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A correlation found between contact allergy to stent material and restenosis of the coronary arteries

A correlation found between contact allergy to stent material and restenosis of the coronary arteries
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  Contact Dermatitis 2009: 60: 158–164Printed in Singapore. All rights reserved  #  2009 The AuthorsJournal compilation  #  2009 Blackwell Munksgaard  CONTACT DERMATITIS A correlation found between contact allergy to stentmaterial and restenosis of the coronary arteries C ECILIA  S VEDMAN 1 , S USANNE  E KQVIST 1 , H ALVOR  M O ¨ LLER 1 , J ONAS  B JO ¨ RK 2 , C ARL -M AGNUS  P RIPP 3 , B IRGITTA  G RUVBERGER 1 ,E VA  H OLMSTRO ¨ M 4 , C ARL -G UNNAR  G USTAVSSON 5 AND  M AGNUS  B RUZE 11 Department of Occupational and Environmental Dermatology, Malmo ¨ University Hospital, Malmo ¨, Universityof Lund,  2 Competence Centre for Clinical Research, Lund University Hospital, Lund, University of Lund, 3 Department of Thoracic Intervention, Blekinge Hospital, Karlskrona,  4 Department of Dermatology,Malmo ¨ University Hospital, Malmo ¨, University of Lund, and  5 Department of Cardiology,Malmo ¨ University Hospital, Malmo ¨, University of Lund, Sweden Background:  Metallic implants, stents, are increasingly being used especially in patients with stenosisof the cardiac vessels. Ten to thirty per cent of the patients suffer from restenosis regardless of aetiology. We have shown increased frequency of contact allergy to stent metals in stented patients. Objectives:  To we evaluate whether contact allergy to stent material is a risk factor for restenosis. Methods:  Patients with stainless steel stents, with or without gold plating, were epicutaneously testedand answered a questionnaire. The restenosis rate was evaluated. Results:  We found a correlation between contact allergy to gold, gold stent, and restenosis (OR 2.3,CI 1.0–5.1,  P  ¼  0.04). The risk for restenosis was threefold increased when the patient was goldallergic and stented with a gold-plated stent. An increased degree of chest pain in gold-allergicpatients stented with gold-plated stent was found. Conclusions:  We found a correlation between contact allergy to gold, gold-stent, and restenosis.It may be of importance to consider contact allergy when developing new materials for stenting. Key words:  contact allergy; dental gold; gold allergy; PCI; restenosis; sensitization; stent; TLR. #  Blackwell Munksgaard, 2009.Conflicts of interest: The authors have declared no conflicts. Accepted for publication 14 November 2008 Percutaneous coronary interventions (PCI) (1–4)are common procedures to treat patients withcoronary artery disease. Intravascular stentingreduces the rate of restenosis, i.e. the recurrenceof stenosis at the site of a previously successfulintervention (2–5).Restenosis usually appears within 3–6 months(6–8) after intervention but may occur later (7).The in-stent restenosis rate with traditional stentsis usually reported with values from 10% to 30%(1, 7). Restenosis is often defined as target lesionrevascularization (TLR) (8–10) (see below). Thefactors predisposing to in-stent restenosis are stilllargely unknown (1, 6, 11). There is a continuousdevelopment of new stent materials. The choice of stent is based on recommendations, for example,biological stents for certain risk groups, but in thegeneral stented population, the choice of stentbetween those currently used will be random.Recently, contact allergy to metal compoundsreleased from stainless steel stents was suggestedto possibly cause in-stent stenosis (12).We have previously shown a high prevalence of contact allergy to gold in patients stented withgold-plated stents (13). Studies have reportedhigherrestenosisrateswithgold-platedstentsthanwith stainless steel stents of the same configura-tion (14–16), but the possible correlation to con-tact allergy was not evaluated.Gold and nickel are metals that often causecontact allergy. The aims of the present retrospec-tive study were to evaluate the frequency of   contact allergy to stent metals and other potentialcontact allergens in a stented population and toinvestigate any possible relationship between stentmaterial, contact allergy, and restenosis. In thepresent paper, we discuss our results with regardsto restenosis. The other findings have been (17) orwill be published elsewhere (18). Materials and Methods The study was performed as a retrospective studyof patients (17, 18) from the