Antithrombotic strategies for preventing long-term major adverse cardiovascular events in patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention

Introduction: Balancing the risk of recurrent ischemia and bleeding among patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention (PCI) is challenging. Postprocedural antithrombotic therapy aims to reduce the risk related to coronary artery disease, stent placement, and atrial fibrillation, with acceptable risks of bleeding.

Areas covered: This review summarizes evidence and recommendations related to long-term antithrombotic strategies in such patients. An overview of the findings from recent meta-analyses and select observational studies is provided, and important completed and ongoing randomized trials are described in detail. Recommendations pertaining to treatment intensity and duration, including the choice of specific anticoagulant and antiplatelet agents, are given.

Expert opinion: Triple therapy (oral anticoagulation with dual antiplatelet therapy) is associated with an increased bleeding risk compared with double therapy (oral anticoagulation with a single antiplatelet agent), but double therapy does not appear to be associated with an increased risk of recurrent ischemia or death. Completed trials make a compelling case for double therapy with clopidogrel, not aspirin, when compared with full-intensity triple antithrombotic therapy. We believe that double therapy with an anticoagulant and clopidogrel should generally be favored instead of triple antithrombotic therapy.     

Antiplatelet therapy in acute coronary syndromes

Introduction: Coronary thrombosis is a frequent cause of death and myocardial infarction most often explained by superimposition of a platelet-rich thrombus on existing coronary artery disease. Therefore, antiplatelet drugs are essential in the treatment and secondary prevention of acute coronary syndromes (ACS) and during percutaneous coronary intervention. Several novel antiplatelet drugs are now available.

Areas covered: For several years, aspirin and clopidogrel remained the cornerstone of treatment for ACS. However, prasugrel and ticagrelor have a more consistent, faster-acting and more potent antiplatelet effect than clopidogrel, which translates into improved clinical outcomes, although at the expense of an increased bleeding risk. Importantly, some patients experience cardiovascular events despite current antiplatelet treatment, because platelet activation may occur via pathways not inhibited by these agents. Therefore, improved antiplatelet strategies are warranted.

Expert opinion: Despite undisputable benefits of current antiplatelet strategies, a considerable number of patients continue to experience adverse thrombotic events, although clinical outcomes have been improved with new oral P2Y₁₂ antagonists. New drugs have been developed, including intravenous P2Y₁₂ antagonists and oral antagonist targeting the protease-activated receptor-1 platelet activation pathway stimulated by thrombin. This review provides an overview of current and novel antiplatelet strategies and also discusses unmet needs related to antiplatelet therapy for ACS.     

Investigational new drugs for the treatment of acute coronary syndrome

Introduction: Ischemic heart disease is the most common cause of death worldwide. Despite improvements in interventional and pharmacological therapy for acute coronary syndrome (ACS), the risk of recurrent myocardial ischemia and mortality early after ACS remains high. Our improved understanding of the increasing role of inflammation in the pathogenesis of ACS and its relationship to atherosclerotic plaque rupture and thrombosis has led to the development of more potent anti-thrombotic and novel anti-inflammatory therapies for the treatment of ACS.

Areas covered: In this review, the authors explore: the developing pharmacotherapy in the field of cardiology for ACS; antiplatelet agents (both further development of classical modalities together with pioneering agents); evolving use of anticoagulation in its treatment, and exploration in the use of novel anti-inflammatories and biological agents.

Expert opinion: Data from trials involving the use of immunological and cellular-based treatments show promising results and herald further possible reduction in infarct burden in ACS alongside the possibility of recovery in cardiac function following infarction.     

Thromboembolic and bleeding risks in patients undergoing atrial fibrillation ablation: oral anticoagulation perspectives

Introduction: Atrial fibrillation (AF) is a cause of significant morbidity and mortality. Catheter ablation for AF (CAAF) has emerged as an effective treatment option of rhythm control for patients with symptomatic AF. However, the risk of thromboembolism and bleeding in the periprocedural period represent a worrisome complication of this therapy. The reported incidence of thromboembolic and bleeding events associated with CAAF varies from 0.9% to 5% depending on the CAAF strategy and the anticoagulation regimen used in the periprocedural period.

