Terapia de Anticoagulação em Pacientes com Fibrilação Atrial não Valvar em Ambiente de Cuidado de Saúde Privado no Brasil: Um Estudo de Mundo Real

Pedro Gabriel Melo de Barros e Silva; Henry Sznejder; Rafael Vasconcellos; Georgette M Charles; Hugo Tannus F Mendonca-Filho; Jack Mardekian; Rodrigo Nascimento; Stephen Dukacz; Manuela Di Fusco

doi:10.36660/abc.20180076

. 2020 Apr 6;114(3):457–466. [Article in Portuguese] doi: 10.36660/abc.20180076

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Terapia de Anticoagulação em Pacientes com Fibrilação Atrial não Valvar em Ambiente de Cuidado de Saúde Privado no Brasil: Um Estudo de Mundo Real

Pedro Gabriel Melo de Barros e Silva ^1,^2,^✉, Henry Sznejder ², Rafael Vasconcellos ³, Georgette M Charles ⁴, Hugo Tannus F Mendonca-Filho ², Jack Mardekian ⁵, Rodrigo Nascimento ⁶, Stephen Dukacz ⁵, Manuela Di Fusco ⁵

PMCID: PMC7792730 PMID: 32049154

Resumo

Fundamento:

A segurança e a eficácia da varfarina dependem da qualidade do controle da anticoagulação. Estudos observacionais associam controle deficiente com aumento de morbidade, mortalidade e custos com saúde.

Objetivos:

Desenvolver um perfil de pacientes com fibrilação atrial não valvar (FANV) tratados com varfarina em ambiente ambulatorial e hospitalar privado brasileiro, avaliar a qualidade do controle da anticoagulação e sua associação com resultados clínicos e econômicos.

Métodos:

Este estudo retrospectivo, por meio de um conjunto de dados de seguros privados de saúde no Brasil, identificou pacientes com FANV tratados com varfarina entre 01 de maio de 2014 a 30 de abril de 2016, descreveu seu manejo da anticoagulação e quantificou os custos relacionados à doença. Foram recuperados dados demográficos, histórico clínico, medicação concomitante e tempo na faixa terapêutica (TTR) dos valores da razão normalizada internacional (RNI). Os pacientes foram agrupados em quartis de TTR, com um bom controle sendo definido como TTR ≥65% (método de Rosendaal). Sangramentos maiores e custos médicos diretos por todas as causas foram calculados e comparados entre subgrupos de controle bons e ruins. Valores de p < 0,05 foram considerados estatisticamente significantes.

Resultados:

A análise incluiu 1220 pacientes (mediana de seguimento: 1,5 anos; IIQ: 0,5–2,0). Em média, cada paciente recebeu 0,95 medidas mensais de RNI (RNI média: 2,60 ± 0,88, com 26,1% dos valores < 2 e 24,8% > 3), (mediana de TTR: 58%; IIQ: 47-68%), (TTR médio: 56,6% ± 18,9%). Apenas 31% dos pacientes estavam bem controlados (TTR médio: 78% ± 10%), com 1,6% apresentando grandes sangramentos na mediana do seguimento e custos médicos diretos por membro por ano (PMPY) de R$25.352 (± R$37.762). Pacientes com controle abaixo do ideal (69%) foram associados a 3,3 vezes mais sangramentos graves (5,3% vs. 1,6%; p <0,01) e custos 40% maiores (R$35.384 vs. R$25.352; p < 0,01).

Conclusões:

Mais de 60% dos pacientes estavam abaixo da meta desejada e os custos associados foram significativamente maiores nesta população.

Palavras-chave: Varfarina/uso terapêutico; Anticoagulantes/uso terapêutico; Antcoagulantes/efeitos adversos; Fibrilação Atrial/complicações; Hospitais Privados/economia; Qualidade, Acesso e Avaliação de Assistência à Saúde

Introdução

A fibrilação atrial (FA) é a arritmia cardíaca sustentada mais comum que afeta mais de 33 milhões de pessoas em todo o mundo. A maioria dos casos é de pacientes com FA não valvar (FANV).¹^-³ Os dados epidemiológicos da FA na América Latina são limitados, e uma proporção significativa dos pacientes tem pouco controle dos principais fatores de risco e não recebe tratamento apropriado com anticoagulante (18,3 % - 24,6%).⁴^,⁵

As diretrizes clínicas recomendam o uso de um anticoagulante oral (ACO) na FANV para reduzir o risco de acidente vascular cerebral.²^,³ Durante décadas, os antagonistas da vitamina K (AVK) têm sido a pedra angular da terapia com ACO na FANV, sendo a varfarina a mais utilizada dentre os antagonistas. No entanto, a segurança e a eficácia da varfarina têm limitações, e dependem da alta qualidade do controle da anticoagulação.² Isso é conseguido utilizando-se uma medida padronizada do tempo de coagulação, conhecida como razão normalizada internacional (RNI), e cujo valor desejado está entre 2 e 3.⁶ É necessária uma monitorização frequente da RNI e ajuste da dose para manter os níveis alvo da RNI.²^,³ No entanto, a monitorização pode aumentar os custos médicos e econômicos.⁷

O tempo na faixa terapêutica (TTR, Time in Therapeutic Range) é o meio padrão de avaliar a qualidade em longo prazo do controle da anticoagulação e o perfil de risco-benefício da varfarina.⁶ O TTR representa a porcentagem de tempo em que os valores da RNI de um paciente ficam entre 2 e 3, obtendo o máximo benefício quando o TTR é de 60%-70% ou mais.² Na América Latina, a mediana do TTR estava na extremidade inferior dos níveis recomendados de anticoagulação (cerca de 60%).⁴^,⁸ No Brasil, alguns estudos observacionais no ambiente hospitalar público mostrou que a maioria dos pacientes apresentava um bom controle de anticoagulação, embora os níveis de TTR estivessem na extremidade inferior do limiar.⁹^-¹¹ O manejo do uso de ACO, incluindo o monitoramento da RNI, é caro e inacessível para muitos pacientes na América Latina.⁴ Até o momento, poucos estudos foram realizados em ambientes hospitalares privados na região. Associações de níveis de TTR com resultados clínicos ou econômicos em geral não foram relatadas. O objetivo deste estudo foi desenvolver um perfil de pacientes recebendo varfarina para FANV em ambientes hospitalares privados no Brasil e avaliar a qualidade do controle da anticoagulação e os desfechos clínicos/econômicos.

Métodos

Fontes de dados

Os dados de 1º de maio de 2014 a 30 de abril de 2016 foram extraídos de um grande conjunto de dados de um seguro privado de saúde no Brasil – AMIL. A AMIL é uma das maiores empresas de seguros de saúde do Brasil, com cerca de 4 milhões de beneficiários e programas de assistência clínica com informações integradas e estruturadas sobre doenças prevalentes. O conjunto de dados da AMIL combina registros médicos eletrônicos, contendo informações sobre dados demográficos, registro e histórico clínico dos pacientes, com solicitações médicas de atendimentos ambulatoriais e internações hospitalares, instalações de atendimento ambulatorial e departamentos de emergência.

Para pacientes tratados com varfarina, a AMIL administra um programa privado, por telefone, de monitoramento de anticoagulação denominado VIVA AMIL.¹² Nesse programa, enfermeiros e técnicos de enfermagem treinados realizam chamadas telefônicas mensais para os pacientes para coleta de dados, resultados autorrelatados do último teste de RNI, ocorrência de eventos tromboembólicos e hemorrágicos, regularidade da medicação e efeitos adversos.

Um modelo existente, criado para capturar dados dos pacientes monitorados, foi utilizado para garantir que os resultados dos testes e os eventos e padrões experimentados fossem relatados de forma consistente para atender às necessidades do programa. Foi feita uma chamada inicial para coletar dados clínicos e demográficos (se não estivessem disponíveis), incluindo a presença de condições crônicas e medicamentos em uso. Cada paciente então recebia chamadas mensais, mas também tinha a opção de ligar sempre que necessário.

Caso o paciente não possuísse um resultado atual ou recente de RNI, um(a) enfermeiro(a) forneceria o suporte solicitando o teste e lembrando-o de ligar e relatar os resultados. Quando os resultados de RNI relatados pelo paciente estavam fora da faixa alvo (RNI 2-3), o(a) enfermeiro(a) discutia os ajustes da dose com o paciente e o aconselhava a procurar um médico.

