Differential Effects of Strong and Regular Statins on the Clinical Outcome of Patients With Chronic Kidney Disease Following Coronary Stent Implantation　- The Kumamoto Intervention Conference Study (KICS) Registry.

BACKGROUND: The aim of this study was to examine the effects of different statins on the clinical outcomes of Japanese patients with coronary stent implants. METHODS AND RESULTS: This study included 5,801 consecutive patients (males, 4,160; age, 69.7±11.1 years, mean±SD) who underwent stent implantation between April 2008 and March 2011. They were treated with a strong statin (n=3,042, 52%, atorvastatin, pitavastatin, or rosuvastatin), a regular statin (n=1,082, 19%, pravastatin, simvastatin, or fluvastatin) or no statin (n=1,677, 29%). The patients with chronic kidney disease (CKD) were divided into mild-to-moderate CKD (30≤eGFR<60, n=1,956) and severe CKD (eGFR <30, n=559). Primary endpoints included cardiovascular death and nonfatal myocardial infarction, including stent thrombosis and ischemic stroke. The clinical outcome for the primary endpoint in mild-to-moderate CKD patients treated with a strong statin (hazard ratio 0.50, 95% confidence interval 0.31-0.81; P=0.005) was significantly lower than in those on no statins, but that in the patients treated with a regular statin was not (P=0.160). The clinical outcome for the primary endpoint in severe CKD patients treated with a strong or regular statin was no different than not being on statin therapy (P=0.446, P=0.194, respectively). CONCLUSIONS: In patients with mild-to-moderate CKD, only strong statins were associated with lower risk compared with no statin, but regular statins were not. It is possible that taking a strong statin from the early stage of CKD is useful for suppression of cardiovascular events.

Potassium concentration on admission is an independent risk factor for target lesion revascularization in acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) is accompanied by excessive production of catecholamines, which is characterized by a hypokalemic dip. A polymorphism of the adrenergic receptor has also been reported to be associated with target lesion revascularization (TLR) after coronary intervention. SUBJECTS AND METHODS: We enrolled 276 consecutive patients with AMI within 24 hours of symptom onset, who underwent emergency coronary intervention using bare metal stents and had examinations over a 5-10-month follow-up period. The patients were divided into tertiles based on their serum potassium level on admission (low K, <3.9; mid K, ≥ 3.9, <4.3; and high K, ≥ 4.3). RESULTS: Sixty-four TLRs were observed in the study. Increased potassium concentration was associated significantly with TLR. Patients in the high K group were about two and a half times more likely to have a TLR after AMI compared to those in the low K group. Multiple logistic analysis showed that potassium level on admission was an independent risk factor for TLR (odds ratio 1.69; confidence interval 1.04 to 2.74; P = 0.036). CONCLUSIONS: These findings indicated that increased potassium levels on admission might predict TLRs in AMI patients treated with bare metal stents.

Clinical outcomes following coronary stenting in Japanese patients treated with and without proton pump inhibitor.

BACKGROUND: The aim of this study was to examine the effect of proton-pump inhibitor (PPI) on clinical outcomes in Japanese patients who undergo coronary stent implantation. METHODS AND RESULTS: A total of 1,270 patients (males 915, 69 years) were enrolled and dual antiplatelet therapy of aspirin and a thienopyridine derivative was prescribed (clopidogrel 630, ticlopidine 640). Patients were divided into 2 groups treated with or without PPI. PPI was administered in 331 cases (26%), and non-PPI in 939 (74%). There were no significant differences in cardiovascular death (PPI vs. non-PPI: 5 vs. 11 cases), nonfatal myocardial infarction (3 vs. 5), and stroke (3 vs. 16) between PPI and non-PPI groups, but the ratio of gastrointestinal events had a higher tendency in non-PPI group compared with PPI group (1 vs. 17, P=0.08). In subgroup analysis of patients taking clopidogrel, or patients with acute coronary syndrome, there was no significant difference in the ratio of cardiovascular events (7 vs. 16, 6 vs. 17, NS). The non-PPI group had a tendency of an increased risk of gastrointestinal events compared with the PPI group (0 vs. 9, P=0.06; 1 vs. 7, P=0.14). CONCLUSIONS: In contrast to the negative drug interaction of PPI reported elsewhere, in the present study the intake of PPI was not associated with an increased risk for adverse clinical outcomes in patients treated with stents.

