Efficacy and Safety of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure (EARLIER trial): a multicentre, randomized, double-blind, placebo-controlled trial.

AIMS: A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. METHODS AND RESULTS: In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642-1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213-1.434). The safety profile for eplerenone was as expected. CONCLUSION: The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Clinical Significance and Prognosis of Right Heart Thrombi Associated With Acute Pulmonary Thromboembolism　- Results of a Multicenter Registry of Thrombolysis in Japan.

BACKGROUND: Thrombolytic therapy is standard treatment in acute pulmonary thromboembolism (PTE) with hemodynamic instability. Although right heart thrombi (RHT) appear to increase mortality in acute PTE, large-scale studies of acute PTE with RHT are scarce.Methods and Results:Patient data (from August 2005 to May 2014) obtained from post-marketing surveillance of thrombolytic therapy using a tissue-type plasminogen activator were analyzed retrospectively. Of the 2,698 confirmed cases of acute PTE who underwent echocardiographic assessment, 166 (6.2%) were diagnosed with RHT. PTE patients with RHT, compared with those without RHT, had higher rates of mortality (20.2% vs. 10.4%, P<0.001), hemodynamic instability (53.0% vs. 37.7%, P<0.001), and PTE recurrence (6.6% vs. 2.3%, P=0.003). When considering PTE-related hemodynamic severity (cardiopulmonary arrest/collapse, massive, submassive, and non-massive), mortality was significantly higher in patients with RHT in the massive (19.8% vs. 7.7%, P=0.002) and submassive (8.0% vs. 2.8%, P=0.018) groups, whereas no significant differences was found between those with and without RHT in the cardiopulmonary arrest/collapse (51.7% vs. 52.1%, P=0.960) and non-massive (1.6% vs. 0%, P=0.596) groups. CONCLUSIONS: PTE patients with RHT had higher mortality, severity, and PTE recurrence rates. RHT was particularly associated with worse outcomes in patients with massive or submassive PTE.

Effect of Endovascular Treatment on Systemic Vascular Resistance in Patients with Lower-Limb Peripheral Artery Disease.

Objective: Endovascular treatment (EVT) for lower-limb peripheral artery disease patients reduces blood pressure (BP) and improves prognosis. This study retrospectively examined hemodynamics during EVT to clarify the mechanism. Materials and Methods: Systemic vascular resistance (SVR) was measured using a noninvasive continuous cardiac output monitoring system during EVT. Furthermore, ankle brachial index was measured before and after EVT. Results: The study included 88 lesions of 56 patients (hypertension in 98%). SVR significantly decreased from 2409.1±746.8 dynes·s·cm-5 to 2033.7±635.0 dynes·s·cm-5 (p<0.0001). The difference in SVR before and after EVT was significantly greater in the Fontaine IV group than in the Fontaine IIa group (554.7±406.6 dynes·s·cm-5 vs. 312.9±245.7 dynes·s·cm-5, p=0.0151). The change in SVR was correlated with a change in mean BP in the upper limb (p=0.0026). When the change in pressure gradient between the upper limb and the diseased lower limb was large, mean BP of the upper limb significantly decreased (p=0.0022). Conclusion: EVT can reduce SVR and BP by canceling the pressure gradient between central BP and diseased lower-limb BP.

Prognostic importance of sodium level trajectory in acute heart failure.

Low sodium levels are strongly associated with poor prognosis in acute heart failure (AHF); however, the prognostic impact of the sodium level trajectory overtime has not been determined. A secondary analysis of the AQUAMARINE study in which patients with AHF and renal impairment were randomized to receive either tolvaptan or conventional treatment was performed. Sodium levels were evaluated at the baseline and at 6, 12, 24, and 48 h. We defined 'sodium dipping' as sodium level falling below the baseline level at any time point. The primary endpoint was the combined event of all-cause death and heart failure rehospitalization during follow-up. The analysis included 184 patients with a median follow-up of 21.1 months. Sodium levels more steeply increased during the 48 h in patients without events as compared to sodium levels in patients with events (P = 0.018 in linear-mixed effect model). The sodium dipping group (n = 100; 54.3%) demonstrated significantly less urine output, less body weight reduction, and poorer diuretic response within 48 h compared to the non-dipping group. The sodium dipping group was also significantly associated with a low combined-event-free survival after adjustment for other prognostic factors (HR 1.97; 95% CI 1.06-3.38; P = 0.033). The trajectory of sodium levels during the acute phase is associated with the prognosis of patients with AHF independently of the baseline sodium level.

