Secondary Prevention Of Ischemic Events Research Articles

Aspirin interruption before neurosurgical interventions: A controversial problem.

Aspirin is widely used for primary or secondary prevention of ischemic events. At the same time, chronic aspirin consumption can affect blood clot formation during surgical intervention and increase intraoperative blood loss. This is especially important for high-risk surgery, including neurosurgery. Current European Society of Cardiology guidelines recommend aspirin interruption for at least 7 d before neurosurgical intervention, but this suggestion is not supported by clinical evidence. This narrative review presents evidence that challenges the necessity for aspirin interruption in neurosurgical patients, describes options for aspirin effect monitoring and the clinical implication of these methods, and summarizes current clinical data on bleeding risk associated with chronic aspirin therapy in neurosurgical patients, including brain tumor surgery, cerebrovascular procedures, and spinal surgery.

A prospective observational study based on angiographic profile in coronary artery disease patients with coronary intervention

Background: An enlargement of the coronary artery that restricts optimal blood flow to the heart tissue is called coronary artery disease. The most common cause is arteriosclerosis. Platelet aggregation inhibition is the mainstay of primary and secondary prevention of ischemic events associated with coronary artery atherosclerosis.
 Objective: Study of the angiographic profile of patients with coronary artery disease undergoing percutaneous coronary intervention, coronary artery bypass graft and medical management.
 Methods: This prospective observational study included all patients who underwent PCI, CABG and medical treatment at a tertiary hospital between August 2021 and February 2022. Demographic and angiographic data were collected for all patients. The details of the procedure, clinical symptoms, comorbidities, diagnostic tests such as coronary angiography, 2D echocardiography, and treatment, including anticoagulant therapy, of these patients were reviewed.
 Results and discussion: A total of 100 patients (mean age - 58 years) with 71% males and 29% females were included in the study. Hypertension and Diabetes were the most common risk factors, present in 60% and 35% patients respectively. Smokers were observed in 16% patients respectively. Single vessel disease (SVD) was most common angiographic pattern, observed in 57% patients. Anterior wall MI was the most common mode of presentation (75%). Chest Pain was most common symptom, observed in 95% patients; PTCA was the most frequently employed procedure (71%) followed by CABG (10%) and Medical Management (19%); and Among 100 patients in 2DEcho Mild LV Dysfunction (Grade-1) were most prevalent (32%). The most commonly affected vessel was the right coronary artery (RCA) (51%). Drug-eluting stents were used in 71% of cases. Out of 100 patients, 51 patients received 1 stent and 20 patients received 2 stents.
 Conclusion: This prospective study of percutaneous coronary intervention provides insight into the patterns of coronary artery disease with angiographic features. Our aim was to profile patients undergoing percutaneous coronary intervention to alleviate symptoms and improve survival in patients with coronary artery disease

Central Retinal Artery Occlusion: Can We Effectively Manage This Ocular Emergency in a Hospital Setting?

Central retinal artery occlusion (CRAO) is an ophthalmological emergency characterized by partial or complete occlusion of the central retinal artery. It is the ocular equivalent of an ischemic cerebral stroke. Patients frequently present with a significant, abrupt, painless loss of vision in one eye, with only around 20% of those affected getting functional visual acuity restored in the affected eye. Despite more than 150 years of clinical research, no consensus has been achieved regarding the most effective method of treating CRAO. The efficacy of all proposed treatments is debatable, and many of them have ambiguous risk profiles that present particular diagnostic and management difficulties and cause variations in clinical practice. In certain circumstances, thrombolysis may be attempted as a treatment option. However, the evidence to support the general use of thrombolytics in treating acute CRAO remains elusive. It is known that the risk factors predisposing to other cardiovascular and cerebrovascular events are often present in CRAO. Accordingly, identifying patients at the highest risk of stroke and secondary prevention of ischemic events remains the primary focus of management. This review offers a summary of all the current treatment options available for managing CRAO, with particular reference to their limitations and inconsistent results found in relevant studies until 2022.