Clinical outcomes of percutaneous coronary intervention for acute coronary syndrome between hospitals with and without onsite cardiac surgery backup.

BACKGROUND: Based on the 2011 American College of Cardiology/American Heart Association percutaneous coronary intervention (PCI) guideline, it is recommended that PCI should be performed at hospital with onsite cardiac surgery. But, data suggest that there is no significant difference in clinical outcomes following primary or elective PCI between the two groups. We examined the impact of with or without onsite cardiac surgery on clinical outcomes following PCI for acute coronary syndrome (ACS). METHODS AND RESULTS: From August 2008 to March 2011, subjects (n=3241) were enrolled from the Kumamoto Intervention Conference Study (KICS). Patients were assigned to two groups treated in hospitals with (n=2764) or without (n=477) onsite cardiac surgery. Clinical events were followed up for 12 months. Primary endpoint was in-hospital death, cardiovascular death, myocardial infarction, and stroke. And we monitored in-hospital events, non-cardiovascular deaths, bleeding complications, revascularizations, and emergent coronary artery bypass grafting (CABG). There was no overall significant difference in primary endpoint between hospitals with and without onsite cardiac surgery [ACS, 7.6% vs. 8.0%, p=0.737; ST-segment elevation myocardial infarction (STEMI), 10.4% vs. 7.5%, p=0.200]. There was also no significant difference when events in primary endpoint were considered separately. In other events, revascularization was more frequently seen in hospitals with onsite surgery (ACS, 20.0% vs. 13.0%, p<0.001; STEMI, 21.9% vs. 14.5%, p=0.009). We performed propensity score matching analysis to correct for the disparate patient numbers between the two groups, and there was also no significant difference for primary endpoint (ACS, 8.6% vs. 7.5%, p=0.547; STEMI, 11.2% vs. 7.5%, p=0.210). CONCLUSIONS: There is no significant difference in clinical outcomes following PCI for ACS between hospitals with and without onsite cardiac surgery backup in Japan.

Influence of weather conditions on the frequent onset of acute myocardial infarction.

BACKGROUND: This study was conducted to clarify the influence of weather conditions on the onset of acute myocardial infarction (AMI) in Kumamoto. METHODS: We studied 642 consecutive patients (males 433, females 209; 71±13 years) who were admitted with AMI. Days of frequent onset (F-days) were defined as days on which ≥2 patients had been admitted for AMI, whereas days of non-frequent onset (N-days) indicated those with fewer than 2 admissions for AMI. Meteorological factors, including the mean atmospheric pressure and rainfall, the mean, maximum, and minimum temperature, intra-day temperature difference, humidity, wind speed, and the number of sunlight hours, were analyzed. All variables were measured on the day of onset of AMI and on each of the 2 days immediately prior to the day of onset. RESULTS: There were 86 F-days and 1740 N-days. F-days were significantly associated with lower air temperature (mean, maximum, and minimum), higher intra-day temperature difference, lower humidity, and longer daily duration of sunlight compared with N-days. In addition, meteorological factors for frequent onset of AMI affected older subjects to a greater extent than either young or female subjects. Multiple logistic regression analysis showed that minimum temperature two days before onset was associated with the frequent onset of AMI (odds ratio, 0.805; p<0.05). CONCLUSION: Lower minimum temperature on the 2nd day preceding the onset is an independent risk factor for the frequent onset of AMI. The association between low ambient temperature and frequent onset of AMI was stronger in elderly and female subjects.

Comparison of frequency of interferon-gamma-positive CD4+ T cells before and after percutaneous coronary intervention and the effect of statin therapy in patients with stable angina pectoris.

We investigated the effect of statin therapy on T-cell activation in patients who underwent percutaneous coronary intervention by using flow cytometric analysis. The increased frequency of interferon-gamma-positive CD4(+) T cells after percutaneous coronary intervention was significant in the group treated without statins but not in the group treated with statins.

Plasminogen activator inhibitor contributes to the coronary wall thickening in patients with angiographically normal coronary.

