QRS Fragmentation and the Risk of Sudden Cardiac Death in MADIT II

QRS Fragmentation and the Risk of Sudden Cardiac Death in MADIT II. Background: QRS fragmentation (fQRS) has been reported as a useful ECG parameter in predicting mortality in high‐risk postinfarction patients. Its prognostic value for sudden cardiac death (SCD) and ventricular arrhythmias in ischemic cardiomyopathy (ICM) remains unknown. Methods: MADIT II enrollment 12‐lead ECGs were analyzed for fQRS defined as RSR’ patterns (≥1 R’ or notching of S or R wave) in patients with a normal QRS duration and >2 notches on the R or S wave in patients with abnormal QRS duration, present in 2 contiguous leads. Exclusion criteria included a paced rhythm and an uninterpretable or incomplete ECG. Study endpoints included SCD, SCD or appropriate implantable cardioverter defibrillator (ICD) shock, and total mortality (TM). Results: Of the 1,232 ECGs reviewed, 1,040 were of suitable quality for fQRS analysis. QRS fragmentation was found in 33% of patients in any leads, in 10% of patients in anterior leads, in 8% of patients in lateral leads and in 21% of patients in inferior leads. Anterior and lateral location of QRS fragmentation was not associated with follow‐up events. Inferior location of fQRS was found to be predictive of SCD/ICD shock (hazard ratio [HR] 1.46, P = 0.032), SCD (HR 2.05, P = 0.007), and TM (HR 1.44, P = 0.036). This association was driven primarily by the increase in events found in LBBB patients: SCD/ICD shock (HR 2.05, P = 0.046), SCD (HR 4.24, P = 0.002), and TM (HR 2.82, P = 0.001). Conclusions: Fragmented QRS, especially identified in inferior leads, is predictive of SCD, SCD or appropriate ICD shock, and all‐cause mortality in patients with ICM. Identifying inferior fQRS in patients with LBBB is of particular prognostic significance and should reinforce the use of ICD therapy in this high‐risk group. (J Cardiovasc Electrophysiol, Vol. 23, pp. 1343‐1348, December 2012)     

Are MADIT II Criteria for Implantable Cardioverter Defibrillator Implantation Appropriate for Chinese Patients?

MADIT II Criteria for Implantable Cardioverter. Background: MADIT‐II demonstrated that prophylactic implantation of an implantable cardioverter‐defibrillator (ICD) device prevents sudden cardiac death (SCD) in patients with myocardial infarction (MI) and impaired left ventricular ejection fraction (LVEF). It remains unclear whether the MADIT‐II criteria for ICD implantation are appropriate for Chinese patients. Methods and Results: We compared the clinical characteristics and outcome for a cohort of consecutive Chinese patients who satisfied MADIT‐II criteria for ICD implantation with the original published MADIT‐II population. Seventy consecutive patients who satisfied MADIT‐II criteria but did not undergo ICD implantation (age: 67 years, male: 77%) were studied. Their baseline demographics were comparable with the original MADIT‐II cohort with the exception of a higher incidence of diabetes mellitus. After follow‐up of 35 months, most deaths (78%) were due to cardiac causes (72% due to SCD). The 2‐year SCD rate (10.0%) was comparable with that of the MADIT‐II conventional group (12.1%), but higher than the MADIT‐II defibrillator group (4.9%). Similarly, the 2‐year non‐SCD rate was 3.0%, also comparable with the MADIT‐II conventional group (4.6%), but lower than the MADIT‐II defibrillator group (7.0%). Cox regression analysis revealed that advance NYHA function class (Hazard Ratio [HR]: 3.5, 95% Confidence Interval [CI]: 1.48–8.24, P = 0.004) and the lack of statin therapy (HR: 3.7, 95%CI: 1.35–10.17, P = 0.011) were independent predictors for mortality in the MADIT‐II eligible patients. Conclusion: Chinese patients who satisfy MADIT‐II criteria for ICD implantation are at similar risk of SCD and non‐SCD as the original MADIT‐II subjects. Implantation of an ICD in Chinese patients is appropriate. (J Cardiovasc Electrophysiol, Vol. 21, pp. 231–235, March 2010)     

Risk Stratification Using Heart Rate Turbulence and Ventricular Arrhythmia in MADIT II: Usefulness and Limitations of a 10‐Minute Holter Recording

