Tongue diagnostic parameters-based diagnostic signature in coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention.

BACKGROUND: Credible diagnostic stratification remains a challenge for coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention. Tongue diagnostic parameters-based diagnostic signatures might predict clopidogrel resistance. METHODS: Clinical and tongue diagnostic parameters data were obtained from coronary artery disease patients with clopidogrel resistance after percutaneous coronary intervention patients and then analyzed. Tongue diagnostic parameters-based diagnostic signatures were developed through univariate and multivariate logistic regression analysis. The diagnostic prediction was assessed using a receiver operating characteristic curve. RESULTS: A total of 101 patients were consecutively identified. Then, tongue diagnostic parameters were identified as significantly associated with clopidogrel resistance diagnosis and were combined with risk factors to develop a model. The receiver operating characteristic curve analysis showed that tongue diagnostic parameters-based diagnostic signatures performed well in diagnosing clopidogrel resistance with an area under the receiver operating characteristic curve value of 0.819. CONCLUSIONS: This study identified a novel tongue diagnostic parameters-based diagnostic signature to reliably distinguish clopidogrel resistance diagnosis in coronary artery disease patients undergoing percutaneous coronary intervention. Further larger, multicenter prospective studies are desired to validate this model.

Clopidogrel resistance is common in patients undergoing vascular and coronary interventions.

OBJECTIVES: "Clopidogrel resistance," also defined as heightened platelet reactivity (HPR) while on clopidogrel therapy, may lead to a sub-optimal antiplatelet effect and a potential thrombotic event. There is limited literature addressing the prevalence of HPR in a large cohort of patients receiving either coronary or endovascular interventions. METHODS: In a large integrated healthcare system, patients with a P2Y12 reaction units (PRU) test were identified. HPR was defined as a PRU ≥ 200 during clopidogrel therapy. Vascular and coronary interventions were identified utilizing CPT codes, HPR prevalence was calculated, and Fischer's exact test was used to determine significance. RESULTS: From an initial cohort of 2,405,957 patients (October 2014 to January 2020), we identified 3301 patients with PRU tests administered. Of these, 1789 tests had a PRU ≥ 200 (HPR overall prevalence, 54%). We then identified 1195 patients who underwent either an endovascular or coronary procedure and had a PRU measurement. This corresponded to 935 coronary and 260 endovascular interventions. In the coronary cohort, the HPR prevalence was 54% (503/935). In the vascular cohort, the HPR prevalence was 53% (137/260); there was no difference between cohorts in HPR prevalence (p = 0.78). CONCLUSION: "Clopidogrel resistance" or HPR was found to be present in nearly half of patients with cardiovascular disease undergoing intervention. Our data suggest HPR is more common in the cardiovascular patient population than previously appreciated. Evaluating patients for HPR is both inexpensive ($25) and rapid (< 10 min). Future randomized studies are warranted to determine whether HPR has a clinically detectable effect on revascularization outcomes.

Medical adjuvant treatment to increase patency of arteriovenous fistulae and grafts.

