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Real-World Safety of Sacubitril/Valsartan in Women and Men With Heart Failure and Reduced Ejection Fraction: A Meta-analysis

Open AccessPublished:September 14, 2021DOI:https://doi.org/10.1016/j.cjco.2021.09.009

      Abstract

      Background

      Sacubitril/valsartan (SV) is a novel and effective therapy for heart failure with reduced ejection fraction (HFrEF). Despite several sex-specific particularities that may influence drug effects, there has been no prior study evaluating the safety of SV in women with HFrEF in the “real-world.”

      Methods

      We performed a literature search to identify observational studies evaluating SV. We contacted all authors to obtain sex-specific data on major adverse outcomes. We compared all-cause and cardiovascular (CV) deaths, heart failure hospitalizations, hyperkalemia, and hypotension in men and women.

      Results

      We identified five cohort studies enrolling 8,981 patients; 6,092 men (67.8%) and 2,889 women (32.2%). The mean age was 67 years in both sexes. The rates for all-cause mortality, CV mortality, heart failure hospitalizations, hypotension, and hyperkalemia were similar between women and men. Although the unadjusted aggregate rates of all-cause and CV mortalities were numerically higher in men than in women, these differences did not reach statistical differences.

      Conclusion

      Our meta-analysis showed similar rates of major adverse events in men and women with HFrEF treated with SV. Larger observational studies with longer duration and a higher number of women are needed to confirm the long-term safety of SV in women in the clinical practice.

      Résumé

      Contexte

      Le sacubitril/valsartan (SV) est un médicament novateur et efficace contre l’insuffisance cardiaque à fraction d’éjection réduite (ICFER). Malgré le fait que plusieurs particularités sexospécifiques peuvent influencer les effets du médicament, aucune étude préalable n’a été menée pour évaluer l’innocuité du SV chez les femmes atteintes d’ICFER dans la "vraie vie".

      Méthodologie

      Nous avons effectué une recherche de la littérature pour recenser les études observationnelles évaluant le SV Nous avons communiqué avec tous les auteurs pour obtenir des données sexospécifiques sur les principaux issus défavorables. Nous avons comparé les données sur les décès toutes causes confondues et les décès d’origine cardiovasculaire (CV), les hospitalisations pour cause d’insuffisance cardiaque, l’hyperkaliémie et l’hypotension tant chez les hommes que chez les femmes.

      Résultats

      Nous avons recensé cinq études de cohortes auxquelles ont participé 8 981 patients, soit 6 092 hommes (67,8 %) et 2 889 femmes (32,2 %). L’âge moyen était de 67 ans chez les patients des deux sexes. Les taux de décès toutes causes confondues, de décès d’origine CV, d’hospitalisation pour cause d’insuffisance cardiaque, d’hypotension et d’hyperkaliémie chez les femmes étaient similaires à ceux notés chez les hommes. Les taux globaux non ajustés de décès toutes causes confondues et de décès d’origine CV étaient numériquement plus élevés chez les hommes que chez les femmes, mais il n’y avait pas de différence sur le plan statistique.

      Conclusion

      Notre méta-analyse a mis en évidence des taux similaires d’événements indésirables majeurs chez les hommes et chez les femmes atteints d’ICFER traités par le SV. Des études observationnelles à plus grande échelle avec de plus longue durée et un nombre plus élevé de femmes devront être menées pour confirmer l’innocuité à long terme du SV en pratique clinique chez les femmes.
      Sacubitril/valsartan (SV) is the first commercially available angiotensin receptor–neprilysin inhibitor
      • Gu J.
      • Noe A.
      • Chandra P.
      • al-Fayoumi S.
      • et al.
      Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor and neprilysin inhibitor.
      approved by the US Food and Drug Administration in 2015.
      ENTRESTO (saubitril and valsartan)
      Food and Drug Administration Website.
      SV is superior to renin-angiotensin-aldosterone inhibition alone in reduction of all-cause and cardiovascular (CV) mortality in patients who have heart failure with reduced ejection fraction (HFrEF).
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ,
      • Nielsen E.E.
      • Feinberg J.B.P.
      • Bu F.L.
      • et al.
      Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.
      In patients with heart failure and preserved left ventricle ejection fraction, SV tended to be more effective in women compared with men.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      ,
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      It remains unclear whether SV has different efficacy and effectiveness in women and men with HFrEF.
      Moreover, the applicability of findings from randomized control trials (RCT) to the real-world setting may be limited, as women were generally underrepresented in most HFrEF trials.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Nielsen E.E.
      • Feinberg J.B.P.
      • Bu F.L.
      • et al.
      Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure.
      • Pascual-Figal D.
      • Wachter R.
      • Senni M.
      • et al.
      NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
      Furthermore, women with HFrEF are generally older and with more comorbidities than men with HFrEF.
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women.
      Outside the clinical trial context, SV may be less well tolerated in women than in men. Nordberg Backelin et al.
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      reported that women were at increased risk of SV discontinuation compared with men. Consequently, we aim to compare the safety of SV in women to men with HFrEF in a meta-analysis of observational studies.

