Patent foramen ovale closure in women with and without nickel hypersensitivity; a subgroup analysis of a randomized trial

Abstract Background Although the lifetime stroke risk associated with PFO is low, transcatheter PFO closure has demonstrated efficacy in secondary stroke prevention. Randomized trials have shown significant reductions in recurrent stroke risk compared to antithrombotic treatment alone. There are only two Food and Drug Administration (FDA) and CE-approved devices for PFO closure: the Amplatzer PFO Occluder and the Gore Cardioform Septal Occluder (GSO). Both devices are constructed from nitinol, an alloy of nickel and titanium. Nickel is a potent allergen responsible for type IV hypersensitivity in 20% of the population. While skin hypersensitivity, primarily expressed as contact dermatitis, is well-characterized, the impact of systemic exposure to nickel from implanted nitinol devices remains poorly understood. Purpose Considering that women are more susceptible to develop allergies, aim of our gender-based analysis is to evaluate whether women with nickel hypersensitivity have an increased risk of adverse events following PFO closure. Methods This is a subgroup analysis of INSPIRE trial. Briefly, the INSPIRE (Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder) trial was an investigator-initiated, multicenter, prospective, double-blinded, randomized trial with blinded endpoint assessment, exploring whether patients with nickel hypersensitivity have an increased risk of adverse events following PFO closure. Nickel hypersensitivity was assessed using skin patch testing. The primary endpoint was device syndrome, a composite of patient-reported symptoms (chest pain, palpitations, migraines, dyspnea, and rash). In addition to the composite outcomes listed as the primary endpoint, the secondary endpoints included documented atrial arrhythmias atrial fibrillation (AF), atrial flutter, or supraventricular tachycardia, major or minor bleeding, ischemic or hemorrhagic stroke, and all-cause mortality. Results A total of 96 patients were included in the analysis. Forty-five of the included patients (46.9) were women. The majority of them (N=25, 55.6%) were treated with the Amplatzer PFO Occluder and the rest with GSO. Of these, 23 (51.1%) were diagnosed with nickel hypersensitivity. No significant difference was observed in baseline characteristics. The incidence of the device syndrome was significantly higher in women with nickel hypersensitivity compared to those without 18 (78.3%) vs. 4 (18.2%), p 0.001. More specifically, palpitations 12 (52.2%) vs. 3 (13.6%), p=0.011 were significantly more frequent in women with nickel hypersensitivity. No significant differences were observed in the rest analyses. Conclusions Our subgroup analysis of INSPIRE trial showed that the risk of developing device syndrome within the first 90 days post-procedure is significantly higher in women with nickel hypersensitivity compared to those without, in line with our main analysis.