Multicenter Unsustained Tachycardia Trial Research Articles

Implantable Cardioverter-Defibrillators and Wearable Defibrillators: Guidelines and Updates.

Implantable cardioverter-defibrillators (ICDs) have been a preferred treatment for ventricular arrhythmias. Clinical data have consistently supported their use; however, determining which patients will or will not benefit from treatment remains difficult.A documented episode of sustained ventricular tachycardia/ventricular fibrillation (VT/VF) without reversible cause warrants ICD implantation (class IA indication) to potentially treat episodes in the future.1 In patients without prior VT/VF, decreased left ventricular ejection fraction (LVEF) is the primary indication for preemptive ICD implantation. If the LVEF is ≤0.35 despite maximal guideline-directed medical therapy, or coronary revascularization was performed 90 or more days previously, then ICD implantation is a class I indication,1 in ischemic or nonischemic cardiomyopathy. An LVEF ≤0.35 in a patient with myocardial infarction (MI) who has been on medical therapy for 40 days also meets the guidelines for ICD implantation.1In addition to LVEF, other factors indicate which patients may benefit from ICD therapy. Diagnostic electrophysiologic studies (EPS), for example, have been part of risk-stratifying patients for more than 20 years. The Multicenter Unsustained Tachycardia Trial (Mustt) investigators categorized post-MI patients with nonsustained VT and an LVEF ≤0.40 according to whether ventricular arrhythmias were induced during EPS; the patients with inducible VT during EPS benefited from ICD implantation.2 Inducible VT/VF during EPS is also an indication for ICD implantation in patients with coronary artery disease who are at risk for ventricular arrhythmias, which present as unexplained syncope, immediately after MI.1Cardiac imaging is another diagnostic method that is playing a more prominent role in stratifying the risks of sudden death. In particular, cardiac magnetic resonance (CMR) has shown promise in evaluating intrinsic myocardial scarring and predicting cardiac death in patients with hypertrophic cardiomyopathy.3 However, its usefulness in determining the need for ICD therapy has not been fully established. An ongoing clinical trial, Cardioverter-Defibrillator Implantation to Prevent Tachyarrhythmias following Acute Myocardial Infarction (Protect-ICD) (NCT 03588286), is evaluating the use of both EPS and CMR to identify which post-MI patients could benefit from ICD treatment.It is unclear how best to monitor and prevent ventricular arrhythmias in patients with a decreased LVEF who are still undergoing optimal medical therapy within 90 days after MI. While being considered for ICD treatment, these patients may benefit from treatment with a wearable cardioverter-defibrillator. This vest-like device, which is worn under clothing, continuously monitors heart rhythm and delivers a shock to restore sinus rhythm in patients who have sustained VT/VF. Currently, using a wearable defibrillator is a class IIB indication in patients who are at high risk for sudden death but do not meet other immediate indications for ICD therapy.1 The Vest Prevention of Early Sudden Death Trial (VEST) investigators randomized post-MI patients with LVEF ≤0.35 in a 2:1 ratio to receive a wearable defibrillator and medical therapy (device group) or medical therapy alone (control group). There were no differences between groups in the primary outcome of arrhythmic death (device group, 1.6%; control group, 2.4%; P=0.18), whereas the overall mortality rate was lower in the device group (3.1% vs 4.9%; P=0.04).4An inherent limitation of the wearable defibrillator is compliance. For example, VEST trial participants wore it for only 14 hr/d, on average.4 In addition, the relatively low event rate suggests that the trial was underpowered to evaluate differences within the groups. Although no clear benefit was found with regard to arrhythmic death, the lower mortality rate in the defibrillator group suggested benefit from monitoring rhythm.In summary, ICD treatment remains important in managing ventricular arrhythmias. Current guidelines support ICD implantation in patients with prior episodes of VT/VF, and LVEF ≤0.35, or both. Further studies should clarify the value of wearable defibrillators and confirm the roles of EPS and CMR in determining which patients will benefit most from ICD implantation.

