Nickel hypersensitivity and coronary artery stents

INTRODUCTION — There is growing concern within the medical, surgical, and patient communities about possible allergic (hypersensitivity) reactions to foreign materials implanted in the body. A question that has generated consults to allergy and dermatology specialists is whether hypersensitivity reactions to materials in intracoronary artery stents could be associated with stent restenosis.

Many coronary stents are made from stainless steel, which is steel with added nickel and chromium, and nickel is one of the most common causes of allergic contact dermatitis (ACD). Some may also contain cobalt, molybdenum, or other metals. Thus, a possible association between metal hypersensitivity and stent restenosis has been questioned.

The evidence supporting and refuting an association between metal hypersensitivity and intracoronary artery stent restenosis will be reviewed here. Restenosis of intracoronary stents is discussed separately. (See "Intracoronary stent restenosis".)

BACKGROUND — A brief review of nickel hypersensitivity and the composition of intracoronary stents is helpful in understanding the studies presented in this topic.

Metal hypersensitivity — The most common form of metal hypersensitivity is allergic contact dermatitis (ACD) caused by nickel. Cobalt, chromium, molybdenum, and gold are less often implicated in ACD [1]. Estimates of the prevalence of nickel sensitivity in the general population are up to 19 percent [1,2]. Nickel is found in many commercial products, including zippers, buttons, jewelry, watches, eyeglass frames, and mobile phones, and many of these items have been linked to ACD reactions.

Allergic contact dermatitis — ACD is a form of cutaneous hypersensitivity that may develop in susceptible individuals when the skin has direct and repeated contact with an allergen. The development of ACD involves two phases: an initial induction phase, during which sensitization to the allergen occurs, followed by an elicitation phase, when reexposure to the allergen results in cutaneous inflammation at the site of contact. It presents clinically as a red, pruritic rash, often with areas of vesiculation (picture 1).

ACD is usually a subacute or chronic disorder mediated by allergen-specific T cells in the skin. It is a type IV (or delayed) hypersensitivity that does not involve sudden or immediate allergic reactions, systemic features, or escalation to anaphylaxis, which are characteristics of type I hypersensitivity reactions.

ACD is diagnosable by allergen patch testing, which involves placement of the allergen on the skin surface for 48 hours under occlusion, followed by removal and examination of the test sites for inflammatory changes at 48 hours and, in some cases, again usually 24 to 72 hours after the initial examination. The diagnosis and treatment of ACD are reviewed in more detail separately. (See "Allergic contact dermatitis in children".)

Risk factors — Risk factors for the development of nickel hypersensitivity include environmental exposure to nickel, especially through body piercing, as well as mutations in the filaggrin gene [1-5].

Materials in coronary stents — Coronary stents are most commonly made from stainless-steel alloys (ie, mixtures), non-stainless-steel cobalt and chromium alloys, and platinum and cobalt alloys.

The stents most commonly used in the United States are composed of 316L stainless steel, which contains nickel (approximately 12 percent), chromium (as chromate, 17 percent), and molybdenum (approximately 2 percent) [6]. Cobalt-chromium alloys may contain from 9 to 35 percent of nickel [7], and platinum-cobalt alloys can have lower amounts (9 percent) of nickel.

Stents made from these metals are available as either bare-metal devices or drug-eluting devices coated with polymers containing immunosuppressive medications, such as sirolimus, everolimus, zotarolimus, or paclitaxel. In the United States, the majority of stenting procedures use drug-eluting stents. (See "Percutaneous coronary intervention with intracoronary stents: Overview".)

POSSIBLE MANIFESTATIONS OF METAL HYPERSENSITIVITY IN IMPLANT RECIPIENTS — It is not clear that having one or more coronary stents placed is a significant nickel exposure. Interventional closure devices made of nitinol, an alloy containing 55 percent of nickel, are used in the treatment of atrial septal defect and patent foramen ovale (eg, Amplatzer device). A study of 67 patients demonstrated significant increases in serum nickel levels in the days after implantation, although the highest levels were still within the normal range [8]. Elevations in serum nickel peaked at one month and fell gradually thereafter. Sensitization to nickel was not assessed, but the patients in this study reported no symptoms to suggest problems with the devices. In vitro, bare-metal stents placed in solutions thought to mimic physiologic sweat have been shown to release detectable levels of nickel ions. The clinical relevance of this observation remains undetermined [9]. Well-documented case reports of "systemic" allergic dermatitis to patent foramen ovale closure devices have been published, however [10].

