Sema Güneri

Anticoagulation With Otamixaban and Ischemic Events in Non–ST-Segment Elevation Acute Coronary Syndromes: The TAO Randomized Clinical Trial

IMPORTANCE The optimal anticoagulant for patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) managed with an invasive strategy remains controversial. OBJECTIVE To compare the clinical efficacy and safety of otamixaban, a novel intravenous direct factor Xa inhibitor, with that of unfractionated heparin plus downstream eptifibatide in patients with NSTE-ACS undergoing a planned early invasive strategy. DESIGN, SETTING, AND PARTICIPANTS Randomized, double-blind, active-controlled superiority trial that enrolled 13,229 patients with NSTE-ACS and a planned early invasive strategy, at 568 active sites in 55 countries and conducted between April 2010 and February 2013. A planned interim analysis was conducted for otamixaban dose selection. INTERVENTIONS Eligible participants were randomized to otamixaban (bolus and infusion, at 1 of 2 doses) or unfractionated heparin plus, at the time of percutaneous coronary intervention, eptifibatide. The otamixaban dose selected at interim analysis was an intravenous bolus of 0.080 mg/kg followed by an infusion of 0.140 mg/kg per hour. MAIN OUTCOMES AND MEASURES The primary efficacy outcome was the composite of all-cause death or new myocardial infarction through day 7. RESULTS Rates of the primary efficacy outcome were 5.5% (279 of 5105 patients) randomized to receive otamixaban and 5.7% (310 of 5466 patients) randomized to receive unfractionated heparin plus eptifibatide (adjusted relative risk, 0.99 [95% CI, 0.85-1.16]; P = .93). There were no differences for the secondary end points, including procedural thrombotic complications. The primary safety outcome of Thrombosis in Myocardial Infarction major or minor bleeding through day 7 was increased by otamixaban (3.1% vs 1.5%; relative risk, 2.13 [95% CI, 1.63-2.78]; P < .001). Results were consistent across prespecified subgroups. CONCLUSIONS AND RELEVANCE Otamixaban did not reduce the rate of ischemic events relative to unfractionated heparin plus eptifibatide but did increase bleeding. These findings do not support the use of otamixaban for patients with NSTE-ACS undergoing planned early percutaneous coronary intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01076764.

The relationship between resistant hypertension and arterial stiffness.

Objectives: With growing awareness of arterial stiffness (AS) in the past 10 years, it was realized that resistant hypertension (RH) and AS share the same associated conditions such as older age, isolated systolic hypertension (HT), obesity, chronic kidney disease (CKD), and so on. Until now, there is no study investigating the role of AS in RH. In our study we aimed to determine whether there is an association between RH and AS. Methods: Among 87 patients enrolled in this study, 30 were resistant hypertensives (Group 1), 29 were controlled hypertensives (Group 2), and 28 were normotensives (Group 3). Arterial stiffness was measured by both applanation tonometry and echocardiography; augmentation index, pulse wave velocity (PWV), aortic strain, and aortic distensibility were recorded in each patient. Diastolic function parameters were also assessed. Results: In resistant hypertensive group, augmentation index and PWV were significantly higher than Group 2 and Group 3 (P = .03 and P < .01). Aortic strain and aortic distensibility parameters were significantly lower in RH group (P < .01 and P < .01). Arterial stiffness parameters were similar among Group 2 and Group 3. Among diastolic function parameters, left atrial volume index and left ventricular mass index significantly differ between groups. These two parameters were significantly lower in control group (P < .01 and P = .02) whereas similar in Group 1 and Group 2. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) levels were significantly different between groups as expected. When the correlation between two methods of AS was analyzed, a significant strong inverse correlation was found between echocardiographic and tonometric parameters. Conclusion: Arterial stiffness was found to be associated with RH. The inconsistency of this association in controlled hypertensives suggests a possible role of AS in RH pathogenesis. This study also showed that aortic strain and distensibility correlate well with the PWV which is the gold standard in the assessment of AS. This finding is important for the evaluation of AS more commonly in daily practice as echocardiography is a more feasible device than applanation tonometry.