Seleção de Pacientes

Os pacientes com 18 anos ou mais foram incluídos caso apresentassem diagnóstico de FA (CID-10-CM código I48) ou fossem avaliados para FA em um formulário específico do sistema no prontuário eletrônico, se tivessem recebido pelo menos uma prescrição de AVK durante o estudo, tivessem cobertura contínua do plano de saúde e se fossem acompanhados pelo programa de monitoramento por telefone por pelo menos 4 meses, com um registro das ligações em pelo menos 50% dos meses durante o período do estudo. Foram excluídos pacientes com evidência de estenose mitral moderada/grave, tromboembolismo venoso (TEV) ou válvula protética mecânica. O protocolo de pesquisa foi aprovado pelo Conselho de Ética Institucional local.

Variáveis e medidas de desfechos

As principais características dos pacientes que receberam varfarina foram analisadas a partir de solicitações, registros médicos eletrônicos e autorrelatos: dados demográficos e histórico clínico (escore CHA₂DS₂-VASc, comorbidades, AVC ou sangramento prévio, RNI e TTR). Especificamente, os pacientes foram classificados como tendo insuficiência renal crônica quando havia pelo menos um dos códigos selecionados da CID-10 (Apêndice A) vinculados a eles no conjunto de dados durante todo o período do estudo, ou se houvesse insuficiência renal crônica no formulário de coleta de dados manejado pelo(a) enfermeiro(a). A utilização concomitante de medicamentos e os padrões de frequência da RNI também foram avaliados.

Consistente com as diretrizes e estudos anteriores,²^,⁶ a qualidade do controle da RNI foi baseada na porcentagem de tempo durante o qual um paciente que recebeu warfarina esteve dentro da faixa terapêutica (2,0-3,0) durante todo o período de seguimento. Um controle bom foi definido como TTR ≥ 65%. O número de testes de RNI para cada paciente foi obtido através do conjunto de dados de solicitações, o qual não registrou os valores de RNI. Durante as chamadas de monitoramento telefônico, o(a) enfermeiro(a) com treinamento solicitava ao paciente que informasse os valores dos testes RNI realizados desde a última chamada. A frequência do teste de RNI foi utilizada para calcular o número das RNI total e média por paciente. Como a RNI é um procedimento de baixa complexidade e baixo custo, o teste poderia ter sido pago diretamente pelo paciente e, portanto, não ter sido relatado nas solicitações. Para reduzir o impacto dos testes RNI não relatados, durante as chamadas de monitoramento telefônico o(a) enfermeiro(a) solicitava ao paciente que informasse também a data do teste de RNI, juntamente com os valores de RNI. Nos casos em que uma solicitação correspondente estava ausente, as informações de frequência do teste no prontuário eletrônico eram adicionadas manualmente pelo(a) enfermeiro(a). A TTR foi calculada pelo método de Rosendaal, calculado com os valores de RNI registrados nos prontuários eletrônicos.¹³

Os desfechos clínicos avaliados foram eventos hemorrágicos maiores e menores, identificados utilizando os códigos da CID-10 de solicitações de pacientes internados, listados no Apêndice A.¹⁴ Também foram consideradas situações autorreferidas. Os códigos de diagnóstico utilizados para sangramentos maiores foram baseados em um algoritmo administrativo validado baseado em solicitações, bem como na definição da International Society on Thrombosis and Hemostasis de sangramentos maiores.¹⁵^,¹⁶ As taxas de sangramento foram calculadas como o número de pacientes com pelo menos um autorrelato de episódio de sangramento durante o período de monitoramento dividido pelo número total de pacientes. Para avaliar os desfechos, os pacientes foram acompanhados até 30 de abril de 2016, a menos que a interrupção do plano de saúde ou a morte ocorresse primeiro.

Os custos médicos diretos por todas as causas foram avaliados a partir das solicitações de cada paciente para consultas eletivas em consultório, atendimentos de emergência, testes/procedimentos ambulatoriais, internações e transição para tratamento/assistência domiciliar. Os custos representaram os custos reais pagos pelo provedor de seguros (AMIL). Os custos desembolsados pelos pacientes não foram incluídos. Os custos estavam disponíveis na base de dados durante o período do estudo e foram anualizados dividindo-os pelos meses do período do estudo e multiplicando-os por 12. Após esse cálculo, os custos foram expressos por membro por ano (PMPY, per member per year), em reais (R$) e convertido para dólares americanos. Foi obtido um fator de conversão de 0,33 USD/BRL pela média das taxas de câmbio diárias em cada ano do período do estudo (1º de maio de 2014 a 30 de abril de 2016). As taxas de câmbio diárias foram obtidas dos registros históricos de uma calculadora pública de conversão de moeda.¹⁷

Os custos bancados pelos pacientes não foram incluídos. Finalmente, as características-chave, resultados clínicos e econômicos foram observados e comparados entre os quartis de TTR.

Métodos estatísticos

Devido à natureza exploratória do estudo, as principais características e desfechos foram analisados descritivamente.

As estatísticas descritivas foram relatadas como contagens, porcentagens, médias, medianas, desvios-padrão e quartis. As variáveis contínuas foram descritas como média e desvio padrão ou mediana e respectivo intervalo interquartil, dependendo se uma distribuição normal foi ou não encontrada. As variáveis categóricas foram descritas como frequências e porcentagens. As comparações foram feitas entre variáveis contínuas utilizando um teste t de duas amostras independentes e não pareadas e entre variáveis categóricas através do teste do qui-quadrado. Valores de p < 0,05 nos testes bicaudais foram considerados estatisticamente significantes. Todas as análises foram realizadas utilizando-se o software SAS 9.4.

Análise de subgrupos

As principais características, os resultados clínicos e econômicos foram analisados para a população em geral e para pacientes com controle ruim (TTR < 65%) e bom (TTR ≥ 65%).

Análise de sensibilidade

Para verificar a consistência da análise principal, algumas características dos pacientes – níveis de RNI, TTR e custos PMPY – foram observadas para um grupo de pacientes acompanhados por pelo menos 6 meses, com registros das chamadas em pelo menos 50% dos meses durante o período do estudo.

Resultados

Características dos pacientes

Um total de 1.220 pacientes com FANV foram incluídos na análise principal (Figura 1). No geral, o seguimento médio foi de 1,5 anos (intervalo interquartil [IIQ]: 0,5–2,0 anos). As principais características dos pacientes estão listadas na Tabela 1. A média de idade foi de 63,9 ± 14,7 anos, e 50,7% eram do sexo feminino. A escore médio no CHA₂DS₂-VASc foi de 2,45 ± 0,88. A maioria dos pacientes (85,7%) era da região sudeste do Brasil. Aproximadamente 10% dos pacientes estavam em terapia concomitante com estatina e uma parcela menor dos pacientes (~ 4%) estava recebendo terapia concomitante de antiagregantes plaquetários com aspirina e/ou Clopidogrel. A hipertensão foi a comorbidade mais prevalente (38,5%), seguida por insuficiência cardíaca (19,8%), acidente vascular cerebral anterior (13,7%) e diabetes (13,6%).

Tabela 1. Características e dados dos pacientes por quartil de TTR.

Valores	Período (meses)
			4 – 24			6 – 24 (Análise de sensibilidade)
	Q1 N = 303	Q2 N = 306	Q3 N = 305	Q4 N = 306	Total N = 1220	N = 934
Dados demográficos
Idade (média/±DP)	62,02 (±15,92)	64,58 (±13,83)	64,49 (±14,48)	64,30 (±14,63)	63,85 (±14,75)	64,75 (±14,03)
Feminino (%)	50,8	55,2	52,5	44,1	50,7	51,5
Anti-coagulação
RNI (média/±DP)	2,56 (± 1,25)	2,67 (± 1,10)	2,61 (± 0,89)	2,54 (± 0,62)	2,60 (±0,88)	2,60 (±0,96)
RNI (mediana/IIQ)	2,22 (1,70-3,16)	2,50 (1,97-3,20)	2,48 (2,06-2,98)	2,44 (2,13-2,78)	2,44 (1,99-3,00)	2,43 (2,00-3,00)
TTR (média/±DP)	32,6% (±11,5%)	51,2% (±3,3%)	62,0% (±3,2%)	80,2% (±9,8%)	56,6% (±18,9%)	58,0% (±16,2%)
TTR (mediana/IIQ)	36% (28-42%)	52% (48-54%)	62% (59-65%)	78% (72-86%)	58% (47-68%)	57,0% (45-68%)
Testes INR por paciente (média/±DP)	12,79 (±8,09)	17,49 (±9,65)	18,00 (±9,27)	14,20 (±8,40)	15,63 (±9,13)	18,44 (±8,60)
Fatores de risco e condições basais
CHA₂DS₂-VASc (média/±DP)	2,38 (±1,72)	2,46 (±1,69)	2,55 (±1,69)	2,44 (±1,74)	2,45 (±1,71)	2,58 (±1,72)
AVC (%)	13,9	12,1	11,5	17,3	13,7	14,6
Hipertensão (%)	33,3	39,2	43,6	37,9	38,5	41,3
Diabetes (%)	13,2	14,4	15,4	11,4	13,6	14,5
Doença renal crônica (%)	4,6	2,0	4,3	2,6	3,4	3,0
Insuficiência cardíaca congestiva (%)	20,5	18,3	21,3	19,0	19,8	21,1
Região
Sudeste	86,8	85,9	85,6	84,3	85,7	85,9
Central	6,9	8,2	8,5	9,8	8,4	8,6
Sul e Nordeste	6,3	6,0	5,9	5,9	6,0	5,5
Medicamentos concomitantes
Fenprocoumona	11	6	5	11	33	26
Aspirina	10	6	15	0	31	25
Clopidogrel	7	5	2	2	16	9
Aspirina + clopidogrel	3	0	1	0	4	2
Estatinas	27	29	33	29	118	99
Nitrato	2	3	5	6	16	14
Amiodarona	1	3	3	3	10	7
Seguimento
Meses de monitorização (média/±DP)	13,87 (± 7,37)	16,04 (± 7,29)	18,02 (± 7,02)	17,24 (± 7,11)	16,30 (± 7,36)	18,13 (± 6,45)
Meses de monitorização (mediana/IIQ)	14,00 (7,0-20,0)	17,00 (9,0-23,0)	21,00 (12,0-24,0)	19,00 (11,0-23,0)	18,00 (10,0-23,0)	20,00 (13,0-23,0)

