RESEARCH LETTER
A significant dilemma in the treatment of heart failure patients with sacubitril/valsartan or sodium-glucose co-transporter 2 inhibitors: Whether to add mineralocorticoid receptor antagonists
Um importante dilema no tratamento da insuficiência cardíaca com sacubitril/valsartan ou com inibidores do cotransportador de glicose e sódio 2: adicionar ou não antagonistas dos recetores dos mineralocorticoides?
Dimitrios Patouliasa,
, Christodoulos Papadopoulosb, Konstantinos Stavropoulosa, Konstantinos Imprialosa, Aristi Boulmpoub, Michael Doumasa,c
Corresponding author
a Second Propedeutic Department of Internal Medicine, Aristotle University of Thessaloniki, General Hospital “Hippokration”, Greece
b Third Department of Cardiology, Aristotle University of Thessaloniki, General Hospital “Hippokration”, Greece
c Veterans Affairs Medical Center, George Washington University, Washington, District of Columbia, United States
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CI: confidence interval; M-H: Mantel-Haenszel; MRA: mineralocorticoid receptor agonist; SGLT2: sodium-glucose co-transporter 2.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Heart failure (HF) is associated with significant cardiovascular morbidity and mortality across all categories (with preserved, mid-range or reduced left ventricular ejection fraction). Recently introduced drug classes, especially sodium-glucose co-transporter 2 (SGLT2) inhibitors and angiotensin receptor-neprilysin inhibitors (sacubitril/valsartan), have provided significant cardiovascular benefits for subjects with HF, as shown in recent hallmark trials, and represent a step forward in the therapeutic management of these patients.<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">1,2</span></a> These drug classes have accordingly been prioritized in the treatment algorithm of patients with HF, especially for those with reduced ejection fraction, according to the latest HF guidelines published by the European Society of Cardiology.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">3</span></a> At the same time, mineralocorticoid receptor agonists (MRAs) constitute a drug class with established cardioprotective action in patients with HF. We therefore sought to determine whether combining SGLT2 inhibitors or sacubitril/valsartan and MRAs leads to a further decrease in the risk for surrogate cardiovascular endpoints among patients with HF.</p><p id="par0010" class="elsevierStylePara elsevierViewall">We searched PubMed for randomized controlled trials (RCTs) assessing the effect on surrogate cardiovascular endpoints of SGLT2 inhibitors and sacubitril/valsartan versus placebo or active comparator among subjects with HF. We extracted data corresponding to subgroup analyses according to prior treatment with MRAs. We set as the primary endpoint the composite of hospitalization for HF or cardiovascular death.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Two reviewers (D.P. and C.P.) independently extracted data of interest from the eligible studies. As we assessed only a dichotomous variable, differences were calculated with the use of risk ratios (RR) with 95% confidence interval (CI), after implementation of the Mantel-Haenszel random effects model. Statistical heterogeneity among studies was assessed by means of I2 statistics. All analyses were performed at the 0.05 significance level.</p><p id="par0020" class="elsevierStylePara elsevierViewall">We finally included five RCTs in our analysis, of which three assessed the cardiovascular efficacy and safety of SGLT2 inhibitors compared to placebo and two addressed the cardiovascular efficacy and safety of sacubitril/valsartan versus enalapril or valsartan.<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">4–8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">We pooled data on a total of 14 462 subjects with HF assigned to either an SGLT2 inhibitor or placebo and 13 195 subjects with HF randomized to either sacubitril/valsartan or a renin-angiotensin system (RAS) blocker.</p><p id="par0030" class="elsevierStylePara elsevierViewall">As shown in <a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>, prior treatment with an MRA did not affect the cardiovascular efficacy of SGLT2 inhibitors compared to placebo: patients receiving a combination of an SGLT2 inhibitor and an MRA experienced a 21% decrease in the risk for the primary composite endpoint (RR=0.79, 95% CI: 0.73-0.87, I2=0%), while patients without prior use of MRAs assigned to an SGLT2 inhibitor experienced a 22% decrease in the risk for the same endpoint (RR=0.78, 95% CI: 0.69-0.87, I2=0%). No difference between subgroups was detected (p=0.74).