Jaapjan D. Snoep

Late stent malapposition risk is higher after drug-eluting stent compared with bare-metal stent implantation and associates with late stent thrombosis.

AIMS Late stent malapposition (LSM) may be acquired (LASM) or persistent. LSM may play a role in patients who develop late stent thrombosis (ST). Our objective was to compare the risk of LASM in bare metal stents (BMS) with drug-eluting stents (DES) and to investigate the possible association of both acquired and persistent LSM with (very) late ST. METHODS AND RESULTS We searched PubMed and relevant sources from January 2002 to December 2007. Inclusion criteria were: (a) intra-vascular ultrasonography (IVUS) at both post-stent implantation and follow-up; (b) 6-9-month-follow-up IVUS; (c) implantation of either BMS or the following DES: sirolimus, paclitaxel, everolimus, or zotarolimus; and (d) follow-up for LSM. Of 33 articles retrieved for detailed evaluation, 17 met the inclusion criteria. The risk of LASM in patients with DES was four times higher compared with BMS (OR = 4.36, CI 95% 1.74-10.94) in randomized clinical trials. The risk of (very) late ST in patients with LSM (five studies) was higher compared with those without LSM (OR = 6.51, CI 95% 1.34-34.91). CONCLUSION In our meta-analysis, the risk of LASM is strongly increased after DES implantation compared with BMS. Furthermore, LSM seems to be associated with late and very late ST.

Aspirin in the prevention and treatment of venous thromboembolism

Summary.  This review summarizes available evidence on effects of aspirin on incidence and outcomes of venous thromboembolism (VTE). From a pathophysiological point of view, inhibition of platelet aggregation is associated with an impaired thrombus formation both in an experimental model of venous thrombosis and in vivo. Epidemiological evidence in support of a beneficial effect of acetylsalicylic acid on VTE incidence is provided by the Antiplatelet Trialists’ Collaboration meta‐analysis of studies on the use of antiplatelet agents in cardiovascular risk reduction, showing a significant 25% risk reduction of pulmonary embolism. Moreover, a meta‐analysis on older trials of antiplatelet agents in postsurgical VTE prevention and the large Pulmonary Embolism Prevention trial demonstrate a protective effect of the same magnitude: 25–30%. However, as low‐molecular‐weight heparins (LMWH) and vitamin K antagonists (VKA) have shown a superior efficacy and safety profile, and no direct comparisons have been made between aspirin, LMWH and VKA in prolonged use, the most recent guidelines advise against aspirin monotherapy for thromboprophylaxis in the surgical patient. Currently, there is no evidence to support a role for aspirin in air travel‐related VTE. Regarding prevention of recurrent VTE, studies are ongoing to determine the potential role of aspirin after a first unprovoked VTE.

Effect of aspirin intake at bedtime versus on awakening on circadian rhythm of platelet reactivity. A randomised cross-over trial.

The risk of acute cardiovascular events is highest during morning hours, and platelet activity peaks during morning hours. The effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity is not known. It was our objective to evaluate the effect of timing of aspirin intake on circadian rhythm and morning peak of platelet reactivity. A randomised open-label cross-over trial in healthy subjects (n=14) was conducted. Participants used acetylsalicylic acid (80 mg) on awakening or at bedtime for two periods of two weeks, separated by a four-week wash-out period. At the end of both periods blood was drawn every 3 hours to measure COX-1-dependent (VerifyNow-Aspirin; Serum Thromboxane B2 [STxB2]) and COX-1-independent (flow cytometry surface CD62p expression; microaggregation) platelet activity. VerifyNow platelet reactivity over the whole day was similar with intake on awakening and at bedtime (mean difference: -9 [95 % confidence interval (CI) -21 to 4]). However, the morning increase in COX-1-dependent platelet activity was reduced by intake of aspirin at bedtime compared with on awakening (mean difference VerifyNow: -23 Aspirin Reaction Units [CI -50 to 4]; STxB2: -1.7 ng/ml [CI -2.7 to -0.8]). COX-1-independent assays were not affected by aspirin intake or its timing. Low-dose aspirin taken at bedtime compared with intake on awakening reduces COX-1-dependent platelet reactivity during morning hours in healthy subjects. Future clinical trials are required to investigate whether simply switching to aspirin intake at bedtime reduces the risk of cardiovascular events during the high risk morning hours.

