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A substantial proportion of patients with heart failure and kidney disease have poorly controlled blood pressures. This study aimed to evaluate patterns of blood pressure after initiation of an angiotensin receptor neprilysin inhibitor (ARNI) or an angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) across the spectrum of kidney function.Between 2016 and 2020, we evaluated 26,091 patients admitted to a Veterans Affairs hospital for an acute heart failure exacerbation with reduced ejection fraction. We assessed patterns of systolic and diastolic blood pressure among those started on ARNI or ACEI/ARB over 6 months, overall and across estimated glomerular filtration rate (eGFR). To account for differential treatment factors, we applied 1:1 propensity score matching using 15 known baseline covariates.There were 13,781 individuals treated with an ACEI or ARB and 2589 individuals treated with an ARNI prescription. After propensity score matching, 839 patients were matched in each of the ARNI and ACEI/ARB groups. Mean baseline estimated glomerular filtration rate (eGFR) was 63.8 (standard deviation 21.6), and 10% had stage 4 or 5 chronic kidney disease. Patients in the ARNI group experienced greater systolic blood pressure reduction at month 3 (-5.2 mmHg vs -2.2 mmHg, ARNI vs ACEI/ARB; P0.001), and month 6 (-4.7 mmHg vs -1.85 mmHg, ARNI vs ACEI/ARB; P0.001). These differences in systolic blood pressure by 6 months did not vary by eGFR above and below 60 mL/min/1.73mThe use of ARNI was associated with significant reduction in blood pressure as compared to the ACEI/ARB group overall and across the eGFR spectrum, including in advanced chronic kidney disease.

The impact of the TOPCAT trial publication on spironolactone initiation and subsequent hospitalizations for hyperkalemia among patients with heart failure with preserved ejection fraction (HFpEF) has not been evaluated empirically.We designed a cohort study using US Medicare fee-for-service data. Annual cohorts of patients with HFpEF from 2013 to 2018 were identified based on a validated claims-based phenotyping model. We determined spironolactone initiation in each annual cohort overall and within subgroups with hyperkalemia risk factors of baseline renin-angiotensin system inhibitors use, chronic kidney disease, and diabetes. We reported incidence rates of hospitalization for hyperkalemia within 6 months of treatment initiation. A total of 621,171 patients with HFpEF (mean age 80 ± 8 years, 62.9% female) were included. We identified 40,241 initiations of spironolactone with initiation rate/100 person-years of 16.8 (95% confidence interval [CI] 16.4-17.1) in 2013 and increasing to 19.9 (95% CI 19.4-20.5) in 2018. Among initiators, we identified a total of 164 hyperkalemia hospitalization with stable incidence rates per 1000 person-years between 2013 (12.0, 95% CI 8.8-16.1) and 2018 (10.6, 95% CI 6.2-17.0). These results were consistent for all subgroups.After the dissemination of TOPCAT findings, we noted a steady increase in the initiation of spironolactone, but not in hyperkalemia hospitalizations.

Clinical practice guidelines support sustained use of renin-angiotensin-aldosterone-system (RAAS) inhibitors over time in heart failure with reduced ejection fraction, yet few data are available regarding the frequency, timing or predictors of early treatment discontinuation in clinical practice.Among prevalent or new users of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, we estimated the frequency and independent predictors of treatment discontinuation during follow-up. Among sites with5 users of a given RAAS inhibitor, we evaluated practice variation in the proportion of patients with treatment discontinuation.Over median follow-up of 18 months, frequency of drug discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.7% (444 of 3509 users), 10.4% (140 of 1352 users), and 20.4% (435 of 2129 users), respectively. An additional, 149 (11.0%) of ARNI users were switched to ACEis/ARBs, and 447 (12.7%) of ACEi/ARB users were switched to ARNIs during follow-up. Across sites, the median proportion of discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.5% (25th-75th percentiles 6.9%-18.9%), 18.8% (25th-75th percentiles 12.5%-28.6%), and 19.6% (25th-75th percentiles 10.7%-27.0%), respectively. Chronic kidney disease was the only independent predictor of increased risk of discontinuation of each of the RAAS inhibitor classes (P0.02 for all). Higher Kansas City Cardiomyopathy Questionnaire overall summary scores independently predicted lower risk of discontinuation of ACEis/ARBs and ARNIs (both P0.001) but not of MRAs. Investigator clinical experience was predictive of lower risks of discontinuation of ACEis/ARBs and MRAs (P0.02) but not of ARNIs. All other independent predictors of discontinuation were unique to individual therapeutic classes.One in 10 patients discontinue ACEis/ARBs or ARNIs, and 1 in 5 discontinue MRAs in routine clinical practice of heart failure with reduced ejection fraction. Unique patient-level and clinician/practice-level factors are associated with premature discontinuation of individual RAAS inhibitors, which may help to guide structured efforts to promote treatment persistence in clinical care.

