Localized Hypersensitivity and Late Coronary ThrombosisSecondary to a Sirolimus-Eluting Stent

Should We Be Cautious?

Renu Virmani, MD; Giulio Guagliumi, MD; Andrew Farb, MD; Giuseppe Musumeci, MD;Niccolo Grieco, MD; Teresio Motta, MD; Laurian Mihalcsik, MD; Maurizio Tespili, MD;

Orazio Valsecchi, MD; Frank D. Kolodgie, PhD

Background—The US Food and Drug Administration recently issued a warning of subacute thrombosis and hypersensi-tivity reactions to sirolimus-eluting stents (Cypher). The cause and incidence of these events have not been determined.

Methods and Results—We present findings of a 58-year-old man who died of late stent thrombosis 18 months afterreceiving 2 Cypher stents for unstable angina. Although angiographic and intravascular ultrasound results at 8 monthsdemonstrated the absence of neointimal formation, vessel enlargement was present. An autopsy showed aneurysmaldilation of the stented arterial segments with a severe localized hypersensitivity reaction consisting predominantly of Tlymphocytes and eosinophils.

Conclusions—The known pharmacokinetic elution profile of Cypher stents and the presence of polymer fragmentssurrounded by giant cells and eosinophils suggest that a reaction to the polymer may have caused late stent thrombosis.Careful long-term follow-up of patients with vessel enlargement after Cypher stent placement is recommended.(Circulation. 2004;109:r38-r42.)

Key Words: sirolimus � stents � thrombosis � death, sudden

The drug-eluting stent (DES) era was ushered in with thefirst published human study by Sousa et al1 in 2001

showing a nearly complete abolition of neointimal hyperpla-sia by use of the sirolimus-eluting stent (Cypher, CordisJohnson & Johnson). Cypher stents are coated with a thinlayer of a poly-n-butyl methacrylate and polyethylene–vinylacetate copolymer containing 140 �g sirolimus (Wyeth-Ayers).2 Since the approval of Cypher stents in Europe andthe United States, a total of 450 000 units have been distrib-uted worldwide as of October 20, 2003,3 reflecting anincreasing percentage of the �1.5 million individuals treatedannually with coronary stents. The incidence of subacute andlate stent thrombosis within the first 30 days in patientsrandomized to Cypher in clinical trials is reported to be nodifferent from that with control bare metal stents.4–6 Long-term published follow-up data are available only up to 2 yearsin 45 patients in the “First in Man” study7 and up to 1 year in120 patients enrolled in the Randomized Study withSirolimus-Coated Bx Velocity Balloon-Expandable Stent(RAVEL) trial.8,9 The Food and Drug Administration, along

with Cordis Johnson & Johnson, have posted adverse eventinformation for physicians; there have been �290 reports ofsubacute thrombosis (of which 60 have been fatal) and 50reports of possible hypersensitivity reactions.3 The rates andreasons of these adverse outcomes associated with Cypherstent use are unknown.

This report describes the first case of fatal acute myocar-dial infarction and cardiac rupture as a result of late throm-bosis of a Cypher stent deployed 18 months previously. Thepatient, enrolled in the European Sirolimus Eluting Stent inDe Novo Native Coronary Lesions (E-SIRIUS) trial, devel-oped a hypersensitivity reaction limited to the coronary arterywall surrounding the stent.

Case ReportA 58-year-old man was first seen in December 2001 withunstable angina. The patient was a smoker, with hyperlipid-emia, without a history of diabetes and hypertension. Acoronary angiogram showed a �20-mm-long 95% diameterstenosis extending from the proximal to mid left circumflex

Received December 1, 2003; revision received December 17, 2003; accepted December 29, 2003.From the Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, Washington, DC (R.V., A.F., F.D.K.), and the Cardiovascular

(G.G., G.M., N.G., L.M., M.T., O.V.) and Pathology (T.M.) Departments, Ospedali Riuniti di Bergamo, Bergamo, Italy.Dr Guagliumi has a consultant agreement with Cordis, the manufacturer of the stent that is the subject of this article.The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of

the Department of the Army or the Department of Defense.Correspondence to Renu Virmani, MD, Chair, Department of Cardiovascular Pathology, Armed Forces Institute of Pathology, 6825 16th St NW,

Washington, DC. E-mail virmani@afip.osd.mil© 2004 American Heart Association, Inc.

