Possible differential benefits of edetate disodium in post-myocardial infarction patients with diabetes treated with different hypoglycemic strategies in the Trial to Assess Chelation Therapy (TACT).

BACKGROUND: The NIH-funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stable patients age ≥50 who were ≥6 months post myocardial infarction to 40 infusions of an edetate disodium-based regimen or placebo. In 633 patients with diabetes, edetate disodium significantly reduced the primary composite endpoint of mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44-0.79, p < 0.001). The principal secondary endpoint of a composite of cardiovascular death, myocardial infarction, or stroke was also reduced (HR 0.60, 95% CI 0.39-0.91, p = 0.017). It is unknown if the treatment effect differs by diabetes therapy. METHODS: We grouped the subset of 633 patients with diabetes according to glucose-lowering therapy at time of randomization. The log-rank test was used to compare active therapy versus placebo. All treatment comparisons were performed using 2-sided significance tests at the significance level of 0.05 and were as randomized. Relative risks were expressed as HR with associated 95% CI, calculated using the Cox proportional hazards model. RESULTS: There were 162 (25.7%) patients treated with insulin; 301 (47.5%) with oral hypoglycemics only; and 170 (26.8%) receiving no pharmacologic treatment for diabetes. Patients on insulin reached the primary endpoint more frequently than patients on no pharmacologic treatment [61 (38%) vs 49 (29%) (HR 1.56, 95% CI 1.07-2.27, p = 0.022)] or oral hypoglycemics [61 (38%) vs 87 (29%) (HR 1.46, 1.05-2.03, p = 0.024)]. The primary endpoint occurred less frequently with edetate disodium based therapy versus placebo in patients on insulin [19 (26%) vs 42 (48%) (HR 0.42, 95% CI 0.25-0.74, log-rank p = 0.002)], marginally in patients on oral hypoglycemics [38 (25%) vs 49 (34%) (HR 0.66, 95% CI 0.43-1.01, log-rank p = 0.041)], and no significant difference in patients not treated with a pharmacologic therapy [23 (25%) vs 26 (34%) (HR 0.69, 95% CI 0.39-1.20, log-rank p = 0.225)]. The interaction between randomized intravenous treatment and type of diabetes therapy was not statistically significant (p = 0.203). CONCLUSIONS: Edetate disodium treatment in stable, post-myocardial infarction patients with diabetes suggests that patients on insulin therapy at baseline may accrue the greatest benefit. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov identifier: http://clinicaltrials.gov/ct2/show/NCT00044213?term=TACT&rank=7 identifier Trial to Assess Chelation Therapy (TACT), NCT00044213.

Differential Outcomes With Edetate Disodium-Based Treatment Among Stable Post Anterior vs. Non-Anterior Myocardial Infarction Patients.

BACKGROUND: The Trial to Assess Chelation Therapy (TACT) found that chelation therapy significantly reduced clinical events in patients with a history of myocardial infarction (MI). The initial report of TACT included the observation of an interaction between edetate disodium infusions and MI location, as well as diabetes. Thus, we examined in greater detail the effect of edetate disodium chelation therapy as a function of MI location and diabetes. METHODS: Patients (n = 1708) at least 6 weeks post-MI and age ≥ 50 were randomized to receive 40 infusions of a 500 mL chelation solution or placebo (median follow-up 55 months). The effect of edetate disodium on the primary outcome (all-cause mortality, MI, stroke, hospitalization for angina, or coronary revascularization) was assessed as a function of MI location using log-rank test and Cox regression model, adjusting for other prognostic variables. RESULTS: Among patients with post anterior MI (n = 674), chelation was associated with a lower risk of the primary endpoint (HR 0.63, 95% CI 0.47-0.86, p = 0.003) among anterior MI patients, but not in post non-anterior MI (n = 1034) patients (HR 0.96, 95% CI 0.77-1.20, p = 0.702) (p-for-interaction = 0.032). The point estimates for each component of the primary endpoint favored chelation therapy. The differing treatment effect in patients with post anterior vs. non-anterior MI was consistent among patients with or without diabetes and remained significant after adjusting for other prognostic variables (p < 0.01). CONCLUSIONS: Edetate disodium infusions reduced the risk of cardiovascular events among patients with a prior anterior MI. Future studies should focus on replicating these results and understanding the mechanisms of benefit.

