Occurrence Of Adverse Cardiac Events Research Articles

Safety and efficacy of linagliptin in patients with type 2 diabetes mellitus and coronary artery disease: Analysis of pooled events from 19 clinical trials

AimsTo examine the safety and efficacy of linagliptin in patients with type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) using pooled data from the global clinical trials program. MethodsPatient-level data were pooled from randomized, placebo-controlled clinical trials of linagliptin (5mg, monotherapy or combination therapy). Safety/efficacy analyses were conducted for patients with CAD and ≥12 and ≥24weeks of treatment, respectively. ResultsThe safety analysis included 19 trials (linagliptin, n=451; placebo, n=272) and the efficacy analysis, 12 trials (linagliptin, n=328; placebo, n=198); mean (± standard deviation) exposure to study treatment was 212 (144) days linagliptin and 245 (171) days placebo. Occurrence of cardiac adverse events (AEs) was similar for linagliptin- and placebo-treated patients (9.1% and 9.2%, respectively); exposure-adjusted incidence rates (per 100 patient-years) were 16.6 and 14.0, respectively. Overall incidence of AEs was numerically lower with linagliptin than placebo. After 24weeks, mean adjusted change (standard error) from baseline glycosylated hemoglobin was −0.64% (0.04) with linagliptin vs. –0.08% (0.05) with placebo (P<.001). ConclusionsThis comprehensive pooled analysis showed that addition of linagliptin to treatment regimens of patients with T2DM and CAD was not associated with an increased incidence of cardiac AEs, was well tolerated, and was effective.

Validation of the HEART Score System in Emergency Department Patients with Chest Pain and Possible Acute Coronary Syndrome

Chest pain is one of the most common complaints of patients seeking consult in the emergency room (ER). The HEART score is a novel scoring system that utilizes the patient’s history, electrocardiogram, age, risk factors, and troponin level (HEART) to aid clinicians in the stratification of patients with chest pain in the ER. This study aims to determine the validity of the HEART score in predicting outcome in patients with chest pain seen in our ER. Methods: Patients who presented with chest pain in the ER of the Philippine Heart Center were included in the study, and their HEART scores were determined prospectively. Patients were followed up for 30 days, and the occurrence of acute myocardial infarction, revascularization and/or death were noted. The sensitivity, specificity, and positive and negative predictive values were then calculated in each HEART score. Results: Three hundred twenty-eight patients were included. One hundred seventy-six patients (53.7%) reached at least one endpoint. HEART scores 0–3 yielded excellent sensitivity and negative predictive values. A score ≥7 showed high specificity and positive predictive values. The measured C-statistic for the HEART score was 0.951. Conclusion: The HEART score is an easy, reliable, and convenient scoring system for stratifying patients with chest pain in the ER. It can be applied in our local setting, and it has an excellent ability to predict the occurrence of adverse cardiac events. Keyword: HEART score

Prevalence of potential drug interactions with azithromycin in Colombia, 2012-2013

Objective To determine the prevalence of potential drug interactions between azithromycin and different IA and III antiarrhythmic groups in a national database of drug prescriptions in 2012-2013. Methods Retrospective study based on a population database of medicine dispensation. Data from patients who received azithromycin between January 1, 2012 and June 30, 2013 were extracted along with data from patients who received azithromycin in combination with other medications shown to cause heart arrhythmias when used concomitantly. Frequencies and proportions were established. Results 13 859 patients receiving azithromycin alone or in combination with other drugs were identified. The average time of use was 4.5 ± 0.9 days. A total of 702 patients (5.1 %) received azithromycin plus 19 other potentially risky drugs. The most frequently associated were loratadine (77.1 %), diphenhydramine (16.5 %) and amitriptyline (8.1 %). Combinations with a single drug were the most frequent (n=533, 75.9 %), predominantly azithromycin+loratadine. The maximum number of combined drugs was six (n=2, 0.3 %). Conclusions Identification of drug prescriptions through population databases is an effective way to find potential drug interactions. The frequency of potential interactions between azithromycin and other drugs is common in Colombian patients. Future research should assess the risk of occurrence of adverse cardiac events.

