Prescribing trends of SGLT2 inhibitors among HFrEF and HFpEF patients with and without T2DM, 2013-2021.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are recommended for treatment of heart failure (HF), regardless of type 2 diabetes (T2DM) status. However, limited data exist on SGLT2i prescribing in HF patients without T2DM or across HF subtypes. METHODS: This was a serial, cross-sectional study of US MarketScan commercial and Medicare claims (2013-2021). Prevalence of SGLT2i was calculated by calendar year among HFrEF and HFpEF patients and stratified by T2DM status. RESULTS: Among 218,066 HFrEF patients [mean (SD): 54.9 (8.92) years; 66.4% male], the prevalence of SGLT2i use increased from 0.3 to 18.6%, while among 150,437 HFpEF patients [56.5 (7.77) years; 47.6% male], it rose from 0.5 to 9.9%. These increases were driven by the subgroup with comorbid T2DM. SGLT2i prevalence use ratios among patients with T2DM compared to those without decreased from > 100 in 2018 to 3.8 in 2021 among HFrEF patients, and from 83.1 in 2018 to 17.5 in 2021, coinciding with the publication of landmark trials and corresponding changes in clinical guidelines. CONCLUSIONS: SGLT2i use rose rapidly following changes in guidelines but remained low among those without T2DM. By the end of the study, approximately 1 in 3 HFrEF and 1 in 5 HFpEF patients with T2DM were using an SGLT2i, compared to only 1 in 11 HFrEF and 1 in 85 HFpEF patients without T2DM. Future work identifying barriers with the uptake of GDMT, including SGLT2i, among HF patients is needed.

Cost-Utility Analysis of Vericiguat in Heart Failure with Reduced Ejection Fraction After Worsening Heart Failure Events in China.

OBJECTIVE: Vericiguat is a new medication to demonstrate clinical efficacy in heart failure with reduced ejection fraction (HFrEF) after worsening heart failure (WHF) events, but its cost-utility was unknown. We aimed to assess the cost-utility of combining the application of vericiguat with standard treatment in HFrEF patients who had WHF events. METHODS: A multistate Markov model was implemented to mimic the economic results of HFrEF patients who had WHF events in China after receiving vericiguat or placebo. An analysis of cost-utility was conducted; most parameters were set according to the published studies and related databases. All the utilities and costs were decreased at a rate of 5% annually. The incremental cost-effectiveness ratios (ICERs) were the primary outcome measure. We also conducted sensitivity analyses. RESULTS: Over a 20 year lifetime horizon, additional use of vericiguat led to an elevated cost from US$9725.03 to US$20,660.76 at the current vericiguat costs. This was related to increased quality-adjusted life years (QALYs) from 2.50 to 2.66, along with an ICER of US$65,057.24 per QALY, which was over the willingness-to-pay (WTP) threshold of US$36,096.30 per QALY. If the vericiguat costs were discounted at 80%, it contributed to an ICER of US$12,226.77 per QALY. Additional use of vericiguat for patients with plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) of ≤ 5314 pg per ml produced an ICER of US$23,688.46 per QALY. The outcomes of the one-way sensitivity analysis showed the risk of death from cardiovascular disease in both groups was variable with the highest sensitivity. The probabilistic sensitivity analysis showed that 41.6% of the mimicked population receiving vericiguat combined with standard therapy was cost-effective at the WTP threshold of US$36,096.30 per QALY. CONCLUSIONS: From the perspective of Chinese public healthcare system, the combined use of vericiguat and standard treatment in patients with HFrEF following WHF events did not generate advantages in cost-utility in China but was a cost-effective therapeutic strategy for those who with plasma NT-proBNP of ≤ 5314 pg per ml.

Health and Economic Evaluation of Sacubitril-Valsartan for Heart Failure Management.

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown. Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF. Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023. Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs. Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%). Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Serial Assessment of High-Sensitivity Cardiac Troponin and the Effect of Dapagliflozin in Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of the DAPA-HF Trial.