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CHA₂DS₂-VASc: insuficiência cardíaca congestiva, hipertensão, idade, diabetes mellitus, acidente vascular cerebral/AIT, doença vascular, idade, categoria sexual; IIQ: Intervalo interquartil; DP: desvio padrão; TTR: tempo na faixa terapêutica.

Controle de anticoagulação

Cada paciente teve uma média de 15,63 (± 9,13) testes de RNI durante uma mediana de 18 meses de seguimento, equivalente a aproximadamente 0,95 testes por mês. O valor médio da RNI foi de 2,60 ± 0,88, o valor mediano da RNI foi de 2,44 (IIQ: 1,99 – 3,00). Entre todos os valores de RNI medidos, 49,1% estavam dentro da faixa terapêutica (2,0-3,0), enquanto 26,1% de todos os valores de RNI foram < 2,0 e 24,8% > 3,0 (Figura 2A). A mediana e a média dos níveis de TTR dos pacientes foram 58% (IIQ 47% -68%) e 56,6% (± 18,9%), respectivamente. A distribuição de TTR é mostrada na Figura 2B. Apenas 377 pacientes (31%) exibiram controle bom (TTR ≥ 65%), e 843 pacientes (69%) apresentaram controle abaixo do ideal (TTR < 65%).

Desfechos clínicos

Entre todos os pacientes, as taxas de sangramentos maiores e menores dos pacientes no programa foram de 4,2% e 10,3%, respectivamente (Figura 3). A taxa de sangramento maior entre pacientes bem controlados (TTR ≥ 65) foi de 1,6%, enquanto para pacientes com controle abaixo do ideal (TTR < 65%) foi de 5,3%. Portanto, a taxa de sangramento maior foi 3,3 vezes maior nos pacientes com controle abaixo do ideal quando comparados aos pacientes com controle bom (p < 0,01). Embora a tendência não tenha sido tão forte com sangramentos menores, um menor número de sangramentos menores foi observado nos subgrupos com TTR maior.

Uma análise exploratória foi realizada para observar o valor mais próximo da RNI antes do evento em uma amostra de pacientes admitidos devido a um acidente vascular cerebral. Dos 15 pacientes, 12 (80%) apresentaram acidente vascular cerebral hemorrágico ou inespecífico, apesar de apresentarem um RNI dentro da faixa terapêutica 2-3 (Informações suplementares).

Resultados econômicos

O custo PMPY em toda a coorte foi de R$32.284 (US$10.679). Os custos de internação representaram aproximadamente 64% de todos os custos (R$20.710 ou US$6.851); os custos ambulatoriais representaram aproximadamente 36% (R$11.573 ou US$3.828). O custo médio de monitoramento da RNI PMPY foi de R$362 (US$120), variando de R$296 (US$98) a R$417 (US$138) e representando < 1% dos custos diretos totais (Tabela 2).

Tabela 2. Custos de PMPY com e sem grandes sangramentos (R $).

Valores. Os custos são expressos como (média/±DP)	Q1	Q2	Q3	Q4	Total
Todos os pacientes
Número de pacientes	303	306	305	306	1220
Custo por paciente (total)	39,171 (± 59,728)	33,996 (± 48,637)	31,797 (± 42,030)	24,236 (± 35,158)	32,284 (± 47,480)
Custo por paciente ambulatorial	14,417 (± 31,295)	11,425 (± 18,544)	11,760 (± 17,866)	8,719 (± 12,084)	11,573 (± 21,218)
Custo por paciente internado	24,754 (± 45,652)	22,570 (± 43,267)	20,037 (± 40,199)	15,517 (± 35,849)	20,710 (± 41,725)
Custo de INR por paciente	296 (± 187)	405 (± 223)	417 (± 214)	329 (± 194)	362 (± 211)
Sem sangramentos maiores
Número de pacientes	285	292	291	301	1169
Custo por paciente (total)	36,704 (± 58,663)	33,217 (± 49,138)	30,244 (± 40,852)	24,106 (± 35,376)	30,981 (± 46,858)
Custo por paciente ambulatorial	13,957 (± 31,658)	11,381 (± 18,955)	11,771 (± 18,261)	8,672 (± 12,181)	11,409 (± 21,419)
Custo por paciente internado	22,747 (± 44,912)	21,835 (± 44,213)	18,473 (± 38,417)	15,434 (± 36,298)	19,572 (± 41,328)
Custo de INR por paciente	291 (± 182)	400 (± 220)	416 (± 216)	329 (± 195)	359 (± 210)
Com sangramentos maiores
Número de pacientes	18	14	14	5	51
Custo por paciente (total)	78,236 (± 64,550)	50,248 (± 33,950)	64,092 (± 53,895)	32,072 (± 17,703)	62,145 (± 52,163)
Custo por paciente ambulatorial	21,698 (± 25,175)	12,343 (± 6,755)	11,540 (± 6,290)	11,565 (± 3,997)	15,348 (± 16,170)
Custo por paciente internado	56,538 (± 49,698)	37,905 (± 30,108)	52,552 (± 50,731)	20,507 (± 15,797)	46,796 (± 44,386)
Custo de INR por paciente	382 (± 247)	523 (± 259)	432 (± 190)	357 (± 164)	432 (± 231)

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Fator de conversão: 0,33 USD/BRL

O custo PMPY foi de R$25.352 (± R$37.762) ou US$8.386 (± US$12.492) por paciente bem controlado (TTR ≥ 65%) e R$35.384 (± R$50.900) ou US$11.705 (± US$16.838) por paciente com controle abaixo do ideal (TTR < 65%). Assim, pacientes com controle sub-ótimo de varfarina foram associados a custos 40% maiores, em média (p < 0,01).

Os custos PMPY com e sem sangramentos maiores foram de R$62.145 (US$20.558) e R$30.981 (US$10.249), respectivamente. Em todos os casos, os custos hospitalares foram maiores que os custos ambulatoriais (Tabela 2).

Métricas por quartil de TTR

Algumas características e desfechos importantes foram observados nos quartis de TTR para verificar quais, caso existissem, eram mais prevalentes em pacientes com menor TTR em comparação com a população geral e pacientes com maior TTR. Conforme mostrado na Tabela 1, os pacientes com TTR mais baixo eram com mais frequência mulheres, apresentaram mais comorbidades (diabetes, doença renal, insuficiência cardíaca), menos testes de RNI e um período de monitoramento geral mais baixo.

Análises de sensibilidade

Um total de 934 pacientes foram incluídos nas análises de sensibilidade. Um valor médio idêntico de RNI de 2,60 ± 0,96 e um valor mediano semelhante de RNI (2,43; IIQ: 2,00-3,00) foram observados nesse grupo de pacientes. As medianas e médias dos níveis de TTR foram quase as mesmas, 57% (IIQ 45% -68%) e 58% ± 16,2%, respectivamente. Nesse grupo de pacientes, os custos PMPY, incluindo pacientes internados e ambulatoriais, também foram bastante semelhantes, R$31.229 (US$10.331), versus R$32.284 (US$10.680) para a análise principal.

