C©2006Cardiovascular Research Foundation PublicationsTM and CRF PublicationsTM

Used with permission from the Academy of Transcatheter Cardiovascular Therapeutics

Proceedings of the TCT: Questions Surround Antithrombotic Therapy in

Coronary DES Implantation

JENNIFER WHITE, M.P.H.

From the Clinical Trials Manager, Pulmonary and Critical Care Research, Mount Sinai Medical Center, New York, NY

(J Interven Cardiol 2006;19:232–235)

Introduction

The majority of percutaneous coronary interventions(PCI) performed today use drug-eluting stents (DES),which have dramatically reduced restenosis rates andimproved clinical outcomes in patients with cardiovas-cular disease. However, late stent thrombosis after DESimplantation has emerged as a concern.

Recent data demonstrate that late thrombosis rates at3 years postimplantation are 1.1% with the sirolimus-eluting Cypher (Cordis) stent and 1.3% with thepaclitaxel-eluting Taxus (Boston Scientific) stent.1

While these rates are not significantly greater than thosefor bare-metal stents (BMS), the consequences are se-rious. Stent thrombosis has been associated with a 20–48% mortality rate and a 60–70% myocardial infarc-tion rate,2 making the proper dose and duration of dualantiplatelet therapy, utilized to combat these compli-cations, even more important in today’s clinical prac-tice. However, questions about dual antiplatelet therapyhave not been definitively answered.

Antiplatelet Therapy Duration andThrombosis Rates

SIRIUS Data. In the SIRIUS trials, antiplateletregimens showed variation with respect to duration,dose, and the actual drugs used (see Table 1 for

Address for reprints: Jennifer White, M.P.H., Clinical Trials Man-ager, Pulmonary and Critical Care Research, Mount Sinai MedicalCenter, New York, NY

trial regimens and guideline recommendations). In theSIRIUS trial, patients received oral aspirin (325 mgdaily) and oral clopidogrel (a loading dose of 300–375mg 24 hours before the procedure and then 75 mg dailyfor 3 months).3 Stent thrombosis was infrequent, andthe rate was similar in the Cypher and bare-metal treat-ment groups. There were no acute stent thromboses (oc-curring less than 24 hours after placement of the stent);there was 1 case of subacute stent thrombosis (occur-ring between 1 and 30 days after placement) in eachgroup; and there were four late stent thromboses (occur-ring between 31 and 270 days after placement)—one inthe sirolimus-stent group and three in the standard-stentgroup. The cumulative frequency of stent thrombosiswas 0.4% in the sirolimus-stent group and 0.8% in thestandard-stent group.

In the C-SIRIUS trial, which assessed the safety andeffectiveness of the Cypher stent in treating single denovo long lesions in small native coronary arteries, pa-tients were premedicated with 81–325 mg of aspirin,begun at least 12 hours before the procedure, and clo-pidogrel, administered as a loading dose of 300 mg be-fore or immediately after the procedure. Patients weredischarged on a regimen of aspirin (81–325 mg perday indefinitely) and clopidogrel (75 mg per day for2 months only).4 Stent thrombosis occurred in one pa-tient in each group (on day 8 in a Cypher patient after aninitially successful intervention involving three stentsin a small right coronary artery, and on day 57 in aBMS patient), requiring target lesion revascularizationin both cases.

In the E-SIRIUS trial, in which restenosis risk wascompared between Cypher and BMS, patients were

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QUESTIONS SURROUND ANTITHROMBOTIC THERAPY

Table 1. Antiplatelet Regimens and Thrombosis Rates

Preprocedural Treatment Postprocedural TreatmentIncidence of

Trial Aspirin Clopidogrel Aspirin Clopidogrel Thrombosis

SIRIUS 325 mg daily 300–375 mg 24 hours

before

325 mg daily 75 mg daily for 3

months

2 cases for DES (0.4%)

versus 4 cases for BMS

(0.8%) after 270 days

C SIRIUS 81–325 mg at least

12 hours before

300 mg before or

immediately after

81–325 mg daily

indefinitely

75 mg daily for 2

months

1 case for each group (day

4 for DES versus day

57 for BMS)

E SIRIUS 100 mg at least

12 hours before

75 mg for at least 3 days

before; 300 mg before

or immediately after;

or 250 mg of

ticlopidine twice in 24

hours before

100 mg daily

indefinitely

75 mg daily or 250

mg ticlopidine

twice daily for 2

months

2 cases for DES (days 5

and 10) versus 0 cases

for BMS after 9 months

TAXUS II 75 mg 300 mg 24 hours before

catheterization or 4

hours before stent

placement

75 mg daily

indefinitely

75 mg daily or 250

mg ticlopidine

twice daily for at

least 6 months

0.5% for DES after 12

months

TAXUS IV 325 mg daily 300 mg 325 mg daily

indefinitely

75 mg daily for 6

months

0.6% for DES versus

0.8% for BMS after 9

months

Roiron et al.