Kyselina acetylsalicylová v primární prevenci kardiovaskulárních onemocnění

Acetylsalicylic acid is an effective and widely accepted essential drug in the secondary prevention of ischemic events. Its role in primary prevention has been studied for several decades and still remains controversial. Initial studies showed a reduction in both myocardial infarctions and ischemic strokes, without affecting overall or cardiovascular mortality, but the enrolled subjects were not treated with modern drugs and procedures in primary preventive care as they do today. Recently published studies have also not shown a mortality benefit, but in some sub-populations and groups of patients, the clinical benefit of aspirin continues to outweigh the risks associated with its long-term use. This review article will discuss the development of ASA in primary prevention, the results of the latest studies of the year 2018 and their meta-analyses, current indications for ASA treatment, as well as future perspectives.

Protease-activated receptor-mediated platelet aggregation in patients with type 2 diabetes on potent P2Y12 inhibitors.

BackgroundAntiplatelet therapy is a cornerstone in the secondary prevention of ischemic events following percutaneous coronary intervention (PCI). The new P2Y12 receptor inhibitors prasugrel and ticagrelor have been shown to improve patients' outcomes. Whether or not these drugs have equal efficacy in individuals with or without diabetes is disputed. Furthermore, platelets can be activated by thrombin, which is, at least in part, independent of P2Y12‐mediated platelet activation. Protease‐activated receptor (PAR)‐1 and −4 are thrombin receptors on human platelets. We sought to compare the in vitro efficacy of prasugrel (n = 121) and ticagrelor (n = 99) to inhibit PAR‐mediated platelet aggregation in individuals with type 2 diabetes (prasugrel n = 26, ticagrelor n = 29).Materials and MethodsWe compared P2Y12‐, PAR‐1‐ and PAR‐4‐mediated platelet aggregation as assessed by multiple electrode platelet aggregometry between prasugrel‐ and ticagrelor‐treated patients without and with type 2 diabetes who underwent acute PCI.ResultsOverall, there were no differences of P2Y12‐, PAR‐1‐ and PAR‐4‐mediated platelet aggregation between prasugrel‐ and ticagrelor‐treated patients. However, both drugs inhibited P2Y12‐mediated platelet aggregation stronger, and thereby to a similar extent in patients with type 2 diabetes than in those without diabetes. There was no correlation between either P2Y12‐, or PAR‐1‐ or PAR‐4‐mediated platelet aggregation and levels of HbA1c or the body mass index (BMI). However, we observed patients with high residual platelet reactivity in response to PAR‐1 and PAR‐4 stimulation in all cohorts.ConclusionPrasugrel and ticagrelor inhibit P2Y12‐ and PAR‐mediated platelet aggregation in individuals with diabetes to a similar extent, irrespective of HbA1c levels and BMI.

A retrospective observational study of the use of gastroprotection for patients on dual antiplatelet therapy in an acute trust in England

