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a disritmia mantida mais comum&#44; aumentando em preval&#234;ncia &#224; medida que a idade avan&#231;a&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Estima-se que 1&#37;-2&#37; da popula&#231;&#227;o sofra de FA&#44; sendo expect&#225;vel que estes valores aumentem com o envelhecimento da popula&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; No estudo FAMA&#44; numa amostra populacional portuguesa com idade superior a 40 anos&#44; foi verificada uma preval&#234;ncia global de FA de 2&#44;5&#37;&#44; com aumento significativo depois dos 70 anos&#58; 0&#44;2&#37;&#44; entre 40-49 anos&#59; 1&#44;0&#37; entre 50-59 anos&#59; 1&#44;6&#37; entre 60-69 anos&#59; 6&#44;6&#37; entre 70-79 anos&#59; e 10&#44;4&#37; no grupo com 80 ou mais anos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; As estimativas para 2012 s&#227;o de cerca de 143 mil casos de FA em Portugal&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Esta patologia pode ser assintom&#225;tica e persistir sem diagn&#243;stico cl&#237;nico&#46; 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a uma duplica&#231;&#227;o da taxa de mortalidade<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> como tamb&#233;m a uma maior morbilidade que surge em consequ&#234;ncia da principal complica&#231;&#227;o da doen&#231;a&#58; o AVCI&#46; De facto&#44; a incid&#234;ncia de AVCI aumenta tr&#234;s a quatro vezes nos indiv&#237;duos com FA<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#44; tornando esta arritmia uma das principais causas de AVCI<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; No estudo de Framingham&#44; o risco anual de AVCI atribu&#237;vel a FA foi de 1&#44;5&#37; entre os 50-59 anos e de 23&#44;5&#37; entre os 80-89 anos<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Adicionalmente&#44; os AVCI associados a FA s&#227;o geralmente mais graves&#44; implicando tamb&#233;m maiores custos<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Atualmente&#44; a principal estrat&#233;gia terap&#234;utica dispon&#237;vel &#233; a utiliza&#231;&#227;o de antagonistas da vitamina K&#44; geralmente representados pela varfarina&#44; que permite reduzir o risco de AVCI em 64&#37; em compara&#231;&#227;o com placebo e em cerca de 40&#37; em compara&#231;&#227;o com o &#225;cido acetilsalic&#237;lico &#40;AAS&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; No entanto&#44; as complica&#231;&#245;es associadas &#224; sua utiliza&#231;&#227;o &#40;como as intera&#231;&#245;es medicamentosas e o controlo diet&#233;tico&#41; aliadas &#224;s dificuldades de controlo do INR &#40;e consequente diminui&#231;&#227;o de efic&#225;cia e de seguran&#231;a&#41; conduzem a que frequentemente os doentes eleg&#237;veis para anticoagula&#231;&#227;o n&#227;o sejam medicados com varfarina&#46; Os dados nacionais indicam que entre os doentes eleg&#237;veis&#44; apenas 38&#37; s&#227;o medicados com varfarina&#44; sendo que 40&#37; n&#227;o recebem qualquer terap&#234;utica antitromb&#243;tica<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleInf">&#46;</span></p><p id="par0030" class="elsevierStylePara elsevierViewall">Tal facto tem motivado o desenvolvimento de alternativas terap&#234;uticas&#44; com um perfil de efic&#225;cia e seguran&#231;a pelo menos id&#234;ntico ao da varfarina&#44; mas sem necessidade de controlo laboratorial de rotina&#46; Por&#233;m&#44; todas as alternativas desenvolvidas t&#234;m falhado&#44; como os antiagregantes plaquet&#225;rios &#40;&#225;cido acetilsalic&#237;lico e clopidogrel&#41; por insuficiente prote&#231;&#227;o anti-isqu&#233;mica<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> ou os anticoagulantes &#40;ximelagatrano e idraparinux&#41; por deficiente seguran&#231;a<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">O dabigatrano &#233; um anticoagulante oral que atua por inibi&#231;&#227;o direta e seletiva da trombina&#44; com um efeito dose-resposta previs&#237;vel&#44; pelo que n&#227;o necessita de monitoriza&#231;&#227;o de rotina da coagula&#231;&#227;o&#46; No ensaio cl&#237;nico RE-LY<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#44; em que foram seguidos mais de 18<span class="elsevierStyleHsp" style=""></span>000 doentes com FA n&#227;o valvular durante cerca de dois anos&#44; o dabigatrano na dose de 150<span class="elsevierStyleHsp" style=""></span>mg duas vezes ao dia demonstrou ser mais eficaz que a varfarina na redu&#231;&#227;o do risco de AVC e de embolismo sist&#233;mico&#44; com um risco de hemorragia <span class="elsevierStyleItalic">major</span> semelhante&#44; tendo a dose de 110<span class="elsevierStyleHsp" style=""></span>mg duas vezes ao dia demonstrado uma efic&#225;cia compar&#225;vel &#224; da varfarina&#44; com uma redu&#231;&#227;o significativa do risco de hemorragia <span class="elsevierStyleItalic">major</span>&#46; Com ambas as doses de dabigatrano observaram-se taxas de hemorragia intracraniana muito inferiores &#224; da varfarina&#46; O dabigatrano foi aprovado pela <span class="elsevierStyleItalic">European Medicines Agency</span> para a preven&#231;&#227;o do AVC e embolismo sist&#233;mico em doentes com FA n&#227;o valvular em agosto de 2011&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Neste contexto&#44; o dabigatrano representa uma importante inova&#231;&#227;o n&#227;o s&#243; para os doentes com FA medicados com varfarina&#44; como tamb&#233;m para aqueles que seguem outro esquema terap&#234;utico&#46; Sendo fundamental a utiliza&#231;&#227;o racional dos recursos dispon&#237;veis para a presta&#231;&#227;o de cuidados de sa&#250;de&#44; &#233; necess&#225;rio verificar se o custo acrescido de qualquer novo medicamento &#233; justificado pelos ganhos em sa&#250;de proporcionados&#46; Com esse objetivo procedeu-se &#224; avalia&#231;&#227;o econ&#243;mica da utiliza&#231;&#227;o do dabigatrano na preven&#231;&#227;o de acidentes vasculares cerebrais em doentes com fibrilha&#231;&#227;o auricular n&#227;o valvular&#44; 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ao fim da sua vida&#46; Consequentemente&#44; em cada trimestre &#233; aplicada uma determinada probabilidade de ocorr&#234;ncia mutuamente exclusiva dos eventos mais relevantes para esta popula&#231;&#227;o&#58; morte&#44; AVC isqu&#233;mico e hemorr&#225;gico&#44; acidente isqu&#233;mico transit&#243;rio &#40;AIT&#41;&#44; embolia sist&#233;mica&#44; enfarte agudo do mioc&#225;rdio &#40;EAM&#41;&#44; e hemorragias intra e extracranianas&#46; Tamb&#233;m &#233; simulada a ocorr&#234;ncia de hemorragias <span class="elsevierStyleItalic">minor</span>&#44; sendo que tal pode suceder em concomit&#226;ncia com os restantes eventos&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Assume-se que um indiv&#237;duo que tenha sofrido um evento cerebral &#40;AVC &#8211; quer isqu&#233;mico quer hemorr&#225;gico &#8211; ou hemorragia intracraniana&#41; pode perder a capacidade de ser independente&#46; Assim&#44; de acordo com a escala modificada de Rankin &#40;para os AVC&#41; ou com a escala de Glasgow <span class="elsevierStyleItalic">Outcomes</span> &#40;para a hemorragia intracraniana&#41;&#44; estes doentes poder&#227;o continuar independentes&#44; passar a ser moderadamente dependentes&#44; ou completamente dependentes&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Por outro lado&#44; no modelo&#44; admite-se que o tratamento seja descontinuado permanentemente caso ocorra um AVC hemorr&#225;gico ou uma hemorragia intracraniana&#44; ou descontinuado temporariamente devido a hemorragias extracranianas ou outras raz&#245;es n&#227;o especificadas&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Este tipo de simula&#231;&#227;o da evolu&#231;&#227;o de uma coorte permite estimar os custos e as consequ&#234;ncias cl&#237;nicas associadas a cada op&#231;&#227;o terap&#234;utica&#46; Neste caso&#44; o modelo permite prever os custos&#44; os anos de vida&#44; e os anos de vida ajustados pela qualidade &#40;AVAQ&#41; associados &#224;s alternativas em an&#225;lise&#44; tornando poss&#237;vel calcular quer o custo por ano de vida quer o custo por AVAQ decorrente da op&#231;&#227;o pela estrat&#233;gia terap&#234;utica com melhores resultados cl&#237;nicos&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Comparador</span><p id="par0065" class="elsevierStylePara elsevierViewall">Um dos aspetos fundamentais na elabora&#231;&#227;o de um estudo de avalia&#231;&#227;o econ&#243;mica &#233; a escolha do comparador&#44; isto &#233;&#44; da op&#231;&#227;o terap&#234;utica que ser&#225; substitu&#237;da pelo medicamento sob avalia&#231;&#227;o&#46; O dabigatrano &#233; uma alternativa n&#227;o s&#243; para a varfarina como para as outras op&#231;&#245;es terap&#234;uticas utilizadas nesta popula&#231;&#227;o&#44; nomeadamente a utiliza&#231;&#227;o de AAS e a n&#227;o prescri&#231;&#227;o de medicamentos antitromb&#243;ticos&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">No estudo FAMA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#44; conforme referido anteriormente&#44; verificou-se que apenas 38&#37; dos doentes eleg&#237;veis eram medicados com varfarina e que 40&#37; n&#227;o eram tratados&#44; tendo sido assumido para efeitos de modeliza&#231;&#227;o que os restantes seriam medicados com AAS&#46; Consequentemente&#44; o comparador utilizado neste estudo &#233; uma combina&#231;&#227;o ponderada de varfarina&#44; AAS e n&#227;o tratamento&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Dados cl&#237;nicos e epidemiol&#243;gicos</span><p id="par0075" class="elsevierStylePara elsevierViewall">O modelo utiliza os resultados do ensaio cl&#237;nico RE-LY<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#44; em que foi realizada uma compara&#231;&#227;o direta entre a utiliza&#231;&#227;o de varfarina e de dabigatrano em mais de 18<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleHsp" style=""></span>doentes com FA n&#227;o valvular&#46; Os doentes do estudo RE-LY que apresentavam risco moderado a elevado de AVCI receberam de forma aleat&#243;ria dabigatrano &#40;110<span class="elsevierStyleHsp" style=""></span>mg ou 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span>&#41; ou varfarina com dose ajustada a um INR alvo entre 2&#44;0 e 3&#44;0&#44; durante um per&#237;odo m&#233;dio de dois anos&#46; O estudo decorreu entre dezembro de 2005 e mar&#231;o de 2009 em 44 pa&#237;ses de todo o mundo&#44; tendo Portugal participado com nove centros que inclu&#237;ram 117 doentes&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Neste estudo foi poss&#237;vel estimar a taxa de ocorr&#234;ncia dos diversos eventos considerados nos indiv&#237;duos a tomar varfarina bem como os riscos relativos aplic&#225;veis &#224;s pessoas medicadas com dabigatrano&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">No final do estudo verificou-se que a dose de 110<span class="elsevierStyleHsp" style=""></span>mg permitiu uma redu&#231;&#227;o de 10&#37; no indicador prim&#225;rio &#8211; incid&#234;ncia de AVC ou embolias sist&#233;micas &#8211; embora sem diferen&#231;a estatisticamente significativa na an&#225;lise de superioridade&#46; O perfil de seguran&#231;a obtido foi superior&#44; verificando-se uma redu&#231;&#227;o de 20&#37; nas hemorragias <span class="elsevierStyleItalic">major</span> comparativamente &#224; varfarina &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;003&#41;&#46; A dose de 150<span class="elsevierStyleHsp" style=""></span>mg apresentou uma efic&#225;cia superior &#224; da varfarina&#44; com uma redu&#231;&#227;o de 35&#37; na incid&#234;ncia do indicador prim&#225;rio &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e de 7&#37; nas hemorragias <span class="elsevierStyleItalic">major</span> &#40;sem signific&#226;ncia estat&#237;stica&#41;&#46; O tratamento com dabigatrano diminuiu de forma marcada a incid&#234;ncia de hemorragias intracranianas tendo estas sido reduzidas em 70&#37; com a dose de 110<span class="elsevierStyleHsp" style=""></span>mg &#40;p<span class="elsevierStyleHsp" style=""></span>&#60; 0&#44;001&#41; e em 59&#37; com a dose de 150<span class="elsevierStyleHsp" style=""></span>mg &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A dispepsia &#40;incluindo dor abdominal&#41; foi o &#250;nico efeito adverso significativamente mais comum com dabigatrano do que com a varfarina&#44; ocorrendo em 5&#44;8&#37; dos doentes do grupo da varfarina e em 11&#44;8 e 11&#44;3&#37; dos doentes dos grupos de 110<span class="elsevierStyleHsp" style=""></span>mg e 150<span class="elsevierStyleHsp" style=""></span>mg de dabigatrano&#44; respetivamente &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001 para ambas as compara&#231;&#245;es&#41;&#46; Globalmente&#44; as taxas de outros eventos adversos foram semelhantes entre os grupos de tratamento&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Adicionalmente foi realizada uma meta-an&#225;lise que permitiu estimar o risco relativo