Areas covered: The different anticoagulation regimens used prior to, during, and after CAAF to minimize the risk of thromboembolic and bleeding events are reviewed. The use of uninterrupted oral anticoagulation and appropriate heparin dosing to achieve safe activated clotting time levels are also detailed. A comprehensive approach with assessment of individual risk for thromboembolic and bleeding complications, and understanding the pharmacokinetics of the anticoagulant agents available is also reviewed.

Expert opinion: The key advances done in the periprocedural anticoagulation field include the use of uninterrupted anticoagulation strategies in patients undergoing AF ablation and efforts to simplify the selection of patients who need LAA thrombus screening prior to ablation.     

Bivalirudin during percutaneous coronary intervention in acute coronary syndromes

Introduction: Anticoagulant therapy is critical to prevent ischemic recurrences and complications in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Unfractionated heparin (UFH), an injectable anticoagulant has several limitations: lack of predictability of its biological efficacy, platelets activation, heparin-induced thrombopenia and bleedings. Bivalirudin, a synthetic direct thrombin inhibitor has biological properties that promised better clinical outcome in ACS patients undergoing PCI.

Areas covered: The present review aimed to summarize two decades of randomized clinical trials that compared bivalirudin to UFH in ACS patients treated with PCI. Early trials highlighted a reduction of bleedings with bivalirudin compared to UFH in combination with glycoprotein inhibitors (GPI). Recent studies questioned this reduction given that GPI are less and less used during PCI. Further, trials raised concerns about the risk of stent thrombosis in patients treated with bivalirudin. In light of this data, bivalirudin has been downgraded in international guidelines and appears as a second line anticoagulant agent after UFH.

Expert opinion: The highly questioned reduction of bleedings under bivalirudin and the potential risk of stent thrombosis are unwarranted. Based on clinical trials, UFH has no equivalent in terms of anticoagulation in ACS patients undergoing PCI.     

Review of pharmacoeconomic evaluation of genotype-guided antiplatelet therapy

Introduction: Clopidogrel is an antiplatelet agent widely prescribed for acute coronary syndrome (ACS), and it is activated by the CYP enzyme system to active metabolite. CYP2C19 loss-of-function (LOF) allele(s) affect the responsiveness of clopidogrel, but not the new antiplatelet agents (prasugrel and ticagrelor). We reviewed the pharmacoeconomic studies on genotype-guided use of new antiplatelet agents.

Areas covered: A literature search was conducted between the period of 2000 and 2014. Seven studies including cost-effectiveness and risk-benefit analyses of CYP2C19 genotype-guided antiplatelet therapy in ACS patients were reviewed. Genotype-guided prasugrel was found to be cost-effective when compared with universal antiplatelet therapy in four studies. Three studies showed genotype-guided ticagrelor to be cost-effective in ACS patients with percutaneous coronary intervention (PCI), and universal ticagrelor to be cost-effective in ACS patients. Drug cost of antiplatelet agents and relative risk of the new antiplatelet versus clopidogrel for clinical events were common influential factors of cost-effectiveness analyses.

Expert opinion: All studies in the present review focused on selecting antiplatelet agents for carriers of CYP2C19 LOF allele(s). Cost-effectiveness of genotype-guided use of antiplatelets was demonstrated in high-risk ACS patients.     

When are the cardiovascular and stroke risks too high? Pharmacotherapy for stroke prophylaxis

Introduction: Stroke is a significant source of morbidity and mortality in developed countries. Cardioembolic strokes represent approximately 15–30% of all ischemic strokes. They are frequently related to atrial fibrillation (AF) and have a worse prognosis and high recurrence rates when compared to other causes (e.g. atherosclerosis).

