Statin use, survival and incidence of thrombosis among older patients with polycythemia vera and essential thrombocythemia.

BACKGROUND: Polycythemia vera (PV) and essential thrombocythemia (ET) are linked to increased risk of cardiovascular morbidity and mortality. In addition to the reduction in of arterial thrombotic events, statins may prevent venous thrombosis including among patients with cancer. As previous registry- and claims-based studies revealed that the use of statins may improve the survival of patients with various malignancies we evaluated their impact on outcomes of older adults with PV and ET. METHODS: We identified 4010 older adults (aged 66-99 years at diagnosis) with PV (n = 1809) and ET (n = 2201) in a population-based cohort study using the Surveillance, Epidemiology, and End Results-Medicare database with median follow-up of 3.92 (interquartile range: 2.58-5.75) years. Propensity score matching (PSM) and inverse probability of treatment weighting (IPTW) approaches were utilized to assess potential association between statins and overall survival. Multivariable competing risk models with death as a competing risk were used to evaluate possible relationship between statins and the incidence of thrombosis. RESULTS: 55.8% of the patients used statins within the first year after PV/ET diagnosis, and statin use was associated with a 22% reduction in all-cause mortality (PSM: hazard ratio [HR] = 0.78, 95% confidence interval [CI]: 0.63-0.98, p = 0.03; IPTW: HR = 0.79, 95% CI: 0.64-0.97, p = 0.03). Statins also reduced the risk of thrombosis in this patient population (PSM: HR = 0.63, 95% CI: 0.51-0.78, p < 0.01; IPTW: HR = 0.57, 95% CI: 0.49-0.66, p < 0.01) as well as in PV and ET subgroups. CONCLUSIONS: These findings suggest that it may be important to incorporate statins into the therapeutic strategy for older adults with PV and ET.

Assessment of rotation thromboelastometry parameters in patients with essential thrombocythemia at diagnosis and after hydroxyurea therapy.

Patients with essential thrombocythemia suffer from thrombotic complications that are the main source of mortality. Due to its complex pathogenesis, no existing single laboratory method is able to identify the patients at highest risk for developing thrombosis. Twenty patients with essential thrombocythemia at diagnosis, 15 healthy volunteers and 20 patients treated with hydroxyurea were compared with regard to certain rotation thromboelastometry parameters. Clotting time (CT), clot formation time (CFT), α-angle, and maximum clot firmness (MCF) were assessed by using the INTEM, EXTEM, FIBTEM, and NATEM tests. Patients with essential thrombocythemia at diagnosis demonstrated significantly higher mean platelet count and markedly lower mean red blood count than controls. CT and CFT readings were found to be markedly lower in essential thrombocythemia patients at diagnosis than in the control group according to the EXTEM test. Patients at diagnosis had markedly lower CT values (EXTEM, FIBTEM) than patients on hydroxyurea therapy. Alpha angle values were markedly higher in essential thrombocythemia patients at diagnosis than in controls, according to the EXTEM, FIBTEM and NATEM tests. MCF readings were significantly higher in essential thrombocythemia patients at diagnosis than in controls according to EXTEM, INTEM, FIBTEM, and NATEM tests. Patients on hydroxyurea therapy had markedly lower MCF values according to EXTEM test than patients at diagnosis. Patients with essential thrombocythemia demonstrate a prothrombotic state at the time of diagnosis, which is reflected in changes by certain rotation thromboelastometry parameters. The hydroxyurea therapy induces downregulation of the prothrombotic features seen in essential thrombocythemia patients at diagnosis.

It is time to change thrombosis risk assessment for PV and ET?

Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms to be diagnosed according to the WHO classification. Molecular profiling must include the analysis of JAK2 (looking for the V617F point-mutation in PV and ET, screening exon 12 for mutations only in V617F-negative PV), CALR and MPL mutations (both in V617F-negative ET). The current risk stratification to predict thrombosis requires two parameters: age over 60 years and prior history of thrombosis. On the basis of these two risk factors patients can be stratified in low-risk and high-risk and receive a proper treatment. However, a modern stratification of thrombotic risk might consider "new" low-risk patients: conventional low-risk plus absence of leukocytosis from diagnosis onwards and a hematocrit level below 45% during the course of disease for PV; conventional low-risk plus absence of leukocytosis from diagnosis onwards, JAK2 negativity, CALR positivity, and absence of cardiovascular risk factors for ET.

Eltrombopag for the treatment of chronic idiopathic (immune) thrombocytopenic purpura (ITP).

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of eltrombopag for the treatment of adults with chronic idiopathic (immune) thrombocytopenic purpura (ITP), based on a review of the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. ITP is an autoimmune disorder by which antibodies are formed against platelets with annual incidence rates in the UK/USA ranging from 1.13 to 6.62 cases per 100,000 adults. Eltrombopag increases the production of platelets at a rate that outpaces their destruction by the immune system, and has a UK marketing authorisation both for the treatment of adult ITP in splenectomised patients who are refractory to other treatments and as a second-line treatment for adult non-splenectomised patients for whom surgery is contraindicated. Both splenectomised and non-splenectomised patient groups were considered in the analysis. Two economic models were presented, one for a watch-and-rescue treatment scenario and the second for the long-term treatment of patients with more severe ITP. The submission's evidence was sourced from the relatively high-quality RAISE [RAndomized placebo-controlled Idiopathic thrombocytopenic purpura (ITP) Study with Eltrombopag] randomised controlled trial. The study indicated a statistically significant difference in favour of eltrombopag compared with placebo in the odds of achieving the primary outcome of a platelet count of between 50 and 400 × 109/l during the 6-month treatment period (odds ratio 8.2, 99% confidence interval 3.6 to 18.7). In the eltrombopag group, 50/83 (60%) non-splenectomised patients and 18/49 (37%) splenectomised patients achieved this outcome. Median duration of response for all patients was 10.9 weeks (splenectomised patients 6 weeks and non-splenectomised patients 13.4 weeks). Patients treated with eltrombopag required less rescue medication and had lower odds of bleeding events than placebo-treated subjects in both patient groups. In the watch-and-rescue economic model, the ERG found that substantial reductions in the cost of eltrombopag are needed for the incremental cost-effectiveness ratio (ICER) to fall below £ 30,000. Further analyses found that the ICER varied from £33,561 to £ 103,500 per quality-adjusted life-year (QALY) (splenectomised) and from £ 39,657 to £ 150,245 per QALY (non-splenectomised). Other than bleeding, no adverse events were modelled. In relation to the long-term treatment model, the ERG found that using non-randomised non-comparative data may result in biased estimates of unknown magnitude and direction. None of the treatment sequences resulted in an ICER approaching the recommended threshold of £ 30,000. The base-case results, using a 2-year time horizon and prescribing eltrombopag as second-line treatment post rituximab, were found to be favourable towards eltrombopag. In conclusion, based on the MS and additional ERG work, eltrombopag appears to be a safe treatment for ITP (although long-term follow-up studies are awaited) and has short-term efficacy. However, there is no robust evidence on long-term efficacy or cost-effectiveness of eltrombopag, and there is a lack of robust direct evidence on the effectiveness and cost-effectiveness of eltrombopag compared with other relevant comparators. NICE did not recommend eltrombopag for the treatment of chronic ITP within its marketing authorisation for splenectomised or non-splenectomised patients.

Emerging drugs for the therapy of primary and post essential thrombocythemia, post polycythemia vera myelofibrosis.

