Abstract Objective : This study was designed to compare the efficacy and tolerability of a new generic formulation of ramipril (test) and the branded formulation of ramipril (reference) to satisfy ...regulatory requirements for marketing of the generic product for use in Korean patients with mild to moderate hypertension. Methods : This was an 8-week, multicenter, prospective, randomized, open-label, parallel-group non-inferiority trial in adult patients (age > 18 years) with mild to moderate essential hypertension (sitting dia-stolic blood pressure SiDBP 90–109 mm Hg). After a 2-week washout of previous antihypertensive medications, eligible patients were randomized to receive either ramipril 5 mg/d in the morning (low-dose group: baseline SiDBP 90–99 mm Hg) or ramipril 10 mg/d (high-dose group: baseline SiDBP 100–109 mm Hg) for the first 4 weeks. If SiDBP was ≥ 90 mm Hg after 4 weeks of treatment, the dose was increased to 10 mg/d for the remaining 4 weeks in the low-dose group, and hydrochlorothiazide 12.5 mg was added to the regimen for the remaining 4 weeks in the high-dose group. The primary end point was the change in SiDBP from baseline to week 8. Secondary end points included a noninferiority analysis of the test and reference formulations with respect to the change in mean sitting systolic blood pressure (SiSBP) from baseline to week 8; SiDBP and SiSBP response rates (proportion of patients achieving an SiDBP < 90 mm Hg and SiSBP < 140 mm Hg, respectively) at 8 weeks; and changes from baseline in SiSBP, pulse wave velocity (PWV), exercise capacity, left-ventricular diastolic function (LVDF), and levels of brain natriuretic peptide (BNP) and high-sensitivity C-reactive protein (hs-CRP). Laboratory and clinical adverse events (AEs) were monitored at each study visit (4 and 8 weeks). Results : The modified intent-to-treat population consisted of 89 patients (45 test, 44 reference; 60 men, 29 women; mean age, 49.7 years; mean weight, 69.9 kg). At week 8, mean (SD) SiSBP and SiDBP were significantly decreased from baseline in both groups (test: from 145.0 9.7/98.1 5.3 mm Hg to 132.2 11.1/ 91.8 7.1 mm Hg P < 0.001; reference: from 145.1 11.4/98.0 5.7 mm Hg to 134.0 14.6/92.5 7.9 mm Hg P < 0.001). The changes in blood pressure at week 8 did not differ significantly between the test and reference groups or between the low- and highdose groups in a subgroup analysis. Blood pressure response rates at 8 weeks did not differ significantly between the groups receiving the test and reference formulations (SiDBP: 26.7% and 31.8%, respectively; SiSBP: 37.8% and 40.9%). In addition, there were no significant between-group differences in the change in PWV (−63.8 and −38.7 cm/sec), LVDF at rest or after exercise, or levels of BNP or hs-CRP. The incidence of AEs was 64.4% in the test formulation group and 68.2% in the reference group formulation ( P = NS). The most common AE in both groups was cough (10/45 22.2% and 10/44 22.7%). Conclusions : There were no significant differences in the efficacy and tolerability of the test and reference formulations of ramipril in these Korean adults with mild to moderate hypertension. The new generic formulation was noninferior to the reference formulation in terms of the change in SiDBP at week 8.
The clinical outcomes and predictors of outcomes in isolated tricuspid regurgitation (TR) are poorly defined. The aim of this study was to investigate the determinants of outcomes in severe isolated ...TR.
Seventy-four patients (mean age, 63 ± 12 years; 34 men) with severe isolated TR who satisfied the criteria of (1) TR jet area > 30% of right atrial area or TR jet area > 10 cm(2) and (2) a plethora of inferior vena cava or systolic flow reversal of the hepatic vein were retrospectively analyzed. The primary end points were hospitalization for worsening heart failure, tricuspid valve (TV) surgery, and cardiovascular death.
During the median follow-up period of 53 months, 25 events occurred (three cardiovascular deaths, nine TV surgeries, and 13 hospitalizations for worsening heart failure). Univariate Cox analysis showed that younger age, female gender, larger effective regurgitant orifice, vena contracta width (VCW), and increased right atrial and right ventricular size were associated with cardiovascular events. Increased TV tethering distance and tethering area were also associated with cardiovascular events. In multivariate Cox regression analysis, larger VCW (hazard ratio, 1.72; 95% confidence interval, 1.15-2.57, P < 0.01) was an independent predictor of cardiovascular events. Compared with patients with VCW ≤ 7 mm, those with VCW > 7 mm had poorer long-term outcomes (adjusted hazard ratio, 19.9; P < .01). Increased VCW was also an independent predictor of cardiovascular death and TV surgery (hazard ratio, 1.2; 95% confidence interval, 1.00-1.45; P = .04).
