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Smoking enhances the P2Y12 receptor inhibitory effects of clopidogrel. Nicotine increases P2Y12 receptor expression in platelet lysates from healthy volunteers. However, the impact of cigarette smoking on platelet P2Y12 receptor binding in clopidogrel-treated patients with coronary artery disease (CAD) is unknown. Clopidogrel-naive patients with stable CAD (n = 20) were enrolled and stratified according to smoking status. P2Y12 receptor binding activity was determined by radioligand receptor binding prior and 24 h after a 600-mg loading dose of clopidogrel. Baseline P2Y12 receptor binding was 1.8-fold higher in smokers compared with nonsmokers. After a 600-mg loading dose of clopidogrel, smokers showed a 6.4-fold reduction in P2Y12 receptor binding indicative of marked clopidogrel-mediated blockade, while there were minimal changes among nonsmokers. Among patients with stable CAD, smokers have more P2Y12 receptor binding than nonsmokers and have a higher degree of clopidogrel-mediated platelet inhibition.

Intravenous adenosine is the standard of care for fractional flow reserve (FFR) testing of intermediate coronary stenoses. Regadenoson has a similar mechanism of action and greater ease of use than adenosine, but there is limited information on how these medications compare for FFR assessment. This

ObjectivesThe purpose of this study was to assess the in vitro P2Y12 receptor inhibitory effects of cangrelor on platelets from patients on maintenance prasugrel therapy treated with 2 reloading dose regimens.BackgroundDespite its more potent and rapid antiplatelet effects compared with clopidogrel, recent studies have shown variability in prasugrel-mediated P2Y12 receptor inhibition, particularly in high-risk settings. Cangrelor is a potent intravenous P2Y12 receptor inhibitor.MethodsA total of 60 patients with coronary artery disease on maintenance prasugrel (10 mg/day) therapy were randomized to a 30- or 60-mg reload of prasugrel. The platelet reactivity index (PRI), as assessed by whole-blood vasodilator-stimulated phosphoprotein, was measured with and without in vitro incubation of cangrelor (500 nM) at baseline, and at 1 and 4 h after reload.ResultsIn the absence of cangrelor, prasugrel reloading reduced PRI (p < 0.001 for both doses), although a 60-mg reload had greater platelet inhibition compared with a 30-mg reload at 4 h (p = 0.001). Cangrelor was associated with a reduction in PRI values during the overall study time course in patients reloaded with 30 mg (p = 0.001) and 60 mg (p < 0.001) of prasugrel. In patients reloaded with 30 mg prasugrel, cangrelor decreased PRI at each time point (baseline, p < 0.001; 1 h, p = 0.013; 4 h, p = 0.001). In patients reloaded with 60 mg prasugrel, cangrelor decreased PRI at baseline (p < 0.001) and 1 h (p = 0.002); levels of platelet reactivity comparable to those achieved with cangrelor were observed only at 4 h (p = 0.325). The intergroup comparisons with cangrelor were not significant at any time point.ConclusionsIn patients on maintenance prasugrel therapy exposed to a reloading dose (30 or 60 mg) of prasugrel, in vitro cangrelor is associated with further platelet P2Y12 receptor inhibitory effects.

This study sought to assess radiation exposure and operator discomfort when using left radial approach (LRA) versus right radial approach (RRA) for coronary diagnostic and percutaneous interventions.The transradial approach is increasingly being adopted as the preferred vascular access for coronary interventions. Currently, most are performed using an RRA. This is in part due to the perceived increased operator physical discomforts as well increased radiation exposure with an LRA.One hundred patients were randomized to an LRA or RRA. Each operator (n = 5) had an independent randomization process, and patients were stratified according to obesity status. Operator radiation was measured using separate sets of radiation dosimeter badges placed externally on the head and thyroid and internally on the sternum. Operator physical discomfort was surveyed at 2 time points: during vascular access and at the end of the procedure. Moderate to severe physical discomfort was defined as a score of4.There were no significant differences in baseline and procedural variables between groups. There was a significant increase in external radiation exposure using the RRA versus LRA (head: median: 6.12 [interquartile range (IQR): 2.6 to 16.6] mRems vs. median: 12.0 [IQR: 6.4 to 22.0] mRems, p = 0.02; thyroid: median: 10.10 [IQR: 4.3 to 25] mRems vs. median: 18.70 [IQR: 11.0 to 38] mRems, p = 0.001). More discomfort was reported with the LRA during access (LRA: 22% vs. RRA: 4%; p = 0.017), but not during the procedure (LRA: 10.0% vs. RRA: 4.0%, p = 0.43). This difference was almost entirely noted in obese patients (LRA: 30.0% vs. RRA: 3.7%, p = 0.005).LRA is as effective as RRA, showing a safer profile with decreased radiation exposure to the operator, at the expense of more operator discomfort only during vascular access and limited to obese patients.

SummaryIncreased body weight is independently associated with impaired clopidogrel pharmacodynamic (PD) response. Prasugrel has more potent PD effects compared with clopidogrel, although its PD effects in obese patients are unknown. The aim of this prospective, randomised, study was to compare the PD effects of standard-dose prasugrel [60 mg loading dose (LD)/10 mg daily maintenance dose (MD)] with highdose clopidogrel (900 mg LD/150 mg daily MD) in non-diabetic obese [body mass index (BMI) ≥30 kg/m2] patients, with coronary artery disease (CAD) on aspirin therapy. PD assessments (baseline, 2 hours post-LD and 6 ± 2 days after MD) were conducted using four platelet function assays, and the platelet reactivity index (PRI) assessed by VASP was used for sample size estimation. A total of 42 patients with a BMI of 36.42 ± 5.6 kg/m2 completed the study. There were no differences in baseline PD measures between groups. At 2 hours post-LD, prasugrel was associated with lower PRI compared with clopidogrel (24.3 ± 5.5 vs 58.7 ± 5.7, p≤0.001), with consistent findings for all assays. At one-week, PRI values on prasugrel MD were lower than clopidogrel MD without reaching statistical significance (34.7 ± 5.8 vs 42.9 ± 5.8, p=0.32), with consistent findings for all assays. Accordingly, rates of high on-treatment platelet reactivity were markedly reduced after prasugrel LD, but not after MD. In conclusion, in non-diabetic obese patients with CAD, standard prasugrel dosing achieved more potent PD effects than high-dose clopidogrel in the acute phase of treatment, but this was not sustained during maintenance phase treatment. Whether an intensified prasugrel regimen is required in obese patients warrants investigation.

