Clopidogrel is a prodrug that is converted in the liver to an active thiol metabolite, which irreversibly inhibits the platelet P2Y12 adenosine diphosphate receptor. This mechanism requires cytochrome P450 2C19 (CYP 2C19) enzyme. Proton pump inhibitors (PPIs) competes against CYP 2C19 and inhibits the conversion of clopidogrel into its active metabolite, therefore, clopidogrel-PPIs drugs interaction may exist. These interactions could result in competitive inhibition decreasing the conversion of the clopidogrel pro-drug to the active metabolite and could potentially translate into an increased risk for cardiovascular events by inadequate platelet P2Y12 receptor inhibition. Many studies including retrospective cohort studies and studies using platelet function tests demonstrated the possible interactions between clopidogrel and PPIs leading to a decrease in the antiplatelet efficacy of clopidogrel and worse cardiovascular clinical outcomes than clopidogrel alone. In contrast, few comparative trials using clinical outcomes found no serious drug interactions between them. In this review, we introduce possible harmful effects of combined use of clopidogrel and PPIs on platelet function. In addition, we suggest how to overcome clopidogrel-PPIs interactions.
Adenosine Diphosphate ; Blood Platelets ; Cohort Studies ; Cytochrome P-450 Enzyme System ; Drug Interactions ; Liver ; Platelet Function Tests ; Proton Pump Inhibitors ; Proton Pumps ; Protons ; Retrospective Studies ; Ticlopidine

BACKGROUND AND OBJECTIVES: The aim of this study was to compare the effects of a combination of niacin and simvastatin to simvastatin alone, on plaque regression and inflammatory makers. SUBJECTS AND METHODS: The study had a prospective, randomized design. Subjects were patients with intermediate coronary artery stenosis. A total of 28 patients received a combination of niacin 1,000 mg plus simvastatin 40 mg (N+S group, n=14); the other group received simvastatin 40 mg alone (S group, n=14). All patients had a baseline and a 9-month follow-up coronary angiogram and an intravascular ultrasound procedure. Parameters such as normalized total atheroma volume (nTAV) and percent atheroma volume (PAV) were analyzed before and after treatment as were inflammatory markers such as high sensitivity C-reactive protein (hs-CRP), Matrix me-talloproteinase-9 (MMP-9) and soluble CD40 ligand (sCD40L). RESULTS: There was no difference in baseline characteristics between the two groups. The nTAV and PAV in the N+S group before and after treatment were not different than those in the S group. But the degree of changes (delta) in nTAV in the N+S group was greater than that in the S group (-21.6+/-10.68 vs. 5.25+/-42.19, respectively, p=0.024). Also, the change in PAV in the NS group was higher than that in the S group (-1.2+/-2.5 vs. -0.6+/-5, respectively, p=0.047. Changes in hs-CRP, MMP-9, and sCD40L in the NS group were significantly greater than those of the S group (-0.71+/-1.25, 73.5+/-64.9, -1,970+/-1,925 vs. -0.32+/-0.96, 62.5+/-30.6, -1,673+/-2,628, respectively). CONCLUSION: The combination of niacin plus simvastatin decreases coronary plaque volume and attenuates the inflammatory response in patients with intermediate coronary artery stenosis.
C-Reactive Protein ; CD40 Ligand ; Coronary Stenosis ; Coronary Vessels ; Follow-Up Studies ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors ; Inflammation ; Niacin ; Oxidative Stress ; Plaque, Atherosclerotic ; Prospective Studies ; Simvastatin ; Ultrasonography, Interventional

BACKGROUND AND OBJECTIVES: The clinical outcome of patient with an acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI), with or without achievement of target low density lipoprotein-cholesterol (LDL-C), has little known information. This study investigated if target LDL-C level (below 70 mg/dL) achievements in patients with AMI showed better clinical outcomes or not. SUBJECTS AND METHODS: Between May 2008 and September 2012, this study enrolled 13473 AMI patients in a large-scale, prospective, multicenter Korean Myocardial Infarction (KorMI) registry. 12720 patients survived and 6746 patients completed a 1-year clinical follow up. Among them 3315 patients received serial lipid profile follow-ups. Propensity score matching was applied to adjust for differences in clinical baseline and angiographic characteristics, producing a total of 1292 patients (646 target LDL-C achievers vs. 646 non-achievers). The primary end point was the composite of a 1-year major adverse cardiac event (MACE) including cardiac death, recurrent myocardial infarction (MI), target lesion revascularization (TLR) and coronary artery bypass grafting. RESULTS: After propensity score matching, baseline clinical and angiographic characteristics were similar between the two groups. Clinical outcomes of the propensity score matched patients who showed no significant differences in cardiac death (0.5% vs. 0.5%, p=1.000), recurrent MI (1.1% vs. 0.8%, p=0.562), TLR (5.0% vs. 4.5%, p=0.649), MACEs (6.5% vs. 5.9%, p=0.644) and stent thrombosis (2.5% vs. 1.9%, p=0.560). CONCLUSION: In this propensity-matched comparison, AMI patients undergoing PCI with a target LDL-C (below 70 mg/dL) achievement did not show better clinical outcomes.
Coronary Artery Bypass ; Death ; Follow-Up Studies ; Humans ; Myocardial Infarction* ; Percutaneous Coronary Intervention ; Propensity Score ; Prospective Studies ; Stents ; Thrombosis ; Treatment Outcome

