Non-splenectomized Patients Research Articles

PSY22 - Economic Evaluation of Romiplostim Vs Eltrombopag In The Treatment of Adult Patients With Chronic Immune Thrombocytopenia In Mexico

Romiplostim and eltrombopag are both indicated for the treatment of chronic immune thrombocytopenia (ITP) in splenectomized who are refractory to conventional treatments and rescue therapies, and in non-splenectomized where surgery is contra-indicated. The aim of this analysis was to assess the expected costs and outcomes with both therapies for the treatment of chronic ITP from the perspective of the public health system in Mexico. A decision tree model was developed simulating the pathway of splenectomized and non-splenectomised patients with romiplostim or eltrombopag over a time horizon of 24 weeks. The effectiveness was measured by the overall platelet response (OPR) rate (at least 4 weeks with platelet response). The efficacy estimates for eltrombopag were obtained using an adjusted indirect treatment comparison. Only direct medical costs were considered, including drug acquisition, drug administration, laboratory tests, medical visits, and bleeding related events. Sensitivity analysis was conducted to evaluate robustness of the results. All costs were expressed in 2016 US dollars. The proportion of patients achieving OPR was higher with romiplostim (79.6%) than with eltrombopag (37.4%). The cost per treated patient was 30% lower with romiplostim than eltrombopag ($15,860 Vs. $23,212), driven mainly by cost-savings in the bleeding related costs with romiplostim (-50%). The average cost per patient achieving OPR was also lower with romiplostim vs. eltrombopag ($19,916 Vs. $62,107). The results were consistent and robust to variations in the main inputs. The results of this analysis suggest that romiplostim is a dominant treatment strategy vs. eltrombopag in patients with chronic ITP, as it is associated with more than twice as many patients achieving OPR as well as with cost-savings vs. eltrombopag in the bleeding related events, especially in those events requiring rescue therapy with immunoglobulin. Romiplostim is expected to result in significant savings for the healthcare institutions in Mexico.

Oral all-trans retinoic acid plus danazol versus danazol as second-line treatment in adults with primary immune thrombocytopenia: a multicentre, randomised, open-label, phase 2 trial

Primary immune thrombocytopenia is a severe bleeding disorder. About 50-85% of patients achieve initial remission from first-line therapies, but optimal second-line treatment remains a challenge. All-trans retinoic acid (ATRA) has an immunomodulatory effect on haemopoiesis, making it a possible treatment option. We aimed to evaluate the efficacy and safety of ATRA plus danazol versus danazol in non-splenectomised patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. We did a multicentre, randomised, open-label, phase 2 study of adult patients (≥18 years) with primary immune thrombocytopenia from five different tertiary medical centres in China. Those eligible were non-splenectomised, resistant to corticosteroid treatment or relapsed, and had a platelet count less than 30 × 109 per L. Masked statisticians used simple randomisation to assign patients (1:1) to receive oral ATRA (10 mg twice daily) plus oral danazol (200 mg twice daily) or oral danazol monotherapy (200 mg twice daily) for 16 weeks. Neither clinicians nor patients were masked to group assignments. All patients were assessed every week during the first 8 weeks of treatment, and at 2-week intervals thereafter. The primary endpoint was 12-month sustained response defined as platelet count of 30 × 109 per L or more and at least a doubling of baseline platelet count (partial response), or a platelet count of 100 × 109 per L or more (complete response) and the absence of bleeding without rescue medication at the 12-month follow-up. All randomly allocated patients, except for those who withdrew consent, were included in the modified intention-to-treat population and efficacy assessment, and all patients who received at least one dose of the study agents were included in the safety analysis. Study enrolment was stopped early because the trial results crossed the interim analysis efficacy boundary for sustained response. This trial is registered with ClinicalTrials.gov, number NCT01667263. From June 1, 2012, to July 1, 2016, we screened 130 patients for eligibility; 34 were excluded and 96 were randomly assigned. 93 patients were included in the modified intention-to-treat analysis: 45 in the ATRA plus danazol group and 48 in the danazol group. At the 12-month follow-up, sustained response was achieved more frequently in patients receiving ATRA plus danazol than in those receiving danazol monotherapy (28 [62%] of 45 vs 12 [25%] of 48; odds ratio 4·94, 95% CI 2·03-12·02, p=0·00037). Only two grade 3 adverse events were reported: one (2%) patient receiving ATRA plus danazol with dry skin, and one (2%) patient receiving danazol monotherapy with liver injury. There was no grade 4 or worse adverse event or treatment-related death in either group. Patients with primary immune thrombocytopenia given ATRA plus danazol had a rapid and sustained response compared with danazol monotherapy. This finding suggests that ATRA represents a promising candidate for patients with corticosteroid-resistant or relapsed primary immune thrombocytopenia. National Natural Science Foundation of China, Beijing Natural Science Foundation, Beijing Municipal Science and Technology Commission, and the National Key Research and Development Program of China.

