Real-World Analysis of Dispensed International Units of Coagulation Factor VIII and Resultant Expenditures for Hemophilia A Patients: A Comparison Between Standard Half-Life and Extended Half-Life Products.

PURPOSE: To identify international units (IUs) dispensed and consequent expenditures for standard half-life (SHL) versus extended half-life (EHL) recombinant factor VIII (rFVIII) replacement products in hemophilia A patients in a real-world setting. DESIGN: Two U.S. claims databases were analyzed. METHODOLOGY: Number of IUs dispensed and quarterly expenditures for rFVIII products were collected from the Optum Clinformatics Data Mart and Truven Health MarketScan Databases. Truven claims were also analyzed for factor IUs dispensed and expenditures for patients with data for ≥3 months before and after switching to an EHL product. RESULTS: The Optum and Truven databases, respectively, included 276 (SHL, n=243; EHL, n=33) and 500 (SHL, n=409; EHL, n=91) hemophilia A patients. Median quarterly factor IUs dispensed in Optum were 10% higher with EHL versus SHL products over nine quarters, and 45% higher with EHL versus SHL products in Truven over 10 quarters. Median quarterly expenditures in the EHL cohort were 51% (individual quarterly medians range, 1%-101%) higher than in the SHL cohort in Optum and 122% higher (individual quarterly medians range, 1%-189%) in Truven. Twenty-nine Truven patients switched to an EHL product; median factor IUs dispensed varied quarterly. The lowest SHL and highest EHL values occurred in the quarter immediately before switching and the first quarter post-switch, respectively. Overall median quarterly expenditures were higher post-switch; this was consistent over seven quarters. CONCLUSION: We found higher expenditures over two years for hemophilia A patients using EHL versus SHL products. Switching to an EHL rFVIII product was associated with variable factor IUs dispensed and consistently higher expenditures.

Dental procedures in 24 patients with chronic immune thrombocytopenia in prospective clinical studies of eltrombopag.

Primary immune thrombocytopenia (ITP) is an autoimmune disease characterized by chronically low peripheral blood platelet counts. Eltrombopag is an oral, non-peptide, thrombopoietin-receptor agonist that increases platelet production. This report examines peri-procedural platelet counts and bleeding complications among chronic ITP patients requiring dental procedures while participating in clinical studies with eltrombopag. A total of 494 patients participated in five clinical studies of eltrombopag in chronic ITP. Information about dental procedures was collected prospectively in four studies and retrospectively in one study. Twenty-four patients (22 eltrombopag, 2 placebo) underwent 32 dental procedures (dental cleaning, tooth repair, artificial crown, dental prosthesis, tooth extraction, dental or wisdom teeth extraction, dental root extraction, and endodontic procedures, among others) during study treatment or up to 10 days later. Supplemental ITP therapy (e.g., corticosteroids, platelet transfusions) was given before the dental procedure to increase platelet counts in three eltrombopag-treated patients and both placebo-treated patients. The mean pre-procedure platelet count ± standard deviation for all procedures in the overall population of patients, eltrombopag group, and placebo group prior to undergoing dental procedures was 96 000 ± 81 069/µl,103 517 ± 81 522/µl, and 23 333 ± 9291/µl, respectively. Two patients in each group had platelet counts below 30 000/µl before the procedure. No patient who had a dental procedure experienced a bleeding adverse event. Among patients with chronic ITP who required a dental procedure during clinical studies of eltrombopag, supplemental ITP treatment was required for both patients who received placebo but was not required for most patients who received eltrombopag. No bleeding complications were reported. These data imply that patients with chronic ITP who receive eltrombopag and experience increases in platelet counts fulfill current pre-procedural platelet count recommendations to undergo invasive dental procedures, and may have a lower risk of bleeding complications and a reduced need for supplemental ITP treatment.

Bleeds and resource use in hemophilia B: retrospective observational study.