Department of Tho-racic Surgery, Blekinge Hospital, Karlskrona,Sweden. The same personnel performed the study,from November 2003 to May 2004, at the hospi-tals of Ljungby, Va ¨xjo ¨, Karlskrona, Karlshamn,and at the Department of Occupational and Envi-ronmental Dermatology in Malmo ¨, Sweden. Thestudy was performed in a double-blinded manner,i.e. the cardiologist did not know the study resultssince they were collected after intervention, thedermatologists did not know the patient’s cardiachistory, and the patient was unaware of the testresult until the final reading, only then were patchtest result discussed and explained. Patients Seven hundred and fifteen consecutive patients,treated with PCI and stented during the years1997–2002, were asked to participate. Six hundredand twenty eight (87.8%) agreed to participate inthe study, of these, 144 (22.9%) patients agreed toanswer the questionnaire only and 484 (77.1%) – the study sample – also underwent the clinicalinvestigation with patch testing.Of the patients who did not participate (87)4 patients declined due to disease (non-cardiac),12 did not want to participate at all, and 71 neveranswered.In the study sample, 103 (21.3%) were femalesand 381 (78.7%) males, with a mean age of 67.3(range 42–89) years. Stents The stents used were anatomically and function-ally identical. Both were made of stainless steel(316L), one had no plating (NIR stent; MedinolLtd, Jerusalem, Israel) (Ni stent) and one waselectroplated with 99.9% pure gold (NIRROYAL; Medinol Ltd) (Au stent). One hundredand forty-six patients (females:males; 33:113)had been stented with Au stents, 314 patients(females:males; 68 :246) with Ni stents, and 24(females: males; 2:22) had been treated with bothtypes of stents. These two stents were the mostfrequently used at the time in the cardiologydepartment investigated. The choice betweenthe two stents, which at the time were consideredto perform equally, was random. When consid-ering the patients stented with Au stent asa group, 170 patients, the total number of Austents used was 220, the stent length (mean   SD) was 17.6    6.8 mm, and stent diameter(mean    SD) was 3.0    0.4 mm. For thepatients stented with Ni stent, 338 patients, thetotal number of stents used was 426, mean stentlength was 17.7    6.7 mm and mean stent diam-eter was 3.1    0.5 mm. TLR rate Restenosis may be studied by anatomical meth-ods such as angiography and intravascular ultra-sound. An alternative approach is to study theclinical effect of restenosis (8, 10), most often asthe rate measuring how many stented lesions haveto be retreated due to clinically driven repeatangiography given a specific time period, this isusually referred to as TLR. If readmitted, the car-diologist in charge evaluated TLR and decided onreintervention. An in-stent lumen reduction of at least 50% of diameter was considered to bea restenosis. The patients were followed in a data-base, and it was thus possible to check the studysample with regards to new stenosis and resteno-sis during the years 1997–2002 provided that thepatients had been readmitted to the same hos-pital. Restenosis usually occurs during the first6 months after PCI (8, 19), and in this study, thepatients were followed between 6 months and5 years after stent implantation, this being morethan adequate time space for TLR rate evalua-tions. In the questionnaire, patients without aregistered repeat angiography were asked if theyhad been hospitalized in other hospitals after thestent implantation. Questionnaire and medical history The invitation to participate in the study includeda questionnaire regarding topical, systemic, andoccupational exposure to gold, as well as nicotinehabits and piercing. The patients were also askedto fill in the Canadian Cardiovascular SocietyAngina Classification (CCS) (20) in order to eva-luate their present cardiac status. The question-naire was answered by everyone who agreed toparticipate.At first visit, a short standardized medical his-torywas taken bytheclinician. Informationaboutrisk factors for atherosclerotic disease, medica-tion, and skin disease was collected. Contact Dermatitis 2009: 60: 158–164  CONTACT ALLERGY TO STENT AND RESTENOSIS 159  Patch testing All patients underwent epicutaneous (patch)testing with the preparations included in theEuropean baseline series (21) supplemented withtest preparations of metals, preservatives, textiledyes, plastics, fragrances, and corticosteroids.Gold sodium thiosulfate was tested initially ata concentration of 