Heart Failure With Preserved Ejection Fraction Trials Research Articles

Abstract 29: Blood Pressure Phenotypes in an Interventional Study of Participants with Heart Failure with Preserved Ejection Fraction

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) affects engenders high morbidity and mortality. Hypertension is a major risk factor for HFpEF progression. We aimed to evaluate the prevalence of and factors associated with abnormal home blood pressure (BP) phenotypes in a trial cohort of individuals with hypertension and HFpEF. Methods: We evaluated baseline office and home BP measurements in 36 participants of BLOCK HFpEF, an ongoing trial of antihypertensive treatment in HFpEF (NCT04434664). Office BP was measured using a standardized approach with the average of 3 seated readings. Home BP was measured for the first 7 days of the trial, prior to initiating the intervention. Participants were asked to perform nocturnal home BP one night, taken 3 times while sleeping. We used a conservative threshold for controlled BPs, defined as office systolic BP (SBP) <140 mmHg, office diastolic BP (DBP) <90 mmHg, home daytime SBP <135 mmHg, and home daytime DBP <85 mmHg. White coat effect was defined as elevated office and controlled home BP. Masked uncontrolled hypertension was defined as controlled office and elevated home BP. Sustained hypertension was defined as controlled office and elevated home BP. Nocturnal hypertension was defined as nighttime SBP ≥120 mmHg or DBP ≥70 mmHg. Results: Of the 36 participants with home BP data, 7 (19%) had controlled hypertension, 6 (17%) had white coat effect, 6 (17%) had masked uncontrolled hypertension, and 17 (47%) had sustained hypertension. 27 participants completed nighttime home BP readings, among whom 23 (85%) had nocturnal hypertension. Of those with nocturnal hypertension, 2 (9%) had controlled hypertension based on their daytime home BPs, 3 (13%) had white coat effect, 5 (22%) had masked uncontrolled hypertension, and 13 (56%) had sustained hypertension. There was no significant difference in age, sex, race, history of atrial fibrillation, and history of diabetes mellitus across BP phenotypes. The mean number of cardiology visits in the two years before enrollment was 4.3 (SD 2.8), which did not differ across home BP phenotypes. Conclusion: Masked uncontrolled hypertension and nocturnal hypertension were common in patients enrolled in the BLOCK HFpEF trial. These home BP phenotypes cannot be determined using office BP alone. While this is a small sample, patients with HFpEF may particularly benefit from careful BP phenotyping using out-of-office monitoring, including nocturnal BP monitoring.

Rates and predictors of cardiovascular and non-cardiovascular outcomes in heart failure with preserved ejection fraction.

The detailed sub-categories of death and hospitalization, and the impact of comorbidities on cause-specific outcomes, remain poorly understood in heart failure (HF) with preserved ejection fraction (HFpEF). We sought to evaluate rates and predictors of cardiovascular (CV) and non-CV outcomes in HFpEF. The Karolinska-Rennes study was a bi-national prospective observational study designed to characterize HFpEF (ejection fraction ≥45%). Patients were followed for cause-specific death and hospitalization. Baseline characteristics were pre-selected based on clinical relevance and potential eligibility criteria for HFpEF trials. The associations between characteristics and cause-specific outcomes were assessed with univariable and multivariable Cox regressions. Five hundred thirty-nine patients [56% females; median (inter-quartile range) age 79 (72-84) years; NT-proBNP/BNP 2448 (1290-4790)/429 (229-805) ng/L] were included. Over 1196 patient-years follow-up [median (min, max) 744days (13-1959)], there were 159 (29%) deaths (13 per 100 patient-years: CV 5.1 per 100, dominated by HF 3.9 per 100; and non-CV 5.8 per 100, dominated by cancer, 2.3 per 100). There were 723 hospitalizations in 338 patients (63%; 60 per 100 patient-years: CV 33 per 100, dominated by HF 17 per 100; and non-CV 27 per 100, dominated by lung disease 5 per 100). Higher age and natriuretic peptides, lower serum natraemia and NYHA class III-IV were independent predictors of CV death; lower serum natraemia, anaemia and stroke of non-CV death; and anaemia and lower serum natraemia of non-CV death or hospitalizations. There were no apparent predictors of CV death or hospitalization. In a clinical cohort hospitalized and diagnosed with HFpEF, death and hospitalization rates were roughly similar for CV and non-CV causes. CV deaths were predicted primarily by severity of HF; non-CV deaths primarily by anaemia and prior stroke. Lower serum sodium predicted both. Hospitalizations were difficult to predict.

