Multicenter Automatic Defibrillator Implantation Trial Research Articles

Emerging Role of Multimodality Imaging to Evaluate Patients at Risk for Sudden Cardiac Death

Accurate identification of patients at high risk for sudden cardiac death (SCD) has been one of the objectives of research in the last years. With an annual incidence between 184 000 and 462000, SCD is a major public-health problem.The most common cause of SCD is a malignant ventricular arrhythmia and, in the majority of patients with SCD, the underlying anatomic substrate can be identified.2,3 Ischemic heart disease, idiopathic dilated cardiomyopathy (DCM), and hypertrophic cardiomyopathy are the most frequent structural heart diseases associated with SCD. Regardless of the underlying structural heart disease, the use of implantable cardioverter defibrillators (ICD) for secondary prevention of SCD is supported by extensive evidence demonstrating the superiority of ICD over antiarrhythmic drug therapy in reducing SCD and all-cause mortality of patients resuscitated from cardiac arrest.4 Furthermore, in patients with ischemic and nonischemic heart failure, the superior efficacy of ICD over antiarrhythmic therapy for primary prevention of SCD has been demonstrated in multiple randomized controlled trials with >6000 patients included.4 However, recommendations for ICD implantation for primary prevention in patients with other structural heart diseases such as hypertrophic cardiomyopathy or right ventricular arrhythmogenic dysplasia rely on prospective registries or retrospectively analyzed series and predictive markers of SCD have not been definitively established. Based on inclusion criteria of multicenter ICD trials for primary prevention, left ventricular ejection fraction (LVEF) ≤35% is one of the major criteria for ICD implantation.However, patients with reduced LVEF constitute a small proportion of the individuals who die suddenly and most of the SCD events occur in patients who do not have symptoms or signs of cardiac disease yet.6 In addition, in the Multicenter Automatic Defibrillator Implantation Trial II (MADIT II), only 35% of patients randomized to the ICD arm received appropriate therapy during 3 years’ follow-up.7 …

Reduction in Life-Threatening Ventricular Tachyarrhythmias in Statin-Treated Patients With Nonischemic Cardiomyopathy Enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)

This study hypothesized that time-dependent statin therapy will reduce the risk of life-threatening ventricular tachyarrhythmias among patients with nonischemic cardiomyopathy (NICM) enrolled in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). Prior studies suggested that statin therapy exerts antiarrhythmic properties among patients with coronary artery disease. However, data regarding the effect of statins on arrhythmic risk among patients with NICM are limited. Multivariate Cox proportional hazards regression modeling was used to assess the effect of statin therapy, evaluated as a time-dependent covariate, on the risk of appropriate defibrillator therapy for fast ventricular tachycardia (VT) (defined as a rate faster than 180 beats/min)/ventricular fibrillation (VF) or death (primary endpoint) and appropriate defibrillator shocks (secondary endpoint) among 821 patients with NICM enrolled in the MADIT-CRT trial. Statin users (n = 499) were older and had a higher prevalence of diabetes and hypertension yet were less frequently smokers. Multivariate analysis showed that time-dependent statin therapy was independently associated with a significant 77% reduction in the risk of fast VT/VF or death (p < 0.001) and with a significant 46% reduction in the risk of appropriate implantable cardioverter defibrillator shocks (p = 0.01). Consistent with these findings, the cumulative probability of fast VT/VF or death at 4 years of follow-up was significantly lower among patients who were treated with statins (11%) as compared with study patients who were not treated with statins (19%; p = 0.006 for the overall difference during follow-up). Statin use was associated with a significant reduction in the risk of life-threatening ventricular tachyarrhythmias among patients with NICM.

Response to Letter Regarding Article, “Predictors of Response to Cardiac Resynchronization Therapy in The Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)”

We agree with Varma et al that the findings of our current Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) substudy (regarding factors associated with response to cardiac resynchronization therapy with a defibrillator (CRT-D)1 and the previous MADIT-CRT report by Singh et al (regarding the effect of left ventricular [LV] lead position on clinical outcomes in the same trial)2 may appear contradictory. However, caution is necessary in comparing the results of the 2 studies for the following reasons. (1) In the present study, we identified 7 factors associated with significant reductions in left ventricular volumes (ie, echocardiographic response) in the study patients treated with CRT-D and used …

Predictors of Super-Response to Cardiac Resynchronization Therapy and Associated Improvement in Clinical Outcome: The MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) Study

