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Antiplatelet agents for chronic kidney disease

  1. Suetonia C Palmer1,*,
  2. Lucia Di Micco2,
  3. Mona Razavian3,
  4. Jonathan C Craig4,5,
  5. Vlado Perkovic3,
  6. Fabio Pellegrini6,7,
  7. Meg J Jardine8,
  8. Angela C Webster4,5,9,
  9. Sophia Zoungas10,
  10. Giovanni FM Strippoli4,5,11,12,13

Editorial Group: Cochrane Renal Group

Published Online: 30 APR 2013

Assessed as up-to-date: 24 JAN 2011

DOI: 10.1002/14651858.CD008834.pub3


How to Cite

Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, Jardine MJ, Webster AC, Zoungas S, Strippoli GFM. Antiplatelet agents for chronic kidney disease. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008834. DOI: 10.1002/14651858.CD008834.pub3.

Author Information

  1. 1

    University of Otago Christchurch, Department of Medicine, Christchurch, New Zealand

  2. 2

    University of Naples "Federico II", Division of Nephrology, Naples, Italy

  3. 3

    The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia

  4. 4

    The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia

  5. 5

    The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia

  6. 6

    Consorzio Mario Negri Sud, Unit of Biostatistics, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy

  7. 7

    IRCCS "Casa Sollievo della Sofferenza", Unit of Biostatistics, San Giovanni Rotondo (FG), Chieti, Italy

  8. 8

    Concord Repatriation General Hospital, Department of Renal Medicine, Concord, NSW, Australia

  9. 9

    The University of Sydney at Westmead, Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, NSW, Australia

  10. 10

    Monash University, School of Public Health and Preventive Medicine, Monash Applied Research Stream, Clayton, VIC, Australia

  11. 11

    University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy

  12. 12

    Mario Negri Sud Consortium, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy

  13. 13

    Diaverum, Medical-Scientific Office, Lund, Sweden

*Suetonia C Palmer, Department of Medicine, University of Otago Christchurch, 2 Riccarton Ave, PO Box 4345, Christchurch, 8140, New Zealand. suetonia.palmer@otago.ac.nz.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 30 APR 2013

SEARCH

 

Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of the condition

Cardiovascular disease is the leading cause of morbidity and mortality among people at all stages of chronic kidney disease (CKD) (Casas 2005; Keith 2004; Mann 2001; Norris 2006; Sarnak 2003; Weiner 2004a; Weiner 2004b) including kidney transplant recipients (Aakhus 1999; ANZDATA 2009; Kasiske 2000; Ojo 2000; USRDS 2010). Compared with the general population, the risk of cardiovascular disease is increased two-fold in people with the early stages of CKD (Go 2004) and 30- to 50-fold in people who need dialysis (de Jager 2009; Fort 2005) in whom it accounts for half of all deaths (Collins 2003). Population representative surveys in Australia (AusDiab 2003) and the United States (NHANES 2010) have shown that CKD (defined as proteinuria or reduction of glomerular filtration rate (GFR) below 60 mL/min/1.73 m²) affects approximately 16% of the adult population. With the increasing prevalence of some of the known risk factors for CKD, including hypertension, obesity and diabetes (Fields 2004; Koren-Morag 2006; Mokdad 2003), the burden of CKD and its complications are projected to increase and to contribute significantly to global healthcare expenditure.

 

How the intervention might work

Antiplatelet agents prevent arterial occlusion from thrombus via direct prevention of platelet aggregation. Current available data suggest antiplatelet agents might be beneficial in patients with CKD for primary (ATT 2002; HOT Study 2010; Ruilope 2001) and secondary (Berger 2003; McCullough 2002) prevention of cardiovascular events. Antiplatelet agents may have beneficial effects on the kidney, possibly reducing proteinuria and protecting kidney function in people with glomerulonephritis (Taji 2006; Zäuner 1994), and improving graft function in kidney transplant recipients (Bonomini 1986; Frascà 1986). However, some have reported that the efficacy of antiplatelet therapy in CKD might be lower than for other high cardiovascular risk populations (Best 2008). Despite this, the Kidney Disease Outcomes Quality Initiative guideline program (KDOQI) has supported the use of aspirin for primary prevention of cardiovascular disease in CKD. Antiplatelet agents appear to have a modest effect on the preservation of arteriovenous fistula patency (Dember 2008). Their use for fistula preservation and as part of a multifactorial intervention strategy for patients with CKD is advocated by guideline groups (CARI 2000; Renal Association 2010).

 

Why it is important to do this review

To date, there has been no formal meta-analysis of the benefits and harms of antiplatelet agents in patients with CKD. In contrast to the general population, people with CKD have a different profile of causes for major cardiovascular events, including a greater preponderance for arrhythmia and congestive heart failure (Amann 2003; Curtis 2005; Dikow 2005; Foley 1995; Remppis 2008), altered pharmacokinetics (Mosenkis 2004; Scheen 2008) and impaired haemostasis (Kaw 2006; Remuzzi 1988; Wattanakit 2008; Zwaginga 1991). Compared with people who do not have CKD, these factors might expose the CKD population to a different spectrum of risk and benefit from antiplatelet therapy.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

To evaluate the benefits and harms of antiplatelet therapy in people with any form of CKD, including those with CKD not receiving renal replacement therapy, patients receiving any form of dialysis, and kidney transplant recipients.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Criteria for considering studies for this review

 

Types of studies

All randomised controlled trials (RCTs) and quasi-RCTs (RCTs in which allocation to treatment was obtained by alternation, use of alternate medical records, date of birth or other predictable methods) of antiplatelet agents in people with CKD were included.

 

Types of participants

Participants with CKD, including those who needed renal replacement therapy (dialysis), had a functioning kidney transplant, or whose kidney function was impaired (defined as a reduced GFR < 60 mL/min/1.73 m²), the presence of other markers of kidney damage such as proteinuria (KDOQI stages 1 to 5), or an elevated serum creatinine (SCr) level (SCr > 120 μmol/L). Data from subgroups of participants with CKD within studies with broader inclusion criteria (e.g. people from the general population, people with diabetes, people with cardiovascular disease) were also included.

 

Types of interventions

Interventions included any antiplatelet agent. Agents could be administered at any dose or route of administration, and compared with placebo, no treatment, different dose of the same or different antiplatelet agents, different administration regimens of the same or different agent, or different combinations of antiplatelet agents. Antiplatelet agents included, but were not limited to: acetylsalicylic acid (aspirin), adenosine reuptake inhibitors (dipyridamole), adenosine diphosphate receptor inhibitors (ticlopidine and clopidogrel), phosphodiesterase 3 inhibitors (cilostazol), P2Y₁₂ antagonists (prasugrel, ticagrelor, cangrelor, elinogrel), glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide, tirofiban, defibrotide), and sulfinpyrazone.

 

Types of outcome measures

 

Primary outcomes

  • Myocardial infarction (nonfatal or fatal)
  • Stroke (nonfatal or fatal)
  • All-cause mortality
  • Cardiovascular mortality
  • Bleeding-related death
  • Major bleeding
  • Minor bleeding
  • Haemorrhagic stroke
  • End-stage kidney disease (ESKD)
  • Kidney transplant graft loss
  • Transplant rejection
  • Dialysis vascular outcomes (failure, early thrombosis, loss of unassisted patency, failure to attain suitability for dialysis, and need for access intervention)
  • Hospitalisation
  • Treatment withdrawal.

 

Secondary outcomes

  • End of treatment SCr
  • End of treatment proteinuria.

 

Search methods for identification of studies

A systematic and comprehensive literature search was carried out to identify eligible RCTs. There was no language restriction.

 

Electronic searches

We searched the Cochrane Renal Group's Specialised Register (to 24 January 2011) through contact with the Trials Search Co-ordinator using search terms relevant to this review.

The Cochrane Renal Group’s Specialised Register contains studies identified from:

  1. Quarterly searches of the Cochrane Central Register of Controlled Trials CENTRAL
  2. Weekly searches of MEDLINE OVID SP
  3. Handsearching of renal-related journals and the proceedings of major renal conferences
  4. Searching of the current year of EMBASE OVID SP
  5. Weekly current awareness alerts for selected renal 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 the Cochrane Renal Group. 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 the Cochrane Renal Group.

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

 

Data collection and analysis

 

Selection of studies

All RCTs enrolling participants with CKD were considered as well as studies in broader populations in which outcome data for subgroups with CKD could be disaggregated. Based on the search strategy described, we identified titles and abstracts that were potentially relevant to this systematic review. Three independent authors (MR, LDM, SP) screened the titles and abstracts and selected those that met the inclusion criteria. Discrepancies in selection were resolved by discussion or by the review of an experienced arbitrator (GFMS). Studies reported in non-English language journals were translated before assessment.

 

Data extraction and management

Three authors independently read the full text of extracted articles and included studies that met the inclusion criteria. Where more than one publication of one study existed, reports were grouped together and the publication with the most complete data was used in the analyses.

The same independent authors used standardised data forms to extract data on:

  • Study design
  • Participants: baseline characteristics including age, gender, race, diabetic status (proportion with diabetes), hypertension status (proportion with hypertension), smoking status (proportion of smokers), visceral obesity (proportion with visceral obesity as defined by authors), previous cardiovascular events (proportion with existing cardiovascular disease), and stage of CKD (dialysis, predialysis, transplant)
  • Interventions and comparisons: antiplatelet agent, dose and route of administration, duration of treatment
  • Outcomes: as listed in Types of outcome measures.

 

Assessment of risk of bias in included studies

The risk of bias in included studies was formally assessed by looking at standard quality domains using the risk of bias assessment tool (Higgins 2011). The items assessed were sequence generation, allocation concealment, blinding (participants, investigators, and outcome assessors), completeness of outcome data, selective reporting and other potential sources of bias. We made explicit judgements (Appendix 2) regarding whether studies were at high risk of bias, according to criteria in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We explored the impact of bias by undertaking sensitivity analyses.

 

Measures of treatment effect

For dichotomous outcomes (e.g. such as death, cardiovascular events), results were expressed as risk ratio (RR) with 95% confidence intervals (CI). Where continuous scales of measurement were used to assess the effects of treatment (e.g. creatinine clearance (CrCl), GFR, SCr, proteinuria), the mean difference (MD) and its 95% CI was used. The final results are presented in International System (SI) units. When crude event data were not reported by investigators, available reported risk estimates and their 95% CIs were included in meta-analyses (CURE Study 2007; PLATO Study 2010).

 

Dealing with missing data

Where possible, data for each outcome of interest were evaluated, regardless of whether the analysis was based on intention-to-treat. In particular, dropout rates were investigated and reported in detail, including dropout due to discontinuation of study drug, treatment failure, death, withdrawal of consent, or loss to follow-up. Corresponding authors of all large studies with broader inclusion were contacted to obtain data for the subgroup of CKD.

 

Assessment of heterogeneity

We tested for heterogeneity using the Cochran Q test, which follows a Chi² distribution with n-1 degrees of freedom, with an alpha of < 0.10 used for statistical significance. The extent of heterogeneity was assessed with I², which ranges between 0% and 100% and expresses the proportion of between group variability that is attributable to heterogeneity rather than chance (Higgins 2003). I² values above 75% are typically held to signify extreme heterogeneity, whereas 25% and 50% correspond to low and medium levels of heterogeneity, respectively.

 

Assessment of reporting biases

We evaluated asymmetries in the inverted funnel plots (i.e. for systematic differences in the effect sizes between more precise and less precise studies). There are many potential explanations for why an inverted funnel plot may be asymmetric, including chance, heterogeneity, publication and reporting bias (Sterne 2011). Insufficient data were available to evaluate the robustness of the results according to publication, namely, publication as full manuscript in a peer reviewed journal versus studies published as abstracts/text/letters/editorials and publication.

 

Data synthesis

Data were pooled using the random-effects model. The GRADE approach developed by Grades of Recommendation, Assessment, Development and Evaluation Working Group (GRADE Working Group) was used for evaluating the quality of evidence for outcomes to be reported. Based on the GRADE approach, the quality of a body of evidence, in terms of the extent to which one can be confident that an estimate of effect or association is close to the quantity of specific interest, was defined. Quality of a body of evidence involves consideration of within-study risk of bias (methodological quality), directness of evidence, heterogeneity, precision of effect estimates and risk of publication bias ( Table 1). Factors that might decrease the quality level of a body of evidence were considered ( Table 2).

 

Subgroup analysis and investigation of heterogeneity

Heterogeneity was explored using subgroup analyses according to the following parameters (where sufficient numbers of studies were available):

  • Population characteristics
    • Stage of CKD (pre-dialysis, dialysis, transplant)
    • Presence or absence of comorbidities (diabetes, hypertension, dyslipidaemia, smoking, obesity, family history of cardiovascular disease, baseline cardiovascular disease); percentage of patients with these comorbidities in each study
    • Age
    • Gender
    • Mean systolic blood pressure (BP) (below 140 mm Hg versus 140 mm Hg or above)
    • Ethnicity (proportion white)
    • Presence or absence of previous cardiovascular events (e.g. primary versus secondary prevention) 
    • Time on dialysis (fewer than three years versus three years or more) and modalities of dialysis (haemodialysis versus peritoneal dialysis)
    • Time with a functioning transplant (fewer than three years versus three years or more).

  • Intervention characteristics
    • Types, doses and route of administration of the antiplatelet agents
    • Duration of intervention (less than six months, six to 12 months, greater than 12 months).

We performed univariate meta-regression according to previously described methods when sufficient studies were identified (Palmer 2007). Univariate meta-regression was conducted using SAS (SAS Institute Inc, Cary, NC; Release 9·1, 2002-2003).

 

Sensitivity analysis

Sensitivity analyses were undertaken to explore the robustness of findings to key decisions in the review process. We assessed the risks of mortality, nonfatal and fatal myocardial infarction, and major bleeding only including studies with adequate allocation concealment, or at low risk of bias due to completeness of follow-up. Insufficient data were available to perform indirect comparisons of antiplatelet agent versus antiplatelet agent (Song 2003).

 

Results

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Description of studies

See Characteristics of included studies; Characteristics of excluded studies; and Characteristics of ongoing studies.

 

Results of the search

Electronic searching of MEDLINE, EMBASE, CENTRAL and the Cochrane Renal Group's Specialised Register (24 January 2011) identified 1075 citations (Figure 1). Searching of reference lists (8), previous systematic reviews (4), trials' registries (2), and data received from investigators (4) provided data for people with CKD from 18 other studies. We removed 64 duplicate citations to screen 1029 citations by title and abstract. Of these, 847 citations were excluded because they were not original investigations (reviews, commentaries, editorials), not RCTs, not appropriate interventions, had irrelevant outcomes, were animal studies or were conducted in children, or were not in people with CKD. We then assessed 182 full text articles for eligibility. Of these, 102 were excluded: 3 were commentaries, 16 were not RCTs, 28 were not appropriate interventions, 40 did not provide outcome data for participants with CKD, and 15 did not provide outcome data relevant to this review. Two ongoing studies (3 citations) were identified and will be assessed for inclusion in a future update of this review (FAVOURED Trial; NCT01198379).

