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Effects of Antiplatelet Therapy on Mortality and Cardiovascular andBleeding Outcomes in Persons With Chronic Kidney DiseaseA Systematic Review and Meta-analysis

Suetonia C. Palmer, MB ChB, PhD; Lucia Di Micco, MD; Mona Razavian, MB BS; Jonathan C. Craig, MB ChB, DCh, MM, PhD;

Vlado Perkovic, MB BS, PhD; Fabio Pellegrini, MSc; Massimiliano Copetti, MSc, PhD; Giusi Graziano, MSc; Gianni Tognoni, MD;

Meg Jardine, MB BS, PhD; Angela Webster, MB BS, PhD; Antonio Nicolucci, MD; Sophia Zoungas, MD, PhD; and

Giovanni F.M. Strippoli, MD, PhD, MPH, MM

Background:Antiplatelet agents are used to prevent cardiovascularevents; however, treatment effects may differ in persons withchronic kidney disease (CKD) because atherosclerotic disease is lessprevalent, whereas bleeding hazards may be increased in thispopulation.

Purpose: To summarize the effects of antiplatelet treatment oncardiovascular events, mortality, and bleeding in persons with CKD.

Data Sources:Embase and Cochrane databases through November2011 without language restriction.

Study Selection: Randomized trials that included adults with CKDand compared antiplatelet agents with standard care, placebo, orno treatment.

Data Extraction: Data for populations, interventions, outcomes,and risk for bias were extracted. Quality of evidence for treatmenteffects on myocardial infarction, death, and bleeding was summa-rized by using Grading of Recommendations Assessment, Develop-ment, and Evaluation guidelines.

Data Synthesis: Nine trials (all post hoc subgroup analyses forCKD) involving 9969 persons who had acute coronary syndromesor were undergoing percutaneous coronary intervention and 31

trials involving 11 701 persons with stable or no cardiovasculardisease were identified. Low-quality evidence has found that inpersons with acute coronary syndromes, glycoprotein IIb/IIIa inhib-itors or clopidogrel plus standard care compared with standard carealone had little or no effect on all-cause or cardiovascular mortalityor on myocardial infarction but increased serious bleeding. Com-pared with placebo or no treatment in persons with stable or nocardiovascular disease, antiplatelet agents prevented myocardial in-farction but had uncertain effects on mortality and increased minorbleeding according to generally low-quality evidence.

Limitations:Data for antiplatelet agents in persons with CKD arefrequently derived from post hoc analyses of trials of broader pop-ulations. Definitions for bleeding outcomes and trial duration wereheterogeneous.

Conclusion: Benefits for antiplatelet therapy among persons withCKD are uncertain and are potentially outweighed by bleedinghazards.

Primary Funding Source: None.

Ann Intern Med.2012;156:445-459. www.annals.org

For author affiliations, see end of text.

Chronic kidney disease (CKD) is an important publichealth challenge. Approximately 10% to 15% of theadult population worldwide has CKD, and prevalence isincreasing because of the epidemics of diabetes mellitusand obesity (1). Chronic kidney disease causes illness andpremature death. Nearly 50% of persons aged 70 years orolder (1) and between 33% and 50% of persons with acutemyocardial ischemia have CKD (2). Even in early-stageCKD, the risk for premature cardiovascular disease is in-creased by 25% to 30% (3) and is more than 30- to 50-

fold higher in persons with end-stage kidney disease (4).Antiplatelet agents are widely used to prevent cardio-vascular events by inhibiting intravascular thrombosis. Anti-platelet drugs reduce vascular deaths by 15% and seriouscardiovascular events by 20% in persons at high risk for avascular event (5). Extrapolating these benefits of antiplate-let therapy to persons with CKD is problematic becausenonatherosclerotic conditions (cardiac failure, sudden car-diac death, and arrhythmia) are more common causes ofcardiovascular events in persons with CKD than in thegeneral population (5, 6). The bleeding risk of antiplateletagents may be greater (7) among persons with CKD be-cause of impaired hemostasis (8).

Treating complications of CKD imposes an importanteconomic burden. Health costs of treating a person withCKD are nearly 3-fold higher than those for a person with-out CKD, and the cost of treating end-stage kidney diseaseis 10-fold higher (9, 10). Together, increasing use of healthresources, continued poor outcomes, and emergence ofperformance measures directed to the care of persons withCKD (11) necessitate careful evaluation of all health careinterventions in this growing population. The aim of ourstudy was to summarize the benefits and harms of anti-

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platelet agents in persons with CKD, focusing on cardio-vascular events, mortality, and bleeding.

METHODSWe conducted a systematic review based on standard

methods, including a published, peer-reviewed protocol

(12) and reporting in accordance with the Preferred Re-porting Items for Systematic Reviews and Meta-Analysesstatement (13).

Data Sources and Searches

We searched Embase from 1980 to November 2011,the Cochrane Central Register of Controlled Trialsthrough Issue 4 of 2011, and the Cochrane Renal Groupsspecialized register through November 2011 without lan-guage restriction by using a search strategy designed by aspecialist information manager (Appendix Table 1, avail-able at www.annals.org). The Cochrane Renal Groups reg-ister was populated by weekly Ovid MEDLINE AutoAlerts,

quarterly searches from the Cochrane Central Register ofControlled Trials, and hand-searching. We contacted in-vestigators to request unpublished data for persons whohad CKD at baseline. We received and included additionaldata from these investigators for 3 trials that were not iden-tified by our initial search (1416). We screened the ref-erence lists of retrieved publications, including a meta-analysis (5), for potentially eligible trials.

Study Selection

We included trials that compared antiplatelet agentswith placebo, standard care, or no treatment in adultswith CKD (as defined by the National Kidney Founda-

tion Kidney Disease Outcomes Quality Initiative crite-ria [17]) or trials of broader populations for which datafor participants with CKD could be disaggregated. Pe-diatric trials were excluded. We excluded 5 trials report-ing follow-up shorter than 2 months (1822) because

we wanted to focus on longer-term outcomes. Sensitiv-

ity analyses, including only trials with follow-up longerthan 1 year, were conducted.

Data Extraction and Quality Assessment

Two or more independent authors screened the titleand abstract of retrieved citations and reviewed the full textof potentially eligible citations to identify trials that ful-filled the inclusion criteria. For included trials, we ex-tracted data on population characteristics; interventions;and outcomes, including fatal or nonfatal myocardial in-farction or stroke, death (total and cause-specific), coronaryartery revascularization, major or minor bleeding (Appen-dix Table 2, available at www.annals.org) (6, 1416, 23

58), end-stage kidney disease, all-cause hospitalization, andtreatment withdrawal. Risk of bias was assessed accordingto standardized methods (59).

Data Synthesis and Analysis

Relative risks (RRs) and 95% CIs were calculated fromthe numbers of events and participants at risk for events.

When crude event rates were not provided, the reportedrisk ratio was extracted (27). Relative risks and CIs werethen summarized by using an exact bivariate random-effects meta-analysis method following the approach pro-posed by Stijnen and colleagues (60). Sensitivity analyses tocheck for robustness of our findings were performed with

the inverse of the sample size in the opposite treatmentarm (61) and the arcsine methods (62). If exact bivariaterandom effects could not be used because crude event data

were not available, we used a Bayesian meta-analysis fol-lowing Greenlands data equivalents approach (63).

We tested for heterogeneity of treatment effects be-tween studies with the Cochran Q and I2 test statistics(64). Potential sources of heterogeneity in intervention ef-fects were explored by prespecified subgroup analysis (typeof antiplatelet regimen or stage of CKD [predialysis, dial-ysis, or kidney transplantation]) by reporting results ofanalyses when 4 or more studies were available for each

subgroup. To assess potential bias from small study effects,we constructed funnel plots displaying the log RR on thehorizontal axis and the SE of the log RR on the verticalaxis. To evaluate the presence and extent of publicationbias, we used the Egger regression test (65).

We conducted sensitivity analyses, excluding shortertrials (12 months) and those published only in internaldrug company reports. We summarized the quality of evi-dence according to the Grading of Recommendations As-sessment, Development, and Evaluation guidelines (66).

We conducted analyses by using SAS, version 9.1 (SASInstitute, Cary, North Carolina) (67); WinBugs, version1.4.3 (Imperial College and Medical Research Council,

Context

Antiplatelet agents are given for cardiovascular prevention

to patients with chronic kidney disease (CKD).

