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.

To assess the relative risks and benefits of drugs to rehydrate sickled red blood cells.

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.

Randomized or quasi-randomized controlled trials of drugs to rehydrate sickled red blood cells compared to placebo or an alternative treatment.

Both authors independently selected studies for inclusion, assessed study quality and extracted data.

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.

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.

Author(s)

Nagalla Srikanth, Ballas Samir K

Summary

Drugs that aim to reduce the loss of water from red blood cells in people with sickle cell disease

Review question

We reviewed the evidence to assess the relative risks and benefits of drugs to rehydrate sickled red blood cells.

Background

Sickle cell disease is an inherited condition that causes red blood cells to become sickle shaped when they lose water. This leads to a high risk of the blood vessels becoming blocked. Such blockages can cause pain, stroke and damage to organs. Recent therapies aim to stop the cells becoming sickle shaped by preventing them losing water.

Search date

The evidence is current to: 08 October 2018.

Study characteristics

The review included three studies with 524 people with sickle cell disease aged between 12 and 65 years of age. The intervention in one study was zinc sulphate and in two studies was senicapoc. Each study was compared to a placebo group (a substance which contains no medication). For each study people were selected for one treatment or the other randomly. The studies lasted from three months to 18 months.

Key results

The study with zinc sulphate showed that this drug may be able to reduce the number of sickle cell crises without causing toxic effects (low-quality evidence). There were 145 participants in this study and results showed a significant reduction in the total number of serious sickle-related crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15) (moderate-quality evidence). However, our analysis was limited since not all data were reported. Changes to red blood cell measurements and blood counts were not consistent (very low-quality evidence). No serious adverse events were noted in the study. The two studies with senicapoc demonstrated that this drug increases the red blood survival and has a role in preventing red blood cell dehydration in people with sickle cell disease (very low-quality evidence). The higher dose of the drug was more effective compared to the lower dose. But these changes in the red blood cells did not translate into positive clinical outcomes in terms of reduction in the number of sickle cell crises (low-quality evidence). Senicapoc had a favourable safety profile. More longer-term research is needed on these drugs and others that might prevent water loss in red blood cells.

Given this is no longer an active area of research, this review will no longer be regularly updated.

Quality of the evidence

The quality of the evidence was mixed across outcomes.

Reviewer's Conclusions

Implications for practice

There is low-quality evidence that zinc sulphate is associated with a reduction in pain crises, and also with reductions in other sickle cell-related crises. This was despite the treatment not being associated with an improvement in any of the hematological outcomes. While these results are encouraging, widespread introduction of this agent in the management of people with sickle cell disease is not indicated at present.

Senicapoc clearly improves the red blood cell survival in a dose-dependent manner (very low-quality evidence). But the improvement in the laboratory measures did not translate into clinical benefits. There was no reduction in the incidence of sickle cell crises with the use of senicapoc (low-quality evidence). Therefore, currently this drug cannot be used in clinical practice for the prevention of vaso-occlusive crises.

Implications for research

More studies are needed to evaluate the effect of zinc sulphate and of piracetam on the basic mechanisms of sickle cell disease. Further multicenter randomized controlled trials of zinc sulphate in people with sickle cell disease should be conducted. To investigate whether the findings previously reported are consistent and sustained, these future studies should be larger and longer term than the one reported in this review. Senicapoc improved red blood cell survival and decreased hemolysis. Further studies are needed to ascertain if this drug will be beneficial in some of the other complications of sickle cell disease such as pulmonary hypertension.