Antiplatelet agents for chronic kidney disease

  • Review
  • Intervention

Authors

  • Suetonia C Palmer,

    Corresponding author
    1. University of Otago Christchurch, Department of Medicine, Christchurch, New Zealand
    • 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.

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  • Lucia Di Micco,

    1. University of Naples "Federico II", Division of Nephrology, Naples, Italy
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  • Mona Razavian,

    1. The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia
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  • Jonathan C Craig,

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
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  • Vlado Perkovic,

    1. The George Institute for Global Health, Renal and Metabolic Division, Camperdown, NSW, Australia
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  • Fabio Pellegrini,

    1. Consorzio Mario Negri Sud, Unit of Biostatistics, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy
    2. IRCCS "Casa Sollievo della Sofferenza", Unit of Biostatistics, San Giovanni Rotondo (FG), Chieti, Italy
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  • Meg J Jardine,

    1. Concord Repatriation General Hospital, Department of Renal Medicine, Concord, NSW, Australia
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  • Angela C Webster,

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    3. The University of Sydney at Westmead, Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead, NSW, Australia
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  • Sophia Zoungas,

    1. Monash University, School of Public Health and Preventive Medicine, Monash Applied Research Stream, Clayton, VIC, Australia
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  • Giovanni FM Strippoli

    1. The University of Sydney, Sydney School of Public Health, Sydney, NSW, Australia
    2. The Children's Hospital at Westmead, Cochrane Renal Group, Centre for Kidney Research, Westmead, NSW, Australia
    3. University of Bari, Department of Emergency and Organ Transplantation, Bari, Italy
    4. Mario Negri Sud Consortium, Department of Clinical Pharmacology and Epidemiology, Santa Maria Imbaro, Italy
    5. Diaverum, Medical-Scientific Office, Lund, Sweden
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Abstract

Background

Antiplatelet agents are widely used to prevent cardiovascular events. The risks and benefits of antiplatelet treatment may be different in people with chronic kidney disease (CKD) for whom occlusive atherosclerotic events are less prevalent, and bleeding hazards might be increased.

Objectives

To summarise the effects of antiplatelet treatment (antiplatelet agent versus control or other antiplatelet agent) for the prevention of cardiovascular and adverse kidney outcomes in individuals with CKD.

Search methods

In January 2011 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Cochrane Renal Group's Specialised Register without language restriction.

Selection criteria

We selected randomised controlled trials of any antiplatelet treatment versus placebo or no treatment, or direct head-to-head antiplatelet agent studies in people with CKD. Studies were included if they enrolled participants with CKD, or included people in broader at-risk populations in which data for subgroups with CKD could be disaggregated.

Data collection and analysis

Two authors independently extracted data from primary study reports and any available supplementary information for study population, interventions, outcomes, and risks of bias. Risk ratios (RR) and 95% confidence intervals (CI) were calculated from numbers of events and numbers of participants at risk which were extracted from each included study. The reported RRs were extracted where crude event rates were not provided. Data was pooled using the random-effects model.

Main results

We included 50 studies, enrolling 27,139 participants; 44 studies (21,460 participants) compared an antiplatelet agent with placebo or no treatment, and six studies (5679 participants) directly compared one antiplatelet agent with another. Compared to placebo or no treatment, antiplatelet agents reduced the risk of myocardial infarction (17 studies; RR 0.87, 95% CI 0.76 to 0.99), but not all-cause mortality (30 studies; RR 0.93, 95% CI 0.81 to 1.06), cardiovascular mortality (19 studies; RR 0.89, 95% CI 0.70 to 1.12) or stroke (11 studies; RR 1.00, 95% CI 0.58 to 1.72). Antiplatelet agents increased the risk of major (27 studies; RR 1.33, 95% CI 1.10 to 1.65) and minor bleeding (18 studies; RR 1.49, 95% CI 1.12 to 1.97). In terms of dialysis access outcomes, antiplatelet agents reduced access thrombosis or patency failure but had no effect on suitability for dialysis. Meta-regression analysis indicated no differences in the relative benefit or harms of treatment (risk of all-cause mortality, myocardial infarction, or major bleeding) by type of antiplatelet agent or stage of CKD. Limited data were available for direct head-to-head comparisons of antiplatelet drugs, treatment in kidney transplant recipients, primary prevention, or risk of ESKD.

Authors' conclusions

Antiplatelet agents reduce myocardial infarction but increase major bleeding. Risks may outweigh benefits among people with low annual risks of cardiovascular events, including those with early stages of CKD who do not have clinically-evident occlusive cardiovascular disease.

Plain language summary

Are anti-blood clotting drugs beneficial for people with chronic kidney disease?

People with chronic kidney disease (CKD) have an increased risk of heart disease that can block blood supply to the heart or brain causing heart attack or stroke. Drugs that prevent blood clots forming (antiplatelet agents) can prevent deaths caused by clots in arteries in the general adult population. However, there may be fewer benefits for people who have CKD, because blood clots in arteries is a less common cause of death or reason to be admitted to hospital compared with heart failure or sudden death in these people. People with CKD also have an increased tendency for bleeding due to changes in blood clotting mechanisms. Antiplatelet agents may therefore be more hazardous when CKD is present. This review evaluated the benefits and harms of antiplatelet agents to prevent cardiovascular disease and death, and improve dialysis vascular access function in people who have CKD. We identified 44 studies comparing antiplatelet agents with placebo or no treatment and six studies directly comparing one antiplatelet agent with another.

Antiplatelet agents prevent heart attack, but not death or stroke, and increase major and minor bleeding in people with CKD. Dialysis access (fistula or Gortex graft) is maintained with antiplatelet treatment, but antiplatelet drugs do not clearly improve fistula maturation or suitability for dialysis. Benefits (fewer deaths and heart attacks) and harms (bleeding) occur irrespective of the stage of CKD or type of antiplatelet used. More studies of anti-blood clotting drugs are needed in people who have CKD, especially in those who have received kidney transplants. We also need studies that compare one anti-clotting drug versus another, particularly newer drugs, and that determine the best treatment for people with both CKD and acute cardiovascular disease and that assess treatment to improve maturation of dialysis vascular access.

Background

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

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

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).

Table 1. Levels of quality of the body of evidence using the GRADE approach
Underlying methodology Quality rating
RCTs, or double-upgraded observational studiesHigh
Downgraded RCTs, or upgraded observational studiesModerate
Double-downgraded RCTs, or observational studiesLow
Triple-downgraded RCTs, or downgraded observational studies; or case series/case reportsVery low
Factors that may decrease the quality of a body of evidence
1. Limitations in the design and implementation of available studies suggesting high likelihood of bias
2. Indirectness of evidence (indirect population, intervention, control, outcomes)
3. Unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses)
4. Imprecision of results (wide confidence intervals)
5. High probability of publication bias
Table 2. Summary of outcomes for antiplatelet medication versus placebo/no treatment
  1. *There were no significant differences among antiplatelet types in any of the reported outcomes listed.

OutcomeAspirin: RR (95% CI)Thienopyridines: RR (95% CI)Glycoprotein IIb/IIIa inhibitors: RR (95% CI)All medications: RR (95% CI)*
Fatal or nonfatal myocardial infarction0.68 (0.46 to 0.99)0.83 (0.57 to 1.21)0.93 (0.81 to 1.07)0.87 (0.76 to 0.99)
All-cause death0.88 (0.61 to 1.27)1.10 (0.80 to 1.51)0.83 (0.60 to 1.16)0.95 (0.83 to 1.07)
Major bleeding1.37 (0.71 to 2.55)1.27 (0.85 to 1.91)1.45 (1.04 to 2.04)1.35 (1.10 to 1.65)

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

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).

Figure 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.

Figure 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).

Figure 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

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

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.

Table 3. Evidence ratings and recommendations for antiplatelet agents to prevent cardiovascular and dialysis access outcomes in people with chronic kidney disease
  1. ¹Evidence rating based on number of studies, study design, study quality, and consistency of results.
    ²Recommendation based on efficacy, trade-offs between benefits and harms, and quality of evidence.
    I, recommend; II, suggest; III, no recommendation.

  Overall evidence rating¹   Recommendation² 
Intervention High Moderate Low Comment I II III Comment
Cardiovascular outcomes (mortality and myocardial infarction)
Antiplatelet versus placebo or no treatment  17 RCTs for myocardial infarction, 30 RCTs for all-cause mortality, no heterogeneity, moderate methodological quality  No effect on mortality, moderate effect on myocardial infarction, bleeding harms evident. Risks probably outweigh harms in people with a low annual risk of myocardial infarction
Thienopyridine versus clopidogrel  2 RCTs, high levels of heterogeneity, good methodological quality, post-hoc analyses of larger studies  Undetermined effect, potential for harm
Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor  1 RCT, good methodological quality, post hoc analysis of larger studies  Undetermined effect, potential for harm
Vascular access outcomes
Antiplatelet versus placebo or no treatment  17 RCTs for patency, 5 RCTs for suitability for dialysis  Large effect size on patency preservation with short-term use, imprecise effect on access maturation, bleeding harms documented
Thienopyridine versus clopidogrel  No RCTs  Undetermined effect, potential for harm
Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor  No RCTs  Undetermined effect, potential for harm

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.

Table 4. Absolute risks of antiplatelet treatment on myocardial infarction, vascular access thrombosis, and bleeding
  1. Calculated on summary estimates of RR (0.87 for myocardial infarction and 1.35 for major bleeding).
    *Annual risk of bleeding was estimated to be 2.5% per year irrespective of cardiovascular risk (Holden 2008). Low cardiovascular risk would include individuals with chronic kidney disease (CKD) without clinical evidence for cardiovascular disease (Weiner 2006). Intermediate cardiovascular risk would include individuals with CKD and pre-existing cardiovascular disease and individuals requiring dialysis (Anavekar 2004; Weiner 2006). High cardiovascular risk would include individuals with CKD and recent myocardial infarction or other acute cardiovascular event (Anavekar 2004). *Vascular access outcomes are per six months of antiplatelet treatment and the absolute risk is based on data from the control group in the present review.

Cardiovascular risk groupMyocardial infarction preventedVascular access thrombosis or patency failure prevented*Major bleeding incurred
Low risk (2%/year)2/1000-7/1000
Intermediate risk (10% risk/year)13/1000-7/1000
High risk (25% risk/year)32/1000200/10007/1000

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. 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

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 Fistula71502Risk Ratio (IV, Random, 95% CI)0.56 [0.40, 0.78]
15.2 Shunt/graft51052Risk Ratio (IV, Random, 95% CI)0.80 [0.62, 1.03]
15.3 Fistula or graft116Risk Ratio (IV, Random, 95% CI)0.50 [0.06, 4.47]
15.4 Catheter138Risk 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]
Analysis 1.1.

Comparison 1 Antiplatelet agents versus control, Outcome 1 Fatal or nonfatal myocardial infarction.

Analysis 1.2.

Comparison 1 Antiplatelet agents versus control, Outcome 2 Fatal or nonfatal stroke.

Analysis 1.3.

Comparison 1 Antiplatelet agents versus control, Outcome 3 Haemorrhagic stroke.

Analysis 1.4.

Comparison 1 Antiplatelet agents versus control, Outcome 4 All-cause mortality.

Analysis 1.5.

Comparison 1 Antiplatelet agents versus control, Outcome 5 Cardiovascular mortality.

Analysis 1.6.

Comparison 1 Antiplatelet agents versus control, Outcome 6 Fatal bleeding.

Analysis 1.7.

Comparison 1 Antiplatelet agents versus control, Outcome 7 Major bleeding.

Analysis 1.8.

Comparison 1 Antiplatelet agents versus control, Outcome 8 Minor bleeding.

Analysis 1.9.

Comparison 1 Antiplatelet agents versus control, Outcome 9 End-stage kidney disease.

Analysis 1.10.

Comparison 1 Antiplatelet agents versus control, Outcome 10 Doubling of serum creatinine.

Analysis 1.11.

Comparison 1 Antiplatelet agents versus control, Outcome 11 Kidney transplant graft loss.

Analysis 1.12.

Comparison 1 Antiplatelet agents versus control, Outcome 12 Transplant rejection.

Analysis 1.13.

Comparison 1 Antiplatelet agents versus control, Outcome 13 End of treatment creatinine clearance.

Analysis 1.14.

Comparison 1 Antiplatelet agents versus control, Outcome 14 End of treatment proteinuria.

Analysis 1.15.

Comparison 1 Antiplatelet agents versus control, Outcome 15 Dialysis access failure (thrombosis or loss of patency).

Analysis 1.16.

Comparison 1 Antiplatelet agents versus control, Outcome 16 Early access thrombosis (before 8 weeks).

Analysis 1.17.

Comparison 1 Antiplatelet agents versus control, Outcome 17 Loss of primary unassisted patency.

Analysis 1.18.

Comparison 1 Antiplatelet agents versus control, Outcome 18 Failure to attain suitability for dialysis.

Analysis 1.19.

Comparison 1 Antiplatelet agents versus control, Outcome 19 Need for intervention to attain patency or assist maturation.

Analysis 1.20.

Comparison 1 Antiplatelet agents versus control, Outcome 20 All-cause hospitalisation.

Analysis 1.21.

Comparison 1 Antiplatelet agents versus control, Outcome 21 Cardiovascular hospitalisation.

Analysis 1.22.

Comparison 1 Antiplatelet agents versus control, Outcome 22 Treatment withdrawal.

Comparison 2. Thienopyridine versus clopidogrel
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Fatal or nonfatal myocardial infarction1 Risk Ratio (IV, Random, 95% CI)Totals not selected
2 All-cause mortality1 Risk Ratio (IV, Random, 95% CI)Totals not selected
3 Cardiovascular mortality1 Risk Ratio (IV, Random, 95% CI)Totals not selected
4 Major bleeding1 Risk Ratio (IV, Random, 95% CI)Totals not selected
5 Minor bleeding1 Risk Ratio (IV, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Thienopyridine versus clopidogrel, Outcome 1 Fatal or nonfatal myocardial infarction.