Contribution

This review found that glycoprotein IIb/IIIa inhibitors or

clopidogrel increased major bleeding but had little or noeffect on myocardial infarction, death or coronary revascu-larization in patients with CKD who had acute coronary

syndromes or were undergoing percutaneous coronaryrevascularization. Antiplatelet regimens in other patientswith CKD who had or were at risk for cardiovascular dis-

ease increased minor bleeding, reduced myocardial infarc-tion, and had uncertain effects on mortality.

Caution

Evidence was weak, derived primarily from subgroupanalysis of trials.

Implication

Risks of antiplatelet agents may outweigh potentialbenefits in some patients with CKD.

The Editors

Review Effects of Antiplatelet Therapy in Persons With CKD

446 20 March 2012 Annals of Internal MedicineVolume 156 Number 6 www.annals.org


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Cambridge, United Kingdom); and Comprehensive Meta-analysis, version 2 (Biostat, Englewood, New Jersey). De-tails of the SAS macro routines based on the linear andnonlinear mixed models (namely Proc MIXED and ProcNLMIXED) are available from the authors on request.

Role of the Funding Source

This project received no specific funding. Dr. Palmerreceived support from an unrestricted Amgen DompeConsorzio Mario Negri fellowship. The authors had fullresponsibility for data collection, data interpretation, and

writing of the report. Drs. Palmer and Strippoli had fullaccess to all of the data and had the final responsibility tosubmit the manuscript for publication.

RESULTSDescription of Trials

Searching identified 1460 publications. Of these pub-lications, 196 were reviewed in full text (Figure 1) and 40

eligible trials or patient subgroups of randomized trials(21 670 participants) were included (Appendix Table 3,available at www.annals.org) (6, 1416, 2358). Thirty-sixtrials (20 942 participants) provided extractable data forinclusion in meta-analyses (6, 1416, 2331, 3437, 3945, 4758). We included unpublished subgroup data forpersons with CKD that were provided by the investigatorsof 12 trials (11 732 participants) (6, 1416, 2325, 28,30, 37, 50, 58).Appendix Table 4 (available at www.annals.org) provides reasons for missing data in the meta-analyses.

Information for 4 trials (14, 4345), including 2 in-ternal company reports (44, 45), were available only in a

previously published meta-analysis of antiplatelet agents(5). For 2 studies, the most complete information was pro-vided in conference proceedings (32, 46), although neitherof these trials provided extractable data for meta-analyses.

Appendix Table 5 (available at www.annals.org) describesthe sources of additional unpublished data.

Nine trials (9969 participants) provided informationon antiplatelet treatment among persons with CKD whopresented with an acute coronary syndrome or were sched-uled to undergo coronary artery intervention and wereconsidered at high risk for subsequent vessel closure (1416, 2328). All data for these trials were published (26, 27)

or unpublished (1416, 2325, 28) post hoc analyses forthe subgroup of participants with CKD from larger trials.Trials provided data for glycoprotein IIb/IIIa inhibitors(abciximab, eptifibatide, or tirofiban) (7 trials, 5471 partic-ipants) (1416, 2326) or clopidogrel (2 trials, 4498 par-ticipants) (27, 28), and all involved coadministration ofaspirin with (14, 15, 2326) or without (16, 27, 28) hep-arin as nonrandomized interventions. Median follow-up

was 12 months.The remaining 31 trials provided data for antiplatelet

treatment among 11 701 persons with CKD who had sta-ble or no cardiovascular disease. Twelve trials assessed theeffects of antiplatelet agents on mortality, progression of

kidney disease, or safety in 6970 patients with glomerulo-nephritis (4 trials, 119 participants) (29, 31, 33, 34) ordiabetic nephropathy (6 trials, 2990 participants) (30, 32,3538) or who had an impaired glomerular filtration rateregardless of cause (2 trials, 3861 participants) (6, 58).These trials generally involved administration of aspirin (6,

30, 36, 38), dipyridamole (36), aspirin and dipyridamole(29, 31, 32, 36), or a thienopyridine (clopidogrel or ticlo-pidine) (34, 37). One trial involved administration of as-pirin as a co-intervention (37). Median follow-up was 12months.

Seventeen trials provided data for antiplatelet treat-ment in 4471 persons receiving or who would soon requiredialysis (3954, 58). These trials involved administrationof a range of antiplatelet agents (aspirin, dipyridamole,clopidogrel, sulfinpyrazone, ticlopidine, or picotamide),and 3 involved administration of additional antiplateletagents or oral anticoagulation as nonrandomized co-interventions (39, 49, 52). Trials were generally of shorter

duration (median, 6 months). Four trials administered an-tiplatelet treatment to 260 kidney transplant recipients(5558).

Risk of Bias in Included Trials

Nine trials of acute coronary syndromes or percutane-ous coronary intervention generally had low risk of bias,

with a high proportion reporting adequate allocation con-cealment (78%), intention-to-treat analysis (89%), blind-ing of outcome assessors (100%), and freedom from selec-tive outcome reporting (89%). However, all were post hocanalyses of trials of broader populations. In more than75% of the remaining 31 trials, methods for random se-

quence generation, allocation concealment, blinding ofoutcome assessors, completeness to follow-up, or the riskfor selective reporting or other biases were unclear or inad-equate (Appendix Figure, available at www.annals.org).

Meta-analysis

Figure 2shows the overall results of all meta-analyses.TheTablesummarizes the quality of the available evidence(4, 6673). Meta-analysis by using exact bivariate randomeffects is reported because sensitivity analyses suggestedthat the effect estimates were robust regardless of the sta-tistical model used.

Effects on Vascular Events Among Patients With AcuteCoronary Syndromes or Requiring PercutaneousCoronary InterventionFatal or Nonfatal Myocardial Infarction and Stroke

Low-quality evidence found that antiplatelet treatmentplus standard care had little or no effect on myocardialinfarction (7 trials, 5261 participants; RR, 0.89 [CI, 0.76to 1.05]), with no evidence of significant heterogeneity(Tableand Figure 3). Including only trials of glycoproteinIIb/IIIa inhibitors provided similar treatment effects (6 tri-als, 4850 participants; RR, 0.87 [CI, 0.74 to 1.03]) (1416, 2325). In the 4 trials (1786 participants) reportingmyocardial infarction at 1 year, the RR was 0.79 (CI, 0.37

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to 1.72) with additional antiplatelet therapy (14, 15, 24,28). One trial provided data on only 6 fatal or nonfatalstrokes in 411 persons, finding that clopidogrel in additionto standard therapy had uncertain effects on stroke (RR,0.51 [CI, 0.09 to 2.77]) (Figure 3).

All-Cause and Cardiovascular Mortality

Low- or very low-quality evidence found that anti-platelet therapy in addition to standard treatment had littleor no effect on all-cause mortality (8 trials, 9347 partici-pants; RR, 0.89 [CI, 0.75 to 1.05]) and uncertain effects

Figure 1. Summary of evidence search and selection.

Duplicate citations removed (n= 63)

Citations screened by title and abstract (n= 1397)

Citations identified in databases (n= 1450)

CENTRAL: 628

EMBASE: 757

Cochrane Renal Register: 65

Citations from other sources (n= 10)

Previous systematic review: 3

Trials registries: 4

Received data from investigators: 3

Citations excluded (n= 1201)

Not original investigations (e.g., reviews): 187

Nonrandomized studies: 215

Not antiplatelet vs. placebo trial: 520

Irrelevant outcome: 57

Animal study: 12

Pediatric: 23

No data for CKD: 187

Full-text articles assessed for eligibility (n= 196)

Citations excluded (n= 126)

Trial duration

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on cardiovascular mortality (2 trials, 4498 participants;RR, 0.96 [CI, 0.79 to 1.16]) without heterogeneity in theanalyses (Table and Figure 3). Including only trials thatevaluated glycoprotein IIb/IIIa inhibitors provided a simi-lar effect estimate for mortality (6 trials, 4849 participants;RR, 0.86 [CI, 0.69 to 1.07]) (1416, 2325). No data

were available for the effects of glycoprotein IIb/IIIa inhib-itors on cardiovascular mortality. Limiting analyses to trialsreporting outcomes at 1 year did not meaningfully alter therisk for death (5 trials, 5873 participants; RR, 0.89 [CI,0.74 to 1.07]) (14, 15, 24, 27, 28).

