Acute Intraprocedural Thrombosis After Flow Diverter Stent Implantation: Risk Factors and Relevance of Standard Observation Time for Early Detection and Management

Despite increasing clinical experience and technological progress, procedural complications still occur occasionally in the endovascular treatment of intracranial aneurysms with thromboembolic complications representing the leading cause of morbidity and mortality [1].

Flow diversion has revolutionized the treatment of a large number of intracranial aneurysms in the past years, extending the indications to aneurysms that were previously difficult to treat with traditional endovascular techniques [2]. However, especially flow diverter stents (FDS) carry a relatively high risk of thromboembolic complications since they have a much higher metal mesh density compared to other conventional stents. This increases the risk of thrombus formation within the stent, potentially leading to stent occlusion, distal embolism, and occlusion of vessels originating from the aneurysm or the parent vessel which is covered by the stent [3].

Prevention of clot formation is the most effective way to avoid thromboembolic complications; however, once a thrombus forms immediate action is require as an untreated clot can enlarge and lead to irreversible ischemic complications downstream. Early angiographic signs, such as a contrast filling defect within or adjacent to the stent or the occlusion of covered side branches, allow the detection of acute intraprocedural thrombosis (AIT) after insertion of the FDS [4]. Prompt pharmacological treatment with immediate intravenous administration of a glycoprotein IIb/IIIa receptor inhibitor can effectively prevent further thrombus formation and subsequent ischemic brain damage by promptly dissolving the thrombus [5, 6]. Therefore, an active monitoring protocol after implantation of FDS was established in our department to identify any spontaneous AIT during the procedure and treat it accordingly. This study aimed to demonstrate that an angiographic active surveillance time is justified and effective to detect and treat AIT. Furthermore, we analyzed several patient-related and procedure-related factors to investigate risk factors for the occurrence of AIT.

In this study, using a systematic angiographic active surveillance protocol after FDS implantation, we could demonstrate that AIT is present in 7.5% in the early stage after FDS implantation. This complication can be early detected, and safely and effectively be treated to prevent ischemic complications. Furthermore, hypertension and side branches originating from the aneurysmal sac were identified as potential risk factors for the occurrence of AIT.

Ischemic stroke due to thromboembolism is the most frequent perioperative and postoperative complication associated with FDS implantation [7]. The reported stroke rates vary between 4% and 6% [8‐10]. Thromboembolic complications can be divided in acute intraprocedural, subacute postprocedural and delayed complications [7]. In the case of AIT, immediate action is required, as an untreated clot can enlarge and quickly progress to occlude both the FDS and the parent vessel, and subsequently lead to a disabling stroke due to ischemia of the downstream vascular territory.

Despite all reasonable precautions being taken, such as appropriate pharmacological preparation and platelet reactivity testing, a subgroup of patients still develop acute thrombosis. Therefore, early recognition and subsequent treatment of AIT is a major factor for good outcome. There are currently no recommendations regarding a regular waiting time after FDS implantation and many centers terminate the procedure after an inconspicuous DSA instantly after FDS placement. The average time, after which AIT was detected in our study, was 16 min, which shows that AIT does by far not always occur immediately. Indeed, we experienced two cases of AIT at the 30 min control angiogram which raises the consideration that even a longer observation time could be justified. If the intervention is ended prematurely, the risk of missing such a relevant complication, that can be prevented by active surveillance followed by immediate treatment, is high. Since most patients are treated while under general anesthesia, most neurological deficits are detected not until the patient is awake again, which may imply a structural, often not fully reversible damage to the brain parenchyma that could potentially have been avoided. We strongly believe that these arguments are sufficient to justify the prolongation of the procedure for 30 min after device deployment for active angiographic surveillance after FDS implantation.

We observed two cases of later stent rethrombosis in this series with an incidence of 16.7% (related to the 12 patients who developed AIT). Therefore, we suggest additional careful clinical surveillance in the first postoperative days, as well as instructing the patient to promptly seek medical attention in case of new neurological symptoms.

