Current Pharmaceutical Design - Volume 22, Issue 29, 2016

The role of platelets in atherosclerotic process and subsequently in the pathophysiology of cardiovascular disease is essential as platelets in addition to their contribution to thrombosis and hemostasis modulating inflammatory reactions and immune response. Platelets after adhesion on the injured vascular endothelium and activation release a wide range of molecules stored in platelets granules such as chemokines, proinflammatory molecules and other biological response modulators accelerating interaction among platelets, endothelial cells and leukocytes. These interactions establish a localized inflammatory response that promotes the atherosclerotic process. Moreover, activated platelets give rise to microparticles another active participant within the blood stream. The purpose of this review is to present the role of platelets in the above mechanisms giving an emphasis on the nature of the platelet derived- molecules and their contribution to the atherosclerotic process.

Anti-platelet drugs are necessary in treating patients with coronary artery disease, ischemic stroke and peripheral arterial disease. However, despite the use of adequate anti-platelet therapy, some patients will experience a recurrent atherothrombotic vascular event. These patients are characterized as low- or non-responders to therapy. Individual responsiveness to anti-platelet therapy as the use of clopidogrel and/or aspirin varies widely among patients. Such an individual variability is mainly determined by environmental and genetic factors. In this review, we focused on the underlying genetic mechanisms that might influence response to anti-platelet drugs.

The vascular endothelium comprises a continuous single cell layer of endothelial cells which line the entire cardiovascular system. Impaired endothelial function underlies the pathogenesis and contributes to the progression of atherosclerosis. Oxidative stress, vasoconstriction, inflammation, proliferation and thrombosis occur in dysfunctional endothelium while the latter, is primarily mediated by platelet activation and adherence to vascular wall. Despite the primary action of antiplatelet agents including aspirin, P2Y12 ADP receptor antagonists and glycoprotein IIb/IIIa inhibitors, a growing body of literature suggests that an important mechanism of their action involves complex modulation of endothelial function via platelet-endothelial interactions, modification of the inflammatory cytokine cascade and nitric oxide mediated effects. These agents represent the mainstay in pharmacological treatment of all aspects of cardiovascular disease both in primary and secondary prevention. However beyond these properties, it is important to note that pharmacological modification of endothelial dysfunction has been postulated as a therapeutic target for reduction of cardiovascular events.

Background: Acute coronary syndromes (ACS) represent the final step in the chronic process of atherothrombotic coronary disease which begins early in life as thickening of intima layer and progresses to fibroatheroma and fibrocalcific lesions with vulnerable characteristics. Methods: As abrupt occlusion in the settings of ACS happens due to platelet aggregation and mobilization antiplatelet treatment has gained significant interest especially in the settings of primary percutaneous intervention and the aim of this review article is to understand the current evidence justifying the use and combination of different antiplatelet agents. Results: Beyond aspirin, several antiplatelet agents (ADP receptor inhibitors, Glycoprotein IIb/IIIa inhibitors and varopaxar) are used in combination to effectively inhibit platelet activity. However the best choice, initiation, combination and duration of antithrombotic treatment, in order to maximize the effectiveness of therapy and reduce the hazard of bleeding, depends on the clinical setting and patient specific characteristics and is an issue of intense scientific interest. Conclusion: Early and potent platelet inhibition with safety reassurance can be achieved by a combination of antiplatelet agents and is essential for the management of ACS. Therefore in this review article we focus on the current evidence regarding rational, safety and effectiveness of current antiplatelet approaches in acute coronary syndromes.

Background: Apart from the acute thrombotic complications that lead to acute coronary syndromes (ACS), platelet activation also plays an important role in the initiation and progression of atherosclerosis. In addition, it is speculated that anti-platelet therapy can be beneficial for patients with stable coronary artery disease (CAD). Of note, patients on optimal anti-platelet treatment still experience thrombotic events, whereas complications, such as bleeding, cannot be ignored. In this light, novel antiplatelet regimens have been used to minimize the residual platelet activation without compromising normal haemostasis. Methods: We performed a thorough search of the literature in order to review the beneficial role of novel antiplatelets in patients with stable CAD. We have also focused on studies that examine the effect of these drugs on platelet reactivity as well as on cardiovascular outcomes. Conclusion: Specific agents, such as vorapaxar and cilostazol, have been found to reduce platelet reactivity as well as to improve patients’ prognosis. Of note, the use of novel antiplatelets is of clinical importance in patients with increased thrombotic status and in those with resistance to classic antiplatelets. However, the available data on most of the novel antiplatelets are mainly derived from studies including ACS patients undergoing angioplasty Therefore, large randomized controlled studies are required to evaluate the clinical benefit of novel antiplatelets in patients with stable CAD.

