High-dose Clopidogrel Research Articles

Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis

Abstract Background Carriers of cytochrome 2C19 (CYP2C19) loss of function (LoF) alleles treated with clopidogrel have impaired drug metabolism resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. Purpose To assess the comparative effects of different alternative antiplatelet agents in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI). Methods Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing PCI were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios (OR) and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR as defined in each trial. Standard-dose of clopidogrel (75 mg daily) was used as reference treatment. Antiplatelet strategies were ranked according to P-scores, ranging between 0 (poor performance) and 1 (good performance). Results A total of 13 RCTs testing 6 alternative strategies (i.e., clopidogrel 150 mg, prasugrel 3.75 mg, 5 mg, and 10 mg, ticagrelor 90 mg bid, and adjunctive cilostazol 100 mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10 mg (MD -128.61; 95% CI -145.09; -111.49) and ticagrelor 90 mg bid (MD -125.61; 95% CI -170.66; -80.56), followed by prasugrel 5 mg (MD -118.03; 95% CI -143.15; -92.92) and prasugrel 3.75 mg (MD -73.00; 95% CI -108.97; -37.03). High-dose clopidogrel was associated with a modest (MD -32.11; 95% CI -51.33; -12.90) and adjunctive cilostazol with a non-significant (MD -44.11; 95% CI -98.05; -9.82) reduction in PRU compared with standard-dose clopidogrel (Figure 1). Rates of HPR were reduced with all treatments compared with standard-dose clopidogrel. Ranking of treatments for the primary endpoint showed that standard-dose prasugrel ranked as the best treatment (P-score=0.884), followed by ticagrelor (P-score=0.835), low-dose prasugrel (0.767), very-low dose prasugrel (P-score=0.474), cilostazol (P-score=0.306), high-dose clopidogrel (P-score=0.224), and standard-dose clopidogrel (P-score=0.009) (Figure 2). Conclusion Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, followed by reduced-dose of prasugrel, while double-dose clopidogrel and adjunctive cilostazol showed only modest effects. The clinical implications of these pharmacodynamically effective strategies warrant further investigation.

Outcomes of Ticagrelor Versus High-dose Clopidogrel in CYP2C19 Intermediate Metabolizer Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes.

Guidelines on antiplatelet recommendation for CYP2C19 intermediate metabolizer (IM) havenotcometoanagreement. This study aimed to evaluate the clinical benefit of ticagrelor when compared with high-dose clopidogrel in CYP2C19 IM after percutaneous coronary intervention for acute coronary syndromes. Patients were enrolled according to CYP2C19 genotype and individual antiplatelet therapy. Patient characteristics and clinical outcomes were collected through electronic medical record system. The primary outcome was major adverse cardiac and cerebrovascular event (MACCE), namely a composite of death from cardiovascular causes, myocardial infarction, stroke, and stent thrombosis within 12 months. The secondary outcome was Bleeding Academic Research Consortium scale bleeding events within 12 months. The Cox proportional hazards regression model was performed, with inverse probability treatment weighting (IPTW) adjusting for potential confounders. A total of 532 CYP2C19 IM were enrolled in this retrospective single-center study. No statistically significant difference in incidence rate of MACCE was found between patients receiving ticagrelor versus clopidogrel (7.01 vs. 9.52 per 100 patient-years; IPTW-adjusted hazard ratio 0.71; 95% confidence interval: 0.32-1.58; adjusted log-rank P = 0.396), but the incidence rate of Bleeding Academic Research Consortium type 2, 3, or 5 bleeding events was statistically higher in the loss of function-ticagrelor group than in the loss of function-clopidogrel group (13.53 vs. 6.16 per 100 patient-years; IPTW-adjusted hazard ratio: 2.29; 95% confidence interval: 1.10-4.78; adjusted log-rank P = 0.027). Ticagrelor treatment in CYP2C19 IM resulted in a statistically higher risk of bleeding compared with high-dose clopidogrel, whereas a clear association between treatments and MACCE warrants further investigations.

Comparative effects of different antiplatelet strategies in carriers of CYP2C19 loss-of-function alleles: a network meta-analysis.