INTRODUCTION: Angiographically normal coronary arteries have concealed intimal thickening that importantly contribute to coronary arterial disease activity. Increased plasma levels of plasminogen activator inhibitor (PAI) are associated with myocardial infarction and atherosclerosis. However, it remains unclear whether the PAI contributes to vascular wall thickening detected by intravascular ultrasound (IVUS) in normal coronary angiogram. The aim of this study was to evaluate if the PAI activity contributes to the extent of atherosclerotic changes in angiographically normal coronary arteries using IVUS technique. MATERIALS AND METHODS: We studied 33 consecutive patients with normal coronary angiograms. These patients were divided into a high level of plasma PAI activity group (H-PAI; n=12) and a normal range of PAI activity group (N-PAI; n=21), according to the plasma PAI activity levels. RESULTS: The average of "percent intima+media area (%I+M area)" and "maximal intima+media (I+M) thickness" were significantly greater in the H-PAI group as compared with those in the N-PAI group (p<0.05). Minimal lumen diameter and lumen area were comparable between these groups. The plasma PAI activity level was the independent predictor of increase in maximal I+M thickness, in multiple regression analysis with the traditional risk factors as covariates. CONCLUSIONS: Thickened intima+media of angiographically normal coronary arteries were associated with high plasma level of PAI activity, independently of other traditional risk factors. PAI may contribute to the pathogenesis of coronary intimal thickening that might increase coronary arterial tone.

Feasibility of virtual 3-Fr percutaneous coronary intervention using standard guiding catheters.

INTRODUCTION: Recent studies have reported the efficacy of sheathless percutaneous coronary intervention (PCI) using hydrophilic-coated 5-Fr guiding catheters that are one to two Fr sizes smaller in diameter than the corresponding introducer sheath (virtual 3-Fr PCI). However, the limited number of shapes of hydrophilic-coated guiding catheters occasionally makes them difficult to engage and control. AIM: To evaluate the efficacy and feasibility of virtual 3-Fr PCI using standard guiding catheters of various shapes. MATERIAL AND METHODS: We identified 35 consecutive patients with stable angina, who underwent virtual 3-Fr PCI using either hydrophilic-coated guiding catheters (Works™, Medikit, Japan) or standard guiding catheters (Heartrail™, Terumo, Japan). RESULTS: Thirty-five patients were identified (63% men; mean age 70 ±13 years). In 2 cases, hydrophilic-coated guiding catheters were exchanged to standard guiding catheters because of difficulty in engaging the target coronary arteries. Ultimately, standard guiding catheters were used in 20 patients (57%) and hydrophilic-coated catheters were used in 15 (43%). One of 20 patients treated with standard guiding catheters and 1 of 15 treated with hydrophilic-coated guiding catheters underwent the 4-in-3 "slender mother and child" PCI technique due to difficulty of stent deployment. There were no differences between the two groups in PCI procedural variables such as procedural time, fluoroscopy time, radiation dose, or contrast dye volume. There were no access site-related complications in this study. CONCLUSIONS: These findings indicate that virtual 3-Fr PCI using standard guiding catheters is as efficient and safe as virtual 3-Fr PCI using hydrophilic-coated guiding catheters.

Current cigarette smoking is an independent risk factor for subacute stent thrombosis in acute myocardial infarction patients.

BACKGROUND: Acute myocardial infarction (AMI) is prevalent and has serious consequences including re-infarction and death. Cigarette smoking is a coronary risk factor for AMI, although a "smoker's paradox" for AMI has been reported in Western countries. On the other hand, some researchers have reported that smoking is associated with subacute stent thrombosis (SAST) after AMI. However, the occurrence of this condition is not well documented in Japan. The aim of this study was to clarify how prior smoking status may affect prognosis, including SAST, in Japanese patients with AMI. METHODS: A total of 266 consecutive patients with AMI were enrolled retrospectively in the study if they had undergone emergency coronary intervention (bare metal stent) within 24h of symptom onset, and had a 5-10 month follow-up examination. The patients were divided into three groups based on their cigarette smoking status (non-smokers, past smokers, and current smokers). RESULTS: Current smokers were significantly younger than the other two groups, although their levels of low density lipoprotein-cholesterol and triglyceride were significantly higher. White blood cell count and hemoglobin level on admission were also significantly higher in current smokers compared with the other two groups. The incidence of SAST was significantly higher in current smokers than in the other groups, although the occurrence of heart failure after AMI was similar in the three groups. On the other hand, improvement in left ventricular ejection fraction was observed in non-smokers and past smokers, but not in current smokers. Multiple logistic analysis revealed that current smoking was an independent risk factor for SAST (odds ratio 5.4; p<0.05). Current smokers were about five times more likely to have a SAST compared with non-smokers. CONCLUSIONS: These findings indicate that current cigarette smoking predicts SAST after primary percutaneous coronary intervention for AMI in Japanese patients.

