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. 2021 Jan 9;1(1):CD008394.
doi: 10.1002/14651858.CD008394.pub4.

Interventions for treating leg ulcers in people with sickle cell disease

Arturo J Martí-Carvajal  1   2 , Jennifer M Knight-Madden  3 , Maria José Martinez-Zapata  4
Affiliations

Interventions for treating leg ulcers in people with sickle cell disease

Arturo J Martí-Carvajal et al. Cochrane Database Syst Rev. .

Abstract
in English, Persian, French, Spanish

Background: The frequency of skin ulceration makes an important contributor to the morbidity burden in people with sickle cell disease. Many treatment options are available to the healthcare professional, although it is uncertain which treatments have been assessed for effectiveness in people with sickle cell disease. This is an update of a previously published Cochrane Review.

Objectives: To assess the clinical effectiveness and harms of interventions for treating leg ulcers in people with sickle cell disease.

Search methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We searched LILACS (1982 to January 2020), ISI Web of Knowledge (1985 to January 2020), and the Clinical Trials Search Portal of the World Health Organization (January 2020). We checked the reference lists of all the trials identified. We also contacted those groups or individuals who may have completed relevant randomised trials in this area. Date of the last search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register: 13 January 2020; date of the last search of the Cochrane Wounds Group Trials Register: 17 February 2017.

Selection criteria: Randomised controlled trials of interventions for treating leg ulcers in people with sickle cell disease compared to placebo or an alternative treatment.

Data collection and analysis: Two authors independently selected studies for inclusion. All three authors independently assessed the risk of bias of the included studies and extracted data. We used GRADE to assess the quality of the evidence.

Main results: Six studies met the inclusion criteria (198 participants with 250 ulcers). Each trial investigated a different intervention and within this review we have grouped these as systemic pharmaceutical interventions (L-cartinine, arginine butyrate, isoxsuprine) and topical pharmaceutical interventions (Solcoseryl® cream, arginine-glycine-aspartic acid (RGD) peptide dressing and topical antibiotics). No trials on non-pharmaceutical interventions were included in the review. All trials had an overall unclear or high risk of bias, and drug companies sponsored four of them. We were unable to pool findings due to the heterogeneity in outcome definitions, and inconsistency between the units of randomisation and analysis. Three interventions reported on the change in ulcer size (arginine butyrate, RGD peptide, L-cartinine). Of these, only arginine butyrate showed a reduction of ulcer size compared with a control group, mean reduction -5.10 cm² (95% CI -9.65 to -0.55), but we are uncertain whether this reduces ulcer size compared to standard care alone as the certainty of the evidence has been assessed as very low. Three trials reported on complete leg ulcer closure (isoxsuprine, arginine butyrate, RGD peptide matrix; very low quality of evidence). None reported a clinical benefit. No trial reported on: the time to complete ulcer healing; ulcer-free survival following treatment for sickle cell leg ulcers; quality of life measures; incidence of amputation or harms.

Authors' conclusions: Given the very low quality of the evidence identified in this updated Cochrane Review we are uncertain whether any of the assessed pharmaceutical interventions reduce ulcer size or result in leg ulcer closure in treated participants compared to controls. However, this intervention was assessed as having a high risk of bias due to inadequacies in the single trial report. Other included studies were also assessed as having an unclear or high risk of bias. The harm profile of the all interventions remains inconclusive.