Carriers of cytochrome 2C19 (CYP2C19) loss-of-function (LoF) alleles treated with clopidogrel have impaired drug metabolism, resulting in reduced active metabolite levels, high platelet reactivity (HPR), and an increased risk of thrombotic events. Several alternative antiplatelet therapies have been proposed to overcome HPR in these patients, but their comparative effects remain poorly explored. Randomized controlled trials (RCTs) comparing different oral antiplatelet therapies in carriers of CYP2C19 LoF alleles undergoing percutaneous coronary interventions (PCI) were included. A frequentist network meta-analysis was conducted to estimate mean difference (MD) or odds ratios and 95% confidence intervals (CI). The primary outcome was platelet reactivity assessed by VerifyNow and reported as P2Y12 reaction unit (PRU). The secondary outcome was the rate of HPR. Standard dose of clopidogrel (75mg daily) was used as a reference treatment. A total of 12 RCTs testing 6 alternative strategies (i.e. clopidogrel 150mg, prasugrel 3.75mg, 5mg, and 10mg, ticagrelor 90mg bid, and adjunctive cilostazol 100mg bid) were included in the network. Compared with standard-dose clopidogrel, the greatest reduction in PRU was observed with prasugrel 10mg (MD -127.91; 95% CI -141.04; -114.78) and ticagrelor 90mg bid (MD -124.91; 95% CI -161.78; -88.04), followed by prasugrel 5mg (MD -76.33; 95% CI -98.01; -54.65) and prasugrel 3.75mg (MD -73.00; 95% CI -100.28; -45.72). Among other strategies, adjunctive cilostazol (MD -42.64; 95% CI -64.72; -20.57) and high-dose clopidogrel (MD -32.11; 95% CI -51.33; -12.90) were associated with a modest reduction in PRU compared with standard-dose clopidogrel. Among carriers of CYP2C19 LoF alleles undergoing PCI, standard-dose prasugrel or ticagrelor are most effective in reducing platelet reactivity, while double-dose clopidogrel and additional cilostazol showed modest effects. Reduced-dose of prasugrel may represent a balanced strategy to overcome HPR without a significant increase in bleeding. The clinical implications of these pharmacodynamic findings warrant further investigation.

Effects of Different Doses of Clopidogrel plus Early Rehabilitation Therapy on Motor Function and Inflammatory Factors in Patients with Ischemic Stroke.

This prospective randomized controlled study was intended to assess the effects of different doses of clopidogrel plus early rehabilitation therapy on motor function and inflammatory factors in patients with ischemic stroke. Between August 2018 and October 2020, 90 cases of ischemic stroke treated in the Second People's Hospital of Yibin were randomized at a ratio of 1 : 1 to receive either oral 50 mg/d clopidogrel plus early rehabilitation therapy (low-dose group) or oral 75 mg/d clopidogrel plus early rehabilitation therapy (high-dose group), with 45 cases in each group. The outcome measures including the Barthel Index (BI), National Institutes of Health Stroke Scale (NIHSS), Fugl-Meyer simplified scale, hypersensitive C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and occurrence of adverse events were collected. After treatment, the high-dose group had higher BI results than the low-dose group. All eligible patients showed significantly declined NIHSS scores, and the high-dose group had markedly lower results (P < 0.05). After treatment, the Fugl-Meyer scores of both upper and lower extremities of the high-dose group were significantly higher than those in the low-dose group. The high-dose group achieved a greater decrease in inflammatory factor levels after treatment versus the low-dose group. The two groups showed a similar incidence of adverse events. High-dose clopidogrel plus early rehabilitation outperforms the low-dose treatment for patients with ischemic stroke by effectively mitigating the inflammatory response in the body, promoting the restoration of neurological function, improving the level of motor function, and enhancing the patient's quality of life, with manageable safety.

High-Dose Clopidogrel versus Ticagrelor in CYP2C19 intermediate or poor metabolizers after percutaneous coronary intervention: A Meta-Analysis of Randomized Trials.

For patients after percutaneous coronary interventions (PCI), clopidogrel combined with aspirin is a conventional dual antiplatelet therapy (DAPT) method. Because the genetic polymorphism of CYP2C19gene leads to clopidogrel resistance, guidelines for antiplatelet recommendations in CYP2C19 of ultrarapid metabolizers (UM), extended metabolizers (EM) and poor metabolizers (PM) are clear. However, there is no clear recommendation as to whether ticagrelor or double dose clopidogrel is the best antiplatelet regimen for CYP2C19 of intermediate metabolizers (IM). To evaluate the efficacy and safety of ticagrelor (combined with aspirin) and high-dose clopidogrel (combined with aspirin) in patients after PCI with CYP2C19loss-of-function (LOF) alleles. We searched the following databases to select RCTs of comparing ticagrelor with high-dose clopidogrel in patients after PCI with CYP2C19 LOF alleles: CNKI, Wanfang Data, PubMed, Clinical trials, Cochrane, Web of Science and Embase. Major adverse cardiovascular events (MACEs), platelet function and TIMI bleeding event were defined as the outcomes. revman 5.3software was used to perform meta-analysis. A total of 14 RCTs with 2351 patients were enrolled. Meta-analysis showed that compared with high-dose clopidogrel, ticagrelor had reduced incidence of MACEs (OR=0.32, 95% Cl: 0.23-0.44, p<0.00001), stent thrombosis (OR: 0.24, 95%CI: 0.13-0.44, p<0.00001), myocardial infarction OR: 0.42, 95%CI: 0.22-0.80, p=0.008), revascularization (OR: 0.29, 95%CI: 0.10-0.82, p=0.02) and unstable angina (OR: 0.47, 95%CI: 0.29-0.77, p=0.003) in patients after PCI with CYP2C19 LOF alleles. A subgroup analysis showed that ticagrelor reduced the risk of MACEs compared with high-dose clopidogrel regardless of the type of metabolizer. Compared with high-dose clopidogrel, ticagrelor significantly reduced the risk of MACE with longer follow-up period (more than 3months) without increasing the risk of bleeding (OR: 0.89, 95%CI: 0.53-1.49, p=0.30), while elevated dyspnoea (OR: 5.62, 95%CI: 3.07-10.28, p<0.00001). For patients carrying CYP2C19 LOF alleles after PCI, ticagrelor may be better than high-dose clopidogrel in reducing the risk of MACEs, while dyspnoea incidents should be alerted.