de ocorr&#234;ncia dos diversos eventos nos doentes sob terap&#234;utica com AAS e naqueles sem tratamento<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; Na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a> encontram-se os valores obtidos&#44; sendo o risco inicial de AVCI estratificado de acordo com o &#237;ndice CHADS<span class="elsevierStyleInf">2</span>&#46; Realce-se que os valores obtidos s&#227;o diferentes dos apresentados na publica&#231;&#227;o dos resultados cl&#237;nicos do RE-LY dado terem sido adaptados &#224; aprova&#231;&#227;o da <span class="elsevierStyleItalic">European Medicines Agency</span> que&#44; em termos gerais&#44; indica que a dose de 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> deve ser usada em doentes com menos de 80 anos e a dose de 110<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> naqueles com 80 ou mais anos<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Como se constata pela leitura da tabela&#44; quando comparado com varfarina&#44; o dabigatrano permite uma redu&#231;&#227;o significativa dos eventos considerados&#44; nomeadamente AVC isqu&#233;micos e hemorr&#225;gicos&#44; embolias sist&#233;micas&#44; AITs&#44; hemorragias intra e extracranianas &#40;nestas apenas nos doentes com idade inferior a 80 anos&#41;&#44; e hemorragias <span class="elsevierStyleItalic">minor</span>&#46; Naturalmente&#44; estas vantagens cl&#237;nicas s&#227;o ainda mais vincadas quando se consideram as alternativas AAS e n&#227;o tratamento&#46; Verificou-se ainda uma diferen&#231;a num&#233;rica na taxa de EAM&#44; favor&#225;vel &#224; varfarina&#44; embora esta diferen&#231;a n&#227;o tenha atingido significado estat&#237;stico<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Em termos epidemiol&#243;gicos&#44; foram considerados os dados portugueses obtidos no estudo FAMA para definir a propor&#231;&#227;o de homens e de mulheres na popula&#231;&#227;o com FA em Portugal&#44; bem como para estimar a idade m&#233;dia<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Os dados dispon&#237;veis indicam que 55&#37; dos doentes com menos de 80 anos s&#227;o homens&#44; descendo esta percentagem para 26&#37; quando se considera a faixa et&#225;ria mais elevada&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Qualidade de vida</span><p id="par0110" class="elsevierStylePara elsevierViewall">A estima&#231;&#227;o dos AVAQ associados a cada uma das op&#231;&#245;es implica incorporar o facto da qualidade de vida das pessoas diminuir com a exist&#234;ncia de doen&#231;a e com a ocorr&#234;ncia de eventos&#46; Assim&#44; &#233; importante analisar a qualidade de vida inicial dos doentes que constituem a popula&#231;&#227;o em an&#225;lise e estimar o impacto da ocorr&#234;ncia de eventos nessa mesma qualidade de vida&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Para tal&#44; foram utilizados os resultados de uma meta-an&#225;lise<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> que incorporou resultados de 20 estudos de avalia&#231;&#227;o de qualidade de vida e de um estudo em que os autores estimaram valores de utilidade para v&#225;rias doen&#231;as cr&#243;nicas utilizando uma amostra representativa da popula&#231;&#227;o norte-americana atrav&#233;s de dados recolhidos pelo <span class="elsevierStyleItalic">Medical Expenditure Panel Survey</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46; A primeira&#44; relativa a indiv&#237;duos com hist&#243;ria de AVCI&#44; permitiu estabelecer ponderadores por n&#237;vel de depend&#234;ncia ap&#243;s ocorr&#234;ncia de AVCI&#59; o segundo foi utilizado para valorizar o impacto da ocorr&#234;ncia de eventos na qualidade de vida &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Tabela 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Dados econ&#243;micos</span><p id="par0120" class="elsevierStylePara elsevierViewall">Os recursos consumidos no tratamento e seguimento de eventos foram estimados a partir das respostas de um painel de peritos composto por seis especialistas com comprovada experi&#234;ncia cl&#237;nica &#40;dois cardiologistas&#44; dois cl&#237;nicos gerais e dois neurologistas&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A conjuga&#231;&#227;o dos recursos identificados pelo painel com os respetivos custos unit&#225;rios &#40;l&#237;quidos de IVA<a class="elsevierStyleCrossRef" href="#fn1"><span class="elsevierStyleSup">a</span></a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a> permitiu a estima&#231;&#227;o dos custos incorridos durante o tratamento dos epis&#243;dios agudos e durante o seguimento dos doentes&#46; Os custos com o dabigatrano s&#227;o baseados no pre&#231;o proposto pela empresa detentora da patente para ambas as dosagens &#40;110<span class="elsevierStyleHsp" style=""></span>mg e 150<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46; Os custos s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0015">Tabela 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Nos resultados apresentados adiante&#44; a valoriza&#231;&#227;o dos custos foi realizada de acordo com a perspetiva da sociedade&#44; ou seja&#44; os custos foram considerados na sua totalidade&#44; independentemente de serem financiados pelo Estado ou pelos doentes&#46; Os resultados na perspetiva do Estado tamb&#233;m foram calculados&#44; sendo os custos incrementais e consequentemente os r&#225;cios custo-efetividade aproximadamente 70&#37; dos apresentados&#46; Tal reflete o facto da taxa de comparticipa&#231;&#227;o atribu&#237;vel ao dabigatrano ser de 69&#37;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Resultados</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Cen&#225;rio principal</span><p id="par0135" class="elsevierStylePara elsevierViewall">Naturalmente&#44; os resultados obtidos refletem a evid&#234;ncia cl&#237;nica dispon&#237;vel&#58; o dabigatrano permite uma diminui&#231;&#227;o de quase todos os eventos considerados&#44; nomeadamente AVCI&#44; embolia sist&#233;mica&#44; AIT&#44; AVCH e hemorragias intracranianas&#44; registando-se uma maior incid&#234;ncia de EAM e de hemorragias extracranianas &#40;devido ao maior risco ap&#243;s os 80 anos em doentes a tomar 110<span class="elsevierStyleHsp" style=""></span>mg de dabigatrano&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A menor ocorr&#234;ncia de eventos reflete-se quer nos anos de vida quer nos AVAQ de que beneficiam os doentes medicados com dabigatrano&#46; O dabigatrano permite obter mais 0&#44;415 anos de vida e 0&#44;439 AVAQ por doente quando o come&#231;o da terap&#234;utica se faz antes dos 80 anos&#44; sendo estes ganhos de 0&#44;143 anos de vida e 0&#44;166 AVAQ quando a terap&#234;utica se inicia ap&#243;s os 80&#46; Em termos m&#233;dios&#44; assumindo que 69&#37; da popula&#231;&#227;o com FA tem idade inferior a 80 anos<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; o dabigatrano proporciona 0&#44;331 anos de vida e 0&#44;354 AVAQ&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Os custos di&#225;rios da terap&#234;utica com dabigatrano s&#227;o superiores aos da varfarina ou AAS&#46; Contudo&#44; considerando os custos dos eventos e do acompanhamento dos doentes&#44; o tratamento com dabigatrano permite atenuar entre 20-30&#37; esse incremento de custos&#46; Verifica-se ent&#227;o um aumento do custo da terap&#234;utica preventiva de 5572&#160;&#8364; para doentes com idade inferior a 80 anos&#44; de 2300&#160;&#8364; para doentes com idade superior a 80 anos&#44; e de 4558&#160;&#8364; em termos m&#233;dios&#59; o aumento dos custos totais &#233; de 3763&#160;&#8364;&#44; 1231&#160;&#8364; e 2978&#160;&#8364;&#44; respetivamente&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A conjuga&#231;&#227;o dos resultados cl&#237;nicos e econ&#243;micos permite calcular os r&#225;cios custo efetividade incrementais &#40;RCEI&#41; por AVAQ e por ano de vida &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Tabela 4</a>&#41;&#46; Mesmo n&#227;o existindo em Portugal nenhum limite pr&#233;-fixado &#224; disponibilidade a pagar por ano de vida ou por AVAQ ganho&#44; &#233; poss&#237;vel afirmar que os valores obtidos &#8211; aproximadamente 10<span class="elsevierStyleHsp" style=""></span>000 &#8364; quer por ano de vida quer por AVAQ &#8211; s&#227;o aceit&#225;veis para a realidade portuguesa&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">An&#225;lise de sensibilidade</span><p id="par0155" class="elsevierStylePara elsevierViewall">Na prossecu&#231;&#227;o de todas as avalia&#231;&#245;es econ&#243;micas &#233; necess&#225;rio assumir hip&#243;teses que permitam constituir um cen&#225;rio principal&#46; Por&#233;m&#44; como essas hip&#243;teses podem condicionar os resultados obtidos&#44; &#233; importante analisar o impacto de se assumirem valores alternativos para os par&#226;metros relevantes&#46; Para tal&#44; &#233; usual realizar-se uma an&#225;lise da sensibilidade do resultado final &#224;s hip&#243;teses assumidas&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Neste contexto&#44; &#233; importante salientar que existem dois tipos de par&#226;metros&#58; uns para os quais &#233; poss&#237;vel associar uma distribui&#231;&#227;o estat&#237;stica que reflita a incerteza&#44; como as probabilidades de ocorr&#234;ncia dos v&#225;rios eventos considerados&#59; outros cuja incerteza n&#227;o &#233; pass&#237;vel de ser assim caracterizada&#44; como a taxa de atualiza&#231;&#227;o ou o horizonte temporal&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Relativamente aos primeiros&#44; &#233; poss&#237;vel realizar uma an&#225;lise de sensibilidade probabil&#237;stica simulando simultaneamente diferentes ocorr&#234;ncias dos diversos par&#226;metros&#46; Na <a class="elsevierStyleCrossRef" href="#fig0010">Figura 2</a> apresentam-se&#44; a t&#237;tulo exemplificativo&#44; os resultados relativos a custos e anos de vida incrementais das 1000 simula&#231;&#245;es realizadas para a popula&#231;&#227;o que inicia terap&#234;utica antes dos 80 anos&#46; Uma vantagem deste tipo de an&#225;lise de sensibilidade &#233; que permite definir a propor&#231;&#227;o de simula&#231;&#245;es em que o r&#225;cio custo-efetividade &#233; inferior a determinada disposi&#231;&#227;o a pagar &#40;ver <a class="elsevierStyleCrossRef" href="#tbl0025">Tabela 5</a>&#41;&#46; Constata-se que considerando valores tradicionalmente assumidos como aproximados da disponibilidade a pagar pelos ganhos em sa&#250;de&#44; a ado&#231;&#227;o de dabigatrano ser&#225; muito provavelmente custo-efetiva&#46; De facto&#44; na quase totalidade das 1000 simula&#231;&#245;es realizadas&#44; o dabigatrano est&#225; associado a um r&#225;cio custo-efetividade inferior a 15<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&#44; quando o limite geralmente utilizado em Portugal ser&#225; cerca do dobro deste valor&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Quanto aos restantes par&#226;metros &#233; mais relevante realizar uma an&#225;lise de sensibilidade univariada que permita avaliar o impacto de se assumirem valores diferentes dos utilizados no cen&#225;rio principal&#46; Na <a class="elsevierStyleCrossRef" href="#tbl0030">Tabela 6</a>&#44; apresentam-se os resultados para diferentes taxas de atualiza&#231;&#227;o&#44; horizonte temporal&#44; e custos&#46; Realce-se que quer a taxa de atualiza&#231;&#227;o &#40;5&#37;&#41; quer o horizonte temporal <span class="elsevierStyleItalic">&#40;lifetime&#41;</span> utilizados no cen&#225;rio principal decorrem do estipulado nas orienta&#231;&#245;es metodol&#243;gicas em vigor em Portugal<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">25</span></a>&#46; Todavia&#44; se a an&#225;lise relativa &#224; taxa de atualiza&#231;&#227;o reflete uma incerteza real quanto ao seu valor &#243;timo&#44; j&#225; a relativa ao horizonte temporal servir&#225; apenas para averiguar a amplitude temporal do impacto do medicamento em avalia&#231;&#227;o&#44; dado que em termos metodol&#243;gicos &#233; consensual que as diferen&#231;as entre as op&#231;&#245;es terap&#234;uticas devem ser avaliadas at&#233; ao momento em que essas mesmas diferen&#231;as cessem&#44; o que no caso de terap&#234;uticas cr&#243;nicas acontece no momento da morte&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Relativamente aos custos &#233; importante salientar que&#44; em teoria&#44; poderiam ser inclu&#237;dos na an&#225;lise de sensibilidade probabil&#237;stica&#46; No entanto&#44; dado que foram estimados a partir do consenso de um painel de peritos sobre os recursos consumidos pela popula&#231;&#227;o em an&#225;lise&#44; a avalia&#231;&#227;o do seu impacto no resultado final parece ser mais esclarecedora atrav&#233;s de uma an&#225;lise de sensibilidade univariada&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">A an&#225;lise de sensibilidade univariada permite concluir que os par&#226;metros considerados&#44; com exce&#231;&#227;o do horizonte temporal&#44; n&#227;o t&#234;m grande impacto