Ilaria Cavallari

Impact of chronic kidney disease on platelet reactivity and outcomes of patients receiving clopidogrel and undergoing percutaneous coronary intervention.

The impact of chronic kidney disease (CKD) on residual platelet reactivity (PR) in patients undergoing percutaneous coronary intervention (PCI) is still debatable. We sought to investigate the interaction between PR and renal function and the related clinical outcomes in patients with coronary artery disease treated with PCI. Immediately before PCI, we measured PR (as P2Y12 reaction units [PRUs]) in 800 patients on clopidogrel with the VerifyNow P2Y12 assay. High PR was defined as a PRU value of ≥240 and low PR as a PRU value of ≤178. Based on a glomerular filtration rate of < or ≥60 ml/min/1.73 m2, patients were respectively grouped into those with or without moderate-to-severe CKD. Primary end point was the incidence of 30-day net adverse clinical events (NACEs). Patients with moderate-to-severe CKD (n=173, 21.6%) and those without showed similar PRU values (208±67 vs 207±75, p=0.819). Yet, NACEs were significantly higher in patients with moderate-to-severe CKD (19.7% vs 9.1%, p<0.001), in terms of both ischemic (12.1% vs 7.2%, p=0.036) and bleeding events (8.7% vs 2.1%, p<0.001). NACEs were significantly higher when moderate-to-severe CKD was associated with either high PR or low PR (25.4%, p for trend<0.001); this association was the strongest predictor of NACE at multivariate analysis (odds ratio 3.4, 95% confidence interval 2.0 to 5.6, p<0.001). In conclusion, we did not find an association between moderate-to-severe CKD and residual PR on clopidogrel. However, the association of moderate-to-severe CKD with either high or low PR was a strong determinant of adverse events after PCI.

Thromboembolic Risk, Bleeding Outcomes and Effect of Different Antithrombotic Strategies in Very Elderly Patients With Atrial Fibrillation: A Sub‐Analysis From the PREFER in AF ( PRE vention o F Thromboembolic Events– E uropean R egistry in A trial F ibrillation)

Background Increasing age predisposes to both thromboembolic and bleeding events in patients with atrial fibrillation; therefore, balancing risks and benefits of antithrombotic strategies in older populations is crucial. We investigated 1‐year outcome with different antithrombotic approaches in very elderly atrial fibrillation patients (age ≥85 years) compared with younger patients. Methods and Results We accessed individual patients’ data from the prospective PREFER in AF (PREvention oF thromboembolic events‐European Registry in Atrial Fibrillation), compared outcomes with and without oral anticoagulation (OAC), and estimated weighed net clinical benefit in different age groups. A total of 6412 patients, 505 of whom were aged ≥85 years, were analyzed. In patients aged <85 years, the incidence of thromboembolic events was 2.8%/year without OAC versus 2.3%/year with OAC (0.5% absolute reduction); in patients aged ≥85 years, it was 6.3%/year versus 4.3%/year (2% absolute reduction). In very elderly patients, the risk of major bleeding was higher than in younger patients, but similar in patients on OAC and in those on antiplatelet therapy or without antithrombotic treatment (4.0%/year versus 4.2%/year; P=0.77). OAC was overall associated with weighted net clinical benefit, assigning weights to nonfatal events according to their prognostic implication for subsequent death (−2.19%; CI, −4.23%, −0.15%; P=0.036). We found a significant gradient of this benefit as a function of age, with the oldest patients deriving the highest benefit. Conclusions Because the risk of stroke increases with age more than the risk of bleeding, the absolute benefit of OAC is highest in very elderly patients, where it, by far, outweighs the risk of bleeding, with the greatest net clinical benefit in such patients.

Insulin-Requiring Versus Noninsulin-Requiring Diabetes and Thromboembolic Risk in Patients With Atrial Fibrillation: PREFER in AF.

