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Ticlopidine exerts its anti-platelet effects mainly by antagonizing platelet p2y12 receptors. Previously, a few studies have shown that ticlopidine can induce liver injury, but the exact mechanism of hepatotoxicity remains unclear. Oxidative stress, metabolic disorders, hepatocyte apoptosis, lipid peroxidation, and inflammatory responses can all lead to hepatic liver damage, which can cause hepatotoxicity. In this study, in order to deeply explore the potential molecular mechanisms of ticlopidine -induced hepatotoxicity, we used zebrafish as a model organism to comprehensively evaluate the hepatotoxicity of ticlopidine and its associated mechanism. Three days post-fertilization, zebrafish larvae were exposed to varying concentrations (1.5, 1.75 and 2 μg/mL) of ticlopidine for 72 h, in contrast, adult zebrafish were exposed exposure to 4 μg/mL of ticlopidine for 28 days. Ticlopidine-exposed zebrafish larvae showed changes in liver morphology, shortened body length, and delayed development of the swim bladder development. Liver tissues of ticlopidine-exposed zebrafish larvae and adults stained with Hematoxylin & Eosin revealed vacuolization and increased cellular interstitial spaces in liver tissues. Furthermore, using Oil Red O and periodic acid-Schiff staining methods and evaluating different metabolic enzymes of ticlopidine-exposed zebrafish larvae and adults suggested abnormal liver metabolism and liver injury in both ticlopidine-exposed zebrafish larvae and adults. Ticlopidine also significantly elevated inflammation and oxidative stress and reduced hepatocyte proliferation. During the rescue intervention using N-acetylcysteine, we observed significant improvement in ticlopidine-induced morphological changes in the liver, shortened body length, delayed swim bladder development, and proliferation of liver tissues showed significant improvement. In conclusion, ticlopidine might inhibit normal development and liver proliferation in zebrafish by upregulation of oxidative stress levels, thus leading to embryonic developmental toxicity and hepatotoxicity. In this study, we used zebrafish as a model organism to elucidate the developmental toxicity and hepatotoxicity induced by ticlopidine upregulation of oxidative stress signaling pathway in zebrafish, providing a theoretical basis for clinical application. • The administration of Ticlopidine, a potent platelet aggregation inhibitor, induces hepatic injury. • Exposure to Ticlopidine leads to increased oxidative stress, associated with phenotypic changes observed in zebrafish. • Exposure to ticlopidine in zebrafish larvae led to reduced hepatic cellular proliferation. • Administration of the antioxidant N-acetylcysteine can rescue the adverse phenotype resulting from ticlopidine exposure. [ABSTRACT FROM AUTHOR]

Taking 12 -N-p -chlorobenzyl sophoridinol 2 as a lead, a series of novel sophoridinic derivatives with various 3′-substituents at the 11–side chain were synthesized and evaluated for their anticancer activity from sophoridine ( 1 ), a natural antitumor medicine. Among them, the sophoridinic ketones 5a – b , alkenes 7a – b and sophoridinic amines 14a – b displayed reasonable antiproliferative activity with IC 50 values ranging from 3.8 to 5.4 μmol/L. Especially, compounds 5a and 7b exhibited an equipotency in both adriamycin (AMD)-susceptible and resistant MCF-7 breast carcinoma cells, indicating a different mechanism from AMD. The primary mechanism of action of 5a was to arrest the cell cycle at the G0/G1 phase, consistent with that of parent compound 1 . Thus, we consider 12-chlorobenzyl sophoridinic derivatives with a tricyclic scaffold to be a new class of promising antitumor agents with an advantage of inhibiting drug-resistant cancer cells. [ABSTRACT FROM AUTHOR]

Objectives: As the prevalence of peripheral artery disease (PAD) increases there is growing concern about the associated healthcare burden. This burden has not been well-characterized in high-risk patients with concurrent diabetes and/or acute coronary syndrome (ACS). The objective of this analysis was to assess comorbidities, medication use, outcomes, services and costs for 3 high-risk symptomatic PAD groups.Methods: This retrospective longitudinal analysis used the MarketScan Commercial Claims and Encounters Database (2005-2013). The 3 high-risk symptomatic PAD groups were (1) symptomatic PAD with/without diabetes, (2) symptomatic PAD with/without prior ACS, and (3) symptomatic PAD with/without diabetes and prior ACS. The study time frame was a period of 1-year before the earliest date of a symptomatic PAD record and 3 years post.Results: In all, 16,663 symptomatic PAD patients were identified across the three risk groups. Mean age ranged from 66.4-67.4 years; the majority (55.0%-63.3%) were men. At 3 years post index, patients with symptomatic PAD and a risk factor had significantly higher use of beta-blockers, ACE inhibitors and statins (P<0.0007), and higher rates of all-cause and symptomatic PAD-related medical services, diagnoses and procedures (P<0.05). Clopidogrel and statins were used by ≤ 41.2% and ≤ 66.7% of symptomatic PAD patients without risk, respectively, and ≤ 68.9% and ≤ 80.2% of patients with risks. All cause and symptomatic PAD-related treatment costs (P<0.0001) were higher for symptomatic PAD patients with risks versus patients without risks where annualized all-cause cost differences ranged from $7,482 to $13,504 and annualized PAD-related cost differences ranged from $605 to $1,997.Conclusions: Symptomatic PAD patients with diabetes and/or prior ACS have significantly higher medical resource use and costs compared to symptomatic PAD patients without these risk factors. The utilization rate of secondary prevention therapies is suboptimal; therefore, greater effort must be made to increase utilization and optimize treatment to minimize the impact of symptomatic PAD. [ABSTRACT FROM AUTHOR]

Background: Nonsustained ventricular tachycardia (NSVT) is common after acute coronary syndrome (ACS) and a marker of increased risk of arrhythmogenic death. However, the prognostic significance of NSVT when evaluated with other contemporary risk markers and at later time points after ACS remains uncertain.Methods and Results: In the Platelet Inhibition and Patient Outcomes (PLATO) trial, continuous ECGs were performed during the first 7 days after ACS (n=2866) and repeated for another 7 days at day 30 (n=1991). Median follow-up was 1 year. There was a time-varying interaction between NSVT and cardiovascular death such that NSVT was significantly associated with increased risk within the first 30 days after randomization (22/999 [2.2%] versus 16/1825 [0.9%]; adjusted hazard ratio, 2.84; 95% confidence interval, 1.39-5.79; P=0.004) but not after 30 days (28/929 [3.0%] versus 42/1734 [2.4%]; P=0.71). Detection of NSVT during the convalescent phase (n=428/1991; 21.5%) was also associated with an increased risk of cardiovascular death, and was most marked within the first 2 months after detection (1.9% versus 0.3%; adjusted hazard ratio, 5.48; 95% confidence interval, 1.07-28.20; P=0.01), and then decreasing over time such that the relationship was no longer significant by ≈5 months after ACS.Conclusions: NSVT occurred frequently during the acute and convalescent phases of ACS. The risk of cardiovascular death associated with NSVT was the greatest during the first 30 days after presentation; however, patients with NSVT detected during the convalescent phase were also at a significantly increased risk of cardiovascular death that persisted for an additional several months after the index event.Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT00391872. [ABSTRACT FROM AUTHOR]

Objective: Appendix 1 Statements of knowledge of correct medication use Appendix 2 Statements of self-efficacy of correct medication use Appendix 3 Statements of skills of correct medication use To characterize the experiences and feasibility of offering pharmacogenetic (PGx) testing in a community pharmacy setting.Design: Pharmacists were invited to complete a survey about PGx testing for each patient who was offered testing. If the patient consented, pharmacists were also asked to complete a follow-up survey about the process of returning PGx testing results to patients and follow-up with the prescribing provider.Setting: Community pharmacies in North Carolina from August through November 2014.Participants: Pharmacists at five community pharmacies.Main Outcome Measures: Patient consent for testing, time to introduce PGx testing initially and communicate results, interpretation of test results, and recommended medication changes.Results: Of the 69 patients offered testing, 56 (81%) consented. Pre-test counseling typically lasted 1-5 minutes (81%), and most patients (55%) did not have any questions about the testing. Most pharmacists reported test results to patients by phone (84%), with discussions taking less than 1 minute (48%) or 1-5 minutes (52%). Most pharmacists believed the patients understood their results either very well (54%) or somewhat well (41%). Pharmacists correctly interpreted 47 of the 53 test results (89%). All of the incorrect interpretations were for patients with test results indicating a dosing or drug change (6/19; 32%). Pharmacists reported contacting the ordering physician for four patients to discuss results indicating a dosage or drug change.Conclusion: The provision of PGx services in a community pharmacy setting appears feasible, requiring little additional time from the pharmacist, and many patients seem interested in PGx testing. Additional training may be necessary to improve test result interpretation, as well as for communication with both patients and ordering physicians. [ABSTRACT FROM AUTHOR]

