Article Text
PDF
Abstract
Background Neurointerventionists lack guidelines for the use of antithrombotic therapies in their clinical practice; consequently, there is likely to be significant heterogeneity in antithrombotic use between centers. Through a nationwide survey, we aimed to obtain an exhaustive cross-sectional overview of antithrombotic use in neurointerventional procedures in France.
Methods In April 2021, French neurointerventional surgery centers were invited to participate in a nationwide 51-question survey disseminated through an active trainee-led research collaborative network (the JENI-RC).
Results All 40 centers answered the survey. Fifty-one percent of centers reported using ticagrelor and 43% used clopidogrel as premedication before intracranial stenting. For flow diversion treatment, dual antiplatelet therapy was maintained for 3 or 6 months in 39% and 53% of centers, respectively, and aspirin was prescribed for 12 months or more than 12 months in 63% and 26% of centers, respectively. For unruptured aneurysms, the most common heparin bolus dose was 50 IU/kg (59%), and only 35% of centers monitored heparin activity for dose adjustment. Tirofiban was used in 64% of centers to treat thromboembolic complications. Fifteen percent of these comprehensive stroke centers reported using tenecteplase to treat acute ischemic strokes. Cangrelor appeared as an emergent drug in specific indications.
Conclusion This nationwide survey highlights the important heterogeneity in clinical practices across centers. There is a pressing need for trials and guidelines to further evaluate and harmonize antithrombotic regimens in the neurointerventional field.
- Drug
- Intervention
- Pharmacology
- Platelets
- Standards
Data availability statement
Data are available upon reasonable request.
Statistics from Altmetric.com
Introduction
Antithrombotic treatments are very frequently used in neurointerventional surgery (NIS), sometimes in combination.1–3 Numerous antithrombotic drugs are now available, and some were recently approved.4 Clinical situations faced by neurointerventionists are very diverse and sometimes require balancing hemorrhagic and ischemic risks.5–7 The European and American Cardiology Societies have both released recommendations guiding the use of antiplatelet medications during percutaneous procedures.8 9 By contrast, at present there are no data-driven guidelines published by NIS societies on this specific topic.
By means of a nationwide survey, we aimed to obtain an exhaustive cross-sectional overview of antithrombotic use in neurointerventional procedures in France.
Methods
Through the trainee-led research collaborative network ‘Jeunes en Neuroradiologie Interventionnelle’,10 a survey was distributed electronically to a delegate physician (a member of the network) at every NIS center in France in April 2021.
A total of 51 questions, spanning ischemic and hemorrhagic pathologies encountered by neurointerventionists, were included in the survey. The full version of the questionnaire is available in English and French in online supplemental file 1 and online supplemental file 2.
Supplemental material
Supplemental material
Results
All 40 French centers answered the survey. Three of the centers offer endovascular management of acute ischemic strokes but not intracranial aneurysm management.
A written protocol describing the use of antithrombotic therapies was available in 58% of NIS centers.
Unruptured aneurysms
Premedication
Dual antiplatelet therapy (DAPT) is commonly prescribed before stent implantation for treatment of unruptured aneurysms (figure 1). Of the centers, 56%, 39%, and 5% used a daily dose of aspirin of 75 mg, 160 mg, and 300 mg, respectively. Aspirin was associated with clopidogrel, ticagrelor, or prasugrel in 43%, 51%, and 6% of centers, respectively.
Premedication for treatment of unruptured aneurysms and duration of dual antiplatelet therapy (DAPT) as a function of the treatment strategy.
Clopidogrel resistance was tested for in 15/16 (94%) of the centers using this drug as first-line therapy. The vasodilator-stimulated phosphoprotein (VASP) test (43%) and VerifyNow system (36%) were most commonly used to evaluate platelet inhibition.11 When insufficient P2Y12 inhibition was found, most centers switched to using ticagrelor (87%).
All centers using clopidogrel reported initiating DAPT at least 5 days before treatment. In contrast, only 26% of centers using ticagrelor reported initiating DAPT at least 5 days before treatment; indeed, in 63% of centers it was given the day before.
