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1.  Balancing Potency of Platelet Inhibition with Bleeding Risk in the Early Treatment of Acute Coronary Syndrome 
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).
Data Sources:
American College of Cardiology/American Heart Association (ACC/AHA) 2007 guidelines for the management of patients with unstable angina (UA) and non-ST-segment elevation myocardial infarction (NSTEMI), AHA/ACC 2007 focused update for the management of patients with STEMI, selected clinical articles identified through the PubMed database (1965-February 2008), and manual searches for relevant articles identified from those retrieved.
Study Selection:
English-language controlled studies and randomized clinical trials that assessed the efficacy and safety of antiplatelet therapy in treating patients with all ACS manifestations.
Data Extraction and Synthesis:
Clinical data, including treatment regimens and patient demographics and outcomes, were extracted and critically analyzed from the selected studies and clinical trials. Pertinent data from relevant patient registries were also evaluated to assess current clinical practice.
As platelet activation and aggregation are central to ACS pathology, antiplatelet agents are critical to early treatment. A widely accepted first-line treatment is aspirin, which acts to decrease platelet activation via inhibition of thromboxane A2 synthesis. Thienopyridines, which inhibit ADP-induced platelet activation, and glycoprotein (GP) receptor antagonists, which bind to platelet GP IIb/IIIa receptors and hinder their role in platelet aggregation and thrombus formation, provide complementary mechanisms of platelet inhibition and are often employed in combination with aspirin. 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. 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.
PMCID: PMC2729217  PMID: 19718378
2.  Meta-Analysis of Bleeding Complications Associated with Cardiac Rhythm Device Implantation 
Many patients receiving cardiac rhythm devices have conditions requiring antiplatelet (AP) and/or anticoagulant (AC) therapy. Current guidelines recommend a heparin bridging strategy (HBS) for anticoagulated patients with moderate/high risk for thrombosis. Several studies reported lower bleeding risk with continued oral anticoagulation rather than HBS. The best strategy for perioperative management of patients on AP therapy is less clear. The present study was designed as a meta-analysis of device implantation associated bleeding complications using different AC/AP therapies.
Methods and Results
PubMed and Cochrane Database searches identified articles based on design, outcomes and available data. Device recipients were grouped as follows: no therapy (NT), aspirin only, AC held, AC continued, dual AP, HBS. The primary outcome was defined as a bleeding complication including hematoma, transfusion or prolonged hospital stay. Thirteen articles were identified for analysis including 5978 patients. The combined incidence of bleeding complications was 274/5978 (4.6%), ranging from 2.2% (NT) to 14.6% (HBS). The estimated odds of bleeding were increased by 8.3 (95% CI 5.5-12.9) times in the HBS group, 5.0 (95% CI 3.0-8.3) for dual AP therapy, 1.7 (95% CI 1.0-3.1) for AC held, 1.6 (95% CI 0.9-2.6) for AC continued, and 1.5 (95% CI 0.9-2.3) for aspirin only, relative to the NT group. HBS significantly increased bleeding events compared with holding or continuing AC. Continuing AC did not increase bleeding events compared with NT.
Continuing AC appears safer than HBS for device implantation. Dual AP therapy but not continuing AC carries a significant risk of bleeding.
PMCID: PMC3626087  PMID: 22534249
anticoagulants; heparin; implantable cardioverter-defibrillator; pacemakers
3.  Interaction between clopidogrel and proton-pump inhibitors and management strategies in patients with cardiovascular diseases 
Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in ‘high risk’ and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided.
PMCID: PMC3108705  PMID: 21701635
cardiovascular disease; gastrointestinal; proton-pump inhibitor; antiplatelet therapy
4.  Emergency Department Administration of Thienopyridines in NSTEMI: Results from the ACTION Registry®-GWTG™ Registry 
AHA/ACC guidelines recommend that patients with definite unstable angina or non-ST segment elevation myocardial infarction (NSTEMI) receive dual antiplatelet therapy on presentation to the hospital when undergoing early invasive management or “as soon as possible” after admission when being managed conservatively. The guidelines do not specify whether these medications should be administered in the emergency department (ED). Our aim was to determine whether ED administration of a thienopyridine was associated with clinical outcomes among patients with NSTEMI.
We examined thienopyridine use in 39,454 patients with NSTEMI who received a thienopyridine within 24 hours of presentation in the NCDR’s ACTIONRegistry®-GWTG™ from 1/2007–6/2010. Patients who were not seen initially in the ED, were transferred in, or were missing time data were excluded. We analyzed the association between ED administration of thienopyridines and outcomes and patient demographics.
Of the cohort receiving a thienopyridine within 24 hours, 9534 (24.2%) received it in the ED. ED administration of a thienopyridine was not associated with in-hospital major bleeding (multivariable adjusted OR 0.99; 95% confidence interval [CI]: 0.91–1.09) or in-hospital mortality (adjusted 1.02, 95% CI 0.86–1.20). Independent predictors most strongly associated with ED thienopyridine administration were elevated troponin, ED length of stay, prior percutaneous coronary intervention, and initial electrocardiogram showing ischemic changes.