Managing patients with myelofibrosis (MF) (both those with primary myelofibrosis or having evolved from an antecedent polycythemia vera or essential thrombocythemia) present many challenges to the hematologist. MF patients suffer from a variable, but severe range of disease manifestations including massive splenomegaly, cytopenias, significant constitutional symptoms, possible transformation to blast phase and premature death. Cure is achievable through allogeneic stem cell transplantation; yet, this therapy is either inappropriate or not an option for most patients. Current available therapies are palliative, but can sometimes be of significant value to MF patients. The discovery of the JAK2-V617F mutation, and other pathogenetic insights into the pathophysiology of myeloproliferative neoplasms, has ushered in an era of potential new therapies for MF. Over a dozen JAK2 inhibitors are in development, with the leading compounds such as INCB018424, TG101348 and others showing promising early results particularly for control of disease associated splenomegaly and symptoms. Parallel trials with immunomodulatory therapy for MF associated anemia and stromal manifestations of the disease are continuing. The future may well see the approval of a range of agents for MF patients, with differing mechanisms of action, efficacy and toxicity profiles.

Anagrelide: new drug. Essential thrombocythaemia: further evaluation needed for this last-resort treatment.

(1) For patients aged over 60 years who have essential thrombocythaemia, and are considered to be at increased risk of thromboembolism, the standard cytotoxic agent is hydroxycarbamide (hydroxyurea), which reduces the risk of thrombocytosis but adversely affects other blood cell lines. It may also increase the risk of progression to cancer. (2) Anagrelide, initially studied as an antiplatelet drug, was approved in Europe for the treatment of essential thrombocythaemia in high-risk patients when other treatments fail or are poorly tolerated. (3) Evaluation data includes a trial versus hydroxycarbamide that was prematurely halted because of an excess of cardiovascular events among patients on anagrelide. Among 809 patients who were also receiving aspirin as an antithrombotic (and who may not have met strict criteria for essential thrombocythaemia), arterial or venous thrombosis and haemorrhage were significantly more frequent with anagrelide, during a median follow-up of 39 months (55 versus 36 patients). (4) According to the results of 3 non comparative trials involving about 500 patients, and the European Medicines Agency report analysing these and other study populations, anagrelide reduces the platelet count to below 600 times 10 to the 9th power/litre in two-thirds of patients. No data are available on the clinical implications of this reduction in platelets. (5) Between 10% and 20% of patients treated with anagrelide experience cardiovascular adverse effects (palpitations, myocardial infarction, heart failure) or neurological adverse effects (headache, stroke, transient ischaemic attack). Gastrointestinal disturbances are also frequent (diarrhoea, nausea, abdominal pain, pancreatitis). Some of these adverse effects can be fatal. (6) Follow-up is too short to show whether anagrelide affects the risk of progression to cancer. (7) In practice, anagrelide has a less favourable risk-benefit balance than hydroxycarbamide, which remains the first-line cytotoxic agent in this setting. Anagrelide therapy can be considered if hydroxycarbamide fails or is poorly tolerated, provided patients are included in a long-term clinical trial.

Pharmacotherapy of essential thrombocythaemia: economic considerations.

The clinical course of essential thrombocythaemia (ET) is mainly outlined by a predisposition to both thromboembolic, and more rarely, haemorrhagic complications. The individual clinical course is, however, variable, ranging from an event-free course to life-threatening thromboembolic episodes. In order to treat ET patients economically, it is necessary, above all, to consider if cytoreductive therapy is really indicated. Risk stratification according to clinical criteria such as age, previous ET-related events and platelet count may help to define patients at risk. In low-risk ET patients, a watch-and-wait strategy seems to be feasible. There is a clear indication for cytoreductive therapy in high risk ET patients as demonstrated in a Phase III clinical trial. Because of the lack of Phase III trials, it is not clear which of the cytoreductive drugs - hydroxyurea, pipobroman, IFN-alpha, pegylated-IFNs or anagrelide - is the best therapeutic option. Factors that influence the choice out of the available drugs are efficacy, safety and cost. The efficacy and safety data of the available drugs for ET are derived from Phase II studies or observational studies. IFN-alpha is the most expensive drug. Newer drugs like anagrelide or pegylated-IFNs are still expensive, but may have a better cost-benefit effect in patients < 60 years of age. Two cost-effectiveness analyses revealed a result in favour of anagrelide, however, in these cost-effectiveness models, assumptions were based on non-randomised trials. For patients > 60 years of age, hydroxyurea may be the best therapeutic option with regard to both the efficacy and cost-effectiveness.