Relationship between portopulmonary hypertension and splenectomy: Mayo Clinic experience and review of published works.

Portopulmonary hypertension is a serious complication of portal hypertension that can lead to right heart failure and death. To our knowledge, an association between portopulmonary hypertension and prior splenectomy has not been described previously. The goals of this study were to describe the frequency of splenectomy in portopulmonary hypertension and compare selected parameters between portopulmonary hypertension subgroups. This is a retrospective analysis of patients diagnosed with portopulmonary hypertension between 1 January 1988 and 30 June 2015 at Mayo Clinic (Rochester, MN, USA). We compared age, sex, right ventricle systolic pressure by echocardiography, and right heart catheterization measurements/calculations among subgroups of portopulmonary hypertension patients with splenectomy and/or autoimmune liver disease (autoimmune hepatitis/primary biliary cirrhosis/primary sclerosing cholangitis). The cohort consisted of 141 patients, of whom 8 (6%) had a history of splenectomy prior to the development of portopulmonary hypertension. Twenty-seven (19%) portopulmonary hypertension patients had autoimmune liver disease, and 5 of 8 (62.5%) splenectomized portopulmonary hypertension patients had autoimmune liver disease. No significant difference was noted in right heart catheterization measurements/calculations between splenectomized and non-splenectomized portopulmonary hypertension patients. Right ventricle systolic pressure by echocardiography was significantly higher in those splenectomized. Prior history of splenectomy in portopulmonary hypertension was 6% in this cohort. The combination of autoimmune liver disease and splenectomy in portopulmonary hypertension was not uncommon. History of splenectomy in patients with portal hypertension and/or autoimmune liver disease may have clinical implications.

Cost of Bleeding-related Episodes in Adult Patients With Primary Immune Thrombocytopenia: A Population-based Retrospective Cohort Study of Administrative Claims Data for Commercial Payers in the United States

PurposeWe estimated the real-world costs of bleeding-related episodes (BREs) in adults with primary immune thrombocytopenia (ITP). MethodsThis retrospective cohort study used the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases. We identified adult patients diagnosed with primary ITP between 2007 and 2012, defined by at least 2 outpatient claims separated by ≥30 days or 1 inpatient claim (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code for primary ITP [287.31]). BRE was defined according to a combination of diagnosis codes and/or procedure codes indicating bleeding or use of rescue therapies. Costs were estimated using total reimbursed amount received by providers (including out-of-pocket costs and reimbursement from insurance, adjusted to 2015 US dollars). FindingsIn 6551 patients, 14,115 BREs were identified, mean (SD) age was 55 (18) years, and 62% of patients were women. Mean total reimbursement per BRE was $6022, with significantly higher mean inpatient ($45,114) versus outpatient ($2150) reimbursements (P < 0.0001). Mean BRE reimbursements were higher in splenectomized patients compared with nonsplenectomized patients ($8365 vs $5858); however, the difference was not statistically significant. Mean reimbursement for BREs associated with bleeding alone was $10,396, and with rescue therapy alone it was $2787. Reimbursement for BREs that included both bleeding and rescue therapy was $11,065. ImplicationsThe real-world reimbursement rates of BREs in adult patients with primary ITP can be substantial, with significantly higher values among patients requiring hospitalization and for those with bleeding events. Additionally, there is a trend toward higher reimbursement rates among splenectomized patients.

25: ASSOCIATION OF SERUM GAMMA- INTERFERON AND IL-10 CONCENTRATIONS WITH INSULIN RESISTANCE IN MAJOR THALASSEMIA PATIENTS

Background and aims:Thalassemia is one of the most prevalent hematologic disorders worldwide. Thalassemia is the most common inherited anemia and genetic disease. Diabetes mellitus and insulin resistance is one of...