Analysis 2.2.

Comparison 2 Thienopyridine versus clopidogrel, Outcome 2 All-cause mortality.

Analysis 2.3.

Comparison 2 Thienopyridine versus clopidogrel, Outcome 3 Cardiovascular mortality.

Analysis 2.4.

Comparison 2 Thienopyridine versus clopidogrel, Outcome 4 Major bleeding.

Analysis 2.5.

Comparison 2 Thienopyridine versus clopidogrel, Outcome 5 Minor bleeding.

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 myocardial1 Risk Ratio (IV, Random, 95% CI)Totals not selected
2 All-cause mortality1 Risk Ratio (IV, Random, 95% CI)Totals not selected
Analysis 3.1.

Comparison 3 Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor, Outcome 1 Fatal or nonfatal myocardial.

Analysis 3.2.

Comparison 3 Glycoprotein IIb/IIIa inhibitor versus glycoprotein IIb/IIIa inhibitor, Outcome 2 All-cause mortality.

Appendices

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 bias Assessment 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

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

DateEventDescription
9 July 2013AmendedFeedback and reply incorporated

History

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. 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

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

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

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

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Abdul-Rahman 2007

Methods
  • Study design: no treatment RCT

  • Study duration: 12 months

  • Lost to follow-up: 0

Participants
  • Country: Saudi Arabia

  • Setting: Hospital

Inclusion criteria

  • Haemodialysis patients with tunnelled central venous catheter

  • Treatment group 1: number (19); age (44.7 ± 7.4 years); M/F (9/10)

  • Treatment group 2: number (20); age (48.3 ± 11.5 years); M/F (8/12)

  • Control group: number (19); age (45.4 ± 9.5 years); M/F (7/12)

Exclusion criteria

  • Blood loss requiring either hospitalisation or transfusion in previous 3 months; demonstrated advanced proliferative diabetic retinopathy; life expectancy < 12 months because of advanced organ-systemic disease or malignancy; uncontrolled hypertension (systolic BP, BP, > 200 mm Hg or diastolic BP > 110 mm Hg on 3 different occasions in a period of 2 weeks); platelet count < 100,000/cm³, INR > 1.3, or partial thromboplastin time 5 sec longer than control; medical conditions that would make anticoagulant or antiplatelet therapy dangerous; receiving dipyridamole, sulphinpyrazone, ticlopidine, clopidogrel, or nonsteroidal anti-inflammatory drugs

Interventions

Treatment group 1

  • Aspirin

  • Dose, duration, frequency, administration: 81 mg/d for 12 months

Treatment group 2

  • Warfarin

  • Dose, duration, frequency, administration: 2-5 mg/d for 12 months, adjusted dose targeting adjusted international normalised ratio of 1.5 to 2.0

Control group

  • No treatment

Outcomes
  • Haemodialysis tunnelled catheter thrombosis

  • Major bleeding event, defined as confirmed retroperitoneal, intra-articular or cerebral haemorrhage, or any bleeding episode that resulted in a 2 g/dL decrease in Hb concentration

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk

Quote: "Neither the details of the randomisation sequence nor the identity of the medication assignment was known to the participants or the assigned physician."

Comment: No information provided

Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Low risk

Quote: "Neither the details of the randomisation sequence nor the identity of the medication assignment was known to the participants or the assigned physician...The presence of catheter thrombosis was determined by a staff member blinded to the treatment"

Comment: Insufficient information, no information about placebo

Incomplete outcome data (attrition bias)
All outcomes
Low riskNo losses to follow-up
Selective reporting (reporting bias)Unclear riskNo prespecified outcomes in the protocol
Other biasUnclear riskInsufficient information

Anderson 1974

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 24 months

  • Lost to follow-up: 0

Participants
  • Country: Great Britain

  • Setting: Hospital

Inclusion criteria

  • Kidney transplant (living and cadaver donor) patients

  • Treatment group: number (15); age (NS); sex (NS)

  • Control group: number (12); age (NS); sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Dipyridamole

  • Dose, duration, frequency, administration: initially given 1 mg/kg/d iv, then 600 mg/d for 24 months

Control group

  • Placebo

  • Dose, duration, frequency, administration: NS

Outcomes
  • Rejection

  • Graft loss

  • End of treatment SCr

  • End of treatment CrCl

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskPharmacy-controlled randomisation
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
High riskData missing without reason
Selective reporting (reporting bias)Unclear riskInsufficient information
Other biasUnclear riskInsufficient information

Andrassy 1974

Methods
  • Study design: RCT

  • Study duration: 1 month

  • Loss to follow-up: All patients included in analyses

Participants
  • Country: Germany

  • Setting: 5 university hospitals

Inclusion criteria

  • ESKD

  • Treatment group: number (45); age (NS); sex (NS)

  • Control group: number (47); age (NS); sex (NS)

Exclusion criteria: Not clear

Interventions

Treatment group

  • Aspirin

  • Dose, duration, frequency, administration: 1 g microencapsulated 1 day prior to access surgery, on day of surgery, and subsequently every other day until the 28th day after surgery

Control group

  • Placebo

Outcomes
  • Fistula function

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Low riskIndependent statistician
Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnclear
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll participants were accounted for
Selective reporting (reporting bias)Unclear riskInsufficient information
Other biasUnclear riskInsufficient information

CHARISMA Study 2009

Methods
  • Study design: placebo controlled RCT (post hoc analysis)

  • Study duration: 28 months (median), range 18 to 42 months

  • Lost to follow-up: 0.4% (in the main study)

Participants
  • Country: International

  • Setting: Multicentre

Inclusion criteria

  • Age ≥ 45 years and one of the following conditions: multiple atherothrombotic risk factors (type 1 or 2 diabetes with drug therapy, diabetic kidney disease, ankle-brachial index < 0.9, asymptomatic carotid stenosis ≥ 70% of luminal diameter, ≥ 1 carotid plaque as evidenced by intima-media thickness, systolic BP ≥ 150 mm Hg, despite the therapy for at least 3 months, primary hypercholesterolaemia, current smoking > 15 cigarettes/d, male sex and age ≥65 years or female sex and age ≥ 70 years), documented coronary disease (angina with documented multivessel coronary disease, history of multivessel percutaneous coronary intervention, history of multivessel coronary-artery bypass grafting, myocardial infarction), documented cerebrovascular disease (transient ischaemic attack during previous 5 years, ischaemic stroke during previous 5 years), or documented symptomatic peripheral arterial disease (current intermittent claudication and previous intervention; e.g. amputation, peripheral bypass, or angioplasty) (Inclusion criteria of the main study); only patients with diabetic kidney disease were included in the post hoc analysis of the study

  • Treatment group: number (1006); age (63.1 years); M/F (661/345)

  • Control group: number (1003); age (63 years); M/F (677/326)

Exclusion criteria:

  • Oral antithrombotic medications or nonsteroidal anti-inflammatory drugs on a long term basis (although cyclooxygenase-2 inhibitors were permitted); established indications for clopidogrel therapy (such as a recent acute coronary syndrome); scheduled to undergo a revascularisation were not allowed to enrol until the procedure had been completed; such patients were excluded if they were considered to require clopidogrel after revascularisation

Interventions

Treatment group

  • Clopidogrel + aspirin

  • Dose, duration, frequency, administration

    • Clopidogrel: 75 mg/d for 18 to 42 months

    • Aspirin: 75 to 162 mg/d for 18 to 42 months

Control group

  • Clopidogrel placebo + aspirin

  • Dose, duration, frequency, administration

    • Clopidogrel placebo: 1 tablet/d for 18 to 42 months

    • Aspirin: 75 to 162 mg/d for 18 to 42 months

Outcomes

Primary endpoints

  • Occurrence of myocardial infarction, stroke (of any cause), or death from cardiovascular causes (including haemorrhage)

Primary safety end point

  • Severe bleeding, according to the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) definition, which includes fatal bleeding and intracranial haemorrhage, or bleeding that caused haemodynamic compromise requiring blood or fluid replacement, inotropic support, or surgical intervention

  • Moderate bleeding according to the GUSTO criteria (bleeding that led to transfusion but did not meet the criteria for severe bleeding);

  • Fatal bleeding

  • Primary intracranial haemorrhage

Secondary endpoints

  • First occurrence of myocardial infarction, stroke, death from cardiovascular cause, or hospitalisation for unstable angina, a transient ischaemic attack, or a revascularisation procedure (coronary, cerebral, or peripheral)

  • Death from any cause and death from cardiovascular causes as well as myocardial infarction, ischaemic stroke, any stroke, and hospitalisation for unstable angina, transient ischaemic attack, or revascularisation, considered separately

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSequence generation based on a pre-established randomisation scheme
Allocation concealment (selection bias)Low riskStudy-drug assignment performed centrally by an interactive voice-response system
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of patients and investigators, including blinding of outcomes assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow risk
Selective reporting (reporting bias)Low riskThe study protocol is available and all of the study's pre-specified outcomes that are of interest in the review have been reported in the pre-specified way
Other biasLow riskThe CHARISMA study was supported by the Sanofi Aventis, Bridgewater, New Jersey/Bristol-Myers Squibb, New York, New York, partnership

Cheng 1998

Methods
  • Study design: RCT

  • Study duration: 54 (26 to 56) (median and range) months

  • Lost to follow-up: 5.6%

Participants
  • Country: China

  • Setting: Hospital

Inclusion criteria

  • 21 to 65 years of age, with biopsy proven IgAN and at least 2 features suggestive of progressive disease, namely, proteinuria persistently above 1g/d, mean arterial BP persistently > 107 mm Hg, kidney impairment (SCr > 0.12 but ˜0.4 mmol/L) and the presence of tubulointerstitial scarring, tubular atrophy and global or segmental glomerulosclerosis on initial kidney biopsy

  • Treatment group: number (19); age (38.5 ± 8.7 years); M/F (9/10)

  • Control group: number (12); age (37.2 ± 7.0 years); M/F (8/4)

Exclusion criteria

  • Past history of myocardial infarction or stroke; resting MBP < 80 mm Hg; previous history of allergy or intolerance to nadolol, captopril and ticlopidine

Interventions

Treatment group

  • Captopril + ticlopidine

  • Dose, duration, frequency, administration

    • Captopril: starting dose 6.25 mg twice/d for a median time of 54 months

    • Ticlopidine: 250 mg twice/d for a median of 54 months

Control group

  • Captopril

  • Dose, duration, frequency, administration: starting dose was 6.25 mg twice/d for a median of 54 months

Outcomes
  • Urinary protein and albumin excretion

  • Doubling of SCr levels

  • ESKD

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for missing outcome data unlikely to be related to true outcome
Selective reporting (reporting bias)High riskReporting of one of primary outcome (doubling of SCr) is unclear so that it cannot be entered in a meta-analysis
Other biasUnclear riskInsufficient information

CREDO Study 2008

Methods
  • Study design: placebo-controlled RCT (post hoc analysis)

  • Study duration: 1 year

  • Lost to follow-up: 4%

Participants
  • Country: US/Canada

  • Setting: Multicentre

Inclusion criteria

  • Symptomatic coronary artery disease with objective evidence of ischaemia (e.g., symptoms of angina pectoris, positive stress test results, or dynamic electrocardiographic [ECG] changes); were referred for PCI, or thought to be at high likelihood for requiring PCI with either stent placement with or without conventional balloon angioplasty or another revascularization device; were at least 21 years old; provided informed consent before randomisation; and agreed to comply with all protocol-specified procedures.

  • Treatment group: number (203); GFR < 60 mL/min; age (NS); sex (NS)

  • Control group: number (208); GFR < 60 mL/min; age (NS); sex (NS)

Exclusion criteria:

  • Contraindications to antithrombotic/antiplatelet therapy; > 50% stenosis of the left main coronary artery; failed coronary intervention in the previous 2 weeks; coronary anatomy not amenable to stent placement; persistent ST elevation within 24 hours prior to randomisation; planned staged interventional procedure; and administration of the following medications prior to randomisation: GpIIb-IIIa inhibitor within 7 days, clopidogrel within 10 days, or thrombolytics within 24 hours

Interventions

Treatment group

  • Clopidogrel + aspirin

  • Dose, duration, frequency, administration

    • Clopidogrel: loading dose of clopidogrel 300 mg (prior to PCI) followed by 75 mg/d for 1 year

    • Aspirin: 325 mg/d for the first 28 days then 81 to 325 mg/d for 1 year

Control group

  • Placebo + aspirin

  • Dose, duration, frequency, administration

    • Matching placebo (prior to PCI), then clopidogrel for 28 days followed by matching placebo until the end of 12 months period

    • Aspirin: 325 mg/d for the first 28 days then 81 to 325 mg/d for 1 year

Outcomes

Primary endpoints

  • Composite of death, MI, and stroke in the intent-to-treat population at 1 year

  • Individual components of the composite endpoints (pre-specified secondary analyses)

  • Need for target vessel revascularisation or any revascularisation at 1 year

Secondary endpoints

  • Major bleeding events and of early discontinuation of study drugs at 28 days and 1 year. Bleeding was defined as major, minor, or insignificant using a modification of the Thrombolysis in Myocardial Infarction (TIMI) bleeding criteria

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPatients were randomly assigned to groups using a prospective randomisation schedule. The randomisation was performed in blocks of two and stratified by centre. When a patient was ready to be randomised, the site dispensed a drug package that contained a unique 4-digit random number; this number was entered on the case report form and provided an identifier of the treatment assigned
Allocation concealment (selection bias)Low riskOn randomisation, the site dispensed a drug package that contained a unique 4-digit number; this number was entered on the case report form and provided an identifier of the treatment assigned
Blinding (performance bias and detection bias)
All outcomes
Low riskThe study was conducted on a double-blind basis: investigators were blind to treatment allocation from randomisation until the end of the study period
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients included in intention-to-treat and safety analysis
Selective reporting (reporting bias)Low riskOutcomes were reported in pre-specified manner
Other biasLow riskNo other risks

Creek 1990

Methods
  • Study design: RCT

  • Study duration: 5 months

  • Lost to follow-up: No information available

Participants
  • Country: NS

  • Setting: NS

Inclusion criteria

  • Haemodialysis patients

  • Treatment group: number (144); age (NS); sex (NS)

  • Control group: number 141 patients; age (NS); sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 500 mg/d for 5 months

Control group

  • NS

  • Dose, duration, frequency, administration: NS

Outcomes
  • All-cause mortality

  • Cardiovascular mortality

  • Myocardial infarction

  • Stroke

  • Major bleeding

NotesPublished in an earlier meta-analysis ATT 2002
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available
Allocation concealment (selection bias)Unclear riskNo information available
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information available
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information available
Selective reporting (reporting bias)Unclear riskNo information available
Other biasHigh riskFull study report not available

CURE Study 2007

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 12 months

  • Lost to follow-up: 0.1% (6 patients in the clopidogrel group and 7 in the placebo group)

Participants

Country: 28 countries

Setting: 482 centres

Inclusion criteria

  • Patients were included in the study if they had been hospitalised within 24 hours of onset of symptoms, had positive troponin or creatine kinase-MB levels, or ischaemic changes on electrocardiogram, other than ST-segment elevation ≥ 2 mm. A total of 4087 individuals in the study who had an eGFR < 64 mL/min were included in the systematic review. The numbers of individuals in each treatment group were not reported.

