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Reasons for inability of clopidogrelto inhibit platelet aggregation earlyafter coronary artery bypass surgeryTo the Editor:Clopidogrel administration for platelet in-hibition after coronary artery surgery andinterventional cardiology is currently atopic of much-deserved attention and de-bate. I read with interest the recent articlein the Journal by Lim and colleagues.1 Onthe basis of the results of an interim anal-ysis of their prospective, double-blind, ran-domized, controlled trial to compare theefficacy of clopidogrel and aspirin as anti-platelet agents, Lim and colleagues con-clude that clopidogrel, unlike aspirin, didnot inhibit platelet aggregation in the first 5postoperative days and therefore should notbe used as a sole antiplatelet agent earlyafter coronary surgery. According to theauthors, the ineffectiveness of clopidogrelwas an “unexpected” finding. However,plenty of evidence is available from pub-lished studies to suggest a logical explana-tion for this unexpected finding.

Clopidogrel is a pro-drug, which is con-verted to an active, unstable drug by cyto-chrome P450 (CYP). The active drug irre-versibly blocks 1 specific platelet: adenosine5’-diphosphate receptor (P2Y12). It was re-cently suggested that the most abundant hu-man CYP isoform, 3A4, activates clopi-dogrel.2 Certain lipophilic statins (ie,simvastatin, atorvastatin, and lovastatin),which are substrates of the CYP3A4 isoform,competitively inhibit the metabolic activationof clopidogrel. As a result, the relative clopi-dogrel-induced platelet inhibition is dimin-ished, especially if administered in a lowdose.3 Furthermore, clopidogrel administra-tion results in interindividual variability inplatelet inhibition. This variable platelet inhi-bition response to clopidogrel has been rec-ognized by all who have tested clopidogrelefficacy by platelet aggregometry and corre-lates with CYP3A4 metabolic activity.4 Inaddition, it is extremely important to remem-ber that platelet inhibition by clopidogrel is

dose-related up to a dose of 400 mg and that

he Journal of Thoracic and Cardiovascular

inhibition at a higher dose remains stablefrom 2 to 72 hours.5

A closer look at the study by Lim andcolleagues1 clearly reveals that all of theseconfounding factors are present and thatthey influence the results of their interimanalysis. In my opinion, the conclusion ofthis study would be different if a largerdose of clopidogrel were used and nonre-sponders (�10%) and low responders(�20%), as well as those on statins, wereexcluded.

Shahzad G. Raja, MRCSDepartment of Cardiac Surgery

Royal Hospital for Sick ChildrenYorkhill NHS Trust

Glasgow G3 8SJUnited Kingdom

References

1. Lim E, Cornelissen J, Routledge T, KirtlandS, Charman SC, Bellm S, et al. Clopidogreldid not inhibit platelet function early aftercoronary bypass surgery: a prospective ran-domized trial. J Thorac Cardiovasc Surg.2004;128:432-5.

2. Clarke TA, Waskell LA. Clopidogrel is me-tabolized by human cytochrome P450 3A andinhibited by atorvastatin. Drug Metab Dis-pos. 2003;31:53-9.

3. Neubauer H, Gunesdogan B, Hanefeld C,Spiecker M, Mugge A. Lipophilic statins in-terfere with the inhibitory effects of clopi-dogrel on platelet function—a flow cytometrystudy. Eur Heart J. 2003;24:1744-9.

4. Lau WC, Gurbel PA, Watkins PB, Neer CJ,Hopp AS, Carville DG, et al. Contribution ofhepatic cytochrome P450 3A4 metabolic ac-tivity to the phenomenon of clopidogrel re-sistance. Circulation. 2004;109:166-71.

