Prognostic impact of chronic nitrate therapy in patients with vasospastic angina: multicentre registry study of the Japanese coronary spasm association.

AIMS: Although nitrates are widely used as a concomitant therapy with calcium channel blockers (CCBs) for vasospastic angina (VSA), their prognostic contribution remains unclear. The present study aimed to examine the prognostic impact of chronic nitrate therapy in patients with VSA. METHODS AND RESULTS: A total of 1429 VSA patients (median 66 years; male/female, 1090/339) were enrolled. The primary endpoint was defined as major adverse cardiac events (MACE). The propensity score matching and multivariable Cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. Among the study patients, 695 (49%) were treated with nitrates, including conventional nitrates [e.g. nitroglycerin (GTN), isosorbide mono- and dinitrate] in 551 and nicorandil in 306. Calcium channel blockers were used in >90% of patients. During the median follow-up period of 32 months, 85 patients (5.9%) reached the primary endpoint. Propensity score-matched analysis demonstrated that the cumulative incidence of MACE was comparable between the patients with and those without nitrates [11 vs. 8% at 5 years; hazard ratio (HR): 1.28; 95% confidence interval (CI): 0.72-2.28, P = 0.40]. Although nicorandil itself had a neutral prognostic effect on VSA (HR: 0.80; 95% CI: 0.28-2.27, P = 0.67), multivariable Cox model revealed the potential harm of concomitant use of conventional nitrates and nicorandil (HR: 2.14; 95% CI: 1.02-4.47; P = 0.044), particularly when GTN and nicorandil were simultaneously administered. CONCLUSIONS: Chronic nitrate therapy did not improve the long-term prognosis of VSA patients when combined with CCBs. Furthermore, the VSA patients with multiple nitrates would have increased risk for cardiac events.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

AIMS: Provocation tests of coronary artery spasm are useful for the diagnosis of vasospastic angina (VSA). However, these tests are thought to have a potential risk of arrhythmic complications, including ventricular tachycardia (VT), ventricular fibrillation (VF), and brady-arrhythmias. We aimed to elucidate the safety and the clinical implications of the spasm provocation tests in the nationwide multicentre registry study by the Japanese Coronary Spasm Association. METHODS AND RESULTS: A total of 1244 VSA patients (M/F, 938/306; median 66 years) who underwent the spasm provocation tests were enrolled from 47 institutes. The primary endpoint was defined as major adverse cardiac events (MACEs). The provocation tests were performed with either acetylcholine (ACh, 57%) or ergonovine (40%). During the provocation tests, VT/VF and brady-arrhythmias developed at a rate of 3.2 and 2.7%, respectively. Overall incidence of arrhythmic complications was 6.8%, a comparable incidence of those during spontaneous angina attack (7.0%). Multivariable logistic regression analysis demonstrated that diffuse right coronary artery spasm (P < 0.01) and the use of ACh (P < 0.05) had a significant correlation with provocation-related VT/VF. During the median follow-up of 32 months, 69 patients (5.5%) reached the primary endpoint. The multivariable Cox proportional hazard model revealed that mixed (focal plus diffuse) type multivessel spasm had an important association with MACEs (adjusted hazard ratio, 2.84; 95% confidence interval, 1.34-6.03; P < 0.01), whereas provocation-related arrhythmias did not. CONCLUSION: The spasm provocation tests have an acceptable level of safety and the evaluation of spasm type may provide useful information for the risk prediction of VSA patients.

Gender differences in the clinical characteristics and outcomes of patients with vasospastic angina--a report from the Japanese Coronary Spasm Association.

BACKGROUND: Accumulating evidence has demonstrated the gender differences in the clinical characteristics and outcomes of patients with ischemic heart disease. However, it remains to be elucidated whether it is also the case for vasospastic angina (VSA). METHODS AND RESULTS: We enrolled a total of 1,429 VSA patients (male/female, 1090/339; median age 66 years) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. As compared with male patients, female patients were characterized by older age (median 69 vs. 66 years), lower incidence of smoking (20% vs. 72%) and less significant organic stenosis (9% vs. 16%) (all P=0.001). Multivariate analysis demonstrated that the predictors of major adverse cardiac events (MACE) were considerably different by genders; women were more associated with age and electrical abnormalities, whereas men with structural abnormalities. Overall 5-year MACE-free survival was comparable between both genders. However, when the patients were divided into 3 groups by age [young (<50 years), middle-aged (50-64 years) and elderly (≥65 years)], the survival was significantly lower in the young female group (young 82%, middle-aged 92%, elderly 96%, P<0.01), where a significant interaction was noted between age and smoking. In contrast, the survival was comparable among the 3 age groups of male patients. CONCLUSIONS: These results indicate that there are gender differences in the characteristics and outcomes of VSA patients, suggesting the importance of gender-specific management of the disorder.