Granting clinical staff privileges to physicians is the primary mechanism institutions use to uphold quality care. The Joint Commission requires that medical staff privileges be based on professional criteria specified in medical staff bylaws. Physicians themselves are charged with defining the

ObjectivesThis study sought to assess radiation exposure and operator discomfort when using left radial approach (LRA) versus right radial approach (RRA) for coronary diagnostic and percutaneous interventions.BackgroundThe transradial approach is increasingly being adopted as the preferred vascular access for coronary interventions. Currently, most are performed using an RRA. This is in part due to the perceived increased operator physical discomforts as well increased radiation exposure with an LRA.MethodsOne hundred patients were randomized to an LRA or RRA. Each operator (n = 5) had an independent randomization process, and patients were stratified according to obesity status. Operator radiation was measured using separate sets of radiation dosimeter badges placed externally on the head and thyroid and internally on the sternum. Operator physical discomfort was surveyed at 2 time points: during vascular access and at the end of the procedure. Moderate to severe physical discomfort was defined as a score of >4.ResultsThere were no significant differences in baseline and procedural variables between groups. There was a significant increase in external radiation exposure using the RRA versus LRA (head: median: 6.12 [interquartile range (IQR): 2.6 to 16.6] mRems vs. median: 12.0 [IQR: 6.4 to 22.0] mRems, p = 0.02; thyroid: median: 10.10 [IQR: 4.3 to 25] mRems vs. median: 18.70 [IQR: 11.0 to 38] mRems, p = 0.001). More discomfort was reported with the LRA during access (LRA: 22% vs. RRA: 4%; p = 0.017), but not during the procedure (LRA: 10.0% vs. RRA: 4.0%, p = 0.43). This difference was almost entirely noted in obese patients (LRA: 30.0% vs. RRA: 3.7%, p = 0.005).ConclusionsLRA is as effective as RRA, showing a safer profile with decreased radiation exposure to the operator, at the expense of more operator discomfort only during vascular access and limited to obese patients.

Platelets from patients with diabetes mellitus (DM) are hyper-reactive and whether cangrelor, a potent intravenous P2Y(12) receptor blocker, has differential pharmacodynamic (PD) effects according DM status is unknown. The aim of this investigation was to evaluate the in vitro PD effects of cangrelor in coronary artery disease (CAD) patients with and without DM. This prospective study enrolled 120 clopidogrel-naïve patients with CAD on aspirin therapy. PD assessments using cangrelor (500 nmol/l) in vitro included vasodilator-stimulated phosphoprotein assay to obtain the P2Y(12) reactivity index (PRI), and multiple electrode aggregometry (MEA). In a 20 patients subgroup, dose-dependent response was assessed following exposure to escalating concentrations (baseline, 5, 50, 500 and 5,000 nmol/l); thrombin generation processes were evaluated by thromboelastography (TEG). PD data were evaluable in 103 patients. No differences in baseline PD parameters were observed in DM (n = 48) and non-DM (n = 45) subjects. Cangrelor reduced PRI values irrespective of DM status (p0.0001), yielding no difference in patients with and without DM (16.1 ± 12.3 vs. 16.8 ± 11.3; p = 0.346). All MEA values were significantly reduced, although this was of greater magnitude with purinergic compared to non-purinergic agonists. A trend analysis showed a dose-dependent effect on platelet inhibition, with no interaction due to DM status, whereas no significant dose-dependent effect was observed for TEG-derived parameters. Therefore, in vitro cangrelor provides potent and dose-dependent blockade of the platelet P2Y(12) receptor, with no differential effect in DM and non-DM patients. In addition, in vitro cangrelor exerts moderate inhibitory effects on non-purinergic platelet signaling pathways, without modulating platelet-derived thrombin generation processes.

Variability in the onset of platelet inhibitory effects induced by oral P2Y12 receptor antagonists, including ticagrelor, has been shown in high-risk settings. These findings underscore the need for intravenous P2Y12 inhibiting therapies, such as cangrelor, with immediate effects. However, to date

Objectives To determine an estimate patient volume with severe AS meeting PARTNER-B criteria, with the objective of providing insights into the annual volume needed to sustain a TAVR program. Background While the prevalence of AS is well documented, potential TAVR candidates remains less established. A better understanding of this population is critical for the development of TAVR programs. Though no clear volume has been determined, societies suggest a minimum of 20–24 annual cases to establish a TAVR program. Methods A total of 21,652 patients were screened from a single center echocardiography registry over a 3-year period. From them, 833 patients with AS were identified representing our study population. Severity was stratified by echocardiographic criteria. Those identified to have moderate-to-severe and severe AS were further investigated to determine clinical status and surgical candidacy. Nonsurgical candidates were cross referenced with the PARTNER-B exclusion criteria to determine eligibility for TAVR. Results Symptomatic AS was present in 133 patients (16%). Fifty (38%) were considered nonsurgical candidates. Nonsurgical patients had higher STS score (11.1 ± 10.8 vs. 4.0 ± 3.3, P < 0.001). After applying PARTNERS-B exclusion criteria, only 18 patients (14%) were considered TAVR candidates. These findings indicate that to meet the recommended annual volume of 20–24 TAVR cases, a minimum of 150–170 symptomatic severe AS patients are required. Conclusion In real world clinical practice, the prevalence of AS meeting PARTNERS-B criteria for TAVR can be low. These findings suggest that either high volume valvular centers or regional referral centers will need to be considered as part of the strategy to incorporate this new technology into clinical practice. © 2012 Wiley Periodicals, Inc.

