Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder (INSPIRE)

Investigation of Nickel Sensitization After Percutaneous Implantation of Patent Foramen Ovale Occluder; a RandomizEd Trial.

Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes in selected patients. The devices used for the specific purpose contain and release nickel, which is considered as the most allergen metal in nature. Skin patch tests are considered as gold-standard for documenting nickel allergy. While the allergic contact dermatitis induced by nickel is well described, literature is inadequate on explaining the effect of nickel release on the clinical manifestations of patients implanted with such devices.

Our prospective, randomized, blinded trial will try to investigate the above by performing nickel skin patch tests to all patients, 14 days before and 90 days after the implantation. During follow-up, clinical manifestations and transthoracic echocardiographic findings will be evaluated and associated with patch skin tests.

Study Overview

• Status: Completed
• Conditions: Foramen Ovale, Patent; Metal Allergy; Nickel Sensitivity; Dermatitis Contact Irritant
• Intervention / Treatment: Device: Percutaneous Patent Foramen Ovale Closure

Detailed Description

Percutaneous PFO closure has been established as a first-line therapy for preventing recurrent strokes, after embolic stroke of unknown source (ESUS) and a patent foramen ovale. The PFO closure is achieved by the implantation of suitable devices, which occlude the shunt between the two atria and prevent the creation and detachment of thrombi. Until today, there are two devices approved by FDA for the specific purpose; Amplatzer PFO Occluder and Gore Cardioform Septal Occluder. Despite the architectonic differences between these devices, the main material of both is nitinol, an alloy of nickel and titanium. While titanium is an extremely rare allergen, nickel is considered as one of the most common allergens and the most frequent metal allergen in nature, with a prevalence about 20%. The main clinical expression of nickel hypersensitivity is allergic contact dermatitis, but cases with systemic allergic reaction have been described as well. It has been observed that nickel is released by the implanted devices and circulates through bloodstream, having the potential to cause systemic clinical picture. Device syndrome includes signs and symptoms (i.e. palpitations, dyspnea, chest pain, rash, etc.), which are appeared after the device placement and are associated with hypersensitivity reaction. The existing literature is considered as inadequate for explaining the effect of nickel release in the patients implanted with an occluder.

The aim of our study is to evaluate whether patients with nickel hypersensitivity have an increased risk of adverse events following PFO closure, to assess the potential influence of device selection, and to evaluate potential sensitization or desensitization in patients without or with pre-existing nickel allergy, respectively.

Nickel hypersensitivity was assessed using skin patch testing prior to the procedure. The primary endpoint was device syndrome, a composite of patient-reported symptoms (chest pain, palpitations, migraines, dyspnea, and rash). Secondary endpoints included arrhythmias, bleeding, stroke, and all-cause mortality.

• Study Type: Interventional
• Enrollment (Actual): 96
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Greece
  • Attica
    • Athens, Attica, Greece, 115 28
      • First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age: at least 14 years old
• Well-documented indication for percutaneous PFO closure

Exclusion Criteria:

• Corticosteroid treatment
• Patient's refusal to participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Amplatzer PFO Occluder; Patients randomized in this arm will be implanted with Amplatzer PFO Occluder.	Device: Percutaneous Patent Foramen Ovale Closure; Patients with well-documented embolic stroke of unknown source (ESUS) and a patent foramen ovale (PFO) are indicated for percutaneous closure of PFO. The intervention is performed through the right femoral vein. The interventional cardiologist introduces the sheath and advances the device via inferior vena cava to right atrium. Then, the catheter is passed through the PFO, the device is deployed and the occlusion is achieved. The procedure is performed under fluoroscopy guidance with or without transesophageal echocardiography guidance.; Other Names: Transcatheter PFO occlusion
Active Comparator: Gore Cardioform Septal; Patients randomized in this arm will be implanted with Gore Cardioform Septal Occluder.	Device: Percutaneous Patent Foramen Ovale Closure; Patients with well-documented embolic stroke of unknown source (ESUS) and a patent foramen ovale (PFO) are indicated for percutaneous closure of PFO. The intervention is performed through the right femoral vein. The interventional cardiologist introduces the sheath and advances the device via inferior vena cava to right atrium. Then, the catheter is passed through the PFO, the device is deployed and the occlusion is achieved. The procedure is performed under fluoroscopy guidance with or without transesophageal echocardiography guidance.; Other Names: Transcatheter PFO occlusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Device syndrome, a composite endpoint consisting of patient-reported new-onset chest pain, palpitations, new-onset or worsening migraines, dyspnea, and rash	Clinical signs and symptoms during the first 90 days after the procedure will be evaluated through a questionnaire.	The first 90 days after the procedure