Impact of statins in patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Statins are generally used for patients with coronary artery disease. However, the impact of statins in patients with vasospastic angina (VSA) is not fully understood. METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without statins were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure, and appropriate implantable cardioverter defibrillator shock. Propensity score matching and a multivariable Cox proportional hazard model were used to adjust for selection bias in treatment and potential confounding factors. RESULTS: In the whole population, 469 patients received statins, while 960 patients did not receive statins. Patients with statins had a greater prevalence of comorbidities, including hypertension, diabetes, dyslipidemia, and smoking, in comparison to those without statins. The prevalence rates of previous myocardial infarction, significant organic stenosis, and medication use (including calcium channel blockers, angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, and beta blockers) were greater in patients with statins than in those without statins. After propensity matching (n = 211 for both groups), a Kaplan-Meier curve analysis revealed that the incidence of MACE was comparable between patients with and without statins (p = 0.686). MACEs occurred in 6.0% of patients with statins and in 5.9% of those without statins (p = 0.98). CONCLUSION: In this multicenter registry study, statin therapy did not reduce clinical events in VSA patients.

[Prognosis of type A acute aortic dissection treated conservatively].

We examined 58 cases of type A acute aortic dissection treated from 2003 to 2005 in our hospital. Thirty-three patients were treated surgically and 25 patients were treated conservatively. Among the 25 patients treated conservatively, 13 patients had open false lumen, and were eligible for surgical therapy. Surgical therapy was abandoned however, for various reasons (stroke, advanced age, malignancy, renal disease, lung disease, or patient's reject). Thirteen patients (52%) treated conservatively died while only 1 patient (3%) treated surgically died. Patients with thrombosed false lumen had good prognosis while those with open false lumen or ischemic complication had poor prognosis. It is concluded that patients with thrombosed false lumen of type A acute aortic dissection could receive conservative therapy with surgical team's back up and close computed tomography (CT) follow up to detect recanalization and enlargement of the aorta.

The impact of antiplatelet therapy on patients with vasospastic angina: A multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Antiplatelet therapy (APT) is generally used in patients with coronary artery disease. However, for patients with vasospastic angina (VSA), the impact of APT is not fully understood. METHODS: In a multicenter registry study of the Japanese Coronary Spasm Association (n = 1429), patients with or without APT were compared. The primary endpoint was major adverse cardiac events (MACEs), defined as cardiac death, non-fatal myocardial infarction, unstable angina, heart failure and appropriate ICD (Implantable cardioverter defibrillator) shock. Propensity score matching and a multivariable cox proportional hazard model were used to adjust for selection bias for treatment and potential confounding factors. RESULTS: In the whole population, 669 patients received APT, while 760 patients did not receive APT. Patients with APT had a greater prevalence of comorbidities, such as hypertension, diabetes, dyslipidemia and smoking, than those without APT. The prevalences of previous myocardial infarction, spontaneous ST changes, significant organic stenosis and medications including calcium channel blocker, nitrate, statin and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker were greater in patients with APT than those without APT. After propensity matching (n = 335 for both groups), during the median follow-up period of 32 months, the incidence rate of MACE was comparable between the patients with and without APT (P = 0.24). MACEs occurred in 5.7% of patients with APT and in 3.6% of those without APT (P = 0.20). All-cause death occurred in 0.6% of patients with APT and 1.8% of those without APT (p = 0.16). CONCLUSION: In this multicenter registry study, anti-platelet therapy exerted no beneficial effects for VSA patients.

A randomized controlled trial of eicosapentaenoic acid in patients with coronary heart disease on statins.