Background: We evaluated the usefulness of heart rate turbulence (HRT) parameters and frequency of ventricular premature beats (VPBs) for risk‐stratifying postinfarction patients with depressed left ventricular function enrolled in Multicenter Automatic Defibrillator Trial II (MADIT II). Methods: In 884 MADIT II patients, 10‐minute Holter monitoring at enrollment was used to evaluate HRT parameters and frequency of VPBs. The primary endpoints were defined as all‐cause mortality in patients randomized to conventional treatment and as appropriate therapy for ventricular tachycardia or fibrillation in patients randomized to implantable cardioverter defibrillator (ICD) therapy. Results: The median turbulence slope was lower in patients who died in comparison to survivors in the conventional arm (2.3 vs 4.5 ms/RR; P < 0.05); but it was not a significant predictor of mortality after adjustment for clinical covariates (age, ejection fraction, beta‐blocker use, and BUN levels). There was no association between HRT parameters and arrhythmic events in ICD patients. Conventionally treated patients who died and ICD patients who had appropriate ICD therapy had significantly more frequent VPBs than those without such adverse events. After adjustment for clinical covariates, frequent VPBs>3/10 min were associated with death in the conventional arm (HR = 1.63; P = 0.070) and were predictive for appropriate ICD therapy in the ICD arm (HR = 1.75; P = 0.003). Conclusion: In postinfarction patients with severe left ventricular dysfunction, frequent VPBs are associated with increased risk of mortality and with appropriate ICD therapy. HRT obtained from 10‐min Holter ECG showed a trend toward the association with mortality in univariate analysis but HRT parameters were not predictive of the outcome in multivariate analyses.     

Efficacy of Medical Therapy for the Reduction of Heart Failure Events in Patients with Implanted Cardioverter Defibrillators

Background : Prophylactic therapy with the implantable cardioverter defibrillator (ICD) reduces the mortality among patients with left ventricular dysfunction; however, life-prolonging device therapy has been shown to be associated with an increased risk for subsequent heart failure (HF) events. There are limited data on the effect of the primary types of HF medications, angiotensin converting enzyme inhibitors (ACE-I), and beta-blockers on HF progression in ICD-treated patients.
Methods : Multivariate Cox proportional hazards regression analysis was used to assess the effect of time-dependent medical therapy with ACE-I and beta-blockers on the development of HF in patients with an ICD in the Multicenter Automatic Defibrillator Trail (MADIT) II.
Results: In multivariate analysis, ICD therapy was associated with a significant 39% increase in the risk of HF as compared with conventional medical therapy. ACE-I and beta-blockers exhibited a graded efficacy for the reduction in the risk of HF events in ICD-treated patients: the greatest risk reduction of HF was seen in patients taking combination therapy (HR = 0.36, P < 0.001), followed by patients using beta-blockers only (HR = 0.51, P = 0.017) and ACE-I only (HR = 0.64, P = 0.071). Beta-blocker subtypes (metoprolol [HR = 0.49, P = 0.001] and carvedilol [HR = 0.58, P = 0.004]) exhibited similar efficacy. Consistent results were demonstrated when the combined endpoint of HF or death was assessed.
Conclusions : ICD-treated patients experience an increased risk for HF events that can be significantly attenuated by medical therapy with beta-blockers and ACE-inhibitors.     

Improved outcome with preventive cardiac resynchronization therapy in the elderly: a MADIT-CRT substudy

Preventive Cardiac Resynchronization in the Elderly. Background: Elderly patients comprise a large portion of patients with heart failure (HF). Limited data exist on the effectiveness of cardiac resynchronization therapy with defibrillator (CRT‐D) in patients with mild HF symptoms in this population. Methods and Results: The benefit of CRT‐D compared with ICD‐only therapy in reducing HF or death was assessed by age categories (prespecified as <60 [n = 548], 60–74 [n = 941], and ≥75 [n = 331] years) among 1,820 patients in MADIT‐CRT. In patients with ICD‐only, there was a graded age‐related increase in the Kaplan–Meier cumulative probability of HF or death at 3‐year follow‐up (19%, 33%, and 36%, in patients aged <60, 60–74, and ≥75 years, respectively, P = 0.003). Multivariate analysis demonstrated that CRT‐D therapy was associated with a significant reduction in the risks of HF or death in patients aged 60–74, and ≥75 years (HR = 0.57, P = <0.001 and HR = 0.59, P = 0.017, respectively), and no significant benefit in patients aged <60 years (HR = 0.81, P = 0.3; P‐value for all treatment‐by‐age interactions >0.10). There was no significant difference in the rate of device‐related adverse events within 90 days following CRT‐D implantation among age‐subgroups (16.7%, 15.7%, and 11.7%, in patients <60, 60–74, and ≥75 years, respectively, P = 0.42) . Conclusion: CRT‐D was associated with a significant clinical benefit in older patients (≥60 years) during an average 2.4‐year follow‐up. These effects were preserved for the elderly patients ≥75 years of age but attenuated in patients <60 years. Elderly patients had no increase in device‐related adverse events compared with younger patients . (J Cardiovasc Electrophysiol, Vol. 22, pp. 892‐897, August 2011)     

Implantable cardioverter‐defibrillators in heart failure patients with reduced ejection fraction and diabetes

Aim

There is limited information on the outcomes after primary prevention implantable cardioverter‐defibrillator (ICD) implantation in patients with heart failure (HF) and diabetes. This analysis evaluates the effectiveness of a strategy of ICD plus medical therapy vs. medical therapy alone among patients with HF and diabetes.