Although interventional technology and skills have markedly advanced, percutaneous coronary intervention (PCI) for coronary chronic total occlusion (CTO) lesions remains challenging. Indeed, CTO PCI is technically complex, carries the potential for a relatively high likelihood of failure and acute complications, and requires specifically skilled operators and a demanding use of resources. In addition, controversy persists surrounding appropriate indications for attempting CTO revascularization. Finally, there is a wide uncertainty on the actual benefits achieved with successful CTO recanalization. A growing number of studies have reported procedural results and/or assessed functional effects and long-term clinical outcomes of CTO PCI. We therefore sought to review and critically appraise the evidence base for procedural outcomes and potential clinical benefits of CTO PCI.

The purpose of this study is to assess the pharmacodynamic effects of different prasugrel dosing regimens in patients on maintenance prasugrel therapy.There are a growing number of patients on chronic prasugrel therapy regimens, leading to questions about the dosing regimen of prasugrel to administer if percutaneous coronary intervention is required.This is a prospective pharmacodynamic study in patients (n = 64) receiving maintenance prasugrel therapy who were randomly allocated to a 10 mg, 30 mg, or 60 mg dose of prasugrel. Pharmacodynamic assessments using multiple assays were conducted at 3 timepoints (baseline and 1 h and 4 h after dosing).Intragroup comparisons showed that a 60 mg dose reduced the platelet reactivity index (PRI) after 1 h (p = 0.004) and 4 h (p0.001, primary endpoint; p = 0.002 between 1 h and 4 h). A 30 mg dose also reduced PRI levels at 1 h (p = 0.006) and 4 h (p0.001; p = 0.044 between 1 h and 4 h). A 10 mg dose was associated with modest pharmacodynamic effects. Intragroup comparisons showed similar findings with VerifyNow-P2Y12 and light transmission aggregometry. Intergroup comparisons showed that a 60 mg dose achieved lower PRI levels than 30 mg at 4 h (p = 0.05), and a numerical trend toward better pharmacodynamic effects at 1 h (p = 0.171). Intergroup comparisons were similar with VerifyNow-P2Y12, but not light transmission aggregometry.For patients on maintenance prasugrel therapy, a 60 mg dosing strategy is associated with faster and higher platelet inhibition compared with lower doses, as assessed by P2Y(12) specific assays. (Impact of Prasugrel Re-load on Platelet Aggregation in Patients on Chronic Prasugrel Therapy; NCT01201772).

We appreciate the constructive comments raised by Santos et al regarding our article in which we showed that increasing the frequency of administration of low-dose aspirin has more potent platelet inhibitory effects than increasing the daily dose in patients with type 2 diabetes mellitus.1 Indeed, our analysis has several consistencies in findings from those demonstrated by Santos et al in their previous investigation.2 The authors correctly raise an important observation regarding a potential cause that may interfere with aspirin-induced pharmacodynamic effects mediated by cell-cell interactions, namely platelets and …

This study sought to assess the presence of a dose-response effect of cigarette smoking and its impact on high on-treatment platelet reactivity (HPR) in patients with diabetes mellitus treated with clopidogrel.Cigarette smoking is an inducer of cytochrome P450 1A2, a hepatic enzyme involved in clopidogrel metabolism. If cigarette smoking is associated with a dose-response effect on pharmacodynamic measures in clopidogrel-treated patients is unknown.A total of 134 type 2 diabetes mellitus patients on maintenance aspirin and clopidogrel therapy were studied. Patients were divided into 3 groups according to cotinine levels:3 ng/ml (nonsmokers), 3 to 199 ng/ml (light smokers), and ≥ 200 ng/ml (heavy smokers). Platelet function was assessed by light transmittance aggregometry, VerifyNow P2Y12 assay (Accumetrics, San Diego, California), and vasodilator-stimulated phosphoprotein. Rates of HPR were defined using established cutoff values.A dose-response effect was observed for all pharmacodynamic parameters tested. Serum cotinine levels were inversely associated with platelet reactivity as assessed by light transmittance aggregometry using 5 and 20 μmol/l adenosine diphosphate (p0.0001 for all). Accordingly, platelet disaggregation increased with levels of serum cotinine (p0.0001). Similar results were found with P2Y(12) reaction units (p0.0001) and inhibition of platelet aggregation (p = 0.005) as defined by VerifyNow P2Y12 testing, and platelet reactivity index (p = 0.002) as assessed by vasodilator-stimulated phosphoprotein. Higher serum cotinine levels were significantly associated with lower rates of HPR, as defined according to various pharmacodynamic cutoff measures.Cigarette smoking is associated with a dose-response effect on clopidogrel-induced antiplatelet effects and lower rates of HPR in diabetes mellitus patients.

Background— Patients with type 2 diabetes mellitus (T2DM) have reduced aspirin-induced pharmacodynamic effects. This may be attributed to increased platelet turnover rates resulting in an increased proportion of non–aspirin-inhibited platelets during the daily dosing interval. The hypothesis of this study was that an increase in the frequency of drug administration [twice daily (bid) versus once daily (od)] may provide more effective platelet inhibition in T2DM patients. Methods and Results— T2DM patients with stable coronary artery disease were prospectively recruited. Patients modified their aspirin regimen on a weekly basis according to the following scheme: 81 mg/od, 81 mg/bid, 162 mg/od, 162 mg/bid, and 325 mg/od. Pharmacodynamic assessments included light-transmittance aggregometry after arachidonic acid, collagen and adenosine diphosphate stimuli; VerifyNow-Aspirin assay; and serum thromboxane B 2 (TXB 2 ) levels. Twenty patients were analyzed. All patients were sensitive and compliant to aspirin irrespective of dose, as assessed by arachidonic acid–induced aggregation. When aspirin was administered once daily, there was no significant effect on platelet reactivity by increasing the once-daily dosing using aspirin-sensitive assays (collagen-induced aggregation and VerifyNow-Aspirin). An increase in aspirin dose by means of a second daily administration was associated with a significant reduction in platelet reactivity assessed by collagen-induced aggregation and VerifyNow-Aspirin between 81 mg/od and 81 mg/bid ( P P 2 levels ( P =0.003). Conclusions— Aspirin dosing regimens are associated with different pharmacodynamic effects in platelets from T2DM patients and stable coronary artery disease, with a twice-daily, low-dose aspirin administration resulting in greater platelet inhibition than once-daily administration as assessed by aspirin-sensitive assays and a dose-dependent effect on serum TXB 2 levels. The clinical implications of a modified aspirin regimen tailored to T2DM patients warrant further investigation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01201785.