Acute myocardial infarction caused by left anterior descending artery occlusion presenting as inferior ST elevation and anterior ST depression.

We report a case of acute myocardial infarction caused by left anterior descending artery occlusion presenting as ST elevation in the inferior leads and ST depression in the precordial leads, suggesting an involvement of the right coronary artery (RCA). However, coronary angiography (CAG) showed a complete occlusion of the proximal left anterior descending (LAD) coronary artery and collaterals from the left circumflex coronary artery and the RCA. Although he underwent primary percutaneous coronary intervention (PCI), he had chest pain at four days after primary PCI. His electrocardiogram (ECG) showed precordial ST elevation, suggesting an involvement of the LAD. Emergent CAG showed a complete occlusion of the proximal LAD without collaterals, but his ECG showed precordial ST elevation that was different from ST changes seen on admission. These unusual ST-segment changes might be associated with a weaker anterior ischemia due to collaterals and a strong inferior ischemia due to wrapped LAD artery. .

A case of postpartum spontaneous coronary artery dissection.

Spontaneous coronary artery dissection is rare and usually affects younger women in the peripartum period. Here, we report an interesting case of a 34-year-old woman with spontaneous coronary artery dissection that occurred 1 month after childbirth. Emergency coronary angiography showed stenosis of the left anterior descending artery, but immediately afterwards, a new occlusion of the right coronary artery occurred. Intravascular ultrasound was used to image both right and left coronary arteries. The new occlusion of the right coronary artery was probably iatrogenic, but the left coronary artery occlusion was spontaneous. The patient underwent percutaneous coronary intervention in the right coronary artery because of her unstable hemodynamic condition. Revascularization of the left coronary artery was performed by bypass grafting. The patient was discharged on postoperative day 30. As the optimal treatment for spontaneous coronary artery dissection has not yet been established, treatments should be based on the patient's clinical presentation.

Successful percutaneous coronary intervention using a 4-in-3 "Slender Mother and Child" PCI technique.

We report two cases of successful percutaneous coronary intervention (PCI) using a 4-in-3 "Slender Mother and Child" PCI technique. In both cases, coronary angiography revealed severe stenosis of the right coronary artery (RCA). In both cases, 5-Fr sheathless guiding catheters were inserted into the RCA (virtual 3-Fr PCI) but stents could not pass through because of stents previously implanted at the proximal site of the target lesions. After 4-Fr straight "child" guiding catheters were inserted into the 5-Fr sheathless "slender mother" guiding catheters, they were deployed successfully at the target lesions. This system might be useful to improve stent delivery in virtual 3-Fr PCI.

Access site-related complications after transradial catheterization can be reduced with smaller sheath size and statins.

The aim of this study was to investigate the risk factors for access site-related complications after transradial coronary angiography (CAG) or percutaneous coronary intervention (PCI). Transradial PCI has been shown to reduce access site-related bleeding complications compared with procedures performed through a femoral approach. Although previous studies focused on risk factors for access site-related complications after a transfemoral approach or transfemoral and transradial approaches, it is uncertain which factors affect vascular complications after transradial catheterization. We enrolled 500 consecutive patients who underwent transradial CAG or PCI. We determined the incidence and risk factors for access site-related complications such as radial artery occlusion and bleeding complications. Age, sheath size, the dose of heparin and the frequency of PCI (vs. CAG) were significantly greater in patients with than without bleeding complications. However, body mass index (BMI) was significantly lower in patients with than without bleeding complications. Sheath size was significantly higher and the frequency of statin use was significantly lower in patients with than without radial artery occlusion. Multiple logistic analysis revealed that sheath size [odds ratio (OR) 5.5; P < 0.05] and BMI (OR 0.86; P < 0.01) were risk factors for bleeding complications; and sheath size (OR 5.2; P < 0.05) and the lack of statin pretreatment (OR 0.50; P < 0.05) were risk factors for occlusive complications. In conclusion, these findings indicate that down-sizing of the devices used in transradial procedures might attenuate access site-related complications after transradial CAG or PCI. Statin pretreatment might also be a strategy that could prevent radial artery occlusion after transradial procedures.

