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resistance among stable patients with cardiovascular disease. J Am CollCardiol 2003;41:961–5.

. Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovas-cular prevention: implications of aspirin resistance. J Am Coll Cardiol2008;51:1829–43.

. Cox D, Maree AO, Dooley M, Conroy R, Byrne MF, Fitzgerald DJ.Effect of enteric coating on antiplatelet activity of low-dose aspirin inhealthy volunteers. Stroke 2006;37:2153–8.

. Maree AO, Curtin RJ, Dooley M, et al. Platelet response to low-doseenteric-coated aspirin in patients with stable cardiovascular disease.J Am Coll Cardiol 2005;46:1258–63.

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e thank the 2 authors for their interest in our review (1), inhich a number of issues were raised regarding definition, possible

auses, detection, and treatment of “aspirin resistance.” Themergence of the latter requires, first of all, the selection of specific,eproducible, simple, and standardized platelet function tests thatould distinguish patients responding to COX-1–related aspirinffects from those patients in whom the administration of aspirinails to inhibit production of thromboxane A2 through COX-1–elated pathway(s). The latter is viewed by us as a true incident oflaboratory aspirin resistance.”

The most specific test for the assessment of aspirin effects isight transmission platelet aggregometry with low concentrationsf arachidonic acid and adenosine diphosphate. This method isidely used in almost all large prospective studies of aspirin

esistance and is closely associated with occurrence of cardiovas-ular events. Its use allows the clinician to assess platelet functiony forming macroaggregates of platelets and is characterized byore serious limitations. First and foremost, platelet aggregometry

equires the use of different agonists at different concentrations andheir (ex vivo) addition to platelet-rich plasma. A frequently usedgonist, arachidonic acid, has been criticized for its possible lyticffects on platelets, resulting in an increase of the light transmis-ion through platelets suspension without an increase in the levelf macroaggregates (2). Another frequently used agonist, adeno-ine diphosphate at low concentrations, can partly activate therachidonic acid cascade, but its main effect is not specific for theOX-1 pathway. Also, the adjustment of platelet count inlatelet-rich plasma by adding autologous platelet-poor plasma,hich is mandatory for platelet aggregometry, can itself suppresslatelet function (3). Thus, laboratory preparation and the use ofgonists for platelet aggregometry can cause unpredictable results,ar from reflecting true platelet function per se in cardiovascularisease patients taking aspirin.

Thus, we would agree with the comments that we should avoidhe use of agonists for the “ideal test” of aspirin resistance, but thisuggestion probably requires the revision of the current definitionf “laboratory aspirin resistance.” From the physiological point ofiew, platelet aggregometry in platelet-rich plasma is also an initro time-consuming test that neglects interactions of plateletsith leucocytes and erythrocytes at the time of blood sampling.his problem is partly overcome with the use of whole blood

ggregometry and semiautomated point-of-care platelet functionssays that use whole blood (e.g., the PFA-100 test, Siemensealth Diagnostics, Newark, Delaware), which again exhibits a

umber of other limitations.It was thought that the use of light transmission aggregometry

n combination with other platelet function tests could avoid the

imitations of different tests and provide a comprehensive assess- d

ent of platelet function. However, this alternative approach raisesnother important question as to how interpret different, andometimes polarized, results of different tests. One of the latesttudies (4) assessing the prevalence of aspirin resistance witheveral major platelet function tests (e.g., light transmission aggre-ometry, whole blood aggregometry, PFA-100, VerifyNow-spirin [Accumetrics, San Diego, California], and urinary 11-ehydrothromboxane B2) yielded a prevalence ranging from 6.7%by VerifyNow-Aspirin) to 59.5% (by PFA-100). These resultsgain confirm the lack of correlation between laboratory tests ofspirin resistance.

We would agree with the comments that flow cytometry is an inivo quantitative test for the detection of activated platelets andelease of microparticles with the surface markers specific forhromboxane A2 pathway at an early stage of platelet activation,nd that it may be viewed as an important tool for future studies onrue prevalence of “laboratory aspirin resistance.” Nonetheless, thexpense of flow cytometry and the need to assay samples inighly-specialized laboratory centers would make it difficult tomploy flow cytometry in large-scale prospective studies.

