Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Evidence-Based Cardiovascular Disease Medicines' Availability in Low-Cost Generic Drug Programs in the United States : A Cross-Sectional Study.

BACKGROUND: Low-cost generic programs (LCGPs) that expand access to affordable cardiovascular disease (CVD) medicines can assist patients in achieving desired cardiovascular outcomes. It is important that LCGPs offer CVD medicines that promote evidence-based prescribing. OBJECTIVE: To evaluate LCGPs' coverage of evidence-based CVD medications using a clinical framework that examines coverage of core treatments, coverage of options with the highest-quality evidence, and the variety of medication options and strengths that create choices and allow dosing titration. DESIGN: Cross-sectional study. SETTING: Publicly available LCGPs in March and April 2023 in the United States. PARTICIPANTS: 19 LCGPs. MEASUREMENTS: Proportion of LCGPs that offered evidence-based CVD medicines within a clinical framework for 6 CVDs (atrial fibrillation, heart failure, hyperlipidemia, hypertension, post-acute coronary syndrome secondary prevention, and stable angina) according to 4 availability metrics (breadth, choice, high-quality evidence, and titratability). RESULTS: The availability of CVD medication varied by program, drug, and CVD condition. Some programs had more breadth and choice of coverage for most CVDs (H-E-B, Kroger, Mark Cuban Cost Plus Drug Company, and Walmart), whereas many had more focused coverage and others markedly limited offerings. Nearly all LCGPs offered angiotensin-converting enzyme inhibitors, ß-blockers, thiazides, and moderate-intensity statins, but availability was low for higher-cost or lower-use generics (antiplatelets and antiarrhythmics). Core pharmacotherapy coverage and choices were limited for atrial fibrillation and heart failure but widely available for hypertension and hyperlipidemia. LIMITATION: In-depth cost analysis was not investigated. CONCLUSION: Coverage of evidence-based medications for the 6 CVDs investigated varied by LCGP and condition. Because high availability of core CVD pharmacotherapy can enhance optimal disease state management, LCGPs should identify existing limitations in their coverage and continuously revise their formularies to improve the comprehensiveness of CVD medication coverage. PRIMARY FUNDING SOURCE: None.

Sex Differences in Clinical Characteristics and Outcomes After Myocardial Infarction With Low Ejection Fraction: Insights From PARADISE-MI.

Background Studies demonstrated sex differences in outcomes following acute myocardial infarction, with women more likely to develop heart failure (HF). Sacubitril/valsartan has been shown to reduce cardiovascular death and HF hospitalizations in patients with HF with reduced ejection fraction. Methods and Results A total of 5661 patients (1363 women [24%]) with acute myocardial infarction complicated by reduced left ventricular ejection fraction (≤40%), pulmonary congestion, or both and ≥1 of 8 risk-augmenting factors were randomized to receive sacubitril/valsartan or ramipril. The primary outcome was cardiovascular death or incident HF. Baseline characteristics, clinical outcomes, and safety events were compared according to sex, a prespecified subgroup. Female participants were older and had more comorbidities. After multivariable adjustment, women and men were at similar risks for cardiovascular death or all-cause death. Women were more likely to have first HF hospitalization (hazard ratio [HR], 1.34 [95% CI, 1.05-1.70]; P=0.02) and total HF hospitalizations (HR, 1.39 [95% CI, 1.05-1.84]; P=0.02). Sex did not significantly modify the treatment effect of sacubitril/valsartan compared with ramipril on the primary outcome (P for interaction=0.11). Conclusions In contemporary patients who presented with reduced left ventricular ejection fraction, pulmonary congestion, or both, following acute myocardial infarction, women had a higher incidence of HF during follow-up. Sex did not modify the treatment effect of sacubitril/valsartan relative to ramipril. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02924727.

The design of the Dashboard Activated Services and Telehealth for Heart Failure (DASH-HF) study: A pragmatic quality improvement randomized implementation trial for patients with heart failure with reduced ejection fraction.