The acute hemodynamic effects of sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), may result in early changes in kidney function, raising concerns about acute kidney injury (AKI), particularly in those who are naïve to renin-angiotensin system inhibitors (RASis).We conducted a cohort study using U.S. Medicare fee-for-service claims data (2014-2017). Patients with HFrEF ≥ 65 years newly initiating ARNI or RASi, with no prior use of either drug class, were included. The primary outcome was hospitalization due to AKI as the primary discharge diagnosis, and the secondary outcome included AKI as a primary or secondary discharge diagnosis. AKI risks were described under an as-treated follow-up approach, with censoring on treatment discontinuation, switch, insurance disenrollment, death, or administrative censoring as well as an intent-to-treat approach. Propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 pre-exposure characteristics. Cumulative incidence functions were used to report absolute risks, and Cox proportional hazards models were used to provide hazard ratios (HR) and 95% confidence intervals (CI).We included 27,166 patients with a mean (SD) age of 73 (7.3) years, and 4155 (15.3%) were initiating ARNI. After propensity score weighting, the 180-day cumulative incidence was 2.7% (2.4%-3.1%) among RASi initiators and 2.7% (2.2%-3.5%) among ARNI initiators for the primary outcome, and it was 6.5% (6.0%-7.1%) and 6.1% (5.2%-7.1%), respectively, for the secondary outcome under as-treated follow-up. HR (95% CI) comparing ARNI with RASi were 0.91 (95% CI: 0.72-1.16) for the primary outcome and 0.92 (95% CI: 0.79-1.08) for the secondary outcome. Similar results were observed in the intent-to-treat analysis.Among a large cohort of U.S. Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi treatment. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi-naïve.

Background Maintaining a steady medication supply during a public health crisis is a major health priority. We leveraged a large U.S. pharmacy-claims database to understand the use of evidence-based therapies in heart failure (HF) care during the coronavirus disease-2019 (COVID-19) pandemic. Methods We analyzed 27,027,650 individual claims from an all-payer pharmacy-claims database across 56,155 chain, independent and mail-order pharmacies in 14,164 zip codes in 50 states. Prescriptions dispensed (in 2-week intervals) of evidence-based HF therapies in 2020 were indexed to comparable timeframes in 2019. We normalized these year-to-year changes in HF medical therapies relative to those observed with a stable basket of drugs. Results Fills of losartan, lisinopril, carvedilol, and metoprolol all peaked in the weeks of March 2020 and demonstrated trajectories thereafter that were relatively consistent with the reference set of drugs. Fills of spironolactone (+4%) and eplerenone (+18%) showed modest trends toward increased relative use during 2020. Fills of empagliflozin (+75%), dapagliflozin (+65%) and sacubitril/valsartan (+61%) showed striking longitudinal increases throughout 2020 that deviated substantially from year-to-year trends of the overall basket of drugs. For all 3 therapies, fills of all quantity sizes increased relatively throughout 2020. For both generic and brand-name therapies, prescription fill patterns from mail-order pharmacies increased substantially over expected trends beginning in March 2020 Conclusion Prescription fills of most established generic therapies used in HF care were maintained, whereas those of sacubitril/valsartan and the sodium-glucose cotransporter-2 inhibitors steeply increased during the COVID-19 pandemic. These nationwide pharmacy claims data provide reassurance about therapeutic access, during a public health crisis, to evidence-based medications used in HF care.

