Nickel Elution Properties of Contemporary Interatrial Shunt Closure Devices

Abstract: Objectives. We sought to compare nickel elution properties of contemporary interatrial shunt closure devices in vitro. Introduction. There are two United States Food and Drug Administration (FDA)-approved devices for percutaneous closure of secundum atrial septal defect: the Amplatzer septal occluder (ASO; St Jude Medical Corporation) and Gore Helex septal occluder (HSO; W.L. Gore & Associates). The new Gore septal occluder (GSO) device is in clinical trials. These are also used off-label for patent foramen ovale closure in highly selected patients. These devices have high nickel content. Nickel allergy is the most common reason for surgical device explantation. Nickel elution properties of contemporary devices remain unknown. Methods. We compared nickel elution properties of 4 devices – ASO, GSO, HSO, and sternal wire (SW) — while Dulbecco’s phosphate-buffered saline (DPBS) served as control. Three samples of each device were submerged in DPBS. Nickel content was measured at 14 intervals over 90 days. Results. Nickel elution at 24 hours, compared to control (0.005 ± 0.0 mg/L), was significantly higher for ASO (2.98 ± 1.65 mg/L; P=.04) and SW (0.03 ± 0.014 mg/L; P=.03). Nickel levels at 90 days, compared to control (0.005 ± 0.0 mg/L) and adjusting for multiple comparisons, were significantly higher for ASO (19.80 ± 2.30 mg/L; P=.01) and similar for HSO (P=.34), GSO (P=.34), and SW (P=.34). ASO had significantly higher nickel elution compared to HSO, GSO, and SW (P=.01). Conclusion. There is substantial variability in nickel elution; devices with less exposed nickel (HSO and GSO) have minimal elution. The safety of low nickel elution devices in patients with nickel allergy needs to be evaluated in prospective trials. 

J INVASIVE CARDIOL 2015;27(1):99-104

Key words: atrial septal defect, nickel allergy, shunt closure devices

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Percutaneous closure of atrial septal defect (ASD) is shown to be an effective, minimally invasive alternative to surgical closure.^1-3 Currently, for closure of ostium secundum ASD, only two devices are approved by the United States (US) Food and Drug Administration (FDA): the Amplatzer septal occluder (ASO; St. Jude Medical Corporation);¹ and the Gore Helex septal occluder (HSO; W.L. Gore & Associates).³ Additionally, a new device, the Gore septal occluder (GSO) is currently in clinical trials within the US in pursuit of ASD and PFO indications⁴ (NCT01711983, REDUCE trial NCT00738894). These devices are known to also be used off-label to close patent foramen ovale (PFO) in selected patients with recurrent stroke and failed medical therapy.⁵

Interatrial shunt closure devices are composed partially of nitinol (Nickel-Titanium/Naval Ordinance Laboratory), which is an alloy with high nickel content (nickel 55% and titanium 45%). Nitinol’s unique properties, such as superelasticity, shape memory, radioopacity, magnetic resonance imaging compatibility, and resistance to fatigue and corrosion, allow the construction of large devices, like ASD occluders, that can be deployed percutaneously using small catheters. The thermal shape memory property provides reconfiguration of the original shape, without deformation, at body temperatures. After implantation of interatrial shunt closure devices, significant nickel elution from the device to the blood stream has been observed, exposing these patients to high systemic nickel levels^6,7 and severe nickel hypersensitivity reactions have been reported.^8-10 Nickel hypersensitivity is common and occurs in up to 20% of the general population,¹¹ and is more prevalent in females.^12,13 However, nickel metabolism is similar between nickel sensitive and normal controls.¹⁴ Nickel allergy can be both topical and systemic¹⁵ with a dose-response relationship.¹⁴

After interatrial shunt closure device implantation, systemic nickel allergy can be severe and is noted to be the most common reason for surgical device explantation.⁵ This has raised concerns regarding high nickel elution, nickel hypersensitivity, and nickel toxicity after percutaneous interatrial shunt closure.^7,16 FDA labeling for both ASO and GSO devices includes warning for potential allergic reaction to nickel in patients with known nickel hypersensitivity.^17,18 However, the FDA does not require or recommend testing for nickel allergy before device implantation.

