Nickel for Your Thoughts: Survey of the Congenital Cardiovascular Interventional Study Consortium (CCISC) for Nickel Allergy

ABSTRACT: Objective. Nickel allergy (NA) occurring after implantation of a nitinol-containing device is rare and not well understood. This study aimed to evaluate the current practices and experience of interventional cardiologists with NA after closure of congenital heart defects (CHD) with nitinol-containing devices. Study Design. E-mail invitations were sent to the 96 members of the Congenital Cardiovascular Interventional Study Consortium (CCISC). The survey was Internet-based and mainly consisted of multiple-choice questions. Results. A total of 50 responses (52%) were returned and the median number of device closures was 300 for all responders. While 80% of responders believe that NA exists, only 44% routinely inquire about NA prior to device closure and no responders perform skin testing prior to device closure. Slightly more than half of responders (58%) utilize antiplatelet medications (97% aspirin) in the days prior to device closure. Of the 50 survey responders having a total experience of 16,075 implants, 7 operators reported 33 cases of NA among 1,600 implants. Atrial septal defect closure was associated with all well-described cases of NA. Reaction occurred anywhere from 2 days up to 1 month after implantation and manifested as headaches, rash/urticaria, difficulty breathing, fever or pericardial effusion. All patients responded to medical management and no longer require medication. Conclusions. While a majority of interventional cardiologists believe that NA exists, it remains a rare and poorly defined phenomenon. Although CCISC survey responders indicate that their patients with NA responded to medical therapy, further investigation of risk factors and safety is warranted. Key Words: Congenital heart defects; nitinol; transcatheter device closure; atrial septal defect; survey J INVASIVE CARDIOL 2009;21:326–329 Percutaneous transcatheter interventions for various forms of congenital heart disease (CHD) have become commonplace in the past decade. A significant proportion of these procedures involve closure of a congenital defect with a nitinol-containing device. Nitinol is a nickel-titanium alloy with shape-memory characteristics, good resistance to fatigue and superelasticity that is relatively biologically inert. Given the relatively high nickel content of nitinol, the safety and biocompatibility of these closure devices have been questioned. Prior studies have demonstrated that nickel is released into the bloodstream and excreted in the urine after closure of atrial septal defects (ASD) using nitinol devices, and that the elevated concentrations can be measured for anywhere from a few months to a year after implantation.1,2 Although the overall incidence of nickel hypersensitivity has been reported in up to 15% of the general population,3 there are few reports of nickel allergy (NA) developing after device implantation in the literature,4–8 with the majority of these cases occurring in adults after patent foramen ovale (PFO) or large ASD closure. Little is known regarding the incidence, risk factors and outcomes of those individuals who develop NA after device implantation. This study aimed to evaluate the current practices and experience with NA after closure of congenital defects with nitinol-containing devices among experienced congenital cardiac interventionists. Survey Methods The Congenital Cardiovascular Interventional Study Consortium (CCISC) consists of interventional pediatric cardiologists who are active in the design, collection and reporting of scientific studies in interventional cardiovascular care for individuals with CHD. There are 96 cardiologists with e-mail addresses listed on the CCISC server, and an e-mail invitation with a link to the survey was sent to all cardiologists. One reminder e-mail was sent during the study period. The survey was conducted from November 2008 through December 2008. The survey was Internet-based and consisted primarily of multiple-choice questions (Appendix 1). Basic information collected from each operator included an estimate of the approximate number of device closures performed with a nitinol-containing device and their typical preprocedural practices with regard to NA. NA was not specifically defined for the responders in the survey. If the operator felt that one of their patients had developed a NA reaction, then they were directed to an additional survey (Appendix 2) where they were asked to provide specific information on that particular case. Data were analyzed using descriptive statistics. Results Preprocedural practices. There were 50 individuals on the CCISC list-server (52% response rate) who responded to the survey, but not all respondents answered all questions. The median number of closures with a nitinol-containing device was 300. The total number of device implantations was 16,075. While 39/49 (80%) of responders believe that NA exists, only 22/50 (44%) routinely inquire about NA prior to device closure and no responders perform