BACKGROUND: While left atrial (LA) mechanical dysfunction in heart failure with preserved ejection fraction (HFpEF) is associated with poor clinical outcomes, the influence of LA myopathy on temporal changes in cardiovascular biomarkers is unclear. METHODS AND RESULTS: We evaluated biomarker correlates of LA myopathy, as defined by reduced LA strain, and the associations of LA strain with longitudinal changes in biomarkers among participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. LA speckle-tracking was performed on baseline echocardiograms of RELAX participants to measure LA reservoir and LA contractile strain. Of the 216 RELAX participants, 169 (78%) had measurable LA strain and biomarker data. Participants with LA reservoir strain below median (13.5%, interquartile range: 10–22.5%) were older, more likely to have atrial fibrillation, and had higher jugular venous pressure (P

Randomized controlled trials (RCTs) may report outcomes different from those prespecified on trial registration websites, protocols, and statistical analysis plans (SAPs). This study sought to investigate prevalence and characteristics of heart failure (HF) RCTs that report outcomes different from those prespecified.MEDLINE via PubMed was searched to include phase II-IV HF RCTs in nine high-impact journals from 2010 to 2020. Outcomes reported in trial publications were compared with pre-specified outcomes in protocols, registration websites, and SAPs. Chi-squared or Fisher exact test were used to analyze correlations between trial characteristics and inconsistencies. Among 216 trials, 32 inconsistencies were observed in 28 trials (13.0%). Among 32 inconsistencies, 2 (6.3%) pertained to omission of prespecified primary outcomes, 4 (12.5%) pertained to omission of prespecified secondary outcomes, 2 (6.3%) pertained to changing prespecified primary outcomes to secondary outcomes, and 2 (6.3%) pertained to changing pre-specified secondary outcomes to primary outcomes. Three inconsistencies (9.4%) pertained to addition of new primary outcomes, 17 (53.1%) pertained to addition of new secondary outcomes, and 2 (6.3%,) pertained to change in timing of assessment of primary outcomes. Majority of the inconsistencies favored statistically significant findings., Seventy-eight (36.1%) were registered retrospectively. Single-center recruitment was associated with outcome inconsistencies (β=-0.14; 95% CI, -0.22 - -0.01,p=0.035).More than one in ten trials reported outcomes inconsistent with those specified in trial registration websites, SAPs, and protocols. An action plan is warranted to minimize selective reporting and improve transparency.

The sodium-glucose cotransporter-2 (SGLT-2) inhibitors form the latest pillar in the management of heart failure with reduced ejection fraction (HFrEF) and appear to be effective across a range of patient profiles. There is increasing interest in initiating SGLT-2 inhibitors during hospitalization, yet little is known about the putative benefits of this implementation strategy.We evaluated Medicare beneficiaries with HFrEF (≤ 40%) hospitalized at 228 sites in the Get With The Guidelines-Heart Failure (GWTG-HF) registry in 2016 who had linked claims data for ≥ 1 year postdischarge. We identified those eligible for dapagliflozin under the latest U.S. Food and Drug Administration label (excluding estimated glomerular filtration rates25 mL/min per 1.73 mAmong 7523 patients hospitalized for HFrEF, 6576 (87%) would be candidates for dapagliflozin (mean age 79 ± 8 years, 39% women, 11% Black). Among eligible candidates, discharge use of β-blockers, ACEi/ARB, MRA, ARNI, and triple therapy (ACEi/ARB/ARNI+β-blocker+MRA) was recorded in 88%, 64%, 29%, 3%, and 20%, respectively. Among treatment-eligible patients, the 1-year incidence (95% CI) of mortality was 37% (36-38%) and of HF readmission was 33% (32-34%), and each exceeded 25% across all key subgroups. Among 1333 beneficiaries eligible for dapagliflozin who were already on triple therapy, the 1-year incidence of mortality was 26% (24%-29%) and the 1-year readmission due to HF was 30% (27%-32%). Applying the relative risk reductions observed in DAPA-HF, absolute risk reductions with complete implementation of dapagliflozin among treatment-eligible Medicare beneficiaries are projected to be 5% (1%-9%) for mortality and 9% (5%-12%) for HF readmission by 1 year. The projected number of Medicare beneficiaries who would need to be treated for 1 year to prevent 1 death is 19 (11-114), and 12 (8-21) would need to be treated to prevent 1 readmission due to HF.Medicare beneficiaries with HFrEF who are eligible for dapagliflozin after hospitalization due to HF, including those well-treated with other disease-modifying therapies, face high risks of mortality and HF readmission by 1 year. If the benefits of reductions in death and hospitalizations due to HF observed in clinical trials can be fully realized, the absolute benefits of implementation of SGLT-2 inhibitors among treatment-eligible candidates are anticipated to be substantial in this high-risk postdischarge setting.