Candidate markers for thromboembolic complications in adult Egyptian patients with β-thalassemia

Background Increased risk for thromboembolic complications in patients with thalassemia major has been attributed to the chronic hypercoagulable state. However, the underlying mechanisms are multifactorial. Objectives To investigate the candidate markers of possible tendency to thrombophilia in adult patients with thalassemia major. Methods Genetic polymorphisms of prothrombotic factors have been analyzed in 30 splenectomized patients (group I) and 30 nonsplenectomized patients (group II) as well as 30 age matched and sex matched healthy controls. In addition to routine hematological and coagulation parameters, estimation of protein C and protein S free antigen, antithrombin III activity, factor VIII, and factor IX levels was done. Plasma soluble endothelial protein C receptor levels were measured by ELISA, and factor V Leiden1691G-A, factor II polymorphism (G20210A), and methylenetetrahydrofolate reductase mutation (C677T) were detected by real-time PCR. Results A significant increase of soluble endothelial protein C receptor was observed in patients (in group I more than group II), whereas protein C and protein S were significantly reduced together with more frequent congenital thrombophilic mutations. Conclusion With the prolonged life expectancy of patients with β-thalassemia, more caution should be considered toward thromboembolic complications. Thus, after the first thrombotic event or even when they are exposed to thrombotic risk factors, they should be investigated for congenital thrombophilia, and prophylactic antithrombotic agents may be recommended.

Transformation in Pre-Treatment Presentations of Gaucher Disease during the First Two Decades of Imiglucerase Enzyme Replacement Therapy: A Report from the International Collaborative Gaucher Group Gaucher Registry

Transformation in Pre-Treatment Presentations of Gaucher Disease during the First Two Decades of Imiglucerase Enzyme Replacement Therapy: A Report from the International Collaborative Gaucher Group Gaucher Registry

Long-term complications of splenectomy in adult immune thrombocytopenia.

The recent large decrease in splenectomy use for chronic immune thrombocytopenia (ITP) is partly due to still-unsolved questions about long-term safety. We performed the first single-center exposed/unexposed cohort study evaluating the long-term incidence of splenectomy complications in patients with primary ITP. Overall, 83 patients who underwent splenectomy more than 10 years ago (exposed) were matched with 83 nonsplenectomized patients (unexposed) on the date of ITP diagnosis ±5 years, age and gender. After a median follow-up of 192 months (range 0.5-528), 43 patients (52%) achieved overall response after splenectomy. Splenectomized patients experienced more venous thromboembolism (VTE) than controls (n = 13 vs n = 2, P = 0.005). On multivariate analysis, splenectomy was an independent risk factor of VTE (hazard ratio = 4.006, P = 0.032 [95% confidence interval: 1.13-14.21]). Splenectomized patients presented more severe infections on long-term follow-up: all required hospitalization, and 5/26 (19%) infections led to severe sepsis or septic shock and to death for 3 cases (none in controls). However, the incidence of malignancy was similar in both groups, as was cardiovascular risk, which appeared to be related more to ITP than splenectomy. Finally, splenectomy did not significantly decrease overall survival. Despite the risk of thrombosis and severe sepsis, splenectomy remains an effective and curative treatment for ITP.

Splenectomy and its relation to non-transfusion-transmitted infection in thalassemic patients

Background Splenectomy has been associated with an increasedsusceptibility to infection. Overwhelming postspelenectomy infec-tion (OPSI) can lead to high mortality. Decreased IgM and tuftsinconcentration on splenectomized patients seems to play a role ininfection’s susceptibility. Many studies have been performed todetermine the risk factors of infection in thalassemic patients.Objective To find out morbidity patterns and risk factors for pre-dicting the likelihood of infection in splenectomized thalassemicpatients.Methods A retrospective cross sectional study was conducted onconfirmed thalassemic children who came to Department of ChildHealth, Cipto Mangunkusumo Hospital within the period of 1973-2003. Splenectomized patients were categorized as cases groupand non-splenectomized patients as control group. Risk factors fordevelopment of common cold and diarrhea were analyzed usingchi-square test with level of significance &lt;0.05.Results A total of 300 thalassemic patients, 100 of them were sple-nectomized, were enrolled in this study. The 15-year-age group orabove is the most common group underwent splenectomy (35%).Common cold is the most common mild infection in both splenec-tomized group (75%) and non-splenectomized (71%). A significantassociation was found between the risk of infection and splenec-tomy in thalassemic patients (OR=3.8;CI=2.2;6.62; P=0.000). As-sociation between time after splenectomy and frequency of com-mon cold in thalassemia was significant (OR=2.85;CI=1.16;7.14;P=0.011). Severe infection and acute diarrhea were considerednot significantly different between the two groups.Conclusion Splenectomy in thalassemia can increase the sus-ceptibility of non-transfusion-transmitted mild infection. Furtherstudy is needed to elaborate this finding

The spleen dictates platelet destruction, anti-platelet antibody production, and lymphocyte distribution patterns in a murine model of immune thrombocytopenia.