Marked decrease in BNP levels in 2 related patients with reversible dilated cardiomyopathy.

Two male patients, one in his thirties and the other in his fifties, were admitted to different hospitals for congestive heart failure (CHF). In both patients, laboratory findings indicated high plasma B-type natriuretic peptide (BNP) levels (266.0 and 902.7 pg/mL, respectively) and echocardiography showed large left ventricular diastolic dimensions (LVDd) (67 and 73 mm, respectively) and low ejection fractions (EF) (26% and 18%, respectively). Coronary arteriography revealed no organic stenosis in either patient. Following treatment, plasma BNP levels decreased to below the limit of measurement (4 pg/mL) in both patients and echocardiography revealed improved LVDd (61 and 52 mm, respectively) and EF (41% and 45%, respectively). Because these patients are related, genetic factors might have affected low plasma BNP levels. Moreover, these results suggest that marked decrease in plasma BNP during follow up may be an indicator of preserved neurohormonal and organ systems.

Heart rate on admission is an independent risk factor for poor cardiac function and in-hospital death after acute myocardial infarction.

BACKGROUND: Increased resting heart rate (HR) due to sympathetic hyperactivity is associated with coronary risk factors and increased cardiovascular events. Acute myocardial infarction (AMI) is accompanied by autonomic imbalance, which is characterized by sympathetic activation and parasympathetic inactivation. Although an increased HR in patients with acute coronary syndrome has been reported to be associated with 30-day and 6-month mortality before the coronary intervention era, it is unclear if an increased HR on admission is associated with the prognosis of AMI in the coronary intervention era. METHODS: We enrolled 200 consecutive patients with AMI within 24 h of symptom onset. All patients underwent coronary angiography. They were divided into quartiles based on resting HR on admission. RESULTS: There was no difference in coronary risk factors and previous medical treatment among the four groups. Anterior AMI was significantly lower in the lowest quartile compared with other quartiles. There was no difference in peak creatine kinase value among the four groups, however left ventricular ejection fraction (LVEF) before discharge evaluated by echocardiography in the highest quartile group was significantly reduced compared to other quartiles. An increased HR was significantly associated with in-hospital death. Patients in the highest quartile of HR were about nine times more likely to have a poor prognosis after AMI compared to those in the lowest quartile. Multiple logistic analysis revealed that HR ≥93 was an independent risk factor for in-hospital death. HR was significantly associated with Killip class and LVEF on admission. CONCLUSIONS: These findings indicate that increased HR on admission predicts for poor cardiac function and in-hospital death after AMI.

The relationship between endothelial function in the brachial artery and intima plus media thickening of the coronary arteries in patients with chest pain syndrome.

Endothelial dysfunction precedes the development of clinical atherosclerosis. A decrease in endothelium-derived nitric oxide activity shows impaired vasodilator function and causes arterial intimal hyperplasia or thickening. Others and we have reported the close relation of endothelial function in brachial artery and coronary artery. To compare the flow-mediated endothelium-dependent vasodilation (FMD) in brachial artery and the intima+media area in coronary artery, we measured brachial artery vasodilator response following transient occlusion with high resolution ultrasound transducer and intima+media area in coronary arteries with intravascular ultrasound in 25 patients with normal coronary angiograms (age 61.6+/-8.7 years old, men 14 and women 11). FMD was measured at least 7 days after the cessation of all vasodilators. The mean FMD of 25 patients was 3.83+/-2.38%, the mean intima+media area in coronary arteries of 25 patients was 39.9+/-15.5% of total vessel wall. FMD has a close negative relation with the largest percent intima+media area (r=-0.77, p<0.01). Especially, the patients whose FMD was less than 3.83% had larger percent intima+media area than those whose FMD was 3.83% or more (48.7+/-10.7% versus 30.3+/-14.2%, p<0.01). There is an intima+media thickening even in the patients who had normal coronary angiograms, and that the percent intima+media area correlated with FMD. The measurement of FMD is useful for screening the coronary artery intima+media thickening noninvasively. The pathogenesis of acute coronary syndrome has been reported to be the plaque rupture even in the patients with normal coronary angiograms. Thus, we must pay much attention in the patients with impaired FMD even in the normal coronary angiograms.

