al12 reported that a minimal stent CSA �5.0 mm2 dif-ferentiated SES with a follow-up minimum lumen CSA�4.0 or �4.0 mm2. This finding is supported in thepresent study. In particular, the frequency of stent under-expansion was greater in the present SES failure seriesthan in 1 previous study of restenotic bare metal stents, inwhich 20% had a minimum stent CSA �5.0 mm2.13 Bysuppressing neointima, sirolimus may increase the per-centage of restenoses secondary to underexpansion orother mechanical complications; even a little neointimamay result in a significant stenosis at the site of under-expansion.

Seven of the SES restenoses involved bifurcationstenting; all showed stent underexpansion. Experiencehas shown that it is difficult to expand both of thebifurcation stents equally, even using final kissingballoon inflations. In a recent report by Colombo etal,14 the cases of restenosis in bifurcation-stented le-sions that were imaged with IVUS showed stent un-derexpansion.

1. Sousa JE, Costa MA, Sousa AG, Abizaid AC, Seixas AC, Abizaid AS, FeresF, Mattos LA, Falotico R, et al. Two-year angiographic and intravascular ultra-sound follow-up after implantation of sirolimus-eluting stents in human coronaryarteries. Circulation 2003;107:381–383.2. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M,Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. Arandomized comparison of a sirolimus-eluting stent with a standard stent forcoronary revascularization. N Engl J Med 2002;346:1773–1780.3. Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O’ShaughnessyC, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE.Sirolimus-eluting stents versus standard stents in patients with stenosis in a nativecoronary artery. N Engl J Med 2003;349:1315–1323.

4. Hoffmann R, Mintz GS, Dussaillant GR, Popma JJ, Pichard AD, Satler LF,Kent KM, Griffin J, Leon MB. Patterns and mechanisms of in-stent restenosis. Aserial intravascular ultrasound study. Circulation 1996;94:1247–1254.5. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, PintoFJ, Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. Standards for acquisition,measurement, and reporting of intravascular ultrasound Studies: a report of theAmerican College of Cardiology Task Force on Clinical Expert ConsensusDocuments. J Am Coll Cardiol 2001;37:1478–1492.6. Painter JA, Mintz GS, Wong SC, Popma JJ, Pichard AD, Kent KM, Satler LF,Leon MB. Serial intravascular ultrasound studies fail to show evidence of chronicPalmaz-Schatz stent recoil. Am J Cardiol 1995;75:398–400.7. Mehran R, Dangas G, Abizaid AS, Mintz GS, Lansky AJ, Satler LF, PichardAD, Kent KM, Stone GW, Leon MB. Angiographic patterns of in-stent resteno-sis: classification and implications for long-term outcome. Circulation 1999;100:1872–1878.8. Lemos PA, Saia F, Ligthart JM, Arampatzis CA, Sianos G, Tanabe K, HoyeA, Degertekin M, Daemen J, McFadden E, et al. Coronary restenosis aftersirolimus-eluting stent implantation: morphological description and mechan-ical analysis from a consecutive series of cases. Circulation 2003;108:257–260.9. Uren NG, Schwarzacher SP, Metz JA, Lee DP, Honda Y, Yeung AC,Fitzgerald PJ, Yock PG. Predictors and outcomes of stent thrombosis: an intra-vascular ultrasound registry. Eur Heart J 2002;23:124–132.10. Cheneau E, Leborgne L, Mintz GS, Kotani J, Pichard AD, Satler LF, Canos D,Castagna M, Weissman NJ, Waksman R. Predictors of subacute stent thrombosis:results of a systematic intravascular ultrasound study. Circulation 2003;108:43–47.11. Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, DudekD, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME. Randomized study toassess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108:788–794.12. Sonoda S, Morino Y, Ako Y, Terashima M, Hassan AH, Bonneau HN, LeonMB, Moses JW, Yock PG, Honda Y, Kuntz RE, Fitzgerald PJ. Impact of finalstent dimensions on long-term results following sirolimus-eluting stent implan-tation: serial IVUS analysis from the SIRIUS trial. J Am Coll Cardiol 2004;43:1959–1963.13. Castagna MT, Mintz GS, Leiboff BO, Ahmed JM, Mehran R, Satler LF, KentKM, Pichard AD, Weissman NJ. The contribution of “mechanical” problems toin-stent restenosis: an intravascular ultrasonographic analysis of 1090 consecu-tive in-stent restenosis lesions. Am Heart J 2001;142:970–974.14. Colombo A, Moses JW, Morice MC, Ludwig J, Holmes DR Jr, Spanos V,Louvard Y, Desmedt B, Di Mario C, Leon MB. Randomized study to evaluatesirolimus-eluting stents implanted at coronary bifurcation lesions. Circulation2004;109:1244–1249.

