Primary results from the Japanese Heart Failure and Sudden Cardiac Death Prevention Trial (HINODE).

AIMS: The HINODE study aimed to analyse rates of mortality, appropriately treated ventricular arrhythmias (VA), and heart failure in Japanese patients and compared with those in Western patients. METHODS AND RESULTS: After treatment decisions following contemporary practice in Japan, patients were prospectively enrolled into four cohorts: (i) internal cardioverter-defibrillator (ICD), (ii) cardiac resynchronization therapy (CRT) defibrillator (CRT-D), (iii) standard medical therapy ('non-device': ND), or (iv) pacing (indicated for CRT; received pacemaker or CRT pacing). Cohorts 1-3 required a left ventricular ejection fraction ≤35%, a history of heart failure, and a need for primary prevention of sudden cardiac death based on two to five previously identified risk factors. Endpoint outcomes were adjudicated by the independent committees. ICD and CRT-D cohorts, considered as high-voltage (HV) cohorts, were pooled for Kaplan-Meier analysis and propensity-matched to Multicenter Automatic Defibrillator Implantation Trial-Reduce Inappropriate Therapy (MADIT-RIT) arm B and C patients. The study enrolled 354 patients followed for 19.6 ± 6.5 months, with a minimum of 12 months. Propensity-matched HV cohorts showed comparable VA (P = 0.61) and mortality rates (P = 0.29) for HINODE and MADIT-RIT. The ND cohort presented a high crossover rate to ICD therapy (6.1%, n = 7/115), and the CRT-D cohort showed elevated mortality rates. The pacing cohort revealed that patients implanted with pacemakers had higher mortality (26.0%) than those with CRT-Pacing (8.4%, P = 0.05). CONCLUSIONS: The mortality and VA event rates of landmark trials are applicable to patients with primary prevention in Japan. Patients who did not receive guideline-indicated CRT devices had poor outcomes.

Familial antithrombin III deficiency in a Malay patient with massive thrombosis

Patients with low antithrombin III (AT III) has increased risk for arteriovenous thromboembolic (TE) disease. We report a 28-year-old Malay lady who presented with spontaneous right calf pain and swelling of one week duration. She was on oral contraceptive pills and had a history of travelling for a long distance prior to the presentation. Her brother who was diagnosed with AT III deficiency had arterial thrombosis at a young age. She was diagnosed as having right popliteal vein thrombosis by ultrasound and treated with subcutaneous fondaparinux. While on treatment, she developed massive bilateral pulmonary embolism (PE). Thrombophilia study showed reduced AT III activity (38μl/dl) and normal results for protein C, protein S, activated protein C resistance and lupus anticoagulant assays. This patient has heterozygous AT III deficiency added with significant acquired factors responsible for the TE events. Those with AT III deficiency may have resistance to heparin therapy and require higher doses of heparin.

Deterioration of left ventricular systolic function in extended Pacing to Avoid Cardiac Enlargement (PACE) trial: the predictive value of early systolic dyssynchrony.

AIMS: Biventricular (BiV) pacing was superior to right ventricular apical (RVA) pacing at extended follow-up in the Pacing to Avoid Cardiac Enlargement (PACE) trial. Early pacing-induced systolic dyssynchrony (DYS) might be related to mid-term result. However, it remains unknown whether early pacing-induced DYS can predict long-term reduction of left ventricular (LV) systolic function. METHODS AND RESULTS: Patients with standard pacing indications and normal LV ejection fraction (LVEF) were randomized either to BiV (n = 89) or RVA (n = 88) pacing. Seventy-four patients in the RVA group and 72 in the BiV pacing group completed follow-up longer than 2 years. Serial echocardiography was performed with DYS assessed by tissue Doppler imaging, and the early pacing-induced DYS was defined as >33 ms by using standard deviation of the time to peak systolic velocity (Dyssynchrony Index) in a 12-segment model of LV at 1 month. There were 46 (32%) patients having early pacing-induced DYS that was more prevalent in the RVA pacing group than that in the BiV pacing group (50.7 vs. 12.3%, χ(2) = 25.1, P < 0.001) despite the similar DYS between the two groups at baseline (30 ± 13 vs. 26 ± 11 ms, P = 0.051). At a median follow-up of 4.8 years, patients developing early DYS had lower LVEF (53.2 ± 9.4 vs. 60.9 ± 8.0%, P < 0.001) and larger LV end-systolic volume (40.3 ± 23.7 vs. 29.3 ± 13.4 mL, P < 0.001) than those without DYS. Significant EF reduction (defined as ≥5%) occurred in 71.7% (33 in 46) of patients with DYS, but only in 30% (30 in 100) in those without DYS (χ(2) = 22.4, P < 0.001). Further analysis showed that both DYS at 1 month [odds ratio (OR): 3.113, P = 0.013] and RVA pacing (OR: 7.873, P < 0.001) independently predicted the deterioration of LV systolic function with pacing period of 4.8 years. CONCLUSION: Early pacing-induced DYS is a significant predictor of reduction of LV systolic function for long-term pacing, which could be prevented by BiV pacing at relatively long-period follow-up. CLINICAL TRIAL REGISTRATION: Centre for Clinical Trials number, CUHK_CCT00037 (URL: http://www.cct.cuhk.edu.hk/Registry/publictrialrecord.aspx?trialid=CUHK_CCT00037).

Long-term follow-up results of the pacing to avoid cardiac enlargement (PACE) trial.

