Introduction
The patent foramen ovale (PFO) is considered as the frequent potential source of cardioembolism in younger patients presenting with ischemic stroke of undetermined source [1, 2] and the guidelines established the transcatheter closure of PFO as the procedure of choice for secondary prevention [3]. The indication for atrial septal defect (ASD) closure is its hemodynamic significance, expressed mainly as right ventricular volume overload [4]. Despite good safety profiles of occluders, the procedures could be rarely complicated by severe device-related adverse effects including in some cases nickel allergy to the nitinol [5, 6].
The Cocoon PFO Occluder (Vascular Innovations Co., Nonthaburi, Thailand) is a device containing a nitinol double disc enhanced by a nanoplatinum coating minimizing the issue of nickel hypersensitivity. However, there is shortage of data regarding the safety outcomes of various PFO and ASD occluding devices, including the Cocoon Occluder, in patients with a confirmed diagnosis of nickel-related allergy. Thus, the following retrospective study aimed to address that knowledge gap.
Methods
The study included 21 consecutive patients (2015–2025) aged ≥ 18 years with clinical indications for percutaneous PFO/ASD closure and confirmed nickel hypersensitivity. In cases of suspected allergy, skin patch testing was performed. Transesophageal echocardiography (TEE) was the diagnostic method used to confirm presence and significance of PFO (bubble test) and feasibility to percutaneous closure of ASD. Indications for closure included a history of cryptogenic stroke, multiple TIAs, or a hemodynamically significant left-right shunt. Each patient with PFO underwent comprehensive evaluation for thrombophilia and autoimmune disorders, and the final decision regarding the qualification for the procedure was made collaboratively by a multidisciplinary cardio-neurology team. In patients with ASD, the technical feasibility of percutaneous defect closure was assessed and contraindications were excluded.
All patients underwent closure with the Cocoon Occluder using a femoral access under both TEE and fluoroscopic guidance. The occluder size was selected based on the anatomy assessed by TEE, and in the case of ASD, additionally using the stop flow method. The follow-up visits were held up to 6 weeks after procedures with follow-up transthoracic echocardiography assessment, and after up to 1 year, with TEE examination. The safety outcomes were defined as any major adverse events (MAEs) detected during the follow-up including arrhythmias, neurological disorders, endocarditis and device-related adverse events such as malposition, embolization, thrombosis, and in particular, the incidence of any nickel-related allergic events.
Statistical analysis
Categorical variables were expressed as numbers and percentages while continuous variables were expressed as mean with standard deviation or median with interquartile range according to their distribution, assessed by the Shapiro-Wilk test. Statistical analysis was performed using Statistica, version 13 TIBCO Software Inc.
Results and discussion
The final analysis included 21 patients aged 42.6 ±15.6 years. The characteristics of the study group are presented in Table I. Two patients were diagnosed with coagulation disorders – one with a protein S deficiency and a heterozygous A1298C mutation, and the other with heterozygosity for the Leiden mutation.
Table I
Baseline characteristics of patients included in the study (n = 21)
| Clinical characteristics | Value |
|---|---|
| Age [years] mean (SD) | 42.6 (15.6) |
| Men, % | 3 (14.3%) |
| BMI [kg/m2] mean (SD) | 26.0 (5.1) |
| Arterial hypertension, % | 6 (28.6%) |
| Atrial fibrillation*, % | 2 (9.5%) |
| Diabetes mellitus, % | 0 (0%) |
| Dyslipidemia, % | 6 (28.6%) |
| Coronary artery disease, % | 1 (4.8%) |
| Coagulation disorders, % | 2 (9.5%) |
| Autoimmune disorders, % | 1 (4.8%) |
| Deep vein thrombosis, % | 3 (14.3%) |
| Pulmonary embolism, % | 1 (4.8%) |
| Intractable migraines, % | 8 (38.1%) |
| Indication for the procedure | |
| Stroke, % | 16 (76.2%) |
| Multiple TIAs, % | 1 (4.8%) |
| Hemodynamically significant ASD, % | 4 (19%) |
| Nickel allergy | |
| Previously known nickel allergy, % | 21 (100%) |
| Positive patch test results, % | 20 (95.2%) |
| Positive blood test, % | 1 (4.8%) |
| Skin symptoms, % | 13 (62%) |
| Allergy to other metals, % | 8 (38.1%) |
| Echocardiographic data | |
| EF, %, median (Q1–Q3) | 60.0 (60.0–65.0) |
| ASD diameter [mm] median (Q1–Q3) | 14.0 (11.5–17) |
| PFO, % | 17 (81%) |
| PFO length [mm] median (Q1–Q3) | 8.5 (7.5–10.5) |
| PFO diameter [mm] mean (SD) | 3.5 (0.93) |
| Shunt at Valsalva maneuver (0/1/2/3), % | 0 (0%)/3 (14.3%)/0 (0%)/13 (62%) |
| Atrial septal aneurysm, % | 1 (4.8%) |
| Left atrial appendage velocity [m/s] mean (SD) | 0.75 (0.19) |
| Periprocedural data | |
| PFO occluder size 18 mm, % | 9 (42.9%) |
| PFO occluder size 25 mm, % | 8 (38.1%) |
| ASD occluder size 12 mm, % | 1 (4.8%) |
| ASD occluder size 14 mm, % | 1 (4.8%) |
| ASD occluder size 16 mm, % | 1 (4.8%) |
| ASD occluder size 20 mm, % | 1 (4.8%) |
| Radiation dose, Gy, median (Q1–Q3) | 0.006 (0.002–0.012) |
| Intraprocedural MAE, % | 0 (0.0%) |
| Length of hospital stay [days] median (Q1–Q3) | 2.0 (2.0–3.0) |
The most common indication for the procedure was stroke (n = 16), transient ischemic attacks (n = 1) (both with PFO) and hemodynamically significant ASD (n = 4).