P28 Multi-system and cavernous sinus inflammatory syndrome presenting with evolving multiple cranial neuropathies following zoledronate infusion

Case report - IntroductionBisphosphonates are known to rarely cause multi-system inflammation, including multiple cranial neuropathies. This is possibly via provoking transient cytokine storm. The literature reports bisphosphonate-associated orbital inflammatory syndrome, and one case of retrobulbar optic neuritis following zoledronate. Bisphosphonate manufacturers report conjunctivitis, blurred vision, scleritis, orbital inflammation, uveitis and episcleritis as ocular side effects. Separately, neurological sequalae, including cranial neuropathies, are reported following COVID-19 infection and vaccination. Here, we report the first case of cavernous sinus inflammation temporally related to both zoledronate infusion, and more remotely, to Pfizer-BioNTech COVID-19 vaccination. Case report - Case descriptionA 76-year-old white man developed fever, bony leg pain – which rendered him unable to walk – and frontal headache, within 8 hours of his first zoledronate infusion for osteoporosis. A few weeks earlier he received his first Pfizer-BioNTech COVID-19 vaccine. His General Practitioner commenced a short course of low-dose oral prednisolone for the episode.One week later, off prednisolone, the headache localised around the left eye. He developed horizontal diplopia associated with abduction deficit. He was diagnosed with left VIth nerve palsy. He was started on high-dose steroids and clopidogrel (with PPI) with neuroimaging to exclude stroke or venous sinus thrombosis. Two weeks later, the diplopia worsened over 4 days, with new left adduction deficit (-2 limitation), left ptosis 1-2mm and anisocoria 0.5-1mm R>L suggestive of partial third nerve palsy and early Horner’s syndrome. Ocular and neurological examinations were otherwise normal. He wore varifocals and had migraines, osteoporosis, and asthma, for which he used inhalers. He worked in visual arts and was an ex-smoker (>50 years) with moderate alcohol intake. Blood results revealed CRP 38mg/L, but otherwise normal inflammation/vasculitis/infection screen; anti-thyroglobulin antibodies were >4000 U/ml; GQ1P, Creatinine Kinase, anti-ganglioside, and Anti-AChR/MuSK antibodies were normal. CT head and Optical Coherence Tomography were unremarkable. An enhanced MRI of the brain and orbits revealed abnormal thickening and T2 hyper-intensity of the left oculomotor nerve, most notably involving the left canalicular portion. The left cavernous sinus also appeared asymmetrically bulky with a rind of abnormal enhancing soft tissue in the left cavernous sinus. Subtle STIR hyper-intensity was also observed in the ipsilateral CN III-innervated extra-ocular muscles.After a 6-week course of tapering prednisolone, the vertical diplopia and leg swelling persisted; the horizontal diplopia and headaches had resolved. By 3 months, there was resolution with mild residual visual changes. Case report - DiscussionWe report a constellation of symptoms relating to multi-system inflammatory syndrome involving the cavernous sinus. There is a lack of epidemiological data on the incidence of this rare presentation in the population. This case has close temporal association to bisphosphonate infusion (<12h) and weaker association to coronavirus vaccination (<3wk). It is difficult to determine whether this is a rare presentation of a known drug reaction, a more delayed presentation of a vaccine reaction or whether these events were coincidental. A further possibility in this case is a combined predisposition resulting from both vaccination and bisphosphonate infusion. This case highlights a wider issue relating to the challenging possibility of ascertainment bias and increased ‘Yellow Card’ reporting of rare presentations during this historic global coronavirus pandemic, which may or may not have any true causal association to vaccination. There is difficulty in disentangling a true vaccine reaction from an unrelated presentation of a rare condition with an unknown baseline incidence rate. This is especially topical given that the majority of the population are receiving the coronavirus vaccination at this time. We also question what a plausible cut-off point would be to propose a temporal relationship for an adverse reaction; in the literature, adverse reactions have been postulated to develop beyond 1 month after the provoking agent. Case report - Key learning pointsThis case highlights the need for urgent assessment, investigations including neurological imaging and consultant input in patients with evolving cranial neuropathy. The priority is to rule out thrombotic, compressive, inflammatory and infectious pathology in the cavernous sinus, venous sinus, orbit and orbital apex.Pathology of the cavernous sinus presents with variable involvement of CN III, IV, V and VI and Horner’s syndrome. A differential for this case would be superior orbital fissure syndrome, which also presents with multiple oculomotor cranial neuropathies; it involves these cranial nerves and the ophthalmic branch of CN V. Orbital apex syndrome is SOF with a loss of vision due to additional CNII involvement.The neuro-radiology differential included inflammatory, infiltrative, granulomatous and neoplastic aetiologies and that there was sufficient existing evidence to exclude brainstem pathology.Through communication between specialties, the temporal relationship was established, and clinical examination and extensive investigation further honed the differential to either inflammatory or vascular. Since it was temporally related to the zolendronate infusion, it seemed plausible it was related. We demonstrate the need for multi-disciplinary collaboration for these patients between rheumatology, ophthalmology and neuro-radiology.

