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Impact of Final Activated Clotting Time After TransradialCoronary Stenting With Maximal Antiplatelet Therapy

Olivier F. Bertrand, MD, PhD*, Josep Rodés-Cabau, MD, Stéphane Rinfret, MD, MSc,Éric Larose, DVM, MD, Rodrigo Bagur, MD, Guy Proulx, MD, Onil Gleeton, MD,

Olivier Costerousse, PhD, Robert De Larochellière, MD, and Louis Roy, MD

The optimal value of activated clotting time (ACT) during percutaneous coronary inter-vention (PCI) with unfractionated heparin remains controversial. No data are available onthe relation between the ACT at the end of the procedure (final ACT) and the clinicaloutcomes after transradial PCI and maximal antiplatelet therapy. By dividing the finalACT values in tertiles, we analyzed the ischemic and bleeding events in 1,234 consecutivepatients with acute coronary syndrome recruited in the EArly Discharge after TransradialStenting of CoronarY Arteries (EASY) trial. All patients were pretreated with aspirin andclopidogrel. After radial sheath insertion, patients received 70 IU/kg unfractionated hep-arin. Abciximab was given before the first balloon inflation. The median final ACT valuewas 312 seconds (interquartile range 279 to 344). At 30 days, the rate of major adversecardiac events, including death, myocardial infarction, and target vessel revascularization,from the lower to upper tertiles was 4%, 4%, and 2%, respectively (p � 0.16), and the rateof major bleeding was 2%, 1% and 0.7%, respectively (p � 0.20). During the 3 years offollow-up, the incidence of myocardial infarction was less in the tertile with the greatestACT value (>330 seconds) than in the other 2 tertiles (4%, 8%, and 8%, respectively; p �0.038). Troponin-T and creatine kinase-MB release after PCI indicated that the effect wasrelated to periprocedural myonecrosis protection. After adjustment for baseline and pro-cedural differences, a final ACT of >330 seconds remained associated with a 47% relativereduction in myocardial infarction (odds ratio 0.53, 95% confidence interval 0.29 to 0.93, p �0.024). Death and target vessel revascularization remained similar in all tertiles for <3 years.In conclusion, with the combination of aspirin, clopidogrel pretreatment, and abciximab, afinal ACT value of >330 seconds appears protective against peri-PCI myonecrosis, and thisbenefit was maintained for <3 years. With a transradial approach and maximal antiplatelettherapy, greater ACT values did not correlate with an increased risk of bleeding. © 2009

Elsevier Inc. All rights reserved. (Am J Cardiol 2009;104:1235–1240)

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No data have yet been reported on the clinical effect ofhe final activated clotting time (ACT) after transradialercutaneous coronary intervention (PCI) and maximal an-iplatelet therapy, including aspirin, clopidogrel, abciximab,nd unfractionated heparin (UFH). The objective of theresent analysis was to evaluate the relation between thenal ACT value and acute and late bleeding and ischemicutcomes in patients with acute coronary syndrome re-ruited in the EArly Discharge after Transradial Stenting oforonarY Arteries (EASY) trial.

Institut Universitaire de Cardiologie et de Pneumologie de Québec,uebec, Quebec, Canada. Manuscript received May 13, 2009; revisedanuscript received and accepted June 16, 2009.

The EASY trial was an investigator-initiated trial supported by unre-tricted grants from Eli Lilly, Indianapolis, Indiana, Bristol-Myers SquibbNew York, New York)/Sanofi-Aventis, Paris, France, Régie Régionale deuébec, Quebec, Canada, and Corporation de l’Institut de Cardiologie deuébec, Montreal, Québec, Canada. Drs. Bertrand, Rinfret, and Larose are

esearch-scholars from the Fonds de la Recherche en Santé du Québec,ontreal, Quebec, Canada.

*Corresponding author: Tel: (418) 6568711; fax: (418) 6564544.

tE-mail address: olivier.bertrand@criucpq.ulaval.ca (O. Bertrand).