Sensitization and elicitation to metal — In theory, sensitization to nickel and other metals as a result of coronary stent placement is possible, although it has not been convincingly demonstrated. No study has performed patch testing to stent materials before and after coronary stent placement. One study evaluated the prevalence of gold and nickel hypersensitivity in patients who had previously received gold-plated stainless-steel stents or bare stainless-steel stents [11]. Patients with gold-plated coronary stents had a statistically higher rate of positive patch testing to gold compared with an age- and sex-matched control group with dermatitis but without stent implants (54 of 146; 37 percent versus 85 of 447; 19 percent), implying that gold metal sensitization could have occurred as a result of stent implantation. However, there were no clinical correlates described in this analysis related to stent failure or restenosis. In addition, a similar association was not found for nickel sensitization in those patients with bare-metal stainless stents. Of more concern is the possibility of an implanted metal device causing an allergic reaction in someone already sensitized to a metal component of the device.

Cutaneous inflammation — For stainless-steel coronary stents (either bare-metal or drug-eluting stents) specifically, we are not aware of any case reports of localized cutaneous adverse reactions suggestive of nickel allergic contact dermatitis (ACD) after placement. A very small number of cases of generalized cutaneous symptoms (diffuse pruritus or nonurticarial rash) have been reported, although a causal relationship to stent placement was not demonstrated [6,12]. Two single case reports describe generalized pruritus and eczema without stenosis after endovascular femoral artery stent placement. This may suggest that some nickel-containing stents may carry a higher risk of a generalized reaction [7,13].

The evidence for cutaneous reactions suggestive of metal ACD consists of case reports of patients with implanted orthopedic devices or oral implants [14-17]. Reported manifestations were eczematous dermatitis or, in the case of oral devices, irritation of mucosal surfaces adjacent to the device. In the orthopedic case reports, development of an eczematous dermatitis of the skin overlying the implant site has been described in patients with metal hypersensitivity [18,19]. Diffuse dermatitis has also been described after implantation of various types of nickel-containing orthopedic implants [20,21].

Stent restenosis — The issue that has raised persistent questions with regard to metal hypersensitivity and intracoronary stents is implant failure in the form of restenosis. Case reports and retrospective series suggested an association between nickel sensitivity (as demonstrated by patch testing) and stent restenosis, but higher-quality evidence provided by prospective studies has not confirmed this relationship.

Most studies have examined the rates of nickel sensitivity as determined by patch testing to nickel in patients who have previously received nickel-containing stents. However, false positives are possible with patch testing since some patients with a positive patch test to nickel do not have clinical ACD. Likewise, many patients with a clinical history suggestive of metal-associated dermatitis do not have positive patch tests to metals [6]. The sensitivity and specificity of patch testing in patients with ACD is approximately 70 percent [22].

Initial restenosis of bare-metal stents — Concern of an increased rate of stent restenosis in nickel-allergic patients with bare-metal stainless-steel stents first arose from retrospective studies [6,23-25]. As an example, one study described 131 consecutive patients who underwent repeat coronary angiography because of clinical concern about stent restenosis [6]. Patch testing to metals (including nickel, molybdenum, and chromate) identified 10 patients (8 percent) with sensitivity to nickel or molybdenum, a prevalence not different from that expected in the general population. However, all 10 of these patients had restenosis, whereas only 79 of the 121 patients (65 percent) with negative patch testing had restenosis, a statistically significant difference. Additionally, a subsequent report described 61 consecutively recruited patients who underwent coronary angiography, followed by patch testing. Of the 31 subjects with stent restenosis (>50 percent occlusion) on angiography, 7 had positive metal patch testing compared with 0 from the 30 without stent restenosis [26].

Prospective studies, however, have not confirmed an association between stent restenosis and nickel sensitivity [27,28]:

●A prospective study described 109 consecutive patients who underwent both coronary angiography and patch testing to nickel six months after bare-metal stent placement [27]. Stenosis was identified in 20 patients (18 percent) but was not associated with a higher incidence of positive patch tests to nickel.

●A prospective study of 43 patients with bare-metal stents also did not find an increased risk of restenosis in patients with positive patch testing to nickel [28]. Coronary angiography six months after stent placement found that 37 percent of patients had >50 percent restenosis. All patients underwent patch testing to nickel. Three patients were sensitive to nickel, of whom one (33 percent) had stent restenosis. Thus, the rate of restenosis in nickel-allergic patients was similar to the rate in the group as a whole.

Moreover, a retrospective study of 29 patients with reported metal allergy (11 of whom had positive patch testing to metals) who underwent coronary stent placement noted no increased incidence of target lesion revascularization in comparison with matched control patients [29].

Drug-eluting stents — There are few studies comparing bare-metal stents and drug-eluting stents with respect to nickel sensitivity and rates of restenosis. It is theoretically possible that the immunosuppressive drugs eluted by these stents suppress local inflammatory responses, including hypersensitivity responses.