There was no association between ED thienopyridine administration and in-hospital major bleeding or mortality. ED length of stay, ECG changes and elevated troponin were associated with ED thienopyridine administration.
PMCID: PMC4045403  PMID: 23702070
Thienopyridines; Non-ST segment elevation myocardial infarction; Outcomes
5.  Antiplatelet and Antithrombin Strategies in Acute Coronary Syndrome: State-Of-The-Art Review 
Current Cardiology Reviews  2012;8(3):239-249.
Antiplatelet and antithrombotic agents significantly alter the clinical course of patients with acute coronary syndrome (ACS) and hence form the bedrock of the management pathway of this closely related continuum of coronary pathologies. The contemporary therapeutic armamentarium for the treatment of ACS now reflects the many technical and pharmacological advances that took place over the last two decades. In the original 1996 American College of Cardiology/American Heart Association (ACC/AHA) guidelines for the management of acute myocardial infarction, only one antiplatelet agent (Aspirin) and one anticoagulant (unfractionated heparin) were recommended as class I therapies. Since then many newer agents have been developed and approved for routine clinical use in ACS patients. Recent research has focussed on improving efficacy on one hand and reducing bleeding complications on the other. This review focuses on the mechanism, efficacy, safety profile and clinical trial evidence of P2 Y12 receptor antagonist antiplatelet agents, glycoprotein IIb/IIIa receptor inhibitors (GPI), protease-activated receptor-1 (PAR-1) inhibitors, thrombin inhibitor bivalirudin and Factor Xa inhibitors fondaparinaux and rivaroxaban.
PMCID: PMC3465830  PMID: 22935021
Acute coronary syndrome; ACS; antiplatelet agents; antithrombotic agents; bivalirudin; cangrelor; NSTEMI; STEMI.
6.  Platelet Inhibitors in Non-ST-Segment Elevation Acute Coronary Syndromes and Percutaneous Coronary Intervention: Glycoprotein IIb/IIIa Inhibitors, Clopidogrel, or Both? 
The role of glycoprotein (Gp) IIb/IIIa receptor antagonists remains controversial and these agents are infrequently utilized during non-ST-segment elevation acute coronary syndromes (NSTE-ACS) despite American Heart Association/American College of Cardiology guidelines. Despite recommendations, the NRMI-4 (National Registry of Myocardial Infarction 4) and CRUSADE (Can rapid risk stratification of unstable angina patients suppress adverse outcomes with early implementation of the ACC/AHA guidelines?) registries observed that only 25%–32% of eligible patients received early Gp IIb/IIIa therapy, despite a 6.3% absolute mortality reduction in NRMI-4 and a 2% absolute mortality reduction in CRUSADE. A pooled analysis of Gp IIb/IIIa data from these registries suggest a major reduction in mortality (Odds Ratio = 0.43, 95% Confidence Index 0.25–0.74, p = 0.002) with early Gp IIb/IIIa therapy, yet clinicians fail to utilize this option in NSTE-ACS. The evidence-based approach to NSTE-ACS involves aspirin, clopidogrel, low-molecular weight heparins, or unfractionated heparin in concert with Gp IIb/IIIa receptor antagonists, however, newer percutaneous coronary intervention (PCI)-based trials challenge current recommendations. Novel strategies emerging in NSTE-ACS include omitting Gp IIb/IIIa inhibitors altogether or using Gp IIb/IIIa inhibitors with higher doses of clopidogrel in selected patients. The ISAR-REACT (Intracoronary stenting and antithrombotic regimen–Rapid early action for coronary treatment) and ISAR-SWEET (ISAR–Is abciximab a superior way to eliminate elevated thrombotic risk in diabetics) trials question the value of abciximab when 600 mg of clopidogrel concurrently administered during PCI. The CLEAR-PLATELETS (Clopidogrel loading with eptifibatide to arrest the reactivity of platelets) and PEACE (Platelet activity extinction in non-Q-wave MI with ASA, clopidogrel, and eptifibatide) trials suggest more durable platelet inhibition when Gp IIb/IIIa inhibitors are used with higher doses clopidogrel. The ISAR-COOL (ISAR: Cooling off strategy) trial found no difference in ischemic outcomes when Gp IIb/IIIa inhibitors were excluded and ARMYDA-2 (Antiplatelet therapy for reduction of myocardial damage during angioplasty) suggested higher doses of clopidogrel are more appropriate during PCI when Gp IIb/IIIa inhibitors are not utilized. This constellation of new trials forces reconsideration of current recommendations in regards to patient risk stratification, choice of antithrombotic therapy, doses, and timing. These new data will impact emerging guidelines and updates are currently in progress.