2.0% w/w petrolatum (pet.)and if retested at 5.0% w/w, whereas nickelsulfate hexahydrate was tested at 5.0% w/wpet. and when retested at 15.0% and 30.0% w/vaqua (18).The test technique used was IQ Chamber 1 (Chemotechnique Diagnostics, Vellinge, Sweden)attached to Scanpor 1 (Norgesplaster, Vennesla,Norway) tape, 20  m l on each patch unit for liquidpreparations was used. The patch tests wereremoved from the back after 2 days and readingswere performed, according to International Con-tact Dermatitis Research Group guidelines (22),on D3 and D7.If the test reaction on D3 was doubtful to gold,nickel, or molybdenum, i.e. redness without infil-tration, infiltration only on part of the reactionsite, or, for example, a follicular reaction, thepatient was retested. The retest was performedwith the same or higher concentration (see above)to elucidate the nature of the reaction, whethertruly positive, false positive, or irritant.The retest patches were removed from the backafter 2 days (D5) and readings were performed onD7 and D10. If the reaction after retest was againdoubtful, or absent, the result was considerednegative. Ethics The patients gave written informed consent to thestudy, which was approved by the Ethics Commit-tee of the Faculty of Medicine, Lund University.The study was conducted in accordance with theethical standards specified in the Declaration of Helsinki and International Conference on Har-monisation (ICH) guidelines on Good ClinicalPractice. Statistics The statistical analyses were conducted using  SPSS release 12.0.1 (SPSS Inc, Chicago, IL, USA).We regarded  P  <  0.05 as statistically significant.Fisher’s exact test was used to investigate differ-ences in the prevalence of restenosis between Ni-and Au-stented patients and between allergic andnon-allergic patients as well as between males andfemales within the two groups with different typesof stents. The association between gold allergyand restenosis in Au stents was investigated fur-ther by controlling for age, sex, diabetes mellitus,dental gold restorations, stent length, and stentdiameter in a multivariable logistic regressionmodel. We used Mann–Whitney’s  U  -test to studythe association between gold allergy and chestpain (scale 1–5, ranging from no to severe chestpain) within the group of Au-stented patients.After dichotomizing the chest pain variable (noor mild; class 0 or 1, versus moderate or severechest pain; class 2, 3, 4), the association betweengold allergy and chest pain was investigated fur-ther by controlling for age and sex using logisticregression. Results The questionnaire and medical history Within the study sample, no differences werefound in the stented groups regarding risk factorsfor cardiac disease, medication, or exposure togold-including dental gold restorations (Table 1).Thedifferentgroups ofmedications usedarelistedin Table 2. Patch test results and TLR The frequency of nickel allergy was 13.1% in theNi-stented group and 9.6% in the Au-stentedgroup (Table 3). In the Au-stented group, the fre-quency of gold allergy was 39.0% and in the Ni-stented group, 32.5% (Table 4).With regards to restenosis, there was a statisti-cally significant difference ( P  ¼  0.0016) betweenthe Ni-stented patients ( n  ¼  44, 13.1%) and theAu-stented patients ( n  ¼  42, 24.7%).In the Ni-stented patient group (338 patients,the group also containing the group stented withboth Ni andAustents), thedifference in restenosis Table 1.  Patient characteristica (table modified from reference 18)Au stent, n  ¼  146Ni stent, n  ¼  314Au  þ  Nistent, n  ¼  24Mean age (years) 66.4 67.4 70.8Women % 22.6 21.7 8.3Smoking % 13.9 10.7 8.7Diabetes mellitus % 17.4 18.8 9.1Medication forhypertension %99.2 99.0 100Medicationfor hypercholesterolaemia %91.5 87.9 90.9Skin disease % 31.5 22.1 8.7Any allergy % 23.7 21.6 17.4Ear piercing% 15.1 14.2 8.7Gold exposure,occupational %0.7 1.0 0.0Dental gold restorations % 57.9 64.7 60.0160 SVEDMAN ET AL.  