Individualizing decisions for patients with prophylactic implantable cardiac defibrillators subject to device advisories: a commentary.
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Arrhythmias, Cardiac↗
Biomedical subjects
J Thomas Bigger
Publications and source records attributed to J Thomas Bigger.
"Indeterminate" microvolt T-wave alternans tests predict high risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction.
OBJECTIVES: This study tested the hypothesis that an "indeterminate" microvolt T-wave alternans (MTWA) test, when due to ectopy, unsustained MTWA, or low exercise heart rate (HR), has prognostic significance similar to a positive MTWA test. BACKGROUND: MTWA testing, used to stratify risk of sudden or total mortality in patients with structural heart disease, has been limited by a substantial number of "indeterminate" tests. Indeterminate tests are due to patient factors--excessive ventricular ectopy during exercise, unsustained MTWA, or failure to achieve a HR of 105 beats/min for 1 min--or technical factors such as a noisy recording or an exercise protocol that causes an excessively rapid rise in HR. METHODS: Patients in sinus rhythm with left ventricular ejection fraction < or =0.40 underwent MTWA exercise tests, analyzed with the spectral method and classified by a computerized interpretation algorithm. The primary end point was all-cause mortality or documented non-fatal sustained ventricular arrhythmia (SVA). "Indeterminate" tests were reviewed jointly by 2 readers blinded to subsequent events to determine the primary reason for indeterminacy. RESULTS: Participants (N = 549) were 56 +/- 13 years and 71% male; 49% had ischemic cardiomyopathy. There were 40 deaths and 11 non-fatal SVA. Most (94%) indeterminate results were due to patient factors. The 2-year rate for death or SVA was 17.8% in patients with an "indeterminate" MTWA test compared with 12.3% in those with a positive test. CONCLUSIONS: In patients with left ventricular dysfunction, an "indeterminate" MTWA test due to patient factors predicted death or SVA at least as well as a positive test.
Adult↗
Cost-effectiveness of a microvolt T-wave alternans screening strategy for implantable cardioverter-defibrillator placement in the MADIT-II-eligible population.
OBJECTIVES: This study was designed to compare the cost-effectiveness of implantable cardioverter-defibrillator (ICD) placement with and without risk stratification with microvolt T-wave alternans (MTWA) testing in the MADIT-II (Second Multicenter Automatic Defibrillator Implantation Trial) eligible population. BACKGROUND: Implantable cardioverter-defibrillators have been shown to prevent mortality in the MADIT-II population. Microvolt T-wave alternans testing has been shown to be effective in risk stratifying MADIT-II-eligible patients. METHODS: On the basis of published data, cost-effectiveness of three therapeutic strategies in MADIT-II-eligible patients was assessed using a Markov model: 1) ICD placement in all; 2) ICD placement in patients testing MTWA non-negative;, and 3) medical management. Outcomes of expected cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness were determined for patient lifetime. RESULTS: Under base-case assumptions, providing ICDs only to those who test MTWA non-negative produced a gain of 1.14 QALYs at an incremental cost of 55,700 dollars when compared to medical therapy, resulting in an incremental cost-effectiveness ratio (ICER) of 48,700 dollars/QALY. When compared with a MTWA risk-stratification strategy, placing ICDs in all patients resulted in an ICER of 88,700 dollars/QALY. Most (83%) of the potential benefit was achieved by implanting ICDs in the 67% of patients who tested MTWA non-negative. Results were most sensitive to the effectiveness of MTWA as a risk-stratification tool, MTWA negative screen rate, cost and efficacy of ICD therapy, and patient risk for arrhythmic death. CONCLUSIONS: Risk stratification with MTWA testing in MADIT-II-eligible patients improves the cost-effectiveness of ICDs. Implanting defibrillators in all MADIT-II-eligible patients, however, is not cost-effective, with one-third of patients deriving little additional benefit at great expense.
Aged↗
Onset of major depression associated with acute coronary syndromes: relationship of onset, major depressive disorder history, and episode severity to sertraline benefit.