BACKGROUND: Circulating high-sensitivity cardiac troponin T (hsTnT) predominantly reflects myocardial injury, and higher levels are associated with a higher risk of worsening heart failure and death in patients with heart failure with reduced ejection fraction. Less is known about the prognostic significance of changes in hsTnT over time, the effects of dapagliflozin on clinical outcomes in relation to baseline hsTnT levels, and the effect of dapagliflozin on hsTnT levels. METHODS: DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) was a randomized, double-blind, placebo-controlled trial of dapagliflozin (10 mg daily) in patients with New York Heart Association class II to IV symptoms and left ventricular ejection fraction ≤40% (median follow-up, 18.2 months). hsTnT (Roche Diagnostics) was measured at baseline in 3112 patients and at 1 year in 2506 patients. The primary end point was adjudicated worsening heart failure or cardiovascular death. Clinical end points were analyzed according to baseline hsTnT and change in hsTnT from baseline to 1 year. Comparative treatment effects on clinical end points with dapagliflozin versus placebo were assessed by baseline hsTnT. The effect of dapagliflozin on hsTnT was explored. RESULTS: Median baseline hsTnT concentration was 20.0 (25th-75th percentile, 13.7-30.2) ng/L. Over 1 year, 67.9% of patients had a ≥10% relative increase or decrease in hsTnT concentrations, and 43.5% had a ≥20% relative change. A stepwise gradient of higher risk for the primary end point was observed across increasing quartiles of baseline hsTnT concentration (adjusted hazard ratio Q4 versus Q1, 3.44 [95% CI, 2.46-4.82]). Relative and absolute increases in hsTnT over 1 year were associated with higher subsequent risk of the primary end point. The relative reduction in the primary end point with dapagliflozin was consistent across quartiles of baseline hsTnT (P-interaction=0.55), but patients in the top quartile tended to have the greatest absolute risk reduction (absolute risk difference, 7.5% [95% CI, 1.0%-14.0%]). Dapagliflozin tended to attenuate the increase in hsTnT over time compared with placebo (relative least squares mean reduction, -3% [-6% to 0%]; P=0.076). CONCLUSIONS: Higher baseline hsTnT and greater increase in hsTnT over 1 year are associated with worse clinical outcomes. Dapagliflozin consistently reduced the risk of the primary end point, irrespective of baseline hsTnT levels. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03036124.

Diuretic Changes, Health Care Resource Utilization, and Clinical Outcomes for Heart Failure With Reduced Ejection Fraction: From the Change the Management of Patients With Heart Failure Registry.

BACKGROUND: Diuretics are a mainstay therapy for the symptomatic treatment of heart failure. However, in contemporary US outpatient practice, the degree to which diuretic dosing changes over time and the associations with clinical outcomes and health care resource utilization are unknown. METHODS: Among 3426 US outpatients with chronic heart failure with reduced ejection fraction in the Change the Management of Patients with Heart Failure registry with complete medication data and who were prescribed a loop diuretic, diuretic dose increase was defined as: (1) change to a total daily dose higher than their previous total daily dose, (2) addition of metolazone to the regimen, (3) change from furosemide to either bumetanide or torsemide, and the change persists for at least 7 days. Adjusted hazard ratios or rate ratios along with 95% CIs were reported for clinical outcomes among patients with an increase in oral diuretic dose versus no increase in diuretic dose. RESULTS: Overall, 796 (23%) had a diuretic dose increase (18 episodes per 100 patient-years). The proportion of patients with dyspnea at rest (38% versus 26%), dyspnea at exertion (79% versus 67%), orthopnea (32% versus 21%), edema (60% versus 43%), and weight gain (40% versus 23%) were significantly (all P <0.001) higher in the diuretic increase group. Baseline angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (hazard ratio, 0.75 [95% CI, 0.65-0.87]) use were associated with lower likelihood of diuretic increase over time. Patients with a diuretic dose increase had a significantly higher number of heart failure hospitalizations (rate ratio, 2.53 [95% CI, 2.10-3.05]), emergency department visits (rate ratio, 1.84 [95% CI, 1.56-2.17]), and home health visits (rate ratio, 1.88 [95% CI, 1.39-2.54]), but not all-cause mortality (hazard ratio, 1.10 [95% CI, 0.89-1.36]). Similarly, greater furosemide dose equivalent increases were associated with greater resource utilization but not with mortality, compared with smaller increases. CONCLUSIONS: In this contemporary US registry, 1 in 4 patients with heart failure with reduced ejection fraction had outpatient escalation of diuretic therapy over longitudinal follow-up, and these patients were more likely to have sign/symptoms of congestion. Outpatient diuretic dose escalation of any magnitude was associated with heart failure hospitalizations and resource utilization, but not all-cause mortality.