Meta-Analysis of Medium and Long-Term Efficacy of Loading Statins After Coronary Artery Bypass Grafting

The aim of this study was to evaluate the medium- and long-term efficacy of loading statins after coronary artery bypass grafting (CABG) by comparing using a loading dose of statins or a regular dose of statins in patients undergoing CABG. We conducted a literature search of numerous databases for randomized controlled trials on the efficacy of a loading dose of statins in patients undergoing CABG. The quality of included studies was evaluated according to the Newcastle-Ottawa Scale. Statistical results of treatment were represented by weighted mean difference, odds ratio, and 95% confidence interval. There were 8 studies including 8,676 patients (4,352 who had a loading dose of statins and 4,324 who had a regular dose). Meta-analysis showed statistically significant differences in the following in patients who took a loading dose of statins: lower level of low-density lipoprotein cholesterol (LDL-C) after CABG (p < 0.00001), fewer deaths caused by myocardial infarction (p = 0.005), fewer patients with myocardial infarction (p = 0.004), fewer patients undergoing secondary CABG (p < 0.00001), and fewer patients undergoing graft restenosis by intravascular ultrasonography (p < 0.0001). Comparing patients receiving a loading dose of statins with those receiving a regular dose after CABG, the medium- and long-term efficacy of a loading dose showed significant reduction in LDL-C, lower occurrence of adverse cardiac events, and reduction in graft restenosis. Although the incidence of drug-related side effects was slightly higher in the loading-dose group, in the majority of patients they were not serious. Overall, a loading dose of statins is superior to regular dosing of statins after CABG.

Exercise stress echocardiography with tissue Doppler imaging in risk stratification of mild to moderate aortic stenosis.

Patients with mild to moderate aortic stenosis (AS) seem to have a worse outcome than commonly expected. Early identification of subjects who may develop a rapid disease progression or cardiovascular events is critical in order to apply adequate risk management. Observational prospective single-centre study. To determine the prognostic role of exercise stress echocardiography (ESE) in patients with mild and moderate asymptomatic AS. Ninety consecutive patients (mean age 74 ± 12 years) with isolated mild and moderate AS were enrolled into the study protocol over a 20 months period. Follow-up time was 12 months. A complete echocardiographic study with tissue Doppler imaging (TDI) was performed at baseline and during semi-supine symptom-limited exercise test to evaluate: (1) the occurrence of symptoms, (2) ST segment changes, (3) transaortic pressure gradient, (4) the E/A ratio, (5) the E/e' ratio and (6) the systolic pulmonary artery pressure. During the 1 year follow-up time, we evaluated the occurrence of adverse cardiac events, defined as any of the following: (1) cardio-vascular hospitalization; (2) requirement for aortic valve replacement; (3) cardiac death. During follow-up, three patients died, 11 underwent aortic valve replacement and 26 had cardiovascular hospitalizations. On univariate analysis, patients who exhibited symptoms during exercise (HR 2.93, p = 0.003); the occurrence of a ≥ 2 mm exercise-induced ST segment depression (HR 3.12, p = 0.001); a ≥ 15 mmHg increase in mean transaortic pressure gradient during exercise (HR 2.77, p = 0.001); a ≥ 50 mmHg exercise-induced increase in systolic pulmonary artery pressure (HR 2.90, p = 0.009); an exercise-induced pseudo-normalization of the E/A ratio (E/A ≥ 1) (HR 7.50, p = 0.0001) and, particularly, a ≥ 15 exercise-induced increase in the E/e' ratio (HR 7.69, p = 0.0001) had a significantly higher risk of cardiac events during the follow-up time. On multivariate analysis, only the latter covariate (HR 6.04, p = 0.009) was independently associated with adverse cardiac events. A ≥ 15 stress-induced increase in E/e' ratio is highly predictive of cardiac events in patients with mild to moderate AS. Assessment of diastolic function using TDI during ESE provides additional prognostic information in such patients.