Effects on Adverse Events (Major and Minor Bleeding,

Including Hemorrhagic Stroke)

All 9 trials (9863 participants) in persons with CKDand acute coronary syndromes or requiring percutaneous

coronary intervention provided information on major andminor bleeding events (Figure 3). Definitions of bleedingoutcomes varied. Major bleeding was defined as an intra-cranial hemorrhage, a decrease in hemoglobin level of 50g/L or more, or a decrease in hematocrit level of 15% ormore in 7 trials (1416, 2325, 28); a decrease in hemo-

globin level of more than 40 g/L, bleeding necessitatingtransfusion of 2 units or more of blood, bleeding necessi-tating corrective surgery, or intracranial or retroperitonealhemorrhage in 1 trial (26); or substantially disabling bleed-ing, intraocular bleeding leading to loss of vision, or bleed-ing necessitating transfusion of 2 units or more of blood in1 trial (27). Minor bleeding included blood loss, a decreasein hemoglobin level of 30 g/L or more, or no observedblood loss with a decrease in hemoglobin level of 40 g/L ormore (6 trials) (14, 16, 23, 25); interruption of study med-

Figure 2. Summary of treatment effects for antiplatelet agents in persons with chronic kidney disease.

Variable

ACS or PCI

Fatal or nonfatal myocardial infarction

Fatal or nonfatal stroke

Coronary revascularization

Cardiovascular death*

All-cause mortality*

All-cause hospitalization

End-stage kidney disease

Major bleeding*

Minor bleeding*

Hemorrhagic stroke

Withdrawal from treatment

At-risk or stable cardiovascular disease




Cardiovascular death

All-cause mortality

All-cause hospitalization

End-stage kidney disease

Major bleeding

Minor bleeding

Hemorrhagic stroke

Withdrawal from treatment

Relative Risk

by Using a

Random-Effects Model (95% CI)

0.89 (0.761.05)

0.51 (0.092.77)

0.93 (0.841.04)

0.96 (0.791.16)

0.89 (0.751.05)

1.40 (1.051.86)

1.47 (1.251.72)

1.08 (0.472.49)

0.66 (0.510.87)

0.66 (0.162.78)

0.91 (0.601.36)

0.87 (0.611.24)

0.95 (0.781.14)

0.70 (0.242.04)

1.29 (0.692.42)

1.70 (1.442.02)

1.42 (0.543.73)

0.87 (0.421.78)

Antiplatelet

Therapy

411/3097

2/203

933/3098

6/203

232/3097

292/3347

585/3347

18/2342

100/4533

80/4533

150/4335

346/5330

333/1768

52/423

92/5131

421/3603

10/1006

213/1290

Control

322/2164

4/208

701/2167

4/208

183/2163

161/2429

313/2429

12/1693

153/4600

90/4600

165/4371

379/5302

352/1767

64/402

64/5099

247/3599

7/1003

211/1225

Trials, n

Events/Participants, n/n

7

1

7

2

8

9

9

5

10

10

16

21

3

8

18

8

1

11

I2, %

2

0

0

0

42

69

0

0

25

26

0

0

0

0

0

0

Favors Antiplatelet

Therapy

Favors Control

0.5 1.0 2.0

Summary estimates are provided by using random-effects meta-analysis. ACS acute coronary syndrome; PCI percutaneous coronary intervention.* Number of events and number of participants from the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Events) trial (27) were notavailable and therefore not included in the summary totals for cardiovascular death, all-cause mortality, or major or minor bleeding.




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ication (1 trial) (27); or bleeding that was incompletelydefined (2 trials) (26, 28).According to low-quality evidence, antiplatelet therapy

in addition to standard care increased major (RR, 1.40 [CI,1.07 to 1.86]) and minor (RR, 1.47 [CI, 1.25 to 1.72])bleeding, although significant heterogeneity was present inthe analyses (Table and Figure 3). Excluding the 2 trialsthat randomly assigned participants to clopidogrel (27,28) resulted in similar effect estimates for major (7 tri-als, 5365 participants; RR, 1.36 [CI, 0.78 to 2.38]) andminor (RR, 1.38 [CI, 1.18 to 1.61]) bleeding with per-sistent heterogeneity in both analyses. Antiplatelet ther-apy increased major bleeding in analyses limited to trials

reporting outcomes at 1 year or more (5 trials, 5868participants; RR, 1.47 [CI, 1.00 to 2.10]) (14, 15, 24,27, 28). In the 5 trials that reported data for hemor-rhagic stroke (1416, 24, 25), treatment hazards of an-tiplatelet therapy were uncertain (4035 participants;RR, 1.08 [CI, 0.47 to 2.49]) (Figure 2).

Effects on Other Outcomes

Antiplatelet treatment had little or no effect on cor-onary artery revascularization (7 trials, 5265 partici-pants; RR, 0.93 [CI, 0.84 to 1.04]) (Figure 3). No data

were available for treatment effects on all-cause hospi-

Table. Evidence Profile for the Effect of Antiplatelet Regimens on Outcomes of Randomized, Controlled Trials in Persons With CKD*

Variable Studies,(Participants),n (n)

Quality Assessment

Study Limitations(Decrease inQuality Score)

Consistency(Decrease inQuality Score)

Directness Precision(Decrease inQuality

Score)

PublicationBias(Decrease in

QualityScore)

ACS or Undergoing PCI

Myocardial infarction 7 (5261) Post hoc subgroupanalyses for CKD(1)

No inconsistency Direct; no information for dialysisor transplantation settings

Imprecision(1)

No importantpublicationbias

Al l-cause m ortal ity 8 (9347) Post hoc subgroupanalyses for CKD(1)


Imprecision(1)


Cardiovascularmortality

2 (4295) Post hoc subgroupanalyses forCKD; at risk forselective report-ing for thisoutcome (1)


Imprecision(1)

Likely (1)

Major bleeding 9 (9863) Post hoc subgroupanalyses for CKD(1)

Unexplainedheterogeneity(1)

Direct; no information for dialysisor transplantation settings

No importantimprecision


At Risk for or With Stable Cardiovascular Disease

Myocardial infarction 8 (9190) Serious l imitations(1)

No inconsistency Direct; unable to explore differ-ences in treatment effectsbased on stage of kidneydisease or antiplatelet type

No importantimprecision


Al l-cause m ortal ity 9 (8667) Ser ious l imitat ions(1)


Imprecision(1)


Cardiovascularmortality

9 (10 632) Serious limitations(1)


Imprecision(1)


Major b leeding 10 (10 123) Ser ious l imitat ions(1)


Imprecision(1)


ACS acute coronary syndrome; CKD chronic kidney disease; PCI percutaneous coronary intervention.*Quality assessed according to the Grading of Recommendations Assessment, Development, and Evaluation guidelines. Data obtained from reference 66.Approximate absolute event rates of outcomes per year are derived from previously published data for myocardial infarction (6870), all-cause mortality (4, 6972),cardiovascular mortality (6972), and bleeding (73). Absolute numbers of persons with CKD who avoided events or had major bleeding were calculated from the riskestimate for the outcome (and associated 95% CI) obtained from a meta-analysis of placebo-controlled trials together with the absolute population risk estimated frompreviously published observational cohort studies.Effect considered imprecise when the CI includes possible benefit from both antiplatelet regimen and control approaches.Relative risks and 95% CIs are based on random-effects models.Glycoprotein IIb/IIIa inhibitor or clopidogrel in addition to standard therapy vs. standard therapy alone.Antiplatelet agent vs. placebo, no treatment, or standard care.




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talization, end-stage kidney disease, or withdrawal fromtreatment.

Effects on Clinical Outcomes Among Patients at Risk foror With Stable Cardiovascular DiseaseFatal or Nonfatal Myocardial Infarction and Stroke

Moderate-quality evidence showed that antiplatelettherapy reduced myocardial infarction (10 trials, 9133 par-

ticipants; RR, 0.66 [CI, 0.51 to 0.87]) but had uncertaineffects on stroke (10 trials, 9133 participants; RR, 0.66[CI, 0.16 to 2.78]) (Table and Figure 4) (6, 30, 37, 43,44, 49, 50, 52, 53, 58). There was no significant hetero-geneity in these analyses. Data were insufficient to performprespecified subgroup analyses based on the type of anti-platelet regimen or stage of kidney disease. No data wereprovided by trials enrolling only kidney transplantrecipients.

Limiting meta-analyses to trials in which follow-upduration was 12 months or more did not meaningfullyalter the risk estimates for these outcomes (6 trials, 7721participants; RR for myocardial infarction, 0.69 [CI, 0.52

to 0.92], and RR for stroke, 0.90 [CI, 0.18 to 4.42]) (6,30, 37, 49, 53, 58). Excluding the trial with data reportedonly in an internal report (44) did not alter the risk esti-mate for myocardial infarction (9 trials, 8848 participants;RR, 0.67 [CI, 0.51 to 0.88]).

