Comparison of methods to evaluate clopidogrel-mediated platelet inhibition after percutaneous intervention with stent implantation

SummaryA high on-treatment residual ADP-inducible platelet reactivity in light transmission aggregometry (LTA) has been associated with an increased risk of adverse outcomes after percutaneous coronary intervention (PCI). However, LTA is weakly standardized, and results obtained in one laboratory may not be comparable to those obtained in another one. We therefore sought to determine the test correlating best with LTA to estimate clopidogrel-mediated platelet inhibition in 80 patients on dual antiplatelet therapy after elective percutaneous intervention with stent implantation. We selected the VerifyNow P2Y12 assay, the vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode platelet aggregometry and the Impact-R for comparisons with LTA. Cut-off values for residual ADP-inducible platelet reactivity were defined according to quartiles of each assay. Sensitivities and specificities of the different platelet function tests were based on the results from LTA. The results from all four assays correlated significantly with those from LTA. The VerifyNow P2Y12 assay revealed the strongest correlation (r = 0.61, p < 0.001). Sensitivities and specificities ranged from 35% to 55%, and from 78.3% to 85%, respectively. In conclusion, although all assays correlated significantly with LTA, they need to be improved to become clinically used diagnostic tests. Further, it may be too early to define the gold standard method for assessing residual ADP-inducible platelet reactivity and generally acceptable cut-off values.

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Mean Corpuscular Volume Predicts Adverse Outcomes Following Peripheral Angioplasty With Stenting and Is Associated With On-Treatment Platelet Reactivity

Angiology ◽

10.1177/0003319720943816 ◽

2020 ◽

Vol 72 (1) ◽

pp. 16-23

Author(s):

Maximilian Tscharre ◽

Silvia Lee ◽

Christoph W. Kopp ◽

Simon Panzer ◽

Thomas Gremmel

Keyword(s):

Mean Corpuscular Volume ◽

Cox Regression ◽

Light Transmission ◽

Platelet Reactivity ◽

Adenosine Diphosphate ◽

Adverse Outcomes ◽

Corpuscular Volume ◽

Characteristic Analysis ◽

Cox Regression Analysis ◽

Increased Risk

Structural aspects of red blood cells have been associated with cardiovascular disease. No data linking mean corpuscular volume (MCV) to clinical outcomes and on-treatment platelet reactivity in patients with peripheral artery disease (PAD) are available. We investigated a composite of atherothrombotic events and target vessel restenosis or reocclusion following infrainguinal stenting for stable PAD. Residual platelet reactivity was measured by light transmission aggregometry (LTA) and the VerifyNow assays. We included 104 patients receiving dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. In receiver-operating characteristic analysis, MCV effectively discriminated between patients with and without adverse outcomes and identified a MCV ≤90.8 fL as optimal cutoff. Adverse outcomes occurred significantly more often in patients with low MCV (log-rank P = .002). In univariable Cox regression analysis, low MCV was associated with an increased risk of future adverse outcomes (hazard ratio [HR]: 2.662 [95%CI: 1.304-5.434]; P = .007) and remained significantly associated after adjustment (HR: 2.591 [95%CI: 1.242-5.403]; P = .011). Mean corpuscular volume was inversely correlated with arachidonic acid (AA)- and adenosine diphosphate (ADP)-inducible platelet reactivity by LTA and with the VerifyNow aspirin assay. Low MCV is associated with adverse outcomes over 2 years following infrainguinal stenting. Mean corpuscular volume correlates inversely with AA- and ADP-inducible platelet reactivity during DAPT.

