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Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.
Ehteshami-Afshar, S, Mooney, L, Dewan, P, Desai, AS, Lang, NN, Lefkowitz, MP, Petrie, MC, Rizkala, AR, Rouleau, JL, Solomon, SD, et al
Journal of the American Heart Association. 2021;(4):e019238
Abstract
Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.
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Efficacy and safety of sacubitril/valsartan compared with enalapril in patients with chronic heart failure and reduced ejection fraction: Results from PARADIGM-HF India sub-study.
Jain, AR, Aggarwal, RK, Rao, NS, Billa, G, Kumar, S
Indian heart journal. 2020;(6):535-540
Abstract
OBJECTIVES To determine efficacy and safety of sacubitril/valsartan compared with enalapril in Indian patients of PARADIGM-HF trial. METHODS A randomized, double-blind, active-controlled, phase III sub-study (NCT01035255) was conducted between April 2010 and May 2014. Patients with chronic heart failure (HF), aged >18 years with left ventricular ejection fraction ≤40% were randomized (1:1) to receive either sacubitril/valsartan 200 mg twice-daily or enalapril 10 mg twice-daily. The primary endpoint was to compare efficacy of sacubitril/valsartan to enalapril in delaying time-to-first occurrence of the composite endpoint (cardiovascular [CV] death or HF hospitalization). RESULTS The trial was stopped after a median follow-up of 27 months, because the boundary for benefit with sacubitril/valsartan had crossed. Among 637 Indian patients in PARADIGM-HF (sacubitril/valsartan, n = 322 and enalapril, n = 315), the primary outcome, CV death, and the first hospitalization for HF occurred in 21.81% and 24.76% (HR 0.89; 95% CI, 0.646-1.231), 17.45% and 20.63% (HR 0.87; 95% CI, 0.605-1.236), and 7.48% and 9.52% (HR 0.78; 95% CI, 0.461-1.350) patients in the sacubitril/valsartan and enalapril group, respectively. The all-cause mortality (19.0% vs. 21.9%) and adverse events (78.4% vs. 82.2%) were comparatively lower in the sacubitril/valsartan than enalapril group. No significant difference was seen between the benefits of treatment in Indian and the total PARADIGM-HF cohort (p value for interaction >0.05). CONCLUSION Results support the use of sacubitril/valsartan in Indian patients with chronic HF with reduced ejection fraction with treatment benefits similar to global PARADIGM-HF cohort.
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Clinical Outcomes in Patients With Acute Decompensated Heart Failure Randomly Assigned to Sacubitril/Valsartan or Enalapril in the PIONEER-HF Trial.
Morrow, DA, Velazquez, EJ, DeVore, AD, Desai, AS, Duffy, CI, Ambrosy, AP, Gurmu, Y, McCague, K, Rocha, R, Braunwald, E
Circulation. 2019;(19):2285-2288
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Effect of Smoking and Folate Levels on the Efficacy of Folic Acid Therapy in Prevention of Stroke in Hypertensive Men.
Zhou, Z, Li, J, Yu, Y, Li, Y, Zhang, Y, Liu, L, Song, Y, Zhao, M, Wang, Y, Tang, G, et al
Stroke. 2018;(1):114-120
Abstract
BACKGROUND AND PURPOSE We aimed to examine whether the efficacy of folic acid therapy in the primary prevention of stroke is jointly affected by smoking status and baseline folate levels in a male population in a post hoc analysis of the CSPPT (China Stroke Primary Prevention Trial). METHODS Eligible participants of the CSPPT were randomly assigned to a double-blind daily treatment of a combined enalapril 10-mg and folic acid 0.8-mg tablet or an enalapril 10-mg tablet alone. In total, 8384 male participants of the CSPPT were included in the current analyses. The primary outcome was first stroke. RESULTS The median treatment duration was 4.5 years. In the enalapril-alone group, the first stroke risk varied by baseline folate levels and smoking status (never versus ever). Specifically, there was an inverse association between folate levels and first stroke in never smokers (P for linear trend=0.043). However, no such association was found in ever smokers. A test for interaction between baseline folate levels and smoking status on first stroke was significant (P=0.045). In the total sample, folic acid therapy significantly reduced the risk of first stroke in never smokers with folate deficiency (hazard risk, 0.36; 95% confidence interval, 0.16-0.83) and in ever smokers with normal folate levels (hazard risk, 0.69; 95% confidence interval, 0.48-0.99). CONCLUSIONS Baseline folate levels and smoking status can interactively affect the risk of first stroke. Our data suggest that compared with never smokers, ever smokers may require a higher dosage of folic acid to achieve a greater beneficial effect on stroke. Our findings need to be confirmed by future randomized trials. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00794885.
