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; Giovanni F.M. Strippoli, MD, PhD, MPH, MM
Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, et al. Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease: A Systematic Review and Meta-analysis. Ann Intern Med. 2012;156:445-459. doi: 10.7326/0003-4819-156-6-201203200-00007
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Published: Ann Intern Med. 2012;156(6):445-459.
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.
To summarize the effects of antiplatelet treatment on cardiovascular events, mortality, and bleeding in persons with CKD.
Embase and Cochrane databases through November 2011 without language restriction.
Randomized trials that included adults with CKD and compared antiplatelet agents with standard care, placebo, or no treatment.
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.
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.
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.
Benefits for antiplatelet therapy among persons with CKD are uncertain and are potentially outweighed by bleeding hazards.
Antiplatelet agents are given for cardiovascular prevention to patients with chronic kidney disease (CKD).
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.
Evidence was weak, derived primarily from subgroup analysis of trials.
Risks of antiplatelet agents may outweigh potential benefits in some patients with CKD.
Figure 1. Summary of evidence search and selection.
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).
Appendix Figure. Risk of bias in included studies.
Numbers of trials in each category are shown.
Figure 2. Summary of treatment effects for antiplatelet agents in persons with chronic kidney disease.
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.
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.
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.
Figure 4. Effect of antiplatelet agents on cardiovascular, mortality, and bleeding outcomes in persons with CKD at risk for or with stable cardiovascular disease.
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.
American College of Cardiology, 24–27 March 2012, Chicago
Digestive Disease Week, 20–22 May 2012, San Diego
American Thoracic Society, 20–22 May 2012, San Francisco
American Society of Clinical Oncology, 1–5 June 2012, Chicago
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William G.Kussmaul iii, Interventional Cardiology
Hahnemann University Hospital
March 23, 2012
Caution regarding CKD patients who have coronary stents
Palmer and co-authors have usefully collected information on the use of anti-platelet agents in patients who have both coronary and kidney disease. They conclude that the benefits in both primary and secondary prevention are uncertain, and there may be a greater risk of bleeding than in non-CKD patients. They imply that these agents should not be used in patient with CKD until better data are available.
Unfortunately they may have done a dis-service to those many CKD patients who may have coronary stents, and to their physicians. Almost all patients receiving stents are required to take aspirin and a thienopyridine (most often clopidogrel) for 30 days up to 12 months, depending on the type of stent. The goal is to prevent acute coronary stent thrombosis, a very dangerous event.
While it is certainly true that trials of anti-platelet therapy specifically in CKD patients are lacking, I am hoping that the publication of this systematic review will not result in the premature discontinuation of the drugs in stent patients. After all, the authors' first conclusion is that the evidence is of poor quality. This should be seen as true both for benefits and potential harms.
Evidence-based medicine is to be promoted and practiced. In the absence of good evidence, one can either withhold a treatment until it is proven efficacious, or give it unless it is proven harmful. In the case of coronary stenting, I would urge the latter approach while agreeing with the authors that better studies in patients with CKD and CAD are needed.
R. BrooksRobey, Nephrologist & Associate Chief of Staff for Research, Daniel J. O'Rourke
VA Medical Center & Geisel School of Medicine at Dartmouth
April 13, 2012
Antiplatelet therapy in chronic kidney disease
The systematic review and meta-analysis by Palmer et al. (1) found limited objective evidence to support antiplatelet therapy in patients with chronic kidney disease (CKD). We concur with this assessment, but feel that the authors introduced subjective bias into their analysis and interpretation of the data that potentially underestimates benefits while overemphasizing risks.
The authors previously reported reduced cardiovascular events and mortality in hypertensive CKD patients receiving low dose aspirin relative to their counterparts with normal kidney function (2, 3). Apparent benefits were observed in all outcome categories and were greatest in patients with Stage 3b or greater CKD (estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2) where treatment was associated with up to 40-fold lower event rates (2). Benefits were markedly diminished when Stage 3a CKD patients were included in the analysis (eGFR <60 mL/min/1.73 m2). These data, included in their subsequent meta-analysis, account for over 40% of all patients in some outcome categories (1). Unfortunately, the study design ignored their previously defined major benefit threshold in favor of unstratified data analysis. We suspect that this decision was based on limited availability of properly stratified data and considerations of statistical and clinical heterogeneity. However, by combining datasets with established outcome differences, the authors knowingly introduced subjective bias into their analysis.
In their previous work, the authors confirmed associated bleeding risks in CKD (2) similar to those observed in the general population (4), but they concluded that the risks were "outweighed by the substantial benefits" of therapy (2). They reached a different conclusion in their subsequent review based on assumptions and speculation not fully supported by the data (1). Increased bleeding risks are presumably fully reflected in corresponding overall outcomes.
