Editorial comment
On the trail of the perfect prognosticator in advanced heart failure patients
À procura do melhor preditor de eventos em doentes com insuficiência cardíaca avançada
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Group 1: up to one abnormal parameter; group 2: two abnormal parameters; group 3: three abnormal parameters. CI: 95% confidence interval; ISHLT: International Society for Heart and Lung Transplantation; VCO<span class="elsevierStyleInf">2</span>: carbon dioxide production; VE: minute ventilation.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Tiago Pereira-da-Silva, Rui M. Soares, Ana Luísa Papoila, Iola Pinto, Joana Feliciano, Luís Almeida-Morais, Ana Abreu, Rui Cruz Ferreira" "autores" => array:8 [ 0 => array:2 [ "nombre" => "Tiago" "apellidos" => "Pereira-da-Silva" ] 1 => array:2 [ "nombre" => "Rui" "apellidos" => "M. Soares" ] 2 => array:2 [ "nombre" => "Ana Luísa" "apellidos" => "Papoila" ] 3 => array:2 [ "nombre" => "Iola" "apellidos" => "Pinto" ] 4 => array:2 [ "nombre" => "Joana" "apellidos" => "Feliciano" ] 5 => array:2 [ "nombre" => "Luís" "apellidos" => "Almeida-Morais" ] 6 => array:2 [ "nombre" => "Ana" "apellidos" => "Abreu" ] 7 => array:2 [ "nombre" => "Rui" "apellidos" => "Cruz Ferreira" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2174204918300746?idApp=UINPBA00004E" "url" => "/21742049/0000003700000002/v1_201803200458/S2174204918300746/v1_201803200458/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "On the trail of the perfect prognosticator in advanced heart failure patients" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "139" "paginaFinal" => "141" ] ] "autores" => array:1 [ 0 => array:3 [ "autoresLista" => "Rui Baptista" "autores" => array:1 [ 0 => array:4 [ "nombre" => "Rui" "apellidos" => "Baptista" "email" => array:1 [ 0 => "rui.baptista@fmed.uc.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Serviço de Cardiologia, Cardiologia A, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Faculty of Medicine, University of Coimbra, Coimbra, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "À procura do melhor preditor de eventos em doentes com insuficiência cardíaca avançada" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleDisplayedQuote" id="dsq0005"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">“It appears to me a most excellent thing for the physician to cultivate Prognosis; for by foreseeing and foretelling, in the presence of the sick, the present, the past, and the future, and explaining the omissions which patients have been guilty of, he will be the more readily believed to be acquainted with the circumstances of the sick; so that men will have confidence to intrust themselves to such a physician.”</p><span class="elsevierStyleSource"><span class="elsevierStyleSmallCaps">Hippocrates</span>, <span class="elsevierStyleItalic">The Book of Prognostics</span></span></span></p><p id="par0010" class="elsevierStylePara elsevierViewall">In Greek mythology, nothing could be done to alter one's fate, as the <span class="elsevierStyleItalic">Moirai</span> (the three Fates) made certain that the destiny assigned by them to every human being would take its course without obstruction. In our era, we dare to predict the course of diseases and the ability of our interventions to alter the fate of our patients.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In chronic heart failure (HF), an insidious and progressive syndrome, patients are at high risk of death.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> However, the availability of heart transplantation can dramatically change the prognosis of the most severe patients. These patients must be identified before a major event jeopardizes their eligibility for transplantation.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> At present, prognostication and selection of patients for heart transplantation is a complex issue.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> As the candidate list grows and guidelines expand candidacy, heart transplantation rates remain static.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> This highlights the need for better candidate selection, dynamic delisting and waiting list trimming. Integration of multiple factors, including functional capacity variables, scores, and clinical assessments (e.g. frailty scores), may help to select vulnerable patients for transplantation.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> The aging of the population and heterogeneity in clinical presentation underscore the need for a multiparametric clinical and epidemiological approach to these risk stratification systems.<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The statistical concepts supporting risk stratification scores are complex and can be prone to bias. The most commonly used parameter to assess the performance of a risk score is the concordance statistic (C-statistic). This reflects the probability of a patient in whom an event occurs (in this case, death or heart transplantation) having a worse score than a patient in whom the event does not occur or occurs at a later point of time.