Patients at limited compliance or non-responsiveness to double antiplatelet therapy

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By Carlo Briguori

The safety and efficacy of drug-eluting stents (DES) compared with bare metal stents (BMS) appear to be consistent across different groups of patients, albeit at various levels of absolute benefit and risk. Clinical trials as well as registries consistently confirm lower target lesion revascularisation rates at follow-up with DES compared to BMS. Data from registries and meta-analysis indicated that there is no difference in the risk of early (<30 days) and late (>30 days, <365 days) stent thrombosis between DES and BMS, but that an excess risk emerges after more than one year of follow-up (very late stent thrombosis). A stent thrombosis rate of 0.5–0.6% per year has been reported. Dual antiplatelet therapy (DAT) with clopidogrel and aspirin substantially reduces the risk of stent thrombosis. However, a low effectiveness of DAT has been reported due to low response to clopidogrel/aspirin and patient compliance.

 

The terms “low responsiveness” or “resistance” have been used to describe the occurrence of cardiovascular events despite regular intake of these agents at recommended doses. Clopidogrel resistance has been defined as a situation in which there is incomplete blockade of the platelet membrane P2Y12 receptor, as measured by various laboratory tests specific to clopidogrel’s mechanism of platelet inhibition, in a patient compliant with clopidogrel therapy. The degree of platelet inhibition seen following use of the second-generation thienopyridine clopidogrel varies from patient to patient in a normal or bell-shaped distribution. The variability in non-responders is such that four to 30% of patients treated with clopidogrel do not have an adequate antiplatelet response (Figure 1). Non-responders to clopidogrel were generally responsive to ticlopidine and vice versa. Only 4% of patients are poor responders to both agents, suggesting that poor response was drug-specific and not related to the overall class of thienopyridines. The benefits of increasing the clopidogrel loading dose and/or increasing the maintenance dose on reducing the laboratory evidence for clopidogrel resistance have been shown in a number of randomised trials. The clinical benefit of increasing the clopidogrel loading dose and/or the maintenance dose on reducing the incidence of subsequent adverse cardiac events has been shown in some prospective randomised trials. The clinical significance of in vitro “clopidogrel resistance” has been evaluated in patients with both acute coronary syndrome and stable angina undergoing percutaneous coronary intervention. Patients in the most resistant quartile have a higher rate of cardiovascular events at follow-up.


Clinical conditions limiting compliance to prolonged double antiplatelet therapy include: history of gastrointestinal bleeding, concomitant gastric and/or neoplastic disease, scheduled noncardiac surgery and concomitant oral anticoagulation (due to chronic atrial fibrillation, mechanical heart valve, thrombo-embolic disease or severe depression in left ventricular ejection fraction) (Figure 2).


At present, it is hard to select the most appropriate stent in case of low effectiveness of DAT in some settings of patients. Indeed limited data are available on the balance between the risk for thrombosis and the risk for bleeding in this high risk population (Figure 3). The need for non-thrombogenic or safer stents have pushed companies to develop new generation DES, where much more attention has been focused on the feasibility of avoiding polymer use or, if necessary, the use of absorbable and/or biocompatible polymers. Lately, a renewed interest has been drawn on the stent platform. Indeed, stent surface material, stent bulk material stent design and strut thickness are important and independent predictors of in-stent restenosis.


The surface material used for stents should ideally be biologically inert, corrosion-resistant and elastic; while the bulk material should have a high radial strength and low recoil for optimal scaffolding. Due to the intrinsic disadvantages of the 316L stainless steel, which is poorly biocompatible and with limited radiopacity on fluoroscopy, alternative materials have been investigated. Novel metallic materials for making stents, such as a Co-Cr alloy, allow for thinner struts while preserving radiopacity and radial strength. Moreover, knowing that minor amounts of nickel, molybdenum, and chromium ions eluted from the stainless steel stent surface may trigger an immune and inflammatory response that can potentially result in stent thrombosis and restenosis; an effective stent coating, other than improve stent emo and biocompatibility, may act as a barrier to avoid undesired heavy metal ion release. Among the few stents available today that have been developed to provide an answer to the above-mentioned needs, Chrono Carbostent (Sorin) represents the one with the most clinical proof. Chrono Carbostent consists of a thin-strut (80μm) Co-Cr stent integrally coated with Carbofilm, an extremely thin film (<0.5 mm) of pure carbon, which provides superior bio-haemocompatible properties, resulting in stent thromboresistance. It has been demonstrated that Carbofilm coating shows a lower thrombogenicity than the uncoated material, as it induces minimal platelet adhesion and limits the activation of the intrinsic pathway of coagulation. In vitro and In vivo studies reported a progressive and extensive endothelisation. Clinical experiences confirm these advantages. The SAFE trial, for example, suggests that after optimal implantation of the Carbofilm-coated Carbostent, antiplatelet therapy with aspirin alone is as safe and effective as the double antiplatelet therapy. The release of the latest drug-free stent from CID, Avantgarde, which can potentially further optimise the clinical outcomes of patients at limited compliance or non-responsiveness to DAT, is of great interest. Further clinical data are needed to confirm the excellent pre-clinical animal results.


Carlo Briguori is an interventional cardiologist, Clinica Mediterranea, Naples, Italy.