The amount and rate of blood expelled with different modes of intermittent external pneumatic compression applied to the lower leg were studied on a regional basis in a series of experiments on healthy human volunteers. Radionuclide imaging of the labelled blood pool, with acquisition of counts synchronised to the pressurisation cycle, provided data on regional blood volumes in the leg in relation to time. To determine the changes in blood volume of the lower leg resulting from external pneumatic compression labelled red blood cell counts were determined during 10 different types of compression cycle. Since venous stasis is considered to be a major cause of venous thrombosis the red blood cell counts were used to calculate regional values of the fraction of blood ejected as well as comparative indices proportional to regional flow rate, regional velocity, and regional wall shear stress. All these indices should be maximised for optimal prophylaxis against deep vein thrombosis. The four compartment cuff in each compression mode applied a mean pressure of 45 mm Hg, but different combinations of values were used for intercompartmental pressure gradation (delta p) and for intercompartmental time sequencing to the onset of compression (delta t). Uniform compression (delta p = 0; delta t = 0) was substantially inferior to cycles with gradation and sequencing. The optimal values of delta p were in the range 5-10 mm Hg and of delta t in the range 0-0.5 seconds.
Recurrent joint bleeds are a major cause of morbidity in severe hemophilia. Prophylaxis with efmoroctocog alfa (a recombinant factor VIII Fc fusion protein, [rFVIIIFc]) has demonstrated benefits beyond bleed control, including joint health maintenance.To assess long-term efficacy and safety of rFVIIIFc prophylaxis in severe hemophilia A in phase 3 pivotal (A-LONG/Kids A-LONG) and extension (ASPIRE) studies.Longitudinal analysis included pooled data from A-LONG/Kids A-LONG and ASPIRE. Subgroup analyses investigated outcomes in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score and target joints in subjects with 4 to 5 years follow-up on individualized prophylaxis (IP), and those with the highest annualized bleeding rate (ABR) quartile during Year 1 of IP.Overall, rFVIIIFc consumption remained stable and low ABRs were maintained, with a median treatment duration of 4.2/3.4 years in subjects from A-LONG/Kids A-LONG, respectively. Median overall ABR also remained low (1.0-2.0) in subjects on IP for 4 to 5 years. Sustained improvements in modified Hemophilia Joint Health Score or Hemophilia Joint Health Score were demonstrated over a median follow-up of 3.7 years. In subjects from A-LONG/Kids A-LONG, 99.6% (n = 234)/100% (n = 9) of evaluable baseline target joints were resolved, with no recurrence in 95%/100% of target joints. In IP subjects within the highest ABR quartile in Year 1, continued improvements were observed over a median follow-up of 4.3 years in ABR and joint health, without increased factor consumption. No inhibitors or treatment-related serious adverse events were reported.Previously treated subjects of all ages receiving long-term prophylaxis with rFVIIIFc had sustained clinical benefits, including improved joint health and low ABR.
Summary Ancestral background, specifically African descent, confers higher risk for development of inhibitory antibodies to factor VIII ( FVIII ) in haemophilia A. It has been suggested that differences in the distribution of FVIII gene ( F8 ) haplotypes, and mismatch between endogenous F8 haplotypes and those comprising products used for treatment could contribute to risk. Data from the Hemophilia Inhibitor Genetics Study ( HIGS ) Combined Cohort were used to determine the association between F8 haplotype 3 (H3) vs. haplotypes 1 and 2 (H1 + H2) and inhibitor risk among individuals of genetically determined African descent. Other variables known to affect inhibitor risk including type of F8 mutation and human leucocyte antigen ( HLA ) were included in the analysis. A second research question regarding risk related to mismatch in endogenous F8 haplotype and recombinant FVIII products used for treatment was addressed. Haplotype 3 was associated with higher inhibitor risk among those genetically identified ( N = 49) as of African ancestry, but the association did not remain significant after adjustment for F8 mutation type and the HLA variables. Among subjects of all racial ancestries enrolled in HIGS who reported early use of recombinant products ( N = 223), mismatch in endogenous haplotype and the FVIII proteins constituting the products used did not confer greater risk for inhibitor development. Haplotype 3 was not an independent predictor of inhibitor risk. Furthermore, our findings did not support a higher risk of inhibitors in the presence of a haplotype mismatch between the FVIII molecule infused and that of the individual.
