Cost-Effectiveness of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: The VICTORIA Randomized Clinical Trial.

BACKGROUND: The VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) demonstrated that, in patients with high-risk heart failure, vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization relative to placebo. The hazard ratio for all-cause mortality was 0.95 (95% CI, 0.84-1.07). In a prespecified analysis, treatment effects varied substantially as a function of baseline NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, with survival benefit for vericiguat in the lower NT-proBNP quartiles (hazard ratio, 0.82 [95% CI, 0.69-0.97]) and no benefit in the highest NT-proBNP quartile (hazard ratio, 1.14 [95% CI, 0.95-1.38]). An economic analysis was a major secondary objective of the VICTORIA research program. METHODS: Medical resource use data were collected for all VICTORIA patients (N=5050). Costs were estimated by applying externally derived US cost weights to resource use counts. Life expectancy was projected from patient-level empirical trial survival results with the use of age-based survival modeling methods. Quality-of-life adjustments were based on prospectively collected EQ-5D-based utilities. The primary outcome was the incremental cost-effectiveness ratio, comparing vericiguat with placebo, assessed from the US health care sector perspective over a lifetime horizon. Cost-effectiveness was estimated using the total VICTORIA cohort, both with and without interaction between treatment and baseline NT-proBNP. RESULTS: Life expectancy modeling results varied according to whether the observed heterogeneity of treatment effect by baseline NT-proBNP values was incorporated into the modeling. Including the interaction term, the vericiguat arm had an estimated quality-adjusted life expectancy of 4.56 quality-adjusted life-years (QALYs) compared with 4.13 QALYs for placebo (incremental discounted QALY, 0.43). Without the treatment heterogeneity/interaction term, vericiguat had 4.50 QALYs compared with 4.33 QALYs for placebo (incremental discounted QALY, 0.17). Incremental discounted costs (vericiguat minus placebo) were $28 546 with the treatment interaction and $20 948 without it. Corresponding incremental cost-effectiveness ratios were $66 509 per QALY allowing for treatment heterogeneity and $124 512 without heterogeneity. CONCLUSIONS: Vericiguat use in the VICTORIA trial met criteria for intermediate value, but the incremental cost-effectiveness ratio estimates were sensitive to whether the analysis accounted for observed NT-proBNP treatment effect heterogeneity. The cost-effectiveness of vericiguat was driven by the projected incremental life expectancy among patients in the lowest 3 quartiles of NT-proBNP. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 AHA/ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease" provides an update to and consolidates new evidence since the "2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease" and the corresponding "2014 ACC/AHA/AATS/PCNA/SCAI/STS Focused Update of the Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease." METHODS: A comprehensive literature search was conducted from September 2021 to May 2022. Clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants were identified that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE: This guideline provides an evidenced-based and patient-centered approach to management of patients with chronic coronary disease, considering social determinants of health and incorporating the principles of shared decision-making and team-based care. Relevant topics include general approaches to treatment decisions, guideline-directed management and therapy to reduce symptoms and future cardiovascular events, decision-making pertaining to revascularization in patients with chronic coronary disease, recommendations for management in special populations, patient follow-up and monitoring, evidence gaps, and areas in need of future research. Where applicable, and based on availability of cost-effectiveness data, cost-value recommendations are also provided for clinicians. Many recommendations from previously published guidelines have been updated with new evidence, and new recommendations have been created when supported by published data.

Survival After Invasive or Conservative Management of Stable Coronary Disease.

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. METHODS: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. RESULTS: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85-1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63-0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08-1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. CONCLUSIONS: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04894877.

Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: Results from the CABANA trial.

BACKGROUND: The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. METHODS: The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. RESULTS: At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). CONCLUSIONS: In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2).

BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.

Association Between Age and Outcomes of Catheter Ablation Versus Medical Therapy for Atrial Fibrillation: Results From the CABANA Trial.