Defibrillator implantations for primary prevention in the United States: Inappropriate care or inadequate documentation: Insights from the National Cardiovascular Data ICD Registry

Prior studies have reported that more than 20% of implantable cardioverter-defibrillator (ICD) implantations in the United States do not adhere to trial-based criteria. We sought to investigate the patient characteristics associated with not meeting the inclusion criteria of the clinical trials that have demonstrated the efficacy of primary prevention ICDs. Using data from the National Cardiovascular Data Registry's ICD Registry, we identified patients who received ICDs for primary prevention from January 2006 to December 2008. We determined whether patients met the inclusion criteria of at least 1 of the 4 ICD primary prevention trials: Multicenter Automatic Defibrillator Implantation Trial (MADIT), MADIT-II, Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT), and the Multicenter Unsustained Tachycardia Trial (MUSTT). Among 150,264 patients, 86% met criteria for an ICD implantation based on trial data. The proportion of patients who did not meet trial-based criteria increased as age decreased. In multivariate analysis, the significant predictors for not meeting trial criteria included prior cardiac transplantation (odds ratio [OR] 2.1), pediatric electrophysiology operator (OR 2.0), and high-grade atrioventricular conduction disease (OR 1.4). Among National Cardiovascular Data Registry registrants receiving first-time ICDs for primary prevention, the majority met trial-based criteria. Multivariate analyses suggested that many patients who did not meet the trial-based criteria may have had clinical circumstances that warranted ICD implantation. These findings caution against the use of trial-based indications to determine site quality metrics that could penalize sites that care for younger patients. The planned incorporation of appropriate use criteria into the ICD registry may better characterize patient- and site-level quality and performance.

Survival benefit of the primary prevention implantable cardioverter-defibrillator among older patients: does age matter? An analysis of pooled data from 5 clinical trials.

The impact of patient age on the risks of death or rehospitalization after primary prevention implantable cardioverter-defibrillator (ICD) placement is uncertain. Data from 5 major ICD trials were merged: the Multicenter Automatic Defibrillator Implantation Trial I (MADIT-I), the Multicenter UnSustained Tachycardia Trial (MUSTT), the Multicenter Automatic Defibrillator Implantation Trial II (MADIT-II), the Defibrillators in Nonischemic Cardiomyopathy Treatment Evaluation Trial (DEFINITE), and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT). Median age at enrollment was 62 (interquartile range 53-70) years. Compared with their younger counterparts, older patients had a greater burden of comorbid illness. In unadjusted exploratory analyses, ICD recipients were less likely to die than nonrecipients in all age groups: among patients aged <55 years: hazard ratio 0.48, 95% posterior credible interval 0.33 to 0.69; among patients aged 55 to 64 years: hazard ratio 0.69, 95% posterior credible interval 0.53 to 0.90; among patients aged 65 to 74 years: hazard ratio 0.67, 95% posterior credible interval, 0.53 to 0.85; and among patients aged ≥75 years: hazard ratio 0.54, 95% posterior credible interval 0.37 to 0.78. Sample sizes were limited among patients aged ≥75 years. In adjusted Bayesian-Weibull modeling, point estimates indicate ICD efficacy persists but is attenuated with increasing age. There was evidence of an interaction between age and ICD treatment on survival (two-sided posterior tail probability of no interaction <0.01). Using an adjusted Bayesian logistic regression model, there was no evidence of an interaction between age and ICD treatment on rehospitalization (two-sided posterior tail probability of no interaction 0.44). In this analysis, the survival benefit of the ICD exists but is attenuated with increasing age. The latter finding may be because of the higher burden of comorbid illness, competing causes of death, or limited sample size of older patients. There was no evidence that age modifies the association between ICD treatment and rehospitalization.