Chylous ascites due to constrictive pericarditis.

Chylous ascites due to constrictive pericarditis is an extremely rare clinical entity, possibly caused by the augmented lymph production and high impedance to lymph drainage due to central venous hypertension. The authors describe a patient with chylous ascites caused by constrictive pericarditis in the absence of lymphatic obstruction. Cardiac catheterization is essential for the confirmation of accurate diagnosis of constrictive pericarditis. Magnetic resonance imaging of the heart is also very helpful in the diagnosis. The patient was symptom free and his ascites and edema completely resolved after pericardiectomy.

The effects of chronic usage of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on contrast-induced nephropathy in low-risk patients [corrected].

OBJECTIVE There is conflicting data about the role of renin- angiotensin- aldosterone system (RAAS) blockers in contrast-induced nephropathy (CIN) pathophysiology. In this study, we aimed to investigate the effects of chronic usage of RAAS blocker drugs on development of CIN in low risk patients. METHODS Study was designed as a prospective cohort study. A total of 295 patients were enrolled in the study. Study population was consisted of three subgroups according to prior usage of RAAS blockers: no RAAS blocker group (n=95), angiotensin-converting enzyme inhibitor (ACEI) group (n=106), angiotensin receptor blocker (ARB) group (n=94). CIN was defined as an increase of ≥25% in creatinine over the baseline value or 0.5 mg/dL rise within 48-72 h of angiography. Mehran score was calculated for each patient. Baseline variables and percentage of CIN were compared with ANOVA, Mann-Whitney U, Kruskal-Wallis and Pearson Chi-square tests between groups. In order to determine the independent predictors of CIN, binary logistic regression analyses were performed. RESULTS CIN occurred in 18 patients (17.0%) in the ACEI group, 17 patients (18.1%) in ARB group and 7 patients (7.4%) in the no RAAS group. CIN occurrence was significantly higher in RAAS than no RAAS group (17.5% vs. 7.4%, p=0.01). Chronic RAAS blocker administration was an independent predictor of CIN (OR=2.69; 95% CI: 1.025-7.067; p=0.04). Mehran score was the only other independent predictor for CIN (OR=1.15; 95% CI: 1.019-1.310; p=0.02). CONCLUSION In patients with near normal renal functions who are undergoing elective coronary procedure, chronic usage of ACEI and ARB increases the risk of CIN.

Are complex coronary lesions more frequent in patients with diabetes mellitus

BACKGROUND Coronary atherosclerotic burden is excessive in diabetic patients. Diabetes mellitus (DM) is an independent predictor for both death and myocardial infarction. It is not known whether the prevalence of complex coronary lesions, such as bifurcation and ostial lesions, is different in diabetics from nondiabetics. OBJECTIVE The aim of present study was to investigate the prevalence of these lesions in patients with DM. METHODS One thousand fourteen consecutive patients (mean age 61.3+/-10.7 years) were investigated. Coronary angiograms were examined for bifurcation and ostial lesions using a digital quantitative system. Patients were classified as diabetic (n=281) or nondiabetic (n=733). RESULTS Patient mean age, and rates of hypertension and hyperlipidemia were significantly higher in the diabetic group than in the nondiabetic group (P<0.0001), although smoking was significantly lower (P=0.001). Reasons for coronary angiography and treatment were comparable between the two groups. The prevalence of bifurcation lesions and ostial lesions was significantly greater in the diabetic group than in the nondiabetic group (9.8% versus 4.3% [P=0.001] and 38.4% versus 29.2% [P=0.003] in the diabetic group versus the nondiabetic group). The presence of DM and greater age were found to be independent predictors for bifurcation lesions (OR=2.27 [P=0.004] and OR=1.03 [P=0.01], for DM and age, respectively) and ostial lesions (OR=1.40 [P=0.027] and OR=1.02 [P=0.001], for DM and age, respectively) in multivariate analysis. CONCLUSIONS Complex coronary lesions such as bifurcation and ostial lesions were significantly more common in diabetic patients than in nondiabetic patients. Greater age and the presence of DM were independent predictors for these complex lesions. These results may help to explain the poor prognosis of coronary artery disease among diabetic patients.