CONTEXT: Depression observed following acute coronary syndrome (ACS) is common and associated with an increased risk of death. The Sertraline Antidepressant Heart Attack Trial (SADHART) tested the safety and efficacy of a selective serotonin reuptake inhibitor in this population. No evidence of harm was seen, and sertraline hydrochloride had an overall beneficial effect on mood that occurred primarily in patients with a history of episodes of major depressive disorder (MDD). OBJECTIVES: To determine how frequently the MDD began before ACS and whether onset of the current MDD episode before or after the ACS event influenced response to sertraline. DESIGN, SETTINGS, AND PARTICIPANTS: A randomized, double-blind, placebo-controlled treatment of 369 patients with ACS and MDD was conducted in 40 outpatient clinics in 10 countries between April 1, 1997, and April 30, 2001. MAIN OUTCOME MEASURES: Diagnosis of MDD, number of previous episodes of depression, and episode onset before or after hospitalization were established using the Diagnostic Interview Schedule. Treatment response was measured with the Clinical Global Impression-Improvement scale. RESULTS: Fifty-three percent of MDD episodes began before hospitalization for the index episode of ACS (for 197 of 369 patients), and 94% of the MDD episodes began more than 30 days before the index ACS episode. Episodes of MDD that began prior to ACS responded more frequently to sertraline than to placebo (63% vs 46%, respectively; odds ratio, 2.0; 95% confidence interval, 1.13-3.55) whereas depression with onset beginning after hospitalization showed a high placebo response rate (69% vs 60%, respectively) and low sertraline-placebo response ratio (1.15). Multivariate analysis indicated that time of onset of the current episode, history of MDD, and baseline severity independently predicted the sertraline-placebo response ratio. CONCLUSIONS: Half of the episodes of major depression associated with ACS began long before ACS and therefore were not caused by ACS. Patients whose current episodes of MDD begin before ACS, those with a history of MDD, and those whose episodes are severe should be treated because they will benefit considerably from sertraline. Since these 3 predictors of sertraline response are independent, having more than 1 of them substantially increases the benefit of sertraline while reducing the chance of spontaneous recovery.
Acute Disease↗
Assessment and treatment of depression in patients with cardiovascular disease: National Heart, Lung, and Blood Institute working group report.
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Academic Medical Centers↗
Microvolt T-wave alternans and the risk of death or sustained ventricular arrhythmias in patients with left ventricular dysfunction.
OBJECTIVES: This study hypothesized that microvolt T-wave alternans (MTWA) improves selection of patients for implantable cardioverter-defibrillator (ICD) prophylaxis, especially by identifying patients who are not likely to benefit. BACKGROUND: Many patients with left ventricular dysfunction are now eligible for prophylactic ICDs, but most eligible patients do not benefit; MTWA testing has been proposed to improve patient selection. METHODS: Our study was conducted at 11 clinical centers in the U.S. Patients were eligible if they had a left ventricular ejection fraction (LVEF) < or =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 functional class IV heart failure. Participants underwent an MTWA test and then were followed for about two years. The primary outcome was all-cause mortality or non-fatal 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 non-fatal sustained ventricular arrhythmias) occurred. Comparing patients with normal and abnormal MTWA tests, the hazard ratio for the primary end point was 6.5 at two years (95% confidence interval 2.4 to 18.1, p < 0.001). Survival of patients with normal MTWA tests was 97.5% at two years. The strong association between MTWA and the primary end point was similar in all subgroups tested. CONCLUSIONS: Among patients with heart disease and LVEF < or =0.40, MTWA can identify not only a high-risk group, but also a low-risk group unlikely to benefit from ICD prophylaxis.
Arrhythmias, Cardiac↗
Implantable cardioverter defibrillators and cardiac resynchronization therapy in patients with left ventricular dysfunction: randomized trial evidence through 2004.