Abstract 13828: Aptamer Proteomics for Biomarker Discovery in Heart Failure With Preserved Ejection Fraction: The PARADIGM-HF Proteomic Sub-Study

Introduction: Prognostic markers and biological pathways linked to detrimental clinical outcomes in heart failure with preserved ejection fraction (HFpEF) remain incompletely defined. Goal: To identify serum proteins associated with risk for HF hospitalization (HFH) and cardiovascular (CV) death in patients with HFpEF, including proteins with differential associations with clinical outcomes in HFpEF compared to HFrEF. Methods: We measured serum levels of 4123 unique proteins in 1117 patients with HFpEF in the PARAGON-HF trial using a modified aptamer proteomic assay. Baseline protein concentrations significantly associated with total HFH and CV death were identified by recurrent events regression, accounting for multiple testing, adjusted for age, sex, treatment, and anticoagulant use, and compared to 2515 patients with HFrEF from the PARADIGM-HF and ATMOSPHERE trials. Results: We identified 288 proteins to be robustly associated with the risk of HFH and CV death (335 events over an average of 2.7 years of follow-up) in a HFpEF trial population. Proteins most strongly related to HFpEF outcomes included B2M, TIMP1, SERPINA4, and SVEP1 ( Figure ). Protein-outcome associations in patients with HFpEF did not markedly differ compared to HFrEF. Just 3 proteins (APOE, RTF1, and VWF) were differentially associated with outcomes between the HF subtypes (FDR <0.05). A proteomic risk score derived in HFpEF patients was not superior to a previous proteomic score derived in HFrEF nor to clinical risk factors, NT-proBNP, or high-sensitivity cardiac troponin. Conclusions: Numerous serum proteins linked to metabolic, coagulation, and extracellular matrix regulatory pathways were associated with worse HFpEF prognosis. SVEP1, a cell adhesion protein recently identified as a HFrEF prognosis biomarker, also strongly predicted risk in HFpEF. Our results demonstrate substantial similarities in serum proteomic risk markers across the EF spectrum.

Predictors and Outcomes of Sudden Cardiac Arrest in Heart Failure With Preserved Ejection Fraction: A Nationwide Inpatient Sample Analysis

Sudden cardiac arrest (SCA) is the leading cause of cardiovascular mortality in heart failure with preserved ejection fraction (HFpEF), contributing to around 25% of deaths observed in pivotal HFpEF trials. However, predictors and outcomes of in-hospital SCA in HFpEF have not been well characterized. We queried the Nationwide Inpatient Sample (2016 to 2017) to identify adult hospitalizations with a diagnosis of HFpEF. Patients with acute or chronic conditions associated with SCA (e.g., acute myocardial infarction, acute pulmonary embolism, sarcoidosis) were excluded. We ascertained whether SCA occurred during these hospitalizations, identified predictors of SCA using multivariate logistic regression, and determined outcomes of SCA in HFpEF. Of 2,909,134 hospitalizations, SCA occurred in 1.48% (43,105). The mean age of the SCA group was 72.3 ± 12.4years, 55.8% were women, and 66.4% were White. Presence of third-degree atrioventricular block (odds ratio [OR] 5.95, 95% confidence interval [CI] 5.31 to 6.67), left bundle branch block (OR 1.96, 95% CI 1.72 to 2.25), and liver disease (OR 1.87, 95% CI 1.73 to 2.02) were the leading predictors of SCA in HFpEF. After excluding patients with do-not-resuscitate status, the SCA group versus those without SCA had higher mortality (25.9% vs 1.6%), major bleeding complications (4.1% vs 1.7%), increased use of percutaneous coronary intervention (2.5% vs 0.7%), and mechanical circulatory assist device (1.2% vs 0.1%). These observational inpatient data suggest identifiable risk factors for SCA in HFpEF including cardiac arrhythmias. Further research is warranted to identify the best tools to risk-stratify patients with HFpEF to implement targeted SCA prevention strategies.

