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مقایسه تجویز زودهنگام اریتروپویتین در برابر تجویز تاخیری آن در درمان کم‌خونی در بیماری پیشرفته کلیه

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چکیده

پیشینه

کم‌خونی یک عارضه شایع در افراد مبتلا به بیماری‌های مزمن کلیه (chronic kidney disease; CKD) بوده و عمدتا در نتیجه کمبود نسبی اریتروپویتین (erythropoietin; EPO) ایجاد می‌شود. کم‌خونی ابتدا در طول دوره بیماری پیشرفت می‌کند و میان افراد مبتلا به بیماری پیشرفته کلیه (end‐stage kidney disease; ESKD) به اوج خود می‌رسد. بسیاری از انواع EPO ‐ که عوامل محرک اریتروپوئزیس (erythropoiesis‐stimulating agents; ESAs) هم نامیده می‌شوند ‐ برای درمان کم‌خونی در افراد مبتلا به ESKD استفاده می‌شوند.

ESAها درمان کم‌خونی شدید را میان افراد مبتلا به CKD از طریق تسکین نشانه‌ها و جلوگیری از بروز عوارض مرتبط با ترانسفیوژن خون تغییر داده‌اند. با این حال، هیچ مزیتی در رابطه با نرخ مورتالیتی و رویدادهای کشنده غیر قلبی، به جز کیفیت زندگی، یافت نشده‌اند. علاوه بر این، ارتباط میان استفاده از ESA و افزایش موربیدیتی و مورتالیتی قلبی‌عروقی در بیماران مبتلا به CKD در مطالعاتی که به مقایسه اصلاح کامل کم‌خونی با اصلاح نسبی کم‌خونی پرداختند، گزارش شده است. تا سال 2012، دستورالعمل‌های بالینی شروع درمان با ESA را زمانی توصیه می‌کردند که سطح هموگلوبین کمتر از 11 گرم/دسی‌لیتر بود؛ توصیه فعلی بر شروع EPO زمانی است که سطح هموگلوبین میان 9 و 10 گرم/دسی‌لیتر قرار می‌گیرد. با این حال، مزایای شروع درمان زمانی که سطح هموگلوبین بیشتر از 10 گرم/دسی‌لیتر اما کمتر از 11 گرم/دسی‌لیتر است، هنوز هم نامشخص باقی مانده، به ویژه میان افراد مسن که امید به زندگی آنها محدود است، اما درمان با EPO ممکن است کیفیت زندگی‌شان را بهبود بخشد.

اهداف

ارزیابی مزایا و آسیب‌های بالینی تجویز زودهنگام EPO در برابر تجویز دیرهنگام آن در درمان کم‌خونی در بیماران مبتلا به ESKD که تحت همودیالیز یا دیالیز صفاقی قرار می‌گیرند.

روش‌های جست‌وجو

پایگاه ثبت تخصصی گروه کلیه و پیوند در کاکرین را تا 22 می 2017 از طریق تماس با متخصص اطلاعات و با استفاده از اصطلاحات جست‌وجوی مرتبط با این مرور جست‌وجو کردیم.

معیارهای انتخاب

قصد داشتیم تا کارآزمایی‌های تصادفی‌سازی و کنترل شده (randomised controlled trials; RCTs) و شبه‐RCT‌هایی را در این مرور بگنجانیم که مزایا و آسیب‌های بالینی تجویز زودهنگام EPO را در برابر تجویز دیرهنگام آن در درمان کم‌خونی در بیماران مبتلا به ESKD تحت همودیالیز یا دیالیز صفاقی ارزیابی کردند. مطالعاتی که EPO را با EPO دیگر، دارونما (placebo) یا عدم درمان مقایسه ‌کردند، واجد شرایط ورود بودند.