For many years, splenectomy has been used to treat immune thrombocytopenia (ITP), and this procedure benefits approximately two-thirds of the treated patients. Although splenectomy may raise platelet counts, antibody-coated platelets and cytotoxic T lymphocytes appear to persist or can change over time. To better understand how the spleen may affect anti-platelet immune responses, we used a murine model of ITP demonstrating both antibody-mediated and T lymphocyte-mediated thrombocytopenia. Mice with severe combined immunodeficiency (SCID) were either splenectomized or not and transfused with splenocytes from CD61 (GPIIIa) knockout mice immunized against CD61(+) platelets. Platelet counts and anti-platelet antibody levels were performed weekly. After 4weeks, the mice were sacrificed, and lymphoid organs were harvested and examined by flow cytometry to quantify CD4(+)CD25(+)FoxP3(+) Tregs and conventional cross-presenting XCR1(+) and tolerizing SIRPα+ dendritic cells. The results indicate that compared with control non-splenectomized mice, thrombocytopenia was improved and anti-platelet antibody production was significantly diminished in all splenectomized mice that received immune splenocytes. Splenectomized SCID mice also had a marked reduction in Tregs in the thymus together with an increased proportion of both thymic dendritic cell subsets that correlated with increased platelet counts. Of interest, although splenectomy diminished anti-platelet antibody production and raised platelet counts, marrow megakaryocyte densities were still significantly reduced in mice that received immune splenocytes. These results suggest that the spleen in murine ITP not only is the primary site responsible for platelet destruction, but it also controls, to a significant extent, the antibody response against platelets and the migration patterns of lymphocyte subsets.

Platelet Aggregation Study in Patients With Hemoglobin Eβ Thalassemia in India.

Hemoglobin Eβ thalassemia is a major public health problem in India, especially in the state of West Bengal. Various thromboembolic events are common, especially in splenectomized patients. Platelet hyperactivity most likely plays a pathogenetic role. To investigate the role of platelets in hypercoagulability, platelet aggregation tests were undertaken in the present study. Platelet-rich plasma from 30 patients with Eβ thalassemia (15 splenectomized and 15 nonsplenectomized) were studied and compared with 15 healthy participants. The 4 agonists used were adenosine 5-diphosphate, adrenaline (epinephrine), collagen, and ristocetin. The current study shows both splenectomized and nonsplenectomized patients had abnormal aggregation compared to normal healthy controls. Splenectomized patients had higher platelet aggregation than nonsplenectomized patients for all 4 agonists; but statistically significant difference among 2 groups was found only for collagen. The present study confirms a role of splenic absence in platelet hyperaggregation.

Cost-Effectiveness of Eltrombopag versus Romiplostim for the Treatment of Chronic Immune Thrombocytopenia in England and Wales

ObjectivesTo evaluate the cost-effectiveness of eltrombopag compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia in patients in England and Wales who are splenectomized or ineligible for splenectomy and are refractory to other treatments. MethodsA Markov cohort model in which patients were administered a sequence of treatments was used to predict long-term outcomes associated with each treatment. The model was informed by data from the eltrombopag clinical trial program and the available literature. The analysis was conducted from the perspective of the UK National Health Service, and a lifetime time horizon was used. Deterministic and probabilistic sensitivity analyses were performed. ResultsEltrombopag dominated romiplostim (i.e., eltrombopag was as effective as but less costly than romiplostim) in both splenectomized and nonsplenectomized patients, assuming a class effect for the two treatments. Eltrombopag also dominated romiplostim in most deterministic sensitivity analyses with the exception of when indirect efficacy estimates were incorporated into the model. In this analysis, eltrombopag no longer dominated romiplostim but remained cost-effective versus romiplostim at a willingness-to-pay threshold of £20,000 per quality-adjusted life-year. Probabilistic sensitivity analysis demonstrated that there was a 99% and 92% chance of eltrombopag being cost-effective at a cost-effectiveness threshold of £20,000 per quality-adjusted life-year in splenectomized and nonsplenectomized patients, respectively. ConclusionsResults of this study demonstrate that eltrombopag is cost-effective when compared with romiplostim to be used in the treatment of chronic immune thrombocytopenia, representing good value for the UK National Health Service.

Role of romiplostim in splenectomized and nonsplenectomized patients with immune thrombocytopenia.