002-9149/09/$ – see front matter © 2009 Elsevier Inc. All rights reserved.oi:10.1016/j.amjcard.2009.06.036

ethods

The details of the EASY trial have been previouslyescribed.1 In brief, patients referred for coronary angiog-aphy and possible PCI were enrolled. Patients were ex-luded if they had presented with ST-elevation myocardialnfarction (MI) within 72 hours or a history of left ventric-lar ejection fraction of �30%. The protocol was approvedy Health Canada and the Institut Universitaire de Cardi-logie et de Pneumologie de Québec ethics review boardQuebec, Quebec, Canada), and the protocol was publishedn the Clinical Trials Web site (www.clinicaltrials.gov,linical trial number NCT001169819). All patients provideritten informed consent before the procedure.The study was a randomized, controlled, open-label

tudy comparing same-day home discharge and bolus-onlyf abciximab to overnight hospitalization and bolus fol-owed by a 12-hour infusion of abciximab after uncompli-ated transradial coronary stenting.2 In the case of subopti-al results or clinical complications, patients were excluded

rom same-day discharge after PCI and received the abcix-mab bolus and infusion.3 Abciximab was administered as a.25-mg/kg bolus before the first balloon angioplasty, and

he infusion was given for a total of 12 hours at 0.125

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1236 The American Journal of Cardiology (www.AJConline.org)

g/kg/min to a maximum of 10 �g/min. All patients wereretreated with aspirin and clopidogrel before diagnosticngiography. After radial or ulnar sheath insertion, a mini-al bolus of 70 IU/kg heparin was given intravenously.ascular sheaths were removed at the end of the procedure,

nd a bracelet (Hemostop, Zoom, Piedmont, Quebec, Can-da) remained in place until hemostasis was completed.CT was measured at the end of PCI using a Hemochronevice (International Technidyne, New Albany, Indiana),nd a final ACT value of 300 seconds was targeted. Tropo-in-T, total creatine kinase (CK), and CK-MB were evalu-ted in a central core laboratory from samples collectedmmediately before the procedure, after PCI (4 to 6 hours),nd the next day (12 to 24 hours). Study personnel inter-iewed all patients the day after PCI and at 30 days, 6onths, 12 months, and 3 years. If required, the hospital

harts were consulted, and the referring physicians werenterviewed. The vital status at 3 years was determined for00% of the study population.

The major adverse cardiac event rate, including death,I, and target vessel revascularization was calculated at 30

ays, 6 months, 12 months, and 3 years after the indexrocedure. Angiographic success was defined as a residualesion of �30% after stenting with normal Thrombolysis In

yocardial Infarction 3 flow. Periprocedural MI were clas-ified when any post-PCI CK-MB value was �3 � thepper limit of normal (30 �g/ml in our laboratory). Aroponin-T–based MI definition was also applied (i.e., anyost-PCI value �3 times greater than the baseline value and0.1 ng/ml). In the case of elevated cardiac biomarker

evels before PCI, non–Q-wave MI was adjudicated whenhe elevation after PCI was �50% than the pre-PCI value.

able 1aseline characteristics

ariable

�291(n � 408)

ge (years) 60 � 10en 342 (84%)

revious myocardial infarction 203 (50%)iabetes mellitus 61 (15%)reated dyslipidemia 346 (85%)reated hypertension 200 (49%)moker 136 (33%)revious PCI 79 (19%)nstable angina pectoris 281 (69%)on–ST-elevation myocardial infarction 105 (26%)revious coronary bypass 35 (9%)lopidogrel �12 h 366 (90%)ow-molecular-weight heparin before PCI 92 (23%)lycoprotein IIb/IIIa inhibitors before PCI 18 (4%)reatinine (�mol/L) 90 � 20emoglobin (g/L) 141 � 13latelet (109/L) 241 � 57ematocrit (%) 41.4 � 3.8reatinine clearance (ml/min) 90.5 � 29.4eight (kg) 81 � 16eparin dosage (IU) 5,725 � 1368eparin dose (IU/kg) 71 � 10

