Desai, Akshay S.

Abstract Aims Trends in upright seated pulmonary artery pressure (PAP) with synchronous measurement of weight, blood pressure (BP), and heart rate (HR) have not been compared prior to heart failure events (HFE) and other causes of hospitalization during remote monitoring. Methods We analysed 24-month data from patients in the PROACTIVE-HF trial. Participants (N = 456) used the CordellaTM HF daily to measure seated PAP, weight, BP, and HR, all taken and transmitted within minutes. Events that were analysed included HFE, those potentially related to HF treatment (HF-TRE), and others (non-HFE). Parameters were trended from 60-days before (D-60) to 30-days after (D + 30) the day of the event (D = 0), and their concurrent changes were compared between D-60 and D = 0, and D = 0 and D + 30 using a mixed effects model. Results There were 196 HFE, 276 non-HFE, and 66 HF-TRE. Prior to HFE, average mean PAP (mPAP) increased from 27.8 ± 10.9 mmHg at D-60 to 32.6 ± 11.2 mmHg at D = 0 (P < .001), and decreased to 30.0 ± 12.4 mmHg at D + 30 (P = .001). Kinetics of mPAP before HFE differed by left ventricular ejection fraction (LVEF); mPAP rose by 3.4 ± 6.8 mmHg in 2 weeks before HFE in those with LVEF >40%, whereas a similar magnitude (3.1 ± 9.1 mmHg) of mPAP rise occurred over 6-weeks before HFE in those with LVEF ≤40%. No consistent changes in weight, SBP, or HR prior to HFE were observed (P > .05). Changes in vital signs but not mPAP were noted prior to HF-TRE and non-HFE. Conclusion Seated mPAP increased weeks in advance of HFE and vital signs did not change consistently before HFE. Differential kinetics of mPAP prior to HFE by the LVEF suggest that an uptrend in seated mPAP may need to be addressed more rapidly in those with LVEF>40%. Changes in vital signs with non-HFE and HF-TRE need further validation.

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28–30) in 1809 of 2895 patients (62.5%), borderline (score 24–27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06–1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21–2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.

BACKGROUND: A hypothetical concern has been raised that sacubitril/valsartan might cause cognitive impairment because neprilysin is one of several enzymes degrading amyloid-β peptides in the brain, some of which are neurotoxic and linked to Alzheimer-type dementia. To address this, we examined the effect of sacubitril/valsartan compared with valsartan on cognitive function in patients with heart failure with preserved ejection fraction in a prespecified substudy of PARAGON-HF (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). METHODS: In PARAGON-HF, serial assessment of cognitive function was conducted in a subset of patients with the Mini-Mental State Examination (MMSE; score range, 0–30, with lower scores reflecting worse cognitive function). The prespecified primary analysis of this substudy was the change from baseline in MMSE score at 96 weeks. Other post hoc analyses included cognitive decline (fall in MMSE score of ≥3 points), cognitive impairment (MMSE score <24), or the occurrence of dementia-related adverse events. RESULTS: Among 2895 patients included in the MMSE substudy with baseline MMSE score measured, 1453 patients were assigned to sacubitril/valsartan and 1442 to valsartan. Their mean age was 73 years, and the median follow-up was 32 months. The mean±SD MMSE score at randomization was 27.4±3.0 in the sacubitril/valsartan group, with 10% having an MMSE score <24; the corresponding numbers were nearly identical in the valsartan group. The mean change from baseline to 96 weeks in the sacubitril/valsartan group was −0.05 (SE, 0.07); the corresponding change in the valsartan group was −0.04 (0.07). The mean between-treatment difference at week 96 was −0.01 (95% CI, −0.20 to 0.19; P =0.95). Analyses of a ≥3-point decline in MMSE, decrease to a score <24, dementia-related adverse events, and combinations of these showed no difference between sacubitril/valsartan and valsartan. No difference was found in the subgroup of patients tested for apolipoprotein E ε4 allele genotype. CONCLUSIONS: Patients with heart failure with preserved ejection fraction in PARAGON-HF had relatively low baseline MMSE scores. Cognitive change, measured by MMSE, did not differ between treatment with sacubitril/valsartan and treatment with valsartan in patients with heart failure with preserved ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920711.

BACKGROUND: The rate of stroke in patients with heart failure (HF) and preserved ejection fraction but without atrial fibrillation (AF), is uncertain as is whether it is possible to reliably predict the risk of stroke in these patients. METHODS: We validated a previously developed simple risk model for stroke among patients enrolled in the I-Preserve trial (Irbesartan in Heart Failure With Preserved Systolic Function) and PARAGON-HF trial (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction). The risk model consisted of 3 variables: history of previous stroke, insulin-treated diabetes, and plasma N-terminal pro-B-type natriuretic peptide level. RESULTS: Of the 8924 patients included in the pooled trial dataset, 5126 patients did not have AF at baseline. Among patients without AF, 190 (3.7%) experienced a stroke over a median follow-up of 3.6 years (rate 10.5 per 1000 patient-years). The risk for stroke increased with increasing risk score: second tertile hazard ratio, 1.78 (95% CI, 1.17–2.71); third tertile hazard ratio, 3.03 (95% CI, 2.06–4.47), with the first tertile as reference. For patients in the third tertile, the occurrence rate of stroke was 17.7 per 1000 patient-years, similar to that in patients with AF not receiving anticoagulation (20.7 per 1000 patient-years), and those with AF who were receiving anticoagulation (14.5 per 1000 patient-years). Model discrimination was good with a C index of 0.81 (0.68–0.91) and a simple score could be created from the model. CONCLUSIONS: A simple risk model can detect a subset of HF and preserved ejection fraction patients without AF who have a higher risk for stroke. The balance of risk-to-benefit in these individuals may justify the use of prophylactic anticoagulation, but this hypothesis needs to be prospectively evaluated. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifiers: NCT00095238 and NCT01920711.

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 .