The authors investigated predictors of left ventricular ejection fraction (LVEF) super-response to cardiac resynchronization therapy with defibrillator (CRT-D) and whether super-response translated into improved event-free survival in patients with mildly symptomatic heart failure (HF). Few data exist on predictors of super-response to CRT-D and associated morbidity and mortality in mildly symptomatic HF populations. Patients were assigned to CRT-D with paired echocardiograms at baseline and at 12 months (n = 752). Super-response was defined by the top quartile of LVEF change. Best-subset regression analysis identified predictors of LVEF super-response. Kaplan-Meier survival analysis and Cox proportional hazards regression were performed to investigate associations of response category with development of nonfatal HF event or all-cause death. All 191 super-responders experienced an LVEF increase of ≥14.5% (mean LVEF increase 17.5 ± 2.7%). Six predictors were associated with LVEF super-response to CRT-D therapy: female sex (odds ratio [OR]: 1.96; p = 0.001), no prior myocardial infarction (OR: 1.80; p = 0.005), QRS duration ≥150 ms (OR: 1.79; p = 0.007), left bundle branch block (OR: 2.05; p = 0.006), body mass index <30 kg/m(2) (OR: 1.51; p = 0.035), and smaller baseline left atrial volume index (OR: 1.47; p < 0.001). Cumulative probability of HF or all-cause death at 2 years was 4% in super-responders, 11% in responders, and 26% in hypo-responders (log-rank p < 0.001 overall). In multivariate analysis, hyporesponse was associated with increased risk of HF or all-cause death, compared with super-response (hazard ratio: 5.25; 95% confidence interval: 2.01 to 13.74; p = 0.001). Six baseline factors predicted LVEF super-response in CRT-D-treated patients with mild HF. Super-response was associated with reduced risk of subsequent cardiac events. (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

So you implanted an implantable cardioverter defibrillator, now what to do with it?

This editorial refers to ‘Long-term follow-up on high-rate cut-off programming for implantable cardioverter defibrillators in primary prevention patients with left ventricular systolic dysfunction’ by N. Clementy et al ., on page 968 It is well established that patients with a low ejection fraction, be it ischaemic cardiomyopathy or not, benefit from implantable cardioverter defibrillator (ICD) therapy.1,2 Since the hallmark studies, this has been shown repeatedly in real-world studies and in a meta-analysis.3,4 However, this therapy comes with implant-related complications and the psychological strain of shocks, both appropriate and inappropriate.5 Recently, the relation between shocks and mortality has been investigated. The initial question of who to implant with an ICD is closely followed by many others. Single-chamber or dual-chamber pacing (and sensing)? How many zones to programme? Which cut-off rate (and duration to intervention) should be used? What is the benefit or disadvantage of anti-tachycardia pacing (ATP), and how should this be programmed? Finally, which detection intervals and parameters are optimal to treat all important arrhythmias, while avoiding unnecessary and inappropriate shocks. Most of these questions have never been studied systematically. Ventricular pacing can have detrimental effects in patients with left ventricular dysfunction and should be avoided. It is clear now that pacing should be atrial, or at 40 b.p.m. in the ventricle.6 The effects of zone programming have never been studied as such. In MADIT (Multicenter Automatic Defibrillator Implantation Trial) II, programming was left to physician discretion, and both single- and double-chamber devices were used.1 In SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) only single-chamber devices …

Modes of death in defibrillator patients: Learning from clinical experience

Historically, mortality rates from trials with implantable cardioverter-defibrillator (ICD) treatment arms for primary and secondary prevention have ranged from 6% to 8%. 1 Moss A.J. Hall W.J. Cannom D.S. et al. Multicenter Automatic Defibrillator Implantation Trial InvestigatorsImproved survival with an implanted defibrillator in patients with coronary disease at high risk for ventricular arrhythmia. N Engl J Med. 1996; 335: 1933-1940 Crossref PubMed Scopus (3537) Google Scholar , 2 Moss A.J. Zareba W. Hall W.J. et al. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med. 2002; 346: 877-883 Crossref PubMed Scopus (5558) Google Scholar , 3 Connolly S.J. Gent M. Roberts R.S. et al. Canadian Implantable Defibrillator Study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone. Circulation. 2000; 101: 1297-1302 Crossref PubMed Scopus (1357) Google Scholar , 4 The AVID InvestigatorsCauses of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Am Coll Cardiol. 1999; 34: 1552-1559 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Mortality rates for cardiac resynchronization therapy with defibrillators (CRT-D) have ranged from 9% to 12%. 5 Bristow M.R. Saxon L.A. Boehmer J. et al. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med. 2004; 350: 2140-2150 Crossref PubMed Scopus (4734) Google Scholar , 6 Cleland J.G. Daubert J.C. Erdmann E. et al. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med. 2005; 352: 1539-1549 Crossref PubMed Scopus (5130) Google Scholar Annual heart failure mortality rates have been reported at ∼3% 4 The AVID InvestigatorsCauses of death in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. J Am Coll Cardiol. 1999; 34: 1552-1559 Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar , with sudden cardiac death rates at 20%–27% in primary prevention trials (MADIT-I, MADIT-II) and 30%–36% in secondary prevention trials (AVID, CIDS). The mode of death in implantable cardioverter-defibrillator and cardiac resynchronization therapy with defibrillator patients: Results from routine clinical practiceHeart RhythmVol. 9Issue 10PreviewAlthough data on the mode of death of implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy with defibrillator (CRT-D) patients have been examined in randomized clinical trials, in routine clinical practice data are scarce. To provide reasonable expectations and prognosis for patients and physicians, this study assessed the mode of death in routine clinical practice. Full-Text PDF