Mechanisms of Diuresis for Acute Decompensated Heart Failure by Tolvaptan.

Tolvaptan, a vasopressin type 2 receptor antagonist, does not affect kidney circulation or cause worsening of renal function (WRF) in patients with acute decompensated heart failure (ADHF). Bioelectrical impedance analysis (BIA) can be used to evaluate intravascular volume by calculating the ratio of extracellular water (ECW) to intracellular water (ICW). There have been no reports examining the mechanisms of tolvaptan-induced diuresis using BIA. We investigated whether tolvaptan decreases excess volume while maintaining intravascular volume in ADHF patients.Study patients included 29 ADHF patients (age 48-95, men 69%) diagnosed between April 2013 and May 2016 and who underwent BIA before and after treatment. Fifteen patients were treated with tolvaptan in addition to conventional diuresis therapy (tolvaptan group), and 14 patients were treated with conventional diuresis therapy only (control group). In the control group, the numerical value of serum creatinine (Cre) significantly increased from 0.89 ± 0.22 mg/ dL to 1.07 ± 0.29 mg/dL (P = 0.004), and the ECW/ICW significantly decreased from 0.696 ± 0.036 to 0.673 ± 0.032 (P = 0.004). These values were not significantly different from those obtained for the tolvaptan group. Furthermore, regression analysis showed a negative correlation between ΔCre and ΔECW/ICW, which are the differences between values before and after treatment (ΔCre = -0.002-5.668 × ΔECW/ICW, r2 = 0.306, P = 0.002).Our findings suggest that WRF is caused by a reduction in intravascular volume and that tolvaptan treatment can decrease the excess volume while maintaining intravascular volume.

Malondialdehyde-Modified Low Density Lipoprotein as Oxidative-Stress Marker in Vasospastic Angina Patients.

Vasospastic angina (VSA) is caused by endothelial dysfunction and hypercontraction of vascular smooth muscle cells. Although oxidative-stress can induce endothelial dysfunction, the relationship of VSA and the oxidative-stress marker malondialdehyde-modified low density lipoprotein (MDA-LDL) remains unclear. PURPOSE: Serum MDA-LDL was evaluated in candidate VSA patients.The subjects were 84 patients admitted to our hospital because of chest pain at rest. We stratified the patients into 3 groups; definite VSA, suspected VSA, and unlikely VSA according to a Japanese Circulation Society (JCS) guideline. The patients classified as definite VSA or suspected VSA were considered as "clinical VSA".Forty cases were classified as definite VSA, 35 as suspected VSA, and 9 as unlikely VSA. Thus, clinical VSA was the diagnosis in 75 cases. The patient characteristics showed that the average age of the patients was 60.2 years old (men, 61%). The serum MDA-LDL level of the clinical VSA group (126.3 ± 38.0 U/L) was significantly higher than the unlikely VSA group (98.7 ± 31.1 U/L). Serum MDA-LDL was positively correlated with total cholesterol (T-Chol), lowdensity lipoprotein cholesterol (LDL-C), triglycerides, and fasting blood glucose. Multivariate analysis showed that serum MDA-LDL was the most predictive marker for making a diagnosis of clinical VSA (Odds ratio 1.064, 95% confidence interval 1.014-1.145, P = 0.008). In a population with positive or borderline ECG change, the positive rate in the acetylcholine provocation test was significantly higher in the MDA-LDL higher group compared to the MDA-LDL lower group (81% versus 37%, P = 0.032).: Serum MDA-LDL might be a useful biomarker of VSA and have additional value for the diagnosis of clinical VSA.

Early treatment with tolvaptan improves diuretic response in acute heart failure with renal dysfunction.

