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1.  Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison 
Objective To evaluate whether smoking status is associated with the efficacy of antiplatelet treatment in the prevention of cardiovascular events.
Design Systematic review, meta-analysis, and indirect comparisons.
Data sources Medline (1966 to present) and Embase (1974 to present), with supplementary searches in databases of abstracts from major cardiology conferences, the Cumulative Index to Nursing and Allied Health (CINAHL) and the CAB Abstracts databases, and Google Scholar.
Study selection Randomized trials of clopidogrel, prasugrel, or ticagrelor that examined clinical outcomes among subgroups of smokers and nonsmokers.
Data extraction Two authors independently extracted all data, including information on the patient populations included in the trials, treatment types and doses, definitions of clinical outcomes and duration of follow-up, definitions of smoking subgroups and number of patients in each group, and effect estimates and 95% confidence intervals for each smoking status subgroup.
Results Of nine eligible randomized trials, one investigated clopidogrel compared with aspirin, four investigated clopidogrel plus aspirin compared with aspirin alone, and one investigated double dose compared with standard dose clopidogrel; these trials include 74 489 patients, of whom 21 717 (29%) were smokers. Among smokers, patients randomized to clopidogrel experienced a 25% reduction in the primary composite clinical outcome of cardiovascular death, myocardial infarction, and stroke compared with patients in the control groups (relative risk 0.75, 95% confidence interval 0.67 to 0.83). In nonsmokers, however, clopidogrel produced just an 8% reduction in the composite outcome (0.92, 0.87 to 0.98). Two studies investigated prasugrel plus aspirin compared with clopidogrel plus aspirin, and one study investigated ticagrelor plus aspirin compared with clopidogrel plus aspirin. In smokers, the relative risk was 0.71 (0.61 to 0.82) for prasugrel compared with clopidogrel and 0.83 (0.68 to 1.00) for ticagrelor compared with clopidogrel. Corresponding relative risks were 0.92 (0.83 to 1.01) and 0.89 (0.79 to 1.00) among nonsmokers.
Conclusions In randomized clinical trials of antiplatelet drugs, the reported clinical benefit of clopidogrel in reducing cardiovascular death, myocardial infarction, and stroke was seen primarily in smokers, with little benefit in nonsmokers.
PMCID: PMC3775704  PMID: 24046285
2.  Ticagrelor: An investigational oral antiplatelet treatment for reduction of major adverse cardiac events in patients with acute coronary syndrome 
Acute coronary syndromes (ACS) are the leading cause of mortality and one of the main reasons for hospital admissions in the developed nations. Due to high rates of mortality and reinfarction, ACS represent a major public health concern. Platelets play a central role in atherothrombosis, the main pathologic substrate in ACS. Sufficient inhibition of platelet aggregation is therefore one of the key targets in the treatment of ACS. Blockade of the P2Y12 subtype of adenosine diphosphate (ADP) receptor on platelet cell membranes has been established as a key mechanism of platelet inhibition. Clopidogrel, an ADP receptor antagonist and a second-generation thienopyridine, has been demonstrated to be of clinical benefit in patients with ACS when added to aspirin. A delayed onset of action due to two-step conversion to the active metabolite, irreversible binding to P2Y12 receptors, and broad interindividual variability in levels of platelet response are the main limitations of clopidogrel. Prasugrel, a novel third-generation thienopyridine, provides faster and stronger inhibition of platelet aggregation than clopigodrel. However, like the active metabolite of clopidogrel, prasugrel binds irreversibly to the P2Y12 ADP receptor site, causing inhibition of platelet aggregation for the life of the platelet. Although in a randomized, double-blind trial prasugrel demonstrated superiority for multiple cardiovascular endpoints compared with standard-dose clopidogrel, it was also associated with an increased bleeding risk, including fatal bleeding. This review discusses the optimal antiplatelet regimens for management of patients with ACS, with special focus on ticagrelor, the first oral agent in a new chemical class of nonthienopyridine antiplatelet agents termed cyclopentyltriazolo-pyrimidines. Faster and greater platelet inhibition than clopidogrel, quick recovery of platelet function, and high efficacy regardless of clopidogrel response status, are the obvious advantages of ticagrelor as compared with thienopyridines. The prospective, randomized Platelet Inhibition and Patient Outcomes trial has established the clinical utility, enhanced efficacy, and similar safety of ticagrelor as compared with clopidogrel in a wide range of patients with ACS managed with contemporary antithrombotic therapies and invasive strategies when indicated. Dyspnea, ventricular pauses ≥3 seconds, and elevation of serum creatinine and uric acid are the most common known adverse effects associated with ticagrelor, and require further comprehensive assessment.
PMCID: PMC2964949  PMID: 21057581
ticagrelor; acute coronary syndrome; platelets; percutaneous coronary intervention
3.  Effect of Co-Administration of Rivaroxaban and Clopidogrel on Bleeding Time, Pharmacodynamics and Pharmacokinetics: A Phase I Study 
Pharmaceuticals  2012;5(3):279-296.
Dual antiplatelet therapy with acetylsalicylic acid and a thienopyridine, such as clopidogrel, is effective for the secondary prevention of cardiovascular events in patients with acute coronary syndrome, but there is still a substantial residual risk of recurrence. Although anticoagulant therapy with a vitamin K antagonist (e.g. warfarin) in conjunction with antiplatelet therapy has been shown to reduce the risk of cardiovascular events, the rates of bleeding were increased with these combination therapies; hence, triple therapy with warfarin is currently only recommended in patients at low risk of bleeding. In addition, there are other limitations associated with vitamin K antagonist therapy, including the need for routine coagulation monitoring and dose adjustment to maintain the treatment within the therapeutic range. Rivaroxaban is an oral, direct Factor Xa inhibitor; in clinical practice, it is likely that rivaroxaban will be given to patients who also receive antiplatelet therapy, such as clopidogrel. This randomized, non-blinded, three-way crossover study investigated the effect of rivaroxaban on bleeding time when co­administered with clopidogrel. In addition, the influence of clopidogrel on the safety, tolerability, pharmacodynamics and pharmacokinetics of rivaroxaban was investigated. Of 27 healthy male subjects who received a single 300 mg dose of clopidogrel, 14 were identified as clopidogrel responders and were then randomized to the following three treatments: (A) two doses of clopidogrel on two consecutive days (300 mg on day 1; 75 mg on day 2); (B) one dose of rivaroxaban (15 mg); or (C) a combination of treatments A and B (rivaroxaban given on day 2). All treatments were well tolerated. Bleeding time with co­administration of rivaroxaban and clopidogrel was significantly prolonged in four subjects, compared with either drug alone: combination treatment increased the overall least squares-means to 3.77 times baseline (90% confidence interval [CI] 2.82–4.73), compared with 1.13 times baseline (90% CI 0.17–2.09) with rivaroxaban and 1.96 times baseline (90% CI 0.10–2.91) with clopidogrel. Co-administration of clopidogrel had no significant effect on the pharmacokinetics of rivaroxaban and, when compared with rivaroxaban alone, had no further effects on Factor Xa activity or prothrombin time. Inhibition of ADP-stimulated platelet aggregation by clopidogrel was not affected by rivaroxaban. As expected, owing to the mode of action of each study drug, the results of this study demonstrated that co­administration of the Factor Xa inhibitor rivaroxaban and the antiplatelet clopidogrel increased the bleeding time in healthy subjects without affecting other pharmacokinetic or pharmacodynamic parameters of each drug.
