-analysis: An illustrated, step-by-step guide. The National Medical Journal of India 2004; 17(2): فهرست منابع صفحة 11

13 22. The University of Edinburgh-based Centre for Cognitive Ageing and Cognitive Epidemiology. Systematic reviews and meta-analyses: a step-by-step guide. Available at: Last accessed: August O Connor D, Green S, Higgins JPT (editors). Defining the review question and developing criteria for including studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, Version [updated March 2011]. The Cochrane Collaboration, Available at: Last accessed: August Clarke M, Oxman AD, Paulsen E, Higgins JPT, Green S (editors). Appendix A: Guide to the contents of a Cochrane Methodology protocol and review. In: Higgins JPT, Green S (editors), Cochrane Handbook for Systematic Reviews of Interventions Version (updated March 2011). The Cochrane Collaboration, Available at: Last accessed: August Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, Version [updated March 2011]. The Cochrane Collaboration, Available at: Last accessed: August Higgins JPT, Altman DG, Sterne JAC (editors). Assessing risk of bias in included studies. In: Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions, Version [updated March 2011]. The Cochrane Collaboration, Available at: Last accessed: August Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. BMC Med 2010; 8: Hopewell S, Clarke M, Moher D, Wager E, Middleton P, Altman DG, et al, the CONSORT Group. CONSORT for reporting randomized controlled trials in journal and conference abstracts: explanation and elaboration. PLoS Med 2008; 5: e CONSORT 2010 Statement: The transparent reporting of trials. Available at: Last accessed: August Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 2002; 21: فهرست منابع صفحة 12

14 قسمت سوم- روش اجراي طرح The present systematic review will be done in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guideline (18, 19; PRISMA checklist is attached to the proposal draft). This systematic review is designed methodologically according to the Standards for systematic reviews (13, 20-22). Eligibility criteria for considering studies for this review Types of studies Peer-reviewed prospective randomized controlled clinical trials (parallel group or cross-over trials) with at least four weeks of follow-up will be including in the meta-analysis. This will be performed by completing the Defining a question and eligibility criteria checklist (23; also attached to the proposal draft), describing in detail all the elements which would be explored within the review. Studies will be excluding if they do not provide data that allow us to calculate standard deviation (SD) / standard errors (SE) for effect estimates. Types of participants Participants (male/female) of any age with chronic kidney disease condition (stages 3, 4 or 5, according to KDIGO guideline [17]) in whom Pentoxiphylline is prescribed for treating anemia, will be including in final analysis. Types of interventions Pentoxiphylline administration at any dose for more than four weeks Types of outcome measures Primary outcomes: Changes in hemoglobin, hematocrit or the needed dose of erythropoietin, as compared to control group Secondary outcome: Adverse reactions of Pentoxiphylline therapy صفحة 13 روش اجراي طرح

15 Search methods for identification of studies Electronic searches The Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews will be searched for related reviews. Online databases (PubMed/Medline, ISI Web of Science, EmBase, and Scopus) will be searched from January 1970 to December 2014 using selected MeSH terms and free text terms related to the studied topic, including Pentoxiphylline, [using the set operator] AND Anemia, Hemoglobin, and Hematocrit, limited to studies in humans. We will also review reference lists of the identified publications for additional pertinent studies. Clinical trial registries ( and will be searched with the same protocol to identify suitable trials and investigators contacted if a trial appeared relevant. No language restrictions will be imposing. Only manuscripts with Full-Text accessibility will be including in final analysis. Search results will be examined with regard to title and abstract and suitable trials identified. Duplicate published researches will be excluding at the final analysis. Data collection Data collection Data will be extracted independently by two reviewers using a standard form (24; details are provided below; also attached to the proposal draft) and then cross-checked. Inconsistencies between authors will be agreed by consensus. All numeric calculations and extractions from tables, graphs or figures will be confirmed by a second reviewer. In the case of missing information in the included studies, investigators will be contacted (by , letter and/or fax) to obtain the missing information. Data Extraction Name of the author Year of publication Location/Country Clinical setting (primary/secondary care; inpatient/outpatient/residential care) صفحة 14 روش اجراي طرح