 FigureFigure 1. Study flow diagram; study identification and selection process

We included 50 studies (27,139 participants) published in 77 reports; 44 studies (21,460 participants) compared an antiplatelet agent with placebo or no treatment (Abdul-Rahman 2007; Anderson 1974; Andrassy 1974; CHARISMA Study 2009; Cheng 1998; CREDO Study 2008; Creek 1990; CURE Study 2007; Dember 2008; Dixon 2009; Dodd 1980; Donadio 1984; Ell 1982; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; ETDRS 1992; Fiskerstrand 1985; Frascà 1997; Ghorbani 2009; Giustina 1998; Gonzalez 1995; Gröntoft 1985; Gröntoft 1998; Harter 1979; HOT Study 2010; IMPACT II Study 1997; Kaegi 1974; Kaufman 2003; Khajehdehi 2002; Kobayashi 1980; Kooistra 1994; Michie 1977; Middleton 1992; PRISM-PLUS Study 2002; PURSUIT Study 1998; Quarto Di Palo 1991; RAPPORT Study 1998; Schulze 1990; Sreedhara 1994; STOP Study 1995; Taber 1992; UK-HARP-I Study 2005; Zäuner 1994) and six studies (5679 participants) compared an antiplatelet agent with another antiplatelet agent (Frascà 1986; Kauffmann 1980; Ogawa 2008; PLATO Study 2010; TARGET Study 2001; TRITON-TIMI 38 2007).The overall characteristics of the included studies are provided in Characteristics of included studies. Information for three studies (1238 participants: Creek 1990; Ell 1982; Middleton 1992) including two internal study reports (Creek 1990; Middleton 1992) were only available in a previously published meta-analysis of antiplatelet agents (ATT 2002). For three studies (94 participants), the most complete data were provided in published conference proceedings (Dodd 1980; Gonzalez 1995; Taber 1992). One study was reported in German (Schulze 1990).

 

Antiplatelet versus placebo or no treatment studies

We included 44 studies comparing an antiplatelet to placebo or no treatment that were published between 1974 and 2010 (21,460 participants). The cohort size ranged from 16 to 4087 participants (median 100 participants). Data were available for the subgroup with CKD within a broader population in 12 studies (15,782 participants: CHARISMA Study 2009; CREDO Study 2008; CURE Study 2007; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; ETDRS 1992; HOT Study 2010; IMPACT II Study 1997; PRISM-PLUS Study 2002; PURSUIT Study 1998; RAPPORT Study 1998). The duration of follow-up ranged from one to 61 months (median nine months).

We identified 19 studies that were conducted in people with CKD not yet requiring dialysis (16,065 participants: CHARISMA Study 2009; Cheng 1998; CREDO Study 2008; CURE Study 2007; Donadio 1984; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; ETDRS 1992; Frascà 1997; Giustina 1998; Gonzalez 1995; HOT Study 2010; IMPACT II Study 1997; Khajehdehi 2002; PRISM-PLUS Study 2002; PURSUIT Study 1998; RAPPORT Study 1998; Zäuner 1994). A further 21 studies were in people on dialysis (4820 participants: Abdul-Rahman 2007; Andrassy 1974; Creek 1990; Dember 2008; Dixon 2009; Dodd 1980; Ell 1982; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Gröntoft 1998; Harter 1979; Kaegi 1974; Kaufman 2003; Kobayashi 1980; Kooistra 1994; Michie 1977; Middleton 1992; Sreedhara 1994; STOP Study 1995; Taber 1992). Three studies enrolled kidney transplant recipients (137 participants: Anderson 1974; Quarto Di Palo 1991; Schulze 1990) and one study (UK-HARP-I Study 2005; 448 participants) included people with CKD, transplant recipients and participants on dialysis.

In the 19 studies in people with CKD, two were in those with acute coronary syndromes (4698 participants: CURE Study 2007; PRISM-PLUS Study 2002); five enrolled participants with acute or stable coronary artery disease undergoing percutaneous intervention (2243 participants: EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; IMPACT II Study 1997; RAPPORT Study 1998); and one study enrolled people undergoing elective percutaneous coronary intervention (CREDO Study 2008).

Five studies enrolled people with diabetic kidney disease (2358 participants: CHARISMA Study 2009; ETDRS 1992; Giustina 1998; Gonzalez 1995; Khajehdehi 2002); four were in individuals with glomerulonephritis (119 participants: Cheng 1998; Donadio 1984; Frascà 1997; Zäuner 1994) and one study evaluated 3619 people with hypertension and CKD in a larger primary prevention study (HOT Study 2010).

The mean age of participants ranged from 30 to 75 years, with participants in studies of acute and stable coronary artery disease tending to be older (59 to 75 years) than those on dialysis (43 to 62 years) or with glomerulonephritis (30 to 45 years). The proportion of people with diabetes in the included studies was between 0% and 20% in two studies (HOT Study 2010; UK-HARP-I Study 2005); 20% to 70% in 13 studies (Abdul-Rahman 2007; CREDO Study 2008; CURE Study 2007; Dember 2008; Dixon 2009; EPIC Study 1994; EPISTENT Study 1998; Ghorbani 2009; IMPACT II Study 1997; Kaufman 2003; PRISM-PLUS Study 2002; PURSUIT Study 1998; RAPPORT Study 1998); and 100% in five studies (CHARISMA Study 2009; ETDRS 1992; Giustina 1998; Gröntoft 1998; Khajehdehi 2002).

In the 44 studies that compared an antiplatelet agent with placebo or no treatment, the interventions included:

Non-randomised co-interventions were reported in 21 studies and included: angiotensin-converting enzyme inhibitors (2 studies, 89 participants: Cheng 1998; Gonzalez 1995); anticoagulation (2 studies, 873 participants: Kaegi 1974; STOP Study 1995); aspirin (4 studies, 6569 participants: CHARISMA Study 2009; CREDO Study 2008; CURE Study 2007; RAPPORT Study 1998); aspirin and heparin (5 studies, 5041 participants: EPIC Study 1994; EPILOG Study 1997; IMPACT II Study 1997; PRISM-PLUS Study 2002; PURSUIT Study 1998); aspirin, heparin and ticlopidine (1 study, 368 participants: EPISTENT Study 1998); immunosuppression (2 studies, 47 participants: Anderson 1974; Frascà 1997); avoidance of hypertension (1 study, 92 participants: Andrassy 1974); hypoglycaemic treatment and diet (1 study, 30 participants: Giustina 1998); and symptomatic therapy (1 study, 18 participants: Zäuner 1994). Two studies administered aspirin with either a BP target (3619 participants: HOT Study 2010) or simvastatin (448 participants: UK-HARP-I Study 2005) in a two-by-two factorial design.

 

Vascular access studies

We identified 21 studies that reported outcomes for dialysis vascular access in 4826 participants. Generally, these studies were small; only four studies included more than 500 participants (Dember 2008; Dixon 2009; Middleton 1992; STOP Study 1995), and nine studies enrolled fewer than 100 participants (Abdul-Rahman 2007; Andrassy 1974; Ell 1982; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Harter 1979; Kaegi 1974; Michie 1977). Ticlopidine was most commonly administered (6 studies, 760 participants: Creek 1990; Ell 1982; Fiskerstrand 1985; Gröntoft 1985; Gröntoft 1998; Kobayashi 1980) followed by aspirin (5 studies, 331 participants: Abdul-Rahman 2007; Andrassy 1974; Harter 1979; Kooistra 1994; Sreedhara 1994). The combination of dipyridamole and aspirin was prescribed to 1575 participants in three studies (Dixon 2009; Middleton 1992; Sreedhara 1994); two studies each evaluated clopidogrel (970 participants: Dember 2008; Ghorbani 2009) and sulphinpyrazone (78 participants: Kaegi 1974; Michie 1977); and single studies assessed dipyridamole (23 participants: Sreedhara 1994), picotamide (811 participants: STOP Study 1995) and the combination of clopidogrel and aspirin (200 participants: Kaufman 2003).

Studies evaluated treatment to maintain patency of an arteriovenous fistula (6 studies, 1259 participants: Andrassy 1974; Dember 2008; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Kooistra 1994); graft (4 studies, 975 participants: Dixon 2009; Kaufman 2003; Sreedhara 1994; Taber 1992); fistula or graft (2 studies, 1069 participants: Gröntoft 1998; STOP Study 1995); fistula or shunt (2 studies, 68 participants: Dodd 1980; Ell 1982); graft or shunt (1 study, 107 participants: Kobayashi 1980); shunt (3 studies, 1009 participants: Harter 1979; Kaegi 1974; Middleton 1992); fistula, graft or shunt (1 study, 16 participants: Michie 1977) or central venous catheter (1 study, 38 participants: Abdul-Rahman 2007). Antiplatelet agents were administered at the time of access surgery in 11 studies (2215 participants: Andrassy 1974; Dember 2008; Dixon 2009; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Gröntoft 1998; Harter 1979; Michie 1977; Sreedhara 1994; Taber 1992); of these, six studies started treatment one to two days before surgery (Andrassy 1974; Fiskerstrand 1985; Gröntoft 1985; Michie 1977; Sreedhara 1994; Taber 1992); two studies began antiplatelet treatment from seven to 10 days before access creation (Ghorbani 2009; Gröntoft 1998); two began treatment one to two days after surgery (Dember 2008; Dixon 2009); and one study commenced therapy one month after access surgery (Harter 1979). The duration of intervention varied from one month to five years, with a median of five months (interquartile range two to six months). Two recent large studies stratified randomisation according to the position of the dialysis access: forearm versus upper arm (Dember 2008); or other (Dixon 2009).

 

Antiplatelet versus antiplatelet studies

Six studies (5679 participants) compared an antiplatelet drug with a second antiplatelet drug in people with CKD and were published between 1980 and 2010. Since 2005, data for the subgroup of participants with CKD in larger studies of at-risk patients have become available for three studies (5517 participants: PLATO Study 2010; TARGET Study 2001; TRITON-TIMI 38 2007). We received unpublished data for the subgroup of participants with CKD in two larger studies of people scheduled to undergo percutaneous coronary intervention (TARGET Study 2001; TRITON-TIMI 38 2007). Four studies (5557 participants) enrolled people with CKD; three studies (5517 participants) enrolled people with acute or stable coronary artery disease undergoing percutaneous intervention; one the study (40 participants) enrolled people with diabetic kidney disease (Ogawa 2008). Two studies evaluated antiplatelet agents in 112 kidney transplant recipients (Frascà 1986; Kauffmann 1980). Study duration ranged from four to 48 months (median 12 months).

The mean age was available in four studies and ranged from 34 years in a study of kidney transplant recipients (Frascà 1986) to 74 years in people with acute coronary syndromes undergoing percutaneous coronary intervention (PLATO Study 2010; TRITON-TIMI 38 2007). People with diabetes were excluded from Frascà 1986, but made up approximately one-third of participants in PLATO Study 2010 and TRITON-TIMI 38 2007; all participants in the Ogawa 2008 study had been diagnosed with diabetes.

In the studies that compared an antiplatelet with another antiplatelet, interventions included:

  • Aspirin versus sarpogrelate (40 participants; Ogawa 2008)
  • Dipyridamole versus defibrotide (80 participants; Frascà 1986)
  • Aspirin versus dipyridamole (42 participants; Kauffmann 1980)
  • Thienopyridine versus thienopyridine
  • Glycoprotein IIb/IIIa inhibitor

Non-randomised co-interventions included immunosuppression (Frascà 1986; Kauffmann 1980); aspirin (PLATO Study 2010; TRITON-TIMI 38 2007); and aspirin and heparin (TARGET Study 2001).

 

Risk of bias in included studies

The risk of bias in the included studies is summarised in Figure 2 and results for individual studies are reported in the Characteristics of included studies table. Overall, random sequence generation was unclear or not adequate in 98% of studies. Data follow-up were generally complete in half of the studies, whereas selective reporting was likely in 60% of studies.

 FigureFigure 2. Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies

 

Allocation

Allocation concealment was adequate in 19 studies (38%), not adequate in one (allocation to treatment according to medical record number; 2%), and unclear in the remaining 30 studies (60%).

 

Blinding

Participants, investigators, and outcome assessors were blinded in 20 studies (40%), were not all blinded in four (8%), and blinding was unclear in the remaining 26 studies (52%).

 

Incomplete outcome data

Data follow-up was complete in 50% of the studies, incomplete in 12 (24%) and unclear in the remaining 13 studies (26%).

 

Selective reporting

Reporting of outcomes was complete in 20 studies (40%), clearly selective in three (6%), and unclear in 27 studies (54%).

 

Other potential sources of bias

Other potential sources of bias were identified in 15 studies including a change in the analysis plan after recruitment (Kaegi 1974) full study reports were not available for six studies (Creek 1990; Dodd 1980; Ell 1982; Gonzalez 1995; Middleton 1992; Taber 1992); and/or data not available for meta-analysis (Frascà 1997); baseline differences in treatment groups (Harter 1979); and early termination of one or more arms of the study (6 studies: Dember 2008; EPILOG Study 1997; Kaufman 2003; PRISM-PLUS Study 2002; PURSUIT Study 1998; UK-HARP-I Study 2005).

 

Effects of interventions

 

Antiplatelet versus placebo or no treatment

Summary effects of antiplatelet agents versus placebo or no treatment for myocardial infarction, all-cause mortality, and major bleeding are summarised in  Table 2.

 

Fatal or nonfatal myocardial infarction

Seventeen studies (14,451 participants) reported effects of antiplatelet treatment on fatal or nonfatal myocardial infarction. Antiplatelet therapy reduced the risk of myocardial infarction by 13% ( Analysis 1.1: RR 0.87, 95% CI 0.76 to 0.99). There was no evidence of significant heterogeneity in this meta-analysis (Tau² = 0.00; Chi² = 14.47, df = 14 (P = 0.42); I² = 3%).

 
Subgroup analysis for myocardial infarction - stratified by stage of CKD

There was no difference in fatal or nonfatal myocardial infarction based on stage of CKD. The RR in people with earlier stages of CKD was 0.84 (95% CI 0.70 to 0.99; 10 studies, 11,074 participants) (CHARISMA Study 2009; CREDO Study 2008; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; ETDRS 1992; HOT Study 2010; IMPACT II Study 1997; PURSUIT Study 1998; RAPPORT Study 1998) whereas the risk in people requiring dialysis was 0.82 (95% CI 0.47 to 1.42; 6 studies, 2929 participants) (Creek 1990; Dember 2008; Dixon 2009; Ell 1982; Kaufman 2003; STOP Study 1995; P = 0.94).

 
Subgroup analysis for myocardial infarction - stratified by antiplatelet type

There was no difference between antiplatelet types, suggesting the overall risk for myocardial infarction was the most robust (test for subgroup differences P = 0.20). The RR of myocardial infarction was 0.68 (95% CI 0.46 to 0.99) for aspirin (3 studies, 4252 participants: ETDRS 1992; HOT Study 2010; UK-HARP-I Study 2005), 0.83 (95% CI 0.57 to 1.21) for thienopyridines (5 studies, 3689 participants: CHARISMA Study 2009; CREDO Study 2008; Creek 1990; Dember 2008; Ell 1982) and 0.93 (95% CI 0.81 to 1.07) for glycoprotein IIb/IIIa inhibitors (6 studies, 4850 participants: EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; IMPACT II Study 1997; PURSUIT Study 1998; RAPPORT Study 1998). There were insufficient numbers of studies that were clearly primary prevention studies to enable analysis of whether the type of intervention (primary versus secondary prevention) was an effect modifier on the risk of myocardial infarction.

Among studies comparing antiplatelet agents with placebo/no treatment, less precise (smaller studies) with smaller or no treatment effect were not available on the funnel plot (Figure 3).

 FigureFigure 3. Funnel plot of comparison of antiplatelet agents versus control for the outcome of fatal or nonfatal myocardial infarction

 

Fatal or nonfatal stroke

Eleven studies (9544 participants) reported the risk of fatal or nonfatal stroke. Antiplatelet therapy did not alter the risk of stroke ( Analysis 1.2: RR 1.00, 95% CI 0.58 to 1.72). There was no significant heterogeneity in this meta-analysis (Tau² = 0.23; Chi² = 14.15, df = 8 (P = 0.08); I² = 43%).

Six studies (6044 participants) reported the risk of haemorrhagic stroke ( Analysis 1.3: RR 1.22, 95% CI 0.69 to 2.17). There was no heterogeneity in this meta-analysis (Tau² = 0.00; Chi² = 1.38, df = 5 (P = 0.93); I² = 0%).

 

Mortality

All-cause mortality was reported in 29 studies (16,152 participants). Antiplatelet treatment did not lower all-cause mortality ( Analysis 1.4: RR 0.95, 95% CI 0.83 to 1.07). There was no heterogeneity in this meta-analysis (Tau² = 0.01; Chi² = 22.99, df = 20 (P = 0.29); I² = 13%). When data from CURE Study 2007 (4087 participants), which were available only as a risk estimate and its variance were included in this meta-analysis, the risk of all-cause mortality remained similar between antiplatelet and control (30 studies, 20,239 participants: RR 0.93, 95% CI 0.81 to 1.06), without significant heterogeneity.