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Rationale and design of the comParIson Of sacubitril/valsartaN versus Enalapril on Effect on nt-pRo-bnp in patients stabilized from an acute Heart Failure episode (PIONEER-HF) trial.
Velazquez, EJ, Morrow, DA, DeVore, AD, Ambrosy, AP, Duffy, CI, McCague, K, Hernandez, AF, Rocha, RA, Braunwald, E
American heart journal. 2018;:145-151
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Abstract
OBJECTIVE The objective is to assess the safety, tolerability, and efficacy of sacubitril/valsartan compared with enalapril in patients with heart failure (HF) with a reduced ejection fraction (EF) stabilized during hospitalization for acute decompensated HF. BACKGROUND Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitor, improves survival among ambulatory HF patients with a reduced EF. However, there is very limited experience with the in-hospital initiation of sacubitril/valsartan in patients who have been stabilized following hospitalization for acute decompensated HF. METHODS PIONEER-HF is a 12-week, prospective, multicenter, double-blind, randomized controlled trial enrolling a planned 882 patients at more than 100 participating sites in the United States. Medically stable patients >18 years of age with an EF <40% and an amino terminal-pro b-type natriuretic peptide >1600 pg/mL or b-type natriuretic peptide >400 pg/mL are eligible for participation no earlier than 24 hours and up to 10 days from initial presentation while still hospitalized. Patients are randomly assigned 1:1 to in-hospital initiation of sacubitril/valsartan titrated to 97/103 mg by mouth twice daily versus enalapril titrated to 10 mg by mouth twice daily for 8 weeks. All patients receive open-label treatment with sacubitril/valsartan for the remaining 4 weeks of the study. The primary efficacy end point is the time-averaged proportional change in amino terminal-pro b-type natriuretic peptide from baseline through weeks 4 and 8. Secondary and exploratory end points include serum and urinary biomarkers as well as clinical outcomes. Safety end points include the incidence of angioedema, hypotension, renal insufficiency, and hyperkalemia. CONCLUSION The PIONEER-HF trial will inform clinical practice by providing evidence on the safety, tolerability, and efficacy of in-hospital initiation of sacubitril/valsartan among patients who have been stabilized following an admission for acute decompensated HF with a reduced EF.
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Estimated 5-Year Number Needed to Treat to Prevent Cardiovascular Death or Heart Failure Hospitalization With Angiotensin Receptor-Neprilysin Inhibition vs Standard Therapy for Patients With Heart Failure With Reduced Ejection Fraction: An Analysis of Data From the PARADIGM-HF Trial.
Srivastava, PK, Claggett, BL, Solomon, SD, McMurray, JJV, Packer, M, Zile, MR, Desai, AS, Rouleau, JL, Swedberg, K, Fonarow, GC
JAMA cardiology. 2018;(12):1226-1231
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Abstract
IMPORTANCE The addition of receptor-neprilysin inhibition to standard therapy, including a renin-angiotensin system blocker, has been demonstrated to improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with standard therapy alone. The long-term absolute risk reduction from angiotensin receptor neprilysin inhibitor (ARNI) therapy, and whether it merits widespread use among diverse subpopulations, has not been well described. OBJECTIVE To calculate estimated 5-year number needed to treat (NNT) values overall and for different subpopulations for the Prospective Comparison of ARNI with Angiotensin-Converting Enzyme Inhibitor (ACEI) to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) cohort. DESIGN, SETTING, AND PARTICIPANTS Overall and subpopulation 5-year NNT values were estimated for different end points using data from PARADIGM-HF, a double-blind, randomized trial of sacubitril-valsartan vs enalapril. This multicenter, international study included 8399 men and women with HFrEF (ejection fraction, ≤40%). The study began in December 2009 and ended in March 2014. Analyses began in March 2018. INTERVENTIONS Random assignment to sacubitril-valsartan or enalapril. MAIN OUTCOMES AND MEASURES Cardiovascular death or HF hospitalization, cardiovascular death, and all-cause mortality. RESULTS The final cohort of 8399 individuals included 1832 women (21.8%) and 5544 white individuals (66.0%), with a mean (SD) age of 63.8 (11.4) years. The 5-year estimated NNT for the primary outcome of cardiovascular death or HF hospitalization with ARNI therapy incremental to ACEI therapy in the overall cohort was 14. The 5-year estimated NNT values were calculated for different clinically relevant subpopulations and ranged from 12 to 19. The 5-year estimated NNT for all-cause mortality in the overall cohort with ARNI incremental to ACEI was 21, with values ranging from 16 to 31 among different subgroups. Compared with imputed placebo, the 5-year estimated NNT for all-cause mortality with ARNI was 11. The 5-year estimated NNT values were also calculated for other HFrEF therapies compared with controls from landmark trials for all-cause mortality and were found to be 18 for ACEI, 24 for angiotensin receptor blockers, 8 for β-blockers, 15 for mineralocorticoid antagonists, 14 for implantable cardioverter defibrillator, and 14 for cardiac resynchronization therapy. CONCLUSIONS AND RELEVANCE The 5-year estimated NNT with ARNI therapy incremental to ACEI therapy overall and for clinically relevant subpopulations of patients with HFrEF are comparable with those for well-established HF therapeutics. These data further support guideline recommendations for use of ARNI therapy among eligible patients with HFrEF.
