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To review available evidence and examine issues surrounding the use of advanced antiplatelet therapy in an effort to provide a practical guide for emergency physicians caring for patients with acute coronary syndromes (ACS). Clinical data, including treatment regimens and patient demographics and outcomes, were extracted and critically analyzed from the selected studies and clinical trials. As platelet activation and aggregation are central to ACS pathology, antiplatelet agents are critical to early treatment. Acute coronary syndrome (ACS) describes a spectrum of atherothrombosis, including unstable angina (UA), non?ST-segment elevation myocardial infarction (NSTEMI) and ST-segment elevation myocardial infarction (STEMI). Emergency physicians (EPs) must choose appropriate antiplatelet therapy based on the underlying risk of ischemic complications and the anticipated course of treatment, i.e. In addition to disease-related ischemia and necrosis, high-risk patients who undergo angiography face the potential added burden of periprocedural ischemia.
This review aims to examine issues and barriers surrounding antiplatelet therapy use and to provide a practical guide for EPs regarding their optimal use in ACS patients. True pharmacological resistance is probably uncommon and likely the result of genetic polymorphism. Laboratory platelet aggregation tests, traditionally used to evaluate bleeding disorders, have recently been employed to correlate ex vivo results of antiplatelet therapy with clinical outcomes.
Rapid inhibition of platelet aggregation is often accomplished by administering a loading dose of an antiplatelet agent. Although a higher clopidogrel loading dose more rapidly inhibits platelet aggregation, it is unclear whether this translates into improved clinical outcomes.
Loading doses of the recently approved antiplatelet agent, prasugrel, have also been assessed. Patients with hemodynamic instability (cardiogenic shock), mechanical complications (acute mitral regurgitation), diabetes, impaired left ventricular function, concomitant vascular disease, and multivessel disease are at higher risk for urgent CABG.2,48 As shown in the Bypass Angioplasty Revascularization Investigation study of patients with diabetes,49 such patients may have improved survival with CABG compared to PCI. Based on an analysis of NSTEMI patients from the TACTICS-TIMI-18 trials, Sadanandan et al.50 developed a predictive risk score to identify patients who are likely to require CABG during index hospitalization. The risk of bleeding is the most important safety consideration when initiating antiplatelet therapy. In contrast to the well-established safety and efficacy data of dual treatment with aspirin and clopidogrel, data related to dual therapy with aspirin and prasugrel are only emerging, and their overall clinical significance is yet unknown. The safety profiles of AZD6140 and cangrelor, two emerging antiplatelet agents which are reversible inhibitors of the P2Y12 receptor, also remain to be determined. GPI inhibition is associated with a small, significant increased incidence of bleeding, most commonly at the vascular access site (Table 2).
Overall, a large body of evidence supports an acceptable safety profile for dual antiplatelet therapy with aspirin and clopidogrel in all ACS patients, a differential safety profile with GPIs, and an unclear safety profile for the novel agents prasugrel, AZD6140, and cangrelor. Results from various studies supporting these guidelines are of particular interest to EPs. Although it is important for EPs to appreciate the added periprocedural protection that upstream administration of advanced antiplatelet therapy affords their ACS patients, the ideal timing of clopidogrel initiation is uncertain. The EP’s role in treating ACS patients is to provide rapid, accurate diagnosis and institute timely, risk-directed treatment. Choice and timing of antiplatelet therapy in the ED must also take into consideration future interventions the patients may receive during their hospital course.
Emerging investigational antiplatelet agents may show promise in ACS treatment; however, use of these agents should be approached with caution. Every five years since 1995 in France, nationwide surveys of patients admitted to intensive care units for acute myocardial infarction during a one-month period have been implemented. Mean age from 1995 to 2010 remained stable in NSTEMI patients (68 years) and decreased from 66 to 63 years in STEMI patients. The initial severity of infarction declined progressively, in particular with fewer patients having signs of heart failure. This press release accompanies both a presentation and an ESC press conference at the ESC Congress 2012. About the European Society of Cardiology The European Society of Cardiology (ESC) represents more than 75,000 cardiology professionals across Europe and the Mediterranean. About ESC Congress 2012 ESC Congress 2012 will take place from 25 to 29 August at the Messe München centre in Munich, Germany. Frequency of Diagnosed &Undiagnosed DM and IGT by Age Rising Prevalence of Diabetes Mellitus Adapted from M Harris.


People with DM2 and CVD Derive Less Benefit from Preventive and Interventional Therapies Patients with diabetes treated with antiplatelet treatments continue to have a higher risk of adverse CV events compared with nondiabetic patients 1 ? Reduced antiplatelet drug responsiveness may play a role in these worse outcomes Diabetes may abolish the beneficial effect of primary percutaneous coronary intervention on long-term risk of reinfarction after acute ST-segment elevation MI 2 1.Angiolillo DJ.
