In this issue of Congestive Heart Failure, the editor of this department addresses a topic on which there is conflicting data. Dr Tepper selected 2 of the most relevant abstracts for review. His comments on the conflicting data-and the polarized viewpoints among physicians that often result-provide insights on the clinical implications of the controversy.

Context. Because acute decompensated heart failure (HF) causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival. Objective. To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival. Methods. The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial that compared the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated HF who required inotropic support. The trial was conducted at 75 centers in 9 countries, and patients were randomized between March 2003 and December 2004. Interventions. Intravenous levosimendan (n=664) or intravenous dobutamine (n=663). Main Outcome Measure. All-cause mortality at 180 days. Results. All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74–1.13; P=.40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P

Background. Depression is widely recognized as a risk factor in patients with coronary heart disease. Patients with heart failure (HF) have been less frequently studied, however, and the effect of depression on prognosis, independent of disease severity, is uncertain. Methods. A total of 204 outpatients who had a diagnosis of HF, with a ventricular ejection fraction of ≤40%, underwent baseline assessments including evaluation of depressive symptoms using the Beck Depression Inventory (BDI) and of HF severity determined by plasma N-terminal pro-B-type natriuretic peptide. Cox proportional hazards regression analyses were used to examine the effects of depressive symptoms on a combined primary end point of death and hospitalizations because of cardiovascular disease (hereafter referred to as cardiovascular hospitalization) during a median follow-up of 3 years. Results. Symptoms of depression (BDI score) were associated with risk of death or cardiovascular hospitalization (P<.001) after controlling for established risk factors including HF disease severity, ejection fraction, HF etiology, age, and medications. Clinically significant symptoms of depression (BDI score ≥10) were associated with a hazard ratio of 1.56 (95% confidence interval, 1.07–2.29) for the combined end point of death or cardiovascular hospitalization. Contrary to our expectation, antidepressant medication use was associated with increased likelihood of death or cardiovascular hospitalization (hazard ratio, 1.75; 95% confidence interval, 1.14–2.68; P=.01) after controlling for severity of depressive symptoms and for established risk factors. Conclusions. Symptoms of depression were associated with an adverse prognosis in patients with HF after controlling for HF severity. The unexpected association of antidepressant medications with worse clinical outcome suggests that patients with HF who require an antidepressant medication may need to be monitored more closely.—Sherwood A, Blumenthal JA, Trivedi R, et al. Relationship of depression to death or hospitalization in patients with heart failure. Arch Intern Med.2007;167:367–373. Depression is widely considered a significant psychosocial risk factor in patients with coronary artery disease.1 Depression is associated with a substantially increased risk of developing HF in individuals at risk and has been associated with adverse outcomes in patients with established HF. In the present study,2 clinically significant depression—defined as a score of ≥10 on the BDI self-assessment—was identified in 94 of 204 patients with predominantly New York Heart Assocation class II or III HF and left ventricular systolic dysfunction. About one quarter of the patients died and about half were hospitalized due to cardiovascular disease for an average of 3 years. The hazard ratio for death or cardiovascular hospitalization went up significantly with increasing baseline levels of N-terminal pro-B-type natriuretic peptide and with higher BDI scores. Age, left ventricular ejection fraction, and HF etiology showed no independent effects on the composite end point. If depression has an independent effect on HF severity, the pathophysiologic mechanisms could be behavioral, physiologic, or a combination of both. The authors observe that people who are depressed may be less active than others, more likely to smoke, and less likely to comply with prescribed therapies. The authors also observed that increased symptoms of depression are associated with worsened prognosis and that HF disease severity does not account for the association of depression with adverse outcomes. The effect size for depressive symptoms seems to be at least as great as traditional HF disease markers, including left ventricular ejection fraction. Remarkably, the use of antidepressant medications—selective serotonin reuptake inhibitors in 80% of cases—elevated risk. The authors cautioned that observations associating antidepressant medication use with poorer prognosis in patients with HF were unexpected and should be interpreted cautiously because of their novelty and the absence of an established explanatory mechanism. The observations made in the present study do not imply that antidepressant treatment is contraindicated in patients with HF, nor do the findings suggest that antidepressant therapy is not useful. A larger observational cohort study, which might focus on the extent and history of antidepressant use, or a randomized clinical trial evaluating the safety and efficacy of antidepressant treatment in patients with HF with clinical depression is needed to more fully understand the potential effect of treating depression on clinical outcomes. In the interim, patients with HF who require antidepressant medication may need to be monitored more closely. Essentially, it would be a misinterpretation of the data to suggest that antidepressants somehow caused an increase in events.