5. Thebault JJ, Kieffer G, Cariou R. Single-dosepharmacodynamics of clopidogrel. SeminThromb Hemost. 1999;25(Suppl 2):3-8.

doi:10.1016/j.jtcvs.2004.09.027

Letters to theEditor

Reply to the Editor:The opinion on the interaction betweenstatins and clopidogrel is still subject to

fierce debate.1,2 However, excluding sub-

Surgery ● Volume 129, Number 2 475

Letters to the Editor

jects from the analysis because they are onstatins effectively excludes the majority ofpatients undergoing coronary surgery. Wereport that clopidogrel, unlike aspirin, didnot inhibit platelet aggregation in the first 5postoperative days, a result that is applica-ble to the wider population of patients ir-respective of the eventual outcome of thedrug interaction debate.

Little consideration has been given tothe suggestion of excluding nonrespondersand low responders from the analysis. If wedid that for any arm of any trial only thefavorable responders would be left, givingthe false impression of treatment efficacy.It is plausible that increasing the dose ofclopidogrel may increase antiplatelet ef-fects in similar conditions (but this shouldnot be assumed). However, the current rec-ommended dose is 75 mg per day, and aloading dose of clopidogrel is only indi-cated in unstable angina (300 mg singleloading dose).3 This information is consis-tent with the product information sheet is-sued by Sanofi-Synthelabo (New York,NY).

Our aim was to report the results of anintention-to-treat randomized clinical trial,using approved drug doses, with findingsthat can be generalized to the wide popu-lation undergoing coronary surgery, not tomanipulate analyses to favor any particulararm.

Eric Lim

Papworth Hospital

Cambridge

United Kingdom

References

1. Saw J, Steinhubl SR, Berger PB, Kereiakes DJ,Serebruany VL, Brennan D, et al. Lack of ad-verse clopidogrel-atorvastatin clinical interac-tion from secondary analysis of a randomized,placebo-controlled clopidogrel trial. Circula-tion. 2003;108:921-4.

2. Mitsios JV, Papathanasiou AI, Rodis FI,Elisaf M, Goudevenos JA, Tselepis AD.Atorvastatin does not affect the antiplateletpotency of clopidogrel when it is adminis-tered concomitantly for 5 weeks in patientswith acute coronary syndromes. Circulation.2004;109:1335-8.

3. British National Formulary. London: BritishMedical Association and the Royal Pharma-ceutical Society of Great Britain; 2003.

doi:10.1016/j.jtcvs.2004.09.028

476 The Journal of Thoracic and Cardiova

Clinical efficacy of retrogradecoronary sinus perfusion in off-pumpsurgeryTo the Editor:I read with great interest the article byCastella and Buckberg1on retrograde coro-nary sinus perfusion in off-pump surgery.My colleagues and I have been constantlystimulated by the pioneering work of DrBuckberg on myocardial preservation. It isindeed very gratifying and encouraging toknow that the technique we2 have beenusing regularly since September 1997 toperform off-pump coronary artery bypassgrafting (OPCABG) with no ischemia dur-ing periods of construction of the distalanastomosis has been proven by the veryelegant work of Castella and Buckberg1 tobe effective in reducing systolic and dia-

Figure 1. Technique of retrograde perfusioncoronary artery bypass grafting. A, Antegrnary sinus cannula; S, stenosed coronary a

P, pressure monitoring line.

scular Surgery ● February 2005

stolic dysfunction during periods of coro-nary occlusion. In our technique, after mid-sternotomy a retrograde coronary sinuscatheter is inserted and connected to anantegrade cannula in the ascending aorta.2

Perfusion is now allowed through this routefrom the aorta to the coronary sinus, on-ward through the capillaries to the myocar-dium, and out through the arterioles at thesite of ischemia. There is ample proof thatischemia is relieved as evidenced by thefollowing facts: (1) reversion of electro-cardiographic changes of ischemia, (2) vig-orous backbleeding of dark blood on tem-porary release of the distal snare afterarteriotomy, and (3) a good oxygen extrac-tion ratio across the myocardium calculatedby sampling blood from the antegrade can-nula and from the arteriotomy.3

ring combined carotid endarterectomy andcardioplegia cannula; R, retrograde coro-; CEA, carotid endarterectomy in progress;

duadertery