meta-analysis

0.7% for DES versus 0.8%

for BMS

ACC/AHA

Guidelines

80–325 mg at least

12 hours before

300 mg 75 mg daily for 1–9

months

ACCP guidelines 75–325 mg 300 mg at least 16 hours

before or 600 mg less

than 6 hours before

75–162 mg daily

indefinitely

75 daily for 9–12

months

premedicated with 100 mg of aspirin, started at least12 hours before the procedure. Patients also receivedclopidogrel, administered at 75 mg for at least 3 daysbefore the intervention or as a loading dose of 300 mgbefore or immediately after the procedure. As an alter-native to clopidogrel, 250 mg of ticlopidine could begiven twice in the 24 hours preceding the intervention.Patients were discharged with a regimen of aspirin (100mg daily indefinitely) and clopidogrel (75 mg dailyfor 2 months) or ticlopidine (250 mg twice daily for 2months).5 At 9 months, there was no late stent throm-bosis in any study patient. Subacute stent thrombosisoccurred in two patients in the Cypher group, at 5 and10 days postprocedure, resulting in 1 Q-wave myocar-dial infarction (MI) and 1 non-Q-wave MI. No sub-acute stent thrombosis occurred in the control group(P = 0.25 vs Cypher patients).

TAXUS Data. In TAXUS-II, meanwhile, patientsreceived 300 mg of clopidogrel 24 hours beforecatheterization or at least 4 hours before placementof the randomly assigned stents (unless treatment was

initiated previously) and 75 mg of aspirin. After stentplacement, patients received clopidogrel at 75 mg perday (or 250 mg of ticlopidine twice daily) for at least6 months and aspirin 75 at mg per day, maintained in-definitely. At 12 months, the late stent thrombosis ratein the Taxus arms (slow- and moderate-release stents)was a low 0.7%.6

In TAXUS-IV, patients received 325 mg of aspirinand a 300-mg oral dose of clopidogrel before catheter-ization. Postprocedure, patients took 325 mg of aspirindaily indefinitely and 75 mg of clopidogrel daily for6 months. The stent thrombosis rate at 9 months was0.6% in Taxus patients versus 0.8% in BMS patients(P = 0.75).7

Roiron et al. performed a meta-analysis of ran-domized controlled trials comparing sirolimus- orpaclitaxel-eluting stents to bare stents or to eachother (sirolimus vs paclitaxel).8 The occurrence ofstent thrombosis was 0.7% with DES vs 0.8% withBMS (OR 0.71, 95% CI 0.41–1.25, P = 0.24)without heterogeneity between trials but with a

Vol. 19, No. 3, 2006 Journal of Interventional Cardiology 233

WHITE

trend toward more stent thrombosis in the paclitaxelsubgroup.

Guidelines Also Differ in Duration of Therapy

Dual antiplatelet therapy with aspirin and clopido-grel has replaced aspirin and systemic anticoagula-tion with warfarin as the preferred antithrombotic ther-apy after PCI with stent placement.9 However, currentguidelines still leave the question of duration somewhatopen.

The American College of Cardiology/AmericanHeart Association (ACC/AHA) recommendations forPCI suggest an empiric dose of aspirin of 80–325 mg,given at least 2 hours before PCI, and a loading dose of300 mg of clopidogrel followed by 75 mg per day forat least 1 month and for up to 9 months.10,11 The morerecently published American College of Chest Physi-cians (ACCP) guidelines echo the ACC/AHA guide-lines, recommending pretreatment with 75–325 mg as-pirin and a loading dose of 300 mg of clopidogrelat least 16 hours prior to planned PCI or, if clopido-grel is started <6 hours prior, a 600-mg loading dose.However, the ACCP guidelines also recommend in-definite aspirin therapy with 75–162 mg per day inaddition to clopidogrel at 75 mg per day for 9–12months. GP IIb/IIIa antagonists (abciximab or eptifib-atide) should be used in all high-risk patients.12

Question May Be Difficult to Resolve

Determining the optimal duration of antithrombotictreatment regimens is difficult because of the numeroustreatment options, the difficulty in showing treatmenteffect against the background of low procedural com-plication rates from conventional PCI, and the financialconstraints on interventional practices.13 Furthermore,formal identification of predictors of late DES throm-bosis is not easily accomplished, given that reports ofthis event are primarily anecdotal.

