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Biomedical subjects

B M Ewenstein

Publications and source records attributed to B M Ewenstein.

At least 19 recordsLinked to original sources
PubMed2005

A cost minimization model for the treatment of minor bleeding episodes in patients with haemophilia A and high-titre inhibitors.

Treatment of acute bleeding episodes in patients with haemophilia A and inhibitory antibodies to factor VIII (FVIII) most often involves the use of bypassing haemostatic agents, such as activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa). We constructed a cost minimization model to compare the costs of initial treatment with aPCC vs. rFVIIa in the home treatment of minor bleeding episodes. We developed a clinical scenario describing such a case and presented it to a panel of US haemophilia specialists. For each product class, we asked panellists to provide dosing regimens required to achieve complete resolution of a minor haemarthrosis in a child with high-titre inhibitors, and for the probabilities of success at two time points (8-12 and 24 h). Consensus among the panellists was refined by a second round of the process, and the median values resulting were used as inputs to a decision analysis model. Sensitivity analyses were conducted to determine threshold values for key variables. The base case model found that initial treatment with aPCC would result in a mean cost per episode of 21 000 dollars, compared with 33 400 dollars for initial treatment with rFVIIa. Sensitivity analyses over a range of clinically plausible values for cost, dosing, and efficacy did not change the selection of aPCC as the dominant strategy.

Autoantibodies↗
PubMed2004

Hemophilia therapy innovation: development of an advanced category recombinant factor VIII by a plasma/albumin-free method. Proceedings of a Special Symposium at the XIXth Congress of the International Society on Thrombosis and Haemostasis, July 12-18, 2003, Birmingham, UK.

Replacement therapy for hemophilia A has evolved from the early use of whole blood, citrated plasma, and cryoprecipitate, to purified factor VIII (FVIII) concentrates, first derived from plasma, then produced by recombinant DNA technology. Recombinant FVIII (rFVIII) concentrates have provided improved safety for patients with hemophilia A since they significantly reduce the risk of transmission of blood-borne infections. Nevertheless, human- or animal-derived plasma proteins are still included at some step in preparation of all previously licensed rFVIII, thereby introducing the potential for transmission of human or animal pathogens. Anti-hemophilic factor (recombinant), plasma/albumin-free method (rAHF-PFM), a novel advanced category rFVIII produced without the addition of human or animal plasma proteins, has been developed with the goal of providing the greatest possible margin of safety to hemophilia patients. This report, based on a symposium of the XIXth International Society on Thrombosis and Haemostasis Congress, provides an overview of the rAHF-PFM development program as well as current findings from the global clinical evaluation of rAHF-PFM in pediatric and adult previously treated patients.

Adult↗
PubMed2004

Successful treatment for patients with von Willebrand disease undergoing urgent surgery using factor VIII/VWF concentrate (Humate-P).

von Willebrand disease (VWD) is characterized by insufficient von Willebrand factor (VWF) activity. It has been proposed that VWF:ristocetin cofactor (VWF:RCo) activity may be useful in evaluating the response to VWD treatment in patients who require replacement therapy. This prospective, open-label, non-randomized study evaluated the safety and efficacy of a factor VIII (FVIII)/VWF concentrate (Humate-P) used in treatment regimens based on VWF:RCo activity in subjects with VWD in situations requiring urgent and necessary surgery. This article summarizes the results for 39 subjects with 42 evaluable surgical treatment events, 100% of which were rated as excellent/good for overall efficacy (achievement of haemostasis). The median loading dose based upon VWF:RCo activity was 82.3 international units/kilogram (IU kg(-1); range 32.5-216.8 IU kg(-1)), and the median maintenance dose per infusion was 52.8 IU kg(-1) (range 24.2-196.5 IU kg(-1)) for a median of 3 days (range 1-50 days). The median number of infusions per event was 6 (range 1-67 infusions). Three unanticipated adverse events (peripheral oedema, extremity pain and pseudo-thrombocytopenia) from two surgical treatment events were reported that were potentially treatment-related. No serious drug-related adverse events (AEs) were observed, and no thrombotic events were reported in this study. This study supports the safety and efficacy of the FVIII/VWF concentrate Humate-P for the prevention of surgical haemorrhage in patients with VWD when administered in doses calculated in VWF:RCo units.

