Javier Botas

Drug-Eluting Stent Thrombosis Results From the Multicenter Spanish Registry ESTROFA (Estudio ESpañol sobre TROmbosis de stents FArmacoactivos)

OBJECTIVES This study sought to assess the incidence, predictors, and outcome of drug-eluting stent(DES) thrombosis in real-world clinical practice. BACKGROUND The DES thromboses in randomized trials could not be comparable to those observed in clinical practice, frequently including off-label indications. METHODS We designed a large-scale, nonindustry-linked multicentered registry, with 20 centers in Spain. The participant centers provided follow-up data for their patients treated with DES, reporting a detailed standardized form in the event of any angiography-documented DES-associated thrombosis occurring. RESULTS Of 23,500 patients treated with DES, definite stent thrombosis(ST) developed in 301: 24 acute, 125 subacute, and 152 late. Of the late, 62 occurred >1 year(very late ST). The cumulative incidence was 2% at 3 years. Antiplatelet treatment had been discontinued in 95 cases(31.6%). No differences in incidences were found among stent types. Independent predictors for subacute ST analyzed in a subgroup of 14,120 cases were diabetes, renal failure, acute coronary syndrome, ST-segment elevation myocardial infarction, stent length, and left anterior descending artery stenting, and for late ST were ST-segment elevation myocardial infarction, stenting in left anterior descending artery, and stent length. Mortality at 1-year follow-up was 16% and ST recurrence 4.6%. Older age, left ventricular ejection fraction <45%, nonrestoration of Thrombolysis In Myocardial Infarction flow grade 3, and additional stenting were independent predictors for mortality. CONCLUSIONS The cumulative incidence of ST after DES implantation was 2% at 3 years. No differences were found among stent types. Patient profiles differed between early and late ST. Short-term prognosis is poor, especially when restoration of normal flow fails.

Incidence and severity of transplant coronary artery disease early and up to 15 years after transplantation as detected by intravascular ultrasound

OBJECTIVES The purpose of this study was to quantify the severity of transplant coronary artery disease and to assess lesion characteristics early and up to 15 years after heart transplantation by using intracoronary ultrasound. BACKGROUND Intravascular ultrasound has the ability to measure the components of the arterial wall and has been shown to be a sensitive method for detection of transplant coronary artery disease. METHODS A total of 304 intracoronary ultrasound studies were performed in 174 heart transplant recipients at baseline and up to 15 (mean 3.3 +/- 0.2) years after transplantation. Mean intimal thickness and an intimal index were calculated, and lesion characteristics (eccentricity, calcification) were assessed for all coronary sites imaged (mean 3.0 +/- 0.1 sites/study). The Stanford classification was used to grade lesion severity. RESULTS Compared with findings in patients studied at baseline (< 2 months after transplantation, n = 50), mean intimal thickness (0.09 +/- 0.02 vs. 0.16 +/- 0.02 mm, p < 0.01), intimal index (0.07 +/- 0.01 vs. 0.14 +/- 0.02, p < 0.01) and mean severity class (1.5 +/- 0.2 vs. 2.3 +/- 0.2, p < 0.01) were significantly higher at year 1 (n = 52) after transplantation. Thereafter, all three variables further increased over time and reached highest values between years 5 and 15. Calcification of lesions was detected in 2% to 12% of studies up to 5 years after transplantation, with a significant increase to 24% at years 6 to 10 (p < 0.05). CONCLUSIONS Severity of transplant coronary artery disease appeared to progress with time after transplantation in this cross-sectional study. This characteristic was most prominent during the 1st 2 years after transplantation, whereas calcification of plaques occurred to a significant extent only later in the process. These data may serve as a reference for comparison of intravascular ultrasound findings in other studies of patients with transplant coronary artery disease.

Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.

