Increased acute care utilisation, comorbidities and mortality in adults with haemophilia: A population-based cohort study from 2012 to 2019.

INTRODUCTION: Improvements in treatment strategies have led to increased life expectancy of persons with haemophilia (PWH). Consequently, age-related comorbidities become increasingly relevant. AIM: To evaluate the prevalence of age-related comorbidities, mortality, health service utilisation and predictors of hospitalisation in PWH compared to the general population. METHODS: We conducted a population-based retrospective cohort study using linked administrative data. Men with haemophilia were identified in Alberta, Canada (2012-2019) with a validated case definition and were age-matched with male population controls. We calculated the prevalence of major comorbidities, all-cause mortality, and examined health service utilisation including Emergency Department visits and hospitalisations. Logistic regression was applied to identify predictors of hospitalisation. RESULTS: We identified 198 and 329 persons with moderately severe haemophilia and mild/moderate, respectively. Moderately severe haemophilia had a higher risk of death (standardised mortality ratio 3.2, 95% confidence interval [CI] 1.4-6.3) compared to the general population. PWH had a significantly higher prevalence of hypertension, liver diseases and malignancies than controls. Moderately severe haemophilia was associated with significantly higher rates of hospitalisations (52.5% vs. 14.5%), Emergency Department visits (89.1% vs. 62.7%) and intensive care admissions (8.9% vs. 2.3%). Age > 65 years (adjusted odds ratio [aOR] 6.8) and presence of multiple comorbidities (aOR 3.9) were significant predictors of hospitalisations among PWH. CONCLUSION: Despite advanced care, haemophilia is associated with higher acute care utilisation than the general population, highlighting the substantial burden of illness on patients and the health care system.

Geographic disparities in the care and outcomes in adult chronic immune thrombocytopenia.

INTRODUCTION: Despite expert-based recommendations, real-world adherence to immune thrombocytopenia (ITP) guidelines is unclear. The impact of geographic and socioeconomic disparities on the quality of care and outcomes is unknown. We sought to determine the association between geographic remoteness and material deprivation on ITP care and outcomes. METHODS: We conducted a multi-centre retrospective cohort study of adults with chronic ITP requiring a second-line therapy between 2012 and 2019 in the province of Alberta, Canada. Socioeconomic status was measured using the Pampalon material deprivation index quintiles. Geographic disparities were assessed by the driving distance to a major centre, with geographic remoteness defined as >200 km from major centre. We examined the impact of geographic and material deprivation on quality of care, resource utilization (hospitalizations, transfusions), and outcomes (major bleeding, all-cause mortality and ITP-related mortality). Cox proportional hazards models were used to examine the impact of geographic remoteness, rural residence and material deprivation on overall survival and ITP-related survival. RESULTS: We included 326 ITP patients, median age of ITP diagnosis was 57 years, 182 (56 %) were female. Most patients (58 %) lived within 20 km of a major centre, whereas 49 (15 %) lived in a geographically remote area (>200 km). Geographic remoteness was significantly associated with material deprivation and lower likelihood of management by hematologists (84 % vs 99 %, P = 0.0001). It was also associated with lower rates of hepatitis C (71 % vs 89 %, P = 0.005) and hepatitis B testing (69 % vs 86 %, P = 0.03), and a non-significant trend towards lower rates of HIV testing (73 % vs 83 %, P = 0.051) compared with those <20 km from a major centre. Incomplete hyposplenic vaccinations among splenectomized patients (52 %), early splenectomy within 12 months of ITP diagnosis (35 %), inappropriate platelet transfusions (41 %), and inappropriate hospitalizations for asymptomatic thrombocytopenia (16 %) were common regardless of geographic distribution. There were 28 (9 %) ITP-related deaths (major bleeding or infections), most occurred within the first year of ITP diagnosis. Material deprivation, but not geographic remoteness, was an independent predictor of all-cause mortality (aHR 1.9, 95 % CI 1.1-3.3 in the most deprived quintile vs least deprived quintile). Rural residence trended towards increased hazard of ITP-related deaths (aHR 1.7, 95 % CI 0.9-3.2). CONCLUSION: We demonstrated substantial deviations of ITP care from consensus guidelines, and geographic disparities in access to care and diagnostic workup. Future quality improvement initiatives are critical to improve the quality of care and reduce inequities.

Treatment patterns and outcomes of second-line rituximab and thrombopoietin receptor agonists in adult immune thrombocytopenia: A Canadian retrospective cohort study.

