Doi:10.1510/icvts.2006.143156

Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 Should high risk patients receive clopidogrel as well as aspirin post Babu Kunadiana, Andrew R. Thornleya, Thotala N. Babub, Joel Dunninga,* of Cardiothoracic Surgery, James Cook University Hospital, Middlesbrough, UK of Cardiology, Lincoln Medical Health Center, New York, USA Received 31 August 2006; accepted 1 September 2006 A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether clopidogrel should be given in addition to aspirin in high risk patients after coronary bypass surgery to reduce thrombotic complications. High riskpatients would include patients recently post MI or patients with a patent stent in situ. Altogether 511 papers were identified using thebelow mentioned search and all major international guidelines were included. Eleven presented the best evidence to answer the clinicalquestion. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. The2004 American College of Chest Physicians (ACCP) guidelines recommend 9–12 months of clopidogrel in addition to aspirin for patientsundergoing coronary arterial bypass grafting (CABG) for non-ST segment elevation acute coronary syndrome (grade 1C). This is based onsubanalyses of the CURE and CAPRIE studies that showed significant reductions in the incidence of death, myocardial infarction and strokein patients who had CABG during these trials. A randomised trial is currently underway to investigate this further. Thus, patients post CABGwho have had a recent NSTEMI or have a stent not covered by a graft should have clopidogrel in addition to aspirin for 9–12 months.
ᮊ 2006 Published by European Association for Cardio-Thoracic Surgery. All rights reserved.
Keywords: Clopidogrel; Cardiac surgical procedures; Antiplatelet therapy 1. Introduction
cardiac surgery.mp OR exp Cardiac surgical ProceduresyORcardiac operation.mp OR heart operation.mpx AND wclopi- A best evidence topic was constructed according to a structured protocol. This protocol is fully described in theICVTS 5. Search outcome
2. Clinical scenario
A total of 511 papers were found. In addition, all major You are reviewing a 55-year-old patient in the clinic who guidelines were included and their reference lists searched.
underwent coronary bypass grafts 6-weeks ago after he Of note, this topic updates a previous related BET suffered a non-ST segment myocardial infarction (NSTEMI) Eleven papers were deemed to represent the best evidence the week before. You notice that the cardiologist saw him last week and restarted his clopidogrel in addition to theaspirin you gave him. The cardiologist wrote in his letter 6. Discussion
that he recommenced this on the basis of the 2004 ACCP The American College of Chest Physicians (ACCP) seventh guidelines. You resolve to investigate this further.
conference on antithrombotic and thrombolytic therapypublished their guidelines in 2004 For patients who 3. Three-part question
undergo CABG for non-ST segment elevation ACS, they In patients post wurgent coronary arterial bypass graftingx recommend that clopidogrel should be started in addition should wclopidogrel be given in addition to aspirinx to reduce to aspirin post-surgery and continued for 9–12 months. This the chance of wthrombotic complicationsx.
recommendation is based on the CAPRIE study and theCURE study.
4. Search strategy
The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study reported an 8.7% relative risk reduction in the primary composite endpoint (first wExp Thoracic surgeryyOR thoracic surgery.mp OR CABG.
occurrence of ischaemic stroke, myocardial infarction or mp OR coronary art$ bypass.mp OR heart surgery.mp OR vascular death) favour of clopidogrel (75 mgyday) over (325 mgyday) in a multicentre RCT of 19,185 E-mail address: joeldunning@doctors.org.uk (J. Dunning).
patients with a history of recent ischaemic stroke, recent ᮊ 2006 Published by European Association for Cardio-Thoracic Surgery B. Kunadian et al. / Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 Underlying values and preferences: For patients with coronary artery disease aspirin, we recommend clopidogrel,300 mg, as a loading dose 6 h afteroperation followed by 75 mgyd po(Grade 1C).
per year, Ps0.004 (36.3% RR, 95% CI, (Clopidogrel 2.4% vs. 3.9%, Ps0.037) (Clopidogrel 10.6% vs. 14.6%,Ps0.015) relative risk reduction compared to aspirin B. Kunadian et al. / Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 relative risk reduction relative to aspirin relative risk reduction relative to aspirin relative risk reduction relative to aspirin Clopidogrel 1.3% vs. placebo 1.1%(relative risk, 1.26; 95% CI,0.93 to 1.71).