Discussão

No geral, foi observado que a qualidade do controle da anticoagulação estava abaixo do ideal: apenas metade de todos os valores de RNI obtidos estavam na faixa terapêutica (RNI: 2-3), e os pacientes passavam um pouco mais da metade do tempo dentro da faixa terapêutica. O TTR variou em toda a população, e até dois terços dos pacientes não estavam adequadamente controlados (TTR < 65%). Esses pacientes foram associados a resultados clínicos e econômicos mais desfavoráveis, ou seja, mais sangramentos maiores e custos mais altos.

Dados epidemiológicos sugerem que houve mais de 700.000 AVCs no Brasil em 2010, representando mais de 141.000 mortes.¹⁸ Embora existam várias causas subjacentes ao AVC, estima-se que aproximadamente 20% dos acidentes vasculares cerebrais isquêmicos sejam atribuíveis à fibrilação atrial,¹⁹ e AVCs com fibrilação atrial tendem a ser maiores e associados a piores desfechos.²⁰

A terapia de anticoagulação tem o potencial de reduzir bastante o risco de derrame em pacientes com fibrilação atrial. Foi demonstrado que a varfarina reduz o risco de acidente vascular cerebral isquêmico em 64% e a mortalidade em 26%, mas a utilidade da varfarina é variável devido à estreita faixa terapêutica, com o risco de eventos isquêmicos aumentando quando a RNI está abaixo de 2 e o risco de eventos hemorrágicos acima de 3.5.²¹

Os custos associados aos acidentes vasculares cerebrais são significativos e sustentados. Estimou-se que o custo de acidentes vasculares cerebrais isquêmicos em 2008 no Brasil foi de US$329 milhões, o custo de internação por paciente foi de US$1902 e o tempo médio de permanência foi superior a 13 dias.²⁰ Os eventos hemorrágicos também representam um custo substancial como parte do manejo global do risco de AVC em pacientes com fibrilação atrial que recebem tratamento com anticoagulante oral.²² Um estudo nos EUA mostrou que a não adesão e a subutilização de varfarina pelos pacientes segurados com FA têm um impacto negativo na saúde e nos custos. Também foi demonstrado que o grau de controle da anticoagulação está diretamente correlacionado a melhores resultados para pacientes com fibrilação atrial em tratamento com varfarina.²³^-²⁵

Poucos estudos avaliaram a extensão do controle da anticoagulação com varfarina em países da América Latina. Pesquisas anteriores relataram níveis próximos do aceitável do controle de anticoagulação no Brasil, com níveis de TTR próximos a 60% em ambientes controlados²⁶^-²⁸ e entre 60 e 65% no mundo real.⁹^-¹¹ No entanto, esses estudos foram realizados principalmente em um ou dois hospitais públicos ou clínicas de anticoagulação, em populações com tamanho limitado de amostra e amplo uso de varfarina.

O TTR é a medida aceita do controle da anticoagulação em pacientes com varfarina, e está correlacionado com os desfechos clínicos. Embora seja frequentemente relatado por centro ou mesmo por país em ensaios clínicos, há uma heterogeneidade substancial no TTR de cada paciente.²⁹^,³⁰ Os resultados do presente estudo são consistentes com esse conceito, pois mesmo com a população geral de pacientes apresentando um TTR razoável, a maioria dos pacientes apresentou, na realidade, um TTR abaixo do limiar considerado ideal.²³

O presente estudo promove a compreensão do modelo de assistência em anticoagulação na prática clínica de rotina. É representativo de uma população relativamente jovem com FA, apresentando uma prevalência mais baixa de comorbidades do que a relatada em outros estudos observacionais e ambientes controlados.²⁶^-²⁸^,³¹ Além disso, o estudo é representativo de dados do mundo real em um ambiente hospitalar específico da AMIL, incluindo um programa estruturado e chamadas telefônicas, e não é generalizável para outros ambientes hospitalares, como o setor público. A abordagem para gerenciar e monitorar regularmente os pacientes através do programa de atendimento foi considerada bastante singular. Estudos que abordaram uma pergunta de pesquisa semelhante⁹^-¹¹ não relataram a existência de um programa tão dedicado para os pacientes tratados com varfarina. A monitorização da RNI foi realizada aproximadamente uma vez por mês, uma frequência maior do que em outros estudos observacionais³², embora menor do que em ambientes controlados.²⁶ Apesar do seguimento regular, apenas cerca de metade (49,1%) de todos os valores de RNI obtidos estavam na faixa terapêutica, e uma parcela limitada da população apresentou um controle bom de TTR. Os resultados da TTR foram consistentes com pesquisas anteriores na prática assistencial, indicando que os pacientes recebendo varfarina passam apenas um pouco mais da metade do tempo dentro da faixa terapêutica.³² Os níveis de TTR relatados para a população geral tratada com varfarina neste estudo estavam ligeiramente abaixo do limite inferior da faixa recomendada.⁹^,¹¹^,²⁵ Um achado interessante é que a distribuição de TTR na Figura 2B mostrou uma inclinação para a direita, o que significa que havia um nicho de pacientes com controle muito alto do TTR. Cerca de 22% dos pacientes apresentaram TTR > 70%.

Dados internacionais que avaliaram a associação entre controle da anticoagulação e desfechos do uso de varfarina indicam que pacientes com controle deficiente de varfarina apresentam resultados clínicos e econômicos mais desfavoráveis do que pacientes bem controlados.²¹^,³³ Os resultados do presente estudo estão bastante alinhados com trabalhos anteriores e contribuem ainda mais para o entendimento de como o controle da varfarina pode impactar tanto nos eventos clínicos quanto nos custos na prática brasileira de rotina. A alta qualidade do controle da anticoagulação foi associada a uma menor incidência de sangramentos maiores e menores e a uma economia substancial dos custos médicos diretos, devido à redução dos custos hospitalares e ambulatoriais. Pacientes com controle abaixo do ideal apresentaram 3,3 vezes mais sangramentos maiores e custos PMPY 40% mais altos do que pacientes bem controlados.

Apesar do tratamento com anticoagulação, os acidentes vasculares cerebrais ainda ocorrerão como foram observados neste estudo, tanto isquêmicos quanto hemorrágicos. É importante ressaltar que, dentre 10 derrames hemorrágicos confirmados identificados neste estudo, o valor de RNI prévio para 7 dos 10 eventos estava dentro da faixa terapêutica de 2 a 3, sendo que os outros 3 apresentaram valores de 3,66, 3,87 e 5,13. Isso é consistente com os achados de uma subanálise do estudo ARISTOTLE, que mostrou que para cerca de 80% das hemorragias intracranianas que ocorreram em pacientes tratados com varfarina, o RNI prévio estava entre 2 e 3.³⁴

Uma pesquisa anterior explorou preditores de TTR baixo,⁶^,²⁶^,³² sugerindo que pacientes com menor TTR na maioria das vezes eram mulheres, tinham menos escolaridade e mais comorbidades, especificamente diabetes, doença renal crônica, insuficiência cardíaca e acidente vascular cerebral anterior. Com bastante consistência neste estudo, pacientes do sexo feminino e pacientes com mais comorbidades, como doença renal crônica e cardiopatia isquêmica, também tenderam a apresentar valores mais baixos de TTR. Além disso, pacientes com menor TTR tinham menos testes de RNI e um período de monitoramento global mais curto. Os resultados sugerem que é necessário identificar pacientes com labilidade das RNIs e avaliar mais oportunidades para melhorar seu TTR, como educação ou seguimento mais próximo. Caso contrário, outras formas de anticoagulação, como a classe de anticoagulante não-vitamina K, aprovada mais recentemente, devem ser consideradas. Essa classe não requer monitoramento de rotina, possui menos interações medicamento-medicamento e medicamento-alimento do que a varfarina e demonstrou ser pelo menos tão segura e eficaz quanto a varfarina bem controlada, além de apresentar menor taxa de hemorragia intracraniana.³⁵

Limitações

Nosso estudo tem vários pontos fortes e limitações. A coorte de pacientes do estudo foi uma das maiores até agora entre os estudos do mundo real no Brasil. O uso combinado de solicitações e o programa de assistência agregaram valor significativo ao estudo, principalmente ao permitir a análise dos valores de RNI, geralmente não disponíveis nas solicitações. No entanto, dada a sua natureza observacional retrospectiva, apenas associações puderam ser concluídas. Este estudo observou variações do TTR ao longo do tempo e, por isso, foi vulnerável aos efeitos de medições repetidas como uma intervenção. Nenhuma técnica estatística avançada foi utilizada para equilibrar as características dos subgrupos de TTR nos pacientes e, portanto, nenhuma conclusão inferencial sobre cofatores pôde ser obtida. Não foi possível calcular o escore médio de risco HAS-BLED, pois nem todos os pontos de dados dos componentes do escore foram capturados no conjunto de dados (por ex., etilismo). A incidência de outros desfechos como acidente vascular cerebral, mortalidade, descontinuação e aderência não foi analisada. Não foram realizadas análises de sensibilidade em outros limiares específicos de TTR (por exemplo, 60% ou 70%). A estabilidade da RNI ao longo do tempo não foi avaliada. Somente custos médicos diretos estavam disponíveis; estes se referiam aos custos de todas as causas incorridos por cada paciente, desconsiderando o motivo da utilização e, consequentemente, podem ter sido superestimados. A utilização de recursos de saúde e subgrupos de pacientes não foram avaliados.

