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Antiplatelet and antithrombotic therapy after drug-eluting stents: what is next?

Cardiovascular Pharmacology and Pharmacotherapy


This session brought together four experts from Europe and the USA with the aim of providing contemporary insights into the utility of the novel, more potent, antiplatelet agents specifically in the setting of drug-eluting stent (DES) implantation.
There exists a mortality paradox between prevention of stent thrombosis/ischaemic events and occurrence of bleeding; both events carry increased risk, and more potent agents may decrease the former at the expense of the latter. Therefore, identification of patients that might benefit most from such drugs is clearly important, as well as defining how long such agents should be continued in the current DES age.
Dr. Dominick Angiolillo (University of Florida, Jacksonville, FL, USA) explored the pros and cons of platelet function tests and their potential utility in determining individual susceptibility to bleeding or thrombotic/ischaemic events. Whilst a range of well-validated diagnostic tests is available, the high profile failure of studies such as GRAVITAS, TRIGGER-PCI and ARCTIC to identify a clear role for individualised testing has fuelled the debate as to which test (if any) and at what timepoint in therapy such measurements should be made; that said, individual trial flaws including selection of low-risk study cohorts, variable timing of testing and inappropriate platelet reactivity cutpoints may have affected these results.
However, the large scale ADAPT-DES study has highlighted substantial overlap in platelet reactivity between patients suffering stent thrombosis and those remaining free from events, further questioning whether or not ‘responder status’ adjudged by these tests might be important/relevant. There is no doubt that prevailing evidence has yet to define the role of platelet function testing in individual patients, likely due to the design of the trials hitherto aimed at answering this important question, and perhaps better-designed trials are needed to determine once and for all the clinical impact of these tests.
Dr. Roberta Rossini (Bergamo, IT) highlighted the issues surrounding premature cessation of dual antiplatelet therapy (DAPT) after stent implantation. Premature discontinuation of DAPT within the recommended 12-month treatment period after PCI with DES remains prevalent in both randomised controlled trials and real-world registries, most frequently due to unplanned non-cardiac surgery or bleeding events. Around 5% of patients after PCI will undergo surgery of some form within 12 months of PCI, and current evidence suggests a particular hazard for stent thrombosis if DAPT is discontinued for more than 5 days before such surgery, somewhat mitigated by postponing surgery if possible, thereby extending length of time since PCI. Further studies examining strategies to ‘bridge’ to such surgical episodes are needed, as well as emphasis in communication between the broader care team to ensure DAPT is maintained for appropriate lengths of time in individual patients.
Dr. Stefan James (Uppsala, SE) described the tension between prevention of bleeding and ischaemic events as like being ‘caught between Scylla and Charybdis’; novel agents such as prasugrel and ticagrelor clearly reduce the latter but do increase the former to varying degrees. Complicating this further, use of clinical factors to identify patients at high risk of either is difficult owing to overlapping risk factors for both such eventualities, including age, sex, heart rate & Killip status at presentation, renal function, diabetic status etc.
The pivotal TRITON-TIMI 38 and PLATO studies have confirmed the anti-ischaemic efficacy of such agents over clopidogrel, with the cost, certainly in the case of prasugrel, of an increase in total bleeding events. ‘Off-target’ actions and pharmacokinetic factors associated with ticagrelor may mitigate this bleeding risk somewhat, resulting in an overall mortality benefit. What we don’t currently know for sure is the optimum duration of DAPT post-DES, with recent studies using clopidogrel such as PRODIGY showing no reduction in ischaemic events with prolonged DAPT to 24 months, but increased hazard for bleeding events. Tantalisingly, the forthcoming GLOBAL-LEADERS study will address the utility of ticagrelor monotherapy following DES implantation, possibly thereby removing bleeding hazard associated with aspirin but maintaining the protection against adverse ischaemic events seen in PLATO.
Dr. Franz Weidinger (Vienna, AU) closed the session by examining the interaction between developments in stent technology and DAPT requirement. Newer-generation DES appear to have an improved safety profile in terms of occurrence of stent thrombosis compared with first-generation DES; data from the SCAAR registry suggests that stent thrombosis rates are now as low as around 1% at 12 months post-DES, rising only 0.3-0.4% year-on-year following. Factors that may have affected this include thinner struts, more biocompatible metals and stent coatings including biodegradable polymers, as well as improvements in drug dosage and release kinetics. That said, stent thrombosis is only partially stent-related, with important contributions from improved implantation techniques, patient and compliance factors and, of course, type of antiplatelet therapy.
In summary:

  • Both stent thrombosis and bleeding events post-PCI with DES carry a mortality hazard.
  • Use of platelet function testing has thus far failed to define the clinical impact of triaging therapy for patients that may be at increased risk of either stent thrombosis or bleeding.
  • Premature cessation of DAPT, often related to unplanned surgery, carries a mortality hazard.
  • Newer agents such as prasugrel and ticagrelor reduce stent thrombosis and recurrent ischaemic events at the expense of increased bleeding.
  • Newer-generation stents have lower stent thrombosis rates; however, such improved safety may be multifactorial.

References


Session Title: Antiplatelet and antithrombotic therapy after drug-eluting stents: what is next?

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.