Bariatric surgery may play a role in the management of morbidly obese patients with end-stage heart failure through increasing eligibility and improving the outcomes of destination therapies. We conducted a nationally representative, retrospective cohort study of patients with previous bariatric surgery undergoing either heart transplantation or left ventricular assist device implantation. Of 200 patients, < 6% experienced in-hospital mortality after destination therapy, comparable to that reported in the general population of heart recipients. Risk-adjusted outcomes differed minimally from those of obese patients undergoing destination therapy without previous bariatric surgery. This study provides important safety benchmarking data and demonstrates the feasibility of bariatric surgery as a potential bridge to left ventricular assist device implantation or heart transplantation in obese patients with end-stage heart failure.

The comparative effectiveness of differing dosages of guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) on clinical and patient-reported outcomes in clinical practice in the United States is unknown. This study sought to characterize associations between the dosing of GDMT and outcomes for patients with HFrEF in U.S. clinical practice.This analysis included 4832 outpatients who had chronic HFrEF across 150 practices in the U.S. in the Change the Management of Patients with Heart Failure (CHAMP-HF) registry with no contraindication and available dosing data for at least 1 GDMT at baseline. Baseline dosing of angiotensin-converting enzyme (ACEI)/angiotensin II receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), beta-blocker, and mineralocorticoid receptor antagonist (MRA) therapies were examined. For each medication class, multivariable models assessed associations between medication dosing and clinical outcomes over 24 months (all-cause mortality, HF hospitalization) and patient-reported outcomes at 12 months (change in the Kansas City Cardiomyopathy Questionnaire Overall Summary score [KCCQ-OS]).After adjustment, compared with target dosing, lower dosing was associated with higher all-cause mortality for ACEIs/ARBs/ARNIs (50% to100% target dosage, HR 1.16 [95% CI 0.87-1.55];50% target dosage, HR 1.37 [95% CI 1.05-1.79]; none, HR 1.75 [95% CI 1.32-2.34; overall P0.001) and beta-blockers (50% to100% target dosage, HR 1.30 [95% CI 1.00-1.69];50% target dosage, HR 1.41 [95% CI 1.11-1.79; none, HR 1.24 [95% CI 0.92-1.67]; overall P= 0.042). Lower dosing of ACEIs/ARBs/ARNIs was independently associated with higher risk of HF hospitalization (50% to100% target dosage, HR 1.08 [95% CI 0.90-1.30];50% target dosage, HR 1.23 [1.04-1.47]; none, HR 1.29 [1.04-1.60]; overall P= 0.046), but beta-blocker dosing was not (overall P= 0.085). Target dosing of MRAs was not associated with risk of mortality or HF hospitalization. For each GDMT, compared with target dosing, lower dosing was not associated with change in the KCCQ-OS at 12 months, with the potential exception of worsening KCCQ-OS scores with lower dosing of ACEIs/ARBs/ARNIs.In this contemporary U.S. outpatient HFrEF registry, target dosing of ACEI/ARB/ARNI and beta-blocker therapy was associated with reduced mortality and was variably associated with HF hospitalization and patient-reported outcomes. MRA dosing was not associated with outcomes. The totality of these findings support the benefits of target dosing of GDMT in routine practice, as tolerated, with unmeasured differences among patients receiving differing dosages potentially explaining the differing results seen here compared with randomized clinical trials.