Objectives The aim of this study was to assess the association between genetic variants of the insulin receptor substrate (IRS)-1 gene, platelet function, and long-term outcomes in patients with type 2 diabetes mellitus (DM) and stable coronary artery disease while on aspirin and clopidogrel therapy. Background The effects of pharmacogenetic determinants on platelet function and cardiovascular outcomes in type DM patients are unknown. Methods The association between IRS-1 genetic variants, platelet function, and the risk of major adverse cardiac events (MACE) at 2 years was assessed in 187 patients with type 2 DM and stable coronary artery disease on maintenance aspirin and clopidogrel therapy. Results Seven tag single nucleotide polymorphisms were selected. Individuals with high platelet reactivity were more frequent among carriers of the C allele (GC and CC genotypes; approximately 20% of population) of the rs956115 marker (44.4% vs. 20.5%; odds ratio: 3.1, 95% confidence interval [CI]: 1.44 to 6.67; p = 0.006). These patients were at higher risk of MACE (28.0% vs. 10.9%; hazard ratio: 2.90, 95% CI: 1.38 to 6.11; p = 0.005). The C allele carriers of the rs956115 marker were more commonly associated with a hyperreactive platelet phenotype. This was confirmed in an external validation cohort of patients with type 2 DM but not in an external validation cohort of patients without DM. Carriers of the C allele of the rs956115 marker also had a significantly higher risk of MACE compared with noncarriers (30.6% vs. 11.4%; hazard ratio: 2.88, 95% CI: 1.35 to 6.14; p = 0.006). Conclusions Type 2 DM patients who are carriers of the C allele of the rs956115 marker of the IRS-1 gene have a hyperreactive platelet phenotype and increased risk of MACE.

SummaryPatients with end-stage renal disease (ESRD) have abnormalities in the cellular and plasmatic systems regulating blood homeostasis, which may contribute to their risk for thrombotic and bleeding complications. However, their relative contributions in this population are poorly understood. The aim of this study was to evaluate the distribution of enzymatic and cellular abnormalities in ESRD patients on haemodialysis as assessed by thromboelastography (TEG®). Whole blood samples were analysed by TEG in ESRD patients (n=70) and in a control group (n=70) of subjects with coronary artery disease. Profiles were constructed considering the maximum amplitude (MA), a marker of platelet function, and reaction time (R), a marker of thrombin generation, values. R values were higher in ESRD patients compared with the control group (8.2 ± 2.8 vs. 5.7 ± 1.9 minutes [min], p

The importance of intravascular ultrasound (IVUS) as an adjunctive technology facilitating optimal coronary interventional procedural technique has become increasingly evident over the past decade. IVUS is currently appreciated as an invaluable tool enabling better assessment of reference vessel size and coronary lesion morphology, including gross plaque characteristics and lesion length. Accordingly, the adjunctive use of IVUS with angiography offers distinct advantages in the setting of performing coronary interventions.1 The structural information acquired by ultrasound imaging has helped us plan and better execute the optimal coronary interventional procedures to achieve improved procedural efficiency and outcomes. These benefits have become more critical as we progressively approach more complex coronary lesions with catheter-based therapies. In addition, IVUS has shown to be a useful tool to investigate other possible structural causes relating to adverse events, including stent thrombosis. Late-acquired stent malapposition, stent fracture, inadequate lesion coverage, and excessive stent overlap are all readily detected by IVUS. Article see p 111 The most recent ACC/AHA/SCAI percutaneous coronary intervention (PCI) guidelines2 equivocally address the use of preinterventional IVUS for the assessment of lesion characteristics and vessel dimensions as a means to select an optimal revascularization strategy (class IIb, level of evidence C). The importance of IVUS in assessing postprocedural results appears to be more clearly defined. Appropriate stent expansion, optimal wall apposition, and detection of postdeployment stent edge issues, such as dissections, are all well assessed by IVUS.3 Evaluation of these anatomic features has possible implications regarding the safety and efficacy of PCI.4,5 Current ACC/AHA/SCAI PCI guidelines2 support IVUS use to assess postinterventional results (class IIa, level of evidence B). The role of IVUS in the long-term post-PCI management of patients with in-stent restenosis remains to be established. Once …

Objectives We sought to assess the impact of renal function on platelet reactivity in patients with diabetes mellitus (DM) and coronary artery disease on aspirin and clopidogrel therapy. Background Diabetes mellitus is a key risk factor for chronic kidney disease (CKD). In aspirin-treated DM patients the presence of moderate/severe CKD is associated with reduced clinical efficacy of adjunctive clopidogrel therapy. Whether these findings may be attributed to differences in clopidogrel-induced effects is unknown. Methods This was a cross-sectional observational study in which DM patients taking maintenance aspirin and clopidogrel therapy were studied. Patients were categorized into 2 groups according to the presence or absence of moderate/severe CKD. Platelet aggregation after adenosine diphosphate (ADP) and collagen stimuli were assessed with light transmittance aggregometry and defined patients with high post-treatment platelet reactivity (HPPR). Markers of platelet activation, including glycoprotein IIb/IIIa activation and P-selectin expression, were also determined using flow cytometry. Results A total of 306 DM patients were analyzed. Patients with moderate/severe CKD (n = 84) had significantly higher ADP-induced (60 ± 13% vs. 52 ± 15%, p = 0.001) and collagen-induced (49 ± 20% vs. 41 ± 20%, p = 0.004) platelet aggregation compared with those without (n = 222). After adjustment for potential confounders, patients with moderate/severe CKD were more likely to have HPPR after ADP (adjusted odds ratio: 3.8, 95% confidence interval: 1.7 to 8.5, p = 0.001) and collagen (adjusted odds ratio: 2.4; 95% confidence interval: 1.1 to 5.4; p = 0.029) stimuli. Markers of platelet activation were significantly increased in patients with HPPR. Conclusions In DM patients with coronary artery disease taking maintenance aspirin and clopidogrel therapy, impaired renal function is associated with reduced clopidogrel-induced antiplatelet effects and a greater prevalence of HPPR.

