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Annals of Internal Medicine
Review
Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease
A 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 cardiovascular events; however, treatment effects may differ in persons with chronic kidney disease (CKD) because atherosclerotic disease is less prevalent, whereas bleeding hazards may be increased in this population. Purpose: To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD. Data Sources: Embase and Cochrane databases through November 2011 without language restriction. Study Selection: Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment. Data Extraction: Data for populations, interventions, outcomes, and risk for bias were extracted. Quality of evidence for treatment effects on myocardial infarction, death, and bleeding was summarized by using Grading of Recommendations Assessment, Development, and Evaluation guidelines. Data Synthesis: Nine trials (all post hoc subgroup analyses for CKD) involving 9969 persons who had acute coronary syndromes or were undergoing percutaneous coronary intervention and 31
trials involving 11 701 persons with stable or no cardiovascular disease were identified. Low-quality evidence has found that in persons with acute coronary syndromes, glycoprotein IIb/IIIa inhibitors or clopidogrel plus standard care compared with standard care alone had little or no effect on all-cause or cardiovascular mortality or on myocardial infarction but increased serious bleeding. Compared with placebo or no treatment in persons with stable or no cardiovascular disease, antiplatelet agents prevented myocardial infarction but had uncertain effects on mortality and increased minor bleeding according to generally low-quality evidence. Limitations: Data for antiplatelet agents in persons with CKD are frequently derived from post hoc analyses of trials of broader populations. Definitions for bleeding outcomes and trial duration were heterogeneous. Conclusion: Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards. Primary Funding Source: None.
Ann Intern Med. 2012;156:445-459. For author affiliations, see end of text. www.annals.org
hronic kidney disease (CKD) is an important public health challenge. Approximately 10% to 15% of the adult population worldwide has CKD, and prevalence is increasing because of the epidemics of diabetes mellitus and obesity (1). Chronic kidney disease causes illness and premature death. Nearly 50% of persons aged 70 years or older (1) and between 33% and 50% of persons with acute myocardial ischemia have CKD (2). Even in early-stage CKD, the risk for premature cardiovascular disease is increased by 25% to 30% (3) and is more than 30- to 50fold higher in persons with end-stage kidney disease (4). Antiplatelet agents are widely used to prevent cardiovascular events by inhibiting intravascular thrombosis. Antiplatelet drugs reduce vascular deaths by 15% and serious cardiovascular events by 20% in persons at high risk for a vascular event (5). Extrapolating these benets of antiplatelet therapy to persons with CKD is problematic because nonatherosclerotic conditions (cardiac failure, sudden cardiac death, and arrhythmia) are more common causes of cardiovascular events in persons with CKD than in the general population (5, 6). The bleeding risk of antiplatelet agents may be greater (7) among persons with CKD because of impaired hemostasis (8).
Treating complications of CKD imposes an important economic burden. Health costs of treating a person with CKD are nearly 3-fold higher than those for a person without CKD, and the cost of treating end-stage kidney disease is 10-fold higher (9, 10). Together, increasing use of health resources, continued poor outcomes, and emergence of performance measures directed to the care of persons with CKD (11) necessitate careful evaluation of all health care interventions in this growing population. The aim of our study was to summarize the benets and harms of anti-
See also: Print Editors Notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446 Web-Only Appendix Tables Appendix Figure CME quiz (preview on page I-29) Conversion of graphics into slides
2012 American College of Physicians 445
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Review
Context
Effects of Antiplatelet Therapy in Persons With CKD
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 no effect on myocardial infarction, death or coronary revascularization in patients with CKD who had acute coronary syndromes or were undergoing percutaneous coronary revascularization. Antiplatelet regimens in other patients with CKD who had or were at risk for cardiovascular disease increased minor bleeding, reduced myocardial infarction, and had uncertain effects on mortality.
tion Kidney Disease Outcomes Quality Initiative criteria [17]) or trials of broader populations for which data for participants with CKD could be disaggregated. Pediatric trials were excluded. We excluded 5 trials reporting follow-up shorter than 2 months (18 22) because we wanted to focus on longer-term outcomes. Sensitivity analyses, including only trials with follow-up longer than 1 year, were conducted.
Data Extraction and Quality Assessment
Caution
Evidence was weak, derived primarily from subgroup analysis of trials.
Implication
Risks of antiplatelet agents may outweigh potential benefits in some patients with CKD. The Editors
Two or more independent authors screened the title and abstract of retrieved citations and reviewed the full text of potentially eligible citations to identify trials that fullled the inclusion criteria. For included trials, we extracted data on population characteristics; interventions; and outcomes, including fatal or nonfatal myocardial infarction or stroke, death (total and cause-specic), coronary artery revascularization, major or minor bleeding (Appendix Table 2, available at www.annals.org) (6, 14 16, 23 58), end-stage kidney disease, all-cause hospitalization, and treatment withdrawal. Risk of bias was assessed according to standardized methods (59).
Data Synthesis and Analysis
platelet agents in persons with CKD, focusing on cardiovascular events, mortality, and bleeding.
METHODS
We conducted a systematic review based on standard methods, including a published, peer-reviewed protocol (12) and reporting in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (13).
Data Sources and Searches
We searched Embase from 1980 to November 2011, the Cochrane Central Register of Controlled Trials through Issue 4 of 2011, and the Cochrane Renal Groups specialized register through November 2011 without language restriction by using a search strategy designed by a specialist information manager (Appendix Table 1, available at www.annals.org). The Cochrane Renal Groups register was populated by weekly Ovid MEDLINE AutoAlerts, quarterly searches from the Cochrane Central Register of Controlled Trials, and hand-searching. We contacted investigators to request unpublished data for persons who had CKD at baseline. We received and included additional data from these investigators for 3 trials that were not identied by our initial search (14 16). We screened the reference lists of retrieved publications, including a metaanalysis (5), for potentially eligible trials.
Study Selection
We included trials that compared antiplatelet agents with placebo, standard care, or no treatment in adults with CKD (as dened by the National Kidney Founda446 20 March 2012 Annals of Internal Medicine Volume 156 Number 6
Relative risks (RRs) and 95% CIs were calculated from the numbers of events and participants at risk for events. When crude event rates were not provided, the reported risk ratio was extracted (27). Relative risks and CIs were then summarized by using an exact bivariate randomeffects meta-analysis method following the approach proposed by Stijnen and colleagues (60). Sensitivity analyses to check for robustness of our ndings were performed with the inverse of the sample size in the opposite treatment arm (61) and the arcsine methods (62). If exact bivariate random effects could not be used because crude event data were not available, we used a Bayesian meta-analysis following Greenlands data equivalents approach (63). We tested for heterogeneity of treatment effects between studies with the Cochran Q and I2 test statistics (64). Potential sources of heterogeneity in intervention effects were explored by prespecied subgroup analysis (type of antiplatelet regimen or stage of CKD [predialysis, dialysis, or kidney transplantation]) by reporting results of analyses 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 the horizontal axis and the SE of the log RR on the vertical axis. To evaluate the presence and extent of publication bias, we used the Egger regression test (65). We conducted sensitivity analyses, excluding shorter trials (12 months) and those published only in internal drug company reports. We summarized the quality of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation guidelines (66). We conducted analyses by using SAS, version 9.1 (SAS Institute, Cary, North Carolina) (67); WinBugs, version 1.4.3 (Imperial College and Medical Research Council,
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Cambridge, United Kingdom); and Comprehensive Metaanalysis, version 2 (Biostat, Englewood, New Jersey). Details of the SAS macro routines based on the linear and nonlinear mixed models (namely Proc MIXED and Proc NLMIXED) are available from the authors on request.
Role of the Funding Source
This project received no specic funding. Dr. Palmer received support from an unrestricted Amgen Dompe Consorzio Mario Negri fellowship. The authors had full responsibility for data collection, data interpretation, and writing of the report. Drs. Palmer and Strippoli had full access to all of the data and had the nal responsibility to submit the manuscript for publication.
RESULTS
Description of Trials
Searching identied 1460 publications. Of these publications, 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, 14 16, 2358). Thirty-six trials (20 942 participants) provided extractable data for inclusion in meta-analyses (6, 14 16, 2331, 34 37, 39 45, 4758). We included unpublished subgroup data for persons with CKD that were provided by the investigators of 12 trials (11 732 participants) (6, 14 16, 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, 43 45), including 2 internal 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 provided in conference proceedings (32, 46), although neither of these trials provided extractable data for meta-analyses. Appendix Table 5 (available at www.annals.org) describes the sources of additional unpublished data. Nine trials (9969 participants) provided information on antiplatelet treatment among persons with CKD who presented with an acute coronary syndrome or were scheduled to undergo coronary artery intervention and were considered at high risk for subsequent vessel closure (14 16, 2328). All data for these trials were published (26, 27) or unpublished (14 16, 2325, 28) post hoc analyses for the subgroup of participants with CKD from larger trials. Trials provided data for glycoprotein IIb/IIIa inhibitors (abciximab, eptibatide, or tiroban) (7 trials, 5471 participants) (14 16, 2326) or clopidogrel (2 trials, 4498 participants) (27, 28), and all involved coadministration of aspirin with (14, 15, 2326) or without (16, 27, 28) heparin 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 stable or no cardiovascular disease. Twelve trials assessed the effects of antiplatelet agents on mortality, progression of
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kidney disease, or safety in 6970 patients with glomerulonephritis (4 trials, 119 participants) (29, 31, 33, 34) or diabetic nephropathy (6 trials, 2990 participants) (30, 32, 3538) or who had an impaired glomerular ltration rate regardless 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 ticlopidine) (34, 37). One trial involved administration of aspirin as a co-intervention (37). Median follow-up was 12 months. Seventeen trials provided data for antiplatelet treatment in 4471 persons receiving or who would soon require dialysis (39 54, 58). These trials involved administration of a range of antiplatelet agents (aspirin, dipyridamole, clopidogrel, sulnpyrazone, ticlopidine, or picotamide), and 3 involved administration of additional antiplatelet agents or oral anticoagulation as nonrandomized cointerventions (39, 49, 52). Trials were generally of shorter duration (median, 6 months). Four trials administered antiplatelet treatment to 260 kidney transplant recipients (5558).
Risk of Bias in Included Trials
Nine trials of acute coronary syndromes or percutaneous coronary intervention generally had low risk of bias, with a high proportion reporting adequate allocation concealment (78%), intention-to-treat analysis (89%), blinding of outcome assessors (100%), and freedom from selective outcome reporting (89%). However, all were post hoc analyses of trials of broader populations. In more than 75% of the remaining 31 trials, methods for random sequence generation, allocation concealment, blinding of outcome assessors, completeness to follow-up, or the risk for selective reporting or other biases were unclear or inadequate (Appendix Figure, available at www.annals.org).
Meta-analysis
Figure 2 shows the overall results of all meta-analyses. The Table summarizes the quality of the available evidence (4, 66 73). Meta-analysis by using exact bivariate random effects is reported because sensitivity analyses suggested that the effect estimates were robust regardless of the statistical model used.
Effects on Vascular Events Among Patients With Acute Coronary Syndromes or Requiring Percutaneous Coronary Intervention
Fatal or Nonfatal Myocardial Infarction and Stroke
Low-quality evidence found that antiplatelet treatment plus standard care had little or no effect on myocardial infarction (7 trials, 5261 participants; RR, 0.89 [CI, 0.76 to 1.05]), with no evidence of signicant heterogeneity (Table and Figure 3). Including only trials of glycoprotein IIb/IIIa inhibitors provided similar treatment effects (6 trials, 4850 participants; RR, 0.87 [CI, 0.74 to 1.03]) (14 16, 2325). In the 4 trials (1786 participants) reporting myocardial infarction at 1 year, the RR was 0.79 (CI, 0.37
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Figure 1. Summary of evidence search and selection.

