Srikanth Nagalla1, Samir K Ballas. 1. Division of Hematology and Oncology, UT Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, Texas, USA, 75390.
Abstract
BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group's Haemoglobinopathies Trials Register: 08 October 2018. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups (low-quality evidence). A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS' CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated.
BACKGROUND: Sickle cell disease is an inherited disorder of hemoglobin, resulting in abnormal red blood cells. These are rigid and may block blood vessels leading to acute painful crises and other complications. Recent research has focused on therapies to rehydrate the sickled cells by reducing the loss of water and ions from them. Little is known about the effectiveness and safety of such drugs. This is an updated version of a previously published review. OBJECTIVES: To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register. We also searched online trials registries for any ongoing trials (01 July 2018).Last search of the Group's Haemoglobinopathies Trials Register: 08 October 2018. SELECTION CRITERIA: Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment. DATA COLLECTION AND ANALYSIS: Both authors independently selected studies for inclusion, assessed study quality and extracted data. MAIN RESULTS: Of the 51 studies identified, three met the inclusion criteria, including 524 people with sickle cell disease aged between 12 and 65 years of age. One study tested the effectiveness of zinc sulphate as compared to placebo and the remaining two assessed senicapoc versus placebo. No deaths were seen in any of the studies (low-quality evidence). The zinc sulphate study showed a significant reduction in painful crises (in a total of 145 participants) over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, analysis was restricted due to limited statistical data. Changes to red blood cell parameters and blood counts were inconsistent (very low-quality evidence). No serious adverse events were noted in the study. The Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo showed that the high dose senicapoc showed significant improvement in change in hemoglobin level, the number and proportion of dense red blood cells, red blood cell count and indices and hematocrit value (very low-quality evidence). The results with low-dose senicapoc were similar to the high-dose senicapoc group but of lesser magnitude. There was no difference in the frequency of painful crises between the three groups (low-quality evidence). A subsequent Phase III study of senicapoc was terminated early since there was no difference observed between the treatment and control groups in the primary end point of painful crises. AUTHORS' CONCLUSIONS: While the results of zinc for reducing sickle-related crises are encouraging, larger and longer-term multicenter studies are needed to evaluate the effectiveness of this therapy for people with sickle cell disease.While the Phase II and the prematurely terminated phase III studies of senicapoc showed that the drug improved red blood cell survival (depending on dose), this did not lead to fewer painful crises.Given this is no longer an active area of research, this review will no longer be regularly updated.
Authors: Mohsen A F El-Hazmi; I Al-Fawaz; A Warsy; A Opawoye; H Taleb; Z Howsawi; A Mohamed; A Wadood Aly; S Refai; P Sugathan; A Rab; H Ahmed; M Abulaban; A Abdulkader; M Farid Journal: Saudi Med J Date: 1998-01 Impact factor: 1.484