PMCID: PMC1993977  PMID: 17319468
acute coronary syndromes; glycoprotein IIb/IIIa inhibitors; tirofiban; abciximab; eptifibatide; clopidogrel
7.  Anticoagulant and Antiplatelet Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease 
Thrombosis  2012;2012:184573.
Anticoagulation represents the mainstay of therapy for most patients with atrial fibrillation. Patients on oral anticoagulation often require concomitant antiplatelet therapy, mostly because of coronary artery disease. After coronary stent implantation, dual antiplatelet therapy is necessary. However, the combination of oral anticoagulation and antiplatelet therapy increases the bleeding risk. Risk scores such as the CHA2DS2-Vasc score and the HAS-BLED score help to identify both bleeding and stroke risk in individual patients. The guidelines of the European Society of Cardiology provide a rather detailed recommendation for patients on oral anticoagulation after coronary stent implantation. However, robust evidence is lacking for some of the recommendations, and especially for new oral anticoagulants and new antiplatelets few or no data are available. This review addresses some of the critical points of the guidelines and discusses potential advantages of new anticoagulants in patients with atrial fibrillation after stent implantation.
PMCID: PMC3347779  PMID: 22577538
8.  A randomised controlled trial of antiplatelet therapy in combination with Rt-PA thrombolysis in ischemic stroke: rationale and design of the ARTIS-Trial 
Trials  2010;11:51.
Thrombolysis with intravenous rt-PA is currently the only approved acute therapy for ischemic stroke. Re-occlusion after initial recanalization occurs in up to 34% in patients treated with rt-PA, probably caused by platelet activation. In acute myocardial infarction, the combination of thrombolysis and antiplatelet therapy leads to a greater reduction of mortality compared to thrombolysis alone. In patients with acute ischemic stroke, several studies showed that patients already on antiplatelet treatment prior to thrombolysis had an equal or even better outcome compared to patients without prior antiplatelet treatment, despite an increased risk of intracerebral bleeding. Based on the fear of intracerebral haemorrhage, current international guidelines recommend postponing antiplatelet therapy until 24 hours after thrombolysis. Remarkably, prior use of antiplatelet therapy is not a contra-indication for thrombolysis. We hypothesize that antiplatelet therapy in combination with rt-PA thrombolysis will improve outcome by enhancing fibrinolysis and preventing re-occlusion.
ARTIS is a randomised multi-center controlled trial with blind endpoint assessment. Our objective is to investigate whether immediate addition of aspirin to rt-PA thrombolysis improves functional outcome in ischemic stroke. Patients with acute ischemic stroke eligible for rt-PA thrombolysis are randomised to receive 300 mg aspirin within 1.5 hours after start of thrombolysis or standard care, consisting of antiplatelet therapy after 24 hours. Primary outcome is poor functional health at 3 months follow-up (modified Rankin Scale 3 - 6).
This is the first clinical trial investigating the combination of rt-PA and acute aspirin by means of a simple and cheap adjustment of current antiplatelet regimen. We expect the net benefit of improved functional outcome will overcome the possible slightly increased risk of intracerebral haemorrhage.
Trial registration
The Netherlands National Trial Register NTR822. The condensed rationale of the ARTIS-Trial has already been published in Cerebrovascular Diseases.
PMCID: PMC2886039  PMID: 20459856
9.  Evaluation of proper prescribing of cardiac medications at hospital discharge for patients with acute coronary syndromes (ACS) in two Lebanese hospitals 
SpringerPlus  2014;3:159.
Coronary artery disease (CAD) is the major leading cause of death worldwide. The national practice guidelines from the American College of Cardiology (ACC) and American Heart Association (AHA) promote the use of several medical therapies for secondary prevention for patients with CAD. The purpose of this study was to evaluate whether ACS patients, admitted into two tertiary referral medical centers in Beirut, Lebanon, are discharged on optimal medical therapy based on the current AHA/ACC guidelines.
We reviewed the medical records of all patients with ACS who were admitted to the coronary care units (CCU) of two hospitals in Beirut, Lebanon between May and August 2012. Discharge prescriptions were reviewed and rating for the appropriateness of discharge cardiac medications was based on the AHA/ACC guidelines. We assessed whether patients were discharged on antiplatelet therapy, β-blockers, angiotensin converting enzymes inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), statins, and nitrates, unless contraindicated or not tolerated. In addition, we assessed whether patients and/or their caregivers were counseled about their disease(s) and discharge medications.
186 patients with a mean age of 63 ± 11.78 years, 70.4% of which were males, were admitted with ACS and were included in the study. Fifty three (28.5%) patients had ST elevation MI (STEMI), 64 (34.4%) had non-ST-elevation myocardial infarction (NSTEMI) and 69 (37.1%) had unstable angina (USA). Sixty two patients (33.3%) were treated with medical therapy and 124 patients (66.7%) underwent percutaneous coronary intervention (PCI).