Adolescent↗
PubMed2004

The economic impact of factor VIII inhibitors in patients with haemophilia.

The impact on the cost of care for haemophilia patients with inhibitors is not well defined. To quantify the effect on health care expenditures associated with inhibitors to factor VIII (FVIII) or FIX, we conducted a retrospective cohort study examining product use and outcomes in adult and paediatric haemophilia patients with and without inhibitors. Twelve patients with inhibitors to FVIII or FIX (cases) identified in the haemophilia surveillance system (HSS) at two centres were matched on age, severity of haemophilia, and treatment centre to haemophilia patients without inhibitors. Patients with HIV or significant liver disease were excluded from the study. All eligible non-inhibitor control patients were selected for inclusion in the study, resulting in a total of 28 controls. We then tracked product usage and hospitalizations from programme entry until 1998 or loss to follow-up, producing a total database of 184 person-years of experience. A descriptive matched analysis was conducted to examine annual differences in the cost of product used and hospitalizations. We found that the median cost for factor products among haemophilia patients with inhibitors was $55,853/year, $2,760 less than comparable haemophilia patients without inhibitors. The median number of hospitalizations per year was 1.0 for both inhibitor and non-inhibitor patients and the median number of days hospitalized was virtually the same. Although these findings do not appear to support the belief that there is a substantial increase in the cost of care for haemophilia patients with inhibitors, it does document that a few outlier patients can drive the cost of treatment for this disease. As the largest component of the cost of care is that of factor concentrate, it becomes imperative in the current health care environment to better define the true costs and benefits of treatments designed to eradicate or manage inhibitors. A careful cost accounting of immune tolerance induction (ITI) and other therapeutic strategies, taking into account successes and failures and duration and intensity of therapy, should help to better define the costs and benefits of such approaches. Methods to identify high cost inhibitor patients should be developed so that these strategies may be targeted to appropriate candidates.

Adolescent↗
PubMed2004

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate): a prospective pharmacovigilance study.

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.

Adolescent↗
PubMed2004

Clinical evaluation of an advanced category antihaemophilic factor prepared using a plasma/albumin-free method: pharmacokinetics, efficacy, and safety in previously treated patients with haemophilia A.

The efficacy and safety of an advanced category recombinant antihaemophilic factor produced by a plasma- and albumin-free method (rAHF-PFM) was studied in 111 previously treated subjects with haemophilia A. The study comprised a randomized, double-blinded, crossover pharmacokinetic comparison of rAHF-PFM and RECOMBINATE rAHF (R-FVIII); prophylaxis (three to four times per week with 25-40 IU kg(-1) rAHF-PFM) for at least 75 exposure days; and treatment of episodic haemorrhagic events. Median age was 18 years, 96% of subjects had baseline factor VIII <1%, and 108 received study drug. Bioequivalence, based on area under the plasma concentration vs. time curve and adjusted in vivo recovery, was demonstrated for rAHF-PFM and R-FVIII. Mean (+/-SD) half-life for rAHF-PFM was 12.0 +/- 4.3 h. Among 510 bleeding events, 473 (93%) were managed with one or two infusions of rAHF-PFM and 439 (86%) had efficacy ratings of excellent or good. Subjects who were less adherent to the prophylactic regimen had a higher bleeding rate (9.9 episodes subject(-1) year(-1)) than subjects who were more adherent (4.4 episodes subject(-1) year(-1); P < 0.03). One subject developed a low titre, non-persistent inhibitor (2.0 BU) after 26 exposure days. These data demonstrate that rAHF-PFM is bioequivalent to R-FVIII, and suggest that rAHF-PFM is efficacious and safe, without increased immunogenicity, for the treatment of haemophilia A.

Adolescent↗
PubMed2004

Consensus recommendations for use of central venous access devices in haemophilia.