Background The coronavirus disease 2019 (COVID-19) pandemic has increased burden on healthcare systems with subsequent reductions in non-emergent hospitalizations and procedures. While there are widespread reports of intentional reductions in elective hospitalizations, trends in urgent or emergent hospitalizations including heart failure (HF) hospitalizations have not been adequately characterized. Methods We evaluated trends of HF hospitalizations before and during the COVID-19 pandemic at the University of Mississippi Medical Center using electronic health records and discharge database. We also compared HF hospitalization trends during the same time frame in 2019 to account for seasonal variation in HF presentations. Results Prior to the COVID-19 pandemic in our medical center, a mean of 30 patients per week were admitted with a principal diagnosis of HF. After the first case of COVID-19 was diagnosed in Mississippi, there was a sharp 50% decline in the number of HF hospitalizations that declined even further after a “state of emergency” was declared in Mississippi. Conclusions Based on observations from a large academic medical center, there has been a significant reduction in the number of patients hospitalized for HF during the COVID-19 pandemic. Further investigation of these trends is warranted to determine the effects of the COVID-19 pandemic on long-term HF outcomes.

Introduction Implementation of GDMT for HFrEF remains low. We assessed the feasibility of a virtual GDMT Team for optimization of GDMT during hospitalization for non-CV conditions. Hypothesis A GDMT Team will improve GDMT optimization compared with usual care. Methods Consecutive hospitalized patients with HFrEF≤40% were prospectively identified. Patients with critical illness, cardiology consult, de-novo HF, COVID-19 & SBP ≤90mmHg were excluded. February 3 to March 1, 2020 served as a pre-intervention period during which patients were screened, but did not receive GDMT Team interventions. From March 2 to June 21, 2020, a pharmacist-physician team provided up to 1 suggestion daily for GDMT optimization (evidence-based s-blockers, ACEi/ARB/ARNI, & MRA) to treating teams based on an evidence-based algorithm. The primary outcome of a composite GDMT optimization score, the net of positive therapeutic changes (+1 for new initiations/uptitrations) & negative therapeutic changes (-1 for discontinuations/downtitrations) during hospitalization, was compared between the pre- vs. post-intervention periods. Multivariable linear regression models were built adjusting associations for clinical factors. Safety outcomes requiring intervention or GDMT downtitration were identified. Results Of 187 encounters, 84 (45%) met eligibility criteria: 28 pre-intervention, 56 post-intervention. Mean age was 68±11 yrs, 70% men, and 61% White. Of 88 GDMT Team suggestions, 49 (56%) were followed by discharge. During the intervention, cumulative COVID-19 hospitalizations rose from 0 to 11085 in MA. Mean GDMT optimization score was -0.14 (95% CI: -0.58 to +0.30) pre-intervention & +0.64 (95% CI: +0.35 to +0.93) post-intervention (P=0.004). In a model inclusive of demographics, comorbidities, vital signs, potassium levels, eGFR, & LVEF, the intervention was the only factor associated with higher GDMT optimization score (β coeff 0.89; P=0.008). Safety events included 1 instance each of AKI, hyperkalemia, bradycardia, & hypotension. Conclusion Admission for non-CV conditions is a feasible setting for GDMT optimization. A virtual GDMT Team was associated with improved GDMT; this implementation strategy warrants testing in a prospective RCT.