BACKGROUND: People with end-stage renal disease (ESRD) often require either the formation of an arteriovenous fistula (AVF) or an interposition prosthetic arteriovenous graft (AVG) for haemodialysis. These access sites should ideally have a long life and a low rate of complications (e.g. thrombosis, infection, stenosis, aneurysm formation and distal limb ischaemia). Although some of the complications may be unavoidable, any adjuvant technique or medical treatment aimed at decreasing complications would be welcome. This is the fourth update of the review first published in 2003. OBJECTIVES: To assess the effects of adjuvant drug treatment in people with ESRD on haemodialysis via autologous AVFs or prosthetic interposition AVGs. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase and CINAHL databases and ClinicalTrials.gov trials register to 6 August 2020. SELECTION CRITERIA: Randomised controlled trials of active drug versus placebo in people with ESRD undergoing haemodialysis via an AVF or prosthetic interposition AVG. DATA COLLECTION AND ANALYSIS: For this update, two review authors (IM, MFAK) independently selected trials for inclusion, extracted data, assessed risk of bias and assessed the certainty of the evidence according to GRADE. We resolved disagreements by discussion or consultation with another review author (ADS). The primary outcome was the long-term fistula or graft patency rate. Secondary outcomes included duration of hospital stay; complications such as infection, aneurysm formation, stenosis and distal limb ischaemia; and number of related surgical or radiological interventions. MAIN RESULTS: For this update, one additional study was suitable for inclusion, making a total of 13 trials with 2080 participants. Overall the certainty of the evidence was low or moderate due to short follow-up periods, heterogeneity between trials, small sample sizes, and risk of bias due to incomplete reporting. Medical adjuvant treatments used in the included trials were aspirin, ticlopidine, dipyridamole, dipyridamole plus aspirin, warfarin, fish oil, clopidogrel, sulphinpyrazone and glyceryl trinitrate (GTN) patch.  All included studies reported on graft patency by measuring graft thrombosis. There was insufficient evidence to determine if there was a difference in graft patency in studies comparing aspirin versus placebo (odds ratio (OR) 0.40, 95% confidence interval (CI) 0.07 to 2.25; 3 studies, 175 participants; low-certainty evidence). The meta-analysis for graft patency comparing ticlopidine versus placebo favoured ticlopidine (OR 0.45, 95% CI 0.25 to 0.82; 3 studies, 339 participants; moderate-certainty evidence). There was insufficient evidence to determine if there was a difference in graft patency in studies comparing fish oil versus placebo (OR 0.24, 95% CI 0.03 to 1.95; 2 studies, 220 participants; low-certainty evidence); and studies comparing clopidogrel and placebo (OR 0.40, 95% CI 0.13 to 1.19; 2 studies, 959 participants; moderate-certainty evidence). Similarly, there was insufficient evidence to determine if there was a difference in graft patency comparing the effect of dipyridamole versus placebo (OR 0.46, 95% CI 0.11 to 1.94; 1 study, 42 participants, moderate-certainty evidence) and dipyridamole plus aspirin versus placebo (OR 0.64, CI 0.16 to 2.56; 1 study, 41 participants; moderate-certainty evidence); comparing low-intensity warfarin with placebo (OR 1.76, 95% CI 0.78 to 3.99; 1 study, 107 participants; low-certainty evidence); comparing sulphinpyrazone versus placebo (OR 0.43, 95% CI 0.03 to 5.98; 1 study, 16 participants; low-certainty evidence) and comparing GTN patch and placebo (OR 1.26, 95% CI 0.63 to 2.54; 1 study, 167 participants; moderate-certainty evidence). The single trial evaluating warfarin was terminated early because of major bleeding events in the warfarin group. Only two studies published data on the secondary outcome of related interventions (surgical or radiological); there was insufficient evidence to determine if there was a difference in related interventions between placebo and treatment groups. None of the included studies reported on the duration of hospital stay.  Most studies reported complications ranging from mortality to nausea. However, data on complications were limited and reporting varied between studies. AUTHORS' CONCLUSIONS: The meta-analyses of three studies for ticlopidine (an antiplatelet treatment), which all used the same dose of treatment but with a short follow-up of only one month, suggest ticlopidine may have a beneficial effect as an adjuvant treatment to increase the patency of AVFs and AVGs in the short term. There was insufficient evidence to determine if there was a difference in graft patency between placebo and other treatments such as aspirin, fish oil, clopidogrel, dipyridamole, dipyridamole plus aspirin, warfarin, sulphinpyrazone and GTN patch. The certainty of the evidence was low to moderate due to short follow-up periods, the small number of studies for each comparison, small sample sizes, heterogeneity between trials and risk of bias due to incomplete reporting. Therefore, it appears reasonable to suggest further prospective studies be undertaken to assess the use of these antiplatelet drugs in renal patients with an AVF or AVG.

Oxypeucedanin is a Mechanism-based Inactivator of CYP2B6 and CYP2D6.

BACKGROUND: Herbal medicine Angelica dahurica is widely employed for the treatment of rheumatism and pain relief in China. Oxypeucedanin is a major component in the herb. OBJECTIVES: The objectives of this study are aimed at the investigation of mechanism-based inactivation of CYP2B6 and CYP2D6 by oxypeucedanin, characterization of the reactive metabolites associated with the enzyme inactivation, and identification of the P450s participating in the bioactivation of oxypeucedanin. METHODS: Oxypeucedanin was incubated with liver microsomes or recombinant CYPs2B6 and 2D6 under designed conditions, and the enzyme activities were measured by monitoring the generation of the corresponding products. The resulting reactive intermediates were trapped with GSH and analyzed by LC-MS/MS. RESULTS: Microsomal incubation with oxypeucedanin induced a time-, concentration-, and NADPH-dependent inhibition of CYPs2B6 and 2D6 with kinetic values of KI/kinact 1.82 µM/0.07 min-1 (CYP2B6) and 8.47 µM/0.044 min-1 (CYP2D6), respectively. Ticlopidine and quinidine attenuated the observed time-dependent enzyme inhibitions. An epoxide and/or γ-ketoenal intermediate(s) derived from oxypeucedanin was/were trapped in microsomal incubations. CYP3A4 was the primary enzyme involved in the bioactivation of oxypeucedanin. CONCLUSION: Oxypeucedanin was a mechanism-based inactivator of CYP2B6 and CYP2D6. An epoxide and/or γ- ketoenal intermediate(s) may be responsible for the inactivation of the two enzymes.

Incidence of neutropenia in patients with ticlopidine/Ginkgo biloba extract combination drug for vascular events: A post-marketing cohort study.

BACKGROUND AND PURPOSE: The ticlopidine/Ginkgo biloba ext. combination drug (Yuclid) is used as an antiplatelet agent for prevention of vascular events since its approval in 2008. The purpose of this study is to explore the safety of ticlopidine/Ginkgo biloba combination, mainly regarding the incidence of neutropenia, through a post-marketing surveillance study. METHODS: From March 2009 to October 2015, a total of 4839 subjects had been enrolled in this study. The enrollments were conducted by 152 doctors of 89 hospitals according to the regulations for post-marketing surveillance programs in Korea. If a subject was administered the drug once, he/she was included in the safety analysis set for any adverse events and bleedings, and the primary safety evaluation regarding neutropenia was conducted in subjects who completed 3-month blood test follow-up. We predefined that 1% reduction in neutropenia incidence by ticlopidine/Ginkgo biloba ext. combination from the previously reported incidence of ticlopidine of 2.3% was clinically meaningful. RESULTS: Among the safety analysis set of 4831 patients (99.8% of the enrolled subjects), 3150 (65.1%) completed evaluation for neutropenia at 3 months which is the primary safety endpoint. The major causes of dropout were no follow-up visit at 3 months (n = 1016) and violation of the follow-up period (n = 503). Nine patients experienced neutropenia (Absolute neutrophil count [ANC] ≤ 1200mm3) and the estimated cumulative incidence at 3 months is 0.29% (95% confidence interval, 0.13%- 0.54%). Severe neutropenia (ANC ≤ 450mm3) did not occur in any patients. CONCLUSIONS: The incidence of neutropenia with addition of Ginkgo biloba ext. to ticlopidine may be lower than the previously reported incidence of neutropenia with ticlopidine, which needs to be confirmed in randomized controlled trials.

Recurrent retinal vein thrombosis: prevention with Aspirin, Pycnogenol®, ticlopidine, or sulodexide.

BACKGROUND: The aim of this study is to evaluate the use of Aspirin, Pycnogenol®, ticlopidine, and sulodexide to reduce the incidence of new RTV (retinal vein thrombosis) after a first episode. Pycnogenol® is an anti-inflammatory, anti-edema, mild antiplatelet-antithrombotic agent. METHODS: The registry study evaluated the number of repeated episodes of RVT in 12 months. Possible managements were: standard management (SM); SM + Aspirin (100 mg/once day; if there were no tolerability problems); SM + Pycnogenol (100 mg/day); SM and ticlopidine (200 mg/day); SM + sulodexide (500 ULS/day). The number of subjects age and sex, distribution, the percent of smokers, the vision were comparable at inclusion. RESULTS: 307 subjects completed the study, 44 in the SM group, 90 in the Pycnogenol® group, 90 in the aspirin group, 45 in the ticlopidine group and 38 in the sulodexide group. At 12 months, recurrent RVT was documented in 22.7% of controls (SM), 3.3% of Pycnogenol® subjects (P<0.05 vs. SM; 19.4% difference). There were RVTs in 15.5% subjects using Aspirin (-7.2% vs. SM). Ticlopidine also reduced (P<0.05) the incidence of RVT in comparison with SM (-9.1%). Sulodexide reduced the occurrence of new RVT (-9.5% vs. SM). Edema was better controlled with the supplement than with all other treatments (P<0.05) (edema present in only 5.5% of the Pycnogenol® subjects). Pycnogenol® had a very good tolerability and safety profile (no patient had to stop treatment). CONCLUSIONS: Pycnogenol® is the only product able to control edema and this may reduce the incidence of recurrent RVT. This retrospective registry indicates that Aspirin, Pycnogenol®, ticlopidine an sulodexide reduce recurrent RVT without side effects. Larger studies should be planned to involve a wider range of conditions, diseases and risk factors associated with RVT and to its recurrence.

Interaction study between antiplatelet agents, anticoagulants, thyroid replacement therapy and a bioavailable formulation of curcumin (Meriva®).

OBJECTIVE: The objective of this clinical study is to evaluate possible interactions between antiplatelet agents, anticoagulants, thyroid hormone replacement therapy and a formulation of curcumin (Meriva®) that resulted effective for the complementary treatment of osteoarthritis. PATIENTS AND METHODS: Interaction between antiplatelet agents and Meriva® was evaluated by measuring anti-platelet activity with the in-vivo bleeding-time (BT) in patients assuming acetylsalicylic acid or ticlopidine or clopidogrel from at least 2 years. The BT was evaluated before and after 10 days of supplementation with Meriva®. The interaction between anticoagulants and Meriva® was evaluated in patients using warfarin or dabigatran for previous venous thrombosis. The INR level was evaluated before and after 10 days of supplementation with the curcumin formulation. Thyroid function tests in hypothyroid patients using LT4 replacement therapy (Eutirox®) were evaluated before and after 15 days of supplementation with Meriva®. Similarly, levels of glycemia and glycated hemoglobin were evaluated in diabetic patients in treatment with metformin, before and after 10 days of supplementation with the studied product. RESULTS: After 10 days of supplementation with Meriva® the average BT value was not significantly different for patients assuming acetylsalicylic acid, ticlopidine or clopidogrel at standard dosages. Similarly, after 10 days of Meriva® treatment, the INR level in the two groups of patients assuming warfarin or dabigatran was not statistically different from that observed at baseline. In the analyzed patients assuming LT4 or metformin, no interactions between the therapy and Meriva® were observed. CONCLUSIONS: Results from this non-interaction clinical study suggest that Meriva® does not interfere with the antiplatelet activity of the most common antiplatelet agents nor alters the INR values in stable patients assuming warfarin or dabigatran. Similarly, dosages of LT4 or metformin do not need to be adjusted in case of complementary treatment with Meriva®.

[Anti-Thrombotic Treatment of Patients with Peripheral Artery Disease (PAD)]. / Antithrombotische Therapie bei peripherer arterieller Verschlusskrankheit.

Patients with peripheral artery disease are at high-risk for cardiovascular events. Anti-thrombotic treatment is very important for secondary prevention. In symptomatic patients single antiplatelet therapy with clopidogrel or Aspirin is recommended. After peripheral revascularisation transient dual antiplatelet therapy is widely used although there is only little evidence. Following peripheral bypass surgery most patients are treated with single antiplatelet therapy, in some cases (prostetic bypass grafts) dual antiplated therapy can be useful and selected patients with complex venous grafts might profit from anticoagulation with vitamin K antagonists.The recent publication of the COMPASS (Cardiovascular OutcoMes for People Using Anticoagulation StrategieS) study showed relevant reduction of MACE (Major Adverse Cariac Events) and MALE (Major Adverse Limb Events) for the combined therapy of rivaroxaban 2 × 2,5 mg compared to Aspirin 100 mg with increased risk for gastrointestinal bleeding. In the current VOYAGER PAD (Vascular Outcomes Study of Aspirin along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) study this concept is tested after peripheral revascularisation.

Prevention of recurrent venous thrombosis and post-thrombotic syndrome.

BACKGROUND: This retrospective registry study evaluated different managements on the development of post-thrombotic syndrome (PTS) and recurrent deep venous thrombosis (R-DVT). The effects of aspirin (100 mg/day), added to the "standard management" (SM) (IUA consensus), were observed in patients after a proximal DVT. METHODS: The study started after the anticoagulant period. Comparable groups used the mild-antithrombotic agent Pycnogenol® (200 mg/day), ticlopidine (250 mg/day) or sulodexide (500 ULS/day). RESULTS: The groups were comparable for sex and age distribution and clinical pictures. In the SM group, 222 patients completed the follow-up (72 months). With SM, the percentage of patients with R-DVT (requiring anticoagulants) was 17.2%; 19.8% of SM patients had a PTS. In the aspirin group (202 subjects), R-DVT was observed in 14.8% of patients; 17.32% had a PTS. The reduction in R-DVT and PTS with aspirin was significant (P<0.05) vs. the SM. There was no tolerability problem in subjects using Pycnogenol® (137 patients); they had a much lower incidence of R-DVT (5.8%) and PTS (6.5%) vs. SM and aspirin (P<0.05). Ticlopidine (121 patients) reduced the incidence of R-DVT (12.4%) and PTS (19.8% of patients) (P<0.05 vs. SM). With sulodexide the incidence of R-DVT was 6.7% (P<0.05 vs. SM); the incidence of PTS was 16.6% (P<0.05 vs. SM). The combined R-DVT+PT syndrome was observed in 14.9% of subjects using SM and in 12.9% of subjects using aspirin (P<0.05 vs. SM), in 3.6% of subjects managed with Pycnogenol® (<0.05% vs. aspirin and all other managements). The incidence was 10.74% with ticlopidine and 6.7% with sulodexide (both significantly lower than SM). CONCLUSIONS: Interaction between PTS and R-DVT are complex; recurrences cause more PTSs, and a post-thrombotic limb is prone to R-DVT. Aspirin, for patients that can tolerate it, reduces the occurrence of PTS and R-DVT. In addition, ticlopidine and sulodexide are effective. Pycnogenol® is the most effective and safe for R-DVT and particularly PTS. Its full range of anti-thrombotic activity is now under evaluation.

Panax quinquefolius saponins combined with dual antiplatelet drug therapy alleviate gastric mucosal injury and thrombogenesis through the COX/PG pathway in a rat model of acute myocardial infarction.

OBJECTIVES: Previous studies have found that Panax quinquefolius saponins (PQS) combined with dual antiplatelet therapy (DAPT) of aspirin and clopidogrel enhances antithrombotic effects while reducing gastric mucosal injury induced by DAPT. We investigated the effects of the combined drug therapy (PQS+DAPT) through the COX/PG pathways. METHODS: Acute myocardial infarction (AMI) was induced in Wistar rats by ligation of the left anterior descending (LAD) coronary artery, and the animals were randomly divided into Model, DAPT, and PQS+DAPT groups. Rats in the sham group did not undergo artery ligation. They were intragastrically treated for 14 days. Myocardial infarct size; myocardial pathology; platelet aggregation rate, CD62p activation, concentrations of thromboxane B2 (TXB2), 6-keto-PGF1α, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor (PAI), the TXB2/6-keto-PGF1α ratio were measured. The ultrastructure of the gastric mucosa was observed by scanning electron microscopy. The expression of PGE2 and 6-keto-PGF1α in gastric mucosa was measured by radioimmunoassay, and levels of COX-1, COX-2, and VEGF in gastric mucosa were assessed using immunohistochemistry. RESULTS: The addition of Panax quinquefolius saponins (PQS+DAPT) to standard DAPT therapy significantly decreased the myocardial infarct area, degree of myocardial lesions, TXB2 and PAI levels, and the TXB2/6-keto-PGF1α ratio, while increasing 6-keto-PGF1α and t-PA levels and reducing the degree of gastric mucosal injury. Expression of PGE2, 6-keto-PGF1α, COX-2, and VEGF in the gastric mucosa was upregulated in the PQS+DAPT group compared with the standard DAPT group. CONCLUSION: PQS increases the degree of DAPT inhibition of myocardial necrosis and antiplatelet effects in AMI rats, as well as reducing damage to the gastric mucosa caused by DAPT. The mechanism may be related to inhibition of TXB2 and PAI activity and elevation of 6-keto-PGF1α and t-PA levels in blood, and may be associated with upregulated expression of COX-2, PGE2, PGI2, and VEGF in gastric tissue.

Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone.

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb-drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 µM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone-drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

A Multicenter, Randomized, Double-Blind, and Placebo-Controlled Study of the Effects of Tongxinluo Capsules in Acute Coronary Syndrome Patients with High On-Treatment Platelet Reactivity.

BACKGROUND: High platelet reactivity (HPR) during clopidogrel treatment predicts postpercutaneous coronary intervention (PCI) ischemic events strongly and independently. Tongxinluo capsules (TCs) are a traditional Chinese medicine formulation used as antiplatelet treatment. However, its efficacy against HPR is not known. The aim of the present study was to evaluate the effects of TCs in acute coronary syndrome (ACS) patients with HPR. METHODS: This multicenter, randomized, double-blind, placebo-controlled study prospectively analyzed 136 ACS patients with HPR who underwent PCI. The patients were enrolled from November 2013 to May 2014 and randomized to receive placebo or TCs in addition to standard dual antiplatelet therapy (DAPT) with aspirin and clopidogrel. The primary end points were the prevalence of HPR at 30 days and the mean change in P2Y12reaction units (PRUs) between baseline and 30 days. Survival curves were constructed with Kaplan-Meier estimates and compared by log-rank tests between the two groups. RESULTS: Both groups had a significantly reduced prevalence of HPR at 30 days versus baseline, but the TC group, compared with the placebo group, had greater reduction (15.8% vs. 24.8%, P = 0.013), especially among patients with one cytochrome P450 2C19 loss of function (LOF) allele (χ2 = 2.931, P = 0.047). The TC group also had a lower prevalence of HPR (33.3% vs. 54.2%, t = 5.284, P = 0.022) and superior performance in light transmittance aggregometry and higher levels of high-sensitivity C-reactive protein (hsCRP), but the composite prevalence of ischemic events did not differ significantly (χ2 = 1.587, P = 0.208). CONCLUSIONS: In addition to standard DAPT with aspirin and clopidogrel, TCs further reduce PRU and hsCRP levels, especially in patients carrying only one LOF allele. The data suggest that TCs could be used in combination therapy for ACS patients with HPR undergoing PCI.

An Evaluation of the Cost-effectiveness of Comprehensive MTM Integrated with Point-of-Care Phenotypic and Genetic Testing for U.S. Elderly Patients After Percutaneous Coronary Intervention.

BACKGROUND: Poor health outcomes after percutaneous coronary intervention (PCI) in elderly patients is an area of concern among policymakers and administrators. In an effort to determine the best strategy to improve outcomes among elderly patients who underwent PCI, several studies have evaluated the cost-effectiveness of genotype-guided antiplatelet therapy compared with universal use of any one of the antiplatelet drugs indicated for patients with acute coronary syndrome (ACS) who underwent PCI. The results have either been in favor of genotype-guided antiplatelet therapy or universal use of ticagrelor. However, no study has yet evaluated the cost-effectiveness of pharmacist-provided face-to-face medication therapy management (MTM) combined with point-of-care genotype-guided antiplatelet therapy (POCP) when compared with universal use of ticagrelor or clopidogrel for the elderly after PCI. OBJECTIVE: To evaluate the cost-effectiveness of a pharmacist integration of MTM with POCP (MTM-POCP) when compared with universal use of ticagrelor or clopidogrel combined with MTM (MTM-ticagrelor or MTM-clopidogrel). METHODS: We conducted a cost-effectiveness analysis from the perspective of the U.S. health care system. A hybrid model, consisting of a 1-year decision tree and a 20-year Markov model, was used to simulate a cohort of elderly patients (aged at least 65 years) with ACS who underwent PCI. Treatment strategies available to patients were POCP, POCP-MTM, MTM-clopidogrel, or MTM-ticagrelor. Data used to populate the model were obtained from the PLATO trial and other published studies. Outcome measures were costs, quality-adjusted life-years (QALYs) and incremental cost per QALY gained. A deterministic and probabilistic sensitivity analysis was conducted to account for the joint uncertainty around the key parameters of the model. Finally, a benchmark willingness to pay of $50,000-200,000 was considered. RESULTS: The use of PCOP (with dual antiplatelet therapy) resulted in 5.29 QALYs, at a cost of $50,207. MTM-clopidogrel resulted in 5.34 QALYs, at a cost of $50,011. The use of POCP-MTM resulted in 5.36 QALYs, at a cost of $50,270. Finally, MTM-ticagrelor resulted in 5.42 QALYs, at a cost of $53,346. MTM-ticagrelor was found to be cost-effective compared with MTM-clopidogrel or MTM-POCP, irrespective of the willingness to pay. The deterministic and probabilistic sensitivity analyses confirmed the robustness of the base-case analysis. CONCLUSIONS: The combination of MTM-ticagrelor was cost-effective when compared with MTM-POCP or MTM-clopidogrel. The transitional probabilities, however, were mostly based on published studies. Analysis based on a prospective randomized clinical study, comparing all the treatment strategies included in this study, is warranted to confirm our findings. DISCLOSURES: No outside funding supported this study. The authors have no conflicts of interest to declare. Study concept and design were contributed by Okere and Diaby. Ezendu took the lead in data collection, along with Okere. Data interpretation was performed by all the authors. The manuscript was written by Okere, Diaby, and Berthe and revised by Okere and Diaby.

Anti-platelet effects of epigallocatechin-3-gallate in addition to the concomitant aspirin, clopidogrel or ticagrelor treatment.

BACKGROUND/AIMS: Although epigallocatechin-3-gallate (EGCG), which is found in high contents in the dried leaves of green tea, has been reported to have an anti-platelet effect, synergistic effects of EGCG in addition to current anti-platelet medications remains to be elucidated. METHODS: Blood samples were obtained from 40 participants who took aspirin (ASA, n = 10), clopidogrel (CPD, n = 10), ticagrelor (TCG, n = 10) and no anti-platelet medication (Control, n = 10). Ex vivo platelet aggregation and adhesion under various stimulators were analyzed by multiple electrode aggregometry (MEA) and Impact-R systems. PAC-1 and P-selectin expressions in human platelets were analyzed by flow cytometry. RESULTS: In MEA analysis, adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP)-induced platelet aggregations were lower in the CPD and the TCG groups; arachidonic acid (AA)-induced platelet aggregation was lower in the ASA group, whereas collagen (COL)-induced platelet aggregations were comparable among four groups. EGCG significantly reduced ADP- and COL-induced platelet aggregation in dose-dependent manner (ADP, p = 0.04; COL, p < 0.01). There were no additional suppressions of platelet aggregation stimulated by AA in the ASA group, and by ADP in the CPD and TCG groups. Moreover, EGCG suppressed shear stress-induced platelet adhesion on Impact-R, and had no effect on P-selectin and PAC-1 expressions. CONCLUSIONS: Ex vivo treatment of EGCG inhibited platelet adhesion and aggregation without changes in P-selectin and PAC-1 expression. There was no additional suppressions in platelet aggregation stimulated by AA in the ASA group and ADP in the CPD and TCG groups.

Clopidogrel Therapy in Patients with Cardiovascular Disease Undergoing Transurethral Resection of the Prostate: A Step Towards Individualization.

OBJECTIVES: The objective of this study was to test platelet function pre- and peri-operatively in clopidogrel-treated patients undergoing transurethral resection of the prostate. METHODS: This was a pilot study involving 20 male patients treated with clopidogrel (75 mg/day) for the secondary prevention of cardiovascular disease and scheduled for elective transurethral resection of the prostate. Platelet function testing with light transmittance aggregometry in platelet-rich plasma of four samples (T0, T1, T2, and T3 drawn on the same day, 3 and 7 days of clopidogrel cessation and 24-h post-operatively, respectively) was performed and evaluated in each patient. P-selectin membrane expression was evaluated using monoclonal antibodies. RESULTS: The platelet response to adenosine diphosphate 5 µΜ and 20 µΜ at T0 were 42 ± 15 and 60 ± 14%, respectively. After discontinuation of clopidogrel, corresponding maximum aggregation values at T1 were 60 ± 16 and 74 ± 14%, and increased to 69 ± 16 and 79 ± 18% at T2. No significant difference in platelet aggregation values were noted between T1 and T2, while similar aggregation values were recorded at T3. CONCLUSIONS: Our findings indicate that in patients undergoing transurethral resection of the prostate, platelet activation is similar 3 and 7 days from clopidogrel cessation. These results may be of relevance in subjects at increased thrombotic risk prior to a surgical procedure carrying a high-bleeding risk.

Intramuscular hematoma with motor weakness after trigger point injection: A case report.

RATIONALE: Although trigger point injection is known as an easy and low-risk procedure, it is contraindicated to patients with hemorrhagic disorders or who regularly take anticoagulants/antiplatelets. However, taking clopidogrel is not a defined contraindication to this low-risk procedure. PATIENT CONCERNS: The chief complaint of a 76-year old woman regularly taking clopidogrel was low back and left buttock pain which prolonged for several years. DIAGNOSES: The patient was diagnosed with L4-5 and L5-S1 spinal stenosis at the orthopedics department and was referred for lumbar spinal epidural steroid injection. INTERVENTION: She was treated with trigger point injection. OUTCOMES: Three hours after the injection, she complained motor weakness and pain in the injection area. A hematoma on left gluteus medium muscle was detected with ultrasonography and ultrasound-guided needle aspiration was accomplished to relieve the symptom. LESSONS: Trigger point injection for patients taking clopidogrel should be done with a caution to prevent such complication.

Effects of Dual-Dose Clopidogrel, Clopidogrel Combined with Tongxinluo Capsule, and Ticagrelor on Patients with Coronary Heart Disease and CYP2C19*2 Gene Mutation After Percutaneous Coronary Interventions (PCI).