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Fentanyl Delays the Platelet Inhibition Effects of Oral Ticagrelor: Full Report of the PACIFY Randomized Clinical Trial

Thrombosis and Haemostasis ◽

10.1055/s-0038-1666862 ◽

2018 ◽

Vol 118 (08) ◽

pp. 1409-1418 ◽

Cited By ~ 13

Author(s):

Khalil Ibrahim ◽

Rohan Shah ◽

Rakesh Goli ◽

Thomas Kickler ◽

William Clarke ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Trial ◽

Troponin I ◽

Light Transmission ◽

Myocardial Damage ◽

Platelet Inhibition ◽

Adverse Outcomes ◽

Clinical Trial Registration ◽

Time Curve ◽

Platelet Aggregometry

Morphine delays oral P2Y12 platelet inhibitor absorption and is associated with adverse outcomes after myocardial infarction. Consequently, many physicians and first responders are now considering fentanyl as an alternative. We conducted a single-centre trial randomizing cardiac patients undergoing coronary angiography to intravenous fentanyl or not. All participants received local anaesthetic and intravenous midazolam. Those requiring percutaneous coronary intervention (PCI) with stenting received 180 mg oral ticagrelor intra-procedurally. The primary outcome was area under the ticagrelor plasma concentration–time curve (AUC0–24 hours). The secondary outcomes were platelet function assessed at 2 hours after loading, measured by P2Y12 reaction units (PRUs) and light transmission platelet aggregometry. Troponin-I was measured post-PCI using a high-sensitivity troponin-I assay (hs-TnI). All participants completed a survey of pain and anxiety. Of the 212 randomized, 70 patients required coronary stenting and were loaded with ticagrelor. Two participants in the no-fentanyl arm crossed over to receive fentanyl for pain. In as-treated analyses, ticagrelor concentrations were higher in the no-fentanyl arm (AUC0–24 hours 70% larger, p = 0.03). Platelets were more inhibited by 2 hours in the no-fentanyl arm (71 vs. 113 by PRU, p = 0.03, and 25% vs. 41% for adenosine diphosphate response by platelet aggregation, p < 0.01). Mean hs-TnI was higher with fentanyl at 2 hours post-PCI (11.9 vs. 7.0 ng/L, p = 0.04) with a rate of enzymatic myocardial infarction of 11% for fentanyl and 0% for no-fentanyl (p = 0.08). No statistical differences in self-reported pain or anxiety were found. In conclusion, fentanyl administration can impair ticagrelor absorption and delay platelet inhibition, resulting in mild excess of myocardial damage. This newly described drug interaction should be recognized by physicians and suggests that the interaction between opioids and oral P2Y12 platelet inhibitors is a drug class effect associated with all opioids. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02683707 (NCT02683707).

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Why Me? To Be an Ultra-Responder to Antiplatelet Therapy: A Case Report

Frontiers in Neurology ◽

10.3389/fneur.2021.663308 ◽

2021 ◽

Vol 12 ◽

Author(s):

Francesca Rosafio ◽

Guido Bigliardi ◽

Nicoletta Lelli ◽

Laura Vandelli ◽

Federica Naldi ◽

...

Keyword(s):

Case Report ◽

Primary Prevention ◽

Cerebrovascular Disease ◽

Antiplatelet Therapy ◽

Platelet Reactivity ◽

Cavernous Angioma ◽

Platelet Inhibition ◽

Sudden Onset ◽

Platelet Aggregometry ◽

Increased Risk

Background: Platelet function testing is a valid tool to investigate the clinical response to antiplatelet therapy in different clinical settings; in particular, it might supply helpful information in patients with cerebrovascular disease. Oral antiplatelet treatment, such as Aspirin (ASA) and Clopidogrel, is the gold standard in secondary stroke prevention of non-cardiogenic ischemic stroke; conversely, its application as a primary prevention therapy is not routinely recommended in patients with vascular risk factors. Multiple electrode platelet aggregometry (MEA) impedance aggregometer is a validated device to test platelet inhibition induced by ASA or Clopidogrel.Case Report: We report the case of a 78-year-old patient without relevant clinical history, taking ASA as primary prevention strategy, who was admitted for sudden onset of dysarthria and left facial hyposthenia during physical effort. Brain CT revealed two small subcortical bilateral spontaneous intracranial hemorrhages. Platelet aggregometry with MEA performed upon admission revealed a very strong platelet inhibition induced by ASA (result of the ASPI Test was 5 U, consistent with an ultra-responsiveness to ASA, and the cutoff value of correct responsiveness is <40 U). MRI at longitudinal follow-up revealed the presence of two small cavernous angioma underlying hemorrhagic spots.Conclusion: The evaluation of platelet reactivity in stroke patients undergoing antiplatelet therapies, not commonly performed in clinical practice, could be useful to optimize prevention strategies; the verification of the biological effectiveness of ASA or Clopidogrel could be a valid tool in the definition of each patient's risk profile, particularly in patients with cerebrovascular disease known to be at increased risk for both hemorrhagic and thrombotic complications.