Interindividual variable response to antiplatelet therapy [11], unpredictable patient compliance with medication, potential drug interactions, and the presence of comorbidities are already known to be linked to a higher risk of thromboembolic complications, but there are most likely other multifactorial variables [12]. Risk factors for AIT, specifically after FDS placement, have been scarcely investigated so far and the data we rely on come largely from the cardiologic field. A study investigating predictors of ischemic stroke after intraprocedural thrombosis found that current smoking was the only independent predictor [13]; however, to draw a conclusion not only based on flow diversion (pipeline embolization device) but also on stent-assisted coiling. Cardiologists report conflicting data regarding a history of aHT, for which both positive and negative associations with device-associated thromboses have been reported. In our multivariate regression analysis, we found a higher rate of AIT in patients with known aHT and in the presence of a side branch originating from the aneurysm. In one study, aHT was shown to be a protective factor for thrombosis of cardiologic drug-eluting stent (DES); however, only for delayed and not early occurrence [14]. On the other hand, different studies unanimously reported that high scores in the CHA2DS2-VASc score, which incorporates important cardiovascular risk factors as aHT, correlates with a higher incidence of DES thrombosis [15, 16]. Regarding the side branches originating from the aneurysm, further investigations are needed to better understand the effects of physical and mechanical properties of the stent on the dynamics of blood flow in this particular angioarchitecture. Interestingly, there was no increased rate of AIT in small parent vessels (mean diameter < 2.5 mm). The fear of a higher risk of stent occlusion, acute and delayed, given the lower volume flow rate and higher metal-to-cross-sectional flow area ratio, represents to date one of the main concerns to use FDS in the distal vasculature [17]. Another interesting aspect is that no cases of AIT were seen in the acute SAH patients, where there is a known hypercoagulable state [18].

The reported complication rate for AIT after FDS placement varies between 2% and 6% with most data relying on the PED (Medtronic Neurovascular) [4, 6, 9, 19, 20], which is the most widely used FDS in the USA. A recently published multicenter analysis about the FRED flow diverter (MicroVention) reported a similar complication rate of 5.5% [21]. The rate in our study was slightly higher at 7.5%; however, we considered not only thrombosis exclusively limited to the stent lumen but also acute occlusion of covered side branches, which are also caused by thrombus within or directly adjacent to the stent. The latter is reported to occur in about 2% of patients treated with PED [22] and up to 5% when considering different FDS [23]. Prevention of device-associated thrombosis is one of the strongest drivers of innovation, and lately new FDS with allegedly less thrombogenic materials or antithrombotic coatings are being developed, showing promising preliminary results [24]; however, further systematic studies are still lacking so far.

Various rescue strategies are available with i.v. antiplatelet drugs representing the first-line approach due to the platelet-rich composition of the acutely formed thrombi [6, 7]. Different glycoprotein (GP) IIb/IIIa receptor antagonist are available for this purpose: abciximab (ReoPro, Eli Lilly Inc.), tirofiban (Aggrastat, Medicure International Inc.), and eptifibatide (Integrilin, Millenium Pharmaceuticals Inc.). These drugs have different pharmacokinetic and pharmacodynamic properties, nevertheless, they seem to have comparable efficacy and safety profiles even if direct comparison studies are lacking. Usually, these drugs are given intravenously, although some authors report likewise efficacy of intra-arterial administration with the advantage of a lower overall dosage [4, 6, 7]. Intracranial hemorrhage is one of the main associated risks of antiplatelet medications. Even though we had none of these in our series it is reported to be as high as 7% (2/30 cases) [6], thus all glycoprotein (GP) IIb/IIIa receptor antagonists should be applied with great caution. Further on, if thrombus dissolvement cannot be achieved pharmacologically, other actions, such as direct thrombus aspiration or stent retriever thrombectomy through the stent lumen might be required, which was not necessary in this study.

An arguable drawback of an active surveillance strategy is the augmentation of the radiation dose. The whole treatment usually requires only a few DSA runs in total in an uncomplicated FDS implantation. Adding several DSA runs for active surveillance during the 30 min control phase, can significantly increase the radiation dose. Therefore, to answer the question if the benefit of early AIT detection outweighs this increase in radiation dose, further studies are needed. After further investigation of risk factors for AIT, in the future, the presented active surveillance protocol could be tailored dependent on the individual patient risk for AIT.

The main limitation of this report is the institution-based, nonrandomized, retrospective cohort design of the study. Furthermore, the angiographic and clinical data were not analyzed by an independent core laboratory and no control group was used for comparison. Another important limitation is that two types of FDS were predominately used (FRED and PED), even though many other FDS are available on the market; however, we still assume that our results may be representative, as precisely these FDS types are currently the most used worldwide. Additionally, to our knowledge, this is the only study presenting a systematic active surveillance protocol after FDS placement to date.

Active surveillance for 30 min after FDS implantation is an effective strategy for the early detection and the subsequent treatment of AIT, which was present in about 7% of patients. Early identification and treatment of this complication by systemic application of Gp IIb/IIIa antagonists is highly effective, preventing subsequent disabling sequelae. Hypertension and side branches originating from the aneurysmal sac were independent risk factors for AIT; however, further studies are needed to confirm and better understand the underlying pathophysiological mechanisms.