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Augmentation Therapy for Emphysema due to Alpha-1 Antitrypsin Deficiency: Pro
Tratamiento aumentativo para el enfisema por déficit de alfa-1 antitripsina: Pro
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array:4 [ "autoresLista" => "Miriam Barrecheguren, Marc Miravitlles" "autores" => array:2 [ 0 => array:3 [ "nombre" => "Miriam" "apellidos" => "Barrecheguren" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 1 => array:4 [ "nombre" => "Marc" "apellidos" => "Miravitlles" "email" => array:1 [ 0 => "mmiravitlles@vhebron.net" ] "referencia" => array:3 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Servicio de Neumología, Hospital Universitari Vall d’Hebron, Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "CIBER de Enfermedades Respiratorias (CIBERES), Spain" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento aumentativo para el enfisema por déficit de alfa-1 antitripsina: Pro" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Alpha-1 antitrypsin deficiency (AATD) is a hereditary disease characterized by low plasma levels of alpha-1 antitrypsin (AAT) and an increased risk of developing liver disease and pulmonary emphysema. AAT protects the lung tissue from destruction by elastase released by the neutrophils, so individuals with serum AAT concentrations below 0.50<span class="elsevierStyleHsp" style=""></span>g/l have a high risk of developing emphysema, particularly if they are smokers.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The only specific treatment available to date has been intravenous infusion of purified AAT derived from donor plasma. The aim of this therapy is restore AAT to normal levels, in order to inhibit the destructive action of proteases and thus prevent or decelerate the development of emphysema.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">This augmentation therapy has been shown to be effective, both biochemically and clinically. Biochemical efficacy is demonstrated by protective levels of AAT being maintained in blood and lung tissue,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">2</span></a> and by the inhibition of elastase in the lung.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">3</span></a> Moreover, this in vivo anti-elastase activity is confirmed by a reduction in urinary levels of desmosine and isodesmosine, indirect markers of elastin degradation in the lung and, thus, markers of reduced lung tissue destruction.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">4</span></a> Clinical evidence of this phenomenon is demonstrated by a change in the natural history of the disease, as observed in the 3 clinical trials conducted to date.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">5–7</span></a> Initially, 2 trials with small patient numbers<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a> showed a reduction in lung density loss measured by computed tomography (CT) in patients receiving replacement therapy compared to placebo. Although the differences in both studies were at the limit of statistical significance due to the small sample size, a combined analysis found that replacement treatment was statistically highly superior.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">5</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">More recently, the RAPID study confirmed the efficacy of replacement therapy in preserving the pulmonary parenchyma.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> This study, the largest conducted to date, included 180 patients with AATD and FEV1 35%–70%, randomized to receive replacement therapy or placebo for 2 years. Results showed that augmentation treatment delayed lung density loss. Moreover, in a 2-year open-label extension of the same study in which all patients received active treatment,<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">7</span></a> lung density loss decelerated significantly and to the same extent in patients who had previously received placebo (late treatment starters) and treatment (early treatment starters). However, lung density lost by the late starters during the first phase of the study was not recovered. This reduction in lung tissue loss has been also extrapolated to improved survival, with an estimated gain of 5.6 life years.<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">8</span></a> These data are consistent with results obtained from the American registry, which reported a significant reduction in mortality in severely ill patients who received treatment.<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">9</span></a> This increase in survival has been used to calculate the cost-effectiveness of augmentation therapy.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a> Using an estimated gain of between 7.4 and 10.6 years life years with augmentation treatment according to sex and smoking habit, the cost per year of life gained is between $59<span class="elsevierStyleHsp" style=""></span>234 and $248<span class="elsevierStyleHsp" style=""></span>361. While this may appear high at first glance, the cost/effectiveness ratio is similar to other widely used treatments, such as simvastatin for the prevention of ischemic heart disease at $195<span class="elsevierStyleHsp" style=""></span>000 per year of life gained.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">10</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Why are questions still being raised about augmentation therapy?<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">11</span></a> Mainly because we are trying to evaluate its clinical efficacy using the same criteria applied to drug treatment for chronic obstructive pulmonary disease (COPD). If we base our conclusions on rate of decline of FEV1as the primary outcome of treatment efficacy, a great many patients will be needed to achieve sufficient statistical power.