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Secondary Stroke Prevention, and the Role of Antiplatelet Therapies
Howard S. Kirshner
Clinical Medicine : Therapeutics , 2009,
Abstract: This review considers treatments of proved efficacy in secondary stroke prevention, with an emphasis on antiplatelet therapy. Most strokes could be prevented, if readily available lifestyle and risk factor modifications could be applied to everyone. In secondary stroke prevention, the same lifestyle and risk factor modifications are also important, along with anticoagulation for patients with cardiac sources of embolus, carotid procedures for patients with significant internal carotid artery stenosis, and antiplatelet therapy. For patients with noncardioembolic ischemic strokes, FDA-approved antiplatelet agents are recommended and preferred over anticoagulants. ASA, clopidogrel, and ASA + ER-DP are recognized as accepted first-line options for secondary prevention of noncardioembolic ischemic stroke. Combined antiplatelet therapy with ASA + clopidogrel has not been shown to carry benefit greater than risk in stroke or TIA patients. Aspirin and extended release dipyridamole appeared to carry a greater benefit over aspirin alone in individual studies, leading to a recommendation of this agent in the AHA guidelines, but the recently completed PRoFESS trial showed no difference in efficacy between clopidogrel and aspirin with extended release dipyridamole, and clopidogrel had better tolerability and reduced bleeding risk.
Tailored antiplatelet therapy can overcome clopidogrel and aspirin resistance - The BOchum CLopidogrel and Aspirin Plan (BOCLA-Plan) to improve antiplatelet therapy
Horst Neubauer, Andreas FC Kaiser, Heinz G Endres, Jan C Krüger, Andreas Engelhardt, Sebastian Lask, Fenena Pepinghege, Andreas Kusber, Andreas Mügge
BMC Medicine , 2011, DOI: 10.1186/1741-7015-9-3
Abstract: Platelet function testing using whole blood aggregometry (Chronolog 590) was performed 48 hours following coronary stenting (for either acute coronary syndromes or stable coronary artery disease) on 504 patients. The antiplatelet therapy included a loading dose of 600 mg clopidogrel and 500 mg ASA, followed by 75 mg clopidogrel and 100 mg ASA once daily. Clopidogrel low responders (CLR: >5 ohm; adenosine diphosphate (ADP) 5 μM) and/or ASA low responders (ALR: >0 ohm; arachidonic acid 10 μM) were treated according to a structured therapy plan: in the case of CLR, the maintenance + dose was doubled (repeated loading dose followed by 150 mg daily), and when still ineffective ticlopidine or prasugrel, if available and not contraindicated, were used. ALR was treated by increasing the dose to 300 mg in a first step or to 500 mg ASA when the first modification did not take effect sufficiently. In addition, ADP receptor antagonist 2-methylthioadenosine 5'-monophosphate triethylammonium salt (MeSAMP) testing and ASA incubation were performed to rule out either a platelet ADP-receptor defect or an ASA pharmacokinetic resistance.Of the total cohort of 504 patients, we detected 30.8% clopidogrel low-responders and 19.4% aspirin low-responders. For ALR, with a dose adjustment of 300 mg ASA daily, 94.6% of ALR were effectively treated and the residual 5.4% by administration of daily dosages of 500 mg ASA. This means that after modification of the ASA maintenance dose, all initial ALRs had an adequate antiplatelet response.The results for clopidogrel revealed that 69% of the CLR were treated effectively by increasing the clopidogrel dose to 150 mg daily. When prasugrel was not available or contraindicated, 12.7% of the remaining low responders showed an adequate result after being switched to ticlopidine. Consequently, by applying the therapy algorithm, we were able to reduce the CLR prevalence by 86.6%. On including prasugrel in the therapy plan, we were finally able to eliminate
Bleeding tendency in dual antiplatelet therapy with aspirin/clopidogrel: rescue of the template bleeding time in a single-center prospective study
Raul Altman, Ana J Rivas, Claudio D Gonzalez
Thrombosis Journal , 2012, DOI: 10.1186/1477-9560-10-3
Abstract: In a single-center prospective study, 100 patients under long-term aspirin/clopidogrel treatment, the effect of therapy was assayed by template bleeding time (BT) and the inhibition of platelet aggregation (IPA) by light transmission aggregometry (LTA). Arachidonic acid (0.625 mmol/L) and adenosine diphosphate (ADP; 2, 4, and 8 μmol/L) were used as platelet agonists.Bleeding episodes (28 nuisance, 2 hematuria [1 severe], 1 severe proctorrhagia, 1 severe epistaxis) were significantly more frequent in patients with longer BT. Template BT ≥ 24 min was associated with bleeding episodes (28 of 32). Risk of bleeding increased 17.4% for each 1 min increase in BT. Correlation was found between BT and IPAmax in response to ADP 2 μmol/L but not to ADP 4 or 8 μmol/L.In patients