Effect of Dexamethasone-Eluting Stents on SystemicInflammatory Response in Patients With UnstableAngina Pectoris or Recent Myocardial InfarctionUndergoing Percutaneous Coronary Intervention

Giuseppe Patti, MD, Vincenzo Pasceri, MD, PhD, Patrizia Carminati, MD,Andrea D’Ambrosio, MD, Addolorata Carcagnì, MD, and Germano Di Sciascio, MD

The effect of treatment with steroid-eluting stents onsystemic inflammatory response was investigated inpatients with unstable angina pectoris or recent myo-cardial infarction who underwent percutaneous inter-vention. Compared with controls, dexamethasone-eluting stents significantly reduced C-reactive proteinpeak levels 48 hours after the procedure; this effectpersisted for 7 days and was particularly evident inpatients with elevated (>3 mg/L) preprocedural C-re-

active protein values. Patients receiving a dexam-ethasone-eluting stent had lower adverse events dur-ing follow-up. �2005 by Excerpta Medica Inc.

(Am J Cardiol 2005;95:502–505)

Inflammatory markers are elevated in acute ischemicsyndromes1,2; they also increase after coronary

stent implantation and may correlate with prognosisafter percutaneous coronary intervention (PCI).3,4 Ac-cordingly, treatment with oral prednisone in patientswith persistently elevated C-reactive protein (CRP)levels after coronary stenting was associated withreduced 1-year adverse events.5 Recently, drug-elut-ing stents have been introduced in clinical practice,and dexamethasone-eluting stents (Dexamet, AbbottVascular Devices, Galway, Ireland) have demon-strated clinical efficacy in preliminary studies.6 The

From the Department of Cardiovascular Sciences, Campus Bio-Medico University of Rome, Rome; and the Interventional CardiologyUnit, San Filippo Neri Hospital of Rome, Rome, Italy.. Dr. Di Sciascio’saddress is: Department of Cardiovascular Sciences, Campus Bio-Medico University, Via E. Longoni 83, 00155 Rome, Italy. E-mail:g.disciascio@unicampus.it. Manuscript received June 8, 2004; re-vised manuscript received and accepted October 4, 2004.

502 ©2005 by Excerpta Medica Inc. All rights reserved. 0002-9149/05/$–see front matterThe American Journal of Cardiology Vol. 95 February 15, 2005 doi:10.1016/j.amjcard.2004.10.021

goal of this study was to assess whether treatment ofa single unstable coronary plaque with dexametha-sone-eluting stents may influence systemic signs ofinflammation after PCI.