Overall: number (4087); age (69.6 ± 9.9 years); M/F (1994/2093)

Exclusion criteria

  • Contraindications to antithrombotic or antiplatelet therapy; high risk for bleeding; administration of oral anticoagulants; coronary revascularisation in the previous 3 months; administration of IV glycoprotein IIb/IIIa inhibitors in the previous 3 days; planned long-term (> 3 months) administration of a non-steroid anti-inflammatory medication; impaired kidney function was not an exclusion criterion but no patients with ESKD were randomised

Interventions

Treatment group

  • Clopidogrel + aspirin

  • Dose, duration, frequency, administration

    • Clopidogrel: 300 mg loading followed by 75 mg/d for 3 to 12 months (mean duration 9 months)

    • Aspirin: 75–325 mg once/d

Control group

  • Placebo + aspirin

  • Dose, duration, frequency, administration

    • Matching placebo loading followed by matching placebo for 3 to 12 months (mean duration 9 months)

    • Aspirin: 75–325 mg once/d

Outcomes

Primary outcome

  • Composite of cardiovascular death, non-fatal myocardial infarction, or stroke

Safety related outcomes

  • Life-threatening, major (requiring transfusion of ≥ 2 units of blood) or minor bleeds

Secondary outcome

  • Need for revascularisation

Notes.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskPermuted-block, computerised randomisation, stratified according to clinical centre
Allocation concealment (selection bias)Low riskCentral, 24-hour, computerised randomisation service
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blinded, data assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk0.1% were lost to follow-up
Selective reporting (reporting bias)Low riskAll outcomes reported
Other biasLow riskThe CURE study was supported by Sanofi-Synthelabo and Bristol-Meyers Squibb. The study was designed and coordinated and data were analysed independently by an international steering committee and the Canadian Cardiovascular Collaboration Project Office at Hamilton, Ontario, Canada

Dember 2008

Methods
  • Study design: placebo controlled RCT

  • Study duration: 71 days

  • Lost to follow-up: 3.1%

Participants
  • Country: US

  • Setting: multicentre (9)

Inclusion criteria

  • Individuals undergoing creation of a new upper extremity fistula were eligible for enrolment if they were receiving maintenance treatment with haemodialysis or were expected to begin maintenance haemodialysis within 6 months

  • Treatment group: number (441); age (52.7 ± 14.7 years); M/F (273/168)

  • Control group: number (436); age (54.5 ± 14.4 years); M/F(275/161)

Exclusion criteria

  • Active bleeding or bleeding events requiring red blood cell transfusions within the previous 12 weeks; platelet count > 75,000/μL; known coagulopathy; acute ulcer disease; systolic BP > 200 mm Hg or diastolic BP > 115 mm Hg; advanced liver disease; inability to discontinue antiplatelet or anticoagulant therapy including aspirin during the study drug administration period; pregnancy; current substance abuse

Interventions

Treatment group

  • Clopidogrel

  • Dose, duration, frequency, administration: loading dose of 300 mg on day 1 followed by 75 mg/d for 6 weeks

Control group

  • Placebo

  • Dose, duration, frequency, administration: matching placebo taken once/d for 6 weeks

Outcomes
  • Thrombosis (fistula patency) 6 weeks after fistula creation

  • Failure to attain suitability for dialysis (fistula suitability was defined as the ability to use the fistula for dialysis with 2 needles and maintain a dialysis machine blood flow rate adequate for optimal dialysis (300 mL/min) during 8 of 12 dialysis sessions occurring during a 30-day suitability ascertainment period)

  • Fatal, life-threatening, intermediate, major and minor bleeding

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated permuted block randomisation with stratification by location of the fistula (forearm vs upper arm) and by centre"
Allocation concealment (selection bias)Unclear risk"Randomisation is performed after surgery following confirmation of fistula creation by the clinical center study team"
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"Participants and members of the study team were blinded to treatment assignment". Unclear whether outcome assessors were blinded
Incomplete outcome data (attrition bias)
All outcomes
Low risk3.1% were lost to follow-up. Missing outcome data balanced in numbers across groups, with similar reasons across groups
Selective reporting (reporting bias)Low riskThe study protocol is available and the study's prespecified outcomes have been reported in the pre-specified way
Other biasHigh riskThe study was terminated early by the Data Safety Monitoring Board based in the prespecified stopping rule for efficacy of the intervention of the primary endpoint

Dixon 2009

Methods
  • Study design: placebo controlled RCT

  • Study duration: 5 years and 1 month (4.5 years for recruitment + 6 additional months of follow-up)

  • Lost to follow-up: 12% (before the primary outcome was reached), additional 30.5% before the secondary outcome was reached)

Participants
  • Country: US

  • Setting: multicentre (13)

Inclusion criteria

  • Patients at least 18 years old scheduled to have a new arteriovenous graft placed for the purpose of haemodialysis and patients currently undergoing long-term haemodialysis or expected to undergo it within 6 months after randomisation

  • Treatment group: number (321); age (59.1 ± 13.5 years); M/F (132/189)

  • Control group: number (328); age (57.5 ± 14.9 years); M/F (125/203)

Exclusion criteria

  • Pregnancy or breast-feeding; increased risk of bleeding or a known bleeding disorder; active oesophagitis, gastritis, or peptic ulcer disease; a platelet count < 75,000/mm³; advanced liver disease; patients requiring an anticoagulant or antiplatelet agent other than aspirin; patients with a known allergy or adverse reaction to extended-release dipyridamole + aspirin or with uncontrolled hypertension

Interventions

Treatment group

  • Dipyridamole + aspirin

  • Dose, duration, frequency, administration

    • Extended-release dipyridamole 200 mg + immediate-release aspirin 25 mg, twice/d until the occurrence of the primary outcome (4.5 years + 6 additional months of follow-up)

    • Aspirin: one capsule

Control group

  • Placebo

  • Dose, duration, frequency, administration: one identical-looking placebo capsule, twice/d, until the occurrence of the primary outcome (4.5 years + 6 additional months of follow-up)

Outcomes

Primary outcome

  • Loss of primary unassisted graft patency defined as first occurrence of graft thrombosis

Secondary outcome

  • Death from any cause

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was stratified according to clinical center and access location (forearm or alternative site) with the use of a random permuted-block design"
Allocation concealment (selection bias)Low risk"Randomization is performed centrally via the Internet using a Web browser following verification of eligibility by the Data Coordinating Center (Cleveland Clinic)"
Blinding (performance bias and detection bias)
All outcomes
Low riskStudy personnel and patients were unaware of the treatment assignments
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients accounted for
Selective reporting (reporting bias)Low riskThe study protocol is available and the study's pre-specified outcomes have been reported in the pre-specified way
Other biasUnclear riskInsufficient data

Dodd 1980

Methods

Study design: RCT

Study duration: one month

Loss to follow-up: unclear

Participants
  • Country: UK

  • Setting: University hospital centre

Inclusion criteria

  • Poorly described; individuals with A-V shunts

  • Uncertain number of patients enrolled

  • Number of patients included in treatment and control groups: NS

  • Age and sex: NS

Exclusion criteria: NS

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 250 mg twice/d

Control group

  • Matching placebo

Outcomes
  • Fistula function

NotesAbstract only. Limited data available. Not included in meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskAbstract only data
Allocation concealment (selection bias)Unclear riskAbstract only data
Blinding (performance bias and detection bias)
All outcomes
Low riskAbstract only data
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskAbstract only data
Selective reporting (reporting bias)Unclear riskAbstract only data
Other biasHigh riskAbstract only data

Donadio 1984

Methods
  • Study design: Placebo-controlled RCT

  • Study duration: 12 months

  • Lost to follow-up: 20%

Participants
  • Country: US

  • Setting: Hospital

Inclusion criteria

  • Biopsy proven MPGN

  • Treatment group: number (25); age (32 years); 52.4% male

  • Control group: number (25); age (29 years); 63.2% male

Exclusion criteria

  • Systemic lupus erythematosus; essential mixed cryoglobulinaemia; poststreptococcal GN; requirement of dialysis

Interventions

Treatment group

  • Dipyridamole + aspirin

  • Dose, duration, frequency, administration

    • Dipyridamole: 75 mg 3 times/d for one year

    • Aspirin: 325 mg 3 times/ d for one year

Control group

  • Placebo

  • Dose, duration, frequency, administration: 3 tablets/d for one year

Outcomes
  • Loss of kidney function (defined as a decline of 25% or more in iothalamate clearance from the pretreatment clearance)

  • Proteinuria

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Treatment was assigned randomly by our statistician in such a manner to achieve maximal balance between the two stratification factors"
Allocation concealment (selection bias)Low risk"Treatment assignment was communicated to a pharmacist, who dispensed the medicines to the patient"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blinding. "Patients were informed of their treatment assignment after one year." Blinding of investigators and outcome assessors unclear
Incomplete outcome data (attrition bias)
All outcomes
High risk

10/50 participants not included in analyses (20%)

 

Selective reporting (reporting bias)Unclear riskNo prespecified outcomes
Other biasUnclear riskInsufficient information

Ell 1982

Methods
  • Study design: RCT

  • Study duration: 3 months

  • Lost to follow-up: no information available

Participants
  • Country: No information available

  • Setting: No information available

Inclusion criteria

  • Haemodialysis patients

  • Number: treatment group (24); control group (26)

  • Age: NS

  • Sex: NS

Exclusion criteria: No information available

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 500 mg/d for 3 months

Control group

  • NS

  • Dose, duration, frequency, administration: NS

Outcomes
  • All-cause mortality

  • Cardiovascular mortality

  • Myocardial infarction

  • Stroke

  • Major bleeding

NotesPublished results from an earlier systematic review ATT 2002
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available
Allocation concealment (selection bias)Unclear riskNo information available
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information available
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information available
Selective reporting (reporting bias)Unclear riskNo information available
Other biasHigh riskFull study report not available

EPIC Study 1994

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 1 year

  • Lost to follow-up: 0

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Patients scheduled to undergo coronary angioplasty or directional atherectomy with high risk for abrupt vessel closure

  • Treatment group : number (334); age (NS); sex (NS)

  • Control group 1: number (185); age (60 years); sex (72% male)

Exclusion criteria

  • Age > 80 years; bleeding diathesis; major surgery within the preceding 6 weeks; stroke within the preceding 2 years

Interventions

Treatment group

  • c7E3 Fab

    • Dose, duration, frequency, administration: bolus dose of 0.25 mg/kg, followed by an infusion of 10 μg/min

  • Aspirin

    • Dose, duration, frequency, administration: 325 mg/d; at least 2 hours before angioplasty or atherectomy and daily after

  • Heparin

    • Dose, duration, frequency, administration: 10,000 to 12,000 U iv as bolus, followed by incremental bolus of up to 3000 U at 15 minutes intervals, but no more than 20,000 U during the procedure. Heparin was continued by constant infusion for at least 12 hours

Control group

  • Placebo bolus

Placebo infusion

  • Aspirin (as above)

  • Heparin (as above)

Outcomes
  • Composite of death from any cause, nonfatal myocardial infarction, coronary artery bypass grafting or repeat percutaneous intervention for acute ischaemia, and insertion of a coronary endovascular stent because of procedural failure or placement of an intra-aortic counter-pulsation balloon pump to relieve refractory ischaemia. Other components of the primary outcome were an unplanned repeat angioplasty to treat recurrent ischaemia, urgent coronary surgery to treat recurrent ischaemia or failure of an angioplasty, placement of an intracoronary stent to treat imminent or complete abrupt closure of the vessel undergoing angioplasty, and placement of an intra-aortic balloon pump for recurrent ischaemia when a repeat revascularisation procedure was contraindicated

  • Major, minor or insignificant bleeding events (according to TIMI criteria)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskCentral randomisation by telephone.
Blinding (performance bias and detection bias)
All outcomes
Low riskOutcomes assessors blinded: "Events were classified by...at least 2 members...blinded to the patients treatment"
Incomplete outcome data (attrition bias)
All outcomes
Low riskData available for all baseline participants
Selective reporting (reporting bias)Low riskThe study protocol is available and the study's prespecified outcomes have been reported in the pre-specified way
Other biasLow riskNo other biases

EPILOG Study 1997

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 1 year

  • Lost to follow-up: 3%

Participants
  • Country: US and Canada

  • Setting: Multicentre

Inclusion criteria

  • Patients undergoing elective or urgent percutaneous coronary revascularisation with a device approved by the Food and Drug Administration were eligible for inclusion if they were over 21 years old and had a target lesion in which there was stenosis of at least 60% of the diameter of the vessel

  • Treatment group: (325); age and sex (NS)

  • Control group: (163); age and sex (NS)

Exclusion criteria

  • Patients who had either acute myocardial infarction or unstable angina with associated electrocardiographic changes during the previous 24 hours; planned stent implantation or rotational atherectomy; percutaneous coronary intervention performed within the previous three months; a left main coronary artery stenosis of more than 50% not protected by collateral vessels; concurrent warfarin therapy or a baseline prothrombin time > 1.2 times the control value; cerebrovascular accident within the previous two years or a residual neurologic deficit; intracranial neoplasm, aneurysm, or arteriovenous malformation; history of vasculitis, known haemorrhagic diathesis, or active internal bleeding; hypertension, with a systolic BP > 180 mm Hg or a diastolic BP > 100 mm Hg; and major surgery, gastrointestinal bleeding, or genitourinary bleeding within the previous 6 weeks

Interventions

Treatment group

  • Aciximab + standard dose heparin + aspirin

  • Dose, duration, frequency, administration

    • Aspirin: 325 mg orally two hours before the percutaneous revascularisation procedure and daily thereafter.

