|Year : 2015 | Volume
| Issue : 2 | Page : 55-59
Anti-thrombotic Regime for Percutaneous Intervention in Peripheral Arterial Disease: A Need of the Hour
Pallavi Kawatra1, Sanjay C Desai2, Cuckoo Aiyappa1
1 Department of Pharmacology, M.S. Ramaiah Medical College, Bengaluru, Karnataka, India
2 Department of Vascular Surgery, M.S. Ramaiah Medical College, Bengaluru, Karnataka, India
|Date of Web Publication||31-Jul-2015|
Dr. Pallavi Kawatra
Department of Pharmacology, M.S. Ramaiah Medical College, Bengaluru, Karnataka
Source of Support: None, Conflict of Interest: None
Peripheral arterial disease, a significant contributor to morbidity and mortality, is an imperative marker of a coexisting subclinical coronary artery disease. Since most of the patients become symptomatic at a later stage, a surgical approach becomes inevitable in these patients. With the introduction of percutaneous transluminal angioplasty, it has been possible to preclude numerous amputations. However, this procedure comes with the drawback of restenosis on the long term. In order to overcome this problem, a plethora of inconsistent regimes, pertaining to anti-thrombotics are being prescribed. In the face of the current scenario, to overcome the preordained outcome of restenosis, this systematic review highlights the problem of restenosis experienced in daily practice. It also discusses some commonly used anti-thrombotics and their success in various clinical trials suggesting the absolute need of a protocol for prescribing these drugs before and after angioplasty.
Keywords: Anti-thrombotics, percutaneous transluminal angioplasty, peripheral arterial disease, restenosis Anti-thrombotics, percutaneous transluminal angioplasty, peripheral arterial disease, restenosis
|How to cite this article:|
Kawatra P, Desai SC, Aiyappa C. Anti-thrombotic Regime for Percutaneous Intervention in Peripheral Arterial Disease: A Need of the Hour. Indian J Vasc Endovasc Surg 2015;2:55-9
|How to cite this URL:|
Kawatra P, Desai SC, Aiyappa C. Anti-thrombotic Regime for Percutaneous Intervention in Peripheral Arterial Disease: A Need of the Hour. Indian J Vasc Endovasc Surg [serial online] 2015 [cited 2022 May 26];2:55-9. Available from: https://www.indjvascsurg.org/text.asp?2015/2/2/55/161942
| Introduction|| |
Peripheral arterial disease (PAD) can be described as a condition which comprises of the occlusion of peripheral arteries of the extremities and excludes the thoracic and intracranial vessels. It effects about 12% of the population in the United States.  Numerable factors such as atherosclerosis, instigated by the altered lifestyles, and various risk factors such as smoking, diabetes mellitus, hypertension result in narrowing of the arteries over a period of time.  Patients with PAD have approximately the same risk of death from cardiovascular diseases, as do patients with the history of coronary or cerebral vascular disease, the risk being particularly high in patients of large vessel disease.  Therefore, it may be considered as a surrogate marker of subclinical coronary artery diseases (CAD). PAD encompasses a broad spectrum of symptoms with which an individual may present, most frequently being intermittent claudication.  It is an ailment which effects the quality of life and interferes with the daily activities.
Options of both medical and surgical modalities are available in order to treat this condition. Drugs like statins, antiplatelet such as aspirin and clopidogrel, cilostazol are invariably given to these patients,  even though the prescription pattern may vary among physicians and surgeon.  With the introduction of promising surgical interventions, it has now been possible to forestall a number of amputations. Percutaneous transluminal angioplasty (PTA) has proven to be a useful modality in revascularization of iliac, femoropopliteal and below the knee arteries. Nevertheless, restenosis remains a limitation of this procedure which the surgeons stumble upon during a long term follow-up. This re-occlusion may be encountered as early as on the table while doing the procedure. According to a previous study significantly increased levels of thrombin-anti-thrombin III complexes, prothrombin fragments, and D-dimers are found even 1 h after PTA.  This systematic review has been formulated after an extensive search on PubMed and Google Scholar using keywords like anti-thrombotics and PTA in order to outline some commonly used anti-thrombotics by vascular surgeons. Unlike in cardiology, where a lot of trials have been conducted, there is not enough data to determine a protocol regarding the use of antiplatelet prior and after angioplasty for PADs.