8.5%, Placebo group 11.5%, Ps0.02) 16.7% relative risk reduction (Clopidogrel (Clopidogrel 15.4% vs. 24.1%, Ps0.05) 83 patientsunderwent initialCABG withoutindex PCI 320 patientsunderwent repeatCABG or PCIafter index PCI P-0.0001), myocardial infarction (0% vs.
intervention (0.6% vs. 6.8%, P-0.0001), death (2.2% vs. 8.3%, P-0.0001), and B. Kunadian et al. / Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 There was no difference in the incidence of In hospitalised patients in whom an early Patients where PCI is planned should haveclopidogrel started and continued for1 month coronary events(MI, CVA,angina, mortality,need forcoronaryintervention,hospitalisation forcoronaryischaemia) andbleedingcomplications Therapy duringPercutaneousCoronaryIntervention 6 of these patients had all antiplatelets B. Kunadian et al. / Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 anaesthesia wereincluded in thestudy(1–39 days,average:13 days).
1996–1998 at asingle centre myocardial infarction or symptomatic peripheral arterial endpoint of death, myocardial infarction or stroke A disease A sub-analysis of the CAPRIE database showed subgroup analysis of patients who underwent CABG without that in 1480 patients with a previous history of cardiac PCI had a modest reduction of 1-year events (RRR 16.7%) surgery, clopidogrel was associated with a relative risk with clopidogrel But this was a post hoc analysis and reduction of 39% for vascular death, 38% for myocardial the number of patients in this group was small.
infarction, 25% for all-cause rehospitalisation, and 27% for The recent observational study by Gurbuz et al. rehospitalisation for ischaemia or bleeding. A major draw- showed that clopidogrel therapy with aspirin was indepen- back of this study is the lack of information about the type dently associated with decreased symptom recurrence and of cardiac surgery previously performed in these patients.
adverse cardiac events following OPCAB. However, extend- The CURE (Clopidogrel in Unstable angina to prevent ing clopidogrel use beyond 30 days did not have a signifi- Recurrent Events trial) randomised patients with acute coronary syndromes (ns12,562) to treatment with clopi- In order to provide convincing evidence of combination of dogrel (300 mg then 75 mgyday) or placebo in addition to clopidogrel and aspirin versus aspirin alone on saphenous aspirin (75–325 mgyday). The antiplatelet combination vein graft disease after CABG, a double-blinded, randomis- resulted in a 20% risk reduction relative to aspirin alone ed control is currently underway. The CASCADE (Clopidogrel (9.3% vs. 11.4%, P-0.001) in the primary endpoint of After Surgery for Coronary Artery Disease) is randomising cardiovascular death, myocardial infarction or stroke over 100 patients to clopidogrel or placebo in addition to 162 mg a mean nine-month treatment period The antiplatelet of aspirin post CABG, with one year angiography as the combination produced a 19.0% reduction relative to aspirin alone in the risk of cardiovascular death, myocardial infarc- With regard to the other high risk group of patients, tion or stroke among those patients who underwent CABG namely patients post percutaneous intervention (PCI) hav- surgery during the initial hospitalisation and an 11.0% ing CABG, we found no studies that looked at the outcome relative risk reduction among patients who underwent CABG of stent patency post-CABG. The ACCP guidelines surgery at any time during the treatment period. The recommend clopidogrel in addition to aspirin for all clinical benefits of aspirin plus clopidogrel were mainly patients post PCI for 9–12 months (Grade 1A). A small evident during the preoperative period with 18% relative study by Kaluza et al. demonstrated that there was an risk reductions in the primary endpoint seen before CABG instent thrombosis rate of around 20% with a similar mor- surgery compared to 3% relative risk reduction following tality in patients having surgery of any type shortly post CABG surgery relative to aspirin alone The main pitfall PCI. Therefore, if the stent is not covered by a graft of the study is that patients who did not take the drug intraoperatively then it would seem reasonable to follow after surgery were still included in the clopidogrel group the ACCP guideline with 9–12 months of clopidogrel. How- and the effect of clopidogrel was not adjusted for other ever, if the stent is covered by a graft more distally, there is no evidence to support continuation of clopidogrel.
