Francisco Marín

Anticoagulant and antiplatelet therapy use in 426 patients with atrial fibrillation undergoing percutaneous coronary intervention and stent implantation implications for bleeding risk and prognosis.

OBJECTIVES This study was designed to review outcomes in relation to antithrombotic therapy management strategies for patients with atrial fibrillation (AF) who undergo percutaneous coronary intervention (PCI) with stenting. BACKGROUND There is limited evidence on the optimal antithrombotic therapy management strategies for patients with AF who undergo PCI with stenting. METHODS We reviewed 426 patients (70.9% men, mean age 71.5 +/- 8.5 years) with AF undergoing PCI with stenting between 2001 and 2006. We recorded clinical and demographic characteristics of the patients, stroke risk factors, and antithrombotic therapy use before PCI and at discharge. Clinical follow-up was performed, and all bleeding episodes, thromboembolism, and major adverse cardiac events (MACE) (i.e., death, acute myocardial infarction, or target lesion revascularization) were recorded. RESULTS The most commonly associated comorbidities were hypertension (74.5%), diabetes mellitus (40.2%), chronic renal failure (14.9%), and congestive heart failure (26.7%); 80% of patients had >or=2 stroke risk factors. Of the drugs prescribed at discharge, aspirin plus clopidogrel were used in 174 patients (40.8%), whereas 213 patients (50%) were discharged with triple therapy (coumarins, aspirin, and clopidogrel). Complete follow-up was achieved in 87.5% (median 594 days; range 0 to 2,190). The incidence of adverse events was high (36.6%), with major bleeding in 12.3%, thromboembolic events in 4.2%, and MACE in 32.3%. All-cause mortality was high (22.6%). In a multivariate analysis, non-anticoagulation with coumarins increased mortality (17.8% vs. 27.8%; hazard ratio [HR] = 3.43; 95% confidence interval [CI] 1.61 to 7.54; p = 0.002) and MACE (26.5% vs. 38.7%; HR = 4.9; 95% CI 2.17 to 11.1; p < 0.01) In a Cox-regression analysis, non-anticoagulation (p < 0.01) and age (p = 0.02) were independent predictors of MACE. CONCLUSIONS Patients with AF undergoing PCI with stenting represent a high-risk population because of age, comorbidities, and presence of stroke risk factors. These patients have a high mortality and MACE rate, which is reduced by anticoagulation therapy.

Cessation of oral anticoagulation in relation to mortality and the risk of thrombotic events in patients with atrial fibrillation

Bleeding risk (often perceived, rather than actual) is a common reason for cessation of oral anticoagulation with Vitamin K antagonists (VKA). We investigate clinical outcomes in a consecutive population of VKA naïve atrial fibrillation (AF) patients, who initiated VKA therapy in our clinic. We included consecutive VKA-naïve patients with non valvular AF, initiated on VKA therapy in our anticoagulation outpatient clinic in 2009. During follow-up, adverse events [thrombotic/vascular events (stroke, acute coronary syndrome, acute heart failure and cardiac death), major bleeding and death], and VKA cessation were recorded. At the end of the follow-up, we determined time within therapeutic range (TTR), using a linear approximation (Rosendaal method). We studied 529 patients (49% male, median age 76), median follow-up 835 days (IQR 719-954). During this period 114 patients stopped VKA treatment. 63 patients suffered a thrombotic/cardiovascular event (5.17%/year, 27 thrombotic/ischaemic strokes), 51 major bleeding (4.19%/year) and 48 died (3.94%/year). Median TTR was 54% (34-57). On multivariate analysis (adjusted by CHA₂DS₂-VASc score), VKA cessation was associated with death [Hazard Ratio (HR) 3.43; p<0.001], stroke [4.21; p=0.001] and thrombotic/cardiovascular events [2.72; p<0.001]. Independent risk factors for major bleeding were age [1.08; p<0.001], previous stroke [1.85; p=0.049], and TTR [0.97; p=0.001], but not VKA cessation. In conclusion, in AF patients AF, VKA cessation is independently associated with mortality stroke and cardiovascular events. Specifically, VKA cessation independently increased the risk of stroke, even after adjusting for CHA₂DS₂-VASc score. TTR was an independent risk factor for major bleeding following initiation of VKA therapy.