Abstract Introduction Dual antiplatelet therapy (DAPT), a combination of aspirin and either clopidogrel, prasugrel or ticagrelor, is recommended for secondary prevention of ischaemic events (heart attack and stroke) in people with coronary artery disease. Patients taking DAPT may be at high gastrointestinal (GI) bleed risk if other factors (including advanced age, or concomitant use of medicines that are known to increase the risk of GI bleeds) are present. Such patients should be considered for gastroprotection e.g. a proton pump inhibitor (PPI) or H2 receptor antagonist. Aim To assess whether gastroprotection was prescribed for inpatients taking DAPT in a 750-bed acute hospital in England. Methods This was a retrospective analysis of existing data. Patient episodes involving prescription of DAPT upon discharge between April 2020 and April 2021 were extracted from the e-prescribing system (WellSky). Electronic records of the identified patient episodes were searched for co-prescription of either PPI or H2 antagonist. We also ascertained if patients on DAPT should have received gastro-protection using age 71 and over, and concomitant drugs as separate risk factors. Results Over this 13-month period there were 1693 patient episodes (mean age 72 years, 63% male) when DAPT was prescribed at discharge, of which gastroprotection was also prescribed in 1210 (71%). Of the 483 episodes when gastroprotection was not prescribed, 223 (46%) met the criterion of age as a risk factor for gastroprotection. There were a further 20 episodes of patients aged under 71 years not on gastroprotection but receiving an SSRI, NSAID, prednisolone, nicorandil or an anticoagulant. Conclusion We identified that gastroprotection was potentially missing in 243 (14%) of the total DAPT patient episodes. Though there is evidence for the use of PPIs reducing the risk of GI bleeding in patients treated with DAPT after percutaneous coronary intervention or acute coronary syndrome (1), studies have reported that gastroprotection has been missed in the at risk group (2). When considering newly initiated gastroprotection, various factors are considered e.g. any possible interaction with a PPI if one of the antiplatelets is clopidogrel. In addition, PPIs have adverse effects such as low sodium / magnesium, and this may be a reason for consideration of a H2 antagonist. Further work is required to make our prescribers and pharmacy team aware of the importance of considering gastroprotection for this patient cohort. The strength of this study is the extraction of data from our electronic prescribing system for a large cohort of patients prescribed specified antiplatelet medication. Our study has some potential limitations. First, it was conducted in a single centre in England; this might restrict the generalisability of our findings. Second, the retrospective nature of this study may introduce bias or other uncertainties. Third, we did not ascertain the indication for DAPT nor if patients came in on these drugs as opposed to being started during their admission. Fourth, we did not check risk factors for gastroprotection other than age and selected concomitantly prescribed drugs. Finally, we did not check if those not prescribed gastroprotection had significant contraindications other than electrolyte abnormalities. References (1) Guo H, Ye Z, Huang R. Clinical outcomes of concomitant use of proton pump inhibitors and dual antiplatelet therapy: a systematic review and meta-analysis. Front Pharmacol. 2021 Aug 2;12:694698. (2) Sehested TSG, Carlson N, Hansen PW, Gerds TA, Charlot MG, Torp-Pedersen C, et al. Reduced risk of gastrointestinal bleeding associated with proton pump inhibitor therapy in patients treated with dual antiplatelet therapy after myocardial infarction. Eur Heart J. 2019;40(24):1963–70.

A retrospective observational study of the use of gastroprotection for patients on dual antiplatelet therapy.

Dual antiplatelet therapy is recommended for secondary prevention of ischaemic events in coronary artery disease. Some patients, who may be at high bleed risk if other factors are present, should be considered for gastroprotection. In our survey, we assessed whether gastroprotection was prescribed for hospital inpatients, especially high-risk patients, who were receiving dual antiplatelet therapy at discharge, and the type of gastroprotection prescribed. We found that over 13 months, a total of 1,693 patient episodes were prescribed dual antiplatelet therapy at discharge, of which 71% also received gastroprotection. Of the patient episodes who were not prescribed gastroprotection, 46% (223/483) met the criterion of age as a risk factor for gastroprotection. A further 30 episodes met other risk criteria of certain concomitant drugs or prior comorbidity. There is a need among clinicians and pharmacy teams within the hospital for recognition and management of this opportunity to improve the care of these patients.

Aspirin for Primary Prevention of Cardiovascular Disease in the 21st Century: A Review of the Evidence

Aspirin (ASA) is the most commonly prescribed antiplatelet agent. Although the evidence for efficacy of aspirin for secondary prevention of ischemic events in patients with established cardiovascular disease is strong, its role in primary prevention has been subject of controversies over the past decades. In fact, historical trials have shown only modest benefit in terms of reduction of ischemic events, mostly myocardial infarction and to a lesser extent stroke, and only at the expense of an increased risk of bleeding. These observations have led to divergent recommendations from professional societies on the use of ASA for primary prevention of cardiovascular disease manifestations. However, recent results from three trials of primary prevention have shown either no benefit or modest benefit on combined ischemic end points, without any impact on hard cardiovascular events such as myocardial infarction or stroke, accompanied by an increased risk of bleeding. Overall, this translated into neutral net benefit or even harm with the use of aspirin in patients with no overt cardiovascular disease. These results have accordingly led to a downgrade in the current recommendations on the use of ASA for primary prevention. This article provides an overview on the current evidence on the use of aspirin for primary prevention of cardiovascular disease.