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
Duplicate citations removed (n = 63) Citations screened by title and abstract (n = 1397) 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 <2 mo: 37 Commentaries: 3 Nonrandomized studies: 16 Not antiplatelet vs. placebo trial: 36 Ongoing trials (7 citations): 5 No data for CKD: 27
Randomized trials in 70 publications (21 670 participants) included in systematic review (n = 40) Trials (728 participants) not included in meta-analyses (n = 4)*
Randomized trials (20 942 participants) included in meta-analysis (n = 36) Randomized trials (9969 participants) in ACS or PCI (n = 9) Myocardial infarction: 7 (5261 participants) Stroke: 1 (411 participants) All-cause mortality: 8 (9347 participants) Cardiovascular mortality: 2 (4498 participants) Major bleeding: 9 (9863 participants) Minor bleeding: 9 (9863 participants) Randomized trials (10 973 participants) in at-risk persons with CKD (n = 27) Myocardial infarction: 10 (9133 participants) Stroke: 10 (9133 participants) All-cause mortality: 21 (10 632 participants) Cardiovascular mortality: 16 (8706 participants) Major bleeding: 18 (10 230 participants) Minor bleeding: 8 (7202 participants)
ACS acute coronary syndrome; CENTRAL Cochrane Central Register of Controlled Trials; CKD chronic kidney disease; PCI percutaneous coronary intervention. * Four trials could not be included in the meta-analyses because data were not provided in an extractable format (32, 33, 38, 46).
to 1.72) with additional antiplatelet therapy (14, 15, 24, 28). One trial provided data on only 6 fatal or nonfatal strokes in 411 persons, nding that clopidogrel in addition to standard therapy had uncertain effects on stroke (RR, 0.51 [CI, 0.09 to 2.77]) (Figure 3).
448 20 March 2012 Annals of Internal Medicine Volume 156 Number 6
All-Cause and Cardiovascular Mortality
Low- or very low-quality evidence found that antiplatelet therapy in addition to standard treatment had little or no effect on all-cause mortality (8 trials, 9347 participants; RR, 0.89 [CI, 0.75 to 1.05]) and uncertain effects
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on cardiovascular mortality (2 trials, 4498 participants; RR, 0.96 [CI, 0.79 to 1.16]) without heterogeneity in the analyses (Table and Figure 3). Including only trials that evaluated glycoprotein IIb/IIIa inhibitors provided a similar effect estimate for mortality (6 trials, 4849 participants; RR, 0.86 [CI, 0.69 to 1.07]) (14 16, 2325). No data were available for the effects of glycoprotein IIb/IIIa inhibitors on cardiovascular mortality. Limiting analyses to trials reporting outcomes at 1 year did not meaningfully alter the risk 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 CKD and acute coronary syndromes or requiring percutaneous
coronary intervention provided information on major and minor bleeding events (Figure 3). Denitions of bleeding outcomes varied. Major bleeding was dened as an intracranial hemorrhage, a decrease in hemoglobin level of 50 g/L or more, or a decrease in hematocrit level of 15% or more in 7 trials (14 16, 2325, 28); a decrease in hemoglobin level of more than 40 g/L, bleeding necessitating transfusion of 2 units or more of blood, bleeding necessitating corrective surgery, or intracranial or retroperitoneal hemorrhage in 1 trial (26); or substantially disabling bleeding, intraocular bleeding leading to loss of vision, or bleeding necessitating transfusion of 2 units or more of blood in 1 trial (27). Minor bleeding included blood loss, a decrease in hemoglobin level of 30 g/L or more, or no observed blood loss with a decrease in hemoglobin level of 40 g/L or more (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 Trials, n 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 7 1 7 2 8 9 9 5 411/3097 2/203 933/3098 6/203 232/3097 292/3347 585/3347 18/2342 322/2164 4/208 701/2167 4/208 183/2163 161/2429 313/2429 12/1693 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) 42 69 0 2 0 0 0 Events/Participants, n/n Antiplatelet Therapy Control Relative Risk by Using a Random-Effects Model (95% CI)
I 2, %
At-risk or stable cardiovascular disease 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 10 10 16 21 3 8 18 8 1 11 100/4533 80/4533 150/4335 346/5330 333/1768 52/423 92/5131 421/3603 10/1006 213/1290 153/4600 90/4600 165/4371 379/5302 352/1767 64/402 64/5099 247/3599 7/1003 211/1225 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)
0.5 1.0 2.0
0 25 26 0 0 0 0 0 0
Favors Antiplatelet Therapy
Favors Control
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 not available and therefore not included in the summary totals for cardiovascular death, all-cause mortality, or major or minor bleeding.
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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 in Quality Score) Consistency (Decrease in Quality Score) Directness Precision (Decrease in Quality Score) Publication Bias (Decrease in Quality Score)
ACS or Undergoing PCI Myocardial infarction 7 (5261) Post hoc subgroup analyses for CKD (1) Post hoc subgroup analyses for CKD (1) Post hoc subgroup analyses for CKD; at risk for selective reporting for this outcome (1) Post hoc subgroup analyses for CKD (1) No inconsistency Direct; no information for dialysis or transplantation settings Direct; no information for dialysis or transplantation settings Direct; no information for dialysis or transplantation settings Imprecision (1) Imprecision (1) Imprecision (1) No important publication bias No important publication bias Likely (1)
All-cause mortality
8 (9347)
No inconsistency
Cardiovascular mortality
2 (4295)
No inconsistency
Major bleeding
9 (9863)
Unexplained Direct; no information for dialysis No important heterogeneity or transplantation settings imprecision (1) At Risk for or With Stable Cardiovascular Disease No inconsistency Direct; unable to explore differences in treatment effects based on stage of kidney disease or antiplatelet type Direct; unable to explore differences in treatment effects based on stage of kidney disease or antiplatelet type Direct; unable to explore differences in treatment effects based on stage of kidney disease or antiplatelet type Direct; unable to explore differences in treatment effects based on stage of kidney disease or antiplatelet type No important imprecision
No important publication bias
Myocardial infarction
8 (9190)
Serious limitations (1)
No important publication bias No important publication bias No important publication bias No important publication bias
All-cause mortality
9 (8667)
No inconsistency
Imprecision (1)
Cardiovascular mortality
9 (10 632)
No inconsistency
Imprecision (1)
Major bleeding
10 (10 123)
No inconsistency
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 (68 70), all-cause mortality (4, 69 72), cardiovascular mortality (69 72), and bleeding (73). Absolute numbers of persons with CKD who avoided events or had major bleeding were calculated from the risk estimate for the outcome (and associated 95% CI) obtained from a meta-analysis of placebo-controlled trials together with the absolute population risk estimated from previously published observational cohort studies. Effect considered imprecise when the CI includes possible benet 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.
ication (1 trial) (27); or bleeding that was incompletely dened (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 signicant heterogeneity was present in the analyses (Table and Figure 3). Excluding the 2 trials that randomly assigned participants to clopidogrel (27, 28) resulted in similar effect estimates for major (7 trials, 5365 participants; RR, 1.36 [CI, 0.78 to 2.38]) and minor (RR, 1.38 [CI, 1.18 to 1.61]) bleeding with persistent heterogeneity in both analyses. Antiplatelet therapy increased major bleeding in analyses limited to trials
reporting outcomes at 1 year or more (5 trials, 5868 participants; RR, 1.47 [CI, 1.00 to 2.10]) (14, 15, 24, 27, 28). In the 5 trials that reported data for hemorrhagic stroke (14 16, 24, 25), treatment hazards of antiplatelet 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 coronary artery revascularization (7 trials, 5265 participants; RR, 0.93 [CI, 0.84 to 1.04]) (Figure 3). No data were available for treatment effects on all-cause hospiwww.annals.org
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TableContinued
Summary of Findings Relative Risk (95% CI) Best Estimate of Control Group Risk, % Absolute Effect per 1 y of Treatment per 1000 Persons Treated (95% CI) Quality of Evidence
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 reported only in an internal report (44) did not alter the risk estimate for myocardial infarction (9 trials, 8848 participants; RR, 0.67 [CI, 0.51 to 0.88]).
All-Cause and Cardiovascular Mortality
ACS or Undergoing PCI 0.89 (0.761.05) 30 33 fewer (72 fewer 15 more) 44 fewer (100 fewer20 more) 10 fewer (53 fewer 40 more) Low
0.89 (0.751.05)
40
Low
0.96 (0.791.16)
25
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 (312 fewer); dialysis, 34 fewer (1349 fewer) CKD, 3 fewer (10 fewer6 more); dialysis, 26 fewer (78 fewer48 more) CKD, 1 fewer (6 fewer5 more); dialysis, 9 fewer (40 fewer36 more) 7 more (8 fewer35 more) Moderate
0.87 (0.611.24)
CKD, 2.5; dialysis, 20
Low
0.91 (0.601.36)
CKD, 1.5; dialysis, 10
Low
1.29 (0.692.42)
2.5
Low
talization, end-stage kidney disease, or withdrawal from treatment.