• • •Fifty consecutive patients with

unstable coronary syndromes and1-vessel coronary artery disease whounderwent PCI with dexamethasone-eluting stent implantation were pro-spectively enrolled in the study. Allpatients had unstable angina (Braun-wald class IIB to IIIB) or anginaafter recent myocardial infarction(�1 month) and significant coronarystenoses (reduction �70% of the lu-men diameter). Another criterion in-cluded angiographic evidence of“vulnerable plaque,” i.e., ulcerated,thrombus-rich, eccentric or irregularlesions (also defined as “complex le-sions” in this study)7,8 that wasdeemed responsible for instabilityand could be treated with single stentimplantation. Study patients werecompared with a control group of 50consecutive patients with similar an-giographic and clinical characteris-tics who underwent PCI with a non–drug-eluting stent in the 4 monthspreceding study enrollment. Dexa-methasone-eluting stents (Dexamet)are phosphorylcholine-coated stentsloaded with 0.5 �g/mm2 of a dexa-methasone base on the arterial side(in a 15-mm-long device, 40 �g ofthe drug is bonded); drug release ki-netics allow 80% delivery in 7 daysin vivo. The control group received aBiodivYsio phosphorylcholine-coatedstent (Biocompatibles CardiovascularLTD, Galway, Ireland) consisting ofthe same platform as Dexamet withoutthe drug. PCI was performed with con-ventional techniques by the femoralapproach. Quantitative coronary an-giography was performed with elec-tronic calipers. Procedural success wasdefined as a reduction in stenosis to�30% residual narrowing, with im-provement in ischemic symptoms andwithout major in-hospital complica-tions (defined as myocardial infarction,emergency bypass surgery, or death).All patients received aspirin (100 mg/day) and clopidogrel 300 mg �6 hoursbefore the procedure; therapy with clo-pidogrel (75 mg/day) was continuedfor �4 weeks and aspirin (100 mg/day) indefinitely. Glycoprotein IIb/IIIainhibitor therapy was administered atthe clinician’s discretion. No patient

had clinical and/or laboratory evidence of inflammatorydiseases, malignancy, infection, or recent (�2 months)surgery or trauma. All patients gave informed consent tothe study.

FIGURE 1. CRP levels at baseline (pre) and at 6, 24, and 48 hours and 7 days afterPCI in patients who received dexamethasone (Dexamet)-eluting versus non–drug-elut-ing coronary stents. Peak CRP values (at 48 hours) and at 7 days were significantlylower in patients taking Dexamet than in controls.

TABLE 1 Demographic and Clinical Characteristics of Patients

VariableDexamet Controls

p Value(n � 50) (n � 50)

Men 41 (82%) 40 (80%) 1Age (yrs) 60 � 9 63 � 11 0.21Diabetes mellitus 13 (26%) 15 (30%) 0.82Systemic hypertension 32 (64%) 32 (64%) 1Total serum cholesterol �200 mg/dl 34 (68%) 30 (60%) 0.53Smokers 14 (28%) 12 (24%) 0.82Unstable angina pectoris 26 (52%) 27 (54%) 1Recent (�1 mo) myocardial infarction 24 (48%) 23 (46%) 11-vessel coronary artery disease 50 (100%) 50 (100%) 1Left ventricular ejection fraction (%) 54 � 9 56 � 7 0.29Statin use 37 (74%) 35 (70%) 0.82Angiotensin-converting enzyme inhibitors 37 (74%) 33 (66%) 0.51

TABLE 2 Angiographic/Procedural Characteristics

VariableDexamet Controls

p Value(n � 50) (n � 50)

Treated coronary arteryLeft anterior descending 27 28 1Left circumflex 11 8 0.61Right 12 14 0.82

Lesion type B2/C 50 (100%) 50 (100%) 1Reference diameter (mm) 3.2 � 0.5 3.1 � 0.6 0.69Stenosis before PCI (% diameter2) 85 � 10 82 � 10 0.62Minimal lumen diameter after PCI (mm) 3.3 � 0.5 3.2 � 0.6 0.67Bifurcations with kissing balloon 2 (4%) 2 (4%) 1Stent diameter (mm) 3.2 � 0.3 3.1 � 0.4 0.70Stent length (mm) 15.1 � 6.1 15.5 � 5.9 0.45Direct stenting 13 (26%) 13 (26%) 1Deployment pressure (atm) 13.3 � 1.5 13.0 � 1.4 0.88Duration of stent deployment (s) 27 � 6 29 � 6 0.22No-reflow phenomenon 2 (4%) 2 (4%) 1Glycoprotein IIb/IIIa inhibitor (tirofiban)