گردآوری و تجزیه‌وتحلیل داده‌ها

اینطور برنامه‌ریزی شد که دو نویسنده به‌طور مستقل از هم داده‌ها را از مطالعات وارد شده استخراج کرده، و خطر سوگیری (bias) را با استفاده از ابزار خطر سوگیری کاکرین ارزیابی کنند. برای پیامدهای دو حالتی (dichotomous outcome) (مورتالیتی به هر علتی (all‐cause mortality)، مورتالیتی قلبی‌عروقی، انفارکتوس کلی میوکارد، سکته مغزی کلی، ترومبوز، دسترسی عروقی، عوارض جانبی درمان، ترانسفیوژن)، قصد داشتیم از خطر نسبی (RR) با 95% فواصل اطمینان (CI) استفاده کنیم. برنامه‌ریزی کردیم تا تفاوت میانگین (MD) و CI %95 را برای داده‌‏های پیوسته (continuous data) (سطح هموگلوبین) و تفاوت میانگین استاندارد شده (SMD) را با CI %95 برای کیفیت زندگی، در صورت استفاده از مقیاس‌های مختلف، محاسبه کنیم.

نتایج اصلی

جست‌وجوهای انجام شده در متون علمی موجب دستیابی به 1910 رکورد شد، از این تعداد 1534 مورد پس از حذف موارد تکراری غربال شدند، و 1376 مورد پس از ارزیابی عنوان و چکیده حذف شدند. تعداد 158 مقاله را با متن کامل ارزیابی کرده و 18 مطالعه (66 رکورد) را شناسایی کردیم که به‌طور بالقوه واجد شرایط گنجاندن در این مرور بودند. با این حال، هیچ کدام با معیارهای ورود ما مطابقت نداشتند و حذف شدند.

نتیجه‌گیری‌های نویسندگان

هیچ شواهدی را برای ارزیابی مزایا و آسیب‌های تجویز زودهنگام EPO در برابر تجویز دیرهنگام آن در درمان کم‌خونی در ESKD پیدا نکردیم.

PICOs

Population
Intervention
Comparison
Outcome

The PICO model is widely used and taught in evidence-based health care as a strategy for formulating questions and search strategies and for characterizing clinical studies or meta-analyses. PICO stands for four different potential components of a clinical question: Patient, Population or Problem; Intervention; Comparison; Outcome.

See more on using PICO in the Cochrane Handbook.

خلاصه به زبان ساده

مقایسه تجویز زودهنگام اریتروپویتین در برابر تجویز تاخیری آن در درمان کم‌خونی در بیماری پیشرفته کلیه

کم‌خونی (سطح پائین هموگلوبین) یک عارضه شایع میان افراد مبتلا به بیماری پیشرفته کلیه (end‐stage kidney disease; ESKD) است که تحت درمان دیالیز قرار می‌گیرند. در شرایطی که کلیه‌ها دیگر کار نمی‌کنند، درمان دیالیز مواد زائد سمّی را از خون پاک می‌کند. درمان کم‌خونی مبتنی بر استفاده از اریتروپویتین (erythropoietin; EPO، هورمونی که سطح هموگلوبین را افزایش می‌دهد)، برای بهبود خستگی و تنگی نفس است که از نشانه‌های شایع کم‌خونی شدید به حساب می‌آیند. به‌طور گسترده‌ای پذیرفته شده که درمان EPO باید زمانی آغاز شود که سطح هموگلوبین کمتر یا مساوی 10 گرم/دسی‌لیتر (شروع دیرهنگام) باشد. با این حال، زمانی که سطح هموگلوبین بیشتر از 10 گرم/دسی‌لیتر اما کمتر از 11 گرم/دسی‌لیتر باشد (شروع زودهنگام)، مشخص نیست شروع درمان با EPO با مزایا یا آسیب‌های بالینی همراه است یا خیر.

این مرور را انجام دادیم تا مشخص کنیم که مزایا و آسیب‌های بالینی مرتبط با تجویز زودهنگام EPO در برابر تجویز دیرهنگام آن وجود دارد یا خیر.

متون علمی را تا 8 جولای 2015 جست‌وجو کردیم، اما هیچ مطالعه‌ای را نیافتیم که تاثیر تجویز زودهنگام EPO را در برابر تجویز دیرهنگام آن برای درمان کم‌خونی مرتبط با ESKD بررسی کرده باشد. مزایا و آسیب‌های تجویز زودهنگام EPO در برابر تجویز دیرهنگام آن هنوز هم ناشناخته باقی مانده است.

Authors' conclusions

Implications for practice

We found no studies assessing early versus delayed EPO for ESKD‐related anaemia. Benefits and harms remain unknown.