BACKGROUND: Gaps in the receipt and dosing of guideline-directed medical therapy (GDMT) persist for patients with heart failure with reduced ejection fraction (HFrEF) [1]. In 2020, the Veterans Affairs (VA) developed a heart failure (HF) specific population dashboard to monitor care quality and performance on standard HFrEF performance measures [2]. METHODS: The Dashboard Activated Services and Telehealth for HF (DASH-HF) study is a pragmatic randomized quality improvement study designed to evaluate the utility of proactive population management clinics using the VA's HF dashboard to optimize GDMT for patients with HFrEF. Panel management telemedicine clinics incorporated multidisciplinary clinicians to perform chart review and impromptu telephone encounters to evaluate current HFrEF management and opportunities to optimize GDMT. The study will evaluate the efficacy of proactive panel management to usual care at 6 months as quantified by the GDMT optimization potential score. Secondary outcomes include hospitalizations, mortality, and clinician time per intervention. The study completed enrollment and randomization of 300 participants. The intervention was performed from September to December 2021. CONCLUSION: DASH-HF will contribute to the literature by evaluating use of the existing VA dashboard to identify HF patients with the lowest adherence to GDMT and proactively target this group for the intervention. REGISTRATION: https://clinicaltrials.gov/. Unique identifier: NCT05001165.

Prior Authorization, Copayments, and Utilization of Sacubitril/Valsartan in Medicare and Commercial Plans in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Slow uptake of sacubitril/valsartan in patients with heart failure with reduced ejection fraction has been reported, which may negatively impact clinical outcomes. We characterized prior authorization (PA) burden, prescription copayment, and utilization of sacubitril/valsartan by insurance plan type to identify potential barriers to its use. METHODS: We conducted a national population-level, cross-sectional study using PA data from an insurance coverage website accessed in March 2019 and IQVIA National Prescription Audit data from August 2018 to July 2019. Primary outcomes were proportion of plans requiring PA, frequency of specific PA criteria, number of sacubitril/valsartan prescriptions, and copayments per insurance plan type. RESULTS: Overall, 48.1% (1394/2896) of insurance plans required PA for sacubitril/valsartan. Fewer Medicare (27.7%) than commercial (57.2%) plans required PA (P<0.001). For both plan types, the most frequently required PA criteria were ejection fraction (71.6%, 90.9%) and New York Heart Association class (60.4%, 90.8%) for Medicare and commercial plans, respectively. Copayment amounts varied by plan type, with more sacubitril/valsartan prescriptions for commercial plans not requiring a patient copayment (32.4%) compared with Medicare plans (19.3%; P<0.001). There were 814 437 sacubitril/valsartan prescriptions for Medicare and 822 292 for commercial plans dispensed from August 2018 to July 2019. Based on estimated heart failure with reduced ejection fraction populations for each plan type, 4-fold more sacubitril/valsartan prescriptions were dispensed in commercial than in Medicare plans (820 versus 215 prescriptions/1000 individuals in the heart failure with reduced ejection fraction population). The estimated proportion of heart failure with reduced ejection fraction patients prescribed sacubitril/valsartan was 3.6% (1.5%-6.8%) for Medicare and 13.7% (4.9%-31.8%) for commercial plan populations. CONCLUSIONS: Despite commercial plans having greater PA requirements than Medicare, population-adjusted use of sacubitril/valsartan was higher in commercial plans. Given that commercial plans had more prescriptions with low copayments than Medicare, copayment policies may be more influential on sacubitril/valsartan use than its PA policies. Low sacubitril/valsartan use in both plan types highlights the multifactorial nature of medication underutilization that includes factors beyond the drug policies that we evaluated.

Evaluation of Patients with Heart Failure to Determine Eligibility for Treatment with Sacubitril/Valsartan: Insights from a Veterans Administration Healthcare System.