| Role of Angioplasty in Peripheral Arterial Disease|| |
Revascularization can be obtained by two types of procedures: Endovascular or surgery. Endovascular surgery includes angioplasty, stenting, and atherectomy.  PTA, is a technique whereby a catheter is inserted into the artery at the site of occlusion and the balloon is inflated in order to reinstate the patency of the vessel. Charles Theodore Dotter, also known as the father of intervention, revolutionized the treatment of peripheral atherosclerotic lesions with the introduction of the PTA in 1964. His first patient, Laura Shaw, was initially advised an amputation by her treating surgeon. However, when approached to Dotter, he considered the stenosis in the superficial femoral artery as a perfect model to test his catheter and eventually succeeded in making her walk on her feet.  Individuals with debilitating condition, unable to perform daily activities or suffering from critical limb ischemia are potential candidates for revascularization procedures. Peripheral percutaneous intervention is less invasive than open surgical bypass yet restore vessel patency, unlike pharmacotherapy.  It is suggested to be one of the primary options for treatment of infrainguinal arterial occlusive disease.  Though the success of this procedure may be subjected to various factors, a success rate of 90-95% has been attained so far for stenotic lesions and a slightly lower rate of 80-90% for complete occlusions.  It has been found to improve the 3 years overall survival rate up to 92.3% in one of the studies performed on 385 patients by Morris-Stiff et al.  However, re-occlusion is the main drawback encountered in the clinical practice since PTA induces a prothrombotic condition. The use of nitinol stents have been found to be superior to the conventional balloon angioplasty with better patency rates over a period of 12 months. , Therefore, an appropriate regime of antiplatelet before and after the procedure becomes the need of the hour.
| Pathology of Restenosis|| |
Restenosis is the recurrence of stenosis associated with the threshold for restenosis being >50%. It may be acute due to the formation of a blood clot or it may occur chronically over a period of time. This is essentially due to vascular injury occurring following the disruption of the atheromatous plaque during the procedure of angioplasty. The expansile force on the non-distensible plaque, results in its fragmentation, which initiates platelet deposition through the processes of platelet adhesion and recruitment of circulating platelets to form an enlarging mural platelet thrombus. Thrombin produced by simultaneous activation of the coagulation cascade by sub endothelial connective tissue structures enhances platelet deposition and stabilizes the forming thrombus with enmeshing fibrin. 
A number of factors may contribute to the occurrence of this restenosis such as the coexisting comorbidities, location of plaque, length of the segment effected, the vessel diameter, and the degree of occlusion. The narrower vessels are known to be more prone to stenosis in the long term. Simultaneously, an altered permeability leads to a direct interaction between the various components of the blood with vessel wall. 
Endothelium normally functions as a barrier to the various cellular components of the blood and even function to secrete PGI2 in order to prevent the platelets from aggregating. The role of PGI2 analogues on restenosis has already been demonstrated in animal models.  Thus, a direct injury to the vessel wall induces a denudation of the endothelial lining. It results in the exposure of the sub endothelial collagen which stems the release of adenosine diphosphate (ADP) and 5 hydroxytryptamine from the platelets resulting in an increase of their adhesion and aggregation. There is also a concomitant activation of the cox enzyme which leads to the production of thromboxane A2 and can contribute to the thrombus formation. An essential component of restenosis is the occurrence of intimal hyperplasia which is attributed to the various cells such as macrophages, mitogens, and growth factors like platelet derived growth factor (PDGF), which subsequently results in the reduction of the vessel compliance. Smooth muscle cells (SMCs) undergo phenotypic changes which are responsible for their proliferation.  In the initial phase of stenting, formation of thrombin-anti-thrombin complexes occurs, which signifies the activation of the coagulation cascade. The consequence of this is an increase probability of the occurrence of an early occlusion within 4 weeks of the intervention.
| Incidence of Restenosis|| |
In a study done in 2003, where stenting was done for peripheral arteries, the range of restenosis following 1-year varied from 32% to 35%.  Although stenting decreases the incidence by 10%, the chances of in stent restenosis still remains high. Prevention of restenosis in the coronary vasculature has been demonstrated with cilostazol, trapidil, probucol, tranilast, nitric oxide donors, and clopidogrel. Given the similarities in revascularization procedures and in the pathophysiology of restenosis, it is possible that these results may be extrapolated to the setting of restenosis in the peripheral vasculature, making trials with these agents imperative. 
| Present Treatment|| |
Aspirin is one of the oldest antiplatelet drugs which is known to be relegate the cardiovascular complications in patients of PAD.  As per the previous studies, use of aspirin is associated with a lower incidence of re-occlusion following PTA. However, due to the absence of any protocol, the dose to be used has not been standardized. One of the studies, which followed up about 207 patients for a period of 24 months, suggests that there is no marked difference in the efficacy between low dose and high dose aspirin.  In a meta-analysis of 287 studies, which compared the use of antiplatelet therapy against control, and even compared the different antiplatelet regimes, it was concluded that aspirin in a dose of 75-100 mg daily is effective in preventing episodes of occlusive vascular events in high risk patients. 