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> A value of 1.0 reflects perfect concordance between the prediction and outcome, whereas a C-statistic of 0.5 indicates random concordance. Usually, scores display C-statistics of 0.6 to 0.9. HF risk stratification scores usually display values between 0.75 and 0.85, commonly classified as good concordance. Other indices can also be used in this context, like the net reclassification index (NRI), which measures how often addition of a new variable, such as VE/VCO<span class="elsevierStyleInf">2</span> slope, results in a change in classification that can be used to assess the effect of changes of this magnitude on the C-statistic.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">9</span></a> Importantly, without an assessment of the clinical impact of the change in classification, the NRI can be misleading, as it overemphasizes the importance of small increases in the C-statistic.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Several risk stratification scores have been developed to help physicians identify the high-risk vulnerable patients who would benefit from early heart transplantation listing. The most commonly used score is the Seattle Heart Failure Model (SHFM), which is based on 24 clinical variables.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> Both the SHFM and the HF Survival Score (HFSS)<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> are recommended in the latest heart transplantation guidelines.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> Some scores also include functional capacity variables, particularly from cardiopulmonary exercise testing (CPET); these include the HFSS, the HF-ACTION score<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> and the recently developed Metabolic Exercise Cardiac Kidney Indexes (MECKI) score.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a> The latter score, combining information on hemoglobin, sodium, kidney function, left ventricular ejection fraction and two CPET parameters – peak oxygen consumption (VO<span class="elsevierStyleInf">2</span> max) in proportion to expected VO<span class="elsevierStyleInf">2</span> and the VE/VCO<span class="elsevierStyleInf">2</span> slope – have recently demonstrated superiority (C-statistic 0.781) over the commonly used SHFM (0.739) and HFSS (0.723).<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> These results were recently supported by a report by a Portuguese group that again demonstrated the superiority of the MECKI score, with C-statistics between 0.83 and 0.87 for endpoints including heart transplantation, values that indicate good agreement with predictions.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">14</span></a> The good discriminative power of the MECKI score is evident and may be related to the inclusion of both VO<span class="elsevierStyleInf">2</span> max and VE/VCO<span class="elsevierStyleInf">2</span> in the score's composition.</p><p id="par0030" class="elsevierStylePara elsevierViewall">Risk scores can also be subject to bias. Sources of potential biases include selection bias, as most scores are developed in homogeneous, highly selected randomized controlled trial cohorts exposed to standard of care interventions. Using real-world data, as Pereira-da-Silva et al.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a> have done in this issue of the <span class="elsevierStyleItalic">Journal</span>, may help to minimize this source of bias. The authors aimed to identify which prognostic factors can best discriminate HF patients who will progress to death or transplantation, focusing specifically on variables obtained from CPET testing. Enrolling 263 patients spanning a nine-year period, the authors developed a two-step model for assessing HF risk. In a highly specific first step, high-risk patients are identified by a VE/VCO<span class="elsevierStyleInf">2</span> slope of ≥39, with a C-statistic of 0.79, without the contribution of any other variable. The VE/VCO<span class="elsevierStyleInf">2</span> slope is a particularly interesting parameter, as it reflects ventilatory efficiency and is associated with pulmonary hypertension.<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">16</span></a> It also possesses prognostic value at submaximal levels of effort, increasing the usefulness of CPET in a population that is not accustomed to exercise or may be reluctant to provide maximal effort. In fact, VE/VCO<span class="elsevierStyleInf">2</span> >35 is recommended as a listing criterion in the presence of submaximal CPET (respiratory exchange ratio <1.05).<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> In the second step, after excluding high-risk patients, low-risk patients were identified by a VE/VCO<span class="elsevierStyleInf">2</span> slope <39, in association with serum sodium >136 mmol/l, serum creatinine <1.0 mg/dl or variation in end-tidal carbon dioxide partial pressure of >0.45 kPa. The presence of two or three factors had an additive effect for a better prognosis. These results are clinically significant, as most studies in this area have focused on identifying high-risk patients. Identification of a low-risk population may help advanced HF physicians to step down care in some selected patients, thereby optimizing resources and intensity of care.