Cost-effectiveness model of a phase II clinical trial of a new pharmaceutical for essential thrombocythemia: is it helpful to policy makers?

Essential thrombocythemia (ET) is a rare, chronic myeloproliferative disorder of unknown origin characterized by thrombocytosis, excessive megakaryocytes, hemorrhages, and thrombotic complications. Because of the high costs of care for persons with rare diseases, policymakers are concerned with both clinical effectiveness and cost-effectiveness of new treatments. Although the clinical efficacy of all new pharmaceutical agents for rare diseases is evaluated extensively in clinical trial settings before approval by the Food and Drug Administration (FDA), comparative phase III trials of a new agent with its major competitor are sometimes not possible to carry out, and estimates of cost-effectiveness are therefore difficult to obtain. We describe methodologic issues associated with the development of economic models of new pharmaceutical agents for rare diseases and illustrate these issues with an analysis of a new therapy for ET. Anagrelide is a newly approved platelet aggregation inhibitor that can be used as primary therapy for ET. The agent reduces platelet counts by 50% in more than 70% of ET patients. Economic models suggest that, over the first year of anagrelide therapy, monthly costs for therapy and complications decreased from $775 to $490, the effectiveness improved to 98%, and the cost-effectiveness improved to $1,505 per major complication (gastrointestinal bleed, transient ischemic attack or stroke, or preinfarction angina or myocardial infarction) prevented. Sensitivity analyses indicate that, after the first 3 months of treatment, total costs of anagrelide treatment were in the range of $1,505 to $1,615 per major complication prevented. To make well-informed therapeutic decisions, policymakers and physicians require head-to-head studies of a new pharmaceutical agent with its major competitor. However, economic models can be used to derive estimates of cost-effectiveness of new pharmaceutical agents when such data are lacking. The interpretation of these models raises general issues related to the perspective of the investigator, study design, estimation of costs of care, rates of response, toxicity, survival, and the ability to generalize the results to other settings, as well as methodologic issues that are unique to rare diseases. If a comparative study found better therapeutic outcomes, then cost-effectiveness models would be of limited usefulness. Almost all physicians would use the drug with the better therapeutic profile.

Anagrelide, a selective thrombocytopenic agent.

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of anagrelide are reviewed. Anagrelide is a selective thrombocytopenic agent with FDA-approved labeling for the treatment of essential thrombocythemia. Clinical trials have shown that the drug may have a role in the treatment of other chronic myeloproliferative disorders, including polycythemia vera, chronic myeloid leukemia, and agnogenic myeloid metaplasia. The mechanism by which anagrelide reduces platelet count is not yet clear. The current hypothesis is that anagrelide affects the late (postmitotic) phases of megakaryocyte development. Anagrelide has a large volume of distribution and is extensively metabolized; less than 1% is recovered unchanged in the urine. Plasma half-life after a 0.5-mg dose is 1.3 hours. Anagrelide's efficacy and safety have been evaluated in open-label, noncomparative trials, in which the response rate was 60-93%. Adverse effects include headache, diarrhea, edema, palpitations, and abdominal pain. Patients with renal or hepatic dysfunction need to be closely monitored for signs of toxicity. The recommended starting dosage is 0.5 mg four times a day or 1 mg twice a day, with dosage adjustment to the lowest effective amount required to reduce and maintain platelet count below 600 x 10(9)/L. The wholesale acquisition price for 0.5-mg capsules is $350 per 100. Whether anagrelide will replace hydroxyurea as first-line therapy in some or all patients remains to be determined. Anagrelide is effective in the treatment of essential thrombocythemia and may have a role in the treatment of other myeloproliferative disorders.