The REPLACE Death After Replacement Evaluation Score for Predicting Mortality After Device Replacement or Upgrade

The use of cardiovascular implantable electronic devices (CIED) has made remarkable progress during the past 20 years. Overall, devices, leads, and delivery systems have evolved resulting in easier implantation, improved long-term reliability and better battery life span. Article see p 1048 Implantable cardioverter defibrillators (ICD), initially reserved for highly selected patients, where the benefit of secondary prevention outweighed potential side effects, are now a safe and widespread therapy that has become part of the standard care in patients with heart failure and severe systolic dysfunction. Present-day guidelines1,2 take into account all evidence from multiple large randomized trials (the Multicenter Automatic Defibrillator Implantation Trials [MADIT I, MADIT II], the Multicenter Unsustained Tachycardia Trial [MUSTT], and the Sudden Cardiac Death in Heart Failure Trial [SCD-HeFT]) that favor their use for the primary prevention of sudden cardiac death in patients with heart failure, which is currently the main indicator for ICD in developed countries.3,4 Cardiac resynchronization therapy (CRT) has been shown to improve clinical status, left ventricular performance, and to reduce mortality in patients with heart failure and systolic dysfunction and wide QRS. After the initial studies that focused on patients with clinically severe heart failure (New York Heart Association class III or IV), the MADIT-CRT trial, the Resynchronization–Defibrillation for Ambulatory Heart Failure Trial (RAFT), and the Resynchronization Reverses Remodeling in Systolic Left Ventricular Dysfunction trial (REVERSE) clearly proved that CRT’s beneficial effects also extend to those less severe patients (baseline New York Heart Association class II), which led to the recent update of CRT guidelines.1 All the evidence resulted in a dramatic increase of the number of complex device implantations in developed countries.5,6 Since its creation in 2006, the NCDR ICD Registry has recently reported having accrued a …

Controversy surrounding the best time for ICD implantation after myocardial infarction

Controversy surrounding the best time for ICD implantation after myocardial infarction

“Please implant a defibrillator in my patient”: It's déjà vu all over again

“Please implant a defibrillator in my patient”: It's déjà vu all over again

Pleomorphic Ventricular Tachycardia and Risk for Sudden Cardiac Death

Increasing implantable cardioverter-defibrillator (ICD) use in response to broad indications in recent years has heightened the need to better refine selection for patients most likely to benefit. Although no single test adequately predicts sudden cardiac death risk, it seems intuitive that the best markers should be those that directly reflect electric instability and abnormalities of the underlying myocardial substrate. The advanced recording capacity of ICDs allows detailed investigation of spontaneous ventricular tachycardia (VT) episodes that would previously have been inaccessible and to potentially aid in documenting characteristics of clinically significant VTs. Different VTs occurring in the same patient can vary in stability, duration, and hemodynamic consequence. The ability to document and monitor for certain distinguishing features might provide new insights into the underlying pathophysiology and thus help to inform assessments of risk. Although ICDs discriminate between VTs primarily based on differences in rate, stored electrograms (EGMs) also have been used to help identify the arrhythmia origin and in a recent study, to help discriminate likely regions of origin for different “clinical” VTs while pace mapping in patients postinfarction.1 Article see p 33 In this issue of Circulation: Arrhythmia and Electrophysiology , Hadid et al2 analyze stored EGMs to evaluate the incidence and predictive value of pleomorphic VT and multiple VT morphologies among patients enrolled in the DATAS (Dual Chamber and Atrial Tachyarrhythmias Adverse Events Study) trial,3 in which ICDs were implanted under standard class I indications according to the 1998 American College of Cardiology/American Heart Association guidelines, as well as for MUSTT (Multicenter Unsustained Tachycardia Trial) criteria after November 2001. This study is the first to use ICD EGMs to systematically study pleomorphic VT, which was defined as a single VT episode having >1 stable ICD EGM morphology, each lasting at least 6 consecutive beats. The incidence …

Relation between time from myocardial infarction to enrolment and patient outcomes in the Multicenter UnSustained Tachycardia Trial

