A Budget Impact Model of Hemophilia Bypassing Agent Prophylaxis Relative to Recombinant Factor VIIa On-Demand.

BACKGROUND: Hemophilia patients use factor-clotting concentrates (factor VIII for hemophilia A and factor IX for hemophilia B) for improved blood clotting. These products are used to prevent or stop bleeding episodes. However, some hemophilia patients develop inhibitors (i.e., the patient's immune system develops antibodies against these factor concentrates). Hence, these patients do not respond well to the factor concentrates. A majority of hemophilia patients with inhibitors are managed on-demand with the following bypassing agents: recombinant factor VIIa (rFVIIa) and activated prothrombin complex concentrate (aPCC). The recently published U.S. registries Dosing Observational Study in Hemophilia (DOSE) and Hemostasis and Thrombosis Research Society (HTRS) reported higher rFVIIa on-demand use for bleed management than previously described. OBJECTIVE: To estimate aPCC and rFVIIa prophylaxis costs relative to rFVIIa on-demand treatment cost based on rFVIIa doses reported in U.S. registries. METHODS: A literature-based cost model was developed assuming a base case on-demand annual bleed rate (ABR) of 28.7 per inhibitor patient, which was taken from a randomized phase 3 clinical trial. The doses for rFVIIa on-demand were taken from the median dose per bleed reported by the DOSE and HTRS registries. Model inputs for aPCC and rFVIIa prophylaxis (i.e., dosing and efficacy) were derived from respective randomized clinical trials. Cost analysis was from the U.S. payer perspective, and only direct drug costs were considered. The drug cost was based on the Medicare Part B 2014 average sale price (ASP). Two-way sensitivity and threshold analyses were performed by simultaneously varying on-demand ABR, prophylaxis efficacy, and unit drug cost. In addition to studying relative costs associated with on-demand and prophylaxis treatments, relative cost per bleeding episode avoided were also calculated for aPCC and rFVIIa prophylaxis treatments. The prophylaxis efficacy reported in the trials were used to determine the number of bleeding episodes avoided. RESULTS: Based on the median on-demand dose of 695 mcg per kg per bleed, reported by the DOSE registry, the annual rFVIIa on-demand cost was $34,009 per kg of body weight. The annual rFVIIa on-demand cost was $22,020 per kg of body weight when the median dose of 450 mcg per kg per bleed reported by the HTRS registry was considered. The annual cost rose to $38,461 per kg of body weight when the rFVIIa on-demand dose of 786 mcg per kg per bleed among patients infusing an initial dose ≥ 250 mcg per kg was considered. The aPCC (85 units per kg per every other day) and rFVIIa (90 mcg per kg per every day) annual prophylaxis costs were $26,536 and $60,700, respectively. Also, aPCC and rFVIIa prophyaxis treatments were estimated to prevent a total of 20.8 and 12.9 annual bleeding episodes, respectively. When compared with the on-demand dose of 695 mcg per kg per bleed (DOSE registry), the annual aPCC and rFVIIa prophylaxis costs were 21.9% lower and 78.4% higher, respectively. Additionally, aPCC prophylaxis saved $360 per kg for each bleeding episode avoided. rFVIIa prophylaxis cost $2,066 per kg for each bleeding episode avoided. Compared with the on-demand dose of 450 mcg per kg per bleed (HTRS registry), aPCC and rFVIIa prophylaxis costs were 20.5% and 174.9% higher, respectively. In this case, aPCC and rFVIIa prophylaxis treatment costs were $217 per kg and $2,995 per kg, respectively, for each bleeding episode avoided. aPCC and rFVIIa prophylaxis costs were 31.0% lower and 57.8% higher, respectively, when compared with the rFVIIa on-demand dose of 786 mcg per kg per bleed, among patients infusing an initial dose ≥ 250 mcg per kg (HTRS registry). In this case, aPCC prophylaxis saved $573 per kg for each bleeding episode avoided, while rFVIIa prophylaxis costs $1,724 per kg for each bleeding episode avoided. Results of the 2-way sensitivity analyses were robust in the majority of the scenarios considered. CONCLUSIONS: aPCC prophylaxis may be cost saving for managing hemophilia patients with inhibitors who bleed frequently and infuse significant quantities of rFVIIa on-demand.