fter hospital discharge, non–Q-wave MI was classified 7

sing the American College of Cardiology/European Soci-ty of Cardiology nomenclature (i.e., using any cardiaciomarker values greater than the upper limits of normal).2

ajor bleeding was graded using the Randomized Eval-ation in PCI Linking Angiomax to Reduced Clinicalvents-2 trial (REPLACE-2) classification.4 Local hema-

omas were graded according to the EASY trial-specificcale: grade 1, �5-cm diameter, nonsignificant; grade 2,10-cm diameter, mild; grade 3, �10 cm but distal to the

lbow, moderate; grade 4, extending above the elbow, se-ere; and grade 5, anywhere, with ischemic threat of theand (i.e., compartment syndrome).5

Categorical variables are expressed as numbers and per-entages and continuous variables as mean � SD. Theaseline and procedural characteristics were comparedmong the ACT tertiles using the chi-square test for cate-orical variables and the Kruskal-Wallis test for continuousariables. Survival curves were constructed using Kaplan-eier techniques, and comparisons were made using the

og-rank test. The baseline clinical and angiographic char-cteristics and procedure-related variables that were predic-ors of the final ACT on univariate analysis were included in

stepwise logistic multivariate regression model to ascer-ain their independent role. Stepwise logistic regressionnalysis was also used to evaluate the relation between ACTnd the incidence of MI, adjusting for the following vari-bles: body mass index, unstable angina, angiographic suc-ess, compromised/suboccluded side branch, and Throm-olysis In Myocardial Infarction flow after stenting. Oddsatios (ORs) and 95% confidence intervals (CIs) were cal-ulated. A probability value of �0.05 was considered sig-ificant. Statistical tests were performed using JMP, version

ACT Tertile(n � 1,234)

p Value

291–330(n � 409)

�330(n � 417)

60 � 11 61 � 10 0.27332 (81%) 292 (70%) �0.0001176 (43%) 161 (39%) 0.005167 (16%) 82 (20%) 0.18

351 (86%) 361 (87%) 0.77219 (54%) 216 (52%) 0.43134 (33%) 131 (31%) 0.8382 (20%) 80 (19%) 0.95

272 (67%) 257 (62%) 0.08297 (24%) 78 (19%) 0.05321 (5%) 24 (6%) 0.10

374 (91%) 379 (91%) 0.6881 (20%) 63 (15%) 0.02320 (5%) 17 (4%) 0.8587 � 18 89 � 21 0.34

141 � 13 139 � 14 0.033241 � 58 236 � 64 0.08641.4 � 3.9 40.8 � 4.0 0.08792.9 � 30.5 89.8 � 52.6 0.027

81 � 16 81 � 17 0.445,799 � 1317 5,828 � 1258 0.43

72 � 9 73 � 10 0.0023

.0, software (SAS Institute, Cary, North Carolina).

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1237Coronary Artery Disease/ACT and Transradial PCI

esults

Of the 1,348 patients recruited in the trial, 79 wereretreated with enoxaparin, did not receive a bolus of UFH,

able 2rocedural characteristics

ariable

�(n

o. of narrowed coronary arteries1 2172 1403 51o. of narrowed vessels dilated2 127�3 65atients with �1 B2/C lesion 273tent size (mm) 2.96tent length (mm) 18otal stent length (mm) 32atheter sheath (Fr)5 1736 2307 5inal activated clotting time (s) 255uration (min) 58ngiographic success 379ompromised/suboccluded branch 15hrombolysis in myocardial infarction �3 after stenting 11

able 3vents at 30 days

ariable ACT Tertile(n � 1,234)

pValue

�291(n � 408)

291–330(n � 409)