Quantifying nickel elution by various devices is important. Nickel elution properties of various contemporary inter-atrial shunt closure devices have not been studied. We designed this in-vitro study to compare nickel elution properties of contemporary ASD devices.

Methods

In this in vitro study, we compared the nickel elution behavior of 4 devices, ie, the ASO, GSO, HSO, and sternal wire (SW). Additionally, Dulbecco’s Phosphate-Buffered Saline (DPBS) 1X was utilized as a control. DPBS solution was chosen as control and as extraction solution because it has physiological pH and is the recommended solution for simulation of the physiological environment like circulating blood.¹⁹ SWs, used in cardiac surgery cases to close sternotomy, were chosen as one of comparison groups as they are made of stainless-steel, which has less nickel content (13%-15% nickel) compared to nitinol (55% nickel) used in interatrial shunt closure devices. Three device samples (finished, implantable device specimen) from each group were submerged in DPBS. Solution was maintained continuously for 90 days at 37 ± 1°C using a heated water bath. Samples were extracted in clean, chemically inert, closed containers with minimal dead space. Nickel elution was measured by blinded personal using inductively coupled plasma mass spectrometry (ICP-MS) to perform nickel analysis at 24 hours, 48 hours, 72 hours, then weekly to 60 days, and thereafter every 10 days to 90 days.

Statistical analysis. Nickel elution by each device type at various time points is reported as mean ± standard deviation. When nickel levels were measured to be below the detection threshold of plasma mass spectroscopy, the levels were set at half value of detection limit to allow computing means, standard deviations, statistical comparisons, and tests for significance. Mean nickel elution at various time points was compared using analysis of variance (ANOVA) method; pairwise analysis was undertaken if a significant P-value was noted. The P-values for pairwise group comparisons were adjusted for multiplicity using Holm’s multiple comparison procedure. Like the Bonferroni procedure, the Holm procedure maintains the desired alpha (0.05) regardless of the correlation structure of the outcome variable among the groups, while being more powerful than the Bonferroni procedure.^20,21 Paired t-test was used for within-group comparisons for nickel elution over time. The cumulative nickel elution over time by device type was displayed graphically using scatter and line plot. P-value ≤.05 was considered to be significant.

Results

Nickel elution at 24 hours, compared to the control group, was significantly higher for Amplatzer ASO and SW group (2.98 vs 0.005 mg/L, P=.04; and .03 vs 0.005 mg/L, P=.03 respectively). However, nickel elution for HSO and GSO devices at 24 hours was insignificant (0.009 mg/L and 0.005 mg/L respectively, P=.10). Nickel elution for ASO device, compared to all other devices and control group, was significantly higher at the first measured time point of 24 hours (P=.01) and the difference increased throughout the study (Table 1). 

At 90-day measurements, the nickel elution was substantially higher for the ASO group compared to the HSO, GSO, SW, and control group (19.80 ±2.30 mg/L, 0.016 ± 0.009 mg/L, 0.009 ± 0.004 mg/L, and 0.005 ± 0.0 mg/L, respectively; P<.001) (Table 1). After adjusting for multiple comparisons, the cumulative nickel levels at 90 days, for each device type, were similar to the control group except for the ASO device, which showed significantly elevated nickel levels (adjusted P=.01) (Table 2). The ASO device continued to show steadily increasing nickel levels, while the nickel elution plateaued for most devices by the 24-day measurement (Figure 1). 

Cumulative nickel levels at 90 days for each device compared to the respective levels at 24 hours were significantly higher for the ASO device (19.80 vs 2.98 mg/L; P=.01), but not for HSO (0.016 vs 0.009 mg/L; P=.20) or GSO (0.009 vs 0.005 mg/L; P=.20) (Table 1). After adjusting for multiple comparisons, only the ASO device demonstrated significantly higher nickel elution compared with the control group, which was statistically significant as early as 72 hours (adjusted P=.05) and remained significantly elevated for all subsequent time points (adjusted P<.01) (Appendix 1). 