Critical limb ischemia (CLI) is one of the most severe forms of peripheral artery diseases, but current treatment strategies do not guarantee complete recovery of vascular blood flow or reduce the risk of mortality. Recently, human bone marrow derived mesenchymal stem cells (MSCs) have been reported to have a paracrine influence on angiogenesis in several ischemic diseases. However, little evidence is available regarding optimal cell doses and injection frequencies. Thus, the authors undertook this study to investigate the effects of cell dose and injection frequency on cell survival and paracrine effects. MSCs were injected at 10⁶ or 10⁵ per injection (high and low doses) either once (single injection) or once in two consecutive weeks (double injection) into ischemic legs. Mice were sacrificed 4 weeks after first injection. Angiogenic effects were confirmed in vitro and in vivo, and M2 macrophage infiltration into ischemic tissues and rates of limb salvage were documented. MSCs were found to induce angiogenesis through a paracrine effect in vitro, and were found to survive in ischemic muscle for up to 4 weeks dependent on cell dose and injection frequency. In addition, double high dose and low dose of MSC injections increased vessel formation, and decreased fibrosis volumes and apoptotic cell numbers, whereas a single high dose did not. Our results showed MSCs protect against ischemic injury in a paracrine manner, and suggest that increasing injection frequency is more important than MSC dosage for the treatment CLI.
Animals* ; Bone Marrow* ; Cell Count ; Cell Survival ; Extremities* ; Fibrosis ; Humans ; In Vitro Techniques ; Ischemia* ; Leg ; Limb Salvage ; Macrophages ; Mesenchymal Stromal Cells* ; Mice ; Models, Animal* ; Mortality ; Peripheral Arterial Disease

BACKGROUND AND OBJECTIVES: Clopidogrel resistance or low-responsiveness may be associated with recurrent atherothrombotic events after drug-eluting stent (DES) implantation. We prospectively evaluated the association between clopidogrel resistance assessed by the Verifynow(TM) P2Y12 assay (Accumetrics, San Diego, CA, USA) and stent thrombosis (ST) or cardiac death (CD) in patients with acute coronary syndrome (ACS) within 6 months after DES implantation. SUBJECTS AND METHODS: We enrolled 237 consecutive patients (160 males, 65.2+/-10.3 years) with ACS who received a DES implantation. The composite endpoint was defined to CD or ST by Academic Research Consortium definitions within 6 months post-implantation. Clopidogrel resistance was defined as <20% inhibition of the P2Y12 receptor. RESULTS: Baseline demographic characteristics were similar between 142 normal individuals and 95 clopidogrel resistant patients. CD occurred in one case (0.7%) in the normal group and two cases (2.13%) in the resistant group (p=0.344). There was no episode of ST in the normal group and four episodes in the resistant group (4.2%, four definite ST) (p=0.035). Univariate logistic regression revealed an adjusted odds ratio (OR) for composite end point of CD or ST of 9.646 {95% confidence interval (CI) 1.139-81.679}, and multivariate logistic regression for composite end point revealed an OR of 12.074 (95% CI 1.205-120.992). CONCLUSION: Clopidogrel low-responsiveness assessed by the Verifynow(TM) P2Y12 assay is an independent predictor of ST and composite end point of ST or CD in patients with ACS within 6 months after DES implantation.
Acute Coronary Syndrome ; Blood Platelets ; Death ; Drug-Eluting Stents ; Humans ; Logistic Models ; Male ; Odds Ratio ; Prospective Studies ; Pyridines ; Stents ; Thrombosis ; Ticlopidine

Although metabolic syndrome (MetS) is associated with increased cardiovascular mortality and the development of atherosclerosis, consensus is still lacking on the status of cardiovascular function and geometry in MetS patients. We investigated the relation between MetS and left ventricle (LV) geometry and function, carotid intima-media thickness (IMT) and arterial stiffness in a community-based cohort of 702 adult subjects. Subjects were categorized into three groups according to the number of MetS components present, as defined by the Adult Treatment Panel III guidelines: 1) Absent (0 criteria), 2) Pre-MetS (1-2 criteria) or 3) MetS (> or =3 criteria). In female subjects, LV mass, LV mass/height(2.7), deceleration time, and aortic pulse wave velocity increased, and E/A ration decreased in a stepwise manner across the three groups. These changes were not observed in male subjects. The mean carotid IMT was higher in the MetS group than in the other two groups. The degree of MetS clustering is found to be strongly correlated with geometric eccentricity of LV hypertrophy, diastolic dysfunction and arterial changes irrespective of age and blood pressure status, particularly in females. Waist circumference is found to have the most powerful effect on cardiovascular parameters.
Adult ; Aged ; Cardiovascular Diseases/etiology/*physiopathology ; Cardiovascular System/pathology/*physiopathology ; Carotid Arteries/anatomy & histology/physiology ; *Cohort Studies ; Female ; Heart Ventricles/anatomy & histology ; Humans ; Korea ; Male ; Metabolic Syndrome X/complications/*physiopathology ; Middle Aged ; *Rural Population ; Ventricular Function, Left/physiology

