Current Vascular Pharmacology - Volume 16, Issue 5, 2018

Cardiogenic Shock (CS) is a major challenge in current cardiology. Over the last decade, cardiogenic shock mortality has decreased somewhat, but it still remains high, particularly when associated with ischaemic heart disease. The challenges are numerous and include prevention, accurate diagnosis, prompt management and effective therapies to support a failing heart and prevent multi-organ failure. Despite improvements in the care of Acute Coronary Syndrome (ACS), it remains the most common cause of CS. In addition to existing medical therapy, mechanical circulatory support has been proposed for the management of ventricular failure. The intra-aortic balloon pump was amongst the first widely used percutaneous mechanical support devices, and more recently, systems providing a higher level of support have been developed. Although the evidence supporting their use is limited, they have the potential to significantly reduce CS-associated mortality. In this narrative review, we summarize the available evidence and discuss the future directions regarding percutaneous mechanical circulatory support in patients with left ventricular dysfunction and CS complicating ACS.

Background: Acute Coronary Syndrome (ACS) patients, despite treatment with Dual Anti- Platelet Therapy (DAPT), have up to 10% risk of recurrent Major Adverse Cardiac Events (MACE) in the short term. Methods: Here we review studies using more potent antithrombotic agent combinations to reduce this risk, namely Triple Therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date. Results: Generally speaking, TT leads to an increase in bleeding. Vorapaxar showed a signal for reducing ischaemic events, but increased intracranial haemorrhage 3-fold in the subacute phase of ACS, although remains an option for secondary prevention beyond the immediate subacute phase, particularly if prasugrel or ticagrelor are not available. Non-Vitamin K Oral Anticoagulants (NOACs) all increased bleeding, with only modest reduction in MACE noted with low dose rivaroxaban. Rivaroxaban can be considered combined with aspirin and clopidogrel in ACS patients at high ischaemic and low bleeding risk, without prior stroke/TIA. The combination of P2Y12 inhibitor and NOAC, without aspirin, looks promising. DAPT may be replaced, not by TT, but by dual therapy comprising a NOAC with a P2Y12 inhibitor. Conclusion: More potent antithrombotic regimens increase bleeding and should only be considered on an individual basis, after careful risk stratification. Accurate risk stratification of ACS patients, for both ischaemic and bleeding risk, is essential to allow individualised treatment.

Transvascular Aortic Valve Replacement (TAVR) has emerged as a treatment option in patients with severe aortic stenosis who are inoperable and has recently been evaluated in patients with intermediate surgical risk. The number of procedures is increasing worldwide in parallel with the demographic changes in industrial countries. The risk for cerebral embolism is of main concern and represents a major determinant for prognosis and quality of live after TAVR. The empiric antithrombotic therapy consists of Dual Antiplatelet Therapy (DAPT); However the risk-benefit of this approach is lacking evidence from randomized, placebo-controlled trials regarding choice and duration of antithrombotic treatment. Although anticoagulation is generally not recommended in patients with aortic bioprosthesis without atrial fibrillation, there is current uncertainty whether combination of antiplatelet and anticoagulant therapy or anticoagulation alone might represent a more favorable antithrombotic regimen compared to the current empiric standard of DAPT. In addition, so far undetected atrial fibrillation is highly prevalent in the elderly population undergoing TAVR. In particular, the favorable safety profile of Non-Vitamin K Oral Anticoagulants (NOAC) offers an attractive option. A number of trials are currently underway to investigate the benefit of NOAC in patients with and without atrial fibrillation undergoing TAVR. The present article reviews the available evidence concerning stroke risk in TAVR patients and the current and future role of antithrombotic therapy during and after the procedure.

Platelet activation plays a central role in triggering and complicating acute coronary syndromes, especially in case of stent thrombosis and myocardial infarction. On top of aspirin, P2Y12- inhibitors are successfully used to treat and prevent these events for a duration of one year after an acute coronary episode or 6 months after drug-eluting stent implantation. However, patients with acute coronary syndromes remain at heightened risk for recurrent ischemic events after the recommended durations of P2Y12-inhibitors and therefore, prolonging treatment is often considered in clinical practice. However, the higher risk for bleeding limits the utility of such approach to a restricted group who is still poorly defined by available measures. This review aims to discuss potential benefits and highlight important pitfalls of prolonged treatment with P2Y12-inhibitors, with a focus on ticagrelor, an attractive reversible P2Y12-inhibitor in patients after myocardial infarction.