Non-cardiac surgery in patients with coronary artery disease: risk evaluation and periprocedural management.

Perioperative cardiovascular complications are important causes of morbidity and mortality associated with non-cardiac surgery, particularly in patients with coronary artery disease (CAD). Although preoperative cardiac risk assessment can facilitate the identification of vulnerable patients and implementation of adequate preventive measures, excessive evaluation might lead to undue resource utilization and surgical delay. Owing to conflicting data, there remains some uncertainty regarding the most beneficial perioperative strategy for patients with CAD. Antithrombotic agents are the cornerstone of secondary prevention of ischaemic events but substantially increase the risk of bleeding. Given that 5-25% of patients undergoing coronary stent implantation require non-cardiac surgery within 2 years, surgery is the most common reason for premature cessation of dual antiplatelet therapy. Perioperative management of antiplatelet therapy, which necessitates concomitant evaluation of the individual thrombotic and bleeding risks related to both clinical and procedural factors, poses a recurring dilemma in clinical practice. Current guidelines do not provide detailed recommendations on this topic, and the optimal approach in these patients is yet to be determined. This Review summarizes the current data guiding preoperative risk stratification as well as periprocedural management of patients with CAD undergoing non-cardiac surgery, including those treated with stents.

Intracerebral haemorrhage, microbleeds and antithrombotic drugs.

Antithrombotic therapy is a cornerstone for secondary prevention of ischaemic events, cerebral and extra-cerebral. A number of clinical questions remain unanswered concerning the impact of antithrombotic drugs on the risk of first-ever and recurrent macro or micro cerebral haemorrhages, raising the clinical dilemma on the risk/benefit balance of giving antiplatelets and anticoagulants in patients with potential high risk of brain bleeds. High field magnetic resonance imaging (MRI) blood-weighted sequences, including susceptibility weighted imaging (SWI), have expanded the spectrum of these clinical questions, because of their increasing sensitivity in detecting radiological markers of small vessel disease. This review will summarise the literature, focusing on four main clinical questions: how do cerebral microbleeds impact the risk of cerebrovascular events in healthy patients, in patients with previous ischaemic stroke or transient ischaemic attack, and in patients with intracerebral haemorrhage? Is the risk/benefit balance of oral anticoagulants shifted by the presence of microbleeds in patients with atrial fibrillation after recent ischaemic stroke or transient ischaemic attack? Should we restart antiplatelet drugs after symptomatic intracerebral haemorrhage or not? Are oral anticoagulants allowed in patients with a history of atrial fibrillation and previous intracerebral haemorrhage?

Aspirin antiplatelet effects are associated with body weight

BackgroundAspirin is indispensable in secondary prevention of ischemic events. Recently, it was reported that clinical aspirin effects are hampered in patients above 70 kg body weight. It is well known that a plethora of reasons beside obesity is associated with increased platelet reactivity and insufficient aspirin effects (HTPR). However, data regarding an association between pharmacodynamic response to aspirin and body weight are missing. MethodsIn this pilot study, we included 59 patients from University Hospital Duesseldorf. Impedance aggregometry was used to assess pharmacodynamic response to aspirin. ResultsAA-induced platelet reactivity was significantly higher in patients above 70 kg (<70 kg: 28.27 ± 26.33 vs. >70 kg: 45.93 ± 27.1, p = .035) and correlated well with the bodyweight of patients in this study (r = 0.33, R2 = 0.09, p = .016). According to this, insufficient pharmacodynamic response (HTPR) to aspirin was significantly more frequent in patients over 70 kg (<70 kg: 25% vs. >70 kg: 43%, p = .035). ConclusionInsufficient pharmacodynamic response to aspirin is associated with body weight. This finding may play a role in the impaired clinical efficacy of aspirin in patients >70 kg. An optimal aspirin regime in these patients needs to be evaluated in large scale trials.