Contact Dermatitis 2009: 60: 158–164  rate betweenallergic patients with restenosisin thenickel stent ( n  ¼  8, 17.8%) and not allergic withrestenosis ( n  ¼  36, 12.3%) was not statisticallysignificant ( P  >  0.3) (Table 5).In the Au-stented group (170 patients, thegroup containing also patients stented with bothNi and Au stents), the difference in restenosisbetween gold-allergic Au-stented patients withrestenosis ( n  ¼  23, 33.8%) and not allergic withrestenosis in the Au stent ( n  ¼  19, 18.6%) wasstatistically significant ( P  ¼  0.03) (Table 5). Ina multivariate logistic regression model wheresex, age, and dental gold restorations were con-sidered, we could still demonstrate a correlation(OR 2.3, CI 1.0–5.1,  P  ¼  0.04) between goldallergy, Au stent, and restenosis. When adjustingfor number of stents, stent length and diameterin a multivariate logistic regression model thecorrelation remained (OR 2.3, CI 1.0–5.0,  P  ¼ 0.04), equally considering other risk factors forcardiac disease and restenosis such as diabetesmellitus the correlation between gold allergy,Au stent and restenosis remained (OR 2.2, CI1.1–5.0,  P  ¼  0.05).When the two sexes were regarded separately,there were no statistically significant differencesbetween gold-allergic patients with restenosisand non-allergic with restenosis, females  P  ¼  0.24and males  P  ¼  0.06 (Table 5). Patch test result and questionnaire In the gold-stented patients, the questionnaireshowed an increased degree of chest pain amongthe gold-allergic patients ( P  ¼  0.046).After dichotomizing the chest pain variable forthe gold-stented patients, the association betweengold allergy and chest pain was furtherinvestigated.With this analysis, the OR was 2.2 (95% CI1.1–4.4,  P  ¼  0.02). When controlling further forage and sex, the OR was 1.9 (95% CI 0.92–3.8, P  ¼  0.09). When performing the same analysis onpatients with nickel allergy and nickel stent, therewas no significant difference. Discussion We have confirmed that patients with gold-platedstents have a statistically significantly higher fre-quency of in-stent restenosis compared withpatients with the same stent without gold plating(14–16). Furthermore, in the present retrospectivestudy, we also show a statistically significantcorrelation between gold-plated stents, contactallergy to gold, and restenosis. Regarding nickel,no such correlation was found. There was a highfrequency of contact allergy to gold in the gold-stented group, suggesting a causal role for goldstents in the induction of gold allergy. However,gold allergy was frequent not only in the groupstented with Au stents but also in the groupstented with Ni stents. A significant correlationbetween dental gold restorations and contact Table 2.  Medications in the study populationMedication % of populationAcetylsalicylic acid 81Cox 2 inhibitors 5Anticoagulants 4Calcium blockers 20Angiotensin II antagonists 10ACE inhibitors 28Beta blockers 67Loop diuretics 18Statins 86ACE, angiotensin converting enzyme inhibitors. Table 3.  Contact allergy to nickel in Ni-stented patients andAu-stented patients (those with nickel plus gold stents excluded)Contactallergyto nickelNi stent patients Au stent patients P -valueTotalno.Allergic(%)Totalno.Allergic(%)All 314 41 (13.1) 146 14 (9.6)  > 0.3Females 68 23 (33.8) 33 6 (18.2) 0.16Males 246 18 (7.3) 113 8 (7.1)  > 0.3 Table 4.  Contact allergy to gold in Au-stented and Ni-stentedpatients (those with nickel plus gold stents excluded)Contactallergyto goldNi stent patients Au stent patients P -valueTotalnoAllergic(%)TotalnoAllergic(%)All 314 102 (32.5) 146 57 (39.0) 0.17Females 68 26 (38.2) 33 18 (54.5) 0.14Males 246 76 (30.9) 113 39 (34.5)  > 0.3 Table 5.  The frequency of restenosis in 338 Ni-stented patients(70 females and 268 males) with nickel (Ni) allergy,  n  ¼  45 (24females and 21 males) and without nickel allergy,  n  ¼  293(46 females and 247 males) and the frequency of restenosis in170 (35 females and 135 males) Au-stented patients with gold(Au) allergy,  n  ¼  68 (19 females and 49 males) and without goldallergy,  n  ¼  102 (16 females and 86 males)Stent patients with restenosisNi-stentedpatientsContact allergyto Ni,  n  (%)No contactallergy to Ni,  n  (%) P -valueAll 8 (17.8) 36 (12.3)  > 0.3Females 3 (12.5) 6 (13.0)  > 0.3Males 5 (23.8) 30 (12.1) 0.17Au-stentedpatientsContact allergyto Au,  n  (%)No contactallergy to Au,  n  (%)All 23 (33.8) 19 (18.6) 0.03Females 6 (31.6) 2 (12.5) 0.24Males 17 (34.7) 17 (19.8) 0.065 Contact Dermatitis 2009: 60: 158–164  CONTACT ALLERGY TO STENT AND RESTENOSIS 161  allergy to gold has been demonstrated (23) as wellas between the gold concentration in blood andthe amount of dental gold (24). Thus, patientsmay have been sensitized through their dentalrestorations before having been stented (18).Periodontal disease has been argued to be cor-related with coronary disease (25). It is difficultto conclude – with the limitations of our studybeing retrospective – as to whether dental statuscould be a confounding factor also for restenosis.However, in a multivariate logistic regressionmodel where