infusion (pts)13 (26%) 10 (20%) 0.64

Postprocedural �2 times increase increatine kinase-MB

0 0 –

Postprocedural �2 times increase increatine kinase-MB

4 (8%) 4 (8%) 1

BRIEF REPORTS 503

Plasma levels of CRP were obtained at 5 differenttimes: 3 to 6 hours before the procedure and at 6, 24,and 48 hours and 7 days after stent implantation.Follow-up of all patients was done by office visits,phone interviews, or rehospitalization for recurrentsymptoms. All patients underwent postprocedurefunctional testing. Repeat coronary angiography was

not performed routinely but only forpositive stress testing or for severerecurrent anginal symptoms; how-ever, clinical follow-up was ob-tained in 100% of patients (includ-ing the control group). Venousblood samples were collected in sy-ringes and anticoagulated with so-dium citrate. High-sensitivity CRPwas determined by the KRIPTOR-ultrasensitive immunofluorescentassay (BRAHMS, Hennigsdorf/Berlin, Germany), with a detectionlimit of 0.06 mg/L; the 90th per-centile of the normal distributionfor CRP values is �3 mg/L.

Values are expressed as mean �SD. The nonparametric U-MannWhitney test was used to comparecontinuous data; proportions werecompared by Fisher’s exact test. The2-way analysis of variance test withBonferroni’s correction was appliedfor comparison of CRP levels be-tween the 2 groups at different timepoints. Actuarial event-free survivalcurves were obtained with theKaplan-Meier method. A p value�0.05 was considered significant.

Clinical and angiographic charac-teristics are listed in Tables 1 and 2.Success was achieved in all 100 pa-tients without major in-hospital com-plications; 4 patients in the steroid-eluting stent group and 4 in thecontrol group had a mild postproce-dural increase in troponin I and cre-atine kinase-MB levels (�2 timesthe upper normal limit). In patientstreated with Dexamet, baseline CRPvalues were 3.4 � 3.1 mg/L (Figure1); post-PCI levels increased to 4.0� 3.3 mg/L at 6 hours (p � 0.18),5.6 � 5 mg/L at 24 hours (p � 0.02),5.6 � 3.8 mg/L at 48 hours (p �0.02), and 3.8 � 3.2 mg/L at 7 days(p � 0.5). In the control group, base-line CRP values were 3.6 � 5.5mg/L; they increased after the proce-dure to 4.3 � 3.6 mg/L at 6 hours (p� 0.68), 6.4 � 7.4 mg/L at 24 hours(p � 0.01), peaked to 12.8 � 10.0mg/L at 48 hours (p � 0.001), andremained elevated (10.3 � 11.0mg/L) at 7 days (p � 0.001) (Figure

1). At 48 hours and 7 days, both the absolute valuesand percent increases in CRP from baseline weresignificantly higher in the control group versus thesteroid-eluting stent group (Figures 1 and 2). In pa-tients with preprocedural CRP values �3 mg/L (n �26), the attenuation of inflammatory responses withDexamet was greater than it was in patients with

FIGURE 2. CRP increase (percent) from baseline at different time points in patientstreated with Dexamet versus controls.

FIGURE 3. CRP percent increase from baseline in patients treated with Dexamet ac-cording to preprocedural CRP values (<3 vs >3 mg/L). In patients with CRP >3mg/L, the response is significantly blunted versus those with CRP <3 mg/L.

FIGURE 4. Event-free (death, myocardial infarction, target lesion revascularization)actuarial survival curves in the 2 groups.