BACKGROUND: Poor response to diuretics is associated with worse prognosis in patients with acute heart failure (AHF). We hypothesized that treatment with tolvaptan improves diuretic response in patients with AHF. METHODS: We performed a secondary analysis of the AQUAMARINE open-label randomized study in which a total of 217 AHF patients with renal impairment (eGFR < 60 mL/min/1.73 m2) were randomized to either tolvaptan or conventional treatment. We evaluated diuretic response to 40 mg furosemide or its equivalent based on two different parameters: change in body weight and net fluid loss within 48 h. RESULTS: The mean time from patient presentation to randomization was 2.9 h. Patients with a better diuretic response showed greater relief of dyspnea and less worsening of renal function. Tolvaptan patients showed a significantly better diuretic response measured by diuretic response based both body weight [-1.16 (IQR -3.00 to -0.57) kg/40 mg vs. -0.51 (IQR -1.13 to -0.20) kg/40 mg; P < 0.001] and net fluid loss [2125.0 (IQR 1370.0-3856.3) mL/40 mg vs. 1296.3 (IQR 725.2-1726.5) mL/40 mg; P < 0.001]. Higher diastolic blood pressure and use of tolvaptan were independent predictors of a better diuretic response. CONCLUSIONS: Better diuretic response was associated with greater dyspnea relief and less WRF. Early treatment with tolvaptan significantly improved diuretic response in AHF patients with renal dysfunction.

Factors and values at admission that predict a fulminant course of acute myocarditis: data from Tokyo CCU network database.

Prognosis of acute myocarditis is generally benign, but fulminant cases exist which require advanced life support devices, such as percutaneous cardio-pulmonary support (PCPS) and ventricular assist devices (VAD), and lead to fatal outcomes. The purpose of this study was to identify predictors and their values at admission which might foreshadow a fulminant course of myocarditis. Data from 138 patients (mean age 42.0 years, 79 males) with a diagnosis of acute myocarditis in the Tokyo CCU Network database from 2007 to 2009 were analyzed retrospectively. Patients were divided into fulminant (in-hospital death, or PCPS or VAD requirement, N = 42) and non-fulminant groups (N = 96). Clinical data at admission were compared between them. Overall in-hospital mortality was 14.5%. On multivariate analysis, low systolic blood pressure (BPsys, odds ratio (OR)/mmHg 0.97; 95% confidence interval (CI) 0.93-1.00, p = 0.032) and electrocardiographic QRS complex prolongation (OR/10 ms 1.28; 95% CI 1.10-1.59, p = 0.0034) at admission were independent factors associated with a fulminant course. By receiver operator characteristic curve analysis, the area under the curve predicting a fulminant course was 0.769 for low BPsys and 0.821 for prolongation of QRS duration. The optimal cut-off value was 101 mmHg for BPsys (sensitivity 79.5%, specificity 68.0%), and 120 ms for QRS duration (sensitivity 72.2%, specificity 88.0%). Systolic hypotension and prolonged QRS on admission are predictors of a fulminant course of myocarditis.

Prognostic impact of early treatment with tolvaptan in patients with acute heart failure and renal dysfunction.

BACKGROUND: Renal dysfunction is a common comorbidity in acute heart failure (AHF) patients. The prognostic significance of early treatment with tolvaptan in AHF patients complicated with renal dysfunction has not been elucidated. METHODS: Post hoc analysis was performed on a randomized clinical study for prespecified prognostic endpoints and prespecified subgroups. 217 AHF patients with renal dysfunction (eGFR 15 to 60mL/min/1.73m(2)) were randomized within 6h from hospitalization to either tolvaptan treatment for 2days or conventional treatment. The primary outcome was the combined endpoint of all-cause death and HF readmission. RESULTS: During follow-up (636days, median) 99 patients experienced combined endpoint and 53 patients died. There was no significant difference in event-free survival rate for either the combined events (Log-rank: P=0.197) or all-cause death (Log-rank: P=0.894) between tolvaptan and conventional groups. In prespecified subgroup analysis, in patients whose BUN/creatinine ratio was above the median (>20), tolvaptan significantly reduced the risk of combined events (HR: 0.52, 95% CI: 0.30-0.91, P=0.021) with a significant interaction (P value for interaction=0.045). Likewise, in patients whose eGFR was 30mL/min/1.73m(2) or above, tolvaptan reduced the risk of combined events (HR: 0.54, 95% CI: 0.32-0.90, P=0.017) with a significant interaction (P value for interaction=0.015). CONCLUSION: Short-term use of tolvaptan in acute-phase in AHF with renal dysfunction showed a neutral effect on prognosis. Patients with relatively preserved renal function and relatively high BUN/creatinine ratios are potentially favorable subgroups for treatment with tolvaptan.