Design and Rationale of the Femoral Closure versus Radial Compression Devices Related to Percutaneous Coronary Interventions (FERARI) Study

BACKGROUNDBleeding events after percutaneous coronary interventions (PCI) are associated with patients’ age, gender, and the presence of chronic kidney disease, antithrombotic treatment, as well as arterial access site. Patients being treated by PCI using radial access site are associated with an improved prognosis. However, the safety of femoral closure devices has never been compared to radial compression devices following PCI. Therefore, the aim of this study is to evaluate the safety of femoral closure compared to radial compression devices in patients treated by PCI envisaging access site bleedings as well as short- and long-term prognostic outcomes.METHODSThe Femoral Closure versus Radial Compression Devices Related to Percutaneous Coronary Interventions (FERARI) study is a single-center observational study comparing 400 consecutive patients undergoing PCI either using radial compression devices (TR Band™) or femoral closure devices (Angio-Seal™) at the corresponding access site. The primary outcome consists of the occurrence of vascular complications at the arterial access site, including major bleedings as defined by common classification systems. Secondary outcomes consist of the occurrence of adverse cardiac events, including all-cause mortality, target lesion revascularization, and target vessel revascularization during 30 days and 12 months of follow-up.RESULTSStudy enrollment was initiated in February 2014. The enrollment phase is expected to last until May 2015.CONCLUSIONSThe FERARI study intends to comparatively evaluate the safety and prognostic outcome of patients being treated by radial or femoral arterial closure devices following PCI during daily clinical practice.

Tailoring of the dopamine coated surface with VEGF loaded heparin/poly-L-lysine particles for anticoagulation and accelerate in situ endothelialization.

Coronary artery disease is a great threat to human health and is the leading killer worldwide. Percutaneous coronary intervention is the most effective therapy; however, thrombus, and restenosis caused by endothelium injury continue to be problematic after treatment. It is widely accepted that surface biofunctional modification to improve blood compatibility and accelerate endothelialization may be an effective approach to prevent the occurrence of adverse cardiac events. In this study, novel VEGF-loaded heparin/poly-L-lysine (Hep/PLL) particles were developed and immobilized on a dopamine coated titanium surface. The size, distribution, zeta potential, and morphology of the prepared particles were subsequently characterized. The influence of changes in the surface physicochemical properties after particle immobilization was assessed for blood compatibility and cytocompatibility. Surface-modified VEGF-loaded particles significantly inhibited platelet adhesion and activation and were effective in promoting the proliferation and survival of endothelial progenitor cells and endothelial cells. Moreover, Hep/PLL particles were also beneficial for controlling the long-term release of VEGF, which may facilitate endothelium regeneration. In conclusion, VEGF-loaded Hep/PLL particles were successfully immobilized on the Ti surface, and the biocompatibility was significantly improved. This study demonstrates a potential application for the multifunctional modification of stent surfaces for clinical use.

Left ventricular systolic function and the pattern of late-gadolinium-enhancement independently and additively predict adverse cardiac events in muscular dystrophy patients.

BackgroundCardiac involvement is a frequent finding in patients with Duchenne (DMD) and Becker (BMD) muscular dystrophies. With this study, we aimed at elucidating the relationship between the phenotypic expression of cardiac involvement and the occurrence of adverse cardiac events in DMD/BMD patients.MethodsEighty-eight male DMD/BMD patients (age 29 ± 14 yrs) were prospectively enrolled. All patients underwent cardiovascular magnetic resonance (CMR) comprising cine- and late-gadolinium-enhancement (LGE)-CMR at study entry and were subsequently followed-up for adverse cardiac events. The primary endpoint was defined as all-cause/cardiac death or cardiac transplantation. Secondary endpoints were (1) hospitalization for heart failure and/or (2) occurrence of non-/sustained ventricular tachycardia (VT).ResultsDuring a mean follow-up time of 47 ± 18 months, the primary endpoint was observed in three (3%) and the secondary endpoint in 21 (24%) patients. On multivariable analysis, LV-EF (HR, 95% CI: 0.94, 0.89-0.97, p = 0.001) and the presence of “transmural” LGE (HR, 95% CI: 2.89, 1.09-7.68, p = 0.033) were the only independent predictors for secondary endpoints. A cut-off for LV-EF of 45% was associated with the highest hazard ratio (HR, 95% CI: 11.50, 4.49-29.43, p < 0.0001) in a Cox regression survival analysis. In the group of patients with a LV-EF (>45%), those patients already showing “transmural” LGE had a significantly lower event-free-survival (HR, 95% CI: 13.48, 1.89-96.12, p = 0.009) compared to those without.ConclusionsAn impaired LV systolic function (LV-EF ≤45%) and a “transmural” pattern of myocardial fibrosis independently predict the occurrence of adverse cardiac events in DMD/BMD patients. Even in DMD/BMD patients with relatively preserved LV-EF (>45%), the simple and visually assessable parameter “transmural LGE” is of additive prognostic value.