Background: In the era of dual antiplatelet therapy of aspirin and clopidogrel and systematic stent implantation, Glycoprotein IIb/IIIa Inhibitors (GPI), including abciximab, eptifibatide and tirofiban, proved beneficial in improving early outcome of Percutaneous Coronary Intervention (PCI), especially in higher risk clinical and/or anatomical subsets. This was associated however, with an increased incidence of bleeding complications. Objective: To review whether the established results of GPI in PCI are maintained in the contemporary era of more effective antiplatelet agents (i.e., prasugrel, ticagrelor and cangrelor) and safer anticoagulants (i.e., bivalirudin) and interventional techniques (i.e., radial approach). Methods: The most relevant evidence on the use of GPI in stable coronary artery disease, non-STelevation coronary syndromes and ST-elevation myocardial infarction was reviewed. Results: Overall the relative efficacy and safety of GPI in contemporary PCI is maintained, largely irrespective of the use of more effective antiplatelet agents and/or safer anticoagulants and interventional techniques. However, an increase in the absolute occurrence of major and/or minor bleeding and/or need for blood transfusions is generally observed. Conclusion: Because of the persistent benefit of GPI in limiting early ischemic complications, especially in higher risk clinical and/or anatomical subsets, and the associated risk of increased bleeding complications, also in contemporary PCI, these agents should currently be used on a selective rather than routine basis, including bail out administration for peri-procedural thrombotic complications.

With over 1.5 billion people, East Asians are the most populous race in the world. Health status in this population is an important global issue. In the contemporary trials of antithrombotic treatment, East Asian patients have a lower risk for atherothrombotic diseases (especially, Coronary Artery Disease [CAD]) and a higher risk for bleeding (especially, gastrointestinal bleeding and hemorrhagic stroke). Despite these observations, antithrombotic treatment strategies in East Asian patients are mainly based on the American or European guidelines that are derived from randomized, controlled trials including mostly Caucasians. Despite a low response to clopidogrel, East Asian patients with CAD show a similar or even a lower rate of ischemic event occurrence and higher bleeding risk compared with Caucasian patients. The latter is referred to as the “East Asian Paradox”, suggesting a dissimilar therapeutic window for antiplatelet therapy than Caucasians. In addition, different net clinical benefits have been observed between the races with potent P2Y12 inhibitors that may be related to racial differences in pharmacokinetic and pharmacodynamic profiles. Furthermore, there is emerging concern regarding differences between East Asian vs. Western patients in pharmacodynamic and clinical efficacies of anticoagulant agents. We now summarize experimental and clinical evidence of the efficacy and safety of antithrombotic agents in the East Asian population. We suggest the concept of “race-tailored antithrombotic treatment” in CAD patients and/or in patients undergoing percutaneous coronary intervention.

Background: The very significant benefit of P2Y12 receptor inhibitor administration in patients with ST-elevation myocardial infarction (STEMI), in reducing future ischaemic events and stent thrombosis, is undisputed. Morphine analgesia is very frequently co-administered to these patients for pain relief, along with antiplatelet therapy, at the time of presentation, and prior to reperfusion with primary percutaneous coronary intervention. Methods: Research and online content related to opiates use in STEMI was reviewed. Bibliographies of retrieved studies were searched manually for additional studies and reviews. Results: There is sufficient data from pharmacokinetic and pharmacodynamic studies showing that the co-administration of morphine with oral P2Y12 receptor inhibitor results in delayed antiplatelet effects. However, whether this results in adverse outcomes remains unclear. Data from studies reporting the effect of morphine on clinical outcomes in STEMI are inconsistent, although they tend to be underpowered to show an effect on hard clinical outcomes, but some clearly show a relationship between morphine use and infarct size. Strategies to overcome the potentially significant negative impact of morphine on platelet reactivity in STEMI are discussed. Conclusion: Whilst clearly definitive, adequately powered, randomised controlled trials are lacking, we would recommend avoiding the combination of morphine with oral P2Y12 receptor inhibitors and recommend alternative strategies including intravenous platelet inhibitor strategies, in high risk patients.

Dual antiplatelet therapy with aspirin and oral P2Y12-receptor inhibitors prevents ischemic events in patients undergoing Percutaneous Coronary Intervention (PCI). However, oral administration of antiplatelet drugs cause delay of onset of platelet inhibition in P2Y12-inhibitor naïve patients. Cangrelor is a novel P2Y12-receptor inhibitor which is administrated intravenously and thus allows immediate antiplatelet inhibition during PCI. Due to its unique pharmacokinetics with fast onset of platelet inhibition and very short plasma half-life it allows effective and controllable periprocedural platelet inhibition. It could reduce short-term ischemic events in large randomized clinical trials. The present article reviews the available evidence and application on cangrelor use in clinical practice.