BACKGROUND Coronary endothelial vasodilator dysfunction is a common finding in cardiac transplant recipients and may represent an early marker for the development of intimal thickening and graft atherosclerosis. The present study tested the hypothesis that endothelial dysfunction precedes intimal thickening and that administration of L-arginine, the precursor of endothelium-derived relaxing factor, improves endothelial vasodilator function of coronary conduit and resistance vessels if given at an early stage of graft atherosclerosis. METHODS AND RESULTS Acetylcholine (10(-6), 10(-5), 10(-4) mol/L) was infused into the left anterior descending or circumflex artery and repeated after intravenous infusion of L-arginine (10 mg.kg-1.min-1 over 20 minutes) in 18 cardiac transplant recipients. Epicardial responses were evaluated by quantitative angiography, and the microcirculation was studied by determination of coronary blood flow with a Doppler flow velocity wire. Intimal thickening was assessed by intravascular ultrasound (n = 14). In epicardial coronary arteries, acetylcholine tended to elicit vasoconstriction. Epicardial coronary vasoconstriction elicited by acetylcholine was attenuated by infusion of L-arginine (10(-4) mol/L, -6.8% versus -2.8%; P < .01); this beneficial effect was observed predominantly in patients with normal intravascular ultrasound characteristics. In coronary resistance vessels, acetylcholine induced vasodilation, reflected by increases in coronary blood flow. The acetylcholine-induced increase in blood flow was significantly enhanced with L-arginine (at a dose of 10(-4) mol/L, + 121% versus 176%; before versus after L-arginine, P < .002). CONCLUSIONS The coronary vasculature of cardiac transplant recipients exhibits a generalized endothelial dysfunction of conduit and resistance vessels. L-Arginine improves endothelial dysfunction of both coronary microvasculature and epicardial coronary arteries. The reversibility of epicardial endothelial dysfunction by L-arginine is more likely in vessels with normal wall morphology.

Primary angioplasty versus systemic thrombolysis in anterior myocardial infarction.

OBJECTIVES This study compares the efficacy of primary angioplasty and systemic thrombolysis with t-PA in reducing the in-hospital mortality of patients with anterior AMI. BACKGROUND Controversy still exists about the relative benefit of primary angioplasty over thrombolysis as treatment for AMI. METHODS Two-hundred and twenty patients with anterior AMI were randomly assigned in our institution to primary angioplasty (109 patients) or systemic thrombolysis with accelerated t-PA (111 patients) within the first five hours from the onset of symptoms. RESULTS Baseline characteristics were similar in both groups. Primary angioplasty was independently associated with a lower in-hospital mortality (2.8% vs. 10.8%, p = 0.02, adjusted odds ratio 0.23, 95% confidence interval 0.06 to 0.85). During hospitalization, patients treated by angioplasty had a lower frequency of postinfarction angina or positive stress test (11.9% vs. 25.2%, p = 0.01) and less frequently underwent percutaneous or surgical revascularization after the initial treatment (22.0% vs. 47.7%, p < 0.001) than did patients treated by t-PA. At six month follow-up, patients treated by angioplasty had a lower cumulative rate of death (4.6% vs. 11.7%, p = 0.05) and revascularization (31.2% vs. 55.9%, p < 0.001) than those treated by t-PA. CONCLUSIONS In centers with an experienced and readily available interventional team, primary angioplasty is superior to t-PA for the treatment of anterior AMI.

Prospective application of pre-defined intravascular ultrasound criteria for assessment of intermediate left main coronary artery lesions results from the multicenter LITRO study.

OBJECTIVES This study is a prospective validation of 6 mm(2) as a minimum lumen area (MLA) cutoff value for revascularization of left main coronary artery (LMCA) lesions. BACKGROUND Lesions involving the LMCA are prognostically relevant. Angiography has important limitations in the evaluation of LMCA lesions with intermediate severity. An MLA of 6 mm(2) assessed by intravascular ultrasound has been proposed as a cutoff value to determine lesion severity, but there are no large studies evaluating the prospective application and safety of this approach. METHODS We have designed a multicenter, prospective study. Consecutive patients with intermediate lesions in unprotected LMCA were evaluated with intravascular ultrasound. An MLA <6 mm(2) was used as criterion for revascularization. RESULTS A total of 354 patients were included in 22 centers. LMCA revascularization was performed in 90.5% (152 of 168) of patients with an MLA <6 mm(2) and was deferred in 96% (179 of 186) of patients with an MLA of 6 mm(2) or more. A large scatter was observed between both groups regarding angiographic parameters. In a 2-year follow-up period, cardiac death-free survival was 97.7% in the deferred group versus 94.5% in the revascularized group (p = 0.5), and event-free survival was 87.3% versus 80.6%, respectively (p = 0.3). In the 2-year period, only 8 (4.4%) patients in the deferred group required subsequent LMCA revascularization, none with an infarction. CONCLUSIONS Angiographic measurements are not reliable in the assessment of intermediate LMCA lesions. An MLA of 6 mm(2) or more is a safe value for deferring revascularization of the LMCA, given the application of the clinical and angiographic inclusion criteria used in this study.