We sought to assess the relation between time from myocardial infarction (MI) to enrolment and patient outcomes and to examine the association between these outcomes and implantable cardioverter defibrillator (ICD) therapy. We analysed the Multicenter UnSustained Tachycardia Trial database (n = 1650). In examining all endpoints, Cox proportional hazards models were used to adjust for potential confounders. There was no significant association between time from MI to enrolment and any of the outcomes (P > 0.1). Inducibility by an electrophysiology study (EPS) was associated with a higher risk of arrhythmic death or cardiac arrest [adjusted hazard ratio (HR) 2.51; 95% confidence interval (CI) 1.64-3.84] and all-cause death (adjusted HR 1.45; 95% CI 1.04-2.03) only in patients who had an MI <or=6 months prior to enrolment. ICD therapy was associated with improved survival in patients who had an MI <or=6 months (adjusted HR 0.35; 95% CI 0.17-0.74) and >6 months before enrolment (adjusted HR 0.34; 95% CI 0.21-0.54). The risk of arrhythmic death or cardiac arrest and all-cause death did not vary as a function of time from the most recent MI to enrolment. Inducibility by an EPS was associated with worse outcomes only in patients with an MI <or=6 months prior to enrolment. Although ICD therapy was associated with improved survival regardless of the time from MI to enrolment, this finding needs to be verified by a randomized clinical trial.

Mode of Induction of Ventricular Tachycardia and Prognosis in Patients with Coronary Disease: The Multicenter UnSustained Tachycardia Trial (MUSTT)

Programmed stimulation is an important prognostic tool in the evaluation of patients with an ejection fraction <or=40% after myocardial infarction. Many believe that ventricular tachycardia (VT) requiring 3 ventricular extrastimuli (VES) for induction is less likely to occur spontaneously and has less predictive value. However, it is unknown whether the mode of VT induction is associated with long-term prognosis. We analyzed a cohort of 371 patients enrolled in MUSTT who had inducible monomorphic VT and who were not treated with antiarrhythmic drugs or an implantable cardioverter defibrillator during the trial. Patients in whom sustained VT was induced with 1 or 2 VES or burst pacing (single VES n = 15, double VES n = 127, burst n = 7, total n = 149) were compared with those in whom VT was induced with 3 VES (n = 222). Compared with the others, patients requiring 3 VES were closer to their most recent myocardial infarction (17 vs 51 months, P = 0.035) and showed a trend toward a lower ejection fraction (26% vs 30%, P = 0.057). VT requiring 3 VES had a shorter cycle length (240 vs 260 ms, P < 0.001). Despite these findings, there was no difference in the incidence of arrhythmic death or cardiac arrest (HR 1.02; 95% CI 0.69-1.51) or all-cause mortality (HR 1.03; 95% CI 0.76-1.39) according to the mode of induction in adjusted analyses. The prognostic significance of VT induced by 3 VES is similar to that of VT induced by 1 or 2 VES, or burst pacing, in patients with coronary disease and abnormal LV function.

The Role of Electrophysiology Study in Risk Stratification of Sudden Cardiac Death

Patients with ischemic heart disease and left ventricular systolic dysfunction are at high risk of sudden cardiac death. However, most of these high-risk patients will never develop potential fatal ventricular arrhythmias. Thus, modalities that stratify patients according to their risk of sudden cardiac death are needed. The electrophysiology study has, for decades, been used to prognosticate on patients' risk of sudden cardiac death. Recent data from the Multicenter Unsustained Tachycardia Trial (MUSTT) and Multicenter Automatic Defibrillator Implantation Trial II (MADIT II) demonstrate that in patients with ischemic heart disease and left ventricular systolic dysfunction, an electrophysiology study can help identify patients who are at high risk of sudden cardiac death. However, in these patient populations, the prognostic ability of an electrophysiology study is only modest and the negative predictive value is poor. In the future, combining the results of noninvasive modalities with invasive electrophysiology testing may improve our prognostic ability. Furthermore, expanding the role of the electrophysiology study to include therapeutic ablations may alter a patient's future risk of sudden cardiac death.