Elevated Levels of Circulating DNA and Chromatin Are Independently Associated With Severe Coronary Atherosclerosis and a Prothrombotic State

Aberrant neutrophil activation occurs during the advanced stages of atherosclerosis. Once primed, neutrophils can undergo apoptosis or release neutrophil extracellular traps. This extracellular DNA exerts potent proinflammatory, prothrombotic, and cytotoxic properties. The goal of this study was to examine the relationships among extracellular DNA formation, coronary atherosclerosis, and the presence of a prothrombotic state. In a prospective, observational, cross-sectional cohort of 282 individuals with suspected coronary artery disease, we examined the severity, extent, and phenotype of coronary atherosclerosis using coronary computed tomographic angiography. Double-stranded DNA, nucleosomes, citrullinated histone H4, and myeloperoxidase-DNA complexes, considered in vivo markers of cell death and NETosis, respectively, were established. We further measured various plasma markers of coagulation activation and inflammation. Plasma double-stranded DNA, nucleosomes, and myeloperoxidase-DNA complexes were positively associated with thrombin generation and significantly elevated in patients with severe coronary atherosclerosis or extremely calcified coronary arteries. Multinomial regression analysis, adjusted for confounding factors, identified high plasma nucleosome levels as an independent risk factor of severe coronary stenosis (odds ratio, 2.14; 95% confidence interval, 1.26-3.63; P=0.005). Markers of neutrophil extracellular traps, such as myeloperoxidase-DNA complexes, predicted the number of atherosclerotic coronary vessels and the occurrence of major adverse cardiac events. Our report provides evidence demonstrating that markers of cell death and neutrophil extracellular trap formation are independently associated with coronary artery disease, prothrombotic state, and occurrence of adverse cardiac events. These biomarkers could potentially aid in the prediction of cardiovascular risk in patients with chest discomfort.

High risk of severe cardiac adverse events in patients with mitochondrial m.3243A&gt;G mutation

To determine the long-term incidence of cardiac life-threatening complications and death in patients with the m.3243A>G mutation, and to identify cardiac prognostic factors. We retrospectively included patients carrying the m.3243A>G mutation who were admitted to the Neuromuscular Disease Clinic of Pitié Salpêtrière Hospital between January 1992 and December 2010. We collected information relative to their yearly neurologic and cardiac investigations, their mutation load in blood, urine, and muscle at initial admission, and the occurrence of cardiac life-threatening adverse events and death during follow-up. Forty-one patients (median age = 47 years [36-55 years], men = 13) were included, of whom 38 had clinical manifestations of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and 3 were asymptomatic. One patient had a personal history of cardiac transplantation. Cardiac investigations displayed left ventricular hypertrophy, left ventricular dysfunction, or both abnormalities in 18 patients, along with Wolff-Parkinson-White syndrome in 7, conduction system disease in 4, and atrial fibrillation in 1. Over a median 5-year (3-9 years) follow-up period, 11 patients died, including 3 due to heart failure; 7 had life-threatening adverse events, including 6 hospitalizations for severe heart failure and 1 resuscitated cardiac arrest. By multivariate analysis, left ventricular hypertrophy was the only parameter independently associated with occurrence of cardiac adverse events. Patients with the m.3243A>G mutation have a high incidence of cardiac death and life-threatening adverse events. Left ventricular hypertrophy was the only parameter independently associated with occurrence of these events.

PREVENTION OF CONTRAST-INDUCED NEPHROPATHY WITH ASCORBIC ACID

ObjectivesA single-center prospective randomised controlled trials was performed, 149 patients were divided randomly into control group (n=78, receiving only 0.9% sodium chloride solution for routine hydration) and intervention group (n=71,...

