A randomized, double-blind, placebo-controlled trial assessing the efficacy of S66913 in patients with paroxysmal atrial fibrillation.

Aims: Antiarrhythmic drugs (AADs) for the treatment of atrial fibrillation (AF) are associated with limited efficacy and adverse effects. Inhibition of the atrial current IKur, absent from the ventricle, is expected to be antiarrhythmic, without adverse cardiac effects, particularly ventricular pro-arrhythmic effects. Methods and results: A randomized clinical trial in symptomatic paroxysmal AF patients being considered for ablation. The primary endpoint was AF burden (AFB) as measured by insertable continuous monitoring (ICM) devices. Screened patients had an ICM implanted and were included if AFB was between 1% and 70% after 4 weeks of recording. They were randomly allocated to 4-week treatment of a selective IKur inhibitor S66913 (5 mg, 25 mg, or 100 mg orally per day) or placebo. The study was to enroll 160 patients. The study was terminated prematurely, due to non-study related preclinical safety concerns, after 58 patients had been enrolled. The median AFB ranged from 4.3% to 10.3% at baseline in the four treatment groups. S66913 had no significant effect on AFB or on AFB plus atrial tachycardia (AT) burden, at any dosage; nor on any secondary endpoints including the number and duration of AT or AF episodes, and symptoms. The drug was well tolerated with no safety concern during the treatment or the extended clinical follow-up. Conclusions: DIAGRAF-IKUR was the first study to show that using ICM to assess the effect of an AAD is feasible. The selective IKur inhibitor S66913 was safe but had no clinically meaningful effect at the time of early termination of the study.

Association of genetic polymorphisms in the fibrinogen and platelet glycoprotein genes with unstable angina in Chinese patients.

BACKGROUND: Inherited predisposition has been associated with coronary artery disease (CAD) in the white population. HYPOTHESIS: The objective of this study was to investigate the association between the risk of unstable angina (UA) and genetic factors believed to be associated with an increased tendency toward thrombosis (the variable number of tandem repeats [VNTR] polymorphism of the platelet glycoprotein [GP] Ib alpha gene, Pl(A1/A2) of the platelet GP IIIa gene, 448G/A of the Bbeta fibrinogen gene and Thr312Ala of the Aalpha fibrinogen gene) in Chinese patients with UA. METHODS: We performed a case/control study evaluating 69 Chinese patients (43 men, 26 women) with UA and 69 control subjects without CAD, individually matched for age and gender. The restriction fragment length polymorphism (RFLP) method was used to determine the genetic polymorphisms. RESULTS: The frequencies of GP Ib alpha C/B genotype and Bbeta fibrinogen 448A allele were higher in patients with UA (46.4 vs. 30.4%, odds ratio [OR] 1.977, 95% confidence interval [CI] 0.98-3.97, p = 0.054, and 49.3 vs. 20.3%, OR 3.816, 95% CI 1.797-8.103, p = 0.000, respectively). Only four subjects (two cases, two controls) with GP IIIa Pl(A2) allele were found, and there was no association between Aalpha fibrinogen Thr312Ala polymorphism and UA. CONCLUSIONS: Chinese patients with UA had increased frequencies of GP Ib alpha C/B genotype and Bbeta fibrinogen 448A allele. These data suggest that some genetic factors may influence the development of UA.

[Risk factors for stroke in Chinese with non valvular atrial fibrillation: a case-control study].

OBJECTIVE: The aim of this study is to identify the risk factors in Chinese with nonvalvular atrial fibrillation and stroke, using case-control methodology. METHODS: A total of 4 511 adult patients diagnosed with atrial fibrillation were identified from 18 hospitals over a 2-year period. There were 1 086 patients with rheumatic valvular atrial fibrillation and 3 425 patients with nonvalvular atrial fibrillation. Among the nonvalvular atrial fibrillation patients, 827 had ischemic stroke. The data of the patients having nonvalvular atrial fibrillation with stroke was compared with those having nonvalvular atrial fibrillation without stroke (n = 2 598). The effect of each variable on stroke was assessed with a logistic regression analysis. RESULTS: The studied cases with stroke and controls without stroke were similar in terms of percentage with sex, a past history of congestive heart failure, myocardial infarction, and mean left atrial size. Cases were significantly older than controls (73.3 +/- 9.2 vs. 68.2 +/- 12.3, P < 0.001) and more likely to have a history of hypertension (71.0% versus 51.6%, P < 0.001) and diabetes (17.9% vs. 11.1%, P = 0.001). There is strong evidence that left atrial (LA) thrombi make AF patients highly risky for stroke. In multivariate analysis, age > or = 75 (OR 1.76; 95% CI 1.08 approximately 2.98), history of hypertension (OR 1.52; 95% CI 1.28 approximately 1.80), diabetes (OR 1.39; 95% CI 1.11 approximately 1.76), high systolic blood pressure (OR 1.71; 95% CI 1.21 approximately 2.28), LA thrombi (OR 2.77; 95% CI 1.25 approximately 6.13) were independently associated with stroke. The lack of the association between left ventricular dysfunction and stroke is due to the relatively incorrect diagnosis of heart failure in the context of atrial fibrillation. CONCLUSIONS: Our analysis suggests that old age, hypertension, diabetes, high systolic blood pressure and LA thrombi detected with echocardiography are independent risk factors, which should be considered when decision of long-term anticoagulation therapy to prevent stroke with nonvalvular atrial fibrillation is to be made.

The relationship between pulse wave velocity and pulse pressure in Chinese patients with essential hypertension.

Aortic pulse wave velocity (PWV) is a significant and independent predictor of cardiovascular disease in hypertensive subjects and in patients with end-stage renal disease, but there have been few studies on PWV in Chinese patients with essential hypertension. In this cross-sectional study, we investigated 3,156 consecutive patients (mean age: 53.7 +/- 11.58 years) of the Hypertension Division of Ruijin Hospital in Shanghai. Together with sphygmomanometric blood pressure measurements, aortic PWV was measured using a validated automatic device. PWV in patients with pulse pressure (PP) > or = 60 mmHg was significantly greater than that in patients with PP < 60 mmHg (p < 0.01). PP and PWV were positively related to age (PP: r = 0.396, p = 0.001; PWV: r = 0.531, p = 0.001). After adjustment by age and heart rate, PWV was still closely related to PP (r = 0.249, p = 0.001). At any given systolic blood pressure (SBP), PWV significantly decreased with the increase of diastolic blood pressure (DBP), whereas at any given DBP there was a significant increase of PWV with the increase of SBP. In conclusion, PWV was the major determinant of PP, and was highest in Chinese patients with isolated systolic hypertension, followed by those with systolic and diastolic hypertension, isolated diastolic hypertension, and normal blood pressure.