Although many studies have shown that implantable cardioverter defibrillator (ICD) therapy improves the survival of patients with significant left ventricular dysfunction, the magnitude of effectiveness of ICD therapy in clinically defined subgroups remains uncertain. Similarly, although studies have shown an improvement in patients' hemodynamics and quality of life with cardiac resynchronization therapy (CRT), there is a continuing uncertainty about the effect of CRT on patients' survival and the magnitude of improvement in quality of life with this therapy. On August 24, 2004, an ad hoc group of experts representing clinical cardiovascular medicine, biostatistics, economics, and health policy were joined by representatives of the Food and Drug Administration, Centers for Medicare and Medicaid Services (Baltimore, Md), Agency for Healthcare Research and Quality (Rockville, Md), and the device industry for a 1-day round table to review the available clinical trial evidence on the effect of ICD therapy in the primary prevention of sudden cardiac death and the effect of CRT in patients with congestive heart failure. The meeting was organized by the Duke Clinical Research Institute, Durham, NC, and funded in part by the Agency for Healthcare Research and Quality. This document summarizes the evidence reviewed at that meeting and the discussions of that evidence.
Death, Sudden, Cardiac↗
Heart rate variability: measurement and clinical utility.
Electrocardiographic RR intervals fluctuate cyclically, modulated by ventilation, baroreflexes, and other genetic and environmental factors that are mediated through the autonomic nervous system. Short term electrocardiographic recordings (5 to 15 minutes), made under controlled conditions, e.g., lying supine or standing or tilted upright can elucidate physiologic, pharmacologic, or pathologic changes in autonomic nervous system function. Long-term, usually 24-hour recordings, can be used to assess autonomic nervous responses during normal daily activities in health, disease, and in response to therapeutic interventions, e.g., exercise or drugs. RR interval variability is useful for assessing risk of cardiovascular death or arrhythmic events, especially when combined with other tests, e.g., left ventricular ejection fraction or ventricular arrhythmias.
Autonomic Nervous System↗
Microvolt T-wave alternans distinguishes between patients likely and patients not likely to benefit from implanted cardiac defibrillator therapy: a solution to the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II conundrum.
BACKGROUND: In 2003, the Centers for Medicaid and Medicare Services recommended QRS duration as a means to identify MADIT II-like patients suitable for implanted cardiac defibrillator (ICD) therapy. We compared the ability of microvolt T-wave alternans and QRS duration to identify groups at high and low risk of dying among heart failure patients who met MADIT II criteria for ICD prophylaxis. METHODS AND RESULTS: Patients with MADIT II characteristics and sinus rhythm had a microvolt T-wave alternans exercise test and a 12-lead ECG. Our primary end point was 2-year all-cause mortality. Of 177 MADIT II-like patients, 32% had a QRS duration >120 ms, and 68% had an abnormal (positive or indeterminate) microvolt T-wave alternans test. During an average follow-up of 20+/-6 months, 20 patients died. We compared patients with an abnormal microvolt T-wave alternans test to those with a normal (negative) test, and patients with a QRS >120 ms with those with a QRS < or =120 ms; the hazard ratios for 2-year mortality were 4.8 (P=0.020) and 1.5 (P=0.367), respectively. The actuarial mortality rate was substantially lower among patients with a normal microvolt T-wave alternans test (3.8%; 95% confidence interval: 0, 9.0) than the mortality rate in patients with a narrow QRS (12.0%; 95% confidence interval: 5.6, 18.5). The corresponding false-negative rates are 3.5% and 10.2%, respectively. CONCLUSIONS: Among MADIT II-like patients, a microvolt T-wave alternans test is better than QRS duration at identifying a high-risk group and also better at identifying a low-risk group unlikely to benefit from ICD therapy.
Aged↗
Sudden cardiac death in patients with diabetes.
Sudden cardiac death (SCD) affects over 450,000 people in the United States annually. The mechanisms involved are poorly understood. The predictors currently known include traditional coronary heart disease risk factors, electrocardiographic abnormalities, cardiac autonomic neuropathy, left ventricular hypertrophy, cardiomyopathy, and conduction abnormalities. Diabetes mellitus and impaired glucose tolerance are of special importance due to their increased prevalence reaching epidemic proportions and the elevated risk of SCD in people with these disorders. This article reviews the current predictors of SCD with a focus on people with diabetes, hoping to offer physicians and researchers a better understanding of and a solid ground for further needed research on this important cause of premature death.
Death, Sudden, Cardiac↗
Seasonal variation of mortality in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study registry.
