Lyndon C. Box

A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study

AIMSnPatients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with non-diabetics following P2Y(12) receptor blockade. Whether inhibition of P2Y(12) signalling can be enhanced by adjunctive treatment with cilostazol in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of cilostazol in T2DM patients on standard aspirin and clopidogrel treatment.nnnMETHODS AND RESULTSnThis was a prospective, double-blind, double-dummy, placebo-controlled, randomized, cross-over platelet function study. T2DM patients on dual antiplatelet therapy were assigned to receive cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. Platelet function was performed at three time points: at baseline, 14 days after randomization, and 14 days after treatment cross-over. The P2Y(12) reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. In addition to this flow cytometric evaluation, light transmittance aggregometry and VerifyNow testing were performed. A total of 25 T2DM patients were randomized; five patients discontinued treatment due to side effects. The P2Y(12) reactivity index was significantly lower following cilostazol treatment compared with placebo (36.3 +/- 20 vs. 59.9 +/- 16%; P = 0.0002). All other P2Y(12)-specific functional assessments showed enhanced inhibition of this signalling pathway following treatment with cilostazol.nnnCONCLUSIONnAdjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y(12) signalling.

Impact of adjunctive cilostazol therapy on platelet function profiles in patients with and without diabetes mellitus on aspirin and clopidogrel therapy.

Cilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilator-stimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.

Operator Radiation Exposure and Physical Discomfort During a Right Versus Left Radial Approach for Coronary Interventions: A Randomized Evaluation

OBJECTIVESnThis 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.nnnBACKGROUNDnThe 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.nnnMETHODSnOne hundred patients were randomized to an LRA or RRA. Each operator (nxa0= 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.nnnRESULTSnThere 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, pxa0= 0.02; thyroid: median: 10.10 [IQR: 4.3 to 25] mRems vs. median: 18.70 [IQR: 11.0 to 38] mRems, pxa0=xa00.001). More discomfort was reported with the LRA during access (LRA: 22% vs. RRA: 4%; pxa0=xa00.017), but not during the procedure (LRA: 10.0% vs. RRA: 4.0%, pxa0= 0.43). This difference was almost entirely noted inxa0obese patients (LRA: 30.0% vs. RRA: 3.7%, pxa0= 0.005).nnnCONCLUSIONSnLRA 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.

Heterogeneity of atherosclerotic plaque characteristics in human coronary artery disease: a three-dimensional intravascular ultrasound study.

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.

SCAI expert consensus statement: 2016 best practices in the cardiac catheterization laboratory: (Endorsed by the cardiological society of india, and sociedad Latino Americana de Cardiologia intervencionista; Affirmation of value by the Canadian Association of interventional cardiology-Association canadienne de cardiologie d'intervention).

The SCAI Expert Consensus Statement: 2012 Best Practices in the Cardiac Catheterization Laboratory provides standards for preprocedure, intraprocedure, and postprocedure evaluation and management, and served as a patient-centered approach to safety and quality in the cardiac catheterization laboratory (CCL) [1]. It was noted that the CCL is a setting in which elective, urgent, and emergent percutaneous procedures are performed, and that high throughput and increasing patient complexity demand optimal periprocedural communication, clinical management, documentation, and protocol. Regulations primarily targeted at open surgical suites have the potential to negatively impact the quality of care because they shift the focus to performance measures that are not necessarily relevant to the CCL. Accordingly, directives were tailored to the percutaneous setting in order to assure quality and optimal patient safety while maintaining efficiency.

Pharmacodynamic Effects of Prasugrel Dosing Regimens in Patients on Maintenance Prasugrel Therapy Results of a Prospective Randomized Study

OBJECTIVESnThe purpose of this study is to assess the pharmacodynamic effects of different prasugrel dosing regimens in patients on maintenance prasugrel therapy.nnnBACKGROUNDnThere 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.nnnMETHODSnThis 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).nnnRESULTSnIntragroup comparisons showed that a 60 mg dose reduced the platelet reactivity index (PRI) after 1 h (p = 0.004) and 4 h (p < 0.001, 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 (p < 0.001; 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.nnnCONCLUSIONSnFor 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).

Variable histological and ultrasonic characteristics of restenosis after drug-eluting stents

Bare-metal stents have undergone intense pathological and clinical examination, but histological characterization of drug-eluting stent (DES) restenosis (ISR) remains unknown. We report a series of cases (n=6) with intravascular ultrasound (IVUS) and pathological examinations over 8 months after DES deployment. Tissue samples were obtained using atherectomy devices in 5 cases and a thrombectomy catheter in 1 case. Histology revealed not only smooth muscle cell proliferation, which correlated with homogeneous hypoechoic tissue by IVUS in one case, but also demonstrated delayed healing features such as organized fibrin deposition in 3 cases (one with homogeneous echolucent tissue by IVUS), macrophage and T-lymphocyte infiltration in others. IVUS appearance of ISR components varied from echolucent to echodense images. This report suggests a variable histological and IVUS pattern of ISR after DES implantation. Further investigations are necessary to define the potentially pro-thrombotic histological features of ISR after DES implantation, and the relationship between the molecular mechanisms of thrombosis and DES restenosis.

Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus

Patients with type 2 diabetes mellitus (T2DM) have impaired clopidogrel-induced antiplatelet effects, which may be in part attributed to their reduced sensitivity to insulin and consequently, results in upregulation of the P2Y12 signalling pathway. It has been hypothesised that insulin sensitising strategies may enhance clopidogrel-mediated P2Y12 inhibitory effects. The aim of this pilot pharmacodynamics (PD) study was to assess the impact of pioglitazone on clopidogrel-mediated P2Y12 inhibitory effects in patients with T2DM. This was a prospective, randomised, double-blind, placebo-controlled, cross-over PD study. Patients with T2DM and stable coronary artery disease on maintenance aspirin and clopidogrel were randomised to receive either pioglitazone 30 mg or matching placebo daily for 14 days. PD assessments were measured at baseline, 14 days after randomisation, at the end of the wash-out period, and 14 days after cross-over. The primary endpoint measure was maximal platelet aggregation (MPA) to 20 μM adenosine diphosphate (ADP) as assessed by light transmittance aggregometry (LTA). Flow cytometric analysis of vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI), and VerifyNow P2Y12 testing were also performed. A total of 15 randomised patients completed the study. MPA to 20 μM ADP (primary endpoint) was not significantly different with pioglitazone compared with placebo (49.53 ± 4.76 vs. 52.52 ± 3.89%; p = 0.594). Similarly, other PD measures did not differ significantly between the groups. In conclusion, in patients with T2DM on maintenance aspirin and clopidogrel therapy, the adjunctive use of pioglitazone does not result in enhanced inhibition of platelet P2Y12 mediated signalling.

An algorithm for identification of ST-elevation myocardial infarction patients by emergency medicine services

OBJECTIVEnST-elevation myocardial infarction (STEMI) identification by emergency medicine services (EMS) leading to pre-hospital catheterization laboratory (CL) activation shortens ischemic time and improves outcomes. We examined the incremental value of addition of a screening clinical tool (CT), containing clinical information and a Zoll electrocardiogram (ECG)-resident STEMI identification program (ZI) to ZI alone.nnnMETHODSnAll EMS-performed and ZI-analyzed ECGs transmitted to a percutaneous coronary intervention hospital from October 2009 to January 2011 were reviewed for diagnostic accuracy. ZI performance was also compared to ECG interpretations by 2 experienced readers The CT was then retrospectively applied to determine the incremental benefit above the ZI alone.nnnRESULTSnST-elevation myocardial infarction was confirmed in 23 (7.5%) of 305 patients. ZI was positive in 37 (12.1%): sensitivity: 95.6% and specificity: 94.6%, positive predictive value (PPV), 59.5%, negative predictive value (NPV), 99.6%, and accuracy of 93.8%. Moderate agreement was observed among the readers and ZI. CT criteria for CL activation were met in 24 (7.8%): 20 (83.3%) were confirmed STEMIs: sensitivity: 86.9%, specificity: 98.5%, a PPV: 83.3%, and NPV: 98.6%, accuracy of 97.7%. CT + ZI increased PPV (P<0.05) and specificity (P<0.003) by reducing false positive STEMI identifications from 15 (4.9%) to 4 (1.3%).nnnCONCLUSIONSnIn an urban cohort of all EMS transmitted ECGs, ZI has high sensitivity and specificity for STEMI identification. Whereas the PPV was low, reflecting both low STEMI prevalence and presence of STEMI-mimics, the NPV was very high. These findings suggest that a simplified CT combined with computer STEMI interpretation can identify patients for pre-hospital CL activation. Confirmation of these results could improve the design of STEMI care systems.

Achieving timely percutaneous reperfusion for rural ST-elevation myocardial infarction patients by direct transport to an urban PCI-hospital

Backgrounds ST-elevation myocardial infarction (STEMI) guidelines recommend reperfusion by primary percutaneous coronary intervention (PCI) ≤ 90 min from time of first medical contact (FMC). This strategy is challenging in rural areas lacking a nearby PCI-capable hospital. Recommended reperfusion times can be achieved for STEMI patients presenting in rural areas without a nearby PCI-capable hospital by ground transportation to a central PCI-capable hospital by use of protocol-driven emergency medical service (EMS) STEMI field triage protocol. Methods Sixty STEMI patients directly transported by EMS from three rural counties (Nassau, Camden and Charlton Counties) within a 50-mile radius of University of Florida Health-Jacksonville (UFHJ) from 01/01/2009 to 12/31/2013 were identified from its PCI registry. The STEMI field triage protocol incorporated three elements: (1) a cooperative agreement between each of the rural emergency medical service (EMS) agency and UFHJ; (2) performance of a pre-hospital ECG to facilitate STEMI identification and laboratory activation; and (3) direct transfer by ground transportation to the UFHJ cardiac catheterization laboratory. FMC-to-device (FMC2D), door-to-device (D2D), and transit times, the day of week, time of day, and EMS shift times were recorded, and odds ratio (OR) of achieving FMC2D times was calculated. Results FMC2D times were shorter for in-state STEMIs (81 ± 17 vs. 87 ± 19 min), but D2D times were similar (37 ± 18 vs. 39 ± 21 min). FMC2D ≤ 90 min were achieved in 82.7% in-state STEMIs compared to 52.2% for out-of-state STEMIs (OR = 4.4, 95% CI: 1.24–15.57; P = 0.018). FMC2D times were homogenous after adjusting for weekday vs. weekend, EMS shift times. Nine patients did not meet FMC2D ≤ 90 min. Six were within 10 min of target; all patient achieved FMC2D ≤ 120 min. Conclusions Guideline-compliant FMC2D ≤ 90 min is achievable for rural STEMI patients within a 50 mile radius of a PCI-capable hospital by use of protocol-driven EMS ground transportation. As all patients achieved a FMC2D time ≤ 120 min, bypass of non-PCI capable hospitals may be reasonable in this situation.