treated with dual aspirin/clopidogrel therapy, nuisance and internal bleeding were significantly associated with template BT and with IPAmax in response to ADP 2 μmol/L but not in response to ADP 4 μmol/L or 8 μmol/L.Until recently, long-term antiplatelet therapy for the prevention of atherothrombotic disease was limited to aspirin (ASA). The availability of thienopyridines, particularly clopidogrel (CLOP), represented an important addition to the physician's armamentarium. The combination of CLOP and ASA in patients with acute coronary syndrome (ACS) reduces the risk of reinfarction, stroke, and death by 20% compared with ASA alone [1]. Nevertheless, the current therapy options for these patients are suboptimal. Despite the use of available antiplatelet therapies, the recurrence of ischemic events in patients with ACS is still increasing and bleeding remains an important, and often underappreciated, risk with these therapies. Patient noncompliance because of bleeding contributes to thrombosis events.The exact mechanism of benefit has not yet been elucidated but is clearly related not just to inhibition of platelet aggregation (IPA) but also to modification of the many consequences of the platelet activ
Resistance to antiplatelet drugs (aspirin, clopidogrel) in patients undergoing elective percutaneous coronary intervention  [cached]
V.A. Sulimov,E.V. Moroz
Rational Pharmacotherapy in Cardiology , 2012,
Abstract: Aim. To study prevalence of resistance to acetylsalicylic acid, clopidogrel and dual resistance in percutaneous coronary intervention (PCI), to identify clinical risk factors of resistance development, to study effects of concomitant therapy on resistance development, to identify relationship between risk of cardiovascular complications and activity of platelet aggregation, to assess safety of dual antiplatelet therapy, and to suggest possible ways to overcome clopidogrel resistance.Material and Methods. Patients (n=100) with stable angina class II-IV, that were planned for PCI, were included in the study. Patients randomized to group A (n=53) received clopidogrel 75 mg daily for 7 days before PCI, and later were allocated to subgroups of clopidogrel sensitive or resistant depending on platelet aggregation. In resistant subgroup clopidogrel daily dose was increased to 150 mg for the whole next period of observation. Patients randomized to group B (n=47) received a loading dose of clopidogrel 300 mg one day before PCI. Depending on the results of platelet reactivity assessment, patients were split into sensitive or resistant subgroups. Patients of resistant subgroup received the second loading dose of clopidogrel 300 mg before PCI and started to take clopidogrel 150 mg daily after PCI. Patients of sensitive subgroup did not receive the second clopidogrel loading dose and started to take clopidogrel in usual daily dose of 75 mg. The combined endpoint (after 6 and 12 months) included cardiovascular death, recurrent nonfatal myocardial infarction, recurrent angina, acute ischemic stroke, acute impairment of peripheral circulation.Results. Increased reactivity of platelets to acetylsalicylic acid was detected in 21% of patients. Resistance to clopidogrel in both groups was 56%. Double resistance was registered in 8% of patients. The development of resistance to clopidogrel was related with obesity (p=0.014) and hyperglycemia (p=0.017). 4 and 11 cardiovascular events were registered in 6 and 12 months, respectively.Conclusion. To assess efficacy of antiplatelet therapy it is advisable to study platelet aggregation before and shortly after PCI, especially in patients with obesity and glucose metabolism disturbances. Knowledge of changes in platelet aggregation during clopidogrel therapy can be usefull for timely correction of antiplatelet therapy. Increase in clopidogrel dose up to 150 mg a day is one of the possible way to overcome resistance to clopidogrel.
Novel role of antiplatelet agents (aspirin plus clopidogrel) in an incoagulable blood of a victim of russell's viper snakebite
Bawaskar, H. S.;
Journal of Venomous Animals and Toxins including Tropical Diseases , 2006, DOI: 10.1590/S1678-91992006000100011
Abstract: snake antivenom is a specific antidote to the venom action, neutralizing the circulating venom. however, it fails to neutralize the venom fixed to target organs such as platelets, renal tubules, etc. russell's viper venom initiates rapid coagulation in a victim by activating blood platelets, factors v, x, and anticoagulant cofactors. activation of thrombin, resulting in formation of micro-thrombi, fibrinolysis, and a vicious cascade, sets in. inhibition of activated platelets by aspirin (cyclooxygenase inhibitor) and clopidogrel (adp receptor inhibitor) helps to break this vicious circle induced by russell's venom and may initiate the natural physiological clotting mechanism. they can be utilized as an adjuvant treatment.