sex, age, and dental gold restora-tions and risk factors for cardiac disease wereconsidered, we could still demonstrate a correla-tion between gold allergy, Au-stent, and res-tenosis. In our Ni-stented patients with goldallergy, we could not find an increased numberof restenosis. There are, to our knowledge, nostudies on whether there could be a correlationbetween dental status and restenosis and thusdental gold restorations can still be a confound-ing factor.When restenosis is defined as TLR, the resteno-sis rate is lower, sometimes about one-half of theangiographic restenosis rate (8). Therefore, weevaluated the Au-stented patients with the anginaclassification (CCS). We found that in the Au-stented group, the individuals with contact allergyto gold had more chest pain, perhaps indicatinga higher degree of restenosis in the stented vesselscompared with those without gold allergy. Thisfurther supports the fact that contact allergy togold is an independent factor for restenosis whenusing gold-plated stents.What other evidence might support the theorythat contact allergy may be important forrestenosis?In order for a contact allergy to manifest itself,in, for example, the coronary artery, certain con-ditions must prevail. (i) Either a pre-existing con-tact allergy or the capacity of the stent allergen toinduce contact allergy within the coronary artery.(ii) The reaction in the vessel must be one thatcould be provoked by a contact allergen.(i) The capacity of an elemental metal to sensi-tize or elicit contact allergy depends on the rate of formation of allergenic metal ions as the alloy cor-rodes (26). Both for elemental gold and for nickel,ions can be released under the impact of blood,saline, proteins, and mechanical stress (27). Goldrelease from gold used in jewellery has been dem-onstrated (28), and there is a relationship betweenear piercing and nickel and gold allergy (29). Den-dritic cells have been found in atheroscleroticplaques in humans (30). Thus, in the intima of the vessel, there are the possibilities for antigenpresentation (30) meaning that a sensitization orelicitation may occur.(ii) What is known about restenosis? The fac-tors predisposing for restenosis are still largelyunknown, although risk factors such as diabetesmellitus, diameter of the treated artery, length of the lesion, and localization are known (1, 31–33).Stents are made of different materials, aiming forgood biofunctionality and biocompatibility (34).They can contain different metals and be coatedwith active drugs (35) to lower the restenosisrate (1). In-stent restenosis results from excessivefibroproliferative and inflammatory response tothe insult on the arterial wall; it may be focal ordiffuse, restricted to the stent or extend beyondthis (9). The lesions contain macrophages, histio-cytes, and lymphocytes (36). Inflammation andrelease of chemotactic and growth factorshave been shown to play a significant role in theprocess of atherosclerosis (30, 37) and restenosis(38–40), the reaction leading to neointimal pro-liferation (37, 39). Hypersensitivity reactions havebeen discussed with drug-eluting stents (41). InSweden, the gold-plated stent type, introduced toimprove visibility on X-ray, is no longer used afterreports of an increased restenosis rate (14, 15).Danzi et al (42) found that in gold-plated stents,restenosis was diffuse, involving the overall stentlength and extending beyond the margins indicat-ing a greater than average proliferative neointimalresponse.Furthermore, it is known that systemic prov-ocation with gold salt to patients with contactallergy to gold gives a clinical flare-up reaction(43) accompanied by a release of cytokines andacute phase reactants (44). Cytokine releasemay be seen as a general feature of an endo-genous flare-up in contact allergy. Based onthis knowledge, contact allergy to stents, atleast theoretically, cannot be excluded as a pos-sible cofactor in the complex formation of a restenosis. Conclusion In this study, we have shown a correlationbetween gold-plated stents, contact allergy togold, and an increased frequency of restenosis.Regarding nickel, we have not been able to showthis correlation.Inordertoinvestigatetherole ofcontactallergyin the restenosis process, possible confoundingfactors and the possible risk of sensitizationthrough implant material in the vessel, prospec-tive, randomized controlled trials would have tobe performed. 162 SVEDMAN ET AL.  Contact Dermatitis 2009: 60: 158–164
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