All-Cause and Cardiovascular MortalityIn low-quality evidence, antiplatelet therapy had

uncertain effects on all-cause (21 trials, 10 632 partici-pants; RR, 0.87 [CI, 0.61 to 1.24]) (6, 2931, 34, 36,37, 39, 40, 4245, 4850, 5254, 57, 58) and cardio-vascular (16 trials, 8706 participants; RR, 0.91 [CI,0.60 to 1.36]) (6, 2931, 34, 36, 37, 39, 40, 4245,49, 57, 58) mortality, with no significant heterogeneityin analyses (Table and Figure 4). Risk for death fromany cause differed in prespecified subgroups of trialsaccording to the drug used. In 5 trials, aspirin (4340participants; RR, 0.80 [CI, 0.61 to 1.06]) had uncertain

effects on risk for death (6, 30, 36, 48, 58), whereasthienopyridines may increase mortality (7 trials, 3452participants; RR, 1.47 [CI, 1.02 to 2.12]) (P 0.01 forsubgroup interaction) (34, 37, 4244, 52, 54).

Subgroup analysis to explore the effects of CKD stagewas not possible. Estimates for all-cause (13 trials, 8942participants; RR, 0.89 [CI, 0.59 to 1.33]) (6, 2931, 34,36, 37, 45, 48, 49, 53, 57, 58) and cardiovascular (11trials, 8186 participants; RR, 0.92 [CI, 0.56 to 1.51])(6, 2931, 34, 36, 37, 45, 49, 57, 58) mortality did notdiffer when analyses were restricted to trials in whichoutcomes were reported during follow-up of 12 monthsor longer. Excluding 2 trials with data available only ininternal reports (44, 45) did not alter the effects ofantiplatelet treatment on all-cause (19 trials, 9444 par-ticipants; RR, 0.93 [CI, 0.62 to 1.39]) or cardiovascular(14 trials, 7518 participants; RR, 0.94 [CI, 0.55 to1.60]) mortality.

Effects on Adverse Events (Major and Minor Bleeding and

Hemorrhagic Stroke)

Eighteen trials (10 230 participants) reported majorbleeding events (6, 36, 37, 39 45, 48, 49, 5154, 57, 58),and 8 trials (7202 participants) reported minor bleeding

events (6, 29, 36, 37, 40, 42, 52, 58). No trials in thisclinical setting reported data specifically for hemorrhagicstroke. Definitions of major and minor bleeding were gen-erally not well-defined and were not centrally adjudicated

with blinding to treatment allocation, with the exceptionof 2 trials (37, 58). Major bleeding included intracerebralor substantial hemodynamic compromise (37); gastrointes-tinal bleeding (39); hemarthrosis, nasal bleeding, shunthemorrhage, and bleeding at injection site (42); confirmedretroperitoneal, intra-articular, intraocular, or intracranialbleeding or causing the hemoglobin level to decrease by 20g/L or more and requiring hospital admission or transfu-sion (53); or hospital admission or death (58). Minor

TableContinued

Summary of Findings

Relative Risk(95% CI)

Best Estimateof ControlGroup Risk,

%

Absolute Effect per 1 yof Treatment per 1000Persons Treated

(95% CI)

Quality ofEvidence

ACS or Undergoing PCI

0.89 (0.761.05) 30 33 fewer (72 fewer15 more)

Low

0.89 (0.751.05) 40 44 fewer (100fewer20 more)

Low

0.96 (0.791.16) 25 10 fewer (53 fewer40 more)

Very low

1.40 (1.071.86) 2.5 10 more (222 more) Low

At Risk for or With Stable Cardiovascular Disease

0.66 (0.510.87) CKD, 2.5;dialysis, 10

CKD, 9 fewer (312fewer); dialysis, 34fewer (1349 fewer)

Moderate

0.87 (0.611.24) CKD, 2.5;dialysis, 20

CKD, 3 fewer (10fewer6 more);dialysis, 26 fewer (78fewer48 more)

Low

0.91 (0.601.36) CKD, 1.5;dialysis, 10

CKD, 1 fewer (6fewer5 more);dialysis, 9 fewer (40fewer36 more)

Low

1.29 (0.692.42) 2.5 7 more (8 fewer35

more)

Low




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bleeding included occult gastrointestinal or rectal polypbleeding and ecchymoses (29); not needing transfusion orcausing hemodynamic compromise (37); or epistaxis, ec-chymoses, or bruising (58).

According to low-quality evidence, antiplatelet ther-apy significantly increased minor bleeding (RR, 1.70[CI, 1.44 to 2.02]) but had uncertain effects on majorbleeding (RR, 1.29 [CI, 0.69 to 2.42]) ( Table and Fig-ure 4). There was no heterogeneity in these analyses.

Treatment with antiplatelet agents in trials of 1 year orlonger was associated with increased major bleeding (10trials, 8696 participants; RR, 1.55 [CI, 1.07 to 2.26])(6, 36, 37, 45, 48, 49, 51, 53, 57, 58). Excluding the 2trials for which data were available only in internal re-ports (44, 45) also resulted in significantly increasedmajor bleeding in the remaining trials (16 trials, 9042participants; RR, 1.50 [CI, 1.06 to 2.12]). Prespecifiedsubgroup analyses to assess treatment effects in sub-

Figure 3. Effect of antiplatelet agents on cardiovascular, mortality, and bleeding outcomes in persons with CKD and acute coronary

syndromes or undergoing percutaneous coronary intervention.

Study, Year (Reference)


RAPPORT, 1998 (16)

EPILOG, 1997 (24)

EPISTENT, 1998 (15)

CREDO, 2008 (28)

EPIC, 1994 (14)

IMPACT-II, 1997 (23)

PURSUIT, 1998 (25)

Total


CREDO, 2008 (28)

Total


RAPPORT, 1998 (16)EPISTENT, 1998 (15)

CREDO, 2008 (28)

EPILOG, 1997 (24)

EPIC, 1994 (14)


PURSUIT, 1998 (25)

Total

Death due to cardiovascular causes

CREDO, 2008 (28)

CURE, 2007 (27)

Total

All-cause mortality

RAPPORT, 1998 (16)

EPISTENT, 1998 (15)CREDO, 2008 (28)

EPILOG, 1997 (24)


EPIC, 1994 (14)

PURSUIT, 1998 (25)

CURE, 2007 (27)

Total

Relative Risk

by Using a

Random-Effects Model

(95% CI)

0.26 (0.032.09)

0.53 (0.281.00)

0.95 (0.521.75)

1.08 (0.601.92)

0.76 (0.461.25)

1.10 (0.701.71)

0.98 (0.811.07)

0.89 (0.761.05)

0.51 (0.092.77)

0.51 (0.092.77)

0.97 (0.561.69)1.31 (0.852.02)

0.90 (0.601.35)

0.87 (0.631.21)

0.89 (0.681.18)

0.98 (0.751.28)

0.97 (0.881.07)

0.93 (0.841.04)

1.54 (0.445.37)

0.95 (0.771.17)

0.96 (0.791.16)

0.43 (0.091.97)

0.85 (0.332.17)1.28 (0.523.18)

0.61 (0.261.45)

0.51 (0.251.04)

1.06 (0.542.08)

1.04 (0.841.30)

0.95 (0.781.16)

0.89 (0.751.05)

Antiplatelet

Therapy

1/27

18/325

24/231

21/203

33/334

58/547

256/1430

411/3097

2/203

2/203

12/2753/231

36/203

73/325

92/334

124/547

543/1431

933/3098

6/203

2/27

10/23110/203

11/325

15/547

23/334

161/1430

Control

5/35

17/163

15/137

20/208

24/185

25/259

216/1177

322/2164

4/208

4/208

16/3524/137

41/208

42/163

57/185

60/259

461/1180

701/2167

4/208

6/35

7/1378/208

9/163

14/259

12/185

127/1176

Events/Participants,n/n

Weight, %

0.5

5.0

5.5

6.0

8.2

10.1

64.7

100.0

100.0

100.0

2.13.4

3.9

5.9

8.3

8.8

67.6

100.0

2.5

97.5

100.0

0.7

1.92.1

2.3

3.4

3.8

35.9

49.8

100.0

Favors Antiplatelet

Therapy and

Standard Care

Favors

Standard Care

Heterogeneity: 2= 6.14; P= 0.41 (I2= 2%)

Not estimable

Not estimable

Not estimable

Not estimable

Heterogeneity: NA




0.1 1.0 10.0

Continued on following page




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groups of trials based on stage of CKD or antiplateletregimen were not possible.

