Regional Differences in Frequency of Warfarin Therapy and Thromboembolism in Japanese Patients With Non-Valvular Atrial Fibrillation　- Analysis of the J-RHYTHM Registry.

BACKGROUND: The proportion of patients with atrial fibrillation (AF) treated with anticoagulation varies from country to country. In Japan, little is known about regional differences in frequency of warfarin use or prognosis among patients with non-valvular AF (NVAF). METHODS AND RESULTS: In J-RHYTHM Registry, the number of patients recruited from each of 10 geographic regions of Japan was based on region population density. A total of 7,406 NVAF patients were followed up prospectively for 2 years. At baseline, significant differences in various clinical characteristics including age, sex, type of AF, comorbidity, and CHADS2score, were detected among the regions. The highest mean CHADS2score was recorded in Shikoku. Frequency of warfarin use differed between the regions (P<0.001), with lower frequencies observed in Hokkaido and Shikoku. Baseline prothrombin time international normalized ratio differed slightly but significantly between the regions (P<0.05). On univariate analysis, frequency of thromboembolic events differed among the regions (P<0.001), with the highest rate seen in Shikoku. An inverse correlation was detected between frequency of thromboembolic and of major hemorrhagic events (P=0.062). On multivariate analysis, region emerged as an independent risk for thromboembolism. CONCLUSIONS: Thromboembolic risk, frequency of warfarin use, and intensity and quality of warfarin treatment differed significantly between geographic regions of Japan. Region was found to be an independent predictor of thromboembolic events. (Circ J 2016; 80: 1548-1555).

Target international normalized ratio values for preventing thromboembolic and hemorrhagic events in Japanese patients with non-valvular atrial fibrillation: results of the J-RHYTHM Registry.

BACKGROUND: Target anticoagulation levels for warfarin in Japanese patients with non-valvular atrial fibrillation (NVAF) are unclear. METHODS AND RESULTS: Of 7,527 patients with NVAF, 1,002 did not receive warfarin (non-warfarin group), and the remaining patients receiving warfarin were divided into 5 groups based on their baseline international normalized ratio (INR) of prothrombin time (≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0). Patients were followed-up prospectively for 2 years. Primary endpoints were thromboembolic events (cerebral infarction, transient ischemic attack, and systemic embolism), and major hemorrhage requiring hospital admission. During the follow-up period, thromboembolic events occurred in 3.0% of non-warfarin group, but at lower frequencies in the warfarin groups (2.0, 1.3, 1.5, 0.6, and 1.8%/2 years for INR values of ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0059). Major hemorrhage occurred more frequently in warfarin groups (1.5, 1.8, 2.4, 3.3, and 4.1% for INR values ≤1.59, 1.6-1.99, 2.0-2.59, 2.6-2.99, and ≥3.0, respectively; P=0.0041) than in non-warfarin group (0.8%/2 years). These trends were maintained when the analyses were confined to patients aged ≥70 years. CONCLUSIONS: An INR of 1.6-2.6 is safe and effective at preventing thromboembolic events in patients with NVAF, particularly patients aged ≥70 years. An INR of 2.6-2.99 is also effective, but associated with a slightly increased risk in major hemorrhage. (UMIN Clinical Trials Registry UMIN000001569)

Refractory electrical storm in a patient with hypertrophic cardiomyopathy and an implantable cardioverter-defibrillator.