Future adverse cardiac events can be predicted by persistently low plasma adiponectin concentrations in men and marked reductions of adiponectin in women after acute myocardial infarction.

There is conflicting information about whether mortality after AMI is higher in women than men. We investigated the significance of plasma adiponectin concentrations on major adverse cardiac events (MACE) after acute myocardial infarction (AMI) to delineate any differences between men and women. The study patients consisted of 114 men and 42 women with AMI. The incidence of MACE was significantly higher in women than men during the entire follow-up period (p<0.05). Compared with men for post-AMI MACE, the hazard ratio for women was 5.6 after adjustment for prognostic factors. Killip class (p<0.001) and sex differences (p<0.05) were independent predictors of MACE at 1 year post-AMI. Plasma adiponectin levels in women were significantly higher than men on admission (8.66 microg/mL [range: 6.6-14.08] versus 4.71 microg/mL [range: 3.47-7.27], p<0.0001) and during the post-AMI course (all p<0.0001). Multivariate analysis identified plasma adiponectin level on admission as an independent predictor of MACE in men (p<0.001) and the difference between plasma adiponectin levels at discharge and on admission in women (p<0.05). Patterns of serial changes in plasma adiponectin concentrations are different between men and women and plasma adiponectin concentrations can be used to predict future adverse cardiac events in AMI patients.

Increased serum matrix metalloproteinase-1 concentration predicts advanced left ventricular remodeling in patients with acute myocardial infarction.

The left ventricular ejection fraction (LVEF) is one of the major prognostic factors after acute myocardial infarction (AMI) and matrix metalloproteinase-1 (MMP-1) is an enzyme responsible for extracellular collagen degradation and remodeling. The present study investigated whether the concentration of serum MMP-1 was associated with the LVEF after AMI. Blood was sampled on admission, and at 24 h, 3 days, 7 days, 2 weeks and 4 weeks in 24 patients with their first AMI. Left ventriculography was performed 4 weeks after the onset of AMI and the LVEF was calculated by center line method. MMP-1 concentrations were higher at 7 days and at 2 weeks than on admission (p<0.001), and at 7 days (r=-0.655, p=0.0005) and at 2 weeks (r=-0.636, p=0.0008) were negatively correlated with the LVEF. The patients with AMI were divided into high and low LVEF groups according to the results of left ventriculography. Although there were no differences in the clinical characteristics between the 2 LVEF groups, the MMP-1 concentrations at 24 h (p<0.01), 7 days (p<0.01) and 2 weeks (p<0.05) were lower in the high LVEF group than in low LVEF group. A high concentration of MMP-1 at the subacute phase after AMI predicts advanced left ventricular remodeling.

Rationale for the use of combination angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker therapy in heart failure.

BACKGROUND: The present multicenter study investigated whether the combination of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II receptor blocker (ARB) is more beneficial for preventing left ventricular remodeling and suppressing neurohumoral factors than either ACEI or ARB alone. METHODS AND RESULTS: One hundred and six patients with mild-to-moderate congestive heart failure treated in 26 Japanese institutes were randomly assigned to the combination therapy or monotherapy. Changes in physical activity (New York Heart Association functional classes, Specific Activity Scale (SAS)), concentrations of neurohumoral factors (plasma renin activity, angiotensin II, aldosterone, and brain natriuretic peptide (BNP)), and cardiac function for 6 months were compared between the 2 groups. It was found that the combination therapy, which was administered at doses standard in Japan, increased the SAS score (4.5 +/- 1.5 to 4.9 +/- 1.5, p<0.05) and decreased the plasma BNP concentration (183 +/- 163 to 135 +/- 118 pg/ml, p<0.05). In contrast, there were no changes in SAS score (4.5 +/- 1.4 to 4.6 +/- 1.4, NS) or BNP concentration (156 +/- 157 to 151 +/- 185 pg/ml, NS) in the patients receiving monotherapy. CONCLUSIONS: The results of the study demonstrate that the combination therapy, even at the standard doses for Japan, improves physical activity and plasma BNP concentration more than the monotherapy. A larger study is required to assess the effects of the combination therapy on major clinical outcomes.