Effects on Other Outcomes

Antiplatelet therapy had uncertain effects on end-stage

kidney disease, hospitalization, and withdrawal from treat-ment (Figure 2). No data were available for coronary arteryrevascularization in persons with CKD who have stable orno cardiovascular disease.

Small Study Effects and Publication Bias

No asymmetry was observed in the funnel plots for theoutcomes of myocardial infarction, all-cause mortality, ormajor bleeding in trials involving persons at risk for or withstable cardiovascular disease or in those involving acutecardiovascular disease (Egger regression test, P 0.10 forall). This finding suggests that unpublished studies did notcause bias of effect estimates.

DISCUSSION

To our knowledge, this meta-analysis provides thefirst comprehensive summary of the benefits and risks ofantiplatelet treatment in persons with CKD. In general,evidence is of low or very-low quality, with considerablevariation in trial duration; heterogeneity in the defini-tions and assessment of bleeding outcomes; reliance onsubgroup data from major trials, particularly for anti-platelet treatment in acute cardiovascular disease; andsubstantial methodological limitations in data for adults

with CKD and stable cardiovascular disease. Antiplate-let treatment (generally glycoprotein IIb/IIIa inhibitors)given in addition to standard care in persons with acutecoronary syndromes or those undergoing percutaneouscoronary revascularization who also have CKD has littleor no effect on myocardial infarction, death, or coronaryrevascularization but increases major and minor bleed-ing. Evidence for an association between additional anti-

Figure 3Continued


Major bleedingEPISTENT, 1998 (15)

RAPPORT, 1998 (16)

EPILOG, 1997 (24)

PRISM-PLUS, 2002 (26)

CREDO, 2008 (28)

EPIC, 1994 (14)


PURSUIT, 1998 (25)

CURE, 2007 (27)

Total

Minor bleeding

EPISTENT, 1998 (15)

RAPPORT, 1998 (16)

EPILOG, 1997 (24)

CREDO, 2008 (28)EPIC, 1994 (14)


CURE, 2007 (27)

PURSUIT, 1998 (25)

PRISM-PLUS, 2002 (26)

Total

Relative Risk

by Using a

Random-Effects Model

(95% CI)

0.59 (0.171.98)

2.59 (0.877.71)

2.01 (0.685.90)

1.68 (0.714.01)

1.20 (0.572.52)

2.97 (1.605.51)

0.83 (0.461.50)

1.20 (0.951.53)

1.37 (0.892.12)

1.40 (1.071.86)

2.34 (0.806.86)

0.65 (0.251.67)

1.34 (0.642.81)

0.61 (0.311.22)1.87 (1.163.01)

1.63 (1.112.39)

1.50 (1.211.86)

1.93 (1.542.41)

1.10 (0.921.33)

1.47 (1.251.72)

Antiplatelet

Therapy

5/229

8/27

16/325

13/300

14/203

59/334

29/525

148/1404

16/229

5/27

24/325

12/20364/334

103/525

228/1404

133/300

Control

5/134

4/35

4/163

8/311

12/208

11/185

16/241

101/1152

4/134

10/35

9/163

20/20819/185

29/241

97/1152

125/311


Weight, %

4.4

5.3

5.4

7.7

9.5

12.2

12.8

17.6

25.1

100.0

4.9

5.8

7.9

8.611.8

13.5

14.4

16.2

16.8

100.0

Favors Antiplatelet

Therapy and

Standard Care

Favors

Standard Care

Not estimable

Not estimable

Not estimable

Not estimable



0.1 1.0 10.0

Summary estimates are provided by using random-effects meta-analysis. Only trials reporting1 event are shown. CKD chronic kidney disease;CREDO Clopidogrel for the Reduction of Events During Observation; CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events;EPIC Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG Evaluation in PTCA to Improve Long-Term Outcome with

Abciximab GP IIb/IIIa Blockade; EPISTENT Evaluation of Platelet IIb/IIIa Inhibitor for Stenting; IMPACT-II Integrilin to Minimize PlateletAggregation and Coronary Thrombosis-II; NA not applicable; PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management inPatients Limited by Unstable Signs and Symptoms; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression UsingIntegrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial.




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Figure 4. Effect of antiplatelet agents on cardiovascular, mortality, and bleeding outcomes in persons with CKD at risk for or with

stable cardiovascular disease.



Creek, 1990 (44)

UK-HARP-I, 2005 (58)

Kaufman et al, 2003 (50)

Dember et al, 2008 (52)

Dixon et al, 2009 (53)

CHARISMA, 2009 (37)

ETDRS, 1992 (30)

HOT, 2010 (6)

Total


UK-HARP-I, 2005 (58)



STOP, 1995 (49)Dixon et al, 2009 (53)

ETDRS, 1992 (30)

CHARISMA, 2009 (37)

HOT, 2010 (6)

Total

Death due to cardiovascular causes

Ell et al, 1982 (43)

Michie and Wombolt, 1977 (40)

UK-HARP-I, 2005 (58)

Creek, 1990 (44)

STOP, 1995 (49)

Middleton and Deichsel, 1992 (45)

HOT, 2010 (6)

CHARISMA, 2009 (37)

ETDRS, 1992 (30)

Total

All-cause mortality

Ell et al, 1982 (43)

Michie and Wombolt, 1977 (40)

UK-HARP-I, 2005 (58)

Ghorbani et al, 2009 (54)


Sreedhara et al, 1994 (48)


Creek, 1990 (44)

STOP, 1995 (49)

Middleton and Deichsel, 1992 (45)

CHARISMA, 2009 (37)

HOT, 2010 (6)

ETDRS, 1992 (30)

Dixon et al, 2009 (53)

Total

Relative Risk

by Using a

Random-Effects

Model (95% CI)

0.33 (0.017.95)

0.99 (0.0615.8)

0.46 (0.092.46)

0.42 (0.111.63)

1.08 (0.582.02)

0.76 (0.441.31)

0.83 (0.521.31)

0.55 (0.360.85)

0.66 (0.510.87)

2.97 (0.1272.6)

0.13 (0.012.52)

1.98 (0.1821.7)

0.15 (0.021.20)1.70 (0.417.07)

4.03 (1.3512.0)

0.91 (0.501.65)

0.80 (0.531.20)

0.66 (0.162.78)

0.36 (0.028.43)

0.33 (0.027.14)

0.99 (0.0615.8)

1.22 (0.344.46)

0.66 (0.261.69)

0.70 (0.411.21)

0.72 (0.461.11)

1.64 (1.062.54)

0.70 (0.500.97)

0.91 (0.601.36)

0.36 (0.028.43)

0.33 (0.027.14)

0.99 (0.146.97)

1.02 (0.156.95)

0.69 (0.163.01)

0.39 (0.091.61)

0.99 (0.253.93)

0.98 (0.293.31)

0.93 (0.491.76)

0.62 (0.381.03)

1.62 (1.132.32

0.75 (0.551.04)

1.08 (0.841.04)

0.93 (0.751.16)

0.87 (0.611.24)

Antiplatelet

Therapy

0/144

1/225

2/104

3/441

19/321

22/1006

21/79

32/1791

100/4533

1/225

0/104

2/441

1/3985/321

12/79

20/1006

39/1791

80/4533

0/24

0/8

1/225

5/144

7/398

21/451

33/1791

51/1006

32/79

150/4335

0/24

0/8

2/225

2/46

3/104

4/83

4/441

5/144

17/398

23/451

73/1006

62/1791

46/79

105/321

346/5330

Control

1/141

1/223

4/96

7/436

18/328

29/1003

34/106

59/1828

153/4600

0/223

3/96

1/436

7/4133/328

4/106

22/1003

50/1828

90/4600

1/26

1/8

1/223

4/141

11/413

30/452

47/1828

31/1003

39/106

165/4371

1/26

1/8

2/223

2/47

4/96

3/24

4/436

5/141

19/413

37/452

45/1003

84/1828

57/106

115/328

379/5302


Weight, %

0.6

0.8

2.1

3.2

14.8

19.3

27.4

32.0

100.0

2.7

3.1

4.5

5.610.2

14.2

23.8

28.0

100.0

0.9

0.9

1.1

4.7

8.1

16.9

20.8

20.9

25.6

100.0

0.3

0.3

0.7

0.8

1.3

1.4

1.5

1.9

6.0

8.9

14.4

16.6

21.1

24.7

100.0

Favors Antiplatelet

Therapy

Favors

Control

Heterogeneity:2= 4.53; P= 0.87 (I2= 0%)




0.1 1.0 10.0





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platelet therapy and stroke and cardiovascular death in per-sons with CKD and who have acute coronary syndromesor who are undergoing percutaneous coronary interventionis scant.