Increased Major Bleeding Complications Related to Triple Antithrombotic Therapy Usage in Patients With Atrial Fibrillation Undergoing Percutaneous Coronary Artery Stenting

BACKGROUND The optimal antithrombotic therapy strategy for atrial fibrillation (AF) patients who undergo percutaneous coronary intervention with stent implantation (PCI-S) is unknown. We assessed the safety of antithrombotic therapy strategies in AF patients with indication for oral anticoagulation (OAC) undergoing PCI-S. METHODS We studied consecutive AF patients with indication for OAC who underwent PCI-S. We compared patients that received triple antithrombotic therapy (TT) [aspirin, clopidogrel, and coumadin] against other regimes (non-TT) after PCI-S. The primary end point was defined as the occurrence of major bleeding complications that were termed as early major bleeding (EMB) [< or = 48 h] or late major bleeding (LMB) [> 48 h]. Clinical follow-up was performed, and complications were recorded. RESULTS We studied 104 patients (mean age +/- SD, 72 +/- 8 years; 70% men); TT was used in 51 patients (49%). TT was associated with a higher incidence of LMB (21.6% vs non-TT, 3.8%; p = 0.006) but not of EMB (5.8% vs non-TT, 11.3%; p = 0.33). In multivariate analyses, glycoprotein (GP) IIb/IIIa inhibitor use (hazard ratio [HR], 13.5; 95% confidence interval [CI], 1.7 to 108.3; p = 0.014) and PCI-S of three vessels or left main artery disease (HR, 7.9; 95% CI, 1.6 to 39.2; p = 0.01) were independent predictors for EMB. TT use (HR, 7.1; 95% CI, 1.5 to 32.4; p = 0.012), the occurrence of EMB (HR, 6.7; 95% CI, 1.8 to 25.3; p = 0.005), and baseline anemia (HR, 3.8; 95% CI, 1.2 to 12.5; p = 0.027) were independent predictors for LMB. No differences in major cardiovascular events were observed in patients treated with TT vs non-TT (25.5% vs 21.0%; p = 0.53). CONCLUSION A high rate of major bleeding is observed in AF patients with indication for OAC undergoing PCI-S who receive TT. GP IIb/IIIa inhibitor use and multivessel/left main artery disease during PCI-S were independent predictors for EMB, while TT use, occurrence of EMB, and baseline anemia were independent predictors for LMB.

Interleukin-6, endothelial activation and thrombogenesis in chronic atrial fibrillation

BACKGROUND A prothrombotic or hypercoagulable state has been described in AF, which could increase the risk of thromboembolism. As inflammation has been related to thrombogenesis and endothelial activation, we hypothesised that the prothrombotic state in AF (as assessed by an index of thrombogenesis, prothrombin fragment 1+2 [F1+2]) and endothelial activation (soluble E-selectin (sEsel)) could be related to an index of inflammation (interleukin-6 (IL-6)). PATIENTS AND METHODS We studied 191 consecutive patients (98 male; mean age 72.3+/-9.2 years) with chronic non-rheumatic AF who were not on anticoagulant therapy. Plasma IL-6, sEsel and F1+2 were measured by ELISA. Research indices were compared to 74 controls in sinus rhythm matched for age and sex. In 43 patients with AF, the effects of introducing anticoagulation (INR 2.0-3.0) were also studied. RESULTS Patients with AF had elevated levels of F1+2 (p<0.001) and IL-6 (p=0.045), but not sEsel. There was no significant correlation between F1+2 and IL-6. In multivariate analysis, only F1+2 levels were independently associated with the presence of AF (p=0.001). After oral anticoagulation, plasma levels of F1+2 and sEsel were significantly decreased (both p<0.01). CONCLUSION High levels of IL-6 in AF suggest an inflammatory state, which appears to be more related to clinical variables of the patients, rather than to the presence of AF per se. There was no association of inflammation with endothelial activation (sEsel) or the presence of abnormal thrombogenesis (high F1+2 levels) in AF. Moreover, no changes in IL-6 levels were found despite the reduction of the other markers by oral anticoagulant therapy.