16 Ethics approval Inclusion criteria Exclusion criteria Methods: Randomization technique Allocation concealment Blinding of patients/parents/caregivers/clinicians/therapists/assessors Nature of control/placebo Number of drop-outs Participants at baseline: Number (in each group) Gender proportions Age range Diagnosis and criteria used (CKD staging method, definition of Anemia) Sources of recruitment Baseline Hemoglobin Baseline Hematocrit Needed dose of Erythropoietin at baseline Type of study: Single/multi-center; cross-over Interventions: Medication Dose Type of control Assessment of compliance Additional treatment components صفحة 15 روش اجراي طرح

17 Duration Length of follow-up Number/frequency of follow-up appointments and assessments Outcomes: Mean change in Hemoglobin from baseline and SD of change or SD at the end of treatment Mean change in Hematocrit from baseline and SD of change or SD at the end of treatment Mean change in the needed dose of Erythropoietin from baseline and SD of change or SD at the end of treatment Number of patients reported to be affected by Pentoxiphylline adverse effects Intention to treat analysis (Post-baseline data in patients who withdrew will be used as "last observation carried forward" (LOCF) analysis provided less than or equal to 20% of total randomized patients were lost to follow up). Patients in whom Hemoglobin and Hematocrit was actually measured at the end of treatment will also be analyzed. Information on study design, participant characteristics, measurement of anemia improvement, adjustment for potential confounders, and estimates of associations will be extracted independently by two reviewers. Discrepancies will be resolved by discussion. Data analysis Summary of data Overall weighted mean difference (WMD) and 95% CI (confidence interval) will be calculated for the continuous outcomes. If the same continuous outcome is measured differently across studies, an overall standardized mean difference (SMD) and 95% CI will be calculated (25). Meta-analysis Data will be meta-analyzed if possible according to administered dosage of Pentoxiphylline, and duration of therapy. As we find no evidence of heterogeneity, a fixed effects model will be used; otherwise, random effects approach, Meta-regression or sub-group analysis will be used in the case of statistical heterogeneity. روش اجراي طرح صفحة 16

18 Assessment of publication bias Funnel plots (estimated differences in treatment effects against their standard error) will be drawn if sufficient studies are found. Assessment of risk of bias in included studies Methodological quality will be assessed independently by at least two review authors according to the Cochrane Collaboration Handbook (25) and Cochrane Review guidelines (26). Reviewing authors will independently assess the risk of bias within each included study based on the following domains with ratings of Yes (low risk of bias); No (high risk of bias) and Unclear (uncertain risk of bias): Sequence generation Allocation concealment Blinding Incomplete outcome data Selective outcome reporting Dealing with missing data In the first instance, authors will be contacted to provide missing data or clarification of data from included studies. Missing data and drop-outs/attrition will be assessed for each included study, and the extent to which the results/conclusions of the review could be altered by the missing data will be assessed and discussed. Assessing the quality of included trials Quality of included trials will be assessed using CONSORT (Consolidated Standards of Reporting Trials) guidelines for reporting of randomized controlled trials and reporting of randomized trials as conference abstracts (27-29; CONSORT checklist is attached to the proposal draft). صفحة 17 روش اجراي طرح

19 Assessment of heterogeneity Clinical heterogeneity will be assessed by comparing the distribution of important participant factors between trials (e.g. administered dose of Pentoxiphylline, duration of Pentoxiphylline administration, and ), and trial factors (randomization concealment, blinding of outcome assessment, losses to followup, treatment type, co-interventions). Within and between study heterogeneities will be assessed using Cochran s Q-statistics and the heterogeneity test will be used to assess the null hypothesis that all studies evaluated the same effect. The effect of heterogeneity is quantified using I square (30) which provides a measure of the degree of inconsistency between studies. As we find no evidence of heterogeneity, a fixed effects model will be used; otherwise, random effects approach, Meta-regression or sub-group analysis will be used in the case of statistical heterogeneity. In addition, a chi-square test of homogeneity will be employed to determine the strength of evidence that heterogeneity is genuine. Sensitivity analysis Sensitivity analyses will be conducted to assess the impact of the study quality. A sensitivity analysis compares studies fulfilling and not fulfilling the Quality criteria and asks the question, Are the findings robust to the decisions made in the process of obtaining them? This involves the removal of studies that meet certain criteria (e.g., poor quality, commercial sponsorship, conference abstract) to determine their effect on the overall result (13). These will be undertaken by including: 1. Only those with low risk of selection bias (associated with sequence generation or allocation concealment); 2. Only those with low risk of performance bias (associated with issues of blinding); 3. Only those with low risk of attrition bias (associated with completeness of data). Statistical analyses will be carrying out with Comprehensive Meta-analysis Software, version 2.0 (Englewood, NJ BioStat). P values less than 0.05 will be considered statistically significant. All statistical tests will be two-sided. صفحة 18 روش اجراي طرح