Antiplatelet regimens in persons with CKD who haveor are at risk for cardiovascular disease reduce fatal or non-fatal myocardial infarction by approximately 33% but haveuncertain effects on stroke or all-cause and cardiovascularmortality. Summary estimates for the effects of antiplateletagents on major bleeding or hemorrhagic stroke are uncer-tain. Thienopyridines may increase mortality in persons

with CKD and stable cardiovascular disease, although data

are derived from subgroup analyses in few trials and areunreliable.Overall, most trials of persons with CKD and stable or

no cardiovascular disease have methodological or reportinglimitations that reduce the reliability of the evidence.

When absolute treatment effects are estimated, personswith acute coronary syndromes or who have undergonehigh-risk coronary intervention experience no reduction inmyocardial infarction or subsequent need for revasculariza-tion with additional antiplatelet therapy. However, up to2% of these persons may have serious bleeding. Twelvemonths of oral antiplatelet therapy may prevent myocardialinfarction in 1% to 3% of persons at risk for myocardial

infarction, but information about bleeding hazards and es-pecially intracranial hemorrhage is of low or very low qual-ity. Given the quality of the available evidence, specifictrials evaluating antiplatelet agents in persons with CKDand coexisting acute or stable cardiovascular disease arerequired.

Outcome data for antiplatelet agents are scant in sev-eral important clinical settings. We currently have no dataon persons receiving dialysis or kidney transplant recipients

who have acute coronary syndromes or require coronaryartery revascularization, and evidence for persons with ear-lier stages of CKD is entirely derived from post hoc anal-

yses within larger trials. In addition, more and better evi-dence is required for long-term antiplatelet treatment inpersons receiving dialysis or who have undergone kidneytransplantation.

Evidence to support secondary prevention with low-cost antiplatelet drugs (such as aspirin) in persons with arecent occlusive myocardial event and coexisting CKDis not available, and extrapolating data from the generalpopulation may not be appropriate because the biologyof arterial disease and causes of death in persons withCKD may confer a different riskbenefit tradeoff fortherapy. As shown in the general population (74), wide-spread administration of antiplatelet agents may have uncer-

Figure 4Continued


Major bleeding

Middleton and Deichsel, 1992 (45)Kaegi et al, 1974 (39)

Kobayashi et al, 1980 (42)


STOP, 1995 (49)

UK-HARP-I, 2005 (58)

Creek, 1990 (44)

Sreedhara et al, 1994 (48)

Dixon, 2009 (53)

HOT, 2010 (6)

CHARISMA, 2009 (37)

Total

Minor bleeding

Donadio et al, 1984 (29)

UK-HARP-I, 2005 (58)

HOT, 2010 (6)CHARISMA, 2009 (37)

Total

Relative Risk

by Using a

Random-Effects

Model (95% CI)

3.01 (0.1273.6)2.13 (0.2022.3)

1.14 (0.177.80)

0.99 (0.204.87)

1.04 (0.264.12)

0.66 (0.192.31)

0.70 (0.232.15)

0.94 (0.342.62)

0.68 (0.251.89)

2.04 (1.053.96)

1.73 (0.923.24)

1.29 (0.692.42)

5.00 (0.2599.2)

2.81 (1.495.28)

2.28 (1.294.03)1.59 (1.371.83)

1.70 (1.442.02)

Antiplatelet

Therapy

1/4512/30

2/50

3/441

4/398

4/225

5/144

13/83

6/321

26/1791

26/1006

92/5131

2/25

34/225

38/1791347/1006

421/3603

Control

0/4521/32

2/57

3/436

4/413

6/223

7/141

4/24

9/328

13/1828

15/1003

64/5099

0/25

12/223

17/1828218/1003

247/3599


Weight, %

1.01.9

2.8

4.1

5.5

6.6

8.2

9.9

10.0

23.7

26.3

100.0

1.2

19.4

22.357.1

100.0



Favors Antiplatelet

Therapy

Favors

Control

0.1 1.0 10.0

Summary estimates are provided by using random-effects meta-analysis. Only trials reporting1 event are shown. CHARISMA Clopidogrel for HighAtherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CKD chronic kidney disease; ETDRS Early Treatment DiabeticNephropathy Study; GI gastrointestinal; HOT Hypertension Optimal Treatment; STOP Shunt Thrombotic Occlusion Prevention by Picota-mide; UK-HARP-I First United Kingdom Heart and Renal Protection.




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tain value in persons with CKD because of the balance be-tween reduced occlusive events (myocardial infarction) andthe uncertain risk for major bleeding, including intracranialhemorrhage.

Although the values and preferences of patients withCKD are not well-understood (75), it seems unlikely that

many patients would accept the risk for major bleeding toreduce the risk for myocardial infarction without provenreductions in death or the need for coronary revasculariza-tion. The benefits and hazards of antiplatelet therapy toprevent cardiovascular events may be particularly impor-tant for patients receiving hemodialysis and dialysis-relatedanticoagulation who have impaired hemostasis (73). How-ever, these patients may also have greater absolute reduc-tions in occlusive coronary events because of higher base-line risk (71).

Considering the totality of current evidence, using anti-platelet and related agents to prevent cardiovascular eventsin people with CKD may be prudent only in clinical trials

that can further define the role of these drugs. Recent pre-specified subgroup data from the PLATO (Platelet Inhibi-tion and Patient Outcomes) trial indicates that ticagrelor,an oral purinergic receptor inhibitor cleared by extrarenalmechanisms, reduces mortality and major cardiovascularevents better than clopidogrel among persons with CKD andacute coronary syndromes (76). This finding suggests thatnewer antiplatelet agents may potentially act as adjunctivetherapy in persons with impaired kidney function. However,large placebo-controlled trials to assess the relative benefits andtoxicity of these newer antiplatelet agents, in addition to stan-dard care specifically in persons with CKD and acute cardio-

vascular disease, are needed.An earlier collaborative meta-analysis (5) provided

data for the effects of antiplatelet agents in patients receiv-ing hemodialysis, but to our knowledge, outcome data forpersons with earlier stages of CKD have not been previ-ously summarized. In that previous meta-analysis (5), anti-platelet therapy reduced major cardiovascular events (non-fatal myocardial infarction, nonfatal stroke, and vasculardeath) by 41% in persons undergoing hemodialysis; how-ever, CIs approached no effect, and the effects of treatmenton individual components of the outcome were not re-ported. In that previous review (5), a meta-analysis that

included only 46 events summarized bleeding risks withantiplatelet therapy in persons receiving hemodialysis, andestimates wereappropriatelyconsidered unreliable.

We found a lack of a clear reduction in vascular deathswith antiplatelet treatment among persons with CKD; thisfinding is in contrast to findings observed in other popu-lations at high risk for vascular events, including persons

with a history of documented myocardial infarction andstroke (5). Our finding that antiplatelet agents reduce car-diovascular events in persons with CKD to a lesser extentthan in other populations and have no certain effect onmortality in persons with CKD echoes similar treatmenteffects for statin therapy in persons with CKD (77). The

competing mechanisms for cardiovascular disease in thispopulation potentially explain this finding. Progressive kid-ney dysfunction is characterized by vascular stiffening andcalcification, cardiomyopathy, hyperkalemia, and suddencardiac death, in addition to occlusive vascular disease (78).

We found that the proportional increased risk for se-

rious bleeding from antiplatelet agents were 20% to 40%,which is somewhat smaller than that seen in patients withdocumented chronic or acute cardiovascular disease (60%)(5). However, the substantially higher baseline risk forbleeding in persons with CKD (approximately 2.5% peryear [73] compared with 1% in other at-risk populations[5]) means that absolute bleeding risks with antiplatelettherapy might be at least doubled in persons with CKD.

It is also relevant to consider which specific bleedingcomplications are incurred by treatment when deciding

whether the clinical benefits outweigh the potential risks oftreatment in persons with CKD. Reversible hemorrhagefrom the gastrointestinal tract, skin, or dialysis access or

surgical sites may be more acceptable treatment hazardsthan disabling bleeding into an eye, a joint, or the brain orbleeding requiring major surgery. However, insufficientdata were available in the included trials to provide com-prehensive information on specific types of bleeding causedby antiplatelet agents in this population and, consequently,on the relevant riskbenefit tradeoff needed to inform clin-ical decision making.