Trends in Ambulatory Prescribing of Antiplatelet Therapy among US Ischemic Stroke Patients: 2000–2007  [PDF]
Sudeep Karve,Deborah Levine,Eric Seiber,Milap Nahata,Rajesh Balkrishnan
Advances in Pharmacological Sciences , 2012, DOI: 10.1155/2012/846163
Abstract: Objective. Study objectives were to assess temporal trends and identify patient- and practice-level predictors of the prescription of antiplatelet medications in a national sample of ischemic stroke (IS) patients seeking ambulatory care. Methods. IS-related outpatient visits by adults were identified using the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey for the years 2000–2007. We assessed prescribing of antiplatelet medications using the generic drug code and drug entry codes in these data. Temporal trends in antiplatelet prescribing were assessed using the Cochran-Mantel-Haenszel test for trend. Results. We identified 9.5 million IS-related ambulatory visits. Antiplatelet medications were prescribed at 35.5% of visits. Physician office prescribing of the clopidogrel-aspirin combination increased significantly from 0.5% in 2000 to 22.0% in 2007 ( ), whereas prescribing of aspirin decreased from 17.9% to 7.0% ( ) during the same period. Conclusion. We observed a continued increase in prescription of the aspirin-clopidogrel combination from 2000 to 2007. Clinical trial evidence suggests that the aspirin-clopidogrel combination does not provide any additional benefit compared with clopidogrel alone; however, our study findings indicate that even with lack of adequate clinical evidence physician prescribing of this combination has increased in real-world community settings. 1. Introduction In 2008, approximately 7 million individuals were reported to have a history of stroke [1]. Stroke survivors have a 4 to 14% annual risk of recurrent stroke and a 1–5% annual risk of myocardial infarction (MI). To reduce the recurrence of ischemic stroke (IS), the major stroke type accounting for 85% of strokes, modification of vascular risk factors [2–4], and antithrombotic therapy are recommended for stroke survivors [5, 6]. Antithrombotic therapy may include vitamin K antagonist therapy if atrial fibrillation is present (cardioembolic strokes) or antiplatelet therapy (noncardioembolic strokes). Antiplatelet therapy can reduce the relative risk of IS by approximately 15% [7]. Four antiplatelet agents (aspirin, clopidogrel, ticlopidine, and dipyridamole) are used alone or in combination to treat IS patients. However, few clinical trials of IS patients provide direct comparisons among antiplatelet alternatives. As a result, clinicians have uncertainty regarding the selection of antiplatelet therapy for secondary stroke prevention among patients with noncardioembolic IS [8–17]. Between 2001 and 2006, several clinical trials
Thrombelastographic haemostatic status and antiplatelet therapy after coronary artery bypass surgery (TEG-CABG trial): assessing and monitoring the antithrombotic effect of clopidogrel and aspirin versus aspirin alone in hypercoagulable patients: study protocol for a randomized controlled trial
Sulman Rafiq, P?r I Johansson, Mette Zacho, Trine Stissing, Klaus Kofoed, Nikolaj B Lilleoer, Daniel A Steinbrüchel
Trials , 2012, DOI: 10.1186/1745-6215-13-48
Abstract: This is a prospective randomized clinical trial, with an open-label design with blinded evaluation of graft patency. TEG-Hypercoagulability is defined as a TEG maximum amplitude above 69 mm. Two hundred and fifty TEG-Hypercoagulable patients will be randomized to either an interventional group receiving clopidogrel 75 mg daily for three months (after initial oral bolus of 300 mg) together with aspirin 75 mg or a control group receiving aspirin 75 mg daily alone. Monitoring of antiplatelet efficacy and on-treatment platelet reactivity to clopidogrel and aspirin will be conducted with Multiplate aggregometry. Graft patency will be assessed with Multislice computed tomography (MSCT) at three months after surgery.The present trial is the first randomized clinical trial to evaluate whether TEG-Hypercoagulable CABG patients will benefit from intensified antiplatelet therapy after surgery. Monitoring of platelet inhibition from instituted antithrombotic therapy will elucidate platelet resistance patterns after CABG surgery. The results could be helpful in redefining how clinicians can evaluate patients preoperatively for their postoperative thromboembolic risk and tailor individualized postoperative antiplatelet therapy.Clinicaltrials.gov Identifier NCT01046942
Antiplatelet agents and proton pump inhibitors – personalizing treatment  [cached]
Eugene Lin,Rajiv Padmanabhan,Majaz Moonis
Pharmacogenomics and Personalized Medicine , 2010,