Cost-effectiveness evaluation of add-on dapagliflozin for heart failure with reduced ejection fraction from perspective of healthcare systems in Asia-Pacific region.

BACKGROUND: With emerging evidence on the efficacy of adding dapagliflozin to standard care for patients with heart failure with reduced ejection fraction (HFrEF), this study assessed the cost-effectiveness of add-on dapagliflozin to standard care versus standard care alone for HFrEF from the perspective of healthcare systems in the Asia-Pacific region. METHODS: A Markov model was applied to project the outcomes of treatment in terms of lifetime medical cost and quality-adjusted life-years. The transition probabilities between health states in the model were obtained from the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction trial. Country-specific costs and utilities were extracted for modeling. The incremental cost-effectiveness ratio against a country-specific willingness-to-pay threshold was applied to determine the cost-effectiveness of treatment. A series of sensitivity analyses were performed to ensure the robustness of the study results. Costs are presented in 2020 United States dollars. RESULTS: The incremental cost-effectiveness ratios for add-on dapagliflozin versus standard care alone were $5277, $9980, $12,305, $16,705, and $23,227 per quality-adjusted life-year gained in Korea, Australia, Taiwan, Japan, and Singapore, respectively. When using add-on dapagliflozin to standard care versus standard care alone, ~ 100% of simulations were cost-effective at a willingness-to-pay threshold of one gross domestic product per capita of the given Asia-Pacific country; however, the probability of being cost-effective for using add-on dapagliflozin decreased when the time horizon for simulation was restricted to 18 months and when the cardiovascular mortality for the two treatments (43.8% and 33.0%, respectively) was assumed to be the same. The cost-effectiveness results were most sensitive to cardiovascular mortality of treatment. CONCLUSIONS: Adding dapagliflozin to standard care is cost-effective for HFrEF in healthcare systems in the Asia-Pacific region, which supports the rational use of dapagliflozin for HFrEF in this region.

Clinical Effectiveness of Sacubitril/Valsartan Among Patients Hospitalized for Heart Failure With Reduced Ejection Fraction.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real-world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines-Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker. Over 12-month follow-up, compared with a discharge prescription of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all-cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72-0.94; P=0.004) but not all-cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89-1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91-1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all-cause mortality (adjusted HR, 0.69; 95% CI, 0.60-0.79; P<0.001), all-cause hospitalization (adjusted HR, 0.90; 95% CI, 0.82-0.98; P=0.02), but not heart failure hospitalization (adjusted HR, 0.94; 95% CI, 0.82-1.08; P=0.40). Conclusions Among patients hospitalized for HFrEF, prescription of sacubitril/valsartan at discharge was independently associated with reduced postdischarge mortality compared with angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker, and reduced mortality and all-cause hospitalization compared with no sacubitril/valsartan. These findings support the use of sacubitril/valsartan to improve postdischarge outcomes among older patients hospitalized for HFrEF in routine US clinical practice.

Cost-effectiveness of Dapagliflozin for the Treatment of Heart Failure With Reduced Ejection Fraction.

