WO2020101627A1

WO2020101627A1 - A solution developed to be applied to the saphenous vein graft

Info

Publication number: WO2020101627A1
Application number: PCT/TR2019/050946
Authority: WO
Inventors: Ercan AKSIT; Basak BUYUK
Original assignee: Canakkale Onsekiz Mart Universitesi Rektorlugu
Priority date: 2018-11-14
Filing date: 2019-11-14
Publication date: 2020-05-22

Abstract

The invention relates to the application of a solution (1) comprising a locally 5 effective antiplatelet and anticoagulant agent to reduce thrombus formation, and the application of this solution (1) to the saphenous vein graft (5) before performing bypass operation to the artery.

Description

A SOLUTION DEVELOPED TO BE APPLIED TO THE SAPHENOUS

VEIN GRAFT

TECHNICAL FIELD The invention relates to the development of a solution comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation and the application of this solution to the saphenous vein graft before performing bypass operation to the artery.

PRIOR ART Cardiovascular diseases (CVDs) are the most common cause of death in the world. In 2012, 17.3 million people worldwide died due to CVDs, and by 2030 this figure is expected to exceed 23.6 million [1] Particularly in patients with decreased diabetic and ejection fraction; peripheral arterial bypass surgery for three-vessel disease and left main coronary artery disease, and for end-stage peripheral arterial disease, coronary artery bypass surgery is the first treatment option [2-4]. Although the survival rate of artery grafts taken for a single lesion is good, vein grafts are still being used for multi-vessel disease and peripheral artery disease. Despite the development of percutaneous coronary interventions and stents, 400,000 people still have a coronary bypass operation in the United States per year [5]. While the 10-year survival of the internal thoracic artery following coronary artery bypass is between 85-91%, 10-25% of saphenous vein grafts are lost within 1 year [6-7]. The saphenous vein disease which is one of the most significant disadvantages of coronary bypass graft surgery, is associated with cardiac adverse events such as, recurrent angina, recurrent coronary angiography and revascularization, myocardial infarction, and death [8-9]. Although guidelines suggest the use of multiple arteries for bypass veins, multiple arteries could be used in only about 9% of North American coronary bypass operations as true life data [10]. In a study of 3102 patients published in 2016 in the journal NEJM, it has been shown that using bilateral intra thoracic artery as a bypass vessel results in more sternal wound complications in comparison to using a single thoracic artery [11]. Saphenous veins are still the most important cornerstones of surgeons for multiple bypass veins. In a review published in 2017, it was emphasized that treatments that can prevent the blocking of saphenous vein grafts should be developed due to the difficulties of the treatment of occluded saphenous vein grafts [12-13]. Until today, a practical method that has been developed for saphenous vein disease has not yet been included in the literature and guidelines.

Vein graft disease occurs with three mechanisms: the first one is thrombosis in the first month, the other two mechanisms are intimal hyperplasia within 1 month to 1 year and atherosclerosis seen after 1 year. After bypass surgery, up to 10% of the vein grafts are lost due to acute thrombosis within the first one month. Platelet activation and thrombin are the triggers of early graft loss. In 10 years, about half is lost due to intimal hyperplasia and atherosclerosis [14-17]. The researchers conducted experimental studies to overcome saphenous vein disease through these mechanisms. Most of these studies are experimental studies in animals to reduce intimal hyperplasia.

Studies have shown that during the first few hours following the anostomosis of the vein graft, the migration of thrombocytes and neutrophis to the vein wall are intense and fibrin begins to accumulate. The release of the growth factors from thrombocytes, neutrophils and vascular straight muscle cells also lead up to intimal hyperplasia in the later days and months [18]. Breaking this mechanism from the beginning seems to slow down the oncoming processes. In 2004,Torsney

E. et ah, demonstrated in their article in Circulation Magazine, that local acetylsalicylic acid (ASA) administration to the saphenous vein reduced thrombus and neointimal formation by endothelial protection compared to oral ASA by providing endothelial protection. [19]. This publication is the only publication in the literature in which a drug is applied to the vein graft locally to reduce thrombus. Many other studies have been conducted with antiproliferative agents to reduce intimal hyperplasia. In 1999, Hu Y. et ah, demonstrated that in the publications of Circulation Magazine, growth of intimal hyperplasia was decreased by applying growth receptor antagonist locally to mice [20]. In 2011, X.-J. Gong et ah, demonstrated in their article that local Rapamycin administration on rabbits reduced neointimal hyperplasia [21]. In 2010, Rajathurai T. et al., demostrated that the periadventitial effective rapamycin treatment on pigs decreased neointimal hyperplasia and wall thickness in the first 4 weeks compared to the control group but did not have any therapeutic effect after 12 weeks due to the catch-up phenomenon. Moreover, at doses over 120pg, 25% of the grafts were ruptured due to local toxicity and, due to increased straight muscle cell proliferation, they observed increase in saphenous vein disease paradoxically. At the end of the study, they concluded that because of their local toxic effect and poor long-term efficacy, local effective rapamycin treatment would be limited in clinical applicability [22]. Huang WC et al., showed in 2013 in their study conducted on pigs that periadventitial stem cell transplantation reduced intimal thickness [23]. Despite all these animal experiments, a single human study was conducted in 2005 with Edifoligide, which is an E2F Transcription Factor inhibitor. In this“phase three” study, coronary angiographies of 3014 patients after 12th and 18th months were examined. There was no significant difference in saphenous vein graft loss between the two groups [24].