BACKGROUND: The optimal choice of second-line treatment for immune thrombocytopenia (ITP) is unclear. Guidelines recommend either rituximab, splenectomy, or thrombopoietin receptor agonists (TPO-RA). There is, however, scarce data comparing treatment patterns, outcomes and resource utilization across second-line treatments. Despite Canada's universal healthcare system, publicly funded access to second-line ITP therapies is highly variable across provinces/territories. OBJECTIVES: To describe treatment patterns and compare health service utilization and outcomes among recipients of second-line rituximab and TPO-RA for ITP. METHODS: In this multicentre retrospective cohort study, we included adults who received second-line ITP therapies rituximab, eltrombopag and romiplostim (2012-2020) in Alberta, Canada. Patients were identified through a provincially-funded special drug access (STEDT) program. We examined treatment patterns, predictors of second-line treatment, hospitalizations, blood product utilization, and outcomes. Kaplan-Meier survival curves were used to estimate the cumulative incidence of ITP-related hospitalizations (bleeding or infections), overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to examine the impact of second-line therapy on OS. RESULTS: 223 patients received rituximab (67 %), eltrombopag (29 %), and romiplostim (4 %). TPO-RA recipients experienced significantly longer time from ITP diagnosis to second-line therapy compared with rituximab recipients (15.9 vs 6.7 months, P < 0.0001), accompanied by significantly higher platelet and IVIG utilization prior to second-line therapy. Age (adjusted odds ratio [aOR] 1.04, 95 % CI 1.02-1.07, P < 0.0001) and prior intracranial hemorrhage (aOR 12.7, 95 % CI 1.6-272.8, P = 0.03) were significant predictors of second-line TPO-RA. TPO-RA is associated with a trend towards longer median RFS (6.3 vs 3.8 years, P = 0.06) compared with rituximab, and similar rates of ITP-related hospitalizations, major bleeding, and thromboembolism. Age, time period, and Charlson comorbidity index, but not second-line ITP therapy, were significant predictors of OS. CONCLUSIONS: Our study identified older age and intracranial hemorrhage as predictors of second-line TPO-RA prescription in a real-world practice. There were no significant differences in hospitalizations and outcomes between second-line rituximab and TPO-RA, although delayed initiation of TPO-RA was associated with higher blood product utilization.

Time from suspected thrombotic thrombocytopenic purpura to initiation of plasma exchange and impact on survival: A 10-year provincial retrospective cohort study.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) with significant morbidity and mortality. Guidelines recommend initiating plasma exchange within 4-8 h of suspected diagnosis. It is unclear what are real-world practice patterns and whether delays >8 h increases mortality. OBJECTIVES: To determine if delayed initiation of plasma exchange is associated with increased risk of death and complications. METHODS: In this retrospective cohort study, we evaluated the time from suspected diagnosis to plasma exchange in all adults presenting with suspected TTP to apheresis centres in Alberta, Canada (2008-2018). Among patients with acquired TTP, the association between delayed plasma exchange and risk of death was evaluated using Cox regression. RESULTS: Overall 190 episodes of suspected TTP were included among 163 individuals. Acquired TTP was confirmed in 61 patients. Inappropriate Emergency Department triage occurred in 59%. The median time from suspected diagnosis to first plasma exchange was 10.7 h; 59% had delayed plasma exchange >8 h, among whom plasma infusion was administered in only 45%. 36% of suspected TTP and 13% of confirmed TTP patients died. Delayed plasma exchange between 8 and 24 h was not associated with a significantly higher risk of death (adjusted hazards ratio; aHR 0.63, 95% CI 0.08-4.83) in confirmed TTP. On the other hand, the risks of death (aHR 1.40, 95% CI 0.20-9.79) and major thrombotic events (aHR 2.9, 95% CI 0.6-12.8) were markedly increased with >24 h delay. CONCLUSIONS: Our study demonstrated that TTP care in a real-world setting is discordant with expert guidelines due to multiple barriers. There is a gradient of increased mortality risk and thrombotic complications with longer treatment delays, although the study is likely underpowered.

Validation of the PLASMIC score for predicting ADAMTS13 activity <10% in patients with suspected thrombotic thrombocytopenic purpura in Alberta, Canada.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) that requires prompt plasma exchange. Clinical prediction tools may facilitate decision-making in institutions with delayed turnaround time or limited access to ADAMTS13 assays. The PLASMIC score and Bentley score have been shown to predict severe ADAMTS13 deficiency with excellent sensitivity and specificity. OBJECTIVES: To validate the PLASMIC score using a population of suspected TTP, and evaluate its discriminatory power in predicting severe ADAMTS13 deficiency in comparison with Bentley score and clinical gestalt. METHODS: Adults presenting with suspected TTP in Alberta, Canada between 2008 and 2018 with available ADAMTS13 results were included. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for PLASMIC score, Bentley score and clinical gestalt. Receiver operator characteristics analysis assessed the performance of the scoring systems. RESULTS: Among 163 individuals with suspected TTP, ADAMTS13 activity was available in 117 (72%). Severe ADAMTS13 deficiency <10% was present in 62 (53%). High-risk PLASMIC score (≥6) predicted severe ADAMTS13 deficiency with a sensitivity of 81.7%, specificity 71.4%, PPV 75.4% and NPV 78.4% (c-statistic 0.80). Intermediate-high risk Bentley score (≥20) had a lower sensitivity (59.5%) and higher specificity (93.9%) with similar c-statistic (0.77). Clinical gestalt had similar sensitivity as PLASMIC score but very low specificity (16.1%). CONCLUSIONS: Both PLASMIC and Bentley scores had good discriminatory power in identifying severe ADAMTS13 deficiency in a Canadian TMA population compared to clinical gestalt. Integration into institutional clinical pathways may help supplement clinical judgment and reduce costs.