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Aspirin I.V. Loading during Elective Percutaneous Coronary Intervention

Pharmacology ◽

10.1159/000517994 ◽

2021 ◽

pp. 1-5

Author(s):

David Naguib ◽

Carolin Helten ◽

Saif Zako ◽

Philipp Mourikis ◽

René M’Pembele ◽

...

Keyword(s):

Pilot Study ◽

Light Transmission ◽

Platelet Reactivity ◽

Coronary Intervention ◽

Bleeding Complications ◽

Loading Dose ◽

Bleeding Events ◽

Elective Percutaneous Coronary Intervention ◽

Percutaneous Coronary ◽

The Impact

Additional loading dose of acetylsalicylic acid (ASA) during percutaneous coronary interventions (PCIs) despite permanent oral ASA medication is frequently applicated. The impact on platelet reactivity and clinical events is not known. In this pilot study, we aimed to analyze high on-treatment platelet reactivity (HTPR) to aspirin in patients undergoing elective PCI. Platelet reactivity was measured using light-transmission aggregometry in 100 patients on permanent low-dose ASA medication undergoing elective PCI. Platelet reactivity measured by arachidonic acid-induced maximum of aggregation (MoA) in patients with versus without additional peri-procedural ASA loading (500 mg i.v.) was compared. HTPR was defined as MoA >20% for ASA. Major adverse cerebro- and cardiovascular events (MACCEs) and bleeding events were evaluated during hospital course. HTPR rate was similar in both groups (HTPR to ASA: loading vs. control 6% vs. 16%, odds ratio [OR] = 0.33, 95% confidence interval [CI] 0.08–1.35, <i>p</i> = 0.12). In-hospital MACCEs were not different between groups (MACCE: loading vs. control: 0 vs. 0 patient, OR = 1.32, 95% CI 0.03–67.95, <i>p</i> = 0.89). Thrombolysis in myocardial infarction minimal bleedings were numerically higher in patients without ASA loading dose. In this pharmacodynamic pilot study, additional ASA loading did not reduce HTPR to ASA. Furthermore, ASA loading did not increase in-hospital MACCE and bleeding complications.

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Antiplatelet drugs in patients with enhanced platelet turnover: biomarkers versus platelet function testing

Thrombosis and Haemostasis ◽

10.1160/th15-02-0179 ◽

2015 ◽

Vol 114 (09) ◽

pp. 459-468 ◽

Cited By ~ 30

Author(s):

Susanne Gruber ◽

Erik Grove ◽

Thomas Weiss ◽

Johann Wojta ◽

Kurt Huber ◽

...

Keyword(s):

Messenger Rna ◽

Platelet Reactivity ◽

Platelet Inhibition ◽

Antiplatelet Drugs ◽

P2y12 Inhibitors ◽

Reticulated Platelets ◽

Increased Risk ◽

Key Factor ◽

Coronary Syndromes ◽

Function Testing

SummaryPlatelets are key players in atherothrombosis. Antiplatelet therapy comprising aspirin alone or with P2Y12-inhibitors are effective for prevention of atherothrombotic complications. However, there is interindividual variability in the response to antiplatelet drugs, leaving some patients at increased risk of recurrent atherothrombotic events. Several risk factors associated with high on-treatment platelet reactivity (HTPR), including elevated platelet turnover, have been identified. Platelet turnover is adequately estimated from the fraction of reticulated platelets. Reticulated platelets are young platelets, characterised by residual messenger RNA. They are larger, haemostatically more active and there is evidence that platelet turnover is a causal and prognostic factor in atherothrombotic disease. Whether platelet turnover per se represents a key factor in pathogenesis, progression and prognosis of atherothrombotic diseases (with focus on acute coronary syndromes) or whether it merely facilitates insufficient platelet inhibition will be discussed in this state-of-the art review.