skin testing prior to device closure. Slightly more than half of responders 29/48 (58%) pretreat with antiplatelet medications before device closure, the vast majority of whom use aspirin (97%). The length of antiplatelet therapy was reported as: 1 day (10/30 or 33%), 2–4 days (16/30 or 53%), 5–7 days (3/30 or 10%) and > 7 days (1/30 or 3%). Nickel allergy experience. Seven of the 50 responders reported an experience with NA (n = 33) among 1,600 implants. The incidence of NA in the total population was 33/16,075 (0.002%), while the incidence among those who reported NA cases was 33/1720 (0.02%). Thorough descriptions were provided for 6 of these patients: age was reported as 10–20 years (1/6), 21–40 years (4/6) and > 40 years (1/6), with a female predominance (4/6). ASDs were closed for each incident. Amplatzer septal occluders (22 mm, 30 mm and 36 mm) (AGA Medical, Golden Valley, Minnesota) were used to close 3 defects and a 30 mm Helex septal occluder (WL Gore & Associates, Flagstaff, Arizona) was used in the other case. Device type and size were not specified for the other cases. Reactions after device implantation occurred at 2–4 days (2/5), 5–7 days (1/5), 1–2 weeks (1/5) or > 1 month (1/5), and included: headaches (4/5), rash/urticaria (4/5), difficulty breathing (1/5), fever (1/5) and pericardial effusion (1/5). Operators performed skin testing and checked serum antibody levels in 2/6 patients after the reaction occurred. All 6 patients were on antiplatelet therapy at the time of the reaction and 2/6 were started on clopidogrel in addition to aspirin. Additional medications used included antihistamines, beta-blockers and steroids. One patient with headaches improved without any additional medical treatment. A middle-aged male patient developed hypereosinophilia, urticaria, arthralgias and a low-grade fever 2–4 days after device implantation that did not initially respond to antihistamines. High-dose steroids were utilized for 2 months followed by tapering, and he is currently asymptomatic off all medications several years after device placement. A second patient decided to proceed with device closure despite known nickel sensitivity: 48 hours after closure with a Helex septal occluder, she developed erythema and pruritis of the extremities. The patient responded favorably to several weeks of antihistamines and is currently doing well off all medications several months after device implantation. A third patient had a long history of migraines that became more frequent with increasing severity the first month after implantation. While this initially responded to beta-blockers, she developed edema of the eyelids and lips 1 month after implantation, which responded to antihistamines and steroids. Discussion In this survey of experienced congenital cardiac interventionists, we found that the majority of responders believe that NA exists, but less than half routinely inquire about NA prior to device closure, and no responders perform skin testing prior to device closure. Interestingly, ASD closure was associated with all well-described cases of NA and was found to occur with both the Amplatzer and Helex septal occluders. Reactions occurred within 1 month of device implantation and manifested as headaches, rash/urticaria, difficulty breathing, fever or pericardial effusion. All patients with NA were reported to have responded to medical management and no longer require medication. While we calculated the incidence of NA for all operators to be 0.002%, the true incidence of NA is likely to be somewhat higher, as evidenced by the 0.02% incidence among those responders who gave detailed descriptions of the patients and events after implantation. This discrepancy can be partially explained by the fact that the most experienced operators oftentimes will assist other interventionists with device implantation and may not follow the patient after deployment, thereby limiting their knowledge of a subsequent reaction. Interestingly, while the majority of operators believe that NA exists, less than half routinely inquire about NA prior to device closure and no responders perform skin testing prior to device closure. It is likely that this is a reflection of personal experience with NA, and that those operators with prior cases of NA are more likely to question and test for NA prior to intervention.8 In our small series of well-described patients with NA, all responders identified ASD closure as the type of CHD treated. Larger ASO devices (> 24 mm) were implanted in all well-described cases of NA: this correlates with previous work that has reported NA occurring in individuals who underwent PFO closure or in those in which a larger ASO was utilized.4,7,8 Interestingly, there were no cases of NA reported for other forms of CHD, which could be explained by several factors. Device closure of a patent ductus arteriosus (PDA) or ventricular septal defect (VSD) typically makes up a smaller proportion of total cases for operators than do ASD or PFO closure, thus, cases of NA may be missed in this smaller cohort of patients. Excluding the end screw and