Safety and efficacy of protease‐activated receptor‐1 antagonists in patients with coronary artery disease: a meta‐analysis of randomized clinical trials

Summary. Background: Thrombin receptor antagonists blocking protease‐activated receptor‐1 (PAR‐1) on platelets represent a new class of oral antiplatelet agents for patients with atherothrombotic disease manifestations. Objectives: We investigated the safety and efficacy of PAR‐1 antagonists in patients with coronary artery disease (CAD). Patients/Methods: Randomized, placebo‐controlled trials of the PAR‐1 antagonists atopaxar or vorapaxar in CAD patients were identified. The primary safety endpoint was the composite of Thrombolysis In Myocardial Infarction (TIMI) clinically significant bleeding. The primary efficacy endpoint was the composite of death, myocardial infarction (MI) or stroke. Results: A total of 41 647 patients from eight trials were included. PAR‐1 antagonists were associated with higher risks of TIMI clinically significant (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.39–1.57, P < 0.001), major (OR 1.46, 95% CI 1.28–1.67, P < 0.001) and minor (OR 1.67, 95% CI 1.40–2.00, P < 0.001) bleeding than placebo in the fixed‐effects model. PAR‐1 antagonists reduced the composite of death, MI or stroke as compared with placebo (OR 0.87, 95% CI 0.81–0.92, P < 0.001), driven by a lower risk of MI (OR 0.85, 95% CI 0.78–0.92, P < 0.001). Conversely, PAR‐1 antagonists and placebo did not differ in terms of risk of death (OR 0.99, 95% CI 0.90–1.09, P = 0.81) or stroke (OR 0.96, 95% CI 0.84–1.10, P = 0.59). Conclusions: PAR‐1 antagonists decrease ischemic events in patients with CAD as compared with placebo, mainly driven by a reduction in MI, at the cost of an increased risk of clinically significant bleeding.     

Thalassemia trait and arterial thromboembolic events: a systematic review and a meta‐analysis of the literature

Summary. Background: An increased risk of venous thromboembolic events has been reported in thalassemic patients, in particular in patients with thalassemia intermedia. The association between β‐thalassemia trait and atherothrombotic cardiovascular events is not well established. Methods: In a systematic review and meta‐analysis of the literature, we evaluated the association between β‐thalassemia trait and arterial cardiovascular disease. Studies were identified from the MEDLINE and EMBASE (until July 2010) electronic databases. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated with a random‐effects model. Statistical heterogeneity was evaluated with the I² statistic. Results: Of the 354 identified articles, eight case–control studies were eligible for the analysis. β‐Thalassemia trait was associated with a reduced risk of arterial cardiovascular disease (OR 0.45; 95% CI 0.45–0.60). Heterogeneity among studies was low (I² = 13%). The protective effect of β‐thalassemia trait was confined to male patients (OR 0.39; 95% CI 0.24–0.62), and was not observed in female subjects (OR 0.89; 95% CI 0.52–1.53). Conclusions: β‐Thalassemia trait may act as a protective factor against the development of arterial cardiovascular and cerebrovascular disease in male subjects. Larger prospective studies are necessary to confirm these preliminary findings and to further investigate the mechanisms underlying this protective effect.     

Heparin‐associated thrombocytopenia in 24 401 patients with venous thromboembolism: findings from the RIETE Registry1