Limitations of Ejection Fraction for Prediction of Sudden Death Risk in Patients With Coronary Artery Disease: Lessons From the MUSTT Study

We determined the contribution of multiple variables to predict arrhythmic death and total mortality risk in patients with coronary disease and left ventricular dysfunction. We then constructed an algorithm to predict risk of mortality and sudden death. Many factors in addition to ejection fraction (EF) influence the prognosis of patients with coronary disease. However, there are few tools to use this information to guide clinical decisions. We evaluated the relationship between 25 variables and total mortality and arrhythmic death in 674 patients enrolled in the MUSTT (Multicenter Unsustained Tachycardia Trial) study that did not receive antiarrhythmic therapy. We then constructed risk-stratification algorithms to weight the prognostic impact of each variable on arrhythmic death and total mortality risk. The variables having the greatest prognostic impact in multivariable analysis were functional class, history of heart failure, nonsustained ventricular tachycardia not related to bypass surgery, EF, age, left ventricular conduction abnormalities, inducible sustained ventricular tachycardia, enrollment as an inpatient, and atrial fibrillation. The model demonstrates that patients whose only risk factor is EF < or =30% have a predicted 2-year arrhythmic death risk <5%. Multiple variables influence arrhythmic death and total mortality risk. Patients with EF < or =30% but no other risk factor have low predicted mortality risk. Patients with EF >30% and other risk factors may have higher mortality and a higher risk of sudden death than some patients with EF < or =30%. Thus, risk of sudden death in patients with coronary disease depends on multiple variables in addition to EF.

Sudden Death Prevention With Implantable Devices

The “modern” era of the treatment of ventricular tachyarrhythmias with device-based therapy may have begun in 1899, when Prevost and Battelli noted, almost as an afterthought, that direct current shock could terminate ventricular fibrillation (VF) in dogs.1 Three decades later, pioneering work in the field of defibrillation concluded that the passage of electrical current across the heart can both initiate and terminate VF.2,3 Still, little attention was paid to this phenomenon, as evidenced by Paul Dudley White’s Heart Disease , which devoted less than half a page to VF and characterized the arrhythmia as “a condition of little importance so far as we know now.”4 In 1947, the thoracic surgeon Claude Beck saved the first human life by the successful use of cardiac defibrillation in a 14-year-old boy who developed VF during a thoracic surgical procedure and went on to achieve a full recovery.5 These early accomplishments provided the foundation for the landmark work of Mirowski and Mower that ultimately led to the development of the implantable cardioverter-defibrillator (ICD) and its introduction in humans in 1980.6 Pacing may prevent sudden cardiac death due to bradyarrhythmias and in certain circumstances such as torsade de pointes associated with congenital long-QT syndrome (LQTS) and pause-dependent ventricular tachycardia (VT). Although no controlled studies exist, retrospective analyses suggest that recurrent torsade de pointes in patients with LQTS may be prevented by continuous pacing.7 Early clinical data on small numbers of patients suggested that the combination of β-adrenergic blockade plus continuous pacing reduced the number of syncopal events and the anticipated rate of sudden death in high-risk LQTS patients.8 The beneficial effects of pacing may be limited to patients with LQT2 and LQT3, in which the transmural dispersion of repolarization worsens steeply during bradycardia.9 Genotype-phenotype correlation confirms that …

Uncertainty on the Use of Aldosterone Antagonists for Primary Therapy for Sudden Cardiac Death in the Setting of Implanted Devices