Among eligible patients, 98.9% were discharged on aspirin, 89.1% on dual antiplatelet therapy (aspirin + thienopyridine or ticagrelor), 90.5% on a β-blocker, 81.9% on an ACEI or ARB, 89.8% on a statin, and 19.4% on nitroglycerin. Overall, 62.9% of the patients received the optimal cardiovascular drug therapy (the combination of dual antiplatelet therapy, a β-blocker, an ACEIs or an ARB, and a statin), 55.1% were counseled on their disease state(s) and drug therapy, and 92.2% and 55.9% were counseled on smoking cessation and life style changes, respectively.
In patients admitted with ACS, discharge cardiac medications are prescribed at suboptimal rates. Education of healthcare providers and implementation of ACS discharge protocols may help improve compliance with ACC/AHA guidelines. In addition, clinicians should be encouraged to provide adequate patient counseling.
PMCID: PMC4000588  PMID: 24790814
ACS; Cardiac medications; Secondary prevention; Coronary artery disease; CAD
10.  Oral antiplatelet therapy for atherothrombotic disease: overview of current and emerging treatment options 
Clinical presentations of atherothrombotic vascular disease, such as acute coronary syndromes, ischemic stroke or transient ischemic attack, and symptomatic peripheral arterial disease, are major causes of morbidity and mortality worldwide. Platelet activation and aggregation play a seminal role in the arterial thrombus formation that precipitates acute manifestations of atherothrombotic disease. As a result, antiplatelet therapy has become the cornerstone of therapy for the prevention and treatment of atherothrombotic disease. Dual antiplatelet therapy with aspirin and a P2Y12 adenosine diphosphate (ADP) receptor inhibitor, such as clopidogrel or prasugrel, is the current standard-of-care antiplatelet therapy in patients with acute coronary syndromes managed with an early invasive strategy. However, these agents are associated with several important clinical limitations, including significant residual risk for ischemic events, bleeding risk, and variability in the degree of platelet inhibition. The residual risk can be attributed to the fact that aspirin and P2Y12 inhibitors block only the thromboxane A2 and ADP platelet activation pathways but do not affect the other pathways that lead to thrombosis, such as the protease-activated receptor-1 pathway stimulated by thrombin, the most potent platelet agonist. Bleeding risk associated with aspirin and P2Y12 inhibitors can be explained by their inhibitory effects on the thromboxane A2 and ADP pathways, which are critical for protective hemostasis. Interpatient variability in the degree of platelet inhibition in response to antiplatelet therapy may have a genetic component and contribute to poor clinical outcomes. These considerations underscore the clinical need for therapies with a novel mechanism of action that may reduce ischemic events without increasing the bleeding risk.
PMCID: PMC3292409  PMID: 22393298
acute coronary syndromes; antiplatelet therapy; ADP; thromboxane A2; PAR-1; bleeding
11.  The Impact of Vascular Access for In-Hospital Major Bleeding in Patients with Acute Coronary Syndrome at Moderate- to Very High-Bleeding Risk 
Journal of Korean Medical Science  2013;28(9):1307-1315.
The aim of our study was to determine the impact of vascular access on in-hospital major bleeding (IHMB) in acute coronary syndrome (ACS). We analyzed 995 patients with non-ST elevation myocardial infarction and unstable angina at the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) moderate- to very high-bleeding risk scores in trans-radial intervention (TRI) retrospective registry from 16 centers in Korea. A total of 402 patients received TRI and 593 patients did trans-femoral intervention (TFI). The primary end-point was IHMB as defined in the CRUSADE. There were no significant differences in in-hospital and 1-yr mortality rates between two groups. However, TRI had lower incidences of IHMB and blood transfusion than TFI (6.0% vs 9.4%, P = 0.048; 4.5% vs 9.4%, P = 0.003). The patients suffered from IHMB had higher incidences of in-hospital and 1-yr mortality than those free from IHMB (3.1% vs 15.0%, P < 0.001; 7.2% vs 30.0%, P < 0.001). TRI was an independent negative predictor of IHMB (odds ratio, 0.305; 95% confidence interval, 0.109-0.851; P = 0.003). In conclusions, IHMB is still significantly correlated with in-hospital and 1-yr mortality. Our study suggests that compared to TFI, TRI could reduce IHMB in patients with ACS at moderate- to very high-bleeding risk.
PMCID: PMC3763104  PMID: 24015035
Acute Coronary Syndrome; Radial Artery; Hemorrhage
12.  Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: A position statement of the Canadian Cardiovascular Society 
The Canadian Journal of Cardiology  2009;25(12):683-689.