Guided P2Y12 inhibitor therapy after percutaneous coronary intervention

Antiplatelet treatment regimens for patients after percutaneous coronary intervention (PCI) have undergone major changes and substantial improvements. Extensions or a shortening of treatment as well as the use of various scores have been assessed in numerous trials to maximise anti-ischaemic efficacy and minimise bleeding. 1 Collet JP Thiele H Barbato E et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2020; (published online Aug 29.)https://doi.org/10.1093/eurheartj/ehaa575 Crossref PubMed Scopus (122) Google Scholar , 2 Knuuti J Wijns W Saraste A et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477 Crossref PubMed Scopus (1634) Google Scholar The key limitation of these strategies is the inherent time delay in the implementation of any therapy adjustments. At the same time, several clinical trials have investigated tailored and guided antiplatelet treatment. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar Unfortunately, the pioneering trials of tailored treatment did not meet their primary endpoints or show improvement in patients' outcomes. 4 Price MJ Berger PB Teirstein PS et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011; 305: 1097-1105 Crossref PubMed Scopus (1130) Google Scholar , 5 Trenk D Stone GW Gawaz M et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) Study. J Am Coll Cardiol. 2012; 59: 2159-2164 Crossref PubMed Scopus (521) Google Scholar Various explanations have been attributed to these disappointing results, including insufficient intensification of treatment in patients with low response to clopidogrel by limited use of potent P2Y12 inhibitors and preferential inclusion of low-risk patients. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar To address these issues, a series of recent trials included patients at higher risk and investigated the use of platelet function testing (phenotyping) 6 Sibbing D Aradi D Jacobshagen C et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017; 390: 1747-1757 Summary Full Text Full Text PDF PubMed Scopus (295) Google Scholar or genetic testing (genotyping) 7 Claassens DMF Vos GJA Bergmeijer TO et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019; 381: 1621-1631 Crossref PubMed Scopus (212) Google Scholar , 8 Pereira NL Farkouh ME So D et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA. 2020; 324: 761-771 Crossref PubMed Scopus (93) Google Scholar as a strategy by including study groups with a clear distinction of testing versus no testing. Notably, these trials did not provide unequivocal results and were partly limited in sample size and sometimes underpowered to compare specific ischaemic and bleeding endpoints. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysisGuided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. Full-Text PDF

Effectiveness and safety of high dose clopidogrel plus aspirin in ischemic stroke patients with the single CYP2C19 loss-of-function allele: a randomized trial

BackgroundDual antiplatelet aggregation therapy leads to better outcomes in patients with carotid artery stenosis, intracranial artery stenosis, minor strokes, or transient ischaemic attacks. However, carriers of the CYP2C19 loss-of-function allele may not experience the desired effects. We attempted to increase the clopidogrel dose to determine whether it would improve the outcomes of stroke patients who carry a single loss-of-function allele.MethodsWe recruited 131 patients with minor ischaemic stroke, within less than 7 days of stroke onset and a CYP2C19 loss-of-function allele, who had moderate-to-severe cerebral artery stenosis. Patients were divided into the high dose group (clopidogrel 150 mg per day + aspirin 100 mg per day over 21 days.) and a normal dose group (clopidogrel 75 mg per day + aspirin 100 mg per day over 21 days). The reported outcomes included any vascular or major bleeding events as the primary and safety endpoints, respectively.ResultsOne and six vascular events occurred in the high dose and normal dose groups during the 3-months follow-up period, respectively. However, no significant difference was found between the two groups when adjusted for history of diabetes (hazard ratio, 5482; 95% confidence interval, 0.660 to 45.543; P = 0.115). No major bleeding events occurred.ConclusionsIn patients with ischaemic stroke who had a single CYP2C19 loss-of-function allele and moderate to severe cerebral stenosis, fewer vascular events occurred within 3 months with high dose of clopidogrel and aspirin than with normal dose of clopidogrel and aspirin. However, the difference between the two groups was not significant.Trial registrationClinical study of clopidogrel in the treatment of patients with symptomatic moderate to severe cerebral artery stenosis with intermediate metabolites of CYP2C19, URL: http://www.chictr.org.cn/. Unique identifier: ChiCTR1800017411, 07/28/2018;