پیشینه: فراوانی زخم‌های پوستی نقش مهمی را در بار (burden) موربیدیتی در افراد مبتلا به بیماری سلول داسی‏‌شکل ایفا می‌کند. گزینه‌های درمانی بسیاری برای این وضعیت در دسترس هستند، اگرچه مشخص نیست که کدام درمان‌ها برای اثربخشی در افراد مبتلا به بیماری سلول داسی‏‌شکل ارزیابی شده‌اند. این یک به‌روزرسانی از مرور کاکرین است که قبلا منتشر شد. اهداف: ارزیابی اثربخشی و آسیب‌های ناشی از مداخلات برای درمان زخم‌های پا در افراد مبتلا به بیماری سلول داسی‏‌شکل. روش‌های جست‌وجو: به جست‌وجو در پایگاه ثبت کارآزمایی‌های هموگلوبینوپاتی‌ها، مربوط به گروه فیبروز کیستیک و اختلالات ژنتیکی در کاکرین پرداختیم. LILACS (1982 تا ژانویه 2020)، ISI Web of Knowledge (1985 تا ژانویه 2020) و پورتال جست‌وجوی کارآزمایی بالینی سازمان جهانی بهداشت (ژانویه 2020) را جست‌وجو کردیم. فهرست منابع همه کارآزمایی‌های شناسایی‌ شده را بررسی کردیم. همچنین با آن گروه‌ها یا افرادی که ممکن است کارآزمایی‌های تصادفی‌سازی شده مرتبط و پایان یافته داشته باشند، تماس گرفتیم. تاریخ آخرین جست‌وجو در پایگاه ثبت کارآزمایی‌های هموگلوبینوپاتی‌ها مربوط به گروه فیبروز کیستیک و اختلالات ژنتیکی در کاکرین: 13 ژانویه 2020 ؛ تاریخ آخرین جست‌وجو در پایگاه ثبت کارآزمایی‌های گروه زخم در کاکرین: 17 فوریه 2017. معیارهای انتخاب: کارآزمایی‌های تصادفی‌سازی و کنترل شده از مداخلات برای درمان زخم‌های پا در افراد مبتلا به بیماری سلول داسی‏‌شکل در مقایسه با دارونما (placebo) یا درمان جایگزین. گردآوری و تجزیه‌وتحلیل داده‌ها: دو نویسنده به‌طور مستقل از هم مطالعات را برای ورود انتخاب کردند. هر سه نویسنده به‌طور مستقل از هم خطر سوگیری (bias) مطالعات وارد شده را ارزیابی و داده‌ها را استخراج کردند. از رویکرد درجه‌‏بندی توصیه‏، ارزیابی، توسعه و ارزشیابی (GRADE) برای ارزیابی کیفیت شواهد استفاده کردیم. نتایج اصلی: شش مطالعه (198 شرکت‌کننده با 250 زخم) واجد معیارهای ورود بودند. هر کارآزمایی، مداخله متفاوتی را بررسی کرده و در این مرور، این موارد را در قالب مداخلات دارویی سیستمیک (ال‐کارنیتین (L‐cartinine)، آرژنین‌ بوتیرات (arginine butyrate)، ایزوکسوپرین (isoxsuprine)) و مداخلات دارویی موضعی (کرم سولکوسریل (®Solcoseryl)؛ پانسمان پپتیدی آرژنین‐گلیسین‐آسپارتیک اسید (arginine‐glycine‐aspartic acid; RGD) و آنتی‌بیوتیک‌های موضعی) گروه‌بندی کردیم. هیچ کارآزمایی در مورد مداخلات غیر‐دارویی در این مرور وارد نشد. به‌طور کلی، همه کارآزمایی‌ها خطر سوگیری بالا یا نامشخصی داشتند، و شرکت‌های دارویی از هر چهار کارآزمایی حمایت مالی کردند. به دلیل ناهمگونی در تعاریف پیامد، و ناهمگونی میان واحدهای تصادفی‌سازی و تجزیه‌و‌تحلیل، قادر به تجمیع یافته‌ها نبودیم. سه مداخله در مورد تغییر در اندازه زخم گزارش شدند (آرژنین‌ بوتیرات، پپتید RGD، ال‐کارنیتین). از میان آنها، فقط آرژنین بوتیرات در مقایسه با گروه کنترل کاهش اندازه زخم را، با میانگین کاهش 5.10‐ سانتی‌متر مربع ( 95% CI؛ 9.65‐ تا 0.55‐)، نشان داد، اما مطمئن نیستیم که باعث کاهش اندازه زخم در مقایسه با مراقبت‌های استاندارد به‌تنهایی می‌شود یا خیر، زیرا قطعیت شواهد در سطح بسیار پائین بود. سه کارآزمایی در مورد بسته شدن کامل زخم پا گزارش دادند (ایزوکسوپرین؛ آرژنین بوتیرات؛ ماتریکس پپتید RGD؛ شواهد با کیفیت بسیار پائین). هیچ‌کدام مزایای بالینی را گزارش نکردند. هیچ‌یک از کارآزمایی‌ها گزارشی را از این موارد ارائه نکردند: زمان لازم تا ترمیم کامل زخم، بقای بیمار بدون زخم به دنبال درمان زخم‌های پای ناشی از سلول داسی‌شکل، معیارهای کیفیت زندگی، بروز آمپوتاسیون یا آسیب‌ها. نتیجه‌گیری‌های نویسندگان: با توجه به کیفیت بسیار پائین شواهد به دست آمده در این به‌روزرسانی مرور کاکرین، مطمئن نیستیم که هر یک از مداخلات دارویی ارزیابی شده در مقایسه با گروه‌های کنترل، اندازه زخم را کاهش داده یا منجر به بسته شدن زخم پا در شرکت‏‌کنندگان تحت درمان می‌شود یا خیر. با این حال، این مداخله به دلیل وجود ناکفایتی‌ها در گزارش کارآزمایی، با خطر سوگیری بالا ارزیابی شد. سایر مطالعات وارد شده نیز با خطر سوگیری بالا یا نامشخص ارزیابی شدند. مشخصات آسیب همه مداخلات بی‌نتیجه می‌ماند.