Areas covered: This review includes a summary of general and specific scores to assess cardiovascular and stroke risks, with a focus on specific scores available in AF. Recommendations for antithrombotic therapy are also reviewed.

Expert opinion: Several scores are available for the evaluation of stroke risk. They are useful to identify the risk factors that trigger the need for medical interventions. Integrated risk scores with visual interfaces showing the risk of events, with and without the proposed interventions, can aid decision-making. The risk of stroke can definitely be considered too high in those patients with a history of stroke/transient ischemic attack, who need antiplatelet therapy (after a non-cardioembolic stroke) or anticoagulant therapy (after a cardioembolic stroke). For primary prevention of stroke, antiplatelet therapy is not usually recommended, while anticoagulation should be considered if the patient has concomitant AF and at least one additional risk factor unrelated to sex.     

Evaluating current and emerging antithrombotic therapy currently available for the treatment of acute coronary syndrome in geriatric populations

Introduction: Acute coronary syndromes (ACS) represent one of the most perilous presentations of ischemic heart disease. Temporal trends clearly demonstrate that ACS occur later and later in life. Elderly patients with ACS comprise a populous and growing group, with more than half of individuals presenting with myocardial infarction being 75 years or older. Nevertheless, geriatric patients are greatly underrepresented in the landmark ACS trials evaluating innovative pharmacological strategies.

Areas covered: The authors critically summarize recently published research on contemporary and emerging antithrombotic therapy for the treatment of ACS in geriatric patients.

Expert opinion: Elderly ACS patients are characterized by simultaneously increased risk of cardiovascular events and bleeding. Very few studies assessing the efficacy and safety of novel ACS pharmacotherapy in geriatric patients are currently available. Guidelines on the treatment of ACS are based on the overall results of major randomized clinical trials (RCTs), and data supporting the recommended therapy in elderly mainly derive from subanalyses of these RCTs. Properly designed and powered RCTs are necessary to properly evaluate the net effect of current and emerging pharmacotherapy in geriatric patients. Until such data are available, elderly ACS patients should receive treatment according to the general recommendations.     

An update on the use of anticoagulant therapy in ST-segment elevation myocardial infarction

Introduction: Together with antiplatelet therapy, anticoagulants are vital to improve outcomes in patients presenting with ST-segment elevation myocardial infarction.

Challenges lie in finding the optimal balance between the risk of bleeding and preventing thrombotic complications such as reinfarction or stent thrombosis. During the last decade, bivalirudin was introduced as a valid alternative to heparin for patients undergoing primary percutaneous coronary intervention. Several trials have been conducted to identify the agent with the best antithrombotic results at the lowest bleeding complication rate. In a rapidly evolving field with changes in vascular access, available P2Y₁₂ inhibitors, and indications for glycoprotein IIb/IIIa inhibitor administration, conflicting evidence became available.

Areas covered: This paper mainly focuses on the evidence above and gives brief discussion to the recent literature on anticoagulation in fibrinolytic therapy and advances in antiplatelet therapy.

Expert opinion: To date, no robust evidence is available challenging unfractionated heparin as the primary choice for anticoagulation in patients presenting with ST-segment elevation myocardial infarction. Further research should include efforts to refine anticoagulation strategies on an individual patient level. For patients undergoing primary percutaneous coronary intervention, bivalirudin could be used as an alternative to unfractionated heparin, while enoxaparin or fondaparinux is an alternative agent for patients treated with fibrinolytic therapy.     

The risk of bleeding with the use of antiplatelet agents for the treatment of cardiovascular disease

Introduction: In the presence of injured coronary vascular endothelium, platelets become activated to form hemostatic plugs. While this represents a normal healing response to disrupted vascular endothelium, occlusive cardiovascular disease, as a result of maladaptive thrombus formation, is a major cause of morbidity and mortality. Due to the platelet predominance of arterial thrombi, antiplatelet agents are the mainstay of therapy for arterial cardiovascular disease, though come with a significantly increased risk of bleeding.