It is also important to remember that persons in thereal world may have much higher risks for bleeding thantrial participants. Therefore, the absolute numbers of per-sons with CKD affected by serious bleeding complications

from antiplatelet treatment suggested in the Table mayshift the balance toward excess harm.

Our meta-analysis quantifies the benefits and harms ofantiplatelet agents in a large number of persons. However,it has limitations, largely because it relies on trial-levelrather than individual-patient data. First, we could not as-sess whether the stage of kidney disease modified the effectsof antiplatelet therapy. Second, definitions and assessmentsof bleeding were widely heterogeneous; therefore, estimatesof hazards for specific bleeding events were less reliable.Third, overall trial duration varied greatly; in general, thelonger-term effects (3 to 5 y) of antiplatelet treatment are

uncertain.Fourth, the amount of data available overall, and par-ticularly that in persons with advanced CKD, was limited;as a result, insufficient power may explain some of thenegative findings and highlights the need for trials of anti-platelet agents specifically targeting this population. In ad-dition, reliance on data from post hoc analyses in largertrials may reduce the reliability of the summary findings(79). This is particularly true for evidence in persons withCKD and acute cardiovascular disease, for whom availabledata provide hypothesis-generating, rather than confirma-tory, evidence for antiplatelet treatment effects in thispopulationespecially for adverse events. Finally, we were




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unable to determine the relative benefits of antiplateletagents in primary prevention of cardiovascular disease(treating persons without clinically evident cardiovasculardisease) compared with secondary prevention (treating per-sons with established cardiovascular disease) because toofew trials provided data for participants in the primary

prevention setting.In conclusion, evidence for antiplatelet agents in per-sons with CKD and various cardiovascular diseases is oflow quality. Glycoprotein IIb/IIIa inhibitors or clopidogrelgiven in addition to standard care have little or no effect ondeath, myocardial infarction, or coronary revascularizationand may increase major bleeding in persons with CKD andacute coronary syndromes or those having high-risk coro-nary artery intervention. Antiplatelet agents reduce myo-cardial infarction in persons with CKD but have uncertaineffects on stroke and mortality and may increase bleeding.Bleeding hazards and lack of clear efficacy in reducing car-diovascular morbidity and mortality need to be acknowl-

edged when patients with CKD are being counseled aboutacute or long-term antiplatelet therapy.

From University of Otago, Christchurch, New Zealand; University of

Naples Federico II, Naples, Italy; The George Institute for Global

Health and School of Public Health, University of Sydney, Sydney, Aus-tralia; Mario Negri Sud Consortium, Santa Maria Imbaro, Italy; Scien-

tific Institute Casa Sollievo della Sofferenza, Foggia, Italy; Concord

Repatriation General Hospital, Concord, Australia; Diaverum Medical-

Scientific Office, Lund, Sweden; and University of Bari, Bari, Italy.

Financial Support: No specific external funding was received for this

project. Dr. Palmer received support from an unrestricted Amgen

Dompe Consorzio Mario Negri fellowship.

Potential Conflicts of Interest:Dr. Palmer:Grant:Amgen Dompe. Dr.

Razavian: Grant: Amgen. Dr. Perkovic: Grants/grants pending (money toinstitution):Heart Foundation of Australia, Johnson & Johnson, Servier,

Oxford University;Board membership: Baxter;Board membership (money

to institution): Boehringer Ingelheim, Vitae, Abbott, Reata and Abbott;

Payment for lectures including service on speakers bureaus (money to insti-tution): Roche. Dr. Jardine: Grant (money to institution): Royal Austral-

asian College of Physicians. Dr. Nicolucci: Board membership: Merck

Sharp & Dohme; Grants/grants pending (money to institution): MerckSharp & Dohme, Novo Nordisk, Sanofi Aventis, Eli Lilly, Johnson &

Johnson. Dr. Zoungas: Board membership: Merck Sharp & Dohme,

Novo Nordisk, Boehringer Ingelheim, Sanofi Aventis, Bristol-Myers

Squibb/AstraZeneca;Payment for lectures including service on speakers bu-reaus (money to institution): Merck Sharp & Dohme, Novo Nordisk,

Sanofi Aventis, Bristol-Myers Squibb/AstraZeneca, Novartis, Servier;

Payment for development of educational presentations:MediMark Australia.Disclosures can also be viewed at www.acponline.org/authors/icmje

/ConflictOfInterestForms.do?msNumM11-2512.

Reproducible Research Statement: Study protocol, statistical code, anddata set:Available from Dr. Strippoli (e-mail, [email protected]).

Requests for Single Reprints: Giovanni F.M. Strippoli, MD, PhD,MPH, MM, Department of Clinical Pharmacology and Epidemiology,

Consorzio Mario Negri Sud, Via Nazionale 8/a, 66030, Santa Maria

Imbaro, Italy; e-mail, [email protected].

Current author addresses and author contributions are available at www

.annals.org.

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38.Saito Y, Morimoto T, Ogawa H, Nakayama M, Uemura S, Doi N, et al;Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes TrialInvestigators. Low-dose aspirin therapy in patients with type 2 diabetes andreduced glomerular filtration rate: subanalysis from the JPAD trial. DiabetesCare. 2011;34:280-5. [PMID: 21270185]39.Kaegi A, Pineo GF, Shimizu A, Trivedi H, Hirsh J, Gent M.Arteriovenous-shunt thrombosis. Prevention by sulfinpyrazone. N Engl J Med. 1974;290:304-6.[PMID: 4588285]

40. Michie DD, Wombolt DG. Use of sulfinpyrazone to prevent thrombusformation in arteriovenous fistulas and bovine grafts of patients on chronic he-modialysis. Cur Ther Res. 1977;22:196-204.41.Harter HR, Burch JW, Majerus PW, Stanford N, Delmez JA, AndersonCB, et al. Prevention of thrombosis in patients on hemodialysis by low-doseaspirin. N Engl J Med. 1979;301:577-9. [PMID: 112475]42.Kobayashi K, Maeda K, Koshikawa S, Kawaguchi Y, Shimizu N, Naito C.

Antithrombotic therapy with ticlopidine in chronic renal failure patients onmaintenance hemodialysisa multicenter collaborative double blind study.Thromb Res. 1980;20:255-61. [PMID: 7209880]43.Ell S, Mihindukulasuriya JC, OBrien JR, Polak A, Vernham G.Ticlopi-dine in the prevention of blockage of fistulae and shunts. Haemostasis. 1982;12:180.44. Creek R. Ticlopidinepatency of haemodialysis access sites [Internal Re-port]. Guildford Sanofi Winthrop. 1990.45.Middleton DA, Deichsel G. The prophylaxis of thrombosis in new arterio-venous dialysis shunts in the arm by low-dose acetylsalicyclic acid and dipyrid-amole [Internal Report]. Berlin, Germany: Boehringer Ingelheim; 1992.46.Taber T, Maikranz P, Haag B, Dilley R, Gaylord G. Hemodialysis vasculargraft stenosis may be altered by low-molecular weight dextran (LMD), but not byaspirin (ASA) [Abstract]. J Am Soc Nephrol. 1992;3:397.47.Kooistra MP, van Es A, Marx JJ, Hertsig ML, Struyvenberg A. Low-doseaspirin does not prevent thrombovascular accidents in low-risk haemodialysispatients during treatment with recombinant human erythropoietin. Nephrol DialTransplant. 1994;9:1115-20. [PMID: 7800210]48.Sreedhara R, Himmelfarb J, Lazarus JM, Hakim RM. Anti-platelet therapyin graft thrombosis: results of a prospective, randomized, double-blind study.Kidney Int. 1994;45:1477-83. [PMID: 8072261]49.Mileti M, De PG, Bacchi M, Ogliari V, Pecchini F, Bufano G, et al. A trialto evaluate the efficacy of picotamide in preventing thrombotic occlusion of thevascular access in hemodialysis patients. J Nephrol. 1995;8:167-72.