Acute coronary syndrome (ACS) guidelines recommend that most patients receive dual antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) at the time of presentation to prevent recurrent ischemic events. Approximately 10% of ACS patients require coronary artery bypass grafting surgery (CABG) during the index admission. Most studies show that patients who receive ASA and clopidogrel within five days of CABG have an increase in operative bleeding. Current consensus guidelines recommend discontinuation of clopidogrel therapy at least five days before planned CABG to reduce bleeding-related events. However, high-risk individuals may require urgent surgery without delay, to reduce the risk of potentially fatal ischemic events. The present multidisciplinary position statement provides evidence-based recommendations for the optimal use of dual antiplatelet therapy to balance ischemic and bleeding risks in patients with recent ACS who may require urgent CABG.
All ACS patients should be considered for dual antiplatelet therapy with ASA and clopidogrel at the earliest opportunity, despite the possibility of a need for urgent CABG.
For patients who have received clopidogrel and ASA, and require CABG: Those at high risk of an early fatal event (eg, with refractory ischemia despite optimal medical treatment, and with high-risk coronary anatomy (eg, severe left main stenosis with severe right coronary artery disease), should be considered for early surgery without discontinuation of clopidogrel.In patients with a high bleeding risk (eg, previous surgery, complex surgery) who are also at high risk for an ischemic event, consideration should be given to discontinuing clopidogrel for three to five days before surgery.Patients at a lower risk for ischemic events (most patients) should have clopidogrel discontinued five days before surgery.
For patients who have CABG within five days of receiving clopidogrel and ASA, the risk of major bleeding and transfusion can be minimized by applying multiple strategies before and during surgery.
Patients who receive clopidogrel pre-CABG for a recent ACS indication should have clopidogrel restarted after surgery to decrease the risk of recurrent ACS.
For patients with a recent coronary stent, the decision to continue clopidogrel until the time of surgery or to discontinue will depend on the risk and potential impact of stent thrombosis. Restarting clopidogrel after CABG will depend on whether the stented vessel was revascularized, the type of stent and the time from stent implantation. Clopidogrel should be restarted when hemostasis is assured to prevent recurrent acute ischemic events.
PMCID: PMC2807829  PMID: 19960127
Acute coronary syndromes; Clopidogrel; Coronary artery bypass surgery; Dual antiplatelet therapy
13.  Adoption of prasugrel into routine practice: rationale and design of the Rijnmond Collective Cardiology Research (CCR) study in percutaneous coronary intervention for acute coronary syndromes 
Netherlands Heart Journal  2013;22(2):55-61.
Platelet inhibition is crucial in reducing both short- and long-term atherothrombotic risks in patients with acute coronary syndromes (ACS) managed with percutaneous coronary intervention (PCI). Based on randomised trials, recent recommendations in the current guidelines include the endorsement of prasugrel as a first-choice adenosine diphosphate receptor inhibitor. Yet, there is limited experience with the use of prasugrel in routine practice.
The Rijnmond Collective Cardiology Research (CCR) registry is a prospective, observational study that will follow-up 4000 PCI-treated ACS patients in the larger region of Rotterdam, the Netherlands. Based on recently implemented hospital protocols, all patients will receive prasugrel as first-choice antiplatelet agent, unless contraindicated, in accordance with European guidelines, and will be followed for up to 1 year post-discharge for longitudinal assessment of outcomes and bleeding events. This registry exemplifies a collaborative study design that employs a regional PCI registry platform and provides feedback to participating sites regarding their practice patterns, thereby supporting and promoting improvement of quality of care.
The CCR registry will evaluate the adoption of prasugrel into routine clinical practice and thus, will provide important evidence with regard to the benefits and risks of real-world utilisation of prasugrel as antiplatelet therapy in PCI-treated ACS patients.
PMCID: PMC3967557  PMID: 24072688
Acute coronary syndrome; Percutaneous coronary intervention
14.  Management of bleeding and coagulopathy following major trauma: an updated European guideline 
Critical Care  2013;17(2):R76.
Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient. When these recommendations are implemented patient outcomes may be improved.
The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document represents an updated version of the guideline published by the group in 2007 and updated in 2010. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.
Key changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline also includes recommendations and a discussion of thromboprophylactic strategies for all patients following traumatic injury. The most significant addition is a new section that discusses the need for every institution to develop, implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. The remaining recommendations have been re-evaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.
A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensure that established protocols are consistently implemented will ensure a uniform and high standard of care across Europe and beyond.
Please see related letter by Morel et al
PMCID: PMC4056078  PMID: 23601765
15.  Clinical evidence of interaction between clopidogrel and proton pump inhibitors 
World Journal of Cardiology  2011;3(5):153-164.
Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals.
PMCID: PMC3110904  PMID: 21666816
Antiplatelet therapy; Aspirin; Clopidogrel; Proton pump inhibitor
16.  Biliary-Pancreatic Endoscopic and Surgical Procedures in Patients under Dual Antiplatelet Therapy: A Single-Center Study 
Clinical Endoscopy  2013;46(4):395-398.