Importance: Heart failure with reduced ejection fraction produces substantial morbidity, mortality, and health care costs. Dapagliflozin is the first sodium-glucose cotransporter 2 inhibitor approved for the treatment of heart failure with reduced ejection fraction. Objective: To examine the cost-effectiveness of adding dapagliflozin to guideline-directed medical therapy for heart failure with reduced ejection fraction in patients with or without diabetes. Design, Setting, and Participants: This economic evaluation developed and used a Markov cohort model that compared dapagliflozin and guideline-directed medical therapy with guideline-directed medical therapy alone in a hypothetical cohort of US adults with similar clinical characteristics as participants of the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial. Dapagliflozin was assumed to cost $4192 annually. Nonparametric modeling was used to estimate long-term survival. Deterministic and probabilistic sensitivity analyses examined the impact of parameter uncertainty. Data were analyzed between September 2019 and January 2021. Main Outcomes and Measures: Lifetime incremental cost-effectiveness ratio in 2020 US dollars per quality-adjusted life-year (QALY) gained. Results: The simulated cohort had a starting age of 66 years, and 41.8% had diabetes at baseline. Median (interquartile range) survival in the guideline-directed medical therapy arm was 6.8 (3.5-11.3) years. Dapagliflozin was projected to add 0.63 (95% uncertainty interval [UI], 0.25-1.15) QALYs at an incremental lifetime cost of $42 800 (95% UI, $37 100-$50 300), for an incremental cost-effectiveness ratio of $68 300 per QALY gained (95% UI, $54 600-$117 600 per QALY gained; cost-effective in 94% of probabilistic simulations at a threshold of $100 000 per QALY gained). Findings were similar in individuals with or without diabetes but were sensitive to drug cost. Conclusions and Relevance: In this study, adding dapagliflozin to guideline-directed medical therapy was projected to improve long-term clinical outcomes in patients with heart failure with reduced ejection fraction and be cost-effective at current US prices. Scalable strategies for improving uptake of dapagliflozin may improve long-term outcomes in patients with heart failure with reduced ejection fraction.

Optimising the Heart Failure Treatment Pathway: The Role of SGLT2 Inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors were first developed as glucose-lowering therapies for the treatment of diabetes. However, these drugs have now been recognised to prevent worsening heart-failure events, improve health-related quality of life, and reduce mortality in people with heart failure with reduced ejection fraction (HFrEF), including those both with and without diabetes. Despite robust clinical trial data demonstrating favourable outcomes with SGLT2 inhibitors for patients with HFrEF, there is a lack of familiarity with the HF indication for these drugs, which have been the remit of diabetologists to date. In this article we use consensus expert opinion alongside the available evidence and label indication to provide support for the healthcare community treating people with HF regarding positioning of SGLT2 inhibitors within the treatment pathway. By highlighting appropriate prescribing and practical considerations, we hope to encourage greater, and safe, use of SGLT2 inhibitors in this population.

The evolution of guideline-directed medical therapy among decompensated HFrEF patients in sacubitril/valsartan era: Medical expenses and clinical effectiveness.

BACKGROUND: Over recent years, new evolution in guideline-directed medical therapy (GDMT) contributes to clinical benefits in patients with heart failure and reduced ejection fraction (HFrEF). The additional medical expenditure may be a concern due to the current financial constraint. This study aimed to investigate the medical costs and clinical effectiveness of contemporary GDMT in recently hospitalized HFrEF patients. METHODS: Acutely decompensated hospitalized HFrEF patients from two multicenter cohorts of different periods were retrospectively analyzed. A propensity score matching was performed to adjust the baseline characteristics. Annual medication costs, risks of mortality, and recurrent heart failure hospitalizations (HFH) were compared. RESULTS: Following 1:2 propensity score matching, there were 426 patients from the 2017-2018 cohort using sacubitril/valsartan, while 852 patients from 2013 to 2014 did not use so at discharge. Baseline characteristics were similar, whereas the sacubitril/valsartan users were more likely to receive beta-blockers, ivabradine and mineralocorticoid receptor antagonists at discharge (79.3% vs 60.4%, 23.2% vs 0%, and 64.1% vs 49.8%, p < 0.001). The 2017-2018 cohort produced more medication costs by 1277 United States dollar (USD) per person per year, while it resulted in lower rates of HFH and all-cause mortality (10.3 vs 20.3 and 48.8 vs 79.9 per 100 person-year, p < 0.001). Costs of preventing a mortality event and a HFH event with contemporary treatments were 15 758 USD (95% confidence interval [CI] 10 436-29 244) and 5317 USD (95% CI 3388-10 098), respectively. CONCLUSION: The higher adoption of GDMT was associated with greater medical expenses but better clinical outcomes in recently decompensated HFrEF patients.