High platelet reactivity is associated with myocardial infarction in premenopausal women: a population-based case–control study

Summary.  Background: Platelets are involved in the occlusion of coronary arteries after rupture of an atherosclerotic plaque. Furthermore, activated platelets release large quantities of growth factors, chemokines and interleukines that regulate inflammatory reactions. Therefore, we hypothesized that high basal platelet reactivity may contribute to an increased risk of myocardial infarction (MI) in premenopausal women. Methods: We assessed the relation between high platelet reactivity and MI in a population‐based case–control study among premenopausal women (aged < 50 years). We used multivariable logistic regression to quantify the effect of high platelet reactivity, adjusted for potential confounders. Platelet reactivity was estimated by plasma levels of neutrophil activating peptide 2 (NAP‐2), CXC chemokine ligand (CXCL)4, soluble glycoprotein 1b (sGPIb) and soluble P‐selectin. Results: High platelet reactivity (i.e. levels ≥ 90th percentile control subjects) was associated with a 2‐ to 3‐fold increased incidence of MI: the adjusted odds ratios (ORs) were 3.0 [95% confidence interval (CI) 1.4–6.4] for NAP‐2, 2.2 (0.9–5.1) for CXCL4, 1.9 (0.7–4.6) for sP‐selectin and 2.5 (1.1–5.7) for sGPIb. The incidence of MI dose‐dependently increased when more markers were elevated. High platelet reactivity according to both NAP‐2 and sGPIb was associated with an up to tenfold increased incidence (9.9, 95% confidence interval 2.0–48.3). Conclusions: High basal platelet reactivity was associated with a 2‐ to 3‐fold higher incidence of MI compared with normal platelet reactivity in premenopausal women. Our results suggest that high basal platelet reactivity may contribute to a higher risk of MI.

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.

Time-Dependent Effects of Low-Dose Aspirin on Plasma Renin Activity, Aldosterone, Cortisol, and Catecholamines

Studies have shown that aspirin may decrease blood pressure when given at bedtime but not when administered on awakening. However, until now, a biologically plausible mechanism of this striking phenomenon was not revealed. We investigated the effect of 100 mg of aspirin administered at bedtime compared with administration on awakening on plasma renin activity and aldosterone levels over 24 hours and excretion of cortisol and catecholamines in 24-hour urine samples. A randomized, placebo-controlled, double-blind, crossover trial was performed in 16 grade 1 hypertensive subjects. During 2 periods of 2 weeks separated by a 4-week washout period, participants used aspirin both at morning and at night, which was blinded with placebo. After both periods, subjects were admitted for 24 hours to measure the aforementioned parameters. Aspirin intake at bedtime compared with on awakening reduced average (24-hour) plasma renin activity by 0.08 &mgr;g/L per hour (95% CI: 0.03 to 0.13 &mgr;g/L per hour; P=0.003) without affecting aldosterone levels (95% CI: −0.01 to 0.01 nmol/L; P=0.93). Cortisol excretion in 24-hour urine was 52 nmol/24 hours (95% CI: 5 to 99 nmol/24 hours; P=0.05) lower, and dopamine and norepinephrine excretions were 0.25 &mgr;mol/24 hours (95% CI: 0.01 to 0.48 &mgr;mol/24 hours; P=0.04) and 0.22 &mgr;mol/24 hours (95% CI: −0.03 to 0.46 &mgr;mol/24 hours; P=0.02) lower in patients treated with bedtime aspirin. In conclusion, aspirin taken at bedtime compared with on awakening significantly diminished 24-hour plasma renin activity and excretion of cortisol, dopamine, and norepinephrine in 24-hour urine. Decreased activity of these pressor systems forms a biologically plausible explanation for the finding that aspirin at night may reduce blood pressure, whereas aspirin at morning does not.

High levels of low-density lipoprotein cholesterol and triglycerides and suboptimal glycemic control predict diminished ex vivo aspirin responsiveness in patients with Type 2 diabetes.