BACKGROUND: There is a residual risk of coronary heart disease (CHD) despite intensive statin therapy for secondary prevention. The aim of this study was to investigate whether coronary plaque regression and stabilization are reinforced by the addition of eicosapentaenoic acid (EPA) to high-dose pitavastatin (PTV). METHODS: We enrolled 193 CHD patients who underwent percutaneous coronary intervention (PCI) in six hospitals. Patients were randomly allocated to the PTV group (PTV 4mg/day, n=96) or PTV/EPA group (PTV 4mg/day and EPA 1800mg/day, n=97), and prospectively followed for 6-8 months. Coronary plaque volume and composition in nonstenting lesions were analyzed by integrated backscatter intravascular ultrasound (IB-IVUS). RESULTS: The PTV/EPA group showed a greater reduction in total atheroma volume compared to PTV group. IB-IVUS analyses revealed that lipid volume was significantly decreased during follow-up period in only PTV/EPA group. The efficacy of additional EPA therapy on lipid volume reduction was significantly higher in stable angina pectoris (SAP) patients compared to acute coronary syndrome patients. EPA/AA ratio was significantly improved in PTV/EPA group compared to PTV group. There was no significant difference in the incidence of major adverse cardiovascular events and side effects. CONCLUSIONS: Combination EPA/PTV therapy significantly reduced coronary plaque volume compared to PTV therapy alone. Plaque stabilization was also reinforced by EPA/PTV therapy in particular SAP patients. The addition of EPA is a promising option to reduce residual CHD risk under intensive statin therapy.

Plasma Renin Activity Predicts the Improvement in Resistant Hypertension after Percutaneous Transluminal Renal Artery Angioplasty.

Objective Percutaneous transluminal renal artery angioplasty (PTRA) has been recommended for the treatment of renovascular resistant hypertension. However, large randomized trials have reported that PTRA did not improve the outcomes compared with optimal medical therapy in patients with renal artery stenosis (RAS). It is important to identify patients with renovascular hypertension who are likely to respond to PTRA. We herein examined whether or not the plasma renin activity (PRA) could predict the improvement in resistant hypertension after PTRA for RAS. Methods and Results A total of 40 patients (mean age: 63±15 years) with unilateral RAS who received PTRA for resistant hypertension were enrolled in this study. Twenty-two (55%) patients experienced a significant reduction in their blood pressure while using few antihypertensive agents at the 3-month follow up. The median PRA was significantly higher in patients using few antihypertensive agents than in those using more [4.2 ng/mL/hr, interquartile range (IQR) 2.6-8.0 vs. 0.8 ng/mL/hr, IQR 0.4-1.7, p<0.001]. To predict the improvement in hypertension after PTRA, a receiver operating characteristic analysis determined the optimal cut-off value of PRA to be 2.4 ng/mL/hr. A multivariate logistic regression analysis showed that higher PRA (>2.4 ng/mL/hr) was an independent predictor of the improvement in hypertension after PTRA (odds ratio: 22.3, 95% confidence interval: 2.17 to 65.6, p<0.01). Conclusion These findings suggest that the evaluation of preoperative PRA may be a useful tool for predicting the improvement in resistant hypertension after PTRA for patients with RAS.

C-reactive protein elevation predicts the occurrence of atrial structural remodeling in patients with paroxysmal atrial fibrillation.

It has been poorly understood whether inflammation may contribute to atrial structural remodeling and increase the propensity for atrial fibrillation (AF) to persist. We investigated the relationship between C-reactive protein (CRP) elevation and the development of atrial remodeling in AF. The study population comprised 50 consecutive paroxysmal AF (PAF) patients and 50 control patients without AF. All patients underwent echocardiography, and high-sensitivity CRP was routinely measured. C-Reactive protein was significantly higher in the patients with PAF than control patients (0.231+/-0.176 mg/dl vs 0.055+/-0.041 mg/dl, P<0.001). Other predictors of elevated CRP included left ventricular mass (P<0.05), left ventricular end-systolic diameter (P<0.05), and left atrial (LA) diameter (P<0.001). In a multivariate analysis, only CRP and LA diameter were independent predictors of PAF. Elevated CRP levels correlated with LA diameter (r=0.489, P<0.001). Left atrial diameter was increased in PAF patients compared with control patients (P<0.001). We found that a longer duration of AF is associated with higher CRP levels and a larger LA diameter (duration <30 days: CRP 0.166+/-0.139 mg/dl, LA diameter 38.4+/-8.0 mm; duration >30 days: CRP 0.345+/-0.181 mg/dl, LA diameter 45.6+/-6.6 mm; P<0.001). In conclusion, longer AF duration is associated with CRP elevation and atrial structural remodeling, as approximated by larger LA diameter. However, CRP elevation, while correlating with LA diameter, was not an independent predictor of atrial structural remodeling. Thus, it remains unclear whether CRP and the inflammatory state are contributory to LA remodeling or whether LA remodeling or AF induces elevation in CRP and inflammation.

Combination therapy of eicosapentaenoic acid and pitavastatin for coronary plaque regression evaluated by integrated backscatter intravascular ultrasonography (CHERRY study)-rationale and design.