Discussion

In this study, we demonstrated significant variability in in vitro nickel elution from various contemporary interatrial shunt closure devices. The Amplatzer ASO device resulted in significantly higher nickel elution compared to the Gore HSO and GSO devices. The differences were detected as early as 24 hours and increased substantially throughout the study. Nickel elution plateaued for the HSO and GSO devices by 24 days, whereas the nickel levels continued to increase steadily for the ASO device even at 90-day measurements. Our findings are consistent with other in vivo studies demonstrating significantly elevated systemic nickel levels for up to 12 months after interatrial shunt closure with ASO device.^6,7

Significant differences in nickel elution properties of contemporary interatrial shunt closure devices in this study may be explained by differences in structural design and surface treatment of these devices. The ASO structure consists of two retention disks constructed from braided nitinol wires (0.004-0.008˝), with polyester fabric inserts shaped into two flat discs and a middle, or ‘‘waist’’ to fit the defect size. This design has extensive nickel exposed to bloodstream, which results in significant nickel elution (as observed in our study) and high systemic nickel levels documented in prior studies (Figure 2).^6,7 In contrast, the HSO and GSO devices differ from the ASO device in that they are comprised of less nitinol wire. The HSO is constructed of a single helical nitinol wire (0.012˝), whereas the GSO is constructed from five nitinol wire strands. This wire is almost completely encased in a biologically inert expanded polytetrafluoroethylene (ePTFE) membrane (except for the lock loop on both the GSO and HSO, and the eyelets of HSO). This occlusive ePTFE membrane may limit the amount of nickel exposed to the blood stream as compared with other devices (Figure 2). This structural advantage explains our findings that at 90 days, no significant nickel elution was noted from the HSO and GSO devices compared to the control group (Figure 2). Surface treatment of nitinol has been shown to affect bioactive properties of the alloy;²² this may also explain differences in nickel elution between different devices since all companies have different proprietary surface treatments. SW eluted less nickel, which was probably because of low nickel content (13%-15%) and different surface treatment compared with interatrial shunt closure devices.²³

The amount of eluted nickel from implanted devices is clinically important, and sufficient to sensitize patients^24,25 or induce a systemic allergic reaction in previously sensitized patients.²⁶ Systemic nickel levels correlating with severity of nickel allergy reaction have not been studied. However, there are studies suggesting that higher quantity of oral nickel exposure is associated with more severe nickel allergic reaction.¹⁴ Also, large population studies have shown decreased incidence of nickel allergy by reducing nickel exposure.^27,28 European nations have implemented legislation to limit the release of nickel from consumer items with an aim to prevent nickel sensitization. In 1990, the Danish government began regulating nickel in consumer products, and a subsequent study comparing pre- and postregulation eras demonstrated that prevalence of nickel allergy decreased by 56% (6.9% vs 15.6%; P=.01).²⁷ In 2001, the European Union implemented the nickel directive, which restricted nickel release of ≤0.5 µg/cm²/week in consumer items and was aimed at limiting nickel sensitization and reducing the nickel allergy problem.²⁸ 

Our current findings of insignificant nickel elution over 90 days from the HSO device provide mechanistic explanation for our group’s prior published study, which showed that patients with known nickel allergy undergoing interatrial shunt closure with HSO device did not develop an allergic response.²⁹ Rigatelli et al²⁶ described their experience with implantation of Amplatzer and Premere occluder devices in 9 patients with proven nickel allergy. Within 48 hours of implantation, 8 of 9 patients developed “allergic device syndrome” presenting as chest pain, dyspnea, asthenia, and leukocytosis. Conceptually, choosing biomedical permanent implantable devices with fewer nickel elution properties may help prevent significant morbidity and surgical device explantation in patients with nickel allergy.