Significant therapeutic advances have been achieved in the development of new replacement products for patients with haemophilia A and B. These advances have included the development of infusion products with improved pharmacokinetic profiles allowing for extended infusion intervals. However, haemophilia patients with inhibitors have not as yet benefited from these advances and continue to await the development of improved therapeutics that provide more consistent and reliable haemostasis. Patients with inhibitors continue to experience an increased risk of morbidity with poorer quality of life, and higher risk of mortality as compared to their inhibitor-free peers.1, 2 Current bypassing product efficacy is not consistently predictable either in individual patients or in specific bleeding events. Over time, an increased understanding of the mechanism of action of bypassing agents, empirical dose-finding and continued efforts to clinically evaluate the currently available bypassing agents, have shifted the care paradigm to evolve into a more flexible, individually tailored pathway.3, 4 Reports of clinical trials utilizing innovative mechanisms including a novel factor VIII-mimetic bispecific antibody (emicizumab), or RNAi targeting inhibitors of coagulation such as antithrombin, have demonstrated markedly reduced annualized bleeding rates in inhibitor patients. These agents would be utilized as “prophylaxis” in inhibitor patients;5, 6 however, it would be expected that intermittent breakthrough bleeding will necessitate the need for on-demand treatment of mild-moderate (at home) and severe (hospital setting) bleeding events with bypassing agents. The current range of available bypassing products is limited most notably in haemophilia B inhibitor patients with a history of reaction to factor IX-containing products; in addition, for patients utilizing emicizumab, the use of activated prothrombin complex concentrates may increase the risk of unusual adverse events.5 Therefore, the need for improved and an expanded range of bypassing agents continues to represent an area requiring further development. In this issue of Haemophilia, data from the eptacog beta (rhFVIIa) clinical development programme are shared by Wang et al., who describe the PERSEPT 1 phase 3 study results;7 and Ducore et al., who describe the dose-ranging phase 1b study.8 The phase 1b dose-ranging study provided insights that resulted in a computational model that confirmed an apparent greater potency (compared to eptacog alfa) and the optimal phase 3 dosing regimens with eptacog beta. Standard methods to confirm the dose–response using a classic dose escalation study in 10 patients were measured along with FVIIa:C and ex vivo platelet-supplemented thrombin generation assays. The pharmacokinetic data provide a glimpse into the relationship between initial dose, peak plasma eptacog beta activity and thrombin generation at the site of the bleeding; a relationship previously less well defined for eptacog alfa.9, 10 Despite these dose-ranging observations, it appears we will continue to seek pharmacodynamic markers capable of predicting in real time the clinical efficacy of bypassing agents. First presented at the 2016 World Federation of Hemophilia Congress in Orlando, FL, the phase 3 study reported treatment of 465 mild/moderate bleeding events of varying aetiology and location. The results of this pivotal study of eptacog beta are noteworthy as, for the first time, they demonstrate early, dose-proportional and sustained clinical response in a prospective, randomized, crossover, bleeding event (BE) study with a rFVIIa variant. The 27 subjects (adults and adolescents) were assigned by a prospective randomization process to one of two “initial dose regimens” for BEs occurring at home; and were instructed to record symptoms and clinical responses in a journal that included a Visual Analog Scale for pain. Based on preclinical differences in molar potency compared to eptacog alfa, preclinical in vivo and ex vivo work, as well as the results of the phase 1b study, initial doses of eptacog beta of 75 μg/kg and 225 μg/kg were chosen. The protocol called for a 3-hour inter-dose interval in the 75 μg/kg arm and a 9-hour interval following a 225 μg/kg initial dose. The primary endpoint of the PERSEPT 1 study, a sustained clinical response at 12 hours, was reached in both treatment arms of the trial (225 μg/kg, 93.2%, P < 0.001; 75 μg/kg, 84.9%, P < 0.001). At 24 hours, the overall efficacy was 97.9%. A single study BE had early rebleeding that did not resolve by 24 hours; however, no other early rebleeding events were reported (0.2% overall rebleeding incidence). In the 225 μg/kg arm, 85% of treated BEs achieved clinical response with a single infusion of eptacog beta. BEs treated with the 225μg/kg initial dose had twice the clinical response at 3 hours (64%) as compared to response seen in the 75 μg/kg arm. If confirmed in clinical practice, this single-dose efficacy may be attractive to clinicians and patients currently burdened with frequent multiple-dosing regimens. In our centre's experience with eptacog alfa (NovoSeven® RT), we have strived through empiric dose-finding to achieve the most rapid clinical response (presumptive haemostasis). To achieve this end, we have used doses higher than