OBJECTIVES: To describe people with hemophilia B (PWHB) in the US who experience bleeds despite factor replacement therapy and to quantify the associated burden from the third-party payer perspective. STUDY DESIGN: Observational study of adult male PWHB treated with factor IX replacement therapy identified from the PharMetrics Plus claims data from 2010 to 2019. METHODS: Patients with medically recorded bleeds (MRBs) were identified using diagnostic codes. Rates and rate ratios of inpatient admissions, emergency department (ED) visits, and outpatient visits among PWHB with and without MRBs were estimated. The presence of comorbidities was identified using diagnostic codes, and the analysis was stratified by age group. RESULTS: There were 345 PWHB with MRBs and 252 without MRBs. More than half of PWHB with MRBs (56.8%) had 1 or more comorbidity vs 39.3% of PWHB without MRBs. The prevalence of anxiety and depression was high in PWHB, regardless of bleed status and age group, whereas the prevalence of other comorbidities increased with age group. The rate of all-cause inpatient admissions for PWHB with MRBs was 14.8 per 100 person-years (95% CI, 12.8-17.1), 2.5 times higher than for PWHB without MRBs. The rate of all-cause ED visits for PWHB with MRBs was 67.6 per 100 person-years (95% CI, 63.2-72.3), 2.7 times higher than for those without MRBs. CONCLUSIONS: This study reports significant resource use and clinical burden among PWHB who seek medical care. PWHB with MRBs had considerable all-cause resource use compared with PWHB without MRBs. The prevalence of mental illness was consistently high across all age groups.

Real-world outcomes associated with standard half-life and extended half-life factor replacement products for treatment of haemophilia A and B.

: Standard-of-care treatment for haemophilia A or B is to maintain adequate coagulation factor levels through clotting factor administration. The current study aimed to evaluate annualised bleeding rates (ABR) and treatment adherence for haemophilia A or B patients receiving standard half-life (SHL) vs. extended half-life (EHL) factor replacement products. We analysed data from the Adelphi Disease-Specific Programmes, a health record-based survey of United States and European haematologists. Analysis included 651 males with moderate-to-severe haemophilia A or B (the United States, n = 132; Europe, n = 519). The haemophilia A analysis included 501 patients (SHL, n = 435; EHL, n = 66). In the combined United States/European population, mean (SD) ABR was 1.7 (1.69) for the SHL group and 1.8 (2.00) for the EHL group. A total of 72% of patients receiving SHL factor VIII and 75% of patients receiving EHL factor VIII in the combined population were fully adherent (no doses missed of the last 10 doses), as reported by physicians. The haemophilia B analysis included 150 patients (SHL, n = 114; EHL, n = 36). The mean (SD) ABR in the combined population was 2.1 (2.16) for patients receiving SHL factor IX (FIX) and 1.4 (1.48) for patients receiving EHL FIX. The percentage of fully adherent patients (physician-reported) was similar in both treatment groups (SHL FIX, 68%; EHL FIX, 73%). In this preliminary real-world survey in a relatively small sample of patients, measures of ABR and adherence between SHL and EHL products were evaluated. Additional real-world research on prescribing patterns, SHL vs. EHL effectiveness, and adherence is warranted.

Diagnosis and management of venous thromboembolism.

Venous thromboembolic disease is a common disease associated with significant morbidity and mortality. Accurate and timely diagnosis should be guided by the use of validated clinical prediction rules. The mainstay of therapy is anticoagulation, although alternative approaches, such as use of concurrent thrombolysis or placement of vena caval filters, may be appropriate in selected patients. Determination of duration of anticoagulation requires a detailed assessment of the risk factors associated with the event allowing estimation of recurrence risk, and careful assessment of bleeding risk. Although extremely effective, anticoagulants have a narrow therapeutic window; systems should be in place to reduce risk of adverse events associated with these agents.

IgM-lambda paraproteinemia with associated cutaneous lymphoplasmacytic infiltrate in a patient who meets diagnostic criteria for POEMS syndrome.