Methods and results

A patient‐level combined‐analysis was conducted from a combined dataset that included four primary prevention ICD trials of patients with HF or severely reduced ejection fractions: Multicenter Automatic Defibrillator Implantation Trial I (MADIT I), MADIT II, Defibrillators in Non‐Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE), and Sudden Cardiac Death in Heart Failure Trial (SCD‐HeFT). In total, 3359 patients were included in the analysis. The primary outcome of interest was all‐cause death. Compared with patients without diabetes (n = 2363), patients with diabetes (n = 996) were older and had a higher burden of cardiovascular risk factors. During a median follow‐up of 2.6 years, 437 patients without diabetes died (178 with ICD vs. 259 without) and 280 patients with diabetes died (128 with ICD vs. 152 without). ICDs were associated with a reduced risk of all‐cause mortality among patients without diabetes [hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.46–0.67] but not among patients with diabetes (HR 0.88, 95% CI 0.7–1.12; interaction P = 0.015).

Conclusion

Among patients with HF and diabetes, primary prevention ICD in combination with medical therapy vs. medical therapy alone was not significantly associated with a reduced risk of all‐cause death. Further studies are needed to evaluate the effectiveness of ICDs among patients with diabetes.

     

Effectiveness of Cardiac Resynchronization Therapy in Diabetic Patients with Ischemic and Nonischemic Cardiomyopathy

Background: Diabetes mellitus (DM) increases the risk for the development of both ischemic and nonischemic cardiomyopathy. We aimed to identify differences in response to cardiac resynchronization therapy with a defibrillator (CRT‐D) among DM patients with ischemic or nonischemic cardiomyopathy. Methods: Cox proportional hazards regression modeling was used to assess clinical response to CRT‐D (defined as CRT‐D vs. defibrillator‐only reduction in the risk of heart failure [HF] or death) and echocardiographic response (defined as percent reduction in left ventricular end diastolic and systolic volume [LVEDV and LVESV, respectively] at 12 month of follow‐up compared with baseline values) among 552 diabetic patients with ischemic (n = 367) or nonischemic (n = 185) cardiomyopathy enrolled in MADIT‐CRT. Results: The clinical benefit of CRT‐D was more pronounced among nonischemic patients (HR = 0.30 [P < 0.001] than among ischemic patients (HR = 0.59 [P = 0.004]; P for interaction = 0.10). Nonischemic patients also experienced significantly greater reductions in LVESV and LVEDV at 12 months with CRT‐D compared with ischemic patients (P < 0.001 for both). Subgroup analysis showed that the most pronounced reduction in HF or death with CRT‐D therapy occurred in nonischemic patients who were women (83% risk‐reduction [P < 0.001]), had a lower BMI (<30/kg/m²: 79% risk‐reduction [P < 0.001]), or had left bundle branch block at enrollment (82% risk‐reduction [P < 0.001]). Conclusions: The present study shows that treatment with CRT‐D in at‐risk cardiac patients with DM is associated with substantial reductions in the risk of HF or death and improvement in cardiac remodeling in those with ischemic and nonischemic cardiomyopathy, with a more pronounced benefit in patients with nonischemic disease. Ann Noninvasive Electrocardiol 2012;17(1):14–21     

QRS Axis and the Benefit of Cardiac Resynchronization Therapy in Patients with Mildly Symptomatic Heart Failure Enrolled in MADIT‐CRT

Cardiac Resynchronization Therapy and QRS Axis . Background: Mildly symptomatic heart failure (HF) patients derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT‐D) as shown in MADIT‐CRT. The presence of QRS axis deviation may influence response to CRT‐D. The objective of this study was to determine whether QRS axis deviation will be associated with differential benefit from CRT‐D. Methods : Baseline electrocardiograms of 1,820 patients from MADIT‐CRT were evaluated for left axis deviation (LAD: quantitative QRS axis ‐30 to ‐90) or right axis deviation (RAD: QRS axis 90–180) in left bundle branch block (LBBB), right bundle branch block (RBBB), and nonspecific interventricular conduction delay QRS morphologies. The primary endpoints were the first occurrence of a HF event or death and the separate occurrence of all‐cause mortality as in MADIT‐CRT. Results: Among LBBB patients, those with LAD had a higher risk of primary events at 2 years than non‐LAD patients (20% vs 16%; P = 0.024). The same was observed among RBBB patients (20% vs 10%; P = 0.05) but not in IVCD patients (22% vs 23%; P = NS). RAD did not convey any increased risk of the primary combined endpoint in any QRS morphology subgroup. When analyzing the benefit of CRT‐D in the non‐LBBB subgroups, there was no significant difference in hazard ratios for CRT‐D versus ICD for either LAD or RAD. However, LBBB patients without LAD showed a trend toward greater benefit from CRT therapy than LBBB patients with LAD (HR for no LAD: 0.37, 95% CI: 0.26–0.53 and with LAD: 0.54, 95% CI: 0.36–0.79; P value for interaction = 0.18). Conclusions: LAD in non‐LBBB patients (RBBB or IVCD) is not associated with an increased benefit from CRT. In LBBB patients, those without LAD seem to benefit more from CRT‐D than those with LAD. (J Cardiovasc Electrophysiol, Vol. 24, pp. 442‐448, April 2013)     