20 جدول زماني مراحل اجرا و پیشرفت کار زمان اجرا )ماه( رديف نوع فعالیت فرد مسئول طول مدت به ماه 3 مطالعة متون و جمعآوری اطالعات مورد نیاز جهت دانشجو تحت نظارت اساتید راهنما 1 نگارش پروپوزال )دکتر بدری دکتر فیضی( 0 جستوجوی منابع و پایگاههای اطالعاتی جهت یافتن مقاالت مرتبط با موضوع دانشجو تحت نظارت استاد راهنما و مشاور )دکتر بدری دکتر مرتضوی( 2 3 آنالیز مقاالت و استخراج دادهها در جهت دستیابی دانشجو تحت نظارت استاد راهنما و مشاور )دکتر بدری 3 به اهداف طرح دکتر مرتضوی( دانشجو تحت نظارت اساتید 3 تحلیل آماری راهنما 4 )دکتر بدری دکتر فیضی( 2 جمعبندی تهیه مقاله و ارائه گزارش نهائی طرح دانشجو تحت نظارت اساتید راهنما و مشاور )دکتر بدری دکتر فیضی دکتر مرتضوی( 5 جمع کل: 30 ماه جدول متغیرها رتبهاي کیفي اسمي نوع متغیر گسسته کم ي پیوسته نقش متغیر Independent Confounder Confounder Confounder Dependent Dependent نام متغیر Pentoxiphylline administration Administered dose of Pentoxiphylline Duration of treatment with Pentoxiphylline Stage (3, 4, or 5) of CKD Hemoglobin level Hematocrit Needed dose of Erythropoietin Dependent Adverse reactions of Pentoxiphylline therapy (number of affected patients for each adverse effect) Dependent روش اجراي طرح صفحة 19

21 مشكالت اجرايي در انجام طرح و روش حل مشكالت در مطالعات مرور نظاممند یکی از مشکالت پیش رو عدم دستیابی به متن کامل text( )Full مقاالت مورد مطالعه میباشد که در این تحقیق سعی میگردد از طریق پایگاههای اطالعاتی تحت پوشش دانشگاه علوم پزشکی اصفهان و نیز کتابخانههای طرف قرارداد با این دانشگاه امکان دسترسی به مقاالت فراهم گردد. در غیر این صورت مقاله از طریق پایگاه اطالعاتی ارائه دهنده آن خریداری خواهد شد تا بدین ترتیب همه شواهد موجود در خصوص موضوع مورد مطالعه در دسترس قرار گیرد. همچنین در صورتی که در یک مقاله اطالعات مورد نیاز به منظور انجام مطالعات آماری مرتبط با مرور نظاممند ارائه نشده باشد سعی خواهد شد که از طریق تماس با نویسنده مسئول مقاله و ارائه توضیح در خصوص انجام این تحقیق اطالعات الزم از ایشان کسب گردد. پیشنهادات و کاربرد يافتههاي طرح از آنجا که هدف از انجام مطالعات ثانویه از قبیل مطالعات مرور نظاممند در واقع جمععآوری و تحلیعل کلیعه شعواهد موجعود )به دست آمده از مطالعات بالینی کنترل شده( پیرامون موضوع مورد مطالعه است لذا انجام چنین مطالعاتی معیتوانعد شعواهد مستدلی برای مثال در خصوص کارایی یک روش درمانی فراهم آورد و بدین ترتیب در آینده منشأ تصمیمگیریهای بالینی قرار گیرد. مشكالت و پيشنهادات صفحة 21

22 ضمائم Pages 25, 26 PRISMA 2009 checklist Reference No. 19 Pages 27, 28 CONSORT 2010 checklist Reference No. 29 Pages 29, 30 Defining a question and eligibility criteria (Cochrane training) Reference No. 23 Pages Data extraction form Reference No. 24 ضمائم در صورت نیاز به اخذ رضایتنامه کتبی از واحدهای مورد پژوهش نمونهای از فرم مذکور ضمیمه گردد. در صورتی که روش و یا ابزار گردآوری دادهها پرسشنامه و یا چک لیست میباشد لطفا نمونهای از آن ضمیمه شود. در صورت نیاز موافقت کتبی محیط پژوهش اخذ و ضمیمه گردد. در مورد مجریان خارج دانشگاهی لطفا CV علمی مجری ضمیمه گردد ضمائم صفحة 21