BACKGROUNDnDiabetes is a known risk predictor for thromboembolic events in patients with atrial fibrillation (AF), but no study has explored the prognostic weight of insulin in this setting.nnnOBJECTIVESnThis study evaluated the differential role of insulin versus no insulin therapy on thromboembolic risk in patients with diabetes and AF.nnnMETHODSnWe accessed individual patient data from the prospective, real-world, multicenter, PREFER in AF (European Prevention of thromboembolic events-European Registry in Atrial Fibrillation). We compared the rates of stroke/systemic embolism at 1 year according to diabetes status (no diabetes, diabetes without insulin therapy, diabetes on insulin therapy).nnnRESULTSnIn an overall population of 5,717 patients, 1,288 had diabetes, 22.4% of whom were on insulin. For patients with diabetes who were on insulin, there was a significantly increased risk of stroke/systemic embolism at 1 year versus either no diabetes (5.2% vs. 1.9%; hazard ratio: 2.89; 95% confidence interval: 1.67 to 5.02; pxa0= 0.0002) or diabetes without insulin treatment (5.2% vs. 1.8%; hazard ratio: 2.96; 95% confidence interval: 1.49 to 5.87; pxa0= 0.0019). Notably, rates of stroke/embolism were similar in patients with diabetes not receiving insulin versus patients without diabetes (hazard ratio: 0.97; 95% confidence interval: 0.58 to 1.61; pxa0= 0.90). The selective predictive role of insulin-requiring diabetes was independent of potential confounders, including diabetes duration, and was maintained in various subpopulations, including the subgroup receiving anticoagulant therapy.nnnCONCLUSIONSnIn this cohort of anticoagulated patients with AF, the sole presence of diabetes not requiring insulin did not imply an increased thromboembolic risk. Conversely, insulin-requiring diabetes contributed most, if not exclusively, to the overall increase of thromboembolic risk in AF.

The left atrial appendage: from embryology to prevention of thromboembolism

The left atrial appendage (LAA) is the main source of thromboembolism in patients with non-valvular atrial fibrillation (AF). As such, the LAA can be the target of specific occluding device therapies. Optimal management of patients with AF includes a comprehensive knowledge of the many aspects related to LAA structure and thrombosis. Here we provide baseline notions on the anatomy and function of the LAA, and then focus on current imaging tools for the identification of anatomical varieties. We also describe pathogenetic mechanisms of LAA thrombosis in AF patients, and examine the available evidence on treatment strategies for LAA thrombosis, including the use of non-vitamin K antagonist oral anticoagulants and interventional approaches.

Correlation of platelet reactivity and C-reactive protein levels to occurrence of peri-procedural myocardial infarction in patients undergoing percutaneous coronary intervention (from the ARMYDA-CRP study).

The incremental predictive value of high inflammatory status and high on-treatment platelet reactivity (HPR) on the occurrence of periprocedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI) has not been characterized. The aim of this study was to evaluate the correlation of elevated C-reactive protein (CRP) level and/or HPR with the incidence of PMI in patients who undergo PCI. Five hundred consecutive patients treated with clopidogrel who underwent PCI had preprocedural measurement of CRP levels and platelet reactivity using the point-of-care VerifyNow P2Y12 assay. Elevated inflammatory status was defined as CRP >3 mg/L and HPR as P2Y12 reactivity units ≥240. The primary end point was the incidence of PMI in relation to platelet reactivity and/or inflammatory status. Rates of PMI were increased in patients with CRP levels >3 mg/L (10.9% vs 4.6% in those with normal levels, odds ratio 2.4, 95% confidence interval 1.2 to 4.5, p = 0.015) and in patients with HPR (11% vs 5.5% in those without HPR, odds ratio 2.2, 95% confidence interval 1.2-4.4, p = 0.018). The occurrence of PMI was highest in the subgroup with HPR and high inflammatory status (16.6% vs 3.6% in patients with CRP ≤3 mg/L and P2Y12 reactivity units <240, odds ratio 4.3, 95% confidence interval 1.5 to 12.6, p = 0.008). HPR in association with elevated CRP levels resulted in a significant increase in the discriminatory power of a model including clinical and procedural variables in predicting PMI (area under the curve 0.811, p = 0.041). In conclusion, in patients who undergo PCI, baseline stratification according to platelet reactivity and inflammatory status may identify those at higher risk for PMI.