Determining the most appropriate revascularization strategy for patients presenting with unprotected left main coronary (UPLM) disease has been a topic of great recent interest. During this current decade, there have been multiple clinical trials and registries addressing this subject. Previously, UPLM disease has almost exclusively resulted in utilizing a surgical revascularization treatment strategy. However, recent improvements in percutaneous coronary intervention (PCI) techniques in parallel with the benefits of drug-eluting stents (DES) to reduce clinical restenosis have enabled further investigation in catheterization-based treatment strategies as possible alternative therapeutic options. These advances as well as an increased understanding of both the procedural and anatomical challenges involved with complex coronary interventions have allowed further advancements in the field. Better adjunctive antithrombotic pharmacological therapy in the PCI setting has favored such progress. American College of Cardiology/American Heart Association/Society for Coronary Angiography and Interventions guidelines do not currently endorse the performance of PCI as an appropriate alternative to surgical revascularization for patients with UPLM disease. This paper is a review of the current evidence on UPLM PCI and proposes future directions in this evolving field.

Objective: To investigate long-term outcomes of unprotected left main coronary artery (ULMCA) disease treatment using drug-eluting stents (DES). Background: In several studies, DES implantation in ULMCA appeared safe and effective at mid-term; however, to date, there is limited long-term data. Methods: All consecutive patients undergoing sirolimus- or paclitaxel-eluting stent implantation in ULMCA disease at a single institution were evaluated. The primary endpoint was long-term major adverse cardiac events (MACE) defined as cardiac death, nonfatal myocardial infarction, or target lesion revascularization (TLR). Stent thrombosis (ST), according to Academic Research Consortium definitions, was also evaluated. Results: A total of 210 patients were assessed. In-hospital MACE rate was 1%. During a mean follow-up of 28.0 ± 14.5 months, MACE occurred in 26 patients (12.5%): cardiac death in nine patients (4.3%) and TLR in 17 patients (8.2%). The cumulative MACE-free survival rate was 89.0, 87.4, and 85.4% at 1, 2, and 3 years, respectively. ST occurred in three patients (1.4%): one case was definite and the other two were probable/possible ST; there were no cases of very late ST. Binary restenosis occurred in 8.3%. The EuroScore >6 was the only independent predictor of MACE [hazard ratio (HR) 2.24, 95% confidence interval (CI) 1.05-4.77, P = 0.04]. There was a trend toward an increased risk of MACE associated with distal ULMCA location (HR 2.14, 95% CI 0.87-5.29, P = 0.10). Conclusions: Our study showed DES implantation in ULMCA to be feasible, safe, and effective at long term. Randomized trials comparing percutaneous versus surgical revascularization are warranted to define the treatment of choice for ULMCA disease. © 2009 Wiley-Liss, Inc.

Type 2 diabetes mellitus (T2DM) patients have a variable response profile to the P2Y(12) receptor antagonist clopidogrel. P2Y(12) receptor signalling promotes platelet procoagulant activity. The aim of this study was to determine if T2DM patients with suboptimal clopidogrel response have greater platelet procoagulant activity compared with optimal responders and evaluate if this can be modulated by enhancing P2Y(12) receptor inhibition.A total of 50 T2DM patients in a steady state phase of clopidogrel therapy were studied. Suboptimal responders were randomly assigned to standard (75 mg) or high (150 mg) clopidogrel maintenance therapy for one-month. Afterwards, all patients resumed standard therapy. Platelet procoagulant activity assessed by thrombin-induced platelet-fibrin clot formation using thrombelastography (TEG) was determined at baseline, one-month post-randomization, and one-month after resuming standard therapy.In the overall study population, the reaction time (R), a measure of time to initial thrombin induced platelet-fibrin clot formation, and the time to maximum rate of thrombin generation (TMRTG) values were 6.3+/-1.7 and 7.6+/-1.9 minutes, respectively. Suboptimal clopidogrel responders (n=30) had acceleration of R (p=0.002) and TMRTG (p=0.002) compared to optimal responders (n=20). Suboptimal clopidogrel responders treated with a 150 mg dose showed prolongation of R (p=0.0001) and TMRTG (p0.0001), which returned to baseline values after resuming standard dosage. No differences were observed among patients randomized to 75 mg.T2DM patients with suboptimal clopidogrel response have enhanced platelet procoagulant activity compared to patients with optimal response, which can be down-regulated by more potent platelet P2Y(12) inhibition using high clopidogrel maintenance dosing.

Since platelet interactions appear to play an important role in the development of restenosis, attenuation of thromboxane-mediated reactions may improve the long-term outcome following coronary angioplasty. Phase II of the Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART) is a prospective, randomized, placebo-controlled study of thromboxane blockade in the prevention of restenosis following successful coronary angioplasty. Two forms of thromboxane blockade are evaluated: aspirin (a nonspecific inhibitor of thromboxane synthesis) and sulotroban (a specific thromboxane receptor antagonist). The design of this multicenter trial and the rationale for use of sulotroban in the prevention of restenosis are reviewed in this report.

Clinical and anatomic determinants of the initial success of percutaneous transluminal coronary angioplasty were prospectively evaluated in 826 patients enrolled in the Multi-Hospital Eastern Atlantic Restenosis Trial (M-HEART). The 639 men and 187 women ranged in age from 31 to 85 years. Successful angioptasty (residual stenosis

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y(12) receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.