PMCID: PMC3763640  PMID: 24281379
bleeding time; clopidogrel; pharmacodynamics; pharmacokinetics; rivaroxaban
4.  Restrictive access to clopidogrel and mortality following coronary stent implantation 
In Canada, access to clopidogrel is restricted by most provincial drug insurance plans in order to contain costs. Until April 2007, the Régie de l'assurance maladie du Québec (RAMQ) Prescription Drug Insurance Plan reviewed special access forms before approving reimbursement for clopidogrel prescriptions. We investigated the impact of this restrictive process on patient's filling of prescriptions and on all-cause mortality following coronary stenting.
We analyzed prescriptions filled and all-cause mortality in the year following a percutaneous coronary intervention among patients who underwent stent implantation between January 2000 and September 2004. We obtained administrative data from the RAMQ databases. We included patients who filled at least 1 prescription for a nonrestricted cardiovascular drug after hospital discharge. We used Cox proportional models to compare mortality rates as a function of delayed or absent outpatient clopidogrel therapy.
Of 13 663 patients, 1571 (11.5%) did not fill any clopidogrel prescription despite filling at least 1 nonrestricted cardiovascular drug prescription after a percutaneous coronary intervention, and 1174 (8.6%) patients filled their clopidogrel prescription with a delay of at least 1 day (median delay 5 days) after filling the nonrestricted cardiovascular drug prescription. After controlling for pertinent covariables, not filling a clopidogrel prescription (hazard ratio [HR] 1.70, 95% confidence interval [CI] 1.35–2.15) and filling with a delay (HR 1.34, 95% CI 1.01–1.80) were associated with a significant increase in all-cause mortality.
Restricted access to clopidogrel was associated with about 20% of patients either not receiving clopidogrel or receiving therapy after a delay. Delay or absence of clopidogrel therapy increased the risk of all-cause mortality after percutaneous coronary intervention with stenting.
PMCID: PMC2228353  PMID: 18268267
5.  Operative Treatment of HIP Fractures in Patients on Clopidogrel: A Case-Control Study 
Clopidogrel, an inhibitor of ADP-induced platelet aggregation, is indicated for the reduction of atherosclerotic events in patients with atherosclerosis documented by recent stoke, myocardial infarction, acute coronary syndrome, and established peripheral arterial disease. In cardiovascular studies, clopidogrel has been associated with increased chest tube output, transfusion rates, and re-exploration rates. Few studies have addressed the possible complications of clopidogrel in hip fractures. Our study aims to assess the perioperative blood loss and transfusion rates in geriatric patients with hip fractures on clopidogrel. We hypothesize that patients on clopidogrel will have higher perioperative blood loss and transfusion rates.
Materials and Methods
A retrospective, case control study chart review over a five year span was conducted. Of the 2,766 geriatric hip fracture patients surgically treated, 52 patients taking clopidogrel upon admission to the hospital were compared to patients not on the drug. All of the patients in the study were taken to the operating room within two calendar days of admission. statistical analysis was performed using Wilcoxon's, Fisher exact, chi square, and logistic regression methods.
A total of 110 patients were included in the analysis, 52 (47%) were taking clopidogrel at the time of admission. these patients were compared to 58 (53%) patients not on the drug. No significant difference was found with respect to documented perioperative blood loss. Transfusion rates however, did vary. Patients who had been taking clopidogrel, prior to admission and subsequent surgery, had a transfusion rate of 56% while those patients not on the drug had a transfusion rate of 31%. Logistic regression analysis showed taking clopidogrel up to admission was significantly associated (p = .0121) with receiving a blood transfusion following surgical treatment of a hip fracture.
A growing body of evidence supports early (within 48 hrs) surgery for elderly patients with hip fractures. the pharmacokinetics of clopidogrel do not allow for bleeding time to return to normal until the drug has been discontinued for five days. Our study shows that patients taking clopidogrel upon admission for hip fracture are at increased risk of blood transfusions when surgery is performed within two calendar days of admis-sion. this risk must be balanced by the potential benefits of early surgery.
PMCID: PMC3565422  PMID: 23576928
6.  Effects of Cytochrome P450 2C19 and Paraoxonase 1 Polymorphisms on Antiplatelet Response to Clopidogrel Therapy in Patients with Coronary Artery Disease 
PLoS ONE  2014;9(10):e110188.
Clopidogrel is an antiplatelet prodrug that is recommended to reduce the risk of recurrent thrombosis in coronary artery disease (CAD) patients. Paraoxonase 1 (PON1) is suggested to be a rate-limiting enzyme in the conversion of 2-oxo-clopidogrel to active thiol metabolite with inconsistent results. Here, we sought to determine the associations of CYP2C19 and PON1 gene polymorphisms with clopidogrel response and their role in ADP-induced platelet aggregation. Clopidogrel response and platelet aggregation were determined using Multiplate aggregometer in 211 patients with established CAD who received 75 mg clopidogrel and 75–325 mg aspirin daily for at least 14 days. Polymorphisms in CYP2C19 and PON1 were genotyped and tested for association with clopidogrel resistance. Linkage disequilibrium (LD) and their epistatic interaction effects on ADP-induced platelet aggregation were analysed. The prevalence of clopidogrel resistance in this population was approximately 33.2% (n = 70). The frequencies of CYP2C19*2 and *3 were significantly higher in non-responder than those in responders. After adjusting for established risk factors, CYP2C19*2 and *3 alleles independently increased the risk of clopidogrel resistance with adjusted ORs 2.94 (95%CI, 1.65–5.26; p<0.001) and 11.26 (95%CI, 2.47–51.41; p = 0.002, respectively). Patients with *2 or *3 allele and combined with smoking, diabetes and increased platelet count had markedly increased risk of clopidogrel resistance. No association was observed between PON1 Q192R and clopidogrel resistance (adjusted OR = 1.13, 95%CI, 0.70–1.82; p = 0.622). Significantly higher platelet aggregation values were found in CYP2C19*2 and *3 patients when compared with *1/*1 allele carriers (p = 1.98×10−6). For PON1 Q192R genotypes, aggregation values were similar across all genotype groups (p = 0.359). There was no evidence of gene-gene interaction or LD between CYP2C19 and PON1 polymorphisms on ADP-induced platelet aggregation. Our findings indicated that only CYP2C19*2 and *3 alleles had an influence on clopidogrel resistance. The risk of clopidogrel resistance increased further with smoking, diabetes, and increased platelet count.
PMCID: PMC4199712  PMID: 25329996
7.  Perioperative Clopidogrel and Postoperative Events after Hip and Knee Arthroplasties 
Hip and knee arthroplasties are widely performed and vascular disease among patients having these procedures is common. Clopidogrel is a platelet inhibitor that decreases the likelihood of thrombosis. It may cause intraoperative and postoperative bleeding, but its discontinuation increases the risk of vascular events. There is currently no consensus regarding the best perioperative clopidogrel regimen that balances these concerns.
We determined (1) the relationship between time of perioperative clopidogrel administration and postoperative bleeding-related events after hip and knee arthroplasties and (2) patient characteristics or surgical factors that may predict these events.
We retrospectively queried our inpatient pharmacy database for patients who received clopidogrel from 2007 to 2009 and identified 116 patients who underwent hip or knee arthroplasty. We recorded the time of perioperative clopidogrel administration, bleeding-related postoperative events, patient characteristics, and surgical factors.
Patients who withheld clopidogrel 5 or more days before hip or knee arthroplasty had lower rates of reoperation for infection and antibiotics prescribed for the surgical wound. Postoperative events did not vary with timing of clopidogrel resumption after surgery. Advanced age, an American Society of Anesthesiologists (ASA) score of 4, and revision surgery predicted increased readmission, reoperation for hematoma or infection, antibiotic use, and death.
