Current Vascular Pharmacology - Volume 18, Issue 3, 2020

Under physiological conditions, peripheral arteries release endogenous vascular-protective and antithrombotic agents. Endothelial cells actively synthesize vasoactive mediators, which regulate vascular tone and platelet reactivity thus preventing thrombosis. Atherosclerosis disrupts homeostasis and favours thrombosis by triggering pro-thrombotic responses in the vessels, platelet activation, aggregation as well as vasoconstriction, phenomena that ultimately lead to symptomatic lumen restriction or complete occlusion. In the present review, we will discuss the homeostatic role of arterial vessels in releasing vascular-protective agents, such as nitric oxide and prostacyclin, the role of pro- and anti-thrombotic vascular receptors as well as the contribution of circulating platelets and coagulation factors in triggering the pro-thrombotic response(s). We will discuss the pathological consequences of disrupting the protective pathways in the arteries and the pharmacological interventions along these pathways.

Lower extremity artery disease (LEAD) is a marker of a more advanced atherosclerotic process often affecting multiple vascular beds beyond the lower limbs, with a consequent increased risk for all-cause and cardiovascular mortality. Antithrombotic therapy is the cornerstone of management of these patients to prevent ischaemic cardiovascular and limb events and death. In patients with symptomatic LEAD, the efficacy of aspirin has been established long ago for the prevention of cardiovascular events. In the current guidelines, clopidogrel may be preferred over aspirin following its incremental ability to prevent cardiovascular events, while ticagrelor is not superior to clopidogrel in reducing cardiovascular outcomes. Dual antiplatelet therapy (DAPT, aspirin with clopidogrel) is currently recommended for at least 1 month after endovascular interventions irrespective of the stent type. Antiplatelet monotherapy is recommended after infra-inguinal bypass surgery, and DAPT may be considered in below-the-knee bypass with a prosthetic graft. In symptomatic LEAD, the addition of anticoagulant (vitamin K antagonists) to antiplatelet therapy increased the risk of major and life-threatening bleeding without benefit regarding cardiovascular outcomes. In a recent trial, low dose of direct oral anticoagulant rivaroxaban plus aspirin showed promising results, not only to reduce death and major cardiovascular events, but also major limb events including amputation. Yet, this option should be considered especially in very high risk patients, after considering also the bleeding risk. Despite all the evidence accumulated since >40 years, many patients with LEAD remain undertreated and deserve close attention and implementation of guidelines advocating the use of antithrombotic therapies, tailored according to their level of risk.

Lower extremity artery disease (LEAD) represents a major public health burden, affecting hundreds of millions of people worldwide. Although risk-factor modification, exercise training and medical treatment are the mainstays of the management of LEAD, endovascular or surgical revascularisation is recommended when there is the risk of limb amputation and when drug-resistant claudication severely affects patient lifestyle. Over recent years, the number of peripheral vascular interventions (PVI) has soared worldwide, driven by the improvements in endovascular techniques and devices. This growth was accompanied by a large number of clinical trials aimed at assessing the safety and efficacy of the various revascularisation modalities, while very little evidence was collected regarding the best antithrombotic treatment in patients undergoing peripheral revascularisation. In particular, considering the extensive length of diseased vessels usually treated in PVI, an optimised approach to both platelet function and coagulation cascade is of paramount importance. However, the role of antiplatelet and anticoagulant drugs following lower extremity revascularisation is largely extrapolated from the coronary field. Current guidelines recommend long-term single antiplatelet treatment for the majority of both endovascular and surgical revascularisation procedures, preceded by an initial short-term dual antiplatelet treatment in case of PVI. We present an overview of the indications and techniques of both endovascular and surgical peripheral revascularisation, followed by an in-depth analysis of the available evidence regarding type and duration of antiplatelet and anticoagulant treatment following revascularisation.

Bleeding represents the most important complication of antithrombotic treatment, including anticoagulant and antiplatelet therapies. A number of scores were proposed to evaluate the risk of bleeding both for anticoagulant and antiplatelet treatment. In the last decade, 5 bleeding risk scores were published for use in atrial fibrillation patients, and 3 scores for patients receiving anticoagulants for venous thromboembolism therapy or prophylaxis. In addition, 3 scores were recently developed to assess inhospital or short-term bleeding risk in patients receiving antiplatelet therapy after Acute Coronary Syndrome (ACS) and Percutaneous Coronary Intervention (PCI). Furthermore, 3 additional scores have focused on long-term bleeding in outpatients receiving dual antiplatelet therapy after PCI. The aim of this review is to consider the evidence on bleeding scores.

Supplementary estrogen plays important roles for female patients as convenient birth control, relief of postmenopausal symptoms, and in the management of other selected problems. However, as is the case for essentially all medications, there are side effects. Short of a major pulmonary embolus, the most severe side effect of estrogen would appear to be sporadic, rare, and severe hypertriglyceridemia associated with acute pancreatitis. The occurrence of this fortunately rare problem usually happens in the presence of some preexisting and usually mild increase in triglycerides (TG). A case of chronic and severe recurrent acute pancreatitis is described in the introduction and the management was complete estrogen avoidance. Started close to menopause and continued for a relatively short period, estrogens may have some cardiovascular (CV) benefit but the general recommendation is not to prescribe them for CV disease prevention. Estrogens may contribute to decreased diabetes mellitus (DM) risk and control. Administration of estrogens by the transdermal route may decrease some problems such as venous thromboembolism (VTE) and elevation of TG. Administration of estrogen in the right situation brings significant benefit to the female patient but skillful, careful, and knowledgeable use is essential.