In severe isolated TR, VCW is a powerful independent predictor of adverse outcomes. Adverse outcomes were considerable for VCW > 7 mm, which suggests that quantification of TR by Doppler echocardiography is crucial for estimating prognosis. TV surgery might be considered for patients with severe isolated TR with VCW > 7 mm.
Marfan syndrome is a multisystemic connective tissue disorder associated with a mutation affecting fibrillin-1, the main component of microfibrils. Fibrillin-1 gene mutations may affect the carotid ...arterial wall. The aim of this study was to investigate carotid arterial mechanics using Velocity Vector Imaging (VVI) in patients with Marfan syndrome.
Forty-five patients (26 men; mean age, 39 ± 10 years) with Marfan syndrome who fulfilled the Ghent criteria and 45 gender-matched and age-matched healthy volunteers were evaluated. Transverse images of right common carotid artery proximal to the bifurcation were obtained for each subject and divided into six segments. The peak radial velocity, circumferential strain, and strain rate of the six segments were analyzed using VVI. The time to peak radial velocity (T(s)), peak circumferential strain (T(st)), and peak strain rate (T(sr)) of the six segments were calculated. Intima-media thickness was measured for each subject.
The average diameter of the common carotid artery in patients with Marfan syndrome was significantly larger than that of controls. Carotid compliance coefficients and distensibility coefficients as assessed by B-mode echocardiographic images were comparable between the two groups. In VVI analyses, averages and standard deviations of peak radial velocities, circumferential strain, and strain rates were not significantly different between the two groups. However, T(s), T(st), and T(sr) were more delayed (P < .01), and the standard deviations of T(s), T(st), and T(sr) were significantly larger in patients with Marfan syndrome (P = .01, P < .01, and P < .01, respectively), suggesting delayed and dyssynchronous arterial expansion during systole. The presence of Marfan syndrome was independently and significantly related to increased standard deviations of T(st) (β = 0.33, P < .01) and T(sr) (β = 0.44, P < .01), even after adjusting for age in multiple regression analysis.
In patients with Marfan syndrome, carotid arteries assessed with VVI exhibited delayed, dyssynchronous arterial expansion during systole compared with healthy controls. Arterial assessment using VVI may be useful for noninvasively quantifying vascular alterations associated with Marfan syndrome.
Although family history (FH) of coronary artery disease (CAD) is considered a risk factor for future cardiovascular events, the prevalence, extent, severity, and prognosis of young patients with FH ...of CAD have been inadequately studied. From 27,125 consecutive patients who underwent coronary computed tomographic angiography, 6,308 young patients (men aged <55 years and women aged <65 years) without known CAD were identified. Obstructive CAD was defined as >50% stenosis in a coronary artery >2 mm diameter. Risk-adjusted logistic regression, Kaplan-Meier, and Cox proportional-hazards models were used to compare patients with and without FH of CAD. Compared with subjects without FH of CAD, those with FH of CAD (FH+) had higher prevalences of any CAD (40% vs 30%, p <0.001) and obstructive CAD (11% vs 7%, p <0.001), with multivariate odds of FH+ increasing the likelihood of obstructive CAD by 71% (p <0.001). After a mean follow-up period of 2 ± 1 years (42 myocardial infarctions and 39 all-cause deaths), FH+ patients experienced higher annual rates of myocardial infarction (0.5% vs 0.2%, log-rank p = 0.001), with a positive FH the strongest predictor of myocardial infarction (hazard ratio 2.6, 95% confidence interval 1.4 to 4.8, p = 0.002). In conclusion, young FH+ patients have higher presence, extent, and severity of CAD, which are associated with increased risk for myocardial infarction. Compared with other clinical CAD risk factors, positive FH in young patients is the strongest clinical predictor of future unheralded myocardial infarction.