Soluble E-selectin in cardiovascular disease and its risk factors A review of the literature

The initial steps in the pathogenesis of atherosclerosis involve changes to the vascular endothelium, which produces numerous substances involved in the regulation and maintenance of vascular integrity and the homeostasis of the coagulation/fibrinolysis system. A further change in endothelial physiology is an increase in the surface expression of cell adhesion molecules, such as E-selectin, which regulate adhesive interactions between certain blood cells and endothelium. As E-selectin is only expressed on activated endothelium, it therefore provides an opportunity to study pathophysiological aspects of this cell in cardiovascular and other disease. However, a soluble form of E selectin (i.e. sE-selectin) can be found in the plasma. This review will focus on sE-selectin, and its potential role in the pathogenesis of cardiovascular disease as raised levels have been found in hypertension, diabetes and hyperlipidemia, although its association in established atherosclerosis disease and its value as a prognostic factor is more controversial.

Is Thrombogenesis in Atrial Fibrillation Related to Matrix Metalloproteinase-1 and Its Inhibitor, TIMP-1?

Background and Purpose— Decreased matrix metalloproteinase-1 (MMP-1) and increased levels of its inhibitor, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), reflect impaired matrix degradation with an increase in fibrosis. A prothrombotic state has been described in atrial fibrillation (AF), increasing the risk of stroke and thromboembolism. Because structural abnormalities and remodeling of atria have been observed in AF, we hypothesized that the prothrombotic state in AF may be related to abnormal indexes of matrix degradation. Methods— We studied 48 consecutive patients (30 men; age, 70.5±9.0 years) with chronic nonrheumatic AF who were not on anticoagulation. Plasma levels of MMP-1, TIMP-1, and prothrombin fragment 1+2 (F1+2, an index of thrombogenesis) were measured by enzyme-linked immunosorbent assay. M-mode, 2-dimensional, and Doppler echocardiographic studies were performed in all patients. Research indexes were compared with data from 32 control subjects in sinus rhythm who were of similar age and sex. Results— Patients with AF had lower levels of MMP-1 (P =0.011) but increased levels of TIMP-1 (P =0.033) and F1+2 (P <0.001) and a higher ratio of TIMP-1 to MMP-1 (P =0.009) compared with control subjects. After adjustment for sex, age, hypertension, and diabetes, TIMP-1 levels and the ratio of TIMP-1 to MMP-1 correlated with F1+2 levels (r =0.24, P =0.038; and r =0.26, P =0.023, respectively). In multivariate analysis, there was no independent relationship between MMP-1, TIMP-1, or ratio of TIMP-1 to MMP-1 and the presence of AF. Conclusions— Patients with AF have evidence of impaired matrix degradation, but this was not independently associated with the presence of AF on multivariate analysis. However, an independent relationship was found between the MMP/TIMP system and prothrombotic state (assessed by F1+2 levels).

Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: similarities and dissimilarities between North America and Europe.

Antithrombotic therapy in patients with atrial fibrillation undergoing coronary stenting: Similarities and dissimilarities between North America and Europe -

Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?

Chronic Kidney Disease (CKD) constitutes an adverse risk factor in chronic anticoagulated atrial fibrillation (AF) patients, being related to adverse cardiovascular events, mortality and major bleeds. It is unclear if CKD adds independent prognostic information to stroke risk stratification schemes, as the risk factor components of the CHADS2 and CHA2DS2-VASc scores are themselves related to renal dysfunction. The aim of our study was to determine if CKD independently improves the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification scores in AF. We recruited consecutive patients (n=978) patients (49% male; median age 76) with permanent or paroxysmal AF on oral anticoagulants with acenocoumarol, from our out-patient anticoagulation clinic. After a median follow-up of 875 (IQR 706-1059) days, we recorded stroke/transient ischaemic attack (TIA), peripheral embolism, vascular events (acute coronary syndrome, acute heart failure and cardiac death) and all-cause mortality. During follow-up, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) had an acute coronary syndrome and 32 (1.37%/year) had acute heart failure. Also, 102 patients (4.35%/year) died during the following up, 31 of them (1.32%/year) as a result of a thrombotic event. Based on c-statistics and the integrated discrimination improvement (IDI), CKD did not improve the prediction for stroke/systemic embolism, thrombotic events and all-cause mortality using the CHADS2 and CHA2DS2-VASc scores. In conclusion, evaluating renal function in AF patients is important as CKD would confer a poor overall prognosis in terms of thromboembolic events and all-cause mortality. Adding CKD to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.