Background. It is not clear whether long-term antithrombotic treatment has a beneficial effect on the incidence of thromboembolism in chronic heart failure (HF). HELAS (Heart Failure Long-term Antithrombotic Study) is a multi-center, randomized, double-blind, placebo-controlled trial to evaluate antithrombotic treatment in patients with chronic HF. Methods. One hundred ninety-seven HF patients (ejection fraction [EF] <35%) were enrolled. Patients with ischemic cardiomyopathy (ICM) were randomized to receive either aspirin 325 mg or warfarin. Patients with dilated cardiomyopathy (non-ICM) were randomized to receive either warfarin or placebo. Results. Analysis of the data from 312 patient years showed an incidence of 2.2 embolic events per 100 patient years, with no significant difference between groups. The incidence of myocardial infarction (MI), hospitalization, exacerbation of HF, death, and hemorrhage were not different between the groups. No peripheral or pulmonary emboli were reported. Echocardiographic follow-up for 2 years showed an overall increase in left ventricular EF from 28.2%±6% to 30.3%±7%; P<.05, which was most obvious in patients with non-ICM taking warfarin (EF 26.8%±5.3% at baseline, 30.7%±10% at 2 years; P<.05). Conclusions. (1) Overall embolic events are rare in HF regardless of treatment; (2) treatment does not seem to affect outcome.—Cokkinos DV, Haralabopoulos GC, Kostis JB, et al, for the HELAS Investigators. Efficacy of antithrombotic therapy in chronic heart failure: the HELAS study. Eur J Heart Fail. 2006;8:428–32. Comment. The incidence of any thromboembolie event in patients with HF has been reported to range between 2.2 and 2.5 per 100 patient years.1 Stroke has been more common than either peripheral or pulmonary embolism. Three primary factors—severity of myocardial dysfunction, thrombus protruding into the left ventricular cavity, and atrial fibrillation—have been proposed to increase the risk for thromboembolism in patients with HF. The laboratory evidence indicates an increase in platelet activation and plasma viscosity, fibrinogen, von Willebrand factor, and fibrin D-dimer in patients with HF in sinus rhythm.2 The degree of hypercoagulability is related to the severity of the HF, but not to left ventricular EF. It is still unclear how these abnormalities contribute to thrombus formation. Current American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend the use of warfarin in patients with HF and atrial fibrillation or previous thromboembo lie event. The use of anticoagulation in patients with HF and sinus rhythm is still controversial. In the HELAS study, 115 patients with ICM were randomized to either aspirin or warfarin and 82 patients with non-ICM were randomized to either warfarin or placebo, with approximately a 2-year follow-up. There were no significant differences in the primary composite end point of death, MI, hospitalization, HF exacerbation, or hemorrhage over 312 patient years. No peripheral or pulmonary thromboemboli were observed, according to the study. Echocardiography at 2 years disclosed a mean 2% increase in left ventricular EF among warfarin recipients, a significant difference driven by a mean 4% rise among non-ICM patients on warfarin (P<.05 for both differences) . Patients with ICM did not show a significant left ventricular EF benefit. The enrollment at the 40 participating centers was slow and fell far short of the 6000-patient target, so the investigators stopped randomizing patients and proceeded with the analysis. This study is similar to the previous 2 randomized explorations held to clarify this issue. The Warfarin and Antiplatelet Therapy in Heart Failure Trial (WATCH)3 conducted in North America and the United Kingdom enrolled 1587 similar patients (about 40% of its target enrollment) and randomized them to warfarin, clopidogrel, or aspirin, with an almost 2-year follow-up. The rates of death, MI, and stroke, both as individual end points and as composite end points, turned out about the same in the 3 groups. The Warfarin/Aspirin Study in Heart Failure (WASH)4 compared warfarin, aspirin, or neither in 279 patients with HF. The study found no significant differences in the primary end point of death, nonfatal MI, or nonfatal stroke over an average of 27 months. Both of these trials observed a significant increase in the rate of HF hospitalizations with aspirin therapy. This was suggested to be the result of an interaction of aspirin and angiotensin-converting enzyme (ACE) inhibitors. However, the same finding has not been observed in HELAS. This could be due to the fact that the use of ACE inhibitors in HELAS was only 60%. In conclusion, the randomized studies have failed to support the contention that anticoagulation should be provided to patients with HF and sinus rhythm. The incidence of thromboembolic event is low enough not to provide a favorable benefit-to-risk ratio. On the other hand, HELAS failed to reach its target enrollment goal. So this debate continues, and until further trials, anticoagulation must be individualized to the HF patient in sinus rhythm. Anticoagulation should be considered in patients with extensive regional wall motion abnormalities and low EF or mural thrombus. Objectives. The authors aimed to determine whether intensive statin therapy reduces hospitalization for heart failure (HF) in high-risk