De acordo com as normas brasileiras para códigos de procedimento (Apêndice A), a RNI não possui código individual, mas está incluída no código “Teste de coagulação”. Como não foi possível segregar, a medida da RNI foi considerada como teste de coagulação completo, e não como uma porcentagem, para todos os pacientes.

Verificou-se que uma parcela significativa dos pacientes em uso de varfarina (11%) apresentou escore CHA2DS2-VASC igual a zero, superior à porcentagem relatada em outros estudos (6,1%).36 A avaliação do CHA2DS2-VASC está sujeita à documentação clínica do histórico dos pacientes, considerando que detalhes das condições pré-existentes podem ter sido subnotificados.

O programa de monitoramento por telefone foi oferecido a pacientes de uma companhia de seguros de saúde específica e, quando o contrato de um paciente foi rescindido, o acompanhamento não foi possível.

Finalmente, algumas das limitações do estudo são inerentes a um desenho de estudo observacional retrospectivo. Isso inclui possíveis erros de codificação e dados ausentes, os quais podem ter introduzido vieses no estudo e afetado o número de pacientes excluídos, e o fato de os dados avaliados não terem sido originalmente coletados para fins de pesquisa clínica.

Conclusões

Este estudo examinou o perfil dos pacientes, a qualidade da anticoagulação e os desfechos clínicos/econômicos em pacientes tratados com varfarina para FANV em uma companhia privada de seguros de saúde no Brasil. É representativo de uma coorte grande e relativamente jovem de pacientes tratados com varfarina. A qualidade geral do manejo da anti-coagulação ficou abaixo do ideal. Os pacientes recebendo varfarina ficaram dentro da faixa terapêutica por pouco mais da metade do tempo. Até dois terços apresentaram controle abaixo do ideal (TTR < 65%) e isto estava associado a mais eventos de sangramento e custos maiores. Essa análise destaca a importância, em termos de resultados e custos, de um rígido controle de anticoagulação para pacientes com FANV tratados com varfarina, e a dificuldade em manter um TTR adequado, mesmo com um programa bem projetado e executado. Pesquisas adicionais são necessárias, à medida que mais dados do mundo real se tornam disponíveis, para avaliar mais profundamente o uso de varfarina, bem como a adoção de Novos Anticoagulantes Orais (NOACS) versus varfarina.

Footnotes

Fontes de financiamento

O presente estudo foi financiado pela Pfizer.

Vinculação acadêmica

Não há vinculação deste estudo a programas de pós-graduação.

Aprovação ética e consentimento informado

Este estudo foi aprovado pelo Comitê de Ética do Hospital Pró-Cardíaco sob o número de protocolo 1.835.148. Todos os procedimentos envolvidos nesse estudo estão de acordo com a Declaração de Helsinki de 1975, atualizada em 2013.

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Arq Bras Cardiol. 2020 Apr 6;114(3):457–466. [Article in English]

Anticoagulation Therapy in Patients with Non-valvular Atrial Fibrillation in a Private Setting in Brazil: A Real-World Study

Abstract

Background:

The safety and effectiveness of warfarin depend on anticoagulation control quality. Observational studies associate poor control with increased morbidity, mortality and healthcare costs.

Objectives:

To develop a profile of non-valvular atrial fibrillation (NVAF) patients treated with warfarin in a Brazilian private ambulatory and hospital setting, evaluate the quality of anticoagulation control, and its association with clinical and economic outcomes.

Methods:

This retrospective study, through a private health insurance dataset in Brazil, identified NVAF patients treated with warfarin between 01 MAY 2014 to 30 APRIL 2016, described their anticoagulation management, and quantified disease-related costs. Data on demographics, clinical history, concomitant medication and time in therapeutic range (TTR) of international normalized ratio (INR) values were retrieved. Patients were grouped into TTR quartiles, with good control defined as TTR ≥ 65% (Rosendaal method). Major bleeds and all-cause direct medical costs were calculated and compared between good and poor control subgroups. P-values < 0.05 were considered statistically significant.

Results:

The analysis included 1220 patients (median follow-up: 1.5 years; IQR: 0.5–2.0). On average, each patient received 0.95 monthly INR measurements (mean INR: 2.60 ± 0.88, with 26.1% of values < 2 and 24.8% > 3), (median TTR: 58%; IQR: 47–68%), (mean TTR: 56.6% ± 18.9%). Only 31% of patients were well-controlled (mean TTR: 78% ± 10%), with 1.6% having major bleeds within median follow-up, and direct medical costs per member per year (PMPY) of R$25,352(± R$ 37,762). Poorly controlled patients (69%) were associated with 3.3 times more major bleeds (5.3% vs. 1.6%; p < 0.01) and 40% higher costs (R$35,384 vs. R$25,352; p < 0.01).

Conclusions:

More than 60% of the patients were below the desired target and the associated costs were higher.

Keywords: Warfarine/therapeutic use; Anticoagulants/adverse effects; Atrial Fibrillation/comlications; Hospitals, Private/ economics; Health Care Quality, Access and Evaluation

Introduction

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia that affects more than 33 million people worldwide. Most cases are non-valvular AF (NVAF) patients.¹^-³ Epidemiology data for AF in Latin America is limited and a significant proportion of patients has poor control of key risk factors and does not receive appropriate anticoagulation treatment (18.3% – 24.6%).⁴^,⁵

Clinical guidelines recommend the use of an oral anticoagulant (OAC) in NVAF to reduce the risk of stroke.²^,³ For decades, vitamin K antagonists (VKAs), the most commonly used of which is warfarin, have been the cornerstone of OAC therapy for NVAF. However, the safety and efficacy of warfarin have limitations and depend on the tight quality of anticoagulation control.² This is achieved using a standardized measure of clotting time known as the international normalized ratio (INR), which is desired to be between 2 and 3.⁶ Frequent INR monitoring and dose adjustment are needed to maintain target INR levels.²^,³ However, monitoring can increase the medical and economic burden.⁷

Time in therapeutic range (TTR) is the standard means of assessing the long-term quality of anticoagulation control and the risk–benefit profile of warfarin.⁶ TTR represents the proportion of time that a patient's INR values are between 2 and 3, having the maximum benefit when the TTR is 60% to 70% or higher.² In Latin America, the median TTR was at the lower end of the recommended levels of anticoagulation (near 60%).⁴^,⁸ In Brazil, some observational studies in the public setting showed that most patients had good anticoagulation control, though TTR levels were in the lower end of the threshold.⁹^-¹¹ Managing OAC use, including INR monitoring, are costly and inaccessible for many patients in Latin America.⁴ To date, few studies have been conducted in private settings in the region. Associations of TTR levels with clinical or economic outcomes were generally not reported. The objective of this study was to develop a profile of patients receiving warfarin for NVAF in a private setting in Brazil, and to evaluate the quality of anticoagulation control and clinical/economic outcomes.

Methods

Data Sources

Data from May 1, 2014 to April 30, 2016 were pulled from a large private health insurance dataset in Brazil – AMIL. AMIL is one of the largest health insurance companies in Brazil, with over 4 million beneficiaries and clinical care programs with integrated and structured information of prevalent diseases. The AMIL dataset combines electronic medical records containing information on patient demographics, enrolment and clinical history, with medical claims from outpatient and inpatient hospital admissions, ambulatory care facilities and emergency departments.

For warfarin-treated patients, AMIL runs a private anticoagulation phone monitoring program named VIVA AMIL.¹² Within this program, trained nurses and nursing technicians make monthly phone calls to patients to collect patient data, self-reported results of the last INR test, occurrence of thromboembolic and bleeding events, medication regularity and adverse effects.

An existing template, created to capture data from the monitored patients, was used to ensure the test results, experienced events and patterns were reported consistently to meet the program needs. An initial call was made to collect clinical and demographic data (if otherwise not available), including the presence of chronic conditions and medications under use. Each patient then received monthly outbound calls, but patients also had the option to call as needed.