 
Subgroup analysis for mortality - type of antiplatelet treatment

In subgroup analysis for the effect of different antiplatelet types on mortality, there was no evidence of interaction between subgroups (P = 0.46). In five aspirin studies (4340 participants), the RR of all-cause mortality was 0.88 (95% CI 0.61 to 1.27) (ETDRS 1992; HOT Study 2010; Khajehdehi 2002; Sreedhara 1994; UK-HARP-I Study 2005); in 10 studies of thienopyridines (8210 participants), including CURE Study 2007, the risk of all-cause mortality was 1.10 (95% CI 0.80 to 1.51) (CHARISMA Study 2009; Cheng 1998; CREDO Study 2008; Creek 1990; CURE Study 2007; Dember 2008; Ell 1982; Ghorbani 2009; Gröntoft 1998; Kobayashi 1980), and in six studies of glycoprotein IIb/IIIa inhibitors (4849 participants) the risk of all-cause mortality was 0.83 (95% CI 0.60 to 1.16) (EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; IMPACT II Study 1997; PURSUIT Study 1998; RAPPORT Study 1998).

 
Subgroup analysis for mortality - stage of CKD

No differences were seen in all-cause mortality among 15,297 people with earlier stages of CKD (15 studies: RR 0.96, 95% CI 0.82 to 1.14) (CHARISMA Study 2009; Cheng 1998; CREDO Study 2008; CURE Study 2007; Donadio 1984; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; ETDRS 1992; HOT Study 2010; IMPACT II Study 1997; Khajehdehi 2002; PURSUIT Study 1998; RAPPORT Study 1998; Zäuner 1994) and 4363 people requiring dialysis (13 studies: RR 0.82, 95% CI 0.63 to 1.06; P = 0.30) (Creek 1990; Dember 2008; Dixon 2009; Ell 1982; Ghorbani 2009; Gröntoft 1998; Kaegi 1974; Kaufman 2003; Kobayashi 1980; Michie 1977; Middleton 1992; Sreedhara 1994; STOP Study 1995).

Cardiovascular mortality data were available in 18 studies (9337 participants) (CHARISMA Study 2009; Cheng 1998; CREDO Study 2008; Creek 1990; Donadio 1984; Ell 1982; ETDRS 1992; Gröntoft 1998; HOT Study 2010; Kaegi 1974; Khajehdehi 2002; Michie 1977; Quarto Di Palo 1991; STOP Study 1995; UK-HARP-I Study 2005; Zäuner 1994). Overall, antiplatelet agents did not reduce cardiovascular mortality ( Analysis 1.5: RR 0.87, 95% CI 0.65 to 1.15) without evidence of significant heterogeneity (Tau² = 0.06; Chi² = 13.26, df = 9 (P = 0.15); I² = 32%). When we included data from CURE Study 2007 that provided a risk estimate and its variance for cardiovascular mortality, antiplatelet agents were not better than control for reducing this outcome (19 studies, 13,424 participants: RR 0.89, 95% CI 0.70 to 1.12), without significant heterogeneity in the analysis (Chi² = 14.1, df = 11 (P = 0.72); I² = 0%). Studies of glycoprotein IIb/IIIa inhibitors did not provide data for cardiovascular mortality.

Dixon 2009 (649 participants) reported fatal bleeding events. There was no difference between antiplatelet agents and control for this outcome ( Analysis 1.6: RR 5.11, 95% CI 0.25 to 106.00).

 

Bleeding

Major bleeding events were: retroperitoneal, intra-articular, intra-ocular, intracranial or intracerebral haemorrhage, gastrointestinal bleeding, bleeding that was fatal, life-threatening, disabling or required transfusion, corrective surgery or hospitalisation, with or without a fall in haemoglobin level of at least 2 g/dL (Abdul-Rahman 2007; CHARISMA Study 2009; Dixon 2009; Ghorbani 2009; HOT Study 2010; Kaegi 1974; Kobayashi 1980; PRISM-PLUS Study 2002; UK-HARP-I Study 2005) or melaena (Andrassy 1974). Minor bleeding events were usually described as not serious or significant (CHARISMA Study 2009; CREDO Study 2008; CURE Study 2007; Dixon 2009; HOT Study 2010); epistaxis, ecchymoses, or bruising (Andrassy 1974, UK-HARP-I Study 2005); not requiring transfusion, hospitalisation, or an event-related study visit (CHARISMA Study 2009; Kaufman 2003); or bleeding from cannulation sites or haematuria (Gröntoft 1985).

 
Major bleeding

Twenty six studies (15,992 participants) that provided event data for major bleeding (Abdul-Rahman 2007; Andrassy 1974; CHARISMA Study 2009; CREDO Study 2008; Creek 1990; Dember 2008; Dixon 2009; Ell 1982; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; Ghorbani 2009; Harter 1979; HOT Study 2010; IMPACT II Study 1997; Kaegi 1974; Khajehdehi 2002; Kobayashi 1980; Michie 1977; Middleton 1992; PRISM-PLUS Study 2002; PURSUIT Study 1998; Quarto Di Palo 1991; RAPPORT Study 1998; STOP Study 1995; UK-HARP-I Study 2005). Antiplatelet agents significantly increased major bleeding ( Analysis 1.7: RR 1.35, 95% CI 1.10 to 1.65). There was no significant heterogeneity in this analysis (Tau² = 0.02; Chi² = 20.38, df = 18 (P = 0.31); I² = 12%). Addition of the risk estimate for major bleeding reported in CURE Study 2007 (4087 participants) to the meta-analysis resulted in a similar risk of bleeding (RR 1.33, 95% CI 1.09 to 1.64) without evidence of heterogeneity.

 
Subgroup analysis for major bleeding - stratified by stage of CKD

There was no difference in major bleeding based on stage of CKD. The RR of major bleeding was 1.45 (95% CI 1.18 to 1.8) in people with CKD (12 studies) (CHARISMA Study 2009; CREDO Study 2008; CURE Study 2007; EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; HOT Study 2010; IMPACT II Study 1997; Khajehdehi 2002; PRISM-PLUS Study 2002; PURSUIT Study 1998; RAPPORT Study 1998) and 0.93 (95% CI 0.55 to 1.57; P = 0.12) in people on dialysis (13 studies) (Abdul-Rahman 2007; Andrassy 1974; Creek 1990; Dember 2008; Dixon 2009; Ell 1982; Ghorbani 2009; Harter 1979; Kaegi 1974; Kobayashi 1980; Michie 1977; Middleton 1992; STOP Study 1995). The Quarto Di Palo 1991 study in kidney transplant recipient was not included in the subgroup analysis.

 
Subgroup analysis for major bleeding - stratified by antiplatelet type

There was no difference in major bleeding based on antiplatelet type. The RR of major bleeding were 1.34 (95% CI 0.71 to 2.55) in seven aspirin studies (Abdul-Rahman 2007; Andrassy 1974; Ell 1982; Harter 1979; HOT Study 2010; Khajehdehi 2002; UK-HARP-I Study 2005); 1.27 (95% CI 0.85 to 1.91) in seven thienopyridine studies (CHARISMA Study 2009; CREDO Study 2008; Creek 1990; CURE Study 2007; Dember 2008; Ghorbani 2009; Kobayashi 1980); and 1.45 (95% CI 1.04 to 2.04) in seven glycoprotein IIb/IIIa studies (EPIC Study 1994; EPILOG Study 1997; EPISTENT Study 1998; IMPACT II Study 1997; PRISM-PLUS Study 2002; PURSUIT Study 1998; RAPPORT Study 1998; P = 0.88).

Numbers of major bleeding events in studies of dual antiplatelet therapy (Dixon 2009; Khajehdehi 2002; Middleton 1992) were insufficient to determine whether dual antiplatelet therapy was an effect modifier on major bleeding in the available studies.

 
Minor bleeding

Antiplatelet agents increased the risk of minor bleeding ( Analysis 1.8 (18 studies, 13,106 participants): RR 1.54, 95% CI 1.26 to 1.90). There was significant heterogeneity in this analysis (Tau² = 0.06; Chi² = 35.12, df = 13 (P = 0.0008); I² = 63%). When the risk estimate for major bleeding from CURE Study 2007 was included in the analysis, a similar risk of minor bleeding with antiplatelet agents was identified (RR 1.48, 95% CI 1.12 to 1.97) with persistent heterogeneity (Chi² = 33.1 (P = 0.003); I² = 58%).

 
Subgroup analysis for minor bleeding to explore heterogeneity

To explore heterogeneity, we conducted subgroup analyses for minor bleeding according to study and population characteristics as defined a priori in the study protocol. There was no difference in risk of minor bleeding between subgroups based on stage of CKD, presence of cardiovascular disease at baseline, duration of intervention, age or gender of participants, or presence of hypertension or diabetes (P > 0.15 for all). Subgroup analyses based on duration of dialysis or transplantation were not possible due to insufficient numbers of studies.

 

Kidney outcomes

The risk of ESKD was not altered with antiplatelet therapy ( Analysis 1.9 (8 studies, 825 participants): RR 0.96, 95% CI 0.67 to 1.37) without evidence of significant heterogeneity (Tau² = 0.02; Chi² = 4.56, df = 4 (P = 0.34); I² = 12%).

There was no difference between antiplatelet agents and control for the risk doubling of SCr ( Analysis 1.10 (2 studies, 126 participants): RR 0.43, 95% CI 0.12 to 1.47).

The risk of kidney transplant graft loss was not altered by antiplatelet treatment ( Analysis 1.11 (2 studies, 91 participants): RR 1.08, 95% CI 0.58 to 2.01) without evidence of heterogeneity (Tau² = 0.00; Chi² = 0.16, df = 1 (P = 0.69); I² = 0%). Transplant rejection was not altered by antiplatelet therapy ( Analysis 1.12 (2 studies, 97 participants): RR 0.95, 95% CI 0.77 to 1.19).

End of treatment CrCl was similar between antiplatelet and control treatment in two studies ( Analysis 1.13 (68 participants): MD -6.41 mL/min, 95% CI -19.94 to 7.12) with no significant heterogeneity evident in the analyses (Tau² = 61.98; Chi² = 2.01, df = 1 (P = 0.16); I² = 50%). There was no difference between treatment groups for the end of treatment proteinuria ( Analysis 1.14 (2 studies, 54 participants): MD -1.43 g/d, 95% CI -3.84 to 0.98) with high level heterogeneity in the analysis (Tau² = 2.91; Chi² = 26.53, df = 1 (P < 0.0001); I² = 96%) suggesting it was inappropriate to combine the results of these studies. No difference for this outcome was observed within each study individually.

 
Dialysis access outcomes
 
Dialysis access failure (thrombosis or loss of patency)

Overall, 14 studies (2608 participants) reported dialysis access failure (thrombosis or loss of patency) (Abdul-Rahman 2007; Andrassy 1974; Dember 2008; Dixon 2009; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Gröntoft 1998; Harter 1979; Kaegi 1974; Kaufman 2003; Kooistra 1994; Michie 1977; Sreedhara 1994). For all access types, antiplatelet therapy reduced access failure by 32% ( Analysis 1.15 (14 studies, 2608 participants): RR 0.68, 95% CI 0.54 to 0.84). There was significant heterogeneity in this analysis (Tau² = 0.05; Chi² = 22.82, df = 13 (P = 0.04); I² = 43%) which we explored using subgroup analysis by access type: fistula (7 studies, 1502 participants); shunt or graft (5 studies, 1102 participants); fistula or graft (1 study, 16 participants); or central venous catheter (1 study, 38 participants). In these analyses, antiplatelet agents (aspirin, ticlopidine, or clopidogrel) reduced fistula thrombosis or patency failure by 44% ( Analysis 1.15.1: RR 0.56, 95% CI 0.40 to 0.78), but not shunt or graft failure ( Analysis 1.15.2: RR 0.80, 95% CI 0.62 to 1.03). However, the effect estimate was statistically similar for this outcome in fistula studies compared with those evaluating shunts or grafts (P = 0.10 for subgroup interaction). Overall, there was no evidence of subgroup interaction based on access type across all types, suggesting the specific vascular access (fistula, graft, shunt, or central venous catheter) (test for subgroup differences Chi² = 3.58, P = 0.31, I² = 16.2%) was not an effect modifier for the treatment effects observed and indicating the overall effect estimate was the most appropriate. Exclusion of the single study of central venous catheter use did not meaningfully change the overall treatment effect in favour of antiplatelet therapy (RR 0.69, 95% CI 0.55 to 0.86).

 
Early access failure (within eight weeks of access creation)

Six studies (1365 participants) evaluated access outcomes at or before eight weeks after surgery (Andrassy 1974; Dember 2008; Fiskerstrand 1985; Ghorbani 2009; Gröntoft 1985; Gröntoft 1998). Antiplatelet treatment reduced the risk of early access thrombosis ( Analysis 1.16: RR 0.54, 95% CI 0.39 to 0.74). There was no significant heterogeneity in this analysis (Tau² = 0.02; Chi² = 5.64, df = 5 (P = 0.34); I² = 11%).

 
Loss of unassisted patency

Two studies (665 participants: Dixon 2009; Michie 1977) reported loss of unassisted patency in an analysis in which a single recent study provided 99% of the events (Dixon 2009). Antiplatelet treatment did not reduce loss of unassisted patency ( Analysis 1.17: RR 0.95, 95% 0.89 to 1.03) with no heterogeneity (Tau² = 0.00; Chi² = 0.22, df = 1 (P = 0.64); I² = 0%).

 
Failure to attain access suitability of dialysis (maturation)

Five studies (1503 participants) provided data for suitability of vascular access for dialysis as an outcome. The definitions of access suitability included: the ability to use the fistula for dialysis with two needles and maintain a blood flow rate ≥ 300 mL/min during eight of 12 dialysis sessions occurring during a 30 day suitability ascertainment period (Dember 2008); failure to use graft by week 12 in patients with catheter for access (Dixon 2009); fistula ceased to function (Gröntoft 1985); permanent shunt thrombosis (Harter 1979); and failure to develop adequate flow (Michie 1977). Antiplatelet therapy did not reduce the risk of failure to attain access suitability ( Analysis 1.18: RR 0.62, 95% CI 0.33 to 1.16). There was significant heterogeneity in this analysis (Tau² = 0.25; Chi² = 10.11, df = 4 (P = 0.04); I² = 60%) potentially due to the differences in definitions for this outcome in the available studies. An insufficient number of studies reporting this outcome precluded formal subgroup analysis to explore heterogeneity.

 
Need for intervention to attain patency or assist maturation

Four studies (3980 participants) reported the need for the intervention to attain patency or assist maturation described as surgical revision (Kaegi 1974), thrombectomy (Michie 1977), percutaneous intervention to restore patency or promote maturation (Dember 2008), or angioplasty (Dixon 2009). Antiplatelet therapy did not reduce the risk for the need for the intervention to attain patency or assist maturation ( Analysis 1.19: RR 0.79, 95% CI 0.54 to 1.15) with no significant heterogeneity (Tau² = 0.08; Chi² = 3.99, df = 3 (P = 0.26); I² = 25%).

 
Hospitalisation

There were no differences in all-cause hospitalisation between treatment groups in three studies ( Analysis 1.20 (3535 participants): RR 0.97, 95% CI 0.87 to 1.10) without evidence for heterogeneity (Tau² = 0.00; Chi² = 1.85, df = 2 (P = 0.40); I² = 0%). Cardiovascular hospitalisation was similar between antiplatelet treatment and control in the two available studies ( Analysis 1.21 (1526 participants): RR 0.93, 95% CI 0.76 to 1.14). There was significant heterogeneity in this analysis (Tau² = 0.42; Chi² = 6.99, df = 1 (P = 0.008); I² = 86%) potentially due to differences in adjudication of the outcome.