The effect of EDTA-based chelation on patients with diabetes and peripheral artery disease in the Trial to Assess Chelation Therapy (TACT).

OBJECTIVE: Approximately 1 in 7 US adults have diabetes; and over 60% of deaths in patients with diabetes have cardiac disease as a principal or contributing cause. Both coronary and peripheral artery disease (PAD) identify high-risk cohorts among patients with diabetes. We have previously demonstrated improved cardiovascular outcomes with edetate disodium-based chelation in post-MI patients with diabetes, enrolled in the Trial to Assess Chelation Therapy (TACT). In these analyses we further studied the effect size of patients with diabetes and severe disease in 2 vascular beds; coronaries, and lower extremity arteries. We questioned whether greater atherosclerotic burden would attenuate the observed beneficial effect of edetate disodium infusions. RESEARCH DESIGN AND METHODS: The multicenter TACT used a double blind, placebo controlled, 2 × 2 factorial design with 1708 participants, randomly assigned to receive edetate disodium-based chelation, or placebo and high dose oral vitamins or placebo. There were 162 (9.5% of 1708) post-MI patients with a diagnosis of diabetes mellitus and PAD for this post hoc analysis. Patients received up to 40 double-blind intravenous infusions of edetate disodium-based chelation, or placebo. The composite primary endpoint of TACT consisted of death from any cause, myocardial infarction, stroke, coronary revascularization and hospitalization for angina. RESULTS: The median age was 66 years, 15% female, 5% non-Caucasian, and BMI was 31. Insulin was used by 32% of patients. Active infusions significantly reduced the primary endpoint compared with placebo infusions (HR, 0.52; 95% CI, 0.30-0.92; P = 0.0069), with a 30% absolute risk reduction in the primary endpoint. There was a marked reduction in total mortality from 24% to 11%, although of borderline significance (P = 0.052). CONCLUSION: Atherosclerotic disease in multiple vascular beds did not attenuate the beneficial effect of edetate disodium infusions in post MI patients with diabetes. Studies now in progress will prospectively test this post hoc finding.

Effect of high-dose oral multivitamins and minerals in participants not treated with statins in the randomized Trial to Assess Chelation Therapy (TACT).

IMPORTANCE: In a prespecified subgroup analysis of participants not on statin therapy at baseline in the TACT, a high-dose complex oral multivitamins and multimineral regimen was found to have a large unexpected benefit compared with placebo. The regimen tested was substantially different from any vitamin regimen tested in prior clinical trials. OBJECTIVE: To explore these results, we performed detailed additional analyses of participants not on statins at enrollment in TACT. DESIGN: TACT was a factorial trial testing chelation treatments and a 28-component high-dose oral multivitamins and multiminerals regimen versus placebo in post-myocardial infarction (MI) patients 50 years or older. PARTICIPANTS: There were 460 (27%) of 1,708 TACT participants not taking statins at baseline, 224 (49%) were in the active vitamin group and 236 (51%) were in the placebo group. SETTING: Patients were enrolled at 134 sites around the United States and Canada. INTERVENTION: Daily high-dose oral multivitamins and multiminerals (6 tablets, active or placebo). MAIN OUTCOME: The primary end point of TACT was time to the first occurrence of any component of the composite end point: all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: The primary end point occurred in 137 nonstatin participants (30%), of which 51 (23%) of 224 were in the active group and 86 (36%) of 236 were taking placebo (hazard ratio, 0.62; 95% confidence interval, 0.44-0.87; P=.006). Results in the key TACT secondary end point, a combination of cardiovascular mortality, stroke, or recurrent MI, was consistent in favoring the active vitamin group (hazard ratio, 0.46; 95% confidence interval, 0.28-0.75; P=.002). Multiple end point analyses were consistent with these results. CONCLUSION AND RELEVANCE: High-dose oral multivitamin and multimineral supplementation seem to decrease combined cardiac events in a stable, post-MI population not taking statin therapy at baseline. These unexpected findings are being retested in the ongoing TACT2.

Heavy Metals, Cardiovascular Disease, and the Unexpected Benefits of Chelation Therapy.