      Methods

      We performed a meta-analysis of observational studies, according to the standards detailed by the Preferred Reporting Items for Systemic Review and Meta-Analyses statement.
      • Rethlefsen M.L.
      • Kirtley S.
      • Waffenschmidt S.
      • et al.
      for the PRISMA-S Group. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.
      The conceptual basis of our search was sacubitril/valsartan or Entresto and heart failure. We searched the following electronic databases: Pubmed, Google Scholar, and Embase from July 2015 (date of US Food and Drug Administration Act’s approval of Entresto [the commercial name of SV]) to 31 August 2020. We conducted searches using subject terms and keywords searching. We used the following MESH terms and title/abstract search terms:
      ((("heart failure"[MeSH Terms] AND ("sacubitril valsartan"[Title/Abstract] OR "Entresto"[Title/Abstract]) AND ("registries"[MeSH Terms] OR "cohort studies"[MeSH Terms] OR "observational"[Title/Abstract])) OR ("female"[MeSH Terms] OR "women"[Title/Abstract])) AND "reduced ejection fraction"[Title/Abstract]) AND (2015:2020[pdat]) We did not apply any language restriction.
      We included all cohorts with available cardiovascular outcomes in HFrEF patients treated with SV for women and men separately. We excluded review articles, case reports, meeting abstracts, and duplicates. We also examined all references of fully reviewed manuscripts to ensure retrieval of all potentially relevant articles. Two readers independently reviewed the selected studies and completed data extraction (K.N. and T.H.). We evaluated individual studies for biases (Newcastle-Ottawa scale)
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012.
      (Supplemental Table S1). We resolved conflicts by consensus. For studies that did not report sex-specific outcomes, we contacted the individual investigators to obtain sex-specific data.
      For data analysis, we used the longest follow-up period provided in the included studies. We computed the weighted mean age, proportions of diabetes mellitus (DM), hypertension, heart failure hospitalization (HFH), all-cause mortality, CV mortality, hyperkalemia (serum potassium > 5.5 mEq/L), and hypotension (systolic blood pressure < 90 mm Hg). We compared the odds ratios of all major adverse events in women to men by random-effects model SAS version 9.4.