Cardiac resynchronization therapy (CRT): Clinical trials, guidelines, and target populations

Over the last 10 years, several large, well-designed clinical trials have firmly established the role of cardiac resynchronization therapy (CRT) as a recommended treatment strategy for moderate-to-severe heart failure (HF). A review of the relevant results from the MUSTIC, MIRACLE, CONAK-CD, and MIRACLE ICD trials reveals that in patients with New York Heart Association (NYHA) class III-IV HF, CRT produces consistent improvements in quality of life, functional status, and exercise capacity while also providing strong evidence for reverse remodeling and diminished functional mitral regurgitation, resulting in reductions in both HF hospitalizations and all-cause morbidity and mortality. In patients with earlier NYHA class I-II HF, the benefit of CRT has been more controversial. The principal ongoing challenges addressed in this article include the substantial 30% of patients who receive a CRT device but fail to respond, the wide variations in how to define "response" vs "nonresponse," and how to identify patients who will benefit from CRT, especially narrow QRS (<120 ms), those with right bundle branch block, and those with mild-to-moderate (NYHA class I-II) HF. An important result of this uncertainty is the lack of a good sense of the optimal rate of CRT implantation, making consideration of the data reviewed in this article crucial for identifying important gaps of knowledge and mechanisms of action that need to be studied in the near future.

Contemporary and future trends in cardiac resynchronization therapy to enhance response

The rationale for cardiac resynchronization therapy (CRT), expectations in terms of patient benefit, patient selection for CRT, selection of a CRT pacemaker (CRT-P) vs CRT plus implantable cardioverter-defibrillator (CRT-D) platform, and studies evaluating device programming to enhance benefit from CRT are reviewed. The notion of an "optimal" left ventricular (LV) pacing site, the rationale for identifying and avoiding LV pacing in regions of scar, the use of anatomic, hemodynamic, and electrical parameters to identify an optimal LV pacing site, and the potential utility of multisite LV pacing to enhance benefit from CRT are discussed. Finally, the advantages and disadvantages of the various methods for LV lead delivery are reviewed.

Baseline functional capacity and the benefit of cardiac resynchronization therapy in patients with mildly symptomatic heart failure enrolled in MADIT-CRT

Mildly symptomatic heart failure (HF) patients were shown to derive substantial clinical benefit from cardiac resynchronization therapy with defibrillator (CRT-D) in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. However, the relationship between functional capacity (FC) and CRT-D benefit in the trial was not assessed. To evaluate the association between FC and response to CRT-D in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. We evaluated the association between preimplantation FC and the benefit of CRT-D in reducing the risk of HF or death in Multicenter Automatic Defibrillator Implantation Trial in Cardiac Resynchronization Therapy. Functional status was assessed by a 6-minute walk test (6MWT), dichotomized at the median value as poor (<350 m) or good (≥350 m). Implantable cardioverter-defibrillator-only patients with a poor FC had an adjusted 73% increased risk for HF or death (P <.001) and a 2.4-fold (P = .001) increased risk for all-cause mortality. CRT-D therapy was associated with 63% (P <.001) and 44% (P <.001) reductions in the risk of HF or death among left bundle branch block patients with a poor FC and a good FC, respectively (P for interaction = .10). Among left bundle branch block patients with a poor FC, CRT-D was also associated with a significant reduction in the risk of all-cause mortality (hazard ratio 0.52; P = .015) whereas the survival benefit of CRT-D was not observed among those who had a higher FC at enrollment (hazard ratio 1.01; P = .98; P for interaction = .10). Poor FC is a strong independent predictor for mortality and HF events in patients with mildly symptomatic HF. Left bundle branch block patients with poor baseline FC derive a pronounced benefit from CRT-D, manifest by a significant reduction in mortality.