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The effect of acenocoumarol on the antiplatelet effect of clopidogrel

Thrombosis and Haemostasis ◽

10.1160/th15-02-0130 ◽

2015 ◽

Vol 114 (10) ◽

pp. 708-716 ◽

Cited By ~ 2

Author(s):

Thomas Bergmeijer ◽

Johannes Kelder ◽

Christian Hackeng ◽

Jurriën ten Berg ◽

Willem Dewilde ◽

...

Keyword(s):

Platelet Reactivity ◽

Multivariable Analysis ◽

Coumarin Derivative ◽

Concomitant Treatment ◽

Confounding By Indication ◽

Increased Risk ◽

Percutaneous Coronary ◽

Propensity Matching ◽

Multivariable Analyses ◽

The Impact

SummaryPatients exhibiting high on-clopidogrel platelet reactivity (HPR) are at an increased risk of atherothrombotic events following percutaneous coronary interventions (PCI). The use of concomitant medication which is metabolised by the hepatic cytochrome P450 system, such as phenprocoumon, is associated with HPR. We assessed the level of platelet reactivity on clopidogrel in patients who received concomitant treatment with acenocoumarol (another coumarin derivative). Patients scheduled for PCI were included in a prospective, single centre, observational registry. Patients who were adequately pre-treated with clopidogrel were eligible for this analysis, which included 1,582 patients, of whom 104 patients (6.6 %) received concomitant acenocoumarol treatment. Platelet reactivity, as measured with the VerifyNow P2Y12 assay and expressed in P2Y12 Reaction Units (PRU), was significantly higher in patients on concomitant acenocoumarol treatment (mean PRU 229 ± 88 vs 187 ± 95; p< 0.001). In patients with concomitant acenocoumarol use, the proportion of patients with HPR was higher, defined as PRU > 208 (57.7 % vs 41.1 %; p=0.001) and PRU236 (49.0 % vs 31.4 %; p< 0.001). In multivariable analysis, concomitant acenocoumarol use was independently associated with a higher PRU and the occurrence of HPR defined as PRU236 (OR 2.00, [1.07–3.79]), but not with HPR defined as PRU > 208 (OR 1.37, [0.74–2.54]). PRU also was significantly increased after 1:1 propensity matching (+28.2; p< 0.001). As this was an observational study, confounding by indication cannot be excluded, although multivariable analyses and propensity matching were performed. The impact of the findings from this hypothesis-generating study on clinical outcome requires further investigation.

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Clopidogrel pretreatment in primary percutaneous coronary intervention: Prevalence of high on-treatment platelet reactivity and impact on preprocedural patency of the infarct-related artery

Thrombosis and Haemostasis ◽

10.1160/th13-01-0057 ◽

2013 ◽

Vol 110 (07) ◽

pp. 110-117 ◽

Cited By ~ 15

Author(s):

Javier Berdejo ◽

Gerard Roura ◽

Josep Gómez-Lara ◽

Rafael Romaguera ◽

Luis Teruel ◽

...

Keyword(s):