Sex-related differences in chronic heart failure: a community-based study.

AIMS: To evaluate sex-related differences among real-life outpatients with chronic heart failure across the ejection fraction spectrum and to evaluate whether these differences might impact therapy and outcomes. METHODS: A total of 2528 heart failure patients were examined between 2009 and 2015 [mean age 76, 42% females; 59% with heart failure with preserved ejection fraction (HFpEF), 17% with heart failure with mid-range ejection fraction (HFmrEF) and 24% with heart failure with reduced ejection fraction (HFrEF)]. Females showed a higher prevalence of HFpEF than males. RESULTS: Females were older, less obese and with less ischaemic heart disease. They have renal failure and anaemia more frequently than males. There were no differences in terms of heart failure therapy in the HFrEF group, but a lower prescription rate of angiotensin-converting enzyme-I/AT1 blockers in HFmrEF and HFpEF and a higher prescription of mineralocorticoid receptor antagonists in the female group with HFpEF were observed. Crude rate mortality and composite outcome (death/heart failure progression) run similarly across sexes regardless of the ejection fraction categories. After adjustment, risk of mortality was significantly lower in females than males in the HFmrEF and HFpEF groups, whereas similar risk was confirmed across sexes in the HFrEF group. Considering prognostic risk factors, noncardiac comorbidities emerged in the HFpEF group. CONCLUSION: In a community-based heart failure cohort, females were differently distributed within heart failure phenotypes and they presented some different characteristics across ejection fraction categories. Although in an unadjusted model there was no significant difference for adverse outcomes, in an adjusted model females showed a lower risk of mortality in HFpEF and HFmrEF. Concerning sex-related prognostic risk factors, noncardiac comorbidities significantly affected adverse prognosis in females with HFpEF.

Assessment of coronary vasomotor responses to acetylcholine in German and Japanese patients with epicardial coronary spasm-more similarities than differences?

Coronary spasm is an established cause for angina pectoris. Ethnic differences have been suggested among Asian compared to Caucasian patients regarding prevalence, gender distribution, and angiographic patterns of coronary spasm. The aim of this study was to compare contemporary German and Japanese patients with coronary spasm. Between 2011 and 2015, 149 patients with resting angina and unobstructed coronary arteries with acetylcholine-induced epicardial spasm were enrolled in Stuttgart, Germany (n = 69) and Sendai, Japan (n = 80). All patients underwent intracoronary acetylcholine testing according to a standardized protocol. Comprehensive analysis included type of spasm (focal/diffuse), dose of acetylcholine leading to spasm, and frequency of multivessel spasm. Patients in this study were 61 ± 11 years old, predominantly female (54%), and had normal left ventricular ejection fraction (73 ± 9%). Diffuse spasm was the most prevalent type of spasm (85%) whereas focal spasm was found in the remaining 15% of patients. 31% of patients had multivessel spasm. Comparing the German with the Japanese patients, distribution of spasm type (focal/diffuse, p = 0.19) and frequency of multivessel spasm (p = 0.22) were comparable. Moreover, when Japanese patients were compared with German patients and diffuse spasm with focal spasm patients, respectively, no significant differences were observed regarding the acetylcholine dose required to induce spasm (p = 0.078 and p = 0.46, respectively). In conclusion, diffuse epicardial coronary spasm is the most frequent finding among German and Japanese patients with resting angina, unobstructed coronary arteries, and epicardial spasm on acetylcholine testing. Japanese and German patients share several similarities including comparable types of spasm and frequency of multivessel spasm.

Racial and Ethnic Differences in Biomarkers, Health Status, and Cardiac Remodeling in Patients With Heart Failure With Reduced Ejection Fraction Treated With Sacubitril/Valsartan.