Effect of elapsed time from coronary revascularization to implantation of a cardioverter defibrillator on long-term survival in the MADIT-II trial

Coronary Revascularization and Long‐Term Mortality in MADIT‐II. Introduction: Coronary revascularization (CR) may reduce arrhythmia risk and improve long‐term outcome in patients with left ventricular dysfunction. This study was designed to evaluate the effect of elapsed time from CR on long‐term mortality and arrhythmic risk among patients who receive an implantable cardioverter defibrillator (ICD). Methods and Results: We evaluated the risk of 8‐year mortality by elapsed time from CR to ICD implantation (categorized as: no CR; recent CR [<2 years]; or nonrecent CR [≥2 years], and assessed as a continuous measure) among 720 ICD recipients enrolled in the Multicenter Automatic Defibrillator Trial‐II. At 8years of follow‐up, patients who did not undergo CR and those who underwent nonrecent CR had significantly higher mortality rates than patients who underwent recent CR (54%, 54%, and 36%, respectively; P < 0.001). Multivariate analysis demonstrated that no‐ and nonrecent CR were associated with respective 48% (P = 0.022) and 67% (P < 0.001) increases in mortality risk compared with recent CR. Assessment of time from CR as a continuous measure showed that every year elapsed from CR was associated with an adjusted 6% increase in 8‐year mortality (P < 0.001), and in respective 6% (P < 0.001) and 6% (P = 0.003) increased risk for in‐trial appropriate ICD therapy of ventricular tachyarrhythmias and appropriate ICD shocks. Conclusions: We observed a direct relationship between elapsed time from CR and long‐term mortality following ICD implantation. The favorable long‐term effect on outcome of recent CR may be related to a time‐dependent effect of CR on ventricular arrhythmic burden and the need for appropriate ICD shocks. (J Cardiovasc Electrophysiol, Vol. pp. 1‐6)     

Beta‐Blocker Efficacy in High‐Risk Patients with the Congenital Long‐QT Syndrome Types 1 and 2: Implications for Patient Management

β‐Blockers for LQTS Types 1 and 2. Background: Beta‐blockers are the mainstay therapy in patients with the congenital long‐QT syndrome (LQTS) types 1 and 2. However, limited data exist regarding the efficacy and limitations of this form of medical management within high‐risk subsets of these populations. Methods and Results: Multivariate analysis was carried out to identify age‐related gender‐ and genotype‐specific risk factors for cardiac events (comprising syncope, aborted cardiac arrest [ACA] or sudden cardiac death [SCD]) from birth through age 40 years among 971 LQT1 (n = 549) and LQT2 (n = 422) patients from the International LQTS Registry. Risk factors for cardiac events included the LQT1 genotype (HR = 1.49, P = 0.003) and male gender (HR = 1.31, P = 0.04) in the 0–14 years age group; and the LQT2 genotype (HR = 1.67, P < 0.001) and female gender (HR = 2.58, P < 0.001) in the 15–40 years age group. Gender–genotype subset analysis showed enhanced risk among LQT1 males (HR = 1.93, P < 0.001) and LQT2 females (HR = 3.28, P < 0.001) in the 2 respective age groups. Beta‐blocker therapy was associated with a significant risk‐reduction in high‐risk patients, including a 67% reduction (P = 0.02) in LQT1 males and a 71% reduction (P < 0.001) in LQT2 females. Life‐threatening events (ACA/SCD) rarely occurred as a presenting symptom among beta‐blocker‐treated patients. However, high‐risk patients who experienced syncope during beta‐blocker therapy had a relatively high rate of subsequent ACA/SCD (>1 event per 100 patient‐years). Conclusions: The present findings suggest that beta‐blocker therapy should be routinely administered to all high‐risk LQT1 and LQT2 patients without contraindications as a first line measure, whereas primary defibrillator therapy should be recommended for those who experience syncope during medical therapy. (J Cardiovasc Electrophysiol, Vol. 21, pp. 893‐901, August 2010)     

Clinical course and implantable cardioverter defibrillator therapy in postinfarction women with severe left ventricular dysfunction