Contexte: La fréquence des ulcérations cutanées contribue de manière importante à la charge de morbidité des personnes atteintes de drépanocytose. De nombreuses options de traitement sont à la disposition des professionnels de la santé, bien qu'on ne sache pas pour quels traitements a été vérifiée l'efficacité chez les personnes atteintes de drépanocytose. Il s’agit de la mise à jour d'une revue Cochrane déjà publiée.

Objectifs: Évaluer l'efficacité clinique et les risques des interventions pour le traitement des ulcères de jambe chez les personnes atteintes de drépanocytose. STRATÉGIE DE RECHERCHE DOCUMENTAIRE: Nous avons effectué des recherches dans le registre des essais sur les hémoglobinopathies du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques. Nous avons effectué des recherches dans LILACS (1982 à janvier 2020), ISI Web of Knowledge (1985 à janvier 2020) et le Système d'enregistrement international des essais cliniques de l'OMS (ICTRP) (janvier 2020). Nous avons examiné les références bibliographiques de tous les essais identifiés. Nous avons également contacté des groupes ou des personnes susceptibles d'avoir réalisé des essais randomisés pertinents dans ce domaine. Date de la dernière recherche dans le registre des essais sur les hémoglobinopathies du groupe Cochrane sur la mucoviscidose et les autres maladies génétiques : 13 janvier 2020 ; date de la dernière recherche dans le registre des essais du groupe Cochrane sur les plaies et contusions: 17 février 2017. CRITÈRES DE SÉLECTION: Essais contrôlés randomisés d'interventions pour le traitement des ulcères de jambe chez les personnes atteintes de drépanocytose, comparés à un placebo ou à un traitement alternatif. RECUEIL ET ANALYSE DES DONNÉES: Deux auteurs ont sélectionné de manière indépendante les études à inclure. Les trois auteurs ont, de manière indépendante, évalué le risque de biais des études incluses et extrait les données. Nous avons utilisé GRADE pour évaluer la qualité des données probantes. RÉSULTATS PRINCIPAUX: Six études remplissaient les critères d'inclusion (198 participants au total avec 250 ulcères). Chaque essai a porté sur une intervention différente et, dans le cadre de cette étude, nous les avons regroupées en interventions pharmaceutiques systémiques (L‐cartinine, arginine butyrate, isoxsuprine) et en interventions pharmaceutiques topiques (crème Solcoseryl®, pansement de peptides arginine‐glycine‐acide aspartique (RGD) et antibiotiques topiques). Nous n’avons pas inclus dans la revue d’essais portant sur des interventions non pharmaceutiques. Tous les essais présentaient un risque de biais global incertain ou élevé, et les sociétés pharmaceutiques en ont parrainé quatre. Nous n'avons pas pu regrouper les résultats en raison de l'hétérogénéité des définitions des critères de jugement et de l'incohérence entre les unités de randomisation et d'analyse. Trois interventions avaient rapporté le changement de taille de l'ulcère (butyrate d'arginine, peptides RGD, L‐carnitine). Parmi ceux‐ci, seul le butyrate d'arginine a montré une réduction de la taille de l'ulcère par rapport à un groupe de contrôle, réduction moyenne de ‐5,10 cm² (IC à 95 % ‐9,65 à ‐0,55), mais nous ne savons pas si cela réduit la taille de l'ulcère par rapport aux soins standard uniquement car le niveau de confiance des données probantes a été évaluée comme très faible. Trois essais ont rapporté sur la fermeture complète de l'ulcère de jambe (isoxsuprine, butyrate d'arginine, matrice de peptides RGD ; données probantes d’un niveau de confiance très faible). Les essais n’ont pas rapporté un bénéfice clinique. Les essais n’ont pas rapporté sur: le temps nécessaire à la guérison complète de l'ulcère ; survie sans ulcère après traitement des ulcères de jambe chez les patients atteints de drépanocytose ; les mesures de la qualité de vie ; l'incidence de l'amputation ou les risques.