nos r&#225;cios custo-efetividade&#44; j&#225; que as altera&#231;&#245;es introduzidas implicam varia&#231;&#245;es de apenas cerca de 10&#37;&#46; O facto de o horizonte temporal ter um impacto mais relevante &#233; normal&#44; dado que a utiliza&#231;&#227;o de per&#237;odos mais curtos impede a incorpora&#231;&#227;o de parte consider&#225;vel dos ganhos do dabigatrano&#46; Ali&#225;s&#44; tal &#233; comum acontecer nas avalia&#231;&#245;es econ&#243;micas de terap&#234;uticas preventivas&#46; Naturalmente&#44; dada a menor esperan&#231;a de vida da coorte acima dos 80 anos&#44; o impacto da diminui&#231;&#227;o do horizonte temporal nos resultados relevantes para esta popula&#231;&#227;o &#233; bastante menos significativo&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discuss&#227;o</span><p id="par0185" class="elsevierStylePara elsevierViewall">Em primeiro lugar&#44; &#233; relevante referir que se optou por&#44; de forma conservadora&#44; assumir que a varfarina tem a efic&#225;cia que foi obtida no ensaio cl&#237;nico&#46; De facto&#44; sendo o controlo dos n&#237;veis de INR um fator fundamental para se conseguir obter e manter os benef&#237;cios decorrentes da utiliza&#231;&#227;o de varfarina&#44; e sendo expect&#225;vel que esse controlo tenha sido mais f&#225;cil de efetuar nas condi&#231;&#245;es inerentes &#224; realiza&#231;&#227;o do ensaio cl&#237;nico RE-LY&#44; &#233; de admitir que a efetividade da varfarina em condi&#231;&#245;es de pr&#225;tica cl&#237;nica corrente seja inferior &#224; que foi assumida nesta avalia&#231;&#227;o econ&#243;mica&#46; A capacidade da varfarina prevenir AVCI em condi&#231;&#245;es de pr&#225;tica cl&#237;nica pode ser pouco mais de metade da que &#233; estimada nas condi&#231;&#245;es usuais de ensaios cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">26</span></a>&#46; Tal dever-se-&#225; principalmente &#224;s intera&#231;&#245;es com outros medicamentos e com alimentos&#44; &#224; inconveni&#234;ncia da monitoriza&#231;&#227;o&#44; e ao risco de hemorragia&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Por outro lado&#44; principalmente devido &#224;s indica&#231;&#245;es de utiliza&#231;&#227;o do dabigatrano resultantes da aprova&#231;&#227;o pela <span class="elsevierStyleItalic">European Medicines Agency</span>&#44; designadamente a rela&#231;&#227;o entre faixa et&#225;ria e dose di&#225;ria&#44; a pot&#234;ncia estat&#237;stica do ensaio cl&#237;nico RE-LY foi diminu&#237;da&#46; Tal acontece porque todas as observa&#231;&#245;es de indiv&#237;duos com idade inferior a 80 anos aleatorizados para 110<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> e de indiv&#237;duos com idade igual ou superior a 80 e aleatorizados para 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> se tornaram irrelevantes no &#226;mbito desta avalia&#231;&#227;o econ&#243;mica&#46; Assim&#44; parte dos riscos relativos apresentados na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a> n&#227;o s&#227;o estatisticamente significativos&#46; No entanto&#44; a an&#225;lise de sensibilidade probabil&#237;stica&#44; que permite considerar a totalidade da distribui&#231;&#227;o estat&#237;stica de cada risco relativo&#44; mostra que o r&#225;cio custo-efetividade ser&#225; muito provavelmente inferior aos limites m&#225;ximos aceit&#225;veis no contexto portugu&#234;s&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">As an&#225;lises de sensibilidade realizadas mostram que os resultados s&#227;o relativamente robustos &#224; incerteza inerente quer aos dados cl&#237;nicos quer aos custos estimados para Portugal&#46; Neste contexto &#233; importante real&#231;ar que uma varia&#231;&#227;o dos custos em 20&#37; conduziu a altera&#231;&#245;es dos r&#225;cios em cerca de 15&#37;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Finalmente&#44; a compara&#231;&#227;o dos r&#225;cios obtidos para Portugal com os j&#225; publicados para outros pa&#237;ses onde a avalia&#231;&#227;o econ&#243;mica tamb&#233;m &#233; um auxiliar na fundamenta&#231;&#227;o de decis&#245;es de financiamento de medicamentos &#40;designadamente Canad&#225;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> e Reino Unido<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#41; mostra que os resultados s&#227;o conservadores&#46; De facto&#44; as estimativas dos custos associados &#224; monitoriza&#231;&#227;o do INR e&#44; principalmente dos custos decorrentes do AVCI&#44; s&#227;o menores em Portugal do que nos dois pa&#237;ses referidos&#46; Consequentemente&#44; representando estes par&#226;metros as principais &#225;reas em que a introdu&#231;&#227;o do dabigatrano conduz a um inferior consumo de recursos&#44; a sua menor magnitude conduz a r&#225;cios custo-efetividade maiores que os obtidos internacionalmente&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclus&#227;o</span><p id="par0205" class="elsevierStylePara elsevierViewall">Os resultados apresentados mostram que o dabigatrano representa um importante desenvolvimento para os doentes com FA n&#227;o valvular&#44; ao diminuir o risco de AVC isqu&#233;mico e hemorr&#225;gico e de hemorragia intracraniana&#44; bem como as respetivas sequelas a longo prazo&#46; Os custos com dabigatrano s&#227;o parcialmente compensados por uma diminui&#231;&#227;o dos custos devidos &#224; ocorr&#234;ncia de eventos&#44; bem como&#44; por poupan&#231;as com a aus&#234;ncia de monitoriza&#231;&#227;o do INR&#46; Assim&#44; esta avalia&#231;&#227;o econ&#243;mica permite concluir que para al&#233;m de ser uma terap&#234;utica eficaz e segura&#44; conforme ficou demonstrado no ensaio cl&#237;nico RE-LY&#44; o dabigatrano &#233; tamb&#233;m uma op&#231;&#227;o terap&#234;utica custo-efetiva para os doentes portugueses com FA&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Responsabilidades &#233;ticas</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Prote&#231;&#227;o de pessoas e animais</span><p id="par0210" class="elsevierStylePara elsevierViewall">Os autores declaram que para esta investiga&#231;&#227;o n&#227;o se realizaram experi&#234;ncias em seres humanos e&#47;ou animais&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Confidencialidade dos dados</span><p id="par0215" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Direito &#224; privacidade e consentimento escrito</span><p id="par0220" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Financiamento</span><p id="par0225" class="elsevierStylePara elsevierViewall">Este trabalho foi realizado com o apoio financeiro da Boehringer Ingelheim&#44; Lda&#46; O financiamento do projeto foi efetuado diretamente ao CISEP e n&#227;o foi condicional &#224; obten&#231;&#227;o de nenhum tipo espec&#237;fico de resultados&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflito de interesses</span><p id="par0230" class="elsevierStylePara elsevierViewall">Este trabalho foi realizado com o apoio financeiro da Boehringer Ingelheim&#44; Lda&#46;&#46; O financiamento do projeto foi efetuado diretamente ao CISEP e n&#227;o foi condicional &#224; obten&#231;&#227;o de nenhum tipo espec&#237;fico de resultados&#46;</p></span></span>"
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    "fechaAceptado" => "2013-01-19"
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            0 => "Acidente vascular cerebral"
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            2 => "Fibrilha&#231;&#227;o auricular"
            3 => "Dabigatrano"
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            0 => "Stroke"
            1 => "Prevention"
            2 => "Atrial fibrillation"
            3 => "Dabigatran"
            4 => "Cost-effectiveness"
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    "resumen" => array:2 [
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introdu&#231;&#227;o e objetivos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Estimar os r&#225;cios custo-efetividade e custo-utilidade associados &#224; utiliza&#231;&#227;o de dabigatrano na preven&#231;&#227;o de acidentes vasculares cerebrais e embolias sist&#233;micas em doentes com fibrilha&#231;&#227;o auricular n&#227;o valvular em Portugal&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Metodologia</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Foi utilizado um modelo de Markov para simular a evolu&#231;&#227;o dos doentes&#44; estimando a ocorr&#234;ncia de acidentes vasculares cerebrais isqu&#233;micos e hemorr&#225;gicos&#44; de acidentes isqu&#233;micos transit&#243;rios&#44; de embolias sist&#233;micas&#44; de enfartes agudos do mioc&#225;rdio e de hemorragias intra e extracranianas&#46; Os par&#226;metros cl&#237;nicos baseiam-se nos resultados do estudo RE-LY&#44; que compara a utiliza&#231;&#227;o de dabigatrano com a de varfarina&#44; e numa meta-an&#225;lise em que se estimou o risco de ocorr&#234;ncia de cada evento em doentes medicados com &#225;cido acetilsalic&#237;lico ou sem qualquer terap&#234;utica antitromb&#243;tica&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">O dabigatrano proporciona&#44; a cada doente&#44; um incremento de 0&#44;331 e de 0&#44;354 anos de vida ajustados pela qualidade&#46; Na perspetiva da sociedade&#44; estes ganhos cl&#237;nicos implicam um aumento da despesa em 2&#46;978<span class="elsevierStyleHsp" style=""></span>&#8364;&#46; Assim&#44; o custo incremental por ano de vida ganho &#233; de 9&#46;006<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; sendo o custo incremental por ano de vida ajustado pela qualidade de 8&#46;409<span class="elsevierStyleHsp" style=""></span>&#8364;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclus&#245;es</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Os resultados obtidos mostram que o dabigatrano diminui a quantidade de eventos&#44; nomeadamente os de maior gravidade como os acidentes vasculares cerebrais isqu&#233;micos e hemorr&#225;gicos&#44; bem como as respetivas sequelas de longo prazo&#46; Os custos com dabigatrano s&#227;o parcialmente compensados por uma diminui&#231;&#227;o dos custos decorrentes dos eventos&#44; bem como pela aus&#234;ncia de monitoriza&#231;&#227;o do INR&#46; Assim&#44; pode concluir-se que a utiliza&#231;&#227;o de dabigatrano na pr&#225;tica cl&#237;nica portuguesa &#233; custo-efetiva&#46;</p>"
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        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introduction and Objectives</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To estimate the cost-effectiveness and cost-utility of dabigatran in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Portugal&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Methodology</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">A Markov model was used to simulate patients&#8217; clinical course&#44; estimating the occurrence of ischemic and hemorrhagic stroke&#44; transient ischemic attack&#44; systemic embolism&#44; myocardial infarction&#44; and intra- and extracranial hemorrhage&#46; The clinical parameters are based on the results of the RE-LY trial&#44; which compared dabigatran with warfarin&#44; and on a meta-analysis that estimated the risk of each event in patients treated with aspirin or with no antithrombotic therapy&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Dabigatran provides an increase of 0&#46;331 life years and 0&#46;354 quality-adjusted life years for each patient&#46; From a societal perspective&#44; these clinical gains entail an additional expenditure of 2978 euros&#46; Thus&#44; the incremental cost is 9006 euros per life year gained and 8409 euros per quality-adjusted life year&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">The results show that dabigatran reduces the number of events&#44; especially the most severe such as ischemic and hemorrhagic stroke&#44; as well as their long-term sequelae&#46; The expense of dabigatran is partially offset by lower event-related costs and by the fact that INR monitoring is unnecessary&#46; It can thus be concluded that the use of dabigatran in clinical practice in Portugal is cost-effective&#46;</p>"
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          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">AAS&#58; &#225;cido acetilsalic&#237;lico&#59; AIT&#58; acidente isqu&#233;mico transit&#243;rio&#59; AVC&#58; acidente vascular cerebral&#59; <span class="elsevierStyleItalic">bid</span>&#58; duas vezes por dia&#59; EAM&#58; enfarte agudo do mioc&#225;rdio&#46;</p>"
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Varfarina</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#60;&#160;80 anos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#62;&#160;80 anos&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Dabigatrano</td><td class="td" title="\n