Statin pretreatment and risk of in-hospital atrial fibrillation among patients undergoing cardiac surgery: a collaborative meta-analysis of 11 randomized controlled trials

AIMSnStatin pretreatment in patients undergoing cardiac surgery is understood to prevent postoperative atrial fibrillation (AF). However, this is based on observational and limited randomized trial evidence, resulting in uncertainty about any genuine anti-arrhythmic benefits of these agents in this setting. We therefore aimed to quantify precisely the association between statin pretreatment and postoperative AF among patients undergoing cardiac surgery.nnnMETHODS AND RESULTSnA detailed search of MEDLINE and PubMed databases (1st January 1996 to 31st July 2012) was conducted, followed by a review of the reference lists of published studies and correspondence with trial investigators to obtain individual-participant data for meta-analysis. Evidence was combined across prospective, randomized clinical trials that compared the risk of postoperative AF among individuals randomized to statin pretreatment or placebo/control medication before elective cardiac surgery. Postoperative AF was defined as episodes of AF lasting ≥5 min. Overall, 1105 participants from 11 trials were included; of them, 552 received statin therapy preoperatively. Postoperative AF occurred in 19% of these participants when compared with 36% of those not treated with statins (odds ratio 0.41, 95% confidence interval 0.31-0.54, P < 0.00001, using a random-effects model). Atrial fibrillation prevention by statin pretreatment was consistent across different subgroups.nnnCONCLUSIONnShort-term statin pretreatment may reduce the risk of postoperative AF among patients undergoing cardiac surgery.

Relation of Body Circumferences to Cardiometabolic Disease in Overweight-Obese Subjects

Body circumferences have been proposed as potential anthropometric measures for the assessment of cardiometabolic risk as they are independently associated with insulin resistance and diabetes. The aim of this study was to validate neck and wrist circumference and waist-to-hip ratio as practical markers of metabolic dysfunction and atherosclerosis; 120 subjects who underwent coronary angiography and carotid Doppler ultrasound were enrolled in this cross-sectional study. Exclusion criteria were history of diabetes, acute myocardial infarction, body mass index (BMI) <18.5 or ≥45.0xa0kg/m(2). Metabolic dysfunction was ascertained by the calculation of visceral adiposity index (VAI) and by diagnosis of metabolic syndrome (MS). Advanced atherosclerotic disease was defined as ≥70% coronary lumen and/or ≥50% carotid lumen stenosis. No association between body circumferences and VAI or MS was found in subjects with BMI <25xa0kg/m(2). VAI was significantly related to waist-to-hip ratio (R(2)xa0= 0.09, pxa0= 0.008), neck (R(2)xa0= 0.09, pxa0= 0.007), and wrist circumferences (R(2)xa0= 0.05, pxa0= 0.041) in subjects with BMI ≥25xa0kg/m(2). In overweight subjects, higher gender-specific tertiles of wrist circumference were independently associated with an increased risk of MS (odds ratio 2.57, 95% confidence interval 1.11 to 5.96, pxa0= 0.028). VAI was independently associated with carotid intima-media thickness: βxa0= 0.104, R(2)xa0= 0.118, pxa0= 0.003. Carotid intima-media thickness and MS, but not body circumferences, were associated with advanced atherosclerosis. In conclusion, these data indicate that anthropometric measurements, in particular wrist circumference, can be used as practical tools for assessment of metabolic risk in overweight-obese subjects but not as markers of advanced atherosclerosis.

Safety and efficacy of nonvitamin K antagonist oral anticoagulants versus warfarin in diabetic patients with atrial fibrillation: A study-level meta-analysis of phase III randomized trials