Venous access is essential for delivery of haemophilia factor concentrate. Wherever possible, peripheral veins remain the route of choice, and the use of central venous access devices (CVADs) should be limited to cases of clear need in patients with caregivers able to exercise diligence in CVAD care and should continue no longer than necessary. CVADs are of recognized value for repeated administration of coagulation factors in haemophilia, particularly for prophylaxis and immune tolerance therapy and in young children. Evidence to guide best practices has been fragmentary, and standardized methods for CVAD usage have yet to be established. We have developed management recommendations based upon available published evidence as well as extensive clinical experience. These recommendations address patient and CVAD selection; CVAD placement, care and removal; caregiver/patient guidance; and complications, including infection and thrombosis. In the absence of inhibitors, ports are recommended, primarily because of fewer associated infections than with external catheters. For patients with inhibitors, ports also appear to be associated with fewer infections. Infection is the most frequent complication, and recommendations to prevent and treat infections are supported by extensive clinical data and experience. Strict adherence to handwashing and aseptic technique are essential elements of catheter care. Evidence-based data regarding the detection and treatment of CVAD-related thrombotic complications are limited. Caregiver education is an integral part of CVAD use and the procedural practices of users should be regularly re-assessed. These recommendations provide a basis for sound current CVAD practice and are expected to undergo further refinements as new evidence is compiled and clinical experience is gained.

Catheterization, Central Venous↗
PubMed2003

Successful treatment of urgent bleeding in von Willebrand disease with factor VIII/VWF concentrate (Humate-P): use of the ristocetin cofactor assay (VWF:RCo) to measure potency and to guide therapy.

This prospective, open-label, non-randomized study evaluated the safety and efficacy of factor VIII (FVIII)/von Willebrand Factor (VWF) concentrate (Humate-P) using treatment regimens based on VWF:ristocetin cofactor (VWF:RCo) activity in patients with von Willebrand Disease (VWD) in (i) urgent bleeding episodes, or (ii) in patients undergoing urgent and necessary surgery. This article summarizes the results of treatment for the 33 patients with 53 urgent bleeding events. The median loading dose of FVIII/VWF concentrate was 67.0 international units per kilogram (IU kg(-1)) VWF:RCo (range 25.7-143.2 IU kg(-1)), and the median daily maintenance dose per infusion was 74.0 IU kg(-1) (range 16.4-182.9 IU kg(-1)) for a median duration of 2 days (range 1-34 days). The overall efficacy (achievement of haemostasis) of FVIII/VWF concentrate was rated as excellent/good for 98% of the urgent bleeding events. No unexpected treatment-related adverse events or serious drug-related adverse events (AEs) were observed. This study supports the safety and efficacy of Humate-P administered in doses calculated in VWF:RCo units for the treatment of urgent bleeding episodes in patients with VWD.

Coagulants↗
PubMed2002

Porcine factor VIII: pharmacoeconomics of inhibitor therapy.

The treatment of acquired haemophilia is characteristically exceedingly expensive and thus a cost-benefit analysis of the several available treatment strategies is urgently needed. To address this issue, decision-analysis techniques were used to construct a cost-minimization model to compare the cost of treatment with porcine factor VIII (pFVIII), human FVIII (hFVIII) or an activated prothrombin complex concentrate (APCC). This model was based upon the results of a comprehensive literature search of all relevant clinical studies and case series. To supplement these data, a panel of haemophilia specialists was presented with a clinical scenario describing an acquired haemophilia patient with an acute haemorrhage in whom the human and porcine inhibitor titres were initially unknown. Based on this scenario and on their own clinical experience, the expert panel assessed the applicability of the model as initially constructed, assigned probabilities of success to each treatment and recommended appropriate initial dosing and follow-up regimens. This information was incorporated into the model and a simulation was conducted from which the costs of care were calculated. Sensitivity analyses were then conducted on all parameters. The results of the model show that treatment initiated with pFVIII would be more cost effective compared with treatment sequences initiated with an APCC or hFVIII, respectively. The model indicates that initial treatment with pFVIII in this scenario may be the preferred strategy clinically, as well as on economic grounds.

Algorithms↗
PubMed2001

Use of ristocetin cofactor activity in the management of von Willebrand disease.

von Willebrand disease (vWD), the most common of the hereditary bleeding disorders, arises from quantitative or qualitative defects in von Willebrand factor (vWF). vWF is a multimeric plasma protein that plays a key role in primary and secondary haemostasis. In the current classification scheme, vWD is divided into six subtypes that are based on the nature of the vWF defect. Therapeutic strategies depend on the accurate identification of these subtypes. In most clinical situations, desmopressin is effective treatment for the great majority of patients with mild (type 1) disease, while replacement therapy with factor VIII/vWF concentrates that contain high levels of vWF activity is required for most type 2 and nearly all type 3 vWD patients. Several factor VIII/vWF replacement products are available, one of which (Humate P) has been approved for the treatment of vWD by the US Food and Drug Administration. Preliminary results of recent studies support the hypothesis that treatment with factor VIII/vWF concentrates based upon the content of vWF activity as reflected in the ristocetin cofactor assay is practicable, safe and efficacious. The establishment of optimal treatment regimens with respect to dose intensity and duration will require further study.