BACKGROUND: Observational data suggest that catheter ablation may be safe and effective to treat younger and older patients with atrial fibrillation. No large, randomized trial has examined this issue. This report describes outcomes according to age at entry in the CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). METHODS: Patients with atrial fibrillation ≥65 years of age, or <65 with ≥1 risk factor for stroke, were randomly assigned to catheter ablation versus drug therapy. The primary outcome was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Secondary outcomes included all-cause mortality, the composite of mortality or cardiovascular hospitalization, and recurrence of atrial fibrillation. Treatment effect estimates were adjusted for baseline covariables using proportional hazards regression models. RESULTS: Of 2204 patients randomly assigned in CABANA, 766 (34.8%) were <65 years of age, 1130 (51.3%) were 65 to 74 years of age, and 308 (14.0%) were ≥75 years of age. Catheter ablation was associated with a 43% reduction in the primary outcome for patients <65 years of age (adjusted hazard ratio [aHR], 0.57 [95% CI, 0.30-1.09]), a 21% reduction for 65 to 74 years of age (aHR, 0.79 [95% CI, 0.54-1.16]), and an indeterminate effect for age ≥75 years of age (aHR, 1.39 [95% CI, 0.75-2.58]). Four-year event rates for ablation versus drug therapy across age groups, respectively, were 3.2% versus 7.8%, 7.8% versus 9.6%, and 14.8% versus 9.0%. For every 10-year increase in age, the primary outcome aHR increased (ie, less favorable to ablation) an average of 27% (interaction P value=0.215). A similar pattern was seen with all-cause mortality: for every 10-year increase in age, the aHR increased an average of 46% (interaction P value=0.111). Atrial fibrillation recurrence rates were lower with ablation than with drug therapy across age subgroups (aHR 0.47, 0.58, and 0.49, respectively). Treatment-related complications were infrequent for both arms (<3%) regardless of age. CONCLUSIONS: We found age-based variations in clinical outcomes for catheter ablation compared with drug therapy, with the largest relative and absolute benefits of catheter ablation in younger patients. No prognostic benefits for ablation were seen in the oldest patients. No differences were found by age in treatment-related complications or in the relative effectiveness of catheter ablation in preventing recurrent atrial arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00911508.

Comprehensive Quality-of-Life Outcomes With Invasive Versus Conservative Management of Chronic Coronary Disease in ISCHEMIA.

BACKGROUND: ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) compared an initial invasive treatment strategy (INV) with an initial conservative strategy in 5179 participants with chronic coronary disease and moderate or severe ischemia. The ISCHEMIA research program included a comprehensive quality-of-life (QOL) substudy. METHODS: In 1819 participants (907 INV, 912 conservative strategy), we collected a battery of disease-specific and generic QOL instruments by structured interviews at baseline; at 3, 12, 24, and 36 months postrandomization; and at study closeout. Assessments included angina-related QOL (19-item Seattle Angina Questionnaire), generic health status (EQ-5D), depressive symptoms (Patient Health Questionnaire-8), and, for North American patients, cardiac functional status (Duke Activity Status Index). RESULTS: Median age was 67 years, 19.2% were female, and 15.9% were non-White. The estimated mean difference for the 19-item Seattle Angina Questionnaire Summary score favored INV (1.4 points [95% CI, 0.2-2.5] over all follow-up). No differences were observed in patients with rare/absent baseline angina (SAQ Angina Frequency score >80). Among patients with more frequent angina at baseline (SAQ Angina Frequency score <80, 744 patients, 41%), those randomly assigned to INV had a mean 3.7-point higher 19-item Seattle Angina Questionnaire Summary score than conservative strategy (95% CI, 1.6-5.8) with consistent effects across SAQ subscales: Physical Limitations 3.2 points (95% CI, 0.2-6.1), Angina Frequency 3.2 points (95% CI, 1.2-5.1), Quality of Life/Health Perceptions 5.3 points (95% CI, 2.8-7.8). For the Duke Activity Status Index, no difference was estimated overall by treatment, but in patients with baseline SAQ Angina Frequency scores <80, Duke Activity Status Index scores were higher for INV (3.2 points [95% CI, 0.6-5.7]), whereas patients with rare/absent baseline angina showed no treatment-related differences. Moderate to severe depression was infrequent at randomization (11.5%-12.8%) and was unaffected by treatment assignment. CONCLUSIONS: In the ISCHEMIA comprehensive QOL substudy, patients with more frequent baseline angina reported greater improvements in the symptom, physical functioning, and psychological well-being dimensions of QOL when treated with an invasive strategy, whereas patients who had rare/absent angina at baseline reported no consistent treatment-related QOL differences. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01471522.