Holding clopidogrel for at least 5 days before hip or knee arthroplasty may lower the rate of bleeding-related events. We found no increase in events when patients resumed clopidogrel immediately after surgery. Advanced age, ASA score of 4, and revision surgery may be risk factors for bleeding-related events.
Level of Evidence
Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.
PMCID: PMC3314755  PMID: 22402810
Medicine & Public Health; Conservative Orthopedics; Orthopedics; Sports Medicine; Surgery; Surgical Orthopedics; Medicine/Public Health, general
8.  Clopidogrel Resistance is Associated with Long-Term Thrombotic Events in Patients Implanted with Drug-Eluting Stents 
Drugs in R&d  2012;10(4):219-224.
Background: There are limited prospective data on clopidogrel resistance and clinical outcome of patients with selective coronary drug-eluting stent (DES) implantation.
Objective: To investigate whether clopidogrel resistance is associated with longterm thrombotic events in patients with selective coronary DES implantation.
Methods: A total of 154 patients who underwent selective percutaneous coronary intervention (PCI) with DES were enrolled in this study. Platelet aggregation was measured using light transmittance aggregometry (LTA) before clopidogrel administration (baseline) and 24 hours after loading with clopidogrel 300 mg. Clopidogrel resistance was defined as ≤10% absolute difference between baseline aggregation and post-administration aggregation. All patients who received the same anti-platelet treatment were followed up for 1 year after discharge for the incidence of a composite endpoint consisting of cardiovascular death, myocardial infarction (MI) and revascularization, and secondly for the incidence of stent thrombosis.
Results: The incidence of clopidogrel resistance is 20.28% in our study population. Patients who are complicated by diabetes mellitus, smoke, or have a higher body mass index (BMI) tend to have clopidogrel resistance. Patients in the clopidogrel-resistant group have significantly higher incidences of composite endpoints (21.88% vs 4.92%; p = 0.006) and stent thrombosis (12.5% vs 1.64%; p= 0.017) than patients in the clopidogrel-response group during 1-year follow-up.
Conclusions: Diabetes, smoking, and high BMI are associated with clopidogrel resistance, and clopidogrel resistance indicates an increased risk of long-term thrombotic events in patients implanted with DES.
PMCID: PMC3586069  PMID: 21171668
9.  Clopidogrel Resistance is Associated with Long-Term Thrombotic Events in Patients Implanted with Drug-Eluting Stents 
Drugs in R&D  2012;10(4):219-224.
Background: There are limited prospective data on clopidogrel resistance and clinical outcome of patients with selective coronary drug-eluting stent (DES) implantation.
Objective: To investigate whether clopidogrel resistance is associated with longterm thrombotic events in patients with selective coronary DES implantation.
Methods: A total of 154 patients who underwent selective percutaneous coronary intervention (PCI) with DES were enrolled in this study. Platelet aggregation was measured using light transmittance aggregometry (LTA) before clopidogrel administration (baseline) and 24 hours after loading with clopidogrel 300 mg. Clopidogrel resistance was defined as ≤10% absolute difference between baseline aggregation and post-administration aggregation. All patients who received the same anti-platelet treatment were followed up for 1 year after discharge for the incidence of a composite endpoint consisting of cardiovascular death, myocardial infarction (MI) and revascularization, and secondly for the incidence of stent thrombosis.
Results: The incidence of clopidogrel resistance is 20.28% in our study population. Patients who are complicated by diabetes mellitus, smoke, or have a higher body mass index (BMI) tend to have clopidogrel resistance. Patients in the clopidogrel-resistant group have significantly higher incidences of composite endpoints (21.88% vs 4.92%; p = 0.006) and stent thrombosis (12.5% vs 1.64%; p= 0.017) than patients in the clopidogrel-response group during 1-year follow-up.
Conclusions: Diabetes, smoking, and high BMI are associated with clopidogrel resistance, and clopidogrel resistance indicates an increased risk of long-term thrombotic events in patients implanted with DES.
PMCID: PMC3586069  PMID: 21171668
10.  Benefit of Clopidogrel Therapy in Patients With Myocardial Infarction and Chronic Kidney Disease—A Danish Nation‐Wide Cohort Study 
The aim of the present study was to evaluate clopidogrel treatment after incident myocardial infarction (MI) in patients with and without chronic kidney disease (CKD).
Methods and Results
By linking nation‐wide registries, information about patients admitted with incident MI was found. Primary endpoints were all‐cause and cardiovascular (CV) mortality, a composite of all‐cause mortality and recurrent MI, and a composite of fatal and nonfatal bleedings. Effect of clopidogrel use versus clopidogrel nonuse was estimated using an adjusted Cox's regression model stratified according to percutaneous coronary intervention (PCI) treatment.
A total of 69 082 incident MI patients in the period 2002–2011 were included. Clopidogrel treatment was associated with hazard ratios (HRs) for the combined endpoint of all‐cause mortality and recurrent MI in PCI‐treated patients of 0.90 (95% confidence interval [CI], 0.47 to 1.72) in renal replacement therapy (RRT) patients, 0.59 (95% CI: 0.40 to 0.88) in non‐end‐stage CKD patients and 0.69 (95% CI, 0.61 to 0.77) in patients without kidney disease (P for interaction=0.60). In patients not treated with PCI, HRs were 0.90 (95% CI, 0.68 to 1.21) in RRT patients, 0.86 (95% CI, 0.75 to 0.99) in non‐end‐stage CKD patients, and 0.91 (95% CI, 0.87 to 0.95) in patients without kidney disease (P for interaction=0.74). An increase in bleeding events (not significant) was noted for clopidogrel‐treated patients not undergoing PCI and for non‐end‐stage CKD patients undergoing PCI, whereas clopidogrel was associated with less bleedings in PCI‐treated RRT patients and patients without kidney disease.
During a 1‐year follow‐up, after MI, clopidogrel was associated with improved outcomes in patients with non‐end‐stage CKD. Even though no effect difference, compared to patients without CKD, was observed, the benefit associated with the use of clopidogrel after MI in patients requiring RRT is less clear.
PMCID: PMC4310409  PMID: 25146707
kidney; myocardial infarction; revascularization
11.  Effects of Clopidogrel on Mortality, Cardiovascular and Bleeding Outcomes in Patients with Chronic Kidney Disease - Data from Taiwan Acute Coronary Syndrome Full Spectrum Registry 
PLoS ONE  2013;8(8):e71917.
The efficacy of clopidogrel is inconclusive in the chronic kidney disease (CKD) population with acute coronary syndrome (ACS). Furthermore, CKD patients are prone to bleeding with antiplatelet therapy. We investigated the efficacy and safety of clopidogrel in patients with ACS and CKD.
In a Taiwan national-wide registry, 2819 ACS patients were enrolled. CKD is defined as an estimated glomerular filtration rate of less than 60 ml/min per 1.73 m2. The primary endpoints are the combined outcomes of death, non-fatal myocardial infarction and stroke at 12 months.
Overall 949 (33.7%) patients had CKD and 2660 (94.36%) patients received clopidogrel treatment. CKD is associated with increased risk of the primary endpoint at 12 months (HR 2.39, 95% CI 1.82 to 3.15, p<0.01). Clopidogrel use is associated with reduced risk of the primary endpoint at 12 months (HR 0.42, 95% CI: 0.29–0.60, p<0.01). Cox regression analysis showed that clopidogrel reduced death and primary endpoints for CKD population (HR 0.35, 95% CI: 0.21–0.61 and HR 0.48, 95% CI: 0.30–0.77, respectively, both p<0.01). Patients with clopidogrel(−)/CKD(−), clopidogrel(+)/CKD(+) and clopidogrel(−)/CKD(+) have 2.4, 3.0 and 10.4 fold risk to have primary endpoints compared with those receiving clopidogrel treatment without CKD (all p<0.01). Clopidogrel treatment was not associated with increased in-hospital Thrombolysis In Myocardial Infarction (TIMI) bleeding in CKD population.
