- Comparison of current platelet functional tests for the assessment of aspirin and clopidogrel response. A review of the literature. [JOURNAL ARTICLE]
- Thromb Haemost 2016 Jul 21; 116(4)
The two most widely used antiplatelet drugs in the world are aspirin and clopidogrel. However, some patients on aspirin and/or clopidogrel therapy do not respond appropriately to either aspirin or clopidogrel. This phenomenon is usually called "aspirin/clopidogrel resistance". Several platelet function tests have been used in various studies for the assessment of aspirin and clopidogrel resistance in healthy individuals and patients admitted in cardiology departments. An accurate assessment of platelet response to aspirin/clopidogrel could benefit patients by proposing tailored-antiplatelet therapy based on test results. However, there is a clear lack of standardisation of such techniques and their analytical variability may induce misinterpretation. After a quick report of the mechanisms responsible for aspirin/clopidogrel resistance, we describe the pre-analytical aspects and the analytical performances of current platelet function tests (Light-transmission aggregometry, whole-blood aggregometry, VerifyNow®, Platelet Function Analyzer®, thromboelastography, VASP assay) that are used for the assessment of aspirin/clopidogrel resistance in clinical studies. Considering the different variables that have to be taken into account with each of the platelet function tests, a particular attention should be paid when interpreting results.
- Comparing Inverse Probability of Treatment Weighting and Instrumental Variable Methods for the Evaluation of Adenosine Diphosphate Receptor Inhibitors After Percutaneous Coronary Intervention. [JOURNAL ARTICLE]
- JAMA Cardiol 2016 Jul 20.
There is increasing interest in performing comparative effectiveness analyses in large observational databases, yet these analyses must adjust for treatment selection issues.To conduct comparative safety and efficacy analyses of prasugrel vs clopidogrel bisulfate after percutaneous coronary intervention and to evaluate inverse probability of treatment weighting (a propensity score method) and instrumental variable methods.This study used data from the Treatment With Adenosine Diphosphate Receptor Inhibitors-Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome (TRANSLATE-ACS) study. Included in the study were patients undergoing percutaneous coronary intervention for myocardial infarction, 26.0% of whom received prasugrel. The study dates were April 4, 2010, to October 31, 2012.Choice of initial antiplatelet agent (prasugrel or clopidogrel).Safety and efficacy outcomes included 1-year composite major adverse cardiovascular events, moderate to severe bleeding, and stent thrombosis. Hospitalizations for pneumonia, bone fractures, and planned percutaneous coronary intervention were used as the falsification end points.The study cohort comprised 11 784 participants (mean [SD] age, 60.0 [11.6] years, and 28.0% were female). Using inverse probability of treatment weighting adjustment, prasugrel and clopidogrel had similar major adverse cardiovascular events (hazard ratio [HR], 0.98; 95% CI, 0.83-1.16) and bleeding outcomes (1.18; 0.77-1.80), but prasugrel had a lower rate of stent thrombosis (0.51; 0.31-0.85). Using instrumental variable methods, prasugrel use was associated with a lower rate of the major adverse cardiovascular event end point (HR, 0.68; 95% CI, 0.47-1.00) but nonsignificant differences in the rates of bleeding (0.95; 0.41-2.08) and stent thrombosis (0.67; 0.16-2.00). There was no significant treatment difference noted in any of the falsification end-point rates when analyses were performed using inverse probability of treatment weighting, although the bone fracture end point approached statistical significance. Nevertheless, a lower rate of pneumonia-related hospitalizations was noted in the prasugrel-treated patients when analyses were performed using instrumental variable methods.Conclusions regarding the safety and efficacy of antiplatelet therapy varied depending on analytic technique, and none were concordant with the results from randomized trials. In addition, both statistical strategies demonstrated concerning associations when tested in the falsification analyses. A high level of scrutiny and careful attention to assumptions and validity are required when interpreting complex analyses of observational data.
- Outcomes in patients treated with ticagrelor or clopidogrel after acute myocardial infarction: experiences from SWEDEHEART registry. [JOURNAL ARTICLE]
- Eur Heart J 2016 Jul 19.