Romiplostim is a thrombopoietin receptor agonist (TPO-RA) used for the treatment of adult primary immune thrombocytopenia (ITP). ITP is an autoimmune condition characterized by low platelet counts due to increased destruction and reduced platelet production. First-line interventions include corticosteroids, anti-D, and intravenous immunoglobulins, while second-line therapies comprise splenectomy, rituximab, cyclosporine A, and TPO-RAs. The recognition that compromised platelet production is a critical part of the pathogenesis of ITP prompted the development of therapeutic strategies based on the stimulation of the TPO receptor. TPO-RAs enhance megakaryocyte proliferation, increase platelet production, and lead to a reduction in bleeding episodes in ITP patients. This review will summarize current data on the TPO-RA romiplostim, with a particular focus on its relation to splenectomy.

Risk of venous thromboembolism in patients with splenic injury and splenectomy. A nationwide cohort study.

The spleen is a crucial organ in humans. However, little is known about the association of venous thromboembolism (VTE) with splenic injury and splenectomy in trauma patients. The aim of this study was to determine the subsequent risk of VTE following splenic injury and splenectomy. A nationwide retrospective cohort study was conducted by analysing data from the National Health Insurance Research Database in Taiwan. We included 6,162 splenic injury patients (3,033 splenectomised and 3,129 nonsplenectomised patients) and 24,648 comparison patients who were selected by frequency match based on sex, age, and the index year during 2000-2006. All patients were followed until the occurrence of VTE, 31 December, 2011, death, or withdrawal from the insurance program. The age of patients with splenic injury was 41.93 ± 16.44 years. The incidence rates of VTE were 11.81, 8.46, and 5.21 per 10,000 person-years in the splenic injury patients with splenectomy, splenic injury patients without splenectomy, and comparison patients, respectively. Compared with the comparison cohort, splenic injury patients with splenectomy exhibited a 2.21-fold risk of VTE (95% confidence interval [CI], 1.43-3.43), whereas those without splenectomy exhibited a 1.71-fold risk of VTE (95% CI, 1.05-2.80). The overall incidence rate of VTE was 1.97-fold higher in the splenic injury cohort than the comparison cohort (95% CI, 1.38-2.81). Although splenectomy increased the risk of VTE 1.35-fold compared with no splenectomy, the difference was not statistically significant (95% CI, 0.74-2.45). These results may alert physicians and patients to the complications of splenic injury and splenectomy.

Spinal Cord Infarction in a Patient with Hereditary Spherocytosis: A Case Report and Discussion.

The etiology of spinal cord infarcts (SCIs), besides being related to aortic perioperative events, in large subset of SCIs, remains cryptogenic. We present a first case of SCI in a patient with hereditary spherocytosis and discuss the potential pathophysiologic considerations for vascular compromise. A 43-year-old woman with a history of hereditary spherocytosis, post splenectomy status, presented with chest, back, and shoulder pain with subsequent myelopathic picture; SCI extending from C4-T2 was confirmed by MRI. Despite aggressive treatment her stroke progressed leading to her demise. Her autopsy confirmed the SCI and revealed some incidental findings, but the cause of SCI remained unidentified. Exclusion of the known etiologies of SCI by extensive negative workup including autopsy evaluation suggested that SCI in our case was related to her history of hereditary spherocytosis. Both venous and arterial adverse vascular events, at a higher rate, have been associated in patients with hereditary spherocytosis who had their spleens removed compared to nonsplenectomized patients. Postsplenectomy increases in the platelet, red blood cell count, leukocyte count, and cholesterol concentrations are postulated to contribute to increased thrombotic risk. Additional prothrombotic factors include continuous platelet activation and adhesion as well as abnormalities of the red blood cell membrane.

Evaluation of carotid artery dynamics &amp; correlation with cardiac &amp; hepatic iron in β-thalassaemia patients