Effects on Clinical Outcomes Among Patients at Risk for or With Stable Cardiovascular Disease
Fatal or Nonfatal Myocardial Infarction and Stroke
In low-quality evidence, antiplatelet therapy had uncertain effects on all-cause (21 trials, 10 632 participants; RR, 0.87 [CI, 0.61 to 1.24]) (6, 29 31, 34, 36, 37, 39, 40, 42 45, 48 50, 5254, 57, 58) and cardiovascular (16 trials, 8706 participants; RR, 0.91 [CI, 0.60 to 1.36]) (6, 29 31, 34, 36, 37, 39, 40, 42 45, 49, 57, 58) mortality, with no signicant heterogeneity in analyses (Table and Figure 4). Risk for death from any cause differed in prespecied subgroups of trials according to the drug used. In 5 trials, aspirin (4340 participants; RR, 0.80 [CI, 0.61 to 1.06]) had uncertain effects on risk for death (6, 30, 36, 48, 58), whereas thienopyridines may increase mortality (7 trials, 3452 participants; RR, 1.47 [CI, 1.02 to 2.12]) (P 0.01 for subgroup interaction) (34, 37, 42 44, 52, 54). Subgroup analysis to explore the effects of CKD stage was not possible. Estimates for all-cause (13 trials, 8942 participants; RR, 0.89 [CI, 0.59 to 1.33]) (6, 29 31, 34, 36, 37, 45, 48, 49, 53, 57, 58) and cardiovascular (11 trials, 8186 participants; RR, 0.92 [CI, 0.56 to 1.51]) (6, 29 31, 34, 36, 37, 45, 49, 57, 58) mortality did not differ when analyses were restricted to trials in which outcomes were reported during follow-up of 12 months or longer. Excluding 2 trials with data available only in internal reports (44, 45) did not alter the effects of antiplatelet treatment on all-cause (19 trials, 9444 participants; RR, 0.93 [CI, 0.62 to 1.39]) or cardiovascular (14 trials, 7518 participants; RR, 0.94 [CI, 0.55 to 1.60]) mortality.
Effects on Adverse Events (Major and Minor Bleeding and Hemorrhagic Stroke)
Moderate-quality evidence showed that antiplatelet therapy reduced myocardial infarction (10 trials, 9133 participants; RR, 0.66 [CI, 0.51 to 0.87]) but had uncertain effects 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 signicant heterogeneity in these analyses. Data were insufcient to perform prespecied subgroup analyses based on the type of antiplatelet regimen or stage of kidney disease. No data were provided by trials enrolling only kidney transplant recipients. Limiting meta-analyses to trials in which follow-up duration was 12 months or more did not meaningfully alter the risk estimates for these outcomes (6 trials, 7721 participants; RR for myocardial infarction, 0.69 [CI, 0.52
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Eighteen trials (10 230 participants) reported major bleeding 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 this clinical setting reported data specically for hemorrhagic stroke. Denitions of major and minor bleeding were generally not well-dened and were not centrally adjudicated with blinding to treatment allocation, with the exception of 2 trials (37, 58). Major bleeding included intracerebral or substantial hemodynamic compromise (37); gastrointestinal bleeding (39); hemarthrosis, nasal bleeding, shunt hemorrhage, and bleeding at injection site (42); conrmed retroperitoneal, intra-articular, intraocular, or intracranial bleeding or causing the hemoglobin level to decrease by 20 g/L or more and requiring hospital admission or transfusion (53); or hospital admission or death (58). Minor
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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.
Events/Participants, n/n Antiplatelet Therapy Fatal or nonfatal myocardial infarction 1/27 RAPPORT, 1998 (16) 18/325 EPILOG, 1997 (24) 24/231 EPISTENT, 1998 (15) 21/203 CREDO, 2008 (28) 33/334 EPIC, 1994 (14) 58/547 IMPACT-II, 1997 (23) 256/1430 PURSUIT, 1998 (25) 411/3097 Total Fatal or nonfatal stroke CREDO, 2008 (28) Total Coronary revascularization RAPPORT, 1998 (16) EPISTENT, 1998 (15) CREDO, 2008 (28) EPILOG, 1997 (24) EPIC, 1994 (14) IMPACT-II, 1997 (23) 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) IMPACT-II, 1997 (23) EPIC, 1994 (14) PURSUIT, 1998 (25) CURE, 2007 (27) Total Control
Study, Year (Reference)
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)
Weight, %
5/35 17/163 15/137 20/208 24/185 25/259 216/1177 322/2164
0.5 5.0 5.5 6.0 8.2 10.1 64.7 100.0
Heterogeneity: 2 = 6.14; P = 0.41 (I 2 = 2%) 2/203 2/203 4/208 4/208 0.51 (0.092.77) 0.51 (0.092.77) Heterogeneity: NA 12/27 53/231 36/203 73/325 92/334 124/547 543/1431 933/3098 16/35 24/137 41/208 42/163 57/185 60/259 461/1180 701/2167 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) 2.1 3.4 3.9 5.9 8.3 8.8 67.6 100.0 100.0 100.0
Heterogeneity: 2 = 2.71; P = 0.84 (I 2 = 0%) 4/208 6/203 Not estimable Not estimable 2.5 1.54 (0.445.37) 97.5 0.95 (0.771.17) 100.0 0.96 (0.791.16) Heterogeneity: 2 = 0.55; P = 0.46 (I 2 = 0%) 0.7 0.43 (0.091.97) 1.9 0.85 (0.332.17) 2.1 1.28 (0.523.18) 2.3 0.61 (0.261.45) 3.4 0.51 (0.251.04) 3.8 1.06 (0.542.08) 35.9 1.04 (0.841.30) 49.8 0.95 (0.781.16) 100.0 0.89 (0.751.05) Heterogeneity: 2 = 6.57; P = 0.48 (I 2 = 0%)
0.1 1.0 10.0
6/35 2/27 7/137 10/231 8/208 10/203 9/163 11/325 14/259 15/547 12/185 23/334 127/1176 161/1430 Not estimable Not estimable
Favors Antiplatelet Therapy and Standard Care
Favors Standard Care
Continued on following page
bleeding included occult gastrointestinal or rectal polyp bleeding and ecchymoses (29); not needing transfusion or causing hemodynamic compromise (37); or epistaxis, ecchymoses, or bruising (58). According to low-quality evidence, antiplatelet therapy signicantly increased minor bleeding (RR, 1.70 [CI, 1.44 to 2.02]) but had uncertain effects on major bleeding (RR, 1.29 [CI, 0.69 to 2.42]) (Table and Figure 4). There was no heterogeneity in these analyses.
Treatment with antiplatelet agents in trials of 1 year or longer was associated with increased major bleeding (10 trials, 8696 participants; RR, 1.55 [CI, 1.07 to 2.26]) (6, 36, 37, 45, 48, 49, 51, 53, 57, 58). Excluding the 2 trials for which data were available only in internal reports (44, 45) also resulted in signicantly increased major bleeding in the remaining trials (16 trials, 9042 participants; RR, 1.50 [CI, 1.06 to 2.12]). Prespecied subgroup analyses to assess treatment effects in subwww.annals.org
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Figure 3Continued
Study, Year (Reference) Events/Participants, n/n Antiplatelet Therapy Major bleeding EPISTENT, 1998 (15) RAPPORT, 1998 (16) EPILOG, 1997 (24) PRISM-PLUS, 2002 (26) CREDO, 2008 (28) EPIC, 1994 (14) IMPACT-II, 1997 (23) PURSUIT, 1998 (25) CURE, 2007 (27) Total Minor bleeding EPISTENT, 1998 (15) RAPPORT, 1998 (16) EPILOG, 1997 (24) CREDO, 2008 (28) EPIC, 1994 (14) IMPACT-II, 1997 (23) CURE, 2007 (27) PURSUIT, 1998 (25) PRISM-PLUS, 2002 (26) Total Control 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)
Weight, %
5/134 5/229 4/35 8/27 4/163 16/325 8/311 13/300 12/208 14/203 11/185 59/334 16/241 29/525 101/1152 148/1404 Not estimable Not estimable
4.4 5.3 5.4 7.7 9.5 12.2 12.8 17.6 25.1 100.0
Heterogeneity: 2 = 13.7; P = 0.09 (I 2 = 42%) 4/134 16/229 10/35 5/27 9/163 24/325 20/208 12/203 19/185 64/334 29/241 103/525 Not estimable 97/1152 228/1404 125/311 133/300 Not estimable 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) 4.9 5.8 7.9 8.6 11.8 13.5 14.4 16.2 16.8 100.0
Heterogeneity: 2 = 25.5; P = 0.001 (I 2 = 69%)

0.1 1.0 10.0
Favors Antiplatelet Therapy and Standard Care
Favors Standard Care
Summary estimates are provided by using random-effects meta-analysis. Only trials reporting 1 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 Platelet Aggregation and Coronary Thrombosis-II; NA not applicable; PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial.
groups of trials based on stage of CKD or antiplatelet regimen were not possible.
Effects on Other Outcomes
DISCUSSION
To our knowledge, this meta-analysis provides the rst comprehensive summary of the benets and risks of antiplatelet treatment in persons with CKD. In general, evidence is of low or very-low quality, with considerable variation in trial duration; heterogeneity in the denitions and assessment of bleeding outcomes; reliance on subgroup data from major trials, particularly for antiplatelet treatment in acute cardiovascular disease; and substantial methodological limitations in data for adults with CKD and stable cardiovascular disease. Antiplatelet treatment (generally glycoprotein IIb/IIIa inhibitors) given in addition to standard care in persons with acute coronary syndromes or those undergoing percutaneous coronary revascularization who also have CKD has little or no effect on myocardial infarction, death, or coronary revascularization but increases major and minor bleeding. Evidence for an association between additional anti20 March 2012 Annals of Internal Medicine Volume 156 Number 6 453
Antiplatelet therapy had uncertain effects on end-stage kidney disease, hospitalization, and withdrawal from treatment (Figure 2). No data were available for coronary artery revascularization in persons with CKD who have stable or no cardiovascular disease.
Small Study Effects and Publication Bias
No asymmetry was observed in the funnel plots for the outcomes of myocardial infarction, all-cause mortality, or major bleeding in trials involving persons at risk for or with stable cardiovascular disease or in those involving acute cardiovascular disease (Egger regression test, P 0.10 for all). This nding suggests that unpublished studies did not cause bias of effect estimates.
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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.
Study, Year (Reference) Events/Participants, n/n Antiplatelet Therapy Fatal or nonfatal myocardial infarction Creek, 1990 (44) 0/144 UK-HARP-I, 2005 (58) 1/225 Kaufman et al, 2003 (50) 2/104 Dember et al, 2008 (52) 3/441 Dixon et al, 2009 (53) 19/321 CHARISMA, 2009 (37) 22/1006 ETDRS, 1992 (30) 21/79 HOT, 2010 (6) 32/1791 Total 100/4533 Fatal or nonfatal stroke UK-HARP-I, 2005 (58) Kaufman et al, 2003 (50) Dember et al, 2008 (52) 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) Kaufman et al, 2003 (50) Sreedhara et al, 1994 (48) Dember et al, 2008 (52) 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 Control Relative Risk by Using a Random-Effects Model (95% CI)
Weight, %
1/141 1/223 4/96 7/436 18/328 29/1003 34/106 59/1828 153/4600
0.33 (0.017.95) 0.6 0.99 (0.0615.8) 0.8 0.46 (0.092.46) 2.1 0.42 (0.111.63) 3.2 1.08 (0.582.02) 14.8 0.76 (0.441.31) 19.3 0.83 (0.521.31) 27.4 0.55 (0.360.85) 32.0 0.66 (0.510.87) 100.0 Heterogeneity: 2 = 4.53; P = 0.87 (I 2 = 0%) 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) 2.7 3.1 4.5 5.6 10.2 14.2 23.8 28.0 100.0
1/225 0/104 2/441 1/398 5/321 12/79 20/1006 39/1791 80/4533
0/223 3/96 1/436 7/413 3/328 4/106 22/1003 50/1828 90/4600
Heterogeneity: 2 = 11.9; P = 0.22 (I 2 = 25%) 0/24 0/8 1/225 5/144 7/398 21/451 33/1791 51/1006 32/79 150/4335 1/26 1/8 1/223 4/141 11/413 30/452 47/1828 31/1003 39/106 165/4371 0.36 (0.028.43) 0.9 0.33 (0.027.14) 0.9 0.99 (0.0615.8) 1.1 1.22 (0.344.46) 4.7 0.66 (0.261.69) 8.1 0.70 (0.411.21) 16.9 0.72 (0.461.11) 20.8 1.64 (1.062.54) 20.9 0.70 (0.500.97) 25.6 0.91 (0.601.36) 100.0 Heterogeneity: 2 = 10.8; P = 0.21 (I 2 = 26%) 0.36 (0.028.43) 0.3 0.33 (0.027.14) 0.3 0.99 (0.146.97) 0.7 1.02 (0.156.95) 0.8 0.69 (0.163.01) 1.3 0.39 (0.091.61) 1.4 0.99 (0.253.93) 1.5 0.98 (0.293.31) 1.9 0.93 (0.491.76) 6.0 0.62 (0.381.03) 8.9 1.62 (1.132.32 14.4 0.75 (0.551.04) 16.6 1.08 (0.841.04) 21.1 0.93 (0.751.16) 24.7 0.87 (0.611.24) 100.0 Heterogeneity: 2 = 16.6; P = 0.68 (I 2 = 0%)
0.1 1.0 10.0
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
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
Favors Control
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Figure 4Continued
Study, Year (Reference) Events/Participants, n/n Antiplatelet Therapy Major bleeding Middleton and Deichsel, 1992 (45) Kaegi et al, 1974 (39) Kobayashi et al, 1980 (42) Dember et al, 2008 (52) 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 1/451 2/30 2/50 3/441 4/398 4/225 5/144 13/83 6/321 26/1791 26/1006 92/5131 Control 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)
Weight, %
0/452 1/32 2/57 3/436 4/413 6/223 7/141 4/24 9/328 13/1828 15/1003 64/5099
1.0 1.9 2.8 4.1 5.5 6.6 8.2 9.9 10.0 23.7 26.3 100.0
Heterogeneity: 2 = 7.24; P = 0.98 (I 2 = 0%) 2/25 34/225 38/1791 347/1006 421/3603 0/25 12/223 17/1828 218/1003 247/3599 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) 1.2 19.4 22.3 57.1 100.0
Heterogeneity: 2 = 4.72; P = 0.69 (I 2 = 0%)