Cost-Effectiveness of Catheter Ablation Versus Antiarrhythmic Drug Therapy in Atrial Fibrillation: The CABANA Randomized Clinical Trial.

BACKGROUND: In the CABANA trial (Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation), catheter ablation did not significantly reduce the primary end point of death, disabling stroke, serious bleeding, or cardiac arrest compared with drug therapy by intention-to-treat, but did improve the quality of life and freedom from atrial fibrillation recurrence. In the heart failure subgroup, ablation improved both survival and quality of life. Cost-effectiveness was a prespecified CABANA secondary end point. METHODS: Medical resource use data were collected for all CABANA patients (N=2204). Costs for hospital-based care were assigned using prospectively collected bills from US patients (n=1171); physician and medication costs were assigned using the Medicare Fee Schedule and National Average Drug Acquisition Costs, respectively. Extrapolated life expectancies were estimated using age-based survival models. Quality-of-life adjustments were based on EQ-5D-based utilities measured during the trial. The primary outcome was the incremental cost-effectiveness ratio, comparing ablation with drug therapy on the basis of intention-to-treat, and assessed from the US health care sector perspective. RESULTS: Costs in the first 3 months averaged $20 794±SD 1069 higher with ablation compared with drug therapy. The cumulative within-trial 5-year cost difference was $19 245 (95% CI, $11 360-$27 170) and the lifetime mean cost difference was $15 516 (95% CI, -$2963 to $35,512) higher with ablation than with drug therapy. The drug therapy arm accrued an average of 12.5 life-years (LYs) and 10.7 quality-adjusted life-years (QALYs). For the ablation arm, the corresponding estimates were 12.6 LYs and 11.0 QALYs. The incremental cost-effectiveness ratio was $57 893 per QALY gained, with 75% of bootstrap replications yielding an incremental cost-effectiveness ratio <$100 000 per QALY gained. With no quality-of-life/utility adjustments, the incremental cost-effectiveness ratio was $183 318 per LY gained. CONCLUSIONS: Catheter ablation of atrial fibrillation was economically attractive compared with drug therapy in the CABANA Trial overall at present benchmarks for health care value in the United States on the basis of projected incremental QALYs but not LYs alone.

Cost-Effectiveness of Coronary Artery Bypass Surgery Versus Medicine in Ischemic Cardiomyopathy: The STICH Randomized Clinical Trial.

BACKGROUND: The STICH Randomized Clinical Trial (Surgical Treatment for Ischemic Heart Failure) demonstrated that coronary artery bypass grafting (CABG) reduced all-cause mortality rates out to 10 years compared with medical therapy alone (MED) in patients with ischemic cardiomyopathy and reduced left ventricular function (ejection fraction ≤35%). We examined the economic implications of these results. METHODS: We used a decision-analytic patient-level simulation model to estimate the lifetime costs and benefits of CABG and MED using patient-level resource use and clinical data collected in the STICH trial. Patient-level costs were calculated by applying externally derived US cost weights to resource use counts during trial follow-up. A 3% discount rate was applied to both future costs and benefits. The primary outcome was the incremental cost-effectiveness ratio assessed from the US health care sector perspective. RESULTS: For the CABG arm, we estimated 6.53 quality-adjusted life-years (95% CI, 5.70-7.53) and a lifetime cost of $140 059 (95% CI, $106 401 to $180 992). For the MED arm, the corresponding estimates were 5.52 (95% CI, 5.06-6.09) quality-adjusted life-years and $74 894 lifetime cost (95% CI, $58 372 to $93 541). The incremental cost-effectiveness ratio for CABG compared with MED was $63 989 per quality-adjusted life-year gained. At a societal willingness-to-pay threshold of $100 000 per quality-adjusted life-year gained, CABG was found to be economically favorable compared with MED in 87% of microsimulations. CONCLUSIONS: In the STICH trial, in patients with ischemic cardiomyopathy and reduced left ventricular function, CABG was economically attractive relative to MED at current benchmarks for value in the United States. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT00023595.