Clopidogrel could decrease mortality and improve cardiovascular outcomes without increasing risk of bleeding in ACS patients with CKD.
PMCID: PMC3756021  PMID: 24015198
12.  Burden of Total and Cause-Specific Mortality Related to Tobacco Smoking among Adults Aged ≥45 Years in Asia: A Pooled Analysis of 21 Cohorts 
PLoS Medicine  2014;11(4):e1001631.
Wei Zheng and colleagues quantify the burden of tobacco-smoking-related deaths for adults in Asia.
Please see later in the article for the Editors' Summary
Tobacco smoking is a major risk factor for many diseases. We sought to quantify the burden of tobacco-smoking-related deaths in Asia, in parts of which men's smoking prevalence is among the world's highest.
Methods and Findings
We performed pooled analyses of data from 1,049,929 participants in 21 cohorts in Asia to quantify the risks of total and cause-specific mortality associated with tobacco smoking using adjusted hazard ratios and their 95% confidence intervals. We then estimated smoking-related deaths among adults aged ≥45 y in 2004 in Bangladesh, India, mainland China, Japan, Republic of Korea, Singapore, and Taiwan—accounting for ∼71% of Asia's total population. An approximately 1.44-fold (95% CI = 1.37–1.51) and 1.48-fold (1.38–1.58) elevated risk of death from any cause was found in male and female ever-smokers, respectively. In 2004, active tobacco smoking accounted for approximately 15.8% (95% CI = 14.3%–17.2%) and 3.3% (2.6%–4.0%) of deaths, respectively, in men and women aged ≥45 y in the seven countries/regions combined, with a total number of estimated deaths of ∼1,575,500 (95% CI = 1,398,000–1,744,700). Among men, approximately 11.4%, 30.5%, and 19.8% of deaths due to cardiovascular diseases, cancer, and respiratory diseases, respectively, were attributable to tobacco smoking. Corresponding proportions for East Asian women were 3.7%, 4.6%, and 1.7%, respectively. The strongest association with tobacco smoking was found for lung cancer: a 3- to 4-fold elevated risk, accounting for 60.5% and 16.7% of lung cancer deaths, respectively, in Asian men and East Asian women aged ≥45 y.
Tobacco smoking is associated with a substantially elevated risk of mortality, accounting for approximately 2 million deaths in adults aged ≥45 y throughout Asia in 2004. It is likely that smoking-related deaths in Asia will continue to rise over the next few decades if no effective smoking control programs are implemented.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, more than 5 million smokers die from tobacco-related diseases. Tobacco smoking is a major risk factor for cardiovascular disease (conditions that affect the heart and the circulation), respiratory disease (conditions that affect breathing), lung cancer, and several other types of cancer. All told, tobacco smoking kills up to half its users. The ongoing global “epidemic” of tobacco smoking and tobacco-related diseases initially affected people living in the US and other Western countries, where the prevalence of smoking (the proportion of the population that smokes) in men began to rise in the early 1900s, peaking in the 1960s. A similar epidemic occurred in women about 40 years later. Smoking-related deaths began to increase in the second half of the 20th century, and by the 1990s, tobacco smoking accounted for a third of all deaths and about half of cancer deaths among men in the US and other Western countries. More recently, increased awareness of the risks of smoking and the introduction of various tobacco control measures has led to a steady decline in tobacco use and in smoking-related diseases in many developed countries.
Why Was This Study Done?
Unfortunately, less well-developed tobacco control programs, inadequate public awareness of smoking risks, and tobacco company marketing have recently led to sharp increases in the prevalence of smoking in many low- and middle-income countries, particularly in Asia. More than 50% of men in many Asian countries are now smokers, about twice the prevalence in many Western countries, and more women in some Asian countries are smoking than previously. More than half of the world's billion smokers now live in Asia. However, little is known about the burden of tobacco-related mortality (deaths) in this region. In this study, the researchers quantify the risk of total and cause-specific mortality associated with tobacco use among adults aged 45 years or older by undertaking a pooled statistical analysis of data collected from 21 Asian cohorts (groups) about their smoking history and health.
What Did the Researchers Do and Find?
For their study, the researchers used data from more than 1 million participants enrolled in studies undertaken in Bangladesh, India, mainland China, Japan, the Republic of Korea, Singapore, and Taiwan (which together account for 71% of Asia's total population). Smoking prevalences among male and female participants were 65.1% and 7.1%, respectively. Compared with never-smokers, ever-smokers had a higher risk of death from any cause in pooled analyses of all the cohorts (adjusted hazard ratios [HRs] of 1.44 and 1.48 for men and women, respectively; an adjusted HR indicates how often an event occurs in one group compared to another group after adjustment for other characteristics that affect an individual's risk of the event). Compared with never smoking, ever smoking was associated with a higher risk of death due to cardiovascular disease, cancer (particularly lung cancer), and respiratory disease among Asian men and among East Asian women. Moreover, the researchers estimate that, in the countries included in this study, tobacco smoking accounted for 15.8% of all deaths among men and 3.3% of deaths among women in 2004—a total of about 1.5 million deaths, which scales up to 2 million deaths for the population of the whole of Asia. Notably, in 2004, tobacco smoking accounted for 60.5% of lung-cancer deaths among Asian men and 16.7% of lung-cancer deaths among East Asian women.
What Do These Findings Mean?
These findings provide strong evidence that tobacco smoking is associated with a substantially raised risk of death among adults aged 45 years or older throughout Asia. The association between smoking and mortality risk in Asia reported here is weaker than that previously reported for Western countries, possibly because widespread tobacco smoking started several decades later in most Asian countries than in Europe and North America and the deleterious effects of smoking take some years to become evident. The researchers note that certain limitations of their analysis are likely to affect the accuracy of its findings. For example, because no data were available to estimate the impact of secondhand smoke, the estimate of deaths attributable to smoking is likely to be an underestimate. However, the finding that nearly 45% of the global deaths from active tobacco smoking occur in Asia highlights the urgent need to implement comprehensive tobacco control programs in Asia to reduce the burden of tobacco-related disease.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization provides information about the dangers of tobacco (in several languages) and about the WHO Framework Convention on Tobacco Control, an international instrument for tobacco control that came into force in February 2005 and requires parties to implement a set of core tobacco control provisions including legislation to ban tobacco advertising and to increase tobacco taxes; its 2013 report on the global tobacco epidemic is available
The US Centers for Disease Control and Prevention provides detailed information about all aspects of smoking and tobacco use
The UK National Health Services Choices website provides information about the health risks associated with smoking
MedlinePlus has links to further information about the dangers of smoking (in English and Spanish)
SmokeFree, a website provided by the UK National Health Service, offers advice on quitting smoking and includes personal stories from people who have stopped smoking, from the US National Cancer Institute, offers online tools and resources to help people quit smoking
PMCID: PMC3995657  PMID: 24756146
13.  Platelet function testing to predict hyporesponsiveness to clopidogrel in patients with chest pain seen in the emergency department 
A dual antiplatelet regimen has been shown to reduce the risk of major adverse cardiovascular events after percutaneous coronary intervention. However, there is little information available on inhibition of platelet aggregation in patients with a prior coronary stent presenting with chest pain. This study evaluated the prevalence of hyporesponsiveness to clopidogrel and factors associated with this in patients presenting to our emergency department with chest pain who had previously undergone coronary stent placement and were prescribed dual antiplatelet therapy.