    • Abciximab: bolus of 0.25 mg/kg administered 10 to 60 minutes before inflation of the balloon or activation of the device, followed by an infusion of 0.125 mg/kg/min (maximum 10 mg/min) for 12 hours

    • Heparin: initial bolus of 100 U of heparin/kg (maximum 10,000 U) before the interventional procedure, with additional weight-adjusted boluses calculated according to an algorithm intended to achieve and maintain an activated clotting time of at least 300 seconds

Control group

  • Placebo + standard dose heparin + aspirin

  • Dose, duration, frequency, administration

    • Aspirin: 325 mg orally two hours before the percutaneous revascularisation procedure and daily thereafter

    • Heparin: initial bolus of 100 U of heparin/lg (maximum 10,000 U) before the interventional procedure, with additional weight-adjusted boluses calculated according to an algorithm intended to achieve and maintain an activated clotting time of at least 300 seconds

Outcomes
  • The primary efficacy endpoint was a composite of death from any cause, myocardial infarction or reinfarction, or severe myocardial ischaemia requiring urgent coronary bypass surgery or repeated percutaneous coronary revascularisation within 30 days after randomisation. A second efficacy endpoint was a composite of death, myocardial infarction, or coronary bypass surgery or repeated percutaneous revascularisation (urgent or non-urgent) within 6 months after randomisation

  • Bleeding events were classified as major or minor according to the criteria used by the Thrombolysis in Myocardial Infarction Study Group

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low risk"Patients were randomly assigned in a double-blind fashion by means of a central telephone hot line to one of three treatment groups"
Blinding (performance bias and detection bias)
All outcomes
Low riskPatients, investigators and outcomes assessors. "Patients were randomly assigned in a double-blind fashion... To preserve the blinding of all investigators and personnel involved in patient care, a heparin coordinator at each clinical site performed all measurements of activated clotting time and directed the administration of heparin. Endpoint classifications of a clinical events committee, blinded to study group assignment, were used for the final analyses"
Incomplete outcome data (attrition bias)
All outcomes
Low riskMissing outcome data balanced in number across the groups. "Data were incomplete for 3% of the study patients: 30 patients in the placebo group, 30 in the group given abciximab and low-dose heparin, and 24 in the group given abciximab and standard-dose heparin"
Selective reporting (reporting bias)Low riskThe study protocol was available and all pre-specified outcomes were reported as prespecified
Other biasHigh riskSample size was smaller than planned and the study was terminated earlier because a prespecified stopping rule was met after the first interim analysis

EPISTENT Study 1998

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 1 year

  • Lost to follow-up: 1.7% (40 patients)

Participants
  • Country: US and Canada

  • Setting: Multicentre

Inclusion criteria

  • Patients scheduled to undergo elective or urgent percutaneous coronary revascularisation were eligible for inclusion if target lesions had caused stenosis of at least 60% amenable to balloon angioplasty or stenting; the target vessel was not an unprotected left mainstem stenosis

  • Treatment group: number (231); age and sex (NS)

  • Control group: number (137); age and sex (NS)

Exclusion criteria

  • Bleeding diathesis, intracranial neoplasm, history of stroke in the previous 2 years, uncontrolled hypertension (systolic BP > 180 mm Hg, diastolic BP > 100 mm Hg), recent surgery, or percutaneous coronary intervention within the previous 3 months. Concurrent warfarin therapy or an international normalised ratio of more than 1:5 at baseline were excluded

Interventions

Treatment group

  • Stent + abciximab + aspirin + heparin

  • Dose, duration, frequency, administration

    • Abciximab: 0.25 mg/kg bodyweight up to 60 min before intervention, followed by an infusion of 0.125 μg/kg every 1 minute (maximum 10 μg/min) for 12 h

    • Aspirin: 325 mg orally at least 2 h before the intervention, and daily thereafter.

    • Heparin: 70 U/kg (maximum 7000 U) with additional boluses as necessary to achieve and maintain an activated clotting time of at least 200 s

Control group

  • Stent + placebo + aspirin + heparin

  • Dose, duration, frequency, administration

    • Aspirin: 325 mg orally at least 2 h before the intervention, and daily thereafter

    • Ticlopidine: 250 mg twice/d was started at the discretion of the investigator, before the start of the study agent if possible, and was given to all patients in the two stent groups

    • Heparin: initial bolus of 100 U/kg (maximum 10,000 U) with additional boluses to achieve and maintain an activated clotting time of at least 300 s

    • Ticlopidine: 250 mg twice/d was started at the discretion of the investigator, before the start of the study agent if possible, and was given to all patients in the two stent groups

Outcomes
  • The primary endpoint was a combination of death from any cause, myocardial infarction or reinfarction, or severe myocardial ischaemia requiring urgent coronary artery bypass surgery or revascularisation within 30 days of intervention. Secondary endpoints were death or myocardial infarction, and death or large, myocardial infarction defined as new pathological Q waves or a value of creatine kinase or its MB isoenzyme at least five times the upper laboratory limit in the participating hospital

  • Major and minor bleeding

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskCentral allocation, by telephone
Blinding (performance bias and detection bias)
All outcomes
Low risk"Patients and investigators were masked to which study drug was administered by use of identical placebo and abciximab... To maintain masking in the stent groups, a heparin coordinator at each centre took all the measurements of activated clotting time and directed the administration of heparin according to a predetermined algorithm... All endpoint events were assessed by a clinical-events committee that was unaware of study-group assignment"
Incomplete outcome data (attrition bias)
All outcomes
Low riskData provided for all patients
Selective reporting (reporting bias)Low riskThe study protocol was available and all prespecified outcomes were reported as prespecified
Other biasLow riskNo other biases

ETDRS 1992

Methods
  • Study design: RCT

  • Study duration: follow-up of at least 5 years

  • Loss to follow-up: At the end of 5 years follow-up, 8% of patients assigned to aspirin were taking some aspirin or other antiplatelet drug. In the placebo group, 71% were taking only assigned medication and 18% were taking an antiplatelet drug

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Men and women between the ages of 18 and 70 years at the first screening visit, who had a clinical diagnosis of diabetes and diabetic retinopathy. Unpublished data for individual with CKD (185 patients) defined as SCr > 133 µmol/L (1.51 mg/dL) were available

  • Treatment group: number (79); age (55.2 ± 10.5 years); sex (74.6% male)

  • Control group: number (106); age (52.1 ± 11.8 years); sex (66.0% male)

Exclusion criteria

  • Systolic BP > 210 mm Hg and/or diastolic BP > 110 mm Hg despite use of antihypertensive medication; history of gastrointestinal haemorrhage or diagnosis of active gastrointestinal ulcer in the past 2 years; inability or unwillingness to stop taking anticoagulants or antiplatelet drugs; allergy to aspirin; pregnancy or lactation; or poor prognosis for 5 years follow-up because of a prior cardiovascular event, cancer or other chronic disease

Interventions

Treatment group

  • Aspirin

  • Dose, duration, frequency, administration: 650 mg orally/d

Control group

  • Matching placebo

Outcomes
  • Unpublished data for all-cause death, cardiovascular death, stroke, myocardial infarction, ever on dialysis, ever kidney transplantation, dialysis or transplantation, serious CKD, cause specific death

NotesUnpublished data only used
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"the randomization was designed to provide balance in the number of patients assigned to aspirin or placebo within each clinical center". Method not stated
Allocation concealment (selection bias)Unclear riskNS
Blinding (performance bias and detection bias)
All outcomes
Low risk"Neither the patient nor the clinical center personnel were informed of the patient's drug assignment except in the rare event of a medical emergency"
Incomplete outcome data (attrition bias)
All outcomes
Low riskUnpublished data only used
Selective reporting (reporting bias)Low riskUnpublished data only used
Other biasLow riskUnpublished data only used

Fiskerstrand 1985

Methods
  • Study design: RCT

  • Study duration: 1 month

  • Loss to follow-up: 17% (3/18 participants)

Participants
  • Country: Scotland

  • Setting: Single hospital centre

Inclusion criteria

  • Participants requiring access surgery for chronic haemodialysis

  • Treatment group: number (8); age and sex (NS)

  • Control group: number (10); age and sex (NS)

Exclusion criteria

  • Platelet-modifying agent or on anticoagulant therapy (apart from heparin while on haemodialysis); history of active peptic ulcer within the previous 3 years; any known haemorrhagic diathesis not due to uraemia; or platelet count < 100,000/mm³

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 250 mg twice/d after food intake started 2 days prior to access operation

Control group

  • Placebo

Outcomes
  • Adverse events

  • Fistula thrombosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNS
Allocation concealment (selection bias)Unclear riskNS
Blinding (performance bias and detection bias)
All outcomes
Low risk"double-blind randomized trial"
Incomplete outcome data (attrition bias)
All outcomes
High riskNo information provided
Selective reporting (reporting bias)Unclear riskUnable to determine
Other biasUnclear riskUnable to determine

Frascà 1986

Methods
  • Study design: 2 active arm RCT

  • Study duration: 36 months

  • Lost to follow-up: 5%

Participants
  • Country: Italy

  • Setting: Hospital

Inclusion criteria

  • Patients undergoing their first kidney transplant with immediate graft function

  • Treatment group: number (40); age (32 years); sex (NS)

  • Control group: number (40); age (34 years); sex (NS)

Exclusion criteria

  • Diabetes mellitus

Interventions

Treatment group

  • Defibrotide

  • Dose, duration, frequency, administration: Continuous IV infusion at 10 mg/kg/d for 3 to 5 days postoperatively, followed by same dose orally thereafter for 12 to 34 months (mean 24 months)

Control group

  • Dipyridamole

  • Dose, duration, frequency, administration: iv at 0.5 mg/kg/d for 2 to 4 days followed by 6 to 8 mg/kg/d orally thereafter for 14 to 36 months (mean 25 months)

Outcomes
  • Number of patients with rejection, number of patients with second rejection

  • Number of functioning grafts at follow-up

  • Bleeding

  • Death

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
High riskNo information provided
Selective reporting (reporting bias)High riskNo prespecified outcomes
Other biasUnclear riskNo information provided

Frascà 1997

Methods
  • Study design: RCT

  • Study duration: 24 months

  • Lost to follow-up: 0%

Participants
  • Country: Italy

  • Setting: Hospital

Inclusion criteria

  • Patients with IgA nephropathy and reduced kidney function at diagnosis (SCr ≥ 1.4 mg/dL)

  • Treatment group: number (10); age (30 years); sex (80% male)

  • Control group: number 910); age (31 years); sex (100% male)

Exclusion criteria

  • Systemic or hepatic dysfunction; previous treatment for IgA nephropathy

Interventions

Treatment group

  • Defibrotide + prednisone

  • Dose, duration, frequency, administration

    • Defibrotide: 10 mg/kg/d for 24 months

    • Prednisone: 0.5 mg/kg/d on alternate days for 6 months

Control group

  • Prednisone

  • Dose, duration, frequency, administration: 0.5 mg/kg/d on alternate days for 6 months

Outcomes
  • Change in SCr and daily protein excretion before and after treatment

  • Percentage change in CrCl

  • Adverse effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information provided
Selective reporting (reporting bias)Unclear riskNo information provided
Other biasHigh riskNot included in meta-analysis

Ghorbani 2009

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 6 months

  • Lost to follow-up: 19.4% (18/93) discontinued but stated that of 75 patients who completed the study, none were lost to follow-up

Participants
  • Country: Iran

  • Setting: Outpatient haemodialysis unit

Inclusion criteria

  • Patients close to initiation of haemodialysis requiring AVF, chronic haemodialysis patients requiring a new AVF at a different site; > 18 years of age

  • Treatment group: number (46); age (44.23 years); sex (25.8% male)

  • Control group: number (47); age (45.8 years); sex (25.8% male)

Exclusion criteria

  • History of gastrointestinal bleeding or previous bleeding episodes within 6 months prior to initiation of the study; patients already on chronic antiplatelets or anticoagulation; patients with terminal or life threatening disease; pregnancy; malignant hypertension; platelet count < 100,000/mm³ and other medical conditions that would make antiplatelet therapy dangerous