Biological Assay↗
PubMed2001

Management of von Willebrand disease: a survey on current clinical practice from the haemophilia centres of North America.

The optimal treatment of patients with von Willebrand's disease (vWD) remains to be defined. Moreover, it has not been firmly established which, if any, commonly measured parameters of von Willebrand factor (vWF) protein in the plasma are useful in guiding treatment. To better understand what guidelines physicians follow in the management of vWD, we surveyed 194 North American physicians who are members of the Hemophilia Research Society. Ninety-nine per cent of responding physicians depend on factor VIII (FVIII):C, vWF:RCo activity and vWF:AG to diagnose vWD, while only 49% use the bleeding time. The minimal goals of treatment for patients undergoing major surgery/trauma or central nervous system haemorrhage were FVIII:C and vWF:RCo activity greater than 80% while levels of more than 50% for minor surgery and dental extractions were considered adequate. Treatment of vWD was based on the type of vWD with type 1 patients being treated most often with desmopressin acetate (DDAVP) alone, types 2A and 2B patients with a combination of DDAVP and a vWF-containing FVIII product, type 3 patients with vWF-containing concentrate. Viral infections, including human immunodeficiency virus, hepatitis A, B and C viruses, and parvovirus have been seen in vWD and the efficacy of viral attenuation processes is a major criterion for the selection of treatment by physicians. Based on this survey, prospective studies need to be designed to address the clinical efficacy, safety and predictive value of laboratory monitoring of patients with vWD.

Ambulatory Care Facilities↗
PubMed2001

Risk factors for infection with HBV and HCV in a largecohort of hemophiliac males.

BACKGROUND: Before the implementation of donor screening and the development of effective virus-inactivation procedures, persons with hemophilia (PWHs) were at risk of infection with HBV and HCV transmitted through clotting factor concentrates. STUDY DESIGN AND METHODS: Data collected from the medical records of a cohort of 2,772 males with hemophilia who resided in six states of the United States were used to examine relations between demographic and clinical characteristics and laboratory markers of past or present infection with HBV and HCV using logistic regression. RESULTS: Test results were available for 60 percent of the cohort. Among those tested, 30 percent were positive for markers of HBV infection and 64 percent for HCV infection. Factors associated with increased odds of positive HBV markers and HCV infection were greater severity of hemophilia, larger amounts of factor use, and HIV infection. Markers of HBV infection persisted in birth cohorts as late as 1992 and those of HCV infections in birth cohorts through 1991. Compared to same-age US males, PWHs born between 1987 and 1989 were more likely to have markers of HBV and HCV infection. CONCLUSION: PWHs who received clotting factor concentrates before 1990 may be at risk for infection with hepatitis B or hepatitis C and should be tested.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Regulated secretion in endothelial cells: biology and clinical implications.

Vascular endothelial cells are critical participants in maintaining blood flow, with the ability to respond rapidly to injury. We have outlined above how the regulated secretion of a variety of hemostatic and inflammatory mediators contributes to these nearly instantaneous responses. The WPB are the most prominent of these regulated secretory granules, and there is growing evidence of additional granules that release their contents under a variety of conditions. The mechanisms responsible for the targeting of proteins to regulated secretory granules, and of exocytosis of these granules are being elucidated. EC appear to share some characteristics with other secretory cell types, but also are likely to have unique properties related to the storage and secretion of large multimeric proteins such as VWF and multimerin. Understanding these mechanisms may lead to new strategies for treating coronary artery disease, stroke, sickle cell disease, and hemophilia through drugs that modulate sorting and secretion, or by gene transfer approaches that introduce therapeutic molecules into the WPB for regulated release.

Animals↗
PubMed2000

Immune tolerance induction in hemophilia patients with inhibitors: costly can be cheaper.