Response to Salvadori et al.: adverse cardiac events during catecholamine therapy: a role for hydrocortisone?

Dear Editor, We thank Dr. Salvadori and his colleagues for their interest in our work [1] and the constructive comments. In view of the evolving controversy regarding the effects of hydrocortisone therapy in sepsis during the study period (January to December 2009), the use of hydrocortisone was strictly reserved for patients with septic shock requiring escalating norepinephrine doses. This explains why only one patient suffering from septic shock received hydrocortisone (continuous infusion of 200 mg/day) at study enrollment. Unfortunately, this precludes evaluation of the influence of hydrocortisone on the binary occurrence of adverse cardiac events in our study population. At the occurrence of an adverse cardiac event, 15 of 21 septic shock patients (71.4 %) received a continuous hydrocortisone infusion at a median (interquartile range, IQR) daily dose of 192 (192–288) mg. The absolute number of adverse cardiac events did not differ between septic shock patients with or without hydrocortisone therapy [4 (2.5–6) versus 3 (2–7)] in both an unadjusted (p = 0.64) and adjusted (p = 0.12) model (model adjustment for Simplified Acute Physiology Score II, need for renal replacement therapy, presence of chronic liver diseases). Interestingly, however, patients on hydrocortisone developed adverse cardiac events at higher median vasopressor load [0.48 (0.36–0.54) lg/kg/min] than patients who did not receive hydrocortisone [0.18 (0.06–0.43) lg/kg/min] in both an unadjusted (p = 0.005) and adjusted model (p = 0.006). The type of adverse cardiac event had no influence on this association (p = 0.17 and p = 0.13, respectively). Carrying the hypothesis of Salvadori and colleagues on a potentially protective effect of hydrocortisone on the occurrence of adverse cardiac events during catecholamine vasopressor therapy further, one may speculate that hydrocortisone raised the individual threshold at which catecholamine vasopressors may induce adverse cardiac events in our study patients with septic shock. Taking the post hoc character of this analysis and the low number of septic shock patients developing adverse cardiac events (n = 21) into consideration, these data must be regarded as purely hypothesis-generating. Further studies are, therefore, needed to evaluate the influence of a hydrocortisone therapy on the occurrence of adverse (cardiac) events during catecholamine vasopressor therapy in septic shock.

Adverse cardiac events during catecholamine vasopressor therapy: a prospective observational study

To determine the incidence of and risk factors for adverse cardiac events during catecholamine vasopressor therapy in surgical intensive care unit patients with cardiovascular failure. The occurrence of any of seven predefined adverse cardiac events (prolonged elevated heart rate, tachyarrhythmia, myocardial cell damage, acute cardiac arrest or death, pulmonary hypertension-induced right heart dysfunction, reduction of systemic blood flow) was prospectively recorded during catecholamine vasopressor therapy lasting at least 12 h. Fifty-four of 112 study patients developed a total of 114 adverse cardiac events, an incidence of 48.2 % (95 % CI, 38.8-57.6 %). New-onset tachyarrhythmia (49.1 %), prolonged elevated heart rate (23.7 %), and myocardial cell damage (17.5 %) occurred most frequently. Aside from chronic liver diseases, factors independently associated with the occurrence of adverse cardiac events included need for renal replacement therapy, disease severity (assessed by the Simplified Acute Physiology Score II), number of catecholamine vasopressors (OR, 1.73; 95 % CI, 1.08-2.77; p = 0.02) and duration of catecholamine vasopressor therapy (OR, 1.01; 95 % CI, 1-1.01; p = 0.002). Patients developing adverse cardiac events were on catecholamine vasopressors (p < 0.001) and mechanical ventilation (p < 0.001) for longer and had longer intensive care unit stays (p < 0.001) and greater mortality (25.9 vs. 1.7 %; p < 0.001) than patients who did not. Adverse cardiac events occurred in 48.2 % of surgical intensive care unit patients with cardiovascular failure and were related to morbidity and mortality. The extent and duration of catecholamine vasopressor therapy were independently associated with and may contribute to the pathogenesis of adverse cardiac events.

