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Thrombopoietin receptor agonists in ITP
populations.58-62 The annualized incidence was 0.41-0.67 for venous thromboembolism (VTE) and 0.96-1.15 for arterial thrombosis (AT), whereas the control populations had 0.28-0.42 and 0.67-0.91, respectively, showing a slightly but statistically significantly higher risk of VTE and possibly AT in ITP patients.63
Thromboembolic events in the long-term studies and pooled analyses are summarized in Table 4. Online Supplementary Table S1 describes thromboembolic events in phase I-II and in randomized, placebo-controlled stud- ies, while Online Supplementary Table S2 refers to single arm trials. As shown in Online Supplementary Table S1, the exposure time to TPO-RA was generally short and ranged from a few weeks to ≤6 months (or 1 year in a single study17). Overall, there have been 15 events out of 415 patients exposed to romiplostim (3.6%) versus 4 events in 202 controls (2%), and 5 events in the 391 patients exposed to eltrombopag (1.3%) versus none out of 155 controls. Conversely, more consistent and significant data could be derived from the large long-term studies or pooled analyses mainly based on the long-term extension studies, fed by patients who had completed previous trials and in a single-arm study investigating a large number of patients. These studies included greater numbers of patients and report on longer treatment exposure.24,27,50,53 Notably, patients with history of or important risk factors for thrombosis were excluded upfront from the RCT, and patients experiencing TEE during their previous study were excluded from long-term extension studies, resulting in a generally smaller thrombosis risk population in the long-term studies. Despite that, a relatively large number of TEE occurred in the long term-studies.
The incidence per 100 patient-years (censoring after first TEE) ranged from 3.1 to 4.2 with romiplostim and was 2.9 in the single eltrombopag study. Without censoring after first event, the incidence ranged from 4.1 to 7.5 with romi- plostim and 3.4 with eltrombopag.63 In a pooled analysis of romiplostim studies, an incidence rate per 100 patient- years of 5.5 was reported for both patients exposed to romiplostim or to placebo/SoC.46 Unfortunately, the low number and short exposure of placebo/SoC make the fig- ures in non-exposed patients unreliable.
Thrombotic events have also been reported in pediatric trials. In a multicenter retrospective study on 79 children with ITP treated with eltrombopag, romiplostim or both, two cases of pulmonary embolism were reported.64 The randomized controlled trials did not identify any TEE, and overall TEE incidence is clearly lower than in adults.23,33-35,65
The TEE events were neither associated with thrombo- cytosis nor with a higher dose of TPO-RA. At least 30- 50% of cases occurred in patients with lower than normal platelet counts. In general, TEE events tended to happen in the first year of treatment, creating a trend towards lower incidence figures with more prolonged exposure time. Among arterial events, cerebrovascular (stroke) and myocardial (infarction) were predominant and seen more in patients >70 years of age. However, <20% of TEE resulted in permanent disability and only three deaths could be attributed to thrombosis. In a pooled analysis, the annualized risk of thromboembolism in splenec- tomized patients (6.3) was not significantly higher than non-splenectomized patients (4.3).66
The pathogenic mechanisms responsible for the increased thrombotic risk linked to TPO-RA have not yet been identified.67 The expected findings that TPO-RA
lower the threshold of platelet activation have not been demonstrated.68,69 In general, ITP per se seems to be a pro- coagulant condition, as indicated by an increase in the var- ious coagulation activation markers, including D-dimer, prothrombin fragment F1+2 and thrombin generation, and in the antifibrinolytic marker plasminogen activator inhibitor-1 (PAI-1) compared to controls.70,71 No further increase in the coagulation activation markers has been observed after the initiation of TPO-RA.70,71 However, a recent study reported increased PAI-1 levels in patients treated with TPO-RA, possibly leading to the formation of a more fibrinolysis-resistant clot; the study also showed increased microparticle-associated phosphatidylserine procoagulant activity.72 Moreover, levels of soluble P- selectin and basal exposure of P-selectin in quiescent platelets were significantly increased in TPO-RA treated patients compared to pretreatment levels or to untreated patients; however, the significance of these findings is still not known.70,72
In summary, although they have not been substantiated in properly designed trials, the annualized thrombosis rates in adults appear to be 2-3 times higher (annualized incidence rate of TEE of 4-7%) with TPO-RA treatment than in an ITP population not treated with TPO-RA, and even higher if compared to non-ITP control populations.63 On the other hand, most available data on the risk of thrombosis are based on retrospective and registry stud- ies, which probably underestimate the risk of thrombosis in the ITP population. The patient's individual risk profile should be considered when initiating treatment with a TPO-RA to evaluate if the expected reduction in bleeding risk outweighs the risk of thrombotisis. Comorbidities more prevalent in ITP should be considered and/or inves- tigated; these include previous thromboembolism, splenectomy, presence of antiphospholipid antibodies, and concomitant medications like estroprogestinic prepa- rations. Efforts should be made to correct modifiable risk factors, and thrombo-prophylaxis is recommended for surgery, provided the patient has a safe platelet count.67 Furthermore, antiplatelet agents or even anticoagulation could be considered in patients at high risk of thrombosis once platelet counts reach >50x109/L after initiation of TPO-RA.
Rebound thrombocytopenia
In most patients receiving TPO-RA, platelet counts return to pre-therapy baseline values on discontinuation of therapy; however, in up to 10% of patients, platelet counts temporarily drop below pretreatment levels after discontinuation of TPO-RA.18 Endogenous TPO activity, which is regulated by platelet mass, may be suppressed while platelet and MK levels are elevated on TPO-RA and may not rapidly re-equilibrate when TPO-RA are abruptly discontinued. However, the REPEAT study, which involved intermittent administration of eltrombopag, pro- vided reassuring data.73 Nonetheless, when TPO-RA treat- ment is discontinued, tapering is preferred to immediate withdrawal.
Fluctuating platelet counts
Substantial fluctuations in platelet count on stable treat- ment doses may occur and can be difficult to manage. They are more common with romiplostim than eltrombopag, possibly due to the longer dosing intervals and inconsistent delivery with subcutaneous administration.36-38 Some
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