0.1 1.0 10.0
Favors Control
Summary estimates are provided by using random-effects meta-analysis. Only trials reporting 1 event are shown. CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CKD chronic kidney disease; ETDRS Early Treatment Diabetic Nephropathy Study; GI gastrointestinal; HOT Hypertension Optimal Treatment; STOP Shunt Thrombotic Occlusion Prevention by Picotamide; UK-HARP-I First United Kingdom Heart and Renal Protection.
platelet therapy and stroke and cardiovascular death in persons with CKD and who have acute coronary syndromes or who are undergoing percutaneous coronary intervention is scant. Antiplatelet regimens in persons with CKD who have or are at risk for cardiovascular disease reduce fatal or nonfatal myocardial infarction by approximately 33% but have uncertain effects on stroke or all-cause and cardiovascular mortality. Summary estimates for the effects of antiplatelet agents on major bleeding or hemorrhagic stroke are uncertain. Thienopyridines may increase mortality in persons with CKD and stable cardiovascular disease, although data are derived from subgroup analyses in few trials and are unreliable. Overall, most trials of persons with CKD and stable or no cardiovascular disease have methodological or reporting limitations that reduce the reliability of the evidence. When absolute treatment effects are estimated, persons with acute coronary syndromes or who have undergone high-risk coronary intervention experience no reduction in myocardial infarction or subsequent need for revascularization with additional antiplatelet therapy. However, up to 2% of these persons may have serious bleeding. Twelve months of oral antiplatelet therapy may prevent myocardial infarction in 1% to 3% of persons at risk for myocardial
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infarction, but information about bleeding hazards and especially intracranial hemorrhage is of low or very low quality. Given the quality of the available evidence, specic trials evaluating antiplatelet agents in persons with CKD and coexisting acute or stable cardiovascular disease are required. Outcome data for antiplatelet agents are scant in several important clinical settings. We currently have no data on persons receiving dialysis or kidney transplant recipients who have acute coronary syndromes or require coronary artery revascularization, and evidence for persons with earlier stages of CKD is entirely derived from post hoc analyses within larger trials. In addition, more and better evidence is required for long-term antiplatelet treatment in persons receiving dialysis or who have undergone kidney transplantation. Evidence to support secondary prevention with lowcost antiplatelet drugs (such as aspirin) in persons with a recent occlusive myocardial event and coexisting CKD is not available, and extrapolating data from the general population may not be appropriate because the biology of arterial disease and causes of death in persons with CKD may confer a different risk benet tradeoff for therapy. As shown in the general population (74), widespread administration of antiplatelet agents may have uncer20 March 2012 Annals of Internal Medicine Volume 156 Number 6 455
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tain value in persons with CKD because of the balance between reduced occlusive events (myocardial infarction) and the uncertain risk for major bleeding, including intracranial hemorrhage. Although the values and preferences of patients with CKD are not well-understood (75), it seems unlikely that many patients would accept the risk for major bleeding to reduce the risk for myocardial infarction without proven reductions in death or the need for coronary revascularization. The benets and hazards of antiplatelet therapy to prevent cardiovascular events may be particularly important for patients receiving hemodialysis and dialysis-related anticoagulation who have impaired hemostasis (73). However, these patients may also have greater absolute reductions in occlusive coronary events because of higher baseline risk (71). Considering the totality of current evidence, using antiplatelet and related agents to prevent cardiovascular events in people with CKD may be prudent only in clinical trials that can further dene the role of these drugs. Recent prespecied subgroup data from the PLATO (Platelet Inhibition and Patient Outcomes) trial indicates that ticagrelor, an oral purinergic receptor inhibitor cleared by extrarenal mechanisms, reduces mortality and major cardiovascular events better than clopidogrel among persons with CKD and acute coronary syndromes (76). This nding suggests that newer antiplatelet agents may potentially act as adjunctive therapy in persons with impaired kidney function. However, large placebo-controlled trials to assess the relative benets and toxicity of these newer antiplatelet agents, in addition to standard care specically in persons with CKD and acute cardiovascular disease, are needed. An earlier collaborative meta-analysis (5) provided data for the effects of antiplatelet agents in patients receiving hemodialysis, but to our knowledge, outcome data for persons with earlier stages of CKD have not been previously summarized. In that previous meta-analysis (5), antiplatelet therapy reduced major cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, and vascular death) by 41% in persons undergoing hemodialysis; however, CIs approached no effect, and the effects of treatment on individual components of the outcome were not reported. In that previous review (5), a meta-analysis that included only 46 events summarized bleeding risks with antiplatelet therapy in persons receiving hemodialysis, and estimates wereappropriately considered unreliable. We found a lack of a clear reduction in vascular deaths with antiplatelet treatment among persons with CKD; this nding is in contrast to ndings observed in other populations at high risk for vascular events, including persons with a history of documented myocardial infarction and stroke (5). Our nding that antiplatelet agents reduce cardiovascular events in persons with CKD to a lesser extent than in other populations and have no certain effect on mortality in persons with CKD echoes similar treatment effects for statin therapy in persons with CKD (77). The
competing mechanisms for cardiovascular disease in this population potentially explain this nding. Progressive kidney dysfunction is characterized by vascular stiffening and calcication, cardiomyopathy, hyperkalemia, and sudden cardiac death, in addition to occlusive vascular disease (78). We found that the proportional increased risk for serious bleeding from antiplatelet agents were 20% to 40%, which is somewhat smaller than that seen in patients with documented chronic or acute cardiovascular disease (60%) (5). However, the substantially higher baseline risk for bleeding in persons with CKD (approximately 2.5% per year [73] compared with 1% in other at-risk populations [5]) means that absolute bleeding risks with antiplatelet therapy might be at least doubled in persons with CKD. It is also relevant to consider which specic bleeding complications are incurred by treatment when deciding whether the clinical benets outweigh the potential risks of treatment in persons with CKD. Reversible hemorrhage from the gastrointestinal tract, skin, or dialysis access or surgical sites may be more acceptable treatment hazards than disabling bleeding into an eye, a joint, or the brain or bleeding requiring major surgery. However, insufcient data were available in the included trials to provide comprehensive information on specic types of bleeding caused by antiplatelet agents in this population and, consequently, on the relevant risk benet tradeoff needed to inform clinical decision making. It is also important to remember that persons in the real world may have much higher risks for bleeding than trial participants. Therefore, the absolute numbers of persons with CKD affected by serious bleeding complications from antiplatelet treatment suggested in the Table may shift the balance toward excess harm. Our meta-analysis quanties the benets and harms of antiplatelet agents in a large number of persons. However, it has limitations, largely because it relies on trial-level rather than individual-patient data. First, we could not assess whether the stage of kidney disease modied the effects of antiplatelet therapy. Second, denitions and assessments of bleeding were widely heterogeneous; therefore, estimates of hazards for specic bleeding events were less reliable. Third, overall trial duration varied greatly; in general, the longer-term effects (3 to 5 y) of antiplatelet treatment are uncertain. Fourth, the amount of data available overall, and particularly that in persons with advanced CKD, was limited; as a result, insufcient power may explain some of the negative ndings and highlights the need for trials of antiplatelet agents specically targeting this population. In addition, reliance on data from post hoc analyses in larger trials may reduce the reliability of the summary ndings (79). This is particularly true for evidence in persons with CKD and acute cardiovascular disease, for whom available data provide hypothesis-generating, rather than conrmatory, evidence for antiplatelet treatment effects in this population especially for adverse events. Finally, we were
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unable to determine the relative benets of antiplatelet agents in primary prevention of cardiovascular disease (treating persons without clinically evident cardiovascular disease) compared with secondary prevention (treating persons with established cardiovascular disease) because too few trials provided data for participants in the primary prevention setting. In conclusion, evidence for antiplatelet agents in persons with CKD and various cardiovascular diseases is of low quality. Glycoprotein IIb/IIIa inhibitors or clopidogrel given in addition to standard care have little or no effect on death, myocardial infarction, or coronary revascularization and may increase major bleeding in persons with CKD and acute coronary syndromes or those having high-risk coronary artery intervention. Antiplatelet agents reduce myocardial infarction in persons with CKD but have uncertain effects on stroke and mortality and may increase bleeding. Bleeding hazards and lack of clear efcacy in reducing cardiovascular morbidity and mortality need to be acknowledged when patients with CKD are being counseled about acute 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, Australia; Mario Negri Sud Consortium, Santa Maria Imbaro, Italy; Scientic Institute Casa Sollievo della Sofferenza, Foggia, Italy; Concord Repatriation General Hospital, Concord, Australia; Diaverum MedicalScientic Ofce, Lund, Sweden; and University of Bari, Bari, Italy.
Financial Support: No specic external funding was received for this
Current author addresses and author contributions are available at www .annals.org.
References
1. Coresh J, Selvin E, Stevens LA, Manzi J, Kusek JW, Eggers P, et al. Prevalence of chronic kidney disease in the United States. JAMA. 2007;298:2038-47. [PMID: 17986697] 2. Fox CS, Muntner P, Chen AY, Alexander KP, Roe MT, Cannon CP, et al; Acute Coronary Treatment and Intervention Outcomes Network registry. Use of evidence-based therapies in short-term outcomes of ST-segment elevation myocardial infarction and non-ST-segment elevation myocardial infarction in patients with chronic kidney disease: a report from the National Cardiovascular Data Acute Coronary Treatment and Intervention Outcomes Network registry. Circulation. 2010;121:357-65. [PMID: 20065168] 3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351:1296-305. [PMID: 15385656] 4. de Jager DJ, Grootendorst DC, Jager KJ, van Dijk PC, Tomas LM, Ansell D, et al. Cardiovascular and noncardiovascular mortality among patients starting dialysis. JAMA. 2009;302:1782-9. [PMID: 19861670] 5. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86. [PMID: 11786451] 6. Jardine MJ, Ninomiya T, Perkovic V, Cass A, Turnbull F, Gallagher MP, et al. Aspirin is benecial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. J Am Coll Cardiol. 2010;56:956-65. [PMID: 20828648] 7. Derry S, Loke YK. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. BMJ. 2000;321:1183-7. [PMID: 11073508] 8. Remuzzi G. Bleeding in renal failure. Lancet. 1988;1:1205-8. [PMID: 2897015] 9. Smith DH, Gullion CM, Nichols G, Keith DS, Brown JB. Cost of medical care for chronic kidney disease and comorbidity among enrollees in a large HMO population. J Am Soc Nephrol. 2004;15:1300-6. [PMID: 15100370] 10. Hunsicker LG. The consequences and costs of chronic kidney disease before ESRD [Editorial]. J Am Soc Nephrol. 2004;15:1363-4. [PMID: 15100382] 11. Smith KA, Hayward RA. Performance measurement in chronic kidney disease. J Am Soc Nephrol. 2011;22:225-34. [PMID: 21289212] 12. Razavian M, Di Micco L, Palmer SC, Craig JC, Perkovic V, Zoungas S, et al. Antiplatelet agents for chronic kidney disease. Cochrane Database Syst Rev. 2010:CD008834. 13. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151:264-9, W64. [PMID: 19622511] 14. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/ IIIa receptor in high-risk coronary angioplasty. The EPIC Investigation. N Engl J Med. 1994;330:956-61. [PMID: 8121459] 15. EPISTENT Investigators. Randomised placebo-controlled and balloonangioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet. 1998;352:87-92. [PMID: 9672272] 16. Brener SJ, Barr LA, Burchenal JE, Katz S, George BS, Jones AA, et al. Randomized, placebo-controlled trial of platelet glycoprotein IIb/IIIa blockade with primary angioplasty for acute myocardial infarction. ReoPro and Primary PTCA Organization and Randomized Trial (RAPPORT) Investigators. Circulation. 1998;98:734-41. [PMID: 9727542] 17. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classication, and stratication. Am J Kidney Dis. 2002;39:S1-266. [PMID: 11904577] 18. Andrassy K, Malluche H, Bornefeld H, Comberg M, Ritz E, Jesdinsky H, et al. Prevention of p.o. clotting of av. cimino stulae with acetylsalicyl acid. Results of a prospective double blind study. Klin Wochenschr. 1974;52:348-9. [PMID: 4600820] 19. Dodd NJ, Turney JH, Weston MJ. Ticlopidine preserves vascular access for haemodialysis [Abstract]. In: Proceedings of the 6th International Congress of Mediterranean League Against Thrombosis, Monte Carlo, Monaco, 1980. Abstract 326F. 20. Fiskerstrand CE, Thompson IW, Burnet ME, Williams P, Anderton JL. Double-blind randomized trial of the effect of ticlopidine in arteriovenous stulas
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 to institution): 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 institution): Roche. Dr. Jardine: Grant (money to institution): Royal Australasian College of Physicians. Dr. Nicolucci: Board membership: Merck Sharp & Dohme; Grants/grants pending (money to institution): Merck Sharp & Dohme, Novo Nordisk, Sano Aventis, Eli Lilly, Johnson & Johnson. Dr. Zoungas: Board membership: Merck Sharp & Dohme, Novo Nordisk, Boehringer Ingelheim, Sano Aventis, Bristol-Myers Squibb/AstraZeneca; Payment for lectures including service on speakers bureaus (money to institution): Merck Sharp & Dohme, Novo Nordisk, Sano 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 /ConictOfInterestForms.do?msNumM11-2512.
Reproducible Research Statement: Study protocol, statistical code, and
data set: Available from Dr. Strippoli (e-mail, strippoli@negrisud.it).