In the early development of therapy for acute myocardial infarction, it was thought that once the necrotic process had been completed (usually within 24 hours of coronary artery occlusion), additional therapies could not affect outcome. However, after completion of the necrotic process, the myocardial infarction may thin and stretch (involving lengthwise slippage of myocytes), a phenomenon referred to as myocardial infarct expansion. This process causes local left ventricular cavity dilatation followed by gradual global left ventricular dilatation and lengthwise (eccentric) hypertrophy of the noninfarcted tissue. Apoptosis (programmed cell death) and some attempt of the myocardium to regenerate, especially at the infarct border zone, may also contribute to this remodeling process of the ventricle. If the left ventricle remodels in such a way that it becomes very dilated, then the prognosis is poor, and heart failure is more likely to occur.1 These later processes of myocardial infarct expansion and left ventricular remodeling became the target of therapies such as angiotensin-converting enzyme (ACE) inhibition that could be initiated after 24 hours of coronary occlusion. ACE inhibition, angiotensin receptor blockade, and long-term β-blockade have become standard pharmacological approaches for postinfarction left ventricular dysfunction and heart failure. Response by Pitt and Pitt p 2989 Ventricular arrhythmias can occur in both the acute and chronic phases of acute myocardial infarction and can lead to sudden cardiac death (SCD). Reentrant arrhythmias may arise at the border zone of infarcts, causing monomorphic ventricular tachycardia that may occur years after the index infarction. Recurrent myocardial ischemia resulting in an unstable substrate may contribute to polymorphic ventricular tachycardia or ventricular fibrillation. Agents such as β-blockers that are anti-ischemic may reduce sudden death by quieting this unstable substrate. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable defibrillators were shown to reduce mortality in post–myocardial infarction patients with …

Designation and Distribution of Events in the Multicenter UnSustained Tachycardia Trial (MUSTT)

Patients with coronary artery disease, depressed left ventricular ejection fraction, and nonsustained ventricular tachycardia (VT) have a high mortality rate due to arrhythmic (arrhythmic death/cardiac arrest) and other cardiac causes. The Multicenter UnSustained Tachycardia Trial (MUSTT) investigated whether electrophysiologic study (EPS) was helpful in choosing drug or defibrillator therapy in patients induced into sustained VT. The events committee attempted to categorize follow-up events in patients in MUSTT and to present a detailed breakdown of events. A derivative of the Hinkle-Thaler classification was used, incorporating lessons from other multicenter studies. The committee was blinded to results of EPS and implantable cardioverter-defibrillator (ICD) or other antiarrhythmic therapy status of patients. The primary end point was cardiac arrest or death from arrhythmia. Secondary end points were death from all causes, cardiac causes, and spontaneous sustained VT. Classifications were death and cardiac arrest. Each was similarly divided as arrhythmic with 14 subcategories, e.g., unwitnessed or related to EPS and nonarrhythmic with 10 subcategories, e.g., ischemia. Terminal VF in progressive heart failure was considered nonarrhythmic. Events were reviewed by 2 members. Disagreements were resolved by the 2 members or, if needed, by the full committee. Of the 2,202 patients in MUSTT, there were 902 deaths. Sustained VT requiring cardioversion occurred in 182 patients. An additional 94 patients had resuscitated cardiac arrests. Events occurred in 1,027 patients, and all were reviewed. The 3 leading events were deaths that were classed as sudden/unwitnessed (23% of 902), due to progressive heart failure (22%), or due to noncardiovascular causes (18%). Arrhythmic deaths or cardiac arrests were highest in inducible patients randomized to no antiarrhythmic therapy; next were inducible patients receiving an ICD; and lowest were in patients who were noninducible. In conclusion, the classification system provided a detailed breakdown of events in consistent categories, showing utility for event analysis and interpretation and development of therapeutic strategies. The classifications assigned by the committee were used in all MUSTT outcomes reports, thus affecting all reported outcomes and overall interpretations of the MUSTT.

P2-75: Events: Designation & distribution in the Multicenter UnSustained Tachycardia Trial (MUSTT)

P2-75: Events: Designation & distribution in the Multicenter UnSustained Tachycardia Trial (MUSTT)

