Fabiola Sinigaglia

Benefits from new ADP antagonists as compared with clopidogrel in patients with stable angina or acute coronary syndrome undergoing invasive management: a meta-analysis of randomized trials.

Aims: New P2Y12 receptor inhibitors have provided new and more potent antiplatelet strategies, although raising several concerns on possible increase of bleedings. The aim of current meta-analysis was to evaluate the efficacy and safety of new adenosine diphosphate (ADP) receptor antagonists as compared with clopidogrel in elective or ACS patients managed invasively. Methods and Results: Literature archives (Pubmed, EMBASE, Cochrane) and main scientific sessions abstracts were scanned for randomized trials comparing new ADP antagonists with clopidogrel in patients with acute coronary syndromes or stable angina. Primary endpoint was mortality. Secondary endpoints were: (1) nonfatal myocardial infarction (MI), (2) recurrent ischemia symptoms or ischemia-driven revascularization (RI/IDR), (3) stent thrombosis (ST), and (4) safety endpoints, defined as for TIMI major bleeding criteria. A total of 8 randomized clinical trials were finally included, for a total population of 67,851 patients. Mean follow-up was 7.6 months, ranging from 48 hours to 30 months. New ADP antagonists significantly reduced mortality {3.1% vs. 3.6%, odds ratio [OR] [95% confidence interval (CI)], 0.86 [0.79–0.94], P = 0.0008, Phet = 0.18}, with greater impact of oral drugs. Similar benefits were found for MI [6.1% vs. 7%; OR (95% CI) (random-effect model) = 0.88 (0.79–0.98), P = 0.01, Phet = 0.02], RI [2.7% vs. 3.1%; OR (95% CI) = 0.85 (0.77–0.93), P = 0.0005, Phet = 0.09], or ST [1.1% vs. 1.7%; OR (95% CI) = 0.60 (0.51–0.71), P < 0.00001, Phet = 0.13]. By meta-regression analysis, no relationship was observed between benefits in mortality, new MI, RI, and ST with new ADP antagonists and patients risk profile [beta (95% CI) = −0.01 [−0.30 to 0.27], P = 0.94; beta (95% CI) = −0.05 [−1.49 to 1.43], P = 0.96); beta (95% CI) = 0.19 (−0.18 to 0.57), P = 0.31, and beta (95% CI) = −0.08 (−0.86 to 0.70), P = 0.84, respectively]. Conclusions: Present meta-analysis shows that the new ADP antagonists prasugrel, ticagrelor, and cangrelor are associated to significant reduction of mortality, reinfarction, RI, and ST respect to clopidogrel alone, without significant increase in bleeding complications.

Diabetes, glucose control and mean platelet volume: a single-centre cohort study

UNLABELLEDnDiabetes is a major determinant of cardiovascular risk, mainly due to higher prothrombotic status and enhanced platelet reactivity. Mean platelet volume (MPV) has been suggested as indicator of platelet reactivity and moreover, diabetics have been shown to have larger MPV. The aim of our study was to evaluate the impact of diabetes and glycemic control on MPV in a large cohort of patients.nnnMETHODSnOur population is represented by 3414 patients undergoing coronary angiography at Azienda Ospedaliera-Universitaria, Maggiore della Carità, Novara, Italy. We obtained a fasting blood sample for glycemic assessment and for MPV evaluation. History of diabetes and pharmacological treatment, together with main cardiovascular risk factors were recorded. New diagnosis of diabetes was defined as nonfasting glucose >200mg/dL, fasting glucose ≥126mg/dL, or HbA1c >48mmol/L.nnnRESULTSnDiabetes was observed in 1272 patients (37.2%). Diabetes was related to older age, waist circumference, arterial hypertension, smoking, hypercholesterolemia, renal failure, previous MI and PCI, therapy with ACE-inhibitors, ARBs, beta-blockers, diuretics, statins (respectively p<0.001) and ASA (p=0.004). Diabetics had lower haemoglobin (p<0.001), higher fibrinogen (p=0.001) and worst lipid profile (p<0.001). MPV was related with diabetes mellitus (p<0.001) and glycemic control (p=0.05; at linear regression r=0.07; p<0.001 for fasting glycaemia; r=0.09; p<0.001 for HbA1c, respectively). However, this relationship was not confirmed at multivariate analysis (OR[95%CI]=1.2[0.97-1.5], p=0.09 for diabetes, OR[95%CI]=1.05[0.96-1.15], p=0.25 for HbA1c). Independent predictors of MPV above median value (10.8fL) resulted to be age (OR[95%CI]=1.02[1.01-1.03], p=0.002), treatment with ARBs (OR[95%CI]=1.4[1.1-1.8], p=0.007) and haemoglobin levels (OR[95%CI]=1.2[1.15-1.23], p<0.001), while inverse relationship was found with total cholesterol (OR[95%CI]=0.99[0.99-1], p=0.002).nnnCONCLUSIONnLarger MPV is associated with ageing, treatment with ARBs, cholesterol and haemoglobin levels. Diabetes mellitus and glycemic control are not independently associated with larger platelet size.