Interventions

Treatment group

  • Clopidogrel

  • Dose, duration, frequency, administration: 75 mg/d starting 7 to 10 days prior to scheduled access surgery and continued up to 6 weeks postoperatively

Control group

  • Clopidogrel placebo

  • Dose, duration, frequency, administration: 1 tablet/d starting 7 to 10 days prior to scheduled access surgery and continued up to 6 weeks postoperatively

Outcomes
  • Death

  • Severe or life threatening bleeding

  • AVF failure 8 weeks after fistula creation

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low risk"Randomization was performed centrally, by the coordinator center"
Blinding (performance bias and detection bias)
All outcomes
Low riskNeither the details of the randomisation not the identity of the medication assignment was known to the participant or any personnel at the participating sites. Fistula failure was determined by a member of the study team, who was blinded to the treatment allocation
Incomplete outcome data (attrition bias)
All outcomes
High risk75 of 93 patients completed study. Limited information provided
Selective reporting (reporting bias)Unclear riskNo prespecified protocol
Other biasUnclear riskUnable to determine

Giustina 1998

Methods
  • Study design: placebo-controlled RCT

  • Duration: 12 months

  • Lost to follow-up: 9% (3 withdrew due to lack of compliance: 1 in active arm and 2 in placebo arm)

Participants
  • Country: Italy

  • Setting: Hospital

Inclusion criteria

  • 40 to 65 years of age, known duration of diabetes > 12 months; HbA1c < 10%; stable BMI (35 kg/m²); supine BP 140/90 mm Hg; SCr < 106 µmol/L; 24 hour urinary albumin excretion 20 to 200 μg/min; no cardiovascular, hepatic or systemic disease before starting the study

  • Treatment group: number (15); age (56 years); sex (87% male)

  • Control group: number (15); age (57 years); sex (87% male)

Exclusion criteria

  • Presence of kidney or hepatic disease; ECG abnormalities at rest or exercise induced; peptic ulcer disease or previous haemorrhage episodes; treatment with other antiplatelet drugs or ACEi

Interventions

Treatment group

  • Picotamide

  • Dose, duration, frequency, administration: 300 mg three times/d for 12 months

Control group

  • Placebo

  • Dose, duration, frequency, administration: 3 times/d for 12 months

Outcomes
  • End of treatment SCr, CrCl, urine albumin excretion at rest and post exercise

  • Side effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Low risk"Blinded treatment allocation was obtained by central randomisation"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind, but not stated if outcomes assessors and data analysis is blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskOnly 9% of lost to follow-up
Selective reporting (reporting bias)Unclear riskNo prespecified outcomes
Other biasUnclear riskUnable to determine

Gonzalez 1995

Methods
  • Study design: placebo-controlled RCT

  • Duration: 3 years

  • Lost to follow-up: 43%

Participants
  • Country: Spain

  • Setting: Hospital

Inclusion criteria

  • Patients with diabetic kidney disease and retinopathy (mild to moderate kidney impairment)

  • Treatment group: number of participants, age and sex (NS)

  • Control group: number of participants, age and sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Dypridamole + aspirin

  • Dose, duration, frequency, administration

    • Doses and frequencies: NS

    • Duration: 3 years

Control group

  • Placebo

  • Dose, duration, frequency, administration: NS

Outcomes
  • Number reaching ESKD

  • Change in SCr

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information
Selective reporting (reporting bias)Unclear riskNo information
Other biasHigh riskAbstract only

Gröntoft 1985

Methods
  • Study design: RCT

  • Duration: 4 weeks

  • Lost-to-follow-up: 14% (6/42 participants did not complete the study)

Participants
  • Country: Sweden

  • Setting: Two nephrology units in Sweden between 1980 and 1982

Inclusion criteria

  • Patients who were to undergo fistula surgery

  • Overall characteristics: number (42); age (mean 44.6 years, range 24 to 72 years); M/F (28/14)

Exclusion criteria: NS

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 250 mg twice/d orally from two days before surgery until 4 weeks after surgery

Control group

  • Placebo

Outcomes
  • Fistula function

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"randomized double-blind technique"
Incomplete outcome data (attrition bias)
All outcomes
High risk6/42 patients lost to follow-up
Selective reporting (reporting bias)High riskNo prespecified outcomes
Other biasUnclear riskUnable to determine

Gröntoft 1998

Methods
  • Study design: RCT

  • Study duration: 4 weeks

  • Lost to follow-up: 6% (16/258)

Participants
  • Country: Sweden and Finland

  • Setting: Multicentre

Inclusion criteria

  • Patients with CKD, predialysis or when on dialysis who had been selected for surgery of an arteriovenous, saphenous, or artificial graft as haemodialysis site could be admitted to the study. Patients in whom the first operation failed could be re-entered after randomisation after a washout period of 3 weeks

  • Treatment group: number (118); age (56 ± 15 years); M/F (75/43)

  • Control group: number (124); age (58 ± 15 years; M/F (77/47)

Exclusion criteria

  • Known antiplatelet therapy or anticoagulant other than in connection with dialysis sessions or who had history or evidence of hepatic disease, severe or malignant hypertension, gastrointestinal ulcer, haemorrhagic diathesis not due to uraemia, or any underlying lesion capable of causing severe haemorrhage, or who showed leukopenia, granulocytopenia, or thrombocytopaenia at screening were excluded

Interventions

Treatment group

  • Ticlopidine hydrochloride

  • Dose, duration, frequency, administration: 250 mg tablets twice/d with food for a target of 7 (minimum 3) days before the day of scheduled surgery and for 28 days postoperatively

Control group

  • Matching placebo

Outcomes
  • Fistula function

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"After screening, patients were allocated either ticlopidine hydrochloride (250 mg) tablets b.d. or matching bitter placebo by an independent statistician using a minimization scheme (20) based on the four weighted stratification variables of the center"
Allocation concealment (selection bias)Low risk"independent statistician"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo description
Incomplete outcome data (attrition bias)
All outcomes
Low risk6% lost to follow-up
Selective reporting (reporting bias)Low riskSpecified outcomes reported
Other biasUnclear riskUnable to determine

Harter 1979

Methods
  • Study design: placebo-controlled RCT

  • Study duration: Mean 4.7 months

  • Lost to follow-up: 29.5%

Participants
  • Country: USA

  • Setting: Hospital

Inclusion criteria

  • Consecutive patients receiving AV shunt

  • Treatment group: number (19); age (53.3 years); sex (58% male)

  • Control group: number 925); age (46 years); sex (35% male)

Exclusion criteria

  • 2 patients excluded due to recent gastrointestinal haemorrhage, 2 excluded due to possible allergy to aspirin, no other exclusion criteria stated

Interventions

Treatment group

  • Aspirin

  • Dose, duration, frequency, administration: 160 mg/d for mean of 4.6 months

Control group

  • Placebo

  • Dose, duration, frequency, administration: 1 tablet/d for mean duration of 4.7 months

Outcomes
  • Death

  • Bleeding

  • Number of patients with AV shunt thrombosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Low risk"Neither the patients nor the their attendant physicians knew which therapy was received" blinding for data analysis and outcomes assessors not stated
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh percentage (29.5%) of patients left the study
Selective reporting (reporting bias)High riskHigh dropout
Other biasHigh riskDifferences in number of patients in each group - together with differences in duration of dialysis at baseline

HOT Study 2010

Methods
  • Study design: Post-hoc analysis of placebo-controlled RCT, in this analysis patients with MDRD based eGFR < 60 mL/min were studied

  • Duration: 3.8 years

  • Lost to follow-up: 2.6%

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Patients aged 50 to 80 years with diastolic BP between 100 and 115 mm Hg

  • Treatment group: number (9399) patients; age (55.2 years in those with GFR < 60 mL/min); sex (33% males in the CKD population)

  • Control group: number (9391); age (65.1 years in the CKD population); sex (34% men in the CKD population)

Exclusion criteria: NS

Interventions

Treatment group

  • Aspirin

  • Dose, duration, frequency, administration: 75 mg/d for mean duration of 3.8 years

Control group

  • Placebo

  • Dose, duration, frequency, administration: once/d for mean duration of 3.8 years

Outcomes
  • Composite of major cardiovascular events (myocardial infarction, stroke, death), myocardial infarction, stroke, cardiovascular mortality, total mortality

  • Change in GFR

  • Bleeding (major and minor)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Patients were randomised on the basis of the following baseline variables: age, sex (... and diabetes mellitus"
Allocation concealment (selection bias)Low riskCentral randomisation
Blinding (performance bias and detection bias)
All outcomes
Low risk'Randomised in a double-blind manner"
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow percentage of lost to follow-up
Selective reporting (reporting bias)Low riskPrespecified outcomes
Other biasLow riskNo other bias

IMPACT II Study 1997

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 6 months

  • Lost to follow-up: No loss to follow-up at 30 days; 10.9% of patients terminated treatment early

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Patient was scheduled for elective, urgent, or emergency coronary intervention with a device approved by the Food and Drug Administration (balloon angioplasty, directional coronary atherectomy, rotational atherectomy, or excimer laser ablation); the protocol was specifically designed to enrol a representative cross-section of patients undergoing percutaneous revascularisation

  • Treatment group 1: number (547); age and sex (NS)

  • Treatment group 2: number (259); age and sex (NS)

Exclusion criteria

  • History of bleeding diathesis, severe hypertension (BP > 200 mm Hg systolic or > 100 mm Hg diastolic on therapy), major surgery within the previous 6 weeks, history of stroke or other disorders of the central nervous system, pregnancy, gastrointestinal or genitourinary bleeding within the previous 30 days, or other major illness

Interventions

Treatment group 1

  • Eptifibatide (135/0.5 regimen) + aspirin

  • Dose, duration, frequency, administration

    • Eptifibatide: Bolus of 135 μg/kg followed by an infusion of 0.5 μg/kg/min for 20 to 24 hours

    • Aspirin: 325 mg before the procedure, then continued indefinitely

Treatment group 2

Intervention: Eptifibatide (135/0.75 regimen) + aspirin

Dose, duration, frequency, administration:

    • Eptifibatide: Bolus of 135 μg/kg followed by an infusion of 0.75 μg/kg/min for 20 to 24 hours

    • Aspirin: 325 mg before the procedure, then continued indefinitely

Control group

  • Placebo bolus + placebo infusion + aspirin

  • Aspirin: 325 mg before the procedure, then continued indefinitely

After vascular access had been established, a 100 U/kg bolus of heparin was given. Additional heparin was given during the procedure as needed to maintain the activated clotting time between 300 s and 350 s. The protocol recommended that no further heparin be infused after the coronary intervention and that vascular access sheaths be removed within 4 to 6 hours

Outcomes
  • Primary endpoint: thee occurrence within 30 days of death, myocardial infarction, urgent or emergency repeat coronary intervention, urgent or emergency coronary artery bypass surgery, or index placement of an intracoronary stent for abrupt closure. A second assessment was also required after 5 months for ascertainment of long-term events

  • Major bleeding (classified as in the Thrombolysis in Myocardial Infarction (TIMI) study)

  • Stroke

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The allocation schedule was generated by computer"
Allocation concealment (selection bias)Low riskEnrolment by telephone
Blinding (performance bias and detection bias)
All outcomes
Low risk

The Clinical Events Committee was blinded to the treatment assignment.

"An independent Data and Safety Monitoring Board examined the available efficacy and safety data at three interim points during the study and made recommendations to the Executive Committee about conduct and continuation of the study"

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat; missing data balanced in numbers across the groups
Selective reporting (reporting bias)Low riskOutcomes were reported as prespecified
Other biasLow riskNo other biases

Kaegi 1974

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 6 months

  • Lost to follow-up: 16%

Participants
  • Country: Canada

  • Setting: Hospital

Inclusion criteria

  • Chronic haemodialysis patients with straight arteriovenous shunt

  • Treatment group: number (30 entered, 24 completed); age (43 years); sex (66.7% male, 24 males completed study)

  • Control group: number (32 entered, 28 completed); age (44 years); sex (71% male, 28 males completed study)

Exclusion criteria: NS

Interventions

Treatment group

  • Sulfinpyrazone

  • Dose, duration, frequency, administration: 200 mg three times/d for 6 months

Control group

  • Placebo

  • Dose, duration, frequency, administration: identical to treatment

Outcomes
  • Number of patients with fistula thrombosis, fistula thrombosis events, number of arterial and venous fistula revisions

  • Gastrointestinal bleeding

  • Other side effects

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"This was a double blind study, the allocation of the patients to treatment being made according to a prescribed randomised arrangement"
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskStated "double-blind". No information about blinding of data analysis and outcome assessors
Incomplete outcome data (attrition bias)
All outcomes
High riskHigh percentage of withdrawal
Selective reporting (reporting bias)Unclear riskUnable to determine
Other biasHigh riskPost hoc analysis of patients on anticoagulants

Kauffmann 1980

Methods
  • Study design: RCT

  • Study duration: 6 months

  • Lost to follow-up: 0% (35% in the aspirin group were crossed-over to dipyridamole group following gastrointestinal bleeding)

Participants
  • Country: US

  • Setting: Hospital

Inclusion criteria

  • Patients post kidney transplant

  • Treatment group: number (22); age and sex (NS)

  • Control group: number (20); age and sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Dipyridamole

  • Dose, duration, frequency, administration: 100 mg 4 times/d for 6 months

Control group

  • Buffered aspirin (Ascriptin)

  • Dose, duration, frequency, administration: 5 mg twice/d for 6 months

Outcomes
  • Bleeding (including gastrointestinal bleeding)

  • Graft loss

  • Mean SCr at 1, 3 and 6 months

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)High risk"Randomization was achieved by whether the last digit of the patients' hospital number was odd or even"
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
High riskquasi-RCT study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to determine
Selective reporting (reporting bias)Unclear riskNo prespecified outcomes
Other biasUnclear riskUnable to determine