BACKGROUND: Among patients with heart failure and reduced ejection fraction (left ventricular (LV) ejection fraction ≤40%), sacubitril/valsartan (S/V) treatment is associated with improved health status and reverse cardiac remodeling. Data regarding racial and ethnic differences in response to S/V are lacking. METHODS: This was an analysis from the PROVE-HF study (Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure). Longitudinal changes in NT-proBNP (N-terminal pro-B-type natriuretic peptide), cardiac reverse remodeling, and health status scores were compared between groups using multivariate latent growth curve modeling. RESULTS: Among the 782 patients included in this study, 22.7% were non-Hispanic Black (from here referred to as Black), 14.9% were Hispanic, and 62.4% were non-Hispanic White (from here referred to as White). At baseline, compared with White patients, Black and Hispanic patients had lower NT-proBNP (g=0.34) and differences between groups in baseline values for LV end-diastolic volume index and LV end-systolic volume index were negligible (g<0.10). Following S/V initiation, NT-proBNP decreased in all 3 groups (P<0.0001) associated with improvements in LV ejection fraction, LV end-diastolic volume index, and LV end-systolic volume index. Although total improvement in LV measures was similar between groups, Black patients averaged larger gains in the first half of the trial while White patients averaged larger gains in the second half. Improvements in Kansas City Cardiomyopathy Questionnaire-23 Total Symptom scores were seen in all 3 groups. Treatment with S/V was well-tolerated. CONCLUSIONS: Among Black, Hispanic, and White patients with heart failure and reduced ejection fraction, treatment with S/V was associated with similar reduction in NT-proBNP, improvement in health status, and reverse remodeling. More data regarding racial and ethnic responses to heart failure and reduced ejection fraction treatment are needed. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Association between long-term prescription of febuxostat and the progression of heart failure with preserved ejection fraction in patients with hypertension and asymptomatic hyperuricemia.

Both hypertension and hyperuricemia are closely associated with the morbidity and mortality of heart failure. This study was designed to evaluate the influences of long-term xanthine oxidase inhibitor (febuxostat) prescription on left ventricular hypertrophy (LVH), left ventricular (LV) diastolic function, and new-onset heart failure with preserved ejection fraction (HFpEF) in these patients. Using a propensity score matching of 1:2 ratio, this retrospective claims database study compared febuxosatat prescription (n = 96) and non-urate-lowering therapy (n = 192) in patients with hypertensive left ventricular hypertrophy (LVH) and asymptomatic hyperuricemia. With a follow-up of 36 months, febuxostat significantly decreased the level of serum uric acid as well as generated more prominent improvement in LVH and LV diastolic function. Besides, the new-onset symptomatic HFpEF occurred in 2 of 96 patients in febuxostat group and 13 of 192 patients in non-urate-lowering group (P = 0.091). No increased risk for major adverse cardiovascular events in patients prescribed with febuxostat was noted. In conclusion, long-term febuxostat exposure was associated with protective effects in terms of LVH or LV diastolic dysfunction in patients with hypertensive LVH and asymptomatic hyperuricemia. Febuxostat also displayed a trend for reduced risk of new-onset HFpEF in this population.

Preconditioning with levosimendan reduces postoperative low cardiac output in moderate-severe systolic dysfunction patients who will undergo elective coronary artery bypass graft surgery: a cost-effective strategy.

BACKGROUND: Patients with moderate-severe systolic dysfunction undergoing coronary artery bypass graft have a higher incidence of postoperative low cardiac output. Preconditioning with levosimendan may be a useful strategy to prevent this complication. In this context, design cost-effective strategies like preconditioning with levosimendan may become necessary. METHODS: In a sequential assignment of patients with Left Ventricle Ejection Fraction less than 40%, two strategies were compared in terms of cost-effectiveness: standard care (n = 41) versus preconditioning with Levosimendan (n = 13). The adverse effects studied included: postoperative new-onset atrial fibrillation, low cardiac output, renal failure and prolonged mechanical ventilation. The costs were evaluated using deterministic and probabilistic sensitivity analysis, and Monte Carlo simulations were performed. RESULTS: Preconditioning with levosimendan in moderate to severe systolic dysfunction (Left Ventricle Ejection Fraction < 40%), was associated with a lower incidence of postoperative low cardiac output in elective coronary artery bypass graft surgery 2(15.4%) vs 25(61%) (P < 0.01) and lesser intensive care unit length of stay 2(1-4) vs 4(3-6) days (P = 0.03). Average cost on levosimendan group was 14,792€ while the average cost per patient without levosimendan was 17,007€. Patients with no complications represented 53.8% of the total in the levosimendan arm, as compared to 31.7% in the non-levosimendan arm. In all Montecarlo simulations for sensitivity analysis, use of levosimendan was less expensive and more effective. CONCLUSIONS: Preconditioning with levosimendan, is a cost-effective strategy preventing postoperative low cardiac output in patients with moderate-severe left ventricular systolic dysfunction undergoing elective coronary artery bypass graft surgery.