Objectives: Randomised trials have shown the efficacy of antiplatelet therapy with cilostazol to prevent secondary ischaemic stroke. Recently, cilostazol has been reported to prevent the development and/or recurrence of atrial fibrillation (AF), which can potentially prevent cardioembolic stroke in patients undergoing antiplatelet therapy. Herein, we examined the impact of prior antiplatelet therapy with cilostazol on the incidence of cardioembolic stroke, which had not been fully investigated. Methods: Using the multicenter retrospective study of stroke risk in antithrombotic therapy (RESTATE) database, we analysed consecutive patients with primary or secondary stroke under single antiplatelet therapy. We evaluated the characteristics of ischaemic stroke based on the type of antiplatelet agent used: aspirin, ticlopidine/clopidogrel or cilostazol. Results: Of 1069 consecutive patients with primary or secondary stroke during antithrombotic therapy from January to December 2012, 615 patients received single antiplatelet therapy (293 and 322 cases of primary and secondary strokes, respectively). Interestingly, the percentage of cardioembolic infarction was significantly lower in patients taking cilostazol compared with other agents. Multivariate regression analysis found that age (OR: 1.03, 95% CI: 1.01-1.06, P = 0.0029), serum creatinine (OR: 1.17, 95% CI: 1.03-1.34, P = 0.0198), aspirin (OR: 1.75, 95% CI: 1.00-3.22, P = 0.0486), cilostazol (OR: 0.19, 95% CI: 0.03-0.73, P = 0.0125), and smoking (OR: 1.86, 95% CI: 1.16-2.94, P = 0.0102) were independently associated with cardioembolic stroke. Conclusions: Cilostazol may prevent cardioembolic stroke in patients undergoing antiplatelet therapy. This could be a novel strategy for cardioembolic stroke prevention potentially by affecting cardiac remodelling, in contrast to secondary anticoagulant therapy. [ABSTRACT FROM AUTHOR]

Many drugs have been reported to induce lupus in a minority of patients. Ticlopidine hydrochloride inhibits platelet aggregation and is widely used for the prevention of thrombosis. There have been only a few reports of ticlopidine-induced lupus. Here, we review 13 previously reported cases and describe the case of a 71-year-old man with ticlopidine-induced subacute cutaneous lupus erythematosus. His diagnosis was supported by the appearance of papulosquamous skin lesions on sun-exposed areas and detectable anti-Ro/SS-A antibodies, shortly after drug initiation as well as the gradual resolution of these symptoms after the discontinuation of ticlopidine. Our case highlights that when a patient presents with subacute cutaneous lupus erythematosus-like skin lesions, ticlopidine should be considered as a potential causative agent. [ABSTRACT FROM AUTHOR]

Background: Clopidogrel is sometimes substituted for ticlopidine when cerebrovascular or cardiovascular patients develop hematologic abnormalities after ticlopidine treatment. However, the adverse event rate after the substitution to clopidogrel remains undetermined. Therefore, in this study, we aimed to define the risk of adverse events after substituting clopidogrel for ticlopidine without a washout period. Methods: We prospectively enrolled patients older than 20 years who had a history of noncardioembolic strokes, including transient ischemic attacks, were treated with ticlopidine for at least 6 months. This study was conducted from August 26, 2008, when the first patient was enrolled, to January 16, 2012, the date of the last patient examination, at 8 active stroke centers in Hiroshima, Japan. We excluded patients who had severe disabilities, evidence of cardioembolic stroke, or history of a bleeding event. Each patient received clopidogrel (either 50 mg or 75 mg) once a day in place of ticlopidine without a washout period. Follow-up exams were scheduled within 12 months after the medication substitution. The primary end point of this study was adverse events of interest, including clinically significant reduced blood cell counts, hepatic dysfunction, bleeding, and other serious side effects. Results: In this study, 110 patients were enrolled and analyzed in an intent-to-treat manner (modified intent to treat). Within the scheduled follow-up periods, 9 primary end point events were observed in separate patients. The primary end point events were observed at a rate of 8.4% per year (Kaplan–Meier method). At the time of enrolment, 16 patients met the exclusion criteria, of which 8 recovered from their abnormal hematologic results to the institutional normal limit after the substitution of ticlopidine for clopidogrel (57.4% per year). Conclusions: The adverse event rates after the substitution of ticlopidine for clopidogrel is similar to the adverse event rates of patients who were initially treated with clopidogrel. The substitution of clopidogrel for ticlopidine should be considered for patients who develop hematologic abnormalities from ticlopidine treatment. [Copyright &y& Elsevier]