Conclusions des auteurs: Étant donné la très faible qualité des données probantes identifiées dans cette mise à jour de la revue Cochrane, nous ne sommes pas certains que les interventions pharmaceutiques évaluées réduisent la taille des ulcères ou entraînent une fermeture des ulcères de jambe chez les participants traités par rapport aux témoins. Toutefois, cette intervention a été estimée à risque élevé de biais en raison de lacunes dans l'unique rapport d'essai. D'autres études incluses ont également été évaluées comme présentant un risque de biais incertain ou élevé. Le profil de risque de toutes les interventions reste peu concluant.

Antecedentes: La frecuencia de ulceración de la piel contribuye de forma importante a la carga de morbilidad de los pacientes con anemia de células falciformes. El profesional sanitario dispone de muchas opciones de tratamiento, aunque se desconoce qué tratamientos se han evaluado con respecto a la efectividad en pacientes con anemia de células falciformes. Esta es una actualización de una revisión Cochrane publicada anteriormente.

Objetivos: Evaluar la efectividad clínica y los efectos perjudiciales de las intervenciones para el tratamiento de las úlceras de las piernas en pacientes con anemia de células falciformes. MÉTODOS DE BÚSQUEDA: Se realizaron búsquedas en el Registro de ensayos de hemoglobinopatías del Grupo Cochrane de Fibrosis quística y enfermedades genéticas (Cochrane Cystic Fibrosis and Genetic Disorders Group). Se hicieron búsquedas en LILACS (1982 hasta enero de 2020), ISI Web of Knowledge (1985 hasta enero de 2020) y en el Clinical Trials Search Portal de la Organización Mundial de la Salud (enero de 2020). Se comprobaron las listas de referencias de todos los ensayos identificados. Se estableció contacto con grupos o individuos que hubieran completado ensayos aleatorizados relevantes en esta área. Fecha de la búsqueda más reciente en el Registro de ensayos de hemoglobinopatías del Grupo Cochrane de Fibrosis quística y enfermedades genéticas: 13 de enero de 2020; fecha de la última búsqueda en el registro de ensayos del Grupo Cochrane de Heridas: 17 de febrero de 2017. CRITERIOS DE SELECCIÓN: Ensayos controlados aleatorizados de intervenciones para el tratamiento de las úlceras de las piernas en pacientes con anemia de células falciformes en comparación con placebo o un tratamiento alternativo. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Dos autores de la revisión evaluaron de forma independiente los estudios para inclusión. Los tres autores de la revisión, de forma independiente, evaluaron el riesgo de sesgo de los estudios incluidos y extrajeron los datos. Para evaluar la calidad general de la evidencia se utilizaron los criterios GRADE.

Resultados principales: Seis estudios cumplieron los criterios de inclusión (198 participantes con 250 úlceras). Cada ensayo investigó una intervención diferente que en esta revisión se agruparon en intervenciones farmacéuticas sistémicas (L‐carnitina, butirato de arginina, isoxsuprina) e intervenciones farmacéuticas tópicas (crema Solcoseryl®, apósito de matriz peptídica de arginina‐glicina‐ácido aspártico (RGD), antibióticos tópicos). En la revisión no se incluyeron ensayos sobre intervenciones farmacéuticas. Todos los ensayos tuvieron un riesgo general de sesgo poco claro o alto y cuatro recibieron patrocinio de empresas farmacéuticas. No fue posible agrupar los resultados debido a la heterogeneidad en las definiciones de los desenlaces y a la incoherencia entre las unidades de asignación al azar y las de análisis. Tres intervenciones informaron sobre el cambio en el tamaño de la úlcera (butirato de arginina, apósito de matriz peptídica RGD, L‐carnitina). De estas, sólo el butirato de arginina mostró una reducción del tamaño de la úlcera en comparación con un grupo de control, reducción media ‐5,10 cm² (IC del 95%: ‐9,65 a ‐0,55), pero no se sabe si esto reduce el tamaño de la úlcera en comparación con la atención estándar sola, ya que la certeza de la evidencia se ha considerado muy baja. Tres ensayos informaron sobre el cierre completo de la úlcera de la pierna (isoxsuprina, butirato de arginina, matriz peptídica RGD; evidencia de calidad muy baja). Ninguno informó un beneficio clínico. Ningún ensayo informó sobre el tiempo transcurrido hasta la cicatrización completa de la úlcera; la supervivencia sin úlceras después del tratamiento de las úlceras de las piernas en pacientes con anemia de células falciformes, medidas de calidad de vida, la incidencia de amputación o los efectos perjudiciales.