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Effect of sacubitril/valsartan on recurrent events in the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF).
Mogensen, UM, Gong, J, Jhund, PS, Shen, L, Køber, L, Desai, AS, Lefkowitz, MP, Packer, M, Rouleau, JL, Solomon, SD, et al
European journal of heart failure. 2018;(4):760-768
Abstract
AIMS: Recurrent hospitalizations are a major part of the disease burden in heart failure (HF), but conventional analyses consider only the first event. We compared the effect of sacubitril/valsartan vs. enalapril on recurrent events, incorporating all HF hospitalizations and cardiovascular (CV) deaths in PARADIGM-HF, using a variety of statistical approaches advocated for this type of analysis. METHODS AND RESULTS In PARADIGM-HF, a total of 8399 patients were randomized and followed for a median of 27 months. We applied various recurrent event analyses, including a negative binomial model, the Wei, Lin and Weissfeld (WLW), and Lin, Wei, Ying and Yang (LWYY) methods, and a joint frailty model, all adjusted for treatment and region. Among a total of 3181 primary endpoint events (including 1251 CV deaths) during the trial, only 2031 (63.8%) were first events (836 CV deaths). Among a total of 1195 patients with at least one HF hospitalization, 410 (34%) had at least one further HF hospitalization. Sacubitril/valsartan compared with enalapril reduced the risk of recurrent HF hospitalization using the negative binomial model [rate ratio (RR) 0.77, 95% confidence interval (CI) 0.67-0.89], the WLW method [hazard ratio (HR) 0.79, 95% CI 0.71-0.89], the LWYY method (RR 0.78, 95% CI 0.68-0.90), and the joint frailty model (HR 0.75, 95% CI 0.66-0.86) (all P < 0.001). The effect of sacubitril/valsartan vs. enalapril on recurrent HF hospitalizations/CV death was similar. CONCLUSIONS In PARADIGM-HF, approximately one third of patients with a primary endpoint (time-to-first) experienced a further event. Compared with enalapril, sacubitril/valsartan reduced both first and recurrent events. The treatment effect size was similar, regardless of the statistical approach applied.
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Health-Related Quality of Life Outcomes in PARADIGM-HF.
Lewis, EF, Claggett, BL, McMurray, JJV, Packer, M, Lefkowitz, MP, Rouleau, JL, Liu, J, Shi, VC, Zile, MR, Desai, AS, et al
Circulation. Heart failure. 2017;(8)
Abstract
BACKGROUND Patients with heart failure and reduced ejection fraction have impaired health-related quality of life (HRQL) with variable responses to therapies that target mortality and heart failure hospitalizations. In PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor-Neprilysin Inhibitor] With ACEI [Angiotensin-Converting-Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure), sacubitril/valsartan reduced morbidity and mortality compared with enalapril. Another major treatment goal is to improve HRQL. Given improvements in mortality with sacubitril/valsartan, this analysis provides comprehensive assessment of impact of therapy on HRQL in survivors only. METHODS AND RESULTS Patients (after run-in phase) completed disease-specific HRQL using Kansas City Cardiomyopathy Questionnaire (KCCQ) at randomization, 4 month, 8 month, and annual visits. Changes in KCCQ scores were calculated using repeated measures analysis of covariance model that adjusted for treatment and baseline values (principal efficacy prespecified at 8 months). Among the 8399 patients enrolled in PARADIGM-HF, 7623 (91%) completed KCCQ scores at randomization with complete data at 8 months for 6881 patients (90% of baseline). At 8 months, sacubitril/valsartan group noted improvements in both KCCQ clinical summary score (+0.64 versus -0.29; P=0.008) and KCCQ overall summary score (+1.13 versus -0.14; P<0.001) in comparison to enalapril group and significantly less proportion of patients with deterioration (≥5 points decrease) of both KCCQ scores (27% versus 31%; P=0.01). Adjusted change scores demonstrated consistent improvements in sacubitril/valsartan compared with enalapril through 36 months. CONCLUSIONS Change scores in KCCQ clinical summary scores and KCCQ overall summary scores were better in patients treated with sacubitril/valsartan compared with those treated with enalapril, with consistency in most domains, and persist during follow-up beyond 8 months. These findings demonstrate that sacubitril/valsartan leads to better HRQL in surviving patients with heart failure. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01035255.