      Results

      We retrieved a total of 577 citations, evaluated 95 abstracts, and thoroughly reviewed 24 pertinent manuscripts. Of the reviewed manuscripts, 10 studies were relevant for inclusion. We contacted the 10 authors for sex-specific data. The final analysis included 5 observational studies for which sex-specific data could be provided.
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      • Rethlefsen M.L.
      • Kirtley S.
      • Waffenschmidt S.
      • et al.
      for the PRISMA-S Group. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      Of these studies, 2 were prospective
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      ,
      • Rethlefsen M.L.
      • Kirtley S.
      • Waffenschmidt S.
      • et al.
      for the PRISMA-S Group. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.
      and 3 were retrospective cohorts.
      • Wells G.A.
      • Shea B.
      • O’Connell D.
      • et al.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      We presented the selection of studies in Figure 1, their designs in Supplemental Table S1 and their qualities in Supplemental Table S2. All studies were of high quality and did not have any major bias that could affect substantively the results.
      Figure thumbnail gr1
      Figure 1Selection of studies. RCT, randomized controlled trials.
      There were 8,981 patients enrolled in these registries; 6,092 men (67.8%) and 2,889 women (32.2%). The definition of HFrEF varied across the included studies: The cohorts of Vicent et al.
      • Vicent L.
      • Ayesta A.
      • Esteban-Fernández A.
      Sex influence on the efficacy and safety of sacubitril/valsartan.
      and Tan et al.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      included patients with left ventricular ejection fraction (LVEF ) ≤45%, Nordberg Backelin et al.
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      and Russo et al.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      enrolled patients with LVEF ≤ 40%, and the study of Martens et al.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      included patients with LVEF ≤ 35%.
      We summarized the patients' baseline clinical features in Table 1. The weighted mean age was 67.6 ± 5.3 years and 67.5 ± 5.1 years in women and men, respectively. The baseline characteristics and concomitant HF pharmacotherapies were comparable in both sexes. Most of the patients were on β-blockers. The uses of mineralocorticosteroid antagonists were variable among the cohorts with rates as low as 36%
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      to as high as 93%.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      We presented other important comorbidities (pooled for women and men) in Supplemental Table S3.
      Table 1Baseline characteristics and heart failure pharmacotherapies
      Year of publicationMartens et al.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      Vicent et al.
      • Vicent L.
      • Ayesta A.
      • Esteban-Fernández A.
      Sex influence on the efficacy and safety of sacubitril/valsartan.
      Nordberg Backelin et al.
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      Russo et al.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      Tan et al.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      Total
      20192019202020202020
      SexM

      N = 309
      F

      N = 92
      M

      N = 301
      F

      N = 126
      M

      N = 75
      F

      N = 20
      M

      N = 141
      F

      N = 26
      M

      N = 5,268
      F

      N = 2,625
      M

      N = 6,094
      F

      N = 2,889
      Mean age (SD)68 (11.0)69 (12.0)67.8 (12.1)68.8 (13.2)65.3 (12.1)65.9 (12.5)69.0 (13.0)66.0 (9.0)67.8 (11.8)69.2 (12.3)67.6 (5.3)67.5 (5.1)
      Diabetes mellitus, %28.028.041.535.728.025.029.826.054.054.036.1 (23.8, 50.5)
      % (95% confidence intervals).
      55.4 (10.7, 92.8)
      % (95% confidence intervals).
      Hypertension, %55.054.077.765.934.725.052.540.093.092.366.8 (33.1, 89.1)
      % (95% confidence intervals).
      64.5 (18.9, 93.4)
      % (95% confidence intervals).
      β-blockers, %NANA93.088.089.487.097.910087.3 combined for both sexesNA
      Not available due to limited studies with small numbers of patients .
      NA
      Not available due to limited studies with small numbers of patients .
      Mineralocorticoid antagonists, %NANA61.565.046.335.589.492.336.2 combined for both sexesNA
      Not available due to limited studies with small numbers of patients .
      NA
      Not available due to limited studies with small numbers of patients .
      Maximal doses of sacubitril/valsartan, %NANA10.99.564.855.656.057.7NANANA
      Not available due to limited studies with small numbers of patients .
      NA
      Not available due to limited studies with small numbers of patients .
      NA, Not available, SD, standard deviation.
      % (95% confidence intervals).
      Not available due to limited studies with small numbers of patients .
      The follow-up ranged from 2 to 12 months, with approximately half of the patients (48.7%) followed up for 5 months. We presented the pooled incidence rates of major adverse outcomes in Table 2. The pooled all-cause mortality rates were 3.6% and 2.1% for men and women, respectively. The pooled mean rates of hyperkalemia and hypotension were low at 2.1% and 3.6% for men, respectively, and 2.3% and 5.0% for women, respectively.
      Table 2Incidences of major adverse outcomes by individual study
      Martens et al.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      Vicent et al.
      • Vicent L.
      • Ayesta A.
      • Esteban-Fernández A.
      Sex influence on the efficacy and safety of sacubitril/valsartan.
      Nordberg Backelin et al.
      • Nordberg Backelin C.
      • Fu M.
      • Ljungman C.
      Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
      Russo et al.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      Tan et al.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      Total
      SexM