Ticagrelor reduces ischaemic events and mortality in acute coronary syndrome (ACS) vs. clopidogrel. We wished to study clinical outcomes in a large real-world population post-ACS.We performed a prospective cohort study in 45 073 ACS patients enrolled into Swedish Web system for Enhancement and Development of Evidence-based care in Heart Disease Evaluated According to Recommended Therapies who were discharged on ticagrelor (N = 11 954) or clopidogrel (N = 33 119) between 1 January 2010 and 31 December 2013. The primary outcome was a composite of all-cause death, re-admission with myocardial infarction (MI) or stroke, secondary outcomes as the individual components of the primary outcome, and re-admission with bleeding. The risk of the primary outcome with ticagrelor vs. clopidogrel was 11.7 vs. 22.3% (adjusted hazard ratio (HR) 0.85 [95% confidence interval: 0.78-0.93]), risk of death 5.8 vs. 12.9% (adjusted HR 0.83 [0.75-0.92]), and risk of MI 6.1 vs. 10.8% (adjusted HR 0.89 [0.78-1.01]) at 24 months. Re-admission with bleeding with ticagrelor vs. clopidogrel occurred in 5.5 vs. 5.2% (adjusted HR 1.20 [1.04-1.40]). In a subset of patients undergoing percutaneous coronary intervention (PCI) on ticagrelor vs. clopidogrel the PCI-related in-hospital bleeding was 3.7 vs. 2.7% (adjusted odds ratio, OR, 1.57 [1.30-1.90]).Ticagrelor vs. clopidogrel post-ACS was associated with a lower risk of death, MI, or stroke, as well as death alone. Risk of bleeding was higher with ticagrelor. These real-world outcomes are consistent with randomized trial results.
- Efficacy of a two-test protocol for achieving a therapeutic response to clopidogrel prior to elective endovascular intracranial aneurysm treatment and an 'induced' postoperative hyper-response. [JOURNAL ARTICLE]
- J Neurointerv Surg 2016 Jul 19.
Variable response to clopidogrel can impact perioperative risk in elective endovascular intracranial aneurysm treatment. The present study aims to determine the efficacy of a two-test protocol in reaching in-range preoperative P2Y12 reaction units (PRU) of 60-240 and the rate of postoperative conversion to hyper-response.A 17-day two-test protocol (with tests on days 10 and 17) for patients starting clopidogrel in anticipation of elective endovascular intracranial aneurysm treatment was introduced in February 2013 at our institution. Records for patients started on this protocol through December 2014 were reviewed for preoperative and postoperative PRUs, patient and procedural data, and thromboembolic and hemorrhagic events within 30 days. Logistic regression analyses were performed to identify predictors of postoperative hyper-response (p<0.05 considered significant).103 patients (80 women) of mean age 57 years were included. 74 patients (71.8%) were in range at the first test and 92 patients (89.3%) were in range at the second test. A postoperative test was performed in 82 patients (79.6%) at a median of 9 days. 51 patients (62.2%) converted into hyper-responders. There were five non-disabling strokes and one intracranial hemorrhage within 30 days. There were no major strokes (modified Rankin Scale score >2) or deaths. There was no association between out-of-range PRU and thromboembolic or hemorrhagic neurological complications.The protocol achieves in-range preoperative PRU by the second test in almost nine of 10 patients. Nearly two-thirds of patients exhibited postoperative hyper-response to clopidogrel. Out-of-range PRU was not associated with thromboembolic or hemorrhagic neurological complications in this cohort of patients with actively managed P2Y12 inhibition.
- Snapshot of the prescribing practice for the clopidogrel and esomeprazole coprescription and cost evaluation of the application guidelines. [Journal Article]
- Pharmacol Res Perspect 2016 Jun; 4(3):e00234.