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                  \t\t\t\t">AAS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">N&#227;o Tratamento&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">110 <span class="elsevierStyleItalic">bid</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia intracraniana</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia extracraniana fatal</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1782&#44;54&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia extracraniana</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1459&#44;99&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">EAM fatal</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">3185&#44;44&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Custo trimestral de seguimento</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Sem evento</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Independente</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&#44;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Moderadamente dependente</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">145&#44;84&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Dependente</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">2867&#44;10&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Custo trimestral de reabilita&#231;&#227;o ap&#243;s AVCI&#44; AVCH ou HI</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro ano&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&#44;50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Moderadamente dependente</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro trimestre&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Resto do primeiro ano&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anos seguintes&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro trimestre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2337&#44;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Resto do primeiro ano&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1155&#44;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Custos trimestrais de monitoriza&#231;&#227;o de INR</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Se INR dentro dos limites</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#44;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Se INR fora dos limites</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#44;47&nbsp;\t\t\t\t\t\t\n
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                  """
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                  \t\t\t\t\tvoid\n
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                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " colspan="3" align="center" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Menores de 80&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">80 ou mais&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">M&#233;dia&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo incremental &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3763&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1231&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2978&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anos de vida incrementais &#40;b&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;143&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;331&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AVAQ incrementais &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;439&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;166&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;354&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo por ano de vida &#40;a&#47;b&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8592&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo por AVAQ &#40;a&#47;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8577&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7420&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8409&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab359369.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">R&#225;cios custo efetividade incrementais &#40;&#8364;&#41;</p>"
        ]
      ]
      6 => array:7 [
        "identificador" => "tbl0025"
        "etiqueta" => "Tabela 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">AV&#58; anos de vida&#59; AVAQ&#58; anos de vida ajustados pela qualidade&#59; RCEI&#58; r&#225;cio custo-efetividade incremental&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Menores de 80</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Maiores de 80</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AV &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AVAQ &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AV &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AVAQ &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;10<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;15<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;20<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">91&#44;8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;25<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">90&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">94&#44;5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;30<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">100&#44;0&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">93&#44;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">96&#44;4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab359365.png"
              ]
            ]
          ]
        ]
        "descripcion" => array:1 [
          "pt" => "<p id="spar0085" class="elsevierStyleSimplePara elsevierViewall">Distribui&#231;&#227;o das simula&#231;&#245;es por n&#237;vel de RCEI</p>"
        ]
      ]
      7 => array:7 [
        "identificador" => "tbl0030"
        "etiqueta" => "Tabela 6"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0100" class="elsevierStyleSimplePara elsevierViewall">AV&#58; anos de vida&#59; AVAQ&#58; anos de vida ajustados pela qualidade&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Menores de 80</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Maiores de 80</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Por AV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Por AVAQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Por AV&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Por AVAQ&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cen&#225;rio base</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8577&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8592&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7420&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Taxa de atualiza&#231;&#227;o</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>3&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7967&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7665&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8073&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7047&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>7&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10<span class="elsevierStyleHsp" style=""></span>272&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9550&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7800&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Horizonte temporal</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>10 anos&nbsp;\t\t\t\t\t\t\n
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Artigo original
Avaliação económica do dabigatrano na prevenção de acidentes vasculares cerebrais isquémicos em doentes com fibrilhação auricular não valvular
Economic evaluation of dabigatran for stroke prevention in patients with non-valvular atrial fibrillation
Luís Silva Miguela,
Autor para correspondência
luissm@cisep.iseg.utl.pt

Autor para correspondência.
, Evangelista Rochab, Jorge Ferreirac
a Centro de Investigação Sobre Economia Portuguesa, Instituto Superior de Economia e Gestão, Lisboa, Portugal
b Instituto de Medicina Preventiva, Faculdade de Medicina de Lisboa, Lisboa, Portugal
c Serviço de Cardiologia, Hospital de Santa Cruz, Centro Hospitalar de Lisboa Ocidental, Lisboa, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Introdu&#231;&#227;o</span><p id="par0005" class="elsevierStylePara elsevierViewall">A fibrilha&#231;&#227;o auricular &#40;FA&#41; &#233; uma arritmia supraventricular caracterizada pelo funcionamento descoordenado da aur&#237;cula&#44; resultando na degrada&#231;&#227;o da respetiva fun&#231;&#227;o mec&#226;nica e no consequente aumento do risco de eventos tromboemb&#243;licos&#44; como o acidente vascular cerebral isqu&#233;mico &#40;AVCI&#41;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; A FA n&#227;o valvular - casos em que n&#227;o existe doen&#231;a reum&#225;tica da v&#225;lvula mitral&#44; pr&#243;tese valvular card&#237;aca ou repara&#231;&#227;o de v&#225;lvula<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> - &#233; a disritmia mantida mais comum&#44; aumentando em preval&#234;ncia &#224; medida que a idade avan&#231;a&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Estima-se que 1&#37;-2&#37; da popula&#231;&#227;o sofra de FA&#44; sendo expect&#225;vel que estes valores aumentem com o envelhecimento da popula&#231;&#227;o<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a>&#46; No estudo FAMA&#44; numa amostra populacional portuguesa com idade superior a 40 anos&#44; foi verificada uma preval&#234;ncia global de FA de 2&#44;5&#37;&#44; com aumento significativo depois dos 70 anos&#58; 0&#44;2&#37;&#44; entre 40-49 anos&#59; 1&#44;0&#37; entre 50-59 anos&#59; 1&#44;6&#37; entre 60-69 anos&#59; 6&#44;6&#37; entre 70-79 anos&#59; e 10&#44;4&#37; no grupo com 80 ou mais anos<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; As estimativas para 2012 s&#227;o de cerca de 143 mil casos de FA em Portugal&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Esta patologia pode ser assintom&#225;tica e persistir sem diagn&#243;stico cl&#237;nico&#46; De acordo com os dados do <span class="elsevierStyleItalic">Euro Heart Survey</span>&#44; apenas 69&#37; dos doentes declararam presen&#231;a de sintomas<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#46; A triagem adequada &#40;caracteriza&#231;&#227;o do pulso e electrocardiograma&#41; nem sempre &#233; realizada na pr&#225;tica cl&#237;nica e a sensibilidade estimada dos cuidados de sa&#250;de prim&#225;rios para identifica&#231;&#227;o da FA &#233; de 64&#37;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a>&#46; O conhecimento dos doentes sobre o diagn&#243;stico &#233; tamb&#233;m importante&#44; sendo que&#44; em Portugal&#44; os dados do estudo FAMA mostram que apenas 62&#37; dos indiv&#237;duos com FA t&#234;m conhecimento do mesmo<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">O maior risco tromboemb&#243;lico desta popula&#231;&#227;o conduz n&#227;o s&#243; a uma duplica&#231;&#227;o da taxa de mortalidade<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> como tamb&#233;m a uma maior morbilidade que surge em consequ&#234;ncia da principal complica&#231;&#227;o da doen&#231;a&#58; o AVCI&#46; De facto&#44; a incid&#234;ncia de AVCI aumenta tr&#234;s a quatro vezes nos indiv&#237;duos com FA<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a>&#44; tornando esta arritmia uma das principais causas de AVCI<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; No estudo de Framingham&#44; o risco anual de AVCI atribu&#237;vel a FA foi de 1&#44;5&#37; entre os 50-59 anos e de 23&#44;5&#37; entre os 80-89 anos<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a>&#46; Adicionalmente&#44; os AVCI associados a FA s&#227;o geralmente mais graves&#44; implicando tamb&#233;m maiores custos<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a>&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Atualmente&#44; a principal estrat&#233;gia terap&#234;utica dispon&#237;vel &#233; a utiliza&#231;&#227;o de antagonistas da vitamina K&#44; geralmente representados pela varfarina&#44; que permite reduzir o risco de AVCI em 64&#37; em compara&#231;&#227;o com placebo e em cerca de 40&#37; em compara&#231;&#227;o com o &#225;cido acetilsalic&#237;lico &#40;AAS&#41;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a>&#46; No entanto&#44; as complica&#231;&#245;es associadas &#224; sua utiliza&#231;&#227;o &#40;como as intera&#231;&#245;es medicamentosas e o controlo diet&#233;tico&#41; aliadas &#224;s dificuldades de controlo do INR &#40;e consequente diminui&#231;&#227;o de efic&#225;cia e de seguran&#231;a&#41; conduzem a que frequentemente os doentes eleg&#237;veis para anticoagula&#231;&#227;o n&#227;o sejam medicados com varfarina&#46; Os dados nacionais indicam que entre os doentes eleg&#237;veis&#44; apenas 38&#37; s&#227;o medicados com varfarina&#44; sendo que 40&#37; n&#227;o recebem qualquer terap&#234;utica antitromb&#243;tica<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a><span class="elsevierStyleInf">&#46;</span></p><p id="par0030" class="elsevierStylePara elsevierViewall">Tal facto tem