patients. Background. While the relationship between intensive statin therapy and ischemic events is well established, its relationship to the risk of HF after an acute coronary syndrome (ACS) is not well defined. Methods. The Pravastatin or Atorvastatin Evaluation and Infection Trial—Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) study randomized 4162 patients stabilized after ACS to either intensive statin therapy (atorvastatin 80 mg) or moderate statin therapy (pravastatin 40 mg). Hospitalization for HF occurring more than 30 days after randomization was determined during a mean follow-up of 24 months. B-type natriuretic peptide (BNP) levels were measured at baseline (median, 7 days after randomization). Results. Treatment with atorvastatin 80 mg significantly reduced the rate of hospitalization for HF (1.6% vs 3.1%; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.35–0.85; P=.008) independently of a recurrent myocardial infarction (MI) or prior history of HF. The risk of HF increased steadily with increasing quartiles of BNP (HR, 2.6; 95% CI, 1.2–5.5; P=.016 for the highest quartile compared with the lowest). Among patients with elevated levels of BNP (>80 pg/mL), treatment with atorvastatin significantly reduced the risk of HF compared with pravastatin (HR, 0.32; 95% CI, 0.13–0.8; P=.014). A meta-analysis of 4 trials that included 27,546 patients demonstrates a 27% reduction in the odds of hospitalization for HF with intensive statin therapy. Conclusions. Intensive statin therapy reduces the risk of hospitalization for HF after ACS, with the most gain in patients with elevated levels of BNP—Scirica BM, Morrow DA, Cannon CP, et al, for the PROVE IT-TIMI 22 Investigators. Intensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study. J Am Coll Cardiol. 2006;47:2326–2331. Comment. The effects of intensive lipid-lowering therapy in reducing the risk of death and recurrent ischemia in patients hospitalized for ACS are well known.5 The effects of intensive lipid-lowering therapy in reducing the risk of HF after ACS have not been well described in the literature. PROVE IT-TIMI 22 enrolled 4162 patients hospitalized for ACS. Eligible patients included those who were stable and had a total cholesterol level within the first 24 hour after the onset of the index event <240 mg/dL, or <200 mg/dL if they were on prior lipid-lowering therapy. The patients were randomly assigned to receive either pravastatin 40 mg or atorvastatin 80 mg daily. About 75% of patients in PROVE IT-TIMI 22 trial were not on any lipid-lowering therapy. The patients were followed for an average of 24 months. The end point included the rate of hospitalizations for HF. The primary efficacy outcome was the time to first occurrence of HF that occurred 30 days or longer after randomization. There were no significant differences in the baseline characteristics between the two groups, including diabetes, hypertension, rates of prior MI or revascularization, baseline BNP levels, and prior history of HF (3.2% for atorvastatin vs 3.5% for pravastatin). There were also no significant differences in the rates of ST-segment elevation MI or the rate of revascularization for the index event. Treatment with atorvastatin 80 mg was associated with a 1.5% absolute reduction in the rate of hospitalization for HF (HR, 0.55; 95% CI, 0.35–0.85; P=.008), and this effect was not mitigated even after controlling for recurrent MI or history of HF. This benefit continued to hold true even after excluding all patients (n=36) who developed HF after having suffered a recurrent MI or recurrent ischemia requiring hospitalization or revascularization. Patients with elevated baseline levels of BNP (≥80 pg/mL) and randomized to pravastatin had the highest rate of hospitalization for HF (6.9%) compared with atorvastatin (2.2%). Assignment to atorvastatin significantly reduced the risk of the development of HF among patients with elevated levels of BNP (HR, 0.32; 95% CI, 0.13–0.8; P=.014). The concentration of BNP showed a significant graded relationship with the risk of HF, with significantly higher risk of HF among patients in the highest (BNP >65 pg/mL) compared with the lowest quartile (BNP <15 pg/mL) (HR, 2.6; 95% CI, 1.2–5.5; P=.016). The meta-analysis of the 4 trials (Treating to New Targets [TNT], A to Z, PROVE IT, and Incremental Decrease in Clinical End Points Through Aggressive Lipid Lowering [IDEAL]) that compared intensive statin therapy with moderate statin therapy demonstrated a highly significant 27% reduction in the odds of hospitalization for HF (N=27,546; OR, 0.73; 95% CI, 0.63–0.84; P<.001). All in all, the effect of intensive statin therapy on the development of HF is still a matter of debate, although various retrospective and secondary analyses seem to support the contention that intensive statin therapy may lead to a reduced rate of hospitalizations for HF after ACS. The mechanism of such benefit is also not very clear, although a few hypotheses have been proposed.6, 7 The limitation that the end point was a prespecified secondary end point of the previous trial and was chosen to identify only serious presentations of HF may have led to an underestimation of the true incidence of HF in this study. Further randomized trials specifically looking into such analysis need to be conducted to elucidate the effect of intensive statin therapy on the development of HF.