504 THE AMERICAN JOURNAL OF CARDIOLOGY� VOL. 95 FEBRUARY 15, 2005

levels �3 mg/L (n � 24), with a 32% CRP increase at48 hours from baseline versus 231% (p � 0.005)(Figure 3). There was no significant influence of con-comitant medical therapy in postprocedural CRP ele-vation. Clinical follow-up was available in all 100patients (mean 8 � 2 months, range 6 to 12). In theDexamet group, 1 diabetic patient had return of anginaat 4 months and underwent target lesion revascular-ization; in the control group, 5 patients developedeffort angina with positive results on stress testing andunderwent target lesion revascularization for in-stentrestenosis, and 1 patient underwent target vessel re-vascularization for non–ST-segment elevation myo-cardial infarction at 6 months (total event rate 12%).Actuarial event-free survival was 97% for the steroid-eluting stent group and 87% for the control group at 6months (p � 0.05) (Figure 4).

• • •Our study indicates that in patients with unstable

angina or recent myocardial infarction, 1-vessel cor-onary artery disease, and complex “culprit” coronarylesions treated with a single stent, dexamethasone-eluting stents significantly reduced systemic CRP re-sponse after PCI. This effect was observed as early as48 hours after the procedure, persisted at 7 days, andwas particularly evident in patients with elevated (�3mg/L) preprocedural CRP values. CRP is mainly pro-duced by the liver but recent studies have shown localexpression of this protein in atherosclerotic plaques.9Steroids have a powerful anti-inflammatory action byreducing monocytes/macrophages and neutrophil ac-cumulation, cellular adhesion, platelet function,smooth muscle cell proliferation, and collagen synthe-sis; thus, the rationale for administering glucocorti-coids for reduction of restenosis after PCI.10 Aftercoronary stenting, circulating CRP levels increase,peaking at 48 hours.11 In patients with stable angina,long-term oral therapy with prednisone significantlyreduced adverse cardiac events during follow-up in arandomized study (Immunosuppressive Therapy forthe Prevention of Restenosis after Coronary ArteryStent Implantation Study).5 Drug-eluting stents re-lease preloaded pharmacologic agents directly on cor-onary plaque to inhibit neointimal hyperplasia, with-out systemic effects.12 In the recent Study of anti-restenosis with the Biodivysio dexamethasone-elutingstent study,6 dexamethasone-eluting coronary stentswere associated with favorable angiographic and clin-ical results in patients with unstable angina versusthose with stable angina. Our results confirm thatDexamet attenuates the local release of inflammatorymediators that cause systemic increases in CRP,thereby improving the early response to vessel injury.Importantly, concomitant use of “inflammation-mod-ulating” drugs (glycoprotein IIb/IIIa antagonists, sta-tins, clopidogrel, and angiotensin-converting enzymeinhibitors)13 was similar in the study group and con-trols. The more significant anti-inflammatory effect ofdexamethasone-eluting stents observed in patients

with elevated preprocedural CRP values suggests thatpatients with higher baseline inflammatory status maybe more likely to benefit from steroid-eluting stenttreatment. These findings may carry important clinicalimplications, because the degree of inflammatory re-sponse has been shown to correlate with cardiovascu-lar risk after PCI,14–16 and normalization of CRPlevels in the hours after PCI identifies a subset ofpatients with excellent outcome during follow-up.11

Accordingly, a lower incidence of adverse events wasobserved in our study patients at 8 months; this long-term benefit will need to be confirmed by randomizedstudies.