Impact of age on mean platelet volume and its relationship with coronary artery disease: a single-centre cohort study

UNLABELLEDnElderly patients represent a high risk category among subjects with atherosclerosis, due to the presence of comorbidities and suboptimal response to antiplatelet drugs. Mean platelet volume (MPV) has been indicated as a marker of platelet reactivity, with contrasting data on its role on coronary artery disease. Aim of the present study was to evaluate the impact of age on the MPV and its role on the extent of coronary artery disease (CAD).nnnMETHODSnOur population is represented by a cohort of 3750 patients undergoing coronary angiography. Elderly were defined according to age ≥ 75 years. MPV was measured at admission. Significant coronary artery disease was defined as a stenosis >50% in at least 1 coronary vessel, while severe CAD was defined as left main and/or three-vessel disease.nnnRESULTSnA total of 1170 out of 3750 (31.2%) patients were ≥ 75 years old. Advanced age was associated with female gender (p<0.001), hypertension (p<0.001), renal failure (p<0.001), previous myocardial infarction (p=0.03) coronary artery bypass grafting (p<0.001) indication to angiography (p<0.001), therapy with angiotension-receptor blockers, (p=0.003), nitrates, diuretics and calcium-antagonists (p<0.001), serum creatinine (p<0.001), fibrinogen (p<0.001) and C reactive protein (p=0.02), but inversely to percutaneous coronary interventions (p=0.02), dyslipidemia, family history of CAD and smoking (p<0.001, respectively), use of statins (p=0.02) and beta blockers (p=0.003), haemoglobin, total cholesterol and triglycerides (p<0.001, respectively), white blood cells (p=0.009) and platelet count (p=0.006). Elderly patients displayed a significantly larger platelet volume (p<0.001), with a direct linear relationship between age and the MPV (r=0.08, p<0.001), with age being confirmed as an independent predictor of larger MPV (≥10.85fl) at multivariate analysis (adjusted OR [95% CI]=1.18 [1.01-1.40], p=0.04). Among the elderly, MPV value above the median (≥10.85fl) was not associated with a higher prevalence of coronary artery disease (77.3 vs. 79.4%, p=0.39, adjusted OR [95% CI]=0.94 [0.66-1.33], p=0.71), or higher prevalence of severe CAD (35.2 vs. 32.4%, p=0.28, adjusted OR [95% CI]=1.34 [0.99-1.82], p=0.06).nnnCONCLUSIONnAdvanced age was directly associated with larger mean platelet volume that, however, did not contribute to explain the higher prevalence and extent of coronary artery disease observed in elderly patients.

Platelet distribution width and the risk of periprocedural myocardial infarction in patients undergoing percutaneous coronary intervention