Age-related digoxin-alprazolam interaction

A case report of dramatic increases in serum digoxin levels after alprazolam administration prompted our investigation. Twelve inpatients receiving long‐term digoxin (0.25 mg daily) randomly received oral administration of either 1.0 or 0.5 mg alprazolam per day for 7 days. In each dosage group, three patients were older than and three were younger than 65 years of age. The area under the concentration‐time curve for serum digoxin increased significantly in patients receiving 1 mg alprazolam daily, and this increase was more pronounced in patients older than 65 years of age. Clinical digoxin toxicity developed in one elderly patient who was receiving 1 mg/day alprazolam.

The association of beta-fibrinogen 455 G/A gene polymorphism with left atrial thrombus and severe spontaneous echo contrast in atrial fibrillation.

OBJECTIVE The role of coagulation parameters left atrial thrombus formation in atrial fibrillation has not been investigated before. We aimed to investigate the association between the beta-fibrinogen gene polymorphism or glycoprotein IIIa gene polymorphism and presence of left atrial (LA) thrombus or spontaneous echo contrast (SEC) in patients with atrial fibrillation (AF). METHODS Forty-seven patients with AF, in whom transesophageal echocardiography was performed, were included to this cross-sectional observational study. Patients were divided in two groups; those with LA thrombus (n=24) were assigned to group 1 and those without thrombus in group 2 (n=23). DNA analysis was conducted to determine gene polymorphism in all patients. Mann-Whitney U test or Chi-square tests were used for statistical analysis. RESULTS There were no significant differences between groups regarding to demographic and clinical characteristics. The frequency of beta-fibrinogen 455 G/A polymorphism was higher (37.5%) in group 1 as compared to group 2 (15.1%) but it did not reach statistical difference (p=0.23). When we added patients with severe SEC in the study group (patients with severe SEC and/or thrombus n=27) the difference (44.40%-10%) reached the statistical difference (p=0.01). Glycoprotein IIIa Pl A1/A2 polymorphism was not different between groups with (p=0.82) or without SEC (p=0.73). CONCLUSION In patients with atrial fibrillation, beta-fibrinogen 455 G/A gene polymorphism is associated with the presence of left atrial thrombus and severe SEC. Beta-fibrinogen 455 G/A gene polymorphism may be a promising marker for the prediction of thromboembolism risk in patients with atrial fibrillation.

Value of QT dispersion in diagnosis of restenosis after intracoronary stent implantation.

We studied the ECGs of patients with single vessel disease before and after (long term) coronary stent implantation. The interlead variability of the QT interval, known as QT dispersion (QTd), is believed to reflect the regional variations in ventricular repolarization and, thus, may provide an indirect marker of arrhythmogenicity. There are no reliable noninvasive markers of significant restenosis after stent implantation. The effect of coronary revascularization on QTd in patients who underwent coronary stenting has not been investigated extensively. The aim of this study was to evaluate the value of QTd in predicting restenosis after intracoronary stent implantation. QTd with 12 lead surface ECG was measured in 48 patients (21 with restenosis and 27 without restenosis; 33 male; mean age, 58+/-10.8 years) before the procedure and after long-term follow-up (mean, 6.8+/-3.2 months). All patients had coronary angiographic control at the end of the follow-up period. QTd (as the difference between the maximum and minimum QT interval measured from 12 lead ECG) and rate-corrected QT (QTcd) were evaluated at rest. In 27 patients without restenosis, QTd and QTcd decreased from 58+/-14.4 and 62.8+/-20.4 ms to 26.3+/-9.2 and 29.6+/-10.6 ms in the long term follow-up, respectively (P<0.001). However, in 21 patients with restenosis, there was no significant change in QTd and QTcd intervals and they were still increased at the end of the long-term follow-up (P>0.05). In conclusion, increased QT interval dispersion may be an inexpensive and simple marker of restenosis after intracoronary stent implantation.