Cost-Effectiveness of Implantable Cardioverter–Defibrillators

Eight randomized trials have evaluated whether the prophylactic use of an implantable cardioverter-defibrillator (ICD) improves survival among patients who are at risk for sudden death due to left ventricular systolic dysfunction but who have not had a life-threatening ventricular arrhythmia. We assessed the cost-effectiveness of the ICD in the populations represented in these primary-prevention trials. We developed a Markov model of the cost, quality of life, survival, and incremental cost-effectiveness of the prophylactic implantation of an ICD, as compared with control therapy, among patients with survival and mortality rates similar to those in each of the clinical trials. We modeled the efficacy of the ICD as a reduction in the relative risk of death on the basis of the hazard ratios reported in the individual clinical trials. Use of the ICD increased lifetime costs in every trial. Two trials--the Coronary Artery Bypass Graft (CABG) Patch Trial and the Defibrillator in Acute Myocardial Infarction Trial (DINAMIT)--found that the prophylactic implantation of an ICD did not reduce the risk of death and thus was both more expensive and less effective than control therapy. For the other six trials--the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I, MADIT II, the Multicenter Unsustained Tachycardia Trial (MUSTT), the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, the Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) trial, and the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT)--the use of an ICD was projected to add between 1.01 and 2.99 quality-adjusted life-years (QALY) and between 68,300 dollars and 101,500 dollars in cost. Using base-case assumptions, we found that the cost-effectiveness of the ICD as compared with control therapy in these six populations ranged from 34,000 dollars to 70,200 dollars per QALY gained. Sensitivity analyses showed that this cost-effectiveness ratio would remain below 100,000 dollars per QALY as long as the ICD reduced mortality for seven or more years. Prophylactic implantation of an ICD has a cost-effectiveness ratio below 100,000 dollars per QALY gained in populations in which a significant device-related reduction in mortality has been demonstrated.

Optimising the Use of ??-Adrenoceptor Antagonists in Coronary Artery Disease

beta-Adrenoceptor antagonists (beta-blockers) provide multiple benefits to patients with coronary artery disease. The 2001 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for secondary prevention of myocardial infarction (MI) recommend initiating beta-adrenoceptor blockade in all post-MI patients and continuing therapy indefinitely. Atenolol and metoprolol have been shown to decrease vascular mortality in the acute-MI period. In the post-MI period timolol provided a 39% reduction in mortality in the Norwegian Multicenter Study group and propranolol was associated with a 26% reduction in mortality in BHAT (Beta-blocker Heart Attack Trial). beta-Adrenoceptor antagonist therapy results in reduction of myocardial oxygen demand and is therefore also effective for the treatment of angina pectoris. In CAST (Cardiac Arrhythmia Suppression Trial) beta-adrenoceptor antagonist therapy was associated with a significant reduction in arrhythmic death or cardiac arrest. In the post-MI amiodarone trials EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) there was a mortality benefit and decreased arrhythmic death in patients who received both amiodarone and beta-adrenoceptor antagonist therapy, compared with patients receiving amiodarone therapy alone. In the post-MI defibrillator (implantable cardioverter defibrillator [ICD]) trials, AVID (Antiarrhythmic Versus Implantable Defibrillator) and MUSTT (Multicenter Unsustained Tachycardia Trial), beta-adrenoceptor antagonist therapy was independently associated with improved overall survival. The exception was the ICD patients in MUSTT, and the benefit was attenuated in the amiodarone and ICD patients in AVID.AHA/ACC guidelines recommend the use of beta-adrenoceptor antagonists in all patients with symptomatic left ventricular dysfunction, based on several large, controlled heart failure trials. Extended-release metoprolol succinate reduced all-cause mortality by 34% in MERIT-HF (Metoprolol Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure). Bisoprolol was associated with a 34% mortality benefit in CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and carvedilol was associated with a 35% mortality reduction in the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) trial. beta-Adrenoceptor antagonists reduce perioperative mortality in patients undergoing cardiac as well as non-cardiac surgery; however, they remain underutilised. Contraindications to beta-adrenoceptor antagonist therapy include severe bradycardia, high-grade atrioventricular block, marked sinus node dysfunction and acute exacerbations of heart failure. Many of the perceived adverse effects of beta-adrenoceptor antagonists have not been substantiated by large clinical trials.beta-Adrenoceptor antagonists differ with regard to receptor selectivity, receptor affinity, lipophilicity and intrinsic sympathomimetic activity. Beneficial properties of beta-adrenoceptor antagonists may not always be extrapolated as a class effect, and patient selection and drug preparations should follow trial guidelines. The beneficial effects of beta-adrenoceptor antagonists are clearly proven in cardiac patients and those at risk for cardiac disease. They are indicated for heart failure and proven beneficial in patients undergoing cardiac and non-cardiac surgery. These benefits appear to be consistent across most patient subgroups. beta-Adrenoceptor antagonists are generally well tolerated, yet significant morbidity and mortality result from their continued underutilisation.

