Piera Capranzano

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

AIMS Patients 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. METHODS AND RESULTS This 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. CONCLUSION Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y(12) signalling.

Usefulness of SYNTAX score to select patients with left main coronary artery disease to be treated with coronary artery bypass graft.

OBJECTIVES The purpose of our study was to investigate the utility of the SYNTAX (Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery) score in aiding patient selection for percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) in a large contemporary registry of patients undergoing revascularization of left main coronary artery. BACKGROUND The SYNTAX score has been developed as a combination of several validated angiographic classifications aiming to grade the coronary lesions with respect to their functional impact, location, and complexity. METHODS Between March 2002 and December 2008, 819 patients with left main coronary artery disease underwent revascularization in 2 Italian centers. We compared clinical outcomes of PCI versus CABG in patients with SYNTAX score < or =34 and patients with SYNTAX score >34. RESULTS The rates of 2-year mortality were similar between CABG and PCI in the group of patients with SYNTAX score < or =34 (6.2% vs. 8.1%, p = 0.461). Among patients with SYNTAX score >34, those treated with CABG had lower rates of mortality (8.5% vs. 32.7%, p < 0.001) than those treated with PCI. After statistical adjustment, revascularization by PCI resulted in a similar risk of death compared with CABG in patients with SYNTAX score < or =34 (hazard ratio: 0.81, 95% confidence interval: 0.33 to 1.99, p = 0.64) and in a significantly higher risk in patients with SYNTAX score >34 (hazard ratio: 2.54, 95% confidence interval: 1.09 to 5.92, p = 0.031). CONCLUSIONS A SYNTAX score threshold of 34 may usefully identify a cohort of patients with left main disease who benefit most from surgical revascularization in terms of mortality.

Pharmacodynamic Effects of Different Aspirin Dosing Regimens in Type 2 Diabetes Mellitus Patients With Coronary Artery Disease

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 B2 (TXB2) 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<0.05 for both assays) and between 81 mg/od and 162 mg/bid (P<0.05 for both assays). There was no impact of aspirin dosing regimens on adenosine diphosphate–induced aggregation. A dose-dependent effect of aspirin was observed on serum TXB2 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 TXB2 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.

Global Risk Classification and Clinical SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) Score in Patients Undergoing Percutaneous or Surgical Left Main Revascularization

OBJECTIVES The aim of this study was to investigate the ability to predict cardiac mortality of the Global Risk Classification (GRC) and the Clinical SYNTAX (Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery) score (CSS) in left main (LM) patients undergoing percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). BACKGROUND There is a renewed interest in combining clinical and angiographic information to define the risk of patients undergoing LM revascularization. METHODS The GRC and CSS were assessed in patients undergoing LM PCI (n = 400) or CABG (n = 549). Stand-alone clinical (ACEF [age, creatinine, ejection fraction]), EuroSCORE (European System for Cardiac Operative Risk Evaluation) and angiographic (SYNTAX score) risk scores were also investigated. RESULTS The GRC (Hosmer-Lemeshow statistic 0.357, p = 0.550; area under the curve 0.743) and the ACEF (Hosmer-Lemeshow 0.426, p = 0.514; area under the curve 0.741) showed the most balanced predictive characteristics in the PCI and CABG cohorts, respectively. In PCI patients, the CSS used fewer data to achieve similar discrimination but poorer calibration than the GRC. Propensity-adjusted outcomes were comparable between PCI and CABG patients with low, intermediate, or high EuroSCORE, ACEF, GRC, and CSS and those with low or intermediate SYNTAX score. Conversely, in the group with the highest SYNTAX score, the risk of cardiac mortality was significantly higher in PCI patients (hazard ratio: 2.323, 95% confidence interval: 1.091 to 4.945, p = 0.029). CONCLUSIONS In LM patients undergoing PCI, combined scores improve the discrimination accuracy of clinical or angiographic stand-alone tools. In LM patients undergoing CABG, the ACEF score has the best prognostic accuracy compared with other stand-alone or combined scores. The good predictive ability for PCI along with the poor predictive ability for CABG make the SYNTAX score the preferable decision-making tool in LM disease.