BACKGROUND: There are limited data regarding implantable cardioverter defibrillator (ICD) therapy in postinfarction women with severe left ventricular dysfunction. The aim of this study was to evaluate the risk of cardiac events and effects of ICD therapy in women as compared to men enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II). METHODS AND RESULTS: Among 1,232 patients enrolled in MADIT II, there were 192 (16%) women and 1,040 (84%) men. When compared to men, women had an increased frequency of NYHA class > or =II (70 vs 63%; P = 0.067), hypertension (60% vs 52%; P = 0.047), diabetes (42% vs 34%; P = 0.027), and LBBB (25% vs 17%; P = 0.011), and less frequent CABG surgery (42% vs 60%; P < 0.001). The 2-year cumulative mortality in patients randomized to conventional therapy was not significantly different in women and men (30% and 20%, respectively; P = 0.19). Adjusting for relevant clinical covariates, the hazard ratios for ICD effectiveness were similar in women (0.57; 95% CI = 0.28-1.18; P = 0.132) and men (0.66; 95% CI = 0.48-0.91; P = 0.011). The risk of appropriate ICD therapy for VT/VF was lower in women than in men (hazard ratio = 0.60 for female vs male gender; 95% CI = 0.37-0.98; P = 0.039). CONCLUSIONS: MADIT II women had similar mortality and similar ICD effectiveness when compared to men. MADIT II women with ICDs had a lower risk of arrhythmic events with fewer episodes of ventricular tachycardia than men.     

The Influence of Renal Function on Clinical Outcome and Response to β-Blockade in Systolic Heart Failure: Insights From Metoprolol CR/XL Randomized Intervention Trial in Chronic HF (MERIT-HF)

BackgroundLimited information is available on the risk and impact of renal dysfunction on the response to β-blockade and mode of death in systolic heart failure (HF).Methods and ResultsRenal function was estimated with glomerular filtration rate (eGFR) using the simplified Modification of Diet in Renal Disease (MDRD) equation. Patients from the Metoprolol CR/XL Controlled Randomized Intervention Trial in Chronic HF (MERIT-HF) were divided into 3 renal function subgroups (MDRD formula): eGFR_MDRD > 60 (n = 2496), eGFR_MDRD 45 to 60 (n = 976), and eGFR_MDRD < 45 mL/min per 1.73m² body surface area (n = 493). Hazard ratio (HR) was estimated with Cox proportional hazards models adjusted for prespecified risk factors. Placebo patients with eGFR < 45 had significantly higher risk than those with eGFR > 60: HR for all-cause mortality, 1.90 (95% confidence interval [CI], 1.28 to 2.81) comparing placebo patients with eGFR < 45 and eGFR > 60, and for the combined end point of all-cause mortality/hospitalization for worsening HF (time to first event): HR, 1.91 (95% CI, 1.44 to 2.53). No significant increase in risk with deceased renal function was observed for those randomized to metoprolol controlled release (CR)/extended release (XL) due to a highly significant decrease in risk on metoprolol CR/XL in those with eGFR < 45. For total mortality, metoprolol CR/XL vs placebo: HR, 0.41 (95% CI. 0.25 to 0.68; P < .001) in those with eGFR < 45 compared with HR, 0.71 (95% CI, 0.54 to 0.95; P < .021) for those with eGFR > 60; corresponding data for the combined end point was HR, 0.44 (95% CI, 0.31 to 0.63; P < .0001) and HR, 0.75 (0.62 to 0.92; P = .005, respectively; P = .095 for interaction by treatment for total mortality; P = .011 for combined end point). Metoprolol CR/XL was well tolerated in all 3 renal function subgroups.ConclusionsRenal function as estimated by eGFR was a powerful predictor of death and hospitalizations from worsening HF. Metoprolol CR/XL was at least as effective in reducing death and hospitalizations for worsening HF in patients with eGFR < 45 as in those with eGFR > 60.     

Optimal Timing of Implantable Cardioverter‐Defibrillator Implantation After Myocardial Infarction: A Decision Analysis

ICD Implant Timing . Background: The optimal timing of implantable cardioverter defibrillator (ICD) placement for the primary prevention of sudden cardiac death after myocardial infarction (MI) remains unknown. Methods and Results: We developed a Markov model to investigate the optimal timing of ICD implantation after MI (no ICD, ICD at 60 days, 6 months, and 1 year) in patients who meet current guidelines. Estimates of arrhythmic death (baseline risk 6%, range 1–20% per year), nonarrhythmic death, and ICD efficacy were based upon MADIT‐II and other contemporary post‐MI clinical trials. We used both deterministic and stochastic modeling processes in our analysis. After 10 years follow‐up, the baseline probability of survival was higher in those treated with ICD implantation versus not (42% vs 30%, P < 0.001). Survival was highest with ICD implantation at 60 days versus 6 months versus 1 year: 42.4%, 42.3%, and 42.0% (P = 0.0028). ICD implantation at 60 days provided a mean incremental survival of 0.28 months and 0.84 months per patient (compared with implantation at 6 months and 1 year). In sensitivity analyses, patients’ competing risk for nonarrhythmic death was the primary determinant of benefit from ICD implantation. Overall, ICD implantation at 60 days resulted in the greatest life expectancy over a wide range of plausible nonarrhythmic and arrhythmic death rates. Conclusions: The benefits of early ICD implantation are modest when compared with delayed implantation at 6 months/1 year. Our results suggest that making sure a patient receives an ICD, when appropriate, may be more important than the timing of the implantation procedure. (J Cardiovasc Electrophysiol, Vol. pp. 791‐798, July 2010)     