motivado o desenvolvimento de alternativas terap&#234;uticas&#44; com um perfil de efic&#225;cia e seguran&#231;a pelo menos id&#234;ntico ao da varfarina&#44; mas sem necessidade de controlo laboratorial de rotina&#46; Por&#233;m&#44; todas as alternativas desenvolvidas t&#234;m falhado&#44; como os antiagregantes plaquet&#225;rios &#40;&#225;cido acetilsalic&#237;lico e clopidogrel&#41; por insuficiente prote&#231;&#227;o anti-isqu&#233;mica<a class="elsevierStyleCrossRefs" href="#bib0050"><span class="elsevierStyleSup">10&#44;11</span></a> ou os anticoagulantes &#40;ximelagatrano e idraparinux&#41; por deficiente seguran&#231;a<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a>&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">O dabigatrano &#233; um anticoagulante oral que atua por inibi&#231;&#227;o direta e seletiva da trombina&#44; com um efeito dose-resposta previs&#237;vel&#44; pelo que n&#227;o necessita de monitoriza&#231;&#227;o de rotina da coagula&#231;&#227;o&#46; No ensaio cl&#237;nico RE-LY<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#44; em que foram seguidos mais de 18<span class="elsevierStyleHsp" style=""></span>000 doentes com FA n&#227;o valvular durante cerca de dois anos&#44; o dabigatrano na dose de 150<span class="elsevierStyleHsp" style=""></span>mg duas vezes ao dia demonstrou ser mais eficaz que a varfarina na redu&#231;&#227;o do risco de AVC e de embolismo sist&#233;mico&#44; com um risco de hemorragia <span class="elsevierStyleItalic">major</span> semelhante&#44; tendo a dose de 110<span class="elsevierStyleHsp" style=""></span>mg duas vezes ao dia demonstrado uma efic&#225;cia compar&#225;vel &#224; da varfarina&#44; com uma redu&#231;&#227;o significativa do risco de hemorragia <span class="elsevierStyleItalic">major</span>&#46; Com ambas as doses de dabigatrano observaram-se taxas de hemorragia intracraniana muito inferiores &#224; da varfarina&#46; O dabigatrano foi aprovado pela <span class="elsevierStyleItalic">European Medicines Agency</span> para a preven&#231;&#227;o do AVC e embolismo sist&#233;mico em doentes com FA n&#227;o valvular em agosto de 2011&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">Neste contexto&#44; o dabigatrano representa uma importante inova&#231;&#227;o n&#227;o s&#243; para os doentes com FA medicados com varfarina&#44; como tamb&#233;m para aqueles que seguem outro esquema terap&#234;utico&#46; Sendo fundamental a utiliza&#231;&#227;o racional dos recursos dispon&#237;veis para a presta&#231;&#227;o de cuidados de sa&#250;de&#44; &#233; necess&#225;rio verificar se o custo acrescido de qualquer novo medicamento &#233; justificado pelos ganhos em sa&#250;de proporcionados&#46; Com esse objetivo procedeu-se &#224; avalia&#231;&#227;o econ&#243;mica da utiliza&#231;&#227;o do dabigatrano na preven&#231;&#227;o de acidentes vasculares cerebrais em doentes com fibrilha&#231;&#227;o auricular n&#227;o valvular&#44; sendo os m&#233;todos utilizados e os resultados obtidos descritos nas sec&#231;&#245;es seguintes&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">M&#233;todos</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Descri&#231;&#227;o do modelo</span><p id="par0045" class="elsevierStylePara elsevierViewall">O modelo de Markov &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figura 1</a>&#41; utilizado nesta avalia&#231;&#227;o &#233; uma adapta&#231;&#227;o para a realidade portuguesa do j&#225; publicado em estudos econ&#243;micos sobre a introdu&#231;&#227;o do dabigatrano no contexto do Canad&#225;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> e do Reino Unido<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#46; O modelo permite simular a evolu&#231;&#227;o dos doentes em ciclos trimestrais at&#233; ao fim da sua vida&#46; Consequentemente&#44; em cada trimestre &#233; aplicada uma determinada probabilidade de ocorr&#234;ncia mutuamente exclusiva dos eventos mais relevantes para esta popula&#231;&#227;o&#58; morte&#44; AVC isqu&#233;mico e hemorr&#225;gico&#44; acidente isqu&#233;mico transit&#243;rio &#40;AIT&#41;&#44; embolia sist&#233;mica&#44; enfarte agudo do mioc&#225;rdio &#40;EAM&#41;&#44; e hemorragias intra e extracranianas&#46; Tamb&#233;m &#233; simulada a ocorr&#234;ncia de hemorragias <span class="elsevierStyleItalic">minor</span>&#44; sendo que tal pode suceder em concomit&#226;ncia com os restantes eventos&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0050" class="elsevierStylePara elsevierViewall">Assume-se que um indiv&#237;duo que tenha sofrido um evento cerebral &#40;AVC &#8211; quer isqu&#233;mico quer hemorr&#225;gico &#8211; ou hemorragia intracraniana&#41; pode perder a capacidade de ser independente&#46; Assim&#44; de acordo com a escala modificada de Rankin &#40;para os AVC&#41; ou com a escala de Glasgow <span class="elsevierStyleItalic">Outcomes</span> &#40;para a hemorragia intracraniana&#41;&#44; estes doentes poder&#227;o continuar independentes&#44; passar a ser moderadamente dependentes&#44; ou completamente dependentes&#46;</p><p id="par0055" class="elsevierStylePara elsevierViewall">Por outro lado&#44; no modelo&#44; admite-se que o tratamento seja descontinuado permanentemente caso ocorra um AVC hemorr&#225;gico ou uma hemorragia intracraniana&#44; ou descontinuado temporariamente devido a hemorragias extracranianas ou outras raz&#245;es n&#227;o especificadas&#46;</p><p id="par0060" class="elsevierStylePara elsevierViewall">Este tipo de simula&#231;&#227;o da evolu&#231;&#227;o de uma coorte permite estimar os custos e as consequ&#234;ncias cl&#237;nicas associadas a cada op&#231;&#227;o terap&#234;utica&#46; Neste caso&#44; o modelo permite prever os custos&#44; os anos de vida&#44; e os anos de vida ajustados pela qualidade &#40;AVAQ&#41; associados &#224;s alternativas em an&#225;lise&#44; tornando poss&#237;vel calcular quer o custo por ano de vida quer o custo por AVAQ decorrente da op&#231;&#227;o pela estrat&#233;gia terap&#234;utica com melhores resultados cl&#237;nicos&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Comparador</span><p id="par0065" class="elsevierStylePara elsevierViewall">Um dos aspetos fundamentais na elabora&#231;&#227;o de um estudo de avalia&#231;&#227;o econ&#243;mica &#233; a escolha do comparador&#44; isto &#233;&#44; da op&#231;&#227;o terap&#234;utica que ser&#225; substitu&#237;da pelo medicamento sob avalia&#231;&#227;o&#46; O dabigatrano &#233; uma alternativa n&#227;o s&#243; para a varfarina como para as outras op&#231;&#245;es terap&#234;uticas utilizadas nesta popula&#231;&#227;o&#44; nomeadamente a utiliza&#231;&#227;o de AAS e a n&#227;o prescri&#231;&#227;o de medicamentos antitromb&#243;ticos&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">No estudo FAMA<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#44; conforme referido anteriormente&#44; verificou-se que apenas 38&#37; dos doentes eleg&#237;veis eram medicados com varfarina e que 40&#37; n&#227;o eram tratados&#44; tendo sido assumido para efeitos de modeliza&#231;&#227;o que os restantes seriam medicados com AAS&#46; Consequentemente&#44; o comparador utilizado neste estudo &#233; uma combina&#231;&#227;o ponderada de varfarina&#44; AAS e n&#227;o tratamento&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Dados cl&#237;nicos e epidemiol&#243;gicos</span><p id="par0075" class="elsevierStylePara elsevierViewall">O modelo utiliza os resultados do ensaio cl&#237;nico RE-LY<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;15</span></a>&#44; em que foi realizada uma compara&#231;&#227;o direta entre a utiliza&#231;&#227;o de varfarina e de dabigatrano em mais de 18<span class="elsevierStyleHsp" style=""></span>000<span class="elsevierStyleHsp" style=""></span>doentes com FA n&#227;o valvular&#46; Os doentes do estudo RE-LY que apresentavam risco moderado a elevado de AVCI receberam de forma aleat&#243;ria dabigatrano &#40;110<span class="elsevierStyleHsp" style=""></span>mg ou 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span>&#41; ou varfarina com dose ajustada a um INR alvo entre 2&#44;0 e 3&#44;0&#44; durante um per&#237;odo m&#233;dio de dois anos&#46; O estudo decorreu entre dezembro de 2005 e mar&#231;o de 2009 em 44 pa&#237;ses de todo o mundo&#44; tendo Portugal participado com nove centros que inclu&#237;ram 117 doentes&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Neste estudo foi poss&#237;vel estimar a taxa de ocorr&#234;ncia dos diversos eventos considerados nos indiv&#237;duos a tomar varfarina bem como os riscos relativos aplic&#225;veis &#224;s pessoas medicadas com dabigatrano&#46;</p><p id="par0085" class="elsevierStylePara elsevierViewall">No final do estudo verificou-se que a dose de 110<span class="elsevierStyleHsp" style=""></span>mg permitiu uma redu&#231;&#227;o de 10&#37; no indicador prim&#225;rio &#8211; incid&#234;ncia de AVC ou embolias sist&#233;micas &#8211; embora sem diferen&#231;a estatisticamente significativa na an&#225;lise de superioridade&#46; O perfil de seguran&#231;a obtido foi superior&#44; verificando-se uma redu&#231;&#227;o de 20&#37; nas hemorragias <span class="elsevierStyleItalic">major</span> comparativamente &#224; varfarina &#40;p<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#44;003&#41;&#46; A dose de 150<span class="elsevierStyleHsp" style=""></span>mg apresentou uma efic&#225;cia superior &#224; da varfarina&#44; com uma redu&#231;&#227;o de 35&#37; na incid&#234;ncia do indicador prim&#225;rio &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41; e de 7&#37; nas hemorragias <span class="elsevierStyleItalic">major</span> &#40;sem signific&#226;ncia estat&#237;stica&#41;&#46; O tratamento com dabigatrano diminuiu de forma marcada a incid&#234;ncia de hemorragias intracranianas tendo estas sido reduzidas em 70&#37; com a dose de 110<span class="elsevierStyleHsp" style=""></span>mg &#40;p<span class="elsevierStyleHsp" style=""></span>&#60; 0&#44;001&#41; e em 59&#37; com a dose de 150<span class="elsevierStyleHsp" style=""></span>mg &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001&#41;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">A dispepsia &#40;incluindo dor abdominal&#41; foi o &#250;nico efeito adverso significativamente mais comum com dabigatrano do que com a varfarina&#44; ocorrendo em 5&#44;8&#37; dos doentes do grupo da varfarina e em 11&#44;8 e 11&#44;3&#37; dos doentes dos grupos de 110<span class="elsevierStyleHsp" style=""></span>mg e 150<span class="elsevierStyleHsp" style=""></span>mg de dabigatrano&#44; respetivamente &#40;p<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>0&#44;001 para ambas as compara&#231;&#245;es&#41;&#46; Globalmente&#44; as taxas de outros eventos adversos foram semelhantes entre os grupos de tratamento&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Adicionalmente foi realizada uma meta-an&#225;lise que permitiu estimar o risco relativo de ocorr&#234;ncia dos diversos eventos nos doentes sob terap&#234;utica com AAS e naqueles sem tratamento<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a>&#46; Na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a> encontram-se os valores obtidos&#44; sendo o risco inicial de AVCI estratificado de acordo com o &#237;ndice CHADS<span class="elsevierStyleInf">2</span>&#46; Realce-se que os valores obtidos s&#227;o diferentes dos apresentados na publica&#231;&#227;o dos resultados cl&#237;nicos do RE-LY dado terem sido adaptados &#224; aprova&#231;&#227;o da <span class="elsevierStyleItalic">European Medicines Agency</span> que&#44; em termos gerais&#44; indica que a dose de 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> deve ser usada em doentes com menos de 80 anos e a dose de 110<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> naqueles com 80 ou mais anos<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Como se constata pela leitura da tabela&#44; quando comparado com varfarina&#44; o dabigatrano permite uma redu&#231;&#227;o significativa dos eventos considerados&#44; nomeadamente AVC isqu&#233;micos e hemorr&#225;gicos&#44; embolias sist&#233;micas&#44; AITs&#44; hemorragias intra e extracranianas &#40;nestas apenas nos doentes com idade inferior a 80 anos&#41;&#44; e hemorragias <span class="elsevierStyleItalic">minor</span>&#46; Naturalmente&#44; estas vantagens cl&#237;nicas s&#227;o ainda mais vincadas quando se consideram as alternativas AAS e n&#227;o tratamento&#46; Verificou-se ainda uma diferen&#231;a num&#233;rica na taxa de EAM&#44; favor&#225;vel &#224; varfarina&#44; embora esta diferen&#231;a n&#227;o tenha atingido significado estat&#237;stico<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a>&#46;</p><p id="par0105" class="elsevierStylePara elsevierViewall">Em termos epidemiol&#243;gicos&#44; foram considerados os dados portugueses obtidos no estudo FAMA para definir a propor&#231;&#227;o de homens e de mulheres na popula&#231;&#227;o com FA em Portugal&#44; bem como para estimar a idade m&#233;dia<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a>&#46; Os