Toshikazu Goto

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.

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

AIMSnProvocation 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.nnnMETHODS AND RESULTSnA 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.nnnCONCLUSIONnThe 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.

Prognostic Stratification of Patients With Vasospastic Angina A Comprehensive Clinical Risk Score Developed by the Japanese Coronary Spasm Association

OBJECTIVESnThe present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients.nnnBACKGROUNDnPrevious 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.nnnMETHODSnThe 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.nnnRESULTSnMultivariable 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.nnnCONCLUSIONSnWe developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients.

Clinical ResearchCoronary Artery DiseasePrognostic Stratification of Patients With Vasospastic Angina: A Comprehensive Clinical Risk Score Developed by the Japanese Coronary Spasm Association

OBJECTIVESnThe present study aimed to develop a comprehensive clinical risk score for vasospastic angina (VSA) patients.nnnBACKGROUNDnPrevious 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.nnnMETHODSnThe 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.nnnRESULTSnMultivariable 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.nnnCONCLUSIONSnWe developed a novel scoring system, the JCSA risk score, which may provide the comprehensive risk assessment and prognostic stratification for VSA patients.

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

AIMSnAlthough 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.nnnMETHODS AND RESULTSnA 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.nnnCONCLUSIONSnChronic 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 impacts of additive use of olmesartan in hypertensive patients with chronic heart failure: the supplemental benefit of an angiotensin receptor blocker in hypertensive patients with stable heart failure using olmesartan (SUPPORT) trial

We examined whether an additive treatment with an angiotensin receptor blocker, olmesartan, reduces the mortality and morbidity in hypertensive patients with chronic heart failure (CHF) treated with angiotensin-converting enzyme (ACE) inhibitors, β-blockers, or both. In this prospective, randomized, open-label, blinded endpoint study, a total of 1147 hypertensive patients with symptomatic CHF (mean age 66 years, 75% male) were randomized to the addition of olmesartan (n = 578) to baseline therapy vs. control (n = 569). The primary endpoint was a composite of all-cause death, non-fatal acute myocardial infarction, non-fatal stroke, and hospitalization for worsening heart failure. During a median follow-up of 4.4 years, the primary endpoint occurred in 192 patients (33.2%) in the olmesartan group and in 166 patients (29.2%) in the control group [hazard ratio (HR) 1.18; 95% confidence interval (CI), 0.96–1.46, P = 0.112], while renal dysfunction developed more frequently in the olmesartan group (16.8 vs. 10.7%, HR 1.64; 95% CI 1.19–2.26, P = 0.003). Subgroup analysis revealed that addition of olmesartan to combination of ACE inhibitors and β-blockers was associated with increased incidence of the primary endpoint (38.1 vs. 28.2%, HR 1.47; 95% CI 1.11–1.95, P = 0.006), all-cause death (19.4 vs. 13.5%, HR 1.50; 95% CI 1.01–2.23, P = 0.046), and renal dysfunction (21.1 vs. 12.5%, HR 1.85; 95% CI 1.24–2.76, P = 0.003). Additive use of olmesartan did not improve clinical outcomes but worsened renal function in hypertensive CHF patients treated with evidence-based medications. Particularly, the triple combination therapy with olmesartan, ACE inhibitors and β-blockers was associated with increased adverse cardiac events. This study is registered at clinicaltrials.gov-NCT00417222.

Beneficial effects of long-acting nifedipine on coronary vasomotion abnormalities after drug-eluting stent implantation: The NOVEL study

AIMSnIt is widely known that drug-eluting stents (DES) induce coronary vasomotion abnormalities. We have previously demonstrated that chronic treatment with long-acting nifedipine suppresses coronary hyperconstricting responses induced by the first-generation DES (e.g. sirolimus- and pacritaxel-eluting stents) through inhibition of vascular inflammation in pigs. To examine whether this is also the case with the second-generation DES (everolimus-eluting stents, EES) in humans, the most widely used DES in the world, we conducted a prospective, randomized, multicentre trial, termed as the NOVEL Study.nnnMETHODS AND RESULTSnWe evaluated 100 patients with stable angina pectoris who underwent scheduled implantation of EES in the left coronary arteries. They were randomly assigned to receive either conventional treatments alone or additionally long-acting nifedipine (10-60 mg/day) (n = 50 each). After 8-10 months, 37 patients in the control and 38 in the nifedipine group were examined for coronary vasoreactivity to intracoronary acetylcholine (ACh) by quantitative coronary angiography after 48-h withdrawal of nifedipine. Coronary vasoconstricting responses to ACh were significantly enhanced at the distal edge of EES compared with non-stented vessel (P = 0.0001) and were significantly suppressed in the nifedipine group compared with the control group (P = 0.0044). Furthermore, the inflammatory profiles were also improved only in the nifedipine group, which evaluated by serum levels of high-sensitivity CRP (P = 0.0001) and adiponectin (P = 0.0039).nnnCONCLUSIONSnThese results indicate that DES-induced coronary vasomotion abnormalities still remain an important clinical issue even with the second-generation DES, for which long-acting nifedipine exerts beneficial effects associated with its anti-inflammatory effects.nnnTRIAL REGISTRATIONnThis study is registered at the UMIN Clinical Trial Registry (UMIN-CTR; ID=UMIN000015147).

Influence of Left Ventricular Ejection Fraction on the Effects of Supplemental Use of Angiotensin Receptor Blocker Olmesartan in Hypertensive Patients With Heart Failure.

BACKGROUNDnThere is no robust evidence of pharmacological interventions to improve mortality in heart failure (HF) patients with preserved left ventricular ejection fraction (LVEF) (HFpEF). In this subanalysis study of the SUPPORT Trial, we addressed the influence of LVEF on the effects of olmesartan in HF.nnnMETHODSANDRESULTSnAmong 1,147 patients enrolled in the SUPPORT Trial, we examined 429 patients with reduced LVEF (HFrEF, LVEF <50%) and 709 with HFpEF (LVEF ≥50%). During a median follow-up of 4.4 years, 21.9% and 12.5% patients died in the HFrEF and HFpEF groups, respectively. In HFrEF patients, the addition of olmesartan to the combination of angiotensin-converting enzyme inhibitor (ACEI) and β-blocker (BB) was associated with increased incidence of death (hazard ratio (HR) 2.26, P=0.002) and worsening renal function (HR 2.01, P=0.01), whereas its addition to ACEI or BB alone was not. In contrast, in HFpEF patients, the addition of olmesartan to BB alone was significantly associated with reduced mortality (HR 0.32, P=0.03), whereas with ACEIs alone or in combination with BB and ACEI was not. The linear mixed-effect model showed that in HFpEF, the urinary albumin/creatinine ratio was unaltered when BB were combined with olmesartan, but significantly increased when not combined with olmesartan (P=0.01).nnnCONCLUSIONSnLVEF substantially influences the effects of additive use of olmesartan, with beneficial effects noted when combined with BB in hypertensive HFpEF patients. (Circ J 2016; 80: 2155-2164).