According to George Dangas, M.D., Director of theInterventional Cardiology Training Program at the Car-diovascular Research Foundation and Associate Pro-fessor of Medicine at Columbia University MedicalCenter, “the optimal duration of adjunctive clopidogrelin patients undergoing PCI with stent implantation isfor life.” He continues, “therapy for PCI with DES in-

volving complex configurations should continue for atleast 1 year, as long as the treatment is well tolerated.”

Clopidogrel is usually given for 1 month after stentimplantation, but many physicians argue for a longerduration of therapy.14 To date, there are no clear indica-tions from randomized trials about the optimal durationof adjunctive clopidogrel in patients undergoing PCIwith DES implantation. In the Clopidogrel for the Re-duction of Events During Observation (CREDO) trial,a 300-mg loading dose of clopidogrel given prior toelective stent PCI and 4 weeks of open-label clopido-grel at 75 mg per day conferred a nonsignificant 1.1%absolute risk reduction in the occurrence of death or MIcompared with placebo. All the patients randomized toreceive the drug showed a 3.0% absolute risk reduction(P = 0.02) in the composite endpoints of death, MI, orstroke after 1 year. The trial demonstrated the safety andefficacy of clopidogrel treatment before the procedureand the beneficial effects of prolonged (1-year) versusshort-term (1-month) dual antiplatelet therapy.15

To answer this question definitively, Zimarino et al.16

recommend a prospective trial randomizing patients tovarious durations of therapy in different clinical sce-narios using various stent types. The researchers sug-gest that because prolonged (1-year) therapy with as-pirin plus clopidogrel in patients undergoing BMS PCIappears superior to the previously established 4-weektreatment, this practice should be the minimum stan-dard adopted in the expanding reality of DES usage.This prolonged antithrombotic course could have a pro-tective effect against the occurrence of stent throm-bosis, which is frequently delayed following DESimplantation.

Recent Research Sheds Light on Dosage

Three studies presented at TCT 2005 described thebenefits of higher doses of clopidogrel on improvedpatient outcomes without increased safety risks. TheARMYDA-2 (Antiplatelet therapy for Reduction ofMyocardial Damage during Angioplasty) study ran-domized 329 patients with stable angina or non-ST seg-ment elevation MI (non-STEMI) to receive clopidogrelat a dose of 300 or 600 mg prior to PCI. Results of thestudy, presented at the meeting by Germano Di Sci-ascio, M.D., professor and chairman of cardiology atCampus Biomedico University in Rome, indicated thatthe 600-mg dose was superior to the 300-mg dose. Theprimary endpoint (a composite of cardiac death, MI, or

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QUESTIONS SURROUND ANTITHROMBOTIC THERAPY

target vessel revascularization at 30 days) occurred in23% of the 300-mg group vs 4% of the 600-mg group(P = 0.041). This derived primarily from the risk of MI.Five patients in the 600-mg group had an MI, comparedwith 15 in the 300-mg group (P = 0.014), representinga 52% reduction in MI risk. Also, a greater percentageof patients in the 600-mg group were free of adverseevents.

Results of the ISAR-CHOICE (Intracoronary Stent-ing and Antithrombotic Regimen: Choose between 3High Oral doses for Immediate Clopidogrel Effect)study also found the 600-mg loading dose of clopid-ogrel to have a more favorable profile compared withthe 300-mg dose. The study showed peak plasma con-centrations of clopidogrel’s active metabolite withinthe first hour for three doses—300 mg, 600 mg, and900 mg. There was a significant increase in the con-centration from the 300-mg dose to the 600-mg dose,but not between the 600-mg and 900-mg doses. Allthree doses were able to inhibit platelet activity. A re-duction in platelet function—as measured by adenosinediphosphate (ADP) (5 μmol/L) and ADP (20 μmol/L)-induced aggregation—was greater for the 600-mg dosethan the 300-mg dose, but there was no significantdifference between the 600-mg and 900-mg doses.The study’s lead author, Adnan Kastrati, M.D., fromDeutsches Herzzentrum and Medizinische Klinik derTechnischen Universitat Munchen in Munich, Ger-many, hypothesized that the lack of improvement fromthe higher dose may be caused by limited gastrointesti-nal absorption.