Multifactorial Prognostication of the Development of Stent Thrombosis in Patients with Acute Coronary Syndrome after Percutaneous Coronary Intervention on the background of Dual Antiplatelet Therapy

to identify predictors of stent thrombosis in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) for 12 months by creating a miathematical logistic regression model to optimize rehabilitation, secondary prevention of ischemic events in the first year after ACS, as well as a personalized approach to treatment. The analysis used data from the hospital register, which contained information on all PCIs, performed in the Semashko hospital between September 2016 and August 2018 (2378 patients). For this study we selected a sample of 183 ACS patients (146 men and 37 women) after PCI: 25 with definite stent thrombosis confirmed by repeated coronary angiography (CAG) (the main study group), and 158 without developing definite stent thrombosis (the comparison group) according to the observation for 12 months. All patients during hospitalization and 1 year after discharge received standard medical therapy ACS, according to international recommendations. Laboratory tests, electrocardiography (ECG), echocardiography, 24-hour ECG monitoring were performed for in patients. For determining predictors of the development of stent thrombosis we performed a logistic regression analysis. A mathematical model of multifactorial prognostication of stent thrombosis in patients with ACS after PCI was created. The model included the following predictors: Killip class &gt;II; life-threatening paroxysmal tachyarrhythmias (atrial fibrillation and/or ventricular fibrillation) as ACS complication of; left ventricular ejection fraction ≤45%; CA dissection; CAG confirmed CA thrombosis before PCI. The proposed model in patients with ACS allows us to estimate the risk of stent thrombosis after PCI, as well as to improve the accuracy of the event prediction. The model is easy to use, can be applied by practicing cardiologists during hospitalization. This model allows us to personalize secondary prevention in the first year after ACS, and thus help to reduce cardiovascular mortality, incidence of recurrent myocardial infarctions, unstable angina, and emergency revascularization.

Treatment of Nonarteritic Acute Central Retinal Artery Occlusion.

Central retinal artery occlusion (CRAO) is an event most often caused by an embolus originating in the ipsilateral carotid artery, aortic arch, or heart. CRAO may result from partial or complete occlusion of the central retinal artery (CRA), which acts as the primary blood supply to the inner neurosensory retina, and typically results in profound vision loss and permanent visual disability. No consensus has emerged regarding the optimal treatment of CRAO. All proposed treatments are of questionable efficacy and many have uncertain risk profiles. In certain circumstances, thrombolysis may be attempted as a treatment option; however, the evidence to support broad use of thrombolytics in the treatment of acute CRAO remains elusive. It is known that the risk factors that predispose to other cardiovascular and cerebrovascular events are often present in CRAO. Accordingly, identification of patients at highest risk of stroke and secondary prevention of ischemic events remains the primary focus of management. This review offers a summary of the clinical presentation, diagnosis, and prognosis of CRAO, with an emphasis on treatment options.

Comparison of the low-density lipoprotein cholesterol target value and the preventive effect of statins in elderly patients and younger patients.