Study protocol for a randomized controlled trial: Qiliqiangxin in heart failUre: assESsment of reduction in morTality (QUEST).

BACKGROUND: Qiliqiangxin (QLQX) capsule is a Traditional Chinese Medicine (TCM) that has been approved in China for the treatment of chronic heart failure (CHF). Our previous study showed with a background of standard HF treatment, QLQX capsules further reduced the levels of NT-proBNP and the incidence of composite cardiac events (CCEs) in CHF patients. This study aims to further assess the reduction in mortality when using QLQX compared with placebo for heart failure with reduced ejection fraction (HFrEF) patients. METHODS: This study is a randomized, double-blind, placebo-controlled, parallel-group, multi-center, event-driven clinical study of approximately 3080 patients for a targeted 620 events. Patients must have a diagnosis of heart failure for at least 3 months prior to screening. Patients will be randomized 1:1 to receive the placebo or QLQX in addition to their standard medications of CHF. The primary efficacy outcome event is a composite cardiovascular death and re-hospitalization due to the worsening of heart failure. DISCUSSION: The QUEST study is a randomized control study of TCM in chronic heart failure. It will determine the place of QLQX as an new treatment approach and provide additional and innovative information regarding TCM - and the specific used of QLQX in HFrEF. TRIAL REGISTRATION: The trial was registered at http://www.chictr.org.cn. ( Registration No.: ChiCTR1900021929); Date: 2019-03-16.

Reversal of angiotensin-(1-12)-caused positive modulation on left ventricular contractile performance in heart failure: Assessment by pressure-volume analysis.

BACKGROUND: Angiotensin-(1-12) [Ang-(1-12)] is a renin-independent precursor for direct angiotensin-II production by chymase. Substantial evidence suggests that heart failure (HF) may alter cardiac Ang-(1-12) expression and activity; this novel Ang-(1-12)/chymase axis may be the main source for angiotensin-II deleterious actions in HF. We hypothesized that HF alters cardiac response to Ang-(1-12). Its stimulation may produce cardiac negative modulation and exacerbate left ventricle (LV) systolic and diastolic dysfunction. METHODS AND RESULTS: We assessed the effects of Ang-(1-12) (2 nmol/kg/min, iv, 10 min) on LV contractility, LV diastolic filling, and LV-arterial coupling (AVC) in 16 SD male rats with HF-induced by isoproterenol (3 mo after 170 mg/kg sq. for 2 consecutive days) and 10 age-matched male controls. In normal controls, versus baseline, Ang-(1-12) increased LV end-systolic pressure, without altering heart rate, arterial elastance (EA), LV end-diastolic pressure (PED), the time constant of LV relaxation (τ) and ejection fraction (EF). Ang-(1-12) significantly increased the slopes (EES) of LV end-systolic pressure (P)-volume (V) relations and the slopes (MSW) of LV stroke wok-end-diastolic V relations, indicating increased LV contractility. AVC (quantified as EES/EA) improved. In contrast, in HF, versus HF baseline, Ang-(1-12) produced a similar increase in PES, but significantly increased τ, EA, and PED. The early diastolic portion of LV PV loop was shifted upward with reduced in EF. Moreover, Ang-(1-12) significantly decreased EES and MSW, demonstrating decreased LV contractility. AVC was decreased by 43%. CONCLUSIONS: In both normal and HF rats, Ang-(1-12) causes similar vasoconstriction. In normal, Ang-(1-12) increases LV contractile function. In HF, Ang-(1-12) has adverse effects and depresses LV systolic and diastolic functional performance.