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a> For example, the primary outcome of the UPLIFT study was to evaluate the rate of decline of FEV1, and for that 6000 patients were required.<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">13</span></a> Obviously, this sample size is impossible to achieve with a rare disease like AATD. For the same reason, it is equally unfeasible to conduct a study powered to analyze mortality.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">12</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Another argument against this therapy is its ineffectiveness against other COPD variables, such as exacerbations. Although AAT can inhibit the growth of certain bacteria,<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">14</span></a> its antiprotease mechanism does not suggest that it could be beneficial in the prevention of exacerbations. Moreover, a much greater number of patients than those included in the AAT studies would be required to design a study evaluating exacerbations.</p><p id="par0035" class="elsevierStylePara elsevierViewall">Augmentation therapy has also failed to show benefits in patient-reported outcomes, such as dyspnea or physical activity, but this should not be surprising given that AAT replacement is not a symptomatic treatment. In this respect, emphysema could be compared to osteoporosis, another disease caused by tissue destruction, in which treatment efficacy is determined mainly by densitometry and not by clinical parameters. AAT treatment efficacy should also be measured by lung densitometry, which is also the best predictor of mortality.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">1</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">More important evidence in favor of the efficacy of this treatment derives from a post hoc analysis of the RAPID study, which showed that the magnitude of lung tissue loss is inversely related with AAT levels achieved during augmentation therapy.<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">6</span></a> These data on the dose/response effect of the treatment reaffirm its efficacy, and have prompted the design of clinical trials using higher doses of AAT.<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">15</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In conclusion, augmentation therapy has proven its efficacy in reducing loss of lung density and, as such, the progression of emphysema. Clinical trials available to date have shown consistent results and provide sufficient evidence to support the use of this treatment in AATD patients with emphysema. The lack of evidence of its impact on clinical variables such as exacerbations or symptoms must not be used as an argument against its use, since this is an etiological approach rather than a symptomatic treatment, and accordingly, cannot be expected to affect those variables. For this reason, national and international guidelines<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">1,16</span></a> recommend the use of augmentation therapy in AATD patients with emphysema who meet the established criteria.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflict of Interests</span><p id="par0050" class="elsevierStylePara elsevierViewall">Miriam Barrecheguren has received fees for speaking engagements from Grifols and Marc Miravitlles has received fees for speaking engagements from Grifols and CSL Behring and for consultancy services from Grifols.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflict of Interests" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Barrecheguren M, Miravitlles M. Tratamiento aumentativo para el enfisema por déficit de alfa-1 antitripsina: Pro. Arch Bronconeumol. 2018;54:363–364.</p>" ] ] "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" => "European Respiratory Society statement: diagnosis and treatment of pulmonary disease in α1-antitrypsin deficiency" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M. Miravitlles" 1 => "A. Dirksen" 2 => "I. Ferrarotti" 3 => "V. Koblizek" 4 => "P. Lange" 5 => "R. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 6 | 3 | 9 |
| 2024 October | 62 | 34 | 96 |
| 2024 September | 64 | 15 | 79 |
| 2024 August | 93 | 40 | 133 |
| 2024 July | 60 | 30 | 90 |
| 2024 June | 47 | 21 | 68 |
| 2024 May | 66 | 22 | 88 |
| 2024 April | 35 | 25 | 60 |
| 2024 March | 43 | 23 | 66 |
| 2024 February | 35 | 22 | 57 |
| 2023 April | 10 | 1 | 11 |
| 2023 March | 11 | 4 | 15 |
| 2023 February | 47 | 18 | 65 |
| 2023 January | 42 | 28 | 70 |
| 2022 December | 113 | 39 | 152 |
| 2022 November | 90 | 15 | 105 |
| 2022 October | 87 | 32 | 119 |
| 2022 September | 54 | 27 | 81 |
| 2022 August | 43 | 58 | 101 |
| 2022 July | 52 | 42 | 94 |
| 2022 June | 41 | 36 | 77 |
| 2022 May | 52 | 35 | 87 |
| 2022 April | 72 | 35 | 107 |
| 2022 March | 101 | 39 | 140 |
| 2022 February | 78 | 25 | 103 |
| 2022 January | 62 | 38 | 100 |
| 2021 December | 40 | 39 | 79 |
| 2021 November | 38 | 43 | 81 |
| 2021 October | 53 | 59 | 112 |
| 2021 September | 36 | 51 | 87 |
| 2021 August | 35 | 36 | 71 |
| 2021 July | 33 | 31 | 64 |
| 2021 June | 58 | 39 | 97 |
| 2021 May | 56 | 75 | 131 |
| 2021 April | 128 | 69 | 197 |
| 2021 March | 112 | 23 | 135 |
| 2021 February | 65 | 28 | 93 |
| 2021 January | 56 | 18 | 74 |
| 2020 December | 83 | 30 | 113 |
| 2020 November | 65 | 28 | 93 |
| 2020 October | 59 | 21 | 80 |
| 2020 September | 52 | 22 | 74 |
| 2020 August | 52 | 13 | 65 |
| 2020 July | 43 | 32 | 75 |
| 2020 April | 1 | 2 | 3 |
| 2020 March | 22 | 6 | 28 |
| 2020 February | 72 | 19 | 91 |
| 2020 January | 59 | 18 | 77 |
| 2019 December | 45 | 21 | 66 |
| 2019 November | 35 | 16 | 51 |
| 2019 October | 33 | 18 | 51 |
| 2019 September | 40 | 8 | 48 |
| 2019 August | 38 | 27 | 65 |
| 2019 July | 39 | 17 | 56 |
| 2019 June | 31 | 13 | 44 |
| 2019 May | 42 | 12 | 54 |
| 2019 April | 42 | 29 | 71 |
| 2019 March | 49 | 22 | 71 |
| 2019 February | 37 | 16 | 53 |
| 2019 January | 33 | 16 | 49 |
| 2018 December | 3 | 2 | 5 |
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