Association of CYP2C19*2 polymorphisms and high on-treatment platelet reactivity in acute myocardial infarction or coronary artery in-stent restenosis patients during dual antiplatelet therapy

ObjectiveCytochrome CYP2C19 mutant allele is associated with high on-treatment platelet reactivity (HTPR) after standard clopidogrel treatment, which is accompanied by an increased risk of ischemic events. This study assesses the association of CYP2C19 mutant allele with HTRR and its response to antiplatelet therapy in acute myocardial infarction (AMI) or coronary artery in-stent restenosis (ISR). MethodsCYP2C19 (*2, *3, *17) and ABCB1 genotyping were performed in a series of 98 AMI or ISR patients treated with standard-dose clopidogrel (75 mg, term daily). Platelet activity was measured by VerifyNow assay, with HTPR defined as P2Y12 reaction units (PRUs) >208. The patients with HTPR (n = 48) were randomly assigned to receive either high-dose clopidogrel (150 mg, term daily; n = 24) or ticagrelor (90 mg, bid; n = 24). ResultsNo association was observed between CYP2C19*3, ABCB1 genotype and platelet reactivity (PR) (P > .05 for all). A significantly higher frequency of HTPR were observed in the patients carrying CYP2C19*2 homozygotes (n = 9; 9/11, 81.8%) than the CYP2C19*2 allele carriers (n = 26; 26/48, 54.2%, P < .05) and the non-carriers (n = 13; 13/39, 33.3%, P < .001). No patient exhibited HTPR after treatment with ticagrelor irrespective of CYP2C19 genotype, whereas 5 (100%) patients with CYP2C19*2 homozygotes, 7 (50%) CYP2C19*2 allele carriers and 3 (60%) non-carriers after high-dose clopidogrel remained HTPR (P < .05 for all). ConclusionA higher rate of HTPR was observed in AMI or ISR patients with CYP2C19*2 homozygotes than those with one or none allele. In patients carrying CYP2C19*2 homozygotes, ticagrelor is significantly more effective in reducing platelet reactivity than high-dose clopidogrel.

Equipoise in Management of Patients With Acute Symptomatic Carotid Stenosis (Hot Carotid).

To explore differences in antithrombotic management of patients with acutely symptomatic carotid stenosis ("hot carotid") awaiting revascularization with endarterectomy or stenting (CEA/CAS). We used a worldwide electronic survey with practice-related questions and clinical questions about 3 representative scenarios. Respondents chose their preferred antithrombotic regimen (1) in general, (2) if the patient was already on aspirin, or (3) had associated intraluminal thrombus (ILT) and identified clinical/imaging factors that increased or decreased their enthusiasm for additional antithrombotic agents. Responses among different groups were compared using multivariable logistic regression. We received 668 responses from 71 countries. The majority favored CT angiography (70.2%) to evaluate carotid stenosis, CEA (69.1%) over CAS, an aspirin-containing regimen (88.5%), and a clopidogrel-containing regimen (64.4%) if already on aspirin. Whereas diverse antithrombotic regimens were chosen, monotherapy was favored by 54.4%-70.6% of respondents across 3 scenarios. The preferred dual therapy was low-dose aspirin (75-100 mg) plus clopidogrel (22.2%) or high-dose aspirin (160-325 mg) plus clopidogrel if already on aspirin (12.2%). Respondents favoring CAS more often chose ≥2 agents (adjusted odds ratio [aOR] vs CEA: 2.00, 95% confidence interval 1.36-2.95, p = 0.001) or clopidogrel-containing regimens (aOR: 1.77, 1.16-2.70, p = 0.008). Regional differences included respondents from Europe less commonly choosing multiple agents if already on aspirin (aOR vs United States/Canada: 0.57, 0.35-0.93, p = 0.023), those from Asia more often favoring multiple agents (aOR: 1.95, 1.11-3.43, p = 0.020), vs those from the United States/Canada preferentially choosing heparin-containing regimens with ILT (aOR vs rest: 3.35, 2.23-5.03, p < 0.001). Factors increasing enthusiasm for ≥2 antithrombotics included multiple TIAs (57.2%), ILT (58.5%), and ulcerated plaque (57.4%); 56.3% identified MRI microbleeds as decreasing enthusiasm. Our results highlight the heterogeneous management and community equipoise surrounding optimal antithrombotic regimens for hot carotids.