those approved, which have provided an improved response, a decrease in the number of infusions, and in some, prolonged infusion intervals;11 however, the need for continued dosing to consolidate haemostasis to prevent rebleeding remains a concern. Multiple database reviews and reports reveal wide variations in how bypassing agents are currently prescribed both in and out of the hospital setting, variations that are difficult to articulate but often ascribed to the unpredictable nature of inhibitor-related haemorrhage, response to bypassing agents, and provider experience and comfort with specific regimens.9, 10 The predictable response to eptacog beta reported in the PERSEPT 1 trial should be viewed with some optimism, yet also with care, as this was a crossover study in a limited number of patients and treatment was not blinded. At first glance, eptacog beta could be perceived as a biosimilar to eptacog alfa; however, the different binding,13 potency and efficacy demonstrated in these studies preclude that conclusion.14 For many years, variants of rFVIIa have been sought in an effort to improve predictability of clinical response, decrease the incidence of redosing, and prevent rebleeding; however, such attempts have not as yet been successful in the clinical setting.15, 16 If wider clinical use of eptacog beta continues to validate the results reported in these studies, then perhaps an improved variant has been added to the armamentarium, providing a needed expansion of bypassing agents with which to tackle inhibitor-related bleeding. ADS wrote this commentary. The authors stated that they had no interests which might be perceived as posing a conflict or bias.
In the August 2019 issue of Haemophilia, Guedes et al presented a study that aimed to compare, in their view, subjective and objective measures of adherence to prophylaxis in haemophilia.1 Guedes et al defined their objective measure of adherence using a dispensation/vial return measure: a percentage value derived from empty factor vials returned to the haemophilia treatment centre (HTC) relative to the expected number of factor units needed to follow the prescribed prophylactic regimen and additional factor required for bleed management. They compared this measure to two self-report measures of adherence: (1) participant-reported number of missed infusions during the last dispensation period compared to expected amount of factor that should have been infused according to the patient's medical prescription and the number and severity of bleeding episodes reported; and (2) participant-estimated proportion of factor infusions usually missed in a regular month by other patients with haemophilia. Participants also completed a third self-report measure, rating their adherence to haemophilia treatment on a five-point Likert scale ranging from very good to very poor. All self-report measures were obtained during a face-to-face interview with a familiar provider from the HTC. Guedes et al found minimal associations between self-reported adherence and dispensation/vial return measures, with the strongest and most statistically significant correlation occurring between the dispensation/vial return measure and participants' self-report of proportion of missed factor doses. In general, participants self-reported a very high degree of adherence that was greater than adherence measured using the dispensation/vial return method. Based on these findings, Guedes et al question the validity of self-report measures of adherence and argue that their objective measure is superior to self-report measures in assessing adherence to haemophilia treatment. These conclusions generated provocative headlines such as 'Self-reported adherence fails to line up with objective measures in hemophilia'.2, 3 We commend Guedes et al on their attention to the important issue of measurement of adherence to haemophilia treatment regimens. Adherence is a critical and central component of treatment that has historically been inadequately addressed both clinically and in research studies, in part because measurement of adherence in all disease states including haemophilia is complicated and difficult.4-8 Therefore, greater use of well-validated, meaningful, feasible adherence measures has much to offer to haemophilia treatment and research. Despite the Guedes et al characterization of their dispensation/vial return measure as objective, this unidimensional, single-item measure is not objective in the classic sense, and dispensation/vial return measures have their own limitations, some of which Guedes et al acknowledge. Furthermore, a dispensation/vial return measure provides no information about multidimensional aspects of adherence such as dose timing, amount and planning. Tracking returned medication or the time/number of the opening/closing of bottles (another widely used 'objective' measure) provides some relevant adherence data but does not provide the full detail or richness of information about thinking and behaviour involved in medication adherence. Adherence is a multifactorial process involving environment, behaviour and thought; empty vials alone cannot capture these essential factors. Having developed the VERITAS-Pro, we believe the Guedes et al findings must be understood in an appropriate context to avoid generalizations