Abstract: Transient receptor potential A1 (TRPA1) is widely expressed throughout the human and animal organism, including the dorsal root ganglia as well as the bladder, stomach and small intestine. Here, we examined the effect of three platelet aggregation inhibitors on TRPA1: ticlopidine, clopidogrel and prasugrel. Utilising fluorometric Ca2+ influx analysis and electrophysiological whole cell measurements in TRPA1-expressing HEK293 and in human enterochromaffin-like QGP-1 cells, we found that ticlopidine, clopidogrel and prasugrel are direct activators of TRPA1. Although this polymodal channel commonly contributes to the perception of pain, temperature and chemical irritants, recent studies provide evidence for its involvement in the release of serotonin (5-HT) from enterochromaffin cells. Therefore, we further investigated the ability of ticlopidine, clopidogrel and prasugrel to stimulate 5-HT release from QGP-1 cells. We could determine 5-HT in supernatants from cultured QGP-1 cells upon treatment with ticlopidine and clopidogrel but not with prasugrel. These findings indicate that a robust TRPA1 activation by ticlopidine and clopidogrel correlates with the stimulatory effect on the secretion of 5-HT. As recipients of ticlopidine and clopidogrel frequently complain about gastrointestinal adverse events such as nausea, vomiting and diarrhoea, an activation of TRPA1 may contribute to adverse effects of such drugs in the digestive system. [Copyright &y& Elsevier]

There has been a tremendous boom in the arena of anticoagulant therapy recently. Although the indications for these agents reside in the noncritical care environment, over time, the impact of these agents have infiltrated the critical care environment particularly due to devastating complications with associated use. With so many newer agents on the market or coming down the pipeline, it is easy to become overwhelmed. It is important that the critical care practitioner does not ignore these agents but becomes familiar with them to better prepare for the management of patients on one or more anticoagulant agents in the intensive care unit. To equip the critical care practitioners with the knowledge about commonly used anticoagulants, we provide an extensive review of the pharmacology, indications, and adverse effects related to these agents as well as suggestions on preventing or managing complications. [ABSTRACT FROM AUTHOR]

The considerable progress in P2Y12-platelet blockers has important perioperative implications due to a family of novel agents beyond clopidogrel. Although prasugrel is more potent than clopidogrel due to more efficient hepatic metabolism, it is limited clinically by its irreversibility and bleeding risks. Ticagrelor, as the first approved direct and reversible oral P2Y12 blocker, still is limited clinically by its novel side-effect profile. Intravenous reversible P2Y12 blockade is possible now with both cangrelor and elinogrel, although both agents are still in clinical development. Furthermore, elinogrel offers the possibility of both oral and parenteral P2Y12 blockade with a single agent. Future trials likely will continue to evaluate and compare the safety and efficacy of these agents in multiple clinical settings, including the perioperative period. [ABSTRACT FROM AUTHOR]

Summary: Introduction: Cholestatic hepatitis is frequently a drug-related syndrome. We describe the case of a 57-year-old man who developed cholestatic hepatitis two months after starting therapy with ticlopidine following a carotid endarterectomy. Materials and methods: The patient presented with anorexia, nausea, and dark-colored urine. The work-up included laboratory tests and imaging studies of the liver (ultrasound and magnetic resonance imaging). The authors analyze the case using the scale developed by Maria and Victorino for the diagnosis of drug-induced hepatitis, the Naranjo algorithm for adverse drug reactions, and the RUCAM algorithm for causality assessment of hepatotoxicity. They also review data from the MedLine database on cases of ticlopidine-induced cholestatic hepatitis reported during the period 1982–2011. Results: Bilirubin, aminotransferases, alkaline phosphatases, and gamma glutamyl transpeptidase levels were elevated at admission and progressively declined after ticlopidine was discontinued. The absence of biliary obstruction at ultrasonography and magnetic resonance cholangiography, the negative results of viral and immunologic tests, and the resolution of the syndrome after discontinuation of the drug all suggested ticlopidine-induced hepatotoxicity. The assessment of this case with toxicity algorithms confirmed that a causal link to ticlopidine was “probable” or “highly probable.” The patient was treated with ursodesoxycholic acid, clopidogrel (75mg/day), and (after the laboratory parameters had normalized) rosuvastatin (10mg/day). No further clinical and laboratory abnormalities have been observed during two month follow-up. Discussion: The toxicity of ticlopidine is well established: our review revealed reports of 57 cases of ticlopidine-induced cholestatic hepatitis during the period 1982–2011. The mechanisms underlying the toxic effects of this drug are not clear, but they are probably related to the chemical structure of the drug. The syndrome is usually completely reversible with discontinuation of the drug. We stress the importance for the appropriate use of this drug and the need for adequate follow-up of patients. [Copyright &y& Elsevier]

