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Relation of Nickel Allergy with in-Stent Restenosis in Patients Treated with Cobalt Chromium Stents

Background In-stent restenosis (ISR) is the major limitation of percutaneous coronary stenting procedure. The elements like nickel, chromate and molybdenum are known to cause contact allergy. Hypersensitivity reaction, against these metal ions, may be one of the reasons of ISR. Cobalt chromium coronary stents, which are increasingly being used in percutaneous coronary interventions, have more nickel amount than the stainless steel stents. Objective We aimed to investigate the association between nickel hypersensitivity reaction and ISR in patients treated with cobalt chromium coronary stents. Methods Epicutaneous patch tests for nickel were applied to 31 patients who had undergone elective cobalt chromium coronary stent implantation and had ISR in control angiogram. Thirty patients, without ISR, were included as the control group. Patch test results and other clinical variables were compared. Results There was no statistically significant difference of the mean age, sex, body mass index, rate of hypercholesterolemia, diabetes, hypertension and smoking between the patients with and without ISR. All other lesion characteristics were similar in the 2 groups. According to the patch test results, 7 patients had nickel contact allergy. All of these patients were in the ISR group, which was statistically significant (p<0.006). Conclusion Patients treated with cobalt chromium coronary stents and had ISR were found to have significantly more nickel allergy than the control group. Nickel allergy may play role in restenosis pathophysiology.


INTRODUCTION
Percutaneous coronary interventions are commonly used to treat atherosclerotic coronary artery disease. The risk of restenosis could be greatly reduced by intravascular stenting, but in-stent restenosis (ISR) still remains a major clinical problem. The factors predisposing to ISR are still largely unknown. Contact allergy to metal ions eluted from the stainless steel stents, primarily nickel, chromate and molybdenum, has been suggested to be a factor that contributes to in-stent stenosis 1 . All of the studies that have been published dealing with the relationship between ISR and metal allergic reactions were done with the stainless steel stents [1][2][3][4][5] . Cobalt chromium coronary stents has been developed in an attempt to maintain radio-opacity and radial strength, without compromising long-term results, as seen with thicker strut stainless steel or gold-coated stents, and it is increasingly being used in percutaneous coronary interventions. Nickel amount is more in cobalt chromium coronary stents (35% nickel and 20% chromium, respectively) than the stainless steel stents (http://www.medtronic.com/newsroom/content/ 1110132739468.pdf). The aim of this study is to investigate the relation between nickel allergy and ISR in patients treated with cobalt chromium stents.

Statistical analyses
All values are given as the mean±standard deviation.

RESULTS
There were 31 patients with ISR (10 females, 21 males with a mean age of 62±8 years) and 30 patients without ISR (5 females, 25 males with a mean age of 62±6 years). All of the patients had been using statin and aspirin. Angiotensin converting enzyme (ACE) inhibitor and beta blocker use were similar, among the groups, where as oral antidiabetic use was more frequent among the restenosis group (6 vs. 0, p=0.014). Comparisons of the baseline characteristics of the ISR and non-ISR groups were shown in Table 1. There was no statistically significant difference in the mean age, sex, body mass index, rate of hypercholesterolemia, diabetes, hypertension and smoking.
Comparison of the control angiography variables were shown in Table 2. All lesion characteristics were similar across the 2 groups. According to the patch test results, 7 of 31 patients (23%) in ISR group had nickel contact allergy, while none of the 30 patients (0%) in non-ISR group had nickel allergy. The difference was found to be statistically significant (p＜ 0.006). Two patients in the ISR group and one patient in the non-ISR group had positive test result for cobalt.

DISCUSSION
The result of the current study showed that there was a correlation between nickel allergy and ISR in patients treated with cobalt chromium stents, and it is the first of its kind in Turkish population. Oral antidiabetic use was more frequent among the restenosis group in our study. These patients were using metformin (4 patients), repaglinide (1 patient) and acarbose (1 patient). Thiazolidinediones have been shown to reduce coronary restenosis, following PCI 7 . However; such effect has not been obtained with metformin, sulphonylureas and acarbose. Therefore, there was no interference related to oral antidiabetic use in our cohort. The relationship between metal allergic reaction and development of ISR, in patients treated with 316 L stainless steel stents, has been investigated before. Köster et al. 1 showed that a delayed hypersensitivity reaction to nickel and molybdenum might be a part of the inflamma-tory process and one of the triggering factors in ISR. Saito et al. 3 have suggested that the tissue reaction to the metal component of 316 L, especially nickel, may play an important role in chronic refractory ISR. However Norgaz et al. 4 did not found the proposed relationship between nickel allergy and development of ISR in patients having stainless steel stents. Iijima et al. 5 , on the other hand, found that positive patch test (odd ratio 4.39, p=0.02) was a significant predictor of recurrent restenosis in patients treated with 316 L stainless steel stents. The stents they used included 12% nickel, 17% chromate, 2% manganese and 2% molybdenum. The stents we used in the present study had nickel three times more than this amount. Svedman et al. 8 have investigated any possible relationship between contact allergy to stent material, especially nickel and gold, and coronary artery restenosis. They have found that there's a correlation between contact allergy to gold, gold stent, and restenosis. Regarding nickel, no such correlation was found. The amount of nickel is much more in cobalt chromium coronary stents, compared to that of the stainless steel stents. Approximately 80% of individuals with cobalt sensitivity have a co-sensitivity to chromate or nickel 6 . This data may explain the relatively stronger relationship between nickel allergy and ISR in our study group. Metallic ions are most likely potential allergens in coronary stents. The susceptibility of the alloys to corrosion and metal ion elution is also an important factor in the study of metal allergies. Intercellular adhesion molecule (ICAM) 1 is known to be involved in the recruitment of inflammatory cells from the bloodstream 9 . It has been shown that nickel ions are able to either promote or suppress the expression of ICAM-1 on endothelial cells, depending on the concentration and probably the time of exposure 10 . Once the metal sensitization has occurred, it persists for many years 11 . Nickel sensitization may occur by skin contact, oral way or implanted stent material. Oral or coronary contact triggers a weaker response since there are fewer Langerhans cells in these regions, compared to the skin 11 . Our findings suggest that tissue reaction to the metal component of cobalt chromium coronary stents, especially nickel, may play a role in ISR. Taking into account that ISR has a very complex pathophysiological mechanism, every aspect of potential influences should be tried to be eliminated. This may include attempts to screen suitable patients with patch test and choosing drug eluting stents in allergic patients.

Limitations of the study
The study population is relatively small. Time to ISR, plaque burden, minimum lumen diameters before and after the stent implantation has not been evaluated. Relative amount of allergic substance (stent size, length and weight) could be important in restenosis. Relative ratio of ISR could be related with the relative amount of allergic reaction observed. Further improvement of coronary stent biocompatibility is warranted. In terms of nickel allergy, larger cohort studies in different patient populations are also needed.