Background. 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. Methods. 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. Results. 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 and $101,500 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 to $70,200 per QALY gained. Sensitivity analyses showed that this cost-effectiveness ratio would remain below $100,000 per QALY as long as the ICD reduced mortality for seven or more years. Conclusion. 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.—Sanders GD, Hlatky MA, Owens DK. Cost-effectiveness of implantable cardioverter-defibrillatars. N Engl J Med. 2005;353:1471-1480. Comment. As physicians, we are generally too focused on the best possible therapy for our patients regardless of the cost. In view of our increasing national health care expenditure, however, we do need to bring financial equation into clinical medicine. We are not suggesting that one should withhold treatments from patients for fear of increasing health care costs, but we do need to be cognizant of the financial impact of our clinical decisions. The United States currently spends about 15% of its $38,000 per capita annual gross domestic product on health care—about $6,000 per year of life per person. The Centers for Medicare &. Medicaid Services estimate that as many as 500,000 Medicare beneficiaries might be eligible to receive a prophylactic ICD in the United States. Given the substantial cost of the ICD, the economic effect of this strategy deserves a cost-effectiveness analysis. Before proceeding further, we would like to remind readers that the accepted cost-effectiveness threshold for one QALY is about $35,000–$50,000, on the basis of the presumed cost of Medicare's end-stage renal disease program. So, directly or indirectly, all cost-effectiveness analyses try to achieve this Holy Grail, albeit a poor parameter in itself. One should also be aware of the fact that the cost of these devices changes over time, leading to more favorable cost effectiveness analyses in the future. So what may not be cost-effective today may be the best intervention a few years later based on the pricing structure. The authors of the present study demonstrate that the lifetime cost per QALY gained by the implantation of an ICD ranges from $34,000 to $70,200 among patients whose expected relative benefit is 23% or greater, thus approximating the usually accepted threshold. Their baseline analysis also assumed that the receipt of an ICD would not change a patient's quality of life, although such an event could decrease the quality of life of a patient who is bothered by implanted hardware or increase it by increasing a patient's self-assuredness. Even small changes in a patient's quality of life can drive cost effectiveness. Nevertheless, the fundamental message of the authors is that ICDs probably have an acceptable cost-effectiveness ratio when used in populations in which a significant device-related reduction in mortality exists. No therapy should be assumed to have a single, simple value for cost effectiveness, since its cost effectiveness can vary substantially depending on the type of patient being considered. Although this is a well done analysis from a very reputable center, it has multiple inherent limitations. The authors used only summary data from each trial, so projections may not match the results of prospective economic studies that may be done within the individual trials. The authors also made lifetime projections of the clinical and economic outcomes of the prophylactic implantation of an ICD—an approach that required quite a few assumptions. Last but not least, the present analysis is limited to ICDs and cannot be extrapolated to the newer devices that include cardiac resynchronization capability. The added cost and complexity of these combined devices suggest that their cost effectiveness may be quite different from that of ICDs alone.