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Nickel patch test results' change	The possible change (either as continuous or dichotomous outcome) of nickel skin patch test, after the device implantation	90 days after the procedure
The nickel patch tests' results change after Amplatzer Device implantation	Investigating the number of patients received Amplatzer device, who developed nickel sensitization.	The first 90 days after the procedure
The nickel patch tests' results change after Gore Device implantation	Investigating the number of patients received Gore device, who developed nickel sensitization.	The first 90 days after the procedure
Residual interatrial leakage	Evaluation of residual interatrial leakage, by performing transthoracic echocardiography	90 days after the procedure
Rest allergens skin patch test results' change	The possible change (either as continuous or dichotomous outcome) of rest allergen skin patch test, after the device implantation	90 days after the procedure
patient-reported new-onset chest pain	patient-reported new-onset chest pain	90 days after the procedure
palpitations	as described by the patients	90 days after the procedure
new-onset or worsening migraines	as described by the patients	90 days after the procedure
dyspnea	as described by the patients	90 days after the procedure
Atrial arrhythmias	as described by the patients	90 days after the procedure

Collaborators and Investigators

• Sponsor: National and Kapodistrian University of Athens
• Investigators: Study Chair: Konstantinos Toutouzas, MD,PhD, First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens; Principal Investigator: Anastasios Apostolos, MD, First Department of Cardiology, National and Kapodistrian University of Athens, Hippokration General Hospital of Athens; Study Director: Stamatios Gregoriou, MD, PhD, First Department of Dermatology-Venereolgy, National and Kapodistrian University of Athens, Andreas Syggros Hospital

Publications and helpful links

General Publications

• Ahlstrom MG, Thyssen JP, Wennervaldt M, Menne T, Johansen JD. Nickel allergy and allergic contact dermatitis: A clinical review of immunology, epidemiology, exposure, and treatment. Contact Dermatitis. 2019 Oct;81(4):227-241. doi: 10.1111/cod.13327. Epub 2019 Jul 9.
• Prestipino F, Pragliola C, Lusini M, Chello M. Nickel allergy induced systemic reaction to an intracardiac amplatzer device. J Card Surg. 2014 May;29(3):349-50. doi: 10.1111/jocs.12331.
• Apostolos A, Drakopoulou M, Toutouzas K. New migraines after atrial septal defect occlusion. Is the nickel hypersensitivity the start of everything? Med Hypotheses. 2021 Jan;146:110442. doi: 10.1016/j.mehy.2020.110442. Epub 2020 Nov 30. No abstract available.
• Schalock PC, Crawford G, Nedorost S, Scheinman PL, Atwater AR, Mowad C, Brod B, Ehrlich A, Watsky KL, Sasseville D, Silvestri D, Worobec SM, Elliott JF, Honari G, Powell DL, Taylor J, DeKoven J. Patch Testing for Evaluation of Hypersensitivity to Implanted Metal Devices: A Perspective From the American Contact Dermatitis Society. Dermatitis. 2016 Sep-Oct;27(5):241-7. doi: 10.1097/DER.0000000000000210.

Study record dates

Study Major Dates

• Study Start (Actual): December 10, 2020
• Primary Completion (Actual): December 1, 2024
• Study Completion (Actual): December 1, 2024

Study Registration Dates

• First Submitted: January 11, 2021
• First Submitted That Met QC Criteria: January 14, 2021
• First Posted (Actual): January 19, 2021

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 4, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: patent foramen ovale; percutaneous pfo closure; Nickel Hypersensitivity; Nickel Sensitisation; device syndrome; skin patch tests
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Heart Diseases; Skin Diseases; Congenital Abnormalities; Cardiovascular Abnormalities; Heart Defects, Congenital; Skin Diseases, Eczematous; Heart Septal Defects, Atrial; Heart Septal Defects; Dermatitis, Contact; Dermatitis; Foramen Ovale, Patent; Dermatitis, Irritant
• Other Study ID Numbers: NICKEL-PFO TRIAL

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes