[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.

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.

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.

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.

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.

Comparative Effectiveness and Safety Analysis of Dual Antiplatelet Therapies Within an Integrated Delivery System.

BACKGROUND: Dual antiplatelet therapy is a mainstay of care for percutaneous coronary intervention (PCI) patients; however, uncertainty exists in real-world practice about comparative effectiveness and safety outcomes. OBJECTIVE: To evaluate outcomes of different oral P2Y12 inhibitors in PCI patients. METHODS: We retrospectively studied patients treated between July 1, 2010, and December 31, 2013. Patients received clopidogrel, prasugrel, ticagrelor, or more than 1 antiplatelet (switch) during PCI. Outcomes were evaluated for major adverse cardiovascular events (MACE) and bleeding at 1 year. Propensity score matching with Cox proportional hazards analysis was used to determine predictors of MACE and bleeding. RESULTS: A total of 8127 patients were included: clopidogrel (n = 6872), prasugrel (n = 605), ticagrelor (n = 181), and switch (n = 469). Treatment with prasugrel was associated with the lowest risk of MACE using multivariate regression (odds ratio [OR] = 0.57; 95% CI = 0.36-0.92; P = 0.02). In the propensity score-matched analysis, only the prasugrel group was associated with a lower risk of MACE compared with the clopidogrel group. Clopidogrel was associated with the lowest risk of major bleeding using multivariate regression (OR = 0.64; 95% CI = 0.42-0.98; P = 0.042). Both ticagrelor (hazard ratio [HR] = 2.00; 95% CI = 1.11-3.59) and the switch groups (HR = 1.65; 95% CI = 1.09-2.50) were associated with a greater risk of major bleeding compared with clopidogrel. However, no differences were found in the propensity score-matched analysis. CONCLUSIONS: Dual antiplatelet therapies differed in both MACE and bleeds in a real-world setting of PCI. Prasugrel was associated with fewer MACE, whereas clopidogrel had fewer major bleeding events.

Clinically significant bleeding with low-dose rivaroxaban versus aspirin, in addition to P2Y12 inhibition, in acute coronary syndromes (GEMINI-ACS-1): a double-blind, multicentre, randomised trial.

BACKGROUND: Dual antiplatelet therapy (DAPT), aspirin plus a P2Y12 inhibitor, is the standard antithrombotic treatment following acute coronary syndromes. The factor Xa inhibitor rivaroxaban reduced mortality and ischaemic events when added to DAPT, but caused increased bleeding. The safety of a dual pathway antithrombotic therapy approach combining low-dose rivaroxaban (in place of aspirin) with a P2Y12 inhibitor has not been assesssed in acute coronary syndromes. We aimed to assess rivaroxaban 2·5 mg twice daily versus aspirin 100 mg daily, in addition to clopidogrel or ticagrelor (chosen at investigator discretion before randomisation), for patients with acute coronary syndromes started within 10 days after presentation and continued for 6-12 months. METHODS: In this double-blind, multicentre, randomised trial (GEMINI-ACS-1) done at 371 clinical centres in 21 countries, eligible patients were older than 18 years with unstable angina, non-ST segment elevation myocardial infarction (NSTEMI) or ST segment elevation myocardial infarction (STEMI), with positive cardiac biomarkers and either ischaemic electrocardiographic changes or an atherosclerotic culprit lesion identified during angiography. Participants were randomly assigned (1:1) within 10 days after admission for the index acute coronary syndromes event to either aspirin or rivaroxaban based on a computer-generated randomisation schedule. Randomisation was balanced by using randomly permuted blocks with size of four and was stratified based on the background P2Y12 inhibitor (clopidogrel or ticagrelor) intended to be used at the time of randomisation. Investigators and patients were masked to treatment assignment. Patients received a minimum of 180 days of double-blind treatment with rivaroxaban 2·5 mg twice daily or aspirin 100 mg daily. The choice of clopidogrel or ticagrelor during trial conduct was not randomised and was based on investigator preference. The primary endpoint was thrombolysis in myocardial infarction (TIMI) clinically significant bleeding not related to coronary artery bypass grafting (CABG; major, minor, or requiring medical attention) up to day 390. Primary analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT02293395. FINDINGS: Between April 22, 2015, and Oct 14, 2016, 3037 patients with acute coronary syndromes were randomly assigned; 1518 to receive aspirin and 1519 to receive rivaroxaban. 1704 patients (56%) were in the ticagrelor and 1333 (44%) in the clopidogrel strata. Median duration of treatment was 291 days (IQR 239-354). TIMI non-CABG clinically significant bleeding was similar with rivaroxaban versus aspirin therapy (total 154 patients [5%]; 80 participants [5%] of 1519 vs 74 participants [5%] of 1518; HR 1·09 [95% CI 0·80-1·50]; p=0·5840). INTERPRETATION: A dual pathway antithrombotic therapy approach combining low-dose rivaroxaban with a P2Y12 inhibitor for the treatment of patients with acute coronary syndromes had similar risk of clinically significant bleeding as aspirin and a P2Y12 inhibitor. A larger, adequately powered trial would be required to definitively assess the efficacy and safety of this approach. FUNDING: Janssen Research & Development and Bayer AG.

The difference in association between aspirin use and other thrombocyte aggregation inhibitors and survival in patients with colorectal cancer.

BACKGROUND: Several studies have suggested that the association between aspirin and improved cancer survival is mediated through the mechanism of aspirin as thrombocyte aggregation inhibitors (TAI). The aim of this study was to provide epidemiological evidence for this mechanism assessing the association between overall survival and the use of aspirin and non-aspirin TAI in patients with colorectal cancer. METHODS: In this observational study, data from the Netherlands Comprehensive Cancer Organisation were linked to PHARMO Database Network. Patients using aspirin or aspirin in combination with non-aspirin TAI (dual users) were selected and compared with non-users. The association between overall survival and the use of (non-)aspirin TAI was analysed using Cox regression models with the use of (non-)aspirin TAI as a time-varying covariate. RESULTS: In total, 9196 patients were identified with colorectal cancer and 1766 patients used TAI after diagnosis. Non-aspirin TAI were mostly clopidogrel and dipyridamole. Aspirin use was associated with a significant increased overall survival and hazard ratio (HR) 0.41 (95% confidence interval [CI] 0.37-0.47), and the use of non-aspirin TAI was not associated with survival of HR 0.92 (95% CI 0.70-1.22). Dual users did not have an improved overall survival when compared with patients using solely aspirin. CONCLUSIONS: Aspirin use after diagnosis of colorectal cancer was associated with significantly lower mortality rates and this effect remained significant after adjusting for potential confounders. No additional survival benefit was observed in patients using both aspirin and another TAI.

CYP2C19 LOF and GOF-Guided Antiplatelet Therapy in Patients with Acute Coronary Syndrome: A Cost-Effectiveness Analysis.

PURPOSE: This study aimed to examine the cost-effectiveness of CYP2C19 loss-of-function and gain-of-function allele guided (LOF/GOF-guided) antiplatelet therapy in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). METHODS: A life-long decision-analytic model was designed to simulate outcomes of three strategies: universal clopidogrel (75 mg daily), universal alternative P2Y12 inhibitor (prasugrel 10 mg daily or ticagrelor 90 mg twice daily), and LOF/GOF-guided therapy (LOF/GOF allele carriers receiving alternative P2Y12 inhibitor, wild-type patients receiving clopidogrel). Model outcomes included clinical event rates, quality-adjusted life-years (QALYs) gained and direct medical costs from perspective of US healthcare provider. RESULTS: Base-case analysis found nonfatal myocardial infarction (5.62%) and stent thrombosis (1.2%) to be the lowest in universal alternative P2Y12 inhibitor arm, whereas nonfatal stroke (0.72%), cardiovascular death (2.42%), and major bleeding (2.73%) were lowest in LOF/GOF-guided group. LOF/GOF-guided arm gained the highest QALYs (7.5301 QALYs) at lowest life-long cost (USD 76,450). One-way sensitivity analysis showed base-case results were subject to the hazard ratio of cardiovascular death in carriers versus non-carriers of LOF allele and hazard ratio of cardiovascular death in non-carriers of LOF allele versus general patients. In probabilistic sensitivity analysis of 10,000 Monte Carlo simulations, LOF/GOF-guided therapy, universal alternative P2Y12 inhibitor, and universal clopidogrel were the preferred strategy (willingness-to-pay threshold = 50,000 USD/QALY) in 99.07%, 0.04%, and 0.89% of time, respectively. CONCLUSIONS: Using both CYP2C19 GOF and LOF alleles to select antiplatelet therapy appears to be the preferred antiplatelet strategy over universal clopidogrel and universal alternative P2Y12 inhibitor therapy for ACS patients with PCI.

Trial design: Rivaroxaban for the prevention of major cardiovascular events after transcatheter aortic valve replacement: Rationale and design of the GALILEO study.

BACKGROUND: Optimal antithrombotic treatment after transcatheter aortic valve replacement (TAVR) is unknown and determined empirically. The direct factor Xa inhibitor rivaroxaban may potentially reduce TAVR-related thrombotic complications and premature valve failure. DESIGN: GALILEO is an international, randomized, open-label, event-driven, phase III trial in more than 1,520 patients without an indication for oral anticoagulation who underwent a successful TAVR (ClinicalTrials.govNCT02556203). Patients are randomized (1:1 ratio), 1 to 7days after a successful TAVR, to either a rivaroxaban-based strategy or an antiplatelet-based strategy. In the experimental arm, subjects receive rivaroxaban (10mg once daily [OD]) plus acetylsalicylic acid (ASA, 75-100mg OD) for 90days followed by rivaroxaban alone. In the control arm, subjects receive clopidogrel (75mg OD) plus ASA (as above) for 90days followed by ASA alone. In case new-onset atrial fibrillation occurs after randomization, full oral anticoagulation will be implemented with maintenance of the original treatment assignment. The primary efficacy end point is the composite of all-cause death, stroke, myocardial infarction, symptomatic valve thrombosis, pulmonary embolism, deep venous thrombosis, and systemic embolism. The primary safety end point is the composite of life-threatening, disabling, and major bleeding, according to the Valve Academic Research Consortium definitions. CONCLUSIONS: GALILEO will test the hypothesis that a rivaroxaban-based antithrombotic strategy reduces the risk of thromboembolic complications post-TAVR with an acceptable risk of bleeding compared with the currently recommended antiplatelet therapy-based strategy in subjects without need of chronic oral anticoagulation.