POEMS is a rare multisystem paraneoplastic syndrome featuring polyneuropathy, organomegaly, endocrinopathy, a monoclonal protein, and skin changes. In the relatively few reported biopsies of POEMS-associated cutaneous hyperpigmentation, the most common skin finding seen in patients with the disorder, only a non-specific inflammatory infiltrate has been demonstrated histologically. We present the case of a 79-year-old man with polyneuropathy, autoimmune thyroiditis, pancytopenia, and a history of lymphadenopathy who presented to the inpatient dermatology service with cutaneous hyperpigmentation. A skin biopsy of a hyperpigmented area showed a cutaneous lymphoplasmacytic infiltrate, prompting further investigation. A monoclonal IgM-lambda paraprotein was subsequently identified, leading to administration of combination chemotherapy for a diagnosis of POEMS syndrome. The novel finding of a lymphoplasmacytic infiltrate in POEMS-associated hyperpigmentation suggests a diagnostic role for skin biopsy in these patients.

Real-World Analysis of Dispensed IUs of Coagulation Factor IX and Resultant Expenditures in Hemophilia B Patients Receiving Standard Half-Life Versus Extended Half-Life Products and Those Switching from Standard Half-Life to Extended Half-Life Products.

BACKGROUND: Hemophilia B requires replacement therapy with factor IX (FIX) coagulation products to treat and prevent bleeding episodes. A recently introduced extended half-life (EHL) recombinant FIX replacement product provided the opportunity to compare the amount of dispensed factor and expenditures for EHL treatment compared with a standard half-life (SHL) product. OBJECTIVE: To determine factor international units (IUs) dispensed and expenditures associated with switching from nonacog alfa, the most commonly used SHL replacement product, to eftrenonacog alfa, an EHL FIX replacement product. METHODS: Two U.S. claims databases were analyzed. A large national specialty pharmacy dispensation claims database was used to identify the number of IUs dispensed and monthly charges for all patients with hemophilia B from April 2015 to June 2016. Truven Health MarketScan Research Databases (January 2010-July 2016) were used to identify IUs and expenditures for patients with claims data for at least 3 months before and after switching from the SHL to the EHL product. Medians for IUs and expenditures are presented to accommodate for skewness of data distribution. RESULTS: The national specialty pharmacy database analysis included 296 patients with moderate or severe hemophilia B (233 on SHL; 94 on EHL). Median monthly factor dispensed was 11% lower (2,142 IU) in the EHL versus SHL cohort over the study period, while individual monthly reductions ranged from 32% to 47% (9,838 IU to 16,514 IU). Using the wholesale acquisition cost, the median per-patient monthly factor expenditures over the 15-month study period were 94% higher ($23,005) for the EHL than for the SHL product. Individual median monthly expenditure differences ranged from 15% ($6,562) to 49% ($19,624). In the Truven database, 14 patients switched from the SHL to the EHL product. The amount of factor dispensed was variable; in the 1-year period before and after the switch from the SHL to the EHL product, mean IUs dispensed decreased by 3,005 IU, while median IUs dispensed increased by 4,775 IU. Factor replacement expenditures were higher after switching from the SHL to the EHL product in each of the 3-month periods examined before versus after the switch. CONCLUSIONS: This analysis of real-world data showed that switching from the SHL to the EHL product was associated with higher expenditures. Increased expenditures noted in the first 3 months after switching may be related to initial stocking up of the EHL product, but expenditures were sustained throughout the 1-year period of data analysis. Further analysis of these findings with larger numbers of patients should be explored. DISCLOSURES: This study was sponsored by Pfizer. Pfizer employees were involved in the study design; the collection, analysis, and interpretation of data; the review of the manuscript; and the decision to submit for publication. All authors are employees of Pfizer. No author received an honorarium or other form of payment related to the development of this manuscript. All authors participated in the study design, data interpretation, and manuscript review and revisions and granted approval for the submission of the manuscript. Alvir, McDonald, and Tortella also participated in data analysis. Data from this paper were presented in part at the European Association for Haemophilia and Allied Disorders Annual Meeting, February 1-3, 2017, Paris, France; at the International Society for Pharmacoeconomics and Outcomes Research Annual Meeting, May 20-24, 2017, Boston, MA; and at the International Society on Thrombosis and Haemostasis Congress, July 8-13, 2017, Berlin, Germany.

Revascularization strategies and in-hospital management in acute coronary syndromes complicated by hemophilia A or hemophilia B.