Hyponatremia is a relatively common electrolyte disorder. Although severe acute hyponatremia following coronary angiography is rare, potentially lethal neurologic manifestations may result. We describe a patient with severe, symptomatic hyponatremia, an unusual complication of coronary angiography. Lack of familiarity with contrast media-related hyponatremia caused a delay in diagnosis and therapy in our case. The diagnosis of acute hyponatremia should be considered in any patient who develops behavioral or neurologic manifestations following coronary angiography. Prompt diagnosis and treatment is essential to avoid permanent neurologic damage or death.
Coronary Angiography ; Humans ; Hyponatremia ; Neurologic Manifestations ; Recognition (Psychology)

PURPOSE: To detect signals of adverse drug events after imipenem treatment using the Korea Institute of Drug Safety & Risk Management-Korea adverse event reporting system database (KIDS-KD). MATERIALS AND METHODS: We performed data mining using KIDS-KD, which was constructed using spontaneously reported adverse event (AE) reports between December 1988 and June 2014. We detected signals calculated the proportional reporting ratio, reporting odds ratio, and information component of imipenem. We defined a signal as any AE that satisfied all three indices. The signals were compared with drug labels of nine countries. RESULTS: There were 807582 spontaneous AEs reports in the KIDS-KD. Among those, the number of antibiotics related AEs was 192510; 3382 reports were associated with imipenem. The most common imipenem-associated AE was the drug eruption; 353 times. We calculated the signal by comparing with all other antibiotics and drugs; 58 and 53 signals satisfied the three methods. We compared the drug labelling information of nine countries, including the USA, the UK, Japan, Italy, Switzerland, Germany, France, Canada, and South Korea, and discovered that the following signals were currently not included in drug labels: hypokalemia, cardiac arrest, cardiac failure, Parkinson's syndrome, myocardial infarction, and prostate enlargement. Hypokalemia was an additional signal compared with all other antibiotics, and the other signals were not different compared with all other antibiotics and all other drugs. CONCLUSION: We detected new signals that were not listed on the drug labels of nine countries. However, further pharmacoepidemiologic research is needed to evaluate the causality of these signals.
Anti-Bacterial Agents ; Canada ; Data Mining ; Drug Eruptions ; Drug Labeling ; Drug-Related Side Effects and Adverse Reactions ; France ; Germany ; Heart Arrest ; Heart Failure ; Hypokalemia ; Imipenem* ; Italy ; Japan ; Korea* ; Myocardial Infarction ; Odds Ratio ; Pharmacoepidemiology ; Pharmacovigilance ; Prostate ; Switzerland

BACKGROUND/AIMS: Treatment of coronary in-stent restenosis (ISR) is still associated with a high incidence of recurrence. We aimed to compare the efficacy and safety of drug-eluting balloons (DEB) for the treatment of ISR as compared with conventional balloon angioplasty (BA) and drug-eluting stents (DES). METHODS: Between January 2006 and May 2012 a total of 177 patients (188 lesions, 64.1 ± 11.7 years old) who underwent percutaneous coronary intervention for ISR were retrospectively enrolled. Clinical outcomes were compared between patients treated with DEB (n = 58, 32.8%), conventional BA (n = 65, 36.7%), or DES (n = 54, 30.5%). The primary end point was a major adverse cardiac event (MACE), defined as a composite of cardiac death, myocardial infarction, and target lesion revascularization(TLR). RESULTS: Baseline characteristics were not different except for a history of previous MI, which was more frequent in patients treated by conventional BA or DES than in patients treated by DEB (40.0% vs. 48.1% vs. 17.2%, respectively, p = 0.002). The total incidences of MACEs were 10.7%, 7.4%, and 15.4% in patients treated by DEB, DES, or conventional BA, respectively (p > 0.05). TLR was more frequent in patients treated by conventional BA than in patients treated by DEB or DES, but this was not statistically significant (10.8% vs. 6.9% vs. 3.7%, p > 0.05 between all group pairs, respectively). CONCLUSIONS: This study showed that percutaneous coronary intervention using DEB might be a feasible alternative to conventional BA or DES implantation for treatment of coronary ISR. Further large-scaled, randomized study assessing long-term clinical and angiographic outcomes will be needed.
Angioplasty, Balloon* ; Coronary Restenosis ; Death ; Drug-Eluting Stents* ; Humans ; Incidence ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Recurrence ; Retrospective Studies