Although High Density Lipoprotein Cholesterol (HDL-C) levels are inversely proportional to cardiovascular risk in many studies, recent pharmacological interventional studies with HDL-C raising strategies did not show a benefit in terms of vascular events. The HDL particle is heterogenous with anti-atherogenic functions and non-vascular effects. Many factors affect HDL components and may either cause compositional changes, post-translational modifications of proteins, or alter lipids and other cargo molecules; generally these factors cause more than one of these changes, resulting in functional differences. Therefore, the role of lipoproteins change in different physical and disease conditions. Mainly, in proteome, Apolipoprotein A1 (Apo-A1), Myeloperoxidase (MPO), Paroxonase (PON) are affected by inflammation or glycation-related factors; and especially esterification or unesterification of lipids, changes in phospholipid or unsaturated lipid content change the HDL function. Measuring the HDL-C level is probably not a good predictor of its cardiovascular benefits, and methods to evaluate HDL functions are required. In current medical practice, it is not simple and feasible to measure different functions of this lipoprotein, but near-future strategies may be developed. Meanwhile, as we learn more about HDL structure and the role of each component, we can develop therapeutic approaches to improve HDL function. Apo-A1-mimetics, reconstituted HDL, nanoparticles and microRNA therapies could be promising as anti-atherosclerotic therapies. They may even provide useful therapies for the treatment of some non-cardiovascular diseases.

Thromboembolic disease is a complex disorder with a multifactorial aetiology and a severe outcome. In newborns and children it may be missed or diagnosed late, thus worsening the prognosis. The neonatal disease is different from the disorder affecting older children and adults. However, scant epidemiological data and few randomised clinical trials regarding paediatric patients are available, and treatment recommendations are largely based on adult guidelines. Younger patients then have several decades over which they will suffer from the complications of thrombosis and risk of a new thrombotic episode. Current knowledge about neonatal thromboembolic disease and its prevention is reviewed here along with maternal, foetal, neonatal, pharmacological, environmental, lifestyle and occupational contributing factors. Additional data are urgently needed to improve diagnostic and therapeutic strategies and patient outcomes.

Background: Psoriasis is a chronic inflammatory skin disorder of unknown etiology. Increasing evidence suggests that psoriasis is probably an angiogenesis-dependent disease. Thalidomide has been reported being able to inhibit the effects of fibroblast growth factor 2 and vascular endothelial growth factor (VEGF), and inhibit tumour necrosis factor-alpha synthesis, and suppress tumour necrosis factor-induced nuclear factor-kappa B activation in Jurkat cells, resulting in suppression of proliferation inflammation, angiogenesis, and the immune system, which are related to the pathogenesis of psoriasis. Objective: Our study evaluated the influence of thalidomide on the lesional alterations, VEGF expressions and angiogenesis in imiquimod-induced mouse model. Methods: Balb/c female mice (n=48) 8-12 weeks of age were randomly divided into 6 groups including negative control (vaseline cream), positive control (5% imiquimod cream), and experimental groups including low-dose (10 mg/kg.d), moderate-dose (30 mg/kg.d) and high-dose thalidomide (85 mg/kg.d), and acitretin group (6 mg/kg.d). Serum levels of VEGF-A were quantified by enzyme-linked immunosorbent assay. VEGF protein expression was measured by western blotting and the microvessel density by immunohistochemical staining. Results: The total psoriasis area and severity index scores in the moderate- and high-dose thalidomide and acitretin groups decreased significantly (p<0.001 for each), and so were the total Baker's scores in the high-dose thalidomide (p=0.008) and acitretin groups (p=0.021). The mean thickness of the epidermis in the experimental and acitretin groups decreased significantly, respectively (p<0.001 for all); the acitretin group was the thinnest. The cutaneous VEGF protein levels down-expressed significantly in the moderate- and high-dose thalidomide groups (p<0.05 for both), while those in the low-dose thalidomide and acitretin did not (p>0.05 for both). There were no differences for serum VEGF-A levels and the density of microvessels among the positive and experimental groups. Conclusion: Thalidomide can improve the psoriasis-like lesions and inhibit the expression of cutaneous VEGF in imiquimod-induced psoriatic model with dose-dependence, however, it does not alter circulating VEGF-A levels and microvessel density in dermis.