Background: Recent studies have reported that concomitant use of Clopidogrel with proton-pump inhibitors (PPIs) might decrease antiplatelet effects and increase the risk of adverse outcomes after coronary stenting. However, little is known about the difference between Clopidogrel and ticlopidine in concomitant use with PPIs, especially within the Asian population. Methods: We retrospectively analyzed 302 consecutive patients (248 males, mean age 66 ±12 years) undergoing primary stenting for acute myocardial infarction from July 2006 to June 2010. PPIs were administered to 92% (278/302) of the patients. The patients were divided into two groups on the basis of Clopidogrel (Clopidogrel group, n = 187) or ticlopidine (ticlopidine group, n = 91 ) with PPI. Their characteristics, medications, and 30-day clinical outcomes were examined. Results: There were no significant differences in 30-day major adverse cardiac events (cardiac death, non-fatal myocardial infarction, and definite stent thrombosis), bleeding events, and stroke between the two groups. The discontinuation of Clopidogrel due to side effects was significantly less frequent than that of ticlopidine ( 1.1% vs 7.7%, p = 0.003, respectively). Conclusion: Our findings suggest that concomitant use of Clopidogrel with PPIs might be safer than ticlopidine with PPIs in patients undergoing primary stenting for acute myocardial infarction. [ABSTRACT FROM AUTHOR]

Abstract: The current antiplatelet medications in the United States are aspirin, dipyridamole, ticlopidine, clopidogrel, and the newest drug, prasugrel. Antiplatelet medications play important roles in the treatment and prevention of myocardial infarction, stent thrombosis, cerebrovascular accident, and many others. This review highlights important concepts of antiplatelet medications to help nurse practitioners understand their place in therapy, dosing, monitoring, and safety considerations and their roles in various medical conditions. [Copyright &y& Elsevier]

Summary: Background and objectives: The incidence of definite stent thrombosis (ST) after use of drug-eluting stents (DES), as defined by the Academic Research Consortium, is known to be lower in Japan than in western countries. However, a statistical difference in the incidence of early definite ST (EDST) associated with the unrestricted use of DES has not yet been documented. Therefore, the incidence of EDST in our Japanese institute after unrestricted use of DES was retrospectively compared with those reported in western mega-studies. Methods and results: During the 40 months from August 2004 to November 2007 (before approval of clopidogrel in Japan), DES were implanted in 3605 lesions in 1885 patients in our institute; lesion- and patient-associated percentages of DES use were 95.2% and 94.7%, respectively. Mean stent length per lesion was 33.2mm, emergent procedures and ST-elevation myocardial infarctions made up 33.7% and 16.4% of the procedures, respectively, intravascular ultrasonography was used 96.0% of the time, a distal protection device for acute coronary syndrome was used 68.7% of the time, and the mean maximum inflation pressure was 19.5atm. EDST was observed in five lesions (0.139%) in four patients (0.212%). The incidence of patient-associated EDST at our center was significantly lower than in four western mega-studies (0.736%, 66 of 8970 patients; 0.634%, 149 of 23,500; 0.595%, 52 of 8402; 0.997%, 20 of 2006) (p <0.05, <0.01, <0.05, <0.01, respectively, using a χ 2-test). Conclusion: Due to differences in procedural approaches in Japan, the incidence of EDST after unrestricted use of DES was significantly lower than in western countries. [Copyright &y& Elsevier]

The article focuses on a study which investigated the frequency of allergic or hematologic adverse reactions to ticlopidine in patients who have allergic or hematologic adverse reactions to clopidogrel. A review was made on medical records from 2 academic institutions to identify patients who had an allergic or hematologic adverse reaction to either two commercially available thienopyridines. It was observed that some of the patients who had an allergy to clopidogrel had a similar reaction to ticlopidine.