Summary. Background: Whether the treatment of venous thromboembolism (VTE) with unfractionated heparin (UFH) confers a higher risk of thrombocytopenia than does treatment with low molecular weight heparin (LMWH) remains controversial, and very few data are available from routine clinical practice. Objectives: We assessed the incidence, risk factors and prognosis of heparin‐associated thrombocytopenia (HAT) according to the type of heparin therapy, UFH or LMWH. Patients/Methods: Data were obtained from the international prospective Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE), which included 25 369 patients with confirmed VTE until February 2009. Among them, 24 401 patients were treated either with UFH or with LMWH, and had available information about the 6‐month occurrence of confirmed thrombocytopenia, defined as a platelet count ≤ 150 000 mm^–3. Results: One hundred and forty‐one patients receiving UFH and/or LMWH developed thrombocytopenia within a 6‐month period. The incidence of HAT was significantly higher in the UFH group (1.36%, 95% confidence interval [CI] 0.79–2.17) than in the LMWH group (0.54%, 95% CI 0.44–0.64). As compared with LMWH, UFH significantly increased the risk of HAT in female patients (adjusted hazard ratio [HR] 4.90%, 95% CI 2.58–9.31, P = 0.001) but not in male patients (adjusted HR 1.60%, 95% CI 0.64–3.97, P = 0.31); P = 0.027 for comparison. In each gender, the UFH‐associated excess risk was confined to patients with VTE unrelated to cancer. The poor prognosis of patients with thrombocytopenia was not influenced by the type of heparin therapy. Conclusions: In routine clinical practice, treatment of VTE with UFH seems to confer a higher risk of thrombocytopenia than does treatment with LMWH, especially in women and non‐cancerous patients.     

Anticoagulant therapy for venous thromboembolism during pregnancy: a systematic review and a meta‐analysis of the literature

Summary. Venous thromboembolism (VTE) is one of the most relevant causes of maternal death in industrialized countries. Low molecular weight heparin (LMWH), continued throughout the entire pregnancy and puerperium, is currently the preferred treatment for patients with acute VTE occurring during pregnancy. However, information on the efficacy and safety of anticoagulant drugs in this setting is extremely limited. We carried out a systematic review and a meta‐analysis of the literature to provide an estimate of the risk of bleeding complications and VTE recurrence in patients with acute VTE during pregnancy treated with antithrombotic therapy. The weight mean incidence (WMI) of bleeding and thromboembolic events and the corresponding 95% confidence interval (CI) were calculated. Eighteen studies, giving a total of 981 pregnant patients with acute VTE, were included. LMWH was prescribed to 822 patients; the remainder were treated with unfractionated heparin. Anticoagulant therapy was associated with WMIs of major bleeding of 1.41% (95% CI 0.60–2.41%; I) antenatally and 1.90% (95% CI 0.80–3.60%) during the first 24 h after delivery. The estimated WMI of recurrent VTE during pregnancy was 1.97% (95% CI 0.88–3.49%; I² 39.5%). Anticoagulant therapy appears to be safe and effective for the treatment of pregnancy‐related VTE, but the optimal dosing regimens remain uncertain.     

Incidence of arterial cardiovascular events after venous thromboembolism: a systematic review and a meta‐analysis

Summary. Background: Whether patients with unprovoked venous thromboembolism (VTE) have a higher risk of arterial cardiovascular events than the general population and patients with provoked VTE is a matter of debate. Objective: To perform a systematic review and a meta‐analysis aimed at assessing the risk of arterial cardiovascular events in patients with unprovoked VTE as compared with both patients with provoked VTE and controls. Methods: A systematic search was performed. Studies reporting on (i) patients with confirmed VTE, (ii) a follow‐up of at least 6 months and (iii) the incidence of arterial cardiovascular events (acute myocardial infarction and ischemic stroke) were included in the systematic review. Those studies reporting separate incidences of cardiovascular events in patients with unprovoked and provoked VTE or patients with unprovoked VTE and controls were included in the incidence rate meta‐analysis. Results: Overall, 17 studies were included in the systematic review. The weighted mean incidence of arterial cardiovascular events was 0.46% [95% confidence interval (CI) 0.34–0.59] and 0.35% (95% CI 0.24–0.49) per patient‐year in patients with unprovoked and provoked VTE, respectively. Six studies were included in the meta‐analysis. The risk of arterial cardiovascular events appeared to be higher in patients with unprovoked VTE than in controls [incidence rate ratio (IRR) 1.87, 95% CI 1.32–2.65] and than in patients with provoked VTE (IRR 1.86, 95% CI 1.19–2.89). Conclusions: Patients with unprovoked VTE have a higher risk of arterial cardiovascular events than patients with provoked VTE over long‐term follow‐up.     