Half-dose ticagrelor versus high-dose clopidogrel in reducing platelet reactivity in acute coronary syndrome patients with high on-clopidogrel platelet reactivity (divide study).

High on-treatment platelet reactivity (HTPR) after clopidogrel administration in patients with acute coronary syndrome (ACS) has been associated with an increased risk of adverse events. Our previous studies reported that half-dose ticagrelor provides a similar inhibitory effect on adenosine diphosphate (ADP)-induced platelet aggregation as standard-dose ticagrelor, but half-dose of ticagrelor has not been studied in Chinese ACS patients with HTPR. This study aimed to compare the antiplatelet action of half-dose ticagrelor with high-dose clopidogrel in ACS patients with HTPR. In this single-center randomized controlled trial, 80 (of 418 screened, 19.13%) ACS patients with HTPR while on clopidogrel were randomized to either half-dose ticagrelor (90mg LD, then 45mg twice daily) or high-dose clopidogrel (150mg once daily). Platelet function was assessed by thromboelastography (TEG) and light transmission aggregometry (LTA), and adverse events were monitored throughout the study for 30days. The ADP-induced platelet inhibition rate (IR) as measured by TEG was significantly higher for half-dose ticagrelor compared with high-dose clopidogrel (70.40% [61.10%-91.70%] vs. 44.25% [34.67%-79.07%], p = 0.001). The repeated HTPR rate was dramatically higher for high-dose clopidogrel compared with half-dose ticagrelor (6 of 32, 18.75% vs. 1 of 35, 2.85%; p = 0.04). No patients in either treatment group exhibited a major bleeding event or other adverse events. In ACS patients with HTPR, half-dose ticagrelor is more effective than high-dose clopidogrel in reducing platelet reactivity (NCT03062462).

Periprocedural Neuroendovascular Antiplatelet Strategies for Thrombosis Prevention in Clopidogrel-Hyporesponsive Patients.

Patients undergoing neuroendovascular procedures such as cerebral aneurysm coiling and intracranial stent deployment are frequently treated with antiplatelet agents to prevent thrombotic complications. The combination of aspirin and a P2Y12 inhibitor such as clopidogrel is often initiated days before elective procedures or as loading doses for emergent procedures; however, some patients may still experience thrombotic complications. Patients identified as clopidogrel hyporesponders are more likely to experience poor outcomes and may require changes to their regimens. Historically, high-dose clopidogrel regimens were used in response to subtherapeutic results of platelet function assays and point-of-care testing despite limited supporting data. Recently, more data have emerged using alternative P2Y12 inhibitors such as prasugrel and ticagrelor. Dosing for neuroendovascular conditions is often extrapolated from the cardiac literature, although outcomes in cardiac patients may not be relevant to neurologic patients, making prophylactic treatment recommendations challenging for these patients. This review summarizes the literature for antiplatelet prophylaxis in patients undergoing neuroendovascular device placement, focusing on alternative regimens for clopidogrel hyporesponders.

Management of Acute Coronary Syndromes

Management of Acute Coronary Syndromes

Cerium dioxide-doped carboxyl fullerene as novel nanoprobe and catalyst in electrochemical biosensor for amperometric detection of the CYP2C19*2 allele in human serum

The disposition dose of clopidogrel is different in CYP2C19*2 gene carriers and non-carriers. High-dose clopidogrel has been recommended to overcome a low-responsiveness to clopidogrel in patients with the CYP2C19*2 gene. To guide the choice of clopidogrel dosage and catalyse a development in the field of personalized therapy, we developed an ultrasensitive electrochemical biosensor to detect CYP2C19*2 gene. We constructed a novel assay based on cerium dioxide (CeO2)-functionalized carboxyl fullerene (c-C60) supported by Pt nanoparticles (c-C60/CeO2/PtNPs) for signal amplification. Au nanoparticles @ Fe-MIL-88NH2 (AuNPs@Fe-MOFs) were synthesized by one-step method as the support platform to enhance the conductivity and immobilize more biotin-modified capture probe (bio-CP) through the superior affinity and specificity between streptavidin and biotin. c-C60/CeO2/PtNPs were labeled with signal probe to form the signal label. After the sandwich reaction of CYP2C19*2 gene between capture probe and the signal label, a distinguishing electrochemical signal from the catalysis of H2O2 by signal label would be observed. Amperometry was applied to record electrochemical signals. Under optimized conditions, the approach showed a good linear dependence between current and the logarithm of CYP2C19*2 gene concentrations in the range of 1 fM to 50nM with a low detection limit of 0.33fM (S/N = 3). The proposed method showed good specificity to target DNA compared with possible interfering substances. More importantly, the fabricated biosensor achieved accurate quantitative detection of CYP2C19*2 gene in human serum samples demonstrated by excellent correlations with standard DNA sequencing and provided a promising strategy for electrochemical biosensor detection of other gene mutations.

