The INVICTUS rheumatic heart disease research program: Rationale, design and baseline characteristics of a randomized trial of rivaroxaban compared to vitamin K antagonists in rheumatic valvular disease and atrial fibrillation.

BACKGROUND: Rheumatic heart disease (RHD) is a neglected disease affecting 33 million people, mainly in low and middle income countries. Yet very few large trials or registries have been conducted in this population. The INVICTUS program of research in RHD consists of a randomized-controlled trial (RCT) of 4500 patients comparing rivaroxaban with vitamin K antagonists (VKA) in patients with RHD and atrial fibrillation (AF), a registry of 17,000 patients to document the contemporary clinical course of patients with RHD, including a focused sub-study on pregnant women with RHD within the registry. This paper describes the rationale, design, organization and baseline characteristics of the RCT and a summary of the design of the registry and its sub-study. Patients with RHD and AF are considered to be at high risk of embolic strokes, and oral anticoagulation with VKAs is recommended for stroke prevention. But the quality of anticoagulation with VKA is poor in developing countries. A drug which does not require monitoring, and which is safe and effective for preventing stroke in patients with valvular AF, would fulfill a major unmet need. METHODS: The INVestIgation of rheumatiC AF Treatment Using VKAs, rivaroxaban or aspirin Studies (INVICTUS-VKA) trial is an international, multicentre, randomized, open-label, parallel group trial, testing whether rivaroxaban 20 mg given once daily is non-inferior (or superior) to VKA in patients with RHD, AF, and an elevated risk of stroke (mitral stenosis with valve area ≤2 cm2, left atrial spontaneous echo-contrast or thrombus, or a CHA2DS2VASc score ≥2). The primary efficacy outcome is a composite of stroke or systemic embolism and the primary safety outcome is the occurrence of major bleeding. The trial has enrolled 4565 patients from 138 sites in 23 countries from Africa, Asia and South America. The Registry plans to enroll an additional 17,000 patients with RHD and document their treatments, and their clinical course for at least 2 years. The pregnancy sub-study will document the clinical course of pregnant women with RHD. CONCLUSION: INVICTUS is the largest program of clinical research focused on a neglected cardiovascular disease and will provide new information on the clinical course of patients with RHD, and approaches to anticoagulation in those with concomitant AF.

Efficacy and effectiveness of valsartan/amlodipine and valsartan/amlodipine/hydrochlorothiazide in hypertension: randomized controlled versus observational studies.

OBJECTIVE: The aim of this post-hoc analysis was to compare the results from randomized controlled trials (RCTs) and real-world evidence (RWE) studies of valsartan/amlodipine (Val/Aml) and valsartan/amlodipine/hydrochlorothiazide (Val/Aml/HCTZ) in patients with uncontrolled hypertension (>140/90 mmHg). METHODS: Data was pooled from 15 RCTs (N = 5542) and 8 RWE studies (N = 1397) for Val/Aml; and 2 RCTs (N = 804) and 5 RWE studies (N = 9380) for Val/Aml/HCTZ. Patients who received Val/Aml (80/5, 160/5, 160/10, 320/5, or 320/10 mg), Val/Aml/HCTZ (160/5/12.5, 160/5/25, 160/10/12.5, 160/10/25, or 320/10/25 mg) or placebo were considered for this analysis. Only patients with both baseline and follow-up assessment within 60-90 days after baseline had been included in the analysis. Patients with missing values were excluded from the analysis. Using fitted linear mixed-effects model and random factors, treatment interactions and study design with mean sitting systolic blood pressure (msSBP), diastolic BP (msDBP) and pulse pressure (msPP) reductions from baseline to Week 8-12 of treatment were compared. RESULTS: Baseline demographics and patient characteristics were comparable between RCT and RWE datasets and within Val/Aml and Val/Aml/HCTZ treatment groups. In both RCT and RWE studies, least-squares mean (LSM) reduction in msSBP/msDBP and msPP from baseline were significant (p < .05) across all dosages. The efficacy of Val/Aml in RCTs was statistically significantly greater than in RWE studies for msSBP/msDBP (-23.1/-13.8 vs. -17.9/-9.1 mmHg) but the difference was non-significant for msPP (-8.6 vs. -9.3 mmHg; p = .77). For Val/Aml/HCTZ, no direct comparison was available but a similar trend was observed. The difference observed for msSBP and msDBP may be due to routine practice setting, larger populations may have more confounders and different behaviors towards treatment adherence. CONCLUSION: These findings demonstrate that the efficacy of Val/Aml and Val/Aml/HCTZ in RCTs was more pronounced compared with their effectiveness in RWE studies in different ethnic populations although the overall benefit was not different.