Deciphering the Dilemma: Anticoagulation for Heart Failure With Preserved Ejection Fraction (HFpEF).

Impairment in ventricular relaxation and preserved left ventricular ejection fraction are the two main features of heart failure with preserved ejection fraction (HFpEF)a difficult clinical condition. Therapeutic choices for HFpEF patients are still scarce despite itsrising frequency and negative effects on morbidity and mortality, necessitating creative methods to enhance results. The increased thromboembolic risk seen in these individuals raises questions about the relevance of anticoagulation in the therapy of HFpEF. Although anticoagulation has been shown to be beneficial in heart failure with decreased ejection fraction (HFrEF) and other high-risk cardiovascular disorders, its efficacy and safety in HFpEF present a challenging therapeutic challenge. Anticoagulants have been the subject of clinical trials in HFpEF, but the results have been conflicting, giving clinicians only a little information with which to make decisions. The decision-making process is made more difficult by worries about potential bleeding hazards, particularly in susceptible elderly HFpEF patients with other comorbidities. The link between heart failure and anticoagulant medication in HFpEF is thoroughly analyzed in this narrative review. In HFpEF, cardiac fibrosisand endothelial dysfunction create a prothrombotic milieu, as is highlighted in this passage. Also covered are recent developments in innovative biomarker research and cutting-edge imaging techniques, which may provide ways to spot HFpEF patients who might benefit from anticoagulation. This therapeutic conundrum may be resolved by using precision medicine strategies based on risk classification and individualized therapy choices. This review emphasizes the need for more research to establish the best use of anticoagulation in HFpEF within the framework of personalized therapy and shared decision-making. To successfully manage thromboembolic risk and reduce bleeding consequences in HFpEF patients, it is essential to perform well-designed clinical studies and advance our understanding of the pathophysiology of HFpEF. These developments may ultimately improve the prognosis and quality of life for people who suffer from this difficult and mysterious ailment.

Rationale and Design of the SOTA-P-CARDIA Trial (ATRU-V): Sotagliflozin in HFpEF Patients Without Diabetes.

Heart failure with preserved ejection fraction (HFpEF) is now the most common form of heart failure (HF). This syndrome is associated with an elevated morbi-mortality, and effective therapies are urgently needed. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are the first pharmacological class that has demonstrated to reduce hospitalization and cardiovascular mortality in large clinical trials in HFpEF. Furthermore, the dual SGLT 1/2 inhibitor sotagliflozin has shown a reduction in cardiovascular outcomes in diabetic HF patients, regardless of ejection fraction Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) Trial, and prevents the development of HF in patients with diabetes and chronic kidney diseaseSotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk (SCORED) trial. The major objective of theSotagliflozin in Heart Failure With Preserved Ejection Fraction Patients(SOTA-P-CARDIA) trial (NCT05562063) is to investigate whether the observed cardiorenal benefits of sotagliflozin in HF patients with diabetes can be extended to a non-diabetic population. The SOTA-P-CARDIA is a prospective, randomized, double-blinded, placebo-controlled study that will randomize non-diabetic patients with the universal definition of HFpEF (ejection fraction > 50% assessed the day of randomization). Qualifying patients will be randomized, in blocks of 4, to receive either sotagliflozin or placebo for a period of 6months. The primary outcome is changes in left ventricular mass by cardiac magnetic resonance from randomization to end of the study between the groups. Secondary end points include changes in peak VO2; myocardial mechanics, interstitial myocardial fibrosis, and volume of epicardial adipose tissue; distance in the 6-min walk test; and quality of life. Finally, the authors expect that this trial will help to clarify the potential benefits of the use of sotagliflozin in non-diabetic HFpEF patients.