Response shift: a brief overview and proposed research priorities.

AIM: The objective of this overview is to review current methodologies of response shift research in patient-reported outcomes to facilitate and stimulate further research in this area. METHODS: This paper is a narrative overview of research in response shift. RESULTS: The following research priorities emerged: (1) obtain a consensus on terminology and theoretical models used, to ensure that all researchers and clinicians are at the same starting point; (2) determine the clinical importance of response shift; (3) determine the best way to measure and adjust for response shift as a clinically important confounder; (4) ascertain how response shift can best be identified when response shift is the focus of clinical treatment; and (5) establish what methods can be used to translate response shift knowledge into real-world settings. CONCLUSIONS: With the adoption of these research priorities, we anticipate that the theories and processes of response shift will be better understood, current methods to analyze this phenomenon will be improved while new ones may also be developed, and the clinical importance and impact of response shift in measuring changes in health-related quality of life (HRQL) will be determined.

Separating gains and losses in health when calculating the minimum important difference for mapped utility measures.

OBJECTIVE: To estimate the minimum important difference (MID) for a variety of mapped utility measures and to determine whether patients perceiving gains and losses in health status should be treated equally when calculating the MID. METHODS: A longitudinal study within a California managed care population of 6,932 patients was retrospectively analyzed. Utilities were derived from the SF-36 short-form health survey using multiple validated mapping methods. Absolute utility changes for patients who considered their current health as 'somewhat better' or 'somewhat worse' in the prior year were compared to determine if gains and losses in utility values could be combined. The MIDs were calculated and compared using anchor- and distribution-based methods. RESULTS: Two thousand one hundred patients reported 'somewhat better' or 'somewhat worse' health in the first year. When combining these patients, the average MID for all mapped utility measures was 0.03 (SD=0.1), a magnitude similar to that identified by Walters. However, when separated, the mean MID utility change for those reporting 'somewhat better' and 'somewhat worse' health was 0.02 (SD=0.1) and -0.06 (SD=0.1), respectively (P<0.0001). CONCLUSIONS: Researchers should consider the effects of combining gains and losses when determining utility MID values.

Doxepin rinse for management of mucositis pain in patients with cancer: one week follow-up of topical therapy.

This study assessed the effectiveness of oral doxepin rinse for mucositis-related pain management in patients following 1 week of repeated dosing. Patients with oral mucositis due to head and neck radiation therapy or hematopoietic stem cell transplant (HSCT) were recruited to participate in a 1-week follow-up study. Subjects who gave informed consent rinsed with doxepin (5 ml) during the initial visit and were then told to use doxepin rinse over the next week as needed, three to six times per day, and return for a follow-up visit. At each visit, mucositis was scored using the Oral Mucositis Assessment Scale and oral pain was assessed using a visual analogue scale before and after rinsing. The use of a systemic analgesic was recorded, and side effects were documented. At the follow-up visit, subjects were also asked to retrospectively report average pain scores they experienced over the past week, 5 and 15 minutes following rinse. Nine subjects were enrolled in the study. Statistically significant reductions in pain scores were reported for 2 hours following doxepin rinse during the initial visit (p < .05). Patients recalled that their pain significantly dropped within 5 minutes of rinsing over the week of repeated dosing (p < .05). At the follow-up visit, subjects reported statistically significant pain reduction 5 minutes after doxepin rinsing (p < .05). These results indicate that doxepin rinsing continues to produce reduced intensity of pain levels over a 1-week span of repeated dosing.

Cost of care for early- and late-stage oral and pharyngeal cancer in the California Medicaid population.