Do practice gaps exist in evidence-based medication prescription at hospital discharge in patients undergoing coronary artery bypass surgery & coronary angioplasty?

BACKGROUND & OBJECTIVES: Prescription patterns of guideline-directed medical therapy (GDMT) after coronary artery bypass surgery [coronary artery bypass graft (CABG)] and percutaneous coronary intervention (PCI) at hospital discharge are often not optimal. In view of scarce data from the developing world, a retrospective analysis of medication advice to patients following CABG and PCI was conducted. METHODS: Records of 5948 patients (post-PCI: 5152, post-CABG: 796) who underwent revascularization from 2010 to 2014 at a single tertiary care centre in north India were analyzed. RESULTS: While age and gender distributions were similar, diabetes and stable angina were more frequent in CABG group. Prescription rates for aspirin 100 per cent versus 98.2 per cent were similar, while beta-blockers (BBs, 95.2 vs 90%), statins (98.2 vs 91.6%), angiotensin-converting enzyme inhibitors (89.4 vs 41.4%), nitrates (51.2 vs 1.1%) and calcium channel blockers (6.6 vs 1.6%) were more frequently prescribed following PCI. Despite similar baseline left ventricular ejection fraction (48.1 vs 51.1%), diuretics were prescribed almost universally post-CABG (98.2 vs 10.9%, P<0.001). Nearly all (94.4%) post-CABG patients received a prescription for clopidogrel. Patients undergoing PCI were much more likely to receive higher statin dose; 40-80 mg atorvastatin (72 vs <1%, P<0.001) and a higher dose of BB. INTERPRETATION & CONCLUSIONS: Significant differences in prescription of GDMT between PCI and CABG patients existed at hospital discharge. A substantial proportion of post-CABG patients did not receive BB and/or statins. These patients were also less likely to receive high-dose statin or optimal BB dose and more likely to routinely receive clopidogrel and diuretics. Such deviations from GDMT need to be rectified to improve quality of cardiac care after coronary revascularization.

A systematic review of anti-thrombotic therapy in epistaxis.

There is limited guidance available to clinicians regarding the management of antithrombotic therapy during epistaxis, whilst there has been an increase in the use of anticoagulation and antiplatelet therapy. In addition, the introduction of direct oral anticoagulants (DOACs), such as dabigatran and rivaroxaban, over the last decade has significantly increased the complexity of managing the anticoagulated epistaxis patient. We undertook a systemic literature review investigating potential management strategies for each class of anti-thrombotic therapy during epistaxis. A PubMED and Cochrane Library search was performed on 10/03/16 using, but not limited to, the search terms epistaxis, nosebleed, nose bleeding, nasal haemorrhage, nasal bleeding AND each of the following search terms: antithrombotic, anticoagulant, antiplatelet, aspirin, clopidogrel, warfarin, dabigatran, rivaroxaban, apixaban and tranexamic acid. This yielded 3815 results, of which 29 were considered relevant. Other sources such as national and international guidelines related to the management of anti-thrombotics were also utilised. We present the findings related to the management of each class of anti-thrombotic therapy during epistaxis. Overall we found a lack of evidence regarding this topic and further high quality research is needed. This is an area growing in complexity and the support of colleagues in Haematology and Cardiology is increasingly important.

Effect of Ginkgo Biloba Extract on the Pharmacokinetics and Metabolism of Clopidogrel in Rats.

Ginkgo biloba extract (GBE), a traditional herbal product used worldwide as both medicine and supplement, is often supplied with clopidogrel for the treatment of cerebrovascular diseases. The aim of the current study was to explore the effect of GBE on the metabolism and pharmacokinetics of clopidogrel. The in vitro study using rat liver microsomes revealed that GBE significantly induced the conversion of clopidogrel into its active metabolite. The effect of GBE on the pharmacokinetics of clopidogrel was also investigated in vivo. Compared to rats without GBE pretreatment, administration of 4 mg/kg, 20 mg/kg, and 100 mg/kg of GBE significantly decreased the Cmax and the AUC0-∞ of clopidogrel in a dose-dependent manner. As expected, pretreatment of high dose GBE significantly increased the Cmax and AUC0-∞ of the clopidogrel active metabolite. However, no marked change was observed following medium and low dose of GBE, suggesting that the biotransformation of clopidogrel was altered differently by high dose of GBE. Our study suggested that the awareness of the potential herb-drug interactions between GBE and clopidogrel should be increased in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.