Background & objectives:Early atherosclerosis and vascular complication have been described in thalassaemia patients. There is lack of data or guidelines regarding monitoring of vascular health in thalassaemia. This study was conducted to compare carotid artery structural and functional indices such as carotid artery intima-media thickness (CIMT), stiffness index (SI) and Young's elastic modulus (YEM) in β-thalassemia patients with age and sex matched controls, and to correlate these parameters with serum ferritin, cardiac iron, and hepatic iron.Methods:This cross-sectional study included 53 β-thalassaemia patients receiving regular blood transfusions. Carotid artery indices such as CIMT, SI, and YEM were calculated by duplex ultrasound and colour Doppler. Serum ferritin levels were measured by chemiluminescence. Cardiac and hepatic iron estimation were done using MRI T2* sequences analyzed by a special thalassaemia software.Results:Mean CIMT of cases and controls were 0.48 ± 0.04 and 0.44±0.02 mm, respectively and these were significantly different (P<0.001). Similarly significant differences were noted in SI and YEM of cases (2.45±0.79 and 96.12±34.85, respectively) as compared to controls (1.98±0.54 and 68.60±24.29, respectively) (P<0.001). There was significant inverse correlation between stiffness index and cardiac iron overload assessed by MRI cardiac T2* (P=0.03). Mean SI and YEM of cases were (2.1736 ± 0.2986 and 107.3± 41.6, respectively) significantly higher among non-splenectomized patients compared to splenectomized patients (2.0136 ± 0.263 and 86.9 ± 25.2, respectively) (P<0.05).Interpretation & conclusions:CIMT and arterial stiffness indices were significantly increased in β-thalassaemia patients compared to controls which was indicative of early atherogenic changes. This study supports the hypothesis that iron overload is a risk factor for early atherosclerosis and cardiovascular disease.

Cost per Treatment Success of Thrombopoietin Receptor Agonists Vs "Watch and Rescue" Strategy for Treating Adult Non-Splenectomized Patients with Chronic Immune Thrombocytopenia: A US Payer Perspective

Background:Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet count level and increased risk of bleeding. Non-splenectomized patients account for the vast majority of adult patients with ITP in US clinical practice (Cetin et al, Blood, 2014).Two thrombopoietin receptor agonists (TPO-RAs, romiplostim [once-weekly subcutaneous injection] and eltrombopag [once-daily oral agent]) are indicated for the treatment of non-splenectomized adults with chronic ITP who have had an insufficient response to corticosteroids or immunoglobulins. Both TPO-RAs have been shown to increase and maintain platelet counts and reduce the incidence of bleeding-related episode (BRE, defined as a bleeding event and/or use of rescue therapy).Using a US payer perspective and recent price and cost data, this analysis estimates the cost relative to treatment success (measured as overall platelet response) of the two TPO-RAs and a "watch and rescue" strategy (monitoring patients until rescue therapies [eg, intravenous immunoglobulin] are required) in non-splenectomized adults with chronic ITP.Methods:The analysis was conducted based on time horizon (24 weeks) and data for non-splenectomized patients of phase 3 registrational trials of romiplostim (Kuter et al, Lancet, 2008) and eltrombopag (Cheng et al, Lancet, 2011) in adult patients with chronic ITP.Rates of overall platelet response (see definitions based on number of weeks with platelet count ≥ 50 x 109/L in Cooper et al, Int J Technol Assess Health Care, 2014) were estimated using trial data (Kuter et al, Lancet, 2008; NICE Appraisal of Eltrombopag, 2012): 87.8% for romiplostim, 71.8% for eltrombopag, and 14.5% for "watch and rescue" (from pooled data for placebo arms).Drug acquisition cost was calculated using wholesale acquisition cost values as of July 16, 2015 ($5.8256 per mcg for romiplostim, $4.0824 per mg for eltrombopag 25 mg tablet, $3.9875 per mg for eltrombopag 50 or 75 mg tablet) and average dose in the trials (317 mcg/week for romiplostim [assuming 100% wastage of unused dose in an opened vial], 55 mg/day for eltrombopag).Costs for drug administration (for romiplostim only, once per week), physician visit and platelet count monitoring (for all three strategies, once per week in weeks 1-4 and once every 4 weeks in weeks 5-24), and liver function monitoring (for eltrombopag only, once every 2 weeks in weeks 1-4 and once every 4 weeks in weeks 5-24) were obtained from CMS Physician Fee Schedule (July 2015 release) and Clinical Laboratory Fee Schedule (January 2015 release).Cost of BREs (ie, cost for treating bleeding events and/or cost for rescue therapy) was derived on the basis of incidence rates of BRE (0.128 per patient-week for non-responder and 0.031 per patient-week for responder, calculated from data reported in Weitz et al, Curr Med Res Opin, 2012) and average treatment cost per BRE ($6,006, in inflation-adjusted June 2015 $) estimated from BREs identified during 2007-2013 in a study of a large US administrative healthcare claims database (Cetin et al, Blood, 2014).Cost per response was computed as total cost (summation of all the cost items aforementioned) divided by overall platelet response rate.Results:The cost per response results by treatment strategy are summarized in the Table. Compared to the "watch and rescue" strategy, use of any of the two TPO-RAs is associated with a fewer number of BREs, a lower cost for treating BREs, and a lower cost per response. Cost per response estimates of the two TPO-RAs are broadly comparable, with romiplostim associated with lower cost per response than eltrombopag.Conclusion:In non-splenectomized adults with chronic ITP, the use of TPO-RAs represents an efficient way in achieving treatment success, with lower cost per treatment success than the "watch and rescue" strategy.Table 1Cost per Response by Treatment Strategy (time horizon: 24 weeks; 2015 $)RomiplostimEltrombopag"Watch and rescue"Drug acquisition cost$44,321$37,0330Drug administration cost$60000Physician visit and platelet count monitoring cost$711$711$711Liver function monitoring cost0$770Average number of BREs1.031.402.74Cost of BREs$6,164$8,418$16,464Total cost$51,796$46,239$17,175Overall response rate87.8%71.8%14.5%Cost per response$58,990$64,432$118,314 DisclosuresLi:Amgen, Inc.: Employment, Equity Ownership. Sharma:Amgen Inc.: Employment, Other: stock ownership. Zhang:Amgen Inc.: Other: Internship. Campioni:Amgen Inc.: Employment, Other: stock ownership. Fust:Amgen Inc.: Consultancy, Research Funding; Optum: Employment. Lin:Amgen Inc.: Employment, Other: stock ownership. Parthan:Optum: Employment; Amgen Inc.: Consultancy, Research Funding. Wang:Amgen Inc.: Employment, Other: stock ownership. Zur:Optum: Employment; Amgen Inc.: Consultancy, Research Funding. Cetin:Amgen, Inc: Employment, Equity Ownership. Eisen:Amgen Inc: Employment, Other: stock ownership.