Circulation is available at http://www.circulationaha.org DOI: 10.1161/01.CIR.0000116202.41966.D4

1

Special Report

coronary artery (LCx) (Figure 1), a 70% diameter stenosis inthe mid left anterior descending coronary artery (LAD), anda noncritical lesion in the proximal right coronary artery(RCA). The patient was enrolled in the E-SIRIUS trial andrandomized to the sirolimus-eluting stent group.5 The LCxartery lesion was predilated with an undersized balloon

(2.5 mm at 14 atm), and 2 sirolimus-eluting Cypher stents(3.0�18 mm and 2.5�18 mm) were implanted with a 1-mmoverlap. The proximal stent was postdilated with a noncom-pliant balloon. Intravascular ultrasound (IVUS) imaging wasperformed at the end of the stent procedure, and quantitativeangiographic and volumetric IVUS analyses were measuredby independent core laboratories (Brigham and Women’sHospital, Boston, Mass, and Cardialysis, BV, Rotterdam, theNetherlands). The reference laboratory determined a minimalreference lumen and stent diameter of 2.3 mm. The patientwas discharged without in-hospital complications on ticlopi-dine, aspirin, simvastatin, and �-blocker.

Three weeks later, the patient presented to the clinic with askin rash on the trunk, neck, ankle, and wrist with itching andirritation; there was no previous history of allergy. Thereaction was interpreted as an allergic response to ticlopidine,which was discontinued and replaced by clopidogrel 75 mg/dfor 2 months. At this time, the total leukocyte count wasnormal, without eosinophilia. The rash resolved within a fewdays.

At 8 months after stenting, per protocol, the patientunderwent follow-up angiography and IVUS. Angiographicquantitative coronary arteriography and IVUS imaging dem-onstrated an absence of in-stent restenosis or neointimalproliferation (Figures 1 and 2). Laboratory blood tests werenormal, including a total eosinophil count of 140 �L. Thepatient remained asymptomatic at 1-year clinical follow-up,with a negative isotope stress test.

Eighteen months after stenting, the patient developed anepisode of epigastric and retrosternal chest pain with syncopefollowed by prompt recovery. Over the next few days, theindividual experienced recurrent episodes of intermittentchest pain and was admitted to the coronary care unit with adiagnosis of a recent non–Q-wave myocardial infarction(peak creatine kinase of 423 U/L and a troponin I of 34ng/mL). The patient was now asymptomatic and was treated

Figure 1. Baseline angiogram (A, right anterior oblique projec-tion) showing 95% narrowing of mid LCx (arrow). Two overlap-ping Cypher stents (3�18 and 2.5�18 mm) (arrow) were placed(postdeployment angiogram, B). Stents (arrow) were widelypatent 8 months after deployment (C) and similar to angiogramin B. At 18 months (D), there was total occlusion at site of proxi-mal Cypher stent (arrow).

Figure 2. Longitudinal reconstruction ofIVUS of stented LCx (top image, immedi-ately after stent deployment; bottomimage, 8-month follow-up) illustratingborders of artery wall (green line), stent(blue line), and lumen (red line). Noteincreased plaque volume and vessel size(indicative of positive remodeling, arrow-heads) at 8 months, with nearly absentneointimal thickening.

2 Circulation

with heparin, �-blockers, aspirin, and intravenous nitroglyc-erin. There was no fever, and the leukocyte count was normal,without evidence of eosinophilia. Coronary angiography 8days after the onset of chest pain showed occlusion of theLCx at the entrance of the proximal Cypher stent, with TIMIgrade 1 flow. In addition, there was progressive stenosis oflesions in the mid LAD and proximal RCA. A careful attemptto cross the LCx stenosis with a floppy guidewire wasunsuccessful (Figure 1). Soon thereafter, the patient experi-enced a sudden profound hypotension immediately followedby cardiorespiratory arrest and pulseless electrical activity;resuscitation attempts were unsuccessful.

An autopsy limited to the heart and brain was performed. A300-mL hemorrhagic pericardial effusion was present asso-ciated with a ruptured acute transmural basal lateral myocar-dial infarction. The coronary arteries were dissected free fromthe heart and radiographed (Figure 3, A and B). The 2sequential Cypher stents were observed in close appositionbut without overlap (Figure 3B). The adventitial surface ofthe LCx artery in the region of the distal stent was hemor-rhagic, and the proximal stented segment was dilated. The

stented region of the LCx was processed for methylmethac-rylate embedding and sectioned at 3-mm intervals for a totalof 12 sections. The remainder of the epicardial coronaryarteries were sectioned at 3- to 4-mm intervals and embeddedin paraffin.

