Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.

The trial to assess chelation therapy 2 (TACT2): Rationale and design.

BACKGROUND: Intravenous edetate disodium-based infusions reduced cardiovascular events in a prior clinical trial. The Trial to Assess Chelation Therapy 2 (TACT2) will replicate the initial study design. METHODS: TACT2 is an NIH-sponsored, randomized, 2x2 factorial, double masked, placebo-controlled, multicenter clinical trial testing 40 weekly infusions of a multi-component edetate disodium (disodium ethylenediamine tetra-acetic acid, or Na2EDTA)-based chelation solution and twice daily oral, high-dose multivitamin and mineral supplements in patients with diabetes and a prior myocardial infarction (MI). TACT2 completed enrollment of 1000 subjects in December 2020, and infusions in December 2021. Subjects are followed for 2.5 to 5 years. The primary endpoint is time to first occurrence of all-cause mortality, MI, stroke, coronary revascularization, or hospitalization for unstable angina. The trial has >;85% power to detect a 30% relative reduction in the primary endpoint. TACT2 also includes a Trace Metals and Biorepository Core Lab, to test whether benefits of treatment, if present, are due to chelation of lead and cadmium from patients. Design features of TACT2 were chosen to replicate selected features of the first TACT, which demonstrated a significant reduction in cardiovascular outcomes in the EDTA chelation arm compared with placebo among patients with a prior MI, with the largest effect in patients with diabetes. RESULTS: Results are expected in 2024. CONCLUSION: TACT2 may provide definitive evidence of the benefit of edetate disodiumbased chelation on cardiovascular outcomes, as well as the clinical importance of longitudinal changes in toxic metal levels of participants.

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.

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.

Health-Related Quality of Life Outcomes in PARADIGM-HF.

BACKGROUND: Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS: Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS: Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.

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.

Provision of spiritual care to patients with advanced cancer: associations with medical care and quality of life near death.

PURPOSE: To determine whether spiritual care from the medical team impacts medical care received and quality of life (QoL) at the end of life (EoL) and to examine these relationships according to patient religious coping. PATIENTS AND METHODS: Prospective, multisite study of patients with advanced cancer from September 2002 through August 2008. We interviewed 343 patients at baseline and observed them (median, 116 days) until death. Spiritual care was defined by patient-rated support of spiritual needs by the medical team and receipt of pastoral care services. The Brief Religious Coping Scale (RCOPE) assessed positive religious coping. EoL outcomes included patient QoL and receipt of hospice and any aggressive care (eg, resuscitation). Analyses were adjusted for potential confounders and repeated according to median-split religious coping. RESULTS: Patients whose spiritual needs were largely or completely supported by the medical team received more hospice care in comparison with those not supported (adjusted odds ratio [AOR] = 3.53; 95% CI, 1.53 to 8.12, P = .003). High religious coping patients whose spiritual needs were largely or completely supported were more likely to receive hospice (AOR = 4.93; 95% CI, 1.64 to 14.80; P = .004) and less likely to receive aggressive care (AOR = 0.18; 95% CI, 0.04 to 0.79; P = .02) in comparison with those not supported. Spiritual support from the medical team and pastoral care visits were associated with higher QOL scores near death (20.0 [95% CI, 18.9 to 21.1] v 17.3 [95% CI, 15.9 to 18.8], P = .007; and 20.4 [95% CI, 19.2 to 21.1] v 17.7 [95% CI, 16.5 to 18.9], P = .003, respectively). CONCLUSION: Support of terminally ill patients' spiritual needs by the medical team is associated with greater hospice utilization and, among high religious copers, less aggressive care at EoL. Spiritual care is associated with better patient QoL near death.