      N = 309
      F

      N = 92
      M

      N = 301
      F

      N = 126
      M

      N = 75
      F

      N = 20
      M

      N = 141
      F

      N = 26
      M

      N = 5,268
      F

      N = 2,625
      M

      N = 6,092
      F

      N = 2,889
      Duration of follow-up, mo1271212Mean, 6.3
      Heart failure hospitalization, %7.07.0NANA26.720.01.47.77.89.09.2 (1.7, 36.6)
      % (95% confidence intervals.
      9.2 (7.6, 11.1)
      % (95% confidence intervals.
      All-cause mortality, %5.01.03.02.310.715.02.13.82.22.03.6 (1.8, 7.4)
      % (95% confidence intervals.
      2.1 (1.5, 3.0)
      % (95% confidence intervals.
      Cardiovascular mortality, %4.01.02.70.8NANA1.43.8NANA2.9 (1.2, 7.1)
      % (95% confidence intervals.
      1.2 (0.1, 13.2)
      % (95% confidence intervals.
      Hyperkalemia, %4.02.27.310.316.015.00.73.80.40.52.1 (0.3, 11.7)
      % (95% confidence intervals.
      2.3 (0.5, 10.2)
      % (95% confidence intervals.
      Hypotension, %0.61.116.316.78.010.03.53.81.71.73.6 (0.8, 14.1)
      % (95% confidence intervals.
      5.0 (1.2, 18.9)
      % (95% confidence intervals.
      NA, not available.
      % (95% confidence intervals.
      We presented the forest plots comparing all-cause and CV mortalities, hypotension, worsening renal function and hyperkalemia in men and women in Figure 2, Figure 3, Figure 4. There was no significant heterogeneity in all outcomes evaluated. The odds for all-cause mortality, CV mortality, HFH, hypotension, and hyperkalemia were similar between women and men (Figure 2, Figure 3, Figure 4). Both hyperkalemia and symptomatic hypotension were infrequent and occurred at similar frequencies in both sexes. Although the unadjusted rates of all-cause and CV mortalities were numerically higher in men, these differences did not reach statistical differences. For partial adjustment of the variable duration of follow-up between studies, we compared projected incidence rates of adverse outcomes per 100 person-years between men and women (Supplemental Table S4).
      Figure thumbnail gr2
      Figure 2Forest plot comparing all-cause mortality and cardiovascular mortality in women and men treated with sacubitril/valsartan. I2 is 0% for all-cause mortality and 2.23% for cardiovascular mortality. CI, confidence interval; LCI, lower bound of the confidence interval; OR, odds ratio, UCI, upper bound of the confidence interval.
      Figure thumbnail gr3
      Figure 3Forest plot comparing hyperkalemia in women and men treated with sacubitril/valsartan. I2 is 0% for all-cause mortality and 2.23% for cardiovascular mortality. CI, confidence interval; LCI, lower bound of the confidence interval; OR, odds ratio, UCI, upper bound of the confidence interval.
      Figure thumbnail gr4
      Figure 4Forest plot comparing hypotension in women and men treated with sacubitril/valsartan. I2 is 0% for all-cause mortality and 2.23% for cardiovascular mortality. CI, confidence interval; LCI, lower bound of the confidence interval; OR, odds ratio, UCI, upper bound of the confidence interval.
      We also completed sensitivity analyses with fixed-effect models, which may be more sensitive to small differences (Supplemental Table S5). The results of these models were similar to those with random-effect models except for higher I-squared suggesting heterogeneity for CV mortality and HFH (Supplemental Table S5). Additionally, Breslow-Day, Cochran’s Q did not detect any significant heterogeneity (Supplemental Table S5).