ObjectiveTo assess whether the low-density lipoprotein cholesterol (LDL-C) target value and preventive effect of statins are different between elderly and younger patients.MethodsWe investigated 304 patients with previous percutaneous coronary intervention who underwent coronary angiography from January 2007 to December 2016 for examination of recurrent ischemia beyond the early restenosis. Patients were classified into two groups: age ≥ 75 years (elderly group: n = 140) and < 75 years (younger group: n = 164). Relationships between the achieved LDL-C level, incidence of late coronary events, and the effectiveness of statins were evaluated.ResultsDuring follow-up, 179 patients underwent late coronary revascularization. Recurrent ischemia presenting as acute coronary syndrome (ACS) occurred in 83 cases. Kaplan-Meier curve analysis revealed that in the younger group, recurrent ACS was significantly lower in patients with LDL-C < 70 mg/dL than in those with LDL-C ranging from 70 to < 100 mg/dL (P = 0.035); however, there was no difference between these in the elderly group (P = 0.863). Instead, recurrent ACS was less frequent in patients with LDL-C ranging from 70 mg/dL to < 100 mg/dL than in those with LDL-C ≥ 100 mg/dL in the elderly group (P = 0.033). Statin use was associated with decreased recurrent ACS (P = 0.005); moreover, only using statins was an independent predictor in the elderly group (HR: 0.375; P = 0.007).ConclusionsStrict control of LDL-C to < 70 mg/dL was effective for reducing the incidence of recurrent ACS in younger patients. However, LDL-C < 100 mg/dL might be sufficient as the target value of LDL-C-lowering therapy for secondary prevention of ischemic events in Japanese elderly patients.

An Updated Protocol for Evaluating Chest Pain and Managing Acute Coronary Syndromes.

Clinical pathways can optimize care both across and within institutions, but regular updates to these pathways based on new clinical trials, professional guidelines, and Food and Drug Administration approvals are essential. Herein we describe the most recent revisions to the New York-Presbyterian Hospital (Columbia University Medical Center and Weill Cornell Medical Center) clinical pathway for acute coronary syndromes and chest pain, which incorporates novel data regarding the timing and administration of P2Y12 inhibition (including the intravenous P2Y12 inhibitor cangrelor) and the appropriateness of prolonged (>1 year) dual antiplatelet therapy for the secondary prevention of ischemic events.

Abstract 32: Analysis of Serum Clopidogrel Active Metabolite Concentration Identifies Novel Genetic Variants Associated With Clopidogrel Pharmacokinetics

Clopidogrel with aspirin is standard of care for the secondary prevention of ischemic events in patients with acute coronary syndromes. However, substantial inter-individual variation in clopidogrel response results in sub-optimal therapy in some patients and an increased risk of recurrent events. Up to 73% of the variation in clopidogrel efficacy is found to be heritable, and while key genetic variants such as CYP2C19 *2 have been identified, a large portion of the genetic heritability remains unaccounted for. To date, few studies have used clopidogrel active metabolite to evaluate clopidogrel pharmacogenomics. The evaluation of this biomarker may be particularly informative as it enables us to focus almost exclusively on clopidogrel pharmacokinetics and may allow new discoveries leading to a more thorough understanding of clopidogrel activation. Serum clopidogrel active metabolite concentration was measured by HPLC-MS/MS in 506 healthy, Amish participants of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study after a 7-day 75-mg/day clopidogrel intervention. Genome-wide genotyping was performed using Affymetrix 5.0 and 6.0 arrays, and SNPs were imputed to the 1000 Genomes cosmopolitan panel. Mixed models analysis was conducted under an additive model and adjusted for age, sex, BMI, and relatedness among study participants with MMAP (http://edn.som.umaryland.edu/mmap). The most significant signal of our GWAS was the previously identified CYP2C19 / CYP2C9 locus (P= 9.2x10 -15 ), and was fully accounted for by the CYP2C19 *2 variant. In addition to this signal, novel genome-wide significant signals were identified in loci on Chr. 3 (rs187941554, P=4.7x10 -11 ), Chr. 7 (rs73407739, p=3.6x10 -8 ), and Chr. 17 (rs80343429, P=3.7x10 -8 ). In this study we conducted the first ever GWAS of serum clopidogrel active metabolite concentration. Novel associations for clopidogrel efficacy were identified, and further study is required to determine the impact of these variants on clinical care Continual analysis of clopidogrel active metabolite concentration will contribute to a better understanding of the clopidogrel metabolic pathway, and potentially lay the groundwork for improved anti-platelet treatment for CVD patients in the future.