Parental history and venous thromboembolism: a nationwide study of age‐specific and sex‐specific familial risks in Sweden

Summary. Background: The value of parental history as a risk indicator for venous thromboembolism (VTE) has not been determined in a nationwide setting. Objectives: To perform the first nationwide study of age‐specific and sex‐specific familial VTE risks in offspring of parents hospitalized for VTE. Patients/Methods: The Swedish Multigeneration Register of 0–75‐year‐old subjects was linked to the Hospital Discharge Register for 1987–2007. Standardized incidence ratios (SIRs) were calculated for individuals whose parents were hospitalized for VTE as compared with those whose parents were unaffected. Results: Among 45 362 hospitalized offspring cases with VTE, 4865 offspring of affected parents were identified with a familial SIR of 2.00 (95% confidence interval [CI] 1.94–2.05). Familial SIR was slightly higher for male offspring than for female offspring (2.08, 95% CI 2.00–2.16 vs. 1.91, 95% CI 1.84–1.99). The risk in offspring was further increased when both parents were affected (3.97, 95% CI 3.40–4.61), with high familial risks at ages 20–29 years (10.00, 95% CI 5.91–15.84). The familial risks for VTE among offspring were increased from the age of 10 years up to 75 years, with familial SIRs of 3.96 (95% CI 3.13–4.94) at age 10–19 years and 1.48 (95% CI 1.17–1.84) at ages 70–75 years. However, the absolute incidence rate increased with age. Conclusions: Parental history is potentially useful for risk assessments of VTE, although age needs to be considered. Our results support the use of an age‐dependent multicausal model to estimate the risk of VTE.     

Prasugrel vs. clopidogrel for cytochrome P450 2C19‐genotyped subgroups: integration of the TRITON‐TIMI 38 trial data

Summary. Background: Prasugrel is a newly marketed antiplatelet drug with improved cardiac outcomes as compared with clopidogrel for acute coronary syndromes involving percutaneous coronary intervention (PCI). Analysis of a subset of the TRITON‐TIMI 38 trial demonstrated that cytochrome P450 2C19 (CYP2C19) reduced‐function genotypes are associated with differential clinical responses to clopidogrel, but not prasugrel. Whether the CYP2C19 genotype has the potential to influence clinical choice of these drugs prior to PCI for individuals with unstable angina or non‐ST segment elevation myocardial infarction is currently uncertain. Methods and Results: An exploratory, secondary analysis was undertaken to estimate the clinical benefit of prasugrel over clopidogrel in subgroups defined by CYP2C19 genotype, by integrating the published results of the genetic substudy and the overall TRITON‐TIMI 38 trial. Individuals with a CYP2C19 reduced‐metabolizer genotype were estimated to have a substantial reduction in the risk of the composite primary outcome (cardiovascular death, myocardial infarction, or stroke) with prasugrel as compared with clopidogrel [relative risk (RR) 0.57; 95% confidence interval (CI) 0.39–0.83]. For CYP2C19 extensive metabolizers (～ 70% of the population), however, the composite outcome risks with prasugrel and clopidogrel were not substantially different (RR 0.98; 95% CI 0.80–1.20). Conclusions: Integration of the TRITON‐TIMI 38 data suggests that the CYP2C19 genotype can discriminate between individuals who receive extensive benefit from using prasugrel instead of clopidogrel, and individuals with comparable clinical outcomes with prasugrel and clopidorel. Thus, CYP2C19 genotyping has the potential to guide the choice of antiplatelet therapy, and further research is warranted to validate this estimate.     

