Costs and consequences of over-investigation of minor transfusion reactions.

BACKGROUND: Adverse transfusion events create a direct cost burden on the healthcare system through increased morbidity, mortality, extra investigations for diagnosis, patient treatment and increased use of hospital resources. Understanding the costs and impact minor transfusion reactions have on the healthcare system presents an opportunity for potential cost savings and improved clinical practice. AIMS: To determine the cost associated with investigating minor transfusion reactions, to identify opportunities to improve the management of blood transfusion reactions and potential cost savings through the application of current national guidelines. METHODS: A retrospective review of all suspected transfusion reactions reported to the laboratory over a 6-year period was performed. Reports were assessed for appropriateness of clinical management and associated investigations. Cost of inappropriate investigations and associated blood product discard was calculated using current national tariffs. RESULTS: Of the 274 reports, febrile non-haemolytic transfusion reactions were the most common reactions, with 96 (35%) cases. One hundred forty-eight patients were unnecessarily investigated for suspected transfusion reactions totalling AU$ 32 427.00. The initial total value of partially discarded blood products was AU$ 55 656.00. CONCLUSION: The study demonstrated that unnecessary investigation of minor transfusion reactions adds a significant financial burden to the healthcare system.

Perceptions on consumer information in transfusion. A qualitative study of consumers and prescribers.

BACKGROUND AND OBJECTIVES: Fresh blood product transfusion requires patient education for fully informed consent, and written consumer information is frequently used. Few studies have examined consumer preferences regarding written and verbal transfusion information provided. As a qualitative study, this research was designed to explore participant understanding and by analysing and integrating themes, generate a model to understand how transfusion information should be developed and used in practice. MATERIALS AND METHODS: Semi-structured interviews were conducted with healthcare consumers of transfusion information from various hospital clinical departments. Transcripts were coded to qualitatively compare nature/extent of content and opinions regarding transfusion information through thematic analysis. RESULTS: Analysis identified themes relating to healthcare engagement, purpose of information, mode of delivery and content delivered. Differences were identified between perceived purpose of information provided to consumers between 13 transfusion prescribers and consumers. Prescribers viewed information as a tool for obtaining informed consent, whereas consumers desired reassurance and knowledge. Consumers described both the specialized nature and volume of information as limiting their ability to question professionals on whom they were dependent. Information provided should be tailored to consumers and utilize simple, succinct explanations. CONCLUSION: Both groups were satisfied with written information adjunctive to verbal information. These findings will be used to redesign transfusion information and may be employed at the bedside when discussing transfusion. They may have implications for consumer information in other settings.

A pooled post hoc analysis evaluating the safety and tolerability of cariprazine in bipolar depression.

BACKGROUND: The safety and efficacy of cariprazine, a dopamine D3-preferring D3/D2 receptor partial agonist and serotonin 5-HT1A receptor partial agonist, was evaluated in 4 randomized, double-blind, placebo-controlled trials in patients with bipolar depression. METHODS: Safety and tolerability were evaluated in 2 post hoc analyses. Modal dose analysis: pooled data from all 4 flexible/fixed-dose trials (dose groups: <1.5, 1.5, 3 mg/d). Fixed-dose analysis: pooled data from 2 identically designed fixed-dose trials (1.5 and 3 mg/d dose groups). RESULTS: The modal dose and fixed-dose analyses evaluated data from 1775 and 970 patients, respectively. Cariprazine was generally safe and well tolerated; study completion rates were 78% and 82% in the modal dose and fixed-dose analyses, respectively. In modal dose analysis, treatment-emergent adverse events (TEAEs) occurred in 60% of overall cariprazine- and 55% of placebo-treated patients; nausea (8% vs 3%) and akathisia (7% vs 2%) occurred in ≥5% of cariprazine patients and twice the rate of placebo. Metabolic changes were small and generally similar for cariprazine and placebo; mean increase in glucose was 3.1 mg/dL for cariprazine and 2.6 mg/dL for placebo. Fixed-dose and modal dose findings were generally consistent; values for most metabolic parameters were slightly higher for fixed-dose 3 mg/d versus 1.5 mg/d. LIMITATIONS: Post hoc analyses, modal dose groups, short treatment duration. CONCLUSIONS: In modal dose (0.25-3 mg/d) and fixed-dose (1.5 and 3 mg/d) analyses, cariprazine was generally safe and well tolerated in the treatment of bipolar depression. Slightly improved tolerability was observed with fixed-dose cariprazine 1.5 mg/d versus 3 mg/d. TRIAL REGISTRATION: clinicaltrials.gov NCT00852202, NCT01396447, NCT02670538, NCT02670551.