Background A systematic assessment of the temporal trends in heart failure (HF) clinical trials is lacking. Methods and Results A total of 154 phase II–IV HF trials including 162,725 patients published from 2001 to 2012 in 8 high-impact-factor journals were reviewed. The median number of participants and sites per trial were 367 (interquartile range [IQR] 133-1450) and 38 (5–101), respectively. Median enrollment duration was 2.2 (1.5–3.3) years. The majority of studies investigated treatment for chronic HF (82.5%) and investigated HF with reduced ejection fraction (EF) (71.4%), whereas 27 trials (17.5%) enrolled patients with mixed EF and 9 (5.8%) enrolled HF with preserved EF patients alone. Enrollment rates did not significantly change over time (median 0.49 patients site −1 month −1 , IQR 0.34–0.98; P = .53). Trials meeting their primary end point decreased over time from 73.5% in 2001–2003 to 52.5% in 2010–2012 ( P = .08) and were more often smaller and used nonmortality end points. Industry trials were larger with shorter enrollment duration, more concentrated in North America, and more likely to be positive. Trials conducted exclusively outside North America and Western Europe had the highest enrollment rates (median 1.95 patients site −1 month −1 , IQR 1.34–4.11). Conclusions Contemporary HF clinical trials display slow enrollment rates and decreased rates of positive outcomes over time. Positive trials tended to be smaller size with a higher proportion of surrogate end points.

Background Despite the importance of age, sex, and race/ethnicity representativeness in clinical trials, limited data exist regarding the enrollment trends of these groups in contemporary heart failure (HF) trials. Objective We aimed to characterize the representation of older patients, women, and racial and ethnic minorities in HF trials. Methods We performed a systematic search of HF trials published between January 2001 and December 2016 that enrolled over 400 participants using PubMed/MEDLINE and ClinicalTrials.gov. A total of 118 trials that cumulatively enrolled 215,508 subjects were included. Trial findings were compared with large epidemiological studies indexed to hospitalization status and ejection fraction. Results Median number of participants per trial was 994 (IQR 543-1899) enrolled from a median of 82 (IQR 28-171) sites. Overall, 94 (80%) of trials enrolled patients with HF with reduced ejection fraction (HFrEF) exclusively. Mean age of trial participants was 65±11 years and 27% were women; no significant temporal trends were observed (P≥0.60 for both, Figure). Chronic HF with preserved ejection fraction (HFpEF) trials enrolled older participants (mean age of 71±7 years compared to 65±11 year for HFrEF and 66±12 years for acute HF (AHF) trials (P=0.01). Corresponding average ages in US epidemiological studies were 69 years for HFrEF, and 73 year for both HFpEF and AHF patients. HFpEF trials had a higher proportion of women (56%) compared with HFrEF (24%), or AHF (32%), P Conclusion In contemporary HF trials, older patients and women are consistently underrepresented. Race/ethnicity data are reported in less than half of the trials; when reported, such data show that enrollment of non-White patients increased over time

Introduction Heart failure with preserved ejection fraction (HFpEF) disproportionately affects older adults. Age-related changes in physiology and variable pharmacokinetics may affect drug efficacy and safety among older individuals. We examined efficacy and safety of spironolactone by age in the Americas region (N=1767) of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. Methods TOPCAT was an international, multicenter, prospective, randomized trial that enrolled patients with HF and left ventricular ejection fraction ≥ 45%, age 50 or older with eGFR ≥ 30ml/min/1.73 m2 and prior HF hospitalization or elevated natriuretic peptide levels. Participants were randomized to spironolactone or placebo over a mean follow up of 3.3 years. We assessed treatment effect (primary study composite of CV death, aborted cardiac arrest, and hospitalization for HF) and safety (permanent study medication discontinuation due to hyperkalemia, rise in serum creatinine to ≥ 3.0 mg/dL, gynecomastia, or allergic reaction or intolerance) by age categories ( Results Number of participants were 492, 555, and 720 in the Conclusions In patients with HFpEF, the efficacy of spironolactone was consistent across age categories, but treatment-related adverse events were more common in participants age 65 or older. These data support guideline recommendations for use of spironolactone in appropriately selected HFpEF regardless of age, but underscore that closer laboratory surveillance is critical in older individuals.