Questions to consider when choosing a glucose-lowering agent What is the efficacy in A1C reduction?
Adverse Outcomes Among Patients with Type 2 Diabetes Experiencing Severe Hypoglycemia 25 No. Note: Since your browser does not support Javascript, you must press the Continue button once to proceed. Pertinent data from relevant patient registries were also evaluated to assess current clinical practice.
A widely accepted first-line treatment is aspirin, which acts to decrease platelet activation via inhibition of thromboxane A2 synthesis. As treatment decisions are driven by ACS type and severity, initial risk stratification in the emergency department (ED) is essential. Aspirin, which inhibits platelet activation by irreversibly binding to cyclooxygenase-1, is widely accepted as first-line treatment in ACS patients.2 By irreversibly binding the platelet P2Y12 receptor, thienopyridines inhibit adenosine disphosphate-mediated platelet activation.
It is hypothesized that microvascular embolization downstream of the target vessel plays a predominant role in the development of periprocedural infarction risk.6 Hence, it is important to recognize the adjuvant role of pre-catheterization (“upstream”) antiplatelet agents and anticoagulation during coronary intervention to offer protection against both disease-related and periprocedural ischemic insults.
While not a purely systematic review, we sought to identify relevant controlled studies and randomized clinical trials that assessed the efficacy and safety of antiplatelet therapy in treating patients with all ACS manifestations. However, using these inhibition of platelet activity (IPA) results is problematic and currently clinically non-interpretable, partly due to the lack of a standard test for IPA.
As shown in the CURE,8,22 CREDO,7and CLARITY23,24 trials, as well as a meta-analysis thereof ,24 addition of a 300-mg clopidogrel loading dose resulted in significant relative risk reductions in endpoints among all ACS patients, regardless of their intervention strategy (Table 2). In PRINCIPLE, a 60-mg prasugrel loading dose resulted in greater platelet inhibition compared to a 600-mg clopidogrel loading dose as early as 30 minutes after intake.34 Although PRINCIPLE was not powered to detect clinical outcomes, hemorrhagic adverse events were more common in patients taking prasugrel.
Suggested antiplatelet therapy management algorithm for patients presenting to the ED with ACS and requiring CABG. Mehta et al.51 have also developed a multivariate model, based on CRUSADE data, identifying 13 presenting clinical characteristics significantly associated with undergoing CABG during initial hospital stay. If the patient has already received clopidogrel and elective CABG is deemed necessary, clopidogrel should be discontinued for five to seven days prior to surgery in order to balance antiplatelet efficacy with bleeding risk. Cardiovascular death, myocardial infarction, stroke and severe ischemia within the first 24 hours after randomization to aspirin plus placebo or aspirin plus clopidogrel in the CURE study. The primary endpoint occurred in 4% of patients in the high-loading dose group versus 12% of those in the conventional-loading dose group (P=0.041) and was due entirely to periprocedural MI. The guidelines recommend administration as soon as possible, and as the time from administration to PCI increases, so does the periprocedural protection.
Increasing the potency of platelet inhibition by adding a thienopyridine or GPI to standard therapy early in the treatment course improves protection against ischemic and periprocedural events but must be balanced against any unjustifiable increase in bleeding risk. In addition to standard aspirin therapy, early initiation of clopidogrel in the ED is often justified in ACS patients, regardless of their subsequent treatment strategy (medical or interventional).
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The analysis of four French registries from 1995 to 2010 was presented by Professor Nicolas Danchin from the Hopital Européen Georges Pompidou.
The first type, ST-elevation myocardial infarction (STEMI), corresponds to the sudden, permanent occlusion of a coronary artery supplying the myocardium (cardiac muscle), usually manifesting as a prolonged, intense chest pain (what is known as a heart attack); it is a true medical emergency, as prompt reopening of the occluded artery will lead to myocardial salvage and limit the consequences of infarction. From 1995 to 2010 there were increases in the prevalence of obesity (14% to 22%), diabetes (17% to 21%), hypertension (46% to 54%), current smoking (31% to 34%) and hypercholesterolemia (36% to 43%).
The press release has been written by the investigator and edited by the ESC and does not necessarily reflect the opinion of the European Society of Cardiology. Ronald Goldenberg, MD, FRCPC, FACE Consultant Endocrinologist, North York General Hospital and LMC Endocrinology Centers, Thornhill, Ontario Dr. Appropriate therapy must balance the need for potent platelet inhibition with the potential for increased bleeding. For each given test, there is considerable variation among laboratories as the methodology is difficult to standardize. The optimal loading dose of clopidogrel necessary to safely achieve rapid platelet inhibition has been an area of investigation.