Efficacy and safety of cariprazine in bipolar I depression: A double-blind, placebo-controlled phase 3 study.

OBJECTIVE: To assess the efficacy, safety, and tolerability of cariprazine in the treatment of the depressed phase of bipolar I disorder in adults (NCT02670538). METHODS: In this phase 3 double-blind placebo-controlled study, adult patients with bipolar I disorder according to the Diagnostic and Statistical Manual - 5th Edition criteria and a current depressive episode were randomized to placebo (n = 167), cariprazine 1.5 mg/day (n = 168) or cariprazine 3.0 mg/day (n = 158). Efficacy parameters were changes in the Montgomery-Åsberg Depression Rating Scale (MADRS) total scores (primary) and Clinical Global Impressions - Severity (CGI-S) scores (secondary) from baseline to Week 6 compared to placebo. A mixed-model for repeated measures was used to estimate the least-squares mean differences (LSMD); P-values were adjusted for multiplicity. Adverse events (AEs), laboratory results, vital signs, and suicide risk were monitored. RESULTS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms on the primary (MADRS LSMD = -2.5; adjusted P = .0417) and secondary (CGI-S LSMD = -0.3; adjusted P = .0417) efficacy parameters vs placebo; differences were not statistically significant for cariprazine 3.0 mg/day. Common treatment-emergent AEs (≥5% in either cariprazine group and at least twice the incidence of placebo) were akathisia, restlessness, nausea, and fatigue. Mean metabolic parameter changes were low and generally comparable among groups; mean weight increases were ≤0.5 kg for all groups. CONCLUSIONS: Cariprazine 1.5 mg/day significantly reduced depressive symptoms in adults with bipolar I depression compared to placebo, but differences were not significant for cariprazine 3.0 mg/day. The safety and tolerability profiles were similar to previous studies of cariprazine.

Cariprazine Treatment of Bipolar Depression: A Randomized Double-Blind Placebo-Controlled Phase 3 Study.

OBJECTIVE: Cariprazine, a dopamine D3/D2 and 5-HT1A receptor partial agonist, was found to be effective in treating bipolar I depression in a previous phase 2 study. This phase 3 study further assessed the efficacy, safety, and tolerability of cariprazine in bipolar I depression. METHODS: In a double-blind placebo-controlled study, adult participants (18-65 years old) who met DSM-5 criteria for bipolar I disorder and a current depressive episode were randomly assigned to receive placebo (N=158) or cariprazine at 1.5 mg/day (N=157) or 3.0 mg/day (N=165). The primary and secondary efficacy parameters were changes from baseline to week 6 in Montgomery-Åsberg Depression Rating Scale (MADRS) score and Clinical Global Impressions severity (CGI-S) score, respectively. Least squares mean differences were estimated using a mixed model for repeated measures, and p values were adjusted for multiplicity. RESULTS: Both dosages of cariprazine were significantly more effective than placebo in improving depressive symptoms (reducing MADRS total score); the least squares mean differences were -2.5 (95% CI=-4.6, -0.4) for cariprazine at 1.5 mg/day and -3.0 (95% CI=-5.1, -0.9) for cariprazine at 3.0 mg/day. Both cariprazine dosages were associated with lower CGI-S scores compared with placebo, but the differences did not reach statistical significance after adjustment for multiplicity (least squares mean difference, -0.2 [95% CI=-0.5, 0.0] for the 1.5 mg/day group and -0.3 [95% CI=-0.5, 0.0] for the 3.0 mg/day group). Common treatment-emergent adverse events (in at least 5% of participants in either cariprazine treatment group and twice the rate of the placebo group) were nausea, akathisia, dizziness, and sedation. Mean changes in weight and metabolic parameters were relatively small and comparable across groups. CONCLUSIONS: Cariprazine, at both 1.5 mg/day and 3.0 mg/day, was effective, generally well tolerated, and relatively safe in reducing depressive symptoms in adults with bipolar I depression.

Long-term safety and tolerability of cariprazine as adjunctive therapy in major depressive disorder.