M. M. C . HOVENS ,* J . D . SNOEP ,* Y . GROENEVELD , J . T . TAMSMA,* J . C . J . E IKENBOOM§ and M. V . HU ISMAN* *Department of General Internal Medicine and Endocrinology, Vascular Medicine Unit, Leiden University Medical Center, Leiden; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden; Department of Public Health and Primary Care, Leiden University Medical Center, Leiden; and §Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

Effect of β-blockers on platelet aggregation: a systematic review and meta-analysis

Platelets play an important role in cardiovascular disease, and β‐blockers are often prescribed for cardiovascular disease prevention. β‐Blockers may directly affect platelet aggregation, because β‐adrenergic receptors are present on platelets. There is uncertainty about the existence and magnitude of an effect of β‐blockers on platelet aggregation. The aim of this study was to perform a systematic review and meta‐analysis of the effect of β‐blockers on platelet aggregation.

Time-Dependent Effects of Aspirin on Blood Pressure and Morning Platelet Reactivity A Randomized Cross-Over Trial

Aspirin is used for cardiovascular disease (CVD) prevention by millions of patients on a daily basis. Previous studies suggested that aspirin intake at bedtime reduces blood pressure compared with intake on awakening. This has never been studied in patients with CVD. Moreover, platelet reactivity and CVD incidence is highest during morning hours. Bedtime aspirin intake may attenuate morning platelet reactivity. This clinical trial examined the effect of bedtime aspirin intake compared with intake on awakening on 24-hour ambulatory blood pressure measurement and morning platelet reactivity in patients using aspirin for CVD prevention. In this randomized open-label crossover trial, 290 patients were randomized to take 100 mg aspirin on awakening or at bedtime during 2 periods of 3 months. At the end of each period, 24-hour blood pressure and morning platelet reactivity were measured. The primary analysis population comprised 263 (blood pressure) and 133 (platelet reactivity) patients. Aspirin intake at bedtime did not reduce blood pressure compared with intake on awakening (difference systolic/diastolic: −0.1 [95% confidence interval, −1.0, 0.9]/−0.6 [95% confidence interval, −1.2, 0.0] mm Hg). Platelet reactivity during morning hours was reduced with bedtime aspirin intake (difference: −22 aspirin reaction units [95% confidence interval, −35, −9]). The intake of low-dose aspirin at bedtime compared with intake on awakening did not reduce blood pressure of patients with CVD. However, bedtime aspirin reduced morning platelet reactivity. Future studies are needed to assess the effect of this promising simple intervention on the excess of cardiovascular events during the high risk morning hours.

Unraveling the Pharmacogenetics of Clopidogrel The Paraoxonase-1 Controversy

Clopidogrel forms a cornerstone in the treatment of patients undergoing coronary stenting. Although the clinical effectiveness of clopidogrel has been shown repeatedly in large clinical trials, there appears to be a large interindividual response variability that influences the risk of atherothrombotic events.1,2 Studies3,4 have shown that differences in the plasma concentration of the active metabolite of clopidogrel are an important determinant of its antiplatelet effect. Although several environmental factors influence the formation of the active metabolite, most variation appears to be genetic.5 Numerous studies5–7 have shown that polymorphisms in genes encoding the cytochrome (CYP) p450 system, especially CYP2C19, influence bioactivation of clopidogrel and, hence, the risk of cardiovascular events, especially stent thrombosis. Still, polymorphic variation in CYP2C19 seems to explain only 5% to 11% of the response variability to clopidogrel, leaving variation in bioactivation of clopidogrel largely unexplained.5,8 Article see p 422 A new player in the pharmacogenetics of clopidogrel was introduced by Bouman et al,9 who identified paraoxonase-1 (PON1) as a major determinant of the bioactivation and clinical efficacy of clopidogrel in a series of elegant experiments and clinical studies among subjects from European descent. This hepatic esterase is associated with high-density lipoprotein and has antioxidative effects on low-density lipoprotein and macrophages. Bouman et al identified PON1 as the crucial enzyme for the bioactivation of clopidogrel, with its common Q192R polymorphism determining the rate of active thiol metabolite formation. In a case-cohort study among 41 cases with stent thrombosis and 71 control subjects, the Q allele was dose-dependently associated with lower PON1 activity and active metabolite concentrations in plasma, reduced platelet inhibition, and a higher risk of stent thrombosis. Q192R explained >70% of the response variability to clopidogrel. The authors corroborated their findings in a …