Invited Commentary

Invited Commentary

Duration and type of therapy for diabetes: Impact on cardiac risk stratification with stress electrocardiographic-gated SPECT myocardial perfusion imaging

BackgroundStress electrocardiogram(ECG)-gated single photon emission computed tomography (SPECT) imaging is highly effective in risk stratification of diabetic patients for adverse cardiac events. While patients with diabetes are predisposed to a more aggressive progression of vascular disease, the impact of its duration and type of therapy on risk stratification are unknown. MethodsFrom the Hartford Hospital Nuclear Cardiology clinical database, 886 diabetic patients who underwent exercise or pharmacologic stress ECG-gated SPECT were identified, with complete follow-up regarding the occurrence of adverse cardiac events and information regarding the duration of diabetes and the type of therapy (insulin vs oral medication only) at the time of testing. Images were interpreted using the American College of Cardiology/ASNC standard 17-segment scoring model. ResultsOf the 886 diabetic patients, 98 (11%) suffered cardiac death or non-fatal myocardial infarction during follow-up (2.5 ± 1.6 years). A receiver operator characteristics curve demonstrated that diabetes ≥10 years in duration provided the maximal sum of sensitivity and specificity for the prediction of adverse cardiac outcomes. Multivariate analysis identified the following as independent predictors of adverse outcome: Post-stress ejection fraction (EF) <40% (P = .001), age (P = .004), insulin therapy (P = .031), diabetes duration >10 years (P = .038), summed stress score (SSS) >8 (P = .046). For patients with an SSS >8, diabetes duration and type of therapy significantly enhanced risk stratification. Similar findings emerged for patients with a post-stress EF <40%. ConclusionFor diabetic patients undergoing stress ECG-gated SPECT myocardial perfusion imaging, disease duration and type of therapy provide independent and incremental prognostic information. Integration of these variables with this cardiovascular imaging technology significantly enhances cardiac risk stratification.

Study of the corelation between level of preoperative high-sensitivity C-reactive protein and incidence of postoperative adverse cardiac events in elderly patients underwent noncardiac surgery

Objective To investigate the relevance between level of preoperative high-sensitivity C-reactive protein(hsCRP) and the occurrence of postoperative adverse cardiac events in elderly patients underwent noncardiac surgery. Methods 49 patients of more than 65 years that had undergone elective noncardiac surgery were enrolled in the study. And all patients were conformed to the standards of classification of risk factors for clinical history, content of Guidelines on Preoperative Cardiovascular Evaluation for Noncardiac Surgery established by the ACC/AHA .The patients were divided into two groups based on the preoperative hsCRP level:A group:hsCRP ≤ 3mg/L group (n=21) and B group: hsCRP>3mg/L group (n=28). General clinical characteristics of patients were recorded before operation, and 24 hours dynamic ECG was monitored a week prior to and after the operation. All patients taken measures of analgesia after surgery. The incidence of postoperative adverse cardiac events and the hospitalized days was recorded. The distinctions between two groups were analyzed regarding the occurrence of adverse cardiac events and hospitalized days after operation. Results 19 patients had postoperative myocardial ischemia; 4 cases in A group and 15 cases in B group. 7 patients suffered other postoperative adverse cardiac events, including 1 case in A group and the others in B group. There was statistically significant difference considering morbidity of myocardial ischemia in postoperation between the two groups, but there was no statistically significant difference about incidence of other adverse cardiac events and the length of stay in postoperation. Indexes about serious degree of myocardial ischemia:total depression time is(43.5±5.82 )min in A group, is( 135.0±81.2)min in B group. The depression times is(5.2±2.5 )in A group, is( 8.8±3.0)in B group.The longest depression time is( 23.7±9.2)min in A group, is( 84.3±54.1 )min in B group.Total ischemia burden is( 170.1 ±88.8 )mm· min-1 ·24h-1 in A group, is (311.3± 118.8 )mm· min-1 ·24h-1 in B group.There was statistically significant difference between the two groups. Conclusion Level of preoperative hsCRP>3 mg/L was relevant to the incidence of the most common postoperative adverse cardiac events--myocardial ischemia in elderly patients and level of preoperative hsCRP >3 mg/L was one of the risk factors of postoperative myocardial ischemia;Determination of preoperative hsCRP level may improve cardiovascular risk scoring system. Key words: High-sensitivity C-reactive protein; Adverse cardiac events; Noncardiac surgery; The elderly