OBJECTIVES: We postulated that the pattern of death would be nonrandom with respect to temporal variables. BACKGROUND: Previous studies have demonstrated increased sudden death is associated with periods of relative stress, and overall mortality is associated with temporal variables. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, vital status was obtained for 4,450 patients (who had a recent episode of sustained ventricular arrhythmias or unexplained syncope and inducible ventricular tachycardia) through the National Death Index Service as of December 31, 1997 (follow-up 25.5 +/- 13.7 months). RESULTS: Mortality was not associated with the day of the week or with holidays but was associated with season (P = .033). Seasonal variation was present both in northern and southern sites. Mortality was higher during the winter months compared to the remaining months (111.2% in winter vs 96.5% in other months, P = .036). In addition, increased mortality was associated with a high-risk season variable defined (prior to evaluation of treatment arm associations) as spring in the north and winter in the south (P < .001). The hazard ratio for death associated with this "high-risk season" measured 1.25 (P = .001) compared to the other seasons in each region. A test of interaction between "high-risk" season and implantable cardioverter-defibrillator (ICD) status suggested that the group with ICDs experienced reduced mortality during the "high-risk season" compared to the group without ICDs (P = .047). CONCLUSIONS: Mortality was higher in the winter months and in the respective regional "high-risk" seasons. Furthermore, seasonal variation in mortality may have been due to variation in sudden arrhythmic death, and associated increases in mortality were reduced by ICD therapy.
Anti-Arrhythmia Agents↗
Physical health monitoring of patients with schizophrenia.
OBJECTIVE: Schizophrenia is associated with several chronic physical illnesses and a shorter life expectancy, compared with life expectancy in the general population. One approach to improving the health of patients with schizophrenia is to improve the monitoring of physical health that occurs in psychiatric settings. The authors discuss a consensus panel's recommendations for improving the physical health monitoring of patients with schizophrenia who are treated in outpatient settings. METHOD: A consensus meeting including psychiatric and other medical experts assembled on October 17-18, 2002, to evaluate the existing literature and to develop recommendations for physical health monitoring of patients with schizophrenia. Conference participants reviewed the literature in the following areas: 1) weight gain and obesity; 2) diabetes; 3) hyperlipidemia; 4) prolongation of the QT interval on the ECG; 5) prolactin elevation and related sexual side effects; 6) extrapyramidal side effects, akathisia, and tardive dyskinesia; 7) cataracts; and 8) myocarditis. Experts for each topic area formulated monitoring recommendations that were discussed by all of the participants until a consensus was reached. RESULTS: Consensus recommendations included regular monitoring of body mass index, plasma glucose level, lipid profiles, and signs of prolactin elevation or sexual dysfunction. Information from monitoring should guide the selection of antipsychotic agents. Specific recommendations were made for cardiac monitoring of patients who receive medications associated with QT interval prolongation, including thioridazine, mesoridazine, and ziprasidone, and for monitoring for signs of myocarditis in patients treated with clozapine. Patients who receive both first- and second-generation antipsychotic medications should be examined for extrapyramidal symptoms and tardive dyskinesia. Patients with schizophrenia should receive regular visual examinations. CONCLUSIONS: The conference participants recommended that mental health care providers perform physical health monitoring that typically occurs in primary care settings for their patients who do not receive physical health monitoring in those settings. This change in usual practice is recommended on the basis of the conference participants' belief that this additional monitoring will result in the earlier detection of common, serious risk factors that could, without detection and intervention, contribute to impaired health of patients with schizophrenia.
Adult↗
Comparison of the prognostic value of RR-interval variability after acute myocardial infarction in patients with versus those without diabetes mellitus.