 
Withdrawal from treatment

Thirteen studies (2569 participants) reported premature withdrawal from treatment. There was no difference in the risk of withdrawn form treatment between antiplatelet agents and placebo or no treatment ( Analysis 1.22: RR 0.97, 95% CI 0.83 to 1.13) with no heterogeneity (Tau² = 0.00; Chi² = 9.71, df = 11 (P = 0.56); I² = 0%).

 
Subgroup analyses by methodological quality for all-cause mortality and major bleeding

Analyses, including only studies with adequate allocation concealment, blinding, or completeness of follow-up, specified a priori, showed similar results for treatment efficacy for mortality or harm from major bleeding.

 

Antiplatelet versus antiplatelet

Data for a thienopyridine (prasugrel or ticagrelor) compared with clopidogrel were available in two studies (4727 participants: TRITON-TIMI 38 2007; PLATO Study 2010) involving people with CKD. Where possible, data from PLATO Study 2010 were provided as a risk estimate (hazard ratio) together with its 95% CI and were combined with event data from TRITON-TIMI 38 2007 study. Unpublished data for people with CKD were also available for the comparison of a glycoprotein IIb/IIIa inhibitor (abciximab) versus a second glycoprotein IIb/IIIa inhibitor (tirofiban) in 790 people from TARGET Study 2001 at six months for myocardial infarction and 12 months for all-cause mortality.

 

Thienopyridine versus clopidogrel

 
Fatal or nonfatal myocardial infarction

TRITON-TIMI 38 2007 (1490 participants) provided data for nonfatal myocardial infarction comparing prasugrel with clopidogrel. There was no difference between treatment groups for this outcome ( Analysis 2.1: RR 0.78, 95% CI 0.58, 1.05).

 
Fatal or nonfatal stroke

PLATO Study 2010 (3237 participants) reported a risk of intracranial haemorrhage comparing ticagrelor with clopidogrel of 1.79 (95% CI 0.43 to 7.51).

 
All-cause mortality

Two studies (4727 participants) compared a newer generation thienopyridine with clopidogrel for effects on all-cause mortality. When results from these studies were combined, the analysis had a high level of heterogeneity (Chi² = 1747.7, df = 1, P < 0.0001; I² = 99%), suggesting a summary estimate was not appropriate. Individually, prasugrel versus clopidogrel (1490 participants: TRITON-TIMI 38 2007) resulted in a risk for mortality of 0.81 (95% CI 0.56 to 1.18) whereas ticagrelor versus clopidogrel (3237 participants: PLATO Study 2010) had a reported risk estimate of 0.72 (95% CI 0.58 to 0.89).

Cardiovascular mortality was available from TRITON-TIMI 38 2007 (1490 participants). The risk of cardiovascular mortality was similar between the prasugrel and clopidogrel groups ( Analysis 2.3: RR 1.35, 95% CI 0.87 to 2.10).

PLATO Study 2010 (3237 participants) reported the risk between ticagrelor and clopidogrel for fatal bleeding as 0.48 (95% CI 0.15 to 1.54).

 
Bleeding

Two studies comparing prasugrel or ticagrelor to clopidogrel in 4706 individuals with CKD provided data for major bleeding. Major bleeding was defined according to the Thrombolysis In Myocardial Infarction criteria for major bleeding (intracranial haemorrhage, clinically evident bleeding including imaging and a drop in the haemoglobin of ≥5 g/dL (TRITON-TIMI 38 2007) or according to the Platelet Inhibition and Patient Outcomes (PLATO) definition as bleeding that led to clinically significant disability (e.g. intra-ocular bleeding with permanent vision loss) or bleeding either associated with a drop in haemoglobin level of at least 3.0 g/dL but less than 5.0 g/dL or requiring transfusion of two to three units of red cells (PLATO Study 2010). Combining unpublished crude event data (TRITON-TIMI 38 2007) in one study ( Analysis 2.4) with a risk estimate provided in the other study (PLATO Study 2010) by meta-analysis resulted in a summary risk estimate for major bleeding (RR 1.12, 95% CI 0.90 to 1.39). There was no significant heterogeneity in this analysis (Chi² = 1.08, df = 1 (P < 0.30); I² = 8%).

TRITON-TIMI 38 2007 (1469 participants) compared prasugrel with clopidogrel and provided unpublished data for minor bleeding in people with CKD (RR 1.35, 95% CI 0.87 to 2.10;  Analysis 2.5). Minor bleeding was defined as clinically evident bleeding including imaging and a fall in the haemoglobin of between 3 and 5 g/dL (TRITON-TIMI 38 2007).

 

Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor

Investigators of TARGET Study 2001, which compared a glycoprotein IIb/IIIa inhibitor (abciximab) with another glycoprotein IIb/IIIa inhibitor (tirofiban), provided unpublished data for 790 people with CKD for outcomes relevant to this review of myocardial infarction at six months and all-cause mortality at 12 months follow-up.

 
Fatal or nonfatal myocardial infarction

In TARGET Study 2001 (1192 participants), RR for fatal or nonfatal myocardial infarction comparing abciximab with tirofiban was 1.14 (95% CI 0.77 to 1.71;  Analysis 3.1).

 
All-cause mortality

In TARGET Study 2001 (1192 participants), no difference was observed in the risk of all-cause mortality (RR 0.85, 95% CI 0.45 to 1.59;  Analysis 3.2) comparing abciximab with tirofiban.

 

Sensitivity and subgroups analyses

Sensitivity and subgroup analyses were not possible when comparing one antiplatelet with another antiplatelet were not possible due to the insufficient number of available studies.

 

Discussion

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Summary of main results

This review indicated that antiplatelet therapy (aspirin, thienopyridines, or glycoprotein IIb/IIIa inhibitors) lowers the risk for myocardial infarction in people with CKD, but does not reduce total or cardiovascular mortality or stroke. Importantly, antiplatelet treatment increases major bleeding by 33% (including bleeding events that result in hospital admission, transfusion, or disability) and minor bleeding by 48%. There is currently insufficient available evidence to define clearly the role of antiplatelet treatment in primary prevention (preventing cardiovascular events in people without existing cardiovascular disease) in those with CKD.

Antiplatelet treatment started around the time of vascular access surgery was found to reduce vascular access thrombosis or patency failure by a third, but there was insufficient evidence to show that antiplatelet therapy improves dialysis access maturation or access suitability for dialysis. Overall, antiplatelet agents do not prevent ESKD or kidney transplant loss.

Direct comparisons of antiplatelet agents are limited to a few studies in which data for the subgroup of participants with CKD have been recently reported or provided. Currently, there are scant data to recommend that one antiplatelet agent is more efficacious than another in any clinical setting (primary prevention or secondary prevention), particularly for people with acute coronary syndromes or those undergoing percutaneous coronary interventions who frequently have coexistent CKD.

 

Overall completeness and applicability of evidence

While the analyses include data obtained from a comprehensive search and unpublished data from numerous investigators, particularly for cardiovascular events, the data were incomplete in several areas. First, data for transplant recipients were limited and provided by smaller and older studies, published between 1974 and 1991. A more recent study of aspirin included transplant recipients in addition to individuals with CKD and those requiring dialysis (UK-HARP-I Study 2005) but data for the transplant subgroup (133 participants) were not available and would have provided very few events for relevant clinical outcomes. Outcome data for kidney transplant recipients were restricted generally to transplant function or rejection in two studies, and information about major cardiovascular events were scarce. Further, no head-to-head comparisons of antiplatelet agents were available in kidney transplant recipients or for any antiplatelet agent in kidney transplant recipients with acute coronary syndromes. Further research is needed in these populations. Second, no data for cardiovascular mortality were available in studies of glycoprotein IIb/IIIa inhibitors administered in addition to standard therapy at the time of an acute coronary syndrome with or without percutaneous coronary intervention. The data for people with CKD in studies assessing glycoprotein IIb/IIIa inhibitors were disaggregated from within a larger, at-risk populations after publication of the primary studies. Accordingly, to date no studies have specifically evaluated these agents in people with CKD a priori. Third, data for the effects of antiplatelet agents on primary prevention of cardiovascular events in people with CKD were available only from a single study of aspirin in people with hypertension in which data for the subgroup with CKD have become available (HOT Study 2010). The results of this study are consistent with the overall findings of the review showing no clear benefit for mortality, a reduction in myocardial infarction, and a near doubling in the risk of major bleeding (RR 2.04, 95% CI 1.05 to 3.96).

 

Quality of the evidence

Although this review found consistent effect estimates for important clinical outcomes (myocardial infarction, mortality, and bleeding) in analyses that include approximately 15,000 people with CKD and between 500 to 1000 events, our conclusions must be considered more cautiously due to several potential limitations in the available data.

 

Study limitations

While the analyses include data obtained from a comprehensive search and unpublished data from numerous investigators particularly for cardiovascular events, selective reporting of outcomes may reduce the strength of our conclusions. Data for myocardial infarction in smaller studies with smaller treatment benefits were absent because these (less precise) studies did not systematically report cardiovascular events. Accordingly, selective outcome reporting reduced the reliability of this treatment effect (13% reduction) in both magnitude and direction, although the effect of bias could not be determined in the absence of all data for this outcome. The small proportion of studies reporting vascular access outcomes including only 2000 participants reduced the strength of evidence for antiplatelet agents on vascular access function and maturation. Only two thirds of such studies reported access failure or thrombosis, and only 10% to 20% reported on maturation and suitability for dialysis outcomes in these people. Overall, 60% of studies did not report adequate blinding, allocation concealment or random sequence generation, although sensitivity analyses did not find differences in treatment effects when analyses were restricted to studies of higher methodological quality, because lower quality studies tended to be smaller and contributed fewer events to analyses. In addition, the number of major bleeding events in studies of dual antiplatelet therapy were insufficient to determine in indirect evidence whether bleeding risk was increased with dual antiplatelet therapy compared with monotherapy. Data from studies that directly compared two antiplatelet agents against a single antiplatelet agent were absent.

 

Consistency of results

Our major findings, that antiplatelet agents reduce myocardial infarction but not cardiovascular death or overall mortality, and significantly increase major bleeding are strengthened by the consistency of findings across studies. Two thirds of studies reported all-cause mortality in over 15,000 participants and showed no treatment effect in all but one study (CHARISMA Study 2009). Notably, this study of clopidogrel and aspirin versus aspirin alone in people with diabetic kidney disease showed that participants allocated to clopidogrel experienced significantly higher mortality, although the reasons for this finding remain unclear and might be expected by chance across the 30 studies. Similarly, in analyses for cardiovascular mortality that included 19 studies and nearly 10,000 participants, only CHARISMA Study 2009 had a 95% CI that did not include '1' suggesting the null effect of antiplatelet agents on cause-specific mortality is robust. There was also very low heterogeneity in the summary estimate for myocardial infarction, although only 17/44 (˜40%) potentially eligible studies reported this outcome. Approximately two thirds of placebo/no treatment studies reported major bleeding events with a consistent risk across all contributing studies of over 15,000 participants and nearly 600 events. The highly variable definitions of major bleeding in the included studies, together with the relative lack of specific reporting on intracranial haemorrhage (in only eight studies), reduced the ability to weigh the relative benefits of treatment (reducing myocardial infarction) with the comprehensive potential risks of harm for people with CKD. The risks of minor bleeding varied among studies beyond chance alone and could not be explained by subgroup analyses that included analyses for age, gender, pre-existing comorbidities or time on dialysis, reducing the reliability of the effect estimate identified for this outcome.

 

Directness of evidence

Only six studies reported direct comparisons of two antiplatelet agents, and meta-analyses were generally not possible. The small number of studies that directly compared different agents (glycoprotein inhibitors in one study and thienopyridines in two studies) precluded indirect comparisons of the magnitude of effect of each drug class (although such evidence is of lower quality than head-to-head comparisons of antiplatelet treatments). Therefore, we sought to identify whether a specific antiplatelet agent was particularly beneficial (or harmful) and if treatment effects varied with stage of CKD (dialysis versus earlier stages of CKD) using prespecified subgroup analyses categorised by antiplatelet drug type. No differences in treatment effects or harms were found among subgroups (aspirin, thienopyridine, or glycoprotein IIb/IIIa inhibitor) suggesting the effects of antiplatelet treatment observed are applicable to all these antiplatelet types used in the studies.

 

Precision

Effect estimates for major treatment benefits and harms (mortality, myocardial infarction, and major bleeding) had narrow confidence intervals, increasing their certainty and strengthening the evidence within the review for these clinical events. Several outcomes, however, included both few participants and events, indicating the available evidence for benefits (and toxicities) of antiplatelet agents for these outcomes is of lower quality. These outcomes included bleeding-related death, fatal and nonfatal stroke, haemorrhagic stroke, ESKD, transplant function and rejection, dialysis vascular access maturation, and hospitalisation. Effect estimates for direct antiplatelet versus antiplatelet comparisons were also very imprecise.

 

Agreements and disagreements with other studies or reviews

The results of this review expand the available evidence for people with CKD including data for 21,000 participants. An earlier collaborative systematic overview of 287 RCTs of an antiplatelet drug versus control (130,000 participants) or of one antiplatelet treatment versus another (77,000 participants) in people at high risk of cardiovascular disease (acute or previous vascular disease or other predisposing condition) included 2632 people requiring haemodialysis (ATT 2002). This review found that antiplatelet therapy produced a 41% proportional reduction in serious vascular events in this population. However, only 99 vascular events and 46 major extracranial bleeds were available at the time of publication nearly a decade ago (2002), limiting the reliability of the conclusions drawn (ATT 2002). Data for people with earlier stages of CKD were not available in this earlier review and have only recently become more available. A recent systematic review of individual patient data for aspirin in the primary and secondary prevention of vascular disease did not provide specific analyses for individuals based on presence of CKD (ATT 2009).

Notably, our systematic review (that finds a 13% lowering of myocardial infarction, a one third increase in bleeding, and no benefit on mortality outcomes) differs from these two previous studies. We suggest that the benefits of antiplatelet agents on cardiovascular events may be smaller in people with CKD compared with other populations at risk of cardiovascular events, for whom reductions in cardiovascular mortality, myocardial infarction, and stroke are one sixth, one third, and one quarter respectively. The relatively reduced efficacy for antiplatelet agents on total mortality in CKD is potentially explained by the competing mechanisms for cardiovascular death in this population. Progressive kidney dysfunction is characterised by vascular stiffening and calcification, cardiomyopathy, hyperkalaemia, and sudden cardiac death, in addition to occlusive vascular disease. About half of cardiovascular deaths in both dialysis and transplant patients are caused by cardiac arrest and heart failure (ANZDATA 2009) for which the predominant pathogenetic mechanisms include hypertension, volume expansion, vascular calcification, and arrhythmia, rather than platelet aggregation and thrombosis. Therefore, while we find that antiplatelet agents prevent occlusive vascular events (myocardial infarction) in CKD as expected, they have a lower overall effect on nonthrombotic causes of death (both vascular and nonvascular). The results of the present review are consistent with the effects of antiplatelet agents in primary prevention of cardiovascular events, which reduce nonfatal myocardial infarction by 20% but do not prevent stroke or vascular mortality with similar effects in men and women (ATT 2009). Notably, in that review, the authors concluded that aspirin may be of uncertain net value, because reducing occlusive events may not be outweighed by risks of major bleeding.

A previous meta-analysis of medical adjuvant treatment to increase patency of arteriovenous fistulae and grafts included placebo-controlled studies of antiplatelet agents, low-dose warfarin, or fish oil was published in 2008 (Osborn 2008). In that systematic review, antiplatelet agents were considered separately in analyses that combined access types (graft or fistula) and analyses included a maximum of only three studies and 41 events. Analyses in that review may have been insufficient to provide reliable estimates of the benefits or toxicity of antiplatelet agents on vascular access outcomes. Our review also differs from a second recent review of antiplatelet agents for the prevention of arteriovenous fistula thrombosis of 10 studies (approximately 2000 participants), as we considered the outcomes of suitability for dialysis or access maturation, summarised study risks of bias, and explored sources of heterogeneity within treatment effects (Coleman 2010).