Circulating microparticles: new insights into the biochemical basis of microparticle release and activity

Circulating microparticles released from various cell types are present in healthy individuals and the number and composition of their membrane vary in different disorders. Long considered to be cellular debris, microparticles have been recently identified as regulatory vectors of intercellular cross-talk. Indeed, circulating microparticles represent a heterogeneous mixture of spheroids of diverse surface membrane glycoproteins and lipids, with diverse cytoplasm components, the pattern of which depends on the type of stimulation and pathophysiology of parental cells. Despite extensive research into the procoagulant and proinflammatory properties of microparticles, there are few data that can provide information on the mechanism(s) of their formation and biological effects. Although several mechanisms of microparticle release have been suggested, the precise order of the events associated with key features of microparticle formation, transmembrane phosphatidylserine redistribution and cytoskeleton disruption remain to be clarified. In this review, we provide an overview of the molecular mechanisms involved in microparticle formation, as well as the diverse physiological and pathological roles they are able to undertake. Understanding the mechanism(s) governing microparticle release processes may be critical to understanding their precise role in various pathophysiological processes and thus indicate new potential routes to therapy.

Plasma von Willebrand factor, soluble thrombomodulin, and fibrin D-dimer concentrations in acute onset non-rheumatic atrial fibrillation

Objective: To investigate whether new onset acute atrial fibrillation (AF) of < 48 hours’ duration creates a prothrombotic state in the absence of anticoagulation and to assess the evolution in research indices after spontaneous or pharmacological cardioversion. Methods: 24 patients were recruited with first onset acute non-rheumatic AF, in whom sinus rhythm was restored within 48 hours of arrhythmia onset, without anticoagulant treatment. Atrial mechanical function was assessed by transmitral inflow. Soluble thrombomodulin and von Willebrand factor concentrations (both as indices of endothelial damage or dysfunction) and fibrin D-dimer concentrations (as an index of thrombogenesis) were measured. Blood samples were drawn and echocardiographic studies were performed at days 1, 3, 7, and 30 after cardioversion. Research indices were compared with those of 24 healthy participants, 24 patients with chronic AF, and 24 patients with ischaemic heart disease in sinus rhythm. Results: Patients with AF had higher concentrations of soluble thrombomodulin (acute AF 12.1 (4.1) ng/ml; chronic AF 11.8 (4.6) ng/ml), von Willebrand factor (acute AF 137.2 (36.9) ng/ml; chronic AF 133.1 (25.0) ng/ml), and fibrin D-dimer concentrations (acute AF 2.35 (2.68) μg/ml; chronic AF 1.12 (0.65) μg/ml) than did healthy controls (5.9 (2.7) ng/ml, 86.7 (33.2) ng/ml, and 0.39 (0.28) μg/ml, respectively) and patients with ischaemic heart disease (7.4 (3.7) ng/ml, 110.0 (29.0) ng/ml, and 0.99 (0.73) μg/ml, respectively) (all p < 0.05). Day 30 concentrations of fibrin D-dimer were higher in patients with acute AF than in patients with chronic AF (p  =  0.038) but sTM and von Willebrand factor concentrations were not different (both not significant). There were no significant changes in research indices or echocardiographic parameters after cardioversion (all p > 0.05). Conclusions: There was evidence among patients with acute onset AF of endothelial damage or dysfunction and increased thrombogenesis, which persisted up to 30 days after cardioversion.