Percutaneous Coronary Intervention ◽

Primary Percutaneous Coronary Intervention ◽

Light Transmission ◽

Platelet Reactivity ◽

Poor Response ◽

Antiplatelet Agents ◽

Coronary Intervention ◽

Platelet Inhibition ◽

Percutaneous Coronary ◽

Infarct Related Artery

SummaryTo date, there is limited data on levels of platelet inhibition achieved in patients with ST-elevation myocardial infarction (STEMI) who are loaded with clopidogrel and aspirin (ASA) prior to undergoing primary percutaneous coronary intervention (P-PCI). The aim of this investigation was to evaluate the percentage of STEMI patients with high on-treatment platelet reactivity (HPR) to clopidogrel at the time of initiating P-PCI and its association with the initial patency of the infarct-related artery (IRA). This prospective pharmacodynamic study included 50 STEMI patients, previously naïve to oral antiplatelet agents, who received 500-mg ASA and 600-mg clopidogrel loading doses prior to P-PCI. Platelet function assessment was performed at the beginning of the procedure using various assays, including VerifyNow™ system (primary endpoint), light transmission aggregometry and multiple electrode aggregometry. The percentage of patients with suboptimal response to clopidogrel and ASA assessed with the VerifyNow™ system was 88.0% and 28.6%, respectively. Similar results were obtained with the other assays used. A higher percentage of patients with initial patency of the IRA was observed among those patients without HPR compared with those with HPR to clopidogrel (66.7% vs 15.9%; p=0.013), while no differences were observed regarding postprocedural angiographic or electrocardiographic outcomes. In conclusion, this study shows that a high percentage of STEMI patients have inadequate levels of clopidogrel-induced and, to a lesser extent, aspirin-mediated platelet inhibition when starting a P-PCI procedure, and suggests that a poor response to clopidogrel might be associated with impaired initial TIMI flow in the IRA.

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The impact of coronavirus disease 2019 (COVID-19) on older adults with an intellectual disability during the first wave of the pandemic in Ireland

HRB Open Research ◽

10.12688/hrbopenres.13238.2 ◽

2021 ◽

Vol 4 ◽

pp. 93

Author(s):

Mary McCarron ◽

Darren McCausland ◽

Retha Luus ◽

Andrew Allen ◽

Fintan Sheerin ◽

...

Keyword(s):

Intellectual Disability ◽

Repeated Measures ◽

Well Being ◽

Adverse Outcomes ◽

Multiple Infection ◽

Similar Proportion ◽

Related Data ◽

Increased Risk ◽

The Impact ◽

Health And Well Being

Background: People with intellectual disability have increased risk of exposure to and adverse outcomes from coronavirus disease 2019 (COVID-19).They also face challenges to mental health and well-being from COVID-19-related social restrictions and service closures. Methods: Data from a supplemental COVID-19 survey from the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing (IDS-TILDA) (n=710) was used to assess outcomes from the first infection wave of COVID-19 among adults with intellectual disability aged 40+ years in Ireland. Data was gathered on testing, for symptoms and outcomes; procedures to manage COVID-19; and both stress/anxiety and positive experiences during the pandemic. Demographic and health-related data from the main IDS-TILDA dataset was included in analyses. Results: High rates were identified of health conditions associated with poorer COVID-19 outcomes, including overweight/obesity (66.6%, n=365), high cholesterol (38.6%, n=274) and cardiovascular disease (33.7%, n=239). Over half (53.5%, n=380) reported emotional, nervous or psychiatric disorders. Almost two-thirds (62.4%, n=443) were tested for COVID-19, with 10% (n=71) reporting symptoms and 2.5% (n=11) testing positive. There were no instances of COVID-19 related mortality. Common symptoms included fatigue, fever, and cough. Some participants (7.8%, n=55) moved from their usual home, most often to isolate (n=31) or relocate to a family home (n=11). Three-quarters (78.7%) of those who were symptomatic or who tested positive had plans to manage self-isolation and two-thirds were able to comply with guidelines. Over half (55%, n=383) reported some COVID-19 related stress/anxiety; and a similar proportion reported positive aspects during this period (58%, n=381). Conclusions: Our data suggests that people with intellectual disability avoided the worst impacts of COVID-19 during the first infection wave in Ireland. Nevertheless, participants’ health profiles suggest that this population remains at high risk for adverse infection outcomes. Repeated measures are needed to track health and well-being outcomes across multiple infection waves.

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Abstract P369: Polypharmacy, Adverse Outcomes, and Treatment Effectiveness in Elderly Patients With Atrial Fibrillation

Circulation ◽

10.1161/circ.141.suppl_1.p369 ◽

2020 ◽

Vol 141 (Suppl_1) ◽

Cited By ~ 1

Author(s):

Aniqa Alam ◽

Nemin Chen ◽

Pamela L Lutsey ◽

Richard MacLehose ◽

J'Neka Claxton ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Ischemic Stroke ◽

