Dataset Information

Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the PARAGON-HF trial.

ABSTRACT:

Aims

Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.

Methods and results

In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomerular filtration rate (eGFR); (ii) development of end-stage renal disease; or (iii) death attributable to renal causes. A total of 2306 (48.1%) patients had a history of prior HF hospitalization. Incident rates of the renal outcome were highest in those most recently hospitalized and decreased with longer time from last hospitalization. Treatment effect on the renal outcome of sacubitril/valsartan versus valsartan was similar between patients with (hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.24-0.76) and without (HR 0.63; 95% CI: 0.33-1.18; p_interaction = 0.39) a prior history of HF hospitalization and appeared consistent regardless of timing of prior hospitalization for HF (p_interaction = 0.39). Serial eGFR measurements leading up to and after a HF hospitalization (occurring during the study period) and estimated eGFR trajectories using repeated measures regression models with restricted cubic splines were also examined. Patients experiencing a post-randomization HF hospitalization had a significant decline in eGFR prior to hospitalization while patients without HF hospitalization experienced a relatively stable eGFR trajectory (p < 0.001). A change in the rate of decline of eGFR trajectory was observed 12 months preceding a HF hospitalization, and continued in the post-discharge window to 12 months following hospitalization.

Conclusions

Heart failure hospitalization denotes increased risk for kidney disease progression which continues following recovery from HF decompensation in patients with HF with preserved ejection fraction.

Clinical trial registration

PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), ClinicalTrials.gov NCT01920711.

SUBMITTER: Chatur S

PROVIDER: S-EPMC10086974 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Publications

Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the PARAGON-HF trial.

Chatur Safia S Vaduganathan Muthiah M Peikert Alexander A Claggett Brian L BL McCausland Finnian R FR Skali Hicham H Pfeffer Marc A MA Beldhuis Iris E IE Kober Lars L Seferovic Petar P Lefkowitz Martin M McMurray John J V JJV Solomon Scott D SD

European journal of heart failure 20220815 10

<h4>Aims</h4>Worsening renal function may impact long-term outcomes in heart failure (HF). However, little is known about the longitudinal trajectories in renal function in relation to HF hospitalization or how this high-risk clinical event impacts renal outcomes.<h4>Methods and results</h4>In PARAGON-HF, we evaluated the association between recency of prior HF hospitalization (occurring pre-randomization) and subsequent first renal composite outcome: (i) time to ≥50% decline in estimated glomer ...[more]

PMID: 35895867

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Project description:BackgroundPrognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined.Methods and resultsWe measured serum levels of 4123 unique proteins in 1117 patients with HFpEF enrolled in the PARAGON-HF (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction) trial using a modified aptamer proteomic assay. Baseline circulating protein concentrations significantly associated with the primary end point and the timing and occurrence of total heart failure hospitalization and cardiovascular death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared with published analyses in 2515 patients with heart failure with reduced ejection fraction from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and ATMOSPHERE (Efficacy and Safety of Aliskiren and Aliskiren/Enalapril Combination on Morbidity-Mortality in Patients With Chronic Heart Failure) clinical trials. We identified 288 proteins that were robustly associated with the risk of heart failure hospitalization and cardiovascular death in patients with HFpEF. The baseline proteins most strongly related to outcomes included B2M (β-2 microglobulin), TIMP1 (tissue inhibitor of matrix metalloproteinase 1), SERPINA4 (serpin family A member 4), and SVEP1 (sushi, von Willebrand factor type A, EGF, and pentraxin domain containing 1). Overall, the protein-outcome associations in patients with HFpEF did not markedly differ as compared with patients with heart failure with reduced ejection fraction. A proteomic risk score derived in patients with HFpEF was not superior to a previous proteomic score derived in heart failure with reduced ejection fraction nor to clinical risk factors, NT-proBNP (N-terminal pro-B-type natriuretic peptide), or high-sensitivity cardiac troponin.ConclusionsNumerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis in the PARAGON-HF proteomic substudy. Our results demonstrate substantial similarities among serum proteomic risk markers for heart failure hospitalization and cardiovascular death when comparing clinical trial participants with heart failure across the ejection fraction spectrum.RegistrationURL: https://www.clinicaltrials.gov; Unique Identifiers: NCT01920711, NCT01035255, NCT00853658.

Project description:AimsAs 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 heart failure (HF) with preserved ejection fraction (HFpEF).Methods and resultsIn this post hoc analysis of PARAGON-HF, of the 4796 patients, background diuretic therapy was distributed as follows: 341 (7%) on no diuretic, 698 (15%) on non-loop diuretic, and 3757 (78%) were on loop diuretics (1255, 1589, and 913 were on <40, 40 and >40 mg furosemide equivalent doses, respectively). The primary composite outcome of total HF hospitalizations and cardiovascular death was analysed 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 >40 mg of loop diuretic (p < 0.001). The effects of sacubitril/valsartan (vs. 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 (hazard ratio 0.83; 95% confidence interval 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.ConclusionsPatients 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.