Implications for research

This Cochrane Review has highlighted a need for well‐designed, high‐quality RCTs to assess the benefits and harms of early versus delayed erythropoietin for the anaemia of end‐stage kidney disease. The potential study should include main clinical outcomes (patients‐oriented outcomes) such as all‐cause mortality, cardiovascular mortality, quality of life, adverse events and cardiovascular events according to their occurrence during study follow‐up.

The study should be reported according to the Consolidated standards of reporting trials (CONSORT) statement for improving the quality of reporting of efficacy and to get better reports of harms in clinical research (Ioannidis 2004; Moher 2010; Turner 2012). Future studies should be planned according to the recommendations of Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Chan 2013a; Chan 2013b) and the Foundation of Patient‐Centered Outcomes Research (Gabriel 2012; PCORI 2012).

Future studies should be conducted by independent researchers and reported according to the Consolidated Standards of Reporting Trials (CONSORT) guidelines (Ioannidis 2004; Moher 2010) and using the Foundation of Patient‐Centered Outcomes Research recommendations (Gabriel 2012; PCORI 2012).

Background

Description of the condition

Anaemia has been defined by the World Health Organization (WHO) as a haemoglobin concentration less than 13.0 g/dL and 12.0 g/dL respectively for males and non‐pregnant females aged 15 years or over (WHO 2008). This definition is widely accepted for people with anaemia caused by CKD (KDIGO 2012).

Anaemia is a common complication in people with CKD and develops early in the course of the disease. Anaemia increases in frequency with a corresponding decline in kidney function, and peaks in incidence among people with ESKD (Astor 2002). Kidney‐related anaemia develops mainly as a consequence of relative EPO deficiency in relation to haemoglobin levels; EPO levels are 10 to 100 times higher among anaemic patients with normal kidney function (Artunc 2007; Ly 2004; McGonigle 1984).

Description of the intervention

EPO is an essential growth factor for the recruitment, differentiation, maintenance and survival of erythroid progenitor cells. EPO is produced by hepatocytes in the foetal stage, and after birth is synthesised mainly by the kidneys in response to hypoxia (Glaspy 2009; Jelkmann 2011). After cloning the EPO gene in 1983, recombinant human technology enabled development and production of the first erythropoietin ‐ epoetin‐α ‐ which was approved for clinical use in 1989 (Eschbach 1988; Eschbach 1989). Since then, many EPO types ‐ also called erythropoiesis‐stimulating agents (ESAs) ‐ have been produced. According to their action time, they are classified as short‐acting and long‐acting (Horl 2013).

Short‐acting ESAs have a half‐life from six to eight hours intravenously and from 19 to 24 hours subcutaneously; most are administered two to three times weekly (Halstenson 1991). Short‐acting ESAs are more effective when administered subcutaneously. Alfa and beta are the most widely used short‐acting ESAs. Epoetin‐α biosimilars are used in Europe (Schellekens 2008).

Long‐acting ESAs have improved pharmacokinetic and pharmacodynamic characteristics. Dose requirements do not differ according to the route of administration. The combination of a significantly increased half‐life and lower binding affinity for the EPO receptor explains why long‐acting ESAs stimulate erythropoiesis for longer periods. Long‐acting ESAs used for the treatment of kidney‐related anaemia are darbepoetin‐α and the continuous EPO receptor activator (CERA). One darbepoetin dose is given every one or two weeks (Macdougall 1999; Padhi 2006) and CERA is administered biweekly or monthly (Macdougall 2006).

EPO therapy improves cognitive function and quality of life (Astor 2002; Drueke 2006; Pfeffer 2009; Ross 2002) and helps regression of left ventricular hypertrophy (Levin 2002; Parfrey 2009). However, EPO is not free of complications which are mainly hypertensive reactions, thrombosis of arteriovenous fistula in patients on haemodialysis, increased risk of stroke and faster tumour growth; appearance of severe anaemia as part of pure red cell aplasia, and seizures (Del Vecchio 2010; Rizzo 2010; Zhu 2006).