Health Status after Invasive or Conservative Care in Coronary and Advanced Kidney Disease.

BACKGROUND: In the ISCHEMIA-CKD trial, the primary analysis showed no significant difference in the risk of death or myocardial infarction with initial angiography and revascularization plus guideline-based medical therapy (invasive strategy) as compared with guideline-based medical therapy alone (conservative strategy) in participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease (an estimated glomerular filtration rate of <30 ml per minute per 1.73 m2 or receipt of dialysis). A secondary objective of the trial was to assess angina-related health status. METHODS: We assessed health status with the Seattle Angina Questionnaire (SAQ) before randomization and at 1.5, 3, and 6 months and every 6 months thereafter. The primary outcome of this analysis was the SAQ Summary score (ranging from 0 to 100, with higher scores indicating less frequent angina and better function and quality of life). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate the treatment effect with the invasive strategy. RESULTS: Health status was assessed in 705 of 777 participants. Nearly half the participants (49%) had had no angina during the month before randomization. At 3 months, the estimated mean difference between the invasive-strategy group and the conservative-strategy group in the SAQ Summary score was 2.1 points (95% credible interval, -0.4 to 4.6), a result that favored the invasive strategy. The mean difference in score at 3 months was largest among participants with daily or weekly angina at baseline (10.1 points; 95% credible interval, 0.0 to 19.9), smaller among those with monthly angina at baseline (2.2 points; 95% credible interval, -2.0 to 6.2), and nearly absent among those without angina at baseline (0.6 points; 95% credible interval, -1.9 to 3.3). By 6 months, the between-group difference in the overall trial population was attenuated (0.5 points; 95% credible interval, -2.2 to 3.4). CONCLUSIONS: Participants with stable ischemic heart disease, moderate or severe ischemia, and advanced chronic kidney disease did not have substantial or sustained benefits with regard to angina-related health status with an initially invasive strategy as compared with a conservative strategy. (Funded by the National Heart, Lung, and Blood Institute; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Health-Status Outcomes with Invasive or Conservative Care in Coronary Disease.

BACKGROUND: In the ISCHEMIA trial, an invasive strategy with angiographic assessment and revascularization did not reduce clinical events among patients with stable ischemic heart disease and moderate or severe ischemia. A secondary objective of the trial was to assess angina-related health status among these patients. METHODS: We assessed angina-related symptoms, function, and quality of life with the Seattle Angina Questionnaire (SAQ) at randomization, at months 1.5, 3, and 6, and every 6 months thereafter in participants who had been randomly assigned to an invasive treatment strategy (2295 participants) or a conservative strategy (2322). Mixed-effects cumulative probability models within a Bayesian framework were used to estimate differences between the treatment groups. The primary outcome of this health-status analysis was the SAQ summary score (scores range from 0 to 100, with higher scores indicating better health status). All analyses were performed in the overall population and according to baseline angina frequency. RESULTS: At baseline, 35% of patients reported having no angina in the previous month. SAQ summary scores increased in both treatment groups, with increases at 3, 12, and 36 months that were 4.1 points (95% credible interval, 3.2 to 5.0), 4.2 points (95% credible interval, 3.3 to 5.1), and 2.9 points (95% credible interval, 2.2 to 3.7) higher with the invasive strategy than with the conservative strategy. Differences were larger among participants who had more frequent angina at baseline (8.5 vs. 0.1 points at 3 months and 5.3 vs. 1.2 points at 36 months among participants with daily or weekly angina as compared with no angina). CONCLUSIONS: In the overall trial population with moderate or severe ischemia, which included 35% of participants without angina at baseline, patients randomly assigned to the invasive strategy had greater improvement in angina-related health status than those assigned to the conservative strategy. The modest mean differences favoring the invasive strategy in the overall group reflected minimal differences among asymptomatic patients and larger differences among patients who had had angina at baseline. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Management of Coronary Disease in Patients with Advanced Kidney Disease.