It is disconcerting that review of over three decades of investigation identified so few studies to inform the use of antiplatelet agents in CKD (1). Undue reliance on post hoc subgroup analysis of studies not designed nor powered to address this issue is also concerning (1). Nonetheless, the absence of unambiguous evidence of benefit does not constitute unambiguous evidence of an absence of benefit. Caution is warranted, but the totality of the evidence still seems to favor low dose aspirin therapy in CKD (1-3, 5). Acquired uremic platelet dysfunction is largely observed in end-stage kidney disease patients unrepresented in these analyses, so additional studies stratifying data by CKD stage, baseline hematocrit, and the presence or absence of pretreatment platelet functional abnormalities are needed to advance this line of inquiry.
1. Palmer SC, Di Micco L, Razavian M, Craig JC, Perkovic V, Pellegrini F, et al. Effects of Antiplatelet Therapy on Mortality and Cardiovascular and Bleeding Outcomes in Persons With Chronic Kidney Disease: A Systematic Review and Meta-analysis. Annals of Internal Medicine. 2012;156(6):445-59.
2. Jardine MJ, Ninomiya T, Perkovic V, Cass A, Turnbull F, Gallagher MP, et al. Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. Journal of the American College of Cardiology. 2010;56(12):956-65.
3. Choi MJ, Fried LF. Chronic kidney disease and progression. Nephrology Self Assessment Program, American Society of Nephrology. 2011;10(5):491-3.
4. McQuaid KR, Laine L. Systematic review and meta-analysis of adverse events of low-dose aspirin and clopidogrel in randomized controlled trials. The American Journal of Medicine. 2006;119(8):624-38.
5. Daugirdas JT. Handbook of Chronic Kidney Disease Management. Philadelphia: Wolters Kluwer/Lippincott Williams & Wilkins Health; 2011.
Giovanni F.M.Strippoli, , Suetonia C. Palmer and Jonathan C. Craig
Consorzio Mario Negri Sud, Italy
May 6, 2012
Author reply to Kussmaul and Robey
Dr Kussmaul raises an important point - does randomised trial (RCT) evidence tell us whether patients who have chronic kidney disease (CKD) should receive aspirin and clopidogrel for 12 months after coronary artery stenting? In the general population, guidelines recommend antiplatelet therapy with aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) for 12 months after percutaneous stent insertion, unless the risk of morbidity from bleeding outweighs the anticipated benefits, when earlier discontinuation from the P2Y12 inhibitor is reasonable(1). Applying the evidence from the general population to the setting of CKD may be inappropriate because of the increased risks of bleeding. Our systematic review has highlighted that data to address the question of dual antiplatelet therapy after stenting in the setting of CKD are scant. The benefits and harms of aspirin are unknown and the role of clopidogrel after coronary intervention is explored by two RCTs, that both observed uncertain benefits and harms for 12 months of clopidogrel treatment(2, 3). We need to acknowledge this current uncertainty and promote more research.
Drs Robey and O'Rourke query why our review concluding there is little benefit for antiplatelet agents in CKD is so different to that of a post-hoc analysis from a trial of long-term aspirin treatment (HOT study) which contributed data to our review(4). In that RCT, aspirin reduced risks of myocardial infarction by 69% (CI, 15-81), as well as cardiovascular (64% [CI, 10-86]) and all-cause mortality (49% [CI, 6-73]). It should be noted that the number of events in HOT were very small and therefore imprecise and this was a post-hoc subgroup analysis that was not pre-specified at randomization(5). When data from HOT are combined with all other RCTs, the totality of the evidence suggests that benefits of antiplatelet treatment are more modest or absent in people with stable cardiovascular disease and CKD and are consistent across trials of different antiplatelet agents or stages of CKD. We suggest CKD patients should be counseled about treatment uncertainties when considering antiplatelet therapy. We reject the notion of subjective bias in the analysis. The review was conducted using a peer-reviewed protocol specifying all aspects of conduct before data collection and analysis. We certainly agree that "it is disconcerting that review of over three decades of investigation identifies so few studies to inform the use of antiplatelet agents in CKD". Now we know this, it is time to act.
1. Levine GN, Bates ER, Blankenship JC, Bailey SR, Bittl JA, Cercek B, et al. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention: executive summary: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):2574-609.
2. Best PJ, Steinhubl SR, Berger PB, Dasgupta A, Brennan DM, Szczech LA, et al. The efficacy and safety of short- and long-term dual antiplatelet therapy in patients with mild or moderate chronic kidney disease: results from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2008;155(4):687-93.
3. Keltai M, Tonelli M, Mann JF, Sitkei E, Lewis BS, Hawken S, et al. Renal function and outcomes in acute coronary syndrome: impact of clopidogrel. Eur J Cardiovasc Prev Rehabil. 2007;14(2):312-8.
4. Jardine MJ, Ninomiya T, Perkovic V, Cass A, Turnbull F, Gallagher MP, et al. Aspirin is beneficial in hypertensive patients with chronic kidney disease: a post-hoc subgroup analysis of a randomized controlled trial. J Am Coll Cardiol. 2010;56(12):956-65.
5. Sun X, Briel M, Busse JW, You JJ, Akl EA, Mejza F, et al. Credibility of claims of subgroup effects in randomised controlled trials: systematic review. BMJ. 2012;344:e1553.
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