Ticlopidine has inhibitory effects on platelet aggregation via ADP (adenosine diphosphate), platelet release reaction and depolymerization. In clinical practice, it is commonly used to prevent heart, cerebrovascular and other thromboembolic diseases. However, ticlopidine has also been reported to have teratogenic effects on the heart, though its specific molecular mechanism remains unclear. In this study, zebrafish embryos were used as model organisms to examine the toxicity effect of ticlopidine. Zebrafish embryos exposed to 6, 7.5, and 9 mg/L ticlopidine solutions manifested several abnormalities, including body curvature, smaller eyes, slower absorption of the vitella sac, pericardial edema, slower heart rate, increased mortality, longer venous sinus - arterial ball (SV-BA) distance, and increased oxidative stress, which indicated developmental and cardiac toxicity. Abnormal expression of key genes related to heart development was observed, and the level of apoptotic gene expression was up-regulated. Further experiments revealed up-regulation of embryonic oxidative stress following ticlopidine exposure, leading to a decrease in cardiomyocyte proliferation. Conversely, the aromatic hydrocarbon receptor (AHR) inhibitor CH223191 protected embryos from the cardiotoxicity effect of ticlopidine, confirming further the role of up-regulated oxidative stress as the molecular mechanism of ticlopidine-induced cardiotoxicity in zebrafish. In conclusion, ticlopidine exposure leads to developmental and cardiotoxicity in zebrafish embryos. Therefore, further studies are warranted to ascertain such potential harms of ticlopidine in humans, which are vital in providing guidance in the safe use of drugs in clinical practice. • Ticlopidine affects early cardiac development in zebrafish, causing cardiac damage and cardiotoxicity. • Ticlopidine exposure increases oxidative stress and induces a decrease in zebrafish cardiomyocyte proliferation. • The cardiac developmental toxicity induced by ticlopidine is associated with oxidative stress. • The aromatic hydrocarbon receptor (AHR) inhibitor CH223191 can rescue the phenotype caused by ticlopidine exposure. [ABSTRACT FROM AUTHOR]

Background: Antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) reduces major cardiovascular events in patients with ST and non-ST-segment-elevation acute coronary syndromes (ACS). Recent mechanistic and clinical data suggest that higher loading and maintenance doses of clopidogrel may achieve a more rapid and greater degree of platelet inhibition that translates into improved clinical outcomes, but this is yet to be formally evaluated in an adequately powered randomized trial. Objectives: To evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. Design: Multicenter, international, randomized, 2 x 2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA (300-325 mg daily) versus low-dose ASA (75-100 mg daily) in patients with ST or non-ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients. Conclusions: The CURRENT-OASIS 7 trial will help to define optimal dosing regimens for clopidogrel and ASA in patients with ST and non-ST-segment-elevation ACS treated with an early invasive strategy. [ABSTRACT FROM AUTHOR]

Objective: To examine short- and medium-term outcomes of percutaneous coronary interventions (PCIs), with a focus on comparing drug-eluting stents (DESs) with bare-metal stents (BMSs).Design, Setting and Participants: Retrospective analysis of data from the Melbourne Interventional Group (MIG) registry, a large multicentre Australian registry. The study cohort consisted of 6364 consecutive patients undergoing 7167 PCIs between April 2004 and August 2007.Main Outcome Measures: Clinical events including death, myocardial infarction (MI), target lesion revascularisation (TLR), target vessel revascularisation (TVR) and major adverse cardiac events (MACE) (a composite of death, MI and TVR), at 30 days and at 12 months.Results: The cohort was predominantly male (74%), with a mean age of 64.7 years (SD, 12.0 years). DESs were used in 3482 (51.4%) of PCIs. In the overall cohort, rates of clinical events were low at 30 days: mortality (1.9%), MI (2.4%), TLR (2.0%), TVR (2.4%) and MACE (5.7%). At 12 months, event rates were: mortality (5.2%), MI (6.0%), TLR (5.8%), TVR (8.2%) and MACE (16.2%). Patients receiving DESs had similar mortality rates to those receiving BMSs (4.0% v 6.0%; P = 0.62 [propensity score-adjusted]); late thrombosis rates were also similar in the two groups (0.8% v 1.1%; P = 0.38). The proportion of patients receiving DESs fell significantly over time, from 54.9% in the first 24 months to 44.7% in the last 15 months of the study period (P < 0.01). Independent predictors of 12-month mortality included diabetes, renal failure, ST-segment-elevation MI and cardiogenic shock.Conclusion: Our clinical event rates were comparable with international registry outcomes. Rates of mortality and stent thrombosis were no higher in patients with DESs than those with BMSs. Although DESs were used in about half the procedures (preferentially for higher-risk lesions), recent trends suggest their use is in decline. [ABSTRACT FROM AUTHOR]