BACKGROUND: Clinical trials that have assessed the effect of revascularization in patients with stable coronary disease have routinely excluded those with advanced chronic kidney disease. METHODS: We randomly assigned 777 patients with advanced kidney disease and moderate or severe ischemia on stress testing to be treated with an initial invasive strategy consisting of coronary angiography and revascularization (if appropriate) added to medical therapy or an initial conservative strategy consisting of medical therapy alone and angiography reserved for those in whom medical therapy had failed. The primary outcome was a composite of death or nonfatal myocardial infarction. A key secondary outcome was a composite of death, nonfatal myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. RESULTS: At a median follow-up of 2.2 years, a primary outcome event had occurred in 123 patients in the invasive-strategy group and in 129 patients in the conservative-strategy group (estimated 3-year event rate, 36.4% vs. 36.7%; adjusted hazard ratio, 1.01; 95% confidence interval [CI], 0.79 to 1.29; P = 0.95). Results for the key secondary outcome were similar (38.5% vs. 39.7%; hazard ratio, 1.01; 95% CI, 0.79 to 1.29). The invasive strategy was associated with a higher incidence of stroke than the conservative strategy (hazard ratio, 3.76; 95% CI, 1.52 to 9.32; P = 0.004) and with a higher incidence of death or initiation of dialysis (hazard ratio, 1.48; 95% CI, 1.04 to 2.11; P = 0.03). CONCLUSIONS: Among patients with stable coronary disease, advanced chronic kidney disease, and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of death or nonfatal myocardial infarction. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA-CKD ClinicalTrials.gov number, NCT01985360.).

Initial Invasive or Conservative Strategy for Stable Coronary Disease.

BACKGROUND: Among patients with stable coronary disease and moderate or severe ischemia, whether clinical outcomes are better in those who receive an invasive intervention plus medical therapy than in those who receive medical therapy alone is uncertain. METHODS: We randomly assigned 5179 patients with moderate or severe ischemia to an initial invasive strategy (angiography and revascularization when feasible) and medical therapy or to an initial conservative strategy of medical therapy alone and angiography if medical therapy failed. The primary outcome was a composite of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. A key secondary outcome was death from cardiovascular causes or myocardial infarction. RESULTS: Over a median of 3.2 years, 318 primary outcome events occurred in the invasive-strategy group and 352 occurred in the conservative-strategy group. At 6 months, the cumulative event rate was 5.3% in the invasive-strategy group and 3.4% in the conservative-strategy group (difference, 1.9 percentage points; 95% confidence interval [CI], 0.8 to 3.0); at 5 years, the cumulative event rate was 16.4% and 18.2%, respectively (difference, -1.8 percentage points; 95% CI, -4.7 to 1.0). Results were similar with respect to the key secondary outcome. The incidence of the primary outcome was sensitive to the definition of myocardial infarction; a secondary analysis yielded more procedural myocardial infarctions of uncertain clinical importance. There were 145 deaths in the invasive-strategy group and 144 deaths in the conservative-strategy group (hazard ratio, 1.05; 95% CI, 0.83 to 1.32). CONCLUSIONS: Among patients with stable coronary disease and moderate or severe ischemia, we did not find evidence that an initial invasive strategy, as compared with an initial conservative strategy, reduced the risk of ischemic cardiovascular events or death from any cause over a median of 3.2 years. The trial findings were sensitive to the definition of myocardial infarction that was used. (Funded by the National Heart, Lung, and Blood Institute and others; ISCHEMIA ClinicalTrials.gov number, NCT01471522.).

Clinical and cost implications of deferred testing in low-risk patients with stable chest pain: a simulation using the PROMISE trial.

Current guidelines recommend a deferred testing approach in low-risk patients presenting with stable chest pain. After simulating a deferred testing approach using the PROMISE Minimal Risk Score to identify 915 minimal risk participants with cost data from the PROMISE trial, a deferred testing strategy was associated with an adjusted cost savings of -$748.74 (95% CI: -1646.97, 158.06) per participant and 74.6% of samples had better clinical outcomes and lower mean cost. This supports the current guideline recommended deferred testing approach in low-risk patients with stable chest pain.

Patient-Reported Outcome Measures in Cardiovascular Disease: An Evidence Map of the Psychometric Properties of Health Status Instruments.

