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A Randomised Trial to Compare Aspirin vs Hydroxyurea/Aspirin in 'Intermediate Risk' Primary Thrombocythaemia and Aspirin Only With Observation in 'Low Risk'Primary Thrombocythaemia

40 Years
59 Years
Open (Enrolling)
Thrombocythemia, Myeloproliferative Disorder

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Trial Information

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.

Inclusion Criteria:

- The proposal is to include as many patients with PT as possible including previously
diagnosed patients whether or not they have received treatment. Thus all patients are
eligible assuming they meet the diagnostic criteria and they do not have any
exclusion criterion (see below). It will be necessary to stratify patients according
to their previous treatment. This information will be collected on entry to the
study. Informed consent is of course required where there is a change of therapeutic

The diagnostic criteria for primary thrombocythaemia are:

- Platelet count > 600x109/l.

- No evidence of overt polycythaemia(confirmed by RCM if necessary)or of polycythaemia
masked by co-existent iron deficiency.

- No Philadelphia chromosome.

- Absence of peripheral blood and/or marrow appearances of myelodysplasia, or

- No known cause of reactive thrombocytosis. Particular care should be taken to exclude
iron deficiency in pre-menopausal women.


- In asymptomatic patients, the platelet count should be observed for a period of at
least 2 months to confirm >600x109/l, and to allow any cause of reactive
thrombocytosis to become overt.

- If the PCV is above normal upper limit (that is, males >0.51, females >0.48) or in
high normal range in a patient with palpable splenomegaly measure RCM. Iron deficient
primary polycythaemia (polycythaemia vera) is strongly suggested if Hb/PCV is normal
in the presence of iron deficient red cell changes. In this situation, iron therapy
is potentially dangerous.

- Exceeding rarely, bcr-abl positive Philadelphia chromosome negative patients present
with high platelet counts with little or no elevation in WBC count. The features that
suggest it is necessary to examine for bcr-abl, are:- basophilia, left-shift in WBC,
granulocyte count >16x109/l, difficulty in controlling platelet count, megakaryocytes
of low ploidy (NAP is usually unhelpful).

- A normal ESR, CRP or plasma viscosity is useful in excluding a reactive

- Written informed consent obtained in accordance with NCRI requirements.

- Patients with impaired hepatic / renal function are not excluded although the
respective biochemical tests should be monitored during therapy and reduced doses of
cytoreductive agent should be used, particularly in the case of hydroxyurea and renal

Exclusion Criteria:

High risk features (any of the following):

- Age >or= 60 years

- Platelet count > or= 1500x109/l (current or previous) (a)

- History of ischaemia, thrombosis or embolic events (including erythromelalgia) (b)

- Haemorrhage considered to be related to PT (b)

- Presence of hypertension (c)or diabetes (d)

- The manufacturers of hydroxyurea state that it should be avoided in pregnancy and in
lactating women. Similarly, hydroxyurea should not be prescribed for women when
there is doubt about their use of an effective contraceptive method.

- Exclude patient from hydroxyurea therapy and, therefore, from the 'intermediate' risk
randomisation if the patient has current leg ulcers.

Notes on the definition of high risk:

- In patients with borderline counts the allocation of a patient to a high risk group
based on platelet count alone should rely on at least three samples taken on separate
occasions over at least 2 months.

- Documentation of previous thrombo-embolic, ischaemic and haemorrhagic events should
be given on the patient's entry proforma.

- Hypertension is defined as those patients requiring hypotensive therapy.

- Diabetes is defined as those patients requiring therapy with a hypoglycaemic agent.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Does hydroxyurea reduce thrombosis and major haemorrhage when added to aspirin?

Outcome Description:

Reducing thrombosis and major haemorrhage are specific key measurements in this group of patients for whom thrombotic events are very likely to occur.

Outcome Time Frame:

14 years

Safety Issue:


Principal Investigator

Anthony R Green, Prof

Investigator Role:

Study Director

Investigator Affiliation:

Addenbrooke`s Hospital and University of Cambridge


United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:




Start Date:

July 1997

Completion Date:

April 2014

Related Keywords:

  • Thrombocythemia
  • Myeloproliferative Disorder
  • Primary Thrombocythmeia
  • Hydroxyurea
  • Randomised
  • Thrombosis
  • Haemorrhage
  • Myeloproliferative Disorders
  • Thrombocythemia, Essential
  • Thrombocytosis