Objectives: To investigate the long-term prognostic implications of complete versus incomplete revascularization in multivessel coronary artery disease (MVD) patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Background: Coronary artery bypass grafting (CABG) in patients with MVD provides better outcomes when complete revascularization is achieved. There is a paucity of data on the outcomes of complete versus incomplete revascularization of MVD patients undergoing PCI, and currently there is no data available with DES. Methods: Patients with MVD undergoing PCI with DES (sirolimus- or paclitaxel-eluting stent) were included. Comparisons of long-term outcomes between completely versus incompletely revascularized patients were made. The primary outcome measure was the composite of cardiac death, nonfatal myocardial infarction (MI), or any revascularization. Secondary endpoints were the components of the composite endpoint. Results: A total of 508 patients were considered for this analysis: 212 (41.7%) and 296 (58.3%) had complete and incomplete revascularization, respectively. The median follow-up was 27.0 (interquartile range: 23.0–37.1) months. After adjusting for baseline characteristics, the hazard ratio (HR, 95% confidence interval) for complete revascularization was 0.43 (0.29–0.63, P < 0.0001) for the primary composite endpoint. Complete revascularization was associated with better outcomes for components of the composite endpoint: 0.37 (0.15–0.92, P = 0.03) for cardiac death, 0.34 (0.16–0.75 P = 0.008) for the composite of cardiac death or MI and 0.45 (0.29–0.69, P = 0.0003) for any repeat revascularization. This association was confirmed in a propensity-matched population. Conclusions: Complete revascularization with DES of MVD patients is associated with lower rates of long-term adverse events. © 2008 Wiley-Liss, Inc.

Prasugrel (CS-747; LY-640315) is a novel, third-generation oral thienopyridine that is a specific, irreversible antagonist of the platelet adenosine 5′-diphosphate P2Y 12 receptor. Laboratory results with prasugrel support more potent antiplatelet effects, a lower incidence of interpatient variability in antiplatelet response, and a reduced time to onset of antiplatelet activity compared with clopidogrel. Phase II results indicate that prasugrel produces a greater antiplatelet effect than clopidogrel administered even at doses higher than the currently approved 300-mg loading dose and 75-mg/d maintenance dose. Recent phase III data show that prasugrel is superior to clopidogrel in preventing ischemic events in patients with acute coronary syndrome undergoing percutaneous coronary intervention, although this was associated with a greater risk of bleeding.

In patients undergoing coronary stenting, long-term dual antiplatelet therapy with aspirin and clopidogrel reduces atherothrombotic events but also increases the risk of bleeding. The potential for developing bleeding complications is further enhanced in patients also requiring oral anticoagulant treatment ("triple therapy"). The aim of the study is to assess long-term outcomes associated with the use of triple-therapy in patients undergoing coronary stenting and evaluate how these may be affected by targeting international normalized ratio (INR) values to the lower therapeutic range. We prospectively studied 102 consecutive patients undergoing coronary stenting treated with dual antiplatelet therapy also requiring oral anticoagulation. INR was targeted to the lower therapeutic range (2.0 to 2.5). Patients requiring oral anticoagulant therapy because of mechanical valve prosthesis were excluded. Patients were followed for 18 months, and bleeding, defined according to Thrombolysis in Myocardial Infarction criteria, and major adverse cardiac events were recorded. Outcomes were compared with a control group (n = 102) treated only with dual antiplatelet therapy. The mean duration of triple therapy was 157 +/- 134 days. At 18 months, a nonsignificant increase in bleeding was observed in the triple versus dual therapy group (10.8% vs 4.9%, p = 0.1). INR values were higher in patients with bleeding (2.8 +/- 1.1 vs 2.3 +/- 0.2, p = 0.0001). In patients who had INR values within the recommended target (79.4%), the risk of bleeding was significantly lower compared with patients who did not (4.9 vs 33%, p = 0.00019) and with that observed in the control group (4.9%). An INR >2.6 was the only independent predictor of bleeding. There were no significant differences in major adverse cardiac events between groups (5.8% vs 4.9%, p = 0.7). In conclusion, in patients undergoing coronary stenting on triple therapy, targeting lower therapeutic INR values reduces the risk of bleeding complications.

SummaryThe currently recommended maintenance dose of clopidogrel is often associated with inadequate platelet inhibition, suggesting the need for a higher dose. The aim of this pilot study was to assess the functional impact of a high (150 mg/day) maintenance dose of clopidogrel in patients undergoing elective percutaneous coronary intervention (PCI).This is a prospective, randomized, platelet function study which was performed in elective PCI patients assigned to treatment with either a 75 mg (n=20) or 150 mg (n=20) daily maintenance dose of clopidogrel for 30 days;afterwards, all patients resumed standard dosing. Platelet aggregation was performed using light transmittance aggregometry following 20 μM and 5 μM adenosine diphosphate (ADP) stimuli 30 days after randomization and 30 days after resuming standard dosing. Patients treated with 150 mg/day clopidogrel had lower 20 μMADP-induced platelet aggregation compared to patients on 75 mg/day (52.1±9% vs. 64.0±8%; p

A randomized control trial was set up to examine factors that influence restenosis and determine the effects of corticosteroids on restenosis following successful PTCA. The rationale for the study agent chosen, design, recruitment, and feasibility, as well as initial patient demographic data and initial results are presented.

Background: Clopidogrel under-dosing is a cause of inadequate platelet inhibition. Inadequate clopidogrel-induced antiplatelet effects have been associated with an increased risk of stent thrombosis. Updated guidelines for percutaneous coronary interventions (PCI) recommend to increase the dose of clopidogrel to 150mg in high risk patients if Methods: Platelet inhibition was screened by means of the VerifyNow P2Y 12 assay in patients in a steady state phase of dual antiplatelet therapy. Patients with 12 reactivity ratio determined by vasodilator-stimulated phosphoprotein-phosphorylation analysis were also performed. Results: A total of 32 patients were screened to identify 20 with ) . The degree of platelet inhibition achieved following one-month treatment with high dose clopidogrel broadly varied and only eight (40%) patients yielded a degree of platelet inhibition ≥50%. Conclusions: The use of a 150mg maintenance dose of clopidogrel in high risk patients with Platelet function analysis pre and post high clopidogrel maintenance dose therapy