Pursuing the “Holy Grail”

Over the past decade, several large, randomized trials have allowed us to better define the appropriate population for primary prevention implantable cardioverter-defibrillator (ICD) placement, saving thousands of lives every year. MADIT II (Multicenter Automatic Defibrillator Implantation Trial II) and SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) have demonstrated a survival benefit of 31% and 23% over 20 and 45.5 months follow-up, respectively.1,2 However, our selection criteria that are mostly based on the left ventricular ejection fraction (LVEF) are of limited specificity. Long-term follow-up data show that only 35% of patients ever receive an appropriate shock for ventricular tachycardia (VT) and ventricular fibrillation (VF) during a 3-year follow-up.3 Article see p 178 In this issue of Circulation: Cardiovascular Imaging , Wu et al4 report their intriguing results in 235 patients who underwent ICD implantation for primary prevention according to the SCD-HeFT/MADIT II criteria. Ischemia was the most prevalent etiology (58%) of the cardiomyopathy, and all patients underwent cardiac magnetic resonance (CMR) as well as baseline blood draws at the time of implantation. At least 90% of patients were receiving β-blocker and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker therapy. During the median follow-up period of 3.6 years, 19% of patients experienced the primary end point of appropriate ICD shock for VT/VF or cardiac death. The full-width half-maximum method previously published by the group was used to separate delayed enhancement on MRI into dense scar (scar core) or heterogeneous scar (gray zone). Indeed, the investigators found that the gray zone mass was significantly higher in patients who experienced the primary end point, whereas LVEF was only of borderline significance. In a multivariate analysis comparing patients according to tertiles of gray zone, the middle or highest tertile had a hazard ratio of 3.9 (95% CI, 1.2–12.4) and 4.6 (95% …

Evaluating Sex Differences in Medical Device Clinical Trials

THE SAFETY AND EFFECTIVENESS OF MEDICAL TREATments can differ in men and women for many reasons related to different epidemiologic characteristics, physiology, and body size. In general, women have higher bleeding rates and procedural morbidity and mortality than men, which means that their risk/benefit ratios for many implanted medical devices can differ from men. Therefore, sex-specific safety and effectiveness data are necessary for informed patient decision making. In 2008, the US Food and Drug Administration (FDA) convened 2 workshops on this topic that included multiple stakeholders— patient groups, medical device industry representatives, academia, and government officials. In December 2011, the FDA released a draft guidance informed by these workshops, entitled “Evaluation of Sex Differences in Medical Device Clinical Studies.” This document discusses the underrepresentation of women in medical device clinical trials and provides recommendations for increasing enrollment of women and performing sex-specific analyses. A 90-day public comment period began on December 19, 2011. The FDA draft guidance document provides a number of helpful guidelines to support adequate enrollment of women in clinical trials. For studies that have not yet been completed, the draft guidance recommends keeping enrollment open until a prespecified number of women are enrolled. Following this recommendation so that women are enrolled in proportion to disease prevalence would do the most to ensure sufficient data about the effect of a medical device on women. The draft guidance document also recommends that outcomes data be analyzed by sex. By not limiting its guidance to new studies, the FDA is indicating that it hopes changes will occur more immediately. This approach is laudable; the difference between men and women in terms of effectiveness and safety of medical devices has long been understudied. The recommendations in this draft guidance may help ensure safe and effective use of medical devices in both sexes. However, the notation on this guidance stating that it “Contains Nonbinding Recommendations” raises the fundamental question of whether these important guidelines will be followed. This is not a new question. In 1994, FDA issued a “Gender Bias” directive stating that FDA Summaries of Safety and Effectiveness Data, which are released on premarket approval for all high-risk medical devices, should examine clinical trial data for differences in safety and efficacy by sex. However, an examination of compliance with this directive found that it is routinely ignored. Among 78 high-risk cardiovascular devices approved during the years 2000 through 2007, the overall patient population in these studies was 67% men with no increase in the enrollment of women over time, although women make up 46% of all patients with cardiovascular disease. The analyses by sex specified in the 1994 FDA directive occurred in only 41% of studies (51/123). When these analyses were completed, 26% (12/47) identified some difference in device safety or effectiveness by sex. In 28% of device studies (34/123), no sex distribution of the patient population was stated. As a result, clinically important sex-specific differences related to use of many medical devices are unknown. For example, the implantable cardioverter-defibrillator (ICD), a device shown to be lifesaving in selected populations, is commonly implanted in men and women. At the time of device approval, there were gaps in the data because of very low enrollment of women in the pivotal studies. In 2003 the Medicare Coverage and Advisory Committee was convened pursuant to a manufacturer’s request for expanded Medicare coverage of ICDs for primary prevention (which was granted). During the meeting, when asked why there were so few women in the pivotal Multicenter Automatic Defibrillator Implantation Trial II, the trial’s principal investigator stated, “we are contemplating a trial in the