Assessment of Pregabalin-Induced Cardiotoxicity in Rats: Mechanistic Role of Angiotensin 1-7.

Pregabalin (PRG) possesses great therapeutic benefits in the treatment of epilepsy, neuropathic pain, and fibromyalgia. However, clinical data have reported incidence or exacerbation of heart failure following PRG administration. Experimental data exploring cardiac alterations and its underlying mechanisms are quite scarce. The aim of the present work was to investigate the effect of PRG on morphometric, echocardiographic, neurohumoral, and histopathological parameters in rats. It was hypothesized that alterations in cardiac renin angiotensin system (RAS) might be involved in PRG-induced cardiotoxicity. To further emphasize the role of RAS in the mechanism of PRG-induced cardiotoxicity, the protective potential of diminazene aceturate (DIZE), an ACE2 activator, was investigated. Results showed 44% decrease in ejection fraction and sevenfold increase in plasma N-terminal pro-brain natriuretic peptide. Histopathological examination also showed prominent vacuolar changes and edema in cardiomyocytes. In addition, PRG significantly increased angiotensin II (Ang II), angiotensin converting enzyme (ACE) and angiotensin II type 1 receptor (AT1R) levels, while decreased angiotensin 1-7 (Ang 1-7), angiotensin converting enzyme 2 (ACE2), and Mas receptor (MasR) cardiac levels. DIZE co-administration showed prominent protection against PRG-induced echocardiographic, neurohumoral, and histopathological alterations in rats. In addition, downregulation of ACE/Ang II/AT1R and upregulation of ACE2/Ang 1-7/MasR axes were noted in DIZE co-treated rats. These findings showed, for the first time, the detailed cardiac deleterious effects of PRG in rats. The underlying pathophysiological mechanism is probably mediated via altered balance between the RAS axes in favor to the ACE/Ang II/AT1R pathway. Accordingly, ACE2 activators might represent promising therapeutic agents for PRG-induced cardiotoxicity.

Mineralocorticoid Receptor Antagonist Utilization in a Nationally Representative Heart Failure With Reduced Ejection Fraction Outpatient Population: A Cross-Sectional Study.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) improve survival among patients with heart failure with reduced ejection fraction (HFrEF); however, studies have identified low utilization rates. No study has evaluated the prevalence and predictors of MRA prescribing in a nationally representative outpatient cohort. STUDY QUESTION: What is the prevalence and predictors of MRA prescribing among outpatients with HFrEF in the United States? STUDY DESIGN: A national cross-sectional secondary analysis of the National Ambulatory Medical Care Survey from 2007 to 2014 including all office visits for HFrEF in patients aged >55 years. Office visits involving patients with any history of chronic renal failure and hyperkalemia were excluded. MEASURES AND OUTCOMES: The primary end point was the MRA prescribing rate. Multivariable logistic regression models were created to identify predictors of use. RESULTS: In total, 1259 visits were eligible for inclusion, representing more than 30 million visits when weighted. MRAs were initiated or continued in 11.1% of HFrEF visits (95% confidence interval [CI] 8.8-13.8). In the full model, predictors included diabetes mellitus (OR 2.27; 95% CI 1.12-4.61), Northeast region (OR 0.20; 95% CI 0.05-0.74), and ≥4 chronic conditions (OR 0.26; 95% CI 0.10-0.71). Among symptomatic patients, predictors included non-Hispanic black patients (OR 4.55; 95% CI 1.81-11.43), patients aged 65-74 years (OR 3.38; 95% CI 1.53-7.44), and office systolic blood pressure >130 mm Hg (OR 0.31; 95% CI 0.16-0.60). Physician specialty, visit year, patient sex, and payor type were not significant predictors of MRA utilization. CONCLUSIONS: Although significant data support the use of MRA in HFrEF, utilization is lower than previously estimated.