External stent models have been tried, in order to prevent saphenous vein disease. However, as mentioned in a review published in 2017, no external stent model has been effective enough to improve long-term results of saphenous vein disease [25]

In order to prevent saphenous vein graft disease, the researchers operated the patients without interrupting their antiplatelet regimens, and continued to give the antiplatelet agent orally within 6 hours after the operation, but they experienced bleeding complications so much so that they needed transfusion. [26]. Although current guidelines suggest that ASA should continue without interruption before the bypass operation, ADP receptor inhibitors from other antiplatelet agents, such as ticagrelor should be discontinued for 3 days, clopidogrel 5 days and prasugrelin 7 days in advance, all antiplatelet agents are discontinued in the perioperative period because of the fear of bleeding in daily practice and antiplatelet agents are started one day after the operation if there is no bleeding complication [27-30]. Studies have shown that, as the pathogenesis of saphenous vein disease is very well established; in the first hours after the bypass operation, rapid thrombocyte and neutrophil migration to the vein wall and fibrin accumulation has been observed. This mechanism explains why 10% of saphenous vein grafts are lost due to thrombosis in the first month because there is no antiplatelet and anticoagulant agent present in the medium during the initial hours [14]. Several studies have been carried out to prevent stent thrombosis in order to be used during bypass.

The international patent document numbered WO2016178251 of the prior art describes biodegradable polymer coated embolic protection stents suitable for implantation into the patient's body lumen, such as a vessel or coronary artery. Anti-thrombic and anti-platelet drugs are selected from the group consisting of sodium heparin, low molecular weight heparin, hirudin, argatroban, sippogralate, recombinant hirudin, forskolin, vapiprost, prostacyclin.

The United States patent document numbered US2012277726 of the prior art, refers to a method for the treatment of acute myocardial infarction (AMI), Thrombus-Containing Lesion (TCL) and Saphenous Vein Graft Lesion (SVGL), and a drug-eluting implantable medical device. More particularly, the invention relates to a drug-eluting implantable medical device that releases a drug, coated with Nano-carriers for releasing the drug at different rates to address late thrombus formation associated with acute thrombus formation, lower acute thrombus formation and AMI, TCL treatment. The method consist of following steps; implanting a medicament-releasable implantable medical device with nano carriers, at least one drug encapsulated with the first biological agent; releasing the nano-carriers from the drug-releasable insertion device at the target site, and at least one drug in the target site, the nano-carriers at the first release rate, and release of the second biological agent. The drug contains anti-thrombogenic and anti-inflammatory agents.

The United States patent document Numbered US7416558 of the prior art refers to a stent system for delivering a therapeutic agent into the body lumen. The system comprises; a stent configured to contact the wall of the body lumen to maintain the opening of the lumen; a stent cap made of a mesh and defining a distribution sleeve disposed on the stent; the delivery envelope comprises at least one therapeutic agent in quantities sufficient to release it at the treatment site.

In the prior art, drug-coated synthetic vascular grafts are used in coronary artery bypass surgery, but they are not preferred because of the high degree of obstruction. Therefore, the need to develop a solution containing localized antiplatelet and anticoagulant agents coating the natural saphenous vein with this solution has risen. The 10% occlusion rate that has been reported due to thrombosis formation in the first year following the bypass operation with the application of the solution developed in order to reduce thrombosis formation, to the saphenous vein increases the life of saphenous veins and reduces the risk of occlusion.

AIMS OF THE INVENTION

The aim of the invention is to develop a solution comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation and to apply this solution to the natural saphenous vein graft prior to conducting a bypass operation to the artery.

Another aim of the invention is to reduce the occlusion rates of saphenous vein grafts after coronary artery bypass surgery with the application of the developed solution to the saphenous vein graft. Another aim of the invention is to perform a bypass to the artery after administration of the solution containing acetylsalicylic acid, ticagrelor, and unfractionated heparin, which may affect the saphenous vein locally.

Another aim of the invention is to provide tunica adventitious coating on the outer layer of the saphenous vein graft by means of pluronic gel.