Predictors of the post‐thrombotic syndrome with non‐invasive venous examinations in patients 6 weeks after a first episode of deep vein thrombosis

Summary. Background: Post‐thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) affecting a large number of patients. Because of its potential debilitating effects, identification of patients at high risk for the development of this syndrome is relevant, and only a few predictors are known. Objectives: To assess the incidence and potential predictors of PTS. Methods: We prospectively followed 111 consecutive patients for 2 years after a first episode of objectively documented DVT of the leg. With non‐invasive venous examinations, residual thrombosis, valvular reflux, calf muscle pump function and venous outflow resistance were assessed at 6 weeks, 3 months, 6 months, 1 year, and 2 years. The Clinical, Etiologic, Anatomic, and Pathophysiologi classification was used to record the occurrence and severity of PTS. Regression analysis with area under the receiver operating characteristic (ROC) curve was performed to identify potential predictors. Results: The cumulative incidence of PTS was 46% after 3 months, and the incidence and severity did not increase further. Men appeared to be at increased risk as compared with women (risk ratio [RR] 1.4, 95% confidence interval [CI] 0.9–2.2), as were patients over 50 years as compared with younger patients (RR 1.4%, 95% CI 0.9–2.1). Patients with thrombosis localized in the proximal veins at diagnosis had an increased risk of PTS as compared with patients with distal thrombosis (RR 2.3%, 95% CI 1.0–5.6). PTS developed in 32 of 52 patients (62%) with residual thrombosis in the proximal veins 6 weeks after diagnosis, as compared with 17 of 45 patients (38%) without residual proximal thrombosis, leading to a 1.6‐fold increased risk (95% CI 1.0–2.5). The presence of valvular reflux in the superficial veins was also a predictor at 6 weeks, with a 1.6‐fold increased risk as compared with patients without superficial reflux (95% CI 1.1–2.3). A multivariate analysis of these predictors yielded an area under the ROC curve of 0.72 (95% CI 0.62–0.82). Conclusions: PTS develops in half of all patients within 3 months, with no further increase being seen up to 2 years of follow‐up. Male sex, age over 50 years, proximal localization of the thrombus at entry, residual proximal thrombosis and superficial valvular reflux at 6 weeks seem to be the most important predictors of PTS in patients with a first episode of DVT. Duplex scanning 6 weeks after diagnosis appears to be clinically useful for the identification of patients at risk of PTS.     

The minor allele of GP6 T13254C is associated with decreased platelet activation and a reduced risk of recurrent cardiovascular events and mortality: results from the SMILE–Platelets project

Summary. Background: Contradictory results have been published on the effects of T13254C (rs1613662), which distinguishes the two major isoforms of GP6, the gene encoding the platelet receptor glycoprotein VI, on platelet function and the risk of cardiovascular disease. Methods: We performed a population‐based case–control study, the Study of Myocardial Infarctions in Leiden, among 547 male patients with a first myocardial infarction (MI) and 646 control subjects, as well as a prospective cohort study in which the same MI patients were followed for recurrent events (fatal and non‐fatal MI and unstable angina) and mortality (median follow‐up of 12 years). P‐selectin expression by platelets induced by crosslinked collagen‐related peptide (CRP‐XL) was measured by whole blood flow cytometry in 274 MI patients. Results: T13254C was not associated with a first MI, but seemed to be associated with a reduced incidence of recurrent events [per‐allele hazard ratio 0.77, 95% confidence interval (CI) 0.56–1.06] and mortality (hazard ratio 0.57, 95% CI 0.37–0.89). Pooling with the Heart and Estrogen/Progestin Replacement Study revealed hazard ratios of 0.81 (95% CI 0.66–0.99) and 0.73 (95% CI 0.55–0.96). The minor C‐allele was also strongly associated with a reduced percentage of P‐selectin‐expressing platelets. The reduction per C‐allele was 23% (95% CI 18–28%). In an independent study of 219 healthy volunteers, the per‐allele reduction of CRP‐XL‐induced aggregation was 10% (95% CI 2–18%). Conclusion: The minor allele of GP6 T13254C that reduced platelet activation and aggregation also seemed to be associated with a reduced incidence of recurrent cardiovascular events and mortality, but was not associated with first MI.     