      Discussion

      Our meta-analysis showed that women with HFrEF treated with SV had similar all-cause mortality, CV mortality, hyperkalemia, and hypotension as men with HFrEF treated with sacubitril-valsartan. The adverse events were infrequent in both men and women in the real world and comparable to the findings of the pivotal trials.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Nielsen E.E.
      • Feinberg J.B.P.
      • Bu F.L.
      • et al.
      Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure.
      • Pascual-Figal D.
      • Wachter R.
      • Senni M.
      • et al.
      NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
      Overall, our results suggested that the safety with SV can be replicated outside the clinical trial context.
      Current heart failure guidelines
      • Yancy C.W.
      • Jessup M.
      • Bozkurt B.
      • et al.
      ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.
      ,
      • McDonald M.
      • Virani S.
      • Chan M.
      • et al.
      CCS/CHFS Heart Failure Guidelines Update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
      recommended sex-neutral target dose recommendations for SV. The Food and Drug Act
      ENTRESTO (saubitril and valsartan)
      Food and Drug Administration Website.
      did not provide any sex-specific recommendations for SV (apart from a warning of potential fetal toxicity in pregnant women and advised discontinuation of SV in breastfeeding women). However, women have several biological characteristics that may influence the pharmacodynamic and pharmacokinetic of SV.
      • Regitz-Zagrosek V.
      Therapeutic implications of the gender-specific aspects of cardiovascular disease.
      ,
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      Women have reduced body weight, hepatic flow, glomerular filtration rate, plasma volume, and a higher proportion of body fat compared with men.
      • Regitz-Zagrosek V.
      Therapeutic implications of the gender-specific aspects of cardiovascular disease.
      ,
      • Rosano G.M.
      • Lewis B.
      • Agewall S.
      • et al.
      Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
      In particular, women can have high peak plasma concentrations with hydrophilic medication such as SV.
      • Soldin O.P.
      • Mattison D.R.
      Sex differences in pharmacokinetics and pharmacodynamics.
      ,
      • Whitley H.P.
      • Smith W.D.
      Sex-based differences in medications for heart failure.
      The above differences in drug metabolism between women and men emphasize the need for a detailed evaluation of SV in women with HFrEF.
      • Whitley H.P.
      • Smith W.D.
      Sex-based differences in medications for heart failure.
      The proportion of women and the mean age of patients in our observational studies were analogous to those of the landmark studies of SV in HFrEF.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      • Nielsen E.E.
      • Feinberg J.B.P.
      • Bu F.L.
      • et al.
      Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure.
      • Pascual-Figal D.
      • Wachter R.
      • Senni M.
      • et al.
      NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
      The prevalences of hypertension and DM were comparable between the cohorts of the observational studies
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women.
      ,
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      • Vicent L.
      • Ayesta A.
      • Esteban-Fernández A.
      Sex influence on the efficacy and safety of sacubitril/valsartan.
      and those enrolled in the Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure (PARADIGM-HF) trial.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      The overall similarities in the mean age, DM, and hypertension in the cohort studies and RCTs were reassuring and suggested that the benefits of SV shown in the RCTs may be extrapolated to the real world. All-cause mortality was infrequent and comparable to the mortality rates reported in the RCTs evaluating SV with short follow-up durations (Comparison of Pre-discharge and Post-Discharge Treatment Initiation of LCZ696 in Heart Failure Patients With Reduced Ejection-Fraction After an Acute Decompensation Event [TRANSITION] and Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure [PIONEER-HF]).
      • Velazquez E.J.
      • Morrow D.A.
      • DeVore A.D.
      • et al.
      Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure.
      ,
      • Pascual-Figal D.
      • Wachter R.
      • Senni M.
      • et al.
      NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
      The potential superiority in mortality reduction of SV in women compared with men with HF and preserved ejection fraction in the PARAGON-HF trial suggested that this drug may have a differential sex-specific impact.
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      ,
      • McMurray J.J.V.
      • Jackson A.M.
      • Lam C.S.P.
      • et al.
      Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
      There was no sex-interaction noted with SV mortality reduction in the PARADIGM trial.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      It is of note that our sample size of 2,889 women exceeded the 879 women enrolled in the PARADIGM-HF trial.
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      Notwithstanding the lack of significance, all-cause and CV mortalities were numerically lower in women compared with men in our meta-analysis. The short follow-up of the included studies may have limited our statistical power to detect significant differences in mortalities between the men and women.
      Hypotension was infrequent and slightly higher in women in the observational studies. Its incidence was comparable to the rate observed in the PARADIGM-HF trial when limited to hypotension defined as systolic blood pressure of less than 90 mm Hg. In the observational studies, hyperkalemia was rare and similar between men and women. The markedly reduced incidence of hyperkalemia in our meta-analysis of observational studies compared to hyperkalemia observed in the RCTs (2% vs 12%),
      • McMurray J.J.
      • PackerM
      • Desai A.S.
      • et al.
      for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      ,
      • Solomon S.D.
      • McMurray J.J.V.
      • Anand I.S.
      • et al.
      Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
      may reflect less frequent serum potassium monitoring outside the RCT context. The low incidence of clinically significant hyperkalemia in the observational studies was reassuring, considering the appropriate use of concomitant mineralo-corticosteroid antagonists in these cohorts, with rates as high as 93% in one cohort.
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      Approximately 9% of patients in the pooled cohort studies had at least 1 HFH. This incidence was similar between the 2 sexes and comparable with the incidence reported in the PIONEER-HF trial.
      • Pascual-Figal D.
      • Wachter R.
      • Senni M.
      • et al.
      NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
      Finally, we could not ascertain accurately the incidence of worsening renal function, as there were only 3 studies that reported this endpoint in 661 patients.
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women.
      ,
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      ,
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.