One study examined the relationship between nickel sensitivity and restenosis after placement of a sirolimus-eluting stent [30]. In this study, 88 patients underwent metal patch testing and repeat coronary angiography at eight months after placement of the stent. Fourteen patients (16 percent) were patch test positive to metals, including nickel, chromate, and manganese. The rate of restenosis in patch test-positive patients did not significantly differ from restenosis in patch test-negative patients (6.3 percent versus 6.5 percent). In addition, there was also no difference in the degree of luminal loss due to stenosis in patch test-positive or patch test-negative patients.

Recurrent stent restenosis — A small number of studies have noted a possible association between nickel sensitivity and recurrent stent restenosis, suggesting there may be a subset of patients who experience recurrent restenosis in whom the pathogenesis of the restenosis is related to nickel hypersensitivity. However, the data are not conclusive.

●In the prospective study of 109 patients described previously, a group of 65 patients who had undergone angioplasty in response to a first episode of stent restenosis were evaluated six months later with repeat angiography [27]. In this subgroup, 21 percent of patients were sensitive to nickel. Those subjects with a second in-stent restenosis were found to have a significantly higher rate of nickel sensitivity compared with those who did not (39 percent and 12 percent, respectively). Thus, this study did not find an association between nickel sensitivity and initial stent restenosis, as discussed previously, although it did suggest a relationship between nickel hypersensitivity and recurrent restenosis.

●A subsequent study described 128 patients who underwent evaluation for possible second-stent restenosis after having had angioplasty for prior stent restenosis [31]. Nineteen percent of the group was sensitized to nickel. Of the 60 patients with confirmed second in-stent restenosis, 18 (30 percent) were sensitized to nickel compared with 6 of the 68 (9 percent) of the group without further in-stent stenosis, a statistically significant difference.

●Since then, another study has suggested that this association is not relevant to the population of patients with metal-induced ACD. In a retrospective study of 149 dermatitis patients with patch test-positive metal sensitivity who underwent stent placement, 14 percent had initial stent stenosis, which was not different from the 10 to 15 percent stent stenosis rates reported in the general population [32]. Only two of the metal-sensitive patients went on to develop restenosis, suggesting that there was no increased risk of cardiac stent restenosis or recurrent restenosis in patients with dermatitis and metal hypersensitivity.

Thus, two studies have suggested an association, while one did not.

In-stent thrombosis — In-stent thrombosis and systemic hypersensitivity reactions have been reported in patients with drug-eluting coronary stents. The reported symptoms included rash, dyspnea, itching, hives, and fevers. The Research on Adverse Drug Events and Reports (RADAR) project was a large study of hypersensitivity reactions associated with drug-eluting stents collected from the US Food and Drug Administration (FDA) database [12]. It sought to determine whether the likely cause of these reactions was a component of the drug-eluting stents or a concomitantly prescribed medication. Of the 5783 reports of hypersensitivity associated with drug-eluting stents, 17 cases (0.3 percent) were attributed to the stents rather than to medications. Of those 17 cases, there were four autopsy reports of in-stent eosinophilic inflammation, thrombosis, and lack of intimal healing. The conclusion was that hypersensitivity to some component of drug-eluting stents could be a rare cause of systemic hypersensitivity reactions, possibly associated with in-stent thrombosis and death. Information about nickel hypersensitivity was not collected in this study.

Other symptoms — There have been case reports of associated pericarditis, palpitations, chest pain, migraine headaches, and "device hypersensitivity syndrome" after implantation of Amplatzer devices [33-36]. One study drew a link between such symptoms and nickel patch-test positivity [37].

SUMMARY AND RECOMMENDATIONS

●Nickel is a common contact allergen – Intracoronary stents are usually made of stainless steel, which contains nickel, chromium, and molybdenum. Nickel is one of the most common causes of allergic contact dermatitis (ACD). There are also low-nickel versions of both bare-metal and drug-eluting stents. (See 'Background' above.)

●Evidence for nickel allergy as a cause of initial stent restenosis is lacking – Based upon early case reports and retrospective studies, nickel sensitivity was implicated in initial restenosis of bare-metal stents. However, prospective studies have not confirmed an association. There are no data to suggest that nickel sensitivity increases the risk of restenosis of drug-eluting stents either. (See 'Stent restenosis' above.)

●Clinical implications:

•We suggest that possible hypersensitivity to nickel should not be a factor in deciding which coronary stent to choose for a patient (Grade 2C).

•We suggest that possible hypersensitivity to nickel should not be a factor in managing most patients with stent restenosis (Grade 2C).

●Possible role in recurrent stent restenosis – The situation in patients with recurrent restenosis is less clear since two studies found higher rates of repeated restenosis in nickel-sensitive patients whose stents had been previously instrumented, while another did not. Thus, the possibility that nickel sensitivity may contribute to repeat episodes of stent restenosis has not been excluded. (See 'Recurrent stent restenosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Aidan Long, MD, who contributed to earlier versions of this topic review.