Objectives: The objective of this study was to describe the intraplaque variability of coronary atherosclerosis in humans. Background: Atherosclerosis is a heterogeneous process. The degree and patterns of intraplaque heterogeneity are not well described. This study uses 3D intravascular ultrasound (IVUS) to examine variability in individual atherosclerotic plaques in human coronary arteries. Methods: IVUS images of 170 coronary plaques in 98patients were evaluated. Each plaque was divided into proximal, middle, and distal sections. Quantitative and qualitative analyses were performed for each section using a dedicated 3D IVUS protocol. Intralesion heterogeneity was assessed between sections. Results: Heterogeneity in composition was observed in most plaques (89%). The pattern of remodeling was heterogeneous in 23% of lesions. External elastic membrane (EEM) areas demonstrated an average percent deviation of 28.9% ± 15.5%. Positive remodeling was associated with longer lesions (≫ median length of 12.7 mm) (P = 0.031). Soft and calcific sections had a smaller mean EEM area (P = 0.034). Calcific lesions had a smaller mean lumen area (P = 0.027) and a greater percent plaque burden (PPB) (P = 0.001). Neither the location within the vessel or within the plaque was associated with plaque morphology. Greater qualitative heterogeneity was found in patients presenting with acute coronary syndrome (P < 0.001). Conclusions: Our results demonstrate a high degree of heterogeneity in composition and morphological features within individual atherosclerotic plaques in human coronary arteries. Intraplaque heterogeneity represents a challenge for imaging protocols correlating plaque features with cardiovascular events and for the development of future therapeutic options. © 2007 Wiley-Liss, Inc.

Background Wall shear stress (WSS) has been associated with neointimal hyperplasia (NIH) following bare metal stent (BMS) implantation. Drug-eluting stents (DES) almost abolish NIH. Conversely, diabetes mellitus amplifies NIH response. The association between WSS and arterial wall response following DES and BMS implantation in diabetic patients remains to be evaluated. Methods The study involved 20 diabetic patients randomized to BMS (n = 9) or sirolimus-eluting stent (SES; n = 11) implantation in native coronary arteries. A computational fluid dynamic model applied 3D intravascular ultrasound (IVUS) and two-plane angiographic to measure WSS (Pa). IVUS assessments were performed post-procedure and at 9-months follow-up. The target segment encompassed the stent plus 5 mm distal and proximal edges. A total of 93 subsegments were evaluated: in-stent segments divided in three subsegments (proximal, mid and distal; n = 60) and proximal and distal edges (n = 33). Results Stent length was similar between BMS (17.4 ± 7.3 mm) and SES (19.8 ± 6.8 mm) groups. NIH was observed in all BMS subsegments (n = 27) versus one subsegment in the SES group (n = 33). WSS ranged from 0.52 to 4.20 Pa in the BMS and from 0.42 to 3.06 Pa in the SES group. There was no correlation between WSS and NIH in either stent group. In addition, there were no correlation between the change of external elastic membrane (EEM) or plaque growth at the edges and WSS. Conclusion WSS was not associated with NIH after implantation of SES or BMS in diabetic patients. Plaque growth or the change of EEM at the edges were not associated with WSS either.

Background— After treatment with clopidogrel, patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with patients who are not diabetic. Whether platelet inhibition can be enhanced by increasing clopidogrel maintenance dosage in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of a high maintenance dose in T2DM patients with suboptimal clopidogrel-induced antiplatelet effects. Methods and Results— T2DM patients on chronic dual antiplatelet therapy were screened to identify suboptimal clopidogrel responders. The latter were randomized to 30-day treatment with a standard (75 mg; n=20) or high (150 mg; n=20) daily maintenance dose. Platelet function was assessed at 3 time points: baseline, 30 days after randomization, and 30 days after resuming standard dosing. Platelet function parameters included adenosine diphosphate–induced (20 and 5 μmol/L) maximal and late platelet aggregation, inhibition of platelet aggregation, platelet disaggregation, and P2Y 12 reactivity index. A total of 64 T2DM patients were screened to identify 40 suboptimal responders. After randomization, maximal adenosine diphosphate–induced (20 μmol/L) platelet aggregation was significantly reduced in the 150-mg group compared with the 75-mg group ( P =0.002; primary end point). However, suboptimal clopidogrel response was still present in 60% of patients on the 150-mg regimen. All other platelet function parameters showed enhanced clopidogrel-induced antiplatelet effects with 150 mg, which returned to baseline values after resumption of standard dosing. Conclusions— A 150-mg maintenance dose of clopidogrel is associated with enhanced antiplatelet effects compared with 75 mg in high-risk T2DM patients. However, enhanced ex vivo platelet reactivity continues to persist, the clinical implications of which are unknown and need to be evaluated in large-scale clinical trials.

Late loss (LL) has been a fundamental angiographic end-point in drug-eluting stents (DES) clinical trials. However, calculation of LL may be affected by a mismatch between post-procedure (PO) and follow-up (FU) sites of the minimal lumen diameter (MLD). Our aims were to investigate the incidence and methodological implications of the relocation of MLD after bare metal (BMS), sirolimus-eluting (SES), and paclitaxel-eluting (PES) stent implantation. Data from DIABETES I and II trials, which involved diabetic patients treated with BMS, SES, and PES, were analyzed. Angiographic data with matched projections between PO and 9-month angiographic FU were included. In-stent, in-lesion, and in-segment analyses included conventional and customized sub-segmental (5-mm/subsegment) methodology. MLD relocation was considered when the sites of MLD shifted a distance ≫ the intrinsic variability of the method. Conventional LL, site matched LL, maximal LL (MaxLL), and average LL (AvgLL) were calculated. Relationships between various LL and 1-year target lesion revascularization (TLR) were investigated. Post MLD was located distally, outside the stent, in ≥65% of the analyses. At FU, MLD relocation occurred in 70.5% (BMS), 40% (SES), and 35% (PES). MLD shifted ≥11 mm on average, mainly towards the stented segment. MLD relocation still occurred in 42.8% (BMS), 33.7% (SES), and 36.4% (PES), when analysis was restricted to in-stent segment. Among LL measurements, MaxLL showed the best association with TLR rates. Relocation of the MLD is a frequent phenomenon after both BMS and DES, and should be taken into account when calculating LL. Comprehensive LL analyses, including MaxLL and AvgLL, provides a better appraisal of the biological and clinical effectiveness of DES. © 2006 Wiley-Liss, Inc.