The Clopidogrel for the Reduction of Events During Obser- vation (CREDO) trial evaluated the short-term benefits of 7. Clinical bottom line
combined aspirin and clopidogrel pre-treatment and thelong-term benefits of sustained therapy in the setting of The 2004 ACCP guidelines recommend 9–12 months of percutaneous coronary intervention (PCI) in an RCT of 2116 clopidogrel in addition to aspirin for patients undergoing patients. After one year of treatment, patients receiving CABG for non-ST segment elevation ACS. This is based on clopidogrel (75 mgyday) plus aspirin (81–325 mgyday) had subanalyses of the CURE and CAPRIE studies that showed a significant 26.9% relative risk reduction in the combined significant reductions in the incidence of death, myocardial B. Kunadian et al. / Interactive CardioVascular and Thoracic Surgery 5 (2006) 755–760 infarction and stroke in patients who had coronary bypass w7x Steinhubl SR, Berger PB, Mann JT 3rd, Fry ET, DeLago A, Wilmer C, grafting (CABG) during these trials. A randomised trial is Topol EJ. Early and sustained dual oral antiplatelet therapy followingpercutaneous coronary intervention: a randomised controlled trial. J currently underway to investigate this further. Patients post CABG who have had a recent NSTEMI or have a stent not w8x Saw J, Topol EJ, Steinhubl SR, Brennan D, Berger PB, Moliterno DJ, covered by a graft should have clopidogrel in addition to CREDO Investigators. Comparison of long-term usefulness of clopidogrel therapy after the first percutaneous coronary intervention or coronaryartery bypass grafting versus that after the second or repeat interven-tion. Am J Cardiol 2004;94:623–625.
References
w9x Gurbuz AT, Zia AA, Vuran AC, Cui H, Aytac A. Postoperative clopidogrel improves mid-term outcome after off-pump coronary artery bypass w1x Dunning J, Prendergast B, Mackway-Jones K. Towards evidence-based graft surgery: a prospective study. Eur J Cardiothorac Surg 2006;29:190– medicine in cardiothoracic surgery: best BETS. Interact CardioVasc w10x Kulik A, Le May M, Wells GA, Mesana TG, Ruel M. The clopidogrel after w2x Nagarajan DV, Lewis PS, Dunning J. Is clopidogrel beneficial following surgery for coronary artery disease (CASCADE) randomised controlled coronary bypass surgery? Interact Cardiovasc Thorac Surg 2004;3:311– trial: clopidogrel and aspirin versus aspirin alone after coronary bypass surgery wNCT00228423x. Curr Control Trials Cardiovasc Med 2005;6:15.
w3x Stein PD, Schunemann HJ, Dalen JE, Gutterman D. Antithrombotic w11x Popma JJ, Berger P, Ohman EM, Harrington RA, Grines C, Weitz JI.
therapy in patients with saphenous vein and internal mammary artery Antithrombotic therapy during percutaneous coronary intervention: bypass grafts: the seventh ACCP conference on antithrombotic and Seventh ACCP conference on antithrombotic and thrombolytic therapy.
thrombolytic therapy. Chest 2004;126:600S–608S.
w4x Bhatt DL, Chew DP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ. Superiority w12x Kaluza GL, Joseph J, Lee JR, Raizner ME, Raizner AE. Catastrophic of clopidogrel versus aspirin in patients with prior cardiac surgery.
outcomes of noncardiac surgery soon after coronary stenting. J Am Coll w5x Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. Effects w13x Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman of clopidogrel in addition to aspirin in patients with acute coronary JS, Jones RH, Kereiakes D, Kupersmith J, Levin TN, Pepine CJ, Schaeffer syndromes without ST-segment elevation. N Engl J Med 2001;345:494– JW, Smith EE III, Steward DE, Theroux P, Gibbons RJ, Alpert JS, Faxon DP, Fuster V, Gregoratos G, Hiratzka LF, Jacobs AK, Smith SC Jr. ACCy w6x Fox KA, Mehta SR, Peters R, Zhao F, Lakkis N, Gersh BJ, Yusuf S.
AHA guideline update for the management of patients with unstable Benefits and risks of the combination of clopidogrel and aspirin in angina and non-ST-segment elevation myocardial infarction—2002: sum- patients undergoing surgical revascularisation for non-ST-elevation mary article: a report of the American college of cardiologyyAmerican acute coronary syndrome: the Clopidogrel in Unstable angina to prevent heart association task force on practice guidelines (Committee on the Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202– management of patients with unstable angina). Circulation 2002;

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