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0035" class="elsevierStylePara elsevierViewall">When we assessed the cardiovascular efficacy of sacubitril/valsartan versus RAS blockers (<a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>), we found that the combination of sacubitril/valsartan and an MRA compared to the combination of a RAS blocker and an MRA led to a significant 13% decrease in the risk for the primary composite endpoint (RR=0.87, 95% CI: 0.80-0.95, I2=0%). However, among patients without prior use of MRAs, sacubitril/valsartan was not superior to RAS blockers in decreasing the risk for cardiovascular death or hospitalization for heart failure (RR=0.86, 95% CI: 0.68-1.10, I2=88%). Once again, no subgroup difference was detected (p=0.94).</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0040" class="elsevierStylePara elsevierViewall">Overall, although reasonable, a treatment combination of SGLT2 inhibitors or sacubitril/valsartan with MRAs does not provide additional cardiovascular benefits for patients with HF with reduced or preserved ejection fraction. Potentially synergistic effects of these drug classes are yet to be confirmed.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0045" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:2 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1202 "Ancho" => 2508 "Tamanyo" => 322541 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Effect of sodium-glucose co-transporter 2 inhibitors compared to placebo on the risk for the primary composite endpoint according to prior use of mineralocorticoid receptor agonists. CI: confidence interval; LCZ696: sacubitril/valsartan; M-H: Mantel-Haenszel; MRA: mineralocorticoid receptor agonist.</p>" ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1186 "Ancho" => 2508 "Tamanyo" => 328318 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Effect of sacubitril/valsartan compared to active comparator on the risk for the primary composite endpoint according to prior use of mineralocorticoid receptor agonists. CI: confidence interval; M-H: Mantel-Haenszel; MRA: mineralocorticoid receptor agonist; SGLT2: sodium-glucose co-transporter 2.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:8 [ 0 => array:3 [ "identificador" => "bib0045" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Optimization of heart failure with reduced ejection fraction prognosis-modifying drugs: a 2021 heart failure expert consensus paper" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "J. Silva-Cardoso" 1 => "C. Fonseca" 2 => "F. 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Gong" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1161/CIRCHEARTFAILURE.116.003212" "Revista" => array:5 [ "tituloSerie" => "Circ Heart Fail" "fecha" => "2016" "volumen" => "9" "paginaInicial" => "e003212" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27618854" "web" => "Medline" ] ] ] ] ] ] ] ] ] ] ] ] ] "idiomaDefecto" => "en" "url" => "/08702551/0000004100000008/v2_202209110531/S0870255122001986/v2_202209110531/en/main.assets" "Apartado" => array:4 [ "identificador" => "94043" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Research Letter" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/08702551/0000004100000008/v2_202209110531/S0870255122001986/v2_202209110531/en/main.pdf?idApp=UINPBA00004E&text.app=https://revportcardiol.org/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122001986?idApp=UINPBA00004E" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 October | 25 | 16 | 41 |
| 2024 September | 70 | 27 | 97 |
| 2024 August | 68 | 35 | 103 |
| 2024 July | 68 | 38 | 106 |
| 2024 June | 51 | 35 | 86 |
| 2024 May | 51 | 23 | 74 |
| 2024 April | 63 | 29 | 92 |
| 2024 March | 54 | 31 | 85 |
| 2024 February | 47 | 36 | 83 |
| 2024 January | 56 | 24 | 80 |
| 2023 December | 43 | 28 | 71 |
| 2023 November | 65 | 59 | 124 |
| 2023 October | 43 | 28 | 71 |
| 2023 September | 44 | 36 | 80 |
| 2023 August | 38 | 12 | 50 |
| 2023 July | 49 | 15 | 64 |
| 2023 June | 35 | 15 | 50 |
| 2023 May | 58 | 33 | 91 |
| 2023 April | 35 | 13 | 48 |
| 2023 March | 54 | 34 | 88 |
| 2023 February | 43 | 21 | 64 |
| 2023 January | 51 | 23 | 74 |
| 2022 December | 71 | 24 | 95 |
| 2022 November | 55 | 28 | 83 |
| 2022 October | 81 | 33 | 114 |
| 2022 September | 68 | 67 | 135 |
| 2022 August | 127 | 93 | 220 |
| 2022 July | 76 | 41 | 117 |
| 2022 June | 142 | 63 | 205 |
| 2022 May | 39 | 23 | 62 |
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