This review summarizes evidence from 2 lines of research previously thought to be unrelated: the unexpectedly positive results of TACT (Trial to Assess Chelation Therapy), and a body of epidemiological data showing that accumulation of biologically active metals, such as lead and cadmium, is an important risk factor for cardiovascular disease. Considering these 2 areas of work together may lead to the identification of new, modifiable risk factors for atherosclerotic cardiovascular disease. We examine the history of chelation up through the report of TACT. We then describe work connecting higher metal levels in the body with the future risk of cardiovascular disease. We conclude by presenting a brief overview of a newly planned National Institutes of Health trial, TACT2, in which we will attempt to replicate the findings of TACT and to establish that removal of toxic metal stores from the body is a plausible mechanistic explanation for the benefits of edetate disodium treatment.

Quality-of-life outcomes with a disodium EDTA chelation regimen for coronary disease: results from the trial to assess chelation therapy randomized trial.

BACKGROUND: The National Institutes of Health.funded Trial to Assess Chelation Therapy (TACT) randomized 1708 stablecoronary disease patients aged .50 years who were .6 months post.myocardial infarction (2003.2010) to 40 infusions ofa multicomponent EDTA chelation solution or placebo. Chelation reduced the primary composite end point of mortality,recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina (hazard ratio, 0.82; 95%confidence interval, 0.69.0.99; P=0.035). METHODS AND RESULTS: In a randomly selected subset of 911 patients, we prospectively collected a battery of quality-of-life(QOL) instruments at baseline and at 6, 12, and 24 months after randomization. The prespecified primary QOL measures were the Duke Activity Status Index (Table I in the Data Supplement) and the Medical Outcomes Study Short-Form 36 Mental Health Inventory-5. All comparisons were by intention to treat. Baseline clinical and QOL variables were well balanced in the 451 patients randomized to chelation and in the 460 patients randomized to placebo. The Duke Activity Status Index improved in both groups during the first 6 months of therapy, but we found no evidence for a treatment-related difference (mean difference [chelation.placebo] during follow-up, 0.9 [95% confidence interval, .0.7 to 2.6; P=0.27]).There was no statistically significant evidence of a treatment-related difference in the Mental Health Inventory-5 during follow-up (mean difference, 1.0; 95% confidence interval, .0.1 to 2.0; P=0.08). None of the secondary QOL measures showed a consistent treatment-related difference. CONCLUSIONS: In stable, predominantly asymptomatic coronary disease patients with a history of myocardial infarction,EDTA chelation therapy did not have a detectable effect on QOL during 2 years of follow-up. CLINICAL TRIAL REGISTRATION: URL: http://clinicaltrials.gov. Unique identifier: NCT00044213.

EDTA chelation therapy alone and in combination with oral high-dose multivitamins and minerals for coronary disease: The factorial group results of the Trial to Assess Chelation Therapy.

BACKGROUND: Disodium ethylenediaminetetraacetic acid (EDTA) reduced adverse cardiac outcomes in a factorial trial also testing oral vitamins. This report describes the intent-to-treat comparison of the 4 factorial groups overall and in patients with diabetes. METHODS: This was a double-blind, placebo-controlled, 2 × 2 factorial multicenter randomized trial of 1,708 post-myocardial infarction (MI) patients ≥50 years of age and with creatinine ≤2.0 mg/dL randomized to receive 40 EDTA chelation or placebo infusions plus 6 caplets daily of a 28-component multivitamin-multimineral mixture or placebo. The primary end point was a composite of total mortality, MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: Median age was 65 years, 18% were female, 94% were Caucasian, 37% were diabetic, 83% had prior coronary revascularization, and 73% were on statins. Five-year Kaplan-Meier estimates for the primary end point was 31.9% in the chelation + high-dose vitamin group, 33.7% in the chelation + placebo vitamin group, 36.6% in the placebo infusion + active vitamin group, and 40.2% in the placebo infusions + placebo vitamin group. The reduction in primary end point by double active treatment compared with double placebo was significant (hazard ratio 0.74, 95% CI 0.57-0.95, P = .016). In patients with diabetes, the primary end point reduction of double active compared with double placebo was more pronounced (hazard ratio 0.49, 95% CI 0.33-0.75, P < .001). CONCLUSIONS: In stable post-MI patients on evidence-based medical therapy, the combination of oral high-dose vitamins and chelation therapy compared with double placebo reduced clinically important cardiovascular events to an extent that was both statistically significant and of potential clinical relevance.