�330(n � 417)

ajor adverse cardiacevents

18 (4%) 17 (4%) 9 (2%) 0.16

Death 1 (0.2%) 0 (0.0%) 0 (0.0%) 0.36Myocardial infarction 15 (4%) 17 (4%) 8 (2%) 0.16Target vessel

revascularization5 (1.2%) 1 (0.2%) 1 (0.2%) 0.096

ajor bleeding 9 (2%) 6 (1%) 3 (0.7%) 0.20astrointestinal

bleeding3 (0.7%) 3 (0.7%) 0 (0.0%) 0.44

emoglobin decrease 4 (1.0%) 2 (0.5%) 3 (0.7%)oronary artery bypass

grafting related2 (0.5%) 1 (0.2%) 0 (0.0%)

ny transfusion 9 (2.2%) 2 (0.5%) 3 (0.7%) 0.042rade of access site

hematoma0.13

I 20 (4.9%) 20 (4.9%) 28 (6.7%)II 7 (1.7%) 10 (2.4%) 14 (3.4%)III 4 (1.0%) 5 (1.2%) 11 (2.6%)IV 2 (0.5%) 0 (0.0%) 0 (0.0%)hrombocytopenia�100,000/mm3 9 (2.2%) 8 (2.0%) 2 (0.5%) 0.093�50,000/mm3 3 (0.7%) 4 (1.0%) 1 (0.2%) 0.40

nd were excluded from the present analysis. Of the remain- g

ng 1,269 patients who had received an initial bolus of UFH,5 had no ACT measurement. Therefore, our analysis in-luded 1,234 patients (92%) who had received a UFH bolusnd had a final ACT measurement. The median final ACTalue was 312 seconds (interquartile range 279 to 344).atients in the greater ACT tertile (�330 seconds) wereore frequently women (p �0.0001), less often had had a

revious MI (p � 0.0051), and less often had receivedow-molecular-weight heparin before catheterization (p �.023). Their baseline hemoglobin value was also lowerp � 0.033) as was their creatinine clearance (p � 0.027;able 1). Patients in the greatest ACT tertile had less severeoronary artery disease and �2 to 3 dilated lesions com-ared to the other 2 tertile groups. Procedures for the pa-ients in the greatest ACT tertile were more often performedith a 5Fr catheter (52%), and the procedure duration was

ignificantly shorter 42 � 21 versus 46 � 21 versus 58 � 30inutes, respectively; p �0.0001; Table 2). On multivariate

nalysis, the independent predictors of a final ACT �330econds were heparin dose �70 IU/kg (OR 1.57, 95% CI.22 to 2.04, p � 0.0004), female gender (OR 2.30, 95% CI.72 to 3.09, p � 0.0001), lesion B2/C (OR 0.68, 95% CI 0.52o 0.88, p � 0.004), platelet count before PCI �200 � 109/LOR 1.85, 95% CI 1.39 to 2.44, p �0.0001), and procedureuration of �1 hour (OR 2.06, 95% CI 1.49 to 2.89,�0.0001).At 30 days, the incidence of major bleeding was not

ifferent in the higher tertile than in the other 2 (0.7%, 1%,nd 2%, respectively; p � 0.20; Table 3). The rate ofransfusion was significantly greater in the lowest tertile2.2% vs 0.5% and 0.7%, p � 0.042). In contrast, a trendas seen for more mild and moderate hematoma in the

ACT Tertile(n � 1,234)

p Value

291–330(n � 409)

�330(n � 417)

0.0088248 (61%) 269 (65%)127 (31%) 117 (28%)34 (8%) 31 (7%)

�0.0001113 (28%) 100 (24%)31 (8%) 27 (6%)

247 (60%) 208 (50%) �0.00012.97 � 0.43 2.93 � 0.44 0.38

19 � 5 18 � 5 0.05629 � 19 24 � 16 �0.0001

186 (45%) 217 (52%)220 (54%) 199 (48%) 0.038

3 (0.7%) 1 (0.2%)311 � 11 377 � 54 —46 � 21 42 � 21 �0.0001

401 (98%) 407 (98%) 0.000122 (5.4%) 16 (3.8%) 0.417 (1.7%) 5 (1.2%) 0.27

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reatest tertile (p � 0.13). The incidence of major adverse