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, strippoli@negrisud.it.
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chronic kidney disease. Am J Kidney Dis. 2005;45:473-84. [PMID: 15754269] 59. Higgins JPT, Green D, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.1.0. The Cochrane Collaboration. 2008. Accessed at www.cochrane-handbook.org on 11 November 2010. 60. Stijnen T, Hamza TH, Ozdemir P. Random effects meta-analysis of event outcome in the framework of the generalized linear mixed model with applications in sparse data. Stat Med. 2010;29:3046-67. [PMID: 20827667] 61. Sweeting MJ, Sutton AJ, Lambert PC. What to add to nothing? Use and avoidance of continuity corrections in meta-analysis of sparse data. Stat Med. 2004;23:1351-75. [PMID: 15116347] 62. Ru cker G, Schwarzer G, Carpenter J, Olkin I. Why add anything to nothing? The arcsine difference as a measure of treatment effect in meta-analysis with zero cells. Stat Med. 2009;28:721-38. [PMID: 19072749] 63. Greenland S. Bayesian perspectives for epidemiological research: I. Foundations and basic methods. Int J Epidemiol. 2006;35:765-75. [PMID: 16446352] 64. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557-60. [PMID: 12958120] 65. Harbord RM, Egger M, Sterne JA. A modied test for small-study effects in meta-analyses of controlled trials with binary endpoints. Stat Med. 2006;25: 3443-57. [PMID: 16345038] 66. Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schu nemann HJ; GRADE Working Group. What is quality of evidence and why is it important to clinicians? BMJ. 2008;336:995-8. [PMID: 18456631] 67. van Houwelingen HC, Arends LR, Stijnen T. Advanced methods in metaanalysis: multivariate approach and meta-regression. Stat Med. 2002;21:589-624. [PMID: 11836738] 68. Kasiske BL, Maclean JR, Snyder JJ. Acute myocardial infarction and kidney transplantation. J Am Soc Nephrol. 2006;17:900-7. 69. Anavekar NS, McMurray JJ, Velazquez EJ, Solomon SD, Kober L, Rouleau JL, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med. 2004;351:1285-95. [PMID: 15385655] 70. Weiner DE, Tabatabai S, Tighiouart H, Elsayed E, Bansal N, Grifth J, et al. Cardiovascular outcomes and all-cause mortality: exploring the interaction between CKD and cardiovascular disease. Am J Kidney Dis. 2006;48:392-401.
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[PMID: 16931212] 71. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998;339: 799-805. [PMID: 9738087] 72. Trivedi H, Xiang Q, Klein JP. Risk factors for non-fatal myocardial infarction and cardiac death in incident dialysis patients. Nephrol Dial Transplant. 2009;24:258-66. [PMID: 18682489] 73. Holden RM, Harman GJ, Wang M, Holland D, Day AG. Major bleeding in hemodialysis patients. Clin J Am Soc Nephrol. 2008;3:105-10. [PMID: 18003768] 74. Baigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, et al; Antithrombotic Trialists (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. 2009;373:1849-60. [PMID: 19482214] 75. Murray MA, Brunier G, Chung JO, Craig LA, Mills C, Thomas A, et al. A systematic review of factors inuencing decision-making in adults living with chronic kidney disease. Patient Educ Couns. 2009;76:149-58. [PMID: 19324509] 76. James S, Budaj A, Aylward P, Buck KK, Cannon CP, Cornel JH, et al. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation. 2010;122:1056-67. [PMID: 20805430] 77. Strippoli GF, Navaneethan SD, Johnson DW, Perkovic V, Pellegrini F, Nicolucci A, et al. Effects of statins in patients with chronic kidney disease: meta-analysis and meta-regression of randomised controlled trials. BMJ. 2008; 336:645-51. [PMID: 18299289] 78. Australia and New Zealand Dialysis and Transplant Registry (ANZDATA). The 32nd Annual Report2009 report. Accessed at www.anzdata.org.au/v1 /report_2009.html on 16 November 2010. 79. Boutron I, Dutton S, Ravaud P, Altman DG. Reporting and interpretation of randomized controlled trials with statistically nonsignicant results for primary outcomes. JAMA. 2010;303:2058-64. [PMID: 20501928]
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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: Scientic 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. Nicolucci, 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. Razavian, V. Perkovic, M. Jardine, G.F.M. Strippoli.
Appendix Table 1. Search Strategy (to November 2011)

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 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$.tw. 26 abciximab.tw. 27 eptifibatide.tw. 28 tirofiban.tw. 29 defibrotide.tw. 30 picotamide.tw. 31 beraprost.tw. 32 ticlid.tw. 33 aggrenox.tw. 34 ditazole.tw. 35 or/1-34 36 exp Renal Replacement Therapy/ 37 (hemodialysis or haemodialysis).tw 38 (hemofiltration or haemofiltration).tw. 39 (hemodiafiltration or haemodiafiltration).tw. 40 dialysis.tw. 41 (PD or CAPD or CCPD or APD).tw. 42 Kidney Disease/ 43 Chronic Kidney Disease/ 44 Kidney Failure/ 45 Chronic Kidney Failure/ 46 Uremia/ 47 (chronic kidney or chronic renal).tw. 48 (CKF or CKD or CRF or CRD).tw. 49 (end-stage renal or end-stage kidney or endstage renal or endstage kidney).tw. 50 (ESRF or ESKF or ESRD or ESKD).tw. 51 ur?emi$.tw. 52 exp Kidney Transplantation/ 53 or/36-52 54 and/35,53 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
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Appendix Table 1Continued

9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 ((antithrombocytic next agent*) or (anti-thrombocytic next agent*)):ti,ab,kw ((antithrombocytic next therap*) or (anti-thrombocytic next therap*)):ti,ab,kw alprostadil:ti,ab,kw aspirin:ti,ab,kw acetylsalicylic acid:ti,ab,kw ((adenosine next reuptake inhibit*) or (adenosine re-uptake inhibit*)):ti,ab,kw (adenosine next diphosphate next receptor next inhibit*):ti,ab,kw dipyridamole:ti,ab,kw disintegrins:ti,ab,kw epoprostenol:ti,ab,kw iloprost:ti,ab,kw ketanserin:ti,ab,kw milrinone:ti,ab,kw pentoxifylline:ti,ab,kw (S-nitrosoglutathione):ti,ab,kw S-nitrosothiols:ti,ab,kw trapidil:ti,ab,kw ticlopidine:ti,ab,kw clopidogrel:ti,ab,kw (sulfinpyrazone or sulphinpyrazone):ti,ab,kw cilostazol:ti,ab,kw (P2Y12 NEAR/2 antagonis*):ti,ab,kw prasugrel:ti,ab,kw ticagrelor:ti,ab,kw cangrelor:ti,ab,kw elinogrel:ti,ab,kw glycoprotein IIB/IIIA inhibitors:ti,ab,kw abciximab:ti,ab,kw eptifibatide:ti,ab,kw tirofiban:ti,ab,kw defibrotide:ti,ab,kw picotamide:ti,ab,kw beraprost:ti,ab,kw ticlid:ti,ab,kw aggrenox:ti,ab,kw ditazole:ti,ab,kw (#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) dialysis:ti,ab,kw (hemodialysis or haemodialysis):ti,ab,kw (hemofiltration or haemofiltration):ti,ab,kw (hemodiafiltration or haemodiafiltration):ti,ab,kw (PD or CAPD or CCPD or APD):ti,ab,kw (renal next insufficiency):ti,ab,kw (kidney next failure):ti,ab,kw (kidney next disease*):ti,ab,kw ur*emi*:ti,ab,kw ((chronic next kidney) or (chronic next renal)):ti,ab,kw (CKF or CKD or CRF or CRD):ti,ab,kw predialysis:ti,ab,kw ((end-stage next renal) or (end-stage next kidney) or (endstage next renal) or (endstage next kidney)):ti,ab,kw (ESKD or ESRD or ESKF or ESRF):ti,ab,kw ((kidney next transplant*) or (renal next transplant*) or (kidney next *graft*) or (renal next *graft*)):ti,ab,tw (#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) (#45 AND #61)
46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62
CENTRAL Cochrane Central Register of Controlled Trials.
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Cardiovascular Mortality ACS or Undergoing PCI NR Intracranial hemorrhage or 50 g/L decrease in hemoglobin level or 15% decrease in hematocrit; adjudicated by a blinded end points committee Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit or no observed blood loss, 40 g/L decrease in hemoglobin level, or 12% decrease in hematocrit; adjudicated by a blinded end points committee NR Major Bleeding Minor Bleeding MI Stroke NR Intracranial hemorrhage or 50 g/L decrease in hemoglobin level or 15% decrease in hematocrit; adjudicated by a blinded end points committee Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit or no observed blood loss, 40 g/L decrease in hemoglobin level, or 12% decrease in hematocrit; adjudicated by a blinded end points committee New neurologic deficit persisting for at least 24 h NR Intracranial hemorrhage or 50 g/L decrease in hemoglobin level or 15% decrease in hematocrit; adjudicated by a blinded end points committee MI after acute MI at baseline based on an increase in CK-MB level 3 times the upper limit of normal and an increase of 33% above the previous nadir or CK-MB level 100% of the previous level that remained 3 times the upper limit of normal after a 50% decrease from the previous peak; if no acute MI at baseline, then 1 of 2 criteria had to be met: a new Q wave or CK-MB level 3 times the upper limit of normal and an increase of 50% above the previous trough level; adjudicated by a blinded end points committee In persons who had no history of MI or who were enrolled 24 h after any infarction, end point MI during the index hospital admission was defined as any increase in CK-MB level 3 times the upper limit of normal or the development of new significant Q waves; after discharge, an increase in CK-MB level 2 times the upper limit of normal (or new significant Q waves); for patients with an acute MI within the 24 h before the protocol intervention, reinfarction or extension was diagnosed on the basis of 1 or 2 criteria: in persons whose CK-MB level remained 3 times the upper limit of normal, a 25% decrease from a previous peak followed by a minimum 33% increase in the level was required, otherwise a 50% decrease from a previous peak followed by a minimum 100% increase to 3 times the upper limit of normal was required; adjudicated by a blinded end points committee In-hospital MI defined by 1 of 2 criteria: new, clinically significant Q waves or increase in CK level or CK-MB level 3 times normal, representing an increase 50% over previous trough level; after discharge, MI was defined by the occurrence of Q waves or the increase of CK level or CK-MB level 2 times the upper limit of normal; adjudicated by end points committee blinded to treatment allocation Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit or no observed blood loss plus 4 g/L decrease in hemoglobin level or 12% decrease in hematocrit; adjudicated by a blinded end points committee Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit or no observed blood loss, 40 g/L decrease in hemoglobin level, or 12% decrease in hematocrit; adjudicated by a blinded end points committee Intracranial hemorrhage or 50 g/L reduction in hemoglobin level; adjudicated by a blinded end points committee Reinfarction within 24 h of randomization was defined as a re-elevation of the CK-MB level by at least 33% or 100% from the preceding nadir (which was 2 or 2 times normal, respectively) and reached at least a 0.3 times normal value in association with ischemic symptoms; after 24 h, reinfarction was defined as new pathologic Q waves, or re-elevation of CK-MB level to 3 times normal (24 h to discharge) or 2 times normal (after hospital discharge); adjudicated by a blinded end points committee NR NR NR
Appendix Table 2. Definitions of Clinical Outcomes in Included Trials
All-Cause Mortality
EPIC, 1994 (14)
Adjudicated by consensus between 2 members of an independent adjudication committee

