Heart Failure, Investigator-Reported Sleep Apnea and Dapagliflozin:A Patient-Level Pooled Meta-Analysis of DAPA-HF and DELIVER

Background: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. Objectives: To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). Methods: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. Results: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10–1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59–1.03]) and without sleep apnea (HR 0.79 [0.72–0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. Conclusions: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. Clinical trial registration: Unique identifiers: NCT01920711 Condensed Abstract: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions.</p

Dapagliflozin in patients with heart failure with mildly reduced and preserved ejection fraction treated with a mineralocorticoid receptor antagonist or sacubitril/valsartan

Aims: The effects of adding a sodium–glucose cotransporter 2 (SGLT2) inhibitor to a mineralocorticoid receptor antagonist (MRA) or an angiotensin receptor–neprilysin inhibitor (ARNI) in patients with heart failure (HF) and mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) are uncertain, even though the use of all three drugs is recommended in recent guidelines. Methods and results: The efficacy and safety of dapagliflozin added to background MRA or ARNI therapy was examined in patients with HFmrEF/HFpEF enrolled in the DELIVER trial. The primary outcome was the composite of worsening HF or cardiovascular death. Of 6263 patients, 2667 (42.6%) were treated with an MRA and 301 (4.8%) with an ARNI at baseline. Patients taking either were younger, more often men and had lower systolic blood pressure and ejection fraction; they were also more likely to have prior HF hospitalization. The benefit of dapagliflozin was similar whether patients were receiving these therapies. The hazard ratio for the effect of dapagliflozin compared to placebo on the primary outcome was 0.86 (95% confidence interval [CI] 0.74–1.01) for MRA non-users versus 0.76 (95% CI 0.64–0.91) for MRA users (pinteraction = 0.30). The corresponding values for ARNI non-users and users were 0.82 (95% CI 0.73–0.92) and 0.74 (95% CI 0.45–1.22), respectively (pinteraction = 0.75). None of the adverse events examined was more common with dapagliflozin compared to placebo overall or in the MRA and ARNI subgroups. Conclusions: The efficacy and safety of dapagliflozin were similar, regardless of background treatment with an MRA or ARNI. SGLT2 inhibitors may be added to other treatments recommended in recent guidelines for HFmrEF/HFpEF

Heart failure, investigator-reported sleep apnea and dapagliflozin: A patient-level pooled meta-analysis of DAPA-HF and DELIVER

Background: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in different HF phenotypes or how it might modify the effect of HF therapy. Objectives: To examine the prevalence of sleep apnea, its association with outcomes, and the effects of dapagliflozin in HF patients with and without sleep apnea in a pooled analysis of two trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF) and HFmrEF/HFpEF (DELIVER). Methods: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. Results: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10-1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59-1.03]) and without sleep apnea (HR 0.79 [0.72-0.87]) [Pinteraction=0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. Conclusions: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated.An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea

Improving clinical trial efficiency using a machine learning-based risk score to enrich study populations

Aims Prognostic enrichment strategies can make trials more efficient, although potentially at the cost of diminishing external validity. Whether using a risk score to identify a population at increased mortality risk could improve trial efficiency is uncertain. We aimed to assess whether Machine learning Assessment of RisK and EaRly mortality in Heart Failure (MARKER-HF), a previously validated risk score, could improve clinical trial efficiency. Methods and results Mortality rates and association of MARKER-HF with all-cause death by 1 year were evaluated in four community-based heart failure (HF) and five HF clinical trial cohorts. Sample size required to assess effects of an investigational therapy on mortality was calculated assuming varying underlying MARKER-HF risk and proposed treatment effect profiles. Patients from community-based HF cohorts (n = 11 297) had higher observed mortality and MARKER-HF scores than did clinical trial patients (n = 13 165) with HF with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF). MARKER-HF score was strongly associated with risk of 1-year mortality both in the community (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.44-1.52) and clinical trial cohorts with HFrEF (HR 1.41, 95% CI 1.30-1.54), and HFpEF (HR 1.74, 95% CI 1.53-1.98), per 0.1 increase in MARKER-HF. Using MARKER-HF to identify patients for a hypothetical clinical trial assessing mortality reduction with an intervention, enabled a reduction in sample size required to show benefit. Conclusion Using a reliable predictor of mortality such as MARKER-HF to enrich clinical trial populations provides a potential strategy to improve efficiency by requiring a smaller sample size to demonstrate a clinical benefit

Sacubitril/valsartan and loop diuretic requirement in heart failure with preserved ejection fraction in the PARAGON‐HF trial