Role of Compensatory Enlargement and Shrinkage in Transplant Coronary Artery Disease Serial Intravascular Ultrasound Study

BACKGROUND Compensatory enlargement of the vessel wall has been described in the early stages of native atherosclerosis. Whether compensatory enlargement plays a role in transplant coronary artery disease is not known. The objective of this study was to determine, by use of serial intravascular ultrasound (IVUS), whether compensatory dilation occurs in transplant coronary artery disease over time. METHODS AND RESULTS Seventy-five heart transplant recipients with 151 matched coronary segments were selected for the presence of intimal disease progression as detected by serial IVUS examinations 1 to 3 years apart. Intimal disease progression was defined as a > 10% increase in intimal area (IA). IVUS catheter location in follow-up studies was verified angiographically in relation to branch vessels. Luminal area (LA) and total vessel area (TA) were measured at each site. Intimal area (IA = TA-LA) was calculated. Changes in IA (delta IA) and TA (delta TA) between baseline and follow-up IVUS were compared: delta IA, 2.9 +/- 0.2 mm2: delta TA, 2.7 +/- 0.4 mm2. A remodeling index (RI) was defined as RI = delta TA/delta IA. Three subgroups could be distinguished: over compensation (RI > I), partial compensation (RI 0 to 1), and no compensation or shrinkage (RI < or = 0). Seventy-four segments (49%) showed overcompensation, 44 (29%) showed partial compensation, and 33 (22%) showed no compensation or shrinkage. CONCLUSIONS In this study, serial IVUS shows that early after cardiac transplantation, a large proportion of the coronary segments with progression of intimal thickening have compensatory dilation of the vessel wall. However, a substantial number of coronary segments (22%) show no compensatory dilation or shrinkage. The progressive luminal narrowing in transplant patients may be due in part to vessel shrinkage or the lack of compensatory dilation over time.

Influence of Collateral Circulation on In-Hospital Death From Anterior Acute Myocardial Infarction

OBJECTIVES Our purpose was to study whether the in-hospital prognosis of anterior acute myocardial infarction (AMI) is influenced by preexistent collateral circulation to the infarct-related artery. BACKGROUND Collateral circulation exerts beneficial influences on the clinical course after AMI, but demonstration of improved survival is lacking. METHODS We studied 238 consecutive patients with anterior AMI treated by primary angioplasty within the first 6 h of the onset of symptoms. Fifty-eight patients with basal Thrombolysis in Myocardial Infarction (TIMI) flow >1 in the infarct-related artery or with inadequate documentation of collateral circulation were excluded. Collateral channels to the infarct-related artery before angioplasty were angiographically assessed, establishing two groups: 115 patients (64%) without collateral vessels (group A) and 65 patients (36%) with collateral vessels (group B). RESULTS There were no differences in baseline characteristics between groups A and B, except for the greater prevalence of previous angina in group B (15% vs. 34%, p = 0.003). During the hospital stay, 26 patients (23%) in group A and 5 (8%) in group B died (p = 0.01). Cardiogenic shock accounted for 74% of deaths. Cardiogenic shock developed in 30 patients (26%) in group A and in 4 (6%) in group B (p = 0.001). The absence of collateral circulation appeared to be an independent predictor of in-hospital death (odds ratio 3.4, 95% confidence interval 1.2 to 9.6, p = 0.02) and cardiogenic shock (odds ratio 5.6, 95% confidence interval 1.9 to 17, p = 0.002). CONCLUSIONS Preexistent collateral circulation decreases in-hospital death from anterior AMI by reducing the incidence of cardiogenic shock.

Thrombosis of Second-Generation Drug-Eluting Stents in Real Practice: Results From the Multicenter Spanish Registry ESTROFA-2 (Estudio Español Sobre Trombosis de Stents Farmacoactivos de Segunda Generacion-2)

OBJECTIVES This study sought to evaluate second-generation drug-eluting stent (DES) thrombosis in clinical practice. BACKGROUND First-generation DES are associated with a significant incidence of late thrombosis. There is paucity of data regarding real practice late thrombosis incidence and predictors with second-generation DES, zotarolimus-eluting stent (ZES), and everolimus-eluting stents (EES). METHODS A prospective, large-scale, non-industry-linked multicenter registry was designed. Complete clinical-procedural data and systematic follow-up of all patients treated with these stents was reported in a dedicated registry supported by the Spanish Working Group on Interventional Cardiology. RESULTS From 2005 to 2008, 4,768 patients were included in 34 centers: 2,549 treated with ZES, and 2,219 with EES. The cumulative incidence of definite/probable thrombosis for ZES was 1.3% at 1 year and 1.7% at 2 years and for EES 1.4% at 1 year and 1.7% at 2 years (p = 0.8). The increment of definite thrombosis between the first and second year was 0.2% and 0.25%, respectively. In a propensity score analysis, the incidence remained very similar. Ejection fraction (adjusted hazard ratio [HR]: 0.97; 95% confidence interval [CI]: 0.95 to -0.99; p = 0.008), stent diameter (adjusted HR: 0.37; 95% CI: 0.17to 0.81; p = 0.01) and bifurcations (adjusted HR: 2.1; 95% CI: 1.14 to 3.7; p = 0.02) emerged as independent predictors of thrombosis. In the subgroup of patients with bifurcations, the use of ZES was independently associated with a higher thrombosis rate (adjusted HR: 4; 95% CI: 1.1 to 13; p = 0.03). CONCLUSIONS In a real practice setting, the incidence of thrombosis at 2 years with ZES and EES was low and quite similar. The incidence of very late thrombosis resulted lower than was reported in registries of first-generation DES. In the subset of bifurcations, the use of ZES significantly increased the risk of thrombosis.