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Somewhat surprisingly, no additive value was found for very strong prognostic variables, such as creatinine, natriuretic peptides or echocardiographic variables. The lack of invasive hemodynamic data is a caveat, as all patients referred for transplantation should have an invasive assessment for candidacy. It would be interesting from a pathophysiological standpoint to have an invasive characterization of high-risk patients, particularly to help understand which hemodynamic profiles were present in patients with VE/VCO<span class="elsevierStyleInf">2</span> slopes >39. Also, only patients able to perform CPET were enrolled. Finally, the score should be tested in a validation cohort, as models are intervention-dependent.</p><p id="par0040" class="elsevierStylePara elsevierViewall">Despite these important insights from Pereira-da-Silva et al.’s study, several questions remain regarding advanced HF risk assessment. Are we ready to use other variables besides peak VO<span class="elsevierStyleInf">2</span> for risk stratification? Is variability between serial VE/VCO<span class="elsevierStyleInf">2</span> measurements a problem? Do these results correlate with invasive hemodynamics? Can we ignore other clinical variables that are included in other scores, such as the MECKI score? The guidelines recommend against relying solely on scores to select patients for heart transplantation.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> Heart transplantation patient selection remains a complex decision that requires a team-based approach, extensive clinical experience, surgical input, social support and a multiparametric approach.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0050" class="elsevierStylePara elsevierViewall">The author has 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 "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:16 [ 0 => array:3 [ "identificador" => "bib0085" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "How good are we at predicting the fate of someone with acute myeloid leukaemia?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "E. Estey" 1 => "R.P. Gale" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/leu.2017.56" "Revista" => array:6 [ "tituloSerie" => "Leukemia" "fecha" => "2017" "volumen" => "31" "paginaInicial" => "1255" "paginaFinal" => "1258" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28303892" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0090" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Heart failure" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Metra" 1 => "J.R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 6 | 12 |
| 2024 October | 33 | 23 | 56 |
| 2024 September | 35 | 21 | 56 |
| 2024 August | 36 | 22 | 58 |
| 2024 July | 28 | 27 | 55 |
| 2024 June | 23 | 17 | 40 |
| 2024 May | 29 | 30 | 59 |
| 2024 April | 33 | 30 | 63 |
| 2024 March | 33 | 23 | 56 |
| 2024 February | 27 | 32 | 59 |
| 2024 January | 17 | 32 | 49 |
| 2023 December | 16 | 24 | 40 |
| 2023 November | 21 | 21 | 42 |
| 2023 October | 13 | 15 | 28 |
| 2023 September | 18 | 20 | 38 |
| 2023 August | 23 | 17 | 40 |
| 2023 July | 17 | 9 | 26 |
| 2023 June | 17 | 9 | 26 |
| 2023 May | 45 | 19 | 64 |
| 2023 April | 19 | 1 | 20 |
| 2023 March | 69 | 20 | 89 |
| 2023 February | 45 | 16 | 61 |
| 2023 January | 22 | 15 | 37 |
| 2022 December | 46 | 18 | 64 |
| 2022 November | 48 | 26 | 74 |
| 2022 October | 39 | 20 | 59 |
| 2022 September | 18 | 33 | 51 |
| 2022 August | 23 | 26 | 49 |
| 2022 July | 23 | 33 | 56 |
| 2022 June | 17 | 24 | 41 |
| 2022 May | 15 | 38 | 53 |
| 2022 April | 27 | 17 | 44 |
| 2022 March | 24 | 32 | 56 |
| 2022 February | 26 | 30 | 56 |
| 2022 January | 23 | 22 | 45 |
| 2021 December | 17 | 30 | 47 |
| 2021 November | 23 | 33 | 56 |
| 2021 October | 31 | 38 | 69 |
| 2021 September | 19 | 28 | 47 |
| 2021 August | 16 | 33 | 49 |
| 2021 July | 17 | 23 | 40 |
| 2021 June | 15 | 24 | 39 |
| 2021 May | 25 | 42 | 67 |
| 2021 April | 50 | 29 | 79 |
| 2021 March | 30 | 22 | 52 |
| 2021 February | 37 | 16 | 53 |
| 2021 January | 20 | 15 | 35 |
| 2020 December | 25 | 6 | 31 |
| 2020 November | 17 | 24 | 41 |
| 2020 October | 15 | 17 | 32 |
| 2020 September | 37 | 9 | 46 |
| 2020 August | 12 | 11 | 23 |
| 2020 July | 35 | 13 | 48 |
| 2020 June | 23 | 9 | 32 |
| 2020 May | 17 | 3 | 20 |
| 2020 April | 21 | 5 | 26 |
| 2020 March | 33 | 14 | 47 |
| 2020 February | 31 | 24 | 55 |
| 2020 January | 18 | 4 | 22 |
| 2019 December | 21 | 7 | 28 |
| 2019 November | 14 | 11 | 25 |
| 2019 October | 24 | 4 | 28 |
| 2019 September | 10 | 9 | 19 |
| 2019 August | 29 | 4 | 33 |
| 2019 July | 29 | 6 | 35 |
| 2019 June | 31 | 12 | 43 |
| 2019 May | 17 | 9 | 26 |
| 2019 April | 21 | 20 | 41 |
| 2019 March | 12 | 9 | 21 |
| 2019 February | 19 | 7 | 26 |
| 2019 January | 14 | 7 | 21 |
| 2018 December | 14 | 13 | 27 |
| 2018 November | 41 | 10 | 51 |
| 2018 October | 82 | 19 | 101 |
| 2018 September | 31 | 9 | 40 |
| 2018 August | 20 | 7 | 27 |
| 2018 July | 19 | 2 | 21 |
| 2018 June | 26 | 7 | 33 |
| 2018 May | 20 | 4 | 24 |
| 2018 April | 74 | 12 | 86 |
| 2018 March | 47 | 14 | 61 |
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