Areas covered: This review will provide a comprehensive overview of available antiplatelet agents used to treat coronary artery cardiovascular disease. The risks of bleeding with each agent will be considered.

Expert opinion: Available antiplatelet therapies are effective in treating acute thrombotic events and preventing recurrent events, however, they also carry significant bleeding risks. The decision to use or continue antiplatelet agents remains challenging for physicians and necessitates a thorough understanding of the future risk of thrombotic risks of thrombotic or bleeding events in a patient. Clinical prediction rules and risk scores may be useful to support physician decision-making.     

Rationale for administering beta-blocker therapy to patients undergoing coronary artery bypass surgery: a systematic review

Introduction: Secondary preventative therapies are essential for patients undergoing coronary artery bypass graft (CABG) surgery to optimize perioperative and long-term outcomes. Beta-blockers are commonly used to treat patients with coronary artery disease and congestive heart failure (CHF), but their role for CABG patients remains unclear. The goal of this systematic review was to evaluate the rationale for administering beta-blockers to the CABG population and to assess their efficacy before and after coronary surgical revascularization.

Areas covered: A systematic literature review was performed to retrieve relevant articles from the PubMed database published between 1985 and 2017.

Expert opinion: Outside of the surgical field, strong evidence supports the use of beta-blockers for patients with a history of previous myocardial infarction (MI) or CHF. For the CABG population, studies have suggested that perioperative beta-blocker therapy is beneficial, with an associated reduction in mortality, particularly among those with a history of previous MI or CHF. Beta-blocker administration has also clearly been shown to lower the rate of new-onset postoperative atrial fibrillation after CABG. Among the different types of beta-blockers, perioperative carvedilol appears to be the most beneficial. In the absence of contraindications, nearly all CABG patients are candidates for perioperative beta-blocker therapy.     

P2Y12 receptor inhibitors: an evolution in drug design to prevent arterial thrombosis

Introduction: P2Y12 inhibitors are a critical component of dual antiplatelet therapy (DAPT), which is the superior strategy to prevent arterialthrombosis in patients with acute coronary syndromes (ACS) and undergoing stent implantation..

Areas covered: Basic science articles, clinical studies, and reviews from 1992–2017 were searched using Pubmed library to collet impactful literature. After an introduction to the purinergic receptor biology, this review summarizes current knowledge on P2Y12 receptor inhibitors. Furthermore, we describe the subsequent improvements of next-generation P2Y12 receptor inhibitors facing the ambivalent problem of bleeding events versus prevention of arterial thrombosis in a variety of clinical settings. Therefore, we summarize data from relevant preclinical and clinical trials of currently approved P2Y12 receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) and provide strategies of drug switching and management of bleeding events.

Expert opinion: An enormous amount of pharmacologic and clinical data is available for the application of P2Y12 receptor inhibitors. Today prasugrel, ticagrelor and clopidogrel are the standard of care drugs during dual antiplatelet therapy for ACS patients, but have considerable rates of bleeding. Recent and future clinical trials will provide evidence for subsequent escalation and de-escalation strategies of P2Y12 receptor inhibition. These data may pave the way for an evidence-based, individualized P2Y12 receptor inhibitor therapy.     

The genetic basis of antiplatelet and anticoagulant therapy: A pharmacogenetic review of newer antiplatelets (clopidogrel,prasugrel and ticagrelor) and anticoagulants (dabigatran,rivaroxaban, apixaban and edoxaban)

Introduction: The study of pharmacogenomics presents the possibility of individualised optimisation of drug therapy tailored to each patients’ unique physiological traits. Both antiplatelet and anticoagulant drugs play a key role in the management of cardiovascular disease. Despite their importance, there is a substantial volume of literature to suggest marked person-to-person variability in their effect.

Areas covered: This article reviews the data available for the genetic cause for this inter-patient variability of antiplatelet and anticoagulant drugs. The genetic basis for traditional antiplatelets (i.e. aspirin) is compared with the newly available antiplatelet medicines (clopidogrel, prasugrel and ticagrelor). Similarly, the pharmacogenetics of warfarin is compared with the newer direct oral anticoagulants (DOACs) in detail.