: Among adult patients with hemophilia A and hemophilia B the emergent management of acute coronary syndromes (ACSs) is challenging, and exposure to antithrombotic agents and/or revascularization procedures may confer an enhanced risk of bleeding. We sought to identify clinical characteristics and in-hospital outcomes among ACS patients with hemophilia A/hemophilia B, compared with matched noncoagulopathic ACS controls. Case discharges from the Nationwide Inpatient Sample, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality (1998-2011) had International Classification of Diseases, 9th Revision codes for hemophilia A/hemophilia B and ACS. Control discharges were matched to cases by year of discharge and hospital. Discharges in both groups were assessed for cardiovascular risk factors, type of ACS, use of coronary artery bypass grafting, percutaneous coronary intervention (PCI), bare-metal stent and/or drug-eluting stent, bleeding, and death. In total, 237 cases and 148 848 matched controls were identified. Among cases, HIV/Hepatitis C positivity was more common and obesity/hyperlipidemia less common. ST-elevation myocardial infarction (STEMI) occurred less frequently among hemophilia A cases than controls. hemophilia A and hemophilia B cases were more likely to be managed medically. Cases treated with coronary stent placement were more likely to receive a bare-metal stent than controls. Among PCI, bleeding was more common among hemophilia A cases. The death rates were comparable between groups. ACS-hemophilia A/hemophilia B cases were more often treated noninvasively compared with controls, suggesting an avoidance of PCI/coronary artery bypass grafting in this population, and bleeding (among hemophilia A) was more common. These findings support further study of the management of ACS and in-hospital outcomes among individuals with hemophilia.

Anti-interleukin-2 receptor antibody (daclizumab) treatment of corticosteroid-refractory autoimmune thrombocytopenic purpura.

We administered daclizumab, a humanized monoclonal anti-interleukin-2 receptor (IL-2R) antibody, to 11 patients with corticosteroid-refractory autoimmune thrombocytopenic purpura (AITP) every 2 weeks for five treatments. Of nine evaluable patients, one individual experienced a partial response. Lymphocyte phenotyping by flow cytometry indicated post-treatment binding of IL-2Ra by daclizumab in all patients. Mid-study serum soluble IL-2R levels in all patients increased 4-15 -fold over baseline values (p=0.004). Despite these measurable immunologic effects, blockade of the IL-2/IL-2R axis did not effectively abrogate the autoimmune response in this group of patients with corticosteroid-refractory AITP.

Gene therapy for hemophilia: past, present and future.

After numerous preclinical studies demonstrated consistent success in large and small animal models, gene therapy has finally seen initial signs of clinically meaningful success. In a landmark study, Nathwani and colleagues reported sustained factor (F)IX expression in individuals with severe hemophilia B following adeno-associated virus (AAV)-mediated in vivo FIX gene transfer. As the next possible treatment-changing paradigm in hemophilia care, gene therapy may provide patients with sufficient hemostatic improvement to achieve the World Federation of Hemophilia's aspirational goal of "integration of opportunities in all aspects of life… equivalent to someone without a bleeding disorder." Although promising momentum supports the potential of gene therapy to replace protein-based therapeutics for hemophilia, several obstacles remain. The largest challenges appear to be overcoming the cellular immune responses to the AAV capsid; preexisting AAV neutralizing antibodies, which immediately exclude approximately 50% of the target population; and the ability to scale-up vector manufacturing for widespread applicability. Additional obstacles specific to hemophilia A (HA) include designing a vector cassette to accommodate a larger cDNA; avoiding development of inhibitory antibodies; and, perhaps the greatest difficulty to overcome, ensuring adequate expression efficiency. This review discusses the relevance of gene therapy to the hemophilia disease state, previous research progress, the current landscape of clinical trials, and considerations for promoting the future availability of gene therapy for hemophilia.

Late presentation of dyskeratosis congenita as apparently acquired aplastic anaemia due to mutations in telomerase RNA.

