Case series of coronary artery aneurysms after Everolimus eluting stent implantation and comparison with Sirolimus eluting stents

Coronary artery aneurysms are rare, found in 0.3 to 4.9% of patients undergoing coronary angiography. While Kawasaki disease is the most common cause of coronary aneurysm in children, atherosclerosis is the cause in > 90% of adults [1]. The incidence of coronary artery aneurysm after drug eluting stent (DES) deployment varies between 0.2–2.3% and is similar to bare-metal stent (BMS) [2]. Cases have been reported to occur after 3 days to 4 years post percutaneous intervention (PCI). Here we present a case series of coronary aneurysms related to Everolimus eluting second generation stents and compare it with Sirolimus eluting second generation stents at our centre.

The mechanism of stent induced aneurysm has been classified by Aoki et al. into 3 types [2]. Type I Aneurysms are formed due to injury to the arterial wall during dissections or high pressure balloon dilatations. These are more often pseudo-aneurysms. IVUS in these cases may demonstrate a contained rupture with thrombus in the aneurysmal sac with only the outer tunica adventitia. These patients present within one month of the index procedure with rapidly enlarging aneurysm and sometimes pericarditis. It is seen more in chronic total occlusions (CTO) and long diffuse lesions where there is inadvertent injury to the sub intimal space.

Type II stent induced aneurysms present sub acutely due to hypersensitivity reaction to either the stent metal/alloy, the drug polymer or due to the anti-proliferative action of the drug which prevents proper endothelialization. The cobalt chromium stents contain 9–11% nickel compared with stainless steel stents containing 10–14% nickel [3]. Both of them can cause allergy and ISR in patients with comparable rates (2). Here both Xience–Everolimus eluting stents and Treat-Sirolimus eluting stents were used comparably and their baseline characteristics and outcomes have been depicted in Table 1 and Fig. 7. The Xience V/Prime-LL stents used here as has a two layer coating composed of primer layer of PBMA (Poly N Butyl Methacrylate) and a drug reservoir made of poly-vinylidene fluoride-co-hexafluoropropylene (PVDF-HFP) [3]. Fluorinated polymers are bio-compatible as they preferentially adsorb albumin to fibrinogen preventing platelet activation [3]. On the contrary the primer layer containing Methacrylate is known to cause allergic hypersensitivity [5‐8]. They have been shown to induce a marked inflammatory reaction consisting primarily of eosinophils and lymphocytes. Sirolimus and Everolimus both prevent neo-intimal proliferation but also delay re endothelialization. This has been a proposing mechanism for abetting aneurysm formation. While both of them are mTORC1 inhibitors, Sirolimus is more protein bound with a longer terminal half-life. Here we also had two patients who developed stent induced aneurysm formation after implantation of 2nd generation Sirolimus eluting stents whose morphology (Fig. 6A, B) were similar to Everolimus eluting 2nd generation stents.

Figure 7 depicts that the incidence of stent induced aneurysm formation was slightly more with Everolimus eluting Xience stents as compared to Sirolimus eluting 2nd Generation stents (Treat and Nostrum). But by using chi square analysis it does not reach statistical significance (p = 0.054).

Type III stent induced coronary aneurysm are infection related mycotic aneurysms. Patients are toxic with bacteremia and have a high blood leukocyte count. In our series none of the patients presented within 1 month of angioplasty with fever or raised TLC and most of them presented with angina. In addition patient D who had operative repair done, no pus was found in the aneurysmal sac. Hence in our series infective etiology was ruled out.

In our case series as depicted in Table 2, most patients were old (average age of 65.5 years), male (75%) and all of them were hypertensive. Possibly hypertension was associated with more arterial shear stress. The native lesions were long segment lesions with near complete occlusion predisposing to intimal injury. LAD was the most common artery involved as it is exposed to higher wall stress during systole and twice the torsion of other arteries. Second generation Everolimus eluting stents were used in this series and the morphology of aneurysms were similar to two patients with Sirolimus eluting 2nd generation stents. There was significant ISR in all of them. In an aneurysm there is slow flow of blood which predisposes to thrombus formation, but IVUS of patient A did not reveal any thrombus. The patients were followed with standard dual anti platelet drugs to minimize stent thrombosis. In patient C the small aneurysms formed were healed after opening the distal ISR segment.

Coronary aneurysm after stent implantation is a grey area and the exact etiology is difficult to define. In our case series mycotic aneurysms are ruled out. There was no instance of dissection or high pressure balloon dilatation moreover we saw more sub-acute diffuse aneurysms including one extending to Left main artery. Therefore type I aneurysms are unlikely. Within type II aneurysm both the stent metal and more commonly the drug polymer causes hypersensitive coronary vasculitis according to various pathological studies. Also patient C had elevated IgE on follow up. While the cobalt chromium alloy can occasionally cause allergy in patients it is commoner in females [9]. In our series patients were predominantly male (75%). Moreover metal allergy predominantly presents as recurrent ISR rather than aneurysm formation [9]. The primer in Xience stents contains Methacrylate (previously used in Cypher stents and also a component of bone cement) which has been known to cause allergic reactions including coronary aneurysm formation in a number of studies [5‐8] and we hypothesize that it can be an additional causal agent. Treatment of coronary aneurysms may vary [10]. Small chronic aneurysms can be followed up vigilantly. Whereas giant, enlarging, infected aneurysms presenting acutely should be emergently treated with operative repair [11, 12], covered stent [13‐15] or coil. In our study operative aneurysmal repair with grafting had better results especially for giant stent induced type II aneurysms over percutaneous covered stenting.

The major limitations of our study was an absence of histopathological examination of aneurysmal segments to clearly delineate the cause, the use of regionally available stents and limitations related to single centre non randomized study. Also patient A and B had low LVEF and died at an outside hospital so the death was due to heart failure or a possible complication of covered stent deployment cannot be ascertained.

Our case series highlight two valuable research areas. One is the possibility of methacrylate promoting a hypersensitivity reaction and contributing to formation of Type II stent induced coronary aneurysms. Second is identifying the right patient with giant stent induced type II aneurysm who will benefit from operative repair versus covered stent placement. Both needs to be substantiated by further studies.