IMPACT-II, 1997 (23)
Adjudicated by a blinded end points committee
EPILOG, 1997 (24)
Adjudicated by end points committee blinded to treatment allocation
PURSUIT, 1998 (25)

Major Bleeding Intracranial hemorrhage or 50 g/L decrease in hemoglobin level or 15% decrease in hematocrit; adjudicated by a blinded end points committee ND; adjudicated by a blinded end points committee NR Minor Bleeding MI Stroke
All-Cause Mortality
Cardiovascular Mortality
EPISTENT, 1998 (15)
NR

Intracranial hemorrhage or 50 g/L decrease in hemoglobin level; adjudicated by a blinded end points committee Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit, or no observed blood loss, 40 g/L decrease in hemoglobin level, or 12% decrease in hematocrit; adjudicated by a blinded end points committee Observed blood loss, 30 g/L decrease in hemoglobin level, or 10% decrease in hematocrit or no observed blood loss, 40 g/L decrease in hemoglobin level, or 12% decrease in hematocrit; adjudicated by a blinded end points committee Mild bleeding according to PRISM-PLUS bleeding scale; not otherwise defined Reinfarction within 24 h of randomization was defined as a re-elevation of CK-MB level by at least 33% or 100% from the preceding nadir and at least 3 times normal value in association with ischemic symptoms; reinfarction after 24 h was defined as new pathologic Q waves or re-elevation of CK-MB level to 3 times normal (24 h to discharge) or 2 times normal after hospital discharge; adjudicated by a blinded end points committee NR NR NR Other hemorrhage that led to interruption of study medication; determined by central committee blinded to treatment allocation At least 2 of the following factors: ischemic chest pain, elevation of serum levels of cardiac markers, and ECG changes consistent with infarction; determined by central committee blinded to treatment allocation Decrease in hemoglobin level 40 g/L, transfusion 2 units of blood, corrective surgery, intracranial or retroperitoneal hemorrhage Substantially disabling bleeding, intraocular bleeding leading to loss of vision, or bleeding necessitating transfusion 2 units of blood; determined by central committee blinded to treatment allocation Intracranial bleeding or bleeding associated with decrease in hemoglobin level 50 g/L (or decrease in hematocrit 15%); formal adjudication as for death Not major or insignificant; not otherwise defined Q wave or nonQ wave (elevation of CK or CK-MB level 2 times the upper limit of normal; formal adjudication as for death New focal neurologic deficit of vascular origin 24 h; determined by central committee blinded to treatment allocation New focal neurologic deficit 24 h; formal adjudication as for death At Risk for or With Stable Cardiovascular Disease and CKD No events reported during follow-up NR NR NR Not adjudicated; included occult GI bleeding, rectal polyp bleeding, and ecchymoses NR Formally adjudicated by blinded committee; fatal and nonfatal MI Formally adjudicated by blinded committee; fatal and nonfatal stroke
RAPPORT, 1998 (16)
NR
PRISM-PLUS, 2002 (26)
NR (composite end point only)
NR (composite end point only)
CURE, 2007 (27)
Determined by central committee blinded to treatment allocation
Death for which there was no clear nonvascular cause; determined by central committee blinded to treatment allocation
CREDO, 2008 (28)
Mortality from any cause; adjudicated by independent clinical events committee blinded to treatment allocation
Death with clear cardiovascular cause (including hemorrhage) or unknown cause; formal adjudication as for death
Donadio et al, 1984 (29)
No deaths reported during follow-up
ETDRS, 1992 (30)
Blinded adjudication by mortality and morbidity classification committee
Blinded adjudication by mortality and morbidity classification committee; death due to coronary disease, cerebrovascular thrombosis, thromboembolism or infarction, or hemorrhage and other atherosclerotic cerebrovascular disease
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Cardiovascular Mortality No deaths reported during follow-up NR NR NR NR NR NR MI as defined by the ACC; adjudication as for death NR NR NR NR NR NR NR NR NR NR New focal neurologic deficit of vascular origin 24 h; adjudication as for death Fatal or nonfatal stroke; adjudication as for death NR NR NR NR NR No deaths during follow-up NR No deaths reported during follow-up Cardiovascular death, including hemorrhagic death (adjudicated as for death) No bleeding events reported during follow-up Severe according to GUSTO criteria (intracerebral or substantial hemodynamic compromise requiring treatment); adjudicated as for death Fatal, life-threatening, disabling, or requiring hospital admission; investigator-reported NR At Risk for or With Stable Cardiovascular Disease and Receiving Hemodialysis GI bleeding No events reported during follow-up Minor GI bleeding NR NR NR NR NR No deaths reported during follow-up Cause of death not formally adjudicated NR No minor bleeding events reported NR NR NR NR NR NR Major Bleeding Minor Bleeding MI Stroke
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No bleeding events reported during follow-up Minor bleeding according to GUSTO criteria (not requiring transfusion or causing hemodynamic compromise); adjudicated as for death All other reported bleeding events; investigator-reported Fatal or nonfatal MI; adjudication as for death Death due to cardiovascular disease; adjudication as for death NR NR NR NR NR Cause of death not formally adjudicated NR Full text NA No GI bleeding observed during follow-up Serious bleeding included hemarthrosis, nasal bleeding, shunt hemorrhage, and bleeding at injection site No events reported during follow-up Full text NA No nonfatal MI events reported during follow-up Full text NA Full text NA Full text NA Full text NA Full text NA Full text NA No nonfatal MI events reported during follow-up NR No nonfatal stroke events reported during follow-up Nonfatal stroke; not otherwise available NR NR Adjudication methods NR ND NR NR ND NR Fatal and nonfatal MI; not formally adjudicated NR Adjudication methods NR NR GI bleeding; not otherwise defined NR NR NR NR Nonfatal MI; adjudication methods NR Nonfatal cerebrovascular accident; not formally adjudicated NR Nonfatal stroke; adjudication methods NR
All-Cause Mortality
No deaths reported during follow-up NR
NR

Za uner et al, 1994 (31) Gonzalez et al, 1995 (32) Frasc et al, 1997 (33) Cheng et al, 1998 (34) Giustina et al, 1998 (35) Khajehdehi et al, 2002 (36) CHARISMA, 2009 (37)
No deaths reported during follow-up NR
No deaths reported during follow-up Death adjudicated by independent end points committee
HOT, 2010 (6)
JPAD, 2011 (38)
Reviewed and validated by independent end points committee NR
No deaths reported during follow-up Clinical record
Kaegi et al, 1974 (39) Michie and Wombolt, 1977 (40) Harter et al, 1979 (41) Kobayashi et al, 1980 (42)
Method of adjudication NR NR
Ell et al, 1982 (43)
Full text NA
Full text NA
Full text NA
Creek, 1990 (44) Middleton and Deichsel, 1992 (45) Taber et al, 1992 (46) Kooistra et al, 1994 (47)
NR
Adjudication methods NR
Sreedhara et al, 1994 (48) STOP, 1995 (49)
Adjudication methods NR NR

Cardiovascular Mortality No formal adjudication Bleeding event that did not necessitate event-related visit or follow-up monitoring MI associated with hospitalization; not formally adjudicated Major Bleeding Minor Bleeding MI Stroke Stroke associated with hospitalization; not formally adjudicated
All-Cause Mortality
Kaufman et al, 2003 (50)
No formal adjudication
Abdul-Rahman and Al Howaish, 2007 (51) NR ND; adjudicated by clinical center investigator Not major, life-threatening, or fatal; adjudication method NR
NR
NR
NR
NR
NR
Dember et al, 2008 (52) NR

Retroperitoneal, intra-articular, intraocular, or cerebral hemorrhage or 20 g/L decrease in hemoglobin plus hospitalization or transfusion; adjudicated by blinded panel Confirmed retroperitoneal, intra-articular, or intracranial hemorrhage or hemoglobin decrease by 20 g/L; adjudication method NR ND; adjudicated by clinical center investigator Ischemic heart disease events; not otherwise defined Hospitalization for ischemic heart disease; adjudication method NR Cerebrovascular disease events; not otherwise defined Hospitalization for cerebrovascular disease; adjudication method NR NR Confirmed retroperitoneal, intra-articular, intraocular, or intracranial bleeding or bleeding causing hemoglobin level decrease by 20 g/L and requiring hospitalization or transfusion; adjudication method NR Severe bleeding ND; adjudicated by panel blinded to treatment allocation Minor bleeding ND NR At Risk for or With Stable Cardiovascular Disease in Persons With Kidney Transplant NR NR No deaths reported during follow up No major complications; not otherwise defined NR NR NR NR NR NR NR NR NR NR NR NR At Risk for or With Stable Cardiovascular Disease in Persons With CKD or Kidney Transplant or Undergoing Dialysis Coded centrally according to standardized study protocol Fatal or requiring hospitalization; coded centrally according to standardized study protocol Included epistaxis, ecchymoses, or bruising; coded centrally according to standardized study protocol Nonfatal MI; coded centrally according to standardized study protocol Nonfatal stroke; coded centrally according to standardized study protocol
Not formally adjudicated
Dixon et al, 2009 (53)
Ghorbani et al, 2009 (54)
NR
NR
Anderson et al, 1974 (55) Schulze et al, 1990 (56) Quarto Di Palo et al, 1991 (57)
UK-HARP-I, 2005 (58)
Coded centrally according to standardized study protocol
ACC American College of Cardiology; ACS acute coronary syndrome; CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CK creative kinase; CKD chronic kidney disease; CREDO Clopidogrel for the Reduction of Events During Observation; CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events; ECG electrocardiography; 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; ETDRS Early Treatment Diabetic Nephropathy Study; GI gastrointestinal; GUSTO Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HOT Hypertension Optimal Treatment; IMPACT-II Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; JPAD Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; MI myocardial infarction; NA not available; ND not dened; NR not reported; PCI percutaneous coronary intervention; PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial; STOP Shunt Thrombotic Occlusion Prevention by Picotamide; UK-HARP-I First United Kingdom Heart and Renal Protection.
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Intervention Comparison Nonrandomized Co-Interventions Primary Outcome Participants, n Study Duration, mo Age, y Diabetes, % ACS or Undergoing PCI Abciximab, bolus of 0.25 mg/kg 10 g/min infusion, or placebo infusion for 12 h Placebo 519* 12 Death from any cause, nonfatal MI, CABG, or repeat PCI Aspirin heparin 6162 2326 Placebo Aspirin heparin Death from any cause, nonfatal MI, CABG, or repeat PCI 806* 6 6062 2326 Eptifibatide, bolus 135 g/kg infusion of either 0.5 g/kg/min or 0.75 g/kg/min for 2024 h Abciximab, 0.35 mg/kg bolus IV 0.125 g/kg/min IV for 12 h No treatment Aspirin heparin Abciximab, 0.25 mg/kg bolus 0.125 g/kg/min (maximum, 10 g/kg/min for 12 h) Placebo Aspirin, ticlopidine, heparin Death from any cause, MI, or severe myocardial ischemia requiring surgical or PCI Death from any cause, MI or reinfarction, or severe myocardial ischemia requiring urgent CABG or revascularization 488* 12 NA NA 368* 12 59 2021 Placebo Aspirin heparin Death from any cause or nonfatal MI 2617* 6 64 2224 Placebo Aspirin 62* 6 6062 2223 Eptifibatide, bolus dose of 180 g/kg infusion of 2.0 g/kg/min until discharge or for 72 h Abciximab, 0.25 mg/kg bolus 0.125 g/kg/min infusion (maximum, 10 g/min) for 12 h Tirofiban, 0.15 g/kg/min IV for 72 h* Placebo Aspirin heparin Death from any cause, nonfatal reinfarction, or any repeat target vessel revascularization Death, MI, or myocardial ischemia 611* 6 7179 2438 Clopidogrel, 75 mg/d Placebo Aspirin Cardiovascular death, nonfatal MI or stroke 4087* 12 70 28 Clopidogrel, 300 mg loading dose 75 mg/d for 12 mo Clopidogrel (placebo loading dose 75 mg/d for 28 d, then placebo for 12 mo) Aspirin Death, MI, or target vessel revascularization 411* 12 74 28
Appendix Table 3. Characteristics of Populations and Interventions in the Included Trials
Inclusion Criteria
EPIC, 1994 (14)