1. Patti G, D’Ambrosio A, Dobrina A, Dicuonzo G, Giansante C, Fiotti N, AbbateA, Guarnirei G, Di Sciascio G. Interleukin-1 receptor antagonist: a sensitivemarker of instability in patients with coronary artery disease. J Thromb Throm-bolysis 2002;14:139–143.2. Patti G, D’Ambrosio A, Mega S, Giorgi G, Zardi EM, Zardi DM, Dicuonzo G,Dobrina A, Di Sciascio G. Early interleukin-1 receptor antagonist elevation inpatients with acute myocardial infarction. J Am Coll Cardiol 2004;43:35–38.3. Patti G, Di Sciascio G, D’Ambrosio A, Dicuonzo G, Abbate A, Dobrina A.Inflammatory markers and coronary interventions: a potentially useful follow-upmodality after stenting. Catheter Cardiovasc Interventions 2002;56:341–345.4. Patti G, Di Sciascio G, D’Ambrosio A, Dicuonzo G, Abbate A, Dobrina A.Prognostic value of interleukin-1 receptor antagonist in patients undergoingpercutaneous coronary intervention. Am J Cardiol 2002;89:372–376.5. Versaci F, Gaspardone A, Tomai F, Ribichini F, Russo P, Proietti I, Ghini AS,Ferrero V, Chiariello L, Gioffre PA, Romeo F, Crea F. Immunosuppressivetherapy for the prevention of restenosis after coronary artery stent implantation(IMPRESS study). J Am Coll Cardiol 2002;40:1935–1942.6. Liu X, Huang Y, Hanet C, Vandormael M, Legrand V, Dens J, VandenbosscheJL, Missault L, Vrints C, De Scheerder I. Study of anti-restenosis with theBiodivysio dexamethasone-eluting stent (STRIDE)—a multicenter trial (abstr).Eur Heart J 2002;4:265.7. Di Sciascio G, Cowley MJ, Goudreau E, Vetrovec GW, Johnson DE. His-topathologic correlates of unstable ischemic syndromes in patients undergoingdirectional coronary atherectomy: in vivo evidence of thrombosis, ulceration, andinflammation. Am Heart J 1994;128:419–426.8. Goldstein JA, Demetriou D, Grines CL, Pica M, Shoukfeh M, O’Neill WW.Multiple complex coronary plaques in patients with acute myocardial infarction.N Engl J Med 2000;343:915–922.9. Yasojima K, Schwab C, McGeer EG, McGeer PL. Generation of C-reactiveprotein and complement components in atherosclerotic plaques. Am J Pathol2001;158:1039–1051.10. Pepine CJ, Hirshfeld JW, Macdonald RG, Henderson MA, Bass TA, Gold-berg S, Savage MP, Vetrovec G, Cowley M, Taussig AS. A controlled trial ofcorticosteroids to prevent restenosis after coronary angioplasty. M-HEARTGroup. Circulation 1990;81:1753–1761.11. Gaspardone A, Crea F, Versaci F, Tomai F, Pellegrino A, Chiariello L,Gioffre PA. Predictive value of C-reactive protein after successful coronary arterystenting in patients with stable angina. Am J Cardiol 1998;82:515–518.12. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M,Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R, and theRAVEL Study Group. Randomized study with the sirolimus-coated Bx velocityballoon-expandable stent in the treatment of patients with de novo native coro-nary artery lesions. A randomized comparison of a sirolimus-eluting stent with astandard stent for coronary revascularization. N Engl J Med 2002;346:1773–1780.13. Kereiakes DJ. Adjunctive pharmacotherapy before percutaneous coronaryintervention in non-ST-elevation acute coronary syndromes: the role of modu-lating inflammation. Circulation 2003;108(suppl III):III-22–III-27.14. Versaci F, Gaspardone A, Tomai F, Crea F, Chiariello L, Gioffrè PA.Predictive value of C-reactive protein in patients with unstable angina pectorisundergoing coronary artery stent implantation. Am J Cardiol 2000;85:92–95.15. Chew DP, Bhatt DL, Robbins MA, Penn MS, Schneider JP, Lauer MS, TopolEJ, Ellis SG. Incremental prognostic value of elevated baseline C-reactive proteinamong established markers of risk in percutaneous coronary intervention. Circu-lation 2001;104:992–997.16. Chan AW, Bhatt DL, Chew DP, Quinn MJ, Moliterno DJ, Topol EJ, Ellis SG.Early and sustained survival benefit associated with statin therapy at the time ofpercutaneous coronary intervention. Circulation 2002;105:691–696.

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