Electronic health record characterization and outcomes of heart failure with preserved ejection fraction

Electronic health record (EHR)-based identification of heart failure with preserved ejection fraction (HFpEF) in the clinical setting may facilitate screening for clinical trials by improving the understanding of its epidemiology and outcomes; yet, previous data have yielded variable results. We sought to characterize groups identified with HFpEF by different EHR screening strategies and their associated long-term outcomes across a large and diverse population. We retrospectively analyzed 116,499 consecutive patients from an academic referral center who underwent echocardiography, and 9,263 patients who underwent echocardiography within 6 months of right heart catheterization (RHC), between 2008-2018. EHR-based screening strategies identified patients with HFpEF using 1) International Classification of Diseases (ICD)-9/10 codes, 2) H2FpEF score ≥6 and ejection fraction (EF) ≥50%, or 3) RHC wedge pressure ≥15 mmHg and EF ≥50%, when available. Primary outcomes were 1) cumulative incident heart failure hospitalization (HFH), and 2) death, over 10 years. There were 33,461 (29%) patients who met either ICD or H2FpEF-HFpEF definition, of whom 5,310 (16%) met both criteria. Compared to ICD-HFpEF, patients with H2FpEF-HFpEF were more likely older (median age 72 vs. 67), White (78% vs. 64%), and had atrial fibrillation (97% vs. 41%). Among those also with RHC, 6,353 (69%) patients met any HFpEF criteria, of whom only 783 (12%) satisfied all three criteria. Female sex was more common among RHC-HFpEF (55%) compared to other methods (H2FpEF-HFpEF, 47%; ICD-HFpEF, 43%). Atrial fibrillation was substantially higher among HFpEF identified by the H2FpEF score (97%) compared to other methods (49% for ICD and 47% for RHC). Across HFpEF screening methods, 10-year cumulative incidence rates for HFH was 32 to 45% for echocardiography only and 43 to 52% for echocardiography and RHC populations; 10-year risk of death was 54 to 56% for echocardiography only and 52 to 57% for echocardiography and RHC populations. Different EHR-based HFpEF definitions identified cohorts with modest overlap and varying baseline characteristics. Yet, long-term risk for HFH and death were similarly high for cohorts identified among both populations undergoing echocardiography only or echocardiography and RHC. These data aid in identifying relevant subgroups in clinical trials of HFpEF.

The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Heart Failure Management: The Continuing Challenge of Clinical Outcome Endpoints in Heart Failure Trials.

The introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors in the management of heart failure with preserved ejection fraction (HFpEF) may be regarded as the first effective treatment in these patients. However, this proposition must be evaluated from the perspective of the complexity of clinical outcome endpoints in heart failure. The major goals of heart failure treatment have been categorized as: (1) reduction in (cardiovascular) mortality, (2) prevention of recurrent hospitalizations due to worsening heart failure, and (3) improvement in clinical status, functional capacity, and quality of life. The use of the composite primary endpoint of cardiovascular death and hospitalization for heart failure in SGLT2 inhibitor HFpEF trials flowed from the assumption that hospitalization for heart failure is a proxy for subsequent cardiovascular death. The use of this composite endpoint was not justified since the effect of the intervention on both components was clearly distinct. Moreover, the lack of convincing and clinically meaningful effects of SGLT2 inhibitors on metrics of heart failure-related health status indicates that the effect of this class of drugs in HFpEF patients is essentially restricted to an effect on hospitalization for heart failure. In conclusion, SGLT2 inhibitors do not represent a substantial breakthrough in the management of HFpEF.

Cost-effectiveness of Sodium-Glucose Cotransporter-2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction

Adding a sodium-glucose cotransporter-2 inhibitor (SGLT2-I) to standard-of-care treatment in patients with heart failure with preserved ejection fraction (HFpEF) reduces the risk of a composite outcome of worsening heart failure or cardiovascular mortality, but the cost-effectiveness in US patients with HFpEF is uncertain. To evaluate the lifetime cost-effectiveness of standard therapy plus an SGLT2-I compared with standard therapy in individuals with HFpEF. In this economic evaluation conducted from September 8, 2021, to December 12, 2022, a state-transition Markov model simulated monthly health outcomes and direct medical costs. Input parameters including hospitalization rates, mortality rates, costs, and utilities were extracted from HFpEF trials, published literature, and publicly available data sets. The base-case annual cost of SGLT2-I was $4506. A simulated cohort with similar characteristics as participants of the Empagliflozin in Heart Failure With a Preserved Ejection Fraction (EMPEROR-Preserved) and Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction (DELIVER) trials was used. Standard of care plus SGLT2-I vs standard of care. The model simulated hospitalizations, urgent care visits, and cardiovascular and noncardiovascular death. Future medical costs and benefits were discounted by 3% per year. Main outcomes were quality-adjusted life-years (QALYs), direct medical costs (2022 US dollars), and incremental cost-effectiveness ratio (ICER) of SGLT2-I therapy from a US health care sector perspective. The ICER of SGLT2-I therapy was evaluated according to the American College of Cardiology/American Heart Association value framework (high value: <$50 000; intermediate value: $50 000 to <$150 000; and low value: ≥$150 000). The simulated cohort had a mean (SD) age of 71.7 (9.5) years and 6828 of 12 251 participants (55.7%) were male. Standard of care plus SGLT2-I increased quality-adjusted survival by 0.19 QALYs at an increased cost of $26 300 compared with standard of care. The resulting ICER was $141 200 per QALY gained, with 59.1% of 1000 probabilistic iterations indicating intermediate value and 40.9% indicating low value. The ICER was most sensitive to SGLT2-I costs and effect of SGLT2-I therapy on cardiovascular death (eg, increasing to $373 400 per QALY gained if SGLT2-I therapy was assumed to have no effect on mortality). Results of this economic evaluation suggest that at 2022 drug prices, adding an SGLT2-I to standard of care was of intermediate or low economic value compared with standard of care in US adults with HFpEF. Efforts to expand access to SGLT2-I for individuals with HFpEF should be coupled with efforts to lower the cost of SGLT2-I therapy.

Advances in Heart Failure with Preserved Ejection Fraction Management - The Role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin: Is Success a Series of Small Victories?

Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients. The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF. Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy). Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HPpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a "positive" randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials. Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patient with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

Pharmacotherapies in Heart Failure With Preserved Ejection Fraction: A Systematic Review and Network Meta-Analysis.

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF >40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46-1.34), MRA; OR 0.90 (0.70-1.14), ACE OR 0.95 (0.59-1.53), ARB; OR 1.02 (0.87-1.19), ARNI; OR 0.97 (0.74-1.26) and SGLT2i; OR 1.00 (0.84-1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54-1.04), MRA; OR 0.90 (0.75-1.08) ACE; OR 1.05 (0.71-1.54), ARB; OR 1.03 (0.91-1.15), ARNI; OR 0.99 (0.82-1.20) and SGLT2i; OR 1.00 (0.89-1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62-0.82), moderate certainty], ARNI [OR 0.77 (0.63-0.94), low certainty], and MRA [OR 0.81 (0.66-0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations.

Cardiopulmonary Exercise Testing in Heart Failure With Preserved Ejection Fraction: Technique Principles, Current Evidence, and Future Perspectives.

Heart failure with preserved ejection fraction (HFpEF) is a multifactorial clinical syndrome involving a rather complex pathophysiologic substrate and quite a challenging diagnosis. Exercise intolerance is a major feature of HFpEF, and in many cases, diagnosis is suspected in subjects presenting with exertional dyspnea. Cardiopulmonary exercise testing (CPET) is a noninvasive, dynamic technique that provides an integrative evaluation of cardiovascular, pulmonary, hematopoietic, neuropsychological, and metabolic functions during maximal or submaximal exercise. The assessment is based on the principle that system failure typically occurs when the system is under stress, and thus, CPET is currently considered to be the gold standard for identifying exercise intolerance, allowing the differential diagnosis of underlying causes. CPET is used in observational studies and clinical trials in HFpEF; however, in most cases, only a few from a wide variety of CPET parameters are examined, while the technique is largely underused in everyday cardiology practice. This article discusses the basic principles and methodology of CPET and studies that utilized CPET in patients with HFpEF, in an effort to increase awareness of CPET capabilities among practicing cardiologists.

Heart failure with preserved ejection fraction: A distinct heart failure phenotype?

The present work discusses the serious confusion resulting from the arbitrary nomenclature of heart failure with preserved ejection fraction (HFpEF), the presumed underlying pathophysiology, and the supposed features. A consequence of this misconception is that HFpEF trials have recruited patients with entirely different characteristics rendering the extrapolation of the results of one study to the other infeasible and dramatically affecting diagnosis and treatment.