The Relevance of the Primary Prevention Criteria for Implantable Cardioverter Defibrillator Implantation in Korean Symptomatic Severe Heart Failure Patients

Background and ObjectivesImplantable cardioverter defibrillator (ICD) therapy is recommended as the primary tool for prevention of sudden cardiac death (SCD) in symptomatic patients with severe left ventricular dysfunction. There is a paucity of information on whether this recommendation is appropriate for the Korean population with severe heart failure.Subjects and MethodsThe study group consisted of 275 consecutive patients (mean age 65 years, 71% male) who met the ICD implantation criteria for primary prevention (left ventricular ejection fraction ≤30% and New York Heart Association functional class II or III). We analyzed the clinical characteristics and outcomes of an ischemic cardiomyopathy (ICMP) group (n=131) and a non-ischemic cardiomyopathy (NICMP) group (n=144). The outcomes of these 2 groups were compared with the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II) conventional and Defibrillators in the Non-ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) standard therapy groups, respectively.ResultsEighty patients (29%) died during a follow-up period of 40±17 months. The NICMP group had better all-cause mortality rates than the ICMP group (19% vs. 40%, p<0.001), however both groups had a similar incidence of SCD (7% vs. 10%, p=0.272). The 2-year all-cause mortality and SCD for the ICMP group were similar to those of the MADIT-II conventional therapy group (20% vs. 20%, 7% vs. 10%, respectively, all p>0.05). All-cause mortality and the incidence of SCD in the NICMP group were comparable to those of the DEFINITE standard therapy group (13% vs. 17%, 6% vs. 6%, respectively, all p>0.05).ConclusionKorean patients with severe heart failure in both the ICMP and NICMP groups had all-caused mortality and risk of SCD comparable to patients in the MADIT-II and DEFINITE standard therapy groups. Therefore, the primary prevention criteria for ICD implantation would be appropriate in both Korean ICMP and NICMP patients.

Renin-angiotensin blockade as primary prevention during right ventricular pacing: An alternative strategy in managing cardiac dyssynchrony

The potentially deleterious effects of conventional right ventricular apical (RVA) pacing have been recognized increasingly, with particular emphasis on promoting cardiac dyssynchrony.1 Large-scale evaluations have demonstrated that RVA pacing may contribute to poor clinical outcomes. Increased RVA pacing predicted death or congestive heart failure (CHF) hospitalization in patients with implantable cardioverter-defibrillators with baseline depressed left ventricular (LV) function in the Dual Chamber and VVI Implantable Defibrillator trial2,3 and Multicenter Automatic Defibrillator Implantation Trial II4 as well as in patients with pacemakers examined in the Danish study5 and Mode Selection Trial.

Cardiac Resynchronization Therapy Reduces Left Atrial Volume and the Risk of Atrial Tachyarrhythmias in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)

We hypothesized that reductions in left atrial volume (LAV) with a cardiac resynchronization therapy-defibrillator (CRT-D) would translate into a subsequent reduction in the risk of atrial tachyarrhythmias (AT). There is limited information regarding the effect of CRT-D on the risk of AT. Percent reduction in LAV at 1 year following CRT-D implantation (pre-specified as low [lowest quartile: <20% reduction in LAV] and high [≥20% reduction in LAV] response to CRT-D) were related to the risk of subsequent AT (comprising atrial fibrillation, atrial flutter, atrial tachycardia, and supraventricular tachyarrhythmias) among patients enrolled in MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy). The cumulative probability of AT 2.5 years after assessment of echocardiographic response was lowest among high LAV responders to CRT-D (3%) and significantly higher among both low LAV responders to CRT-D (9%) and implantable cardioverter-defibrillator-only patients (7%; p = 0.03 for the difference among the 3 groups). Consistently, multivariate analysis showed that high LAV responders to CRT-D experienced a significant 53% (p = 0.01) reduction in the risk of subsequent AT as compared with implantable cardioverter-defibrillator-only patients, whereas low LAV responders did not derive a significant risk reduction with CRT-D therapy (hazard ratio [HR]: 1.05 [95% confidence interval (CI): 0.54 to 2.00]; p = 0.89). Patients who developed in-trial AT experienced significant increases in the risk for both the combined endpoint of heart failure or death (HR: 2.28 [95% CI: 1.45 to 3.59]; p < 0.001) and the separate occurrence of all-cause mortality (HR: 1.89 [95% CI: 1.08 to 3.62]; p = 0.01). In the MADIT-CRT study, favorable reverse remodeling of the left atrium with CRT-D therapy was associated with a significant reduction in risk of subsequent AT. (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy [MADIT-CRT]; NCT00180271).