Clinical Effectiveness of Tolvaptan in Patients With Acute Heart Failure and Renal Dysfunction.

BACKGROUND: More efficacious and/or safer decongestive therapy is clearly needed in acute heart failure (AHF) patients complicated by renal dysfunction. We tested the hypothesis that adding tolvaptan, an oral vasopressin-2 receptor antagonist, to conventional therapy with loop diuretics would be more effective treatment in this population. METHODS AND RESULTS: A multicenter, open-label, randomized control trial was performed, and 217 AHF patients with renal dysfunction (estimated glomerular filtration rate 15-60 mL • min(-1) • 1.73 m(-2)) were randomized 1:1 to treatment with tolvaptan (n=108) or conventional treatment (n=109). The primary end point was 48-hour urine volume. The tolvaptan group showed more diuresis than the conventional treatment group (6464.4 vs 4999.2 mL; P <.001) despite significantly lower amounts of loop diuretic use (80 mg vs 120 mg; P <.001). Dyspnea relief was achieved significantly more frequently in the tolvaptan group at all time points within 48 hours except 6 hours after enrollment. The rate of worsening of renal function (≥0.3 mg/dL increase from baseline) was similar between the tolvaptan and conventional treatment groups (24.1% vs 27.8%, respectively; P =.642). CONCLUSIONS: Adding tolvaptan to conventional treatment achieved more diuresis and relieved dyspnea symptoms in AHF patients with renal dysfunction. CLINICAL TRIAL REGISTRATION: URL: http://www.umin.ac.jp/ctr/index/htm/ Unique identifier: UMIN000007109.

Rationale and Design of the Double-Blind, Randomized, Placebo-Controlled Multicenter Trial on Efficacy of Early Initiation of Eplerenone Treatment in Patients with Acute Heart Failure (EARLIER).

BACKGROUND AND AIMS: Aldosterone is one of the major factors to cause organ damage during an acute phase of heart failure (HF), and many reports have demonstrated that patients with acute decompensated HF (ADHF) have high blood aldosterone concentrations, and the high aldosterone concentrations predict poor prognosis in patients with HF. These findings suggest that eplerenone, an antagonist of aldosterone receptors may provide a new concept and strategy for the treatment of ADHF, protecting the heart and other organs during chronic phases, depending on the restoration of hemodynamic abnormalities. METHODS: EARLIER is an event-driven clinical trial with an estimated enrolment of 300 patients hospitalized with ADHF with reduced left ventricular ejection fraction. ADHF includes ischemic or non-ischemic HF, and patients can be enrolled within 72 h after the visit to the hospital. We randomize the patients taking standard therapies for ADHF to the eplerenone and placebo groups. Eplerenone, either 25 or 50 mg, is administered for 6 months in the eplerenone group, and the corresponding placebo is administered in the placebo group on top of the standard care. We set the primary endpoint as the incidence of the composite endpoint (cardiac death or first re-hospitalization due to cardiac disease) 6 months after the enrollment, and also check the quality of life, i.e., exercise capacity and safety features of eplerenone. CONCLUSION AND PERSPECTIVES: EARLIER is a clinical trial of eplerenone targeting ADHF and also the first multicenter investigator-initiated phase III trial in the cardiovascular field in Japan, funded by the Japanese government.

Mother-child technique using a novel 4 Fr inner catheter.