Responsiveness to clopidogrel was evaluated in a cohort of 533 consecutive stented patients presenting to the emergency department with chest pain. P2Y12 reaction units (PRU) and percent P2Y12 inhibition with clopidogrel were measured in all patients. Of 533 patients, 221 (41.6%) had PRU ≥ 230. A multivariate logistic regression model was used to determine the relationship between hyporesponsiveness to clopidogrel (defined as PRU ≥ 230) and several potential risk factors, ie, gender, age, race, type 1 or type 2 diabetes, hypertension, smoking, chronic renal failure, and obesity.
There was a greater risk of hyporesponsiveness in African Americans than in non-African American patients (adjusted odds ratio [OR] = 2.165), in patients with type 2 diabetes than in those without (adjusted OR = 2.109), and in women than in men (adjusted OR = 1.813), as well as a greater risk of hyporesponsiveness with increasing age (adjusted OR = 1.167 per decade).
There was a high prevalence of hyporesponsiveness to clopidogrel in patients presenting with chest pain and a prior coronary stent. Non-insulin-dependent diabetes mellitus and African American race were the strongest predictors of hyporesponsiveness to clopidogrel, followed by gender and age.
PMCID: PMC3646472  PMID: 23662064
clopidogrel; platelet function testing; chest pain; emergency department
14.  Clopidogrel and proton pump inhibitors - where do we stand in 2012? 
Clopidogrel in association with aspirine is considered state of the art of medical treatment for acute coronary syndrome by reducing the risk of new ischemic events. Concomitant treatment with proton pump inhibitors in order to prevent gastrointestinal side effects is recommended by clinical guidelines. Clopidogrel needs metabolic activation predominantly by the hepatic cytochrome P450 isoenzyme Cytochrome 2C19 (CYP2C19) and proton pump inhibitors (PPIs) are extensively metabolized by the CYP2C19 isoenzyme as well. Several pharmacodynamic studies investigating a potential clopidogrel-PPI interaction found a significant decrease of the clopidogrel platelet antiaggregation effect for omeprazole, but not for pantoprazole. Initial clinical cohort studies in 2009 reported an increased risk for adverse cardiovascular events, when under clopidogrel and PPI treatment at the same time. These observations led the United States Food and Drug Administration and the European Medecines Agency to discourage the combination of clopidogrel and PPI (especially omeprazole) in the same year. In contrast, more recent retrospective cohort studies including propensity score matching and the only existing randomized trial have not shown any difference concerning adverse cardiovascular events when concomitantly on clopidogrel and PPI or only on clopidogrel. Three meta-analyses report an inverse correlation between clopidogrel-PPI interaction and study quality, with high and moderate quality studies not reporting any association, rising concern about unmeasured confounders biasing the low quality studies. Thus, no definite evidence exists for an effect on mortality. Because PPI induced risk reduction clearly overweighs the possible adverse cardiovascular risk in patients with high risk of gastrointestinal bleeding, combination of clopidogrel with the less CYP2C19 inhibiting pantoprazole should be recommended.
PMCID: PMC3351765  PMID: 22611308
Clopidogrel; Thienopyridine; Proton pump inhibitors; Drug interaction; Platelet reactivity; Antiplatelet therapy; Cytochromes; Acute coronary syndrome; Gastrointestinal bleeding
15.  Clinical evidence of interaction between clopidogrel and proton pump inhibitors 
World Journal of Cardiology  2011;3(5):153-164.
Clopidogrel is approved for reduction of atherothrombotic events in patients with cardiovascular (CV) and cerebrovascular disease. Dual antiplatelet therapy with aspirin and clopidogrel decreases the risk of major adverse cardiac events after acute coronary syndrome or percutaneous coronary intervention, compared with aspirin alone. Due to concern about gastrointestinal bleeding in patients who are receiving clopidogrel and aspirin therapy, current guidelines recommend combined use of a proton pump inhibitor (PPI) to decrease the risk of bleeding. Data from previous pharmacological studies have shown that PPIs, which are extensively metabolized by the cytochrome system, may decrease the ADP-induced platelet aggregation of clopidogrel. Results from retrospective cohort studies have shown a higher incidence of major CV events in patients receiving both clopidogrel and PPIs than in those without PPIs. However, other retrospective analyses of randomized clinical trials have not shown that the concomitant PPI administration is associated with increased CV events among clopidogrel users. These controversial results suggest that large specific studies are needed. This article reviews the metabolism of clopidogrel and PPIs, existing clinical data regarding the interaction between clopidogrel and PPIs, and tries to provide recommendations for health care professionals.
PMCID: PMC3110904  PMID: 21666816
Antiplatelet therapy; Aspirin; Clopidogrel; Proton pump inhibitor
16.  A Survey of the Peri-Operative Management of Urological Patients on Clopidogrel 
Peri-operative management of patients receiving platelet inhibitors, such as clopidogrel presents a dilemma to surgeons in every surgical specialty including urology. The risk of procedure-related bleeding while continuing clopidogrel needs to be weighed against the risk of thrombo-embolism after discontinuing it. The objective of the survey was to determine current UK practice regarding clopidogrel use/cessation in patients undergoing elective urological procedures.
A 10-part questionnaire relating to pre- and postoperative clopidogrel use was mailed to all UK urology consultants listed in the British Association of Urological Surgeons' directory.
A total of 570 questionnaires were sent and 297 (52%) were returned. The majority of respondents stop clopidogrel prior to TUR surgery (96.6%), major urological surgery (91.7%), TRUS biopsy (90.6%), ESWL (81.8%) and cystoscopy and biopsy (70.1%). The time clopidogrel was stopped pre-operatively and restarted postoperatively was very variable and dependent on local guidelines or urologist preference. Almost half (49.5%) of the respondents would stop clopidogrel irrespective of its indication and 40.7% never consulted a cardiologist/haematologist before stopping clopidogrel. Less than half (43.4%) had a protocol/guideline in place concerning stopping clopidogrel before surgery. Of respondents, 43% do not routinely prescribe bridging therapy after discontinuing clopidogrel. Over half (55%) reported bleeding complications in patients who continued their clopidogrel during urological procedures and 22 (7.4%) of respondents reported an adverse thrombo-embolic event after stopping clopidogrel. The vast majority of respondents (92.8%) felt evidence-based guidelines on clopidogrel use during the peri-operative period would be useful.
This survey has highlighted a significant variation in practice with regards to pre- and postoperative management of clopidogrel in patients undergoing urological procedures. The results of this survey highlight the need for evidence-based guidelines for the peri-operative management of patients on clopidogrel.
PMCID: PMC2749402  PMID: 19344548
Clopidogrel; Peri-operative management; Bleeding complications; Thrombosis; Urology; Survey
17.  Smoking and Smoking Cessation in Relation to Mortality 
Smoking causes death in many ways, but the rate of risk reduction after quitting, compared to continuing to smoke, is uncertain. There is inadequate or insufficient evidence to infer the presence or absence of a causal relationship between smoking and ovarian cancer and colorectal cancer.
To assess the relation between cigarette smoking and smoking cessation on total and cause-specific mortality in women.
Design, Setting, and Participants
Prospective observational study of 104,519 female participants in the Nurses’ Health Study followed from 1980 to 2004.
Main Outcome Measure
Hazard ratios for total mortality, further categorized into vascular and respiratory diseases, cancers and other causes.