Gender-specific findings in interventional cardiology: negative for PCI, positive for CRT?

At present, gender-specific disparities still persist in cardiovascular health and care, and specifically in the delivery and outcomes of coronary revascularisation therapy. Of the 1.3 million percutaneous coronary intervention (PCI) procedures performed in 2006 in the USA, only 35% were performed in women. This is rather surprising since the benefits of PCI, particularly in high-risk women with acute coronary syndromes (ACS) and ST-segment elevation myocardial infarction (STEMI), are well known. Moreover, for those women treated with PCI, unadjusted mortality and (vascular and bleeding) complication rates remain significantly higher than in men. In patients undergoing contemporary PCI, using both bare-metal and drug-eluting stents (with sirolimus and paclitaxel), the benefits of reduction in restenosis and repeat target lesion and target vessel revascularisation are independent of gender. However, the hopeful thought that stents would eliminate the difference in mortality in women and men following the stent procedure has not been realised. For patients treated with stents, the gender difference in in-hospital and 30-day mortality has persisted in the setting of both acute myocardial infarction and elective/urgent procedures. Whether these gender differences are explained by pathophysiology, by impaired access to guideline-recommended therapies, by biology or bias, by lack of a robust evidence base in women, or by the artificial comparison between women and men as their control group remains a matter of controversy [1]. Do the ‘negative’ PCI data also hold for cardiac resynchronisation therapy (CRT) in women? A recent study by Mooyaart et al. [2] evaluated in 577 patients (431 men, 147 women) whether a gender difference existed in the long-term outcomes after CRT and whether gender is an independent predictor of mortality, beyond other clinical and echocardiographic characteristics. During a mean follow-up of 34 ± 25 months, 197 patients died (158 men and 39 women). Kaplan-Meier analysis showed a significant difference in long-term survival between the women and men (p = 0.007). The 2-year all-cause mortality rate was 15% in men and 8% in women (p = 0.025). It was clearly revealed that female gender was an independent predictor of long-term survival, together with heart failure aetiology and renal function. In particular, women with heart failure due to a non-ischaemic aetiology showed the best long-term survival rate. The authors concluded that female gender and non-ischaemic aetiology were independently associated with better long-term survival after CRT. These encouraging findings have been confirmed by Arshad et al. [3] who investigated the factors related to gender-specific outcomes for death and heart failure events in the MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy) trial in 1820 patients (453 female, 1367 male). Overall, female patients had a better result from CRT-D therapy than male patients, with a significant 69% reduction in death or heart failure (p < 0.001) and 70% reduction in heart failure alone (p < 0.001). In addition, women showed a significant 72% reduction in all-cause mortality in the total population. These beneficial CRT-D effects among women were associated with consistently greater echocardiographic evidence of reverse cardiac remodelling in women than in men. To summarise, the ‘negative’ PCI findings in women suggest that the ongoing gender disparities in access to and delivery of evidence-based guideline-recommended revascularisation therapies for patients with ACS and STEMI represent potential opportunities to improve care and outcomes, particularly in women. On the other hand, for CRT in women, recent findings offer a more ‘positive’ perspective than in men. Although gender-specific designed prospective studies are required to draw any definite conclusions on the observed survival benefit in women after CRT, the two above-mentioned studies form at least a good basis to treat many women suffering from heart failure with CRT.