Vorapaxar for reduction of thrombotic cardiovascular events in myocardial infarction and peripheral artery disease.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, dosage and administration, cost, and place in therapy of vorapaxar in the secondary prevention of atherosclerotic events are reviewed. Vorapaxar is a highly selective, reversible antagonist of protease-activated receptor-1 expressed on platelets. Vorapaxar competitively inhibits thrombin from activating the receptor, thereby decreasing platelet aggregation. Vorapaxar is rapidly absorbed and distributed, with peak plasma levels being reached within 60-90 minutes. Vorapaxar's effective half-life is three to four days and its terminal elimination half-life is eight days. Vorapaxar sulfate 2.5 mg (equivalent to 2.08 mg of vorapaxar) orally daily without a loading dose was clinically effective for the secondary prevention of ischemic events in patients with a history of myocardial infarction (MI) or with peripheral arterial disease (PAD) without a history of stroke. Phase II and III trials of vorapaxar given with aspirin or a thienopyridine or both demonstrated a reduction in the primary endpoint of cardiovascular death, MI, and stroke in patients with a history of MI or coronary artery disease and PAD. Patients with a history of stroke were found to have an increased rate of intracranial hemorrhage (ICH), which led to a boxed warning placed on vorapaxar's labeling to warn of the increased risk for bleeding in patients with a history of stroke. Vorapaxar is a novel antiplatelet agent that has demonstrated efficacy in reducing atherosclerotic events in patients with a history of MI or PAD without a history of stroke, transient ischemic attack, or ICH when taken in combination with aspirin and clopidogrel.

Direct Oral Anticoagulants in Acute Coronary Syndrome

Patients with acute coronary syndromes (ACS) require a specific antithrombotic therapy in the immediate and the post ACS phase. The current antithrombotic therapy in the acute phase of an ACS combines antiplatelet and anticoagulant drugs in order to reduce ischemic cardiovascular events. In the post ACS phase, dual antiplatelet therapy (DAPT; aspirin and a P2Y12 receptor antagonist) is the current mainstay of antithrombotic treatment and is recommended in the guidelines of the major North American and European clinical cardiology associations (AHA, ACC, and ESC). Recently, the addition of rivaroxaban, a low dose oral direct factor Xa inhibitor (2.5 mg twice daily), to DAPT (aspirin plus second-generation P2Y12 inhibitor) showed a significant reduction of cardiovascular and overall mortality in the major phase III clinical trial ATLAS ACS 2 TIMI 51. This led to the approval of low-dose rivaroxaban in addition to aspirin and clopidogrel by the European Medicines Agency (EMA) in 2013. Other direct oral anticoagulants (apixaban, dabigatran etexilate) have also been assessed in phase II (dabigatran etexilate) and phase III (apixaban) post ACS clinical trials. In the studied dosing regimens, these drugs failed to show a net clinical benefit in addition to dual antiplatelet therapy. The major clinical phase II and III post ACS studies of direct oral anticoagulants are summarized and discussed in this article along with the concept of long-term anticoagulation for the secondary prevention of ischemic events after ACS and implications for the future of antithrombotic therapy in the current era of third-generation P2Y12 receptor inhibitors (Prasugrel and Ticagrelor).

Pharmacodynamic effects of EV-077: results of an in vitro pilot investigation in healthy volunteers