dados dispon&#237;veis indicam que 55&#37; dos doentes com menos de 80 anos s&#227;o homens&#44; descendo esta percentagem para 26&#37; quando se considera a faixa et&#225;ria mais elevada&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Qualidade de vida</span><p id="par0110" class="elsevierStylePara elsevierViewall">A estima&#231;&#227;o dos AVAQ associados a cada uma das op&#231;&#245;es implica incorporar o facto da qualidade de vida das pessoas diminuir com a exist&#234;ncia de doen&#231;a e com a ocorr&#234;ncia de eventos&#46; Assim&#44; &#233; importante analisar a qualidade de vida inicial dos doentes que constituem a popula&#231;&#227;o em an&#225;lise e estimar o impacto da ocorr&#234;ncia de eventos nessa mesma qualidade de vida&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">Para tal&#44; foram utilizados os resultados de uma meta-an&#225;lise<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> que incorporou resultados de 20 estudos de avalia&#231;&#227;o de qualidade de vida e de um estudo em que os autores estimaram valores de utilidade para v&#225;rias doen&#231;as cr&#243;nicas utilizando uma amostra representativa da popula&#231;&#227;o norte-americana atrav&#233;s de dados recolhidos pelo <span class="elsevierStyleItalic">Medical Expenditure Panel Survey</span><a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a>&#46; A primeira&#44; relativa a indiv&#237;duos com hist&#243;ria de AVCI&#44; permitiu estabelecer ponderadores por n&#237;vel de depend&#234;ncia ap&#243;s ocorr&#234;ncia de AVCI&#59; o segundo foi utilizado para valorizar o impacto da ocorr&#234;ncia de eventos na qualidade de vida &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Tabela 2</a>&#41;&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Dados econ&#243;micos</span><p id="par0120" class="elsevierStylePara elsevierViewall">Os recursos consumidos no tratamento e seguimento de eventos foram estimados a partir das respostas de um painel de peritos composto por seis especialistas com comprovada experi&#234;ncia cl&#237;nica &#40;dois cardiologistas&#44; dois cl&#237;nicos gerais e dois neurologistas&#41;&#46;</p><p id="par0125" class="elsevierStylePara elsevierViewall">A conjuga&#231;&#227;o dos recursos identificados pelo painel com os respetivos custos unit&#225;rios &#40;l&#237;quidos de IVA<a class="elsevierStyleCrossRef" href="#fn1"><span class="elsevierStyleSup">a</span></a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#8211;24</span></a> permitiu a estima&#231;&#227;o dos custos incorridos durante o tratamento dos epis&#243;dios agudos e durante o seguimento dos doentes&#46; Os custos com o dabigatrano s&#227;o baseados no pre&#231;o proposto pela empresa detentora da patente para ambas as dosagens &#40;110<span class="elsevierStyleHsp" style=""></span>mg e 150<span class="elsevierStyleHsp" style=""></span>mg&#41;&#46; Os custos s&#227;o apresentados na <a class="elsevierStyleCrossRef" href="#tbl0015">Tabela 3</a>&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">Nos resultados apresentados adiante&#44; a valoriza&#231;&#227;o dos custos foi realizada de acordo com a perspetiva da sociedade&#44; ou seja&#44; os custos foram considerados na sua totalidade&#44; independentemente de serem financiados pelo Estado ou pelos doentes&#46; Os resultados na perspetiva do Estado tamb&#233;m foram calculados&#44; sendo os custos incrementais e consequentemente os r&#225;cios custo-efetividade aproximadamente 70&#37; dos apresentados&#46; Tal reflete o facto da taxa de comparticipa&#231;&#227;o atribu&#237;vel ao dabigatrano ser de 69&#37;&#46;</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Resultados</span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Cen&#225;rio principal</span><p id="par0135" class="elsevierStylePara elsevierViewall">Naturalmente&#44; os resultados obtidos refletem a evid&#234;ncia cl&#237;nica dispon&#237;vel&#58; o dabigatrano permite uma diminui&#231;&#227;o de quase todos os eventos considerados&#44; nomeadamente AVCI&#44; embolia sist&#233;mica&#44; AIT&#44; AVCH e hemorragias intracranianas&#44; registando-se uma maior incid&#234;ncia de EAM e de hemorragias extracranianas &#40;devido ao maior risco ap&#243;s os 80 anos em doentes a tomar 110<span class="elsevierStyleHsp" style=""></span>mg de dabigatrano&#41;&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A menor ocorr&#234;ncia de eventos reflete-se quer nos anos de vida quer nos AVAQ de que beneficiam os doentes medicados com dabigatrano&#46; O dabigatrano permite obter mais 0&#44;415 anos de vida e 0&#44;439 AVAQ por doente quando o come&#231;o da terap&#234;utica se faz antes dos 80 anos&#44; sendo estes ganhos de 0&#44;143 anos de vida e 0&#44;166 AVAQ quando a terap&#234;utica se inicia ap&#243;s os 80&#46; Em termos m&#233;dios&#44; assumindo que 69&#37; da popula&#231;&#227;o com FA tem idade inferior a 80 anos<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a>&#44; o dabigatrano proporciona 0&#44;331 anos de vida e 0&#44;354 AVAQ&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Os custos di&#225;rios da terap&#234;utica com dabigatrano s&#227;o superiores aos da varfarina ou AAS&#46; Contudo&#44; considerando os custos dos eventos e do acompanhamento dos doentes&#44; o tratamento com dabigatrano permite atenuar entre 20-30&#37; esse incremento de custos&#46; Verifica-se ent&#227;o um aumento do custo da terap&#234;utica preventiva de 5572&#160;&#8364; para doentes com idade inferior a 80 anos&#44; de 2300&#160;&#8364; para doentes com idade superior a 80 anos&#44; e de 4558&#160;&#8364; em termos m&#233;dios&#59; o aumento dos custos totais &#233; de 3763&#160;&#8364;&#44; 1231&#160;&#8364; e 2978&#160;&#8364;&#44; respetivamente&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">A conjuga&#231;&#227;o dos resultados cl&#237;nicos e econ&#243;micos permite calcular os r&#225;cios custo efetividade incrementais &#40;RCEI&#41; por AVAQ e por ano de vida &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Tabela 4</a>&#41;&#46; Mesmo n&#227;o existindo em Portugal nenhum limite pr&#233;-fixado &#224; disponibilidade a pagar por ano de vida ou por AVAQ ganho&#44; &#233; poss&#237;vel afirmar que os valores obtidos &#8211; aproximadamente 10<span class="elsevierStyleHsp" style=""></span>000 &#8364; quer por ano de vida quer por AVAQ &#8211; s&#227;o aceit&#225;veis para a realidade portuguesa&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">An&#225;lise de sensibilidade</span><p id="par0155" class="elsevierStylePara elsevierViewall">Na prossecu&#231;&#227;o de todas as avalia&#231;&#245;es econ&#243;micas &#233; necess&#225;rio assumir hip&#243;teses que permitam constituir um cen&#225;rio principal&#46; Por&#233;m&#44; como essas hip&#243;teses podem condicionar os resultados obtidos&#44; &#233; importante analisar o impacto de se assumirem valores alternativos para os par&#226;metros relevantes&#46; Para tal&#44; &#233; usual realizar-se uma an&#225;lise da sensibilidade do resultado final &#224;s hip&#243;teses assumidas&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">Neste contexto&#44; &#233; importante salientar que existem dois tipos de par&#226;metros&#58; uns para os quais &#233; poss&#237;vel associar uma distribui&#231;&#227;o estat&#237;stica que reflita a incerteza&#44; como as probabilidades de ocorr&#234;ncia dos v&#225;rios eventos considerados&#59; outros cuja incerteza n&#227;o &#233; pass&#237;vel de ser assim caracterizada&#44; como a taxa de atualiza&#231;&#227;o ou o horizonte temporal&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Relativamente aos primeiros&#44; &#233; poss&#237;vel realizar uma an&#225;lise de sensibilidade probabil&#237;stica simulando simultaneamente diferentes ocorr&#234;ncias dos diversos par&#226;metros&#46; Na <a class="elsevierStyleCrossRef" href="#fig0010">Figura 2</a> apresentam-se&#44; a t&#237;tulo exemplificativo&#44; os resultados relativos a custos e anos de vida incrementais das 1000 simula&#231;&#245;es realizadas para a popula&#231;&#227;o que inicia terap&#234;utica antes dos 80 anos&#46; Uma vantagem deste tipo de an&#225;lise de sensibilidade &#233; que permite definir a propor&#231;&#227;o de simula&#231;&#245;es em que o r&#225;cio custo-efetividade &#233; inferior a determinada disposi&#231;&#227;o a pagar &#40;ver <a class="elsevierStyleCrossRef" href="#tbl0025">Tabela 5</a>&#41;&#46; Constata-se que considerando valores tradicionalmente assumidos como aproximados da disponibilidade a pagar pelos ganhos em sa&#250;de&#44; a ado&#231;&#227;o de dabigatrano ser&#225; muito provavelmente custo-efetiva&#46; De facto&#44; na quase totalidade das 1000 simula&#231;&#245;es realizadas&#44; o dabigatrano est&#225; associado a um r&#225;cio custo-efetividade inferior a 15<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&#44; quando o limite geralmente utilizado em Portugal ser&#225; cerca do dobro deste valor&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0170" class="elsevierStylePara elsevierViewall">Quanto aos restantes par&#226;metros &#233; mais relevante realizar uma an&#225;lise de sensibilidade univariada que permita avaliar o impacto de se assumirem valores diferentes dos utilizados no cen&#225;rio principal&#46; Na <a class="elsevierStyleCrossRef" href="#tbl0030">Tabela 6</a>&#44; apresentam-se os resultados para diferentes taxas de atualiza&#231;&#227;o&#44; horizonte temporal&#44; e custos&#46; Realce-se que quer a taxa de atualiza&#231;&#227;o &#40;5&#37;&#41; quer o horizonte temporal <span class="elsevierStyleItalic">&#40;lifetime&#41;</span> utilizados no cen&#225;rio principal decorrem do estipulado nas orienta&#231;&#245;es metodol&#243;gicas em vigor em Portugal<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">25</span></a>&#46; Todavia&#44; se a an&#225;lise relativa &#224; taxa de atualiza&#231;&#227;o reflete uma incerteza real quanto ao seu valor &#243;timo&#44; j&#225; a relativa ao horizonte temporal servir&#225; apenas para averiguar a amplitude temporal do impacto do medicamento em avalia&#231;&#227;o&#44; dado que em termos metodol&#243;gicos &#233; consensual que as diferen&#231;as entre as op&#231;&#245;es terap&#234;uticas devem ser avaliadas at&#233; ao momento em que essas mesmas diferen&#231;as cessem&#44; o que no caso de terap&#234;uticas cr&#243;nicas acontece no momento da morte&#46;</p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0175" class="elsevierStylePara elsevierViewall">Relativamente aos custos &#233; importante salientar que&#44; em teoria&#44; poderiam ser inclu&#237;dos na an&#225;lise de sensibilidade probabil&#237;stica&#46; No entanto&#44; dado que foram estimados a partir do consenso de um painel de peritos sobre os recursos consumidos pela popula&#231;&#227;o em an&#225;lise&#44; a avalia&#231;&#227;o do seu impacto no resultado final parece ser mais esclarecedora atrav&#233;s de uma an&#225;lise de sensibilidade univariada&#46;</p><p id="par0180" class="elsevierStylePara elsevierViewall">A an&#225;lise de sensibilidade univariada permite concluir que os par&#226;metros considerados&#44; com exce&#231;&#227;o do horizonte temporal&#44; n&#227;o t&#234;m grande impacto nos r&#225;cios custo-efetividade&#44; j&#225; que as altera&#231;&#245;es introduzidas implicam varia&#231;&#245;es de apenas cerca de 10&#37;&#46; O facto de o horizonte temporal ter um impacto mais relevante &#233; normal&#44; dado que a utiliza&#231;&#227;o de per&#237;odos mais curtos impede a incorpora&#231;&#227;o de parte consider&#225;vel dos ganhos do dabigatrano&#46; Ali&#225;s&#44; tal &#233; comum acontecer nas avalia&#231;&#245;es econ&#243;micas de terap&#234;uticas preventivas&#46; Naturalmente&#44; dada a menor esperan&#231;a de vida da coorte acima dos 80 anos&#44; o impacto da diminui&#231;&#227;o do horizonte temporal nos resultados relevantes para esta popula&#231;&#227;o &#233; bastante menos significativo&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Discuss&#227;o</span><p id="par0185" class="elsevierStylePara elsevierViewall">Em primeiro lugar&#44; &#233; relevante referir que se optou por&#44; de forma conservadora&#44; assumir que a varfarina tem a efic&#225;cia que foi obtida no ensaio cl&#237;nico&#46; De facto&#44; sendo o controlo dos n&#237;veis de INR um fator fundamental para se conseguir obter e manter os benef&#237;cios decorrentes da utiliza&#231;&#227;o de varfarina&#44; e sendo expect&#225;vel que esse controlo tenha sido mais f&#225;cil de efetuar nas condi&#231;&#245;es inerentes &#224; realiza&#231;&#227;o do ensaio cl&#237;nico RE-LY&#44; &#233; de admitir que a efetividade da varfarina em condi&#231;&#245;es de pr&#225;tica cl&#237;nica corrente seja inferior &#224; que foi assumida nesta avalia&#231;&#227;o econ&#243;mica&#46; A capacidade da varfarina prevenir AVCI em condi&#231;&#245;es de pr&#225;tica cl&#237;nica pode ser pouco mais de metade da que &#233; estimada nas condi&#231;&#245;es usuais de ensaios