According to the author of the ALBION trial, GillesMontalescot, M.D., from the Institute of Cardiologyat Pitie-Salpetriere University Hospital in Paris, higherdoses of clopidogrel prior to PCI can help improve out-comes in patients with stable angina or non-STEMI.The ALBION trial involved 103 patients treated withclopidogrel prior to PCI. Patients were randomizedto receive one of three clopidogrel doses: 300 mg,600 mg, or 900 mg. “In comparison to the 300-mg doseof clopidogrel, the 600-mg and 900-mg doses were as-sociated with more rapid and higher levels of inhibitionof platelet aggregation and greater reductions in plateletactivation, particularly when given in the first 24 hoursfollowing a cardiac event,” Dr. Montalescot said. The600-mg and 900-mg doses were associated with ad-vantageous trends for troponin release and ischemicevents. These concentration levels had no significanteffect on various inflammatory markers, and the safetyprofiles for all three doses were similar.

References

1. Stone G. TCT 2005 Crossfire: Trials, Tribulations, CurrentTrends, and Future Projections. Paper presented at Trans-catheter Cardiovascular Therapeutics; October 17, 2005; Wash-ington, DC.

2. Kereiakes DJ, Choo JK, Young JJ, et al. Evaluation of a novelpoint-of-care enoxaparin monitor with central laboratory anti-Xa levels. Thromb Res 2003;112:301–306.

3. Moses JW, Leon MB, Popma JJ, et al. Sirolimus-eluting stentsversus standard stents in patients with stenosis in a native coro-nary artery. N Engl J Med 2003;349:1315–1323.

4. Schampaert E, Cohen EA, Schluter M, et al. The Canadianstudy of the sirolimus-eluting stent in the treatment of patientswith long de novo lesions in small native coronary arteries (C-SIRIUS). J Am Coll Cardiol 2004;43:1110–1115.

5. Schofer J, Schluter M, Gershlick AH, et al. Sirolimus-elutingstents for treatment of patients with long atherosclerotic le-sions in small coronary arteries: Double-blind, randomized con-trolled trial (E-SIRIUS). Lancet 2003;362:1093–1099.

6. Colombo A, Drzewiecki J, Banning A, et al. TAXUS II StudyGroup. Randomized study to assess the effectiveness of slow-and moderate-release polymer-based paclitaxel-eluting stentsfor coronary artery lesions. Circulation 2003;108:788–794.

7. Stone GW, Ellis SG, Cox DA, et al. TAXUS-IV investigators.A polymer-based, paclitaxel-eluting stent in patients with coro-nary artery disease. N Engl J Med 2004;350:221–231.

8. Roiron C, Sanchez P, Bouzamondo A, et al. Drug-elutingstents: An updated meta-analysis of randomized controlled tri-als. Heart 2005 Oct 10. [Epub ahead of print].

9. Popma JJ, Ohman EM, Weitz J, et al. Antithrombotic therapy inpatients undergoing percutaneous coronary intervention. Chest2001;119:321S–336S.

10. Smith SC, Dove JT, Jacobs AK, et al. ACC/AHA guidelines forpercutaneous coronary intervention (revision of the 1993 PTCAguidelines): Executive summary. A report of the American Col-lege of Cardiology/American Heart Association task force onpractice guidelines (Committee to revise the 1993 guidelines forpercutaneous transluminal coronary angioplasty). Endorsed bythe Society for Cardiac Angiography and Interventions. Circu-lation 2001;103:3019–3041.

11. Braunwald E, Antman EM, Beasley JW, et al. ACC/AHAguideline update for the management of patients with unsta-ble angina and non-ST-segment elevation myocardial infarc-tion: 2002. Summary article: A report of the American Collegeof Cardiology/American Heart Association task force on prac-tice guidelines (Committee on the management of patients withunstable angina). Circulation 2002;106:1893–1900.

12. Popma JJ, Berger P, Ohman EM, et al. The seventh ACCPConference on antithrombotic and thrombolytic therapy: An-tithrombotic therapy during percutaneous intervention. Chest2004;126:576S–599S.

13. Stadius ML. Diminishing returns. . .too many choices. . .thesaga of pharmacologic therapy to reduce complications ofpercutaneous coronary interventions. J Am Coll Cardiol2004;44:25–27.

14. Jneid H, Bhatt DL, Corti R, et al. Aspirin and Clopidogrel inacute coronary syndromes. Arch Intern Med 2003;163:1145–1153.

15. Steinhubl SR, Berger PB, Mann JT, III, et al. Early and sustaineddual antiplatelet therapy following percutaneous coronary inter-vention: A randomized controlled trial. JAMA 2002;288:2411–2420.

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