Incidence of Thromboembolic Events Across Eltrombopag Clinical Trials In Chronic Immune Thrombocytopenia (ITP)

Chronic ITP is characterized by decreased platelet counts resulting from autoantibody-mediated peripheral platelet destruction and suboptimal platelet production. Eltrombopag is an oral, thrombopoietin receptor agonist approved for the treatment of ITP in the USA and elsewhere. Thromboembolic events (TEEs) can occur in patients with ITP; it has been speculated that ITP has prothrombotic characteristics and that low platelet counts may prevent a higher incidence of TEEs (Sarpatwari, 2010; Aledort, 2004; Zelcer, 2003). In the UK General Practice Research Database, incidence rates for TEEs were 1.35/100 patient years (PYs) (95% CI [0.99, 1.79]) for patients with ITP vs 1.16/100 PYs (95% CI [0.99, 1.35]) in patients without ITP (Sarpatwari, 2010). Similar results were found in a US claims database study (Bennett, 2008) and in romiplostim studies (Bussel, 2009). In this study we evaluated the incidence of TEEs in patients with chronic ITP treated with eltrombopag.

Data from 446 patients with chronic ITP exposed to eltrombopag were analyzed from 5 eltrombopag clinical trials: two 6-week, randomized, double-blind, phase 2 and 3 studies, with patients on eltrombopag (n=164) or placebo (n=67) (Bussel, 2007; Bussel, 2009); RAISE, a 6-month, randomized, double-blind, phase 3 study, with 135 patients on eltrombopag and 62 on placebo (Cheng, 2010); REPEAT, a phase 2 study with 66 patients on eltrombopag for 3 cycles of 6 weeks on-therapy followed by up to 4 weeks off therapy (Psaila, 2008); and EXTEND, an ongoing extension study with 299 of the same patients on eltrombopag for at least 2 years (Cheng, 2008). The first occurrence of a TEE was used in the calculation of the incidence rates across the ITP program. Confirmed or suspected cases of TEEs were either reported by investigators or identified after sponsor evaluation based on symptoms reported as adverse events (AEs) that were potentially compatible with a TEE. In an additional analysis, the odds ratio for a TEE at different platelet thresholds was investigated to assess if a direct relationship could be established.

Across the ITP program, 20 patients (4.5%, 20/446) exposed to eltrombopag have experienced 27 TEEs. The TEEs were DVT (12), pulmonary embolism (6), MI (4), ischemic stroke (3), suspected prolonged reversible ischemic neurologic deficit (1), and transient ischemic attack (1). No placebo-treated patient experienced a TEE. The PYs of exposure to study medication was approximately 17 times greater than PYs of exposure to placebo (eltrombopag 584.4 PYs; placebo 35.4 PYs). Despite the increased exposure to eltrombopag in the EXTEND study, the incidence of TEEs (3.14/100 PYs, 95% CI [1.92, 4.85]) decreased compared to previously reported data (4.04/100 PYs, 95% CI [2.35, 6.46], Bussel, 2009). There was no clear pattern observed with regard to time to TEE onset; events were reported as early as day 1 and up to day 981 (median time to onset 229 days). The platelet counts most proximal to the events ranged between 14,000/μ L and 482,000/μ L (median 143,000/μ L). The majority of patients (55%, 11) had platelet counts below the normal range at the time of the TEE (<150,000/μ L). 4/20 patients experienced the TEE closest to their maximum platelet count achieved on study, whereas the majority (80%, 16/20) experienced the TEE at a lower platelet count than their maximum platelet count during treatment with eltrombopag. As seen in the Table, no changes in the odds ratio for a TEE at different platelet thresholds were observed. All patients experiencing a TEE had at least one risk factor for TEE; analysis did not reveal any one risk factor that was associated with the majority of cases. Two of 15 patients with TEEs tested had positive results for heterozygous Factor V Leiden mutation.

There is no increase in the incidence rate of TEEs across the ITP program despite longer duration of eltrombopag treatment. The data presented here confirm previous observations that there is no evidence of a correlation between platelet count increases and the occurrence of TEEs in patients with chronic ITP on eltrombopag.

Bussel:GlaxoSmithKline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cheng:GlaxoSmithKline: Consultancy, Honoraria, Speakers Bureau. Saleh:GlaxoSmithKline, Novartis, Imcoline, Celgene: Honoraria, Speakers Bureau. Mayer:GlaxoSmithKline: Employment, Equity Ownership. Vasey:GlaxoSmithKline: Employment. Brainsky:GlaxoSmithKline: Employment.