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Optimal Systolic Blood Pressure Levels for Primary Prevention of Stroke in General Hypertensive Adults: Findings From the CSPPT (China Stroke Primary Prevention Trial).
Fan, F, Yuan, Z, Qin, X, Li, J, Zhang, Y, Li, Y, Yu, T, Ji, M, Ge, J, Zheng, M, et al
Hypertension (Dallas, Tex. : 1979). 2017;(4):697-704
Abstract
We aimed to investigate the relationship of time-averaged on-treatment systolic blood pressure (SBP) with the risk of first stroke in the CSPPT (China Stroke Primary Prevention Trial). A post hoc analysis was conducted using data from 17 720 hypertensive adults without cardiovascular disease, diabetes mellitus, and renal function decline from the CSPPT, a randomized double-blind controlled trial. The primary outcome was first stroke. Over a median follow-up duration of 4.5 years, the association between averaged on-treatment SBP and risk for first stoke followed a U-shape curve, with increased risk above and below the reference range of 120 to 130 mm Hg. Compared with participants with time-averaged on-treatment SBP at 120 to 130 mm Hg (mean, 126.2 mm Hg), the risk of first stroke was not only increased in participants with SBP at 130 to 135 mm Hg (mean, 132.6 mm Hg; 1.5% versus 0.8%; hazard ratio, 1.63; 95% confidence interval, 1.01-2.63) or 135 to 140 mm Hg (mean, 137.5 mm Hg; 1.9% versus 0.8%; hazard ratio, 1.85; 95% confidence interval, 1.17-2.93), but also increased in participants with SBP <120 mm Hg (mean, 116.7 mm Hg; 3.1% versus 0.8%; hazard ratio, 4.37; 95% confidence interval, 2.10-9.07). Similar results were found in various subgroups stratified by age, sex, and treatment group. Furthermore, lower diastolic blood pressure was associated with lower risk of stroke, with a plateau at a time-average on-treatment diastolic blood pressure <80 mm Hg. In conclusion, among adults with hypertension and without a history of stroke or myocardial infarction, diabetes mellitus, or renal function decline, a lower SBP goal of 120 to 130 mm Hg, as compared with a target SBP of 130 to 140 mm Hg or <120 mm Hg, resulted in the lowest risk of first stroke.
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The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF.
Mogensen, UM, Køber, L, Kristensen, SL, Jhund, PS, Gong, J, Lefkowitz, MP, Rizkala, AR, Rouleau, JL, Shi, VC, Swedberg, K, et al
American heart journal. 2017;:35-41
Abstract
BACKGROUND Angiotensin converting enzyme inhibitors (ACE-I), are beneficial both in heart failure with reduced ejection fraction (HF-REF) and after myocardial infarction (MI). We examined the effects of the angiotensin-receptor neprilysin inhibitor sacubitril/valsartan, compared with the ACE-I enalapril, on coronary outcomes in PARADIGM-HF. METHODS AND RESULTS We examined the effect of sacubitril/valsartan compared with enalapril on the following outcomes: i) the primary composite endpoint of cardiovascular (CV) death or HF hospitalization, ii) a pre-defined broader composite including, in addition, MI, stroke, and resuscitated sudden death, and iii) a post hoc coronary composite of CV-death, non-fatal MI, angina hospitalization or coronary revascularization. At baseline, of 8399 patients, 3634 (43.3%) had a prior MI and 4796 (57.1%) had a history of any coronary artery disease. Among all patients, compared with enalapril, sacubitril/valsartan reduced the risk of the primary outcome (HR 0.80 [0.73-0.87], P<.001), the broader composite (HR 0.83 [0.76-0.90], P<.001) and the coronary composite (HR 0.83 [0.75-0.92], P<.001). Although each of the components of the coronary composite occurred less frequently in the sacubitril/valsartan group, compared with the enalapril group, only CV death was reduced significantly. CONCLUSIONS Compared with enalapril, sacubitril/valsartan reduced the risk of both the primary endpoint and a coronary composite outcome in PARADIGM-HF. Additional studies on the effect of sacubitril/valsartan on atherothrombotic outcomes in high-risk patients are merited.