GW28-e1178 Ticagrelor Versus High-Dose (150-mg) Clopidogrel in stable coronary heart disease With High On-Clopidogrel Platelet Reactivity Following Percutaneous Coronary Intervention --- A prospective, randomized, single-center, crossover Study

GW28-e1178 Ticagrelor Versus High-Dose (150-mg) Clopidogrel in stable coronary heart disease With High On-Clopidogrel Platelet Reactivity Following Percutaneous Coronary Intervention --- A prospective, randomized, single-center, crossover Study

High-dose clopidogrel versus ticagrelor for treatment of acute coronary syndromes after percutaneous coronary intervention in CYP2C19 intermediate or poor metabolizers: a prospective, randomized, open-label, single-centre trial.

Objective The present study was designed to compare the outcome and safety of dual antiplatelet therapies (DAPTs) in patients with acute coronary syndrome (ACS) (intermediate metabolizers [IM] or poor metabolizers [PM]) undergoing percutaneous coronary intervention (PCI).Methods and results From September 20, 2013, to June 8, 2014, the study enrolled 329 patients with ACS scheduled for PCI. Of these, 181 (55%) patients with IM or PM were randomized in a 1:1 ratio to receive either high-dose clopidogrel or ticagrelor. The high-dose clopidogrel group received a 600-mg loading dose (LD) and finally 75 mg QD, and the ticagrelor group received 180 mg LD following 90 mg b.i.d. After 6 months of DAPT, the primary end point (composition of death, stroke, recurrent myocardial infarction [MI], and stent thrombosis) occurred in 4.4% of patients receiving ticagrelor compared with 20.0% of those receiving high-dose clopidogrel (P <0.001). Survival probability analysis revealed a higher survival rate with ticagrelor (9...

High-dose bolus tirofiban versus low-dose bolus in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

Aim of the present study was to determine effects of high-dose versus low-dose intravenous (IV) bolus tirofiban on angiographic measures, ST resolution, enzymatic infarct size, and clinical outcomes in patients with acute coronary syndrome (ACS) who were undergoing percutaneous coronary intervention (PCI) and received current pharmacoinvasive therapy. Acute coronary syndrome patients (n=271, 85.6% male; mean age: 57.9±12.6 years) from between 2009 and 2015 who received IV tirofiban therapy following PCI were retrospectively analyzed. All patients had received maintenance tirofiban infusion (0.15 µg/kg/min) after bolus dose and 600 mg clopidogrel. Percentage of patients undergoing drug eluting stent implantation procedure was 33.5%. Tirofiban was administered to all patients in bailout situation or for thrombotic complication after PCI. High-dose IV bolus group (25 µg/kg; n=140) was associated with greater ST segment resolution (66% vs. 50%, p=0.013) and reduced peak troponin release [12.4 ng/dL (range: 6.5-21.5 ng/dL) vs. 16.4 ng/dL (range: 10.1-27.4 ng/dL), p=0.001] compared with low-dose bolus group (10 µg/kg, n=131). Cardiovascular event rates were similar between groups at in-hospital, 1-month, and 6-month follow-up (p=1.000, 1.000, and 0.287, respectively). Percentage of patients with post-procedural Thrombolysis in Myocardial Infarction (TIMI) grade III flow, major, and minor bleeding were similar (p=0.085, 1.000, and 0.965, respectively). Use of high-dose IV bolus tirofiban in addition to aspirin and high-dose clopidogrel improves ST segment resolution, reduces infarct size, and does not increase bleeding events in patients with ACS undergoing PCI compared with low-dose bolus. Angiographic measures and clinical endpoints were similar between groups.

High-dose clopidogrel versus ticagrelor for treatment of acute coronary syndromes after percutaneous coronary intervention in CYP2C19 intermediate or poor metabolizers: a prospective, randomized, open-label, single-centre trial

