Fuentes de la posición de garante en la doctrina penal

The evidence relating to the benefits and risks of antiplatelet treatment in symptomatic carotid artery stenosis is evolving. Historically, we relied on data extrapolated from global ischaemic stroke/TIA studies to guide us on the optimal antiplatelet treatment for carotid artery stenosis210_. Combination therapy with dipyridamole or clopidogrel has greater efficacy but fails to prevent many stroke recurrences211_{. TCD-based studies}37, 212 _{have allowed us to use MES as a surrogate} marker of short term stroke risk to assess the optimal antithrombotic and antiplatelet agents in both patients with symptomatic carotid artery disease and following carotid endarterectomy. Microemboli following acute stroke/TIA or carotid endarterectomy are much more common than the actual recurrent clinical event. The main advantage of this technique is to be able to evaluate antiplatelet, anticoagulant and antithrombotic effect of treatments in a much smaller number of patients than those required with the use of a clinical end point such as stroke37_{. The efficacy of}

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using TCD-detected microemboli as the surrogate marker to evaluate the effectiveness of treatment pertinent to carotid artery disease has been reflected with the increasing published data as summarised by the Table 4 below:

Table 4 Antiplatelet and antithrombotic agents evaluation based on TCD-based studies

Year Authors Research method

Clinical setting Agents evaluated 2013 Saedon et al176 _{Registry Carotid endarterectomy Tirofiban vs.}

Dextran-40 2011 King et al212 _{RCT Symptomatic carotid}

stenosis

Clopidogrel & aspirin vs. Dipyridamole & aspirin

2011 Markus et al168 _{RCT Carotid endarterectomy Von Willebrand} Inhibitor ARC1779 2008 Vogten et al213 _{Prospective Carotid endarterectomy Clopidogrel vs.}

aspirin

2008 McMahon et al178 _{RCT Carotid endarterectomy Un-fractionated} heparin vs. low molecular weight heparin

2008 Van Dellen et al214 _{Case series Carotid endarterectomy Tirofiban} 2007 De Borst et al215 _{RCT Carotid endarterectomy Dipyridamole &}

aspirin vs. dipyridamole & aspirin & clopidogrel vs. Dipyridamole & aspirin & dextran 2005 Markus et al37 _{RCT Symptomatic carotid}

stenosis

Clopidogrel & aspirin vs. aspirin

2005 Tytgat et al216 _{RCT Carotid endarterectomy Aspirin}

2004 Payne et al217 _{RCT Carotid endarterectomy Clopidogrel & aspirin} vs. aspirin

2003 Lennard et al218 _{Case series Symptomatic carotid} stenosis

Dextran-40 2001 Goertlet et al219 _{Prospective Symptomatic carotid}

stenosis

Aspirin 2000 Hayes et al220 _{Prospective Carotid endarterectomy Dextran-40}

1998 Molloy et al221 _{RCT Carotid endarterectomy S-Nitrosoglutathione}

TCD – directed antithrombotic treatments have been shown to reduce the risk of thrombotic stroke acutely in the context of carotid surgery33_{. Dextran was one of the earliest antithrombotic} agents evaluated and used to treat microemboli. It has been extensively studied in the context carotid surgery, where it has been used to treat patients with high levels of postoperative embolisation since the late 1990s167, 222_{. The previous studies suggested a number of potential}

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modes of action involving platelets223_{, von Willebrand factor}224_{, and the fibrinolytic system}225_{. The} most probable explanation comes from the Noorman et al study which showed that Dextran increases tissue – plasmin activator (t-PA) plasma concentration225_{. T-PA is a protein which} activates fibrinolysis by converting plasminogen to plasmin. Noorman et al225 _{demonstrated that} in rats, dextran inhibits mannose receptor-mediated t-PA clearance. The inhibition of t-PA clearance during dextran infusion results in increased endogenous t-PA plasma concentrations. A recent laboratory study in Leicester exploring the potential modes of action of dextran involving platelets, von Willebrand factor and fibrinolytic system further supported the theory that dextran enhances fibrinolysis through blockade of the uptake of t-PA in vivo226 _{. This study also clarified} other potential mechanisms of dextran such as the breakdown effect of von Willebrand factor leading to a reduction of platelet adhesion to the vessel wall and also the dextran effect in causing thrombus instability. In a consecutive carotid endarterectomy series by Naylor et al167_{, the use of} perioperative dextran in 500 consecutive operations resulted in no postoperative strokes. More recent findings from a group of vascular surgeons based in New England found that dextran was not associated with a significant decrease in the incidence of postoperative ipsilateral stroke, all stroke, and stroke or death227_{. The use of dextran in their series was also associated with a} significantly increased risk of myocardial infarction and congestive heart failure227_{. Hayes et al} studied the association between microembolisation and platelet activity based on the hypothesis that the magnitude of postoperative embolisation reflected an enhanced state of platelet

activation and aggregation in susceptible patients228_{. The platelet response to adenosine}

diphosphate was significantly higher in patients who developed high rates MES and these cohorts of patients may respond to the P2Y12 ADP receptor antagonist clopidogrel228_{. Further randomised} controlled trials37, 217 _{of combined platelet inhibition with aspirin plus clopidogrel vs. aspirin in} both patients with symptomatic carotid stenosis and undergoing carotid endarterectomy showed a significant reduction of frequency of MES and stroke recurrence. The use of TCD technique has made it clinically practical and feasible for us to evaluate novel antiplatelet agents or multiple

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antiplatelet treatments such as S-nitroso-glutathione 221_{, tirofiban}214_{, von Willebrand inhibitor} 168_, high dose aspirin175 _{and a combination of aspirin, dipyridamole and clopidogrel} 37, 215, 217_.

Despite extensive studies, there is no consensus on which antiplatelet therapy or combination is most effective in abolishing TCD-detected microemboli, with both the aims of preventing post- carotid endarterectomy thrombotic stroke and recurrent stroke in acute symptomatic carotid artery disease patients.

1.3 Medical Registry – establishing Warwick Carotid Surgery Registry