History of stroke in patients with heart failure: prevalence, baseline characteristics and clinical outcomes

Abstract Background Stroke is an important but neglected comorbidity in patients with heart failure (HF). Little is known about the characteristics and outcomes of HF patients with a history of stroke. Purpose To examine the prevalence of prior stroke in patients with HF and reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF), the clinical characteristics of patients with a history of stroke, and the clinical outcomes in patients with prior stroke compared to those without. Methods Individual patient data analysis using three recent HFrEF trials (ATMOSPHERE, PARADIGM-HF, and DAPA-HF) and HFpEF trials (CHARM-Preserved, I-Preserve, TOPCAT-Americas, and PARAGON-HF). Cox regression was used to analyze clinical outcomes. Results Among 20159 HFrEF patients enrolled, 1683 (8.3%) had a history of stroke and among the 13252 patients with HFpEF 1287 (9.7%) had a prior stroke. Compared to patients without stroke, those with stroke were slightly older and more likely to have a history of hypertension, myocardial infarction, atrial fibrillation, diabetes, carotid artery disease, and peripheral artery disease (for both HFrEF and HFpEF). Patients with a history of stroke had worse NYHA class and KCCQ scores, and a higher rate of fatigue; they also had a higher median NT-proBNP level and lower eGFR than those without prior stroke (whether HFrEF or HFpEF). Systolic BP, pulse pressure and LVEF did not differ susbtantialy between patients with and without a history of stroke. The table shows outcomes according to history of stroke or not, stratified by LVEF phenotype. During follow-up, all fatal and non-fatal outcomes were significantly more common in patients with a history of stroke. The augmentation of risk tended to be greater in patients with HFpEF than HFrEF, but was not statistically different. Conclusion Approximately 1 in 11 patients in recent HF trials had a history of stroke and these patients were at higher risk of fatal and non-fatal events than those without prior stroke. HF hospitalization as well as atherothrombotic events (myocardial infarction and stroke) were more common among patients with prior stroke – patients with prior stroke had at least 30% higher risk of all events examined, regardless of LVEF, and more than double incidence of repeat stroke. Funding Acknowledgement Type of funding sources: Other.

SGLT2 inhibitors in real-world patients with heart failure with preserved ejection fraction

Abstract Introduction The diagnosis and management of heart failure with preserved ejection fraction (HFpEF) is challenging since ejection fraction is normal, clinical signs are often lacking and there are few therapeutic options. Two randomized clinical trials have tested SGLT2i for the treatment of HFpEF: DELIVER (pending results) and EMPEROR-PRESERVED; the findings of the latter trial show that empagliflozin, a sodium-glucose cotransporter inhibitor (SGLT2i) reduces the risk of cardiovascular death or hospitalization for HF in patients with HFpEF regardless the presence of diabetes. The results of this clinical trial have allowed European Medicine Agency (EMA) to extend the indication also to the patients with HFpEF, however the characteristics of the trial population don't often correspond to real-word HF population. Aims This study aims to investigate the eligibility of the EMPEROR-PRESERVED and DELIVER trial to a real-world heart failure population comparing the baseline characteristics of our patients to the recruited patients of clinical trials. Material and methods In this retrospective, observational study, 206 HF outpatients were enrolled from September 2018 to September 2019. The percentages of eligible patients according to EMPEROR PRESERVED and DELIVER inclusion criteria were analyzed, then we analyzed the difference between the characteristics of our HFpEF population and trials population. Results 72 patients (35% of HF population) had heart failure with preserved ejection fraction. The EMPEROR-PRESERVED criteria and DELIVER trial were applied to these patients: 13 (18.1%) and 12 (16.7%) patients respectively fulfilled all enrolment criteria, whereas considering only EMA label criteria (EF &amp;gt;40% and eGFR &amp;gt;20 ml/min) 71 patients (98.6%) were eligible. The eligible patients according EMA criteria were significantly younger (67.3±14.3) than EMPEROR-PRESERVED population (72±9, p&amp;lt;0.001) and DELIVER population (72±10, p&amp;lt;0.001). The ejection fraction was significantly lower (50.2±5.8 vs 54±8.8; p&amp;lt;0.001) whereas eGFR was no significantly different (64.4±22.7 vs 60.6±19.8; p=0.17). Conclusion Only a small percentage of our heart failure with preserved ejection fraction population was eligible for SGLT2 inhibitors according trials criteria, whereas according to EMA label almost all patients are candidate to these drugs. Furthermore, these patients were younger than EMPEROR-PRESERVED and DELIVER population with lower EF. The difference of eligibility between trials and real population is related to inclusion criteria, in particular the trial patients had elevated NT-proBNP levels whereas in the real world this criterion isn't considered. There is a lack of data about real-world patients who are often different from trials population. National and international registries of HF population may resolve this issue. Funding Acknowledgement Type of funding sources: None.