AIMS: We report the results of long-term follow-up of the Pacing to Avoid Cardiac Enlargement (PACE) trial, a prospective, double-blinded, randomized, multicentre study that confirmed the superiority of biventricular (BiV) pacing compared with right ventricular apical (RVA) pacing in prevention of LV adverse remodelling and deterioration of systolic function at 1 and 2 years. METHODS AND RESULTS: Patients with bradycardia and preserved LVEF were randomized to receive RVA (n = 88) or BiV pacing (n = 89). Co-primary endpoints were LV end-systolic volume (LVESV) and LVEF measured by echocardiography. There were 149 patients who had extended follow-up, with a mean duration of 4.8 ± 1.5 years (2.5-7.8 years). The primary endpoint analyses were performed in 146 patients (74 in the RVA group and 72 in the BiV group). In the RVA pacing group, the LVEF decreased while the LVESV increased progressively at follow-up, but remained unchanged in the BiV pacing group. The differences in LVEF between the RVA and BiV groups were -6.3, -9.2, and -10.7% at 1-year, 2-year, and long-term follow-up, respectively (all P < 0.001). The corresponding differences in LVESV were +7.4, +9.9, and +13.1 mL, respectively (all P < 0.001). The deleterious effects of RVA pacing consistently occurred in all the pre-defined subgroups. Furthermore, patients with RVA pacing had a significantly higher prevalence of heart failure hospitalization than the BiV group (23.9% vs. 14.6%, log-rank χ² = 7.55, P = 0.006). CONCLUSION: Left ventricular adverse remodelling and deterioration of systolic function continued at long-term follow-up in patients with RVA pacing; this deterioration was prevented by the use of BiV pacing. Also, heart failure hospitalization was more prevalent in the RVA pacing group.

Early pacing-induced systolic dyssynchrony is a strong predictor of left ventricular adverse remodeling: analysis from the Pacing to Avoid Cardiac Enlargement (PACE) trial.

BACKGROUND: Right ventricular apical (RVA) pacing is associated with adverse left ventricular (LV) remodeling and biventricular (BiV) pacing may prevent it although the mechanisms remain unclear. The current study aimed to assess the role of early pacing-induced systolic dyssynchrony (DYS) to predict adverse LV remodeling. METHODS: Patients with standard pacing indications and normal LV ejection fraction were randomized either to BiV (n=89) or RVA pacing (n=88). Pacing-induced DYS, defined as the standard deviation of the time to peak systolic velocity (Dyssynchrony Index) >33 ms in a 12-segmental model of LV, was measured by tissue Doppler echocardiography at 1 month. RESULTS: At 1 month, 59 patients (33%) had DYS which was more prevalent in RVA than BiV pacing group (52% vs. 15%, χ(2)=28.3, p<0.001), though Dyssynchrony Index was similar at baseline (30 ± 14 vs. 26 ± 11 ms, p=0.06). At 12 months, those developing DYS had significantly lower LV ejection fraction (55.1 ± 9.7 vs. 62.2 ± 7.9%, p<0.001) and larger LV end-systolic volume (35.3 ± 14.3 vs. 27.0 ± 10.4 ml, p<0.001) when compared to those without DYS. Reduction of ejection fraction ≥ 5% occurred in 67% (39 out of 58) of patients with DYS, but only in 18% (21 out of 115) in those without DYS (χ(2)=40.8, p<0.001). Both DYS at 1 month (odds ratio [OR]: 4.725, p=0.001) and RVA pacing (OR: 3.427, p=0.009) were independent predictors for reduction of ejection fraction at 12 months. CONCLUSION: Early pacing-induced DYS is a significant predictor of LV adverse remodeling and the observed benefit of BiV pacing may be related to the prevention of DYS. CLINICAL TRIAL REGISTRATION: Centre for Clinical Trials number, CUHK_CCT00037 (URL: http://www.cct.cuhk.edu.hk/Registry/publictrialrecord.aspx?trialid=CUHK_CCT00037).

Biventricular pacing is superior to right ventricular pacing in bradycardia patients with preserved systolic function: 2-year results of the PACE trial.

AIMS: The Pacing to Avoid Cardiac Enlargement (PACE) trial is a prospective, double-blinded, randomized, multicentre study that reported the superiority of biventricular (BiV) pacing to right ventricular apical (RVA) pacing in the prevention of left ventricular (LV) adverse remodelling and deterioration of systolic function at 1 year. In the current analysis, we report the results at extended 2-year follow-up for changes in LV function and remodelling. METHODS AND RESULTS: Patients (n = 177) with bradycardia and preserved LV ejection fraction (EF ≥45%) were randomized to receive RVA or BiV pacing. The co-primary endpoints were LVEF and LV end-systolic volume (LVESV). Eighty-one (92%) of 88 in the RVA pacing group and 82 (92%) of 89 patients in the BiV pacing group completed 2-year follow-up with a valid echocardiography. In the RVA pacing group, LVEF further decreased from the first to the second year, but it remained unchanged in the BiV pacing group, leading to a significant difference of 9.9 percentage points between groups at 2-year follow-up (P < 0.001). Similarly, LVESV continues to enlarge from the first to the second year in the RVA pacing group, leading to a difference of 13.0 mL (P < 0.001) between groups. Predefined subgroup analysis showed consistent results with the whole study population for both co-primary endpoints, which included patients with pre-existing LV diastolic dysfunction. Eighteen patients in the BiV pacing group (20.2%) and 55 in the RVA pacing group (62.5%) had a significant reduction of LVEF (of ≥5%, P < 0.001). CONCLUSION: Left ventricular adverse remodelling and deterioration of systolic function continues at the second year after RVA pacing. This deterioration is prevented by BiV pacing.