Predictive Characteristics of Holter‐Based Postinfarction Risk Stratifiers Appear Superior to Electrophysiological Testing

Prevalent low-frequency (PLF) oscillation of heart rate and turbulence slope (TS) are both powerful postmyocardial infarction (MI) risk factors. Abnormal composite risk stratifier (CRS) was defined as abnormal PLF or abnormal TS when PLF was not analyzable. We compared the predictive power of CRS with the previously published predictive value of conventional electrophysiological (EP) testing based on the presence of nonsustained ventricular tachycardia (NSVT) and inducibility of sustained ventricular tachycardia/fibrillation (VT/VF) during programmed ventricular stimulation (PVS). PLF and TS were calculated from baseline Holter recordings in the placebo population of European Amiodarone Infarction Myocardial Infarction Trial (EMIAT trial) (n = 633; LVEF </= 40%; 87 deaths; 22-month follow-up). Previously established cut-off values of PLF >/= 0.1 Hz and TS </= 2.5 ms/RR were used. The clinical characteristics of the EMIAT population were similar to those of the Multicenter Unsustained Tachycardia Trial (MUSTT trial). Therefore, we compared the predictive power of CRS and conventional PVS using the values of 35% VT/VF inducibility during PVS in NSVT patients, and a 33% and 50% increase in all-cause and arrhythmic mortality, respectively, associated with VT/VF inducibility in MUSTT. Projecting the predictive power of PVS in MUSTT into the EMIAT population yielded a sensitivity of 13.8% and 14.0% and positive predictive value (PPV) of 27.9% and 14.0% for all-cause and arrhythmic mortality, respectively, whereas an abnormal CRS was associated with sensitivities of 46.0% and 46.5% and PPV of 37.4% and 18.7%. Compared with the noninvasive Holter-based CRS, invasive PVS appears inferior in the identification of high-risk post-MI patients with left ventricular dysfunction.

Electrocardiographic predictors of arrhythmic death and total mortality in the Multicenter Unsustained Tachycardia Trial

Electrocardiographic predictors of arrhythmic death and total mortality in the Multicenter Unsustained Tachycardia Trial

Implantable cardioverter defibrillator therapy in postinfarction patients

In the past few years, new clinical trials were conducted to determine the effectiveness of implantable cardioverter defibrillators (ICDs) for prevention of mortality in patients with ischemic and nonischemic cardiomyopathies. This paper aims to provide an overview of the current state of knowledge regarding ICD therapy in postinfarction patients. Postinfarction patients with severe left ventricular dysfunction are at high risk of sudden cardiac death. Antiarrhythmic therapy does not improve survival in such patients and, therefore, ICDs emerged as treatment of choice for both primary and secondary prevention of mortality after MI. The MADIT (Multicenter Automatic Defibrillator Implantation Trial) and MUSTT (Multicenter Unsustained Tachycardia Trial) trials were the first primary prevention ICD trials documenting a substantial reduction in mortality with an ICD in postinfarction patients with depressed ejection fraction, nonsustained ventricular tachycardia, and inducible sustained ventricular tachycardia. The recently completed MADIT II trial broadened indications for prophylactic use of ICD in postinfarction patients with ejection fraction of 30% or less without a requirement for additional risk stratifiers. The benefit from ICD therapy in patients with low ejection fraction was recently confirmed by results from the SCD-HeFT (Sudden Cardiac Death in Heart Failure) and COMPANION (Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure) trials. Recent clinical trials established ICD as an important therapeutic modality for primary and secondary prevention of mortality in postinfarction patients.