A 63-year-old man with hypertrophic cardiomyopathy (HCM), mid-ventricular obstruction, and an apical aneurysm had an episode of cardiac arrest due to sustained ventricular tachycardia (VT). He was resuscitated and an implantable cardioverter-defibrillator (ICD) was implanted. In the following years, several episodes of VT and ventricular fibrillation were successfully terminated by antitachycardia pacing or ICD shocks. Three years after ICD implantation, he was re-admitted because of refractory electrical storm (ES). Since aggressive pharmacological treatments, direct current cardioversions, and deep sedation were not effective, he underwent epicardial catheter ablation which was successful to terminate ES. However, because of the recurrence of refractory ES after one year, he proceeded to surgical left ventricular myectomy with apical aneurysmectomy which provided him a relatively stable clinical course for six years. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm seems to be most efficacious for ES in patients with HCM and an apical aneurysm. Learning objectives: In patients with hypertrophic cardiomyopathy (HCM), implantable cardioverter-defibrillators (ICDs) are the gold standard of therapy for prophylaxis against sudden death. Electrical storm (ES) caused by recurrent episodes of ventricular tachycardia can cause sudden death even in patients with ICDs. Although epicardial catheter ablation may be an acceptable option, surgical resection of apical aneurysm is most efficacious for ES in patients with HCM, mid-ventricular obstruction, and an apical aneurysm.

Randomized trial of angiotensin II-receptor blocker vs. dihydropiridine calcium channel blocker in the treatment of paroxysmal atrial fibrillation with hypertension (J-RHYTHM II study).

AIMS: Atrial fibrillation (AF) is a common arrhythmia frequently associated with hypertension. This study was designed to test the hypothesis that lowering blood pressure by angiotensin II-receptor blockers (ARB) has more beneficial effects than by conventional calcium channel blockers (CCB) on the frequency of paroxysmal AF with hypertension. METHODS AND RESULTS: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is an open-label randomized comparison between an ARB (candesartan) and a CCB (amlodipine) in the treatment of paroxysmal AF associated with hypertension. Using daily transtelephonic monitoring, we examined asymptomatic and symptomatic paroxysmal AF episodes during a maximum 1 year treatment. The primary endpoint was the difference in AF frequency between the pre-treatment period and the final month of the follow-up. The secondary endpoints included cardiovascular events, development of persistent AF, left atrial dimension, and quality-of-life (QOL). The study enrolled 318 patients (66 years, male/female 219/99, 158 in the ARB group and 160 in the CCB group) treated at 48 sites throughout Japan. At baseline, the frequency of AF episodes (days/month) was 3.8 ± 5.0 in the ARB group vs. 4.8 ± 6.3 in the CCB group (not significant). During the follow-up, blood pressure was significantly lower in the CCB group than in the ARB group (P < 0.001). The AF frequency decreased similarly in both groups, and there was no significant difference in the primary endpoint between the two groups. There were no significant differences between the two groups in the development of persistent AF, changes in left atrial dimension, occurrence of cardiovascular events, or changes in QOL. CONCLUSIONS: In patients with paroxysmal AF and hypertension, treatment of hypertension by candesartan did not have an advantage over amlodipine in the reduction in the frequency of paroxysmal AF (umin CTR C000000427).

Comparison of antiarrhythmics used in patients with paroxysmal atrial fibrillation: subanalysis of J-RHYTHM Study.

BACKGROUND: The J-RHYTHM (Japanese Rhythm Management Trial for Atrial Fibrillation) study demonstrated the benefit of rhythm-control compared with rate-control in Japanese patients with paroxysmal atrial fibrillation (AF), according to AF-specific quality of life scores. However, detailed information on prescribed antiarrhythmic agents remains unclear. METHODS AND RESULTS: Data for 419 patients enrolled in the rhythm-control arm of J-RHYTHM were analyzed. The primary endpoint was defined as a composite of total mortality, cerebral infarction, embolism, bleeding, heart failure, and physical/psychological disability. The secondary endpoint was recurrence of AF. The clinical outcome according to choice of initial antiarrhythmic agent (AA) was assessed by Kaplan-Meier survival curve, and further adjusted by Cox-regression hazard model. The primary endpoint occurred in 16.9%, 6.7%, 15.8% and 23.3% of patients assigned to class Ia, Ib, Ic and III agents (P=0.359). The rate of AF recurrence was significantly higher in patients taking a class III drug (Ia, Ib, Ic, III=20.3, 23.3, 29.1, 50.0%; P=0.002). However, after adjustment for other clinical variables, the choice of AA was not associated with recurrence of AF (class I vs III, P=0.15). CONCLUSIONS: The incidence of each endpoint did not differ according to the choice of AA. The class III drugs seemed to lower the sinus rhythm maintenance rate, which might be confounded by other comorbid conditions. (Circ J 2010; 74: 71 - 76).