cl&#237;nicos<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">26</span></a>&#46; Tal dever-se-&#225; principalmente &#224;s intera&#231;&#245;es com outros medicamentos e com alimentos&#44; &#224; inconveni&#234;ncia da monitoriza&#231;&#227;o&#44; e ao risco de hemorragia&#46;</p><p id="par0190" class="elsevierStylePara elsevierViewall">Por outro lado&#44; principalmente devido &#224;s indica&#231;&#245;es de utiliza&#231;&#227;o do dabigatrano resultantes da aprova&#231;&#227;o pela <span class="elsevierStyleItalic">European Medicines Agency</span>&#44; designadamente a rela&#231;&#227;o entre faixa et&#225;ria e dose di&#225;ria&#44; a pot&#234;ncia estat&#237;stica do ensaio cl&#237;nico RE-LY foi diminu&#237;da&#46; Tal acontece porque todas as observa&#231;&#245;es de indiv&#237;duos com idade inferior a 80 anos aleatorizados para 110<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> e de indiv&#237;duos com idade igual ou superior a 80 e aleatorizados para 150<span class="elsevierStyleHsp" style=""></span>mg <span class="elsevierStyleItalic">bid</span> se tornaram irrelevantes no &#226;mbito desta avalia&#231;&#227;o econ&#243;mica&#46; Assim&#44; parte dos riscos relativos apresentados na <a class="elsevierStyleCrossRef" href="#tbl0005">Tabela 1</a> n&#227;o s&#227;o estatisticamente significativos&#46; No entanto&#44; a an&#225;lise de sensibilidade probabil&#237;stica&#44; que permite considerar a totalidade da distribui&#231;&#227;o estat&#237;stica de cada risco relativo&#44; mostra que o r&#225;cio custo-efetividade ser&#225; muito provavelmente inferior aos limites m&#225;ximos aceit&#225;veis no contexto portugu&#234;s&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">As an&#225;lises de sensibilidade realizadas mostram que os resultados s&#227;o relativamente robustos &#224; incerteza inerente quer aos dados cl&#237;nicos quer aos custos estimados para Portugal&#46; Neste contexto &#233; importante real&#231;ar que uma varia&#231;&#227;o dos custos em 20&#37; conduziu a altera&#231;&#245;es dos r&#225;cios em cerca de 15&#37;&#46;</p><p id="par0200" class="elsevierStylePara elsevierViewall">Finalmente&#44; a compara&#231;&#227;o dos r&#225;cios obtidos para Portugal com os j&#225; publicados para outros pa&#237;ses onde a avalia&#231;&#227;o econ&#243;mica tamb&#233;m &#233; um auxiliar na fundamenta&#231;&#227;o de decis&#245;es de financiamento de medicamentos &#40;designadamente Canad&#225;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> e Reino Unido<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a>&#41; mostra que os resultados s&#227;o conservadores&#46; De facto&#44; as estimativas dos custos associados &#224; monitoriza&#231;&#227;o do INR e&#44; principalmente dos custos decorrentes do AVCI&#44; s&#227;o menores em Portugal do que nos dois pa&#237;ses referidos&#46; Consequentemente&#44; representando estes par&#226;metros as principais &#225;reas em que a introdu&#231;&#227;o do dabigatrano conduz a um inferior consumo de recursos&#44; a sua menor magnitude conduz a r&#225;cios custo-efetividade maiores que os obtidos internacionalmente&#46;</p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclus&#227;o</span><p id="par0205" class="elsevierStylePara elsevierViewall">Os resultados apresentados mostram que o dabigatrano representa um importante desenvolvimento para os doentes com FA n&#227;o valvular&#44; ao diminuir o risco de AVC isqu&#233;mico e hemorr&#225;gico e de hemorragia intracraniana&#44; bem como as respetivas sequelas a longo prazo&#46; Os custos com dabigatrano s&#227;o parcialmente compensados por uma diminui&#231;&#227;o dos custos devidos &#224; ocorr&#234;ncia de eventos&#44; bem como&#44; por poupan&#231;as com a aus&#234;ncia de monitoriza&#231;&#227;o do INR&#46; Assim&#44; esta avalia&#231;&#227;o econ&#243;mica permite concluir que para al&#233;m de ser uma terap&#234;utica eficaz e segura&#44; conforme ficou demonstrado no ensaio cl&#237;nico RE-LY&#44; o dabigatrano &#233; tamb&#233;m uma op&#231;&#227;o terap&#234;utica custo-efetiva para os doentes portugueses com FA&#46;</p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Responsabilidades &#233;ticas</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Prote&#231;&#227;o de pessoas e animais</span><p id="par0210" class="elsevierStylePara elsevierViewall">Os autores declaram que para esta investiga&#231;&#227;o n&#227;o se realizaram experi&#234;ncias em seres humanos e&#47;ou animais&#46;</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Confidencialidade dos dados</span><p id="par0215" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Direito &#224; privacidade e consentimento escrito</span><p id="par0220" class="elsevierStylePara elsevierViewall">Os autores declaram que n&#227;o aparecem dados de pacientes neste artigo&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Financiamento</span><p id="par0225" class="elsevierStylePara elsevierViewall">Este trabalho foi realizado com o apoio financeiro da Boehringer Ingelheim&#44; Lda&#46; O financiamento do projeto foi efetuado diretamente ao CISEP e n&#227;o foi condicional &#224; obten&#231;&#227;o de nenhum tipo espec&#237;fico de resultados&#46;</p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Conflito de interesses</span><p id="par0230" class="elsevierStylePara elsevierViewall">Este trabalho foi realizado com o apoio financeiro da Boehringer Ingelheim&#44; Lda&#46;&#46; O financiamento do projeto foi efetuado diretamente ao CISEP e n&#227;o foi condicional &#224; obten&#231;&#227;o de nenhum tipo espec&#237;fico de resultados&#46;</p></span></span>"
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            0 => "Acidente vascular cerebral"
            1 => "Preven&#231;&#227;o"
            2 => "Fibrilha&#231;&#227;o auricular"
            3 => "Dabigatrano"
            4 => "Custo-efetividade"
            5 => "Portugal"
          ]
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        1 => array:4 [
          "clase" => "abr"
          "titulo" => "Abreviaturas"
          "identificador" => "xpalclavsec245335"
          "palabras" => array:16 [
            0 => "AAS&#193;"
            1 => "AIT"
            2 => "AV"
            3 => "AVAQ"
            4 => "AVC"
            5 => "AVCH"
            6 => "AVCI"
            7 => "bid"
            8 => "EAM"
            9 => "ES"
            10 => "FA"
            11 => "HI"
            12 => "INR"
            13 => "IVA"
            14 => "qd"
            15 => "RCEI"
          ]
        ]
      ]
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec245336"
          "palabras" => array:6 [
            0 => "Stroke"
            1 => "Prevention"
            2 => "Atrial fibrillation"
            3 => "Dabigatran"
            4 => "Cost-effectiveness"
            5 => "Portugal"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0010">Introdu&#231;&#227;o e objetivos</span><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Estimar os r&#225;cios custo-efetividade e custo-utilidade associados &#224; utiliza&#231;&#227;o de dabigatrano na preven&#231;&#227;o de acidentes vasculares cerebrais e embolias sist&#233;micas em doentes com fibrilha&#231;&#227;o auricular n&#227;o valvular em Portugal&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0015">Metodologia</span><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Foi utilizado um modelo de Markov para simular a evolu&#231;&#227;o dos doentes&#44; estimando a ocorr&#234;ncia de acidentes vasculares cerebrais isqu&#233;micos e hemorr&#225;gicos&#44; de acidentes isqu&#233;micos transit&#243;rios&#44; de embolias sist&#233;micas&#44; de enfartes agudos do mioc&#225;rdio e de hemorragias intra e extracranianas&#46; Os par&#226;metros cl&#237;nicos baseiam-se nos resultados do estudo RE-LY&#44; que compara a utiliza&#231;&#227;o de dabigatrano com a de varfarina&#44; e numa meta-an&#225;lise em que se estimou o risco de ocorr&#234;ncia de cada evento em doentes medicados com &#225;cido acetilsalic&#237;lico ou sem qualquer terap&#234;utica antitromb&#243;tica&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0020">Resultados</span><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">O dabigatrano proporciona&#44; a cada doente&#44; um incremento de 0&#44;331 e de 0&#44;354 anos de vida ajustados pela qualidade&#46; Na perspetiva da sociedade&#44; estes ganhos cl&#237;nicos implicam um aumento da despesa em 2&#46;978<span class="elsevierStyleHsp" style=""></span>&#8364;&#46; Assim&#44; o custo incremental por ano de vida ganho &#233; de 9&#46;006<span class="elsevierStyleHsp" style=""></span>&#8364;&#44; sendo o custo incremental por ano de vida ajustado pela qualidade de 8&#46;409<span class="elsevierStyleHsp" style=""></span>&#8364;&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0025">Conclus&#245;es</span><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Os resultados obtidos mostram que o dabigatrano diminui a quantidade de eventos&#44; nomeadamente os de maior gravidade como os acidentes vasculares cerebrais isqu&#233;micos e hemorr&#225;gicos&#44; bem como as respetivas sequelas de longo prazo&#46; Os custos com dabigatrano s&#227;o parcialmente compensados por uma diminui&#231;&#227;o dos custos decorrentes dos eventos&#44; bem como pela aus&#234;ncia de monitoriza&#231;&#227;o do INR&#46; Assim&#44; pode concluir-se que a utiliza&#231;&#227;o de dabigatrano na pr&#225;tica cl&#237;nica portuguesa &#233; custo-efetiva&#46;</p>"
      ]
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span class="elsevierStyleSectionTitle" id="sect0035">Introduction and Objectives</span><p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">To estimate the cost-effectiveness and cost-utility of dabigatran in the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation in Portugal&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0040">Methodology</span><p id="spar0105" class="elsevierStyleSimplePara elsevierViewall">A Markov model was used to simulate patients&#8217; clinical course&#44; estimating the occurrence of ischemic and hemorrhagic stroke&#44; transient ischemic attack&#44; systemic embolism&#44; myocardial infarction&#44; and intra- and extracranial hemorrhage&#46; The clinical parameters are based on the results of the RE-LY trial&#44; which compared dabigatran with warfarin&#44; and on a meta-analysis that estimated the risk of each event in patients treated with aspirin or with no antithrombotic therapy&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0045">Results</span><p id="spar0110" class="elsevierStyleSimplePara elsevierViewall">Dabigatran provides an increase of 0&#46;331 life years and 0&#46;354 quality-adjusted life years for each patient&#46; From a societal perspective&#44; these clinical gains entail an additional expenditure of 2978 euros&#46; Thus&#44; the incremental cost is 9006 euros per life year gained and 8409 euros per quality-adjusted life year&#46;</p> <span class="elsevierStyleSectionTitle" id="sect0050">Conclusions</span><p id="spar0115" class="elsevierStyleSimplePara elsevierViewall">The results show that dabigatran reduces the number of events&#44; especially the most severe such as ischemic and hemorrhagic stroke&#44; as well as their long-term sequelae&#46; The expense of dabigatran is partially offset by lower event-related costs and by the fact that INR monitoring is unnecessary&#46; It can thus be concluded that the use of dabigatran in clinical practice in Portugal is cost-effective&#46;</p>"
      ]
    ]
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      0 => array:2 [
        "etiqueta" => "a"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Os valores respeitantes ao Imposto sobre o Valor Acrescentado &#40;IVA&#41; n&#227;o devem ser inclu&#237;dos nos estudos de avalia&#231;&#227;o econ&#243;mica dado que representam apenas uma transfer&#234;ncia entre o pagador e o Estado&#44; n&#227;o constituindo realmente um custo&#46;</p>"
      ]
    ]
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        "identificador" => "fig0005"
        "etiqueta" => "Figura 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 2340
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Modelo de Markov&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Figura 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
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          "pt" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">An&#225;lise de sensibilidade probabil&#237;stica&#46;</p>"
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      2 => array:7 [
        "identificador" => "tbl0005"
        "etiqueta" => "Tabela 1"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:3 [
          "leyenda" => "<p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">AAS&#58; &#225;cido acetilsalic&#237;lico&#59; AIT&#58; acidente isqu&#233;mico transit&#243;rio&#59; AVC&#58; acidente vascular cerebral&#59; <span class="elsevierStyleItalic">bid</span>&#58; duas vezes por dia&#59; EAM&#58; enfarte agudo do mioc&#225;rdio&#46;</p>"