The development of inhibitory antibodies to factor VIII (FVIII) occurs in approximately 30% to 40% of patients with severe hemophilia A. Management options for patients with inhibitor include eradicating it via immune tolerance induction (ITI) or treating bleeding episodes with large quantities of hemostatic agents. ITI is costly, approaching $1 million for the average 5-year-old, but if successful results in improved clinical outcomes. We constructed a decision analysis using the Markov process to model expected clinical outcomes and costs over a lifetime for a typical 5-year-old hemophiliac with high inhibitor levels. Estimates of relevant variables were based on a thorough review of the medical literature. Outcomes modeled included total lifetime costs as well as life expectancy. The decision analytic model revealed that the ITI strategy was associated with an increase in projected life expectancy of 4.6 years. Total estimated lifetime costs for the ITI strategy were approximately $1.7 million less per patient. Sensitivity analyses over clinically and economically reasonable ranges did not change these findings. The insight that ITI can achieve an improved clinical outcome while being cost-saving is not reflected in many current treatment regimens. This example also illustrates that expensive therapy for patients with a chronic disease may be cost effective when analyzed from a societal perspective over the patient's lifetime. This finding has important policy implications for medical decision makers at many levels and reinforces the need to undertake pharmacoeconomic analyses and choose therapies from a long-term, societal perspective. (Blood. 2000;96:1698-1702)

Cost-Benefit Analysis↗
PubMed2000

Inhibition of CD40 ligand (CD154) in the treatment of factor VIII inhibitors.

The development of persistent, high titer inhibitors represents a serious complication of the treatment of patients with severe hemophilia A. Elimination of these inhibitory antibodies is usually attempted through repeated administration of high doses of factor VIII. Such regimens are costly, time-consuming and often fail when the inhibitor is of very high titer or of longstanding duration. A potential alternative approach to inhibit the production of antifactor VIII antibodies is blockade of the T-cell/B-cell collaboration that is required to generate humoral responses. One cognate receptor pair that is required for T-cell-dependent B-cell activation consists of CD40, which is expressed on B-lymphocytes and other antigen presenting cells, and CD40 ligand (CD40L, CD154), which is transiently expressed on activated T-cells. To determine whether blockade of the CD40-CD40L pathway can inhibit the production of anti-factor VIII antibodies, a clinical study has been designed in which patients with hemophilia A and a high titer inhibitor (> 10 BU) receive monthly exposures to factor VIII in the presence of a humanized mouse monoclonal antibody to human CD40L (hu5c8*). Subjects must be between the ages of 5 and 60 years old and be HIV seronegative. To date, three subjects have received at least three doses of hu5c8 at the initial protocol dose of 10 mg/kg. Preliminary results suggest that anti-CD40L inhibition may be effective in blocking anamnestic responses to factor VIII in some patients. It remains to be determined whether this effect will persist and whether patients may eventually become tolerant to factor VIII in the absence of hu5c8 co-administration.

Adolescent↗
PubMed1999

Targeting of a heterologous protein to a regulated secretion pathway in cultured endothelial cells.

The stimulation of regulated exocytosis in vascular endothelial cells (EC) by a variety of naturally occurring agonists contributes to the interrelated processes of inflammation, thrombosis, and fibrinolysis. The Weibel-Palade body (WPB) is a well-described secretory granule in EC that contains both von Willebrand factor (vWF) and P-selectin, but the mechanisms responsible for the targeting of these proteins into this organelle remain poorly understood. Through adenoviral transduction, we have expressed human growth hormone (GH) as a model of regulated secretory protein sorting in EC. Immunofluorescence microscopy of EC infected with GH-containing recombinant adenovirus (GHrAd) demonstrated a granular distribution of GH that colocalized with vWF. In contrast, EC infected with an rAd expressing the IgG(1) heavy chain (IG), a constitutively secreted protein, did not demonstrate colocalization of IG and vWF. In response to phorbol ester, GH as well as endogenously synthesized vWF were rapidly released from GHrAd-infected EC. By immunofluorescence microscopy, granular colocalization of GH with endogenous tissue-type plasminogen activator (tPA) was also demonstrated, and most of the tPA colocalized with vWF. These data indicate that EC are capable of selectively targeting heterologous proteins, such as GH, to the regulated secretory pathway, which suggests that EC and neuroendocrine cells share common protein targeting recognition signals or receptors.

Adenoviridae↗