The antiplatelet clopidogrel and the proton pump inhibitor esomeprazole demonstrate a pharmacokinetic interaction through CYP2C19 that could translate into clinical inefficacy of clopidogrel. No medical consensus as to their coprescription has been reached, and different guidelines are available. We evaluated the prescribing practices at the Geneva University Hospitals (HUG) by measuring whether the coprescription was staggered as suggested by experts. We estimated the financial impact of different implementation guidelines. We used the HUG electronic patient records to follow the physicians' prescriptions and the administration by nurses from January 2013 to April 2014. We performed a time series analysis to assess 15 years of proton pump inhibitors (PPIs) and antiplatelet drug use. "Extra costs" were calculated assuming that clopidogrel or esomeprazole would replace prasugrel or ticagrelor and pantoprazole or ranitidine, respectively. Only 10.8% of the patient medical orders for the clopidogrel and esomeprazole coprescription specified to stagger the administration, 12.6% specified a concomitant coprescription, and 76.6% had no clear information. A high rate of 49.6% of the nurses staggered the clopidogrel and esomeprazole coprescription when no clear information was given. We found a statistically significant decrease in clopidogrel use after the publication of the OCLA (Omeprazole-CLopidogrel-Aspirin) study and a significant increase in the trend of esomeprazole. Alternative treatments to avoid this interaction are cost ineffective or offer therapeutic options of lesser quality. We observed a high rate of 56.2% of the clopidogrel and esomeprazole coprescription in our hospital and can therefore not ignore the PK/PD interaction. The most common prescription practice was to not specify the time frame of administration, which was translated by nurses in 49.6% of the cases to a scheduled staggered coprescription of clopidogrel and esomeprazole. As long as no consensus has been reached, the medical orders time frame information should be mandatory to allow a clear and harmonious staggering strategy.
- Clopidogrel-Induced Severe Hepatitis: A Case Report and Literature Review. [Journal Article]
- Case Reports Hepatol 2016.:8068276.
Clopidogrel is a commonly prescribed antiplatelet agent that carries a rare risk of hepatotoxicity. We describe a case of severe clopidogrel-induced hepatitis with liver biopsy assessment. Prompt recognition and withdrawal of the offending agent are imperative to prevent progression and potentially fatal liver injury.
- Analysis of hemorrhage volumes after angiogram-negative subarachnoid hemorrhage. [JOURNAL ARTICLE]
- World Neurosurg 2016 Jul 14.
Antiplatelet medication use is associated with worsened outcome after angiogram-negative subarachnoid hemorrhage (SAH). It has been hypothesized that these worsened outcomes may be the result of an association between antiplatelet medication use and increased hemorrhage volumes after angiogram-negative SAH. To test this hypothesis, we performed volumetric analysis of CT-defined hemorrhage after angiogram-negative SAH.A retrospective analysis of patients presenting with non-traumatic, angiogram-negative SAH in the Columbia University Subarachnoid Hemorrhage Outcomes database from 2000 to 2013 was performed. Subarachnoid hemorrhage volumes on admission head CT scans were measured using MIPAV software package (version 7.20; National Institutes of Health) in a semi-automated fashion.A total of 108 presenting CT scans from patients with angiogram-negative SAH were analyzed. In patients with a history of antiplatelet medication use, the mean hemorrhage volume was 14.3 mL. Patients who did not have a history of antiplatelet use had a mean hemorrhage volume of 6.8 mL. This difference was found to be significant (p = 0.0029).Antiplatelet medication use is associated with increased subarachnoid hemorrhage volumes in patients with angiogram-negative SAH. Increased hemorrhage volumes may contribute to poor outcomes in this patient population. Prospective studies are warranted to confirm this association.
- The curative effect comparison of two kinds of therapeutic regimens on decreasing the relative intensity of microembolic signal in CLAIR trial. [Journal Article]
- J Neurol Sci 2016 Aug 15.:18-21.
Microembolic signals (MESs) are direct markers of unstable large artery atherosclerotic plaques. In a previous study, we found that the number of MESs is associated with stroke recurrence and that clopidogrel plus aspirin more effectively reduce the number of MESs than does aspirin alone. Stroke recurrence is associated with not only the number of MESs but also the size of the MES, which can theoretically be estimated by monitoring the MES intensity via transcranial doppler (TCD). Thus, we compared the effects of clopidogrel and aspirin with aspirin alone on MES intensity using TCD.We recruited 100 patients who experienced acute ischemic stroke or transient ischemic attack (TIA) within 7days of symptom onset. All patients also had large artery stenosis in the cerebral or carotid arteries and the presence of MES as revealed by TCD. The patients were randomized to receive either aspirin or clopidogrel and aspirin for 7days. MES monitoring was performed on days 2 and 7.Intent-to-treat (ITT) analysis (46 patients in the dual therapy group, 52 patients in the monotherapy group) and per-protocol (PP) analysis (25 patients in the dual therapy group, 31 patients in the monotherapy group) were performed on 98 patients. The primary finding was that the MES intensity was dramatically reduced in the dual therapy group. ITT analysis of the dual therapy group revealed that the MES intensity was 8.04 (0-16) dB before treatment, 0.00 (0-17) dB on day 2, and 0.00 (0-12) dB on day 7 (P=0.000). In the monotherapy group, the MES intensity was 9.00 (0-20) dB before treatment, 8.25 (0-17) dB on day 2, and 7.0 (0-18) dB on day 7 (P=0.577). PP analysis revealed similar results. No severe hemorrhagic complications were detected. The two patients in this study who experienced stroke recurrence were in the monotherapy group.Clopidogrel and aspirin more effectively decrease the MES intensity than aspirin alone in patients with large artery stenotic minor stroke or TIA.