Objective The present study was designed to compare the outcome and safety of dual antiplatelet therapies (DAPTs) in patients with acute coronary syndrome (ACS) (intermediate metabolizers [IM] or poor metabolizers [PM]) undergoing percutaneous coronary intervention (PCI).Methods and results From September 20, 2013, to June 8, 2014, the study enrolled 329 patients with ACS scheduled for PCI. Of these, 181 (55%) patients with IM or PM were randomized in a 1:1 ratio to receive either high-dose clopidogrel or ticagrelor. The high-dose clopidogrel group received a 600-mg loading dose (LD) and finally 75 mg QD, and the ticagrelor group received 180 mg LD following 90 mg b.i.d. After 6 months of DAPT, the primary end point (composition of death, stroke, recurrent myocardial infarction [MI], and stent thrombosis) occurred in 4.4% of patients receiving ticagrelor compared with 20.0% of those receiving high-dose clopidogrel (P <0.001). Survival probability analysis revealed a higher survival rate with ticagrelor (95% survival probability) than with clopidogrel (87% survival probability), indicating that the incidence rate of death, stroke, and recurrent MI is lower with ticagrelor than with clopidogrel (HR 2.54; 95% CI: 0.89 to 7.21; P= 0.07). Although the rates of major or minor bleeding event were high in the clopidogrel vs ticagrelor groups, they did not differ significantly. Dyspnoea and hyperuricaemia were more commonly observed in the ticagrelor group than the high-dose clopidogrel group (4.5% vs 3.8%, P= 0.03; 1.1% vs 7.7%, P < 0.001).Conclusion Ticagrelor is a more efficacious and safer treatment option in IM or PM patients with ACS compared with high-dose clopidogrel.

Simultaneous administration of high-dose atorvastatin and clopidogrel does not interfere with platelet inhibition during percutaneous coronary intervention.

BackgroundReloading with high-dose atorvastatin shortly before percutaneous coronary interventions (PCIs) has been proposed as a strategy to reduce periprocedural myonecrosis. There has been a concern that statins that are metabolized by cytochrome P450 3A4 may interfere with clopidogrel metabolism at high doses. The impact of simultaneous administration of high doses of atorvastatin and clopidogrel on the efficacy of platelet inhibition has not been established.MethodsSubjects (n=60) were randomized to receive atorvastatin 80 mg together with clopidogrel 600 mg loading dose (n=28) versus clopidogrel 600 mg alone (n=32) at the time of PCI. Platelet aggregation was measured at baseline, 4 hours after clopidogrel loading dose, and 16–24 hours after clopidogrel loading dose by light transmittance aggregometry using adenosine diphosphate as agonist.ResultsPlatelet aggregation was similar at baseline in both the atorvastatin and the control groups (adenosine diphosphate 10 µM: 57%±19% vs 61%±21%; P=0.52). There was no significant difference in platelet aggregation between the atorvastatin and the control groups at 4 hours (37%±18% vs 39%±21%; P=0.72) and 16–24 hours post-clopidogrel loading dose (35%±17% vs 37%±18%; P=0.75). No significant difference in incidence of periprocedural myonecrosis was observed between the atorvastatin and control groups (odds ratio: 1.02; 95% confidence interval 0.37–2.8).ConclusionHigh-dose atorvastatin given simultaneously with clopidogrel loading dose at the time of PCI does not significantly alter platelet inhibition by clopidogrel. Statin reloading with high doses of atorvastatin at the time of PCI appears to be safe without adverse effects on platelet inhibition by clopidogrel (ClinicalTrials.gov: NCT00979940).

Comparative Efficacy and Safety of Prasugrel, Ticagrelor, and Standard-Dose and High-Dose Clopidogrel in Patients Undergoing Percutaneous Coronary Intervention: A Network Meta-analysis.

Authors aimed to compare efficacy and safety of prasugrel, ticagrelor, and standard-dose (SD) and high-dose (HD) clopidogrel in patients undergoing percutaneous coronary intervention (PCI). PubMed, EMBASE, CENTRAL, and clinicaltrials.gov were searched for studies comparing prasugrel, ticagrelor, SD and HD clopidogrel in patients undergoing PCI. Frequentist and Bayesian network meta-analyses were performed besides direct pairwise comparisons. Thirty trials, comprising 34,563 person-year data, were included. Prasugrel emerged as a best drug to prevent definite or probable stent thrombosis, followed by HD clopidogrel and ticagrelor, with SD clopidogrel being the worst. Myocardial infarction was least likely to be prevented by SD clopidogrel after PCI, and remaining 3 were superior to it with little difference among them. SD clopidogrel was least effective in preventing cardiovascular deaths after PCI. Prasugrel was most effective in preventing cardiovascular deaths, although having only small advantage over ticagrelor and HD clopidogrel. Ticagrelor reduced all-cause mortality by a small margin compared with rest of treatments. SD clopidogrel, followed by ticagrelor, resulted in significantly lower thrombolysis in myocardial infarction major bleeding complications compared with prasugrel. Analysis of any bleeding revealed similar trend. HD clopidogrel performed better than prasugrel in terms of bleeding complications. In conclusion, Prasugrel is likely most effective drug to prevent post-PCI ischemic events but at the expense of higher bleeding. Ticagrelor followed by HD clopidogrel seems to strike the right balance between efficacy and safety. HD clopidogrel can be considered as an alternative to newer P2Y12 inhibitors.