23 PRISMA 2009 Checklist Section / Topic # Checklist item TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. ABSTRACT Structured summary 2 INTRODUCTION Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. Rationale 3 Describe the rationale for the review in the context of what is already known. Objectives 4 METHODS Protocol and registration 5 Eligibility criteria 6 Information sources 7 Search 8 Study selection 9 Data collection process 10 Data items 11 Risk of bias in individual studies 12 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2 ) for each meta-analysis. Reported on page # Page 25

24 PRISMA 2009 Checklist Section/topic # Checklist item Reported on page # Risk of bias across studies 15 Additional analyses 16 RESULTS Study selection 17 Study characteristics 18 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). DISCUSSION Summary of evidence 24 Limitations 25 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(6): e doi: /journal.pmed For more information, visit: Page 26

25 CONSORT 2010 checklist of information to include when reporting a randomized trial Section / Topic Item No Checklist item Reported on page No Title and abstract 1a 1b Identification as a randomised trial in the title Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) Introduction Background and objectives 2a 2b Scientific background and explanation of rationale Specific objectives or hypotheses Methods Trial design Participants Interventions 5 Outcomes Sample size Randomisation: Sequence generation Allocation concealment mechanism Page 27 3a 3b 4a 4b 6a 6b 7a 7b 8a 8b 9 Description of trial design (such as parallel, factorial) including allocation ratio Important changes to methods after trial commencement (such as eligibility criteria), with reasons Eligibility criteria for participants Settings and locations where the data were collected The interventions for each group with sufficient details to allow replication, including how and when they were actually administered Completely defined pre-specified primary and secondary outcome measures, including how and when they were assessed Any changes to trial outcomes after the trial commenced, with reasons How sample size was determined When applicable, explanation of any interim analyses and stopping guidelines Method used to generate the random allocation sequence Type of randomisation; details of any restriction (such as blocking and block size) Mechanism used to implement the random allocation sequence (such as sequentially numbered containers), describing any steps taken to conceal the sequence until interventions were assigned Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to interventions If done, who was blinded after assignment to interventions (for example, participants, care providers, those assessing 11a Blinding outcomes) and how 11b If relevant, description of the similarity of interventions 12a Statistical methods used to compare groups for primary and secondary outcomes Statistical methods 12b Methods for additional analyses, such as subgroup analyses and adjusted analyses

26 CONSORT 2010 checklist of information to include when reporting a randomized trial Section / Topic Item No Checklist item Reported on page No Results Participant flow (a diagram is strongly recommended) 13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and were analysed for the primary outcome For each group, losses and exclusions after randomisation, together with reasons Dates defining the periods of recruitment and follow-up Why the trial ended or was stopped 13b Recruitment 14a 14b Baseline data 15 A table showing baseline demographic and clinical characteristics for each group Numbers analysed 16 Outcomes and estimation 17a 17b Ancillary analyses 18 For each group, number of participants (denominator) included in each analysis and whether the analysis was by original assigned groups For each primary and secondary outcome, results for each group, and the estimated effect size and its precision (such as 95% confidence interval) For binary outcomes, presentation of both absolute and relative effect sizes is recommended Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing pre-specified from exploratory Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) Discussion Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses Generalizability 21 Generalizability (external validity, applicability) of the trial findings Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence Other information Registration 23 Registration number and name of trial registry Protocol 24 Where the full trial protocol can be accessed, if available Funding 25 Sources of funding and other support (such as supply of drugs), role of funders We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials. Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see Page 28

27 Defining a question and eligibility criteria Complete the following table, describing in detail all the elements you would like to explore within your review. Consider the prompt questions on the following page to help you. When you have finished, consider which of the elements you have listed will form your eligibility criteria to include/exclude studies from your review. Population Intervention(s) Comparison(s) Outcome(s) Study design(s) Page 29