Dual antiplatelet therapy has to be used for at least 1 month after placement of bare metal coronary stents and for a minimum of 1 year after placement of drug eluting stents. Because of the higher risk of bleeding, guidelines strongly recommend to delay elective surgery until dual antiplatelet therapy is ended. However, no data are available regarding the bleeding risk in patients on combined aspirin/clopidogrel therapy undergoing surgical or high-risk endoscopic procedures.
We retrospectively analyzed the medical reports of patients on dual antiplatelet therapy, the patients who had to undergo emergency biliary-pancreatic surgery or endoscopic retrograde cholangiography with endoscopic sphincterotomy while in our unit between January 2009 and July 2012.
In our series, biliary-pancreatic surgical and endoscopic procedures were safely performed in 11 consecutive patients on dual antiplatelet therapy with no evidence of bleeding.
In emergency, surgical and high risk endoscopic procedures may be performed in patients on dual antiplatelet therapy.
PMCID: PMC3746146  PMID: 23964338
Dual antiplatelet therapy; Sphincterotomy, endoscopic; General surgery
17.  Paradoxical use of invasive cardiac procedures for patients with non-ST segment elevation myocardial infarction: An international perspective from the CRUSADE Initiative and the Canadian ACS Registries I and II 
The Canadian Journal of Cardiology  2007;23(13):1073-1079.
Practice guidelines support an early invasive strategy in patients with non-ST segment elevation acute coronary syndromes, particularly in those at higher risk.
To compare North American rates of invasive cardiac procedure use stratified by risk.
Use of invasive cardiac procedures and other care patterns in patients with non-ST segment elevation acute coronary syndromes from the United States (US) Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) National Quality Improvement Initiative (n=88,097; 465 hospitals) and Canadian ACS Registries I (n=1270; 51 hospitals) and II (n=1473; 36 hospitals) were compared after dividing patients into different risk categories based on predicted risk of in-hospital mortality.
While the overall use of invasive procedures was higher in the US, high-risk patients were least likely to undergo coronary angiography (41% versus 64% in Canada [P<0.0001] and 53% versus 76% in the United States [P<0.0001]) and percutaneous coronary intervention (14% versus 32% in Canada [P<0.0001] and 28% versus 51% in the US [P<0.0001]) compared with low-risk patients in both countries, and had longer median waiting times for these procedures (120 h versus 96 h in Canada [P<0.0001] and 34 h versus 23 h in the US [P<0.0001] for coronary angiography).
The inverse relationship between risk level and the use of invasive cardiac procedures for patients in the US and Canada suggests that a risk stratification-guided approach for triaging patients to an early invasive management strategy is paradoxically used. This incongruous relationship holds true regardless of resource availability or overall rates of cardiac catheterization.
PMCID: PMC2651932  PMID: 17985010
Acute coronary syndromes; Guidelines
18.  Duration of dual antiplatelet treatment in the era of next generation drug-eluting stents 
World Journal of Cardiology  2014;6(4):148-153.
Current percutaneous coronary intervention guidelines recommend dual antiplatelets (aspirin 100 mg + clopidogrel 75 mg daily) for at least 12 mo following drug-eluting stent (DES) implantation if patients are not at high risk of bleeding. Several reports have tried to shorten the dual antiplatelet therapy to 3-6 mo, especially following next-generation DES implantation, for cost-effectiveness. However, the clinical results are inconsistent and the data regarding next-generation DESs limited. In this report, recently published important pivotal reports regarding the optimal duration of dual antiplatelets following DES implantation are summarized.
PMCID: PMC3999335  PMID: 24772255
Drug-eluting stent; Dual antiplatelet treatment; Percutaneous coronary intervention
19.  Management of patients with unstable angina/non-ST-elevation myocardial infarction: a critical review of the 2007 ACC/AHA guidelines 
In 2007, the American College of Cardiology/American Heart Association (ACC/AHA) published new guidelines for the diagnosis and management of patients with unstable angina/non-ST segment elevation myocardial infarction (UA/NSTEMI). These guidelines include some important updates on the use of clopidogrel, fondaparinux, bivalirudin and low-molecular-weight heparins (LMWHs) all of which have published landmark clinical trials in patients with acute coronary syndromes (ACS) since the publication of the 2002 guidelines. While these 2007 guidelines are more comprehensive and up-to-date compared with the recommendations published in 2002, they also raise many questions for practising emergency physicians and cardiologists.
This article presents a critical review of the 2007 ACC/AHA UA/NSTEMI guidelines, highlighting some of the areas of controversy, with the aim of providing some further guidance to practising physicians.
Despite recent updates to the ACC/AHA UA/NSTEMI guidelines, additional factors need to be taken into consideration in the management of UA/NSTEMI patients. Integrating initial responses with early or selectively invasive strategies and the risks of complications in subsequent procedures require careful consideration. Protocol development within an institution is required to risk-stratify patients rapidly, provide optimum precatheterisation medical management and allow seamless and rapid transitions to the catheterisation laboratory in patients at risk for adverse events.