Scheduled to undergo coronary angioplasty or directional arterectomy and at high risk for abrupt vessel closure (acute evolving MI within 12 h that necessitated PCI, early postinfarction angina or unstable angina, or clinical or angiographic features of high risk; unpublished data for participants with eGFR 60 mL/min/1.73 m2 Scheduled for elective, urgent, or emergency PCI; unpublished data for participants with eGFR 60 mL/min/1.73 m2
EPILOG, 1997 (24)
EPISTENT, 1998 (15)
PURSUIT, 1998 (25)
RAPPORT, 1998 (16)
PRISM-PLUS, 2002 (26)
CURE, 2007 (27)
CREDO, 2008 (28)
Undergoing elective or urgent PCI; unpublished data for participants with serum creatinine level 133 mol/L (0.7 mg/dL) and eGFR 60 mL/min/m2 Participants scheduled to undergo elective or urgent PCI if target lesions had caused stenosis of at least 60% amenable to balloon angioplasty or stenting and target vessel was not unprotected left-main stem stenosis; unpublished data for eGFR 60 mL/min/1.73 m2 Ischemic chest pain at rest lasting 10 min or longer within the previous 12 h; unpublished data for participants with eGFR 60 mL/min/1.73 m2 Referred for primary angioplasty within 12 h of the onset of acute MI; unpublished data for participants with eGFR 60 mL/min/1.73 m2 Hospitalization for potential ST-segment elevation or nonST-segment elevation ACS and 24 h from onset; unpublished data for eGFR 60 mL/min ACS without ST-segment elevation, hospitalized within 24 h of symptom onset, positive cardiac markers, or ischemic ECG changes; unpublished data for eGFR 64 mL/min/1.73 m2 Elective PCI planned or considered; unpublished data for participants with eGFR 60 mL/min/1.73 m2

Intervention Comparison Nonrandomized Co-Interventions Primary Outcome Participants, n Study Duration, mo Age, y Diabetes, %
Study, Year (Reference) At Risk for or With Stable Cardiovascular Disease in Persons With CKD Dipyridamole, 75 mg, aspirin, 325 mg (3 times daily) Aspirin, 650 mg/d Placebo Placebo NR 185* 60 53 NR Progression of CKD (kidney function) Death 50 12 2932 NR 100
Inclusion Criteria
Donadio et al, 1984 (29) ETDRS, 1992 (30)
Za uner et al, 1994 (31) No treatment 18 Symptomatic therapy ACE inhibitor Prednisolone Captopril 20 31 58 Dipyridamole aspirin No treatment No treatment No treatment Defibrotide, 10 mg/kg daily Ticlopidine, 250 mg twice daily
Aspirin, 500 mg, dipyridamole, 75 mg (daily)
36
4148
NR
36 24 36
51 3031 3739
100 NR NR

Progression of CKD (proteinuria and kidney function) Progression of CKD (kidney function) Progression of CKD (kidney function and proteinuria) Progression of CKD (urinary albumin excretion and kidney function) Picotamide, 300 mg 3 times daily Placebo Progression of CKD (urinary albumin excretion) Progression of CKD (urinary albumin excretion) 30 12 5657 100 Aspirin, 1000 mg, or dipyridamole, 750 mg, or aspirin, 1000 mg, dipyridamole, 750 mg (daily) Clopidogrel, 75 mg/d Placebo Placebo Aspirin Hypoglycemic agents isocaloric diet NR 76 2 5658 100 MI, stroke, or cardiovascular death 2009* 28 63 100 Aspirin, 75 mg/d Placebo MI, stroke, and cardiovascular death 3619* 46 65; 66** 79; 1112** Aspirin, 81 mg/d or 100 mg/d No treatment Blood pressure targets (factorial design) NR Sudden death; death from coronary, cerebrovascular, and aortic causes; nonfatal acute myocardial infarction, unstable angina, newly developed exertional angina, nonfatal ischemic and hemorrhagic stroke, TIA, or nonfatal aortic and peripheral vascular disease (arteriosclerosis obliterans, aortic dissection, and mesenteric arterial thrombosis) 632* 52 6869 100
Gonzalez et al, 1995 (32) Frasc et al, 1997 (33) Cheng et al, 1998 (34)
Giustina et al, 1998 (35)
Khajehdehi et al, 2002 (36)
Biopsy-proven membranoproliferative glomerulonephritis Clinical diagnosis of diabetes mellitus and diabetic retinopathy; unpublished data for participants with creatinine level 133 mol/l (1.5 mg/dL) Biopsy-proven membranoproliferative glomerulonephritis; urinary protein excretion 3 g/24 h Diabetes mellitus with nephropathy and retinopathy; variable renal function IgA nephropathy; serum creatinine level 124 mol/L (1.4 mg/dL) Aged 2165 y with biopsy-proven IgA nephropathy and 2 of the following factors: urinary protein excretion 1g/24 h, mean arterial pressure 107 mm Hg, serum creatinine level 120400 mol/L (1.34.5 mg/dL) or biopsy-proven tubulointerstitial disease Aged 4065 y, diabetes mellitus 12 mo, HbA1c 10%, BMI 35 kg/m2, blood pressure Type 2 diabetes mellitus with urine protein excretion 500 mg/24 h
CHARISMA, 2009 (37)
HOT, 2010 (6)
Clinically evident cardiovascular disease or multiple atherothrombotic risk factors for cardiovascular disease diabetes mellitus and microalbuminuria with urinary albumin excretion 30 g/mL Aged 5080 y with elevated diastolic blood pressure; eGFR 60 mL/min/1.73m2
JPAD, 2011 (38)
Type 2 diabetes without any history of atherosclerotic disease in persons between 30 and 85 y; eGFR 60 mL/min/1.73 m2
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At Risk for or With Stable Cardiovascular Disease in Persons Undergoing Hemodialysis or Nearing Requirement for Dialysis Placebo Placebo Dialysis access thrombosis 16 3 51 Warfarin sodium or dicumarol NR Dialysis access thrombosis 62 6 4344 NR NR Sulfinpyrazone, 200 mg 3 times daily Sulfinpyrazone, 200 mg 4 times daily Aspirin, 160 mg/d Ticlopidine, 100 mg/d Placebo NR Dialysis access thrombosis 107 3 Placebo NR Dialysis access thrombosis 44 4.7 4653 NR NR NR Ticlopidine, 500 mg/d Ticlopidine, 500 mg/d Aspirin, 50 mg, dipyridamole, 400 mg (daily) No treatment NR Dialysis access thrombosis Aspirin, 650 mg/d Aspirin, 30 mg/d Placebo NR No treatment NR Dialysis access stenosis Dialysis access and systemic thrombosis Dialysis access thrombosis 903 No treatment NA Dialysis access thrombosis 285 No treatment NA Dialysis access thrombosis 50 3 5 18 NA NA NA NA NA NA 18 137 3 3 NR NR NR NR Placebo NR 108 18 54 NR Dipyridamole, 75 mg 3 times daily, or aspirin, 325 mg/d or dipyridamole, 75 mg aspirin, 325 mg (daily) Picotamide, dose unclear Placebo Placebo No treatment NR NR Oral anticoagulant Clopidogrel, 75 mg, aspirin, 325 mg (daily) Aspirin, 81 mg/d Dialysis access thrombosis Dialysis access thrombosis Dialysis access thrombosis 811 200 38 12 67 12 NA 6162 45 NA 4351 3242 Clopidogrel, 75 mg/d for 42 d Placebo Dialysis access thrombosis 877 45 5355 4749 Dipyridamole, 200 mg, aspirin, 25 mg (twice daily) Placebo Antiplatelet or anticoagulant treatment permitted after 6 wk of study drug administration NR Loss of primary unassisted dialysis access patency 649 61 5859 6066 Clopidogrel, 75 mg/d Placebo NR Dialysis access failure 93 6 45 27 Dipyridamole, 600 mg/d Dipyridamole, 150 mg 3 times daily Picotamide, 600 mg/d Placebo No treatment Placebo 27 64 NR 36 24 3 12 NR NR 37 NR NR NR Prednisone azathioprine NR Kidney transplantation function Kidney transplantation function Kidney transplantation function
Inclusion Criteria
Hemodialysis with straight arteriovenous shunt
Kaegi et al, 1974 (39) Michie and Wombolt, 1977 (40) Harter et al, 1979 (41) Kobayashi et al, 1980 (42)
Adults with CKD scheduled to start hemodialysis
Receiving straight arteriovenous shunt for hemodialysis Chronic hemodialysis with arteriovenous external shunt or vascular graft with shunt or graft thrombosis during preceding 4 wk Hemodialysis
Hemodialysis

Hemodialysis
Ell et al, 1982 (43) Creek, 1990 (44) Middleton and Deichsel, 1992 (45) Taber et al, 1992 (46) Kooistra et al, 1994 (47)
Hemodialysis with arteriovenous graft
Sreedhara et al, 1994 (48)
Hemodialysis 6 wk; hematocrit 0.28 during initial period of treatment with recombinant human erythropoietin CKD or hemodialysis; requiring new graft or participant with graft thrombosis requiring new graft or revision
STOP, 1995 (49)
Kaufman et al, 2003 (50) Abdul-Rahman and Al Howaish, 2007 (51) Dember et al, 2008 (52)
Hemodialysis 60 d with internalized arteriovenous graft or fistula Age 21 y, hemodialysis three times weekly, PTFE graft in arm Hemodialysis with tunneled venous catheter
Hemodialysis or expected to begin hemodialysis within 6 mo of undergoing creation of new upper-extremity fistula
Dixon et al, 2009 (53)
Ghorbani et al, 2009 (54)
Age 18 y on hemodialysis or expected to begin hemodialysis within 6 mo of undergoing creation of new arteriovenous graft Age 18 y on hemodialysis requiring arteriovenous fistula at new site or nearing hemodialysis and requiring fistula Kidney transplantation
Deceased donor kidney transplantation
Anderson et al, 1974 (55) Schulze et al, 1990 (56) Quarto Di Palo et al, 1991 (57)
Deceased donor transplantation; serum creatinine level 150 mol/L (1.7 mg/dL)