Despite the advent of drug-eluting stents in Japan, bare metal stents or conventional balloon angioplasty are still indicated in some patients needing elective percutaneous coronary intervention (PCI) and in patients with acute coronary syndrome if these patients develop side effects while taking ticlopidine. In such patients, restenosis is a problem that is difficult to diagnose. To investigate the comparative diagnostic accuracy of the exercise-stress electrocardiogram (ECG) for detecting restenosis after PCI, we measured conventional ST-segment changes and QT dispersion during exercise-stress testing in 173 patients with elective PCI (63 ± 10 years old). Exercise-stress testing was performed 3 to 6 months after successful PCI, and restenosis was confirmed by follow-up coronary angiogram. There were 98 patients with a prior myocardial infarction (prior MI group and 76 patients with no prior myocardial infarction (no MI group). Restenosis was found in 45 patients (46% in the prior MI group and 26 patients (34%) in the no MI group. Conventional ST-segment depression (>1:0 mm, J 60 ms indicating exercise-induced myocardial ischemia had a sensitivity of around 50% and a specificity of around 70% for diagnosing restenosis in both groups. In the prior MI group, QT dispersion was increased by exercise-stress testing in both patients with and without restenosis, whereas in the no MI group, QT dispersion increased only in patients with restenosis. With a cut-off value of >60 ms, QT dispersion had a sensitivity of 54% and a specificity of 68% for detecting restenosis in the no MI group; these values were comparable to those seen with conventional ST-segment changes. In conclusion, due to its low cost, exercise-stress ECG remains useful for diagnosing restenosis following PCI if the clinician understands its limited sensitivity and specificity. The presence of a prior MI must be considered when QT dispersion during exercise-stress testing is used for detecting restenosis. [Copyright &y& Elsevier]

Summary: Chronic radiation enteropathy (CRE) is an undesirable radiation-induced toxicity and a common health problem in patients with pelvic or abdominal malignancies. Damage to microvascular endothelial cells and connective tissue is blamed to cause this adverse effect. It is shown that platelets are the first cellular elements that initiate the homeostatic and inflammatory responses and release of several proinflammatory and fibrinogenic mediators. Antiplatelet agents such as ticlopidine and clopidogrel were shown to prevent CRE and this effect is believed to be directed by their activities against thrombocytes. However, recent studies have shown that these drugs also induce apoptosis in endothelial cells and may lead to decreased expression of endothelial prostacyclin and thrombomodulin (TM) and increased release of von Willebrand factor which are shown to be major contributors of coagulation process. Assuming that radiation induced apoptosis occur 6–10h after irradiation, we think that timing of these antiaggregant drugs with irradiation is important and a 6–10h interval between these may be beneficial to avoid this adverse interaction. [Copyright &y& Elsevier]

Purpose: Platelet inhibition reduces periprocedural cardiac events in patients referred to percutaneous coronary intervention (PCI). In patients with stable angina pectoris, there is no reliable evidence that pretreatment with ticlopidine (Ticlid) plus aspirin decreases adverse cardiac events compared with pretreatment with aspirin alone. This study sought to determine whether treatment with combination of aspirin plus ticlopidine prior to PCI is associated with lower incidence of adverse cardiovascular events in short-term follow-up than pretreatment with aspirin alone. Methods: In a prospective, non-randomized comparison, a total of 241 consecutive patients (163 males; 63 ± 11 years) referred to PCI for stable angina pectoris received 100 mg/d of aspirin alone (group A, 158 patients) or 100 mg/d of aspirin plus 750 mg/d of ticlopidine for at least 3 days (group B, 83 patients) before PCI. The primary end point was the incidence of troponin (T) level greater than 1.5 ng/mL 24 hours after PCI; the secondary end point was the incidence of death, myocardial infarction, ischemia-driven target vessel revascularization, symptomatic stent thrombosis, stroke, and major bleeding in the 3 months after PCI. Results: Both groups were comparable with regard to baseline clinical, angiographic, and procedural characteristics. There was no statistically significant difference in the primary end point (10.1% versus 9.6% versus). Over a follow-up period of 11 ± 5 weeks, in group A the incidence of myocardial infarction was 3.2%, repeat PCI 10.9%, and cardiac surgery 4.5%. The corresponding event rates in group B were myocardial infarction 0%, repeat PCI 12.8%, and cardiac surgery 2.6%. There were no reports of symptomatic stent thrombosis, stroke, major bleeding, of death during follow-up. There was no statistically significant difference in the secondary end point (18.6% versus 15.4%). Conclusions: In the patients referred for elective PCI for stable angina... [ABSTRACT FROM AUTHOR]