and equivalencies between their measures and the VERITAS-Pro (or other systematically developed, well-validated self-report measures of adherence). Using sound, well-established methodology, the multidimensional VERITAS-Pro was developed in a five-step process including input from thirteen haemophilia care specialists, a patient focus group and a pilot study. It was psychometrically tested and validated against pharmacy dispensation data, infusion log data and a general adherence rating (GAR) obtained from the patient/caregiver and two healthcare providers familiar with the patient's treatment regimen and general approach to infusion therapy. The scale includes specific anchors and uses multi-item subscales to assess distinct components of adherence: Timing of infusion, Dose of infusion, Planning for treatment needs, Remembering to infuse, Choosing to skip infusions and Communicating with the HTC. The VERITAS-Pro has been used in clinical practice and in research, referenced in at least 75 articles or abstracts, translated and linguistically or culturally validated in over 30 languages, and psychometrically validated in multiple languages.10-16 No adherence measure is without limitations. We have discussed the limitations of the VERITAS-Pro and other self-report scales in our prior work, including influences of social desirability bias, rater insight/skill in reporting adherence components and risk of some overestimation of adherence. Importantly, in spite of limitations that are present for all self-report scales, well-developed self-report scales are among the most valid assessment instruments for human cognition and behaviour, are widely used in psychology and medicine, and can significantly predict clinical outcomes.17, 18 These measures are inexpensive, non-invasive, minimally burdensome, easy to administer, flexible in the timing and method of administration, and available for multiple informants across a large variety of medication regimens.17, 18 When a gold standard is not available, a combination of (truly) objective and self-report methods has been recommended to provide the most comprehensive measurement of human behaviour.19, 20 Ultimately, adherence involves central, primary components of human thought and behaviour, and self-report scales have unique value in assessing these domains. Although Guedes et al's conclusions about self-report adherence measures extend beyond the scope of their data, their article makes a valuable contribution to the understanding and application of adherence measures. Specifically, their results and conclusions raise appropriate cautions about the validity of self-report measures that are unidimensional/single-item, psychometrically unknown and administered in formats that enhance social desirability effects. Self-report adherence measures should be systematically developed, clearly anchored, operationalized, multidimensional, multi-item, validated and effectively administered. Despite limitations, self-report adherence measures are preferred in clinical care when speed, efficiency and low-cost are necessary and are critical for understanding the complex cognitive and behavioural factors that comprise adherence in clinical settings and research studies.7 Adherence is a human behaviour with multiple characteristics and influences. It should be assessed using a multimethod, multitrait approach that includes self-report and other methodologies. ND, WK, CR, IJ and AD wrote the paper. WK and ND analysed the data. WK is a paid consultant for Shire/Takeda Pharmaceuticals, Homology Medicines and the Indiana Hemophilia and Thrombosis Center. The remaining authors have no competing interests.
Summary. The primary objective of the study was to examine the prevalence of cardiovascular disease (CVD) events and their known risk factors among persons with haemophilia (PWH). This cross-sectional study, covering a 5-year period, included PWH aged ≥35 years who were cared for at a single haemophilia treatment centre in the United States. Medical records were extensively reviewed to collect the information about CVD events and their risk factors such as obesity, hypertension, diabetes, hypercholesterolemia and smoking. Prevalence rates were compared with national population estimates and associations between risk factors and CVD events were examined using logistic regression. The study cohort comprised 185 PWH (102 haemophilia A and 83 haemophilia B). Lifetime prevalence of a CVD event was 19.5% (36/185, 95% confidence interval [CI] 13.8–25.2%). CVD mortality was 5.4% (10/185, 95% CI 2.7–8.1). Compared with US non-Hispanic White males (NHWH), PWH had about twice the prevalence of coronary artery disease, stroke and myocardial infarction. The prevalence of CVD risk factors for PWH was similar to that for US NHWM with 39.5% of PWH exposed to two or more of these risk factors. Both hypertension and smoking were associated significantly with CVD events, with odds ratios of 4.9 and 6.3, respectively. In conclusion, this study revealed that both CVD events and its risk factors were at least equally prevalent among PWH and might have been even higher than among the US NHWM in the United States. Therefore, it is imperative to implement strategies for CVD prevention among PWH.
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