Platelet membrane receptors play a pivotal role in thrombus formation. Expression of platelet membrane receptors are under genetic control and gene sequence variations of receptors pivotal to thrombotic formation have been hypothesized to contribute to different degrees of individual response to aspirin. The aim of the present study was to investigate the impact of functional genetic polymorphisms of platelet membrane receptors on aspirin sensitivity assessed by means of the PFA-100 system in patients with coronary artery disease. Gene sequence variations of three platelet membrane receptors (GPIa/IIa, P2Y12, GPIIb/IIIa) pivotal to thrombus formation were assessed in 76 patients with coronary artery disease on chronic aspirin treatment. Patients with reduced sensitivity to aspirin were defined when closure-times of collagen/epinephrine cartridgesor =193 seconds and coined as PFA-100 non-responders. PFA-100 non-responders were observed in 33% of patients. Patients with diabetes mellitus were more frequently PFA-100 non-responders. Closure times of collagen/ADP coated cartridges were reduced in PFA-100 non-responders. The genotype distribution was similar in PFA-100 responder and non-responder patients for all three genotypes and did not vary in contemporaneous carriers of allelic variants. In conclusion, in vitro determined sensitivity to aspirin assessed using PFA-100 is not associated with gene sequence variations of platelet membrane receptors key to thrombus formation.

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndromes and/or undergoing percutaneous coronary interventions. Clopidogrel, in combination with aspirin, is currently the antiplatelet treatment of choice for prevention of stent thrombosis, and clinical trials have shown that, in high-risk patients, prolonged dual antiplatelet treatment is more effective than aspirin alone in preventing major cardiovascular events. However, despite the use of clopidogrel, a considerable number of patients continue to have cardiovascular events. Numerous in vitro studies have shown that individual responsiveness to clopidogrel is not uniform in all patients and is subject to inter- and intraindividual variability. Notably, there is a growing degree of evidence that recurrence of ischemic complications may be attributed to poor response to clopidogrel. The mechanisms leading to poor clopidogrel effects are not fully elucidated and are likely multifactorial. Although the gold standard definition to assess antiplatelet drug response has not been fully established, there is sufficient evidence to support that persistence of enhanced platelet reactivity despite the use of clopidogrel is a clinically relevant entity. This paper reviews the impact of individual response variability to clopidogrel on clinical outcomes and current and future directions for its management.

Background Patients with small coronary arteries are at high risk for complications after percutaneous coronary intervention (PCI). The objective of our study was to investigate the correlation between angiography, intravascular ultrasound (IVUS), and fractional flow reserve (FFR) in patients with moderate stenoses in small ( Methods and Results Sixty consecutive patients, of 800 scheduled for PCI during the study period, were prospectively enrolled in the study. The FFR was measured after a 2-minute infusion of adenosine. For the preprocedural assessments, 60 patients underwent an FFR measurement, 56 underwent an IVUS, and 60 underwent an angiography; for the postprocedural assessments, 22 patients underwent an FFR measurement, 18 underwent an IVUS, and 22 underwent an angiography. The jeopardy score for the target vessel was calculated. Data were analyzed by an independent core laboratory. Patients with an FFR >0.75 were deferred from PCI. Patients were stratified in 2 groups according to their FFR values (≤0.75 vs >0.75) and were followed for 1 year. Significant (FFR ≤0.75) coronary stenosis was observed in only 35% of the patients. The mean preprocedural FFR values were 0.79 ± 0.13 for the overall population, 0.64 ± 0.08 for the patients with an FFR ≤0.75, and 0.87 ± 0.06 for the patients with an FFR >0.75. There was no correlation between angiography, IVUS, and FFR. The jeopardy score was inversely correlated with FFR (R = −0.32). Only a third of the patients with optimal stenting defined by IVUS achieved an FFR >0.90. After 1 year, 24% of the patients with an FFR ≤0.75 required a repeat PCI. There was no occurrence of myocardial infarction or death, and only 2.6% of the patients deferred from PCI required revascularization. Conclusion Anatomical parameters are limited in determining the hemodynamic significance of small coronary disease. Most moderate stenoses in small coronaries could be safely deferred from PCI based on FFR.

Objectives— Metabolic activity of cytochrome P450 (CYP) 3A4 has been associated with clopidogrel response variability. Because metabolic activity of CYP3A4 is genetically regulated, we hypothesized that genetic variations of this enzyme may contribute to clopidogrel response variability. Methods and Results— The CYP3A4*1B, CYP3A4*3, IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms of the CYP3A4 gene were assessed in 82 patients in a steady phase of clopidogrel therapy. Glycoprotein (platelet glycoprotein (GP) IIb/IIIa receptor activation and platelet aggregation were assessed. A cohort of 45 clopidogrel-naïve patients was studied to determine the modulating effects of these polymorphisms after loading dose (300 mg) administration. Only the IVS7+258A>G, IVS7+894C>T, and IVS10+12G>A polymorphisms were sufficiently polymorphic. During the steady phase of clopidogrel treatment, IVS10+12A allele carriers had reduced GP IIb/IIIa activation ( P =0.025) and better responsiveness ( P =0.02); similarly, clopidogrel-naïve patients carriers of the IVS10+12A allele had reduced GP IIb/IIIa activation during the first 24 hours after a loading dose ( P =0.025), increased platelet inhibition ( P =0.006), and a more optimal drug response ( P =0.003). This polymorphism did not influence platelet aggregation profiles. No association was observed between the other polymorphisms and clopidogrel responsiveness. Conclusions— The IVS10+12G>A polymorphism of the CYP3A4 gene modulates platelet activation in patients treated with clopidogrel and may therefore contribute to clopidogrel response variability.