[Mutation and clinical relevance in a large cohort of unrelated Chinese patients with hypertrophic cardiomyopathy].

OBJECTIVE: To explore the genetic basis and phenotypic correlation with disease severity in a large cohort of Chinese patients with hypertrophic cardiomyopathy (HCM). METHODS: A total of 179 unrelated Chinese HCM patients admitted to our department from 2002 to 2011 were enrolled in this study. Direct gene sequencing of ß-myosin heavy chain (MYH7), myosin binding protein-C ( MYBPC3), and cardiac troponin T (TNNT2) were performed and clinical data were obtained in these patients. RESULTS: A total of 34 mutations were identified in 40 patients (22.3%), 79.4% (27/34) mutations occurred only once and a possible hot spot, A26 in MYH7, was found. Distribution of mutations was 52.9% (18/34) (MYBPC3), 35.3% (12/34) ( MYH7) and 11.8% (4/34) (TNNT2) respectively. Double mutations were identified in 2.2% (4/179) patients. Genotype-positive patients were associated with an earlier symptom onset, severer left ventricular hypertrophy, a higher incidence of syncope, and were more likely to have positive family history of HCM or sudden cardiac death (SCD) , and were more likely to progress into heart failure (24.2% vs. 5.0%, P = 0.002) and at a higher risk of SCD (9.1% vs. 0, P = 0.009) during the 6.5-year follow-up. No statistical difference in any clinical parameters and outcomes was found between patients carrying MYBPC3 and MYH7 mutations. Double mutations were associated with malignant clinical progression in this cohort. Different phenotype severity could be seen in HCM patients with same genotype (e. g. MYH7-1736T, TNNT2-R92W). CONCLUSION: MYBPC3 is the most predominant gene mutation in this HCM cohort. The presence of a sarcomere mutation in patients with HCM is associated with poor clinical outcome, although no specific genes or mutations can exactly predict the severity of clinical phenotypes.

A systematic literature review of risk factors for stroke in China.

Other countries have seen a decline in stroke incidence after improved treatment and prevention of known risk factors for stroke. China is still experiencing significant increases in the incidence rate of total stroke. We systematically reviewed the evidence on the impact of 5 modifiable risk factors (hypertension, dyslipidemia, obesity, diabetes, and smoking) for the risk of stroke in the Chinese population, with the aim to develop more effective prevention and disease management programs. A literature search was conducted in MEDLINE and EMBASE for all observational studies that reported on the association between risk of stroke and any of the 5 risk factors and the composite risk factor. Selected articles were published in either English or Chinese from January 2004 to December 2010. Evidence of the association between hypertension and stroke was the strongest of the 5 factors reported in studies, with adjusted odds ratios ranging between 2.75 and 5.47. The association among obesity, diabetes, smoking, and the risk for stroke was evident, but not as strong as for hypertension. The risk ratios of hypertension to stroke were higher in the Chinese population than those in other countries.

Dobutamine infusion for unmasking long QT syndrome and torsades de pointes.

Prolonged QT interval is usually seen on routine electrocardiogram (ECG), but in some patients it may only be seen immediately before the evolution of torsades de pointes (Tdp). To unmask the potential risk of Tdp in a patient with normal or borderline prolongation of QTc interval and recurrent syncope, dobutamine was given intravenously at a rate of 20 microg/kg/min. Strikingly, QTc prolongation was induced along with syncope after dobutamine infusion. Torsades de pointes occurred 5 d later when the patient received an implantable cardioverter defibrillator (ICD). Genetic testing revealed a mutation of the KNCQ(1)-gene encoding serine instead of glycine. The patient was treated with 75 mg of metoprolol twice daily, and at 12 mo follow-up he had no syncope or chest tightness. The ICD revealed no ventricular tachyarrhythmias or therapy delivered.

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.