Conclusiones de los autores: Dada la muy baja calidad de la evidencia identificada en esta revisión Cochrane actualizada, no se sabe con certeza si alguna de las intervenciones farmacéuticas evaluadas reduce el tamaño de la úlcera o provoca el cierre de la úlcera de la pierna en participantes tratados comparados con controles. Sin embargo, esta intervención se consideró con alto riesgo de sesgo debido a las deficiencias en el informe del único ensayo. Otros estudios incluidos también se consideraron con riesgo de sesgo alto o poco claro. El perfil de efectos perjudiciales de todas las intervenciones continúa sin ser concluyente.

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Conflict of interest statement

In 2004 Arturo Martí‐Carvajal was employed by Eli Lilly to run a four‐hour workshop on 'How to critically appraise clinical trials on osteoporosis and how to teach this'. This activity was not related to his work with the Cochrane Collaboration or any Cochrane Review.

In 2007 Arturo Martí‐Carvajal was employed by Merck to run a four‐hour workshop 'How to critically appraise clinical trials and how to teach this'. This activity was not related to his work with The Cochrane Collaboration or any Cochrane Review.

Jennifer Knight‐Madden and María José Martínez‐Zapata: none known.

Figures

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Study flow diagram ‐ update Juanuary 2020
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Risk of bias graph: review authors' judgements about each risk of bias domain presented as percentages across all included studies
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Risk of bias summary: review authors' judgements about each risk of bias domain for each included study
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5
Albatross plot for three trials about interventions for treating leg ulcers in people with sickle cell disease on complete leg ulcers closure Albatross plot based on total sample size, P values and risk reduction (RR) from three trials (black points) reporting results on complete leg ulcers closure in people with sickle cell disease. Two trials (on the right side) showed positive associations (RR > 1), but neither had a P value < 0.05. One trial (on the left side) showed a negative association (RR < 1), but again did not have a P value < 0.05. This Albatross plot shows a clear heterogeneity among trials as points are spread across the width of the graph. Meta‐analysis of these small trials was not possible due to inconsistency between unit of randomisation and unit of analysis.
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Albatross plot for five trials about interventions for treating leg ulcers in people with sickle cell disease on reducing mean size of leg ulcers Albatross plot based on total sample size, P values and mean difference (MD) from five trials (black points) reporting results on reduction mean size of leg ulcers in people with sickle cell disease. Four trials (on the right side) showed a positive association (MD > 0). One trial (on the left side) shows a negative association (MD < 0), but with a large P value. This albatross plot shows a clear heterogeneity among trials, with no clear, consistent magnitude of effect and points spread across the graph. Meta‐analysis of these small trials was not possible due to inconsistency between unit of randomisation and unit of analysis.
1.1
1.1. Analysis
Comparison 1: Isoxsuprine versus placebo, Outcome 1: Complete leg ulcer closure
1.2
1.2. Analysis
Comparison 1: Isoxsuprine versus placebo, Outcome 2: Change in ulcer size
2.1
2.1. Analysis
Comparison 2: Arginine butyrate plus standard care alone versus standard care alone, Outcome 1: Complete wound closure
2.2
2.2. Analysis
Comparison 2: Arginine butyrate plus standard care alone versus standard care alone, Outcome 2: Change in ulcer size
3.1
3.1. Analysis
Comparison 3: Propionyl‐L‐carnitine versus placebo, Outcome 1: Change in ulcer size (surface area or volume)
4.1
4.1. Analysis
Comparison 4: RGD peptide matrix versus placebo, Outcome 1: Complete leg ulcer closure
4.2
4.2. Analysis
Comparison 4: RGD peptide matrix versus placebo, Outcome 2: Adverse events
5.1
5.1. Analysis
Comparison 5: Solcoseryl® versus antiseptic agent (Eusol), Outcome 1: Reduction in ulcer area
6.1
6.1. Analysis
Comparison 6: Duoderm® versus antiseptic agent (Eusol), Outcome 1: Reduction in ulcer area
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References

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Wethers 1994 {published data only}
    1. Ramirez GM, Wethers DL, Koshy M, Steinberg MH, Phillips G Jr, Siegel RS, et al. Accelerated healing of chronic sickle cell leg ulcers treated with a RGD matrix. In: The National Sickle Cell Disease Program Annual Meeting Conference Proceedings. 1994. - PubMed
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References to studies excluded from this review