However, identification in the ED of patients likely to need urgent CABG remains problematic as these prediction scores are often unreliable prior to diagnostic angiography. As might be expected based on higher levels of platelet inhibition, bleeding risk is increased by combining antiplatelet agents (Table 2). The resultant unfavorable net benefit in these patient subgroups led to the inclusion of the aforementioned black box warning in the prasugrel prescribing information. The ARMYDA-2 trial gave a loading dose 4–6 hours prior to PCI, but the EP is often dealing with a 90-minute treatment window, making the ARMYDA-2 results relevant primarily to those ACS patients not going emergently for PCI. Clopidogrel plus aspirin is a safe and effective therapy recommended by national guidelines for use in ACS patients, regardless of treatment strategy (Table 4). However, care should be taken regarding patients who are highly likely to require early CABG. For optimal viewing of this site, please ensure that Javascript is enabled for your browser.
The second type, non-ST-segment elevation infarction (NSTEMI), is caused by partial or intermittent blockage of an artery, and leads to a more progressive and more limited destruction of myocardial cells; it does not usually require immediate coronary intervention. In STEMI, the use of emergency reperfusion therapy to reopen the blocked artery increased from 49% to 75%; primary PCI increased from 12% to 60% and fibrinolysis decreased from 37% to 14%. Mansoor Husain MD, FRCPC Director, Toronto General Hospital Research Institute and Heart and Stroke Richard Lewar Centre for Excellence Senior Scientist, Division of Experimental Therapeutics Professor of Medicine, University of Toronto Dr. N Eng J Med 2011;365:2002-12 14% 11% Emergency Hospitalizations for Adverse Drug Events in Older Americans Oral agents and insulin account for > 25% of hospitalizations in adults > 65 years! While the higher levels of platelet inhibition that accompany combination therapy improve protection against ischemic and peri-procedural events, the risk of bleeding is also increased. Patients with acute STEMI are candidates for immediate reperfusion therapy with adjunctive antiplatelet and antithrombotic therapy. Ongoing collaboration among EPs, cardiologists, hospitalists and cardiovascular surgeons will undoubtedly improve care for ACS patients. Because of the difficulty in predicting which ACS patients will require emergency CABG, it is essential that emergency physicians, cardiologists, cardiovascular surgeons, and hospitalists develop clear, institution-specific indications for clopidogrel and GPI administration.
Additional data are required to fully establish the net benefit of dual therapy with aspirin and prasugrel. Among STEMI patients treated by fibrinolysis, GPI therapy is not associated with a net clinical benefit as major bleeding is significantly increased in the absence of any mortality reductions (Table 3).57,58 In contrast, the ADMIRAL59 and CADILLAC60 studies showed that benefits from upstream GPI therapy in PCI patients were not compromised by any important increased bleeding risk. The guidelines advocate GPI administration as early as possible in STEMI patients undergoing PCI,32,33,62,63 which supports initiating treatment in the ED. Early use of evidence based medication increased (antiplatelet agents 91% to 97%, beta-blockers 64% to 81%, statins 14 to 90% and ACE inhibitors 46% to 60%). Thus, the challenge in choosing appropriate therapy in the emergency department lies in balancing the need for potent platelet inhibition with the potential for increased risk of bleeding and future interventions the patient is likely to receive during the index hospitalization.
Data from CRUSADE, a national health quality improvement initiative, showed significant improvement in adherence to guideline recommendations for ACS management in the acute setting, as participating hospitals developed more thorough cross-disciplinary pathways and protocols.5 It is through such institutional-level collaboration that EPs can be empowered to initiate early, appropriate anti-ischemic therapy rather than being dependent on the individual, often varied, preferences of on-call specialists.
Specifically, prasugrel is contraindicated in patients with active pathological bleeding or a history of stroke or TIA, should not be given to patients likely to undergo CABG, and is generally not recommended for patients aged ?75 years. Such collaboration decreases reliance on personal preferences and empowers emergency physicians to initiate care and gain ischemia-related reductions while simultaneously maximizing patient safety.
Results from the ASSENT-3 and GUSTO-V trials do not support a favorable balance of benefit over bleeding risk for GP inhibition in STEMI patients undergoing fibrinolysis. For example, the excess bleeding in CURE was significant when the OASIS scale was used but insignificant using the TIMI and GUSTO scales.8 Importantly, even using the stringent OASIS scale, life-threatening bleeding was not significantly greater among dual aspirin and clopidogrel recipients in CURE. This finding illustrates the complexity of balancing increased antiplatelet potency with bleeding risk. Such changes are likely to occur first in the chronic management of coronary artery disease, but at some point in the future may impact ED decision-making as well.



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