Impact of drug alteration to maintain rhythm control in paroxysmal atrial fibrillation. - Subanalysis from J-RHYTHM study -.

BACKGROUND: The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study showed rhythm control was associated with fewer changes in the assigned treatment strategy compared to rate control in atrial fibrillation (AF). The aim was to describe how antiarrhythmics (AAs) were altered in the rhythm control arm and whether altering AAs would impact long-term outcomes. METHODS AND RESULTS: Of 390 enrolled patients, 23.5% altered their AAs (drug alteration [DA] group). The hard endpoint (HE) was defined as a composite of death, stroke, embolism, major bleeding or heart failure hospitalization; soft endpoint (SE) was defined physical/psychological disability requiring alteration of treatment strategy. The patients were followed for 1.7 years. No significant difference was noted in the occurrence of HE (4.0% vs 6.5%, P=0.31), but DA-group patients had higher rates of SE (9.3% vs 18.4%, P=0.017) compared to single AA patients. The DA group was also associated with the occurrence of SE after adjustment (HR 1.90, P=0.042). When the DA group was subdivided according to the use of class III drugs or change of drugs between classes, there were no differences in outcomes. CONCLUSIONS: The need to change AA was associated with physical/psychological disabilities that seemed not to be relieved simply by changing AAs, and this should be considered as a marker for refractory paroxysmal AF requiring other strategies.

Efficacy and safety of rivaroxaban in extreme elderly patients with atrial fibrillation: Analysis of the Shikoku Rivaroxaban Registry Trial (SRRT).

BACKGROUND: The Shikoku Rivaroxaban Registry Trial (SRRT) is a retrospective survey of the use of rivaroxaban for stroke prevention in elderly patients in Shikoku, Japan. METHODS: The SRRT enrolled 1339 patients from 8 hospitals. Patients were divided into two groups according to their age, the extreme elderly group (453 patients aged ≧80 years) and the control group (886 patients aged <80 years). RESULTS: In the extreme elderly group, 41.5% of the patients had low body weight (<50kg) and 65.1% had abnormal renal function (creatinine clearance <50ml/min). The mean CHADS2, CHA2DS2-VASc, and HAS BLED scores were 2.7, 4.4, and 2.3, respectively. There were 333 (73.5%) patients who met the dosing criteria, and of these patients, 81.2% received rivaroxaban 10mg daily. Thromboembolic events occurred in 4 patients (0.94%/person year) and intracranial hemorrhage occurred in 4 patients (0.89%/person year). The incidence of these events was not significantly different from the control group. In addition, all patients with cerebral infarction had been treated with a smaller dose of rivaroxaban than recommended by the dosing criteria, suggesting that dosing criteria should be adhered to. CONCLUSION: These results suggest that rivaroxaban is effective and safe in extreme elderly patients with atrial fibrillation.

Comprehensive arrhythmic surgery for sustained ventricular tachycardia revisited.

A 68-year-old woman with a history of old inferior myocardial infarction was admitted because of sustained ventricular tachycardia. Double vessel coronary disease was found with subtotal obstruction of the right coronary artery (#1) and severe stenosis of the left circumflex coronary artery (#13). Dilated left ventricle with a large ventricular aneurysm at the inferior wall and severely reduced systolic function were also present. A comprehensive surgical ablation using subendocardial resection and cryoablation was performed in combination with aneurysmectomy, left ventricular reconstruction, and coronary bypass grafting to the circumflex coronary artery. An implantable cardioverter-defibrillator was also implanted. She has remained well without recurrence of sustained ventricular tachycardia for one year. Although radiofrequency catheter ablation is nowadays considered a first-line therapy for patients with sustained ventricular tachycardia, surgical ablation remains a valuable option for selected patients, particularly for those requiring left ventricular aneurysmectomy and coronary artery bypass grafting, in order to gain a better long-term prognosis through total cure of ventricular tachycardia. .