A total of 12483 deaths occurred in this cohort, 4485 (35.9%) among never smokers, 3602 (28.9%) among current smokers, and 4396 (35.2%) among past smokers. Compared to never smokers, current smokers had an increased risk of total mortality (hazard ratio = 2.81, 95% confidence interval (CI) = 2.68–2.95) and all major cause-specific mortality evaluated. The hazard ratio for cancers classified by the 2004 Surgeon General’s report to be smoking-related was 7.25 (CI:6.43–8.18) and for other cancers, 1.58 (CI:1.45–1.73). The hazard ratio for colorectal cancer was 1.63 (CI:1.29–2.05) for current smokers and 1.23 (CI:1.02–1.49) for former smokers, compared to never smokers. A significant association was not observed for ovarian cancer. Significant trends were observed for earlier age at initiation for total mortality (P=0.003), respiratory disease mortality (P=0.001), and all smoking-caused cancer mortality (P=0.001). The excess risk for all-cause mortality decreases to the level of a never smoker 20 years after quitting, with different timeframes for risk reduction observed across outcomes. Approximately 64% of deaths among current smokers and 28% of deaths among former smokers were attributable to cigarette smoking.
Most of the excess risk of vascular mortality due to smoking can be eliminated rapidly upon cessation and within 20 years for lung diseases. Postponing the age of smoking initiation has a dramatic impact on risk of respiratory disease, lung cancer, and other smoking-caused cancer deaths and little effect on other cause-specific mortality. These data suggest that smoking increases the risk of colorectal cancer mortality but not ovarian cancer mortality.
PMCID: PMC2879642  PMID: 18460664
18.  Interaction Between Cigarette Smoking and Clinical Benefit of Clopidogrel 
To examine the interaction between cigarette smoking and clinical efficacy of clopidogrel in STEMI.
Cigarette smoking induces CYP1A2, which converts clopidogrel into its active metabolite, and prior studies suggest greater inhibition of platelet aggregation by clopidogrel in smokers of ≥10 cigarettes/day.
The effect of clopidogrel compared with placebo on angiographic and clinical outcomes was examined in CLARITY-TIMI 28, a randomized trial of 3429 STEMI patients, stratified by smoking intensity as follows: not current smokers (N=1732), smokers of 1-9 (N=206), 10-19 (N=354), 20-29 (N=715), and ≥30 cigarettes/day (N=422). Logistic regression was used to adjust for other baseline characteristics and interaction terms to test for effect modification.
Although clopidogrel reduced the rate of the primary endpoint of a closed infarctrelated artery or death/MI before angiography in CLARITY-TIMI 28, the benefit was especially marked among those who smoked ≥10 cigarettes/day (adjusted OR 0.49, 95% CI 0.37-0.66; P<0.0001) as compared to those who did not (adjusted OR 0.72, 95% CI 0.57-0.91; P=0.006; Pinteraction=0.04). Similarly, clopidogrel was significantly more effective at reducing the rate of cardiovascular death, MI, or urgent revascularization through 30 days among those who smoked ≥10 cigarettes/day (adjusted OR 0.54, 95% CI 0.38-0.76; P=0.0004) compared with those who did not (adjusted OR 0.98; 95% CI 0.75-1.28; P=0.87; Pinteraction=0.006).
Cigarette smoking appears to positively modify the beneficial effect of clopidogrel on angiographic and clinical outcomes. This study demonstrates that common clinical factors that influence the metabolism of clopidogrel may impact its clinical effectiveness.
PMCID: PMC2675920  PMID: 19358940
clopidogrel; smoking; cytochrome P450
19.  Ticagrelor vs. clopidogrel in patients with non-ST-elevation acute coronary syndrome with or without revascularization: results from the PLATO trial 
European Heart Journal  2014;35(31):2083-2093.
The optimal platelet inhibition strategy for ACS patients managed without revascularization is unknown.
We aimed to evaluate efficacy and safety of ticagrelor vs. clopidogrel in the non-ST-elevation acute coronary syndrome (NSTE-ACS) subgroup of the PLATO trial, in the total cohort, and in the subgroups managed with and without revascularization within 10 days of randomization.
Methods and results
We performed a retrospective analysis of the primary endpoint of cardiovascular death/myocardial infarction/stroke. Among 18 624 PLATO patients, 11 080 (59%) were categorized as NSTE-ACS at randomization. During the initial 10 days, 74% had angiography, 46% PCI, and 5% CABG. In NSTE-ACS patients, the primary endpoint was reduced with ticagrelor vs. clopidogrel [10.0 vs. 12.3%; hazard ratio (HR) 0.83; 95% confidence interval (CI) = 0.74–0.93], as was myocardial infarction (6.6 vs. 7.7%; HR 0.86; 95% CI = 0.74–0.99), cardiovascular death (3.7 vs. 4.9%; HR 0.77; 95% CI = 0.64–0.93), and all-cause death (4.3 vs. 5.8%; HR 0.76; 95% CI = 0.64–0.90). Major bleeding rate was similar between treatment groups (13.4 vs. 12.6%; HR 1.07; 95% CI = 0.95–1.19), but ticagrelor was associated with an increase in non-CABG major bleeding (4.8 vs. 3.8%; HR 1.28; 95% CI = 1.05–1.56). Within the first 10 days, 5366 (48.4%) patients were managed without revascularization. Regardless of revascularization or not, ticagrelor consistently reduced the primary outcome (HR 0.86 vs. 0.85, interaction P = 0.93), and all-cause death (HR 0.75 vs. 0.73, interaction P = 0.89) with no significant increase in overall major bleeding.
In patients with NSTE-ACS, benefit of ticagrelor over clopidogrel in reducing ischaemic events and total mortality was consistent with the overall PLATO trial, independent of actually performed revascularization during the initial 10 days.
PMCID: PMC4132637  PMID: 24727884
Platelet inhibition; Acute coronary syndrome
20.  Current and Former Smoking and Risk for Venous Thromboembolism: A Systematic Review and Meta-Analysis 
PLoS Medicine  2013;10(9):e1001515.
In a meta-analysis of 32 observational studies involving 3,966,184 participants and 35,151 events, Suhua Wu and colleagues found that current, ever, and former smoking was associated with risk of venous thromboembolism.
Please see later in the article for the Editors' Summary
Smoking is a well-established risk factor for atherosclerotic disease, but its role as an independent risk factor for venous thromboembolism (VTE) remains controversial. We conducted a meta-analysis to summarize all published prospective studies and case-control studies to update the risk for VTE in smokers and determine whether a dose–response relationship exists.
Methods and Findings
We performed a literature search using MEDLINE (source PubMed, January 1, 1966 to June 15, 2013) and EMBASE (January 1, 1980 to June 15, 2013) with no restrictions. Pooled effect estimates were obtained by using random-effects meta-analysis. Thirty-two observational studies involving 3,966,184 participants and 35,151 VTE events were identified. Compared with never smokers, the overall combined relative risks (RRs) for developing VTE were 1.17 (95% CI 1.09–1.25) for ever smokers, 1.23 (95% CI 1.14–1.33) for current smokers, and 1.10 (95% CI 1.03–1.17) for former smokers, respectively. The risk increased by 10.2% (95% CI 8.6%–11.8%) for every additional ten cigarettes per day smoked or by 6.1% (95% CI 3.8%–8.5%) for every additional ten pack-years. Analysis of 13 studies adjusted for body mass index (BMI) yielded a relatively higher RR (1.30; 95% CI 1.24–1.37) for current smokers. The population attributable fractions of VTE were 8.7% (95% CI 4.8%–12.3%) for ever smoking, 5.8% (95% CI 3.6%–8.2%) for current smoking, and 2.7% (95% CI 0.8%–4.5%) for former smoking. Smoking was associated with an absolute risk increase of 24.3 (95% CI 15.4–26.7) cases per 100,000 person-years.
Cigarette smoking is associated with a slightly increased risk for VTE. BMI appears to be a confounding factor in the risk estimates. The relationship between VTE and smoking has clinical relevance with respect to individual screening, risk factor modification, and the primary and secondary prevention of VTE.
