Drugs for preventing red blood cell dehydration in people with sickle cell disease: Cochrane systematic review

Abstract

Assessed as up to date: 2016/03/04

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.

Last search of the Group's Trials Register: 28 November 2015.

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. The first study tested the effectiveness of zinc sulphate to prevent sickle cell-related crises in a total of 145 participants and showed a significant reduction in painful crises over one and a half years, mean difference -2.83 (95% confidence interval -3.51 to -2.15). However, analysis was restricted due to limited statistical data. Changes to red cell parameters and blood counts were inconsistent. No serious adverse events were noted in the study.

The second study was a Phase II dose-finding study of senicapoc (a Gardos channel blocker) compared to placebo. Compared to the placebo group the high dose senicapoc showed significant improvement in change in hemoglobin level, number and proportion of dense red blood cells, red blood cell count and indices and hematocrit. 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. 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 cell survival (depending on dose), this did not lead to fewer painful crises.

We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published.

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: 28 November 2015.

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. 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). However, our analysis was limited since not all data were reported. Changes to red cell measurements and blood counts were not consistent. 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 the prevention on red blood cell dehydration in people with sickle cell disease. 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. 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.

We will continue to run searches to identify any potentially relevant trials; however, we do not plan to update other sections of the review until new trials are published.

Quality of the evidence

All the studies appeared to be well run and we do not think any factors will influence the results in a negative way.

Reviewer's Conclusions

Implications for practice

There is 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 cell survival in a dose-dependent manner. 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. 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 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.