Risk of device syndrome post-PFO closure higher in nickel-hypersensitive patients

Findings from the INSPIRE* study demonstrate a higher risk of developing device syndrome following patent foramen ovale (PFO) closure in individuals with nickel (Ni) hypersensitivity.

In this prospective, double-blind, randomized trial with blinded endpoint assessment, the risk of developing device syndrome within the first 90 days post-procedure is significantly higher in patients with vs without Ni hypersensitivity (71.4 percent vs 20.6 percent; p<0.001).

Device syndrome was defined as a composite endpoint comprising >1 of the following: patient-reported new-onset chest pain, new-onset or worsening palpitations, new-onset or worsening migraines, dyspnoea, or rash. [Congenit Heart Dis 2007;2:416-420]

The group of patients with Ni hypersensitivity also had higher rates of new-onset or worsening migraines (21.4 percent vs 1.5 percent; p=0.002) and palpitations (50 percent vs 14.7 percent; p<0.001) as opposed to the group who were not Ni-hypersensitive. [Circ Cardiovasc Interv 2025;doi:10.1161/CIRCINTERVENTIONS.125.015228]

There were no significant differences in patient-reported chest pain (7.1 percent vs 1.5 percent; p=0.203), dyspnoea (3.6 percent vs 2.9 percent; p=1.000), fever (3.6 percent vs 1.5 percent; p=0.500), rash (7.1 percent vs 0 percent; p=0.083), or arrhythmias (10.7 percent vs 7.4 percent; p=0.688) between the Ni-hypersensitive and non-Ni-hypersensitive arms.

Save for one non-Ni-hypersensitive patient who experienced minor bleeding, there were no reports of major bleeding, ischaemic stroke, transient ischaemic attack, device migration/dislocation/embolization, or death during the 90-day follow-up.

After adjusting for age, sex, device type, and RoPE** score, Ni allergy was associated with a tenfold increase in the odds of device syndrome (adjusted odds ratio, 10.53; p<0.001), but device type did not significantly alter this association (p=0.207).

Nickel: A potent allergen in certain patients

Transcatheter PFO closure has demonstrated efficacy in secondary stroke prevention despite the low lifetime stroke risk attributable to PFO. [J Stroke 2015;17:229-237] “Ni-containing devices are widely used for transcatheter PFO closure … However, the clinical significance of Ni hypersensitivity in PFO closure remains debated,” the investigators said.

There are only two FDA- and CE-approved devices for PFO closure: the Amplatzer PFO Occluder (APO) and Gore Cardioform Septal Occluder (GCSO). Both PFO closure devices are constructed from nitinol, which is an alloy of Ni and titanium. “Ni is a potent allergen responsible for type IV hypersensitivity in >20 percent of the population,” they noted.

The study included 96 patients with cryptogenic stroke and PFO-related ischaemic stroke. After securing approval for PFO closure and providing written informed consent, participants underwent patch testing with the European baseline series 3–21 days prior to PFO closure. Twenty-eight patients were diagnosed with Ni hypersensitivity (median age 44 years).

Of note, the Ni-hypersensitive group had a significantly higher fraction of women (82.1 percent vs 32.4 percent; p<0.001) and a higher rate of autoimmune disorders (14.3 percent vs 1.5 percent; p=0.024) than the non-Ni-hypersensitive group.

After completing their skin patch test, participants were randomized 1:1 to receive the APO or GCSO. After successful PFO closure, patients received dual antiplatelet therapy (acetylsalicylic acid 100 mg and clopidogrel 75 mg) for at least 3 months. Participants with documented acetylsalicylic acid allergy or G6PD deficiency received clopidogrel alone for the same duration.

Takeaways

“Patients with documented Ni hypersensitivity are more likely to develop device syndrome after PFO closure. Both the APO and GCSO can be implanted with comparable outcomes in these patients,” the researchers said.

However, as the trial was designed to detect differences between participants with and without Ni hypersensitivity, the sample may have been insufficiently powered to identify differences between devices, they noted. “Therefore, the comparable results should be interpreted with caution and serve as a foundation for future, larger, and properly designed studies focusing on device comparisons.”