Of the 31 centers using WEB devices, 25 (81%) reported systematic use of premedication with at least one antiplatelet agent before any WEB implantation.
Heparin
The most common intravenous (IV) heparin bolus dose was 50 IU/kg, which was used in 59% of centers, followed by 70 IU/kg in 19%, 60 IU/kg in 8%, <50 IU/kg in 8%, 100 IU/kg in 3%, and 80 IU/kg in 3% of centers. This was systematically followed by a continuous infusion in 72% of centers. The heparin medication was stopped by the end of the procedure in 73% of centers and was prolonged for 24–48 hours in 27% (figure 2). Only 35% of centers monitored heparin treatment during embolization (with the activated clotting time (ACT) test).
Heparinization for treatment of unruptured aneurysms.
Thromboembolic complications
In the event of perioperative thromboembolic complications, 64% of centers used tirofiban, 17% used cangrelor, 14% used eptifibatide, and 5% used abciximab. When glycoprotein (GP) IIb/IIIa inhibitors were used, the bolus was injected intra-arterially (IA) in 38% of centers and IV in 62% (figure 3).
Rescue drugs for thrombotic complications during treatment of unruptured aneurysms.
Postoperative antiplatelet therapy
In cases of single stent-assisted coiling, DAPT was maintained for 3 or 6 months in 62% and 38% of centers, respectively. Aspirin was prescribed for 6, 12, or 12–24 months in 16%, 57%, and 11% of centers, respectively; lifelong aspirin was prescribed in 16% of centers (figure 4).
Ruptured aneurysms. Timing of heparin injection (left) and antiplatelet medication in cases of emergent stenting (right).
In cases of Y-configuration stenting, DAPT was maintained for 3 or 6 months in 48% and 52% of centers, respectively. Aspirin was prescribed for 6, 12, or 12–24 months in 11%, 56%, and 9% of centers, respectively; lifelong aspirin was prescribed in 24% of centers.
In cases of flow diversion, DAPT was maintained for 3, 6, or 12 months in 39%, 53%, and 8% of centers respectively. Aspirin was prescribed for 6, 12, or 12–24 months in 11%, 63%, and 8% of centers, respectively; lifelong aspirin was prescribed in 18% of centers.
Ruptured aneurysms
Heparin
For ruptured aneurysms, 36% of centers injected the heparin bolus immediately after the arterial puncture, whereas this was delayed until after cervical catheterization in 36% of centers, after aneurysm catheterization in 11%, and after the first coil delivery in 14% of centers. One center never used heparin in this situation (figure 1).
The rate of centers using a bolus dose of <50 IU/kg increased from 8% in unruptured aneurysms to 21% in ruptured aneurysm; 50 IU/kg remained the most frequently used dose (64%).
In 62% of centers the heparin bolus dose was reduced or not administered in the presence of an associated intracranial hematoma whereas 78% of centers did not change their practice in the presence of an external shunt at the time of embolization.
Thromboembolic complications
The proportion of centers arterially injecting (rather than IV injecting) GP IIb/IIIa boluses was similar for ruptured and unruptured aneurysms (38%).
Emergent stenting
When stent implants were required for those patients who did not receive platelet inhibitors before embolization, 92% of centers used IV aspirin injections, 30% of centers used GP IIb/IIIa inhibitors in combination with aspirin, 30% used cangrelor, 21% used an oral loading dose of clopidogrel, and 19% used an oral loading dose of ticagrelor.
Acute ischemic stroke
Fibrinolytics
For mothership patients, 15% of these comprehensive stroke centers reported a switch from alteplase to tenecteplase as a first-line fibrinolytic while 85% reported using alteplase.
Heparin
An IV bolus of heparin was occasionally given at the beginning of a mechanical thrombectomy in 28% of centers (in the absence of fibrinolytic injection in 20% and for tandem occlusions in 8% of centers). Seventy-two percent of centers never used IV heparin during the endovascular treatment of acute ischemic stroke.