Kaufman 2003

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 24 months but terminated at 12 months

  • Lost to follow-up: 33%

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Chronic haemodialysis patients with PTFE graft in the arm

  • Treatment group: number (104); age (61 ± 13 years); males (100%)

  • Control group: number (96); age (62 ± 11 years); males (99%)

Exclusion criteria

  • Blood loss requiring transfusion or hospitalisation in the 3 month prior; advanced proliferative diabetic retinopathy; life expectancy of < 24 months; uncontrolled BP; platelet count < 100,000 mm³; INR > 1.3; partial thromboplastin time 5 seconds longer than control; access thrombosis or operation in the previous 14 days;, other conditions that would make anti platelet therapy high risk

Interventions

Treatment group

  • Aspirin + clopidogrel

  • Dose, duration, frequency, administration

    • Aspirin: 325 mg/d

    • Clopidogrel: 75 mg/d for 24 months

Control group

  • Double placebo

  • Dose, duration, frequency, administration: identical placebo

Outcomes
  • Adverse events

  • Bleeding events (major, intermediate, minor)

  • First episode of fistula thrombosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"The randomisation was stratified according to medical centre with a permuted block scheme, with a block size of four and equal allocation. After identifying and obtaining consent from eligible participants, the local study coordinator telephoned the coordinating centre to obtain a randomisation number, which corresponded to a specific medication bottle available in the local research pharmacy" Neither the details of the randomisation sequence nor the identity of the medical assignment was known to the participant or any personnel at the participant sites.
Allocation concealment (selection bias)Low risk"Randomisation was performed centrally, by the coordinating centre"
Blinding (performance bias and detection bias)
All outcomes
Low risk"The presence of access thrombosis was determined by a member of the study team (either the study coordinator or the site principal investigator), who was blinded to treatment allocation. Participants remained in the study and received blinded therapy after the first episode of thrombosis, until the study ended"
Incomplete outcome data (attrition bias)
All outcomes
Low riskReasons for exclusions listed
Selective reporting (reporting bias)Unclear riskUnable to determine
Other biasHigh riskThe study was terminated earlier because of a significantly increased bleeding risk in the active treatment arm. Sample size smaller than planned

Khajehdehi 2002

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 2 months

  • Lost to follow-up: 0%

Participants
  • Country: Iran

  • Setting: Hospital

Inclusion criteria

  • Patients with overt type 2 diabetic kidney disease (proteinuria > 500 mg/d), who had normal kidney function, well-controlled BP and blood sugars and not receiving ACEi

  • Group 1: number (19); age (56.1 ± 7.5 years); M/F (7/12)

  • Group 2: number (19); age (56.8 ± 6.8 years); M/F (8/11)

  • Group 3: number (19); age (57.9 ± 7.0 years); M/F (12/7)

  • Group 4: number (19); age (56.9 ± 6.9 years); M/F (9/10)

Exclusion criteria

  • SCr > 2 mg/dL and blood nitrogen > 20 mg/dL; bacteriuria; recurrent or relapsing UTI; active urine sediment

Interventions

Group 1

  • Aspirin

  • Dose, duration, frequency, administration: 1000 mg/d for 2 months

Group 2

  • Dipyridamole

  • Dose, duration, frequency, administration: 750 mg/d, for 2 months

Group 3

  • Aspirin and dipyridamole

  • Dose, duration, frequency, administration

    • Aspirin: 1000 mg/d for 2 months

    • Dipyridamole: 750 mg/d for 2 months

Group 4

  • Placebo

  • Dose, duration, frequency, administration: 1/d for 2 months

Outcomes
  • Change in 24 hour urine protein

  • SCr

  • Protein:creatinine ratio

  • Creatinine excretion

  • Safety and side-effect profile of interventions

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information
Selective reporting (reporting bias)Unclear riskOutcomes not well specified in the protocol
Other biasUnclear riskInsufficient information

Kobayashi 1980

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 12 weeks

  • Lost to follow-up: 29%

Participants
  • Country: Japan

  • Setting: Multicentre

Inclusion criteria

  • Chronic haemodialysis patients with AV external shunts or vascular grafts who had experienced more than one episode of thrombosis of their fistula during the preceding 4 weeks

  • Treatment group: number (50); age (NS); M/F (17/33)

  • Control group: number (57); age (NS); M/F (23/34)

Exclusion criteria

  • Digestive ulcers; hepatic disorders; severe haematological disorders except anaemia of kidney insufficiency

Interventions

Treatment group

  • Ticlopidine

  • Dose, duration, frequency, administration: 100 mg twice/d for 12 weeks

Control group

  • Placebo

  • Dose, duration, frequency, administration: one capsule twice/d for 12 weeks

Outcomes
  • Frequency of clot removal from fistula and reconstructive surgery

  • Safety and side-effects (including bleeding and gastrointestinal disturbances)

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDefined as double-blind, but no other information provided
Incomplete outcome data (attrition bias)
All outcomes
High riskNo intention-to-treat. High percentage lost to follow-up
Selective reporting (reporting bias)Unclear riskOutcomes not well specified in the protocol
Other biasUnclear riskInsufficient information

Kooistra 1994

Methods
  • Study design: placebo-controlled cross-over RCT

  • Study duration: 6 months

  • Lost to follow-up: 11%

Participants
  • Country: Belgium

  • Setting: Hospital

Inclusion criteria

  • Aged ≥ 18 years with anaemia of CKD who were on chronic dialysis for more than 6 weeks

  • Treatment group: number (68); age and sex (NS)

  • Control group: number (69); age and sex (NS)

Exclusion criteria

  • Uncontrolled hypertension, cardiac failure, angina pectoris above stage two, pregnancy, previous thrombovascular accidents other than thrombosis of fistula and treatment with non-steroidal anti-inflammatory drugs or anticoagulants

Interventions

Treatment group

  • Aspirin then placebo

  • Dose, duration, frequency, administration: after a period of anaemia correction, patients were given aspirin 30 mg/d for 3 months, then had a washout period of 1 to 2 weeks and were then given placebo for 3 months at 1 tablet/d

Control group

  • Placebo then aspirin

  • Dose, duration, frequency, administration: after a period of anaemia correction patients were given one placebo tablet/d for 3 months, then had a washout period of 1 to 2 weeks and were then given aspirin 30 mg/d for 3 months

Outcomes
  • Bleeding

  • Death

  • Systemic thrombovascular events

  • Fistula thrombosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)High risk"The patients were assigned at random to group A or B by the monitor (MH), who was not in charge of the medical care for the patients. The dialysis staff was not aware to which groups the patients were allocated. Placebo- or ASA-containing tablets looked identical. Compliance to the prescription was checked by counting the remaining ASA- or placebo-containing tablets, which were returned after each study period".
Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnable to determine
Incomplete outcome data (attrition bias)
All outcomes
High riskNumber of patients who dropped-out was balanced across groups
Selective reporting (reporting bias)Unclear riskOutcomes reported in the pre-specified way
Other biasUnclear riskCross-over study design

Michie 1977

Methods
  • Study design: placebo controlled RCT

  • Study duration: 3 months

  • Lost to follow-up: 6%

Participants
  • Country: USA

  • Setting: Hospital

Inclusion criteria

  • Adults with CKD scheduled to begin haemodialysis, prior to creation of fistula or graft

  • Treatment group: number (8); age (49 years); males (75%)

  • Control group: number (8); age (53 years); males (50%)

Exclusion criteria: NS

Interventions

Treatment group

  • Sulphinpyrazone

  • Dose, duration, frequency, administration: 200 mg, 4 times/d for 3 months

Control group

  • Identical placebo

  • Dose, duration, frequency, administration: 4 times/d for 3 months

Outcomes
  • Safety of intervention including death and nonfatal serious adverse events

  • Fistula thrombosis

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDefined as double-blind
Incomplete outcome data (attrition bias)
All outcomes
High riskResults not available for all patients
Selective reporting (reporting bias)Unclear riskNo pre-specified outcomes
Other biasUnclear riskInsufficient information

Middleton 1992

Methods
  • Study design: RCT

  • Study duration: 18 months

  • Lost to follow-up: NS

Participants
  • Country: NS

  • Setting: NS

Inclusion criteria

  • Haemodialysis patients

  • Treatment group: number (451); age and sex (NS)

  • Control group: number (452); age and sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Low-dose aspirin + dipyridamole

  • Dose, duration, frequency, administration

    • Aspirin: 50 mg/d for 18 months

    • Dipyridamole: 400 mg/d for 18 months

Control group

  • NS

  • Dose, duration, frequency, administration: NS

Outcomes
  • All-cause mortality

  • Cardiovascular mortality

  • Major bleeding

NotesPublished results from an earlier systematic review ATT 2002
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available
Allocation concealment (selection bias)Unclear riskNo information available
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information available
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information available
Selective reporting (reporting bias)Unclear riskNo information available
Other biasHigh riskFull study report not available

Ogawa 2008

Methods
  • Study design: RCT

  • Study duration: 16 weeks

  • Lost to follow-up: 0%

Participants
  • Country: Japan

  • Setting: Single centre

Inclusion criteria

  • People with diabetes and arteriosclerosis obliterans, maximum internal carotid medial thickness > 1 mm, ACR > 30 mg/g, HbA1C < 8.0%, BP < 180/110 mm Hg and no serious retinopathy

  • Treatment group: number (20); age (68.7 ± 1.61 years); M/F (11/9)

  • Control group: number (20); age (67.4 ± 1.54 years); M/F (10/10)

Exclusion criteria

  • Treated with antiplatelets or anticoagulants; hospitalised in the past 12 months for any reason and those who had their drugs changed in the past 12 months

Interventions

Treatment group

  • Sarpogrelate

  • Dose, duration, frequency, administration: 300 mg/d for 16 weeks

Control group

  • Aspirin

  • Dose, duration, frequency, administration: 100 mg/d for 16 weeks

Outcomes
  • Change in urinary ACR

  • SCr

  • eGFR

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
High riskDefined as single-blind study
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNot reported
Selective reporting (reporting bias)Unclear riskNo pre-specified outcomes
Other biasUnclear riskSample size and follow-up duration as planned

PLATO Study 2010

Methods
  • Study design: Post-hoc analysis of double-blind RCT, in this analysis patients with CrCl < 60 mL/min were studied

  • Duration: 12 months

  • Lost to follow-up: 17.2%

Participants
  • Country: Sweden

  • Setting: Multicentre, international

Inclusion criteria

  • Patients with acute coronary syndrome with onset during the previous 24 hours

  • Overall: number (3237 with GFR < 60 mL/min were included in analysis and the review); age (median 74 years; quartiles 68 to 79); males (60.2%)

Exclusion criteria

  • Contraindication against the use of clopidogrel; fibrinolytic therapy within 24 hours before randomisation; a need for oral anticoagulation therapy; an increased risk of bradycardia; concomitant therapy with a strong cytochrome P-450 inhibitor or inducer

Interventions

Treatment group

  • Ticagrelor + placebo

  • Dose, duration, frequency, administration

    • Ticagrelor: 180 mg loading dose followed by 90 mg twice/d

    • Placebo: matched to clopidogrel

Control group

  • Clopidogrel + placebo

  • Dose, duration, frequency, administration

    • Clopidogrel: those who had not been receiving open-label loading dose and were not taking clopidogrel for at least 5 days were given 300 mg loading dose, followed by 75 mg/d

    • Placebo: matched to ticagrelor

Outcomes
  • Death from vascular causes (stroke, cardiovascular or any other with unknown cause)

  • Myocardial infarction

  • Stroke

  • Bleeding

  • Other adverse effects

  • Increase in SCr percentage above baseline

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandomised 1:1 ratio using a randomisation schedule blocked by site
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
High riskDouble-blind. Blinding of outcome assessors and analysis not stated. "An independent, external data and safety monitoring board (DSMB) monitors safety data on an ongoing basis and has access to unblinded data. An independent central adjudication committee adjudicates all end points and major and minor bleeding events"
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo missing outcome data
Selective reporting (reporting bias)Low riskOutcomes reported in prespecified manner
Other biasUnclear riskInsufficient information

PRISM-PLUS Study 2002

Methods
  • Study design: Post-hoc analysis of a randomised, placebo-controlled RCT, in this analysis patients with CrCl < 60 mL/min were studied

  • Duration: 6 months

  • Lost to follow-up: Tirofiban arm with 345 patients was terminated

Participants
  • Country: Canada

  • Setting: Multicentre

Inclusion criteria

  • Patients with acute coronary syndrome

  • Overall: number (611); age (71.1 to 79.4 years); males (35% to 54%)

Exclusion criteria

  • Patients with severe kidney insufficiency (creatinine ≥ 2.5 mg/dL); ST segment elevation greater 20 minutes; thrombolysis in the previous 48 hours; cardiac angiography in the previous 6 months; bypass operation in the previous 1 month; angina caused by identifiable factors; history of platelet disorder or thrombopenia; active bleeding; high risk of bleeding; stroke in the previous year; platelet count < 150,000

Interventions

Treatment group

  • Tirofiban + heparin

  • Dose, duration, frequency, administration

    • Tirofiban" 0.4 μg/kg/min for 30 minutes, followed by an infusion of 0.1 μg/kg/min

    • Heparin: administered as an intravenous bolus of 5000 U, followed by an infusion of 1000 U/h; the infusion rate was adjusted to achieve an activated partial thromboplastin time twice control

Control group

  • Heparin + tirofiban placebo

  • Dose, duration, frequency, administration

    • Heparin: administered as an intravenous bolus of 5000 U, followed by an infusion of 1000 U/h; the infusion rate was adjusted to achieve an activated partial thromboplastin time twice control