There have been studies reporting significant elevation of systemic nickel levels after ASO device implantation,^6,7 but no such data exist on other contemporary devices like the HSO and GSO. Ries et al⁶ followed serum nickel levels in 67 patients after ASO implantation. They showed that nickel levels were elevated as early as 24 hours and did not return to baseline until about 12 months. Burian et al⁷ followed serial serum and urine nickel levels in 24 patients after ASO implantation. They showed that over 70% of patients were exposed to high systemic nickel levels after device implantation, which returned to a normal range by 6 months. Our findings are in concordance with these prior studies. We found that the ASO device had significant elevation of nickel levels as early as 24 hours and continued to have significant nickel elution at 90 days. Health risk associated with high systemic nickel levels after interatrial shunt closure device implantation has not been studied and remains unknown.

Nickel is a trace element that can be found in plasma (range, 1.4 to 3.4 µg/L) in healthy subjects and is primarily excreted in urine.³⁰ Concerns for nickel toxicity have been raised due to the high nickel content of interatrial shunt closure devices and studies showing excessive systemic nickel levels after implantation.^6,31-33 There are case reports of nickel allergy developing after device implantation.^9,26,34-36 Nickel allergy in patients undergoing percutaneous interatrial shunt closure has been associated with systemic adverse events,⁹ pericarditis,^10,35 increasing migraine headaches,^36,37 and “device syndrome,” which is a combination of chest pain, exertional dyspnea, asthenia, and mild leukocytosis.²⁶ The symptoms from nickel allergy can be very severe, necessitating surgical device explantation.⁵ A large study of international registries noted nickel allergy as the most common reason for device explantation.⁵ Significant adverse events from nickel exposure after other biomedical implants have also been reported.^38-42 Nickel exposure has also been implicated in many cancers^38,43-46 and therefore nickel is classified as a group A carcinogen by the Environmental Protection Agency.⁴⁷ Nickel has also been shown to have proinflammatory effects by stimulating lymphocytes and inducing release of cytokines,^32,48 stimulating interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), and monocytes.³² These proinflammatory effects of nickel have been implicated in more generalized symptoms and conditions like chronic fatigue syndrome, which is associated with increased incidence of nickel allergy.⁴⁸ Cardiac erosion is a rare but serious complication of atrial septal occluder devices. Interestingly, it’s been reported only with Amplatzer devices and no cases have been reported with GSO or HSO devices.^49,50 The mechanism of cardiac erosion is not well understood.

There are no prospective clinical trials comparing nickel levels and correlating them with nickel allergic reactions and health hazards after interatrial shunt closure device implantation. Toxic levels of systemic nickel eluted from implanted devices have not been established. Prospective, randomized, controlled trials comparing various contemporary interatrial shunt closure devices with nickel levels and device allergic reactions are needed.

Study limitations. This is an in vitro study and may not fully represent in vivo conditions. DPBS solution was chosen as the extraction solution because it is the recommended solution for simulation of the physiological environment of circulating blood.¹⁹ The clinical significance of these findings needs to be confirmed in clinical studies. 

Conclusion

There is a substantial variability in nickel elution among the interatrial shunt closure devices. The Amplatzer ASO device has the greatest nickel elution over 90 days. Devices with less exposed nickel to the blood stream, such as the GHO and the GSO, have minimal nickel elution over 90 days. The safety of low nickel elution devices in patients with nickel allergy needs to be evaluated in prospective trials.

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^*Joint first authors.

From the ¹Division of Cardiology, University of Utah School of Medicine, Salt Lake City, Utah; ²Cardiac Aging & Redox Signaling Laboratory, Division of Molecular & Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama; ³Division of Cardiothoracic Surgery, University of Utah School of Medicine, Salt Lake City, Utah; and ⁴Division of Cardiology, Intermountain Medical Center, Salt Lake City, Utah.

Funding: Research grant from W.L. Gore.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Address for correspondence: Divya Ratan Verma, MD, MS, Division of Cardiovascular Medicine, University of Utah School of Medicine, 50 North Medical Drive, Suite 4A100 SOM, Salt Lake City, UT 84132. Email: div.verma@hsc.utah.edu