Jones, Philip G.

BACKGROUND: Recent randomized trials have demonstrated that for patients with severe tricuspid regurgitation (TR), transcatheter tricuspid valve interventions (TTVI) improve patients’ symptoms, function, and quality of life and that the amount of health status improvement correlates with the extent of TR reduction. Defining this relationship in greater detail can potentially provide insight into device selection and patient-specific treatment goals. We therefore sought to better understand the relationship between both baseline TR severity and change in TR after TTVI and the extent of improvement in health status after TTVI. METHODS: As part of the Tri-QOL (Kansas City Cardiomyopathy Questionnaire Validation in Tricuspid Valve Disease) study, data from 11 studies of TTVI devices were transferred to the US Food and Drug Administration to harmonize and anonymize before analysis by an independent center. This secondary, observational analysis used patient-level data from the 6 single-arm studies of patients who underwent TTVI to explore the association of change in KCCQ-OS with TR grade using multivariable models, adjusted for age, sex, chronic lung disease, and baseline KCCQ-OS. The primary model included TR grade at baseline, TR grade at 1 month, and the interaction between the two. RESULTS: Among 1056 patients with ≥severe TR who underwent TTVI, mean age was 79.1±7.1 years, 60.3% were female, and mean baseline Kansas City Cardiomyopathy Questionnaire-overall summary score [KCCQ-OS] was 49.5±22.3. Baseline TR grade was severe in 33.5%, massive in 35.9%, and torrential in 30.6%. One-month after TTVI, TR was none/trace in 21.7%, mild in 27.2%, moderate in 28.1%, and ≥evere in 23.1%, while the mean change in KCCQ-OS was 17.0±21.3 points. In a multivariable model that included TR grade at baseline, TR grade at 1 month, and their interaction, there was a strong association between reduction in TR and improvement in KCCQ-OS, with no consistent evidence of a threshold of TR grade below which there was no further improvement in KCCQ-OS. However, among patients with baseline torrential TR, the extent of health status improvement plateaued for patients achieving moderate or less TR at 1 month (ie, a 3-grade improvement from baseline). CONCLUSIONS: Health status improvement after TTVI was most strongly associated with the degree of TR reduction, although there was minimal additional improvement for most patients beyond a 3-grade reduction in TR. These findings support the goal of achieving mild or less TR with TTVI, although patients with torrential TR at baseline may be well served if moderate TR can be achieved.

ImportanceImproving patients’ health status is a key goal of treating tricuspid regurgitation (TR). The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a heart failure disease-specific health status measure used to capture the health status impact of TR and the benefit of transcatheter tricuspid valve intervention (TTVI), but its validity in this clinical setting is unknown.ObjectiveTo evaluate the psychometric properties of the KCCQ in patients with TR.Design, Setting, and ParticipantsData were pooled from patients with severe TR enrolled in 11 manufacturer-sponsored trials of TTVI. The data were transferred to the US Food and Drug Administration to harmonize and anonymize prior to analysis by an independent center. Data were collected from December 2015 to April 2023, and data analysis was performed from July to October 2023.Main Outcomes and MeasuresPrespecified analyses included evaluation of internal consistency, reproducibility, responsiveness, construct validity, and predictive validity. Outcomes were determined using Cronbach α, score comparisons, intraclass correlation, Cohen d, Spearman correlations with best available reference measures, and association of scores and changes in scores with risk of subsequent clinical events.ResultsThe study cohort was composed of 2693 patients enrolled in either single-arm (n = 1517) or randomized (n = 1176) investigations of TTVI. Mean (SD) patient age was 78.6 (8.0) years, 1658 of 2693 patients (61.6%) were female, and the mean (SD) baseline KCCQ Overall Summary (KCCQ-OS) score was 50 (23). There was strong internal consistency within individual domains (Cronbach α, .77-.83). Among clinically stable patients between 1 and 6 months, there were small mean changes in KCCQ domain and summary scores (differences of −0.1 to 1.9 points), demonstrating reproducibility. In contrast, domain and summary scores of patients who underwent TTVI showed large improvements at 1 month after treatment (mean changes, 12.1-21.4 points), indicating excellent perceived responsiveness. Construct validity was moderately strong when domains were compared with best available reference measures (Spearman correlations, 0.47-0.69). In both cross-sectional and longitudinal analyses, the KCCQ-OS was associated with clinical events, with lower scores associated with an increased risk of mortality (hazard ratio, 1.34 per 10-point decrement; 95% CI, 1.22-1.47) and heart failure hospitalization (hazard ratio, 1.24 per 10-point decrement; 95% CI, 1.17-1.31).Conclusions and RelevanceIn this cohort study, the KCCQ had strong psychometric properties in patients with severe TR, including reliability, responsiveness, and validity. These data support use of the KCCQ in patients with severe TR as a measure of their symptoms, function, and quality of life and also for assessing the impact of interventions, such as TTVI, in rigorously controlled trials.