How the intervention might work

EPO acts as an essential growth factor. It regulates erythropoiesis, maintaining the survival of erythroid progenitors, stimulating their proliferation and differentiation in the bone marrow (Jelkmann 2011). EPO production is markedly up‐regulated by hypoxia via a negative feedback loop; hypoxia induces an increase in EPO hormone production in the kidneys, increasing the mass of circulating red blood cells, thereby increasing the oxygen‐carrying capacity of blood and suppressing further expression of EPO (Bunn 2013). Specifically, EPO binds to the EPO receptor through the high affinity isoform EPO, which is responsible for the erythropoietic effects by activation of several pathways (hypoxia‐inducible factor 1, 2 and 3, Janus kinase‐2, phosphatidylinositol 3‐kinase, protein kinase C, anti‐apoptotic protein) stimulating differentiation of erythroid precursor cells and inhibiting apoptosis of erythroid progenitors (Elliott 2008; Sinclair 2013).

Recombinant human EPO and human EPO have similar biological activity. Increase in red blood cell mass is dependent on the exposure time of the level of EPO; therefore, subcutaneous administration of short‐acting ESAs is more effective (Kaufman 1998). The response to administration of EPO may vary from patient to patient. The dose should be adjusted to reach a haemoglobin monthly increase between 1 and 2 g/dL. If the increase is less than expected, the dose is increased by 25%; if higher, it is decreased by 25%. After reaching the target haemoglobin level, the maintenance dose of EPO is adjusted according to monthly haemoglobin readings (Del Vecchio 2010; KDOQI 2006; KDIGO 2012).

Why it is important to do this review

The importance of this systematic review is based on the following premises.

  1. Many of the clinical manifestations of CKD may be epiphenomena of anaemia, which is associated with the worsening of cognitive functions, exercise capacity, mental acuity, quality of life; depression and fatigue (Finkelstein 2009; Gerson 2004; Weisbord 2008). Increased risk of cardiovascular morbidity and mortality may also be present (Astor 2006; Glassock 2009; Locatelli 2004).

  2. ESAs have changed treatment of kidney‐related anaemia by improving the signs and symptoms of severe anaemia, avoiding the complications of iron overload, transmission of viral diseases and sensitisation for future kidney transplants (Del Vecchio 2010). However, no benefits have been found in RCTs and meta‐analyses when correcting anaemia with regard to patients’ mortality and non‐cardiac fatal events, except for quality of life (Drueke 2006; Johansen 2010; Johansen 2012; Pfeffer 2009). Notwithstanding, a relationship between the use of ESAs and an increased cardiovascular morbidity and mortality in patients with CKD has been reported in studies with fully correcting anaemia comparing with partial anaemia correction (Palmer 2010; Phrommintikul 2007; Singh 2006). Patients with cancer also experience increased cardiovascular morbidity and mortality associated with ESA use (Rizzo 2010; Tonia 2012).

  3. From 2000 to 2009 clinical guidelines from the United States and Europe recommended commencing ESA treatment when haemoglobin was less than 11 g/dL (EBPG 2004; ERBP 2009; ERBP 2010; KDOQI 2000; KDOQI 2006; KDOQI 2007; KDIGO 2008). The 2012 Anaemia Work Group of Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggested starting treatment in dialysis patients when haemoglobin is between 9 to 10 g/dL (Grade 2B), and in some cases, starting treatment when haemoglobin is greater than 10 g/dL (not graded), primarily in older people among whom life expectancy is limited, being more relevant to improve quality of life (KDIGO 2012). The European Renal Best Practice (ERBP) Advisory Board and Canadian Society of Nephrology guidelines agree with KDIGO about whether and when to start ESA therapy in dialysis patients (ERBP 2013; Moist 2013).

Several systematic reviews have investigated ESA treatment for anaemia in patients with CKD and ESKD evaluating haemoglobin level, energy and physical function, fatigue, left ventricular mass index and mortality (Johansen 2010; Johansen 2012; Palmer 2010; Parfrey 2009; Vinhas 2012), but to date, a systematic review on the benefits and harms of early (haemoglobin < 11 g/dL but > 10 g/dL) versus delayed (haemoglobin ≤ 10 g/dL) ESA treatment for anaemia in dialysis patients with ESKD has not been published.