Economic burden and cost determinants of deep vein thrombosis during 2 years following diagnosis: a prospective evaluation

Summary. Background: Few studies have evaluated the long‐term economic consequences of deep vein thrombosis (DVT). None of them have incorporated prospectively collected clinical data to ensure accurate identification of incident cases of DVT and DVT‐related health outcomes of interest, such as post‐thrombotic syndrome (PTS). Objectives: To prospectively quantify medical and non‐medical resource use and costs related to DVT during 2 years following diagnosis, and to identify clinical determinants of costs. Methods: Three hundred and fifty‐five consecutive patients with acute DVT were recruited at seven Canadian hospital centers. Resource use and cost information were retrieved from three sources: weekly patient‐completed cost diaries, nurse‐completed case report forms, and the Quebec provincial administrative healthcare database (RAMQ). Results: The rate of DVT‐related hospitalization was 3.5 per 100 patient‐years (95% confidence interval [CI] 2.2–4.9). Patients reported a mean (standard deviation) of 15.0 (14.5) physician visits and 0.7 (1.2) other healthcare professional visits. The average cost of DVT was $5180 (95% CI $4344–6017) in Canadian dollars, with 51.6% of costs being attributable to non‐medical resource use. Multivariate analysis identified four independent predictors of costs: concomitant pulmonary embolism (relative increase in cost [RIC] 3.16; 95% CI 2.18–4.58), unprovoked DVT (RIC 1.65; 95% CI 1.28–2.13), development of PTS during follow‐up (RIC 1.35; 95% CI 1.05–1.74), and management of DVT in the inpatient setting (RIC 1.79; 95% CI 1.33–2.40). Conclusions: The economic burden of DVT is substantial. The use of measures to prevent the occurrence of PTS and favoring outpatient care of DVT has the potential to diminish costs.     

Risk of venous thrombosis in patients with major illnesses: results from the MEGA study

Summary. Background: The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high‐risk groups that may provide a basis for personalized prevention.Methods: This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case–control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self‐reported history of major illnesses.Results: Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI] 1.0–2.9); kidney disease, OR 3.7 (95% CI 2.3–5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2–1.9); multiple sclerosis, OR 2.4 (95% CI 1.3–4.3); heart failure, OR 1.7 (95% CI 1.2–2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4–9.9); arterial thrombosis, OR 1.5 (95% CI 1.2–1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5–1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2–192.2), increased FIX (OR 35.3; 95% CI 14.2–87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9–228.3), FV Leiden (OR 84.2; 95% CI 19.5–363.6), and blood group non‐O (OR 53.1; 95% CI 30.9–91.4) were associated with increased venous thrombosis risks.Conclusions: All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia.     

Risk factors and clinical outcome of unsuspected pulmonary embolism in cancer patients: a case‐control study

Summary. Background: Little is known about the risk factors and outcome of unsuspected pulmonary embolism (UPE) in cancer patients. Objectives: To assess the risk factors and outcome of UPE in cancer patients. Methods: The charts of 66 patients diagnosed with UPE were reviewed. Two control groups were selected: 132 cancer patients without pulmonary embolism (PE) and 65 cancer patients with clinically suspected PE. Variables associated with UPE were identified by multivariable analysis. Six‐month survival and recurrent venous thromboembolism were compared by use of Cox proportional analysis. Results: Twenty‐seven (40.9%) patients with UPE had symptoms suggesting PE. Adenocarcinoma (odds ratio [OR] 4.45; 95% confidence interval [CI] 1.98–9.97), advanced age (OR 1.18; 95% CI 1.02–1.38), recent chemotherapy (OR 4.62; 95% CI 2.26–9.44), performance status > 2 (OR 7.31; 95% CI 1.90–28.15) and previous venous thromboembolism (OR 4.47; 95% CI 1.16–17.13) were associated with UPE. When adjusted for tumor stage and performance status, 6‐month mortality did not differ between patients with UPE and patients without PE (hazard ratio 1.40; 95% CI 0.53–3.66; P = 0.50). Patients with UPE were more likely to have central venous catheters and chemotherapy and less likely to have proximal clots than patients with clinically suspected PE. Recurrent venous thromboembolism occurred in 6.1% and 7.7% of patients with UPE and symptomatic PE, respectively. Conclusion: UPE is not associated with an increased risk of death. Patients with clinically suspected PE and those with UPE have similar risks of recurrent venous thromboembolism.     