      Limitations

      Our meta-analysis has some limitations worth addressing. First, all meta-analyses are subject to publication bias. It was possible that despite an extensive search, we may have missed important cohort studies evaluating the safety of SV. Furthermore, we could not obtain sex-specific data from five observational studies evaluating SV. However, these studies were small with their combined number of patients totaling only 716 and followed only for 7 months. Therefore, it would be unlikely that inclusion of these studies would substantially alter our findings. Second, because of the novelty of SV as a therapy for HFrEF, the number of studies with sufficient data to be included was modest. Accordingly, the power of our meta-analysis to detect meaningful differences in adverse outcomes between the 2 sexes was limited. Third, we did not obtain individual patient data. Therefore, we could not adjust for patient-level characteristics. Fourth, all of our studies were completed in countries with predominant white populations.
      • Mentzer G.
      • Hsich E.M.
      Heart failure with reduced ejection fraction in women.
      ,
      • Russo V.
      • Bottino R.
      • Rago A.
      • et al.
      The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
      • Martens P.
      • Nuyens D.
      • Rivero-Ayerza M.
      • et al.
      Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      • Vicent L.
      • Ayesta A.
      • Esteban-Fernández A.
      Sex influence on the efficacy and safety of sacubitril/valsartan.
      Consequently, our findings could not be extrapolated to other races. Finally, although we did not explicitly evaluate the short-term safety outcomes of SV therapy, the incidences of long-term safety outcomes did include the short-term adverse outcomes.

      Conclusion

      The safety of SV is similar in women and men in the real world and comparable to that in the RCTs. Future observational studies with a larger number of women and of longer duration are needed to confirm the long-term safety of SV in women in the clinical practice.

      Acknowledgements

      The authors thank Dr Shannon Dunlay for providing sex-specific data of the study by Tan et al.
      • Tan N.Y.
      • Lindsey R.
      • Sangaralingham S.
      • et al.
      Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
      to be included in this report.

      Funding sources

      There was no funding provided for this meta-analysis.

      Disclosures

      Dr Pieter Martens has received consultancy fees and unrestricted research grants from Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Novartis, Novo Nordisk and Vifor pharma. Dr Thao Huynh received research grants from Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Novartis and Pfizer. The other authors do not have any pertinent conflicts of interest to disclose.

