Anagrelide

Anagrelide (Agrylin®, Xagrid®) is an oral imidazoquinazoline agent which is indicated in Europe for the reduction of elevated platelet counts in at-risk patients with essential thrombocythaemia who are intolerant of or refractory to their current therapy, and in the US for the reduction of elevated platelet counts and the amelioration of thrombohaemorrhagic events in patients with thrombocythaemia associated with myeloproliferative disorders

Anagrelide is well established as an effective platelet-lowering agent in most patients with essential thrombocythaemia, including both treatment-naive patients and those refractory to other cytoreductive therapy. Results of the only randomised trial to date (the Primary Thrombocythaemia 1 [PT1] study) indicated that the composite primary endpoint (arterial or venous thrombosis, serious haemorrhage or death from vascular causes) occurred more often in recipients of anagrelide plus aspirin than in those receiving hydroxycarbamide (hydroxyurea) plus aspirin. This trial also indicated that the incidence of the secondary endpoints transient ischaemic attack and gastrointestinal bleeding favoured hydroxycarbamide plus aspirin, while the incidence of venous thrombosis favoured anagrelide plus aspirin. There were no differences between the groups in the incidence of secondary endpoints myocardial infarction, stroke, unstable angina, pulmonary embolism, hepatic-vein thrombosis, other serious haemorrhage or related deaths. The design of the PT1 study has been queried with respect to the heterogeneous nature of the study population (possible inclusion of patients with early myelofibrotic disease) and the concomitant use of aspirin (interaction with anagrelide causing increased bleeding events). Further data are therefore required before the role of anagrelide in essential thrombocythaemia can be finalised. In the meantime, when considering treatment options for patients with this disorder, anagrelide’s positive effects on platelet function, lack of mutagenicity and lack of association with leukaemia or angiogenesis must be balanced against its comparative expense and positive inotropic effects. Thus, the role of anagrelide in the management of high-risk patients with essential thrombocythaemia will ultimately depend on individual patient assessment and future clarification of the potential leukaemogenicity of hydroxycarbamide.

Anagrelide and its active metabolite 3-hydroxy anagrelide specifically, reversibly and dose-dependently block the maturation of late-stage megakaryocytes, thus reducing platelet counts in patients with essential thrombocythaemia. The drug appears to normalise platelet coagulant and endothelial function, does not stimulate myelofibrotic progression and, unlike hydroxycarbamide, is not associated with angiogenesis or damage to DNA. The inhibitory effect of anagrelide, and particularly of the 40-fold more potent 3-hydroxy anagrelide, on phosphodiesterase III results in positive inotropic effects (vasodilation, and increased heart rate and contractility) and potential for pharmacodynamic interactions with other phosphodiesterase inhibitors.

The pharmacokinetics of anagrelide are linear in the 0.5–2mg dose range. After oral administration, anagrelide is rapidly absorbed and the drug is metabolised, mainly during first pass, to two main metabolites, the active 3-hydroxy anagrelide and the inactive 5,6-dichloro-3,4-dihydroquinazol-2-ylamine. Peak plasma concentrations of anagrelide and the active metabolite are reached in about 2 hours. Systemic exposure to 3-hydroxy anagrelide is about twice that of the parent compound in patients with essential thrombocythaemia. The terminal half-lives of anagrelide and the active metabolite are 1.7 and 3.9 hours in this patient group. Since metabolism occurs primarily via cytochrome P450 1A2, interactions with drugs such as fluvoxamine are possible. There is no evidence of an interaction with hydroxycarbamide, digoxin or warfarin. Individual titration of dosages allows the effects of age or hepatic or renal impairment to be taken into consideration.

Early noncomparative trials have clearly indicated that anagrelide lowers platelet counts in most (complete plus partial response in 82–98%; complete response in 38–88%) patients with essential thrombocythaemia. Complete response rates of approximately 50% were seen in patients who were unresponsive to previous hydroxycarbamide treatment in two small trials. Clinically significant reductions usually occurred well within the first month of treatment. Anagrelide and hydroxycarbamide (each with concomitant aspirin) reduced platelet counts to a similar extent after 9 months’ treatment in the randomised nonblind PT1 trial in high-risk patients with essential thrombocythaemia, but hydroxycarbamide appeared to act more quickly.

Previous experience of arterial or venous thrombosis or haemorrhage was relatively high at baseline in the PT1 trial. The overall composite primary ndpoint of serious thrombohaemorrhagic events favoured hydroxycarbamide. Secondary endpoints indicated that while anagrelide plus aspirin was superior to hydroxycarbamide plus aspirin as measured by the lower incidence of deep-vein thrombosis, hydroxycarbamide plus aspirin was superior with respect to the incidence of transient ischaemic attacks and serious gastrointestinal haemorrhage. There were no differences between the groups in the individual incidences of myocardial infarction, stroke, unstable angina pectoris, pulmonary embolism, hepatic-vein thrombosis, other serious haemorrhages or death from thrombosis or haemorrhage. The concomitant administration of aspirin in the PT1 trial is thought o have resulted in a synergistic action resulting in increased bleeding events.

Essential thrombocythaemia was less likely to progress to myelofibrosis in hydroxycarbamide recipients than in anagrelide recipients in the PT1 trial; however, the baseline risk for myelofibrosis was not taken into account in the diagnostic methodology, with subsequent potential for imbalance of prefibrotic conditions. The incidence of transformation to acute myeloid leukaemia/myelodysplasia or polycythaemia vera and deaths from transformation were similar in the two groups, although follow-up was possibly inadequate for reliable estimation.

The most common adverse events associated with oral anagrelide are headache, palpitations, diarrhoea, asthenia, oedema, nausea, abdominal pain and dizziness. The incidence and severity of many adverse events decreases with extended treatment in some but not all patients. The incidence of serious adverse events is higher in older patients. Cardiovascular effects such as congestive heart failure or arrhythmia are uncommon. Palpitations, headache, noncardiac oedema, diarrhoea and abdominal pain were more common in recipients of anagrelide plus aspirin than in those receiving hydroxycarbamide plus aspirin in the PT1 trial of high-risk patients with essential thrombocythaemia. Dermatological events (mainly leg ulcers) and diabetes mellitus occurred more often with hydroxycarbamide and white-cell counts were persistently lower in this group. There were no differences between the groups in the incidence of other gastrointestinal symptoms, anaemia, cardiac failure, arrhythmia or minor haemorrhage.