Finally, we agree with Kapoor on the suggestion that there isncomplete suppression of platelet aggregation with enteric-coatedspirin. Nonetheless, we should not lose sight of the fact that oneommon explanation for aspirin resistance, whether defined asaboratory resistance or clinical resistance (i.e., increased throm-otic events), is noncompliance (5).

rmen Yuri Gasparyan, MD, PhDGregory Y. H. Lip, MD, FRCP

University Department of Medicineity Hospitaludley Roadirmingham, B18 7QHnited Kingdom-mail: g.y.h.lip@bham.ac.uk

doi:10.1016/j.jacc.2008.07.014

EFERENCES

. Gasparyan AY, Watson T, Lip GY. The role of aspirin in cardiovas-cular prevention: implications of aspirin resistance. J Am Coll Cardiol2008;51:1829–43.

. Cattaneo M. Aspirin and clopidogrel: efficacy, safety, and the issue ofdrug resistance. Arterioscler Thromb Vasc Biol 2004;24:1980–7.

. Cattaneo M, Lecchi A, Zighetti ML, Lussana F. Platelet aggregationstudies: autologous platelet-poor plasma inhibits platelet aggregationwhen added to platelet-rich plasma to normalize platelet count. Haema-tologica 2007;92:694–7.

. Lordkipanidzé M, Pharand C, Schampaert E, Turgeon J, Palisaitis DA,Diodati JG. A comparison of six major platelet function tests todetermine the prevalence of aspirin resistance in patients with stablecoronary artery disease. Eur Heart J 2007;28:1702–8.

. Dalen JE. Aspirin resistance: is it real? Is it clinically significant? Am JMed 2007;120:1–4.

Ib or Not IIbhite et al. (1) present an interesting case for the ability to switch

o bivalirudin therapy from heparin (unfractionated heparin ornoxaparin) in non–ST-segment elevation acute coronary syn-

rome. The baseline characteristics of the 2 groups (consistent vs.

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1278 Correspondence JACC Vol. 52, No. 15, 2008October 7, 2008:1276–8

witched), however, show a statistically greater proportion ofigh-risk patients in the consistent treatment group (see Table 1 ofhite et al. [1]). Thus, similarity of the 2 groups is not a strength

f the study as suggested.Removal of the bivalirudin plus glycoprotein (GP) IIb/IIIa

roup from this post-hoc analysis effectively removes a largeopulation that could have increased bleeding complications, andt would be interesting to see whether the end points could be

aintained if the switch from heparin to bivalirudin plus GPIb/IIIa inhibitors was added to the population studied.

Bivalirudin was compared with heparin plus a GP IIb/IIIanhibitor. Although recommended by guidelines, in the settingescribed, the proportion of patients being placed on GP IIb/IIIanhibitors in real-world practice is much lower (i.e., approximately5% in the U.S. [2] and 5% in Australia [3]).

Although one could expect some mortality benefit in thewitched group, because of reduced bleeding over a length of times in the ISAR (Innovative Stratification of Arrhythmic Risk) trials4), the cost effectiveness of bivalirudin is a critical question whenonsidering popular use.

Akshay Mishra, MBBS, MD, DnBarren Walters, MBBS, MPhil, FRACP, FCSANZ, FSCAI

Department of Cardiologyhe Prince Charles Hospitalode Rd. Brisbane, Queensland 4032ustralia-mail: akmish@rediffmail.com

doi:10.1016/j.jacc.2008.06.042

EFERENCES

. White HD, Chew DP, Hoekstra JP, et al. Safety and efficacy ofswitching from either unfractionated heparin or enoxaparin tobivalirudin inpatients with non–ST-segment elevation in acutecoronary syndromes managed with an invasive strategy: results fromthe ACUITY (Acute Catheterization and Urgent InterventionTriage strategY) trial. J Am Coll Cardiol 2008;51:1734 – 41.

. Peterson ED, Pollack CV Jr., Roe MT, et al., for Barron NationalRegistry of Myocardial Infarction (NRMI) 4 Investigators. Early use ofglycoprotein IIb/IIIa inhibitors in non–ST-elevation acute myocardialinfarction: observations from the National Registry of MyocardialInfarction. J Am Coll Cardiol 2003;42:45–53.