In patients with atrial fibrillation (AF), the safety and efficacy of nonvitamin K antagonist oral anticoagulants (NOACs) vs warfarin according to diabetes mellitus (DM) status are not completely characterized. We performed a meta‐analysis to clarify whether in these patients the strategy of oral anticoagulation should be tailored to diabetes status. In this study‐level meta‐analysis, we included 4 randomized phase III trials comparing NOACs and warfarin in patients with nonvalvular AF; a total of 18 134 patients with DM and 40 454 without DM were overall considered. Incidence of the following outcome measures was evaluated during the follow‐up: stroke or systemic embolism, ischemic stroke, major bleeding, intracranial bleeding, and vascular death. Use of NOACs compared with warfarin reduced stroke/systemic embolism in diabetic (Risk Ratios [RR] 0.80, 95% CI 0.68‐0.93; P = .004) and nondiabetic patients (RR 0.83, 0.73‐0.93; P = .001) (P for interaction .72). No interaction between diabetes status and benefits of NOACs was found for the occurrence of ischemic stroke, major bleeding, or intracranial bleeding (P for interaction >.05 for each comparison). Reduction of vascular death rates with NOACs was significant in diabetic patients (4.97% vs 5.99% with warfarin; RR 0.83, 0.72‐0.96; P = .01), in whom absolute the reduction of this outcome measure was higher than in nondiabetics (1.02% vs 0.27%), although no interaction was present (P = .23). Results of this meta‐analysis support the safety and efficacy of NOACs compared with warfarin in diabetic patients with nonvalvular AF.

Prevalence and predictors of dual antiplatelet therapy prolongation beyond one year in patients with acute coronary syndrome

There are limited real-world data on prevalence and predictors of dual antiplatelet therapy (DAPT) prolongation beyond one year after acute coronary syndrome (ACS). We have explored such issue in the START ANTIPLATELET Registry, which is a prospective, observational, multicenter, Italian registry performed in seven Italian cardiology institutions including patients admitted for ACS and followed up to one year. Out of a total population of 840 ACS patients, 596 patients had completed 12-month follow-up being on DAPT. Decision to prolong DAPT beyond one year was taken in 79 patients (13%), whereas in 517 patients DAPT was stopped. The strongest predictors of DAPT continuation were a new cardiovascular events after the index admission event (OR 3.3, 95% CI 1.4–7.7), no bleeding complications (OR 3.2, 95% CI 1.2–8.3) and no anemia during one-year follow-up (OR 2.6, 95% CI 1.1–5.9); other independent predictors were renal failure (OR 2.5, 95% CI 1.3–5.0) and peripheral artery disease (OR 1.8, 95% CI 1.1–3.0). The choice of DAPT prolongation was not correlated with younger ager, presence of diabetes mellitus, coronary angioplasty as initial treatment strategy or type of implanted stent (drug-eluting vs bare metal). In conclusion, this study provides a real-world snapshot on the factors influencing the option to continue DAPT beyond one year after ACS; a low bleeding risk seems to influence the choice to prolong DAPT more than a high ischemic risk.

Meta-Analysis Comparing the Safety and Efficacy of Dual Versus Triple Antithrombotic Therapy in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Intervention

In patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI), the effectiveness and safety of dual compared with triple antithrombotic therapy are a matter of debate, especially when considering the prevention of end points at low incidence, such as myocardial infarction (MI), stent thrombosis, or mortality. This study-level meta-analysis included 4 controlled randomized trials and 6,036 patients with a clinical indication to chronic oral anticoagulation (OAC) after PCI, mainly for atrial fibrillation. Patients receiving dual therapy with a single antiplatelet agent, essentially a P2Y12 inhibitor, plus OAC were compared with those treated with triple therapy (aspirin, a P2Y12 inhibitor, and OAC). The incidence of the following outcomes was evaluated: Thrombolysis In Myocardial Infarction major and minor bleeding, MI, stent thrombosis, stroke, cardiovascular, and all-cause death. Occurrence of Thrombolysis In Myocardial Infarction major bleeding was significantly lower in patients treated with dual therapy: 1.97% versus 3.53% in those on triple therapy (odds ratios 0.55, 95% confidence interval 0.39 to 0.78, pu2009=u20090.0007); rates of minor bleeding were also decreased in the former (57% relative reduction). With dual therapy, there was not a statistically significant difference in all-cause and cardiovascular mortality (3.81% vs 4.01%, pu2009=u20090.37 and 1.62% vs 2.02%, pu2009=u20090.42, respectively). Incidence of MI (3.25% vs 2.78%, pu2009=u20090.61), definite stent thrombosis (0.92% vs 0.66%, pu2009=u20090.46), and stroke (1.28% vs 1.32%, pu2009=u20090.85) was similar in the 2 treatment strategies. In patients with long-term indication to OAC after PCI, compared with triple therapy, dual antithrombotic therapy reduces bleeding, without an excess in thromboembolic and ischemic cardiac events.