PMCID: PMC2705816  PMID: 19222616
20.  Antiplatelet therapy in populations at high risk of atherothrombosis. 
Atherothrombosis is the most common cause of an acute ischemic event. Antiplatelet agents form the cornerstone of atherothrombosis prevention. The purpose of this article is to review the use of antiplatelet agents in patients that are at particularly high risk of atherothrombotic events. To undertake this review, we searched the literature to identify key studies on the use of antiplatelet agents in this group of patients. Antiplatelet agents, such as aspirin and clopidogrel, play a fundamental role in the treatment and management of secondary thrombotic events. The routine use of aspirin is recommended, as it has been shown to reduce the risk of thrombotic events by approximately 25%. Additional benefit has been demonstrated with clopidogrel, both as a monotherapy and in combination with aspirin. In the CAPRIE trial, 19,185 patients with atherosclerotic vascular disease were randomized to receive clopidogrel (75 mg/day) or aspirin (325 mg/day) for a mean duration of follow-up of 1.91 years. Clopidogrel provided an additional 8.7% relative risk reduction in the primary composite endpoint of ischemic stroke, myocardial infraction or vascular death compared with aspirin. In the CURE trial, the addition of clopidogrel to background aspirin was associated with a 20% relative risk reduction in a composite of death from cardiovascular causes, nonfatal myocardial infarction or stroke compared with aspirin alone. In patients undergoing PCI as part of the PCI-CURE substudy, clopidogrel was associated with a 30% relative reduction in the incidence of cardiovascular events in the first 30 days after intervention compared with aspirin. The benefits of antiplatelet therapy continue to be investigated. Whether dual antiplatelet therapy is superior to aspirin monotherapy for high-risk primary prevention is unknown. The ongoing CHARISMA trial aims to determine the relative efficacies of aspirin monotherapy and aspirin/clopidogrel combination therapy in a broad range of high-risk patient populations. In addition, the REACH registry, a worldwide survey of symptomatic and high-risk patients, has been set up to provide vital epidemiological information regarding the risks of atherothrombosis in order to contribute to the development of better preventive strategies and management regimens for at-risk patients.
PMCID: PMC2569272  PMID: 16749646
21.  Efficacy and safety of 12 versus 48 months of dual antiplatelet therapy after implantation of a drug-eluting stent: the OPTImal DUAL antiplatelet therapy (OPTIDUAL) trial: study protocol for a randomized controlled trial 
Trials  2013;14:56.
Dual antiplatelet therapy with aspirin and thienopyridine is required after placement of coronary drug-eluting stents (DES) to prevent thrombotic complications. Current clinical guidelines recommend at least 6 to 12 months of treatment after a DES implantation, but it may be beneficial to apply dual antiplatelet therapy for a longer duration.
The optimal dual antiplatelet therapy (OPTIDUAL) study aims to compare the benefits and risks of dual antiplatelet therapy applied for either 12 or 48 months. We will examine the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention with DES for the treatment of coronary lesions. The OPTIDUAL study is an open-label multicenter, randomized, national trial that will include 1,966 patients treated with DES. All patients will be treated with dual antiplatelet therapy for 12 months (+/− 3). Then, patients with no MACCE or major bleeding will be randomized to receive either 36 additional months of clopidogrel plus aspirin or aspirin only. The primary end-point is the combination of death from all causes, myocardial infarction, stroke and major bleeding. The secondary end points include the individual components of the primary end-point, stent thrombosis, repeat revascularization of the treated vessel and minor bleeding.
This randomized trial is designed to assess the benefits and safety of 12 versus 48 months of dual antiplatelet therapy in patients that receive a DES. We aim to determine whether substantial prolongation of clopidogrel (a thienopyridine) after DES implantation offers an advantage over its discontinuation.
Trial registration Identifier: NCT00822536
PMCID: PMC3598827  PMID: 23433461
Drug-eluting stent; Clopidogrel; Coronary artery disease; Stent thrombosis; Randomized clinical trial
22.  Evaluation of rationality in prescribing, adherence to treatment guidelines, and direct cost of treatment in intensive cardiac care unit: A prospective observational study 
Cardiovascular diseases (CVDs) remain the most common cause of sudden death. Hence, appropriate drug therapy in intensive cardiac care unit (ICCU) is crucial in managing cardiovascular emergencies and to decrease morbidity and mortality.
To evaluate prescribing pattern of drugs and direct cost of therapy in patients admitted in ICCU.
Materials and Methods:
Patients admitted in ICCU of a tertiary care teaching hospital were enrolled. Demographic data, clinical history, and complete drug therapy received during their stay in ICCU were noted. Data were analyzed for drug utilization pattern and direct cost of treatment calculated using patient's hospital and pharmacy bills. Rationality of therapy was evaluated based on American College of Cardiology/American Heart Association (ACC/AHA) guidelines.