BACKGROUND: Patient-reported outcomes (PROs) are important measures of treatment effect and can be used to inform the approval of cardiovascular drugs and devices by the U.S. Food and Drug Administration (FDA). PURPOSE: To catalogue the health status patient-reported outcome measures (PROMs) validated in cardiovascular diseases (CVDs), describe their psychometric properties, and assess adherence with both FDA recommendations and the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) framework. DATA SOURCES: MEDLINE, EMBASE, CINAHL, and Allied and Complementary Medicine Database from inception to August 2022. STUDY SELECTION: Studies that developed and/or validated health status PROMs in CVD populations. DATA EXTRACTION: Two study authors extracted data on CVD type, PROM psychometric properties, and adherence to FDA recommendations. The risk of bias informing the development or validation of PROMs was assessed using the COSMIN framework. DATA SYNTHESIS: Fifty health status PROMs (described in 83 studies) were identified, of which 45 were disease specific and 5 were generic. Eleven (22%) of the 50 PROMs validated in CVDs had minimally important differences (MIDs) established, and 8 (16%) reported on the validation of all psychometric properties recommended by the FDA. By COSMIN standards, only 2 PROMs (4%) had all of their psychometric properties rated as sufficient in quality, and 32 PROMs (64%) had less than 50% of psychometric properties rated as sufficient. LIMITATION: The quality of reporting varied across included studies. CONCLUSION: Of 50 PROMs validated in CVDs, only a small minority reported on the validation of all FDA-recommended psychometric properties, had psychometric properties rated as sufficient by COSMIN, or had MIDs established. Given the use of PROMs to guide FDA approvals of drugs and devices in CVDs, there is a need for better adherence to quality standards in PROM validation. PRIMARY FUNDING SOURCE: None.

Effects of initial invasive vs. initial conservative treatment strategies on recurrent and total cardiovascular events in the ISCHEMIA trial.

AIMS: The International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial prespecified an analysis to determine whether accounting for recurrent cardiovascular events in addition to first events modified understanding of the treatment effects. METHODS AND RESULTS: Patients with stable coronary artery disease (CAD) and moderate or severe ischaemia on stress testing were randomized to either initial invasive (INV) or initial conservative (CON) management. The primary outcome was a composite of cardiovascular death, myocardial infarction (MI), and hospitalization for unstable angina, heart failure, or cardiac arrest. The Ghosh-Lin method was used to estimate mean cumulative incidence of total events with death as a competing risk. The 5179 ISCHEMIA patients experienced 670 index events (318 INV, 352 CON) and 203 recurrent events (102 INV, 101 CON). A single primary event was observed in 9.8% of INV and 10.8% of CON patients while ≥2 primary events were observed in 2.5% and 2.8%, respectively. Patients with recurrent events were older; had more frequent hypertension, diabetes, prior MI, or cerebrovascular disease; and had more multivessel CAD. The average number of primary endpoint events per 100 patients over 4 years was 18.2 in INV [95% confidence interval (CI) 15.8-20.9] and 19.7 in CON (95% CI 17.5-22.2), difference -1.5 (95% CI -5.0 to 2.0, P = 0.398). Comparable results were obtained when all-cause death was substituted for cardiovascular death and when stroke was added as an event. CONCLUSIONS: In stable CAD patients with moderate or severe myocardial ischaemia enrolled in ISCHEMIA, an initial INV treatment strategy did not prevent either net recurrent events or net total events more effectively than an initial CON strategy. CLINICAL TRIAL REGISTRATION: ISCHEMIA ClinicalTrials.gov number, NCT01471522, https://clinicaltrials.gov/ct2/show/NCT01471522.

Association Between Sex and Treatment Outcomes of Atrial Fibrillation Ablation Versus Drug Therapy: Results From the CABANA Trial.