Internal carotid artery stenting
A wide variety of protocols were reported by the centers. Nevertheless, more than 80% based their antiplatelet therapy strategy on a procedural IV aspirin injection.
Intracranial atherosclerotic stenosis
When an intracranial atherosclerotic stenosis was present, the strategies of the centers were approximately equally distributed between angioplasty, stenting, GP IIb/IIIa inhibitors, and abstention.
Discussion
We report here an up-to-date cross-sectional overview of the use of antithrombotic drugs during neurointerventional procedures in France in 2021. We reveal highly heterogeneous practices, supporting the critical need for a prospective assessment of drug regimens to derive optimized approaches and to streamline strategies.
These findings could be explained by the lack of controlled trials in the NIS field. However, some information can be extracted from the existing literature, even though the level of evidence is mostly low. Caution must also be exercised when using evidence from cardiology studies since targeted populations are not equivalent.
Unruptured aneurysms
Aspirin
Most centers used low doses of aspirin (75 mg) for stent implantation; however, 44% of centers used higher doses.
In healthy volunteers, 81 mg has been shown to be sufficient to suppress platelet activity.12 The 2016 American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend a daily aspirin dose of 81 mg (range 75–100 mg) for patients with acute coronary syndrome treated with percutaneous coronary intervention.13 In addition, the efficacy of ticagrelor may be decreased in patients treated with higher aspirin doses (≥300 mg daily) compared with lower aspirin doses (≤100 mg daily).14 Two NIS studies reported percentages of subtherapeutic VerifyNow aspirin results with daily aspirin doses of 325 mg15 and 81 mg16 that were in a similar range (16.2% and 13.5%, respectively).
Clopidogrel versus ticagrelor versus prasugrel
DAPT is typically used after any type of intracranial stenting, but the best P2Y12 antagonist to be used in combination with aspirin is still being discussed. In our study we have seen that clopidogrel, the drug that was originally used as the standard for flow diverter stent implantation,17 has been superseded in France by the use of ticagrelor in 51% of centers.
Small comparative studies suggest that ticagrelor could be safe and effective to replace clopidogrel without the cumbersome resistance tests.18–20 In a meta-analysis including 1005 patients,2 ticragrelor appeared to be as safe as clopidogrel when both ischemic and hemorrhagic complications were considered. Moreover, regimens using ticagrelor were associated with better survival than those using clopidogrel in the included studies. Ticagrelor is given as a twice-daily dose, so patients must be warned that a single missed dose could have direct consequences. The ACC/AHA and European Society of Cardiology (ESC) guidelines on DAPT recommend use of ticagrelor or prasugrel over clopidogrel.8 13
Few studies have reported the use of prasugrel for NIS procedures. Compared with clopidogrel, high prasugrel doses have been associated with high rates of bleeding events.21
Resistance tests
Clopidogrel is a prodrug metabolized by the liver under the influence of several factors, and variability in platelet response to clopidogrel is a common clinical problem; 5–44% of patients are hyporesponsive to clopidogrel.20 22 Clopidogrel hyporesponse is associated with thromboembolic complications.23 However, the clinical benefit of routine assessment of P2Y12 response remained controversial for many years.19 24
Nevertheless, 94% of centers in our study performed clopidogrel resistance testing and a recent randomized controlled trial showed that platelet function testing could reduce thrombotic events in patients with unruptured intracranial aneurysms after stent placement without increasing the rate of major bleeding.25
The dissociation between testing and outcome that was observed for many years might have been due to the variability in assay technology, lack of definitive P2Y12 reaction units (PRU) cut-off values, and diverse therapeutic strategies in the event of hyporesponse (dose escalation, drug replacement, etc). Here we see that most French centers opt for a simple strategy in the event of a clopidogrel hyporesponse, with 87% of centers switching to ticagrelor.