In case the patient did not have a current or recent INR test result, a nurse would support them by requesting the test and reminding them to call back and report the results. In the situation in which the INR results reported by the patient were out of the target range (INR 2-3), the nurse would discuss dose adjustments with the patient and advise them to seek medical advice in person.

Patient Selection

Patients aged 18 or older were included if they had an AF diagnosis (ICD-10-CM code I48) or were assessed for AF in a specific system form in the electronic medical record, if they received at least one prescription for VKA during the study period, had continuous health plan coverage and if they were followed by the phone-monitoring program for at least 4 months with a record of the calls in at least 50% of the months during the study period. Patients with evidence of moderate/severe mitral stenosis, VTE or a mechanical prosthetic valve were excluded. The research protocol was approved by the local Institutional Review Board.

Variables and Outcome Measures

Key characteristics of patients receiving warfarin were analyzed from claims, electronic medical records and self-reports: demographics and clinical history (CHA₂DS₂-VASc score, comorbidities, prior stroke or bleeds, INR and TTR). Specifically, patients were classified as having chronic renal failure when there was at least one of the selected ICD-10 codes (Appendix A) linked to them in the dataset during the entire study period, or if chronic renal failure was present in the data collection form managed by the nurse. Concomitant medication utilization and INR frequency patterns were also assessed.

Consistent with guidelines and prior studies,²^,⁶ the quality of INR control was based on the percentage of time during which a patient receiving warfarin was within therapeutic range (2.0-3.0) over the entire follow-up period. Good control was defined as TTR ≥ 65%. The number of INR tests for each patient was obtained through the claims dataset, which did not record the INR values. During the phone monitoring calls, the trained nurse would ask the patient to report the values of the INR tests undertaken since the last call. The INR test frequency was used to calculate the total and mean INR tests per patient. Since the INR is a low-complexity and low-cost procedure, the test could have been paid out-of-pocket by the patient and therefore not reported in claims. In order to reduce the impact of unstated INR tests, during the phone monitoring calls the nurse would ask the patient to also report the date of the INR test, along with the INR values. For those cases in which a corresponding claim was absent, the nurse would manually add the test frequency information in the electronic medical record. TTR was calculated using the Rosendaal method, computed using the INR values that were recorded in the electronic medical records.¹³

The clinical outcomes assessed were major and minor bleeding events, identified using the ICD-10 codes of inpatient claims listed in Appendix A.¹⁴ Self-reported situations were also considered. The diagnosis codes used for major bleeds were based on a validated administrative claim-based algorithm, as well as the International Society on Thrombosis and Hemostasis definition of major bleeding.¹⁵^,¹⁶ Bleeding rates were calculated as the number of patients with at least one self-reported bleeding episode during the monitoring period, divided by the total number of patients. To assess the outcomes, patients were followed until April 30, 2016, unless health plan disenrollment or death occurred first.

All-cause direct medical costs were assessed from the claims of each patient for office elective visits, emergency department visits, outpatient tests/procedures, inpatient admissions, and home health/care transition admissions. The costs represented the actual costs borne by the insurance provider (AMIL). Out-of-pocket costs were not included. The costs were available in the data source over the study period and were annualized by dividing them by the months of the study period and multiplying them by 12. After this calculation, costs were expressed per member per year (PMPY), in Brazilian Reals (R$) and converted to US dollars. A conversion factor of 0.33 USD/BRL was obtained by averaging the daily exchange rates within each year of the study period (May 1, 2014 to April 30, 2016). The daily exchange rates were obtained from historical records of a public currency exchange calculator.¹⁷

Out-of-pocket costs were not included. Finally, key characteristics, clinical and economic outcomes were observed and compared amongst TTR quartiles.

Statistical methods

Due to the exploratory nature of the study, key characteristics and outcomes were descriptively analyzed.

Descriptive statistics were reported as counts, percentages, means, medians, standard deviations and quartiles. Continuous variables were described as mean and standard deviation or median and respective interquartile range, depending on whether or not a normal distribution was found. Categorical variables were described as frequencies and percentages. Comparisons were made between continuous variables using an independent unpaired two-sample t-test and between categorical variables using the chi-square test. P-values < 0.05 in two-tailed tests were considered statistically significant. All analyses were carried out using SAS 9.4.

Subgroup analysis

The key characteristics, clinical and economic outcomes were analyzed for the overall population and for patients with poor (TTR < 65%) and good (TTR ≥ 65%) control.

Sensitivity analysis

To check for main analysis consistency, some patient characteristics, INR, TTR levels and PMPY costs were observed for a group of patients followed for at least 6 months with records of the calls in at least 50% of the months during the study period.

Results

Patient characteristics

A total of 1,220 patients with NVAF were included for the main analysis (Figure 1). Overall, median follow-up was 1.5 years (interquartile range [IQR]: 0.5–2.0 years). Key patient characteristics are listed in Table 1. The mean age was 63.9 ± 14.7 years and 50.7% were females. The mean CHA₂DS₂-VASc score was 2.45 ± 0.88. Most patients (85.7%) were from the Southeast region of Brazil. Approximately 10% of patients were on concomitant statin therapy and a minority of patients (~4%) were receiving concomitant antiplatelet therapy with aspirin and/or Clopidogrel. Hypertension was the most prevalent comorbidity (38.5%), followed by heart failure (19.8%), prior stroke (13.7%) and diabetes (13.6%).

Table 1. Patient characteristics and metrics per TTR quartile.

Values	Period (months)
			4 – 24			6 – 24 (Sensitivity analysis)
	Q1 N = 303	Q2 N = 306	Q3 N = 305	Q4 N = 306	Total N = 1220	N = 934
Demographics
Age (mean/±SD)	62.02 (±15.92)	64.58 (±13.83)	64.49 (±14.48)	64.30 (±14.63)	63.85 (±14.75)	64.75 (±14.03)
Female (%)	50.8	55.2	52.5	44.1	50.7	51.5
Anticoagulation
INR (mean/±SD)	2.56 (± 1.25)	2.67 (± 1.10)	2.61 (± 0,89)	2.54 (± 0,62)	2.60 (±0.88)	2.60 (±0.96)
INR (median/IQR)	2.22 (1.70-3.16)	2.50 (1.97-3.20)	2.48 (2.06-2.98)	2.44 (2.13-2,78)	2.44 (1.99-3.00)	2.43 (2.00-3.00)
TTR (mean/±SD)	32.6% (±11.5%)	51.2% (±3.3%)	62.0% (±3.2%)	80.2% (±9.8%)	56.6% (±18.9%)	58.0% (±16.2%)
TTR (median/IQR)	36% (28-42%)	52% (48-54%)	62% (59-65%)	78% (72-86%)	58% (47-68%)	57.0% (45-68%)
INR tests per patient (mean/±SD)	12.79 (±8.09)	17.49 (±9.65)	18.00 (±9.27)	14.20 (±8.40)	15.63 (±9.13)	18.44 (±8.60)
Risk factors and baseline conditions
CHA₂DS₂-VASc (mean/±SD)	2.38 (±1.72)	2.46 (±1.69)	2.55 (±1.69)	2.44 (±1.74)	2.45 (±1.71)	2.58 (±1.72)
Stroke (%)	13.9	12.1	11.5	17.3	13.7	14.6
Hypertension (%)	33.3	39.2	43.6	37.9	38.5	41.3
Diabetes (%)	13.2	14.4	15.4	11.4	13.6	14.5
Chronic kidney failure (%)	4.6	2.0	4.3	2.6	3.4	3.0
Congestive heart failure (%)	20.5	18.3	21.3	19.0	19.8	21.1
Region
Southeast	86.8	85.9	85.6	84.3	85.7	85.9
Central	6.9	8.2	8.5	9.8	8.4	8.6
South and Northeast	6.3	6.0	5.9	5.9	6.0	5.5
Concomitant medications
Phenprocoumon	11	6	5	11	33	26
Aspirin	10	6	15	0	31	25
Clopidogrel	7	5	2	2	16	9
Aspirin + clopidogrel	3	0	1	0	4	2
Statins	27	29	33	29	118	99
Nitrate	2	3	5	6	16	14
Amiodarone	1	3	3	3	10	7
Follow-up
Months of monitoring (mean/±SD)	13.87 (± 7.37)	16.04 (± 7.29)	18.02 (± 7.02)	17.24 (± 7.11)	16.30 (± 7.36)	18.13 (± 6.45)
Months of monitoring (median/IQR)	14.00 (7.0-20.0)	17.00 (9.0-23.0)	21.00 (12.0-24.0)	19.00 (11.0-23.0)	18.00 (10.0-23.0)	20.00 (13.0-23.0)

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CHA₂DS₂-VASc: congestive heart failure, hypertension, age, diabetes mellitus, stroke/TIA, vascular disease, age, sex category; IQR: interquartile range; SD: standard deviation; TTR: time in therapeutic range.