Data of 170 patients were collected over 2 months. Mean age of patients was 54.67 ± 13.42 years. Male to female ratio was 2.33:1. Most common comorbid condition was hypertension 76 (44.7%). Most common diagnosis was acute coronary syndrome (ACS) 49.4%. Mean stay in ICCU was 4.42 ± 1.9 days. Mean number of drugs prescribed per patient was 11.43 ± 2.85. Antiplatelet drugs were the most frequently prescribed drug group (86.5%). Mean cost of pharmacotherapy per patient was ‘2701.24 ± 3111.94. Mean direct cost of treatment per patient was ‘10564.74 ± 14968.70. Parenteral drugs constituted 42% of total drugs and 90% of total cost of pharmacotherapy. Cost of pharmacotherapy was positively correlated with number of drugs (P = 0.000) and duration of stay (P = 0.027).
Antiplatelet drugs were the most frequently prescribed drug group. Mean number of drugs per encounter were high, which contributed to the higher cost of pharmacotherapy. ACC/AHA guidelines were followed in majority of the cases.
PMCID: PMC4047688  PMID: 24914255
Acute coronary syndrome; direct treatment cost; drug utilization; intensive cardiac care unit
23.  Effect of Co-Administration of Rivaroxaban and Clopidogrel on Bleeding Time, Pharmacodynamics and Pharmacokinetics: A Phase I Study 
Pharmaceuticals  2012;5(3):279-296.
Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co­administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co­administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval [CI] 2.82–4.73), compared with 1.13 times baseline (90% CI 0.17–2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10–2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics of rivaroxaban and, when compared with rivaroxaban alone, had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co­administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.
PMCID: PMC3763640  PMID: 24281379
bleeding time; clopidogrel; pharmacodynamics; pharmacokinetics; rivaroxaban
24.  High On-Aspirin Platelet Reactivity and Clinical Outcome in Patients With Stable Coronary Artery Disease: Results From ASCET (Aspirin Nonresponsiveness and Clopidogrel Endpoint Trial) 
Patients with stable coronary artery disease on single-antiplatelet therapy with aspirin are still at risk for atherothrombotic events, and high on-aspirin residual platelet reactivity (RPR) has been suggested as a risk factor.
Methods and Results
In this randomized trial, the association between platelet function determined by the PFA100 platelet function analyzer system (Siemens Healthcare Diagnostics, Germany) and clinical outcome in 1001 patients, all on single-antiplatelet therapy with aspirin (160 mg/d) was studied. Patients were randomized to continue with aspirin 160 mg/d or change to clopidogrel 75 mg/d. A composite end point of death, myocardial infarction, ischemic stroke, and unstable angina was used. At 2-year follow-up, 106 primary end points were registered. The prevalence of high RPR was 25.9%. High on-aspirin RPR did not significantly influence the primary end point in the aspirin group (13.3% versus 9.9%, P=0.31). However, in post hoc analysis, patients with von Willebrand factor levels or platelet count below median values and high on-aspirin RPR had a statistically significant higher end point rate than that of patients with low RPR (20% versus 7.5%, P=0.014, and 18.2% versus 10.8%, P=0.039, respectively). The composite end point rate in patients with high on-aspirin RPR treated with clopidogrel was not different from that of patients treated with aspirin (7.6% versus 13.3%, P=0.16).
In stable, aspirin-treated patients with coronary artery disease, high on-aspirin RPR did not relate to clinical outcome and did not identify a group responsive to clopidogrel. Post hoc subgroup analysis raised the possibility that high on-aspirin RPR might be predictive in patients with low von Willebrand factor or platelet count, but these findings will require confirmation in future studies.
Clinical Trial Registration
URL: Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.)
PMCID: PMC3487336  PMID: 23130135
antiplatelet therapy; aspirin; clopidogrel; residual platelet reactivity; angina, stable
25.  Two Cases and Review of the Literature: Primary Percutaneous Angiography and Antiplatelet Management in Patients with Immune Thrombocytopenic Purpura 
ISRN Hematology  2013;2013:174659.
We report two cases of immune thrombocytopenic purpura (ITP) associated with acute coronary artery syndrome highlighting the interventions done in every case along with the medications used during intervention and as outpatient. The first case is that of a woman with ITP exacerbation while on dual antiplatelet therapy and the second case is that of a male presenting with non-ST elevation myocardial infarction (NSTEMI) while in a thrombocytopenic crisis. In both cases antiplatelet therapy was held and thrombopoietic therapy was initiated before resuming full anticoagulation and coronary intervention. Given the paucity of data on ITP and antiplatelets treatment in the setting of acute coronary syndrome, no strict recommendations can be proposed, but antiplatelets appear to be safe acutely and in the long term in this category of patients as long as few measures are undertaken to minimize the risks of bleeding and thrombosis.
PMCID: PMC3888679  PMID: 24459590

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