Repercusión del remodelado inverso del ventrículo izquierdo en la respuesta clínica a la terapia de resincronización cardíaca

Objectives We aimed to study if the presence of reverse remodelling during follow-up in patients successfully implanted with a cardiac resynchronization therapy device is associated with a better clinical evolution. Methods This retrospective study included 86 patients who fitted current indications for cardiac resynchronization therapy. A complete echocardiography study was performed at baseline and 6 months after the device implantation. We studied the possible relationship between the presence of significant reverse remodelling (defined as the reduction of left ventricle end-systolic volume ≥10%) and the occurrence of cardiac adverse events during follow-up (death, transplantation and admission due to heart failure). Results Over a mean follow-up of 14±10 months, we documented cardiac adverse events in 19 patients (7 deaths and 12 heart failure admissions). Patients showing a worse clinical outcome had larger left ventricular end-diastolic (259±62 vs 205±87 ml; p=0.024) and end-systolic volumes (204±57 vs 165±72 mL; p=0.034) in baseline echocardiography. They also showed a wider stimulated QRS complex (136±15 vs 123±16 ms; p=0.02) and a smaller reduction of the end-systolic left ventricular volume (8±19% vs 32±26%; p=0.008) at 6 months. We identified that the presence of significant reverse remodelling was as an independent predictor of a better clinical outcome (OR=5.4; 95% CI=1.69 – 17.6). Conclusion The presence of reverse remodelling is associated with decreased cardiac adverse events in middle-long term in patients undergoing Cardiac Resynchronization Therapy.

Aplidin Cardiac Safety Analysis.

Abstract 4820 BackgroundAplidin (plitidepsin) is a cyclic depsipeptide of marine origin, with activity in relapsed/refractory multiple myeloma and T-cell NHL[1],[2]. Some depsipeptides have been linked to increased cardiac toxicity in the literature[3]. PharmaMar Pharmacovigilance and Clinical Trials Data Management databases were reviewed for cardiac adverse events (CAEs) occurring during clinical trials evaluating plitidepsin as single-agent as of November 2008. Data were analyzed for potential risk factors associations with the occurrence of CAE by univariate and multivariate logistic regression analyses. ResultsForty-six of the 578 patients (8.0%) treated had at least one CAE. Eleven patients of 578 (1.9%) had CAE related to plitidepsin, none of them with fatal outcome.CAEs were retrospectively classified into 3 main groups after clinical review of all available data. The most frequent type of CAE were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Most events occurred randomly during plitidepsin treatment. Of note, no cases of life-threatening ventricular arrhythmias have been reported to date. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous events (M) (n=6; 1.0%) included all other cardiac events that did not fit into the aforementioned categories. None of the M events was related to plitidepsinDemographic, clinical and pharmacological variables were explored by univariate and multivariate analysis. Significant association was found with prostate or pancreas cancer diagnosis (p=0.002), known baseline cardiac risk factors (p=0.002), myalgia at baseline (p=0.004), lower hemoglobin levels (p= 0.006) and ≥ grade 2 hypokalemia (p=0.006). Multivariate analysis confirmed all these associations. Importantly, treatment related variables, such as plitidepsin dose, number of cycles or schedule of administration did not result in any statistically significant association.Serial ECGs performed before and after plitidepsin administration (n=136) did not show any relevant effect on QTc interval.None of the PK parameters analyzed (Cmax and AUC from day 0 to day 28) had any significant impact on the probability of developing a CAE. ConclusionsCAEs observed to date in plitidepsin trials fit into three clinical categories. The most frequent type observed was AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population[4]. All other events were relatively infrequent. No dose-cumulative pattern was observed; moreover, neither plitidepsin dose nor schedule was associated with occurrence of CAEs. Relevant predisposing factors identified in univariate and multivariate analyses were related to patient's baseline and/or disease-related characteristics rather than to drug exposure or treatment-related variables. Data available on 578 adult patients with advanced cancer treated with singe-agent plitidepsin support a favorable cardiac safety profile.[1] Mateos MV, Cibeira MT, Richardson P et al. Blood 2008; 112(11): 3700.[2] Ferme C, Mateos MV, Szyldergemajn S et al. Blood 2008; 112(11): 1566.[3] Shah M., Binkley P. Chan K. et al. Clin Cancer Res 2006; 12(13): 3997-4003[4] Go A, Hylek E., Phillips K. et al. JAMA 2001, 285: 2370-2375. Disclosures:Soto-Matos:PharmaMar SAU: Employment. Szyldergemajn:PharmaMar SAU: Employment. Gomez:PharmaMar SAU: Employment. Extremera:PharmaMar SAU: Employment. Miguel-Lillo:PharmaMar SAU: Employment. Alfaro:PharmaMar SAU: Employment. Coronado:PharmaMar SAU: Employment. Lardelli:PharmaMar SAU: Employment. Roy:PharmaMar SAU: Employment. Corrado:PharmaMar SAU: Employment. Yovine:PharmaMar SAU: Employment. Kahatt:PharmaMar SAU: Employment.