Contemporary practice and technical aspects in coronary intervention with bioresorbable scaffolds: a European perspective

AIMS Next to patient characteristics, the lack of a standardised approach for bioresorbable vascular scaffold (BVS) implantation is perceived as a potential explanation for the heterogeneous results reported so far. To provide some guidance, we sought to find a consensus on the best practices for BVS implantation and management across a broad array of patient and lesion scenarios. METHODS AND RESULTS Fourteen European centres with a high volume of BVS procedures combined their efforts in an informal collaboration. To get the most objective snapshot of different practices among the participating centres, a survey with 45 multiple choice questions was prepared and conducted. The results of the survey represented a basis for the technical advice provided in the document, whereas areas of controversy are highlighted. CONCLUSIONS Consensus criteria for patient and lesion selection, BVS implantation and optimisation, use of intravascular imaging guidance, approach to multiple patient and lesion scenarios, and management of complications, were identified.

EuroSCORE refines the predictive ability of SYNTAX score in patients undergoing left main percutaneous coronary intervention

BACKGROUND Whether SYNTAX score should be used as a stand-alone tool or whether its performance may be improved by the parallel use of clinical scores focusing on comorbidities, such as EuroSCORE, is a matter of debate. METHODS A combined risk model including both clinical and angiographic information was developed, and its performance tested on a contemporary population of 255 patients with left main disease undergoing percutaneous coronary intervention (PCI). A global risk classification (GRC) system was created by combination of SYNTAX score and EuroSCORE strata, and new classes of risk were defined. RESULTS When EuroSCORE was fitted into the SYNTAX score model, c-statistic increased from 0.681 to 0.732 for the prediction of cardiac mortality. The likelihood ratio test for the significance of adding the EuroSCORE term to the model was chi(2) = 4.109 (P = .043) with a net reclassification improvement of 26% (P = .002). GRC showed the best prediction and discriminative ability in terms of two-year cardiac mortality (HR 3.40, 95% CI 1.79-6.43, P < .001; c-statistic 0.756) as compared with SYNTAX score (HR 2.87, 95% CI 1.35-6.10, P = .006; c-statistic 0.747) and EuroSCORE (HR 3.04, 95% CI 1.41-6.57, P = .005; c-statistic 0.708) alone. CONCLUSIONS We found a significant improvement in the prediction of cardiac mortality with the inclusion of EuroSCORE in a SYNTAX score-based model. The degree of reclassification between treatment threshold categories indicates that clinical and angiographic information are both important for assessing individual risk of patients undergoing left main PCI.

Pharmacology of emerging novel platelet inhibitors

A number of promising antiplatelet therapies currently in advanced clinical testing offer hope for improving cardiovascular outcomes in patients with acute coronary syndromes and those undergoing percutaneous interventions. We review the preclinical pharmacology and selected ongoing clinical trials of promising novel platelet inhibitor therapies.

Drug-eluting stent for left main coronary artery disease. The DELTA registry: a multicenter registry evaluating percutaneous coronary intervention versus coronary artery bypass grafting for left main treatment.

OBJECTIVES The aim of this study was to compare, in a large all-comers registry, major adverse cardiac and cerebrovascular events (MACCE) after percutaneous coronary intervention (PCI) with first-generation drug-eluting stents (DES) versus coronary artery bypass grafting (CABG) in unprotected left main coronary artery (ULMCA) stenosis. BACKGROUND Percutaneous coronary intervention with DES implantation in ULMCA has been shown to be a feasible and safe approach at midterm clinical follow-up. METHODS All consecutive patients with ULMCA stenosis treated by PCI with DES versus CABG were analyzed in this multinational registry. A propensity score analysis was performed to adjust for baseline differences in the overall cohort. RESULTS In total 2,775 patients were included: 1,874 were treated with PCI versus 901 with CABG. At 1,295 (interquartile range: 928 to 1,713) days, there were no differences, at the adjusted analysis, in the primary composite endpoint of death, cerebrovascular accidents, and myocardial infarction (MI) (adjusted hazard ratio [HR]: 1.11; 95% confidence interval [CI]: 0.85 to 1.42; p = 0.47), mortality (adjusted HR: 1.16; 95% CI: 0.87 to 1.55; p = 0.32), or composite endpoint of death and MI (adjusted HR: 1.25; 95% CI: 0.95 to 1.64; p = 0.11). An advantage of CABG over PCI was observed in the composite secondary endpoint of MACCE (adjusted HR: 1.64; 95% CI: 1.33 to 2.03; p < 0.0001), driven exclusively by the higher incidence of target vessel revascularization with PCI. CONCLUSIONS In our multinational all-comers registry, no difference was observed in the occurrence of death, cerebrovascular accidents, and MI between PCI and CABG. An advantage of CABG over PCI was observed in the incidence of MACCE, driven by the higher incidence of target vessel revascularization with PCI.