Coronary Computed Tomography Angiography as a Screening Tool for the Detection of Occult Coronary Artery Disease in Asymptomatic Individuals Eue-Keun Choi, Sang Il Choi, Juan J. Rivera, Khurram ...Nasir, Sung-A Chang, Eun Ju Chun, Hyung-Kwan Kim, Dong-Joo Choi, Roger S. Blumenthal, Hyuk-Jae Chang With computed tomography angiography (CTA) (64-slice multidetector row computed tomography), we evaluated the prevalence of occult coronary artery disease (CAD), plaque composition, and the potential of this new technology to impact risk stratification in 1,000 middle-aged asymptomatic subjects. This is the first large population study conducted to assess the use of CTA to identify occult CAD in asymptomatic subjects. Although we found that the prevalence of CAD in an apparently healthy asymptomatic population is not negligible, considering present radiation dose and additional tests and treatment, we cannot conclude that this technology should be immediately implemented as a screening tool.
Background We evaluated interobserver and intraobserver reliability of the classification and treatment of acromioclavicular (AC) joint dislocations and assessed the impact of adding 3-dimensional ...computed tomography (3D CT) on the reliability of classification and treatment choice. Methods Ten surgeons independently reviewed plain radiographs and 3D CT in 28 cases with AC joint dislocation. Images from each case were randomly presented to the observers, with plain radiographs alone being presented first, followed by plain radiographs plus 3D CT 2 weeks later. Four weeks later, they repeated the same survey to evaluate intraobserver reliability. Reliability was assessed on the basis of Fleiss κ values. Results On the basis of plain radiographs alone, interobserver and intraobserver reliability of the Rockwood classification were fair (κ = .214) and moderate (κ = .474), respectively. Interobserver and intraobserver reliability of treatment were both fair (κ = .213 and .399, respectively). On the basis of a combination of plain radiographs and 3D CT, interobserver and intraobserver reliability of the Rockwood classification were slight (κ = .177) and moderate (κ = .565), respectively. Interobserver and intraobserver reliability of treatment were fair (κ = .253) and moderate (κ = .554), respectively. There were no significant differences in reliability between the two groups in terms of any κ values. Conclusion This study suggests an overall lack of reliability of the Rockwood classification of AC joint dislocations and of decisions regarding their treatment. There is especially poor agreement between experienced shoulder surgeons. The addition of 3D CT did not improve reliability of classification and treatment of AC joint dislocations.
Abstract Background Given the lack of promptness and inevitable use of additional contrast agents, the myocardial viability imaging procedures have not been used widely for determining the need to ...performing revascularization. Objective This study is aimed to evaluate the feasibility of myocardial viability assessment, consecutively with diagnostic invasive coronary angiography (ICA) without use of additional contrast agent, using a novel hybrid system comprising ICA and multislice CT (MSCT). Methods In all, 14 Yucatan miniature swine models (female; age, 3 months; weight, 28–30 kg) were subjected to ICA followed by balloon occlusion (90 minutes) and reperfusion of the left anterior descending coronary artery. Two weeks after induction of myocardial infarction, delayed hyperenhancement (DHE) images were obtained, using a novel combined machine comprising ICA and 320-channel MSCT scanner (Aquilion ONE, Toshiba), after 2, 5, 7, 10, 15, and 20 minutes after conventional ICA. The heart was sliced in 10-mm consecutive sections in the short-axis plane and was embedded in a solution of 1% triphenyltetrazolium chloride (TTC). Infarct size was determined as TTC-negative areas as a percentage of total left ventricular area. On MSCT images, infarct size per slice was calculated by dividing the DHE area by the total slice area (%) and compared with histochemical analyses. Results Serial MSCT scans revealed a peak CT attenuation of the infarct area (222.5 ± 36.5 Hounsfield units) with a maximum mean difference in CT attenuation between the infarct areas and normal myocardium of at 2 minutes after contrast injection (106.4; P for difference = 0.002). Furthermore, the percentage difference of infarct size by MSCT vs histopathologic specimen was significantly lower at 2 (8.5% ± 1.8%) and 5 minutes (9.5% ± 1.9%) than those after 7 minutes. Direct comparisons of slice-matched DHE area by MSCT demonstrated excellent correlation with TTC-derived infarct size ( r = 0.952; P < .001). Bland-Altman plots of the differences between DHE by MSCT and TTC-derived infarct measurements plotted against their means showed good agreement between the 2 methods. Conclusion The feasibility of myocardial viability assessment by DHE using MSCT after conventional ICA was proven in experimental models, and the optimal viability images were obtained after 2 to 5 minutes after the final intracoronary injection of contrast agent for conventional ICA.