 

Authors' conclusions

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

 

Implications for practice

Overall evidence ratings and recommendations for antiplatelet agents to prevent cardiovascular and dialysis access outcomes in people with CKD using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system for grading evidence are summarised ( Table 3) (GRADE 2011). This systematic review has shown that antiplatelet treatment in people with CKD for approximately 12 months reduces the risk of myocardial infarction, but not stroke, or all-cause or cardiovascular mortality. Antiplatelet agents given at the time of access surgery reduce thrombosis or failure of vascular access, but effects on suitability for dialysis and access maturation remain unclear. Major bleeding is increased by one third across all antiplatelet drugs and stages of CKD. The relative benefits of treatment in kidney transplant recipients and with primary prevention strategies in CKD are insufficient to inform practice.

Current clinical practice guidelines recommend antiplatelet treatment approaches similar to that of the general population in individuals with acute coronary syndromes (KDOQI 2005; Renal Association 2010) and CKD. The absolute effects of antiplatelet agents on the prevention of myocardial infarction and bleeding are summarised quantitatively in people with different absolute baseline risks for these outcomes based on risk estimates from the present systematic review ( Table 4). This table shows that while antiplatelet treatment in people at high risk of myocardial infarction (dialysis patients) is reasonable (preventing 32 myocardial infarctions in 1000 patients treated for one year versus incurring seven major bleeding events), the harms of antiplatelet treatment probably exceed the benefits for people with lower annual risks of vascular events (transplant recipients or stage 1 to 2 CKD; two myocardial infarctions prevented per 1000 patients treated for one year versus seven major bleeding events), assuming that myocardial infarction and major bleeding are equivalent outcomes. Insufficient information about the nature of major bleeding events incurred (particularly intracranial haemorrhage) in the available studies will make a decision about risk and benefit for intermediate-risk people incompletely informed.

Overall, antiplatelet agents given for four to six months after vascular access surgery will substantially reduce the risk of access failure and thrombosis (preventing 20 patients per 100 at risk experiencing access thrombosis or patency failure over six months of treatment at the risk of three to four experiencing a major bleed), although the effects of antiplatelet therapy of the important outcome of suitability for dialysis remain uncertain.

 
Implications for research

There are currently few data for antiplatelet therapy to prevent cardiovascular events in kidney transplant recipients with chronic or acute coronary artery disease. Specific head-to-head studies of antiplatelet regimens in individuals with CKD and acute coronary syndrome or undergoing percutaneous coronary intervention are required, particularly comparing newer thienopyridines (prasugrel or ticagrelor) versus clopidogrel. Studies should be designed to use standardised criteria to capture systematically all cardiovascular outcomes and major bleeding events in studies in which severe CKD is not an exclusion criterion. More information is required on the relative benefits of glycoprotein IIb/IIIa inhibitors in people with CKD and the effects of therapy on cardiovascular mortality and bleeding. The role of antiplatelet therapy as a primary prevention strategy to reduce cardiovascular and all-cause mortality in individuals with CKD without existing cardiovascular disease appears to be lower research priority.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

  1. We wish to thank the referees for their advice and feedback during the preparation of this review.
  2. The authors would like to thank all study authors who responded to our queries about their studies. We received additional unpublished data from Drs James, Wiviott, Ferris, Lincoff, Balog, Wolski, Baigent, Kaufman, Topol, and Shao.
  3. The authors wish to thank Ms Narelle Willis, Managing Editor of the Cochrane Renal Group and Ms Ruth Mitchell, Trials Search Coordinator of the Cochrane Renal Group for their help with this review.

 

Data and analyses

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
Download statistical data

 
Comparison 1. Antiplatelet agents versus control

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatal or nonfatal myocardial infarction1714451Risk Ratio (IV, Random, 95% CI)0.87 [0.76, 0.99]

 2 Fatal or nonfatal stroke119544Risk Ratio (IV, Random, 95% CI)1.00 [0.58, 1.72]

 3 Haemorrhagic stroke66044Risk Ratio (M-H, Random, 95% CI)1.22 [0.69, 2.17]

 4 All-cause mortality2916152Risk Ratio (IV, Random, 95% CI)0.95 [0.83, 1.07]

 5 Cardiovascular mortality189337Risk Ratio (IV, Random, 95% CI)0.87 [0.65, 1.15]

 6 Fatal bleeding167037Risk Ratio (IV, Random, 95% CI)5.11 [0.25, 106.00]

 7 Major bleeding2615992Risk Ratio (IV, Random, 95% CI)1.35 [1.10, 1.65]

 8 Minor bleeding1813106Risk Ratio (IV, Random, 95% CI)1.54 [1.26, 1.90]

 9 End-stage kidney disease8825Risk Ratio (IV, Random, 95% CI)0.96 [0.67, 1.37]

 10 Doubling of serum creatinine2126Risk Ratio (IV, Random, 95% CI)0.43 [0.12, 1.47]

 11 Kidney transplant graft loss291Risk Ratio (IV, Random, 95% CI)1.08 [0.58, 2.01]

 12 Transplant rejection297Risk Ratio (IV, Random, 95% CI)0.95 [0.77, 1.19]

 13 End of treatment creatinine clearance268Mean Difference (IV, Random, 95% CI)-6.41 [-19.94, 7.12]

 14 End of treatment proteinuria254Mean Difference (IV, Random, 95% CI)-1.43 [-3.84, 0.98]

 15 Dialysis access failure (thrombosis or loss of patency)142608Risk Ratio (IV, Random, 95% CI)0.68 [0.54, 0.84]

    15.1 Fistula
71502Risk Ratio (IV, Random, 95% CI)0.56 [0.40, 0.78]

    15.2 Shunt/graft
51052Risk Ratio (IV, Random, 95% CI)0.80 [0.62, 1.03]

    15.3 Fistula or graft
116Risk Ratio (IV, Random, 95% CI)0.50 [0.06, 4.47]

    15.4 Catheter
138Risk Ratio (IV, Random, 95% CI)0.44 [0.16, 1.20]

 16 Early access thrombosis (before 8 weeks)61365Risk Ratio (IV, Random, 95% CI)0.54 [0.39, 0.74]

 17 Loss of primary unassisted patency2665Risk Ratio (IV, Random, 95% CI)0.95 [0.89, 1.03]

 18 Failure to attain suitability for dialysis51503Risk Ratio (M-H, Random, 95% CI)0.62 [0.33, 1.16]

 19 Need for intervention to attain patency or assist maturation41583Risk Ratio (IV, Random, 95% CI)0.79 [0.54, 1.15]

 20 All-cause hospitalisation33535Risk Ratio (IV, Random, 95% CI)0.97 [0.87, 1.10]

 21 Cardiovascular hospitalisation33535Risk Ratio (IV, Random, 95% CI)0.93 [0.76, 1.14]

 22 Treatment withdrawal132569Risk Ratio (IV, Random, 95% CI)0.97 [0.83, 1.13]

 
Comparison 2. Thienopyridine versus clopidogrel

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatal or nonfatal myocardial infarction1Risk Ratio (IV, Random, 95% CI)Totals not selected

 2 All-cause mortality1Risk Ratio (IV, Random, 95% CI)Totals not selected

 3 Cardiovascular mortality1Risk Ratio (IV, Random, 95% CI)Totals not selected

 4 Major bleeding1Risk Ratio (IV, Random, 95% CI)Totals not selected

 5 Minor bleeding1Risk Ratio (IV, Random, 95% CI)Totals not selected

 
Comparison 3. Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Fatal or nonfatal myocardial1Risk Ratio (IV, Random, 95% CI)Totals not selected

 2 All-cause mortality1Risk Ratio (IV, Random, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Appendix 1. Electronic search strategies


DatabaseSearch terms

CENTRAL
  1. MeSH descriptor Phosphodiesterase Inhibitors explode all trees
  2. MeSH descriptor Adenosine Diphosphate, this term only with qualifier: AI
  3. MeSH descriptor Platelet Glycoprotein GPIIb-IIIa Complex, this term only with qualifier: AI
  4. ((antiplatelet next agent*) or (anti-platelet next agent*)):ti,ab,kw
  5. ((antiplatelet therap*) or (anti-platelet therap*)):ti,ab,kw
  6. (platelet next aggregation next inhibit*):ti,ab,kw
  7. (phosphodiesterase next inhibit*):ti,ab,kw
  8. (thrombocyte next aggregation next inhibit*):ti,ab,kw
  9. ((antithrombocytic next agent*) or (anti-thrombocytic next agent*)):ti,ab,kw
  10. ((antithrombocytic next therap*) or (anti-thrombocytic next therap*)):ti,ab,kw
  11. alprostadil:ti,ab,kw
  12. aspirin:ti,ab,kw
  13. acetylsalicylic acid:ti,ab,kw
  14. ((adenosine next reuptake inhibit*) or (adenosine re-uptake inhibit*)):ti,ab,kw
  15. (adenosine next diphosphate next receptor next inhibit*):ti,ab,kw
  16. dipyridamole:ti,ab,kw
  17. disintegrins:ti,ab,kw
  18. epoprostenol:ti,ab,kw
  19. iloprost:ti,ab,kw
  20. ketanserin:ti,ab,kw
  21. milrinone:ti,ab,kw
  22. pentoxifylline:ti,ab,kw
  23. (S-nitrosoglutathione):ti,ab,kw
  24. S-nitrosothiols:ti,ab,kw
  25. trapidil:ti,ab,kw
  26. ticlopidine:ti,ab,kw
  27. clopidogrel:ti,ab,kw
  28. (sulfinpyrazone or sulphinpyrazone):ti,ab,kw
  29. cilostazol:ti,ab,kw
  30. (P2Y12 NEAR/2 antagonis*):ti,ab,kw
  31. prasugrel:ti,ab,kw
  32. ticagrelor:ti,ab,kw
  33. cangrelor:ti,ab,kw
  34. elinogrel:ti,ab,kw
  35. "glycoprotein IIB/IIIA inhibitors":ti,ab,kw
  36. abciximab:ti,ab,kw
  37. eptifibatide:ti,ab,kw
  38. tirofiban:ti,ab,kw
  39. defibrotide:ti,ab,kw
  40. picotamide:ti,ab,kw
  41. beraprost:ti,ab,kw
  42. ticlid:ti,ab,kw
  43. aggrenox:ti,ab,kw
  44. ditazole:ti,ab,kw
  45. (#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44)
  46. dialysis:ti,ab,kw
  47. (hemodialysis or haemodialysis):ti,ab,kw
  48. (hemofiltration or haemofiltration):ti,ab,kw
  49. (hemodiafiltration or haemodiafiltration):ti,ab,kw
  50. (PD or CAPD or CCPD or APD):ti,ab,kw
  51. (renal next insufficiency):ti,ab,kw
  52. (kidney next failure):ti,ab,kw
  53. (kidney next disease*):ti,ab,kw
  54. ur*emi*:ti,ab,kw
  55. ((chronic next kidney) or (chronic next renal)):ti,ab,kw
  56. (CKF or CKD or CRF or CRD):ti,ab,kw
  57. predialysis:ti,ab,kw
  58. ((end-stage next renal) or (end-stage next kidney) or (endstage next renal) or (endstage next kidney)):ti,ab,kw
  59. (ESKD or ESRD or ESKF or ESRF):ti,ab,kw
  60. ((kidney next transplant*) or (renal next transplant*) or (kidney next *graft*) or (renal next *graft*)):ti,ab,tw
  61. (#46 OR #47 OR #48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55 OR #56 OR #57 OR #58 OR #59 OR #60)
  62. (#45 AND #61)

MEDLINE
  1. exp Platelet Aggregation Inhibitors/
  2. exp Phosphodiesterase Inhibitors/
  3. Adenosine Diphosphate/ai [Antagonists & Inhibitors]
  4. Platelet Glycoprotein GPIIb-IIIa Complex/ai [Antagonists & Inhibitors]
  5. Sulfinpyrazone/
  6. (antiplatelet agents$ or anti-platelet agent$).tw.
  7. (antiplatelet therap$ or anti-platelet therap$).tw.
  8. platelet aggregation inhibit$.tw.
  9. phosphodiesterase inhibit$.tw.
  10. thrombocyte aggregation inhibit$.tw.
  11. (antithrombocytic agent$ or anti-thrombocytic agent$).tw.
  12. (antithrombocytic therap$ or anti-thrombocytic therap$).tw.
  13. alprostadil.tw.
  14. aspirin.tw.
  15. acetylsalicylic acid.tw.
  16. (adenosine reuptake inhibit$ or adenosine re-uptake inhibit$).tw.
  17. adenosine diphosphate receptor inhibit$.tw.
  18. dipyridamole.tw.
  19. disintegrins.tw.
  20. epoprostenol.tw.
  21. iloprost.tw.
  22. ketanserin.tw.
  23. milrinone.tw.
  24. pentoxifylline.tw.
  25. S-nitrosoglutathione.tw.
  26. S-nitrosothioles.tw.
  27. trapidil.tw.
  28. ticlopidine.tw.
  29. clopidogrel.tw.
  30. (sulfinpyrazone or sulphinpyrazone).tw.
  31. cilostazol.tw.
  32. (P2Y12 adj2 antagonis$).tw.
  33. prasugrel.tw.
  34. ticagrelor.tw.
  35. cangrelor.tw.
  36. elinogrel.tw.
  37. "glycoprotein IIB/IIIA inhibitors".tw.
  38. abciximab.tw.
  39. eptifibatide.tw.
  40. tirofiban.tw.
  41. defibrotide.tw.
  42. picotamide.tw.
  43. beraprost.tw.
  44. ticlid.tw.
  45. aggrenox.tw.
  46. ditazole.tw.
  47. or/1-46
  48. exp Renal Dialysis/
  49. (hemodialysis or haemodialysis).tw.
  50. (hemofiltration or haemofiltration).tw.
  51. (hemodiafiltration or haemodiafiltration).tw.
  52. dialysis.tw.
  53. (PD or CAPD or CCPD or APD).tw.
  54. Renal Insufficiency/
  55. Kidney Failure/
  56. exp Renal Insufficiency, Chronic/
  57. Kidney Diseases/
  58. Uremia/
  59. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.
  60. (ESRF or ESKF or ESRD or ESKD).tw.
  61. (chronic kidney or chronic renal).tw.
  62. (CKF or CKD or CRF or CRD).tw.
  63. (predialysis or pre-dialysis).tw.
  64. ur?emi$.tw.
  65. or/48-64
  66. and/47,65

EMBASE
  1. exp Antithrombocytic Agent/
  2. exp Phosphodiesterase Inhibitor/
  3. Defibrotide/
  4. platelet aggregation inhibit$.tw.
  5. (antiplatelet agents$ or anti-platelet agent$).tw.
  6. (antiplatelet therap$ or anti-platelet therap$).tw.
  7. thrombocyte aggregation inhibit$.tw.
  8. (antithrombocytic agent$ or anti-thrombocytic agent$).tw.
  9. (antithrombocytic therap$ or anti-thrombocytic therap$).tw.
  10. adenosine diphosphate receptor inhibit$.tw.
  11. phosphodiesterase inhibit$.tw.
  12. (adenosine reuptake inhibit$ or adenosine re-uptake inhibit$).tw.
  13. aspirin.tw.
  14. acetylsalicylic acid.tw.
  15. dipyridamole.tw.
  16. ticlopidine.tw.
  17. clopidogrel.tw.
  18. (sulfinpyrazone or sulphinpyrazone).tw.
  19. cilostazol.tw.
  20. (P2Y12 adj2 antagonis$).tw.
  21. prasugrel.tw.
  22. ticagrelor.tw.
  23. cangrelor.tw.
  24. elinogrel.tw.
  25. "glycoprotein IIB/IIIA inhibit$".tw.
  26. abciximab.tw.
  27. eptifibatide.tw.
  28. tirofiban.tw.
  29. defibrotide.tw.
  30. picotamide.tw.
  31. beraprost.tw.
  32. ticlid.tw.
  33. aggrenox.tw.
  34. ditazole.tw.
  35. or/1-34
  36. exp Renal Replacement Therapy/
  37. (hemodialysis or haemodialysis).tw
  38. (hemofiltration or haemofiltration).tw.
  39. (hemodiafiltration or haemodiafiltration).tw.
  40. dialysis.tw.
  41. (PD or CAPD or CCPD or APD).tw.
  42. Kidney Disease/
  43. Chronic Kidney Disease/
  44. Kidney Failure/
  45. Chronic Kidney Failure/
  46. Uremia/
  47. (chronic kidney or chronic renal).tw.
  48. (CKF or CKD or CRF or CRD).tw.
  49. (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw.
  50. (ESRF or ESKF or ESRD or ESKD).tw.
  51. ur?emi$.tw.
  52. exp Kidney Transplantation/
  53. or/36-52
  54. and/35,53



 

Appendix 2. Risk of bias assessment tool


Potential source of biasAssessment criteria

Random sequence generation

Selection bias (biased allocation to interventions) due to inadequate generation of a randomised sequence
Low risk of bias: Random number table; computer random number generator; coin tossing; shuffling cards or envelopes; throwing dice; drawing of lots; minimization (minimization may be implemented without a random element, and this is considered to be equivalent to being random).

