Commentary: Anaphylactic Reactions to Endoprostheses Are Still Unpredictable Events

Although allergic reactions to endoprosthesis are uncommon, they have been reported after the implantation of endovascular, orthopedic, dental, and other devices. ¹ Anaphylaxis can present with non-life-threatening symptoms (affecting the cutaneous or gastrointestinal system) or may be very dangerous because of asphyxia (laryngeal edema or severe bronchospasm) or cardiovascular collapse (anaphylactic shock).

Chemically active substances of low molecular weight, such as lipid-soluble organic substances derived from polymer materials or metal ions and metal salts, are considered to be the principal chemical allergens responsible for allergic reaction to endoprostheses. It is know that these haptens become full allergens only following reaction with individual proteins that may be present in the host’s antigen presenting cell. As a result, anaphylactic reactions to endoprostheses are still unpredictable events that are not fully understood.

Hypersensitivity reactions have been reported following implantation of any kind of endovascular device, including bare stents, ² drug-eluting stents, ³ patent foramen ovale occluders, ⁴ pacemakers and implantable cardioverter defibrillators, ⁵ and aortic stent-grafts. ⁶ In the majority of reported cases, symptoms are attributed to nickel allergy, and clinical events are controlled adequately with systemic antihistamine and topical corticosteroid therapy. Only in a few instances do allergic reactions present life-threatening symptoms. The event reported by Sfyroeras et al ⁷ in this issue of the JEVT is significant because it is the first description of an anaphylactic reaction secondary to polymer leakage into the bloodstream with the Ovation Abdominal Stent-Graft System (TriVascular, Santa Rosa, CA, USA), which is the only commercially available stent-graft that has polymer-filled sealing rings. The Nellix Endovascular Aneurysm Sealing System (Endologix, Irvine, CA, USA) uses a similar polymer to fill endobag(s) that encase its stent-graft(s) after deployment.

While the unique sealing mechanism of the Ovation device affords a lower profile and improved sealing ability, patient safety was a primary driver during development of the stent-graft. As part of the process for approval by regulatory agencies around the world, the Ovation System’s polyethylene glycol (PEG)–based polymer was chosen because it is non-thrombogenic and biocompatible; it was designed to be soluble and non-embolic if spilled accidently into the vasculature after mixing.

Moreover, PEG-based polymers have a long history of use in medical products. Prior to approval, TriVascular Ovation fill polymer passed the rigorous biocompatibility testing required by the international standard on biocompatibility (ISO 10993-1), and these results were reviewed in order to receive Conformité Européenne (CE) Mark and Food and Drug Administration (FDA) approval. ⁸ In 2014, the 14-minute CustomSeal Fill Polymer Kit, which replaced the Ovation Fill Polymer Kit, received both CE and FDA approval.

A significant amount of nonclinical testing was performed to evaluate the polymer kit ⁸ :

In early 2012, a caution statement was approved for the Ovation fill polymer and included in the Instructions for Use (IFU); it warned against balloon dilation of the sealing rings within 20 minutes of mixing the polymer to avoid potential damage to or compromise of the sealing rings. At the same time, the IFU were also updated to include instructions to manage patients who experience a hypersensitivity reaction to the device materials in accordance with standard recommendations for treatment of patients with radiocontrast allergies (eg, antihistamines, corticosteroids, and adrenaline).

As reported by Sfyroeras et al, ⁷ in late September 2014, TriVascular initiated a voluntary field safety corrective action (FSCA) related to the 29-mm Ovation Prime aortic body stent-grafts manufactured within a defined time period. Fewer than 30 devices were subject to the FSCA, all of which were held by distributors outside the United States (Canada and Europe). The FSCA was initiated due to an increase in complaints related to rapid emptying of the fill polymer syringe in the 29-mm Ovation Prime stent-grafts during the implant procedure, which could lead to incomplete aortic body graft fill, allergic reaction (from transient hypotension response to more severe cardiovascular collapse), prolonged procedure time, and/or failure to exclude the aneurysm. In the related complaints regarding the 29-mm Ovation Prime aortic body, one procedure was prolonged, and most patients experienced transient hypotension (managed in accordance with the instructions for use) and aneurysm exclusion, although some of these patients had incomplete filling of the graft. There was no associated risk to patients with existing implanted Ovation Prime stent-grafts, and all devices subject to the FSCA were returned to TriVascular and deployed in a non-clinical setting to render them non-implantable. During the root cause investigation, TriVascular identified that the rapid emptying of the fill polymer syringe was attributed to possible stent-graft damage incurred during the loading process, which was addressed by replacement of tooling used during stent-graft loading. The FDA closed the action in December 2014.

As a personal observation, we would recommend all Ovation users (1) load the syringe prudently with only the exact amount of polymer necessary to fill the ring network of the specific aortic body [for 20-mm aortic body = 7 mL, 23-mm = 8 mL, 26-mm = 9 mL, 29-mm = 11 mL, 34-mm = 13 mL] and (2) check the polymer infusion carefully under continuous angioscopy (as done in the case reported by Sfyroeras et al ⁷ ) and stop the infusion promptly if the rings are not visualized after the first 5-mL injection.

In cases of incomplete filling of the aortic body graft resulting in failure to complete the procedure and to exclude the aneurysm, a later endovascular intervention may be planned. The visualization of the aortic main body, which is not radiopaque in the absence of polymer, may be realized by injecting contrast at the level of the suprarenal stent via a percutaneous brachial access. After cannulation of the main body limbs (antegrade or retrograde approaches may be useful), a balloon-expandable stent (eg, Palmaz) can provide the appropriate sealing at the proximal aortic neck. Finally, the aneurysm may be completely excluded by deploying the 2 iliac limb endoprostheses.

In conclusion, we are thankful to the authors for reporting this uncommon complication, which reminds us that allergic reactions may occur, although infrequently, after implantation of any kind of endovascular, orthopedic, or dental endoprosthesis. When it comes to an anaphylactic reaction, this is still an unpredictable event that is not fully understood. Prompt diagnosis and treatment of anaphylaxis is essential to prevent serious adverse outcomes. Immediate intramuscular administration of epinephrine is first-line therapy for anaphylaxis, then oxygen therapy, intravenous fluids, and adjunctive therapies such as antihistamines or inhaled beta₂-agonists may also be essential in the acute setting.