STUDY OBJECTIVE: Despite evidence that supports the use of sacubitril/valsartan - the first angiotensin II receptor blocker-neprilysin inhibitor - for mortality reduction in patients with heart failure (HF), it remains underprescribed. The objective of this study was to evaluate eligibility for initiation of sacubitril/valsartan treatment in patients with HF within the largest Veterans Administration healthcare system in the United States. DESIGN: Cross-sectional study. SETTING: Veterans Affairs Greater Los Angeles Healthcare System (VAGLAHS). PATIENTS: A total of 2985 patients with a HF diagnosis who were alive as of November 1, 2017. MEASUREMENTS AND MAIN RESULTS: Eligibility for sacubitril/valsartan initiation was based on inclusion and exclusion criteria from the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting-Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial and the VA Criteria for Use. The proportion of eligible patients was estimated, and characteristics of eligible patients were compared with those in the PARADIGM-HF trial. Of the 2985 patients with HF who were alive as of November 1, 2017, 965 (32.3%) had HF with reduced ejection fraction (HFrEF). Of these patients with HFrEF, 263 (27.3%) fulfilled eligibility criteria and were considered candidates for sacubitril/valsartan initiation. Of the 702 patients who did not fulfil eligibility criteria, the most common reasons were New York Heart Association functional class I (35.3%) and B-type natriuretic peptide level of 100 pg/ml or lower (22.2%). Compared with patients in the PARADIGM-HF trial, VAGLAHS patients were older (70.4 vs 63.8 yrs) and more likely to be male (98.5% vs 79.0%), and a higher proportion had New York Heart Association functional class III symptoms (35.4% vs 23.1%). Of the 965 patients with HFrEF, 34 (3.5%) had an active sacubitril/valsartan prescription as of November 1, 2017, of whom 27 (79.4%) did not meet criteria. CONCLUSION: Whereas 27% of patients with HFrEF were eligible to initiate sacubitril/valsartan, only 3.5% of these patients were prescribed the medication. Although sacubitril/valsartan reduced morbidity and mortality in clinical trials, it remains underused within this VA healthcare system. This analysis provides important insights into the VA and other healthcare systems regarding the opportunity for optimizing guideline-directed HF therapy.

Impact of a Multidisciplinary Heart Failure Postdischarge Management Clinic on Medication Adherence.

PURPOSE: Disease management programs have been associated with improved adherence to heart failure (HF) medications. However, there remain limited data on the benefit of a comprehensive multidisciplinary HF postdischarge management (PDM) clinic that promptly follows HF-related hospitalization on evidence-based HF medication adherence. OBJECTIVE: The aim of this study was to evaluate the effects of an HF-PDM clinic on adherence to evidence-based HF medication therapy. METHODS: In this retrospective cohort study, we identified patients discharged from the Veterans Affairs Greater Los Angeles Healthcare System between 2009 and 2012 with a primary diagnosis of HF. Data from patients who attended the HF-PDM clinic immediately following HF-related hospitalization between 2010 and 2012 were compared with those from historical controls, who did not attend the HF-PDM clinic, from 2009. The main outcome was adherence to evidence-based HF medications during the 90 days after discharge. Adherence was defined as the proportion of days covered at 90 days after discharge (PDC-90) of ≥0.80. The percentages of patients adherent to each medication were compared between the 2 groups using the χ2 test. A logistic regression model adjusted for potential confounding variables was constructed to evaluate the percentages of patients adherent to evidence-based HF medications. FINDINGS: A total of 277 patients (144 clinic, 133 control) were included in the study. Both univariate and multivariate analyses showed that the clinic was associated with improved medication adherence to angiotensin-converting enzyme inhibitors, a twice-daily ß-blocker, and aldosterone antagonists compared with controls. The most significant increases were in adherence to angiotensin-converting enzyme inhibitors, with mean PDC-90 values of 0.84 (control) versus 0.93 (clinic) (P = 0.008) and 90-day adherence rates of 69% (control) versus 87% (clinic) (P = 0.005). IMPLICATIONS: Care in the multidisciplinary HF-PDM clinic was associated with significant increases in 90-day adherence to evidence-based HF medications in patients who were recently discharged after an HF-related hospitalization.

Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload.

BACKGROUND: In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments. OBJECTIVES: It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response. METHODS: In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach. RESULTS: We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings. CONCLUSIONS: Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557).

Impact of a Multidisciplinary Heart Failure Post-hospitalization Program on Heart Failure Readmission Rates.