High risk of bias: Sequence generated by odd or even date of birth; date (or day) of admission; sequence generated by hospital or clinic record number; allocation by judgement of the clinician; by preference of the participant; based on the results of a laboratory test or a series of tests; by availability of the intervention.

Unclear: Insufficient information about the sequence generation process to permit judgement.

Allocation concealment

Selection bias (biased allocation to interventions) due to inadequate concealment of allocations prior to assignment
Low risk of bias: Randomisation method described that would not allow investigator/participant to know or influence intervention group before eligible participant entered in the study (e.g. central allocation, including telephone, web-based, and pharmacy-controlled, randomisation; sequentially numbered drug containers of identical appearance; sequentially numbered, opaque, sealed envelopes).

High risk of bias: Using an open random allocation schedule (e.g. a list of random numbers); assignment envelopes were used without appropriate safeguards (e.g. if envelopes were unsealed or non-opaque or not sequentially numbered); alternation or rotation; date of birth; case record number; any other explicitly unconcealed procedure.

Unclear: Randomisation stated but no information on method used is available.

Blinding of participants and personnel

Performance bias due to knowledge of the allocated interventions by participants and personnel during the study
Low risk of bias: No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding; blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding or incomplete blinding, and the outcome is likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted, but likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Blinding of outcome assessment

Detection bias due to knowledge of the allocated interventions by outcome assessors.
Low risk of bias: No blinding of outcome assessment, but the review authors judge that the outcome measurement is not likely to be influenced by lack of blinding; blinding of outcome assessment ensured, and unlikely that the blinding could have been broken.

High risk of bias: No blinding of outcome assessment, and the outcome measurement is likely to be influenced by lack of blinding; blinding of outcome assessment, but likely that the blinding could have been broken, and the outcome measurement is likely to be influenced by lack of blinding.

Unclear: Insufficient information to permit judgement

Incomplete outcome data

Attrition bias due to amount, nature or handling of incomplete outcome data.
Low risk of bias: No missing outcome data; reasons for missing outcome data unlikely to be related to true outcome (for survival data, censoring unlikely to be introducing bias); missing outcome data balanced in numbers across intervention groups, with similar reasons for missing data across groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes not enough to have a clinically relevant impact on observed effect size; missing data have been imputed using appropriate methods.

High risk of bias: Reason for missing outcome data likely to be related to true outcome, with either imbalance in numbers or reasons for missing data across intervention groups; for dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate; for continuous outcome data, plausible effect size (difference in means or standardized difference in means) among missing outcomes enough to induce clinically relevant bias in observed effect size; ‘as-treated’ analysis done with substantial departure of the intervention received from that assigned at randomisation; potentially inappropriate application of simple imputation.

Unclear: Insufficient information to permit judgement

Selective reporting

Reporting bias due to selective outcome reporting
Low risk of bias: The study protocol is available and all of the study’s pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way; the study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).

High risk of bias: Not all of the study’s pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified; one or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect); one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.

Unclear: Insufficient information to permit judgement

Other bias

Bias due to problems not covered elsewhere in the table
Low risk of bias: The study appears to be free of other sources of bias.

High risk of bias: Had a potential source of bias related to the specific study design used; stopped early due to some data-dependent process (including a formal-stopping rule); had extreme baseline imbalance; has been claimed to have been fraudulent; had some other problem.

Unclear: Insufficient information to assess whether an important risk of bias exists; insufficient rationale or evidence that an identified problem will introduce bias.



 

Feedback

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Feedback concerning conclusions, 9 May 2013

 

Summary

Dear Editor,

Thank you for a much needed review addressing the gaps in literature regarding the risks and benefits of antiplatelets in the chronic kidney disease (CKD) population. We thought the literature search was very thorough and well done. However, we came up with a few questions upon reading this review and felt that the stated conclusion "antiplatelets reduce myocardial infarction...including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease" may not be accurately reflected by the presented data.

Looking at the first primary outcome - fatal and non-fatal myocardial infarction (MI), it was unclear whether the population studied was addressing primary prevention, secondary prevention or acute treatment of MI as the included populations had different cardiovascular histories. Of the two studies that were given the most weight in the analysis (HOT Study 2010 and PURSUIT Study 1998), one investigated primary prevention of MI using ASA versus placebo, while the other investigated acute treatment of MI using eptifibatide + ASA + heparin compared to ASA + heparin. In the non-CKD population, efficacy of antiplatelets is dependent on the indication (ie. primary or secondary prophylaxis or treatment). Different antiplatelets also have different places in therapy.

We therefore feel that it may be inappropriate to pool these trials together as they were investigating different populations.

In this same analysis, there were also multiple interventions such as single antiplatelets versus placebo (HOT study 2010, Ell study 1982, Creek 1990, Dember 2008, STOP study 1995, UK-HARP-I study 2005, ETDRS 1992), dual antiplatelets versus placebo (Kaufman 2003), as well as dual antiplatelets versus single antiplatelet agents (CREDO study 2008, CHARISMA study 2009, EPILOG study 1997, EPIC study 1994, EPISTENT study 1998, Dixon study 2009, RAPPORT study 1998, PURSUIT study 1998, and IMPACT II 1997). With both placebo and antiplatelet in the "control" arms of one meta-analysis, comparison groups and treatment groups are not clearly delineated from one another. As this was unclear, readers may be misled into believing that the effect is driven purely from antiplatelet compared to placebo, when this is not the case. Even pooling the data on the seven placebo-controlled trials may be inappropriate as they were studied in different patient

populations and indications (e.g. primary prevention, non-cardiovascular outcomes). Similarly, the "treatment arms" of the meta-analysis contained one or more antiplatelet agents, which may have

biased the result towards the treatment arm over single agent or placebo "control". This can also make it difficult to isolate the beneficial agent in the dual antiplatelet studies. Due to the differences in treatment arms and patient populations, we feel it would valuable to investigate the outcomes of these factors in separate analyses.

It should also be mentioned that the patients included in this review were derived as subgroups from larger studies with different baseline cardiovascular risk factors (e.g. diabetes, coronary artery disease, hypertension, etc). As a result, one cannot conclude that patients with only CKD, and no additional cardiovascular risk factors, would benefit from antiplatelet use to decrease cardiovascular outcomes such as fatal and non-fatal MIs. Dixon 2009 and Dember 2008 were two

studies enrolling hemodialysis patients with a primary outcome of AV graft patency or thrombosis; fatal and non-fatal MIs were only reported as an adverse effect and could have been under-reported in the study.

We commend the authors for assessing bias in the included trials and for performing a sensitivity analysis to explore the impact of the bias. We feel that with the relatively high percentage of unclear or high risk of biases that exist in the trials, it would have been beneficial for the authors to report on the results of their sensitivity analyses to clarify the role of the bias and to substantiate the reported results.

We feel that the author's conclusion "antiplatelet agents reduce myocardial infarction" may be too broad of a conclusion to be drawn based on the analysis that was performed looking at fatal and non-fatal MI. As well, their specific reference to "patients with early stages of CKD who do not have a clinically-evident occlusive cardiovascular disease" suggests this effect is shown in the CKD

population when using antiplatelets for primary prevention; however, this aspect was not separated out in their analysis. We feel that the pooling of studies with varying patient populations and treatments is not appropriate in helping clinicians determine whether antiplatelets provide any benefit for MI in patients with CKD. While we did not explore the other identified primary outcomes in this review, we wonder if similar concerns exist for not only the efficacy but also the safety outcomes. We would appreciate an investigation into single antiplatelet therapy versus placebo for various cardiovascular indications. We hope the authors will provide clarification and address these concerns in their future updates.

We look forward to hearing your response to our comments.

Sincerely,

Gloria Su, BSc. Pharm
Wan-Yun Polinna Tsai, BSc. Pharm
Megan Harbin, BSc. Pharm
Asal Taheri, BSc. Pharm
Aaron M Tejani, BSc. Pharm, PharmD

 

Reply

Thanks for the constructive comments.

1. Primary versus secondary prevention versus acute treatment

We combined treatment estimates for all available studies comparing antiplatelet therapy (with or without standard therapy) versus placebo/no treatment (with or without standard therapy alone) to examine treatment effects, which is a standard starting point for meta-analyses. For the outcome of fatal or nonfatal myocardial infarction, there was little or no heterogeneity in the treatment effects observed in all the available trials, suggesting that treatment estimates could be appropriately summarised into a single effect size.

While not necessary in the absence of significant heterogeneity, we explored for pre-specified trial-level variables that might have modified the treatment estimates that we observed. We specifically wished to know whether treatment effects differed for patients with existing cardiovascular disease compared to those without cardiovascular disease but this was not feasible due to as we found insufficient numbers of studies that were clearly primary prevention or secondary prevention studies. However, the lack of heterogeneity in the overall summary estimate suggests that antiplatelet agents have similar effects irrespective of the presence or absence of cardiovascular disease.

2. Multiple interventions:

Unlike the relative lack of primary versus secondary prevention trials, there was sufficient studies to explore any differences in treatment effects based on the class of antiplatelet used. While there were numerous different strategies for antiplatelet treatment in contributing trials, all the treatment interventions could be characterised by an antiplatelet agent in addition to standard care versus no treatment/placebo in addition to standard care. We have called this antiplatelet therapy versus control to acknowledge the heterogeneity of the intervention strategies used (rather than antiplatelet treatment versus placebo).

We used stratified analyses according to overall class of antiplatelet drug where possible but there was lack of power from available studies to understand fully all the various treatment effects for each individual antiplatelet regimen. An individual patient meta-analysis would be needed to give a more fine-grained understanding of the different interventions and their combinations in the CKD population.

3. Deriving patients from subgroups of larger studies:

Patients with CKD were evaluated in post-hoc analyses of larger trials in broader populations. These included trials in populations with acute coronary syndromes requiring percutaneous coronary artery procedures, patients with hypertension and those with diabetes mellitus. Trials of treatment tended to use different interventions (glycoprotein IIb/IIIa inhibitors with or without clopidogrel) whereas trials of primary or secondary prevention did not use these agents, preventing useful stratified analyses for either class of agent or cardiovascular prevention in these trials. We have concluded that the lack of a priori assessment of glycoprotein IIb/IIIa inhibitors in people with CKD is an important limitation of the current evidence.

4. Potential under-reporting of clinical outcomes

We agree that many trials were not designed to evaluate mortality and cardiovascular outcomes and that these events were reported in an ad hoc fashion (not prespecified) which may have underestimated their frequency. We include evaluation of this aspect of trials when considering whether they are at risk of bias due to selective reporting of expected outcomes.

5. Risks of bias

We did not specify risk of bias items as sources of heterogeneity we would explore in stratified analyses. In further updates of this review and if deemed appropriate and feasible, we will explore attrition bias and allocation concealment as potential sources of heterogeneity in subgroup or sensitivity analyses.

6. Conclusions

In conclusion, we thank Dr Su and others for constructive comments to this review. We agree that the review cannot provide high quality information about antiplatelet agents as primary prevention for cardiovascular disease in people with CKD. We acknowledge the limitations of studies in which adults with CKD were studied post hoc and which are heterogeneous for presence of cardiovascular disease and antiplatelet agent studied. We agree that clinical events may be under-reported in available studies and will explore in future versions of this review the effects of risk of bias on the estimated treatment effects of antiplatelet treatment in CKD.

 

Contributors

Suetonia Palmer

Giovanni Strippoli

 

What's new

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Last assessed as up-to-date: 24 January 2011.


DateEventDescription

9 July 2013AmendedFeedback and reply incorporated



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Protocol first published: Issue 11, 2010
Review first published: Issue 2, 2013


DateEventDescription

11 March 2013New citation required but conclusions have not changedMinor amendment to abstract



 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

  1. Draft the protocol: MR, SP
  2. Study selection: MR, LDM, SP
  3. Extract data from studies: MR, LDM, SP
  4. Enter data into RevMan: MR, LDM, SP
  5. Carry out the analysis: MR, LDM, SP
  6. Interpret the analysis: MR, LDM, SP, JC, VP, SZ, AW, MJ, GFMS
  7. Draft the final review: MR, LDM, SP, JC, VP, SZ, AW, MJ, GFMS
  8. Disagreement resolution: GFMS
  9. Update the review: SP, GFMS

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

Vlado Perkovic is supported by a fellowship from the Heart Foundation of Australia and various grants from the Australian National Health and Medical Research Council. He has received speakers fees from Roche, Servier and Astra Zeneca, funding for a clinical trial from Baxter, and serves on Steering Committees for trials funded by Johnson and Johnson, Boehringer Ingelheim, Vitae and Abbott. His employer conducts clinical trials funded by Servier, Johnson and Johnson, Roche and Merck.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms
 

Internal sources

  • No sources of support supplied

 

External sources

  • Suetonia Palmer, New Zealand.
    Don and Lorraine Jacquot Fellowship; Amgen Dompe - Consorzio Mario Negri Sud Fellowship

 

Differences between protocol and review

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. Feedback
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Index terms