      Supplementary Material

      References

        • Gu J.
        • Noe A.
        • Chandra P.
        • al-Fayoumi S.
        • et al.
        Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor and neprilysin inhibitor.
        J Clin Pharmacol. 2010; 50: 401-414
        • ENTRESTO (saubitril and valsartan)
        Food and Drug Administration Website.
        (Accessed April 6, 2020)
        • McMurray J.J.
        • PackerM
        • Desai A.S.
        • et al.
        for the PARADIGME Investigators Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • Nielsen E.E.
        • Feinberg J.B.P.
        • Bu F.L.
        • et al.
        Beneficial and harmful effects of sacubitril/valsartan in patients with heart failure: a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis.
        Open Heart. 2020; 7e001294
        • Solomon S.D.
        • McMurray J.J.V.
        • Anand I.S.
        • et al.
        Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction.
        N Engl J Med. 2019; 381: 1609-1620
        • McMurray J.J.V.
        • Jackson A.M.
        • Lam C.S.P.
        • et al.
        Effects of sacubitril-valsartan versus valsartan in women compared with men with heart failure and preserved ejection fraction.
        Circulation. 2020; 141: 338-351
        • Velazquez E.J.
        • Morrow D.A.
        • DeVore A.D.
        • et al.
        Angiotensin–Neprilysin Inhibition in Acute Decompensated Heart Failure.
        N Engl J Med. 2019; 380: 539-548
        • Pascual-Figal D.
        • Wachter R.
        • Senni M.
        • et al.
        NT-proBNP response to sacubitril/valsartan in hospitalized heart failure patients with reduced ejection fraction.
        JACC Heart Fail. 2020; 8: 822-833
        • Mentzer G.
        • Hsich E.M.
        Heart failure with reduced ejection fraction in women.
        Heart Fail Clin. 2019; 15: 19-27
        • Nordberg Backelin C.
        • Fu M.
        • Ljungman C.
        Early experience of sacubitril-valsartan in heart failure with reduced ejection fraction in real-world clinical setting.
        ESC Heart Fail. 2020; 7: 1049-1055
        • Rethlefsen M.L.
        • Kirtley S.
        • Waffenschmidt S.
        • et al.
        for the PRISMA-S Group. PRISMA-S: an extension to the PRISMA Statement for Reporting Literature Searches in Systematic Reviews.
        Syst Rev. 2021; 10: 39
        • Wells G.A.
        • Shea B.
        • O’Connell D.
        • et al.
        The Newcastle-Ottawa Scale (NOS) for assessing the quality if nonrandomized studies in meta-analyses, 2012.
        • Russo V.
        • Bottino R.
        • Rago A.
        • et al.
        The effect of sacubitril/valsartan on device detected arrhythmias and electrical parameters among dilated cardiomyopathy patients with reduced ejection fraction and implantable cardioverter defibrillator.
        J Clin Med. 2020; 9: 1111
        • Martens P.
        • Nuyens D.
        • Rivero-Ayerza M.
        • et al.
        Sacubitril/valsartan reduces ventricular arrhythmias in parallel with left ventricular reverse remodeling in heart failure with reduced ejection fraction.
        Clin Res Cardiol. 2019; 108: 1074-1082
        • Tan N.Y.
        • Lindsey R.
        • Sangaralingham S.
        • et al.
        Comparative effectiveness of sacubitril-valsartan versus ACE/ARB therapy in heart failure with reduced ejection fraction.
        JACC Heart Fail. 2020; 8: 43-54
        • Vicent L.
        • Ayesta A.
        • Esteban-Fernández A.
        Sex influence on the efficacy and safety of sacubitril/valsartan.
        Cardiology. 2019; 142: 73-78
        • Yancy C.W.
        • Jessup M.
        • Bozkurt B.
        • et al.
        ACC/AHA/HFSA focused update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure.
        J Am Coll Cardiol. 2017; 70: 776-803
        • McDonald M.
        • Virani S.
        • Chan M.
        • et al.
        CCS/CHFS Heart Failure Guidelines Update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction.
        Can J Cardiol. 2021; 37: 531-546
        • Regitz-Zagrosek V.
        Therapeutic implications of the gender-specific aspects of cardiovascular disease.
        Nat Rev Drug Discov. 2006; 5: 425-438
        • Rosano G.M.
        • Lewis B.
        • Agewall S.
        • et al.
        Gender differences in the effect of cardiovascular drugs: a position document of the Working Group on Pharmacology and Drug Therapy of the ESC.
        Eur Heart J. 2015; 36: 2677-2680
        • Soldin O.P.
        • Mattison D.R.
        Sex differences in pharmacokinetics and pharmacodynamics.
        Clin Pharmacokinet. 2009; 48: 143-157
        • Whitley H.P.
        • Smith W.D.
        Sex-based differences in medications for heart failure.
        Lancet. 2019; 394: 1210-1212