Elderly Patients ◽

Rate Control ◽

Treatment Effectiveness ◽

Adverse Outcomes ◽

Pharmacy Claims ◽

Increased Risk ◽

The Impact

Background: Polypharmacy is highly prevalent in elderly individuals with chronic conditions, including atrial fibrillation (AF). The impact of polypharmacy on adverse outcomes and on treatment effectiveness in elderly AF patients remains unaddressed. Methods: We studied 338,810 AF patients ≥75 years of age with 1,761,660 active prescriptions [mean (SD), 5.1 (3.8) per patient] enrolled in the MarketScan Medicare Supplemental database in 2007-2015. Polypharmacy was defined as ≥5 active prescriptions at AF diagnosis based on outpatient pharmacy claims. AF treatments (oral anticoagulation, rhythm and rate control) and cardiovascular endpoints (ischemic stroke, bleeding, heart failure) were defined based on inpatient, outpatient and pharmacy claims. Multivariable Cox models were used to estimate associations of polypharmacy with cardiovascular endpoints and the interaction between polypharmacy and AF treatments in relation to cardiovascular endpoints. Results: Prevalence of polypharmacy was 52% (176,007 of 338,810). Patients with polypharmacy had increased risk of major bleeding [hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.12, 1.20] and heart failure (HR 1.33, 95%CI 1.29, 1.36), but not of ischemic stroke (HR 0.96, 95%CI 0.92, 1.00), compared to those not with polypharmacy (Table). Polypharmacy status did not consistently modify the effectiveness of oral anticoagulants. However, rhythm control (vs. rate control) was more effective in preventing heart failure hospitalization in patients not with polypharmacy (HR 0.87, 95%CI 0.76, 0.99) than among those with polypharmacy (HR 0.98, 95%CI 0.91, 1.07, p for interaction = 0.02). Conclusion: Polypharmacy is frequent among elderly patients with AF, associated with adverse outcomes, and potentially affecting the effectiveness of AF treatments. Optimizing management of polypharmacy in elderly AF patients may lead to improved outcomes.

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Effect of bodyweight on VerifyNow Aspirin platelet function test: a retrospective review

Journal of NeuroInterventional Surgery ◽

10.1136/neurintsurg-2020-016842 ◽

2020 ◽

pp. neurintsurg-2020-016842

Author(s):

Melissa Sandler ◽

Cuong Hoang ◽

Hannah Y Mak ◽

Michael R Levitt

Keyword(s):

Stent Thrombosis ◽

Retrospective Review ◽

Platelet Reactivity ◽

Thrombotic Event ◽

Optimal Dose ◽

Platelet Inhibition ◽

Platelet Function Test ◽

Assay Result ◽

The Mean ◽

The Impact

BackgroundAntiplatelet therapy is used to prevent stent thrombosis in intracranial stents, but the optimal dose of aspirin is unknown. This study sought to determine whether the degree of platelet inhibition with aspirin is affected by bodyweight as observed through a platelet reactivity assay.MethodsThis is a retrospective review of patients who underwent neurovascular stent placement and had a VerifyNow Aspirin assay result. The primary outcome was the correlation between the VerifyNow Aspirin result, bodyweight, and the initial dose of aspirin. Secondary outcomes included the impact of the VerifyNow P2Y12 result and of weight on the incidence of bleeding or a thrombotic event.ResultsOf the 142 included patients, 62.7% weighed ≥70 kg and 88.7% were initiated on aspirin 300–325 mg daily. 83.8% achieved a therapeutic VerifyNow Aspirin result. There was minimal correlation between the VerifyNow Aspirin result, bodyweight, and aspirin dose (R2=0.02). Between patients who weighed <70 kg versus ≥70 kg, there was no difference in the mean aspirin reaction units (ARU) (449 vs 435, p=0.32) or in the incidence of bleeding (28% vs 17.1%, p=0.14) or a thrombotic event (4% vs 5.3%, p=0.59). No patient experienced stent thrombosis and eight patients experienced in-stent stenosis. In a multivariate analysis, only the VerifyNow P2Y12 result predicted the development of either bleeding or a thrombotic event (p<0.01).ConclusionsBodyweight did not influence the likelihood of obtaining a therapeutic VerifyNow Aspirin result. The clinical utility of obtaining VerifyNow Aspirin assays for this patient population is unknown.

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