. Walters DL, Aroney CN, Chew DP, et al. Variations in the applicationof cardiac care in Australia. Med J Aust 2008;188:218–23.

. Ndrepepa G, Berger PB, Mehilli J, et al. Periprocedural bleeding and 1year outcome after percutaneous coronary interventions: appropriatenessof including bleeding as a component of a quadruple end point. J AmColl Cardiol 2008;51:690–7.

eply

e would like to thank Drs. Mishra and Walters for their interestn our work (1). As they accurately point out, there were differencesn 2 of the more than 20 baseline characteristics. However,lthough patients in the heparin plus glycoprotein IIb/IIIa inhib-tor (GPI) group more frequently had increased creatine kinase-

yocardial band, troponin levels, or electrocardiogram changes,ultivariate logistic regression confirmed the results of the uni-

ariate analysis. This adjusted analysis demonstrated that switch-ng from heparin plus a GPI to bivalirudin monotherapy resultedn similar rates of composite ischemia (odds ratio [OR]: 0.97; 95%

onfidence interval [CI]: 0.76 to 1.23; p � 0.77), and significantly

ess non-coronary artery bypass graft major bleeding (OR: 0.47;5% CI: 0.34 to 0.66; p � 0.0001) and net clinical events (OR:.76; 95% CI: 0.62 to 0.94; p � 0.01).

Regarding why we elected not to display the results of theivalirudin plus GPI group, in the main ACUITY (Acute Cath-terization and Urgent Intervention Triage Strategy) trial (2),ivalirudin plus GPI showed no incremental benefit over bivaliru-in alone in terms of reducing ischemia but did result in moreleeding. Given these facts, the more expensive bivalirudin plusPI regimen is unlikely to enter routine clinical practice and, thus,e did not include these data in the article.The third point Drs. Mishra and Walters make is that the

CUITY trial was designed to assess the addition of a treatmentbivalirudin) to guideline-recommended therapy. We believe thathis is the appropriate way to perform trials; it would be detrimen-al for patients to test new treatments in the absence of guideline-ecommended therapies.

Finally, in respect to cost effectiveness, preliminary analysishows bivalirudin to be very cost effective. A prospective analysis3) showed that 30-day costs were lowest with bivalirudin mono-herapy compared with heparin plus GPI (cost savings rangingrom $123 per patient with bivalirudin monotherapy vs. heparin �

PI administration in the catheterization laboratory to $422 peratient with bivalirudin monotherapy vs. heparin � upstreamPI).Thus, adjusted analysis of the switch cohort demonstrates that

he results with bivalirudin monotherapy remain consistent despitelight differences in baseline characteristics. The present studyupports the safety and efficacy of switching to bivalirudin fromnfractionated heparin or enoxaparin in moderate- and high-riskatients with non–ST-segment elevation acute coronary syn-romes and preserves the 50% reduction in major bleeding seenith bivalirudin, with comparable rates of ischemia and, thus,

mproved overall patient outcomes.

Harvey D. White, DSc, FACCregg W. Stone, MD, FACC

n behalf of the ACUITY Investigators

Green Lane Cardiovascular Serviceuckland City Hospitalrivate Bag 92024uckland, 1030ew Zealand-mail: HarveyW@adhb.govt.nz

doi:10.1016/j.jacc.2008.07.017

EFERENCES

. White HD, Chew D, Hoekstra J, et al. Safety and efficacy of switchingfrom either unfractionated heparin or enoxaparin to bivalirudin inpatients with non–ST-segment elevation acute coronary syndromesmanaged with an invasive strategy: results from the ACUITY (AcuteCatheterization and Urgent Intervention Triage strategY) trial. J AmColl Cardiol 2008;51:1734–41.

. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients withacute coronary syndromes. N Engl J Med 2006;355:2203–16.

. Pinto DS, Stone GW, Shi C, et al. Economic evaluation of bivalirudinwith or without glycoprotein IIb/IIIa inhibition versus heparin withroutine glycoprotein IIb/IIIa inhibition for early invasive managementof acute coronary syndromes. Paper presented at: the American College

of Cardiology 57th Annual Scientific Sessions; March 29 to April 1,2008; Chicago, IL.