Aims: As sacubitril/valsartan may potentiate early natriuresis, expert consensus documents recommend diuretic dose reduction on first initiation. However, there are limited data on the effects of sacubitril/valsartan on the background of varying diuretic regimens or on diuretic requirements over time in HFpEF. Methods and Results: In this post hoc analysis of PARAGON-HF, of the 4,796 patients, background diuretic therapy was distributed as follows: 341(7%) on no diuretic, 698(15%) on non-loop diuretic, and 3,757(78%) were on loop diuretics (1,255, 1,589, and 913 were on &lt;40mg, =40mg and &gt;40mg furosemide equivalent doses, respectively). The primary composite outcome of total HF hospitalizations and CV death was analyzed using semiparametric proportional rates methods. The cumulative incidence of the primary composite outcome (first events) was lowest in patients on no diuretic and highest in those on &gt;40mg of loop diuretic (P&lt;0.001). The effects of sacubitril/valsartan (versus valsartan) on the primary composite outcome (recurrent events) did not significantly vary by baseline diuretic use (Pinteraction= 0.65). Treatment effects on safety outcomes were similar across diuretic categories. Sacubitril/valsartan reduced new loop diuretic initiations over the course of the trial (HR 0.83; 95% CI: 0.68-1.00, p=0.055), with similar mean loop diuretic dose and rates of diuretic discontinuation between treatment groups in follow-up. Patients randomized to sacubitril/valsartan experienced a slight early reduction in diuretic initiation or dose escalation at 30 days after initiation (net reduction 1.7%, p=0.02), but these differences were not sustained beyond this timepoint. Conclusions: Patients with HFpEF on higher baseline diuretic doses were at heightened risk of HF events, but similarly benefited from sacubitril/valsartan with a consistent safety profile across a range of diuretic doses. Initiation of sacubitril/valsartan was associated with modestly lower new loop diuretic requirement in follow-up

Trajectory and correlates of pulmonary congestion by lung ultrasound in patients with acute myocardial infarction: insights from PARADISE-MI

Background: PARADISE-MI examined the efficacy of sacubitril/valsartan in acute myocardial infarction (AMI) complicated by reduced left ventricular ejection fraction (LVEF), pulmonary congestion or both. We sought to assess the trajectory of pulmonary congestion using lung ultrasound (LUS) and its association with cardiac structure and function in a prespecified substudy. Methods: Patients without prior heart failure (HF) underwent 8-zone LUS and echocardiography at baseline (±2 days of randomization) and after 8 months. B-lines were quantified offline, blinded to treatment, clinical findings, timepoint and outcomes. Results: Among 152 patients (median age 65, 32% women, mean LVEF 41%), B-lines were detectable in 87% at baseline (median B-line count: 4 [IQR 2-8]). Among 115 patients with LUS data at baseline and follow-up, B-lines decreased significantly from baseline (mean ± SD: -1.6 ± 7.3; p=0.018). The proportion of patients without pulmonary congestion at follow-up was significantly higher in those with fewer B-lines at baseline. Adjusted for baseline, B-lines at follow-up were on average 6 (95% CI: 3, 9) higher in patients who experienced an intercurrent HF event vs. those who did not (p=0.001). A greater number of B-lines at baseline was associated with larger left atrial size, higher E/e’ and E/A ratios, greater degree of mitral regurgitation, worse right ventricular systolic function, and higher tricuspid regurgitation velocity (p trend &lt;0.05 for all). Conclusions: In this AMI cohort, B-lines, indicating pulmonary congestion, were common at baseline and, on average, decreased significantly from baseline to follow-up. Worse pulmonary congestion was associated with prognostically important echocardiographic markers

Knowledge about self-efficacy and outcomes in patients with heart failure and reduced ejection fraction

Background: Although education in self-management is thought to be an important aspect of the care of patients with heart failure, little is known about whether self-rated knowledge of self-management is associated with outcomes. Objectives: To assess the relationship between patient-reported knowledge of self-management and clinical outcomes in patients with heart failure and reduced ejection fraction (HFrEF). Methods: Using individual patient data from 3 recent clinical trials enrolling participants with HFrEF, we examined patient characteristics and clinical outcomes according to responses to the “self-efficacy” questions of the Kansas City Cardiomyopathy Questionnaire (KCCQ). One question quantifies patients' understanding of how to prevent heart failure exacerbations (“prevention” question) and the other how to manage complications when they arise (“response” question). Self-reported answers from patients were pragmatically divided into: poor (do not understand at all, do not understand very well, somewhat understand), fair (mostly understand), and good (completely understand). Cox-proportional hazard models were used to evaluate time-to-first occurrence of each endpoint, and negative binomial regression analysis was performed to compare the composite of total (first and repeat) heart failure hospitalizations and cardiovascular death across the above-defined groups. Results: Of patients (n = 17 629) completing the “prevention” question, 4197 (23.8%), 6897 (39.1%), and 6535 (37.1%) had poor, fair, and good self-rated knowledge, respectively. Of those completing the “response” question (n = 17 637), 4033 (22.9%), 5463 (31.0%), and 8141 (46.2%) patients, respectively, had poor, fair, and good self-rated knowledge. For both questions, patients with “poor” knowledge were older, more often female, and had a worse HF profile but similar treatment. The rates (95%CI) per 100 person-years for the primary composite outcome for “poor”, “moderate” and “good” self-rated knowledge in answer to the “prevention” question were 12.83 (12.11–13.60), 12.08 (11.53–12.65) and 11.55 (11.00–12.12), respectively, and for the “response” question were 12.88 (12.13–13.67), 12.22 (11.60–12.86) and 11.56 (11.07–12.07), respectively. The lower event rates in patients with “good” self-rate knowledge were accounted for by lower rates of cardiovascular (and all-cause) death and not hospitalization for worsening HF. Conclusions: Poor patient-reported “self-efficacy” may be associated with higher rates of mortality. Evaluation of knowledge of “self-efficacy” may provide prognostic information and a guide to which patients may benefit from further education about self-management