Afifi 1979 {published data only}
    1. Afifi AM, Adnan M, Taha M, Amasha ME. Xanthinol nicotinate in the management of leg ulcers associated with haemoglobinopathies. Current Medical Research and Opinion 1979;(5):309-13. [PMID: ] - PubMed
Bonini‐Domingos 2012 {published data only}
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Cacciola 1990b {published data only}
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Connor 2018 {published data only}
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Lucena 2007 {published data only}
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Massenburg 2016 {published data only}
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Meneses 2016 {published data only}
    1. Meneses JV, Fortuna V, Souza ES, Daltro GC, Meyer R, Minniti CP, et al. Autologous stem cell-based therapy for sickle cell leg ulcer: a pilot study. British Journal of Haematology 2016;175(5):949-55. [PMID: ] - PubMed
Minniti 2014 {published data only}
    1. Minniti C, Kato GJ, Gorbach A, Hon C, Delaney KMH, Siedel M, et al. A phase 1 dose-escalation trial of topical sodium nitrite in patients with sickle cell anemia and leg ulcers: evidence of in human effect on blood flow. Haematologica 2014;99(Suppl 1 (S663)):230.
    1. Minniti CP, Gorbach AM, Xu D, Hon YY, Delaney KM, Seidel M, et al. Topical sodium nitrite for chronic leg ulcers in patients with sickle cell anaemia: a phase 1 dose-finding safety and tolerability trial. The Lancet. Haematology 2014;1(3):e95-e103. [PMID: ] - PMC - PubMed
Neves 2010 {published data only}
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Okany 2004 {published data only}
    1. Okany CC, Atimomo CE, Akinyanju OO. Efficacy of natural honey in the healing of leg ulcers in sickle cell anaemia. The Nigerian Postgraduate Medical Journal 2004;11(3):179-81. [PMID: ] - PubMed
Paggiaro 2010 {published data only}
    1. Paggiaro AO, Carvalho VF, Fonseca GHH, Doi A, Ferreira MC. Negative pressure therapy for complex wounds in patients with sickle-cell disease: a case study. Ostomy Wound Management 2010;56(8):62-7. [IDS Number: 644CO ] - PubMed
Sawyer 1979 {published data only}
    1. Sawyer PN, Haque S, Reddy K, Sophie Z, Feller J. Wound healing effects of debrisan on varicose, postoperative, decubitus, and sickle-cell ulcers in man. Vascular Surgery 1979;13(4):251-6.
Serjeant 1970 {published data only}
    1. Serjeant GR, Galloway RE, Gueri MC. Oral zinc sulphate in sickle-cell ulcers. Lancet 1970;2(7679):891-2. [PMID: ] - PubMed
Valentino 2017 {published data only}
    1. Valentino J, Misra H, Lopez L, Paulino GM. Use of pegylated-carboxyhemoglobin bovine for the treatment of sickle cell disease associated leg ulcers: results from a phase 2 safety study. In: Haematologica. Vol. 102 (Suppl 2) Abstract P618. The Hague, The Netherlands: Ferrata Storti Foundation, 2017:243-4. [CENTRAL: CN-01399343] [EMBASE: 617378719] [ISSN 0390-6078]

References to studies awaiting assessment

Friedrisch 2016 {published data only}
    1. Friedrisch JR, Bittar CM, Bittar CM, Meirelles MCG, Daudt LE, Paz AA, et al. L-arginine supplementation decreases hemolysis and pulmonary arterial hypertension in sickle cell disease patients: a randomized, double-blinded, placebo-controlled trial. Haematologica 2016;101 (Suppl 1):618-9. [ABSTRACT NO.: LB2267]
You 2019 {published data only}
    1. NCT02863068. A phase II study of topical sodium nitrite in patients with sickle cell and leg ulcers. //clinicaltrials.gov/show/NCT02863068 (first posted 11 August 2016). [CFGD REGOSTER: SC377a]
    1. You S, Crouch A, Ogu UO, Solorzano C, Sebastian G, Mirander M, et al. Topical sodium nitrite in sickle cell disease and leg ulcers [A phase II study of topical sodium nitrite in patients with sickle cell and leg ulcers]. Blood 2019;134 (Suppl 1):2292. [CENTRAL: CN-01592371] [CFGD REGISTER: SC377b]

References to ongoing studies

NCT04058197 {published data only}
    1. NCT04058197. Deferoxamine for sickle cell chronic leg ulcer treatment (D-SCOUT). https://clinicaltrials.gov/ct2/show/NCT04058197 April 2020.

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