Please see later in the article for the Editors' Summary
Editors' Summary
Blood normally flows throughout the human body, supplying its organs and tissues with oxygen and nutrients. But, when an injury occurs, proteins called clotting factors make the blood gel (coagulate) at the injury site. The resultant clot (thrombus) plugs the wound and prevents blood loss. Occasionally, a thrombus forms inside an uninjured blood vessel and partly or completely blocks the blood flow. Clot formation inside one of the veins deep within the body, usually in a leg, is called deep vein thrombosis (DVT) and can cause pain, swelling, and redness in the affected limb. DVT can be treated with drugs that stop the blood clot from getting larger (anticoagulants) but, if left untreated, part of the clot can break off and travel to the lungs, where it can cause a life-threatening pulmonary embolism. DVT and pulmonary embolism are collectively known as venous thromboembolism (VTE). Risk factors for VTE include having an inherited blood clotting disorder, oral contraceptive use, prolonged inactivity (for example, during a long-haul plane flight), and having surgery. VTEs are present in about a third of all people who die in hospital and, in non-bedridden populations, about 10% of people die within 28 days of a first VTE event.
Why Was This Study Done?
Some but not all studies have reported that smoking is also a risk factor for VTE. A clear demonstration of a significant association (a relationship unlikely to have occurred by chance) between smoking and VTE might help to reduce the burden of VTE because smoking can potentially be reduced by encouraging individuals to quit smoking and through taxation policies and other measures designed to reduce tobacco consumption. In this systematic review and meta-analysis, the researchers examine the link between smoking and the risk of VTE in the general population and investigate whether heavy smokers have a higher risk of VTE than light smokers. A systematic review uses predefined criteria to identify all the research on a given topic; meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 32 observational studies (investigations that record a population's baseline characteristics and subsequent disease development) that provided data on smoking and VTE. Together, the studies involved nearly 4 million participants and recorded 35,151 VTE events. Compared with never smokers, ever smokers (current and former smokers combined) had a relative risk (RR) of developing VTE of 1.17. That is, ever smokers were 17% more likely to develop VTE than never smokers. For current smokers and former smokers, RRs were 1.23 and 1.10, respectively. Analysis of only studies that adjusted for body mass index (a measure of body fat and a known risk factor for conditions that affect the heart and circulation) yielded a slightly higher RR (1.30) for current smokers compared with never smokers. For ever smokers, the population attributable fraction (the proportional reduction in VTE that would accrue in the population if no one smoked) was 8.7%. Notably, the risk of VTE increased by 10.2% for every additional ten cigarettes smoked per day and by 6.1% for every additional ten pack-years. Thus, an individual who smoked one pack of cigarettes per day for 40 years had a 26.7% higher risk of developing VTE than someone who had never smoked. Finally, smoking was associated with an absolute risk increase of 24.3 cases of VTE per 100,000 person-years.
What Do These Findings Mean?
These findings indicate that cigarette smoking is associated with a statistically significant, slightly increased risk for VTE among the general population and reveal a dose-relationship between smoking and VTE risk. They cannot prove that smoking causes VTE—people who smoke may share other unknown characteristics (confounding factors) that are actually responsible for their increased risk of VTE. Indeed, these findings identify body mass index as a potential confounding factor that might affect the accuracy of estimates of the association between smoking and VTE risk. Although the risk of VTE associated with smoking is smaller than the risk associated with some well-established VTE risk factors, smoking is more common (globally, there are 1.1 billion smokers) and may act synergistically with some of these risk factors. Thus, smoking behavior should be considered when screening individuals for VTE and in the prevention of first and subsequent VTE events.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute provides information on deep vein thrombosis (including an animation about how DVT causes pulmonary embolism), and information on pulmonary embolism
The UK National Health Service Choices website has information on deep vein thrombosis, including personal stories, and on pulmonary embolism; SmokeFree is a website provided by the UK National Health Service that offers advice on quitting smoking
The non-profit organization US National Blood Clot Alliance provides detailed information about deep vein thrombosis and pulmonary embolism for patients and professionals and includes a selection of personal stories about these conditions
The World Health Organization provides information about the dangers of tobacco (in several languages), from the US National Cancer Institute, offers online tools and resources to help people quit smoking
MedlinePlus has links to further information about deep vein thrombosis, pulmonary embolism, and the dangers of smoking (in English and Spanish)
PMCID: PMC3775725  PMID: 24068896
21.  Mortality Benefit with Prasugrel in the TRITON-TIMI 38 Coronary Artery Bypass Grafting (CABG) Cohort: Risk-Adjusted Retrospective Data Analysis 
The objective of this study is to characterize the bleeding, transfusion and other outcomes of patients related to the timing of prasugrel or clopidogrel withdrawal prior to coronary artery bypass grafting (CABG).
There is little evidence to guide clinical decision making regarding the use of prasugrel in patients who may need urgent or emergency CABG. Experience with performing CABG in the presence of clopidogrel has raised concern about perioperative bleeding complications that are unresolved.
A subset of the TRITON TIMI 38 study, where patients with acute coronary syndrome were randomized to treatment with aspirin and either clopidogrel or prasugrel, underwent isolated CABG (N=346). A supplemental case report form was designed and administered, and the data combined with the existing TRITON-TIMI 38 database. Baseline imbalances were corrected for using elements of the European System for Cardiac Operative Risk Evaluation and The Society of Thoracic Surgeons predictive algorithm.
A significantly higher mean 12 hr chest tube blood loss (655±580 ml vs. 503±378 ml, p=0.050) was observed with prasugrel compared to clopidogrel, without significant differences in red blood cell transfusion (2.1 units vs. 1.7 units, p=0.442) or the total donor exposure (4.4 units vs. 3.0 units, p=0.463). All-cause mortality was significantly reduced with prasugrel (2.31%) compared to 8.67% with clopidogrel (adjusted odds ratio [OR], 0.26, p=0.025).
Despite an increase in observed bleeding, platelet transfusion and surgical re-exploration for bleeding, prasugrel was associated with a lower rate of death following CABG compared to clopidogrel.
PMCID: PMC3407327  PMID: 22633653
Acute coronary syndrome; prasugrel; coronary artery bypass grafting; mortality; clopidogrel
22.  Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction—a hospital registry-primary care linked cohort (MINAP–GPRD) 
European Heart Journal  2011;32(19):2376-2386.
Adherence to evidence-based treatments and its consequences after acute myocardial infarction (MI) are poorly defined. We examined the extent to which clopidogrel treatment initiated in hospital is continued in primary care; the factors predictive of clopidogrel discontinuation and the hazard of death or recurrent MI.
Methods and results
We linked the Myocardial Ischaemia National Audit Project registry and the General Practice Research Database to examine adherence to clopidogrel in primary care among patients discharged from hospital after MI (2003–2009). Hospital Episode Statistics and national mortality data were linked, documenting all-cause mortality and non-fatal MI. Of the 7543 linked patients, 4650 were prescribed clopidogrel in primary care within 3 months of discharge. The adjusted odds of still being prescribed clopidogrel at 12 months were similar following non-ST-elevation myocardial infarction (NSTEMI) 53% (95% CI, 51–55) and ST-elevation myocardial infarction (STEMI) 54% (95% CI, 52–56), but contrast with statins: NSTEMI 84% (95% CI, 82–85) and STEMI 89% (95% CI, 87–90). Discontinuation within 12 months was more frequent in older patients [>80 vs. 40–49 years, adjusted hazard ratio (HR) 1.50 (95% CI, 1.15–1.94)] and with bleeding events [HR 1.34 (95% CI, 1.03–1.73)]. 18.15 patients per 100 person-years (95% CI, 16.83–19.58) died or experienced non-fatal MI in the first year following discharge. In patients who discontinued clopidogrel within 12 months, the adjusted HR for death or non-fatal MI was 1.45 (95% CI, 1.22–1.73) compared with untreated patients, and 2.62 (95% CI, 2.17–3.17) compared with patients persisting with clopidogrel treatment.