The key role of platelets in pathophysiology of Acute Coronary Syndromes (ACS) has been well recognized. Platelet activation and aggregation, together with tissue factor-pathway activation, lead to acute thrombus formation in the coronary vessels at sites of plaque rupture. Thus, antiplatelet therapy with drugs able to interfere with platelet activation/aggregation represents a cornerstone of ACS treatment in intensive care units and catheterisation labs. Several observational studies have described that residual high platelet reactivity, despite antiplatelet therapy, is associated with increased risk of nonfatal Myocardial Infarction (MI), definite/probable stent thrombosis and cardiovascular mortality. Thus, assessment of platelet function with reliable and reproducible platelet function tests might be crucial to identify patients at high risk of thrombosis or not responding to ongoing antiplatelet strategies. However, despite this promising background, some randomized clinical trials have failed to demonstrate improvement in outcomes when using platelet function tests for clinical decision-making. This review, after describing platelet biology and pathophysiology of ACS, briefly considers the drugs currently approved for use in patients with ACS or treated by the percutaneous coronary intervention (PCI). Finally, we provide an updated overview of the current methods to evaluate platelet reactivity in the clinical setting of ACS illustrating their potential advantages/limitations in current clinical practice.

Post-transplant diabetes mellitus (PTDM) and dyslipidaemia are the most common metabolic complications in kidney transplant recipients (KTR). They are associated with a higher risk of lower graft function and survival, as well as an increased risk of cardiovascular disease (CVD). The aim of this review is to provide current data on the epidemiology, pathophysiology and optimal management of these two principal metabolic complications in KTR. Several risk factors in this metabolic milieu are either already present or emerge after renal transplantation, such as those due to immunosuppressive therapy. However, the exact pathogenic mechanisms have not been fully elucidated. Awareness of these disorders is crucial to estimate CVD risk in KTR and optimize screening and therapeutic strategies. These include lifestyle (preferably according to the Mediterranean pattern) and immunosuppressive regimen modification, as well as the best available anti-diabetic (insulin or oral hypoglycaemic agents) and hypolipidaemic (e.g. statins) regimen according to an individual’s metabolic profile and medical history.

Background: In Marfan Syndrome (MFS), aortic dilatation is one of the main cardiovascular manifestations which deteriorate due to the physiological changes during pregnancy. We aimed to assess the up-to-date management and outcomes of aortic root dilation and dissection (AoD) in pregnancy with MFS. Patients and Methods: A systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Original studies published between January 1, 2001 and December 31, 2018 and which described the management and/or outcomes of AoD during or after pregnancy in women with MFS were included. Literature searches were conducted. The PubMed search was performed using terms "Marfan Syndrome" [Mesh] and "Pregnancy" [Mesh] whereas the Google Scholar search was for “Marfan” and “Pregnancy”, all words anywhere in the article. Results: The literature search yielded 177 articles on PubMed and 13,900 articles on Google Scholar. Assessment of full-text articles for eligibility after removal of duplicates from both databases yielded 12 eligible studies to be included in the final review. Conclusion: Women with MFS are at high risk of aortic dissection during pregnancy and women with aortic root 41-45 mm should consider avoiding pregnancy. Guideline-specific management of aortic aneurysms in pregnancy will reduce the risk of dissection. Diagnosis and Management of MFS need a multidisciplinary approach and team that should start working early in pregnancy. Further studies are needed to optimize medical and surgical approaches in addition to preconception counselling in highrisk subjects.

Background: Dual antiplatelet therapy (DAPT) with aspirin and ticagrelor is recommended for at least 12 months in patients after an acute coronary syndrome (ACS). However, its underuse and premature discontinuation are common in clinical practice. We aimed to investigate the impact of a dedicated follow-up strategy with clinical visits and counselling on adherence levels to ticagrelor in patients after ACS. Methods: PROGRESS (PROmotinG dual antiplatelet therapy adheREnce in the setting of acute coronary Syndromes) is a prospective, randomized trial enrolling 400 ACS patients treated with ticagrelor. Patients were randomized to be followed-up in a dedicated outpatient clinic (In-person follow-up group, [IN-FU], n=200), or with scheduled for phone interviews only (Telephone follow-up group [TEL-FU], n=200), to assess ticagrelor adherence and related complications. DAPT disruption was defined as an interruption of the administration of the drug due to complications or other reasons of non-adherence, and divided according to the duration into short (1-5 days), temporary (6-30 days) and permanent (≥30 days) disruption. The primary endpoint was the rate of DAPT disruption at 1-year follow-up. Results: The rate of ticagrelor disruption at 1 year follow-up was higher in the TEL-FU group than in the IN-FU group (19.6 vs 5.5%; p<0.0001). The IN-FU group reported a significantly lower rate of short (3.0 vs 8.5%; p=0.012) and permanent (2.0 vs 9.6%; p=0.012) disruption than TEL-FU group. The rate of major bleeding did not differ significantly between the 2 groups (p=0.450). Conclusion: The PROGRESS trial showed a net reduction in DAPT disruption in patients followed-up with clinical (in-person) follow-up visits in a dedicated outpatient clinic compared with those scheduled for phone interviews only.