- Recurrent Ischemic Lesions After Acute Atherothrombotic Stroke: Clopidogrel Plus Aspirin Versus Aspirin Alone. [JOURNAL ARTICLE]
- Stroke 2016 Jul 14.
In patients with acute ischemic stroke caused by large artery atherosclerosis, clopidogrel plus aspirin versus aspirin alone might be more effective to prevent recurrent cerebral ischemia. However, there is no clear evidence.In this multicenter, double-blind, placebo-controlled trial, we randomized 358 patients with acute ischemic stroke of presumed large artery atherosclerosis origin within 48 hours of onset to clopidogrel (75 mg/d without loading dose) plus aspirin (300-mg loading followed by 100 mg/d) or to aspirin alone (300-mg loading followed by 100 mg/d) for 30 days. The primary outcome was new symptomatic or asymptomatic ischemic lesion on magnetic resonance imaging within 30 days. Secondary outcomes were 30-day functional disability, clinical stroke recurrence, and composite of major vascular events. Safety outcome was any bleeding.Of 358 patients enrolled, 334 (167 in each group) completed follow-up magnetic resonance imaging. The 30-day new ischemic lesion recurrence rate was comparable between the clopidogrel plus aspirin and the aspirin monotherapy groups (36.5% versus 35.9%; relative risk, 1.02; 95% confidence interval, 0.77-1.35; P=0.91). Of the recurrent ischemic lesions, 94.2% were clinically asymptomatic. There were no differences in secondary outcomes between the 2 groups. Any bleeding were more frequent in the combination group than in the aspirin monotherapy group, but the difference was not significant (16.7% versus 10.7%; P=0.11). One hemorrhagic stroke occurred in the clopidogrel plus aspirin group.Clopidogrel plus aspirin might not be superior to aspirin alone for preventing new ischemic lesion and clinical vascular events in patients with acute ischemic stroke caused by large artery atherosclerosis.URL: http://www.clinicaltrials.gov. Unique identifier: NCT00814268.
- Perioperative outcomes following partial nephrectomy performed on patients remaining on antiplatelet therapy. [JOURNAL ARTICLE]
- J Urol 2016 Jul 11.
We evaluated the risk of bleeding complications in patients undergoing partial nephrectomy (PN) in whom perioperative anti-platelet (AP) therapy was continued, as AP therapy is increasingly utilized and hemorrhage is a significant concern in PN.Two-center retrospective analysis of 1097 patients undergoing PN between 2000-2014. The cohort was split into three groups: Perioperative continuation of AP therapy (Group-1, n=67), AP therapy stopped preoperatively (Group-2, n=254), and no chronic AP therapy (Group-3, n=776). Bleeding complications were defined as any transfusion, or any readmission or secondary procedure performed for hemorrhage. Multivariable analysis (MVA) was performed to elucidate independent risk factors for bleeding complications.Group-1 patients were older (median age 66 vs. 64 and 57 years in Groups-2/-3, p<0.0001), and had greater co-morbidity (median ASA score 3 vs. 2 and 2, p<0.0001). Group-1 had a higher rate of bleeding complications (20.9% vs. 7.1% and 6.4%, p<0.0001) and transfusion rates (16.4% vs. 5.9% and 5.4%, p=0.002). MVA revealed continued AP therapy was an independent predictor for bleeding complications (OR 2.19, 95% CI 1.06-4.51, p=0.03). These findings appear attributable to intraoperative clopidogrel use. On MVA, use of aspirin alone was not associated with bleeding complications (OR 1.64, 95% CI 0.72-3.75, p=0.24).Risk of bleeding complications due to AP therapy use at time of PN may be due to clopidogrel. Need to continue perioperative aspirin alone does not appear to be a contraindication to safe performance of PN.