This is the first study to use linked registries to determine persistence of clopidogrel treatment after MI in primary care. It demonstrates that discontinuation is common and associated with adverse outcomes.
PMCID: PMC3184230  PMID: 21875855
ACS; Myocardial infarction; Clopidogrel; Anti-platelet; Observational
23.  Diabetes: prevention of cardiovascular events  
Clinical Evidence  2006;2006:0601.
Diabetes mellitus is a major risk factor for cardiovascular disease. In the USA, a survey of deaths in 1986 suggested that 60−75% of people with diabetes die from cardiovascular causes.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of promoting smoking cessation; controlling blood pressure; treating dyslipidaemia; blood glucose control; treating multiple risk factors; revascularisation procedures; and antiplatelet drugs in people with diabetes? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 63 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antihypertensive drugs, antihypertensive treatment, aspirin, clopidogrel, coronary artery bypass graft, diet, fibrates, glycaemic control (intensive versus conventional control), heparin (with or without glycoprotein IIb/IIIa inhibitors, or clopidogrel), lower target blood pressures, metformin, multiple risk factor treatment (intensive), percutaneous transluminal coronary angioplasty (plus stent), smoking cessation, statins (aggressive or moderate lipid lowering, low or standard dose), stent (plus glycoprotein IIb/IIIa inhibitors), thrombolysis.
Key Points
People with diabetes mellitus have 2−4 times the risk of cardiovascular disease, and are up to 3 times more likely to die after a myocardial infarction, compared with normoglycaemic people.
Intensive treatment of multiple risk factors in people with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular disease compared with conventional treatment. Promotion of smoking cessation is likely to reduce cardiovascular events in people with diabetes, although no studies have specifically studied this.
Tight control of blood pressure and reduction of cholesterol reduces the risk of cardiovascular events in people with hypertension and diabetes. Angiotensin converting enzyme inhibitors, angiotensin receptor antagonists, beta-blockers, calcium channel blockers and diuretics have all been shown to have similar antihypertensive effects.Reduction of cholesterol with statins reduces cardiovascular morbidity and mortality in people with diabetes regardless of initial cholesterol levels, and fibrates may also be beneficial. Aspirin and clopidogrel have not been consistently shown to reduce cardiovascular events or mortality in people with diabetes and cardiovascular disease compared with controls, and increase the risk of bleeding.Intensive blood glucose control reduces the risk of cardiovascular events in people with type 1 diabetes, but has not been consistently shown to reduce cardiovascular morbidity or mortality in people with type 2 diabetes.
Coronary artery bypass grafts reduce 4 year mortality compared with percutaneous transluminal coronary angioplasty (PTCA) in people with diabetes, although longer term benefits are unclear. PTCA may reduce short term mortality or myocardial infarction compared with thrombolysis in people with diabetes and acute myocardial infarction.Adding glycoprotein IIb/IIIa inhibitors reduces cardiovascular morbidity and mortality compared with placebo in people with acute coronary syndrome or undergoing PTCA plus stenting.
PMCID: PMC2907631
24.  Ticagrelor vs. clopidogrel in patients with acute coronary syndromes and diabetes: a substudy from the PLATelet inhibition and patient Outcomes (PLATO) trial 
European Heart Journal  2010;31(24):3006-3016.
Patients with diabetes mellitus (DM) have high platelet reactivity and are at increased risk of ischaemic events and bleeding post-acute coronary syndromes (ACS). In the PLATelet inhibition and patient Outcomes (PLATO) trial, ticagrelor reduced the primary composite endpoint of cardiovascular death, myocardial infarction, or stroke, but with similar rates of major bleeding compared with clopidogrel. We aimed to investigate the outcome with ticagrelor vs. clopidogrel in patients with DM or poor glycaemic control.
Methods and results
We analysed patients with pre-existing DM (n = 4662), including 1036 patients on insulin, those without DM (n = 13 951), and subgroups based on admission levels of haemoglobin A1c (HbA1c; n = 15 150). In patients with DM, the reduction in the primary composite endpoint (HR: 0.88, 95% CI: 0.76–1.03), all-cause mortality (HR: 0.82, 95% CI: 0.66–1.01), and stent thrombosis (HR: 0.65, 95% CI: 0.36–1.17) with no increase in major bleeding (HR: 0.95, 95% CI: 0.81–1.12) with ticagrelor was consistent with the overall cohort and without significant diabetes status-by-treatment interactions. There was no heterogeneity between patients with or without ongoing insulin treatment. Ticagrelor reduced the primary endpoint, all-cause mortality, and stent thrombosis in patients with HbA1c above the median (HR: 0.80, 95% CI: 0.70–0.91; HR: 0.78, 95% CI: 0.65–0.93; and HR: 0.62, 95% CI: 0.39–1.00, respectively) with similar bleeding rates (HR: 0.98, 95% CI: 0.86–1.12).
Ticagrelor, when compared with clopidogrel, reduced ischaemic events in ACS patients irrespective of diabetic status and glycaemic control, without an increase in major bleeding events.
PMCID: PMC3001588  PMID: 20802246
Acute coronary syndromes; Diabetes; Ticagrelor; Clopidogrel; Mortality; Myocardial infarction
25.  Oral Antiplatelet Therapy in Acute Coronary Syndromes: Recent Developments 
Cardiology and Therapy  2013;2(1):47-56.
The purpose of this article is to summarize the current knowledge about treatment with oral platelet inhibitors in patients with acute coronary syndrome (ACS). Antiplatelet therapy has been shown to improve the prognosis of patients with ACS with ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation ACS (NSTE-ACS). Aspirin should be given with a loading dose of 250–500 mg, followed by 75–100 mg/day. Dual antiplatelet therapy is recommended for all patients with ACS for 12 months regardless of the initial revascularization strategy. Clopidogrel should be administered at first medical contact in STEMI with a loading dose of 600 mg. In patients with ACS and percutaneous coronary intervention (PCI) 2 × 75 mg clopidogrel should be given daily over 7 days, while in all other patients 75 mg per day appears to be sufficient. The two newer adenosine diphosphate-receptor antagonists prasugrel and ticagrelor lead to a more rapid and effective inhibition of platelet aggregation compared with clopidogrel, which was associated with an improved clinical outcome in two large randomized studies. Prasugrel is indicated in patients with ACS undergoing PCI and was most effective in diabetics and in patients with STEMI. In the recent TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes trial in medically treated patients with NSTE-ACS, prasugrel did not significantly reduce ischemic events compared with clopidogrel. Ticagrelor has been studied in the whole spectrum of ACS patients and reduced cardiovascular and total mortality in comparison with clopidogrel. The greatest benefit has been observed in patients with planned conservative treatment and in patients with impaired renal function. Expanding antiplatelet therapy from dual to triple therapy including a platelet thrombin receptor antagonist in the thrombin receptor antagonist for clinical event reduction in acute coronary syndrome trial was not associated with a significant reduction in the primary combined endpoint but an increase in bleeding complications. However, in the Thrombin Receptor Antagonist in Secondary Prevention of atherothrombotic ischemic events study in patients with prior myocardial infarction, vorapaxar on top of standard antiplatelet therapy was effective.
PMCID: PMC4107436  PMID: 25135288
Acute coronary syndromes; Antiplatelets; Cardiology; Clopidogrel; Prasugrel; Ticagrelor

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