Cost of Bleeding-Related Episodes (BREs) in Adult Patients with Primary Immune Thrombocytopenia (ITP): A Population-Based Retrospective Cohort Study of Administrative Claims Data for Commercial Payers in the United States

Background: ITP is a rare disorder characterized by low platelet counts, which leads to an increased tendency to bleed and bruise. Previously, we reported real-world estimates of the incidence of BREs in adult patients with primary ITP using a large administrative commercial claims database in the US, where BREs were defined as a bleeding event and/or the use of a rescue or emergency ITP therapy (Cetin et al., Blood 2014: 124 [21]). We found that the majority of ITP patients experienced at least one BRE. To further advance our understanding of ITP disease burden, we expanded on this work by examining the economic impact of the BREs observed in this study.Methods: The study was conducted using the MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits Databases. Patients diagnosed with primary ITP were identified between the years 2007 and 2012 if they had at least 2 outpatient claims separated by at least 30 days or 1 inpatient claim with ICD-9-CM diagnosis code (287.31) for primary ITP. The occurrence of a BRE, occurring between 2007 and 2013, was defined according to a combination of diagnosis codes and/or procedure codes indicating a form of bleeding, administration of intravenous immunoglobulin, anti-D or IV corticosteroids, or platelet transfusion. For cost estimates, the total reimbursed amount received by the providers (including out-of-pocket costs and reimbursement from insurance) was used. Specifically, for outpatient costs, cost on any records with a BRE-related code (diagnosis or procedure) from the start date of the BRE to (1) the date prior to the start date of the next BRE, or (2) a date followed by three consecutive days without any BRE-related claims, whichever came first, was included. For inpatient costs, cost for all services from the admission date (or BRE start date if not the first BRE during the hospital stay) until the earlier of (1) the date prior to the start date of a new BRE, or (2) the discharge date was counted. All costs were adjusted to 2013 dollars using the appropriate Consumer Price Indices (CPI) (hospital and related services CPI and medical care CPI were used for inpatient and outpatient cost adjustment, respectively). Mean and 95% confidence interval (CI) for BRE costs were estimated and subgroup analyses (splenectomy status and BRE types) were conducted. The differences among subgroups were tested by analysis of variance (ANOVA) at a significance level of 0.05 and the standard errors were clustered at the individual patient level.Results:As previously reported, among 6,651 patients with primary ITP, a total of 14,115 BREs were identified. The mean (SD) age was 55(18) years at the start of corresponding BRE and females accounted for 59% of the population. The mean total cost of a BRE was $5,606 (Table 1), with a mean inpatient BRE cost of $41,545 and a mean outpatient BRE cost of $2,046. The cost per BRE was approximately $2,300 higher in splenectomized patients compared with non-splenectomized patients, but the difference was not statistically significant. The cost of BREs with actual bleeding only was $9,591, whereas with solely rescue therapy was $2,652. The cost of BREs that included both bleeding and rescue therapy use was $10,380.Conclusion:Our study offers insight into the healthcare expenditures incurred by patients with ITP who experience BREs. Higher costs were found among patients requiring hospitalization and in those using bleeding therapy.Table 1Cost of BREs in Adult Patients with Primary ITPGroupNMeanLower 95% CIUpper 95% CIP aOverall14,115$5,606$5,051$6,161<.0001Inpatient b1,272$41,545$36,822$46,269Outpatient c12,843$2,046$1,827$2,266Gender0.0665Male5,415$6,268$5,359$7,178Female8,700$5,194$4,494$5,893Age0.002318-342,071$6,629$5,191$8,06635-441,948$6,047$4,432$7,66145-542,648$5,833$4,640$7,02655-643,359$6,423$5,037$7,80965+4,089$4,060$3,263$4,856Splenectomy status0.1948No13,192$5,455$4,915$5,995Yes923$7,765$4,304$11,225BRE Type<.0001Bleeding & Rescue261$10,380$7,836$12,924Bleeding only5,718$9,591$8,313$10,870Rescue only8,136$2,652$2,368$2,935a Analysis of Variance (ANOVA)b Inpatient group refers to BREs requiring inpatient care and other subsequent patient care in different settings if anyc Outpatient group refers to BREs only requiring outpatient care DisclosuresLin:Amgen, Inc.: Employment, Equity Ownership. Zhang:Amgen, Inc: Other: Internship program. Li:Amgen, Inc.: Employment, Equity Ownership. Altomare:Amgen Inc.: Consultancy, Honoraria. Wasser:Amgen, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cetin:Amgen, Inc: Employment, Equity Ownership.