Traffic exposure and incident venous thromboembolism in the Atherosclerosis Risk in Communities (ARIC) Study

Summary. Background: Two recent case–control studies in Italy reported that long‐term exposure to particulate air pollution or living near major traffic roads was associated with an increased risk of deep vein thrombosis (DVT). No prospective evidence exists on the possible association between long‐term traffic‐related air pollution and incident venous thromboembolism (VTE). Objectives: To examine the association between long‐term traffic exposure and incident VTE in a population‐based prospective cohort study. Methods: We studied 13 143 middle‐aged men and women in the Atherosclerosis Risk in Communities Study without a history of DVT or pulmonary embolism at baseline examination (1987–1989). The Geographical Information System‐mapped traffic density and distance to major roads in the four study communities served as measures of traffic exposure. We examined the association between traffic exposure and incident VTE with proportional hazards regression models. Results: A total of 405 subjects developed VTE in 2005. Traffic density was not significantly associated with VTE. Relative to those in the lowest quartile of traffic density, the adjusted hazard ratios across increasing quartiles were 1.18 (95% confidence interval [CI] 0.88–1.57), 0.99 (95% CI 0.74–1.34) and 1.14 (95% CI 0.86–1.51) (P‐value for trend across quartiles = 0.64). For residents living within 150 m of major roads, as compared with subjects living further away, the adjusted hazard ratio was 1.16 (95% CI 0.95–1.42, P = 0.14). Conclusions: This first prospective study in the general population does not support an association between air pollution exposure or traffic proximity and risk of DVT. More data may be needed to clarify whether traffic or air pollution influences the risk of VTE.     

Bleeding risk in randomized controlled trials comparing warfarin and aspirin: a systematic review and meta‐analysis

Summary. Background: Warfarin and aspirin (acetylsalicylic acid [ASA]) are the most commonly used anticoagulant and antiplatelet drugs in the treatment of cardiovascular disease.Objectives: To provide a pooled estimate of the bleeding risk from randomized controlled trials (RCTs) comparing warfarin and ASA at the dose ranges recommended in evidence‐based guidelines.Patients/Methods: Ovid MEDLINE, Embase and the Cochrane Library, up to September 2011, were searched for RCTs comparing bleeding rates in adult patients randomized to warfarin, target International Normalized Ratio (INR) 2.0–3.5, and ASA, 50–650 mg daily, with at least 3 months of follow‐up. Pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) were calculated with the inverse variance method and the random effects model.Results: Four thousand four hundred and forty‐two abstracts were screened, resulting in eight included studies for final analysis. A pooled estimate derived from the 2904 patients enrolled indicated a trend towards an increase in major bleeding risk in those randomized to warfarin (OR 1.27; 95% CI 0.83–1.94). The pooled OR for intracranial hemorrhage in patients treated with warfarin vs. ASA was 1.64 (95% CI 0.71–3.78), and that for extracranial major bleeding was 1.03 (95% CI 0.61–1.75). Minor bleeding, from a 1748‐patient sample, was more common in warfarin patients (OR 1.50; 95% CI 1.13–2.00).Conclusions: This meta‐analysis failed to find a statistically significant difference in major bleeding between warfarin, target INR 2.0–3.5, and ASA, 50–650 mg daily. The trend towards increased bleeding with warfarin appears to be explained by an excess of intracranial bleeding in warfarin patients.     