Periprocedural myocardial infarction (PMI) still occurs in a large amount of percutaneous coronary interventions (PCI), mainly due to increased platelet activation. Platelet size has been suggested as an indicator of enhanced reactivity and platelet distribution width (PDW) could reflect morphologic changes in platelets, therefore affecting their function and potentially increasing the risk of complications after coronary stenting. Aim of the present study was to evaluate the relationship between PDW and PMI. We included 1,300 consecutive patients undergoing PCI. Myonecrosis biomarkers were dosed at intervals from 6 to 48xa0h after PCI. Periprocedural myonecrosis was defined as troponin I increase by three times the ULN or by 50xa0% of an elevated baseline value, whereas PMI as CKMB increase by three times the ULN or 50xa0% of baseline. We grouped patients according to tertiles values of PDW (<12.1; ≥13.9). Higher PDW was associated with age (pxa0=xa00.03), diabetes (pxa0<xa00.001), previous cerebrovascular accidents (pxa0=xa00.04), therapy with statins (pxa0=xa00.001) and ARBs (pxa0<xa00.001), ASA (pxa0=xa00.02), nitrates (pxa0=xa00.006), calcium antagonists (pxa0=xa00.05) and lower pre-procedural clopidogrel bolus (pxa0=xa00.005). PDW related with haemoglobin levels (pxa0<xa00.001), while inversely to platelet count (pxa0<xa00.001) and glycaemia (pxa0=xa00.003). Patients with larger PDW had lower presence of coronary thrombus (pxa0<xa00.001), higher rate of coronary calcifications (pxa0=xa00.02), higher stenting rate (pxa0=xa00.03) and lower rate of distal embolization (pxa0=xa00.03). Larger PDW did not increase risk of PMI (pxa0=xa00.11; adjusted OR [95xa0% CI]xa0=xa00.94 [0.78–1.1], pxa0=xa00.55) or periprocedural myonecrosis (pxa0=xa00.73; adjusted OR [95xa0% CI]xa0=xa00.95 [0.82–1.1], pxa0=xa00.51). Results were confirmed even in higher-risk subgroups of patients. In patients undergoing coronary stenting, PDW does not increase the risk of periprocedural MI and therefore should not be considered a risk factor for thrombotic periprocedural complications after PCI.

Impact of diabetes on uric acid and its relationship with the extent of coronary artery disease and platelet aggregation: A single-centre cohort study

BACKGROUNDnSerum uric acid (SUA) elevation has been associated with the main determinants of atherosclerosis and metabolic syndrome, although an independent relationship between SUA and coronary artery disease (CAD) has never been confirmed. Recent reports suggested a central role of SUA in diabetic patients, possibly being an early marker of impaired glucose metabolism and best predicting the risk of cardiovascular events in these patients. Aim of current study was to evaluate the relationship between diabetes and uric acid and its association with the extent of CAD and platelet aggregation among diabetics.nnnMETHODSnIn diabetic patients undergoing coronary angiography, fasting samples were collected for uric acid levels assessment. Coronary disease was defined for at least 1 vessel stenosis>50% as evaluated by QCA.nnnRESULTSnDiabetes was observed in 1173 out of 3280 (35.7%) diabetes was related to age, hypercholesterolemia, hypertension, BMI, renal failure, previous MI or coronary revascularization (p<0.001, respectively) and smoking (p=0.001). Diabetics were more frequently treated with ACE-inhibitors, ARBs, b-blockers, calcium-antagonists, diuretics, statins (p<0.001, respectively), and ASA (p=0.004). Diabetics displayed higher glycemia and HbA1c (p<0.001), higher creatinine and triglycerides (p<0.001) but lower total and HDL cholesterol (p<0.001) and haemoglobin (p<0.001). No significant difference was found in SUA levels between diabetic and non diabetic patients (p=0.09). In fact, we identified age, renal failure, hypertension, smoking, BMI, use of diuretics, statins, haemoglobin, triglycerides and HDL cholesterol levels as independent predictors of higher levels of uric acid (3rd tertile,≥6.7mg/dl or 0.39mmol/l). Among diabetic patients, no relationship was found between uric acid and the extent of coronary artery disease (p=0.27; adjusted OR [95%CI]=0.93 [0.76-1.1], p=0.48), or severe (LM-trivessel) CAD (P=0.05; adjusted OR [95%CI]=1.01 [0.86-1.18], p=0.94). Furthermore, SUA levels did not influence platelet aggregation.nnnCONCLUSIONnAgeing, BMI, renal failure, hypertension, smoking, use of statins and diuretics, haemoglobin, HDL cholesterol and tryglicerides levels but not diabetes or glycemic control are independent predictors of hyperuricemia. Among diabetic patients, higher SUA is not independently associated with the extent of CAD or with platelet aggregation.

Homocysteine Levels Influence Platelet Reactivity in Coronary Artery Disease Patients Treated With Acetylsalicylic Acid