Objectives

To assess the clinical benefits and harms of early versus delayed EPO for anaemia in patients with ESKD undergoing haemodialysis or peritoneal dialysis.

Methods

Criteria for considering studies for this review

Types of studies

This review included all RCTs and quasi‐RCTs (RCTs in which allocation to treatment was obtained by alternation, the use of alternate medical records, date of birth or other predictable methods) looking at EPO in people with ESKD on dialysis with anaemia. Studies were considered without language restriction. Studies of at least 12 weeks follow‐up were to be included.

Types of participants

Inclusion criteria

Dialysis patients with anaemia due to ESKD irrespective of gender or age were eligible for inclusion. We planned to accept any definition of anaemia provided in individual studies.

Exclusion criteria

We excluded studies involving patients with functional or absolute iron deficiency.

Types of interventions

This review included studies of early (haemoglobin between 10 and 11 g/dL) versus delayed (haemoglobin ≤ 10 g/dL) treatment with any EPO or EPO against placebo/no treatment, by any route (subcutaneous or intravenous) or dose. The following comparisons were considered for inclusion.

  • EPO versus placebo/no treatment

  • EPO versus EPO

Types of outcome measures

We planned to evaluate all‐cause mortality and cardiovascular mortality according to end‐of‐study reports. We also planned to assess outcomes on mortality at the short (< 6 months), medium (from 6 to 12 months) and long term (> 12 months). We planned to evaluate numbers of adverse and cardiovascular events according to their occurrence during study follow‐up.

Primary outcomes

  1. All‐cause mortality

  2. Cardiovascular mortality

  3. Quality of life (end of treatment scores obtained using validated tools such as the Kidney Disease Quality of Life tool or others as mentioned in the studies).

Secondary outcomes

  1. Adverse events: hypertension (one or more hypertensive events requiring additional antihypertensive medication or as defined by the investigators); seizure ≥ 1 event)

  2. Myocardial infarction (fatal or non‐fatal)

  3. Stroke (ischaemic or haemorrhagic, either fatal or non‐fatal)

  4. Thrombotic events (deep venous thrombosis, peripheral arterial thrombotic events, and dialysis vascular access thrombosis)

  5. Blood transfusions requirements (number of individuals requiring one or more packed red blood cell transfusion)

  6. Haemoglobin level reached at end of study.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Kidney and Transplant Specialised Register up to 22 May 2017 through contact with the Information Specialist using search terms relevant to this review. The Specialised Register contains studies identified from the following sources:

  1. Monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL)

  2. Weekly searches of MEDLINE OVID SP

  3. Handsearching of kidney‐related journals and the proceedings of major kidney conferences

  4. Searching of the current year of EMBASE OVID SP

  5. Weekly current awareness alerts for selected kidney and transplant journals

  6. Searches of the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Studies contained in the Specialised Register are identified through search strategies for CENTRAL, MEDLINE, and EMBASE based on the scope of Cochrane Kidney and Transplant. Details of these strategies, as well as a list of handsearched journals, conference proceedings and current awareness alerts, are available in the Specialised Register section of information about Cochrane Kidney and Transplant.

See Appendix 1 for search terms used in strategies for this review.

Searching other resources

  1. Reference lists of review articles, relevant studies and clinical practice guidelines.

  2. Letters seeking information about unpublished or incomplete studies to investigators known to be involved in previous studies.

Data collection and analysis

Selection of studies

Titles and abstracts were screened independently by two authors who discarded studies that were clearly not eligible and assessed the full text of potentially eligible studies to determine which satisfied inclusion criteria. Disagreements were to be resolved through discussion, with a third author if necessary.

Data extraction and management

Data extraction was to be carried out independently by two authors using standard forms. Studies reported in non‐English language journals were to be translated before assessment. Where more than one publication of one study existed, reports were to be grouped together and the publication with the most complete data used in the analyses. Where relevant outcomes were only published in earlier versions these data were to be used. Any discrepancies between published versions were to be highlighted.

Assessment of risk of bias in included studies

We planned to assess risk of bias using the Cochrane risk of bias assessment tool (Higgins 2011) (Appendix 2).

  • Was there adequate sequence generation (selection bias)?

  • Was allocation adequately concealed (selection bias)?