Anticoagulation control

Each patient had a mean of 15.63 (±9.13) INR tests over a median of 18 months of follow-up, equivalent to approximately 0.95 tests per month. The mean INR value was 2.60± 0.88, the median INR value was 2.44 (IQR: 1.99 – 3.00). Among all measured INR values, 49.1% were within the therapeutic range (2.0–3.0), whereas 26.1% of all INR values were < 2.0, and 24.8% were > 3.0 (Figure 2A). The median and mean patient-level TTRs were 58% (IQR 47%–68%) and 56.6% (±18.9%), respectively. The TTR distribution is reported in Figure 2B. Only 377 patients (31%) exhibited good control (TTR ≥ 65%) and 843 patients (69%) had poor control (TTR < 65%).

Clinical outcomes

Among all patients, the major and minor bleeding rates of patients in the program were 4.2% and 10.3%, respectively (Figure 3). The major bleeding rate among well-controlled patients (TTR ≥ 65) was 1.6%, whereas it was 5.3% for poorly controlled patients (TTR < 65%). Therefore, the major bleeding rate was 3.3 times higher in poorly-controlled patients when compared with well-controlled patients (p < 0.01). While the trend was not as strong with minor bleedings, fewer minor bleeds were observed in subgroups with highest TTR.

An exploratory analysis was conducted to observe the closest INR value prior to the event on a sample of patients admitted for a stroke. Out of 15 patients, 12 (80%) experienced a hemorrhagic or unspecified stroke event, despite having an INR within the therapeutic range 2-3 (Supplementary information).

Economic outcomes

The PMPY cost across the entire cohort was R$32,284 (USD$10,679). Inpatient costs represented ~64% of all costs (R$20,710 or USD$6,851); outpatient costs represented ~36% (R$11,573 or USD$3,828). The mean INR monitoring cost PMPY was R$362 (USD$120), ranging from R$296 (USD$98) to R$417 (USD$138) and representing < 1% of the total direct costs (Table 2).

Table 2. PMPY costs with and without major bleeds (R$).

Values. Costs are expressed as (mean/±SD)	Q1	Q2	Q3	Q4	Total
All patients
Number of patients	303	306	305	306	1220
Cost per patient (total)	39,171 (± 59,728)	33,996 (± 48,637)	31,797 (± 42,030)	24,236 (± 35,158)	32,284 (± 47,480)
Cost per outpatient	14,417 (± 31,295)	11,425 (± 18,544)	11,760 (± 17,866)	8,719 (± 12,084)	11,573 (± 21,218)
Cost per inpatient	24,754 (± 45,652)	22,570 (± 43,267)	20,037 (± 40,199)	15,517 (± 35,849)	20,710 (± 41,725)
NR cost per patient	296 (± 187)	405 (± 223)	417 (± 214)	329 (± 194)	362 (± 211)
Without major bleedings
Number of patients	285	292	291	301	1169
Cost per patient (total)	36,704 (± 58,663)	33,217 (± 49,138)	30,244 (± 40,852)	24,106 (± 35,376)	30,981 (± 46,858)
Cost per outpatient	13,957 (± 31,658)	11,381 (± 18,955)	11,771 (± 18,261)	8,672 (± 12,181)	11,409 (± 21,419)
Cost per inpatient	22,747 (± 44,912)	21,835 (± 44,213)	18,473 (± 38,417)	15,434 (± 36,298)	19,572 (± 41,328)
NR cost per patient	291 (± 182)	400 (± 220)	416 (± 216)	329 (± 195)	359 (± 210)
With major bleedings
Number of patients	18	14	14	5	51
Cost per patient (total)	78,236 (± 64,550)	50,248 (± 33,950)	64,092 (± 53,895)	32,072 (± 17,703)	62,145 (± 52,163)
Cost per outpatient	21,698 (± 25,175)	12,343 (± 6,755)	11,540 (± 6,290)	11,565 (± 3,997)	15,348 (± 16,170)
Cost per inpatient	56,538 (± 49,698)	37,905 (± 30,108)	52,552 (± 50,731)	20,507 (± 15,797)	46,796 (± 44,386)
NR cost per patient	382 (± 247)	523 (± 259)	432 (± 190)	357 (± 164)	432 (± 231)

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Conversion factor: 0.33 USD/BRL.

The PMPY cost was R$25,352 (± R$37,762) or USD$8,386 (± USD$12,492)per well-controlled patient (TTR ≥ 65%) and R$35,384 (± R$50,900) or USD$11,705 (± USD$16,838) per poorly-controlled patient (TTR < 65%). Thus, patients with suboptimal warfarin control were associated with 40% higher costs, on average (p < 0.01).

PMPY costs with and without major bleeds were R$62,145 (USD$20,558) and R$30,981 (USD$10,249), respectively. In all cases, inpatient costs were greater than outpatient costs (Table 2).

Metrics per TTR quartile

Some key characteristics and outcomes were observed across TTR quartiles to see which, if any, were more prevalent in patients with lower TTR compared with the overall population and patients with higher TTR. As shown in Table 1, patients with lower TTR were more often females, had more comorbidities (diabetes, renal disease, heart failure), fewer INR tests and a lower overall monitoring period.

Sensitivity analyses

A total of 934 patients were included in the sensitivity analyses. An identical mean INR value of 2.60 ± 0.96 and a similar median INR (2.43; IQR: 2.00-3.00) were observed in this patient group. The median and mean patient-level TTRs were almost the same, 57% (IQR 45%–68%) and 58% ± 16.2%, respectively. In this group of patients, PMPY costs, including inpatient and outpatient, were also quite similar, R$31,229 (USD$10,331), versus R$32,284 (USD$10,680) for the main analysis.

Discussion

Overall, it was observed that the quality of anticoagulation management was suboptimal: only half of all INR values drawn were in the therapeutic range (INR: 2-3) and patients spent a bit more than half of the time within the therapeutic range. TTR varied across the population and up to two thirds of patients were not adequately controlled (TTR < 65%). These patients were associated with more unfavorable clinical and economic outcomes i.e. more major bleeds and higher costs.

Epidemiological data suggest that there were over 700,000 strokes in Brazil in 2010, accounting for over 141,000 deaths.¹⁸ While there are several underlying causes of stroke, it is estimated that approximately 20% of ischemic strokes are attributable to atrial fibrillation,¹⁹ and strokes associated with atrial fibrillation tend to be larger and associated with worse outcomes.²⁰

Anticoagulation therapy has the potential to greatly reduce the risk of stroke in patients with atrial fibrillation. Warfarin has been shown to reduce the risk of ischemic stroke by 64% and mortality by 26% but the usefulness of warfarin is variable due to the narrow therapeutic range, with the risk of ischemic events increasing when the INR is below 2, and the risk of hemorrhagic events increasing above 3.5.²¹

Costs associated with strokes are significant and sustained. It was estimated that the 2008 cost of ischemic strokes in Brazil was $329 million USD, the per-patient cost of hospitalization was $1902 USD, and the mean length of stay was over 13 days.²⁰ Hemorrhagic events also represent a substantial cost as part of the overall management of stroke risk for atrial fibrillation patients receiving oral anticoagulation treatment.²² A US study has shown that non-adherence and underuse of warfarin by insured patients with AF has a negative impact on health and costs. It has also been demonstrated that the degree of anticoagulation control is directly correlated to improved outcomes for patients with atrial fibrillation receiving warfarin treatment.²³^-²⁵

Few studies have assessed the extent of anticoagulation control with warfarin in Latin American countries. Past research reported close to acceptable levels of anticoagulation control in Brazil, with TTR levels close to 60% in controlled settings²⁶^-²⁸ and between 60 and 65% in the real world.⁹^-¹¹However, these studies were conducted mostly in one or two public hospitals or anticoagulation clinics, in populations with limited sample size and broad use of warfarin.