BACKGROUND: Among patients with atrial fibrillation (AF), women are less likely to receive catheter ablation and may have more complications and less durable results. Most information about sex-specific differences after ablation comes from observational data. We prespecified an examination of outcomes by sex in the 2204-patient CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). METHODS: CABANA randomized patients with AF age ≥65 years or <65 years with ≥1 risk factor for stroke to a strategy of catheter ablation with pulmonary vein isolation versus drug therapy with rate/rhythm control agents. The primary composite outcome was death, disabling stroke, serious bleeding, or cardiac arrest, and key secondary outcomes included AF recurrence. RESULTS: CABANA randomized 819 (37%) women (ablation 413, drug 406) and 1385 men (ablation 695, drug 690). Compared with men, women were older (median age, 69 years versus 67 years for men), were more symptomatic (48% Canadian Cardiovascular Society AF Severity Class 3 or 4 versus 39% for men), had more symptomatic heart failure (42% with New York Heart Association Class ≥II versus 32% for men), and more often had a paroxysmal AF pattern at enrollment (50% versus 39% for men) (P<0.0001 for all). Women were less likely to have ancillary (nonpulmonary vein) ablation procedures performed during the index procedure (55.7% versus 62.2% in men, P=0.043), and complications from treatment were infrequent in both sexes. For the primary outcome, the hazard ratio for those who underwent ablation versus drug therapy was 1.01 (95% CI, 0.62-1.65) in women and 0.73 (95% CI, 0.51-1.05) in men (interaction P value=0.299). The risk of recurrent AF was significantly reduced in patients undergoing ablation compared with those receiving drug therapy regardless of sex, but the effect was greater in men (hazard ratio, 0.64 [95% CI, 0.51-0.82] for women versus hazard ratio, 0.48 [95% CI, 0.40-0.58] for men; interaction P value=0.060). CONCLUSIONS: Clinically relevant treatment-related strategy differences in the primary and secondary clinical outcomes of CABANA were not seen between men and women, and there were no sex differences in adverse events. The CABANA trial results support catheter ablation as an effective treatment strategy for both women and men. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00911508.

Ablation Versus Drug Therapy for Atrial Fibrillation in Heart Failure: Results From the CABANA Trial.

BACKGROUND: In patients with heart failure and atrial fibrillation (AF), several clinical trials have reported improved outcomes, including freedom from AF recurrence, quality of life, and survival, with catheter ablation. This article describes the treatment-related outcomes of the AF patients with heart failure enrolled in the CABANA trial (Catheter Ablation Versus Antiarrhythmic Drug Therapy for Atrial Fibrillation). METHODS: The CABANA trial randomized 2204 patients with AF who were ≥65 years old or <65 years old with ≥1 risk factor for stroke at 126 sites to ablation with pulmonary vein isolation or drug therapy including rate or rhythm control drugs. Of these, 778 (35%) had New York Heart Association class >II at baseline and form the subject of this article. The CABANA trial's primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. RESULTS: Of the 778 patients with heart failure enrolled in CABANA, 378 were assigned to ablation and 400 to drug therapy. Ejection fraction at baseline was available for 571 patients (73.0%), and 9.3% of these had an ejection fraction <40%, whereas 11.7% had ejection fractions between 40% and 50%. In the intention-to-treat analysis, the ablation arm had a 36% relative reduction in the primary composite end point (hazard ratio, 0.64 [95% CI, 0.41-0.99]) and a 43% relative reduction in all-cause mortality (hazard ratio, 0.57 [95% CI, 0.33-0.96]) compared with drug therapy alone over a median follow-up of 48.5 months. AF recurrence was decreased with ablation (hazard ratio, 0.56 [95% CI, 0.42-0.74]). The adjusted mean difference for the AFEQT (Atrial Fibrillation Effect on Quality of Life) summary score averaged over the entire 60-month follow-up was 5.0 points, favoring the ablation arm (95% CI, 2.5-7.4 points), and the MAFSI (Mayo Atrial Fibrillation-Specific Symptom Inventory) frequency score difference was -2.0 points, favoring ablation (95% CI, -2.9 to -1.2). CONCLUSIONS: In patients with AF enrolled in the CABANA trial who had clinically diagnosed stable heart failure at trial entry, catheter ablation produced clinically important improvements in survival, freedom from AF recurrence, and quality of life relative to drug therapy. These results, obtained in a cohort most of whom had preserved left ventricular function, require independent trial verification. Registration: URL: https://www.clinicaltrials.gov/ct2/show/NCT00911508; Unique identifier: NCT0091150.

Outcomes in the ISCHEMIA Trial Based on Coronary Artery Disease and Ischemia Severity.