Atrial fibrillation and atrial vulnerability in patients with Brugada syndrome.

OBJECTIVES: We sought to study atrial vulnerability in patients with Brugada syndrome. BACKGROUND: Atrial fibrillation (AF) often occurs in patients with Brugada syndrome, but atrial vulnerability in Brugada syndrome has not been evaluated. METHODS: The patient group consisted of 18 patients with Brugada syndrome. The control group consisted of 12 age- and gender-matched subjects who had neither organic heart disease nor AF episodes. The incidence and clinical characteristics of AF were evaluated in all 18 patients with Brugada syndrome, and an electrophysiologic study was performed in all 12 control subjects and in 14 of the 18 patients with Brugada syndrome. The atrial effective refractory period of the right atrium (RA-ERP), intra-atrial conduction time (conduction time from the stimulus at the right atrium to atrial deflection at the distal portion of the coronary sinus), duration of local atrial potential, and repetitive atrial firing (occurrence of two or more premature atrial complexes after atrial stimulation) were studied. RESULTS: Spontaneous AF occurred in 7 of the 18 patients with Brugada syndrome but in none of the control subjects. The RA-ERP was not different between the two groups. The intra-atrial conduction time was increased in the Brugada syndrome group versus the control group (168.4 +/- 17.5 vs. 131.8 +/- 13.0 ms, p < 0.001). The duration of atrial potential at the RA-ERP was prolonged in the Brugada syndrome group versus the control group (80.3 +/- 18.0 vs. 59.3 +/- 9.2 ms, p < 0.001). Repetitive atrial firing was induced in nine patients with Brugada syndrome and in six control subjects. Atrial fibrillation was induced in eight patients with Brugada syndrome but in none of the control subjects. In patients with Brugada syndrome without spontaneous AF, the intra-atrial conduction time and duration of atrial potential were also increased. CONCLUSIONS: Atrial vulnerability is increased in patients with Brugada syndrome. Abnormal atrial conduction may be an electrophysiologic basis for induction of AF in patients with Brugada syndrome.

Non-valvular atrial fibrillation patients with low CHADS2 scores benefit from warfarin therapy according to propensity score matching subanalysis using the J-RHYTHM Registry.

INTRODUCTION: Recently, direct-acting oral anticoagulants (DOACs) have been introduced, with increasing use in patients with non-valvular atrial fibrillation (NVAF). However, warfarin continues to be widely used and the benefits and risks of warfarin in NVAF patients warrant closer inspection. MATERIALS AND METHODS: Thromboembolism, major hemorrhage, and total and cardiovascular mortalities were analyzed in 7,406 NVAF patients in the J-RHYTHM Registry from January to July 2009, prior to DOAC introduction. Propensity score matching analysis was performed to reduce the differences in clinical characteristics between non-anticoagulant (n=1002) and warfarin (n=6404) cohorts to reassess warfarin outcomes over 2years. RESULTS: The incidence of thromboembolism was significantly greater in the non-anticoagulant cohort (3.0%) than in the warfarin cohort (1.5%, P<0.001) with less frequent major hemorrhage in the non-anticoagulant cohort (0.8%) than in the warfarin cohort (2.1%, P=0.009). Using propensity score matching, new subsets (n=896 each) were obtained, with matching of the clinical characteristics between warfarin and non-anticoagulant subsets. The warfarin subset had lower risk factors compared with the total warfarin cohort. The incidence of thromboembolism was higher in the non-anticoagulant subset (2.9%) than in the warfarin subset (0.7%, P<0.001). However, major hemorrhage was not significantly different between the two subsets. CONCLUSIONS: Although warfarin was associated with a significantly higher incidence of hemorrhage in the unmatched cohorts, propensity score matching revealed that warfarin reduced thromboembolism without a significant increase in hemorrhage in the matched subsets with lower risks. Propensity score matching reduced selection bias and provided rational comparisons although it had indwelling limitations.

