The TWiTCH trial – a major improvement in the care of children at risk of stroke

The results of the long awaited TWiTCH trial have just been published in the Lancet.

What is TWiTCH? Well it stands for TCD With Transfusions Changing to Hydroxycarbamide, and it was a large, multi-centre clinical trial involving 26 paediatric sickle cell centres in the USA and Canada, co-ordinated by Professor Russell Ware from the Children’s Hospital in Cincinnati. The trial was designed to find out whether hydroxycarbamide could be used instead of blood transfusions to prevent strokes in high risk children with sickle cell disease.

Background: Stroke is a common and devastating complication affecting children with sickle cell anaemia. Without treatment stroke will affect between 10% to 13% of all children, usually before the age of 10 years. Children at high risk of a stroke can be identified by transcranial doppler (TCD); high TCD measurements identify a sub-population of high risk children who have a 40% risk of stroke over the next 3 years.

Transcranial doppler measurements are simple and pain free. The ultrasound probe is applied to the side of the head and records the rate of blood flow in the large arteries supplying the brain. The faster the rate of flow, the narrower the artery and the greater the risk of stroke.

Transcranial doppler is simple and pain free. The ultrasound probe is applied to the side of the head and records the rate of blood flow in the large arteries supplying the brain. The faster the rate of flow, the narrower the artery and the greater the risk of stroke.

The relatvley thin bone over the temporal region allows the ultrasound probe to assess blood flow in the large arteries at the base of the brain.

The relatively thin bone over the temporal region allows the ultrasound probe to assess blood flow in the large arteries at the base of the brain. This is a picture looking down at the base of the skull; the large oval, black hole is where the spinal cord leaves the brain, the eye sockets are at the top and the blood vessels are coloured in red.

It was the STOP trial in 1998 which first showed that if high risk children are put on a regular programme of blood transfusions to maintain their sickle cell level (Hb S) at less than 30% then their risk of a stroke is reduced by a massive 90%. As a result of this trial all children with sickle cell anaemia are now screened regularly by TCD and those at high risk (blood flow velocities >200cm/sec) are offered a regular transfusion programme. The same investigators followed this up with the STOP 2 trial (2005) which asked the question “Is it safe to stop regular blood transfusions after a minimum of 30 months treatment?” Unfortunately, they found that the answer was no. If transfusions were stopped then blood flow velocities began to increase again and with that so did the risk of a stroke.

The conclusion from the two STOP trials was that regular transfusions successfully protected high risk children from a stroke, but once they had been started they needed to continue indefinitely. This is an enormous burden for children and their families to live with and repeated blood transfusions also carry the risk of serious complications such as iron overload, viral transmission and allo-immunisation.

The Bottom Line: What has proved to be so important about the TWiTCH trial was that the investigators were able to show that after 12 months you can safely switch a child from regular transfusions to taking hydroxycarbamide instead. Hydroxycarbamide maintains blood flow velocities at low, stable levels, there is no increase in the risk of stroke and it also avoids the monthly admissions to hospital for a blood transfusion with all the problems that involves.

What They Did: The TWiTCH trial was a classic clinical trial. The investigators identified 121 children aged 4-16 years at high risk of stroke (TCD >200cm/sec) who were already on a regular transfusion programme. 61 children continued on standard, monthly blood transfusion treatment, which maintained their Hb S at <30%, either by simple top-up transfusions or by manual or automated exchange transfusions. The other 60 patients were changed to hydroxycarbamide, initially at a dose of 20mg/kg/day, which was gradually increased, over a period of about 6 months to an individualised maximum tolerated dose. Over the same time period blood transfusions were gradually weaned off and eventually stopped. Each patient was then followed up for 2 years.

What They Found: At the end of the study period the two groups were remarkably similar. TCD’s remained low and were about the same in each group; 143cm/sec in the transfused children and 138cm/sec in the hydroxycarbamide children. No strokes occurred in either group; 6 children did have “mini-strokes” (transient ischaemic attacks or TIA’s), but they were equally divided, with 3 in each treatment group. The children taking hydroxycarbamide did have more episodes of vaso-occlusive pain but apart from that there was no difference in side effects or adverse events in each treatment arm. The TWiTCH trial therefore provides convincing evidence that high risk children with sickle cell can be safely changed from regular monthly transfusions to daily medication with hydroxycarbamide and still keep their low risk of stroke.

An accompanying editorial in the Lancet also makes clear, that the trial opens up important treatment options for children in the developing world. About 90% of the 300,000 children born each year with sickle cell live in sub-Saharan Africa. Treatment with regular blood transfusions, even for one year, is simply not an option for the vast majority of these children because of the cost and safety concerns around the transmission of viral infections by contaminated blood. Hydroxycarbamide, on the other hand, is cheap and requires relatively little laboratory monitoring. A clinical trail is currently underway in Nigeria comparing fixed low dose (10mg/kg/day) and fixed high dose (20mg/kg/day) hydroxycarbamide started as soon as a high risk child is identified by TCD. This trial will hopefully determine whether immediate treatment with hydroxycarbamide can remove the need for an initial period of blood transfusion and whether a more simple, fixed dosing regime is effective.

A word of Warning: We know that patients can find it very difficult to take tablets on a regular daily basis. It is clear from the data in the paper that the children in the hydroxycarbamide treatment arm were very good at taking their hydroxycarbamide and were no doubt encouraged to do so by the trial investigators;. Their MCV (mean cell volume – the size of their red blood cells) increased from 86fl to 107fl and their Hb F (foetal haemoglobin) went up from 8.8% to a very impressive 24.4%. Clearly for the hydroxycarbamide to work it has to be taken regularly every day and it will be interesting to see whether these excellent results in the environment of a clinical trial can be replicated in the real world.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia- TCD With Transfusions Changing to Hydroxycarbamide (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Russell E Ware and 44 others. The Lancet, 2016, volume 387, pages 661-670

For more information about strokes and silent cerebral infarcts in sickle cell you might like to have a look at another blog – “Stroke in children with sickle cell disease” published on 09/01/2015. Other relevant blogs include: “More on hydroxycarbamide” – posted on 07/01/2015 and “Blood transfusion” – posted on 19/06/2015.

 

 

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About rogerjamos

I am a consultant haematologist who has worked in Hackney, London, UK with patients who have sickle cell disease for many years. Knowledge is power; the hope is that this blog will empower patients by putting them in touch with contemporary research into sickle cell disease and facilitating informed discussion on the issues raised. Dr Roger Amos MA, MD, FRCPath
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