Background. Systemic inflammation has long been recognized as a precipitator of acute congestive heart failure (CHF). The impact of inflammation on prognosis in acute CHF, however, is unknown. Methods. This study evaluated the prognostic role of inflammation among 214 consecutive patients presenting to the emergency department with acute CHF. Patients were stratified according to C-reactive protein (CRP) levels determined on admission. The primary end point was all-cause mortality during 24-month follow-up. Results. The median CRP level was 13.0 mg/L, with an intertertile range of 6.0–25.0 mg/L. Initial and long-term outcomes were significantly different, to the detriment of patients with higher CRP levels. Patients in the highest CRP tertile significantly more often required admission to the intensive care unit (33% vs. 14% in patients in the first tertile; p=0.028) and died inhospital (15% vs. 2% in patients in the first tertile; p=0.027). Cumulative 24-month mortality rates were 33.5% in the first, 42.4% in the second, and 53.6% in the third tertile (p=0.0265 by log-rank test). After multivariate adjustment, CRP remained an independent predictor of death (hazard ratio, 1.4; 95% confidence interval, 1.1–1.8 for each step up in tertile; p=0.044). Conclusions. Inflammation is a significant and independent predictor of long-term mortality in patients with acute CHF.—Mueller C, Laule-Kilian K, Christ A, et al. Inflammation and long'term mortality in acute CHE Am Heart J. 2006; 151:845–850. CRP is a nonspecific acute-phase reactant with serum levels that are usually high in patients with inflammation or infection. Various retrospective trials have clearly suggested that high CRP levels amount to higher risk of mortality and morbidity in patients with ischemic heart disease. Despite clinical and economic burden of acute heart failure, it is poorly understood whether acute heart failure is a distinct entity or exacerbation of chronic heart failure. Limited data on the triggers for acute heart failure have suggested a heterogeneous mix of biologic and patient-related factors, including ischemia, arrhythmias, hypertension, and noncompliance.1 Although all these factors clearly can contribute to heart failure decompensation, more fundamental understanding of the biologic basis for acute heart failure is lacking. The lack of such fundamental insights has resulted in correspondingly limited development of new therapies, as evidenced by the similarities between old (oxygen, morphine, nitrates, and loop diuretics)2 and current clinical recommendations. Mueller and colleagues provide potentially important data on a link between inflammation and acute heart failure. In a cohort study of 214 patients presenting with acute dyspnea due to heart failure, the authors of the present study demonstrate that elevation of CRP at the time of acute heart failure presentation is associated with adverse short- and long-term clinical outcomes. Clinical 360-day follow-up data were available for all of the patients. Mean length of follow-up was 783 days. The median CRP level was 13.0 mg/L. The primary end point at 720 days including death or rehospitalization was 46.3%, 58.3%, and 63% in the first, second, and third tertiles, respectively. The patients with admission CRP values in the highest tertile not only had higher rates of intensive care unit admission and inhospital mortality, but they also had significantly higher rates of rehospitalization and long-term mortality. Most of the benefit in the rates of primary end points was confined to the first 3 months of follow-up. These results persisted despite adjustment for an array of other clinical variables on admission. This raises a key issue in understanding the role of inflammatory mediators in heart failure progression: Is inflammation (as represented by CRP elevation) the cause or the result of acute heart failure decompensation? The authors speculate that CRP elevation may be the result of bacterial or endotoxin translocation from the bowel during mesenteric ischemia in the setting of acute heart failure. Elevated CRP may reflect a greater burden of proinflammatory cytokines that acts as a trigger for decompensation and also plays a role in the long-term progression of heart failure. Corresponding to some animal data showing increased diastolic dysfunction after infusion of tumor necrosis factor or interleukin-6, it is notable in the current study that CRP was most elevated in patients with decompensated heart failure and preserved systolic function and retained its strong association with adverse outcomes regardless of ejection fraction. Some limitations of the study deserve to be mentioned. CRP is a nonspecific marker of systemic inflammation. Further research will define which specific inflammatory mediators are most important in the pathogenesis of acute heart failure. Some patients in this study appeared to have concomitant infections, although the association of CRP with outcomes persisted even when these patients were excluded. Finally, the authors did not perform serial measurements of CRP, which would have provided insight into the role of persistent inflammatory activation in long-term heart failure progression. In addition to the association of CRP with outcomes, it is notable that B-type natriuretic peptide and troponin I levels were also most elevated in patients with the highest tertile of CRP values. This finding highlights the fact that these three markers represent potentially important and interrelated processes in the pathophysiology of acute heart failure—myocyte necrosis (troponin), hemodynamic overload (B-type natriuretic peptide), and inflammation (CRP) similar to patients with acute ischemic heart disease. Development of multimarker strategies that incorporate these markers (or some combination of similar markers) will potentially facilitate clinical care and aid in the development of new therapies. Ongoing and future research will be needed to optimize use of available markers for selecting and monitoring response to treatment.