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) postulated that patients with stable coronary artery disease (CAD) and moderate or severe ischemia would benefit from revascularization. We investigated the relationship between severity of CAD and ischemia and trial outcomes, overall and by management strategy. METHODS: In total, 5179 patients with moderate or severe ischemia were randomized to an initial invasive or conservative management strategy. Blinded, core laboratory-interpreted coronary computed tomographic angiography was used to assess anatomic eligibility for randomization. Extent and severity of CAD were classified with the modified Duke Prognostic Index (n=2475, 48%). Ischemia severity was interpreted by independent core laboratories (nuclear, echocardiography, magnetic resonance imaging, exercise tolerance testing, n=5105, 99%). We compared 4-year event rates across subgroups defined by severity of ischemia and CAD. The primary end point for this analysis was all-cause mortality. Secondary end points were myocardial infarction (MI), cardiovascular death or MI, and the trial primary end point (cardiovascular death, MI, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest). RESULTS: Relative to mild/no ischemia, neither moderate ischemia nor severe ischemia was associated with increased mortality (moderate ischemia hazard ratio [HR], 0.89 [95% CI, 0.61-1.30]; severe ischemia HR, 0.83 [95% CI, 0.57-1.21]; P=0.33). Nonfatal MI rates increased with worsening ischemia severity (HR for moderate ischemia, 1.20 [95% CI, 0.86-1.69] versus mild/no ischemia; HR for severe ischemia, 1.37 [95% CI, 0.98-1.91]; P=0.04 for trend, P=NS after adjustment for CAD). Increasing CAD severity was associated with death (HR, 2.72 [95% CI, 1.06-6.98]) and MI (HR, 3.78 [95% CI, 1.63-8.78]) for the most versus least severe CAD subgroup. Ischemia severity did not identify a subgroup with treatment benefit on mortality, MI, the trial primary end point, or cardiovascular death or MI. In the most severe CAD subgroup (n=659), the 4-year rate of cardiovascular death or MI was lower in the invasive strategy group (difference, 6.3% [95% CI, 0.2%-12.4%]), but 4-year all-cause mortality was similar. CONCLUSIONS: Ischemia severity was not associated with increased risk after adjustment for CAD severity. More severe CAD was associated with increased risk. Invasive management did not lower all-cause mortality at 4 years in any ischemia or CAD subgroup. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01471522.

Myocardial Viability and Long-Term Outcomes in Ischemic Cardiomyopathy.

BACKGROUND: The role of assessment of myocardial viability in identifying patients with ischemic cardiomyopathy who might benefit from surgical revascularization remains controversial. Furthermore, although improvement in left ventricular function is one of the goals of revascularization, its relationship to subsequent outcomes is unclear. METHODS: Among 601 patients who had coronary artery disease that was amenable to coronary-artery bypass grafting (CABG) and who had a left ventricular ejection fraction of 35% or lower, we prospectively assessed myocardial viability using single-photon-emission computed tomography, dobutamine echocardiography, or both. Patients were randomly assigned to undergo CABG and receive medical therapy or to receive medical therapy alone. Left ventricular ejection fraction was measured at baseline and after 4 months of follow-up in 318 patients. The primary end point was death from any cause. The median duration of follow-up was 10.4 years. RESULTS: CABG plus medical therapy was associated with a lower incidence of death from any cause than medical therapy alone (182 deaths among 298 patients in the CABG group vs. 209 deaths among 303 patients in the medical-therapy group; adjusted hazard ratio, 0.73; 95% confidence interval, 0.60 to 0.90). However, no significant interaction was observed between the presence or absence of myocardial viability and the beneficial effect of CABG plus medical therapy over medical therapy alone (P = 0.34 for interaction). An increase in left ventricular ejection fraction was observed only among patients with myocardial viability, irrespective of treatment assignment. There was no association between changes in left ventricular ejection fraction and subsequent death. CONCLUSIONS: The findings of this study do not support the concept that myocardial viability is associated with a long-term benefit of CABG in patients with ischemic cardiomyopathy. The presence of viable myocardium was associated with improvement in left ventricular systolic function, irrespective of treatment, but such improvement was not related to long-term survival. (Funded by the National Institutes of Health; STICH ClinicalTrials.gov number, NCT00023595.).