We included studies of antiplatelet agents of fewer than two months follow-up if they provided outcome data for vascular access outcomes.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Abdul-Rahman 2007 {published data only}
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Anderson 1974 {published data only}
  • Anderson M, Dewar P, Fleming LB, Hacking PM, Morley AR, Murray S, et al. A controlled trial of dipyridamole in human renal transplantation and an assessment of platelet function studies in rejection. Clinical Nephrology 1974;2(3):93-9. [MEDLINE: 4603996]
Andrassy 1974 {published data only}
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CHARISMA Study 2009 {published and unpublished data}
  • Bhatt DL, Flather MD, Hacke W, Berger PB, Black HR, Boden WE, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. Journal of the American College of Cardiology 2007;49(19):1982-8. [MEDLINE: 17498584]
  • Dasgupta A, Steinhubl SR, Bhatt DL, Berger PB, Shao M, Mak KH, et al. Clinical outcomes of patients with diabetic nephropathy randomized to clopidogrel plus aspirin versus aspirin alone (a post hoc analysis of the clopidogrel for high atherothrombotic risk and ischemic stabilization, management, and avoidance [CHARISMA] trial). American Journal of Cardiology 2009;103(10):1359-63. [MEDLINE: 19427428]
  • Wang TH, Bhatt DL, Fox KA, Steinhubl SR, Brennan DM, Hacke W, et al. An analysis of mortality rates with dual-antiplatelet therapy in the primary prevention population of the CHARISMA trial. European Heart Journal 2007;28(18):2200-7. [MEDLINE: 17673448]
Cheng 1998 {published data only}
  • Cheng IK, Fang GX, Wong MC, Ji YL, Chan KW, Yeung HW. A randomized prospective comparison of nadolol, captopril with or without ticlopidine on disease progression in IgA nephropathy. Nephrology 1998;4(1-2):19-26. [EMBASE: 1998205046]
CREDO Study 2008 {published and unpublished data}
  • Best PJ, Steinhubl SR, Berger PB, Dasgupta A, Brennan DM, Szczech LA, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. American Heart Journal 2008;155(4):687-93. [MEDLINE: 18371477]
  • Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288(19):2411-20. [MEDLINE: 12435254]
Creek 1990 {published data only}
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CURE Study 2007 {published data only (unpublished sought but not used)}
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Dember 2008 {published data only}
  • Dember LM, Beck GJ, Allon M, Delmez JA, Dixon BS, Greenberg A, et al. Effect of clopidogrel on early failure of arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA 2008;299(18):2164-71. [MEDLINE: 18477783]
  • Dember LM, Kaufman JS, Beck GJ, Dixon BS, Gassman JJ, Greene T, et al. Design of the Dialysis Access Consortium (DAC) Clopidogrel Prevention of Early AV Fistula Thrombosis Trial. Clinical Trials 2005;2(5):413-22. [MEDLINE: 16317810]
  • Dember LM, Kaufman JS, Beck GJ, Dixon BS, Gassman JJ, Greene T, et al. Dialysis access consortium (DAC) trial design: clopidogrel prevention of early AV fistula thrombosis [abstract]. Journal of the American Society of Nephrology 2002;13(Program & Abstracts):229A.
Dixon 2009 {published data only}
  • Dixon B, Beck G, Meyers C, Kusek J, Feldman H, DAC Study Group. Effect of aspirin (ASA) on primary unassisted graft patency in the dialysis access consortium (DAC) graft trial [abstract]. Journal of the American Society of Nephrology 2008;19(Abstract Issue):256A.
  • Dixon BS, Beck GJ, Dember LM, Depner TA, Gassman JJ, Greene T, et al. Design of the Dialysis Access Consortium (DAC) Aggrenox Prevention Of Access Stenosis Trial. Clinical Trials 2005;2(5):400-12. [MEDLINE: 16317809]
  • Dixon BS, Beck GJ, Vazquez MA, Greenberg A, Delmez JA, Allon M, et al. Dialysis Access Consortium (DAC) Trial design: sustained-release dipyridamole plus aspirin (D/A) to prevent graft failure [abstract]. Journal of the American Society of Nephrology 2002;10(Abstract Issue):232A.
  • Dixon BS, Beck GJ, Vazquez MA, Greenberg A, Delmez JA, Allon M, et al. Effect of dipyridamole plus aspirin on hemodialysis graft patency. New England Journal of Medicine 2009;360(21):2191-201. [MEDLINE: 19458364]
Dodd 1980 {published data only}
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Donadio 1984 {published data only}
  • Donadio JV Jr, Anderson CF, Mitchell JC 3rd, Holley KH, Ilstrup DM, Fuster V, et al. Membranoproliferative glomerulonephritis. A prospective clinical trial of platelet-inhibitor therapy. New England Journal of Medicine 1984;310(22):1421-6. [MEDLINE: 6371535]
Ell 1982 {published and unpublished data}
  • Ell S, Mihindukulasuriya JC, O'Brien JR, Polak A, Vernham G. Ticlopidine in the prevention of blockage of fistulae and shunts. Haemostasis 1982; Vol. 12:180.
EPIC Study 1994 {published data only}
  • Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. New England Journal of Medicine 1994;330(14):956-61. [MEDLINE: 8121459]
  • Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, et al. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: results at six months. The EPIC Investigators. Lancet 1994;343(8902):881-6. [MEDLINE: 7908357]
  • Topol EJ, Ferguson JJ, Weisman HF, Tcheng JE, Ellis SG, Kleiman NS, et al. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin beta3 blockade with percutaneous coronary intervention. EPIC Investigator Group. Evaluation of Platelet IIb/IIIa Inhibition for Prevention of Ischemic Complication. JAMA 1997;278(6):479-84. [MEDLINE: 9256222]
EPILOG Study 1997 {unpublished data only}
  • Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. The EPILOG Investigators. New England Journal of Medicine 1997;336(24):1689-96. [MEDLINE: 9182212]
  • Lincoff AM, Tcheng JE, Califf RM, Kereiakes DJ, Kelly TA, Timmis GC, et al. Sustained suppression of ischemic complications of coronary intervention by platelet GP IIb/IIIa blockade with abciximab. One-year outcome in the EPILOG trial. Circulation 1999;99(15):1951-8. [MEDLINE: 10208997]
EPISTENT Study 1998 {unpublished data only}
  • EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998;352(9122):87-92. [MEDLINE: 9672272]
  • Topol EJ, Mark DB, Lincoff AM, Cohen E, Burton J, Kleiman N, et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting. Lancet 1999;354(9195):2019-24. [MEDLINE: 10636365]
ETDRS 1992 {unpublished data only}
  • Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 1992;268(10):1292-300. [MEDLINE: 1507375]
Fiskerstrand 1985 {published data only}
Frascà 1986 {published data only}
  • Frascà GM, Vangelista A, Raimondi C, Bonomini V. Prevention of vascular graft lesions in renal transplant recipients with a new antithrombotic agent (Defibrotide): a controlled study. Life Support System 1986;4(3):231-7. [MEDLINE: 3537545]
Frascà 1997 {published data only}
  • Bonomini V, Vangelista A, Stefoni S, Scolari MP, Frascà GM, Raimondi C. Use of defibrotide in renal transplantation in man. Haemostasis 1986;16 Suppl 1:48-50. [MEDLINE: 3519383]
  • Frascà GM, Cianciolo G. A clinical trial with defibrotide in IgA nephritis (IgA-GN) with impaired renal function [abstract]. Nephrology Dialysis Transplantation 1995;10(6):968.
  • Frascà GM, Martello M, Canova C, Isola E, Vangelista A, Bonomini V. Defibrotide treatment and disease progression in patients with IgA nephropathy and impaired renal function at diagnosis. Clinical Drug Investigation 1997;13(4):185-91. [EMBASE: 1997135783]
  • Frascà GM, Martello M, Sestigiani E, Canova C, Vangelista A, Bonomini V. Effects of defibrotide treatment in patients with IgA nephropathy and reduced renal function. Clinical Drug Investigation 1997;13(4):185-91. [MEDLINE: 8700366]
  • Frascà GM, Martello M, Sestigiani E, Canova C, Vangelista A, Bonomini V. Effects of defibrotide treatment in patients with IgA nephropathy and reduced renal function. Nephrology Dialysis Transplantation 1996;11(2):392-3. [MEDLINE: 8700366]
Ghorbani 2009 {published data only}
  • Ghorbani A, Aalamshah M, Shahbazian H, Ehsanpour A, Aref A. Randomized controlled trial of clopidogrel to prevent primary arteriovenous fistula failure in hemodialysis patients. Indian Journal of Nephrology 2009;19(2):57-61. [EMBASE: 2009390539]
Giustina 1998 {published data only}
  • Giustina A, Perini P, Desenzani P, Bossoni S, Ianniello P, Milani M, et al. Long-term treatment with the dual antithromboxane agent picotamide decreases microalbuminuria in normotensive type 2 diabetic patients. Diabetes 1998;47(3):423-30. [MEDLINE: 9519749]
Gonzalez 1995 {published data only}
  • Gonzalez MT, Castelao AM, Valles M, Cruzado JM, Mauri JM. Platelet antiaggregants (PA) could decrease the rate of progression of chronic renal failure (CRF) in diabetic patients (DP) treated previously with angiotensin converting enzyme inhibitors (ACEI) [abstract]. ISN XIII International Congress of Nephrology; 1995 Jul 2-6; Madrid (Spain). 1995:200.
Gröntoft 1985 {published data only}
  • Gröntoft KC, Mulec H, Gutierrez A, Olander R. Thromboprophylactic effect of ticlopidine in arteriovenous fistulas for haemodialysis. Scandinavian Journal of Urology & Nephrology 1985;19(1):55-7. [MEDLINE: 3895411]
Gröntoft 1998 {published data only}
  • Gröntoft K, Larsson R, Mulec H, Weiss LG, Dickinson JP. Ticlopidine in fistula surgery: double-blind comparison against placebo on the rate of early occlusion of arterio-venous fistulae [abstract]. 12th International Congress of Nephrology; 1993 Jun 13-18; Jerusalem (Israel). 1993:398.
  • Gröntoft KC, Larsson R, Mulec H, Weiss LG, Dickinson JP. Effects of ticlopidine in AV-fistula surgery in uremia. Fistula Study Group. Scandinavian Journal of Urology & Nephrology 1998;32(4):276-83. [MEDLINE: 9764456]
Harter 1979 {published data only}
HOT Study 2010 {published and unpublished data}
  • Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998;351(9118):1755-62. [MEDLINE: 9635947]
  • Jardine MJ, Ninomiya T, Perkovic V, Cass A, Turnbull F, Gallagher MP, et al. Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. Journal of the American College of Cardiology 2010;56(12):956-65. [MEDLINE: 20828648]
  • Kolloch RE, Rahn KH. The Hypertension Optimal Treatment (HOT) study: Results of 12-month treatment related to age [Die 'Hyperyension Optimal Treatment' (HOT)-Studie: Behandlungsergebnisse nach Zwolfmonatiger Therapie in Abhangigkeit vom Alter]. Deutsche Medizinische Wochenschrift 1998;123(1-2):1-5. [MEDLINE: 9465848]
  • Ruilope LM, Salvetti A, Jamerson K, Hansson L, Warnold I, Wedel H, et al. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. Journal of the American Society of Nephrology 2001;12(2):218-25. [MEDLINE: 11158211]
IMPACT II Study 1997 {unpublished data only}
  • Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention: IMPACT-II. Integrilin to Minimise Platelet Aggregation and Coronary Thrombosis-II. Lancet 1997;349(9063):1422-8. [MEDLINE: 9164315]
  • Mandak JS, Blankenship JC, Gardner LH, Berkowitz SD, Aguirre FV, Sigmon KN, et al. Modifiable risk factors for vascular access site complications in the IMPACT II trial of angioplasty with versus without eptifibatide. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis. Journal of the American College of Cardiology 1998;31(7):1518-24. [MEDLINE: 9626829]
Kaegi 1974 {published data only}
Kauffmann 1980 {published data only}
  • Kauffmann HM, Adams MB, Hebert LA, Walczak PM. Platelet inhibitors in human renal homotransplantation: randomized comparison of aspirin versus dipyridamole. Transplantation Proceedings 1980;12(2):311-4. [MEDLINE: 6771905]
Kaufman 2003 {published and unpublished data}
  • Kaufman JS, O'Connor TZ, Zhang JH, Cronin RE, Fiore LD, Ganz MB, et al. Randomized controlled trial of clopidogrel plus aspirin to prevent hemodialysis access graft thrombosis. Journal of the American Society of Nephrology 2003;14(9):2313-21. [MEDLINE: 12937308]
  • Kaufman JS, O’Connor TZ, Zhang JH, Cronin RE, Fiore LD, Ganz MB, et al. Combination aspirin plus clopidogrel in the prevention of hemodialysis access graft thrombosis [abstract]. Journal of the American Society of Nephrology 2001;12(Program & Abstracts):291A.
Khajehdehi 2002 {published data only}
  • Khajehdehi P, Roozbeh J, Mostafavi H. A comparative randomized and placebo-controlled short-term trial of aspirin and dipyridamole for overt type-2 diabetic nephropathy. Scandinavian Journal of Urology & Nephrology 2002;36(2):145-8. [MEDLINE: 12028688]
Kobayashi 1980 {published data only}
  • Kobayashi K, Maeda K, Koshikawa S, Kawaguchi Y, Shimizu N, Naito C. Antithrombotic therapy with ticlopidine in chronic renal failure patients on maintenance hemodialysis: a multicenter collaborative double blind study. Thrombosis Research 1980;20(2):255-61. [MEDLINE: 7209880]
Kooistra 1994 {published data only}
  • Kooistra MP, van Es A. Effects of low dose aspirin on thrombovascular accidents during treatment with rHuEpo: a multicentre, controlled, cross-over study [abstract]. Nephrology Dialysis Transplantation 1993;8:277.
  • Kooistra MP, van Es A, Marx JJ, Hertsig ML, Struyvenberg A. Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin. Nephrology Dialysis Transplantation 1994;9(8):1115-20. [MEDLINE: 7800210]
Michie 1977 {published data only}
  • Michie DD, Wombolt DG. Use of sulfinpyrazone to prevent thrombus formation in arteriovenous fistulas and bovine grafts of patients on chronic hemodialysis. Current Therapeutic Research Clinical & Experimental 1977;22(1):196-204.
Middleton 1992 {published data only}
  • Middleton DA, Deichsel G. The prophylaxis of thrombosis in new arteriovenous dialysis shunts in the arm by low-dose acetylsalicylic acid and dipyridamole. Berlin, Germany: Boehringer Ingelheim. Internal report 1992.
Ogawa 2008 {published data only}
  • Ogawa S, Mori T, Nako K, Ishizuka T, Ito S. Reduced albuminuria with sarpogrelate is accompanied by a decrease in monocyte chemoattractant protein-1 levels in type 2 diabetes. Clinical Journal of the American Society of Nephrology: CJASN 2008;3(2):362-8. [MEDLINE: 18235151]
PLATO Study 2010 {published data only}
  • James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) Trial. Circulation 2010;122(11):1056-67. [MEDLINE: 20805430]
PRISM-PLUS Study 2002 {published data only (unpublished sought but not used)}
  • Januzzi JL Jr, Snapinn SM, DiBattiste PM, Jang IK, Theroux P. Benefits and safety of tirofiban among acute coronary syndrome patients with mild to moderate renal insufficiency: results from the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial. Circulation 2002;105(20):2361-6. [MEDLINE: 12021221]
PURSUIT Study 1998 {unpublished data only}
  • Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. The PURSUIT Trial Investigators. Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. New England Journal of Medicine 1998;339(7):436-43. [MEDLINE: 9705684]
Quarto Di Palo 1991 {published data only}
  • Quarto Di Palo F, Elli A, Rivolta R, Parenti M, Palazzi P, Zanussi C. Prevention of chronic cyclosporine nephrotoxicity in renal transplantation by picotamide. Transplantation Proceedings 1991;23(1 Pt 2):969-71. [MEDLINE: 1989347]
RAPPORT Study 1998 {unpublished data only}
  • Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation 1998;98(8):734-41. [MEDLINE: 9727542]
Schulze 1990 {published data only}
  • Schulze von R, Langkopf B, Sziegoleit W. The effect of dipyridamole on the results of allogenic kidney transplantation [Der Einfluss von Dipyridamol auf die Ergebnisse der allogenen Nieren-transplantation]. Zeitschrift für Urologie und Nephrologie 1990;83(5):255-9. [MEDLINE: 2203215]
Sreedhara 1994 {published data only}
  • Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-platelet therapy in graft thrombosis: results of a prospective, randomized, double blind study. Kidney International 1994;45(5):1477-83. [MEDLINE: 8072261]
  • Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Antiplatelet therapy in expanded polytetrafluoroethylene (EPTFE) graft thrombosis: results of a randomized double blind study [abstract]. Journal of the American Society of Nephrology 1993;4(Program & Abstracts):388.
STOP Study 1995 {published and unpublished data}
  • Mileti M, De PG, Bacchi M, Ogliari V, Pecchini F, Bufano G, et al. A trial to evaluate the efficacy of picotamide in preventing thrombotic occlusion of the vascular access in hemodialysis patients. Journal of Nephrology 1995;8(2):167-72. [EMBASE: 1995200634]
Taber 1992 {published data only}
  • Taber T, Maikranz P, Haag B, Dilley R, Gaylord G. Hemodialysis vascular graft stenosis may be altered by low-molecular weight dextran (LMD), but not by aspirin (ASA) [abstract]. Journal of the American Society of Nephrology 1992;3(3):397.
TARGET Study 2001 {published and unpublished data}
  • Berger PB, Best PJ, Topol EJ, White J, DiBattiste PM, Chan AW, et al. The relation of renal function to ischemic and bleeding outcomes with 2 different glycoprotein IIb/IIIa inhibitors: the do Tirofiban and ReoPro Give Similar Efficacy Outcome (TARGET) trial. American Heart Journal 2005;149(5):869-75. [MEDLINE: 15894970]
  • Topol EJ, Moliterno DJ, Herrmann HC, Powers ER, Grines CL, Cohen DJ, et al. Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. New England Journal of Medicine 2001;344(25):1888-94. [MEDLINE: 11419425]
TRITON-TIMI 38 2007 {unpublished data only}
UK-HARP-I Study 2005 {published and unpublished data}
  • Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A, et al. First United Kingdom Heart and Renal Protection (UK-HARP-I) study: biochemical efficacy and safety of simvastatin and safety of low-dose aspirin in chronic kidney disease. American Journal of Kidney Diseases 2005;45(3):473-84. [MEDLINE: 15754269]
  • Baigent C, UK-HARP Steering Committee. Efficacy and safety of simvastatin and safety of low-dose aspirin among patients with chronic kidney disease: final results of the first UK-heart and renal protection (UK-HARP-I) study [abstract]. Journal of the American Society of Nephrology 2002;13(Program & Abstracts):437A.
Zäuner 1994 {published data only}
  • Zäuner I, Böhler J, Braun N, Grupp C, Heering P, Schollmeyer P. Effect of aspirin and dipyridamole on proteinuria in idiopathic membranoproliferative glomerulonephritis: a multicentre prospective clinical trial. Nephrology Dialysis Transplantation 1994;9(6):619-22. [MEDLINE: 7970086]