The effect of an EDTA-based chelation regimen on patients with diabetes mellitus and prior myocardial infarction in the Trial to Assess Chelation Therapy (TACT).

BACKGROUND: The Trial to Assess Chelation Therapy (TACT) showed clinical benefit of an EDTA-based infusion regimen in patients aged ≥50 years with prior myocardial infarction. Diabetes mellitus before enrollment was a prespecified subgroup. METHODS AND RESULTS: Patients received 40 infusions of EDTA chelation or placebo. A total of 633 (37%) patients had diabetes mellitus (322 EDTA and 311 placebo). EDTA reduced the primary end point (death, reinfarction, stroke, coronary revascularization, or hospitalization for angina; 25% versus 38%; hazard ratio, 0.59; 95% confidence interval [CI], 0.44-0.79; P<0.001) over 5 years. The result remained significant after Bonferroni adjustment for multiple subgroups (99.4% CI, 0.39-0.88; adjusted P=0.002). All-cause mortality was reduced by EDTA chelation (10% versus 16%; hazard ratio, 0.57; 95% CI, 0.36-0.88; P=0.011), as was the secondary end point (cardiovascular death, reinfarction, or stroke; 11% versus 17%; hazard ratio, 0.60; 95% CI, 0.39-0.91; P=0.017). However, after adjusting for multiple subgroups, those results were no longer significant. The number needed to treat to reduce 1 primary end point over 5 years was 6.5 (95% CI, 4.4-12.7). There was no reduction in events in non-diabetes mellitus (n=1075; P=0.877), resulting in a treatment by diabetes mellitus interaction (P=0.004). CONCLUSIONS: Post-myocardial infarction patients with diabetes mellitus aged ≥50 demonstrated a marked reduction in cardiovascular events with EDTA chelation. These findings support efforts to replicate these findings and define the mechanisms of benefit. However, they do not constitute sufficient evidence to indicate the routine use of chelation therapy for all post-myocardial infarction patients with diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00044213.

Effect of disodium EDTA chelation regimen on cardiovascular events in patients with previous myocardial infarction: the TACT randomized trial.

IMPORTANCE: Chelation therapy with disodium EDTA has been used for more than 50 years to treat atherosclerosis without proof of efficacy. OBJECTIVE: To determine if an EDTA-based chelation regimen reduces cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, placebo-controlled, 2 × 2 factorial randomized trial enrolling 1708 patients aged 50 years or older who had experienced a myocardial infarction (MI) at least 6 weeks prior and had serum creatinine levels of 2.0 mg/dL or less. Participants were recruited at 134 US and Canadian sites. Enrollment began in September 2003 and follow-up took place until October 2011 (median, 55 months). Two hundred eighty-nine patients (17% of total; n=115 in the EDTA group and n=174 in the placebo group) withdrew consent during the trial. INTERVENTIONS: Patients were randomized to receive 40 infusions of a 500-mL chelation solution (3 g of disodium EDTA, 7 g of ascorbate, B vitamins, electrolytes, procaine, and heparin) (n=839) vs placebo (n=869) and an oral vitamin-mineral regimen vs an oral placebo. Infusions were administered weekly for 30 weeks, followed by 10 infusions 2 to 8 weeks apart. Fifteen percent discontinued infusions (n=38 [16%] in the chelation group and n=41 [15%] in the placebo group) because of adverse events. MAIN OUTCOME MEASURES: The prespecified primary end point was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. This report describes the intention-to-treat comparison of EDTA chelation vs placebo. To account for multiple interim analyses, the significance threshold required at the final analysis was P = .036. RESULTS: Qualifying previous MIs occurred a median of 4.6 years before enrollment. Median age was 65 years, 18% were female, 9% were nonwhite, and 31% were diabetic. The primary end point occurred in 222 (26%) of the chelation group and 261 (30%) of the placebo group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.99]; P = .035). There was no effect on total mortality (chelation: 87 deaths [10%]; placebo, 93 deaths [11%]; HR, 0.93 [95% CI, 0.70-1.25]; P = .64), but the study was not powered for this comparison. The effect of EDTA chelation on the components of the primary end point other than death was of similar magnitude as its overall effect (MI: chelation, 6%; placebo, 8%; HR, 0.77 [95% CI, 0.54-1.11]; stroke: chelation, 1.2%; placebo, 1.5%; HR, 0.77 [95% CI, 0.34-1.76]; coronary revascularization: chelation, 15%; placebo, 18%; HR, 0.81 [95% CI, 0.64-1.02]; hospitalization for angina: chelation, 1.6%; placebo, 2.1%; HR, 0.72 [95% CI, 0.35-1.47]). Sensitivity analyses examining the effect of patient dropout and treatment adherence did not alter the results. CONCLUSIONS AND RELEVANCE: Among stable patients with a history of MI, use of an intravenous chelation regimen with disodium EDTA, compared with placebo, modestly reduced the risk of adverse cardiovascular outcomes, many of which were revascularization procedures. These results provide evidence to guide further research but are not sufficient to support the routine use of chelation therapy for treatment of patients who have had an MI. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00044213.

Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial.

BACKGROUND: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown. OBJECTIVE: To assess whether oral multivitamins reduce cardiovascular events and are safe. DESIGN: Double-blind, placebo-controlled, 2 x 2 factorial, multicenter, randomized trial. (ClinicalTrials.gov: NCT00044213) SETTING: 134 U.S. and Canadian academic and clinical sites. PATIENTS: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 mol/L (2.0 mg/dL) or less. INTERVENTION: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo. MEASUREMENTS: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events. LIMITATION: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety). CONCLUSION: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate. PRIMARY FUNDING SOURCE: National Institutes of Health.

Design of the Trial to Assess Chelation Therapy (TACT).

TACT is an National Institutes of Health-sponsored, randomized, double-blind, placebo-controlled, 2 × 2 factorial clinical trial testing the benefits and risks of 40 infusions of a multicomponent disodium EDTA chelation solution compared with placebo and of an oral, high-dose multivitamin and mineral supplement. TACT has randomized and will follow up 1,708 patients for an average of approximately 4 years. The primary end point is a composite of all-cause mortality, myocardial infarction, stroke, coronary revascularization, and hospitalization for angina. A 900-patient substudy will examine quality-of-life outcomes. The trial is designed to have >85% power to detect a 25% relative reduction in the primary end point for each treatment factor. Enrollment began in September 2003 and was completed in October 2010.

Diuretic strategies in patients with acute decompensated heart failure.

BACKGROUND: Loop diuretics are an essential component of therapy for patients with acute decompensated heart failure, but there are few prospective data to guide their use. METHODS: In a prospective, double-blind, randomized trial, we assigned 308 patients with acute decompensated heart failure to receive furosemide administered intravenously by means of either a bolus every 12 hours or continuous infusion and at either a low dose (equivalent to the patient's previous oral dose) or a high dose (2.5 times the previous oral dose). The protocol allowed specified dose adjustments after 48 hours. The coprimary end points were patients' global assessment of symptoms, quantified as the area under the curve (AUC) of the score on a visual-analogue scale over the course of 72 hours, and the change in the serum creatinine level from baseline to 72 hours. RESULTS: In the comparison of bolus with continuous infusion, there was no significant difference in patients' global assessment of symptoms (mean AUC, 4236±1440 and 4373±1404, respectively; P=0.47) or in the mean change in the creatinine level (0.05±0.3 mg per deciliter [4.4±26.5 µmol per liter] and 0.07±0.3 mg per deciliter [6.2±26.5 µmol per liter], respectively; P=0.45). In the comparison of the high-dose strategy with the low-dose strategy, there was a nonsignificant trend toward greater improvement in patients' global assessment of symptoms in the high-dose group (mean AUC, 4430±1401 vs. 4171±1436; P=0.06). There was no significant difference between these groups in the mean change in the creatinine level (0.08±0.3 mg per deciliter [7.1±26.5 µmol per liter] with the high-dose strategy and 0.04±0.3 mg per deciliter [3.5±26.5 µmol per liter] with the low-dose strategy, P=0.21). The high-dose strategy was associated with greater diuresis and more favorable outcomes in some secondary measures but also with transient worsening of renal function. CONCLUSIONS: Among patients with acute decompensated heart failure, there were no significant differences in patients' global assessment of symptoms or in the change in renal function when diuretic therapy was administered by bolus as compared with continuous infusion or at a high dose as compared with a low dose. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00577135.).