BACKGROUND AND PURPOSE: Many clinical trials have shown that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) can significantly reduce coronary artery disease in both primary and secondary prevention. A recent study showed that aggressive lipid-lowering therapy with strong statins could achieve coronary artery plaque regression, as evaluated with gray-scale intravascular ultrasound (IVUS). However, it is unknown whether coronary plaque regression and stabilization are reinforced when eicosapentaenoic acid (EPA) is used with a strong statin. METHODS AND SUBJECTS: We aim to assess patients with stable angina or acute coronary syndrome who had undergone successful percutaneous coronary intervention (PCI) with integrated backscatter IVUS (IB-IVUS) guidance. They will be randomly allocated to receive pitavastatin (4mg), or pitavastatin (4mg) plus EPA (1800mg), and prospectively followed for 6-8 months. RESULTS: The primary endpoint will be changes in tissue characteristics in coronary plaques, evaluated by IB-IVUS, and secondary endpoints will include absolute changes in coronary plaque volume, serum lipid levels, and inflammatory markers. The safety profile will also be evaluated. CONCLUSIONS: The combination therapy of EPA and pitavastatin for regression of coronary plaque evaluated by IB-IVUS (CHERRY) study will be the first multicenter study using IB-IVUS to investigate the effects of combination therapy with pitavastatin and EPA on coronary plaque volume and tissue characteristics.

Prognostic stratification of patients with vasospastic angina: a comprehensive clinical risk score developed by the Japanese Coronary Spasm Association.

OBJECTIVES: The present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients. BACKGROUND: Previous studies demonstrated various prognostic factors of future adverse events in VSA patients. However, to apply these prognostic factors in clinical practice, the assessment of their accumulation in individual patients is important. METHODS: The patient database of the multicenter registry study by the Japanese Coronary Spasm Association (JCSA) (n = 1,429; median 66 years; median follow-up 32 months) was utilized for score derivation. RESULTS: Multivariable Cox proportional hazard model selected 7 predictors of major adverse cardiac events (MACE). The integer score was assigned to each predictors proportional to their respective adjusted hazard ratio; history of out-of-hospital cardiac arrest (4 points), smoking, angina at rest alone, organic coronary stenosis, multivessel spasm (2 points each), ST-segment elevation during angina, and beta-blocker use (1 point each). According to the total score in individual patients, 3 risk strata were defined; low (score 0 to 2, n = 598), intermediate (score 3 to 5, n = 639) and high (score 6 or more, n = 192). The incidences of MACE in the low-, intermediate-, and high-risk patients were 2.5%, 7.0%, and 13.0%, respectively (p < 0.001). The Cox model for MACE between the 3 risk strata also showed prognostic utility of the scoring system in various clinical subgroups. The average prediction rate of the scoring system in the internal training and validation sets were 86.6% and 86.5%, respectively. CONCLUSIONS: We developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients.

Clinical characteristics and long-term prognosis of vasospastic angina patients who survived out-of-hospital cardiac arrest: multicenter registry study of the Japanese Coronary Spasm Association.

BACKGROUND: Coronary artery spasm plays an important role in the pathogenesis of ischemic heart disease; however, its role in sudden cardiac death remains to be fully elucidated. We examined the clinical characteristics and outcomes of patients with vasospastic angina (VSA) in our nationwide multicenter registry by the Japanese Coronary Spasm Association. METHODS AND RESULTS: Between September 2007 and December 2008, 1429 patients with VSA (male/female, 1090/339; median, 66 years) were identified. They were characterized by a high prevalence of smoking and included 35 patients who survived out-of-hospital cardiac arrest (OHCA). The OHCA survivors, as compared with the remaining 1394 non-OHCA patients, were characterized by younger age (median, 58 versus 66 years; P<0.001) and higher incidence of left anterior descending coronary artery spasm (72% versus 53%, P<0.05). In the OHCA survivors, 14 patients underwent implantable cardioverter-defibrillator (ICD) implantation while intensively treated with calcium channel blockers. Survival rate free from major adverse cardiac events was significantly lower in the OHCA survivors compared with the non-OHCA patients (72% versus 92% at 5 years, P<0.001), including appropriate ICD shocks for ventricular fibrillation in 2 patients. Multivariable analysis revealed that OHCA events were significantly correlated with major adverse cardiac events (hazard ratio, 3.25; 95% confidence interval, 1.39 to 7.61; P<0.01). CONCLUSIONS: These results from the largest vasospastic angina cohort indicate that vasospasm patients who survived OHCA are high-risk population. Further studies are needed to determine whether implantable cardioverter-defibrillator therapy improves patient prognosis.