Heparin
Although heparin is the main drug used during NIS procedures, there are surprisingly few data available to guide the development of protocols. This absence of consensus was reflected in our study, with bolus doses ranging from 30 IU/kg to 100 IU/kg, followed or not by continuous infusion and with or without ACT monitoring, depending on each center’s protocol.
Low doses of heparin have been associated with a higher thromboembolic risk,26 but caution should be taken when increasing doses, especially when heparin is used in association with antiplatelet antagonists. Indeed, when used in conjunction with ticagrelor, higher heparin doses (70 IU/kg) have been associated with a higher hemorrhagic risk.27
The World Federation of Interventional and Therapeutic Neuroradiology (WFITN) recommends a 5000 IU bolus, then 1000 IU/hour continuously, with a monitored ACT of about 200 s, and does not recommend pursuing anticoagulation postoperatively.28 Nevertheless, because of the risks associated with infratherapeutic ACT,29 it seems reasonable to determine the loading dose based on body weight, and because the ACT is also influenced by other parameters (eg, sex and hematocrit),30 repeated ACT measurements might be useful for accurate dosing.
Peroperative thromboembolic complications
GP IIb/IIIa inhibitors are commonly used in NIS for rescue therapy of acute thrombotic complications and are associated with high rates of recanalization and minimal rates of intracranial hemorrhage.31 Once more, optimal NIS protocols are lacking, and our study revealed a great degree of variability in administration.
Three GP IIb/IIIa inhibitors are available, and our study shows that in France tirofiban is the most commonly used (64%). Because of its short half-life, full restoration of platelet function is observed after 4–8 hours (compared with 12 hours for abciximab), and its reported efficacy is 90–100%.31
In a meta-analysis,32 patients receiving tirofiban or eptifibatide had significantly higher recanalization rates than those treated with abciximab, and no difference in recanalization was seen in patients receiving IA or IV injections.
Interestingly, 17% of centers reported the use of cangrelor, a new P2Y12 intravenous inhibitor, in this indication. While the efficacy of this strategy needs further evaluation, the on/off effect of this drug might be interesting in cases where further surgery is required.33
Postoperative medication
The need for DAPT after intracranial stent implantation is unanimously accepted. In the existing literature there is little evidence to guide the development of DAPT protocols.34
DAPT duration appears to be an important safety parameter. Indeed, in a large monocenter study, 23% of late complications occurred within 30 days of antiplatelet agent cessation.35 In addition, when using clopidogrel, higher rates of late ischemic complications were found with DAPT prescribed for <6 months than with DAPT prescribed for ≥6 months, with no increased risk of hemorrhagic complications.
We have observed a troubling amount of heterogeneity in drugs, doses, and durations of antiplatelet therapies among centers. We strongly appeal for further controlled trials and harmonization to allow better evaluation and improvement of intracranial stenting procedures.
Recent developments in implant surface modification might lead to the DAPT paradigm being questioned.36 Upcoming studies (Coating to Optimize Aneurysm Treatment In The New Flow Diverter Generation, ClinicalTrials.gov identifier: NCT04870047) should be used as an opportunity to gain evidence and refine our antiplatelet protocols.
Ruptured aneurysms
Heparin
In our study, all but one center systematically used heparin loading during endovascular treatment of ruptured aneurysms. Notably, heparin has never been associated with an increased risk of rebleeding.37 38 However, the optimal timing of heparinization is still disputed, and the fear (possibly unfounded) of early rebleeding led here to a delayed heparin load in two-thirds of cases. Balancing the significant thrombotic risk, it might be reasonable to use heparin early during the procedure and at least before intracranial navigation.39
Emergent stenting
Where stent implantation was required, strategies were roughly equally distributed between the combinations of IV aspirin and (1) GP IIb/IIIa inhibitors, (2) oral P2Y12 inhibitors, or (3) IV P2Y12 inhibitors.