The TTR is the accepted measure of anticoagulation control for warfarin patients and is correlated with clinical outcomes. While often reported by center or even country in clinical trials, there is substantial heterogeneity in individual patient ²⁹^,³⁰ The results from this current study are consistent with this concept in that even though the overall patient population had a fair TTR, in fact most of the patients had a TTR which was below the threshold considered optimal.²³

The present study furthers the understanding of the anticoagulation care model in routine clinical practice. It is representative of a relatively young AF population presenting with a lower prevalence of comorbidities than what has been reported in other observational studies and controlled settings.²⁶^-²⁸^,³¹ In addition, the study is representative of real-world data in a specific private setting of AMIL, including a structured program and phone calls, and it is not generalizable to other settings like the public sector. The approach to managing and regularly monitoring the patients through the care program was found to be quite unique. Studies that addressed a similar research question⁹^-¹¹ did not report the existence of such a dedicated program for warfarin patients. INR monitoring was performed approximately once a month, more frequently than in other observational studies³² but less than in controlled settings.²⁶ Despite the regular follow-up, only about half (49.1%) of all INR values drawn were in the therapeutic range and a limited portion of the population had good TTR control. The TTR results were consistent with past research within the care practice, indicating that warfarin patients spend only a bit more than half of the time within the therapeutic range.³² The reported TTR levels for the overall population treated with warfarin in this study were slightly below the lower limit of the recommended threshold interval.⁹^,¹¹^,²⁵ An interesting finding is that the TTR distribution in Figure 2B was skewed to the right, meaning that there was a niche of patients with very high TTR control. Around 22% of patients had TTR > 70%.

International data that assessed the association between warfarin control and outcomes indicate that poor warfarin control patients experience more unfavorable clinical and economic outcomes than well controlled patients.²¹^,³³ The results of the present study are quite aligned with prior work and further contribute to the understanding of how warfarin control could impact on both clinical events and costs in the Brazilian routine practice. High quality of anticoagulation control was associated with a lower incidence of major and minor bleeds and substantial direct medical cost savings from both reduced inpatient and outpatient costs. Poorly-controlled patients had 3.3 times more major bleeds and 40% higher PMPY costs than well-controlled patients.

Despite anticoagulation treatment, strokes will still occur, as observed in this study, both ischemic and hemorrhagic ones. Of note, out of 10 confirmed hemorrhagic strokes that were identified in this study, the preceding INR value for 7 of the 10 was within the therapeutic range of 2 to 3, with the other 3 being 3.66, 3.87, and 5.13. This is consistent with the findings from a sub-analysis of the ARISTOTLE trial which showed that for about 80% of the intracranial hemorrhages that occurred in warfarin-treated patients, the preceding INR was between 2 and 3.³⁴

Past research explored predictors of poor TTR⁶^,²⁶^,³² suggesting that patients with lower TTR were more often females, had less schooling and more comorbidities, specifically diabetes, chronic kidney disease, heart failure and prior stroke. Quite consistently, female patients and patients with more comorbidities such as chronic kidney disease and ischemic heart disease tended to have lower TTR values in this study, too. Moreover, patients with lower TTR had fewer INR tests and a shorter overall monitoring period. The results suggest that there is a need to identify patients with labile INRs and further assess opportunities to improve their TTR, such as education or closer follow-up. Failing that, other forms of anticoagulation such as the more recently approved non-vitamin K anticoagulant class should be considered. This class does not require routine monitoring, has fewer drug-drug and drug-food interactions than warfarin, and has been shown to be at least as safe and efficacious as well-controlled warfarin, and to have a lower rate of intracranial haemorrhage.³⁵

Limitations

Our study has several strengths and limitations. The patient cohort of the study was one of the largest thus far among real-world studies in Brazil. The combined use of claims and the care program added significant value to the study, especially by allowing the analysis of INR values, commonly not available in claims. However, given its retrospective observational nature, only associations could be concluded. This study observed TTR variations over time and as such was vulnerable to the effects of repeated measurements as an intervention. No advanced statistical techniques were used to balance characteristics of the TTR patient subgroups and therefore no inferential conclusions about cofactors could be drawn. We could not calculate the mean HAS-BLED risk score, as not all the data points of the score components were captured in the dataset (i.e. alcohol use). The incidence of other outcomes such as stroke, mortality, discontinuation and adherence was not analyzed. Sensitivity analyses at other specific TTR thresholds (e.g. 60% or 70%) were not conducted. The stability of INR over time was not assessed. Only direct medical costs were available; these referred to all-cause costs incurred by each patient, disregarding the reason for the utilization, consequently, they could have been overestimated. Healthcare resource utilization and patient subgroups were not evaluated.

According to Brazilian standards for procedure codes (Appendix A), INR has no individual code, but it is included within the “Coagulation test” code. As it was not possible to segregate, the INR measurement was considered as the entire coagulation test, and not as a percentage of it, for all patients.

It was found that a significant portion of patients taking warfarin (11%) had CHA₂DS₂-VAS_C scores of zero, which is greater than the proportion reported in other studies (6.1%).³⁶ CHA₂DS₂-VAS_C assessment is subject to the clinical documentation of patients' clinical history, and details of pre-existing conditions might have been underreported.

The phone monitoring program was offered to patients of a specific health insurance company and when a patient's contract terminated, follow-up was not possible.

Finally, some of the study limitations were inherent to a retrospective observational study design. These include potential coding errors and missing data which may have introduced biases into the study and affected the number of excluded patients, and the fact that the data assessed was not originally collected for clinical research purposes.

Conclusions

This study examined patient profiles, quality of anticoagulation and clinical/economic outcomes among NVAF warfarin patients in a private health insurance company in Brazil. It is representative of a large and relatively young cohort of warfarin patients. The overall quality of anticoagulation management was suboptimal. Warfarin patients were within the therapeutic range slightly more than half of the time. Up to two thirds had poor control (TTR < 65%) and were associated with more bleeding events and costs. This analysis highlights the importance, in terms of outcomes and costs, of tight anticoagulation control for NVAF patients treated with warfarin, and the difficulty in maintaining an adequate TTR even with a well-designed and run program. Additional research is needed, as more real-world data becomes available, to further assess the use of warfarin as well as the adoption of NOACs versus warfarin.

Footnotes

Sources of Funding

This study was funded by Pfizer.

Study Association

This study is not associated with any thesis or dissertation work.

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Hospital Pró-Cardíaco under the protocol number 1.835.148. All the procedures in this study were in accordance with the 1975 Helsinki Declaration, updated in 2013.

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PERMALINK

Terapia de Anticoagulação em Pacientes com Fibrilação Atrial não Valvar em Ambiente de Cuidado de Saúde Privado no Brasil: Um Estudo de Mundo Real

Pedro Gabriel Melo de Barros e Silva

Henry Sznejder

Rafael Vasconcellos

Georgette M Charles

Hugo Tannus F Mendonca-Filho

Jack Mardekian

Rodrigo Nascimento

Stephen Dukacz

Manuela Di Fusco

Resumo

Fundamento:

Objetivos:

Métodos:

Resultados:

Conclusões:

Introdução

Métodos

Fontes de dados

Seleção de Pacientes

Variáveis e medidas de desfechos

Métodos estatísticos

Análise de subgrupos

Análise de sensibilidade

Resultados

Características dos pacientes

Figura 1. Fluxograma descrevendo os critérios de inclusão e exclusão.

Tabela 1. Características e dados dos pacientes por quartil de TTR.

Controle de anticoagulação

Figura 2. Resultados de INR e TTR. A. Distribuição das medidas por faixa de INR. B. Distribuição de pacientes por variação de TTR.

Desfechos clínicos

Figura 3. Taxa de sangramento por quartil de TTR.

Resultados econômicos

Tabela 2. Custos de PMPY com e sem grandes sangramentos (R $).

Métricas por quartil de TTR

Análises de sensibilidade

Discussão

Limitações

Conclusões

Footnotes

Referências

Anticoagulation Therapy in Patients with Non-valvular Atrial Fibrillation in a Private Setting in Brazil: A Real-World Study

Pedro Gabriel Melo de Barros e Silva

Henry Sznejder

Rafael Vasconcellos

Georgette M Charles

Hugo Tannus F Mendonca-Filho

Jack Mardekian

Rodrigo Nascimento

Stephen Dukacz

Manuela Di Fusco

Abstract

Background:

Objectives:

Methods:

Results:

Conclusions:

Introduction

Methods

Data Sources

Patient Selection

Variables and Outcome Measures

Statistical methods

Subgroup analysis

Sensitivity analysis

Results

Patient characteristics

Figure 1. Flow chart describing inclusion and exclusion criteria.

Table 1. Patient characteristics and metrics per TTR quartile.

Anticoagulation control

Figure 2. INR and TTR results. A. Measurement distribution per INR range. B. Patient distribution per TTR range.

Clinical outcomes

Figure 3. Bleeding rate per TTR quartile.

Economic outcomes

Table 2. PMPY costs with and without major bleeds (R$).

Metrics per TTR quartile

Sensitivity analyses

Discussion

Limitations