Background: Optimal upfront dual antiplatelet therapy (DAPT) duration after complex percutaneous coronary intervention (PCI) with drug-eluting stents (DES) remains unclear.Objectives: This study investigated the efficacy and safety of long-term (≥12 months) versus short-term (3 or 6 months) DAPT with aspirin and clopidogrel according to PCI complexity.Methods: The authors pooled patient-level data from 6 randomized controlled trials investigating DAPT durations after PCI. Complex PCI was defined as having at least 1 of the following features: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or chronic total occlusion. The primary efficacy endpoint was major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction, or stent thrombosis. The primary safety endpoint was major bleeding. Intention-to-treat was the primary analytic approach.Results: Of 9,577 patients included in the pooled dataset for whom procedural variables were available, 1,680 (17.5%) underwent complex PCI. Overall, 85% of patients received new-generation DES. At a median follow-up time of 392 days (interquartile range: 366 to 710 days), patients who underwent complex PCI had a higher risk of MACE (adjusted hazard ratio [HR]: 1.98; 95% confidence interval [CI]: 1.50 to 2.60; p < 0.0001). Compared with short-term DAPT, long-term DAPT yielded significant reductions in MACE in the complex PCI group (adjusted HR: 0.56; 95% CI: 0.35 to 0.89) versus the noncomplex PCI group (adjusted HR: 1.01; 95% CI: 0.75 to 1.35; pinteraction = 0.01). The magnitude of the benefit with long-term DAPT was progressively greater per increase in procedural complexity. Long-term DAPT was associated with increased risk for major bleeding, which was similar between groups (pinteraction = 0.96). Results were consistent by per-treatment landmark analysis.Conclusions: Alongside other established clinical risk factors, procedural complexity is an important parameter to take into account in tailoring upfront duration of DAPT. [ABSTRACT FROM AUTHOR]

The author comments on a study by Cheema and colleagues which examined clopidogrel hypersensitivity reactions in patients with percutaneous coronary intervention (PCI). He states that although the study shows only a 1.6 percent incidence of hypersensitivity reaction, it will pose a problem as a large number of patients are using clopidogrel. He finds it encouraging that all patients in the trial tolerated clopidogrel therapy with a course of steroids.

The author examines a study by M. J. Price and colleagues who evaluated the effect of high-dose clopidogrel as compared to the standard-dose in patients who had undergone percutaneous coronary intervention (PCI) with drug-eluting stents (DES). It mentions the study focused on patients with high on-treatment platelet reactivity, or clopidogrel non-responders. It is inferred that further trials are required in this area to determine an appropriate management strategy.

The article talks about a study conducted by Kwak and colleagues which highlights the increased risk of bleeding during coronary artery bypass graft surgery (CABG) in patients on dual anti-platelet therapy (DAPT) with aspirin and clopidogrel. It presents an assessment of platelet function to predict blood loss after offpump CABG (OPCABG), and states that the method cannot be related to all CABG surgeries or all types of platelet-function testing without further research.

DUAL-ANTIPLATELET THERAPY WITH ASPIRIN AND CLOPIDOGREL IS recommended for patients with known vascular disease or multiple risk factors for vascular disease. However, little is known about the long-term bleeding risk of such therapy. Thus, Berger and colleagues analyzed the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial to determine the frequency and time course of bleeding in dualantiplatelet- therapy patients both with and without known vascular disease. The 15,603 patients in CHARISMA were randomized to clopidogrel 75 mg/day vs. placebo; all patients took aspirin (75 to 162 mg/day). Median follow-up was 28 months. Severe bleeding (GUSTO criteria) was observed in 1.7% of the clopidogrel group vs. 1.3 % of the placebo group (p = NS). Moderate bleeding rates were 2.1% vs. 1.3%, p < 0.001. Bleeding risk was greatest in the first year on therapy. The frequency of bleeding was not related to the presence or absence of known vascular disease. Moderate bleeding was predictive of all-cause mortality (hazard ratio 2.55; 95% CI 1.71-3.80, p < 0.001); myocardial infarction (HR 2.92, 2.04-4.18, p < 0.0001), and stroke (HR 4.20, 3.05-5.77, p < 0.0001). The authors concluded that there is an increased risk of bleeding with long-term dual-antiplatelet therapy, which is greatest in the first year; bleeding is associated with increased mortality. [ABSTRACT FROM AUTHOR]