Background: Pharmacological properties of the currently available P2Y12 receptor antagonists differ significantly and lead to different degrees of platelets inhibition and cardiovascular outcomes. Methods: We performed a systematic review and meta-analysis of the comparative effects of newer antiplatelet agents versus clopidogrel on major adverse cardiovascular events (MACE), all-cause mortality, myocardial infarction (MI), stroke, major bleeding and stent thrombosis, in patients with acute coronary syndromes (ACS) and/or undergoing percutaneous coronary intervention (PCI). Results: We identified 11 prospective randomized studies comparing newer antiplatelets to clopidogrel. The total number of participants included in meta-analysis was 70239. The total number of participants treated with clopidogrel was 34792 while 35447 patients were assigned to newer P2Y12 inhibitors, of which 29.4% received ticagrelor, 35.2% prasugrel and 35.4% were loaded with intravenous cangrelor. Ticagrelor use was associated with significantly reduced MACE, all-cause mortality, myocardial infarction and stent thrombosis and similar rates of stroke and major bleeding compared to clopidogrel in patients with ACS and/or PCI. Prasugrel use was associated with significantly lower rates of MACE, MI and stent thrombosis but significantly high rates of major bleeding and thus no all-cause mortality benefit compared to clopidogrel. Conclusion: Newer P2Y12 receptor antagonists are associated with better cardiovascular outcomes in patients with ACS and/or undergoing PCI. Prasugrel use resulted in higher major bleeding rates and no overall mortality benefit compared with clopidogrel.

Background: Patients with ST-segment elevation myocardial infarction represent a high-risk population and an effective antiplatelet treatment adjunctive to primary percutaneous coronary intervention is of paramount importance. Methods: This topic will review the current evidence on clinical efficacy and safety of oral antiplatelet therapy in patients with an acute ST-segment elevation myocardial infarction. Unsettled issues and future perspectives for their use in these patients are also discussed. Results: Added to aspirin, clopidogrel, prasugrel and ticagrelor represent viable options regarding oral P2Y12 inhibition, with prasugrel and ticagrelor being preferred over clopidogrel, according to results of large randomized clinical trials. Early clinical efficacy of oral antiplatelet agents in STEMI patients has been questioned, mainly because of their delayed onset of action in the clinical setting of ST-segment elevation myocardial infarction and the recently described adverse effect of morphine on their pharmacodynamic/pharmacokinetic profile. Whether these agents should be administered beyond 1 year after the index event is also under discussion, as there is clinical evidence that prolonged administration may be associated with clinical benefit. Conclusion: Use of oral P2Y12 inhibitors in patients with ST-segment elevation myocardial infarction still faces questions and future research is needed to establish which, when and how should be administered in this clinical setting.

Background: Dual antiplatelet therapy (DAPT) is one of the cornerstones of coronary artery disease (CAD) treatment. Standard DAPT requires one of, P2Y12 receptor inhibitors, clopidogrel, prasugrel or ticagrelor as an adjunct therapy to aspirin administration. The decision over DAPT duration depends on the evaluation of thrombotic risk and the assessment of the probability for major bleeding events. Methods: The goal of this work was to identify which would be the appropriate combination of antiplatelet agents and the optimal duration of DAPT, based on the patient’s medical history and clinical characteristics. A thorough search of PubMed and the Cochrane Database was conducted in order to identify randomized controlled trials, observational studies, current ESC and ACC/AHA guidelines and novel articles on the subject. Results: The decision over DAPT duration is based on a careful approach which requires the evaluation of thrombotic risk and the assessment of the probability for major bleeding events. A series of aspects and special conditions may influence the duration of DAPT after stenting e.g. the type of the implanted stent (DES or BMS) or if the commencement of DAPT is administered in the context of an acute coronary syndrome or in the setting of stable CAD. Current guidelines can assist clinicians in making decisions but treating patients in special groups e.g. with diabetes mellitus or the elderly people can be very demanding. Conclusion: Studies which examined optimal DAPT duration, displayed controversial results, mainly observed because of the discrepancy and heterogeneity between different study designs or the decision of a great proportion of investigators to statistically test for non-inferiority. A careful, patient-centered approach, which considers thrombotic risk versus the risk for bleeding complications and other individual characteristics and comorbidities, is required when deciding DAPT duration.