marker bands, the total nickel weight is greater for a large ASD or PFO implant vis-à-vis a PDA or VSD device, and the nickel in a larger ASO weighs roughly double that of a like-sized PFO occluder (AGA, personal communication). The Amplatzer PFO and ASD occluders also have a greater surface area than comparably-sized PDA and VSD devices, which may permit more nickel to come in contact with endothelium and possibly contribute to the immunologic activation theorized to occur with NA. A recent study by Lertsapcharoen and colleagues demonstrated that platinum-coated nitinol ASD devices can prevent nickel release without changing the superelastic or shape-memory properties of nitinol, but further testing and longer follow up on the fatigue resistance and biological activity of these devices are required.9 Females comprised 66% of reported NA cases and the majority of patients were between the ages of 20–40 years, with none younger than 10 years of age. Rigatelli et al described 9 patients (8 female) with a mean age of 31.3 ± 13.2 years who developed a “device syndrome” within 24 hours of implantation that included chest discomfort, exertional dyspnea and asthenia in the absence of arrhythmias, pericarditis, pericardial effusion, device thrombosis or femoral vascular complications.7 In contrast, responders to our survey identified headaches, rash/urticaria, difficulty breathing, fever or development of pericardial effusion as the predominant symptom(s) of NA, all of which occurred several days to 1 month after implantation. These variations in symptomatology and timing exhibit the protean nature of NA and suggest that it is likely an immunologic phenomenon manifesting as a spectrum of clinical signs. Survey responders reported that all patients who developed NA responded to medical management and that no devices had to be explanted. The resolution of symptoms corresponds to previous reports and suggests that NA is a treatable entity that should not preclude attempted device closure.6–8 The only published device explantation for presumed NA occurred in a middle-aged woman who developed dyspnea, low-grade fever and dependent edema 2 months after deployment of a PFO star device.4 The device was surgically removed 4 months after implantation, but interestingly, did not demonstrate the typical lymphocyte and eosinophil infiltration on histology that usually occurs with a NA reaction.5 Of note, the report did not specify whether the reaction was medically managed prior to surgical removal. NA is sometimes touted as a reason to use the Helex septal occluder instead of the Amplatzer device to close a defect because of the lower nickel content in the Helex device. Our work and a report from Dasika et al suggest that while NA may be more prevalent with Amplatzer devices, NA still occurs with the Helex septal occluder as well.10 In fact, the number of reactions may actually increase as more operators become more vigilant about inquiring about nickel sensitivity prior to device implantation. Study limitations. The rarity of NA occurring after device implantation makes it a difficult subject to study. Surveys based exclusively on interview are subject to recall bias and are generally incomplete with respect to control of extraneous variables. The data collected may not only suffer from partial responses, but may fail to capture all cases, and those identified cannot be verified. In addition, NA was not specifically defined in the survey for the responders and is likely to have a different meaning for different individuals, thereby creating some ambiguity in case selection. It is very possible that some of the alleged cases of nickel allergy were in fact another phenomenon that was attributed to a reaction to nickel. The response rate of 50% is comparable to more conventional methods such as postal mail or fax. All e-mail addresses were checked for current activity and did not generate returned messages, suggesting that all CCISC members received the e-mail and had the opportunity to respond. Conclusion While a majority of experienced interventional cardiologists believe that NA exists, it remains a rare and poorly defined phenomenon that can occur with a variety of nitinol-containing devices. Although CCISC survey responders indicated that all patients with NA responded to medical therapy, further investigation of potential risk factors and nickel safety is warranted. From the *Division of Pediatric Cardiology, Rady Children’s Hospital-San Diego and University of California, San Diego, California and the §Division of Pediatric Cardiology, David Geffen School of Medicine UCLA, Los Angeles, California. The authors report no conflicts of interest regarding the content herein. Manuscript submitted February 10, 2009, provisional acceptance given March 2, 2009, final version accepted March 17, 2009. Address for correspondence: Brent M. Gordon, MD, Rady Children’s Hospital-San Diego and UCSD, Division of Pediatric Cardiology, 3020 Childrens Way, MC 5004, San Diego, CA 92123. E-mail: mcnairygordo@yahoo.com

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