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                0 => """
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Varfarina</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="4" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Risco relativo vs varfarina</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#60;&#160;80 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">&#62;&#160;80 anos&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">Dabigatrano</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">AAS&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">N&#227;o Tratamento&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">150 <span class="elsevierStyleItalic">bid</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">110 <span class="elsevierStyleItalic">bid</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
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                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="7" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleBold">AVC isqu&#233;mico</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " colspan="7" align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">&#205;ndice CHADS2</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Diminui&#231;&#227;o de qualidade de vida associada a cada evento</span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AVCI&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">0&#44;139&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Embolia sist&#233;mica&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;120&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AIT&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hemorragia intracraniana&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;181&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>AVCH&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hemorragia extracraniana&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;181&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hemorragia <span class="elsevierStyleItalic">minor</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;004&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>EAM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;125&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Varfarina 5</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg qd</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">&#193;cido acetilsalic&#237;lico 150</span><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">mg</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">AVC isqu&#233;mico ou hemorr&#225;gico</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">4135&#44;79&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Embolia sist&#233;mica</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">1537&#44;56&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Acidente isqu&#233;mico transit&#243;rio</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">3215&#44;79&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia intracraniana</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia extracraniana fatal</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Hemorragia extracraniana</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">EAM fatal</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">EAM</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t">3108&#44;17&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">118&#44;59&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro ano&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">82&#44;50&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro trimestre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2515&#44;06&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Resto do primeiro ano&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1333&#44;00&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Anos seguintes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">283&#44;50&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Dependente</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Primeiro trimestre&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2337&#44;94&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleHsp" style=""></span>Resto do primeiro ano&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1155&#44;88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">Custos trimestrais de monitoriza&#231;&#227;o de INR</span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Se INR dentro dos limites</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">52&#44;77&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">Se INR fora dos limites</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">57&#44;47&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
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                0 => "xTab359364.png"
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Dados econ&#243;micos &#40;&#8364;&#41;</p>"
        ]
      ]
      5 => array:7 [
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="3" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Sociedade</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Menores de 80&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">80 ou mais&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">M&#233;dia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo incremental &#40;a&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3763&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1231&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2978&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anos de vida incrementais &#40;b&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;415&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;143&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;331&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">AVAQ incrementais &#40;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;439&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;166&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">0&#44;354&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo por ano de vida &#40;a&#47;b&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9071&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8592&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9006&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Custo por AVAQ &#40;a&#47;c&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8577&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7420&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8409&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "pt" => "<p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">R&#225;cios custo efetividade incrementais &#40;&#8364;&#41;</p>"
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      6 => array:7 [
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        "mostrarFloat" => true
        "mostrarDisplay" => false
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0090" class="elsevierStyleSimplePara elsevierViewall">AV&#58; anos de vida&#59; AVAQ&#58; anos de vida ajustados pela qualidade&#59; RCEI&#58; r&#225;cio custo-efetividade incremental&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Menores de 80</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Maiores de 80</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AV &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AVAQ &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AV &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" style="border-bottom: 2px solid black">Custo por AVAQ &#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;10<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">69&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">76&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">53&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">63&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;15<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">97&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">75&#44;1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">83&#44;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCEI &#60;&#160;20<span class="elsevierStyleHsp" style=""></span>000&#160;&#8364;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">99&#44;9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="char" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">84&#44;7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:3 [
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                    0 => array:2 [
                      "doi" => "10.1093/eurheartj/ehq278"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur Heart J&#46;"
                        "fecha" => "2010"
                        "volumen" => "31"
                        "paginaInicial" => "2369"
                        "paginaFinal" => "2429"
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                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20802247"
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                0 => array:1 [
                  "referenciaCompleta" => "Aguiar C&#44; Macedo M&#44; Sousa J&#44; et al&#46; Terap&#234;utica Antitromb&#243;tica da Fibrilha&#231;&#227;o Auricular&#44; Coordena&#231;&#227;o Nacional para as Doen&#231;as Cardiovasculares&#46; Dispon&#237;vel em&#58; <a id="intr0005" class="elsevierStyleInterRef" href="http://www.spc.pt/DL/home/RecomendacoesTAFA.pdf.%202009">http&#58;&#47;&#47;www&#46;spc&#46;pt&#47;DL&#47;home&#47;RecomendacoesTAFA&#46;pdf&#46; 2009</a> &#91;consultado 21 Dez 2012&#93;&#46;"
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                      "titulo" => "Preval&#234;ncia de fibrilha&#231;&#227;o auricular na popula&#231;&#227;o portuguesa com 40 ou mais anos &#8211; Estudo FAMA"
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Informação do artigo
ISSN: 08702551
Idioma original: Português
Dados atualizados diariamente
Ano/Mês Html Pdf Total
2024 Novembro 7 6 13
2024 Outubro 41 29 70
2024 Setembro 63 30 93
2024 Agosto 62 38 100
2024 Julho 33 30 63
2024 Junho 23 26 49
2024 Maio 54 30 84
2024 Abril 55 47 102
2024 Maro 44 27 71
2024 Fevereiro 26 25 51
2024 Janeiro 25 30 55
2023 Dezembro 29 21 50
2023 Novembro 35 48 83
2023 Outubro 26 13 39
2023 Setembro 28 26 54
2023 Agosto 24 18 42
2023 Julho 28 15 43
2023 Junho 19 14 33
2023 Maio 48 28 76
2023 Abril 32 7 39
2023 Maro 75 22 97
2023 Fevereiro 51 17 68
2023 Janeiro 30 11 41
2022 Dezembro 56 25 81
2022 Novembro 104 25 129
2022 Outubro 56 29 85
2022 Setembro 88 34 122
2022 Agosto 47 37 84
2022 Julho 39 43 82
2022 Junho 33 33 66
2022 Maio 38 29 67
2022 Abril 40 36 76
2022 Maro 52 38 90
2022 Fevereiro 30 25 55
2022 Janeiro 44 25 69
2021 Dezembro 29 28 57
2021 Novembro 39 36 75
2021 Outubro 34 27 61
2021 Setembro 27 22 49
2021 Agosto 27 32 59
2021 Julho 17 28 45
2021 Junho 23 18 41
2021 Maio 28 28 56
2021 Abril 29 10 39
2021 Maro 37 22 59
2021 Fevereiro 40 4 44
2021 Janeiro 25 13 38
2020 Dezembro 21 15 36
2020 Novembro 25 8 33
2020 Outubro 33 7 40
2020 Setembro 34 12 46
2020 Agosto 25 11 36
2020 Julho 40 10 50
2020 Junho 50 4 54
2020 Maio 23 8 31
2020 Abril 43 14 57
2020 Maro 61 21 82
2020 Fevereiro 60 16 76
2020 Janeiro 36 13 49
2019 Dezembro 36 19 55
2019 Novembro 24 9 33
2019 Outubro 25 5 30
2019 Setembro 41 15 56
2019 Agosto 27 6 33
2019 Julho 39 9 48
2019 Junho 26 21 47
2019 Maio 46 27 73
2019 Abril 23 27 50
2019 Maro 92 23 115
2019 Fevereiro 94 14 108
2019 Janeiro 80 9 89
2018 Dezembro 136 15 151
2018 Novembro 262 12 274
2018 Outubro 629 24 653
2018 Setembro 94 11 105
2018 Agosto 33 4 37
2018 Julho 61 11 72
2018 Junho 77 11 88
2018 Maio 118 3 121
2018 Abril 128 15 143
2018 Maro 70 10 80
2018 Fevereiro 45 7 52
2018 Janeiro 42 7 49
2017 Dezembro 47 11 58
2017 Novembro 42 18 60
2017 Outubro 41 21 62
2017 Setembro 37 15 52
2017 Agosto 41 7 48
2017 Julho 32 9 41
2017 Junho 52 15 67
2017 Maio 43 17 60
2017 Abril 35 4 39
2017 Maro 38 2 40
2017 Fevereiro 38 8 46
2017 Janeiro 57 2 59
2016 Dezembro 27 2 29
2016 Novembro 28 11 39
2016 Outubro 39 8 47
2016 Setembro 45 16 61
2016 Agosto 18 10 28
2016 Julho 9 16 25
2016 Junho 5 0 5
2016 Maio 2 8 10
2016 Abril 58 2 60
2016 Maro 59 22 81
2016 Fevereiro 70 28 98
2016 Janeiro 61 27 88
2015 Dezembro 70 18 88
2015 Novembro 60 17 77
2015 Outubro 84 23 107
2015 Setembro 52 23 75
2015 Agosto 52 17 69
2015 Julho 73 10 83
2015 Junho 46 12 58
2015 Maio 50 16 66
2015 Abril 69 12 81
2015 Maro 65 13 78
2015 Fevereiro 34 14 48
2015 Janeiro 58 18 76
2014 Dezembro 68 11 79
2014 Novembro 57 20 77
2014 Outubro 78 19 97
2014 Setembro 54 14 68
2014 Agosto 51 20 71
2014 Julho 71 11 82
2014 Junho 86 13 99
2014 Maio 51 24 75
2014 Abril 65 17 82
2014 Maro 90 27 117
2014 Fevereiro 98 32 130
2014 Janeiro 98 26 124
2013 Dezembro 106 32 138
2013 Novembro 109 32 141
2013 Outubro 107 37 144
2013 Setembro 174 108 282
2013 Agosto 28 14 42
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