28 Prompt questions to develop your eligibility criteria Population Intervention(s) Comparison(s) Outcome(s) Study design(s) How is the disease/condition defined? What are the most important characteristics that describe the participants relevant to your review? Are there any relevant demographic factors? (e.g. age, sex, ethnicity) What is the setting? (e.g. hospital, community) Who should make the diagnosis? Are there any comorbidities to be excluded? Are there any other types of people who should be excluded or considered in the review (because they are likely to react to the intervention in a different way)? How will studies involving only a subset of relevant participants be handled? Does the intervention have variations (e.g. dosage, components, mode of delivery, personnel, frequency, duration, timing)? Are all variations to be included (e.g. is there a minimum dose or components without which the intervention may not be expected to work in the same way)? How will trials including the intervention of interest combined with another intervention (cointervention) be handled? Is the intervention provided or accessed differently in different contexts? What are you interested in comparing the intervention to (e.g. an active intervention, no intervention or placebo, any available comparison)? This depends on the primary question of the review. What is the usual alternative to your intervention of interest in practice? If comparing to a specific intervention, describe in detail as above. What are the important outcomes that you plan to measure in your review? Will the outcomes form part of the selection criteria? Which will be your primary outcomes (maximum of 3)? Which will be your secondary outcomes? Which primary and secondary outcomes will be your main outcomes (maximum of 7) to be included in summaries of the completed review such as your Abstract, Plain Language Summary and Summary of Findings Table? These outcomes should be essential for decisionmaking, and have an emphasis on patient-important outcomes. Have you included possible adverse effects? How should the outcomes be measured (e.g. validated tools)? Are there important time points at which outcomes should be measured (e.g. long enough to expect an observable effect)? Have you included outcomes relevant to all potential decision-makers? Most Cochrane reviews include randomized controlled trials as the most appropriate design to answer questions about the effects of interventions. Do you plan to include other study designs (e.g. quasi-randomized studies, non-randomized studies)? If so, which designs will you include, and what is your rationale? Based on O Connor D, Green S, Higgins JPT (editors). Chapter 5: Defining the review question and developing criteria for including studies. In: Higgins JPT, Green S (editors), Cochrane Handbook of Systematic Reviews of Intervention. Version (updated September 2008). The Cochrane Collaboration, Available from: Page 30

29 Data Extraction Title: Authors: Year of publication : Location / Country : Clinical setting or Sources of recruitment (primary/secondary care; inpatient/outpatient/residential care) : Randomization technique : Allocation concealment : Blinding of patients/parents/caregivers/clinicians/therapists/assessors : Nature of control/placebo : Page 31

30 Assessment of how researchers dealt with confounding Method for identifying relevant confounders described If yes, describe the method used: Yes No Relevant confounders described: List confounders described under Data extraction, characteristics of participants: Yes No Method used for controlling for confounding At design stage: matching variables on which subjects matched:. At analysis stage: stratification multivariable regression propensity scores (matching) propensity scores (multivariable regression)... List confounders controlled for under Data extraction, characteristics of participants: Page 32

31 Data extraction Entire study Intervention Control Number of participants identified Number of participants: excluded lost to follow-up Number of participants included All participants accounted for? Yes No Ethics approval Yes No Assessment of compliance Yes No Eligibility / inclusion / exclusion criteria (enter in appropriate column if criteria differ by group) Diagnosis and criteria used (CKD staging method, definition of Anemia) Page 33

32 Characteristics of participants (Enter characteristics, tick if considered to be a confounder, then enter mean and SD, or frequency and percentage for each characteristic, for entire study population and by group. Finally, for each characteristic, tick last column to indicate whether groups were considered different by the researchers.) Characteristic Confounder? Entire study Exposed Unexposed Different? Age Sex CKD stage Baseline Hgb Baseline Hct The needed dose of EPO (at baseline) Others: SD: standard deviation. CKD: chronic kidney disease; Hgb: haemoglobin; Hct: haematocrit; EPO: erythropoietin. Page 34

33 Intervention Medication : Dose : Additional treatment components : Duration : Length of follow-up : Number/frequency of follow-up appointments and assessments : Page 35

34 Effects of intervention Outcomes Number analysed Unadjusted effect estimate and SE / CI Number analysed Adjusted effect estimate and SE / CI Confounders included in adjusted analysis Hgb levels HR OR RR HR OR RR Intervention vs. control SE CI SE CI Haematocrit HR OR RR HR OR RR Intervention vs. control SE CI SE CI Needed dose of EPO HR OR RR HR OR RR Intervention vs. control SE CI SE CI Adverse effects HR OR RR HR OR RR Intervention vs. control SE CI SE CI CI: confidence interval; SE: standard error; HR: hazard s ratio; OR: odd s ratio; RR: risk ratio. Hgb: haemoglobin; EPO: Erythropoietin. Number of patients reported to be affected by Pentoxiphylline adverse effects. Page 36