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1238 The American Journal of Cardiology (www.AJConline.org)

ardiac events, including death, MI, and target vessel revas-ularization, remained similar in the 3 tertile groups for �3ears (Figure 1). However, the MI rate was reduced in thereatest tertile group, and this difference was maintained atyears (4%, 8%, 8%, p � 0.038). The CK-MB and Tro-

onin-T measurements suggested that the protective effectf a final ACT �330 seconds resulted from a reduction ineriprocedural myonecrosis (Figure 2). After adjustment forifferences in the baseline and procedural characteristics, anal ACT �330 seconds remained an independent protec-

ive factor of MI (OR 0.53, 95% CI 0.29 to 0.93, p � 0.024;igure 3). The major adverse cardiac event-free survivalurves remained similar for �3 years (Figure 4).

iscussion

In the present study, we found that a final ACT value330 seconds after transradial coronary stenting and max-

ents are expressed as numbers of patients (percentage of total). Composite

igure 4. Major adverse cardiac event-free survival curves �3 yearsccording to final ACT tertiles. No significant difference was observed.

igure 1. Major cardiac adverse events at 30 days, 6 months, 1 year, and 3 years. Ev

igure 2. Incidence of post-PCI MI according to cardiac biomarkers.

igure 3. Independent predictors of MI. Final ACT of �330 seconds wasssociated with 47% relative reduction in MI; all other independent factors

mal antiplatelet therapy is associated with a 47% relative

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1239Coronary Artery Disease/ACT and Transradial PCI

eduction in the incidence of MI. This protective effect wasaintained for �3 years of follow-up and appeared entirely

elated to a periprocedural reduction in myonecrosis, ashown by cardiac biomarker release after PCI. Furthermore,ith the transradial approach, no relation was found be-

ween the ACT values and bleeding complications, evenith maximal antiplatelet therapy.Given the absence of randomized trials, the dose of UFH

sed with PCI procedures has remained largely empiric, andurrent guidelines recommendations (class Ic) have beenetermined from expert opinions.6,7 Moreover, it has nevereen established at which point in the procedure, the ACTeasurements should be performed. Most studies have as-

essed the relation between the peak ACT (i.e., performed aew minutes after UFH administration) and the clinicalutcomes.8–11 This might introduce a significant bias be-ause the procedure duration could vary widely, especiallyhen associated with the treatment of complex lesions or

nvolving complications. With balloon angioplasty, Narinst al12 showed a strong inverse linear relation between theeak ACT, with values �500 seconds, and the risk of abruptessel closure.12 Because in the EASY trial, patients coulde discharged home, it was thought important to minimizehe risks of post-PCI vessel occlusion. Because the pharma-okinetics of UFH is complex and unpredictable, this couldartly explain why in some studies the UFH dose did notorrelate with ACT values measured 5 to 10 minutes afterFH delivery.13 In contrast, in our study, the weight-ad-

usted UFH dose (but not the unadjusted total UFH dose)as an independent predictor of the final ACT reaching thepper tertile.

With coronary stenting, a progressive shift has occurredoward a reduction of heparin doses. Greater peak ACTalues have also been associated with a greater incidence ofleeding and vascular complications.14–16 With the intro-uction of glycoprotein inhibitors, stenting, and thienopyri-ine treatment, post hoc analyses of large clinical trials haveuggested that a reduction of the UFH dose would reducehe risks of bleeding without compromising the peri-PCIyocardial protection.11,13 Weight-adjusted UFH dosing

as also been subsequently recommended. However, Chewt al15 pooled the data of 6 trials and described a U-shapedurve for ischemic and bleeding complications after PCInd UFH-only therapy. The optimal maximal ACT rangeas 350 to 375 seconds to reduce ischemic events and 325

o 350 seconds to minimize bleeding. With abciximab, the-shape relation was no longer present, and a stable reduc-