Implantable cardioverter-defibrillator therapy and risk of congestive heart failure or death in MADIT II patients with atrial fibrillation

BACKGROUND: Atrial fibrillation (AF) contributes to increased risk of morbidity and mortality. Data regarding the effectiveness of implantable cardioverter-defibrillator (ICD) therapy in AF patients are limited. OBJECTIVES: The purpose of this study was to evaluate the effectiveness of ICD therapy in patients with AF enrolled in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) and to identify their risk for the combined endpoint of hospitalization for congestive heart failure or death. METHODS: The MADIT II cohort served as the source for data on the clinical course, cardiac events, and effectiveness of ICD therapy in AF patients. RESULTS: AF was found as baseline rhythm at enrollment in 102 (8%) MADIT II patients. In comparison to 1,007 patients in sinus rhythm, AF patients were older, more frequently were males, had wider QRS complex, and had higher blood urea nitrogen and creatinine levels (P <.05 for all parameters). ICD therapy was effective in reducing 2-year mortality in AF patients from 39% in 41 conventionally treated patients to 22% in 61 ICD-treated patients (hazard ratio = 0.51, P = .079). However, the combined endpoint of hospitalization for heart failure or death at 2 years was 69% and 59%, respectively (NS). AF was predictive for the combined endpoint of heart failure hospitalization or death (hazard ratio = 1.68, P = .040). New-onset AF in patients with baseline sinus rhythm was associated with increased risk of mortality (hazard ratio = 2.70, P <.001). CONCLUSION: MADIT II patients with AF benefit from ICD therapy, which reduces their mortality. MADIT II patients with AF are at high risk for developing heart failure.     

Heart Failure in Post-MI Patients With Persistent IRA Occlusion: Prevalence,Risk Factors,and the Long-Term Effect of PCI in the Occluded Artery Trial (OAT)

BackgroundThe incidence and predictors of heart failure (HF) after myocardial infarction (MI) with modern post-MI treatment have not been well characterized.Methods and ResultsA total of 2,201 stable patients with persistent infarct-related artery occlusion >24 hours after MI with left ventricular ejection fraction <50% and/or proximal coronary artery occlusion were randomized to percutaneous intervention plus optimal medical therapy (PCI) or optimal medical therapy (MED) alone. Centrally adjudicated HF hospitalizations for New York Heart Association (NYHA) III/IV HF and mortality were determined in patients with and without baseline HF, defined as a history of HF, Killip Class >I at index MI, rales, S3 gallop, NYHA II at randomization, or NYHA >I before index MI. Long-term follow-up data were used to determine 7-year life-table estimated event rates and hazard ratios. There were 150 adjudicated HF hospitalizations during a mean follow-up of 6 years with no difference between the randomized groups (7.4% PCI vs. 7.5% MED, P = .97). Adjudicated HF hospitalization was associated with subsequent death (44.0% vs. 13.1%, HR 3.31, 99% CI 2.21–4.92, P < .001). Baseline HF (present in 32% of patients) increased the risk of adjudicated HF hospitalization (13.6% vs. 4.7%, HR 3.43, 99% CI 2.23–5.26, P < .001) and death (24.7% vs. 10.8%, HR 2.31, 99% CI 1.71–3.10, P < .001).ConclusionsIn the overall Occluded Artery Trial (OAT) population, adjudicated HF hospitalizations occurred in 7.5% of subjects and were associated with increased risk of subsequent death. Baseline or prior HF was common in the OAT population and was associated with increased risk of hospitalization and death.     