Background: Suboptimal platelet inhibition with antiplatelet treatments is associated with a severe prognosis in patients with coronary artery disease (CAD), and the identification of its determinants is still challenging. Homocysteine elevation has emerged as a prothrombotic factor, influencing coagulative status and endothelial function and potentially modulating platelet aggregation. We therefore aimed to evaluate the effects of homocysteine (Hcy) levels on platelet reactivity in patients receiving acetylsalicylic acid (ASA) with or without ADP antagonists. Methods: Patients undergoing coronary angiography and receiving ASA (100–160 mg daily) for >7 days, with or without ADP antagonists, were included. Aggregation tests were performed by multiple electrode aggregometry. Suboptimal platelet inhibition was defined as on-treatment aggregation above the lower limit of normality. Results: Our population is represented by 508 ASA-treated patients, 406 (80.1%) of whom on dual antiplatelet therapy (ASA and ADP antagonists). Hcy levels above the median (15.1 nmol/mL) were associated with male gender (P = 0.04), hypertension (P = 0.004), hypercholesterolemia (P = 0.03), aging, renal failure (P < 0.001, respectively), previous coronary bypass grafting (P = 0.04), therapy with calcium antagonists (P = 0.04) and diuretics (P = 0.001), and multivessel CAD (P = 0.03). Higher Hcy is directly related with serum creatinine and uric acid (P < 0.001). Suboptimal platelet inhibition was found in 16 patients (3.2%) for ASA and for ADP antagonists in 80 patients (19.7%). Hcy levels significantly affected suboptimal response to ASA, but not to ADP-mediated aggregation. In fact, a linear relationship was found between homocysteine and platelet reactivity after stimulation with arachidonic acid (r = 0.14, P = 0.004) and collagen (r = 0.12, P = 0.02), but not with ADP (r = 0.02, P = 0.77). Moreover, after correction for baseline differences, Hcy above the median was confirmed as an independent predictor of impaired ASA response [adjusted odds ratio (95% confidence interval) = 3.7 (1.08–12.4), P = 0.04]. Conclusions: Among patients with CAD, elevated homocysteine is an independent predictor of suboptimal response to ASA, but not to ADP antagonists.

Platelet–larger cell ratio and the risk of periprocedural myocardial infarction after percutaneous coronary revascularization

Periprocedural myocardial infarction (PMI) represents a frequent complication in patients undergoing percutaneous coronary revascularization. Despite great attention focused on pharmacological prevention of periprocedural damage, very little is known about using biomarkers to potentially predict the risk of PMI. Larger platelets have been associated with enhanced reactivity, increased cardiovascular risk, and higher rates of complications after coronary stenting. The platelet–larger cell ratio (P-LCR) identifies the largest-sized fraction of platelets, the proportion potentially more closely related to thrombotic events. The present study evaluated the relationship between P-LCR and PMI. We included 1,285 patients undergoing PCI. Myonecrosis biomarkers were dosed at intervals from 6 to 48 h after PCI. Periprocedural myonecrosis was defined as troponin I increase by three times the upper limit of normal (ULN) or by 50 % of an elevated baseline value, whereas PMI was defined as an increase in creatine kinase MB by 3 × ULN or 50 % of baseline. We grouped patients according to tertile values of P-LCR (<27.5; ≥35.1). Higher P-LCR was associated with age (P = 0.01), diabetes (P = 0.001), previous cerebrovascular accidents (P = 0.007), therapy with statins (P < 0.001), angiotensin receptor blockers (P < 0.001), aspirin (P = 0.002), and nitrates (P = 0.01). P-LCR was related to hemoglobin levels (P < 0.001), and inversely related to platelet count (P < 0.001) and glycemia (P = 0.05). Patients with higher P-LCR had a lower presence of coronary thrombus (P = 0.003). Higher P-LCR values did not increase the risk of PMI (P = 0.10; adjusted odds ratio (OR) (95 % confidence interval (CI)) = 0.97 (0.69–1.38)), P = 0.89) or periprocedural myonecrosis (P = 0.96; adjusted OR (95 % CI) = 1.003 (0.76–1.32), P = 0.99). Results were confirmed even in higher-risk subgroups of patients. P-LCR does not increase the risk of periprocedural myocardial infarction and myonecrosis in patients undergoing coronary stenting.

Platelet HPA-1 a/HPA-1 b polymorphism and the risk of periprocedural myocardial infarction in patients undergoing elective PCI.

