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).
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.
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.
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.
anticoagulants; heparin; implantable cardioverter-defibrillator; pacemakers
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.
cardiovascular disease; gastrointestinal; proton-pump inhibitor; antiplatelet therapy
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.
Acute coronary syndrome; ACS; antiplatelet agents; antithrombotic agents; bivalirudin; cangrelor; NSTEMI; STEMI.
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.
acute coronary syndromes; glycoprotein IIb/IIIa inhibitors; tirofiban; abciximab; eptifibatide; clopidogrel
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.
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.
The Netherlands National Trial Register NTR822. The condensed rationale of the ARTIS-Trial has already been published in Cerebrovascular Diseases.
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.
acute coronary syndromes; antiplatelet therapy; ADP; thromboxane A2; PAR-1; bleeding
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.
Acute Coronary Syndrome; Radial Artery; Hemorrhage
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.
Acute coronary syndromes; Clopidogrel; Coronary artery bypass surgery; Dual antiplatelet therapy
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.
Antiplatelet therapy; Aspirin; Clopidogrel; Proton pump inhibitor
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.
Dual antiplatelet therapy; Sphincterotomy, endoscopic; General surgery
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.
Acute coronary syndromes; 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.
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.
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.
ClinicalTrials.gov Identifier: NCT00822536
Drug-eluting stent; Clopidogrel; Coronary artery disease; Stent thrombosis; Randomized clinical 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: http://www.clinicaltrials.gov Unique identifier: NCT00222261. (J Am Heart Assoc. 2012;1:e000703 doi: 10.1161/JAHA.112.000703.)
antiplatelet therapy; aspirin; clopidogrel; residual platelet reactivity; angina, stable
OBJECTIVES: To describe common barriers that limit the effect of guidelines on patient care, with emphasis on recommendations for triage in the Agency for Health Care Policy and Research (AHCPR) Unstable Angina Clinical Practice Guideline. DATA SOURCES: Previously reported results from a prospective clinical study of 10,785 patients presenting to the emergency department (ED) with symptoms suggestive of acute cardiac ischemia. STUDY DESIGN: Design is an analysis of the AHCPR guideline with regard to recognized barriers in guideline implementation. Presentation of hypothetical scenarios to ED physicians was used to determine interrater reliability in applying the guideline to assess risk and to make triage decisions. PRINCIPAL FINDINGS: The AHCPR guideline's triage recommendations demonstrate (1) poor interobserver reliability in interpretation by ED physicians; (2) limited applicability of recommendations for outpatient management (applies to 6 percent of patients presenting to the ED with unstable angina); (3) incomplete specifications of exceptions that may require deviation from guideline recommendations; (4) unexpected effects on medical care by significantly increasing the demand for limited intensive care beds; and (5) unknown effects on patient outcomes. In addition, analysis of the guideline highlights the need to address organizational barriers, such as administrative policies that conflict with guideline recommendations and the need to adapt the guideline to conform to local systems of care. CONCLUSIONS: Careful analysis of guideline attributes, projected effect on medical care, and organizational factors reveal several barriers to successful guideline implementation that should be addressed in the design of future guideline-based interventions.
The management of patients scheduled for surgery with a coronary stent, and receiving 1 or more antiplatelet drugs, has many controversies. The premature discontinuation of antiplatelet drugs substantially increases the risk of stent thrombosis (ST), myocardial infarction, and cardiac death, and surgery under an altered platelet function could also lead to an increased risk of bleeding in the perioperative period. Because of the conflict in the recommendations, this article reviews the current antiplatelet protocols after positioning a coronary stent, the evidence of increased risk of ST associated with the withdrawal of antiplatelet drugs and increased bleeding risk associated with its maintenance, the different perioperative antiplatelet protocols when patients are scheduled for surgery or need an urgent operation, and the therapeutic options if excessive bleeding occurs.
stent thrombosis; antiplatelet agents; aspirin; clopidogrel; surgical bleeding; perioperative management
Beta-Blockers [BB] have been used extensively in the last 40 years after acute myocardial infarction [AMI] as part of therapy and in secondary prevention. The evidence for “routine” therapy with beta-blocker use post AMI rests largely on results of trials conducted over 25 years ago. However, there remains no clear recommendation regarding the appropriate duration of treatment with BBs in post AMI patients with normal left ventricular ejection fraction [LVEF] who are not experiencing angina, or who require BB for hypertension or dysrhythmia. Based on the latest ACC/AHA guidelines, BBs are recommended for early use in the setting of AMI, except in patients who are at low risk and then indefinitely as secondary prevention after AMI. This recommendation was downgraded to class IIa in low risk patients and the updated 2007 ACC/AHA guidelines suggest that the rationale for BB for secondary prevention is from limited data derived from extrapolations of chronic angina and heart failure trials. In this review, we examine the key trials that have shaped the current guidelines and recommendations. In addition, we attempt to answer the question of the duration of BB use in patients with preserved LVEF after acute MI, as well as which subgroups of patients benefits most from post AMI use of beta blockers.
Acute myocardial infarction; Beta Blockers; Secondary prevention.
Adherence to clinical practice guidelines for management of cardiovascular disease (CVD) is suboptimal. The purposes of this study were to identify practice patterns and barriers among U.S. general internists and family physicians in regard to cardiovascular risk management, and examine the association between physician characteristics and cardiovascular risk management.
A case vignette survey focused on cardiovascular disease risk management was distributed to a random sample of 12,000 U.S. family physicians and general internists between November and December 2006.