Background. Several randomized controlled trials have demonstrated benefit for implantable cardio-verter-defibrillator (ICD) prophylaxis in selected patients. However, the absolute benefit of ICD prophylaxis on mortality is relatively small (5.6% or 7.2%) in patients selected using left ventricular ejection fraction (LVEF).1 Thus, only a few of the ICDs implanted prophylactically ever deliver appropriate therapy. The Center for Medicare & Medicaid Services (CMS) has accepted the scientific validity of these ICD prophylaxis trials, but has recognized the need for better risk stratification because the inconvenience, adverse effects, and cost of implanting ICDs in all patients who meet the criteria are substantial. Microvolt T-wave alternans (MTWA) testing can identify patients at increased risk of sudden cardiac death. The results of a study dealing with the use of MTWA in patients with either ischemic heart disease or nonischemic cardiomyopathy and LVEF ≤0.40 have recently been published. Methods. The study hypothesized that MTWA improves the selection of patients for ICD prophylaxis, especially by identifying patients who are not likely to benefit. The study was conducted at 11 clinical centers in the United States. Patients were eligible if they had an LVEF ≤0.40 and lacked a history of sustained ventricular arrhythmias; patients were excluded for atrial fibrillation, unstable coronary artery disease, or New York Heart Association (NYHA) functional class IV heart failure. Participants underwent an MTWA test and then were followed for approximately 2 years. The primary outcome was all-cause mortality or nonfatal sustained ventricular arrhythmias. Results. Ischemic heart disease was present in 49%, mean LVEF was 0.25, and 66% had an abnormal MTWA test. During 20±6 months of follow-up, 51 end points (40 deaths and 11 nonfatal sustained ventricular arrhythmias) occurred. Comparing patients with normal and abnormal MTWA tests, the hazard ratio for the primary end point was 6.5 at 2 years (95% confidence interval. 2.4–18.1; p<0.001). Survival of patients with normal MTWA tests was 97.5% at 2 years. The strong association between MTWA and the primary end point was similar in all subgroups tested. Conclusions. The authors concluded that among patients with heart disease and LVEF ≤0.40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit from ICD prophylaxis.—Bloomfield DM, Bigger JT, Steinman RC, et al. Microvolt T-wave altemans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction. J Am Coll Cardiol. 2006;47:456–463. Comment. The MTWA test, widely seen as a potential way to screen out patients who meet reimbursement criteria for primary-prevention ICD therapy, but probably won't ever need it, appeared to live up to that hope in this well designed study. MTWA is a simple test that monitors beat-to-beat microvolt-level variations in the shape of the electrocardiographic T wave during exercise stress. The MTWA is a simple, relatively inexpensive, noninvasive test that can be done routinely in a doctor's office using modifications of currently available exercise testing equipment. This study strongly suggests that MTWA testing can identify a large group of patients with left ventricular dysfunction who have an excellent prognosis and are unlikely to benefit from ICD prophylaxis. The investigators followed 549 patients with an LVEF ≤0.40 and no history of sustained ventricular arrhythmia, 66% of whom had tested positive for T-wave alternans. Most of the patients were in NYHA class II or III heart failure; the average LVEF was 0.25. Over a follow-up of up to 2 years, averaging 20 months, the one third of patients with normal baseline MTWA findings had a 2-year survival of 97.5%. The 11 instances of nonfatal sustained ventricular arrhythmias and 40 deaths were highly concentrated among those who had been MTWA-abnormal. Although LVEF wasn't predictive of such events in multivariate analysis, baseline MTWA emerged as a highly significant risk factor. As if to emphasize MTWA's potential risk-stratification advantage, the test identified a low-risk group among patients considered at especially high risk by conventional criteria. The 2-year event rate was 11.8% among those with an LVEF of 0.31–0.40 and an abnormal MTWA, but it was only 3.5% for an LVEF ≤0.30 with a normal MTWA. Based on MADIT-II2 and SCD-HeFT,3 according to the authors, about 18 or 14 ICDs, respectively, must be implanted to save one life. According to the current analysis, exclusion of lower-risk patients using the MTWA test would drop the number of implanted ICDs per life saved to seven. This improvement in numbers needed to treat to save one life can have a very substantial effect on the modern practice of cardiology, especially if one considers the economic factors. Will the medical community adopt this trial immediately, or wait while MTWA is being confirmed in other trials? Only time will tell.