The Relationship Between Hypertensive Retinopathy and Angiotensin Converting Enzyme Gene Polymorphism

OBJECTIVE Hypertensive retinopathy is an important complication and a major site of target organ damage from hypertension. Angiotensin converting enzyme (ACE) has a main role in cardiovascular physiology. It was shown that ACE gene polymorphism is related to plasma concentrations of ACE. We aimed to investigate the relationship between ACE gene polymorphism and hypertensive retinopathy. METHODS One-hundred and eight patients (62 female, mean age; 52.8 +/- 7.0 years) with essential hypertension and 30 healthy volunteers were enrolled in this study. Hypertensive retinopathy was diagnosed in a dark room with direct ophthalmoscopy by a single ophthalmologist who was blinded to clinical data. Polymerase chain reaction analysis was used to detect the insertion/deletion (l/D) polymorphism of the ACE gene. Patients were assigned to Group DD, Group ID and Group II. Three genotypic subgroups were compared for hypertensive retinopathy. RESULTS There were 42 patients (27 female, mean age: 52.4 +/- 7.8) in DD group; 51 patients (28 female, mean age: 53.6 +/- 6.9) in ID group and 15 patients (7 female, mean age: 51.2 +/- 5.6) in II group. Basal characteristics of the patients were similar in the three groups. The genotypic distributions of patients and healthy controls were comparable. Hypertensive retinopathy was determined in 15 (35.7%) patients in DD group, 8 (15.6%) patients in ID group and 2 (13.3%) patients in II group (p<0.05). CONCLUSION We found a significant relationship between ACE gene I/D polymorphism and hypertensive retinopathy. Identification of ACE genotype in hypertensive patients might be useful to discriminate the patients who are more susceptible to hypertensive retinopathy.

Comparison of Site-Reported and Core Laboratory-Reported Creatine Kinase-MB Values in Non–ST-Segment Elevation Acute Coronary Syndrome (from the International Trial SYNERGY)

The effect of nonstandardized creatine kinase (CK)-MB assays on the assessment of myocardial infarction (MI) end points in multicenter international trials has not been evaluated. We compared the site-reported and corresponding core laboratory CK-MB measures from 5 countries participating in the Superior Yield of the New Strategy of Enoxaparin, Revascularization, and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) trial. Samples for CK-MB were collected locally, with corresponding samples sent to a core laboratory at enrollment and after recurrent ischemic events, percutaneous coronary intervention, or coronary artery bypass grafting. The measured values were compared to the reported assay upper limits of normal (ULN) used at the site (or core laboratory for the core laboratory samples). The CK-MB results were available locally and from the core laboratory for 913 patients, constituting 4,693 time-matched laboratory values. The agreement between the core and site laboratory CK-MB/ULN ratio was moderate (concordance correlation coefficient 0.45) and varied considerably by geographic location and site. The CK-MB values were elevated (>or=2 times the ULN) by the core laboratory but normal (<2 times the ULN) by local standards in 708 instances (15%). There were 162 MI end points according to the core laboratory values versus 91 MI end points using the site-reported CK-MB data (kappa statistic 0.48). Compared with patients with no MI by the core or site laboratory values, patients with MI, as determined by both the core and the site laboratories, had significantly lower unadjusted 1-year survival rates (80.6% vs 93.5%, p <0.0001). Patients with MI, as determined by the core laboratory but not by the site laboratory, showed a trend toward a lower 1-year survival rate (89.8% vs 93.5%, p = 0.20). In conclusion, a substantial variation in CK-MB ratios and MI outcomes between the site and core laboratory data was observed in the SYNERGY trial. More MI outcomes were identified by the core laboratory, and patients with MI as defined by core laboratory data had lower 1-year survival, making these events potentially clinically important.