Lack of treatment response is a critical problem in major depressive disorder (MDD). Cariprazine is a D3-preferring dopamine D3/D2 receptor partial agonist and 5-HT1A partial agonist. This phase 3, multicenter, open-label, long-term (26-week), flexible-dose (1.5-4.5 mg/day) study assessed the long-term safety and tolerability of cariprazine used adjunctively with antidepressant therapy in adult patients with MDD who had either completed a lead-in study (n=311) or had been newly recruited (n=131). A higher percentage of continuing patients (66.2%) than new patients (35.9%) completed the study. The most common reason for discontinuation was adverse events (AEs; 13.9%); 79% of patients experienced a treatment-emergent AE [most common: akathisia (15.9%,) headache (11.6%)]. Serious AEs occurred in 2% of patients; two deaths occurred (one traffic accident, one completed suicide, both considered unrelated to treatment). The mean changes in clinical laboratory, cardiovascular, and ophthalmologic parameters were generally not clinically relevant. The mean (SD) changes from the open-label baseline in Montgomery-Åsberg Depression Rating Scale total score and Clinical Global Impression-Severity score at week 26 were -7.3 (9.5) and -1.0 (1.2), respectively. By week 26, 53.3% of patients were in remission (Montgomery-Åsberg Depression Rating Scale total score≤10). The results suggest that cariprazine was generally safe and well tolerated as adjunctive therapy to treat MDD.

Unified infusion rates for 10% intravenous immunoglobulin.

Although manufacturers recommend varying infusion rates for differing intravenous immunoglobulin products (IVIg), there may be improved efficiency and reduced potential for error with the application of a single infusion policy for all IVIg products. During the transition from a 6% to a 10% IVIg, we prospectively evaluated patient reported adverse reactions to IVIg with the 10% product (Intragam 10) given at a rate faster than recommended by the manufacturer. While there was a significant increase in the rate of immediate infusion reactions when compared with the previous IVIg preparation (Intragam P), there was no increase in the rate of reactions post infusion. The rate of reactions was within previously reported expectations for other IVIg products. All reactions were minor, requiring no or minimal intervention and few impacted significantly on the quality of life. Despite an active haemovigilance program, minor adverse reactions were generally not reported. Our results suggest that a fast single rate of IVIg infusion is safe, and may minimise patient attendance and hospital resources with acceptable safety. In implementing a strategy to increase IVIg infusion rates an active process to monitor safety is preferred over standard haemovigiliance or pharmacovigilance processes.

Improving patient blood management in obstetrics: snapshots of a practice improvement partnership.

Iron deficiency and anaemia are common in pregnancy. Audit data from our tertiary obstetrics unit demonstrated 22% of maternity patients experiencing a postpartum haemorrhage received a transfusion; a third of whom were anaemic on admission intrapartum. Australian Patient Blood Management (PBM) Module 5 Obstetrics guidelines focuses on maximising red cell mass at the time of delivery and reducing the reliance on transfusion as a salvage therapy to treat blood loss. A clinical practice improvement partnership began in February 2015 and completed in April 2016; which aimed to implement systems to improve antenatal identification and management of iron deficiency, and improve postpartum anaemia management. In order to develop change strategies, reasons for poor detection and correction of iron deficiency in the antenatal period were identified following a quality improvement methodology. Education was delivered to maternity healthcare providers. Standardised algorithms and an oral iron prescription handout were developed and piloted. Follow-up audit, staff and patient feedback, and other hospital data were collected to measure outcomes. The rate of anaemia on admission intrapartum fell from 12.2% in 2013 to 3.6% in 2016 following the introduction of unselective ferritin screening and other antenatal interventions. Sixty to 70% of maternity patients screened each month had iron deficiency. The algorithms aided staff to become confident in blood test interpretation and management of iron deficiency and anaemia. Patients found the oral iron prescription handout helpful. Additionally, single unit transfusions significantly increased from 35.4% to 50% (p=0.037) over the project timeframe. This project demonstrated the potential to improve patient blood management in obstetrics, reduce anaemia and transfusions by active antenatal interventions.

Transfusion demand control strategies: potential efficacy of hospital and regional interventions.