Coffee consumption and the risk of venous thromboembolism: the Tromsø study

Summary. Background: Several studies have investigated the association between coffee consumption and cardiovascular disease, but little is known about coffee intake and the risk of venous thromboembolism (VTE). Objective: The aim of this prospective cohort study was to investigate the association between coffee consumption and the risk of incident VTE in a general population. Methods: Information about coffee consumption habits was obtained with a self‐administered questionnaire in 26 755 subjects, aged 25–97 years, who participated in the fourth survey of the Tromsø study (1994–1995). Incident VTE events were registered until the end of follow‐up, 1 September 2007. Results: There were 462 incident VTE events (1.60 per 1000 person‐years, 95% confidence interval [CI] 1.46–1.75) during a median of 12.5 years of follow‐up. A daily consumption of three to four cups was borderline associated (hazard ratio [HR] 0.70; 95% CI 0.48–1.02) and a daily consumption of five to six cups (HR 0.67; 95% CI 0.45–0.97) was significantly associated with reduced risk of VTE as compared with coffee abstainers in multivariable analysis adjusted for age, sex, body mass index (BMI), smoking status, physical activity, diabetes, history of cardiovascular disease and cancer. Similar risk estimates were found for provoked and unprovoked VTE, and in sex‐stratified analyses. Conclusion: Our findings suggest a possible U‐shaped relationship between coffee consumption and VTE, and that moderate coffee consumption may be associated with a reduced risk of VTE. However, more studies are needed to establish whether moderate coffee consumption is inversely associated with the risk of VTE.     

Use of the PFA-100™ closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis

Summary. Background: PFA‐100? is a point‐of‐care assay that evaluates platelet reactivity in high‐shear‐stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA‐100?CT_CEPI for ischemic events in aspirin‐treated patients have given variable results. Objectives: To conduct a systematic review and meta‐analysis of studies on the clinical predictive value of a short PFA‐100?CT_CEPI in aspirin‐treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin‐treated patients with symptomatic atherosclerosis, measured the PFA‐100?CT_CEPI, used a CT cut‐off value to define aspirin ‘responders’ and ‘non‐responders’, and reported ischemic events. Results: We selected seven non‐prospective studies (1466 patients) and eight prospective studies (1227 patients). In non‐prospective studies, the PFA‐100?CT_CEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in ‘aspirin non‐responders’ relative to ‘aspirin responders’ was 2.1 [95% confidence interval (CI) 1.4–3.4, P < 0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P = 0.36 and I² = 9.4%). Conclusions: A short PFA‐100?CT_CEPI is associated with increased recurrence of ischemic events in aspirin‐treated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA‐100?CT_CEPI cut‐off needs to be refined in these patients.     

Influence of the paraoxonase‐1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta‐analysis

Summary. Background: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1‐Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1‐Q192R variant on the risk of MACE in clopidogrel‐treated patients is controversial. Objectives: To determine whether the PON1‐Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. Methods: Systematic review and meta‐analysis of studies of the association between the PON1‐Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. Results: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [?0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case–control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case–control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. Conclusions: This meta‐analysis suggests that the PON1‐Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel‐treated patients.     

Multiple electrode aggregometry predicts stent thrombosis better than the vasodilator‐stimulated phosphoprotein phosphorylation assay

Summary. Background and Aim: The prognostic value of the vasodilator‐stimulated phosphoprotein (VASP) phosphorylation assay and multiple electrode aggregometry (MEA) for thrombotic adverse events has been shown in independent studies. As no direct comparison between the two methods has been made so far, we investigated which laboratory approach has a better predictive value for stent thrombosis. Methods: The VASP phosphorylation assay and MEA were performed in 416 patients with coronary artery disease undergoing percutaneous coronary intervention. The rate of stent thrombosis was recorded during a 6‐month follow‐up. Results: Definite stent thrombosis occurred in three patients (0.7%) and probable stent thrombosis in four (1%). Receiver operating characteristic (ROC) analysis demonstrated that MEA distinguishes between patients with or without subsequent stent thrombosis better than the VASP phosphorylation assay: the area under the ROC curve was higher for MEA (0.92; P = 0.012) than for the VASP phosphorylation assay (0.60; P = 0.55). At equal levels of sensitivity (100%), the specificity was greater for MEA than for the VASP phosphorylation assay (86% vs. 37%). Stent thrombosis occurred in 9% of patients with platelet hyperreactivity in MEA, who were simultaneously clopidogrel non‐responders in the VASP phosphorylation assay. Interestingly, clopidogrel non‐responders in the VASP phosphorylation assay without platelet hyperreactivity in MEA did not suffer from stent thrombosis. Conclusions: Platelet hyperreactivity in MEA might be a better risk predictor for stent thrombosis than the assessment of the specific clopidogrel effect with the VASP phosphorylation assay.