Diabetic patients have substantially greater long-term mortality after acute myocardial infarction (AMI) than nondiabetic patients. Traditionally, cardiac autonomic neuropathy is believed to contribute significantly to the increased mortality rate in patients with diabetes mellitus. In contrast, a recent study suggested that RR-interval variability (RRV) did not predict mortality after AMI in diabetic patients. We compared, in diabetic and nondiabetic patients, the relation between low RRV and long-term mortality in the Multicenter Post Infarction Program (MPIP), a longitudinal observational study of 715 survivors of AMI, including 117 diabetic patients. We studied the association between mortality and 6 frequency-domain measurements and 1 time-domain measurement of RRV. We tested 2 hypotheses: (1) RRV is lower in diabetic patients; and (2) low RRV is less predictive of mortality in diabetic patients. Reduced RRV was significantly more frequent in diabetic patients than nondiabetic patients for all measurements, except high-frequency (HF) power. In diabetic patients, the association between reduced RRV and long-term mortality was at least as strong as it was in nondiabetic patients for all measurements except HF power; this pattern was found for all-cause, cardiac, and arrhythmic death. In multivariable models, reduced RRV was significantly associated with all-cause mortality in diabetic patients even when adjusted for left ventricular ejection fraction, heart failure class, and ventricular arrhythmias. In our post-AMI sample, RRV provided valuable prognostic information among diabetic patients. Our findings suggest that cardiac autonomic neuropathy plays a role in the high mortality rate seen in diabetic patients after AMI.
Comorbidity↗
Prevention of type 2 diabetes.
Diabetes is a major public health problem that is approaching epidemic proportions in our society and worldwide. Cardiovascular disease is the major cause of morbidity and mortality in people with diabetes. Control of cardiovascular disease risk factors is achieved only in a minority of patients. Given the magnitude of the problem and the seriousness of diabetes complications, prevention appears to be a logical approach to curb the rising prevalence of the disease. Interventions such as lifestyle modifications and the use of metformin and acarbose have been shown in randomized prospective trials to prevent diabetes in high-risk patients. Other interventions are currently being examined in large prospective studies. It is likely that one or a combination of these approaches will make diabetes prevention a reality in the near future.
Adrenergic beta-Antagonists↗
Issues in subgroup analyses and meta-analyses of clinical trials.
This commentary discusses two techniques commonly used to analyze clinical trials: subgroup analysis and meta-analysis. Subgroup analysis is used to evaluate the consistency of a treatment across multiple groups, usually within a clinical trial. Subgroup analysis often is used to generate or test an hypothesis about risk factors or treatment responses. Meta-analysis (overview) is used primarily to summarize data from several randomized clinical trials and to evaluate consistency among trials. Meta-analysis is a formal way of summarizing the totality of information coming from well-conducted randomized clinical trials. The use and limitations of these two techniques are discussed.
Bias↗
Ambulatory electrocardiogram-based tracking of T wave alternans in postmyocardial infarction patients to assess risk of cardiac arrest or arrhythmic death.
INTRODUCTION: This is the first study to assess T wave alternans (TWA) analyzed from routine ambulatory electrocardiograms (AECGs) to identify postmyocardial infarction (post-MI) patients at increased risk for arrhythmic events. METHODS AND RESULTS: The new method of modified moving average (MMA) analysis was used to measure TWA magnitude in 24-hour AECGs from ATRAMI, a prospective study of 1,284 post-MI patients. Using a nested case-control approach, we defined cases as patients who experienced cardiac arrest due to documented ventricular fibrillation or arrhythmic death during the follow-up period of 21 +/- 8 months. We analyzed 15 cases and 29 controls matched for sex, age, site of MI, left ventricular ejection fraction, thrombolysis, and beta-blockade therapy. TWA was reported as the maximum 15-second value at three predetermined times associated with cardiovascular stress: maximum heart rate, 8:00 A.M., and maximum ST segment deviation. TWA increased significantly from baseline in both leads at each time point (P <<0.01) in cases and controls. TWA in V5 increased more in cases than controls during peak heart rate (P = 0.005) and at 8:00 A.M. (P = 0.02). A 4- to 7-fold higher odds of life-threatening arrhythmias was predicted by TWA level above the 75th percentile during maximum heart rate in leads V1 (odds ratio [OR] 4.2, 95% confidence interval [CI]: 1.1-16.3, P = 0.04) and V5 (OR 7.9, 95% CI: 1.9-33.1, P = 0.005). TWA at 8:00 A.M. also predicted risk in leads V1 (OR = 5.0, 95% CI: 1.2-20.5, P = 0.02) and V5 (OR = 4.2, 95% CI: 1.1-16.3, P = 0.04). CONCLUSION: TWA measurement from routine 24-hour AECGs is a promising approach for risk stratification for cardiac arrest and arrhythmic death in relatively low-risk post-MI patients.