Predictors of Response to Cardiac Resynchronization Therapy in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT)

We hypothesized that combined assessment of factors that are associated with favorable reverse remodeling after cardiac resynchronization-defibrillator therapy (CRT-D) can be used to predict clinical response to the device. The study population comprised 1761 patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). Best-subset regression analysis was performed to identify factors associated with echocardiographic response (defined as percent reduction in left ventricular end-diastolic volume 1 year after CRT-D implantation) and to create a response score. Cox proportional hazards regression analysis was used to evaluate the CRT-D versus defibrillator-only reduction in the risk of heart failure or death by the response score. Seven factors were identified as associated with echocardiographic response to CRT-D and made up the response score (female sex, nonischemic origin, left bundle-branch block, QRS ≥150 milliseconds, prior hospitalization for heart failure, left ventricular end-diastolic volume ≥125 mL/m(2), and left atrial volume <40 mL/m(2)). Multivariate analysis showed a 13% (P<0.001) increase in the clinical benefit of CRT-D per 1-point increment in the response score (range, 0-14) and a significant direct correlation between risk reduction associated with CRT-D and response score quartiles: Patients in the first quartile did not derive a significant reduction in the risk of heart failure or death with CRT-D (hazard ratio=0.87; P=0.52); patients in the second and third quartiles derived 33% (P=0.04) and 36% (P=0.03) risk reductions, respectively; and patients in the upper quartile experienced a 69% (P<0.001) risk reduction (P for trend=0.005). Combined assessment of factors associated with reverse remodeling can be used for improved selection of patients for cardiac resynchronization therapy. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Comparison of Ventricular Tachyarrhythmia Characteristics in Patients With Idiopathic Dilated or Ischemic Cardiomyopathy and Defibrillators Implanted for Primary Prevention

Implantable cardioverter-defibrillator (ICD) therapy for primary prevention is well established in ischemic cardiomyopathy (ICM). Data on the role of ICDs in patients with dilated cardiomyopathy (DCM) and no history of ventricular tachyarrhythmia (VT/VF) are more limited. DCM patients with an impaired left ventricular ejection fraction (LVEF) still represent a low arrhythmic risk subgroup in clinical practice. ICD stored data of DCM patients with an LVEF ≤35% was compared to data of ICM patients meeting Multicenter Automatic Defibrillator Implantation Trial (MADIT) eligibility criteria. VT/VF occurrences and electrical storm (ES) events were analyzed. There were 652 patients followed for 50.9 ± 33.9 months. There were 1978 VT and 241 VF episodes analyzed in 66 out of 203 patients (32.5%) with DCM and in 118 out of 449 patients (26.3%, P = 0.209) with ICM. Freedom of appropriate ICD treatment due to VT/VF or ES events did not differ in both patient populations (log-rank, P>0.05). In patients presenting with VT/VF episodes, mean event rates were comparable in both patient populations (3.2 ± 14.1 for DCM and VT vs 3 ± 13.9 for ICM and VT [P = 0.855], 0.4 ± 1.3 for DCM and VF vs 0.4 ± 1.8 for ICM and VF [P = 0.763], and 0.2 ± 0.7 for DCM and ES vs 0.2 ± 1 for ICM and ES [P = 0.666]). DCM patients with prophylactic ICDs implanted due to heart failure and patients fulfilling MADIT criteria reveal comparable patterns of VT/VF/ES events during long-term follow-up. Incidence, mean number of events, and time to first event did not differ significantly. Findings support the current guidelines for prophylactic ICD therapy in DCM patients with heart failure.

Prediction of Life-Threatening Arrhythmic Events in Patients With Chronic Myocardial Infarction by Contrast-Enhanced CMR

We hypothesized that infarct transmurality assessed with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) predicts arrhythmic events in patients with chronic myocardial infarction. Patients with decreased left ventricular function due to chronic myocardial infarction are at increased risk for life-threatening arrhythmias related to infarcted tissue. LGE-CMR accurately detects infarct morphology. We prospectively enrolled 52 patients with chronic myocardial infarction referred for primary preventive implantable cardioverter-defibrillator (ICD) implantation following MADIT (Multicenter Automatic Defibrillator Implantation Trial) study criteria. Using LGE-CMR, left ventricular volumes, function, and infarct morphology were assessed including calculation of total and relative infarct mass, infarct border, infarct border zone, and infarct transmurality. Patients were followed for 1,235 ± 341 days. The primary combined endpoint including appropriate device therapy (ICD discharge or antitachycardia pacing) or death from cardiac cause occurred in 16 individuals resulting in an annual event rate of 4.7%. Six patients received an appropriate shock, 7 patients received recurrent appropriate antitachycardia pacing for sustained ventricular tachycardia, and 3 patients died of cardiac cause. There was a significant association to relative infarct mass (38 ± 8% vs. 28 ± 14%, p = 0.02), infarct transmurality (24 ± 8 g vs. 16 ± 12 g, p = 0.02), and relative infarct transmurality (RIT) (63 ± 12% vs. 48 ± 23%, p = 0.01). In separate logistic regression models, no variable emerged as significant when combined with RIT. As a single effect, RIT emerged as a predictor of the primary endpoint (p = 0.02). A RIT cutoff at 43% resulted in a sensitivity of 88%, a specificity of 50%, a positive predictive value of 44%, and a negative predictive value of 90%. In patients with chronic myocardial infarction scheduled for primary preventive ICD implantation, infarct transmurality as defined by LGE-CMR identifies a subgroup with increased risk for life-threatening arrhythmias and cardiac death.