Background: Transcatheter aortic valve implantation (TAVI) has undeniably earned a prestigious post in the quiver of interventional cardiologists against symptomatic severe aortic stenosis. Cerebrovascular events are listed within the most frequent complications. Methods: We performed a systematic search of EMBASE, MEDLINE, and the Cochrane library from inception to March 2016 for the following search terms (transcatheter AND antiplatelet) OR (transcatheter AND antithrombotic) to retrieve studies of dual antiplatelet treatment (DAPT) and single antiplatelet treatment (SAPT) in patients after TAVI to study thrombotic, hemorrhagic and cardiovascular events at 30 days post procedure. From a total of 208 records 4 studies met inclusion criteria. Results: In the included studies, 286 patients were enrolled in the DAPT group and 354 patients in the SAPT group. There was no difference in all-cause mortality, cardiovascular mortality, stroke, and myocardial infraction 30 days post TAVI between DAPT and SAPT. However, patients in the DAPT group had a significantly increased incidence of lethal and major bleeding at 30 days of follow-up and the incidence of the combined end-point of stroke, spontaneous MI, all-cause mortality and major bleeding was significantly higher in the DAPT group in comparison to the SAPT group. Conclusion: DAPT compared to SAPT in patients after TAVI increases incidence of hemorrhagic events with no benefits in terms of thrombotic events and cardiovascular mortality. However, these data must be interpreted cautiously and the choice of DAPT over SAPT must be based on an individual patient characteristic according to medical practice criteria.

Background: In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), dual antiplatelet therapy has been shown to effectively prevent stent thrombosis and other ischemic cardiovascular events. The frequent occurrence of atrial fibrillation (AF) and concomitant CAD in the same individuals, suggests that clinicians will encounter many patients treated with PCI who will require anticoagulant treatment for the prevention of the thromboembolic complications of AF. Methods: In this narrative review we provide an overview and update of evidence regarding antiplatelet therapy in patients with AF undergoing PCI. Results: The combination of dual antiplatelet therapy with anticoagulants may further protect a patient from ischemic complications, at the cost, however, of a several-fold increased bleeding risk. The introduction of novel pharmaceutical agents in both categories implies that there is paucity of data regarding the efficacy and, more importantly, the safety of between-drug combinations. Conclusion: Careful consideration of the patient’s individual characteristics and assessment of the risk for bleeding and thrombotic events using validated risk prediction tools is of great importance in order to maximize the benefits for each patient, while minimizing the risk for hemorrhage.

Background: Acetylsalicylic acid and clopidogrel are two antiplatelet agents currently used in the therapy of peripheral arterial disease. Cilostazol also inhibits platelet aggegration. These agents present limitations that novel antiplatelet agents may overcome. Objective: The aim of this manuscript is to review current data on the use of novel antiplatelet agents in peripheral arterial disease. Method: An extensive search in the English medical literature has yielded a number of publications on a number of novel antiplatelet agents; atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel, and prasugrel. Results: Data on atopaxar, vorapaxar, cangrelor, ticagrelor, elinogrel and prasugrel come mainly from cardiology publications. Limitations, side effects and effectiveness of each of these agents are studied, but their use in peripheral arterial disease is limited, especially for those agents that have not still been approved for this indication. As expected, main side effect of most of these agents is haemorrhage, but other important side effects limit the use of some of these agents in specific subgroups of patients. Conclusion: Novel antiplatelet agents demonstrate a range of promising characteristics, but further study and clinical trials are necessary for them to be considered safe and effective.

Background: Stroke is a feared vascular event among healthy people and those with cardiovascular disease, and holds a leading position as a cause of disability and death worldwide. Antiplatelet therapy is central in the management of patients with ischemic nonembolic stroke and transient ischemic attacks. Methods: In this narrative review, we provide an overview and update of evidence regarding antiplatelet treatment in the primary and secondary prevention of stroke. Results: Aspirin, clopidogrel and aspirin plus dipyridamole are the mainstays of antiplatelet treatment post-stroke, while promising agents include triflusal, cilostazol and ticagrelor. Available data are in favor of dual antiplatelet treatment in the early treatment of atherosclerotic large vessel disease. Long-term dual antiplatelet treatment should be individualized keeping in mind the higher rates of bleeding complications. Conclusion: Treatment with an antiplatelet agent is recommended to reduce recurrent stroke and death in patients with a non-cardioembolic ischemic stroke or transient ischemic attack. Moreover, clinicians should carefully assess the pros and cons in each case and individualize the need for prolonged dual antiplatelet therapy.