BACKGROUND In recent years, genetic factors have attracted research interest as important predisposing factors for cardiovascular susceptibility. This study aimed to investigate the influences of dual-dose clopidogrel, clopidogrel combined with tongxinluo, and ticagrelor on the platelet activity and MACE events of patients with CYP2C19*2 gene function deficiency and poor clopidogrel response after PCI. MATERIAL AND METHODS We selected 458 patients with coronary heart disease undergoing PCI, and the genotype of CYP2C19*2 was detected by TaqMan real-time PCR. We finally enrolled 212 patients and divided them into 4 groups: a standard anti-platelet group of 46 patients, a clopidogrel double-dose group of 50 cases, a clopidogrel combined with tongxinluo group of 59 cases, and a ticagrelor group of 57. The platelet inhibition rate was detected by TEG. We analyzed and compared differences in platelet activity and the occurrence of MACE events in these 4 groups at different follow-up times. RESULTS The results showed that inhibition of platelet aggregation was better in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group than in the regular-dose clopidogrel group, and ticagrelor was the best. We also found that the total incidence of MACE was much lower in the double-dose clopidogrel group, the clopidogrel combined with tongxinluo group, and the ticagrelor group, while the incidence of hemorrhage in the ticagrelor group was higher. CONCLUSIONS Adjusting the dose or combining with other drugs improves the efficacy of anti-platelet therapy and reduces the incidence of ischemic events after PCI.

Add-on Antiplatelet Effects of Eicosapentaenoic Acid With Tailored Dose Setting in Patients on Dual Antiplatelet Therapy.

The aim of this study was to investigate the antiplatelet effects of eicosapentaenoic acid (EPA) at a sufficient dose following coronary stent implantation. Thirty-one patients on dual antiplatelet therapy with aspirin and clopidogrel were treated with highly purified EPA-E (Epadel®) for 12 weeks. Based on our previous study, patients with a high baseline EPA/arachidonic acid (AA) ratio (≥ 0.37; n = 11) were given a standard dose (1800 mg daily) of EPA-E, whereas those with a low EPA/AA ratio (< 0.37; n = 20) were given a high dose (2700 mg daily) to reach the target value of > 0.92. Platelet function was then evaluated with agonist-induced aggregation using light transmittance aggregometry and VerifyNow®. After EPA-E treatment, the EPA/AA ratio significantly increased from 0.28 to 1.31 (P < 0.001). Collagen (1, 2, and 4 µg/mL)-induced maximal platelet aggregation (MPA) was significantly suppressed after EPA-E administration (from 28.0 to 24.0, P = 0.033; from 44.0 to 40.0, P = 0.016; from 60.0 to 56.0, P = 0.010; respectively). However, there were no changes in MPA induced by adenosine diphosphate and AA and in P2Y12 reaction units (PRU) and aspirin reaction units. After EPA-E treatment, PRU was significantly suppressed in 8 patients showing high on-treatment platelet reactivity (HTPR) (baseline 305; 266-321 versus on-treatment 256; 233-261, P = 0.012), but not in those without HTPR (201; 156-220 versus 183; 159-233, P = 0.212). In conclusion, EPA treatment at a sufficient dose suppressed platelet aggregation and showed possible add-on effects in patients with clopidogrel hyporesponsiveness.

Development of Novel High Density Gastroretentive Multiparticulate Pulsatile Tablet of Clopidogrel Bisulfate Using Quality by Design Approach.

Myocardial infarction, i.e., heart attack, is a fatal condition which is on the increase all over the world. It is reported that a large number of heart attack occur in morning hours which are attributable to platelet aggregation. Chronotherapy at this stage can be crucial. Clopidogrel bisulfate (CLB) is an antiplatelet agent and has become a drug of choice for prevention of heart attack. It is soluble in acidic pH and has a narrow absorption window. So, its long residence time in stomach is desirable. Therefore, a novel high density tablet was developed comprising multiparticulate pellets with pulsatile release necessary to maintain chronotherapy of heart attack. The pellets were prepared by extrusion-spheronization and coated in fluidized bed processor with different coating material to achieve pulsatile release. The size, shape of pellets, and drug release were evaluated. High density tablet containing coated pellets was formulated and evaluated for retention in stomach. Quality by design tools was used to design and optimize the processes. Timed release observed by dissolution study showed lag time of 6 h followed by burst release of drug up to 94% in 1 h. Density of tablets was found to be 2.2 g cm-3 which is more than gastric fluid. In vivo x-ray studies in rabbit revealed 8 h of gastric retention of tablet at the bottom of the stomach. Thus, CLB high density pulsatile system looks to open up a window of opportunity for developing formulations with drugs that are stable in gastric region and needed chronotheraupetic activity.