No benefit from defibrillation threshold testing in the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial).

OBJECTIVES: This study investigated whether defibrillation threshold (DFT) testing during implantable cardioverter-defibrillator (ICD) implantation predicts clinical outcomes. BACKGROUND: Defibrillation testing is often performed during insertion of ICDs to confirm shock efficacy. There are no prospective data to suggest that this procedure improves outcomes when modern ICDs are implanted for primary prevention of sudden death. METHODS: The analysis included the 811 patients who were randomized to the ICD arm of the SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) and had the device implanted. The DFT testing protocol in SCD-HeFT was designed to limit shock testing in a primary prevention heart failure population. RESULTS: Baseline DFT data were available for 717 patients (88.4%). All 717 patients had a DFT of < or =30 J, the maximum output of the device in this study. The DFT was < or =20 J in 97.8% of patients. There was no survival difference between patients with a lower DFT (< or =10 J, n = 547) and a higher DFT (>10 J, n = 170) (p = 0.41). First shock efficacy was 83.0% for the first clinical ventricular tachyarrhythmia event; there were no differences in shock efficacies when the cohort was subdivided by baseline DFT. CONCLUSIONS: Low baseline DFTs were obtained in patients with stable, optimally treated heart failure during ICD implantation for primary prevention of sudden death. First shock efficacy for ventricular tachyarrhythmias was high regardless of baseline DFT testing results. Baseline DFT testing did not predict long-term mortality or shock efficacy in this study.

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.

Music, imagery, touch, and prayer as adjuncts to interventional cardiac care: the Monitoring and Actualisation of Noetic Trainings (MANTRA) II randomised study.

BACKGROUND: Data from a pilot study suggested that noetic therapies-healing practices that are not mediated by tangible elements-can reduce preprocedural distress and might affect outcomes in patients undergoing percutaneous coronary intervention. We undertook a multicentre, prospective trial of two such practices: intercessory prayer and music, imagery, and touch (MIT) therapy. METHODS: 748 patients undergoing percutaneous coronary intervention or elective catheterisation in nine USA centres were assigned in a 2x2 factorial randomisation either off-site prayer by established congregations of various religions or no off-site prayer (double-blinded) and MIT therapy or none (unmasked). The primary endpoint was combined in-hospital major adverse cardiovascular events and 6-month readmission or death. Prespecified secondary endpoints were 6-month major adverse cardiovascular events, 6 month death or readmission, and 6-month mortality. FINDINGS: 371 patients were assigned prayer and 377 no prayer; 374 were assigned MIT therapy and 374 no MIT therapy. The factorial distribution was: standard care only, 192; prayer only, 182; MIT therapy only, 185; and both prayer and MIT therapy, 189. No significant difference was found for the primary composite endpoint in any treatment comparison. Mortality at 6 months was lower with MIT therapy than with no MIT therapy (hazard ratio 0.35 (95% CI 0.15-0.82, p=0.016). INTERPRETATION: Neither masked prayer nor MIT therapy significantly improved clinical outcome after elective catheterisation or percutaneous coronary intervention.

Influence of gender on arrhythmia characteristics and outcome in the Multicenter UnSustained Tachycardia Trial.

INTRODUCTION: Previous studies have demonstrated gender differences in risk of sudden death in patients with ischemic heart disease. The Multicenter UnSustained Tachycardia Trial (MUSTT) evaluated the ability of therapy guided by electrophysiologic (EP) testing to reduce mortality in patients with coronary disease, ejection fraction < or =40%, and spontaneous nonsustained ventricular tachycardia. METHODS AND RESULTS: We analyzed the influence of gender on results of EP testing and outcome of patients enrolled in MUSTT. Women made up 14% of the overall MUSTT population and were less likely than men to have inducible sustained randomizable ventricular arrhythmias (24% vs 36%, P < 0.001). Baseline characteristics differed between men and women. In randomized patients, women were older, more likely to have had an infarction within 6 months, more likely to have a history of heart failure, and more likely to have recent angina prior to enrollment than men (P < 0.05). In the EP-guided therapy group, there was no difference in implantable cardioverter defibrillator implantation rate in men and women (45% vs 53%, P = 0.38). There also were no significant gender influences on risk of arrhythmic death or cardiac arrest (2-year event rate 9% in women and 12% in men, adjusted hazard ratio 0.88) or overall mortality (2-year event rate 32% in women vs 21% in men, adjusted hazard ratio 1.51). CONCLUSION: The outcome and benefit of EP-guided therapy in this trial did not appear to be influenced by gender. However, due to the small numbers of women in the trial, small differences in outcome may not be apparent. Plans for future primary prevention trials should include careful risk stratification of women who less often have inducible sustained ventricular arrhythmias and better left ventricular function despite more frequent heart failure.