DETAILED DESCRIPTION OF THE INVENTION

The application of the local effective solution to reduce thrombus formation to achieve the objectives of the present invention is illustrated in the figures:

Figure 1: A schematic view of the application of the solution according to the invention.

Figure 2: A schematic view of the application of the solution according to the invention from different angles.

The parts in the figures are numbered one by one and the corresponding numbers are given below: 1. Solution

2. Tunica intima

3. Tunica media

4. Tunica adventitia

5. Saphenous vein graft

6. Pluronic gel

The invention is a solution (1) comprising a locally effective antiplatelet and anticoagulant agent to reduce thrombus formation; wherein, before bypassing the artery, the solution (1) is applied to the tunica adventitia (4) which is the outer layer of the saphenous vein graft (5). The invention is a solution comprising local effective antiplatelet and anticoagulant agents to reduce thrombus formation; comprising any of the agents of cangrelor, ticagrelor, prasugrel, clopidogrel which are ADP receptors in addition to the acetylsalicylic acid which is an antiplatelet agent, and one of unfractionated heparin, enoxaparin sodium, bivalirudin, fondaparinux, dabigatran, apixaban, rivaroxaban or edoxaban agents as the anticoagulant agent. Depending on the patient's age, co-morbid disease, and coagulopathy, the solution (1) comprises tirofiban, abciximab or eptifibatide which inhibits glycoprotein lib / Ilia.

The invention is a solution (1) comprising local effective antiplatelet and anticoagulant agents to reduce thrombus formation; it comprises; the antiplatelet agent, pg/kg or mI/L acetylsalicylic acid by weight pg / kg or pi [L cangrelor or ticagrelor by weight, pg/kg or U/L unfractionated heparin by weight as the anticoagulant agent according to the patient's weight in certain proportions.

The solution (1) covers the tunica adventitia (4), which is the outer layer of the saphenous vein graft (5) with the help of pluronic gel (6) as a local delivery agent. The solution (1) can also be distributed by encapsulation of the nanoparticles. Nanoparticles have several advantages as a delivery system for the local delivery of therapeutic agents. These advantages are; subcellular size, good suspension, easy penetration and continuous intracytoplasmic release capacity without causing trauma to the vessel wall [31,32]. Therefore, two antiplatelets and one anticoagulant loaded nanoparticles will be an innovative treatment strategy to prevent vein graft failure. A study has been shown to prevent stent thrombosis by combining perfluorocarbon nanoparticles with a direct thrombin inhibitor agent [33]

For the controlled release of the solution (1) a local delivery tool is required. The reason is that the patient cannot receive antiplatelet and anticoagulant agents for two days. Thus, according to the invention, the tunica adventitia (4) is coated with pluronic gel (6). Pluronic gel (6) is ideal as a local delivery agent as it can provide

72 hours of controlled release. Alternatively, to the pluronic gel (6), each molecule may be prepared as separate nanoparticles. Again, alternatively, the drugs may be introduced into the vein by a combination of locally effective microparticles/hydrogel. The additional advantage of this combination is that it can be released for longer periods of time [34,35]. Since the saphenous vein graft is also detached from its natural environment, the "organ storage solutions" can be added to the drug solution in addition to the drug solution before being bypassed into the artery in nanoparticles or hydrogel.

By means of the solution (1) and applying said solution (1) developed by means of the invention to the saphenous vein graft (5) which is formed of tunica intima (2), tunica media (3) and tunica adventitia (4) layers, approximately half of the saphenous vein grafts (5) were prolonged in usage life in 10 years following the bypass operation and the possibility of occlusion is reduced.

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Claims

1. The invention is a locally effective solution (1), developed in order to be applied onto the tunica adventitia (4), which is the outer layer of the natural saphenous vein graft (5), before performing bypass operation on the artery, characterized by comprising antiplatelet and anticoagulant agents.

2. A solution (1) according to Claim 1 characterized by comprising any one of kangrelor, ticagrelor, prasugrel, clopidogrel, in addition to acetylsalicylic acid acting as an antiplatelet agent which carries out ADP receptor inhibition.

3. A solution (1) according to Claim 1 characterized by comprising any of the agents of unfractionated heparin, enoxaparin sodium, bivalirudin, fondaparinux, dabigatran, apixaban, rivaroxaban or edoxaban as an anticoagulant agent.

4. A solution (1) according to Claim 2 characterized by comprising any of the agents of tirofiban, abciximab or eptifibatide which carry out glycoprotein Ilb/IIIa inhibition.

5. A solution (1) as claimed in any one of the preceding claims; characterized by the solution (1) comprising pluronic gel (6) being coated over tunica adventitia (4) which is the outer layer of the saphenous vein

(5).