Biomarkers in Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous disorder developing from multiple aetiologies with overlapping pathophysiological mechanisms. HFpEF diagnosis may be challenging, as neither cardiac imaging nor physical examination are sensitive in this situation. Here, we review biomarkers of HFpEF, of which the best supported are related to myocardial stretch and injury, including natriuretic peptides and cardiac troponins. An overview of biomarkers of inflammation, extracellular matrix derangements and fibrosis, senescence, vascular dysfunction, anaemia/iron deficiency and obesity is also provided. Finally, novel biomarkers from -omics technologies, including plasma metabolites and circulating microRNAs, are outlined briefly. A cardiac-centred approach to HFpEF diagnosis using natriuretic peptides seems reasonable at present in clinical practice. A holistic approach including biomarkers that provide information on the non-cardiac components of the HFpEF syndrome may enrich our understanding of the disease and may be useful in classifying HFpEF phenotypes or endotypes that may guide patient selection in HFpEF trials.

Breakthroughs in the treatment of heart failure with mildly reduced and preserved ejection fraction.

Historically, only patients with a left ventricular ejection fraction (LVEF) of less than or equal to 40% were considered to have heart failure (HF). However, it was later found that patients could have elevated cardiac filling pressures and the stigmata of HF signs and symptoms with normal LVEF. This subset of patients has undergone multiple taxonomical variations and is now termed heart failure with preserved ejection fraction (HFpEF) with the lower limit of LVEF assigned as roughly ≥40%–50% in clinical trials and ≥50% in HF guidelines. Patients with LVEF 41%–49% did not clearly fit these designations but bear resemblance to both heart failure with reduced ejection fraction (HFrEF) and HFpEF. This cohort was initially assigned the term HFpEF (borderline), which has also undergone several modifications and is currently termed heart failure with mildly reduced ejection fraction (HFmrEF). Earlier landmark HF trials were heavily focused on patients with HFrEF. Only in the last 2 decades has there been an increasing focus on HFpEF with emergence of key drug therapies including sodium‐glucose cotransport‐2 inhibitors that have shown to improve outcomes across the whole LVEF spectrum. There is yet to be a focused clinical trial to determine therapeutic modalities for HFmrEF; most of the evidence has been extrapolated from subgroup analysis mostly from HFpEF trials. In this review, we provide an overview of the historical basis of HFpEF and HFmrEF and discuss key therapeutic advances in their management.

Phenotyping in heart failure with preserved ejection fraction: A key to find effective treatment.

Heart failure with preserved ejection fraction (HFpEF) is an increasingly widespread medical condition, with excessive morbidity and mortality. Recently, for the first time in HFpEF, a reduction in the primary composite outcome of cardiovascular death or HF hospitalization was shown with empagliflozin. The failure of previous clinical trials in HFpEF might have resulted from suboptimal patient selection and inclusion of patients without "true" or clinically significant HFpEF. Another important factor might be the heterogeneity of HFpEF, and thus there is a growing interest in HFpEF phenotyping. This phenotyping can be based on clinical presentation (e.g., subtypes with predominant atrial fibrillation, obesity, pulmonary hypertension and right ventricular failure, coronary artery disease (CAD), or noncardiac comorbidities), but also on HFpEF etiology. Specific therapies, such as tafamidis in transthyretin-related amyloidosis (ATTR) or mavacamten in hypertrophic cardiomyopathy, have demonstrated their efficacy. However, pathomechanisms leading to the development of different phenotypes of HFpEF seem more complex and subtle. Machine learning and neural network models might help identify specific subgroups within the HFpEF population that either cluster patients with similar genetic, biochemical, echocardiographic or clinical characteristics, or respond similarly to a given treatment. Herein, we review different approaches to HFpEF phenotyping and present some distinct HFpEF subtypes.

Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The PARAGON-HF Trial

ObjectivesIn this study, the authors sought to assess the relationship between AFF and outcomes, the treatment response to sacubitril/valsartan and first-detected AFF in patients with HFpEF enrolled in the PARAGON-HF trial. BackgroundAtrial fibrillation and flutter (AFF) are common in heart failure with preserved ejection fraction (HFpEF) and increase the risk of adverse outcomes. MethodsA total of 4,776 patients formed 3 groups: those with AFF according to electrocardiography (ECG) at enrollment (n = 1,552; 33%), those with history of AFF but without AFF on ECG at enrollment (n = 1,005; 21%), and those without history of AFF or AFF on ECG at enrollment (n = 2,219, 46%). We assessed outcomes, treatment response to sacubitril/valsartan in each group, and the risk associated with first-detected AFF in patients without any known AFF. The primary outcome was a composite of total heart failure hospitalizations and cardiovascular death. ResultsHistory of AFF and AFF at enrollment were associated with higher risk of the primary outcome (risk ratio [RR]: 1.36 [95% CI: 1.12-1.65] and RR: 1.31 [1.11-1.54], respectively), than no AFF. Neither history of AFF nor AFF at enrollment modified the treatment effect of sacubitril/valsartan. Post randomization AFF occurred in 12% of patients without previous AFF and was associated with 2.8-fold higher risk of the primary outcome, but it was not influenced by sacubitril/valsartan. ConclusionsHistory of AFF and AFF on ECG at enrollment were associated with a higher risk of the primary outcome. First-detected AFF was not influenced by sacubitril/valsartan, yet it was associated with increased risk of all subsequent outcomes and may represent a potential target for future HFpEF trials. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711)

Long-term Adherence To Exercise In Adults With Preserved Ejection Fraction Heart Failure

<h3>Background</h3> Despite exercise being one of few strategies to improve outcomes for individuals with heart failure with preserved ejection fraction (HFpEF), exercise clinical trials in HFpEF are plagued by poor interventional adherence. Over the last 2 decades, our research team has developed, tested, and refined Heart failure Exercise And Resistance Training (HEART) Camp, a multi-component behavioral intervention to promote adherence to exercise in HF. We evaluated the effects of this intervention designed to promote adherence to exercise in HF focusing on a subgroup of participants with HFpEF. <h3>Methods and Results</h3> The randomized controlled trial included 204 adults with stable, chronic HF. Of those enrolled, 59 had HFpEF and were the target of this sub-group analysis. We tested adherence to exercise [defined as greater than or equal to 120 minutes of moderate-intensity (40-80% of heart rate reserve) exercise per week validated with a heart rate monitor] at 6, 12, and 18 months. We also tested intervention effects on symptoms (PROMIS-29 and Dyspnea-fatigue index), HF-related health status (Kansas City Cardiomyopathy Questionnaire, KCCQ), and physical function (6-minute walk test, 6MWT). Participants with HFpEF (n=59) were a mean of 64.6 ±9.3 years old, 54% male, 46% non-white with a mean ejection fraction of 55±6. Participants with HFpEF in the HEART Camp intervention group had significantly greater adherence compared to enhanced usual care at both 12 (43% vs. 14%, <i>phi</i>=.32, medium effect) and 18 months (56% vs. 0%, <i>phi</i>=.67, large effect). HEART Camp significantly improved walking distance on the 6MWT (η² = 0.13, large effect) and the KCCQ overall (η²=0.09, medium effect), clinical summary (η²=0.16, large effect), and total symptom (η²=0.14, large effect) scores. <h3>Conclusions</h3> A multi-component, behavioral intervention can be used to improve long-term adherence to exercise, physical function, and patient-reported outcomes in adults with HFpEF. Our results provide strong rationale for a large HFpEF clinical trial to validate these findings and examine interventional mechanisms and delivery modes that may further promote adherence, and improve clinical outcomes, in this population.