Study, Year (Reference) At Risk for or With Stable Cardiovascular Disease in Persons With CKD or Kidney Transplant or Undergoing Dialysis Aspirin, 100 mg/d Safety (bleeding) Placebo Simvastatin (factorial design) 448

12 5254 1012
Inclusion Criteria
UK-HARP-I, 2005 (58)
Age 18 y, predialysis with serum creatinine level 150 mol/L (1.7 mg/dL), hemodialysis or peritoneal dialysis, or kidney transplantation (any kidney function)
ACE angiotensin-converting enzyme; ACS acute coronary syndrome; BMI body mass index; CABG coronary artery bypass grafting; CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CKD chronic kidney disease; CREDO Clopidogrel for the Reduction of Events During Observation; CURE Clopidogrel in Unstable Angina to Prevent Recurrent Events; ECG electrocardiography; eGFR estimated glomerular ltration rate; 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; ETDRS Early Treatment Diabetic Nephropathy Study; HbA1c hemoglobin A1c; HOT Hypertension Optimal Treatment; IMPACT-II Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; IV intravenous; JPAD Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; MI myocardial infarction; NA not available; NR not reported; PCI percutaneous coronary intervention; PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PTFE polytetrauroethylene; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial; STOP Shunt Thrombotic Occlusion Prevention by Picotamide; TIA transient ischemic attack; UK-HARP-I First United Kingdom Heart and Renal Protection. * Participants with CKD from a larger trial population. Unpublished data provided by the authors. Initially given 0.6 g/kg/min for 30 min. Mean ages given for the groups with a creatinine clearance 30 mL/min per 1.73 m2 and 30 60 mL/min per 1.73 m2. Prednisolone, 0.5 mg/kg daily, on alternate days for 6 mo administered as nonrandomized co-intervention. Mean age for eGFR group 4559 mL/min/1.73 m2. ** Mean age for eGFR group 45 mL/min/1.73 m2. Full trial report NA. On the rst day, participants were given a loading dose of 300 mg orally. Initially 1 mg/kg daily IV was given.
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www.annals.org Outcome Cardiovascular Mortality Outcome NR * * Outcome not adjudicated * * * Outcome NR * Outcome NR Outcome NR * * * Outcome NR * * Outcome NR * Outcome not adjudicated * * * * Outcome NR * Outcome not adjudicated Outcome NR * * Outcome NR * Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR Outcome NR * Outcome NR * Outcome NR Outcome NR * Major Bleeding Minor Bleeding Myocardial Infarction Stroke Full text of trial NA; data NA in secondary sources * Full text of trial NR; data NA in secondary sources Outcome NR Outcome NR * Unpublished data; outcome NA for participants with CKD * Abstract-only data source; outcome NR * Crossover trial; data NR for end of treatment of first period of intervention Outcome not adjudicated Unpublished data; outcome NA for participants with CKD Full text of trial NA; data NA in secondary sources Abstract-only data source; outcome NR * Crossover trial; data NR for end of treatment of first period of intervention Outcome not adjudicated Outcome NR Abstract Full text of trial NA; data NA in secondary sources Abstract-only data source; outcome NR * Crossover trial; data NR for end of treatment of first period of intervention Abstract-only data source; outcome NR Unpublished data; outcome not adjudicated Crossover trial; data NR for end of treatment of first period of intervention Outcome not adjudicated * Abstract * Full text of trial NA; data NA in secondary sources Abstract-only data source; outcome NR Unpublished data; outcome NA Crossover trial; data NR for end of treatment of first period of intervention Adverse cardiac events not further adjudicated Outcome NR Abstract * Outcome NR Only data source; outcome NR * Adverse cardiac events not further adjudicated Outcome NR Only data source; outcome NR * Unpublished data; outcome not adjudicated * Outcome NR * * Full text of trial not reported; data NA in secondary unpublished sources * * * Outcome NR * * Outcome NR * Unpublished data; outcome not adjudicated Outcome NR Unpublished data; outcome not adjudicated Unpublished data; outcome NA for participants with CKD Unpublished data; outcome NA Outcome NR Unpublished data; outcome NA
Appendix Table 4. Reasons for Missing Data in Meta-analyses
All-Cause Mortality
Outcome NR
Anderson et al, 1974 (55) Kaegi et al, 1974 (39) Michie and Wombolt, 1977 (40) Harter et al, 1979 (41)
* *
Kobayashi et al, 1980 (42) Ell et al, 1980 (43)
NR for each intervention group separately *

Donadio et al, 1984 (29) Creek, 1990 (44)
* *
Schulze et al, 1990 (56) Quarto di Palo et al, 1991 (57) ETDRS, 1992 (30)
Outcome NR *
Middleton and Deischel, 1992 (45) Taber et al, 1992 (46)
EPIC, 1994 (14)
Abstract-only data source; outcome NR *
Kooistra et al, 1994 (47)
Sreedhara et al, 1994 (48) Za uner et al, 1994 (31) Gonzalez et al, 1995 (32) STOP, 1995 (49)
Crossover trial; data NR for end of treatment of first period of intervention *
* Abstract-only data source; outcome NR *
EPILOG, 1997 (24)
Frasc et al, 1997 (33) PURSUIT, 1998 (25)
Outcome NR *

Outcome Cardiovascular Mortality * * Outcome NR Outcome NR * * * Outcome NR Outcome NR * Outcome NR Outcome NR Outcome NR Number of participants with events or number of participants at risk NR * * * * * Major Bleeding Minor Bleeding Myocardial Infarction Stroke
All-Cause Mortality
EPISTENT trial, 1998 (15) RAPPORT, 1998 (16)

Unpublished data; outcome not adjudicated Unpublished data; outcome not adjudicated * Outcome NR * Number of participants with events or numbers of participants at risk NR Number of participants experiencing 1 event NR * Outcome NR Unpublished data; outcome NA Unpublished data; outcome NA Outcome NR Outcome NR Outcome NR Number of participants with events or number of participants at risk NR * Unpublished data provided; cause of death not adjudicated * Outcome NR Number of participants experiencing 1 event NR * * * Outcome NR * Outcome NR * * * * Outcome NR * Outcome NR Unpublished data; outcome NA * * * * * * * Unpublished data provided; cause of death not adjudicated Outcome not adjudicated * Outcome not adjudicated * * * Outcome not adjudicated * Outcome NR * Outcome NR * * * Outcome reported as minor and intermediate bleeding combined Outcome not adjudicated * Outcome NR Outcome NR * Outcome NR Outcome NR * Outcome NR
Cheng et al, 1998 (34) Giustina et al, 1998 (35) Khajehdehi et al, 2002 (36) PRISM-PLUS, 2002 (26)
* Outcome NR *
Kaufman et al, 2003 (50)
Number of participants with events or number of participants at risk NR *
UK-HARP-I, 2005 (58) Abdul-Rahman and Al Howaish, 2007 (51) CURE, 2007 (27) CREDO, 2008 (28)
* Outcome NR
* *
Dember et al, 2008 (52) CHARISMA, 2009 (37) Dixon et al, 2009 (53)
* * *
Ghorbani et al, 2009 (54) HOT, 2010 (6) JPAD, 2011 (38)
* Outcome NR
CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; 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; ETDRS Early Treatment Diabetic Nephropathy Study; HOT Hypertension Optimal Treatment; IMPACT-II Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; JPAD Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes; NA not available; NR not reported; PRISM-PLUS Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial; STOP Shunt Thrombotic Occlusion Prevention by Picotamide; UK-HARP-I First United Kingdom Heart and Renal Protection. * Data were available and included in meta-analyses.
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Appendix Table 5. Sources of Unpublished Data

Study, Year (Reference) ETDRS, 1992 (30) EPILOG, 1997 (24) EPIC, 1994 (14); EPISTENT, 1998 (15); RAPPORT, 1998 (16); IMPACT-II, 1997 (23); PURSUIT, 1998 (25); and CREDO, 2008 (28) UK-HARP-I, 2005 (58) Kaufman et al, 2003 (50) CHARISMA, 2009 (37) Source Dr. F. Ferris Dr. M. Lincoff; Dr. C. Balog Dr. K. Wolski; Dr. M. Lincoff; and Dr. C. Balog
Dr. C. Baigent Dr. J. Kaufman Dr. E. Topol; Dr. M. Shao
CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance; CREDO Clopidogrel for the Reduction of Events During Observation; EPIC Evaluation of 7E3 for the Prevention of Ischemic Complications; EPILOG Evaluation in PTCA to Improve LongTerm Outcome with Abciximab GP IIb/IIIa Blockade; EPISTENT Evaluation of Platelet IIb/IIIa Inhibitor for Stenting; ETDRS Early Treatment Diabetic Nephropathy Study; IMPACT-II Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis-II; PURSUIT Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy; RAPPORT ReoPro and Primary PTCA Organization and Randomized Trial; UK-HARP-I First United Kingdom Heart and Renal Protection.
Appendix Figure. Risk of bias in included studies.
Adequate sequence generation Allocation concealment Blinding of participants Blinding of investigators Blinding of outcome assessors Analysis by intention-to-treat principle Incomplete outcome data addressed Free of selective reporting Free of other bias 0
5 17 28 28 18 17 20 14 9
25
35 20 8 8 20 15 10 23 23
50 75
3 4 4 2 8 10 3 8
100
Studies, % High risk of bias Uncertain risk of bias Low risk of bias
Numbers of trials in each category are shown.

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Annals of Internal Medicine

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Effects of Antiplatelet Therapy in Persons With CKD

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Effects of Antiplatelet Therapy in Persons With CKD

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Effects of Antiplatelet Therapy in Persons With CKD

Figure 1. Summary of evidence search and selection.

All-Cause and Cardiovascular Mortality

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Effects of Antiplatelet Therapy in Persons With CKD

Favors Antiplatelet Therapy

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Effects of Antiplatelet Therapy in Persons With CKD

No important publication bias

Serious limitations (1)

Serious limitations (1)

Serious limitations (1)

Serious limitations (1)

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Effects of Antiplatelet Therapy in Persons With CKD

10 more (222 more)

CKD, 2.5; dialysis, 20

CKD, 1.5; dialysis, 10

talization, end-stage kidney disease, or withdrawal from treatment.

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Effects of Antiplatelet Therapy in Persons With CKD

Study, Year (Reference)

5/35 17/163 15/137 20/208 24/185 25/259 216/1177 322/2164

0.5 5.0 5.5 6.0 8.2 10.1 64.7 100.0

Favors Antiplatelet Therapy and Standard Care

Favors Standard Care

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Effects of Antiplatelet Therapy in Persons With CKD

Heterogeneity: 2 = 25.5; P = 0.001 (I 2 = 69%)

Favors Antiplatelet Therapy and Standard Care

Favors Standard Care

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Effects of Antiplatelet Therapy in Persons With CKD

1/141 1/223 4/96 7/436 18/328 29/1003 34/106 59/1828 153/4600

1/225 0/104 2/441 1/398 5/321 12/79 20/1006 39/1791 80/4533

0/223 3/96 1/436 7/413 3/328 4/106 22/1003 50/1828 90/4600

Favors Antiplatelet Therapy

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454 20 March 2012 Annals of Internal Medicine Volume 156 Number 6

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Effects of Antiplatelet Therapy in Persons With CKD

Heterogeneity: 2 = 4.72; P = 0.69 (I 2 = 0%)

Favors Antiplatelet Therapy

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Effects of Antiplatelet Therapy in Persons With CKD

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Effects of Antiplatelet Therapy in Persons With CKD

data set: Available from Dr. Strippoli (e-mail, strippoli@negrisud.it).

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Effects of Antiplatelet Therapy in Persons With CKD

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Effects of Antiplatelet Therapy in Persons With CKD

20 March 2012 Annals of Internal Medicine Volume 156 Number 6 459

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Annals of Internal Medicine

Appendix Table 1. Search Strategy (to November 2011)