INTRODUCTION: Contingency plans have been developed to direct appropriate responses to blood shortages. Planning requires an understanding of the potential savings of different conservation strategies. METHOD: The Australian Capital Territory (ACT) Haemovigilance and ACT Pathology transfusion databases were reviewed from March to September 2003. All transfusion episodes were prioritised in accordance with the Australian National Blood Supply Contingency Plan. The number of red cell transfusions related to various indications, their appropriateness and acuity was determined. The potential reduction in red cell usage was modelled for potential red cell reduction interventions. RESULTS: There were 2305 units of red cells captured during the timeframes of the audits. This accounted for an estimated 70% of all red cell transfusions in the ACT. After correcting for the number of red cells transfused at each hospital, red cells were prioritised as category 1 in 59%, 2 in 27% and 3 in 13%. The remainder had insufficient data for classification. Transfusion for elective surgery accounted for 14.7% of red cells used, with 9.0% rated category 3 under the contingency plan. There were 17.3% of red cells transfused for inappropriate indications, when reviewed against national guidelines. After excluding inappropriate transfusions, cancelling elective surgery could potentially save a further 5.5% and 4.3% of blood utilisation for category 3 and 2 patients, respectively. Significant differences were found between hospitals. CONCLUSION: Targeting inappropriate transfusions by vetting particularly for inappropriate transfusions not only re-directs blood away from those unlikely to benefit, but is also more effective at preserving the red blood cells than other measures during times of supply limitation. Contingency planning needs to accommodate the variable case-mix in hospitals, allocate resources for transfusion medicine specialists to review every transfusion request and may be better coordinated at a jurisdictional level.

Demonstration of altered fibroblast contractile activity in hypertensive heart disease.

OBJECTIVE: The aim of this study is to investigate the idea that altered fibroblast contractile activity is involved in the pathogenesis of hypertensive heart disease (HHD). METHODS: Cell area and contraction are quantified using the traction force microscopy technique for cardiac fibroblasts isolated from both normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. RESULTS: The data indicate that there are marked phenotypic differences between the two cell types. For instance, WKY fibroblasts exert an average traction stress of approximately 3.3 kPa and have an area of approximately 2640 microm(2). Under identical conditions the SHR fibroblasts have an area approximately 1.45 times larger (p<0.01) and exert an average stress approximately 1.86 times higher (p<0.01). Challenging WKY fibroblasts with 1 micromol/l angiotensin II (Ang II) gradually causes a approximately 2-fold increase in traction after 1 h while simultaneously causing a approximately 28% decrease in area. In contrast, Ang II has no effect on SHR fibroblasts. The data also show that WKY and SHR cells respond in different ways when challenged with irbesartan (Irb). The addition of 1 micromol/l Irb initially causes WKY cells to decrease their average traction output by approximately 50% after approximately 10 min. Subsequently, contractile activity begins to recover and returns to normal after 1 h. The SHR cells also decrease their tractions by approximately 50%, but this decrease requires 30 min for completion and there is no recovery to the initial contractile state. For both cell types, Irb produces no significant effect on area and the combined effect of equimolar Irb and Ang II is the same as Irb alone. CONCLUSION: These in vitro data suggest that among the many factors producing hypertensive heart disease in SHR's are excessive contraction of their cardiac fibroblasts and defective control of fibroblast contraction by Ang II.

Differential integrin expression by cardiac fibroblasts from hypertensive and exercise-trained rat hearts.

The cardiac fibroblast is the principal cell type responsible for extracellular matrix (ECM) synthesis in the heart during growth and pathophysiological conditions. A dynamic interaction exists between the cardiac ECM and fibroblasts that is sensitive to the local mechanical and chemical tissue environment. We propose here that cardiac fibroblasts structurally and functionally adapt to changing local environments by altering their expression of receptor integrins. Changes in the extracellular environment are communicated in part by integrins, which link the ECM to the cell and regulate phenotype and function. In this report, we analyze integrin protein expression, migration and gel contraction by cardiac fibroblasts from rats subjected to 10 weeks of treadmill exercise (XTR), experimental hypertension (HYP) or controls (CONT). Immunoprecipitation shows that beta1 protein increases in XTR and HYP. Also, alpha1 and alpha2 integrins are lower in XTR and HYP, and alpha5 integrin is higher in XTR and lower in HYP. Functional assays show that XTR and HYP migrate slower on collagen, while XTR migrate faster and HYP slower on fibronectin. Cell isolation procedure, population expansion number or a general adaptation to culture conditions does not explain the differences observed. No significant differences in collagen gel contraction are detected. These results indicate that cardiac fibroblasts retain their in vivo patterns in vitro for a limited number of population expansions. This tissue-specific phenotype is exhibited in early passage (< or =6). However, by late passage (>8), cells begin to show adaptation to the in vitro conditions. These results show that cardiac fibroblasts respond to changing environments in pathophysiological conditions by modulating integrin expression, which is associated with changes in cell migration. They also suggest a pragmatic use for primary cardiac fibroblasts as a model to study the cardiac matrix remodeled by physiological (exercise) and pathological (hypertension) stressors.