BACKGROUND: Mechanisms of benefit with SGLT2is (sodium-glucose cotransporter-2 inhibitors) in heart failure (HF) remain incompletely characterized. Dapagliflozin alters ketone and fatty acid metabolism in HF with reduced ejection fraction though similar effects have not been observed in HF with preserved ejection fraction. We explore whether metabolic effects of SGLT2is vary across the left ventricular ejection fraction spectrum and their relationship with cardiometabolic end points in 2 randomized trials of dapagliflozin in HF. METHODS: Metabolomic profiling of 61 metabolites was performed in 527 participants from DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients With HF With Reduced Ejection Fraction) and PRESERVED-HF (Dapagliflozin in PRESERVED Ejection Fraction HF; 12-week, placebo-controlled trials of dapagliflozin in HF with reduced ejection fraction and HF with preserved ejection fraction, respectively). Linear regression was used to assess changes in principal components analysis–defined metabolite factors with treatment from baseline to 12 weeks, as well as the relationship between changes in metabolite clusters and HF-related end points. RESULTS: The mean age was 66±11 years, 43% were female, and 33% were self-identified as Black. Two principal components analysis–derived metabolite factors (which were comprised of ketone and short-/medium-chain acylcarnitines) increased with dapagliflozin compared with placebo. Ketosis (defined as 3-hydroxybutyrate >500 μM) was achieved in 4.5% with dapagliflozin versus 1.2% with placebo ( P =0.03). There were no appreciable treatment effects on amino acids, including branched-chain amino acids. Increases in several acylcarnitines were consistent across LVEF ( P interaction >0.10), whereas the ketogenic effect diminished at higher LVEF ( P interaction =0.01 for 3-hydroxybutyrate). Increases in metabolites reflecting mitochondrial dysfunction (particularly long-chain acylcarnitines) and aromatic amino acids and decreases in branched-chain amino acids were associated with worse HF-related outcomes in the overall cohort, with consistency across treatment and LVEF. CONCLUSIONS: SGLT2is demonstrate common (fatty acid) and distinct (ketogenic) metabolic signatures across the LVEF spectrum. Changes in key pathways related to fatty acid and amino acid metabolism are associated with HF-related end points and may serve as therapeutic targets across HF subtypes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifiers: NCT03030235 and NCT02653482.