    • Tirofiban placebo: 0.4 μg/kg/min for 30 minutes, followed by an infusion of 0.1 μg/kg/min

Outcomes
  • All-cause mortality

  • Myocardial infarction

  • Bleeding

NotesData not extractable for meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskUnclear
Allocation concealment (selection bias)Low riskRandomisation was performed locally by means of sealed envelopes
Blinding (performance bias and detection bias)
All outcomes
Low risk"All events were evaluated by an endpoints committee whose members were unaware of the patients’ treatment assignments. The investigators remained blinded to treatment until after the six-month visit. Personnel involved in the organization and monitoring of the trial and investigators remained blinded to the nature of treatment in this study group until after final analysis of the results"
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to determine
Selective reporting (reporting bias)High riskOutcomes reported as pre-specified; data not extractable for meta-analysis
Other biasHigh riskThe tirofiban + placebo arm was terminated earlier than planned and not included in the final analysis

PURSUIT Study 1998

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 6 months

  • Lost to follow-up: 18% (discharge from hospital)

Participants
  • Country: US and Europe

  • Setting: Multicentre

Inclusion criteria

  • Patients with symptoms of ischaemic chest pain at rest, lasting ≥ 10 minutes within the previous 24 hours, with transient ST-segment elevation > 0.5 mm, transient or persistent ST-segment depression > 0.5 mm, T-wave inversion > 1 mm within 12 hours before or after chest pain, or a serum concentration of creatine kinase MB isoenzyme (CK-MB) that was above the upper limit of normal for the hospitals where they were evaluated

  • Treatment group: number (1434 with eGFR < 60 mL/min); age and sex (NS)

  • Control group: number (1183 with eGFR < 60 mL/min); age and sex (NS)

Exclusion criteria

  • Persistent ST-segment elevation > 1 mm; active bleeding or a history of bleeding diathesis, gastrointestinal or genitourinary bleeding within 30 days before enrolment; systolic BP > 200 mm Hg or diastolic BP > 110 mm Hg; history of major surgery within the previous 6 weeks; a history of non- haemorrhagic stroke within the previous 30 days or any history of haemorrhagic stroke; kidney failure; pregnancy; planned administration of a platelet glycoprotein IIb/IIIa receptor inhibitor or thrombolytic agent; or the receipt of thrombolytic therapy within the previous 24 hours

Interventions

Treatment group

  • High-dose eptifibatide + aspirin + heparin

  • Dose, duration, frequency, administration

    • Eptifibatide: bolus dose of 180 μg/kg, followed by an infusion of 2.0 μg/kg/min. The study drug was to be infused until discharge from the hospital or for 72 hours, whichever came first. If a coronary intervention was performed near the end of the 72 hour infusion period, the infusion could be continued for an additional 24 hours (total, 96 hours). Cardiac catheterisation and percutaneous or surgical revascularisation were performed at the discretion of the treating physicians

    • Aspirin: 80 to 325 mg/d at the discretion of the treating physicians

    • Heparin (IV): bolus dose of 5000 U, followed by an infusion at a rate of 1000 U/h, with the activated partial-thromboplastin time maintained in the range of 50 to 70 seconds

Control group

  • Placebo + aspirin + heparin

  • Dose, duration, frequency, administration

    • Placebo: Bolus and infusion until discharge from the hospital or for 72 hours, whichever came first

    • Aspirin: 80 to 325 mg/d at the discretion of the treating physicians

    • Heparin (IV): bolus dose of 5000 U, followed by an infusion at a rate of 1000 U/h, with the activated partial-thromboplastin time maintained in the range of 50 to 70 seconds

Outcomes
  • Primary outcome: composite of death from any cause or nonfatal myocardial infarction at 30 days

  • Secondary endpoints: mortality from all causes within 30 days after the index event, a first or recurrent myocardial infarction within 30 days, the composite endpoint (death or non-fatal myocardial infarction) at 96 hours and 7 days, and measures of the safety and efficacy of treatment in patients undergoing percutaneous revascularisation

  • Safety endpoint included mild, moderate and severe bleeding events (according to GUSTO and TIMI classification)

  • Stroke, classified as haemorrhagic, ischaemic, or ischaemic with haemorrhagic conversion

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Low riskRandomisation was performed, in a double-blind manner, by coordinating centres in the United States or the Netherlands
Blinding (performance bias and detection bias)
All outcomes
Low risk

Defined as double-blind

Outcome assessors blinding: "Suspected infarctions were evaluated by a masked clinical- events committee"

Data analysis blinding not stated

Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to determine
Selective reporting (reporting bias)Low riskOutcomes reported as pre-specified
Other biasHigh risk

"It was specified in the protocol that the study would be stopped in the lower-dose group after the independent data safety and monitoring committee had conducted an interim review of safety data, provided the higher dose had an acceptable safety profile. After 3218 patients had been randomly assigned to treatment groups, the committee recommended dropping the lower dose."

Percentage of discontinuation of study drug due to early discharge from hospital not balanced across groups

Quarto Di Palo 1991

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 12 months

  • Lost to follow-up: 0%

Participants
  • Country: Italy

  • Setting: Hospital

Inclusion criteria

  • Patients with cadaveric kidney transplant with creatinine < 140 μmol/L

  • Treatment group: number (18); age (37 years); males (72%)

  • Control group: number (18); age (37 years); males (67%)

Exclusion criteria

  • Creatinine ≥ 140 μmol/L

Interventions

Treatment group

  • Picotamide

  • Dose, duration, frequency, administration: 600 mg/d for 12 months

Control group

  • Identical placebo

  • Dose, duration, frequency, administration: placebo/d for 12 months

Outcomes
  • Change in SCr

  • Safety of treatment

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears to record outcomes for all patients
Selective reporting (reporting bias)Unclear riskUnable to determine
Other biasUnclear riskInsufficient information

RAPPORT Study 1998

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 6 months

  • Lost to follow-up: 0.8% at 30 days; 2.3% at 6 months

Participants
  • Country: US

  • Setting: Multicentre

Inclusion criteria

  • Patients within 12 hours of the onset of acute myocardial infarction, referred for primary angioplasty

  • Treatment group: number (27); age (60 years); males (73%)

  • Control group: number (35); age (62 years); males (72%)

Exclusion criteria

  • Severe thrombocytopenia; baseline prothrombin time > 1.2 times control; ongoing internal bleeding or recent major surgery; previous stroke; severe uncontrolled hypertension; PTCA of the infarct artery within 3 months; cardiogenic shock or prolonged resuscitation; vasculitis; prior administration of abciximab or fibrinolytic therapy; or inability to give written informed consent

Interventions

Treatment group

  • Abciximab

  • Dose, duration, frequency, administration: 0.25 mg/kg bolus followed by a 12 hours infusion of 0.125 μg/kg/min (maximum 10 μg/min)

Control group

  • Matching placebo

  • Dose, duration, frequency, administration: Bolus placebo and 12 hours infusion placebo

Non-randomised co-interventions

  • Heparin + aspirin

  • Dose, duration, frequency, administration: before angioplasty, a 100 U/kg heparin bolus was given, followed by additional weight-adjusted doses to maintain an activated clotting time > 300 seconds during the procedure in both groups. Heparin could be continued for a maximum of 48 hours, with an activated partial thromboplastin time of 60 to 85 seconds maintained. All patients received aspirin and the rest of their medical regimen at the investigator's discretion

Outcomes
  • All-cause mortality

  • Myocardial infarction

  • Major bleeding

  • Minor bleeding

  • Revascularisation

NotesUnpublished data provided for individuals with CKD defined as GFR < 60 mL/min/1.73 m²
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information available
Allocation concealment (selection bias)Unclear riskNo information available
Blinding (performance bias and detection bias)
All outcomes
Low riskThe investigators, central adjudication committee, and sponsors remained blinded to treatment allocation until the database was finalised and the pre-specified analyses were performed
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow percentage of lost to follow-up at 6 months. Intention-to-treat analysis
Selective reporting (reporting bias)Unclear riskNo pre-specified outcomes
Other biasUnclear riskInsufficient information

Schulze 1990

Methods
  • Study design: RCT

  • Study duration: 12 months

  • Lost to follow-up: 0%

Participants
  • Country: Germany

  • Setting: Hospital

Inclusion criteria

  • Patients with cadaveric kidney transplant

  • Treatment group: number (32); age and sex (NS)

  • Control group: number (32); age and sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Dipyridamole

  • Dose, duration, frequency, administration: 150 mg 3 times/d for 12 months

Control group

  • No treatment

Outcomes
  • Loss of graft function at 0, 3, 6 and 12 months

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
High riskNo blinding
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskUnable to determine
Selective reporting (reporting bias)Unclear riskOutcomes not specified in the protocol
Other biasUnclear riskInsufficient information

Sreedhara 1994

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 18 months or until the first thrombotic episode; April 1982 to February 1988

  • Lost to follow-up: 42% (11/108 did not complete the study, 34/108 withdrew due to adverse effects)

Participants
  • Country: USA

  • Setting: three hospitals

Inclusion criteria

  • Patients who required a new ePTFE graft for chronic haemodialysis (Type I) or patients on chronic haemodialysis who had ePTFE graft who developed thrombosis and required revision or thrombectomy (Type II)

  • Treatment group 1: number (29); age (Type I: 56.6 ± 15.0 years; Type II: 62.2 ± 16.7 years); M/F (7/22)

  • Treatment group 2: number (26); age (Type I: 56.7 ± 14.5 years; Type II: 43.0 ± 17.5 years); M/F (16/10)

  • Treatment group 3: number (29); age (Type I: 51.3 ± 17.8 years; Type II: 48.5 ± 22.2 years); M/F (9/20)

  • Control group: number (24); age (Type 1: 55.3 ± 10.6 years; Type II: 57.0 ± 15.8 years); M/F (13/11)

Exclusion criteria

  • Uncontrolled hypertension (defined as sitting diastolic BP of > 110 mm Hg); history of active peptic ulcer disease; haemophilia; von Willebrand's disease or other bleeding disorders; neoplastic disorders and hypersensitivity to aspirin or dipyridamole

Interventions

Treatment group 1

  • Dipyridamole + aspirin placebo

  • Dose, duration, frequency, administration

    • Dipyridamole: 75 mg 3 times/d for 18 months or until first episode of thrombosis

    • Aspirin placebo: once/d for 18 months or until first episode of thrombosis

Treatment group 2

  • Dipyridamole placebo + aspirin

  • Dose, duration, frequency, administration

    • Dipyridamole placebo: 3 times/d for 18 months or until first episode of thrombosis

    • Aspirin: 325 mg/d, for 18 months or until first episode of thrombosis

Treatment group 3

  • Dipyridamole + aspirin

  • Dose, duration, frequency, administration

    • Dipyridamole 75 mg 3 times/d for 18 months or until first episode of thrombosis

    • Aspirin: 325 mg once/d for 18 months or until first episode of thrombosis

Control group

  • Dipyridamole placebo + aspirin placebo

  • Dose, duration, frequency, administration

    • Dipyridamole placebo: 3 times/d for 18 months or until first episode of thrombosis

    • Aspirin placebo: once/d for 18 months or until first episode of thrombosis

Outcomes
  • ePTFE graft thrombosis

  • Adverse reaction to the drugs

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Randomization was done using a predetermined schedule"
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Unclear risk

"Placebo drugs looked identical to actual drugs and were similarly packaged. Neither patients nor investigators could determine the specific treatment protocol assigned to the patients"

Blinding of patients and investigators stated, but not of outcomes assessors and data analysis

Incomplete outcome data (attrition bias)
All outcomes
High riskHigh percentage of lost to follow-up
Selective reporting (reporting bias)High riskOur primary outcomes not reported
Other biasUnclear riskInsufficient information

STOP Study 1995

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 12 months

  • Lost to follow-up: NS

Participants
  • Country: Italy

  • Setting: Multicentre

Inclusion criteria

  • Haemodialysis patients (haemodialysis treatment started at least 60 days earlier) with permanent internal stabilised vascular access (autologous arteriovenous fistula or arteriovenous fistula with prosthetic graft)

  • Treatment group: number (398); age and sex (NS)

  • Control group: number (413); age and sex (NS)

Exclusion criteria

  • History of relevant bleeding; serious hepatic insufficiency; treatment with antiplatelets/NSAIDS; hypersensitivity to study drug

Interventions

Treatment group

  • Picotamide

  • Dose, duration, frequency, administration: NS

Control group

  • Placebo

  • Dose, duration, frequency, administration: NS

Outcomes
  • All-cause mortality

  • Cardiovascular mortality

  • Major bleeding

NotesPublished results from an earlier systematic review ATT 2002 (protocol published)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear risk"Assignment of the randomisation codes is organized in blocks and the patients are enrolled according to the sequential order designated for each centre"
Allocation concealment (selection bias)Low risk"The randomisation key relative to each individual patient is contained in a sealed envelope that must be opened in case of emergency"
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDefined as double-blind. Blinding of data analysis and outcomes assessors not stated
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information available
Selective reporting (reporting bias)Unclear riskNo information available
Other biasUnclear riskNo information available

Taber 1992

Methods
  • Study design: RCT

  • Study duration: 3 months

  • Lost to follow-up: 0%

Participants
  • Country: US

  • Setting: NS

Inclusion criteria

  • Patients who underwent a new haemodialysis vascular graft placement

  • Treatment group: number (12); age and sex (NS)

  • Control group: number (15); age and sex (NS)

Exclusion criteria: NS

Interventions

Treatment group

  • Aspirin

  • Dose, duration, frequency, administration: started two days before and given for 14 days after graft placement

Control group

  • No treatment

Outcomes
  • Graft stenosis (assessed angiographically at 3 months)

NotesConference proceedings only
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo information provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo information provided
Selective reporting (reporting bias)Unclear riskNo information provided
Other biasHigh riskAbstract only