References to studies excluded from this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
CAPRIE Study 1996 {published data only}
  • CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 1996;348(9038):1329-39. [MEDLINE: 8918275]
  • Harker LA, Boissel JP, Pilgrim AJ, Gent M. Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events. Drug Safety 1999;21(4):325-35. [MEDLINE: 10514023]
Caravaca 1995 {published data only}
  • Caravaca F, Lopez-Minguez JR, Arrobas M, Cubero J, Pizarro JL, Cid MC, et al. Haemodynamic changes induced by the correction of anaemia by erythropoietin: role of antiplatelet therapy. Nephrology Dialysis Transplantation 1995;10(9):1720-4. [MEDLINE: 8559495]
Chew 2005 {published data only}
  • Chew DP, Lincoff AM, Gurm H, Wolski K, Cohen DJ, Henry T, et al. Bivalirudin versus heparin and glycoprotein IIb/IIIa inhibition among patients with renal impairment undergoing percutaneous coronary intervention (a subanalysis of the REPLACE-2 trial). American Journal of Cardiology 2005;95(5):581-5. [MEDLINE: 15721095]
Dmoszynska 1990 {published data only}
  • Dmoszynska-Giannopoulou A, Janicka L, Sokolowska B, Ksiazek A, Orlowska G, Janicki K. The effect of sulphinpyrazone and alpha-tocopherol on platelet activation and function in haemodialysed patients. International Urology & Nephrology 1990;22(6):561-6. [MEDLINE: 2093696]
EXCITE Study 2008 {published data only}
  • Mercado N, Brugts JJ, Ix JH, Shlipak MG, Dixon SR, Gersh BJ, et al. Usefulness of proteinuria as a prognostic marker of mortality and cardiovascular events among patients undergoing percutaneous coronary intervention (data from the Evaluation of Oral Xemilofiban in Controlling Thrombotic Events [EXCITE] trial). American Journal of Cardiology 2008;102(9):1151-5. [MEDLINE: 18940282]
Gorter 1998 {published data only}
  • Gorter JW. Preventive treatment of patients after non-disabling cerebral ischaemia of presumed arterial origin: Comparative randomized study with intensive anticoagulant therapy or aspirin treatment [Preventieve behandeling van patienten na niet-invaliderende cerebrale ischemie door vermoedelijk arteriele oorzaak: Vergelijkend, gerandomiseerd onderzoek met intensieve antistollingstherapie of behandeling met acetylsalicylzuur]. Nederlands Tijdschrift voor Geneeskunde 1998;142(6):306-12. [EMBASE: 1998075400]
Hayden 2002 {published data only}
  • Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary prevention of cardiovascular events: a summary of the evidence for the U.S. Preventive Services Task Force. Annals of Internal Medicine 2002;136(2):161-72. [MEDLINE: 11790072]
Huang 2009 {published data only}
  • Huang J. Investigation of platelet function and aspirin resistance in chronic dialysis patient. Available at http://www.clinicaltrials.gov/ct2/show/NCT01045785 (accessed 24 December 2012).
Janicki 2003 {published data only}
  • Janicki K, Bojarska-Szmygin A, Pietura R, Janicka L. Preventive effects of ticlopidine on the incidence of late AV fistula thrombosis complications in haemodialyses patients. Annales Universitatis Mariae Curie-Sklodowska - Sectio d - Medicina 2003;58(1):215-8. [MEDLINE: 15314987]
Kamper 1997 {published data only}
  • Kamper AM, Lins RL, Zachee P, Van Bergen S, Hosten S, Daelemans R. Safety of combining ticlopidine with nadroparin in the routine treatment of chronic hemodialysis patients. Nephron 1997;77(4):484-5. [MEDLINE: 9434075]
Kim 2009 {published data only}
  • Kim KM, Kim HW, Lee JH, Chang JW, Park JS, Kim SB. Effects of beraprost sodium, an oral prostaglandin i2 analog, on hemostatic factors and inflammation in chronic peritoneal dialysis patients. Peritoneal Dialysis International 2009;29(2):178-81. [MEDLINE: 19293355]
Lang 1998 {published data only}
  • Lang J, Cao H, Wei A. Comparative study on effect of Panax notoginseng and ticlid in treating early diabetic nephropathy. Zhongguo Zhong Xi Yi Jie He Za Zhi Zhongguo Zhongxiyi Jiehe Zazhi [Chinese Journal of Integrated Traditional and Western Medicine] 1998;18(12):727-9. [MEDLINE: 11475719]
Lee 1997 {published data only}
Lindsay 1972 {published data only}
  • Lindsay RM, Ferguson D, Prentice CR, Burton JA, McNicol GP. Reduction of thrombus formation on dialyser membranes by aspirin and RA 233. Lancet 1972;2(7790):1287-90. [MEDLINE: 4117813]
Minakata 1998 {published data only}
  • Minakata T, Yonemoto S, Nomura K, Yoshida H. Antiplatelet drugs in diabetic hemodialysis patients: comparison of aspirin vs ticlopidine hydrochloride [abstract]. 35th Congress, European Renal Association, European Dialysis and Transplantation Association; Rimini (Italy). 1998:240.
Movchan 2001 {published data only}
  • Movchan EA, Chuprova AV, Tov NL, Vol'vich NV. Desaggregation therapy of acute glomerulonephritis. Klinicheskaia Meditsina 2001;79(12):44-7. [MEDLINE: 11840813]
NITER Study 2005 {published data only}
  • Scarpioni R, Michieletti E, Cristinelli L, Ugolotti U, Scolari F, Venturelli C, et al. Atherosclerotic renovascular disease: medical therapy versus medical therapy plus renal artery stenting in preventing renal failure progression: the rationale and study design of a prospective, multicenter and randomized trial (NITER). Journal of Nephrology 2005;18(4):423-8. [MEDLINE: 16245247]
Perkovic 2004 {published data only}
  • Perkovic V, Nicholls KM, Foreman A, Becker GJ. A randomised controlled trial of cardiovascular risk factor modification in end stage renal failure [abstract]. Nephrology 2004;9(Suppl 1):A16.
  • Perkovic V, Nicholls KM, Foreman A, Walker RG, Becker GJ. A randomised controlled trial of cardiovascular risk factor modification in end stage kidney disease [abstract]. Journal of the American Society of Nephrology 2004;15:377A-8A.
Peto 1988 {published data only}
  • Peto R, Gray R, Collins R, Wheatley K, Hennekens C, Jamrozik K, et al. Randomised trial of prophylactic daily aspirin in British male doctors. British Medical Journal Clinical Research Ed. 1988;296(6618):313-6. [MEDLINE: 3125882]
Physician Health Study 1989 {published data only}
  • Physicians' Health Study Research Group. Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group. New England Journal of Medicine 1989;321(3):129-35. [MEDLINE: 2664509]
Physician Health Study 1998 {published data only}
  • Physician Health Study. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet 1998;351(9098):233-41. [MEDLINE: 9457092]
RAS-CAD Study 2009 {published data only}
  • Marcantoni C, Zanoli L, Rastelli S, Tripepi G, Matalone M, Di Landro D, et al. Stenting of renal artery stenosis in coronary artery disease (RAS-CAD) study: a prospective, randomized trial. Journal of Nephrology 2009;22(1):13-6. [MEDLINE: 19229814]
RESIST Study 2008 {published data only}
Rubin 1982 {published data only}
Salter 1984 {published data only}
  • Salter MC, Crow MJ, Donaldson DR, Roberts TG, Rajah SM, Davison AM. Prevention of platelet deposition and thrombus formation on hemodialysis membranes: a double-blind randomized trial of aspirin and dipyridamole. Artificial Organs 1984;8(1):57-61. [MEDLINE: 6703927]
STENO-2 Study 2008 {published data only}
  • Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. New England Journal of Medicine 2008;358(6):580-91. [MEDLINE: 18256393]
Swan 1995 {published data only}
  • Halstenson CE, Swan SK, Collins AJ, Ellefson J, Parr K, Blue J, et al. Pharmacologic profile of diaspirin crosslinked hemoglobin (DCLHB) in hemodialysis (HD) patients [abstract]. Journal of the American Society of Nephrology 1994;5(3):451.
  • Swan SK, Halstenson CE, Collins AJ, Colburn WA, Blue J, Przybelski RJ. Pharmacologic profile of diaspirin cross-linked hemoglobin in hemodialysis patients. American Journal of Kidney Diseases 1995;26(6):918-23. [MEDLINE: 7503066]
  • Swan SK, Halstenson CE, Collins AJ, Ellefson J, Parr K, Blue J, et al. Pharmacodynamic and pharmacokinetic parameters of diaspirin cross-linked hemoglobin (DCLHB) in hemodialysis (HD) patients [abstract]. ISN XIII International Congress of Nephrology; 1995 Jul 2-6; Madrid (Spain). 1995:559.
SYMPHONY II 2005 {published data only}
  • Reddan DN, Szczech L, Bhapkar MV, Moliterno DJ, Califf RM, Ohman EM, et al. Renal function, concomitant medication use and outcomes following acute coronary syndromes. Nephrology Dialysis Transplantation 2005;20(10):2105-12. [MEDLINE: 16030030]
SYMPHONY I Study 2000 {published data only (unpublished sought but not used)}
  • Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomised trial. The SYMPHONY Investigators. Sibrafiban versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes. Lancet 2000;355(9201):337-45. [MEDLINE: 10665552]
Trimarchi 2006 {published data only}
Van Der Zaag 2001 {published data only}
  • Van Der Zaag ES, Legemate DA, Tangelder MJ, Algra A, Lawson JA, Eikelboom BC. Prevention of occlusions after bypass surgery with anticoagulant agents or acetylsalicylic acid: a randomised comparison. Nederlands Tijdschrift voor Geneeskunde 2001;145(36):1765. [EMBASE: 2001320548]
Vienken 1996 {published data only}
  • Vienken JA. Thromboxane generation by dialysis membranes is controlled by aspirin administration [abstract]. Nephrology Dialysis Transplantation 1996;11:1472.
Yoshikawa 1999 {published data only}
  • Yoshikawa N, Ito H. Combined therapy with prednisolone, azathioprine, heparin-warfarin, and dipyridamole for paediatric patients with severe IgA nephropathy - is it relevant for adult patients?. Nephrology Dialysis Transplantation 1999;14(5):1097-9. [MEDLINE: 10344344]
Zibari 1995 {published data only}
  • Zibari GB, Gadallah MF, Landreneau MD, McMillian R, Bridges R, Costley K, et al. The efficacy and complications of aspirin versus heparin in postoperative prophylaxis against thrombosis in newly placed hemodialysis access [abstract]. Journal of the American Society of Nephrology 1995;6(3):507.

References to ongoing studies

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
FAVOURED Trial {published data only}
  • Irish A, Dogra G, Mori T, Beller E, Heritier S, Hawley C, et al. Preventing AVF thrombosis: the rationale and design of the Omega-3 fatty acids (Fish Oils) and Aspirin in Vascular access OUtcomes in REnal Disease (FAVOURED) study. BMC Nephrology 2009;10:1. [MEDLINE: 19159453]
  • Irish A, FAVOURED Study Group. High rate of screening failure in the FAVOURED study [abstract]. Nephrology 2009;14(Suppl 1):A45.
NCT01198379 {published data only}
  • Taipei Veterans General Hospital, Taiwan. Efficacy of monitoring of aspirin responsiveness in the prevention of cardiovascular events and decrease in bleeding complications in patients with end-stage kidney disease undergoing hemodialysis. Available at http://clinicaltrials.gov/ct2/show/NCT01198379 (accessed 12 November 2012).

Additional references

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Aakhus 1999
Amann 2003
Anavekar 2004
  • Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L. Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. New England Journal of Medicine 2004;351(13):1285-95. [MEDLINE: 15385655]
ANZDATA 2009
  • Australia, New Zealand Dialysis, Transplant Registry. The 32nd Annual Report 2009 Report - Data to 2008. http://www.anzdata.org.au/v1/report_2009.html (accessed 12 November 2012).
ATT 2002
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ATT 2009
  • Antithrombotic Trialists' (ATT) Collaboration. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009;373(9678):1849-60. [MEDLINE: 19482214]
AusDiab 2003
  • Chadban SJ, Briganti EM, Kerr PG, Dunstan DW, Welborn TA, Zimmet PZ, et al. Prevalence of kidney damage in Australian adults: The AusDiab kidney study. Journal of the American Society of Nephrology 2006;14(7 Suppl 2):S131-8. [MEDLINE: 12819318]
Berger 2003
  • Berger AK, Duval S, Krumholz HM. Aspirin, beta-blocker, and angiotensin-converting enzyme inhibitor therapy in patients with end-stage renal disease and an acute myocardial infarction. Journal of the American College of Cardiology 2003;42(2):201-8. [MEDLINE: 12875751]
Best 2008
  • Best PJ, Steinhubl SR, Berger PB, Dasgupta A, Brennan DM, Szczech LA, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. American Heart Journal 2008;155(4):687-93. [MEDLINE: 18371477]
Bonomini 1986
CARI 2000
  • Caring for Australasians with Renal Impairment (CARI). Vascular access. http://www.cari.org.au/dialysis_va_list_published.php (accessed 12 November 2012).
Casas 2005
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Coleman 2010
Collins 2003
Curtis 2005
de Jager 2009
  • de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA 2009;302(16):1782-9. [MEDLINE: 19861670]
Dikow 2005
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Higgins 2003
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Holden 2008
Kasiske 2000
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KDOQI 2005
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Keith 2004
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Koren-Morag 2006
Mann 2001
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McCullough 2002
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Mokdad 2003
Mosenkis 2004
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Norris 2006
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References to other published versions of this review

  1. Top of page
  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. Feedback
  13. What's new
  14. History
  15. Contributions of authors
  16. Declarations of interest
  17. Sources of support
  18. Differences between protocol and review
  19. Characteristics of studies
  20. References to studies included in this review
  21. References to studies excluded from this review
  22. References to ongoing studies
  23. Additional references
  24. References to other published versions of this review
Palmer 2012
  • Palmer SC, Di Micco L, Razavian M, Craig JC, Ravani P, Perkovic V, et al. Antiplatelet therapy to prevent hemodialysis vascular access failure: systematic review and meta-analysis. American Journal of Kidney Diseases 2013;61(1):112-22. [MEDLINE: 23022428]
Razavian 2010
  • Razavian M, Di Micco L, Palmer SC, Craig JC, Perkovic V, Zoungas S, et al. Antiplatelet agents for chronic kidney disease. Cochrane Database of Systematic Reviews 2010, Issue 11. [DOI: 10.1002/14651858.CD008834]