BACKGROUND: This study documents the direct medical costs associated with treating oral and pharyngeal squamous cell carcinoma (OSCC) as early- or late-stage disease according to the current standard of care. METHODS: This retrospective analysis of California Medicaid claims data calculated direct payments for patients diagnosed with OSCC. Patients were defined as being treated for early- or late-stage disease based on treatment modality. Regression determined significant predictors of year-1 cost of care following diagnosis. RESULTS: Median year-1 cost of care following initial diagnosis was $25,319 for the 229 patients identified. Regression results determined that treatment modality and medical comorbidities were significant in predicting costs (p < .05). Costs for patients treated as having early-stage OSCC were approximately 36% less than for those treated as having late-stage disease (p = .002). CONCLUSION: Treatment for OSCC is a significant cost from Medicaid's perspective, and these data suggest early detection may ease its economic burden.

The efficacy of oral lumenoscopy (ViziLite) in visualizing oral mucosal lesions.

Early diagnosis of oral mucosal lesions has been advocated as a means of improving outcomes of cancer therapy. Improved visualization of mucosal lesions may aid in diagnosis by guiding tissue sampling or referral. This multicenter study reports the effect of chemiluminescent light (ViziLite) upon visualization of mucosal lesions. The chemiluminescent light did not appear to improve visualization of red lesions, but white lesions and lesions that were both red and white showed enhanced brightness and sharpness.

Oral doxepin rinse: the analgesic effect and duration of pain reduction in patients with oral mucositis due to cancer therapy.

This research expands on our prior study, in which we assessed pain reduction after topical doxepin rinse in patients with oral mucositis resulting from cancer and cancer therapy. We continued to enroll patients with painful oral mucositis attributable solely to cancer therapy and performed further analysis on the duration of pain reduction. Fifty-one patients with oral mucositis were enrolled. Mucositis was scored and oral pain was assessed with a visual analog scale before doxepin oral rinse (5 mg/mL) and at regular intervals up to 4 h after rinsing. Of those who reported pain reduction, 95% did so within 15 min of rinsing with doxepin. In the total sample, the average patient reported a 70% maximum decrease in pain (P < 0.0001). Recurrence of pain was slow and at the conclusion of the study 19 patients (37%) still reported a reduction from baseline pain. With this censored data we used Cox-proportional hazards to determine what variables best explained longer duration of pain reduction. Our final model determined that more severe baseline pain, worse mucosal erythema score, or a larger relative maximum reduction in pain were all associated with a slower rate of pain recurrence after oral rinsing (all P < 0.01).

Topical polyene antifungals in hematopoietic cell transplant patients: tolerability and efficacy.

PURPOSE: The effectiveness of amphotericin B oral suspension versus nystatin oral suspension for the prevention of oral colonization by Candida in hematopoietic cell transplant (HCT) patients was examined. METHODS: Prior to hematopoietic cell infusion, 40 patients receiving systemic fluconazole for prophylaxis were randomized to receive either amphotericin B oral suspension or nystatin oral suspension, q.i.d. The study continued to day 21 or until the patient was discharge from the hospital or withdrawn from the study. Oral examinations were conducted twice weekly, and adverse events and compliance were recorded. Cultures were taken for quantitative counts and species identification. Candida isolates were assessed for resistance to the oral antifungal agents. Blood was collected for assessment of amphotericin B levels. RESULTS AND DISCUSSION: Ulcerative mucositis occurred in 84.6% of patients undergoing HCT, and no correlation was observed between the severity of mucositis and the presence of oral Candida and the severity of mucositis. Systemic and topical antifungal treatment resulted in a decrease in the number of colonized patients (54.8% before treatment; 23.1% during treatment); however, oral colonization was not eliminated. Tolerability of the oral rinse products was limited, with greater noncompliance in the amphotericin B than the nystatin group. Reports of altered taste appeared to be greater in the amphotericin B group. Minimal absorption of amphotericin B was seen following oral rinsing (serum levels 0.12-0.50 microg/ml), and no consistent changes in organism susceptibility to polyenes were seen. The results suggest that topical antifungal rinses may further control oropharyngeal colonization by Candida in patients on systemic antifungals receiving HCT, but the effect is limited by tolerability and reformulation and should be considered in order to increase compliance.