50.Kaufman JS, OConnor TZ, Zhang JH, Cronin RE, Fiore LD, Ganz MB,et al; Veterans Affairs Cooperative Study Group on Hemodialysis Access GraftThrombosis.Randomized controlled trial of clopidogrel plus aspirin to preventhemodialysis access graft thrombosis. J Am Soc Nephrol. 2003;14:2313-21.[PMID: 12937308]51.Abdul-Rahman IS, Al Howaish AK. Warfarin versus aspirin in preventingtunneled hemodialysis catheter thrombosis: a prospective randomized study.Hong Kong Journal of Nephrology. 2007;9:23-30.52.Dember LM, Beck GJ, Allon M, Delmez JA, Dixon BS, Greenberg A, et al;Dialysis Access Consortium Study Group. Effect of clopidogrel on early failureof arteriovenous fistulas for hemodialysis: a randomized controlled trial. JAMA.2008;299:2164-71. [PMID: 18477783]53.Dixon BS, Beck GJ, Vazquez MA, Greenberg A, Delmez JA, Allon M, et al;DAC Study Group. Effect of dipyridamole plus aspirin on hemodialysis graftpatency. N Engl J Med. 2009;360:2191-201. [PMID: 19458364]54.Ghorbani A, Aalamshah M, Shahbazian H, Ehsanpour A, Aref A.Random-ized controlled trial of clopidogrel to prevent primary arteriovenous fistula failurein hemodialysis patients. Indian J Nephrol. 2009;19:57-61. [PMID: 20368925]55.Anderson M, Dewar P, Fleming LB, Hacking PM, Morley AR, Murray S,et al.A controlled trial of dipyridamole in human renal transplantation and anassessment of platelet function studies in rejection. Clin Nephrol. 1974;2:93-9.[PMID: 4603996]56.Schulze R, Langkopf B, Sziegoleit W. [The effect of dipyridamole on theresults of allogenic kidney transplantation]. Z Urol Nephrol. 1990;83:255-9.[PMID: 2203215]57. Quarto Di Palo F, Elli A, Rivolta R, Parenti M, Palazzi P, Zanussi C.Prevention of chronic cyclosporine nephrotoxicity in renal transplantation bypicotamide. Transplant Proc. 1991;23:969-71. [PMID: 1989347]58.Baigent C, Landray M, Leaper C, Altmann P, Armitage J, Baxter A, et al.First United Kingdom Heart and Renal Protection (UK-HARP-I) study: bio-chemical efficacy and safety of simvastatin and safety of low-dose aspirin in




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VISITS THEANNALS BOOTH AT SUBSPECIALTY MEETINGS

Annals staff will be at these upcoming meetings:

American College of Cardiology, 2427 March 2012, ChicagoDigestive Disease Week, 2022 May 2012, San DiegoAmerican Thoracic Society, 2022 May 2012, San Francisco

American Society of Clinical Oncology, 15 June 2012, ChicagoAmerican Diabetes Association, 812 June 2012, Philadelphia

Stop by the ACP/Annals booth and register to be a peer reviewer ordiscuss your thoughts for submission or topic coverage with Annals staff.




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Current Author Addresses:Dr. Palmer: Department of Medicine, Uni-

versity of Otago Christchurch, 2 Riccarton Avenue, Christchurch 8140,

New Zealand.

Dr. Di Micco: Division of Nephrology, Univerity of Naples Federico II,

Via Tasso 91/B, 80127 Naples, Italy.

Drs. Razavian, Perkovic, Jardine, and Zoungas: The George Institute for

Global Halth, Level 10, King George V Building, 83-117 Missenden

Road, Camperdown NSW 2050, Australia.Drs. Craig and Webster: University of Sydney School of Public Health,

A27, University of Sydney, NSW 2006, Australia.

Mr. Pellegrini and Dr. Copetti: Scientific Institute Casa Sollievo della

Sofferenza, Unit of Biostatistics, Polioambulatorio Giovanni Paolo II,

Viale Padre Pio, 71013 San Giovanni Rotondo, Foggia, Italy.

Ms. Graziano and Drs. Tognoni, Nicolucci, and Strippoli: Consorzio

Mario Negri Sud, Via Nazionale 8/a, 66030, Santa Maria Imbaro, CH,

Italy.

Author Contributions:Conception and design: S.C. Palmer, J.C. Craig,

V. Perkovic, M. Jardine, A. Webster, G.F.M. Strippoli.

Analysis and interpretation of the data: S.C. Palmer, L. Di Micco, J.C.

Craig, V. Perkovic, F. Pellegrini, M. Copetti, G. Graziano, G. Tognoni,M. Jardine, A. Webster, A. Nicolucci, S. Zoungas, G.F.M. Strippoli.

Drafting of the article: S.C. Palmer, L. Di Micco, M. Copetti, G.F.M.

Strippoli.

Critical revision of the article for important intellectual content: S.C.

Palmer, L. Di Micco, J.C. Craig, V. Perkovic, F. Pellegrini, M. Copetti,

G. Tognoni, M. Jardine, A. Webster, S. Zoungas, G.F.M. Strippoli.

Final approval of the article: S.C. Palmer, J.C. Craig, V. Perkovic, F.

Pellegrini, M. Copetti, G. Tognoni, M. Jardine, A. Webster, A. Nico-

lucci, S. Zoungas, G.F.M. Strippoli.

Statistical expertise: F. Pellegrini, M. Copetti, G. Graziano.

Administrative, technical, or logistic support: V. Perkovic, G.F.M.

Strippoli.

Collection and assembly of data: S.C. Palmer, L. Di Micco, M. Raza-

vian, V. Perkovic, M. Jardine, G.F.M. Strippoli.

Appendix Table 1. Search Strategy (to November 2011)

Embase1 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 phophodiesterase 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/1-3436 exp Renal Replacement Therapy/37 (hemodialysis or haemodialysis).tw38 (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/36-5254 and/35,53

CENTRAL1 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 termonly with qualifier: AI

4 ((antiplatelet next agent*) or (anti-platelet next agent*)):ti,ab,kw5 ((antiplatelet therap*) or (anti-platelet therap*)):ti,ab,kw6 (platelet next aggregation next inhibit*):ti,ab,kw

7 (phosphodiesterase next inhibit*):ti,ab,kw8 (thrombocyte next aggregation next inhibit*):ti,ab,kw


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Appendix Table 1Continued

9 ((antithrombocytic next agent*) or (anti-thrombocytic nextagent*)):ti,ab,kw

10 ((antithrombocytic next therap*) or (anti-thrombocytic nexttherap*)):ti,ab,kw

11 alprostadil:ti,ab,kw

12 aspirin:ti,ab,kw13 acetylsalicylic acid:ti,ab,kw14 ((adenosine next reuptake inhibit*) or (adenosine re-uptake

inhibit*)):ti,ab,kw15 (adenosine next diphosphate next receptor next inhibit*):ti,ab,kw

16 dipyridamole:ti,ab,kw17 disintegrins:ti,ab,kw18 epoprostenol:ti,ab,kw

19 iloprost:ti,ab,kw20 ketanserin:ti,ab,kw21 milrinone:ti,ab,kw

22 pentoxifylline:ti,ab,kw23 (S-nitrosoglutathione):ti,ab,kw24 S-nitrosothiols:ti,ab,kw

25 trapidil:ti,ab,kw26 ticlopidine:ti,ab,kw27 clopidogrel:ti,ab,kw

28 (sulfinpyrazone or sulphinpyrazone):ti,ab,kw29 cilostazol:ti,ab,kw30 (P2Y12 NEAR/2 antagonis*):ti,ab,kw

31 prasugrel:ti,ab,kw32 ticagrelor:ti,ab,kw33 cangrelor:ti,ab,kw

34 elinogrel:ti,ab,kw35 glycoprotein IIB/IIIA inhibitors:ti,ab,kw36 abciximab:ti,ab,kw

37 eptifibatide:ti,ab,kw38 tirofiban:ti,ab,kw39 defibrotide:ti,ab,kw

40 picotamide:ti,ab,kw41 beraprost:ti,ab,kw42 ticlid:ti,ab,kw

43 aggrenox:ti,ab,kw

44 ditazole:ti,ab,kw45 (#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 #17OR #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 #32OR #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,kw48 (hemofiltration or haemofiltration):ti,ab,kw49 (hemodiafiltration or haemodiafiltration):ti,ab,kw

50 (PD or CAPD or CCPD or APD):ti,ab,kw51 (renal next insufficiency):ti,ab,kw52 (kidney next failure):ti,ab,kw

53 (kidney next disease*):ti,ab,kw54 ur*emi*:ti,ab,kw55 ((chronic next kidney) or (chronic next renal)):ti,ab,kw

56 (CKF or CKD or CRF or CRD):ti,ab,kw57 predialysis:ti,ab,kw58 ((end-stage next renal) or (end-stage next kidney) or (endstage next

renal) or (endstage next kidney)):ti,ab,kw59 (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)

CENTRAL Cochrane Central Register of Controlled Trials.

W-138 20 March 2012 Annals of Internal Medicine Volume 156 Number 6 www.annals.org

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