The stented LCx showed an occlusive luminal thrombus,starting at the mouth of the proximal stent and partiallyobstructing the distal stent (Figure 3, C through F). The wallof the stented artery was aneurysmally dilated with anextensive inflammatory infiltrate involving the intima, media,and adventitia consisting of lymphocytes, plasma cells, mac-rophages, and eosinophils. The luminal surface of the prox-imal stent was surrounded by fibrin-rich thrombus withsparse smooth muscle cells, whereas the distal stent showedan extensive inflammatory infiltrate consisting predominantlyof lymphocytes and eosinophils and occasional giant cells(Figure 3, G through J). The abluminal surfaces of theproximal and distal stent were focally malapposed, with thicklayers of fibrin thrombus separating the stent from theunderlying plaque and arterial wall (Figure 3, D and F). Theproximal stented artery also showed focal giant cell reaction

Figure 3. Postmortem radiographs (A and B) showing 2 LCx Cypher stents; note absence of stent overlap (B). Photomicrographs ofrepresentative cross sections of proximal (C and D) and distal (E and F) Cypher stents. Focal strut malapposition with aneurysmal dila-tation (double arrows in D and F) and occlusive luminal thrombosis (Th, C and D) are present. G to J, High-power views of stentedartery from proximal (C and D) and distal (E) boxed areas. G, Luminal thrombus (Th) above stent struts with absence of smooth musclecells. There is diffuse inflammation within intima and media (H, boxed area in D). I, (right box in E), Extensive inflammation consistingprimarily of eosinophils and lymphocytes, with a focal giant cell reaction around stent strut (*) and surrounding polymer. Marked inflam-mation is similarly present in intima, media, and adventitia in J (left box in E). K and L (Luna stains) show giant cells (arrowheads)around a polymer remnant that has separated from stent strut and numerous eosinophils within arterial wall. M through O, Immunohis-tochemical identification of T cells (CD45Ro), B cells (CD20), and macrophages (CD68), respectively; T lymphocytes are predominantinflammatory cell type.

Virmani et al Drug-Eluting Stent Thrombosis 3

surrounding a few polymer remnants that had become sepa-rated from the stent struts (Figure 3K). Although no medialnecrosis or neutrophil infiltrates were observed in any of thesections, the inflammatory cells diffusely infiltrated themedia, causing medial disruption and destruction.

Immunostains for inflammatory cells in the intima, media,and adventitia revealed dominant T-lymphocyte infiltration(CD45Ro) with scattered B lymphocytes (CD20) and lessnumerous macrophages (CD68) (Figure 3, M through O).Luna stains showed an extensive eosinophilic infiltration,especially prominent in the distal stent in the adventitia,media, and intima around stent struts (Figure 3, K and L).Stains for bacteria and fungi were negative. Collectively,these pathological changes are consistent with a localizedhypersensitivity reaction.

Severe arterial stenoses were found in the nonstentedlesions of the LAD and RCA; however, no significantinflammation or eosinophilic infiltrates were present.

DiscussionThis is the first case of a localized hypersensitivity vasculitisin response to a Cypher coronary stent resulting in an acutemyocardial infarction secondary to late in-stent thrombosis at18 months. The hypersensitivity reaction could be caused bythe metallic stent, polymer, or sirolimus. Available patholog-ical evidence, however, supports the hypothesis that hyper-sensitivity to the polymer is the most likely mechanism.

Hypersensitivity to metals such as molybdenum, nickel,and chromium has been reported in 10% of patients under-going stenting.10 To the best of our knowledge, hypersensi-tivity to bare stainless steel stents has been associated withrestenosis and not thrombosis, and a late eosinophil-richinfiltrate has not been reported in human stented arteries. Wehave examined �400 stainless steel stents placed in humancoronary arteries, and of these, �150 have been in place �3months; to date, none of the latter group show an eosinophilicreaction near the stent.11 In bare metal stents, inflammationaround stent struts typically consists of macrophages and Tlymphocytes, with a few B lymphocytes and giant cells.Moreover, the extent of inflammation correlates with thepresence of restenosis, whereas in the present case, there waslittle to no underlying neointima.11 Remarkably, adventitialeosinophilic infiltrates are found primarily in patients withspontaneous coronary dissection. It is usually an acute phe-nomenon occurring soon after dissection of the artery; healedspontaneous dissections typically do not show inflammation.

We recently reported pathological findings of late stentthrombosis �30 days with bare metal stents.12 The mecha-nism of late thrombosis was stenting across a major branchostium with either single or bifurcating stents, brachytherapy,plaque rupture just proximal or distal to the stent, extensivenecrotic core prolapse, and in-stent restenosis with thrombo-sis. In these cases, there was no evidence of excessiveinflammation of the arterial wall or infiltration of eosinophils.Incomplete neointimal healing was present in 12 of 13 caseswith late thrombosis. In the present case, the marked hyper-sensitivity reaction clearly prevented arterial healing and wasprobably not exaggerated during the interval after the onset of

chest pain and death, because this is not observed in thearterial wall in fatal cases of plaque rupture.