AIMS: The aim of this study was to assess the efficacy of the mother and child technique using a 4 Fr inner catheter in coronary angioplasty following the failure of conventional techniques. METHODS AND RESULTS: We identified cases in which a 4 Fr inner catheter had been used to facilitate stent delivery following the failure of conventional techniques. Stent delivery using a 4 Fr inner catheter was performed in 30 cases and was successful in 29 cases. Nineteen cases for RCA, six cases for LAD and five cases for LCx were examined. Direct engagement of a 4 Fr inner catheter was accomplished in eight cases. In the remaining patients, deep engagement of a 4 Fr inner catheter was accomplished with the anchor technique and/or distal balloon deflation technique. Proximal stent delivery followed by distal stent deployment was performed in seven cases by using the distal balloon deflation technique in multiple stent deployment. There were no complications related to deep intubation of a 4 Fr inner catheter. CONCLUSIONS: The use of a 4 Fr inner catheter is safe and highly effective for aiding stent delivery. The anchor technique and/or distal balloon deflation technique could be required for deep engagement of a 4 Fr inner catheter.

Mid-ventricular obstructive hypertrophic cardiomyopathy with an apical aneurysm caused by vasospastic angina.

Mid-ventricular obstructive hypertrophic cardiomyopathy (MVOHCM) is a rare form of cardiomyopathy, characterized by the presence of a pressure gradient between the left ventricular basal and apical chambers and is frequently associated with an apical aneurysm. However, the exact cause of this aneurysm remains unknown. We here describe a patient with MVOHCM in whom the apical aneurysm may be caused by vasospastic angina.

Clinical effectiveness of tolvaptan in patients with acute decompensated heart failure and renal failure: design and rationale of the AQUAMARINE study.

PURPOSE: Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment. METHODS: The Answering question on tolvaptan's efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m(2) will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide. CONCLUSION: This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).

Proximal balloon deflation technique: a novel method to retrieve retained or entrapped equipment from the coronary system.

Complications of retained or entrapped equipment in the coronary system are still encountered during angioplasty procedures. Although these complications are rare, it is extremely difficult to retrieve such equipments. We report on two cases that a retained IVUS catheter or an entrapped filter wire were retrieved from the coronary system using more simplified technique that does not involve in the usage of snare or any other retrieval tool. After placing an additional guidewire and balloon alongside an equipment, it was easily retrieved from the coronary system just after the proximal balloon deflation.

Influence of additional ballooning with a dual wire balloon after a rotational atherectomy to expand drug-eluting stent for calcified lesions.

Calcified lesions have been known as a cause of stent underexpansion which increases the risk of thrombosis and in-stent restenosis. A dual wire balloon has been introduced to create a focal stress pattern in a localized region of the calcification. We evaluated the combination therapy using a dual wire balloon after rotational atherectomy (RA) for heavily calcified lesions. Of 21 consecutive patients with severe calcified lesions, 10 patients were treated with a dual wire balloon after RA, and 11 patients were treated with RA alone or, RA plus the conventional balloon. Finally, drugeluting stents (DES) were implanted in all cases. Baseline characteristics, lesion characteristics, and postdilatation procedures were not different between two groups. Before implantation of DES, a dual wire balloon enabled adequate dilatation with significantly more cracks than RA (1.8 ± 0.4 cracks vs. 1.2 ± 0.6 cracks, P = 0.02). The minimal stent cross sectional area (CSA) and the stent expansion ratio were similar in both groups. However, the symmetrical expansion was significantly accomplished in patients with a dual wire balloon compared to those without it (mean ratio calculated by dividing the shortest diameter by the longest diameter at the site of the minimal stent CSA was 0.83 ± 0.05 vs. 0.76 ± 0.07, P = 0.02). Moreover, no in-stent restenosis was observed in patients treated with a dual wire balloon at follow-up. In conclusion, by using a dual wire balloon after RA, adequate stent expansion and follow-up results were accomplished. This combination therapy is safety and feasible procedure for the treatment of severe calcified lesions.

A novel mother and child technique with a 4F inner catheter based on proper alignment of both catheters.

We occasionally encounter difficult cases of stent and balloon delivery to the distal lesion due to severe calcification or tortuosity of the proximal section. We describe a novel mother and child technique with a 4F inner catheter based on proper alignment of both catheters to deliver balloon, stent, and guide catheter to the distal lesion.