Gene polymorphisms in APOE, NOS3, and LIPC genes may be risk factors for cardiac adverse events after primary CABG

IntroductionCoronary artery disease progression after primary coronary artery bypass grafting may, beside classical atherosclerosis risk factors, be depending on genetic predisposition.MethodsWe investigated 192 CABG patients (18% female, age: 60.9 ± 7.4 years). Clinically cardiac adverse events were defined as need for reoperation (n = 88; 46%), reintervention (n = 58; 30%), or angina (n = 89; 46%). Mean follow-up time measured 10.1 ± 5.1 years. Gene polymorphisms (ApoE, NOS3, LIPC, CETP, SERPINE-1, Prothrombin) were investigated separately and combined (gene risk profile).ResultsAmong classical risk factors, arterial hypertension and hypercholesterinemia significantly influenced CAD progression. Single ApoE, NOS3 and LIPC polymorphisms provided limited information. Patients missing the most common ApoE ε3 allele (5,2%), showed recurrent symptoms (p = 0,077) and had more frequently reintervention (p = 0,001). NOS3 a allele was associated with a significant increase for reintervention (p = 0,041) and recurrent symptoms (p = 0,042).Homozygous LIPC patients had a higher reoperation rate (p = 0.049).A gene risk profile enabled us to discriminate between faster and slower occurrence of cardiac adverse events (p = 0.0012).ConclusionSingle APOE, LIPC and NOS3 polymorphisms permitted limited prognosis of cardiac adverse events in patients after CABG. Risk profile, in contrast, allowed for risk stratification.

Effects of General Anesthetic Agents in Adults Receiving Electroconvulsive Therapy

Our primary objective was to conduct a systematic review to determine the differential effects of general anesthetic agents on electroconvulsive therapy (ECT) induced motor and electroencephalogram seizure duration. Our secondary objective was to determine the differential effects of induction agents on emergence time, recovery time, and the occurrence of adverse cardiac events and drug effects. We searched 4 electronic databases for randomized, crossover, and parallel trials. The weighted mean difference was calculated for continuous variables, whereas the risk difference was assessed for dichotomous variables. We combined crossover- and parallel-designed trials using the inverse variance method, and the random-effects model was used throughout. Forty-one randomized trials involving 14 induction agents were included. The quality of trials was poor. Clinical and statistical heterogeneity were identified throughout. The most commonly studied comparison was methohexital versus propofol, where the mean motor seizure duration with methohexital was longer compared with that of propofol (weighted mean difference, 9.06 seconds; 95% confidence interval, 5.72-12.40). However, combining methohexital or propofol with a short-acting opioid prolonged seizure duration. Small but significant variations in emergence and recovery times were identified. Inadequate data were available to draw conclusions regarding adverse cardiac events and drug effects. No deaths were reported. Whereas the relationship between ECT seizure length and efficacy remains unclear, all of the available induction agents in this review would be appropriate for ECT. When the clinician needs to prolong seizure length, methohexital or the addition of a short-acting opioid to methohexital or propofol should be considered. The small variations in emergence and recovery times should not govern the choice of an induction agent.