Algorithms↗
Cardiovascular health and depression.
Research has shown that depression increases the likelihood that otherwise healthy people will develop ischemic heart disease (IHD) and worsens the prognosis of patients who already have IHD. Moreover, concerns about safety (e.g., cardiac side effects, drug-drug interactions) have caused physicians to be hesitant about using antidepressant agents in patients with IHD. This article is based on a recent roundtable of experts who met to discuss risk, diagnosis, and treatment options for depression in patients with IHD. This article reviews clinical and epidemiological studies that have described a link between depression and the subsequent development of IHD and have examined the role of depression as a predictor of cardiac events in patients with existing IHD. The article addresses the issue of whether depression can be safely and efficaciously treated both in patients with stable IHD and in those with acute coronary syndromes. The authors discuss safety issues related to the potential for interactions between antidepressants and cardiovascular medications, the use of nonpharmacologic treatment options such as psychosocial interventions, and the effect of antidepressant therapy on quality of life in patients with IHD. The article concludes with practical clinical guidance concerning the management of depression in patients who have recently experienced myocardial infarction.
Journal Article↗
Sertraline treatment of major depression in patients with acute MI or unstable angina.
CONTEXT: Major depressive disorder (MDD) occurs in 15% to 23% of patients with acute coronary syndromes and constitutes an independent risk factor for morbidity and mortality. However, no published evidence exists that antidepressant drugs are safe or efficacious in patients with unstable ischemic heart disease. OBJECTIVE: To evaluate the safety and efficacy of sertraline treatment of MDD in patients hospitalized for acute myocardial infarction (MI) or unstable angina and free of other life-threatening medical conditions. DESIGN AND SETTING: Randomized, double-blind, placebo-controlled trial conducted in 40 outpatient cardiology centers and psychiatry clinics in the United States, Europe, Canada, and Australia. Enrollment began in April 1997 and follow-up ended in April 2001. PATIENTS: A total of 369 patients with MDD (64% male; mean age, 57.1 years; mean 17-item Hamilton Depression [HAM-D] score, 19.6; MI, 74%; unstable angina, 26%). INTERVENTION: After a 2-week single-blind placebo run-in, patients were randomly assigned to receive sertraline in flexible dosages of 50 to 200 mg/d (n = 186) or placebo (n = 183) for 24 weeks. MAIN OUTCOME MEASURES: The primary (safety) outcome measure was change from baseline in left ventricular ejection fraction (LVEF); secondary measures included surrogate cardiac measures and cardiovascular adverse events, as well as scores on the HAM-D scale and Clinical Global Impression Improvement scale (CGI-I) in the total randomized sample, in a group with any prior history of MDD, and in a more severe MDD subgroup defined a priori by a HAM-D score of at least 18 and history of 2 or more prior episodes of MDD. RESULTS: Sertraline had no significant effect on mean (SD) LVEF (sertraline: baseline, 54% [10%]; week 16, 54% [11%]; placebo: baseline, 52% [13%]; week 16, 53% [13%]), treatment-emergent increase in ventricular premature complex (VPC) runs (sertraline: 13.1%; placebo: 12.9%), QTc interval greater than 450 milliseconds at end point (sertraline: 12%; placebo: 13%), or other cardiac measures. All comparisons were statistically nonsignificant (P> or = .05). The incidence of severe cardiovascular adverse events was 14.5% with sertraline and 22.4% with placebo. In the total randomized sample, the CGI-I (P =.049), but not the HAM-D (P =.14), favored sertraline. The CGI-I responder rates for sertraline were significantly higher than for placebo in the total sample (67% vs 53%; P =.01), in the group with at least 1 prior episode of depression (72% vs 51%; P =.003), and in the more severe MDD group (78% vs 45%; P =.001). In the latter 2 groups, both CGI-I and HAM-D measures were significantly better in those assigned to sertraline. CONCLUSION: Our results suggest that sertraline is a safe and effective treatment for recurrent depression in patients with recent MI or unstable angina and without other life-threatening medical conditions.
Angina, Unstable↗