Background: Cardiac rehabilitation (CR) is a class Ia recommendation and endorsed performance measure for the quality of care in acute myocardial infarction (AMI) survivors. While participation in CR after AMI is associated with reduced mortality, conflicting data exists on its association with health status outcomes. Methods: Using data from 2 prospective AMI registries (TRIUMPH and PREMIER), we identified patients for whom baseline and follow-up health status scores and documentation of CR participation (attendance of 1 or more sessions within 6 months post-AMI) were available. Health status was assessed by four Seattle Angina Questionnaire (SAQ) domain scores (quality of life [QoL], angina frequency [AF], treatment satisfaction [TS], and physical limitation [PL]), as well as SF-12 physical and mental health composite scores ( PCS & MCS ). We created propensity matched cohorts of CR participants and non-participants to examine the association between CR participation with health status (6 and 12 months) and all-cause mortality (up to 7 years), using conditional repeated measures and proportional hazards models, respectively. Results: Among 3,957 AMI patients from 31 sites, 2,015 patients (51%) participated in CR after discharge. Compared to non-participants, CR participants were more often Caucasian (83.6% vs. 65.4%), had higher rates of health insurance (90.6% vs. 79.3%), but clinically similar baseline SAQ and SF-12 scores in all domains. After propensity matching, all covariates were well-balanced (Standardized Difference <10 for all patient characteristics) between CR participants and non-participants. In the repeated measures analysis, the mean SAQ and SF-12 domain scores were clinically similar for both groups at 6 and 12 months after hospital discharge (Table). Using a conditional proportional hazards model, a decrease in all-cause mortality was noted in the CR participant group (HR 0.59, 95% CI [0.46, 0.75]). Conclusion: In a large, multi-center AMI cohort, we found that although CR participation seemed to improve survival, CR participants had similar health status improvements after AMI as non-participants. Further investigation is required to identify how CR programs can further maximize the health status benefits to post-AMI participants.

Background: The Kansas City Cardiomyopathy Questionnaire (KCCQ) has been psychometrically evaluated in multiple heart failure (HF) populations, but the comparability of its psychometric properties between men and women is unknown. Methods: Data from 3 clinical trials (1 in stable HF with preserved ejection fraction, 1 each in stable and acute HF with reduced ejection fraction) and 1 prospective cohort study (stable HF with reduced ejection fraction), incorporating 6773 men and 3612 women with HF, were used to compare the construct validity, internal and test-retest reliability, ability to detect change, predict mortality and hospitalizations and minimally important differences between the 2 sexes. Interactions of the KCCQ overall summary and subdomain scores by sex were independently examined. Results: The KCCQ-Overall Summary score correlated well with New York Heart Association functional class in both sexes across patients with stable (correlation coefficient: −0.40 in men versus −0.49 in women) and acute (−0.37 in men versus −0.34 in women) HF. All KCCQ subdomains demonstrated concordant relationships with relevant comparison standards with no significant interactions by sex in 19 of 21 of these construct validity analyses. All KCCQ scores were equally predictive and other psychometric evaluations showed similar results by sex: test-retest reliability (intraclass correlation coefficient 0.94 in men versus 0.92 in women), responsive to change (standardized response mean 1.01 in both sexes), as were the minimally important differences and internal reliability. Conclusions: The psychometric properties of the KCCQ, in terms of validity, prognosis, reliability, and sensitivity to change, are comparable in men and women with HF with preserved ejection fraction and HF with reduced ejection fraction.

Background: After left ventricular assist device (LVAD) for end-stage heart failure, cognitive function should improve due to increased cerebral perfusion. However, stroke (a well-known LVAD complication) and even subclinical cerebral ischemia may also occur and manifest as transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods: As part of the INTERMACS registry, cognitive function was assessed before LVAD and at each follow-up with the Trailmaking B Test (TBT), where a subject is timed connecting 25 dots labeled with alternating, consecutive numbers and letters (1, A, 2, B, etc.). The TBT can detect several forms of cognitive impairment, including subclinical stroke. Longer times are worse, and cognitive decline was defined as a clinically important increase from baseline to highest follow-up score using Cohen’s D Effect Size (0.2*baseline SD = 13 s). Patients who completed baseline and at least 1 follow-up TBT were included. Multivariable logistic regression was used to examine the association between patient characteristics and cognitive decline after LVAD. Results: Among 1151 LVAD patients, median age was 60-69, 19% were female, and 40% were INTERMACS profile 1-2 (cardiogenic shock or declining despite inotropes) at implant. Among patients with 12-mo follow-up, mean TBT score improved from 126 at baseline to 123 at 1 yr. In the total cohort, 333 (29%) patients had significant cognitive decline within 12 mo of LVAD placement. Increasing age, chronic renal disease, better baseline TBT score (shorter time), and higher INTERMACS profiles (≥ 3; less severe heart failure) were significantly associated with greater odds of cognitive decline (Figure). Conclusion: In a large LVAD registry, cognitive decline occurred in over a quarter of patients in the year after LVAD and was associated with older age, renal disease, higher baseline cognitive function, and more stable heart failure at implant. These results define the frequency of an important adverse event and provide new insights regarding outcomes after LVAD. Future studies are needed to explore the association of transient and permanent cognitive decline with subsequent stroke, health status, and mortality in patients after LVAD placement.