Responses from a total of 888 practicing primary care physicians who see 60 patients per week were used for analysis. In an asymptomatic patient at low risk for cardiovascular event, 28% of family physicians and 37% of general internists made guideline-based preventive choices for no antiplatelet therapy (p < .01). In a patient at high risk for cardiovascular event, 59% of family physicians and 56% of general internists identified the guideline-based goal for serum fasting LDL level (< 100 mg/dl). Guideline adherence was inversely related to years in practice and volume of patients seen. Cost of medications (87.7%), adherence to medications (74.1%), adequate time for counseling (55.7%), patient education tools (47.1%), knowledge and skills to recommend dietary changes (47.8%) and facilitate patient adherence (52.0%) were cited as significant barriers to CVD risk management.
Despite the benefits demonstrated for managing cardiovascular risks, gaps remain in primary care practitioners' management of risks according to guideline recommendations. Innovative educational approaches that address barriers may facilitate the implementation of guideline-based recommendations in CVD risk management.
The perioperative course of the patients who have undergone coronary stent placement was studied. These patients were on dual antiplatelet therapy and were posted for noncardiac surgery. Clopidogrel had been discontinued for a variable duration before noncardiac surgery. Thromboelastography (TEG) was performed preoperatively to assess their fitness for surgery. The surgery and the postoperative period were uneventful in all the patients. There was no incidence of increased bleeding in any of the patients. Blood transfusion was not required in any patient. We concluded that standard TEG can be used when in dilemma about the fitness of the patient for surgery. Although there are clear guidelines about the patients who are on dual antiplatelet therapy, in clinical practice, it is important to weigh the risk-benefit to the advantage of the patient. If we stop the dual antiplatelet therapy in a patient with drug eluting stent within 1 year of implantation, the risk of major adverse cardiac event increases many fold. If we continue clopidogrel and aspirin during surgery, the risk of bleeding increases but is not life-threatening, except when surgery is performed in closed spaces. Thus, to continue dual antiplatelet medication intraoperatively is better than to stop it. If the medicine has to be withheld, it should be withheld for the minimal possible duration and a TEG should be performed.
Coronary artery stent; noncardiac surgery; thromboelastography
Factors contributing to low adherence to clinical guidelines by clinicians are not well understood. The user interface of ATHENA-HTN, a guideline-based decision support system (DSS) for hypertension, presents a novel opportunity to collect clinician feedback on recommendations displayed at the point of care. We analyzed feedback from 46 clinicians who received ATHENA advisories as part of a 15-month randomized trial to identify potential reasons clinicians may not intensify hypertension therapy when it is recommended. Among the 368 visits for which feedback was provided, clinicians commonly reported they did not follow recommendations because: recorded blood pressure was not representative of the patient’s typical blood pressure; hypertension was not a clinical priority for the visit; or patients were nonadherent to medications. For many visits, current quality-assurance algorithms may incorrectly identify clinically appropriate decisions as guideline nonadherent due to incomplete capture of relevant information. We present recommendations for how automated DSSs may help identify “apparent” barriers and better target decision support.
Diabetes mellitus (DM) is associated with macrovascular and microvascular complications. Platelets have a “key role” in atherogenesis and its thrombotic complications in subjects with DM. Moreover, the concomitant presence of multiple “classical” cardiovascular risk factors in diabetic subjects contributes to enhanced atherothrombotic risk.
Antiplatelet agents are effective in primary and secondary prevention of arterial thrombosis (cardiovascular events, ischaemic stroke, and peripheral arterial occlusive disease). The role of chronic administration of antiplatelet drugs in primary prevention of arterial vascular events is known to be less clear than in secondary prevention, and, also in diabetic patients, the decision to give primary prophylaxis should be taken on an individual-patient basis, after a careful evaluation of the balance between the expected benefits and the risk of major bleedings.
Although, currently, treatment has proven useful in reducing vascular events, diabetic patients continue to have a higher risk of adverse cardiovascular events compared with those in nondiabetic patients.
This paper reviews the role of currently available antiplatelet drugs in primary and secondary prevention of vascular events in diabetic patients and the limitations of these drugs, and it discusses the role of novel and more potent antiplatelets and of new agents currently under clinical development.
Diabetes during pregnancy can lead to severe risks for both mother and fetus when it is not managed properly. The use of rigorously developed guidelines with a robust implementation process can have a positive influence on the management of diabetes during pregnancy. This study aims to compare recommendations and assess the quality of clinical guidelines on gestational diabetes mellitus (GDM) and pre-existing diabetes mellitus during pregnancy.
Guidelines were selected by searching PubMed, the Guideline Clearing House and Google. All guidelines developed since 2000 on diabetes during pregnancy in English or Dutch were considered. Recommendations of the guidelines were compared. Furthermore, the quality was assessed by two authors independently, using the AGREE instrument.
Eight guidelines were included. According to the AGREE instrument, the quality of most guidelines was low. The domains editorial independence, stakeholder involvement and rigour of development had the lowest scores. Recommendations were mainly comparable on glycemic control, preconceptional counseling and prenatal care and labour. Differences between recommendations were found for screening on GDM and induction of labour.
The quality of most guidelines concerning the management of diabetes during pregnancy needs to be improved. A more systematic approach in the development of these guidelines, more attention for updating procedures and piloting of the guidelines and involvement of target users and patients is recommended.
Clinical guidelines; Diabetes mellitus; Gestational diabetes; Pregnancy