Impact of gender on the prognosis of patients with nonvalvular atrial fibrillation.

Treatment guidelines for atrial fibrillation (AF) used in Western countries describe female gender as a risk factor for thromboembolic events in patients with nonvalvular AF (NVAF). The present study aimed to determine the impact of gender on prognosis of Japanese patients with NVAF. A subanalysis of 7,406 patients with NVAF (mean age 70 years) who were followed-up prospectively for 2 years was performed using data from the J-RHYTHM registry. The primary end points were thromboembolic events, major hemorrhaging, total mortality, and cardiovascular mortality. Compared with male subjects (n = 5,241), female subjects (n = 2,165) were older and displayed greater prevalences of paroxysmal AF, heart failure, and hypertension but less prevalences of diabetes, previous cerebral infarction, and coronary artery disease. Male and female patients had mean CHADS2 (Congestive heart failure, Hypertension, Age of 75 years or more, Diabetes mellitus and prior Stroke or transient ischemic attack) scores of 1.6 and 1.8, respectively (p <0.001). Warfarin was given to 87% of male patients and 86% of female patients (p = 0.760), and the 2 genders displayed similar mean international normalized ratio of prothrombin time values at baseline (1.91 vs 1.90, respectively, p = 0.756). Multivariate logistic regression analysis indicated that male gender was an independent risk factor for major hemorrhaging (odds ratio 1.59, 95% confidence interval 1.05 to 2.40, p = 0.027) and all-cause mortality (odds ratio 1.78, 95% confidence interval 1.25 to 2.55, p <0.002) but not for thromboembolic events (odds ratio 1.24, 95% confidence interval 0.83 to 1.86, p = 0.297) or cardiovascular mortality (odds ratio 0.96, 95% confidence interval 0.56 to 1.66, p = 0.893). In conclusion, female gender is not a risk factor for thromboembolic events among Japanese patients with NVAF who were treated mostly with warfarin. However, male gender is a risk factor for major hemorrhaging and all-cause mortality.

Comparison of outcomes using the sirolimus-eluting stent in calcified versus non-calcified native coronary lesions in patients on- versus not on-chronic hemodialysis (from the j-Cypher registry).

The impact of lesion calcium on long-term outcomes after drug-eluting stent implantation has not been adequately addressed. In 10,595 patients (16,803 lesions) who were exclusively treated with sirolimus-eluting stents in the j-Cypher registry, 5-year outcomes were compared between patients with ≥1 lesion with moderate or severe calcification (the calcium group) and those with noncalcified lesions only (the noncalcium group). Analyses were stratified by hemodialysis (HD) status (non-HD stratum [calcium n = 3,191, noncalcium n = 6,824] and HD stratum [calcium n = 415, noncalcium n = 165]). Adjusted risk in the calcium group for death and target lesion revascularization was significant in the non-HD stratum (hazard ratio [HR] 1.34, 95% confidence interval [CI] 1.18 to 1.52, p <0.0001, and HR 1.2, 95% CI 1.07 to 1.36, p = 0.003) and the HD stratum (HR 1.4, 95% CI 1.06 to 1.86, p = 0.02, and HR 2.25, 95% CI 1.51 to 3.36, p <0.0001). Risk for definite stent thrombosis tended to be higher in the calcium group in the HD stratum (HR 5.05, 95% CI 0.66 to 38.9, p = 0.12) but not in then non-HD stratum (HR 1.16, 95% CI 0.81 to 1.67, p = 0.41). The use of rotational atherectomy in patients with severe calcification did not have a significant impact on the cumulative incidence of target lesion revascularization in the non-HD stratum (17.7% [n = 268] with vs 18.2% [n = 588] without rotational atherectomy, p = 0.68) and the HD stratum (54.7% [n = 115] with vs 51.9% [n = 118] without rotational atherectomy, p = 0.19). In conclusion, regardless of HD status, patients with calcified lesions have increased long-term risk for death and target lesion revascularization after sirolimus-eluting stent implantation.