BACKGROUND: Specialized chronic heart failure (HF) clinics have demonstrated significant reductions in readmissions. Limited evidence is available regarding HF clinics in the immediate post-discharge period. OBJECTIVE: To evaluate the effect of a multidisciplinary HF clinic on 90-day readmission rates and all-cause mortality in those recently discharged from a HF hospitalization. METHODS: In this retrospective cohort study, patients discharged with a primary HF diagnosis who attended the HF postdischarge clinic in 2010-2012 were compared with controls from 2009. During 6 clinic visits, patients were seen by a physician assistant, clinical pharmacist specialist, and case manager, with care overseen by a cardiologist. The program focused on optimizing therapy, identifying HF etiology/precipitating factors, medication titration, education, and medication adherence. The primary outcome was 90-day HF readmission. A multivariate Cox proportional hazards model was used to compare outcomes. RESULTS: Among the 277 patients (144 clinic, 133 control) in the study, 7.6% of patients in the clinic and 23.3% of patients in the control group were readmitted for HF within 90 days (aHR (adjusted hazard ratio) = 0.17; 95% CI = 0.07-0.41; P < 0.001; ARR (absolute risk reduction) = 15.7%; NNT (number needed to treat) = 7). Clinic patients had lower 90-day time-to-first HF readmission or all-cause mortality (9.0% vs 28.6%; aHR = 0.28; 95% CI = 0.06-0.31; P < 0.001; ARR = 19.6%; NNT = 6). CONCLUSIONS: The multidisciplinary HF posthospitalization outpatient program was associated with a significant reduction in 90-day HF readmissions in patients who were recently discharged from a HF hospitalization.

Rates and predictors of ACE inhibitor discontinuation subsequent to elevated serum creatinine: a retrospective cohort study.

OBJECTIVES: ACE inhibitors (ACEI) are underutilised despite cardiovascular benefits, in part due to concerns of known transient elevations in serum creatinine (SCr) after initiation. Our objectives were to evaluate rates and predictors of ACEI discontinuation after SCr elevation post-ACEI initiation since limited data are available that examine this issue. SETTING: Primary and tertiary Veterans healthcare system in Los Angeles, California, USA PARTICIPANTS: 3039 outpatients initiating an ACEI with a SCr measured within 6 months prior to and approximately 3 months after initiating an ACEI. Patients were divided into three groups (SCr <1.5, 1.5­2 and >2). PRIMARY AND SECONDARY OUTCOME MEASURES: Rates and factors associated with ACEI discontinuation subsequent to SCr elevation after ACEI initiation and for patients with baseline SCr >2 mg/dL, the change in SCr associated with chronic use. Predictors were identified using multivariate logistic regression modelling. RESULTS: At 3 months follow-up, for those with an increase in SCr, the mean increase post-ACEI initiation was 26%, ranging from −0.01 mg/dL to 0.42 mg/dL varying according to a level of baseline renal function. ACEI discontinuation was higher in patients with elevated baseline SCr (19/165, 11.5%) compared with those with SCr <1.5 (135/2497, 5.4%), and those with SCr 1.5­2.0 (28/377, 7.4%). Male patients, and those with heart failure were less likely to discontinue ACEI after an elevation of SCr post-ACEI initiation, while those taking non-steroidal anti-inflammatory drugs, diuretics and ß-blockers were more likely to discontinue ACEI. CONCLUSIONS: SCr increases <30% on average within 3 months of ACEI initiation, with subsequent discontinuation rates varying by baseline SCr. Elevation in SCr was not associated with ACEI discontinuation rates. In patients with SCr >2 mg/dL at baseline, despite an acute increase in SCr after ACEI initiation, chronic ACEI use was associated with a decrease in SCr in most patients.

Comparative testing of 5 nicotine systems: initial use and preferences.

OBJECTIVE: To test initial reactions to 5 nicotine treatments (NRTs: 2 and 4 mg gum, inhaler, nasal spray, tablet) in a crossover study (n=41). METHODS: Subjects used each medication on arising (1/2 day) and resumed smoking each afternoon. Subjects rated (individually) and ranked (comparatively) treatments on use, reinforcement, withdrawal, craving, and preferences. RESULTS: Overall preferences: inhaler (49%), 4 mg gum (24%), 2 mg gum (10%), 2 mg tablet (10%), nasal spray (7%). Overall results were consistent with ratings and rankings of individual characteristics of drugs. CONCLUSION: Subjects had varied reactions to NRTs that may affect initiation of cessation.