Antiplatelet agents are important for the treatment of patients with atherosclerotic disease manifestations. Antiplatelet agents act by inhibiting platelet activation and aggregation processes, which are mediated by several activating factors including thromboxane A2 (TxA2), adenosine diphosphate (ADP), and thrombin. In particular, TxA2 induced platelet activation is a pivotal pharmacological target as supported by the undisputable benefit of aspirin in secondary prevention of ischemic events [1, 2]. TxA2 is a metabolite of arachidonic acid (AA) deriving from the cyclooxygenase (COX)-1 enzyme, which transforms AA into prostaglandin H2 (PGH2), which is ultimately metabolized into TxA2 by thromboxane synthase (TS) [3]. Low dose of aspirin mainly inhibits COX-1 and subsequently TxA2 production. However, up to one-third of aspirin treated patients aspirin show persistent TxA2 production, which in turn exposes these subjects to an increased risk of atherothrombotic events [4]. These findings underscore the need to identify new TxA2 modulators. TxA2 receptor (TP receptor) antagonists, TS inhibitors, and dual TS inhibitors and TP receptor antagonists have been recently developed [3, 5]. Such antagonists and inhibitors have also beneficial effects on TP receptor mediated vascular inflammation and oxidative stress, thus on the progression and development of atherosclerotic lesions [6]. EV-077 is a novel dual TS inhibitor and TP receptor antagonist in early phases of clinical investigation. Limited data is currently available on the pharmacodynamic effects of this agent on human platelets [7]. In this pilot investigation we describe the pharmacodynamics effects on human platelets of escalating in vitro concentrations of EV-077. Ten healthy volunteers aged 35.1 ± 3.6 years old were recruited for this study. None of the subjects were taking any type of medication, including over the counter and herbal supplements. Venous blood was collected by antecubital puncture, in hirudin (25 lg/mL) and sodium citrate (0.150 M) containing tubes. Plasma citrate concentration was adjusted according to the haematocrit and the resulting free plasma citrate were adjusted to a final plasma concentration of 20 mmol/L as previously described [8]. Whole-blood hirudin-tubes were incubated with escalating concentrations of EV-077 (vehicle, 1, 10, 30, 100, and 300 nM) for 10 min at 37 8C. EV-077 was provided by Evolva SA (Reinach, Switzerland). Platelet-rich plasma (PRP) was obtained by centrifugation of whole-blood citrated tubes at 1179 g for 10 min. After measuring the platelet count, PRP was adjusted to 250,000/lL ± 10 %. This PRP was incubated with vehicle or 100 nM of EV-077 for 10 min at 37 C. Platelet aggregation was determined by impedance aggregometry using Multiplate Analyzer (MEA) (Dynabyte Medical, Munich, Germany) for whole-blood samples stimulated with AA (1 mM) (Dynabite Medical, Munich, Germany) and the TxA2 analog U-46619 (7 lM) (Calbiochem, Merck KGaA, Darmstadt, Germany), as well as with an agonist indirectly related to the TxA2 pathway, collagen (3 lg/mL) (Dynabite Medical, Munich, Germany). Lighttransmission platelet aggregometry (LTA) was performed using PRP by the turbidimetric method in a two-channel aggregometer (Chrono-Log 490 Model, Chrono-Log Corp., A. Tello-Montoliu F. Rollini B. Desai G. Pasqualino R. Patel D. J. Angiolillo (&) University of Florida College of Medicine-Jacksonville, 655 West 8th Street, Jacksonville, FL 32209, USA e-mail: dominick.angiolillo@jax.ufl.edu

Antiplatelet Therapy for Secondary Prevention in Stroke – Making the Right Choice

In 2004, approximately 9 million people worldwide experienced a stroke, with the majority being ischemic in nature. While the prognosis for recovery can be good, long-term survival and functional outcome can be improved. Stroke survivors are at an increased risk for recurrent stroke and other ischemic vascular events and face significant cross-risk for atherothrombotic conditions affecting the coronary and peripheral vascular beds. As such, the secondary prevention of ischemic events in patients with stroke has focused on the treatment of atherosclerosis as a whole, with antiplatelet therapy playing a key role. There is some controversy regarding optimal antiplatelet therapy following stroke. The appropriate use of specific agents, the impact of stroke type and proper dosing, and other questions stem from an incomplete understanding of the issues, variability in clinical trial data, diversity in patient demographics, and differences in antiplatelet regimens. This review evaluates the clinical evidence for antiplatelet therapy in patients that have suffered an ischemic stroke, with an emphasis on balancing the benefits of a particular antiplatelet regimen with its attendant risk profile. The critical assessment of emerging trial data and its impact on existing treatment guidelines may aid in choosing the most appropriate antiplatelet regimen for comprehensive secondary prevention following stroke.