Nassif, Michael E.

BACKGROUND: Heart failure with preserved ejection fraction is associated with significant functional limitations, yet treatments for improving exercise performance have been elusive. We sought to explore the association between prespecified patient characteristics and changes in 6-minute walk distance that constitute a clinically significant response to dapagliflozin. METHODS: We performed a responder analysis to understand patient characteristics associated with clinically meaningful improvement in 6-minute walk test (6MWT) distance ≥15 m among patients randomized to 12 weeks of dapagliflozin versus placebo in the double-blind PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure). RESULTS: A total of 289 randomized patients had 6MWT distance completed at baseline and 12 weeks. Patients randomized to dapagliflozin improved walking distance by ≥15 m more frequently than those on placebo (n=64, 44% versus n=48, 34%). After adjusting for baseline covariates, patients randomized to dapagliflozin were more likely to experience a clinically meaningful improvement in 6MWT distance compared with those that received placebo (adjusted odds ratio, 1.66 [95% CI, 1.00–2.75]; P =0.05). Dapagliflozin-treated patients were also less likely to have a ≥15 m reduction in 6MWT distance compared with placebo-treated patients (adjusted odds ratio, 0.56 [95% CI, 0.33–0.94]; P =0.03). These results were consistent across all prespecified subgroups (all P values for interaction were not significant). CONCLUSIONS: Compared with those on placebo, patients with heart failure with preserved ejection fraction randomized to dapagliflozin were more likely to experience a clinically meaningful improvement and less likely to experience a deterioration in physical function over 12 weeks as measured by 6MWT distance. Beneficial response to dapagliflozin was consistent across prespecified subgroups. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03030235.

BACKGROUND: Patients with heart failure (HF) have a high burden of symptoms and physical limitations, regardless of ejection fraction (EF). Whether the benefits of SGLT2 (sodium-glucose cotransporter-2) inhibitors on these outcomes vary across the full range of EF remains unclear. METHODS: Patient-level data were pooled from the DEFINE-HF trial (Dapagliflozin Effects on Biomarkers, Symptoms, and Functional Status in Patients With Heart Failure With Reduced Ejection Fraction) of 263 participants with reduced EF (≤40%), and PRESERVED-HF trial (Effects of Dapagliflozin on Biomarkers, Symptoms and Functional Status in Patients With Preserved Ejection Fraction Heart Failure) of 324 participants with preserved EF (≥45%). Both were randomized, double-blind 12-week trials of dapagliflozin versus placebo, recruiting participants with New York Heart Association class II or higher and elevated natriuretic peptides. The effect of dapagliflozin on the change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) at 12 weeks was tested with ANCOVA adjusted for sex, baseline KCCQ, EF, atrial fibrillation, estimated glomerular filtration rate, and type 2 diabetes. Interaction of dapagliflozin effects on KCCQ-CSS by EF was assessed using EF both categorically and continuously with restricted cubic spline. Responder analyses, examining proportions of patients with deterioration, and clinically meaningful improvements in KCCQ-CSS were conducted using logistic regression. RESULTS: Of 587 patients randomized (293 dapagliflozin, 294 placebo), EF was ≤40, >40-≤60, and >60% in 262 (45%), 199 (34%), and 126 (21%), respectively. Dapagliflozin improved KCCQ-CSS at 12 weeks (placebo-adjusted difference 5.0 points [95% CI, 2.6–7.5]; P <0.001). This was consistent in participants with EF≤40 (4.6 points [95% CI, 1.0–8.1]; P =0.01), >40 to ≤60 (4.9 points [95% CI, 0.8–9.0]; P =0.02) and >60% (6.8 points [95% CI, 1.5–12.1]; P =0.01; P interaction =0.79). Benefits of dapagliflozin on KCCQ-CSS were also consistent when analyzing EF continuously ( P interaction =0.94). In responder analyses, fewer dapagliflozin-treated patients had deterioration and more had small, moderate, and large KCCQ-CSS improvements versus placebo; these results were also consistent regardless of EF (all P interaction values nonsignificant). CONCLUSIONS: In patients with HF, dapagliflozin significantly improves symptoms and physical limitations after 12 weeks of treatment, with consistent and clinically meaningful benefits across the full range of EF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT02653482 and NCT03030235.

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— 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.