Influence of Preexistent Donor Coronary Artery Disease on the Progression of Transplant Vasculopathy: An Intravascular Ultrasound Study

BACKGROUND Transplant vasculopathy (TxCAD) limits longterm survival of allograft recipients. The possibility that preexistent donor coronary disease (PEDD) might accelerate this process is of concern. The serial progression of sites with and without PEDD as assessed by intravascular ultrasonic imaging is explored in this study. METHODS AND RESULTS Thirty patients with baseline intravascular imaging within 3 weeks of cardiac transplantation who had at least one annual follow-up study were included in this study. Vessel luminal area (LA), total area (TA), intimal index (II = TA - LA/TA), mean intimal thickness (MIT), and Stanford classification were expressed for each image site and for each patient at each study. Progression of sites and of patients with and without PEDD on the baseline study was compared. Patients with PEDD (n = 9) still had significantly more intimal disease than those without PEDD (n = 21) at the first follow-up study (MIT = 0.35 +/- 0.13 versus 0.13 +/- 0.11 mm; II = 0.29 +/- 0.11 versus 0.11 +/- 0.1; class = 3.7 +/- 0.5 versus 2.2 +/- 0.94; P < .001 for all comparisons). However, the increase in intimal thickness during the 1- year interval was not significantly different between the two groups. In 4 patients in whom both types of sites were present, no difference in progression was found. Data were similar for patients and sites studied over > 1 year. CONCLUSIONS PEDD does not accelerate the progression of TxCAD within the first few years after cardiac transplantation. The pathophysiology of TxCAD is most likely immune mediated and does not seem to be accelerated by native coronary artery disease.

Feasibility of serial intracoronary ultrasound imaging for assessment of progression of intimal proliferation in cardiac transplant recipients.

BACKGROUND Serial quantitative coronary angiography is used to assess progression of coronary disease; however, pathology studies have demonstrated angiographic insensitivity for determining atheroma. Intracoronary ultrasound (ICUS) can define and measure the components of the arterial wall and offers the potential for precise quantitative assessment of disease progression on serial examinations. The present study was done to test the feasibility of serially assessing intimal proliferation at the same coronary site with ICUS imaging in cardiac transplant recipients. METHODS AND RESULTS ICUS imaging was done with a 30-MHz, 5F or 4.3F ultrasound imaging catheter at the time of angiography in 70 cardiac allografts (3.8 sites per patient) initially and 1 year later. Mean intimal thickness (IT), luminal area (LA), and total area (TA) of lumen plus intima and an index of intimal thickness (II = TA - LA/TA) were measured at each site. Additionally, vessels were graded using a scale incorporating criteria of intimal thickness and circumferential involvement. Side-by-side comparisons of paired angiograms were performed both to verify the similarity of ICUS imaging site and to detect new angiographic abnormalities. At least one site could be assessed serially by ICUS in 100% of patients, but only 189 of the original 263 coronary sites (72%) (2.7 sites per patient) could be matched satisfactorily on the second study. Thirty-nine patients (56%) had mild IT and 31 patients (44%) had moderate or severe IT on the initial study. Both groups showed the same IT progression the following year (delta = 0.05 +/- 0.13 versus 0.07 +/- 0.15 mm; P = NS). Twenty-seven of the 70 patients (39%) showed progression by ICUS. The 23 patients with ICUS progression and angiographically normal vessels had the same progression in intimal thickening as the 4 patients with ICUS progression but showing angiographic disease (delta = 0.17 +/- 0.13 versus 0.22 +/- 0.10 mm; P = NS). CONCLUSIONS Replication of the intracoronary imaging site by judgment of two observers at an initial study and at a second study 1 year later was possible in at least one vessel site in 100% of the 70 patients and in 72% (189 of 263) of the original imaging sites (2.7 sites per patient). Serial ICUS demonstrates progression of intimal thickening at specific sites in only some cardiac transplant patients. Progression of intimal proliferation can occur in individuals in the presence or absence of initially increased intimal thickening or of angiographic disease at the time of the initial studies. Angiography is insensitive for recognizing early intimal thickening of the coronary vessels.