Aplastic anaemia in adults is usually acquired, but rarely constitutional types of bone marrow failure can occur late in life. We assessed two families with onset of pancytopenia in adults and detected two novel point mutations in the telomerase RNA gene (TERC) in each family. This gene is abnormal in some kindreds with dyskeratosis congenita. Individuals in our families with mutated TERC did not have physical signs of dyskeratosis congenita, and their blood counts were nearly normal, but all had severely shortened telomeres, reduced haemopoietic function, and raised serum erythropoietin and thrombopoietin. Bone marrow failure of variable severity due to dyskeratosis congenita, historically characterised by associated physical anomalies and early pancytopenia, may be present in otherwise phenotypically normal adults, and can masquerade as acquired aplastic anaemia.

Resetting the immune system in immune thrombocytopenic purpura: immunoablative strategies.

As is the case with many chronic disorders, the toxicity of treatment for refractory immune thrombocytopenic purpura (ITP) often rivals that of the disease itself. In recent years, attention has turned to strategies designed to permanently rectify the abnormal immune milieu that has permitted the production of autoreactive antibodies, thereby averting chronic administration of morbidity-causing immunosuppressive medications. Approaches that will be discussed include conventional chemotherapy, high-dose chemotherapy with and without autologous stem cell support, and allogeneic transplantation.

Selective validation of the WHO Bleeding Scale in patients with chronic immune thrombocytopenia.

OBJECTIVE: To evaluate the World Health Organization's (WHO) Bleeding Scale in two studies of eltrombopag in adults with chronic immune thrombocytopenia (ITP). RESEARCH DESIGN AND METHODS: Validated scales assessing bleeding in adults with ITP are lacking. Data from two long-term, phase 3 clinical trials (RAISE: NCT00370331; EXTEND: NCT00351468) that assessed eltrombopag in adults with chronic ITP were analyzed to evaluate the performance of the WHO Bleeding Scale. RESULTS: In RAISE, effect size (0.71), standardized response (0.75), and responsiveness statistics (0.57) were moderate for bleeding and bruising assessments. In EXTEND, effect size (0.62) and responsiveness statistics (0.59) were moderate; the standardized response statistic was 0.487. Intraclass correlation for test-retest reliability was 0.75 in RAISE and 0.71 in EXTEND. A positive correlation was observed between the WHO Bleeding Scale and the ITP Bleeding Scale. Bleeding scores and quality-of-life measures were inversely correlated (p < 0.05 for all). Minimal important differences for the WHO Bleeding Scale were 0.33-0.40 at baseline and last on-treatment assessment in both studies. LIMITATIONS: The majority of bleeding in these studies was mild to moderate, so this analysis cannot provide strong evidence of the validity of the WHO Bleeding Scale in patients with more severe bleeding. Potential limitations to the WHO Bleeding Scale itself include dependence on clinician interpretation of patient recall, inability to distinguish among bleeding events occurring at different anatomical sites, and an inherent assumption of linear increases in severity of bleeding across the response categories. CONCLUSIONS: These findings suggest potential usefulness of the WHO Bleeding Scale in adult patients with chronic ITP for standardizing grading of bleeding across research studies and in clinical practice.

An algorithmic approach to peripheral artery disease in hemophilia: extrapolation of management principles from noncoagulopathic patients.

The development of peripheral artery disease (PAD), a marker for systemic atherosclerosis and ischemic risk, is an increasingly important concern in the aging hemophilia population. A growing body of data suggests that an absence or deficiency of factor VIII or factor IX may not protect against atherogenesis, implying that the prevalence of PAD in men with hemophilia (MWH) may be higher than previously believed. This article describes special considerations in PAD screening, risk-factor modification, and management in older MWH.

Biological rationale for new drugs in the bleeding disorders pipeline.

Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.

What is the evidence for the use of immunomodulatory agents to eradicate inhibitory antibodies in patients with severe hemophilia a who have previously failed to respond to immune tolerance induction?

An 18-year-old man has severe hemophilia A that has been complicated by a high-titer inhibitory antibody (peak 170 BU/mL). He had previously failed a trial of immune tolerance induction (ITI) using daily high-dose (100 units/kg/d) factor VIII (FVIII) for 20 months and would like to know if immunomodulatory agents, with or without another course of ITI, might eradicate the inhibitor.