Optimal treatment strategy for patients with paroxysmal atrial fibrillation: J-RHYTHM Study.

Background Although previous clinical trials demonstrated the non-inferiority of a rate control to rhythm control strategy for management of atrial fibrillation (AF), the optimal treatment strategy for paroxysmal AF (PAF) remains unclear. Methods and Results A randomized, multicenter comparison of rate control vs rhythm control in Japanese patients with PAF (the Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM) study) was conducted. The primary endpoint was a composite of total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure, or physical/psychological disability requiring alteration of treatment strategy. In the study, 823 patients with PAF were followed for a mean period of 578 days. The primary endpoint occurred in 64 patients (15.3%) assigned to rhythm control and in 89 patients (22.0%) to rate control (P=0.0128). No significant differences between the treatment strategies were observed in the incidences of death, stroke, bleeding and heart failure. Meanwhile, significantly fewer patients requested changes of assigned treatment strategy in the rhythm control vs the rate control group, which was accompanied by improvement in AF-specific quality of life scores. Conclusion The J-RHYTHM study showed that rhythm control was associated with fewer primary endpoints than rate control. However, mortality and cardiovascular morbidity were not affected by the treatment strategy (umin-CTR No. C000000106).

Randomized study of angiotensin II type 1 receptor blocker vs dihydropiridine calcium antagonist for the treatment of paroxysmal atrial fibrillation in patients with hypertension.

BACKGROUND: Mega trials of rhythm vs rate control could not demonstrate the usefulness of available antiarrhythmic drugs, so a more effective and safer therapy for atrial fibrillation (AF) is now required. One candidate is the so-called "upstream therapy", which refers to the blockade of upstream modifying elements (renin - angiotensin system, cathecholamines, oxidative stress etc) that contribute to the arrhythmogenic substrate. METHODS AND RESULTS: The Japanese Rhythm Management Trial II for Atrial Fibrillation (J-RHYTHM II study) is a randomized comparative evaluation of an angiotensin II type 1 blocker (candesartan) and a dihydropiridine calcium blocker (amlodipine), both combined with antithrombotic therapy, as an antiarrhythmic therapy for the treatment of paroxysmal AF (PAF) associated with hypertension. To test the usefulness of this therapy, this study will reveal the recurrence rate of asymptomatic as well as symptomatic PAF during 1-year of treatment with candesartan or amlodipine, using daily transtelephonic monitoring. CONCLUSIONS: The J-RHYTHM II study will follow 400 patients with PAF and hypertension who were treated at approximately 50 sites throughout Japan, and will provide clinically important information.

Investigation of the optimal treatment strategy for atrial fibrillation in Japan.

The Japanese Rhythm Management Trial for Atrial Fibrillation (J-RHYTHM study) is a randomized comparative evaluation of rate control and rhythm control, both combined with antithrombotic therapy, as therapeutic strategies for the treatment of atrial fibrillation (AF). This study differs from the earlier AFFIRM and RACE studies in that it has a composite primary end-point representing mortality and also physical/psychological disablement (total mortality, symptomatic cerebral infarction, systemic embolism, major bleeding, hospitalization for heart failure requiring intravenous administration of diuretics, and patient disablement). Patients' will to change the therapeutic strategy to the other is also considered as an end-point representing disablement under the assigned strategy. The secondary end-point includes quality of life scores and the efficacy and safety of drugs used in treating AF. The J-RHYTHM study emphasizes patient-reported experience and perception of AF-specific disablement, and the safety of antiarrhythmics available in Japan; it will follow 2600 patients treated at more than 150 sites in Japan for a 3-year period.