  • Was knowledge of the allocated interventions adequately prevented during the study?

    • Participants and personnel (performance bias)

    • Outcome assessors (detection bias)

  • Were incomplete outcome data adequately addressed (attrition bias)?

  • Are reports of the study free of suggestion of selective outcome reporting (reporting bias)?

  • Was the study apparently free of other problems that could put it at a risk of bias?

Measures of treatment effect

For dichotomous outcomes (all‐cause mortality, cardiovascular mortality, overall myocardial infarction, overall stroke, vascular access thrombosis, adverse effects of treatment, transfusion), we planned to use the risk ratio (RR) with 95% confidence intervals (CI). We planned to calculate the mean difference (MD) and CI 95% for continuous data (haemoglobin level) and the standardised mean difference (SMD) with CI 95% for quality of life if different scales had been used.

Dealing with missing data

We planned to request any further information required from the original author in writing and to include any relevant information obtained in the review.

Assessment of heterogeneity

We planned to analyse heterogeneity using a Chi² test on N‐1 degrees of freedom, with an alpha of 0.05 used for statistical significance, and the I² statistic (Higgins 2003).

Assessment of reporting biases

We planned to construct funnel plots to provide visual assessment of whether treatment estimates were associated with study size.

Data synthesis

We planned to pool data using the random‐effects model and to use the fixed‐effect model to ensure the robustness of the model chosen and the susceptibility to outliers.

Subgroup analysis and investigation of heterogeneity

Subgroup analysis was planned to explore possible sources of heterogeneity (e.g. participants, interventions and study quality). Heterogeneity among participants could be related to age and dialysis modality. Heterogeneity in treatments could be related to dose, type (short versus long acting) and duration of ESA treatment. Quality of life parameters were to be assessed based on the Kidney Disease Quality of Life tool, or as reported in studies (Hays 1997). We planned to perform the following subgroup analyses:

  • Patients on haemodialysis versus peritoneal dialysis

  • Paediatric versus adult participants

  • Use of EPO higher doses versus lower dose

  • EPO short‐acting versus long‐acting

  • Use the Kidney Disease Quality of Life tool versus others as mentioned in the studies.

Sensitivity analysis

We planned to perform sensitivity analysis to explore the influence of the following factors on the effect on size.

  • Repeating the analysis excluding unpublished studies

  • Repeating the analysis taking into account risk of bias

  • Repeating the analysis excluding any very long or large studies to establish how much they dominate the results

  • Repeating the analysis excluding quasi‐RCTs.

'Summary of findings' tables

We were not able to assess quality evidence associated with primary outcomes (all‐cause mortality, cardiovascular mortality, quality of life, cardiovascular events, adverse events, haemoglobin level reached at the end of the study, and blood transfusions requirements) with the GRADE system (Guyatt 2008).

Results

Description of studies

Results of the search

We searched the literature to 8 July 2015 and identified 1910 potentially relevant records (Figure 1). We excluded duplicate records, and assessed titles and abstracts of 1534 records. Of these, 1376 were excluded (not RCT or quasi‐RCT; wrong population; wrong intervention). We obtained the full text of 158 papers for assessment, and excluded 92. We identified 18 potential studies (66 records) none of which met our inclusion criteria.


Study flow diagram

Study flow diagram

Excluded studies

We excluded 18 studies (66 records)

See Characteristics of excluded studies.

Risk of bias in included studies

Risk of bias assessment could not be conducted.

Effects of interventions

No studies met our inclusion criteria.

Discussion

Summary of main results

This Cochrane Review identified no studies assessing benefits or harms of early or delayed EPO to treat anaemia in patients on dialysis. Early versus delayed EPO for the treatment of anaemia among people with ESKD has unknown either benefits or harms.

Potential biases in the review process

We have been unable to identify evidence from RCTs supporting the use of early or delayed erythropoietin for treating anaemia of ESKD. The main limitation of this Cochrane Review is the paucity of evidence of the use of early or delayed erythropoietin for treating anaemia of ESKD.

Agreements and disagreements with other studies or reviews

We found no studies assessing early versus delayed EPO for anaemia associated with ESKD.

Study flow diagram
Figures and Tables -
Figure 1

Study flow diagram