ion in ischemic events compared to UFH-only therapy wasbserved from 250 to �400 seconds. In our study, we foundhat ACTs �330 seconds were protective against peripro-edural myonecrosis compared to lower final ACT values.he prognostic effect of CK-MB and troponin-T releasefter PCI has been debated for years.17–21 A recent meta-nalysis has shown that troponin-T release after electiveCI was associated with a significant risk of death or MIOR 1.59, 95% CI 1.29 to 1.96).20 An important confoundern those studies was the incidence of procedural complica-ions.20,22 In the present study, even taking into accountrocedural complications, a final ACT �330 seconds re-ained a strong independent protective factor. The factors

ssociated with increased cardiac biomarker release in-

luded complications but have also been correlated withore extensive coronary artery disease and atherosclerotic

urden, even with successful procedures.23 Our results sug-est that higher anticoagulation, together with aspirin andlopidogrel pretreatment with abciximab, producing maxi-al antiplatelet therapy could limit the injury produced

uring stent implantation in patients with acute coronaryyndrome.

In the study by Chew et al,15 a steep increase in bleedingomplications was noted with a maximal ACT �350 sec-nds and the femoral approach. In a more recent post hocnalysis of 4 PCI trials with UFH doses of 65 to 90 IU/kg,he previously described U-shaped curve for ischemicvents was not reproduced; however, a direct relation wastill found between greater ACT values and bleeding com-lications.13 In the Enhanced Suppression of the PlateletIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial,nvestigators used an initial UFH bolus of 60 IU/kg to targetn ACT before any device use of 200 to 300 seconds.11

atients were treated with the femoral approach, and theylso described an increase in bleeding (Thrombolysis Inyocardial Infarction criteria) with increasing ACT values

nd eptifibatide treatment. In contrast to our study, CK-MBelease after PCI did not correlate with the ACT. However,heir range of ACT measurements was lower than in ourtudy, thienopyridines pretreatment was not a part of therotocol, and CK-MB was analyzed at local sites witharying upper limits of normal.

Our results with the transradial approach strongly sug-est that this access site is more important than the choice ofntithrombotic agent or ACT level to minimize the risks ofleeding. In the REPLACE-2 study, which compared low-ose, weight-adjusted UFH (65 IU/kg) and glycoproteinnhibitors to the direct antithrombin agent bivalirudin, thencidence of major bleeding events was 4.1% and 2.4%,espectively.4 Using the same definition, the incidence ofajor bleeding in the EASY trial was 1.4%.5 Ongoing trialsith randomization between the standard and reduced,eight-adjusted UFH dose (50 IU/kg) after fondaparinux

OASIS 8 trial, clinical trial number NCT00790907) willurther clarify the balance between the ischemic risk and theleeding risk after PCI in patients with acute coronaryyndrome.

This was a post hoc analysis; therefore, our resultshould be interpreted with caution and viewed primarily asypothesis generating. glycoprotein inhibitors are known toncrease ACT values after UFH therapy.24 Therefore, ouresults should not be extrapolated to other antithromboticegimens or other clinical scenarios. The absolute rate ofajor bleeding in the present trial was low, limiting the

ower of discrimination according to the ACT tertiles.

1. Bertrand OF, De Larochelliere R, Rodes-Cabau J, Proulx G, GleetonO, Nguyen CM, Dery JP, Barbeau G, Noel B, Larose E, Poirier P, RoyL. A randomized study comparing same-day home discharge andabciximab bolus only to overnight hospitalization and abciximab bolusand infusion after transradial coronary stent implantation. Circulation2006;114:2636–2643.

2. Bertrand OF, Rodes-Cabau J, Larose E, Nguyen CM, Roy L, Dery JP,Courtis J, Nault I, Poirier P, Costerousse O, De Larochelliere R.

One-year clinical outcome after abciximab bolus-only compared withabciximab bolus and 12-hour infusion in the Randomized EArly Dis-

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2

2

2

2

1240 The American Journal of Cardiology (www.AJConline.org)

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