Background: While concerns about the safety and procedural success of radial, as opposed to femoral, access for PCI have largely been abated, the association of radial access with patients’ health status recovery has not been explored. To address this gap in knowledge, we compared the symptoms, physical function and quality of life 1 year after PCI in patients treated with radial, as compared with femoral, access. Methods: This is a 10-center study of PCI, in whom 48 of 139 (35%) interventionalists used both radial and femoral approaches between 2009-2010. A total 2628 patients without prior CABG were interviewed and followed for one year. The previously validated Seattle Angina Questionnaire (SAQ) was used to assess disease-specific health status and the EQ-5D was used to quantify generic quality of life. Clinical characteristics and health status outcomes were compared between 296 radial and 2332 femoral PCI procedures. Results: Radial access was used in 11.2% of patients. No demographic (age, gender, race) or clinical factors (e.g. BMI, smoking, diabetes, hypertension, renal disease or prior cardiac history) were associated with radial use, except for an increased use among those with PAD (10.5% radial vs. 6.8% femoral, p=0.022) but reduced use among those with prior PCI (38.3% vs. 32.1%, p=0.037). There was no difference in health status outcomes based on SAQ angina frequency and quality of life, or the EQ-5D at baseline, 6 months or one year (table). Conclusion: In this multi-center observational registry, there was no association of radial access with long-term health status outcomes. These data suggest that there are no offsetting concerns about patients’ long-term health status benefits to counterbalance the peri-procedural safety benefits of a radial approach.

Background— After left ventricular assist device (LVAD) placement for advanced heart failure, increased cerebral perfusion should result in improved cognitive function. However, stroke (a well-known LVAD complication) and subclinical cerebral ischemia may result in transient or permanent cognitive decline. We sought to describe the incidence and predictors of cognitive decline after LVAD using a valid, sensitive assessment tool. Methods and Results— Among 4419 patients in the Interagency Registry for Mechanically Assisted Circulatory Support who underwent LVAD implantation between May 2012 and December 2013, cognitive function was assessed in 1173 patients with the Trail Making B Test before LVAD and at 3, 6, and 12 months. The test detects several forms of cognitive impairment, including subclinical stroke. Cognitive decline was defined as a clinically important increase during follow-up using a moderate Cohen d effect size of 0.5×baseline SD (32 s). The cumulative incidence of cognitive decline in the year after LVAD implantation, treating death and transplantation as competing risks, was 29.2%. In adjusted analysis, older age (≥70 versus <50 years; hazard ratio, 2.24; 95% confidence interval 1.46–3.44; P trend <0.001) and destination therapy (hazard ratio, 1.42; 95% confidence interval, 1.05–1.92) were significantly associated with greater risk of cognitive decline. Conclusions— Cognitive decline occurs commonly in patients in the year after LVAD and is associated with older age and destination therapy. These results could have important implications for patient selection and improved communication of risks before LVAD implantation. Additional studies are needed to explore the association between cognitive decline and subsequent stroke, health status, and mortality in patients after LVAD.