Abstract: Eugene Lin, Rajiv Padmanabhan, Majaz MoonisDepartment of Neurology, University of Massachusetts Medical School and UMass Memorial Medical Center, Worcester, Massachusetts, USAIntroduction: Antiplatelet therapy remains one of the cornerstones in the management of noncardioembolic ischemic stroke. However, a significant percentage of patients have concomitant gastroesophageal reflux or peptic ulcer disease that requires acid-reducing medications, the most powerful and effective being the proton pump inhibitors (PPIs). Antiplatelet efficacy, at least in vivo, and particularly for clopidogrel, has been shown to be reduced with concomitant proton pump inhibitor use. Whether this is clinically relevant is not clear from the limited studies available.Methods: We conducted an extensive review of studies available on Medline related to pharmacodynamic interactions between the antiplatelet medications and proton pump inhibitors as well as clinical studies that addressed this potential interaction.Results: Based on the present pharmacodynamic and clinical studies we did not find a significant interaction that would reduce the efficacy of antiplatelet agents with concomitant user of proton pump inhibitors.Conclusions: Patients on antiplatelet agents after a transient ischemic attack or ischemic stroke can safely use aspirin, and extended release dipyridamole/aspirin with proton pump inhibitors. Patients on clopidogrel may use other acid-reducing drugs besides proton pump inhibitors. In rare cases where proton pump inhibitors and clopidogrel have to be used concurrently, careful close monitoring for recurrent vascular events is required.Keywords: proton pump inhibitors, antiplatelet medications, clopidogrel, ischemic stroke, cardiovascular events
Clinical importance of aspirin and clopidogrel resistance  [cached]
Gergely Feher,Andrea Feher,Gabriella Pusch,Katalin Koltai
World Journal of Cardiology , 2010,
Abstract: Aspirin and clopidogrel are important components of medical therapy for patients with acute coronary syndromes, for those who received coronary artery stents and in the secondary prevention of ischaemic stroke. Despite their use, a significant number of patients experience recurrent adverse ischaemic events. Interindividual variability of platelet aggregation in response to these antiplatelet agents may be an explanation for some of these recurrent events, and small trials have linked “aspirin and/or clopidogrel resistance”, as measured by platelet function tests, to adverse events. We systematically reviewed all available evidence on the prevalence of aspirin/clopidogrel resistance, their possible risk factors and their association with clinical outcomes. We also identified articles showing possible treatments. After analyzing the data on different laboratory methods, we found that aspirin/clopidogrel resistance seems to be associated with poor clinical outcomes and there is currently no standardized or widely accepted definition of clopidogrel resistance. Therefore, we conclude that specific treatment recommendations are not established for patients who exhibit high platelet reactivity during aspirin/clopidogrel therapy or who have poor platelet inhibition by clopidogrel.
Point-of-care platelet function assays demonstrate reduced responsiveness to clopidogrel, but not aspirin, in patients with Drug-Eluting Stent Thrombosis whilst on dual antiplatelet therapy
Alex R Hobson, Graham Petley, Geraint Morton, Keith D Dawkins, Nick P Curzen
Thrombosis Journal , 2008, DOI: 10.1186/1477-9560-6-1
Abstract: From 3004 PCI patients, seven survivors of DES ST whilst on dual antiplatelet therapy were identified and each matched with two patients without ST. Analysis was performed using (a) short Thrombelastogram PlateletMapping? (TEG) and (b) VerifyNow Aspirin and P2Y12 assays. TEG analysis was performed using the Area Under the Curve at 15 minutes (AUC15) as previously described.There were no differences in responses to aspirin. There was significantly greater platelet reactivity on clopidogrel in the ST group using the Accumetrics P2Y12 assay (183 ± 51 vs. 108 ± 31, p = 0.02) and a trend towards greater reactivity using TEG AUC15 (910 ± 328 vs. 618 ± 129, p = 0.07). 57% of the ST group by TEG and 43% of the ST cases by Accumetrics PRU had results > two standard deviations above the expected mean in the control group.This study demonstrates reduced platelet response to clopidogrel in some patients with DES ST compared to matched controls. The availability of point-of-care assays that can detect these responses raises the possibility of prospectively identifying DES patients at risk of ST and manipulating their subsequent risk.Robust evidence demonstrating the ability of drug-eluting stent (DES) technology to reduce restenosis in comparison to bare metal stents (BMS) has led to widespread DES uptake. Balanced against this significant clinical benefit, however, is concern about the incidence of stent thrombosis (ST) in DES patients. Observational and randomised trial data suggest that there is a cumulative incidence of ST in DES patients of between 0.5%–1% per year [1,2], correlating in some series with a similar rate of death and myocardial infarction [3].There are well established procedural risk factors for ST such as stent under-deployment [4], length of stented segment [5], and idiosyncratic factors including a form of hypersensitivity [6]. However, the inappropriate termination of aspirin and clopidogrel therapy appears to be particularly hazardous [7]. In DES patient
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