Survival After Implantable Cardioverter-Defibrillator Shocks

BackgroundThere are conflicting data on the impact of implantable cardioverter-defibrillator (ICD) shocks on subsequent mortality.ObjectivesThe aim of this study was to determine whether the arrhythmic substrate leading to ICD therapy or the therapy itself increases mortality.MethodsThe study cohort included 5,516 ICD recipients who were enrolled in 5 landmark ICD trials (MADIT-II, MADIT-RISK, MADIT-CRT, MADIT-RIT, RAID). The authors evaluated the association of device therapy with subsequent mortality in 4 separate time-dependent models: model I, type of ICD therapy; model II, type of arrhythmia for which ICD therapy was delivered; model III, combined assessment of all arrhythmia and therapy types during follow-up; and model IV, incremental risk associated with repeated ICD shocks.ResultsWhen analyzed by the type of ICD therapy (model I), a first appropriate ICD shock was associated with increased risk of subsequent mortality with or without concomitant occurrence of inappropriate shock during follow-up (hazard ratio [HR]: 2.78 and 2.31; p < 0.001 and p = 0.12), whereas inappropriate shock alone was not associated with mortality risk (HR: 1.23; p = 0.42). Similarly, ICD therapy for ventricular tachycardia (VT) ≥200 beats/min or ventricular fibrillation (VF) (model II) was associated with increased risk of death with or without concomitant therapy for VT <200 beats/min (HRs: 2.25 and 2.62; both p < 0.001), whereas appropriate therapy for VT <200 beats/min or inappropriate therapy (regardless of etiology) did not reach statistical significance (all p > 0.10). Combined assessment of all therapy and arrhythmia types during follow-up (model III) showed that appropriate ICD shocks for VF, shocks for fast VT (≥200 beats/min) without prior antitachycardia pacing (ATP), as well as shocks for fast VT delivered after failed ATP, were associated with the highest risk of subsequent death (HR: all >2.8; p < 0.001). Finally, 2 or more ICD appropriate shocks were not associated with incremental risk to the first appropriate ICD shock (model IV).ConclusionThe combined data from 5 landmark ICD trials suggest that the underlying arrhythmic substrate rather than the ICD therapy is the more important determinant of mortality in ICD recipients.     

Functional Response to Cardiac Resynchronization Therapy is Associated with Improved Clinical Outcome and Absence of Appropriate Shocks

Clinical Outcome in Cardiac Resynchronization Therapy (CRT) Functional Responders . Introduction : We evaluated clinical outcome and incidence of (in)appropriate shocks in consecutive chronic heart failure (CHF) patients treated with CRT with a defibrillator (CRT‐D) according to functional response status. Furthermore, we investigated which factors predict such functional response. Methods and Results : In a large teaching hospital, 179 consecutive CHF patients received CRT‐D in 2005–2010. Patients were considered functional responders if left ventricular ejection fraction (LVEF) increased to ≥35% postimplantation. Analysis was performed on 142 patients, who had CRT‐D as primary prevention, complete data and a baseline LVEF <35%. Endpoints consisted of all‐cause mortality, heart failure (HF) hospitalizations, appropriate shocks and inappropriate shocks. Median follow‐up was 3.0 years (interquartile range [IQR] 1.6–4.4) and median baseline LVEF was 20% (IQR 18–25%). The functional response‐group consisted of 42 patients. In this group no patients died, none were hospitalized for HF, none received appropriate shocks and 3 patients (7.1%) received ≥1 inappropriate shocks. In comparison, the functional nonresponse group consisted of 100 patients, of whom 22 (22%) died (P = 0.003), 17 (17%) were hospitalized for HF (P = 0.007), 17 (17%) had ≥1 appropriate shocks (P = 0.003) and 8 (8.1%) received ≥1 inappropriate shocks (P = 0.78). Multivariable analysis showed that left bundle branch block (LBBB), QRS duration ≥150 milliseconds and no need for diuretics at baseline are independent predictors of functional response. Conclusion : Functional responders to CRT have a good prognosis and rarely need ICD therapy. LBBB, QRS duration ≥150 milliseconds and lack of chronic diuretic use predict functional response. (J Cardiovasc Electrophysiol, Vol. 24, pp. 316‐322, March 2013)     

Heart Rate Turbulence for Prediction of Heart Transplantation and Mortality in Chronic Heart Failure

Background: Previous studies have shown conflicting results about the value of heart rate turbulence (HRT) for risk stratification of patients (pts) with chronic heart failure (CHF). We prospectively evaluated the relation between HRT and progression toward end‐stage heart failure or all‐cause mortality in patients with CHF. Methods: HRT was assessed from 24‐hour Holter recordings in 110 pts with CHF (54 in NYHA class II, 56 in class III–IV; left ventricular ejection fraction (LVEF) 30%± 10%) on optimal pharmacotherapy and quantified as turbulence onset (TO,%), turbulence slope (TS, ms/RR interval), and turbulence timing (beginning of RR sequence for calculation of TS, TT). TO ≥ 0%, TS ≤ 2.5 ms/RR, and TT >10 were considered abnormal. End point was development of end‐stage CHF requiring heart transplantation (OHT) or all‐cause mortality. Results: During a follow‐up of 5.8 ± 1.3 years, 24 pts died and 10 required OHT. TO, TS, TT, and both (TO and TS) were abnormal in 35%, 50%, 30%, and 25% of all patients, respectively. Patients with at least one relatively preserved HRT parameter (TO, TS, or TT) (n = 98) had 5‐year event‐free rate of 83% compared to 33% of those in whom all three parameters were abnormal (n = 12). In multivariate Cox regression analysis, the most powerful predictor of end point events was heart rate variability (SDNN < 70 ms, hazard ratio (HR) 9.41, P < 0.001), followed by LVEF ≤ 35% (HR 6.23), TT ≥ 10 (HR 3.14), and TO ≥ 0 (HR 2.54, P < 0.05). Conclusion : In patients with CHF on optimal pharmacotherapy, HRT can help to predict those at risk for progression toward OHT or death of all causes. Ann Noninvasive Electrocardiol 2010;15(3):230–237     

Empagliflozin in heart failure with preserved ejection fraction with and without atrial fibrillation

Aims

Atrial fibrillation/flutter (AF) is common in heart failure (HF) with preserved left ventricular ejection fraction (LVEF) and associated with worse outcomes. Empagliflozin reduces cardiovascular death or HF hospitalizations and slows estimated glomerular filtration rate (eGFR) decline in patients with HF and LVEF >40%. We aimed to assess the efficacy and safety of empagliflozin in improving outcomes in patients with HF and LVEF >40% with and without AF.