Morphine Is Associated With a Delayed Activity of Oral Antiplatelet Agents in Patients With ST-Elevation Acute Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention

Background—Morphine is recommended in patients with ST-segment–elevation myocardial infarction, including those undergoing primary percutaneous coronary intervention. Suboptimal antiplatelet effect during and after primary percutaneous coronary intervention is associated with increased thrombotic complications. It was hypothesized a potential drug–drug interaction between morphine and antiplatelet agents. We sought to assess platelet inhibition after a loading dose of the currently recommended antiplatelet agents in ST-segment–elevation myocardial infarction patients according to morphine use. Methods and Results—Three hundred patients undergoing primary percutaneous coronary intervention receiving either prasugrel (n=95) or ticagrelor (n=205) loading dose had platelet reactivity assessed by VerifyNow 1, 2, and 4 hours after loading dose. Patients treated with morphine (n=95; 32%) had a higher incidence of vomit (15% versus 2%; P=0.001). P2Y12 reactivity units 2 hours after the loading dose was 187 (153–221) and 133 (102–165) in patient with and without morphine (P<0.001); the difference persisted after excluding patients with vomit (P<0.0001). High residual platelet reactivity (P2Y12 reactivity units ≥208) at 2 hours was found in 53% and 29% patients with and without morphine (P<0.001) and without difference between prasugrel and ticagrelor patients. The independent predictors of high residual platelet reactivity at 2 hours were morphine use (odds ratio, 2.91 [1.71–4.97]; P<0.0001) and age (odds ratio, 1.03 [1.01–1.05]; P=0.010). Morphine remained associated with high residual platelet reactivity after propensity score adjustment (c-statistic, 0.68; 95% confidence interval, 0.66–0.70; P=0.879 for Hosmer–Lemeshow test). Conclusions—In patients with ST-segment–elevation myocardial infarction, morphine use is associated with a delayed onset of action of the oral antiplatelet agents. This association persisted after adjusting for the propensity to receive morphine and after excluding patients with vomit.

Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: A meta-analysis of 50,578 patients

BACKGROUND Warfarin, despite its known limitations, is the reference standard treatment for patients with AF and risk factors for stroke. We performed a meta-analysis of phase III trials that compare novel oral anticoagulants (NOACs) with warfarin to determine whether they improve clinical outcomes of patients with non-valvular atrial fibrillation (AF). METHODS Three randomized trials that compared NOACs with warfarin in AF were selected. The primary efficacy endpoint was the incidence of stroke or systemic embolism. The primary safety endpoint was the incidence of major bleeding. RESULTS A total of 50578 patients were included. NOACs significantly decreased stroke or systemic embolism (2.8% vs 3.5%, odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.91, P<0.001), death (6.0% vs 6.3%, OR 0.88, 95% CI 0.82-0.95, P=0.001) and stroke (2.4% vs 3.0%, OR 0.79, 95% CI 0.71-0.88, P<0.001). The reduction in stroke was mainly driven by fewer hemorrhagic strokes (0.3% vs 0.8%, OR 0.79, 95% CI 0.71-0.88, P<0.001). Major bleeding occurred in 5.0% and 5.6% of patients in the NOACs and warfarin groups (OR 0.85, 95% CI 0.69-1.05, P=0.14 in the random-effects model). NOACs were associated with lower rates of intracranial bleeding (0.6% vs 1.3%, P<0.001) and higher rates of gastrointestinal bleeding (2.3% vs 1.3%, P=0.036). CONCLUSIONS In patients with non-valvular AF, NOACs decrease stroke or systemic embolism, hemorrhagic stroke and mortality, with similar risk of major bleeding compared to warfarin.