A Randomised Trial to Compare Aspirin vs Hydroxyurea/Aspirin in 'Intermediate Risk' Primary Thrombocythaemia and Aspirin Only With Observation in 'Low Risk'Primary Thrombocythaemia
The myeloproliferative disease, primary thrombocythaemia (PT), has a median age of
presentation of 60 years but is increasingly being recognised at an earlier age. The risks
of the untreated condition are micro-vascular and major vessel occlusive events and
haemorrhage. Older patients and those with a previous thrombosis are particularly prone to
experience a significant vascular occlusive event. An anti-aggregating agent, such as
aspirin, has been shown to reduce/alleviate minor ischaemic symptoms. Therefore, except in
patients with haemorrhagic symptoms, peptic ulceration and known side-effects to aspirin,
the use of low-dose aspirin is appropriate.
Myelofibrotic and acute leukaemic transformations can be long-term complications of PT. The
ability of therapeutic agents to delay myelofibrosis or reduce/increase the incidence of
acute leukaemia in prospective studies is unknown. However, examination of retrospective
data provides anxiety about the leukaemogenic risk of the commonly used cytoreductive agent,
hydroxyurea. From an analysis of a few relatively small studies of primary thrombocythaemia,
the incidence of acute leukaemic transformation in selected patients treated with
hydroxyurea has been given as 5-10% over 4-11 years (1).
Based on the risk factors for vascular occlusion, older patients with a thrombotic history
and high platelet count can be separated into a 'high' risk group. There is evidence from a
randomised prospective study of 'high-risk' patients that cytoreduction with hydroxyurea
significantly reduces vascular occlusion (2). The observed reduction in this prospective
study of 29 months median duration was from 24% for those not given cytoreductive treatment
to 3.6% for those receiving hydroxyurea — approximately a six-fold reduction. In another
prospective study where all patients received hydroxyurea, an incidence of major thrombotic
events was 5.6%/year (3). In these high-risk patients, cytoreductive treatment should
therefore be given. The high risk arm of the PT1 trial, which has now closed, assessed the
cytoreductive treatment of choice for these high risk patients and the results suggest that
hydroxyurea plus aspirin is superior to anagrelide plus aspirin (4).
In the patients at lower risk of vascular occlusion the dilemma is that the risk of vascular
occlusion in untreated patients is relatively low, but includes major life-threatening
events. In two small prospective studies of these patients not receiving platelet lowering
agents, the observed major complications were 3% and 4.1% per year and the total
complications were 5.1% and 10.5% per year respectively (1). Cyto-reductive treatment should
prevent such events and one could predict a similar reduction in complications as seen in
the high-risk patients. However, there is evidence that in patients under the age of 40
years the complication rate is only one quarter of that seen in patients aged 40 - 59 years
(5). Therefore it has been decided to divide these patients at lower risk of vascular
occlusion into 'intermediate' and 'low risk' groups. Patients aged 40-59 years will fall
into the 'intermediate risk' group and will be randomised to cytoreduction or not, while all
will receive aspirin. Patients under 40 years will form the 'low-risk' group and will
receive aspirin alone. Cyto-reductive treatment might also delay myelofibrotic
transformation as observed in primary polycythaemia. However, this benefit and the possible
reduction in vaso-occlusive episodes need to be balanced against the potential long-term
risk of increasing acute leukaemic transformation.
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Does hydroxyurea reduce thrombosis and major haemorrhage when added to aspirin?
Reducing thrombosis and major haemorrhage are specific key measurements in this group of patients for whom thrombotic events are very likely to occur.
Anthony R Green, Prof
Addenbrooke`s Hospital and University of Cambridge
United Kingdom: Medicines and Healthcare Products Regulatory Agency