The use of thrombopoietin-receptor agonists (TPO-RAs) in immune thrombocytopenia (ITP): a "real life" retrospective multicenter experience of the Rete Ematologica Pugliese (REP).

Immune thrombocytopenia (ITP) is a disease which sees one-third of patients failing first and subsequent therapeutic approaches, including splenectomy. Thrombopoietin-receptor agonists (TPO-RAs) are recommended for adults who relapse after splenectomy or who have contraindications for splenectomy. In this multicenter study, a total of 124 patients were retrospectively evaluated: 55 (44.3%) were treated by romiplostim and 69 (55.6%) by eltrombopag. Mean age, number of young patients (<60years), time from primary diagnosis of ITP to TPO-RA treatment, and previous lines of therapy were similar in both groups. The overall response rate was 80% (44/55) for romiplostim and 94.2% (65/69) for eltrombopag; the duration of response and the time to response were similar (p = NS). The response rate to both drugs in non-splenectomized patients was higher than that of splenectomized patients (p < 0.05). The mean duration of response was 30months for romiplostim and 15months for eltrombopag, due to later commercialization of eltrombopag. Failure was the most frequent cause of discontinuation. Thrombotic events were the most consistent adverse events and were recorded in 2 and 3% of patients treated by romiplostim and eltrombopag, respectively. In conclusion, romiplostim and eltrombopag are effective in the majority of patients with chronic ITP who failed several lines of therapy; whether TPO-RAs could substitute splenectomy is under discussion and studies are warranted.

Frataxin expression in reticulocytes of non-splenectomized and splenectomized patients with HbE-β-thalassaemia

ObjectivesA previous report revealed that thalassaemic patients with transfusional iron overload developed oxidative stress. The aims of this study were to investigate the FXN mRNA levels in the reticulocytes of patients with HbE-beta-thalassaemia who were treated with regular transfusions, to compare the results with those from normal controls and to evaluate the relationships of the levels of FXN mRNA with malondialdehyde (MDA) and iron parameters in these patients. Design and methodsThe levels of FXN mRNA in the reticulocytes of patients (30 non-splenectomized and 30 splenectomized) and 30 normal individuals were assessed by RT-PCR. The levels of MDA and the transferrin saturations (TSs) were analysed with thiobarbituric acid-reactive substance assay and spectrometry, respectively. The level of ferritin was determined by ELISA. ResultsThe levels of FXN mRNA, MDA, ferritin, and TS in the patients were significantly higher than those in the controls. The levels of FXN mRNA, MDA, and ferritin in the non-splenectomized and splenectomized patients were significantly different, but the levels of TS in these two patient groups were comparable. The relative FXN expression in the patients was found to be correlated with the levels of MDA and ferritin but not correlated with TS. ConclusionsThe elevation of FXN expression in the reticulocytes of these patients seems to be linked to oxidative stress and iron status.