All patients had a diagnosis of nickel hypersensitivity, and they typically showed contact dermatitis after direct nickel exposure with no known systemic reactions. Around half of all patients were diagnosed with the allergy to other metals like palladium (n = 4), cobalt (n = 2), gold (n = 2), or chromium (n = 1).
After the procedure, all patients were treated with dual antiplatelet therapy consisting of acetylsalicylic acid and clopidogrel, except for patients with atrial fibrillation who were treated with aspirin and vitamin K antagonist. Median hospitalization stay lasted 2.0 (2.0–3.0) days.
The median follow-up time was 27.0 (20.0–42.0) months. None of the patients developed serious postprocedural events. One patient developed mild skin dermatitis of unknown etiology 2 weeks after the procedure, which resolved with local corticosteroid treatment. Although a potential link to nickel exposure cannot be excluded, the lack of systemic manifestations suggests a limited clinical impact of nickel hypersensitivity in patients receiving the Cocoon Occluder.
The second patient experienced transient heart palpitations; however, the 24-hour Holter monitoring did not reveal any significant abnormalities. It is worth noting that various forms of transient supraventricular arrhythmia are diagnosed in around 21% of patients in the first month after the procedure [7]. However, this symptom cannot be ruled out as a reaction to nickel, particularly given that one theory of arrhythmia’s mechanism is precisely a hypersensitivity reaction to nickel.
We presented the typical reactions after occluder implantation and the symptoms presented by our patients in Table II.
Table II
Occurrence of typical reactions to occluder devices
As none of our patients exhibited clinically significant symptoms, it appears that transcatheter closure of PFO/ASD using the Cocoon Occluder device may be a safe therapeutic method, even in individuals with a previously diagnosed nickel hypersensitivity. These findings align with the results of Testa et al. who also reported a favorable safety profile for the Cocoon device in their nationwide collaborative project [8].
Current guidelines recommend device closure for patients with a PFO and cryptogenic stroke. However, there is a reported 0.28% risk of severe long-term complications requiring surgical device removal, with chest pain being the most common symptom and in the half of the cases related to nickel hypersensitivity [6].
The first Food and Drug Administration-approved occluder was the Amplatzer (Abbott Laboratories, Chicago, IL, USA), which consequently has been extensively evaluated in large trials, and currently serves as the gold-standard device for PFO closure. Technically, the discs of the device are made from nitinol, composed of nickel and titanium. However, the Amplatzer occluder has been shown to release nickel during the first few months following implantation, leading to a transient systemic increase in serum nickel levels [9]. This has raised concerns regarding its use in patients with nickel hypersensitivity, a condition affecting approximately 10–20% of the general population, with a prevalence that has been increasing over time [10]. Typically manifested as a cutaneous contact dermatitis following the direct exposure to nickel-containing items, the systemic nickel exposure via intracardiac devices can result in potential serious systemic inflammatory reactions resulting in the need for surgical explanation of the device [11, 12]. As reported, mean serum nickel levels before and after Amplatzer occluder implantation at baseline, 24 h, 1 month, 3 months, and 6 months post procedure were 1.05, 1.39, 0.98, 0.79, and 0.74 µg/dl, respectively, meaning that normalization occurred within 3 months [13].
In this context, several alternative strategies and devices have been developed to reduce nickel exposure. The Cocoon Occluder may be considered safer, as its nitinol frame is fully coated with nanoplatinum, which enhances biocompatibility and may reduce the risk of device-related thrombus formation. The nanoplatinum coating acts as an inert barrier that limits direct tissue contact with nickel ions, potentially decreasing the risk of systemic hypersensitivity reactions. Other devices implementing the same strategy for reducing nickel exposure employ titanium-based coatings, such as the CERA® ASD Occluder. Titanium coatings are highly resistant to corrosion and form a stable oxide layer that effectively prevents nickel from leaching and releasing ions into the surrounding tissues. In addition, titanium’s biocompatibility reduces local inflammatory responses and facilitates endothelialization, further improving device safety. Nevertheless, both parylene- and titanium-coated occluders significantly reduced nickel release, with endocardial nickel levels of 17.0 ±8.05 µg/kg at 2 months versus 31.0 ±5.72 µg/kg in uncoated devices [14].
Recently published Inspire trial results showed that patients with nickel hypersensitivity are at a higher risk of developing device syndrome following PFO closure [15]. The study also found that Amplatzer and Gore Cardioform Septal Occluder devices are equally effective and safe [15].
Beyond surface coatings, bioresorbable occluders like the Carag Bioresorbable Septal Occluder are a promising future. These occluders gradually replace metal with native tissue, eliminating long-term risks from nitinol implants. While bioresorbable devices still require a nitinol alloy for initial support, their design reduces exposure to nickel over time, which may be advantageous for individuals with metal hypersensitivity.
Our study aimed to provide new data regarding safety outcomes of PFO/ASD closure in patients with nickel hypersensitivity, however it is clearly limited by its non-randomized and retrospective nature. Another limitation is the fact that we did not measure serum nickel levels. Furthermore, the sample size is relatively small, but, to the best of our knowledge, this is the largest experience so far concerning the real-world safety profile of the Cocoon device in this specific group of patients leading to conclusions that the Cocoon occluder appeared as a safe device alternative with satisfactory procedural and clinical follow-up results in patients with nickel hypersensitivity. Nevertheless, these are preliminary findings requiring larger, comparative studies.