In a consensus statement, NIS experts favored the combination of aspirin and GP inhibitors.6 But, as stated by the authors, the increased availability of cangrelor might modify this recommendation. Indeed, both the immediate platelet inhibition after cangrelor loading and the flexibility brought for bridging protocols in cases where urgent surgery is required could make this recent drug an ideal option for the management of ruptured aneurysms.33 40
Acute ischemic stroke
Fibrinolytics
Evidence from randomized controlled trials suggests that tenecteplase might be at least as efficient as alteplase in the treatment of patients with acute ischemic stroke with large vessel occlusion.41 42 Because of the enthusiasm generated in the neurological community, we have seen that 15% of these comprehensive stroke centers reported a switch to tenecteplase as a first-line fibrinolytic, although it is not yet officially approved for this indication in France.
Heparin
In our study, approximately one-third of centers were using unfractionated heparin in some specific clinical situations at the acute phase of an acute ischemic stroke. The MR CLEAN-MED trial43 recently demonstrated that periprocedural IV aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial hemorrhage without evidence for a beneficial effect on functional outcome, so unfractionated heparin usage should be avoided in this indication.
Emergent cervical internal carotid stenting
There is little evidence to guide clinicians in this complex situation, but some data should be available shortly after the completion of the TITAN trial.44
An expert panel recommended6 a single antiplatelet regimen as a first-line strategy (with IV aspirin or alternatively an IV GP IIb/IIIa inhibitor), followed in the postprocedural period with a DAPT including aspirin and a P2Y12 inhibitor.
Here again, cangrelor might be a good option because of its pharmaceutical characteristics,45 but its use should be investigated in this indication as the shorter half-life could also be a limitation in the event of early interruption.
Refractory occlusion
Intracranial atherosclerotic stenosis-related large vessel occlusions frequently require rescue treatment following mechanical thrombectomy. Multiple reports suggest that tirofiban infusion alone or in association with angioplasty with or without stenting was associated with a decreased risk of reocclusion,46 higher recanalization rates,47 48 and better outcomes,47 48 with no increased risk of symptomatic hemorrhage46 47 or mortality.46–48
Of note, in the acute ischemic stroke context it has been shown that IA infusions compared with IV are associated with an increased risk of intracranial hemorrhage and poorer outcomes.48 49 Once more, authors highlight the need for further studies to develop appropriate protocols.49 One study has recently reported the use of cangrelor in this indication.7
Limitations of the study
A limitation of this study is that a single online questionnaire was collected per center. The reported absence of formal antithrombotic therapy protocols in 42% of NIS centers could reflect the lack of harmonization within centers. Nevertheless, we believe that this exhaustive snapshot of practices at a country level is likely to quite accurately reflect modern hemostatic therapeutic trends in NIS.
Conclusion
This nationwide survey highlights the important heterogeneity of practices across centers. There is a pressing need for trials and guidelines to further evaluate and harmonize antithrombotic regimens in the neurointerventional field.
Supplemental material
Data availability statement
Data are available upon reasonable request.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
Acknowledgments
The authors thank all their colleagues who agreed to complete this survey and the JENI-RC.
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Twitter @jildazz, @gcharbonnier, @GuillaumeTess12, @dumasvictor2, @RaoulPop25, @CRISTIANMIHALEA, @gboulouis
Collaborators JENI Research Collaboration : Julien Boucherit, Gaultier Marnat, Mourad Cheddad El Aouni, Federico Bolognini, Pierre-Olivier Comby, Martin Bretzner, Riyad Hanafi, Maxime Drai, Benoit Testud, Cyril Dargazanli, Liang Liao, Wagih Ben Hassen, Julien Allard, François Delvoye, Pierre-François Manceau, Quentin Alias, Margaux Lefebvre, Dan Sorin Mihoc, Jean Darcourt, Kevin Janot, Vincent L'Allinec, Jean Papaxanthos and Vanessa Chalumeau. Other collaborators : Jacques Duranteau and Laurent Spelle.
Contributors JC, LA, and SF contributed to conception and design of the study. JC contributed to data collection and analysis and drafting the manuscript. SF, CLB, GB, and BK contributed to revising the manuscript for important intellectual content. All authors approved the final version to be published. JC is the guarantor of the overall content.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.