Relation of ejection fraction and inducible ventricular tachycardia to mode of death in patients with coronary artery disease: an analysis of patients enrolled in the multicenter unsustained tachycardia trial.

BACKGROUND: Fifty percent of deaths in patients with coronary disease occur suddenly. Although many factors correlate with increased mortality, there is little information regarding the influence of these factors on mode of death. As such, optimum methods to determine patients most likely to benefit from implantable defibrillator therapy are unclear. METHODS AND RESULTS: We analyzed the relation of ejection fraction and inducible ventricular tachyarrhythmias to mode of death in all 1791 patients enrolled in the Multicenter Unsustained Tachycardia Trial who did not receive antiarrhythmic therapy. Total mortality and arrhythmic deaths/cardiac arrests occurred more frequently in patients with ejection fraction <30% than in those with ejection fraction of 30% to 40%. The percentage of deaths classified as arrhythmic was similar in patients with ejection fraction <30% or > or =30%. The relative contribution of arrhythmic events to total mortality was significantly higher in patients with inducible tachyarrhythmia (58% of deaths in inducible patients versus 46% in noninducible patients, P=0.004). The higher percentage of events that were arrhythmic among patients with inducible tachyarrhythmia appeared more distinct among patients with an ejection fraction > or =30% (61% of events were arrhythmic among inducible patients with ejection fraction > or =30% and only 42% among noninducible patients, P=0.002). CONCLUSIONS: Both low ejection fraction and inducible tachyarrhythmias identify patients with coronary disease at increased mortality risk. Ejection fraction does not discriminate between modes of death, whereas inducible tachyarrhythmia identifies patients for whom death, if it occurs, is significantly more likely to be arrhythmic, especially if ejection fraction is > or =30%.

Prognostic significance of nonsustained ventricular tachycardia identified postoperatively after coronary artery bypass surgery in patients with left ventricular dysfunction.

INTRODUCTION: Nonsustained ventricular tachycardia (NSVT) occurs frequently in the postoperative period (< or = 30 days) after coronary artery bypass graft (CABG) surgery, a setting where many factors may play a role in its genesis. The prognosis of NSVT in this setting in patients with left ventricular (LV) dysfunction is unknown. This study was designed to assess its significance. METHODS AND RESULTS: We compared the outcome of untreated patients enrolled in the Multicenter Unsustained Tachycardia Trial with coronary artery disease (CAD), LV dysfunction, and NSVT identified postoperatively after CABG (n = 228; mean age 67 years, 84% males) versus nonpostoperative settings (n = 1,302; mean age 66 years, 85% males). Sustained monomorphic ventricular tachycardia was induced in 27% and 33% (P = 0.046) of patients with postoperative and nonpostoperative NSVT, respectively. The 2- and 5-year rates of arrhythmic events were 6% and 16%, respectively, in postoperative patients versus 15% and 29% in nonpostoperative patients (unadjusted P = 0.0020, adjusted P = 0.0082). The 2- and 5-year overall mortality rates were 15% and 36%, respectively, for postoperative patients versus 24% and 47% for nonpostoperative patients (unadjusted P = 0.0005, adjusted P = 0.027). Patients whose NSVT was identified early (<10 days) versus late (10-30 days) after CABG had significantly lower 2- (13% vs 23%) and 5-year (30% vs 52%) mortality rates (unadjusted P = 0.024, adjusted P = 0.018). CONCLUSION: In this population of patients with CAD and LV dysfunction, the occurrence of postoperative NSVT, especially within 10 days after CABG, portends a far better outcome than when it occurs in nonpostoperative settings. This suggests that in a such setting, NSVT represents a less specific risk factor for future events and should be considered when assigning risk and treatment of similar patients.