TARGET Study 2001

Methods
  • Study design: RCT

  • Study duration: 6 months (myocardial infarction), 1 year (all-cause mortality)

  • Follow-up: Unclear

Participants
  • Setting: Multicentre (149 hospitals)

  • Countries: Multinational (18 countries)

  • Inclusion criteria

  • Scheduled to undergo a coronary stenting procedure of a newly stenotic or restenotic atherosclerotic lesion in a native vessel or bypass graft. All lesions that were judged to have stenosis > 70% on angiography had to be amenable to stenting for the patient to qualify. Patients who were undergoing an elective procedure or one performed urgently were eligible

  • Definition of CKD: eGFR < 60 mL/min/1.73 m²

  • Treatment group 1: number (388); and sex (NS)

  • Treatment group 2: number (402); age and sex (NS)

Exclusion criteria

  • Cardiogenic shock or an acute myocardial infarction with electrocardiographic evidence of ST-segment elevation; SCr level ≥ 2.5 mg/dL (221 µmol/L); ongoing bleeding or a bleeding diathesis, including platelet count < 120,000 mm³

Interventions

Treatment group 1

  • Tirofiban

  • Dose, duration, frequency, administration: bolus dose of 10 µg/kg followed by an infusion of 0.15 kg/min for 18 to 24 hours

Treatment group 2

  • Abciximab

  • Dose, duration, frequency, administration: bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg/min (maximum 10 µg/min) for 12 hours

Outcomes

Relevant to this review

  • Total mortality

  • Non-fatal myocardial infarction

NotesUnpublished data provided by investigators for individuals with CKD. Unpublished data available for mortality at 12 months and myocardial infarction at 6 months
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble blind, double dummy
Incomplete outcome data (attrition bias)
All outcomes
Low riskData provided by authors
Selective reporting (reporting bias)Low riskAll outcomes prespecified in protocol
Other biasUnclear riskInsufficient information

TRITON-TIMI 38 2007

Methods
  • Study design: RCT

  • Study duration: 14.5 months (median)

  • Lost to follow-up: 0.1 (14 patients)

Participants
  • Country: International (30 countries)

  • Setting: Multicentre (707 sites)

Inclusion criteria

  • Patients with acute coronary syndromes (both patients with moderate-to-high-risk unstable angina or non–ST-elevation myocardial infarction and patients with ST-elevation myocardial infarction). The inclusion criteria for patients with unstable angina or non–ST-elevation myocardial infarction were ischaemic symptoms lasting 10 minutes or more and occurring within 72 hours before randomisation, a TIMI risk score 19 of 3 or more, and either ST-segment deviation ≥ 1 mm or elevated levels of a cardiac biomarker of necrosis. Patients with ST-elevation myocardial infarction could be enrolled within 12 hours after the onset of symptoms if primary PCI was planned or within 14 days after receiving medical treatment for ST-elevation myocardial infarction

  • Overall: number (1490 with eGFR < 60 mL/min/1.73m²); age (74.4 ± 8.3 years); males (51.5%); hypertension (78%); diabetes mellitus (29.9%)

  • Treatment group 1: number (717)

  • Treatment group 2: number (773)

Exclusion criteria

  • Increased risk of bleeding; anaemia; thrombocytopenia; a history of pathologic intracranial findings; or the use of any thienopyridine within 5 days before enrolment

Interventions

Treatment group 1

  • Intervention: Prasugrel

  • Dose, duration, frequency, administration: loading dose of 60 mg of prasugrel. After PCI, patients received maintenance doses of prasugrel (10 mg/d)

Treatment group 2

  • Clopidogrel

  • Dose, duration, frequency, administration: loading dose of 300 mg of clopidogrel. After PCI, patients received maintenance doses of clopidogrel (75 mg/d)

Non-randomised cointervention

  • Daily aspirin was required

  • Dose, duration, frequency, administration: 75 to 162 mg recommended

Outcomes
  • Primary endpoint: composite of the rate of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke

  • Secondary end points at 30 and 90 days: the primary composite end point and a composite of death from cardiovascular causes, nonfatal myocardial infarction, or urgent target-vessel revascularisation

  • Secondary end points for the entire follow-up period: stent thrombosis and a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or re-hospitalisation due to a cardiac Ischaemic event

  • TIMI major bleeding not related to coronary-artery bypass grafting (CABG), non–CABG-related TIMI life-threatening bleeding, and TIMI major or minor bleeding, as previously defined

NotesUnpublished data for participants with eGFR < 60 mL/min/1.73 m²
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding (performance bias and detection bias)
All outcomes
Low riskBlinding of patients, investigators and outcomes assessors
Incomplete outcome data (attrition bias)
All outcomes
Low riskLow percentage of lost to follow-up
Selective reporting (reporting bias)Low riskOutcomes reported as prespecified
Other biasUnclear riskInsufficient information

UK-HARP-I Study 2005

Methods
  • Study design: placebo-controlled RCT

  • Study duration: 12 months

  • Lost to follow-up: 20%

Participants
  • Country: UK

  • Setting: Multicentre

Inclusion criteria

  • Men or women ≥ 18 years were eligible if: (1) they were a predialysis patient with the most recent SCR ≥ 1.7 mg/dL (150 mol/L), a haemodialysis or peritoneal dialysis patient, or had a functioning kidney transplant (with any creatinine level); and (2) their own nephrologist and primary care physician did not consider there was a definite indication for (or contraindication to) cholesterol lowering therapy or aspirin

  • Treatment group 1: number (112); age (54 ± 14 years); M/F (78/34)

  • Treatment group 2: number (112); age (52 ± 15 years); M/F (79/33)

  • Treatment group 3: number (113); age (52 ± 16 years); M/F (81/32)

  • Control group: number (111); age (54 ± 15 years); M/F (76/35)

Exclusion criteria

  • There was no upper limit to blood cholesterol levels, but patients were not to be randomised if their own doctor considered that cholesterol-lowering therapy should be prescribed; evidence of a recent history of acute uraemia, history of chronic liver disease, inflammatory muscle disease (i.e. dermatomyositis or polymyositis) or creatine kinase level > 3 times the upper limit of normal (ULN); previous adverse reaction to a statin or history of aspirin hypersensitivity (e.g. aspirin-induced asthma or angioedema); concurrent treatment with a contraindicated drug (i.e. non-study statin, fibrate, niacin, macrolide antibiotic; systemic azole antifungal, nefazodone, or oral anticoagulant therapy); high immediate risk for bleeding (e.g. active peptic ulceration, recent injury, or haemophilia); child-bearing potential in the absence of a reliable method of contraception; a life-threatening condition other than CKD or vascular disease (e.g. non skin cancer or acquired immunodeficiency syndrome); frequent nonattendance at clinics or known noncompliance with drug treatments; or alcohol or substance abuse

Interventions

Treatment group 1

  • Simvastatin + aspirin

  • Dose, duration, frequency, administration

    • Simvastatin: 20 mg/d for 12 months

    • Aspirin: 100 mg/d for 12 months

Treatment group 2

  • Simvastatin + aspirin placebo

  • Dose, duration, frequency, administration

    • Simvastatin: 20 mg/d for 12 months

    • Aspirin placebo: 1 tablet/d for 12 months

Treatment group 3

  • Aspirin + simvastatin placebo

  • Dose, duration, frequency, administration

    • Aspirin: 100 mg/d for 12 months

    • Simvastatin placebo: 1 tablet/d for 12 months

Control group

  • Simvastatin placebo + aspirin placebo

  • Dose, duration, frequency, administration

    • Simvastatin placebo: 1 tablet/d for 12 months

    • Aspirin placebo: 1 tablet/d for 12 months

Outcomes
  • Safety of aspirin including death and nonfatal serious adverse events (initiation of dialysis therapy, vascular access procedure, kidney transplantation, bleeding episodes, vascular events)

Notes2-by-2 factorial design (aspirin and or simvastatin)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskMinimisation
Allocation concealment (selection bias)Low risk"Randomisation was by telephone to the Clinical Trial Service Unit, University of Oxford, UK"
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo was used
Incomplete outcome data (attrition bias)
All outcomes
Low riskAppears to record outcomes for all patients
Selective reporting (reporting bias)Low riskRelevant outcomes reported
Other biasHigh riskPremature discontinuation of study due to insufficient bleeding events

Zäuner 1994

  1. a

    ACEi - angiotensin-converting enzyme inhibitors; AV - arteriovenous; AVF - arteriovenous fistula; BP - blood pressure; CKD - chronic kidney disease; CrCl - creatinine clearance; ESKD - end-stage kidney disease; eGFR - estimated glomerular filtration rate; GFR - glomerular filtration rate; Hb - haemoglobin; IgAN - IgA nephropathy; M/F - male/female; MPGN - membranoproliferative glomerulonephritis; NS - not stated; PTFE - polytetrafluoroethylene; RCT - randomised controlled trial; SCr - serum creatinine; UTI - urinary tract infection

Methods
  • Study design: no treatment RCT

  • Duration: 36 months

  • Lost to follow-up: 0%

Participants
  • Country: Germany

  • Setting: Multicentre

Inclusion criteria

  • Patients with biopsy proven MPGN and nephrotic syndrome

  • Treatment group: number (10); age (48.0 ± 5.7 years); M/F (8/2)

  • Control group: number (8); age (41.4 ± 5.6 years); M/F (3/5)

Exclusion criteria: NS

Interventions

Treatment group

  • Acetylsalicylic acid + dipyridamole

  • Dose, duration, frequency, administration

    • Oral acetylsalicylic acid: 500 mg/d for 36 months

    • Oral dipyridamole: 75 mg/d for 36 months

Control group

  • No treatment

Outcomes
  • Change in SCr, 24 hour urine protein

  • Nephrotic patients (%) at the end of treatment

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information provided
Allocation concealment (selection bias)Unclear riskNo information provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnable to determine
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo loss to follow-up
Selective reporting (reporting bias)Unclear riskUnable to determine
Other biasUnclear riskInsufficient information

Characteristics of excluded studies [ordered by year of study]

StudyReason for exclusion
  1. a

    CKD, chronic kidney disease; RAS, renal artery stenosis; RCT, randomised controlled trial

SYMPHONY I Study 2000No CKD data available
Lindsay 1972Not appropriate intervention
Rubin 1982Duration of follow-up less than 2 months
Salter 1984Short duration of follow-up
Peto 1988Not CKD population
Physician Health Study 1989Not CKD population
Dmoszynska 1990Duration of follow-up less than 2 months
Caravaca 1995Antiplatelets not randomised
Zibari 1995No CKD data available (authors contacted)
Swan 1995Not appropriate intervention
CAPRIE Study 1996No CKD data available (authors contacted)
Vienken 1996Not RCT
Lee 1997Antiplatelet combined with anticoagulant compared with control
Kamper 1997Duration of follow-up less than 2 months
Minakata 1998Not randomised
Gorter 1998Comparator was anticoagulant
Physician Health Study 1998Not CKD population
Lang 1998Not RCT
Yoshikawa 1999Paediatric population
Movchan 2001Duration of follow-up less than 2 months
Van Der Zaag 2001Comparator was anticoagulant
Hayden 2002Not RCT
Janicki 2003Not RCT
Perkovic 2004Unpublished; and no relevant outcomes as per author communication
SYMPHONY II 2005No CKD data available
NITER Study 2005Intervention did not match inclusion criteria
Chew 2005Intervention did not match inclusion criteria
Trimarchi 2006Not RCT
EXCITE Study 2008Patients with CKD were excluded and data for albuminuria were not reported
RESIST Study 2008Duration of follow-up less than 2 months
STENO-2 Study 2008Antiplatelet combined with multiple non-antiplatelet intervention compared with control
Kim 2009Not RCT
RAS-CAD Study 2009Intervention did not match inclusion criteria. Medical therapy vs. stenting + medical therapy for RAS
Huang 2009Not RCT

Characteristics of ongoing studies [ordered by study ID]

FAVOURED Trial

Trial name or titlePreventing 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
MethodsRCT (factorial-design)
ParticipantsAdult patients with stage IV or V CKD currently on haemodialysis or where haemodialysis is planned to start within 6 months in whom a planned upper or lower arm arteriovenous fistula (AVF) is to be the primary haemodialysis access. Target sample size 1200
InterventionsAspirin or matching placebo and also to omega-3-fatty acids or matching placebo, stratified by study site and upper versus lower AVF
OutcomesPatency of the AVF at three months. Secondary outcome measures will include functional patency at six and twelve months, primary patency time, secondary (assisted) patency time, and adverse events, particularly bleeding.
Starting date21/08/2008
Contact informationPeta-Anne Paul-Brent, Australasian Kidney Trials Network, School of Medicine, Ground Level, Building 33 Princess Alexandra Hospital Ipswich Rd Woolloongabba QLD 4102, p.kerr@uq.edu.au
NotesAustralia & New Zealand Clinical Trials Register (ACTRN12607000569404) available at http://www.anzctr.org.au/trial_view.aspx?id=82388

NCT01198379

Trial name or titleAspirin in the Prevention of Cardiovascular Events in Hemodialysis Patients
MethodsDouble-blind controlled RCT
ParticipantsPatients with end-stage renal disease who are undergoing long-term haemodialysis
InterventionsAspirin 100 mg for 3 years or matching placebo. Target sample size: 250
OutcomesPrimary outcome is aspirin resistance. Secondary outcomes are the incidence of vascular events (myocardial infarction, cardiac death, stroke, vascular access thrombosis, or revascularization procedure)
Starting dateFebruary 2010
Contact informationYing-Hwa Chen, MD, PhD
NotesClinicalTrials.gov Identifier: NCT01198379 available at http://clinicaltrials.gov/ct2/show/NCT01198379

Ancillary