Among the cardiovascular manifestations in the Marfan syndrome (MFS), aortic dissection stands out as a major cause of early mortality. The aim of this study was to test the hypothesis that patients ...with the MFS who experience aortic dissection differ in clinical features and outcomes from those with aortic dissection not related to the MFS. Data from patients diagnosed with aortic dissection from December 1994 to March 2009 at 1 of the major medical centers in Korea were reviewed. The clinical presentations, dissection characteristics, and outcomes of patients with and those without the MFS in a Korean population were compared. Of 445 patients with aortic dissection, 46 (10%) had the MFS. Compared to non-MFS patients, those with the MFS developed aortic dissection at younger ages (33 ± 10 vs 57 ± 13 years, p <0.001) and were less frequently hypertensive (11% vs 73%, p <0.001). During the follow-up period, patients with the MFS more often developed aortic dilatation and expansion of the dissection (39% vs 18%, p = 0.003) and showed a higher rate of reoperation (30% vs 9%, p <0.001). In conclusion, in Korean patients, aortic dissection with the MFS had different characteristics and poorer outcomes than aortic dissection without the MFS. These findings underscore the importance of accurate diagnosis and surveillance of this condition in the MFS.
Patients with chronic kidney disease have a worse cardiovascular prognosis than those without. The aim of this study was to determine the incremental prognostic value of coronary computed tomographic ...angiography in predicting mortality across the entire spectrum of renal function in patients with known or suspected coronary artery disease (CAD). A large international multicenter registry was queried, and patients with left ventricular ejection fraction (LVEF) and creatinine data were screened. National Cholesterol Education Program Adult Treatment Panel III risk was calculated. Coronary computed tomographic angiographic results were evaluated for CAD severity (normal, nonobstructive, or obstructive) and an LVEF <50%. Patients were followed for the end point of all-cause mortality. Among 5,655 patients meeting the study criteria, follow-up was available for 5,572 (98.9%; median follow-up duration 18.6 months). All-cause mortality (66 deaths) significantly increased with every 10-unit decrease in renal function (hazard ratio HR 1.23, 95% confidence interval CI 1.07 to 1.41). All-cause mortality occurred in 0.33% of patients without coronary atherosclerosis, 1.82% of patients with nonobstructive CAD, and 2.43% of patients with obstructive CAD. Multivariate Cox proportional-hazards models revealed that impaired renal function (HR 2.29, 95% CI 1.65 to 3.18), CAD severity (HR 1.81, 95% CI 1.31 to 2.51), and an abnormal LVEF (HR 4.16, 95% CI 2.45 to 7.08) were independent predictors of all-cause mortality. In conclusion, coronary computed tomographic angiographic measures of CAD severity and the LVEF provide effective risk stratification across a wide spectrum of renal function. Furthermore, renal dysfunction, CAD severity, and the LVEF have additive value for predicting all-cause death in patients with suspected obstructive CAD.
Abstract Objectives This study sought to develop a clinical model that identifies patients with and without high-risk coronary artery disease (CAD). Background Although current clinical models help ...to estimate a patient's pre-test probability of obstructive CAD, they do not accurately identify those patients with and without high-risk coronary anatomy. Methods Retrospective analysis of a prospectively collected multinational coronary computed tomographic angiography (CTA) cohort was conducted. High-risk anatomy was defined as left main diameter stenosis ≥50%, 3-vessel disease with diameter stenosis ≥70%, or 2-vessel disease involving the proximal left anterior descending artery. Using a cohort of 27,125, patients with a history of CAD, cardiac transplantation, and congenital heart disease were excluded. The model was derived from 24,251 consecutive patients in the derivation cohort and an additional 7,333 nonoverlapping patients in the validation cohort. Results The risk score consisted of 9 variables: age, sex, diabetes, hypertension, current smoking, hyperlipidemia, family history of CAD, history of peripheral vascular disease, and chest pain symptoms. Patients were divided into 3 risk categories: low (≤7 points), intermediate (8 to 17 points) and high (≥18 points). The model was statistically robust with area under the curve of 0.76 (95% confidence interval CI: 0.75 to 0.78) in the derivation cohort and 0.71 (95% CI: 0.69 to 0.74) in the validation cohort. Patients who scored ≤7 points had a low negative likelihood ratio (<0.1), whereas patients who scored ≥18 points had a high specificity of 99.3% and a positive likelihood ratio (8.48). In the validation group, the prevalence of high-risk CAD was 1% in patients with ≤7 points and 16.7% in those with ≥18 points. Conclusions We propose a scoring system, based on clinical variables, that can be used to identify patients at high and low pre-test probability of having high-risk CAD. Identification of these populations may detect those who may benefit from a trial of medical therapy and those who may benefit most from an invasive strategy.
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