The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial, which involved 15,603 patients suggested that the use of dual antiplatelet nay not significantly reduce the primary endpoint of myocardial infarction (MI) but may be beneficial to patients with a history of MI or ischemic stroke.  In the RELOAD study (the Reload with Clopidogrel before Coronary Angioplasty in Subjects Treated Long Term with Dual Antiplatelet Therapy) a loading dose of clopidogrel in patients already previously on clopidogrel, prior to coronary angioplasty resulted in a significant inhibition of platelet aggregation.  In one of the studies, treatment alone with a loading dose of 600 mg of clopidogrel, 6-24 h before the procedure has been shown to improve the clinical outcome over a period of 1-month due to its benefits in decreasing platelet reactivity.  This can provide a basis of evaluating the effects of clopidogrel for prevention of on table restenosis Clopidogrel might represent a useful alternative in cases in which aspirin is not tolerated or as a combination therapy with aspirin, especially when increased risk factors for re-occlusion are detected, although specific data on this strategy are lacking.  Clopidogrel pretreatment significantly reduces the incidence of cardiovascular death or ischemic complications both before and after percutaneous coronary intervention and without a significant increase in major or minor bleeding. 
| Dual Antiplatelet Therapy|| |
Many interventionists use a combination of aspirin and clopidogrel before and after PTA and stenting in peripheral arteries. It has already been established that the use of dual platelets, aspirin along with clopidogrel combination is superior in patients of CAD undergoing stenting. However, according to a study conducted by Cassar et al., the use of loading dose of a combination of aspirin and clopidogrel in patients prior to angioplasty has found to inhibit the platelet function.  Dual antiplatelets decrease the ADP-stimulated fibrinogen binding and plasma PDGF but it does not have considerable effect on SMC proliferative capacity as measured by ERK 1/2 levels (extracellular regulated kinase-step of the mitogen-activated protein kinase cascade). 
| Cilostazol|| |
In spite of its antiplatelet activity being known for more than two decades, not many trials have evaluated the efficacy of this novel phosphodiesterase inhibitor for prevention of re-occlusion following angioplasty. It is known to prevent both primary and secondary platelet aggregation unlike aspirin, which is known to inhibit only collagen induced platelet aggregation.  It decreases the level of circulating pro coagulants, thereby enhancing its antiplatelet activity.  Its role in prevention of restenosis can be attributed to the fact that it improves the endothelial function and therefore indirectly contributes to decreasing the activation of platelets in the circulation.  Tsuchikane et al. conducted a trial which emphasized on the role of this drug in preventing restenosis following percutaneous transluminal coronary angioplasty when compared with aspirin.  Its main role is due to inhibition of intimal hyperplasia, which is one of the foremost causes of restenosis.  Further, the up regulation of the hepatocyte growth factor as demonstrated in the Cilostazol for RESTenosis trial concluded its inevitable role in inhibition of abnormal proliferation of vascular smooth muscles. 
| Low Molecular Weight Heparin|| |
Heparin is known to inhibit the intimal hyperplasia which is the major contributing factor to restenosis following angioplasty. However, in spite of its marked efficacy in animal models, its effect in clinical practice has been inconsistent. However, this incongruity in results has been ascribed to the difference in the dose and duration of treatment when compared with in vivo models.  The ERA study gaged the anti-proliferative effect of enoxaparin (a low molecular weight heparin) administered once daily for a period of 1-month following angioplasty. Despite the treatment being well-tolerated, it did not show any significant reduction in restenosis and did not alter the course of the clinical outcome.  Another alternative compound, dalteparin, prove to be unsuccessful in averting the complication of restenosis when evaluated in patients undergoing femoropopliteal PTA. 
| Present Guidelines|| |
The RENDOVASC study highlighted the arbitrariness in the antiplatelet regime used in 1,557 patients following endovascular procedures in Spain.  A survey conducted at a national vascular meeting which included 51 respondents highlighted that majority of the surgeons prefer 81 mg of aspirin, though the duration of treatment was highly subjected to variation.  According to the 2014, European Society of Cardiology and the European Association for Cardio-thoracic Surgery guidelines on myocardial revascularization, a dual antiplatelet therapy is advised in patients of Acute Coronary Syndrome for a period of 1-year irrespective of the revascularization procedure.  However, due to a scarcity of sufficient data, such a protocol is lacking for patients of peripheral vascular disease undergoing PTA. As per the American College of Chest Physician guidelines, a single antiplatelet therapy is preferred for patients undergoing angioplasty whereas in patients with critical limb ischemia and rest pain, the use of prostanoids is recommended.  In recent article by Elias, it was henceforth put forward that though a dual antiplatelet may not be of any added benefit to patients of PAD undergoing revascularization, but it may be useful in patients of superficial femoral artery stenting. 
| Conclusion|| |
At present, despite the lack of proper guidelines, antithrombotic treatments are being prescribed to patients of PAD undergoing PTA, on the basis of assessment of individual risk factors, the choice of stent and the profound clinical experience of various vascular surgeons. However, due to paucity of a universal protocol, there is inconsistency in the choice, dose as well as the duration of treatment. Thus, there lies an inevitable need to establish a consensus regarding the adequate regime for such patients in order to yield paramount results without any additional adverse effects.
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