Reduction of the Risk of Recurring Heart Failure Events With Cardiac Resynchronization Therapy: MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy)

The evaluation of the risk of recurring heart failure events (HFEs) was a pre-specified substudy of MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy).There are limited data regarding the effect of cardiac resynchronization therapy with a defibrillator (CRT-D) on the occurrence of recurring heart failure episodes after a first post-implantation HFE.Data with regard to recurring HFEs were prospectively collected for all 1,820 MADIT-CRT participants. The CRT-D versus defibrillator-only risk for nonfatal first- and subsequent-HFEs was assessed by Cox proportional hazards and Andersen-Gill proportional intensity regression modeling, respectively, in efficacy analyses recognizing active device-type during follow-up.Multivariate analysis showed that CRT-D was associated with a significant reduction in the risk of a first HFE (hazard ratio [HR]: 0.54, 95% confidence interval [CI]: 0.44 to 0.67, p < 0.001) and with a similar magnitude of reduction in the risk of HFEs subsequent to a first post-enrollment event (HR: 0.62, 95% CI: 0.45 to 0.85, p = 0.003). The benefit of CRT-D for the prevention of first and subsequent HFEs was pronounced among patients with left bundle branch block (HR: 0.38, 95% CI: 0.29 to 0.49, p < 0.001; and HR: 0.50, 95% CI: 0.33 to 0.76, p = 0.001, respectively) and nonsignificant in non-left bundle branch block patients (HR: 1.12, 95% CI: 0.77 to 1.64, p = 0.55; and HR: 0.99, 95% CI: 0.58 to 1.69, p = 0.96, respectively; p values for interaction: p < 0.001 and p = 0.06, respectively). The occurrences of first and second HFEs were associated with 7- and nearly 19-fold respective increases in the risk of subsequent mortality.In the MADIT-CRT trial, the benefit of cardiac resynchronization therapy for the reduction in recurring HFEs was maintained after the occurrence of a first post-enrollment event. The occurrence of HFEs greatly increased the risk of death. (Multicenter Automatic Defibrillator Implantation With Cardiac Resynchronization Therapy; NCT00180271).

Dyssynchrony, Contractile Function, and Response to Cardiac Resynchronization Therapy

Despite benefits of cardiac resynchronization therapy (CRT) in patients with severe but less symptomatic heart failure, approximately 30% of patients do not fully respond to treatment. We hypothesized that a combined assessment of left ventricular (LV) dyssynchrony and contractile function by strain-based imaging would identify patients who would most benefit from CRT. We studied 1077 patients with New York Heart Association class I/II, LV ejection fraction ≤30% and QRS width ≥130 ms enrolled in the Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy trial with sufficient echocardiographic image quality for cardiac deformation analysis (implantable cardioverter-defibrillator [ICD], n=416; CRT, n=661). Patients were assigned to CRT plus an ICD or to ICD alone in 3:2 random assignment. We assessed the degree to which baseline echocardiographic assessments of dyssynchrony, measured as the standard deviation of time-to-peak transverse strain over 12 segments, contractile function, measured as global longitudinal strain, or both predicted the effect of treatment on the primary outcome of death or heart failure. With 213 primary events occurring over a mean of 2.4 years, the benefit of CRT plus an ICD relative to ICD alone was greatest in patients with mild to moderate dyssynchrony (time-to-peak transverse strain standard deviation, 142 to 230 ms) and greater baseline contractile function (global longitudinal strain ≤-8.7%). Overall, those patients with mild to moderate dyssynchrony and those with best contractile function at baseline demonstrated the greatest benefit from CRT (adjusted hazards ratio, 0.20; 95% confidence interval, 0.09 to 0.44). Dyssynchrony and global longitudinal strain predicted response to CRT independent of each other, QRS width, LV ejection fraction, and presence versus absence of left bundle-branch block, although the observed benefit remained greatest in patients with left bundle-branch block. Both mechanical dyssynchrony and contractile function are important independent correlates of benefit from CRT. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.