Methods and results

In this pre-defined secondary analysis of EMPEROR-Preserved, we compared the effects of empagliflozin versus placebo on the primary and secondary endpoints and safety outcomes, stratified by baseline AF, defined as AF reported in any electrocardiogram before empagliflozin initiation or in medical history. Among 5988 patients randomized, 3135 (52%) had baseline AF; these patients were older, with worse functional class, more previous HF hospitalizations and higher natriuretic peptides compared to those without AF (all p < 0.001). After a median of 26 months, empagliflozin reduced cardiovascular death or HF hospitalization compared to placebo to a similar extent in patients with and without AF (hazard ratio [HR] 0.78 [95% confidence interval 0.66–0.93] vs. 0.78 [0.64–0.95], interaction p = 0.96). Empagliflozin also reduced total HF hospitalizations (HR 0.73 [0.57–0.94] vs. 0.72 [0.54–0.95], interaction p = 0.94) and annual eGFR decline (difference = 1.368 vs. 1.372 ml/min/1.73 m²/year, interaction p = 0.99) consistently in patients with and without AF. There was no increase in serious adverse events with empagliflozin versus placebo in patients with and without AF.

Conclusions

In patients with HF and ejection fraction >40%, empagliflozin reduced the risk of serious HF events and slowed the eGFR decline regardless of baseline AF.     

Effect of intravenous iron replacement on recurrent heart failure hospitalizations and cardiovascular mortality in patients with heart failure and iron deficiency: A Bayesian meta-analysis

Aims

Iron deficiency is common in patients with heart failure (HF) and reduced ejection fraction (HFrEF) and is associated with a poor prognosis. Whether intravenous iron replacement improves recurrent HF hospitalizations and cardiovascular mortality of these patients is uncertain although several trials were conducted. Moreover, none of the trials were powered to assess the effect of intravenous iron in clinically important subgroups. Therefore, we conducted a Bayesian analysis to derive precise estimates of the effect of intravenous iron replacement on recurrent HF hospitalizations and cardiovascular mortality in iron-deficient HFrEF patients using consistent subgroup definitions across trials.

Methods and results

Individual participant data were used from the FAIR-HF (n = 459), CONFIRM-HF (n = 304) and AFFIRM-AHF (n = 1108) trials. These data were re-analysed following as closely as possible the approach taken in the analyses of IRONMAN (n = 1137), for which study level data were used. Definitions of outcomes and subgroups from the FAIR-HF, CONFIRM-HF and AFFIRM-AHF were matched with those used in IRONMAN. The primary endpoint was recurrent HF hospitalizations and cardiovascular mortality. The analysis of recurrent events was based on rate ratios (RR) derived from the Lin-Wei-Yang-Ying model, and the data were pooled using Bayesian random-effects meta-analysis. Compared with placebo, intravenous iron significantly reduced the rates of recurrent HF hospitalizations and cardiovascular mortality (RR 0.73, 95% credible interval [CI] 0.48–0.99; between-trial heterogeneity tau = 0.16). The pooled treatment effects did not provide evidence for any differential effects for subgroups based on sex (ratio of rate ratios [RRR] 1.49 [95% CI 0.95–2.37], age <69.4 vs. ≥69.4 years) (RRR 0.68 [0.40–1.15]), ischaemic versus non-ischaemic aetiology of HF (RRR 0.73 [0.42–1.33]), transferrin saturation <20% vs. ≥20% (RRR 0.75 [0.40–1.34]), estimated glomerular filtration rate ≤60 versus >60 ml/min/1.73 m² (RRR 0.97 [0.56–1.68]), haemoglobin <11.8 versus ≥11.8 (RRR 0.95 [0.53–1.60]), ferritin <35 versus ≥35 μg/L (RRR 1.26 [0.72–2.48]) and New York Heart Association class II versus III/IV (RRR 0.91 [0.54–1.56]).

Conclusions

Treatment of iron-deficient HFrEF patients with intravenous iron – namely with ferric carboxymaltose or ferric derisomaltose – results in significant reduction in recurrent HF hospitalizations and cardiovascular mortality. Results were nominally consistent across the subgroups studied, but for several of these subgroups uncertainty remains present.