Project description:Background Little is known about the impact of chronic obstructive pulmonary disease (COPD) in patients with heart failure with preserved ejection fraction (HFpEF). Methods and Results We examined outcomes in patients with heart failure with preserved ejection fraction, according to COPD status, in the PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction) trial. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and cardiovascular death. Of 4791 patients, 670 (14%) had COPD. Patients with COPD were more likely to be men (58% versus 47%; P<0.001) and had worse New York Heart Association functional class (class III/IV 24% versus 19%), worse Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores (69 versus 76; P<0.001) and more frequent history of heart failure hospitalization (54% versus 47%; P<0.001). The decrement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores with COPD was greater than for other common comorbidities. Patients with COPD had echocardiographic right ventricular enlargement, higher serum creatinine (100 μmol/L versus 96 μmol/L) and neutrophil-to-lymphocyte ratio (2.7 versus 2.5), than those without COPD. After multivariable adjustment, COPD was associated with worse outcomes: adjusted rate ratio for the primary outcome 1.51 (95% CI, 1.25-1.83), total heart failure hospitalization 1.54 (95% CI, 1.24-1.90), cardiovascular death (adjusted hazard ratio [HR], 1.42; 95% CI, 1.10-1.82), and all-cause death (adjusted HR, 1.52; 95% CI, 1.25-1.84). COPD was associated with worse outcomes than other comorbidities and Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores declined more in patients with COPD than in those without. Conclusions Approximately 1 in 7 patients with heart failure with preserved ejection fraction had concomitant COPD, which was associated with greater functional limitation and a higher risk of heart failure hospitalization and death. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Project description:AimsIn the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON-HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios.Methods and resultsEligibility was assessed in the Karolinska-Rennes study (acute HFpEF, LVEF ≥ 45%, and N-terminal pro-B-type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (<54% in women and <52% in men); and (iv) LVEF below mean of normal range (<64% in women and <62% in men). Among 425 patients [age 78 (72-83) years, 57% women, 28% LVEF ≤ 57% (median in PARAGON-HF), the trial scenario, identified 34% as eligible. Left atrial enlargement and/or left ventricular hypertrophy were present in 99%. Inclusion criteria not met were diuretic treatment and New York Heart Association class. Important exclusion criteria were estimated glomerular filtration rate <30 mL/min/1.73 m2 , haemoglobin <10 g/day, and cancer. In the pragmatic scenario, 63% were eligible. In LVEF below lower limit of normal range, 5.4% were eligible, and in LVEF below mean of normal range, 41% were eligible. In patients with LVEF ≤ 57%, eligibility was 42%, 69%, 21%, and 91% according to the trial scenario, pragmatic scenario, LVEF below lower limit of normal range, and LVEF below mean of normal range, respectively.ConclusionsIn real-world HFpEF (LVEF ≥ 45%) with N-terminal pro-B-type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON-HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria.

Project description:AimsThe relationship between serum potassium concentration and outcomes in patients with heart failure and preserved ejection fraction (HFpEF) is not well-established. The aim of this study was to explore the association between serum potassium and clinical outcomes in the PARAGON-HF trial in which 4822 patients with HFpEF were randomised to treatment with sacubitril/valsartan or valsartan.Methods and resultsThe relationship between serum potassium concentrations and the primary study composite outcome of total (first and recurrent) heart failure hospitalisations and cardiovascular death was analysed. Hypo-, normo-, and hyperkalaemia were defined as serum potassium <4 mmol/L, 4-5 mmol/L and >5 mmol/L, respectively. Both screening and time-updated potassium (categorical and continuous spline-transformed) were studied. Patient mean age was 73 years and 52% were women. Patients with higher baseline potassium more often had an ischaemic aetiology and diabetes and mineralocorticoid receptor antagonist treatment. Compared with normokalaemia, both time-updated (but not screening) hypo- and hyperkalaemia were associated with a higher risk of the primary outcome [adjusted hazard ratio (HR) for hypokalaemia 1.55, 95% confidence interval (CI) 1.30-1.85; P < 0.001, and for hyperkalaemia HR 1.21, 95% CI 1.02-1.44; P = 0.025]. Hypokalaemia had a stronger association with a higher risk of all-cause, cardiovascular and non-cardiovascular death than hyperkalaemia. The association of hypokalaemia with increased risk of all-cause and cardiovascular death was most marked in participants with impaired kidney function (interaction P < 0.05). Serum potassium did not significantly differ between sacubitril/valsartan and valsartan throughout the follow-up.ConclusionsBoth hypo- and hyperkalaemia were associated with heart failure hospitalisation but only hypokalaemia was associated with mortality, especially in the context of renal impairment. Hypokalaemia was as strongly associated with death from non-cardiovascular causes as with cardiovascular death. Collectively, these findings suggest that potassium disturbances are a more of a marker of HFpEF severity rather than a direct cause of death.

Project description:AimsThe PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction.Methods and resultsBoth PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61-0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75-0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66-0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86-1.40; Pinteraction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43-1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44-0.83; P = 0.002).ConclusionIn pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting.

Dataset Information

Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the PARAGON-HF trial.

Aims

Methods and results

Conclusions

Clinical trial registration

Publications

Longitudinal trajectories in renal function before and after heart failure hospitalization among patients with heart failure with preserved ejection fraction in the PARAGON-HF trial.

Similar Datasets

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