The hypersensitivity in the present patient was unlikely tohave been caused by sirolimus, because pharmacokineticstudies performed in dogs and rabbits show that the drug isundetectable in the arterial wall by 60 days.2,13 Despitewidespread use of oral sirolimus for transplant rejection(kidney and heart), we know of only 1 case report ofleukoclastic vasculitis to sirolimus.14 Conversely, sirolimushas been shown to suppress eosinophilic infiltration in ananimal model of bronchial hypersensitivity.15 Adverse sideeffects to sirolimus are limited primarily to bone marrowsuppression and hypercholesterolemia and hypertriglyceride-mia.16 Other reported side effects include hypokalemia, hy-perglycemia, diarrhea, and abnormal liver function.17

Polymers like those in latex and vinyl gloves, methyl-methacrylate in dentistry, and polyurethane, among others,have been shown to produce hypersensitivity reactions insome individuals.18–20 However, many nonbioerodable poly-mers [polyurethane, poly(dimethyl)siloxane (silicone), andpolyethylene terephthalate (Dacron)] are known to promoteinflammation when implanted in swine coronary arteries.21–23

Most inflammatory reactions to polymers involve macro-phages and multinucleated giant cells and lymphocytes with-out eosinophils. In studies unrelated to stents, poly-n-butylmethacrylate, a component of bone cement and the samepolymer coating as used in Cypher stents, when implantedsubcutaneously promotes a macrophage and giant cell reac-tion accompanied by tissue damage and fibrosis.24 In addi-tion, the polyethylene–vinyl acetate component of the Cyphercopolymer, when used as an antigen-delivery matrix, hasbeen shown to elicit inflammation in 25% of rabbits.25

Although there are no reports of excessive inflammationwith Cypher stents in animals, our laboratory has observedinflammatory reactions in the arterial walls of pig coronaryarteries with 28- and 90-day stainless steel26 and DESs(including Cypher, R.V., unpublished data, October 2003).Granulomas occur in 10% to 20% of implanted porcinecoronary stents and involve either a few or multiple stentstruts. Inflammatory infiltrates typically consist of lympho-cytes, macrophages, giant cells, neutrophils, and eosinophils.In stainless steel stents, inflammation is usually much lesspronounced at 90 days than at 28 days, whereas the reciprocaleffect is found in DESs with nonerodable polymers. In DESs,there are often greater numbers of eosinophils, localizedprimarily to stent struts, which may extend into the lumen andadjoining media and adventitia. The inflammation is usuallyaccompanied by excessive neointimal thickening, and throm-bosis is infrequent.

The hypersensitivity to the Cypher stents was most likelypresent at 8 months after deployment, because significantvessel enlargement and persistent positive remodeling wasfound by IVUS. Furthermore, there was progressive enlarge-ment of the artery, with aneurysm formation between 8 and18 months. The significant malapposition noted in bothproximal and distal stents probably occurred in the last 10months of life; only focal late malapposition was observed at8 months. In the RAVEL trial, late stent malapposition wasfound in 21% of Cypher stent implants, compared with 4% in

4 Circulation

control BX Velocity stents27; 1 patient with a Cypher stentdeveloped an aneurysm.28 Lower rates of malapposition werereported in the SIRIUS trial (9% in Cypher versus 0% in baremetal stents) without any clinical events present at 18months.29 A regional increase in external elastic membraneremodeling may represent the main cause of late stentmalapposition.30 Although the precise mechanism(s) of latestent malapposition and thrombosis in our case are unknown,inflammatory destruction of the medial wall may have causedfurther dilation accompanied by the accumulation of fibrinbetween stent struts and native plaque, suggesting a relation-ship between malapposition, inflammation, and thrombosis.

In October of 2003, a US Food and Drug AdministrationPublic Health Web Health Alert notified physicians of pos-sible generalized hypersensitivity reactions in 50 patientsreceiving Cypher stents.3 The symptoms included pain, rash,respiratory alterations, hives, itching, fever, and blood pres-sure changes. None of these findings were documented in ourpatient at the time of death, and the hypersensitivity reactionwas localized to the stented arterial segment at 18 months,when the drug is completely eluted off the stent. In this case,the polymer may serve as an antigenic stimulus resulting in aT-lymphocyte and/or foreign body response accompanied byeosinophils. Activated T lymphocytes, specifically CD4helper cells, may secrete interleukins 4 and 13, causing anallergic response with eosinophilic infiltration.31

There is a likely spectrum of allergic responses to DESs insensitive patients, varying from benign reactions to excessiveinflammation with medial destruction, stent malapposition,and aneurysm formation with late in-stent thrombosis. Theenhanced surveillance of patients with DES for late compli-cations along with the development of tests to prescreenindividuals with potential reactions to polymers may helpavoid some of the late-term complications with DES. Con-tinued efforts to improve polymer biocompatibility arewarranted.

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