Expert Opinion: We identify strengths and weaknesses in the research thus far; including shortcomings in trial design and a review of newer analytical techniques. The direction of this research and its real-world implications are discussed.     

Pharmacokinetic drug evaluation of vorapaxar for secondary prevention after acute coronary syndrome

Introduction: Vorapaxar is the first protease-activated receptor-1 inhibitor approved for clinical use. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infarction or symptomatic peripheral artery disease.

Areas covered: This article reviews the pharmacokinetics of vorapaxar and its potential use in secondary prevention after an acute coronary syndrome.

Expert opinion: Vorapaxar inhibits platelet aggregation mediated by thrombin. This effect is carried out without affecting to coagulation parameters and bleeding times. This drug has showed a significant reduction of cardiovascular events in patients with chronic atherosclerosis but not during the admission for an acute coronary syndrome. The rate of major bleeding found in patients treated with vorapaxar in randomized trials was consistently higher than placebo in most of the analyzed subgroups. For this reason, cautious evaluation of risk-benefit profiles should be required before prescribing this drug.     

Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments

Introduction: There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors.

Areas covered: In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2Y₁₂ receptor blockers, PAR-1 inhibitors, direct thrombin inhibitors and factor Xa inhibitors from PubMed since 2008.

Expert opinion: Since thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y₁₂ inhibitors plus aspirin, the degree of adverse event reduction compared to clopidogrel therapy in large scale trials is modest along with significantly greater bleeding. Recent studies suggest that targeting the thrombin pathway in addition to antiplatelet agents in high risk patients may further mitigate the risk of ischemic event occurrences with improved safety profiles.     

Cangrelor for the treatment of patients with Arterial Thrombosis

Introduction: All oral P2Y₁₂ receptor blockers are associated with some degree of delayed onset and offset of pharmacodynamic (PD) effects in patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI). Although intravenous glycoprotein IIb/IIIa inhibitors are associated with rapid onset of action, they are also associated with delayed offset and other limitations such as elevated bleeding risk and thrombocytopenia.

Areas covered: In this review, the authors focus on cangrelor, an intravenous, reversible P2Y₁₂ receptor blocker with fast onset and offset of effects. The authors also describe the pharmacologic effects of cangrelor and its pharmacologic interaction with other P2Y₁₂ receptor inhibitors. Finally, the authors discuss the large-scale clinical trials that compared the efficacy and safety of cangrelor with clopidogrel.

Expert opinion: In ACS patients undergoing PCI, cangrelor is most desirable to effectively prevent periprocedural ischemic events and to avoid excessive bleeding. Indeed, any high-risk patient with ST-segment elevation myocardial infraction or patient who is unable to take oral medications is a potential candidate for intravenous cangrelor therapy. Furthermore, stable patients with coronary artery disease, who are considered for ad hoc PCI following coronary angiography, may be considered for treatment with cangrelor to reduce post-PCI thrombotic events.     

Safety of anticoagulant treatment in cancer patients

Introduction: Patients with cancer are at increased risk of (recurrent) venous thromboembolism. They are also at increased risk of bleeding. This makes treatment of venous thromboembolisms (VTE) in cancer patients challenging.

Areas covered: In this review, we will focus on the safety of anticoagulant treatment of VTE in cancer patients. We will discuss the absolute and relative bleeding risks associated with the various types of anticoagulants, specifically focusing on low-molecular-weight heparins (LMWH), vitamin K antagonist (VKA) and the new oral anticoagulants (NOACs).

Expert opinion: Monotherapy with LMWH is recommended for treatment of acute VTE in cancer patients. The bleeding risk associated with LMWH is comparable to VKAs, but LMWH are more effective in preventing recurrent VTE. More evidence on the efficacy and safety of NOACs in cancer patients is needed.