Abstract Periprocedural myocardial infarction (PMI) represents a relatively common complication of percutaneous coronary intervention (PCI) and large interests have been focused on platelets in order to prevent such a complication. The single nucleotide polymorphism Leu33Pro of platelet glycoprotein IIIa has been related to an increased platelet reactivity, a lower response to antiplatelet agents and higher risk of stent restenosis. Therefore, aim of our study was to evaluate the impact of this polymorphism on PMI in elective patients undergoing PCI. Our population is represented by 422 consecutive patients with cardiac biomarkers within normality undergoing elective PCI. We measured cardiac biomarkers (CK–MB and Troponin I) at baseline, and 8, 24 and 48 hours after the procedure. For all subjects, we performed genetic analysis to assess the presence of Leu33Pro polymorphism. A total of 136 patients (32.2%) were polymorphic. Those patients were younger (pu2009=u20090.03) and more often dislypidemic (pu2009=u20090.01). Angiographic features did not differ according to genetic status. Pharmacological treatment pre and during angioplasty was similar. PCI-related complications did not differ according to genotype, with the only exception of higher rate of distal embolization in polymorphic patients. However, Leu33Pro polymorphism was not associated with increased risk of periprocedural myonecrosis and PMI even after correction for baseline differences, (respectively ORu2009=u20091.22 [0.81–1.84], pu2009=u20090.34 for myonecrosis and ORu2009=u20091.66 [0.85–3.23]; pu2009=u20090.14 for PMI). At subgroup analysis, the Leu33Pro substitution was associated with higher risk of PMI only among diabetics (adjusted ORu2009=u20094.46 [1.12–17.76], pu2009=u20090.03). Among patients undergoing elective PCI, the polymorphism Leu33Pro of platelet glycoprotein IIIa is associated with increased risk of PMI only in diabetic patients.

Relationship Between Glycoprotein IIIa Platelet Receptor Gene Polymorphism and Coronary Artery Disease

Glycoprotein IIb/IIIa (GP IIb/IIIa) is a key receptor for platelet aggregation and adhesion. We investigated whether a single-nucleotide polymorphism of GP IIIa subunit (Leu33Pro-PlA1/PlA2 allele) is associated with the extent of coronary artery disease (CAD) in a consecutive cohort of 1518 patients undergoing coronary angiography. Significant CAD was defined as at least a stenosis >50% and severe CAD as left main disease and/or trivessel disease. Additionally, carotid intima–media thickness (cIMT) was evaluated in 339 patients. The PlA2 allele was observed in 458 (30.2%) patients and associated with hypercholesterolemia (P = .03). No difference was observed in the prevalence of CAD (72.6% vs 70.1%, P = .29; adjusted odds ratio, OR [95% confidence interval, CI] = 0.85 [0.67-1.08], P = .19) and severe CAD (27.5% vs 26.5%, adjusted OR [95% CI] = 0.93 [0.72-1.19], P = .55). Furthermore, Leu33Pro polymorphism did not affect cIMT and the prevalence of carotid plaques. Therefore, this polymorphism cannot be regarded as a risk factor for coronary or carotid atherosclerosis.

Platelet PIA1/PIA2 polymorphism and the risk of periprocedural myocardial infarction in patients with acute coronary syndromes undergoing coronary angioplasty

Acute coronary syndromes (ACSs) represent a high-risk condition, as enhanced platelet reactivity importantly influences myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). In fact, higher rate of periprocedural myocardial infarction (PMI) and reduced event-free survival have been reported in these patients. The single nucleotide polymorphism Leu33Pro of platelet glycoprotein IIIa has been related to an increased platelet reactivity, a lower response to antiplatelet agents and higher risk of stent restenosis. Therefore, our aim was to evaluate the impact of this polymorphism on PMI in patients undergoing PCI for non-ST-segment elevation MI (NSTEMI). Our population is represented by 478 consecutive patients undergoing coronary angioplasty for NSTEMI. Cardiac biomarkers were monitored at intervals from 8 to 48u200ah after the procedure. Genetic analysis was performed to assess the presence of Leu33Pro polymorphism. A total of 156 patients (32.6%) were polymorphic. Clinical features did not differ according to genetic status, neither pharmacological treatment pre and during angioplasty. PlA2 carriers had lower rate of calcifications (Pu200a=u200a0.01) and higher coronary tortuosity (Pu200a=u200a0.03) at angiography and underwent more frequently to thrombectomy (Pu200a=u200a0.05). PCI-related complications did not differ according to genotype. Leu33Pro polymorphism was not associated with increased risk of periprocedural myonecrosis and PMI even after correction for baseline differences, [odds ratio (OR) (95% confidence interval (CI)u200a=u200a0.70 (0.44–1.13), Pu200a=u200a0.15 for PMI and OR (95% CI)u200a=u200a0.77 (0.53–1.11), Pu200a=u200a0.17 for myonecrosis, respectively]. Results were confirmed in high-risk subgroups of patients. In conclusion, among patients undergoing PCI for ACS, the polymorphism Leu33Pro of platelet glycoprotein IIIa is not associated with increased risk of PMI.