The role of real-world evidence in health technology assessment: a case study of direct oral anticoagulants in the atrial fibrillation population

Real-World Evidence (RWE) refers to any “data used for decision-making that are not collected in conventional Randomised Controlled Trials (RCTs), and is increasingly used in Health Technology Assessment (HTA) as an adjustment to the evidence coming from Randomised Controlled Trials (RCTs). RWE can provide additional evidence concerning treatment safety and effectiveness, facilitate the identification of relevant subpopulations, and permit the inclusion and analysis of clinical endpoints not expected in RCTs but observed in real life. However, the use RWE in the context of HTA is still limited. The aim of this thesis is to explore the role of RWE in economic evaluation by exploring methods to use with observational data and the role of RWE for a case study of direct oral anticoagulants (DOACs); a class of drugs, including apixaban, dabigatran and rivaroxaban, used for the prevention of stroke in the population affected by atrial fibrillation (AF). In addition to quantifying resource use and associated healthcare expenditure for the AF population in Scotland and evaluating propensity score methods for estimating the Average Treatment Effect (ATE), specific objectives are assessing cost as well as effectiveness and safety of DOACs using Scottish linked data. Two cohorts, one consisting of patients with a diagnosis of AF or atrial flutter, and the other of patients on any oral anticoagulant (OAC) were identified from inpatient hospital records and prescribing data for the 1997 – 2015 study period. These data were complemented by outpatient attendances, the care home census and mortality records using individual patient data linkage. As a first step, this thesis assessed the predictors of costs and estimated inpatient, outpatient, prescribing and care-home costs associated with AF, using population-based individual-level linked data. Inpatient admissions accounted for the majority of total costs and these were the main cost driver across all age groups. Overall, inpatient cost contributions (~75 %) were constant across age groups.. This is offset by increasing care-home cost contributions. The inclusion of all available cost components is crucial for establishing overall costs, as these often extend beyond hospitalisation. Most importantly, the thesis found that patients’ age has a limited impact on overall AF-related cost, and therefore may not be the main driver of future growth of AF-related costs in an ageing Scottish population. In order to identify an appropriate method for the comparative-effectiveness analysis, propensity score (PS) based method, such as PS matching, covariate adjustment including PS as covariate, and a series of Inverse Probability Weighting (IPW) methods were tested. A cohort of patients were followed from their first oral anticoagulant prescription to first clinical event (stroke and major bleeding) or death, and censoring was applied to treatment switching or discontinuation. In this methodological chapter, the approach that uses propensity scores (PS) as a covariate was identified as the most robust method to be used in the more comprehensive comparative-effectiveness analysis. The comparative-effectiveness analysis, including additional clinical outcomes that were also used in the pivotal RCTs assessing the efficacy of DOACs versus warfarin in the AF population, found no statistically significant differences in risk of stroke for apixaban, dabigatran and rivaroxaban compared with warfarin. There were however, concerns over safety aspects of rivaroxaban, as it was associated with increased risk of all-cause mortality. The hazard ratios estimated from the comparative-effectiveness analysis were used to populate a Markov model to evaluate the lifetime cost- effectiveness of DOACs compared to warfarin; one-way and probabilistic sensitivity analyses were carried out to assess the uncertainty around the findings and identify key drivers. At the £20,000 threshold, apixaban and dabigatran were found to be cost-effective in AF patients who are 50 years old when starting anticoagulation. Rivaroxaban, being the least effective intervention, was dominated by warfarin, being less costly but more effective than rivaroxaban. This thesis shows the potential of RWE in general and within the Scottish healthcare setting. The findings highlight the importance of taking into account resource utilisation beyond hospital care, and assessing several comparative-effectiveness methods to understand strengths and limitation of each. Most importantly, the findings from this thesis have the potential to inform future research, prescribing patterns and provide real-world evidence for other healthcare settings, especially where rivaroxaban is the DOAC most widely prescribed. Finally, this thesis shows that RWE generated from routinely collected linked data in Scotland, may well support the reassessment of prescription drugs accepted conditionally by the Scottish Medicine Consortium (SMC), an independent organisation that advises the NHS Health Boards about medicines, and would therefore support the SMC in making the final acceptance decision

Understanding Pathways into Care homes using Data (UnPiCD study) a retrospective cohort study using national linked health and social care data: a retrospective cohort study using national linked health and social care data

Background: Pathways into care are poorly understood but important life events for individuals and their families. UK policy is to avoid moving-in to care homes from acute hospital settings. This assumes that moves from secondary care represent a system failure. However, those moving to care homes from community and hospital settings may be fundamentally different groups, each requiring differing care approaches. Objective: To characterise individuals who move-in to a care home from hospital and compare with those moving-in from the community. Design and setting: A retrospective cohort study using cross-sectoral data linkage of care home data. Methods: We included adults moving-in to care homes between 1/4/13 and 31/3/16, recorded in the Scottish Care Home Census. Care home data were linked to general and psychiatric hospital admissions, community prescribing and mortality records to ascertain comorbidities, significant diagnoses, hospital resource use, polypharmacy and frailty. Multivariate logistic regression identified predictors of moving-in from hospital compared to from community. Results: We included 23,892 individuals moving-in to a care home, 13,564 (56.8%) from hospital and 10,328 (43.2%) from the community. High frailty risk adjusted Odds Ratio (aOR) 5.11 (95% Confidence Interval (CI): 4.60–5.68), hospital discharge with diagnosis of fracture aOR 3.91 (95%CI: 3.41–4.47) or stroke aOR 8.42 (95%CI: 6.90–10.29) were associated with moving-in from hospital. Discharge from in-patient psychiatry was also a highly significant predictor aOR 19.12 (95%CI: 16.26–22.48). Conclusions: Individuals moving-in to care homes directly from hospital are clinically distinct from those from the community. Linkage of cross-sectoral data can allow exploration of pathways into care at scale

The inpatient, outpatient and social care costs associated with atrial fibrillation in Scotland: a record linkage study

ABSTRACT Background Atrial Fibrillation (AF) is a highly debilitating condition with significant economic burden. Previous studies have estimated the cost of hospitalisations associated with AF in Scotland. However, patients with AF are often elderly with co-morbidities requiring substantial outpatient and social care. Objectives This study seeks to estimate inpatient, outpatient and social care costs associated with AF in a Scottish cohort, by using individual-level linked data. Methods The AF cohort of 50 years and older patients, hospitalised with a known diagnosis of AF or atrial flutter between 1997 and 2014, was followed up for five years following the first AF event. Individual-level data on hospitalisation and discharge to social care home were obtained from the Scottish Morbidity Records (SMR01); whereas data on outpatient attendance were obtained from (SMR00). Death records for the same time period were extracted from National Records of Scotland (NRS). Hospital and outpatient costs associated with the corresponding data were estimated utilising the Scottish National Tariff (SNT) based on Healthcare Resource Groups (HRGs), and the Scottish Health Service Costs report, respectively. Social care costs were identified from the Care Home Census. Following data linkage, the econometric analysis was carried out using a two-part model where, the first part estimates through a probit model the probability of using a healthcare service, and the second part estimates costs conditional on having incurred positive costs. The regression model was adjusted for demographic characteristics, socio-economic status, year of admission and location. Results Overall, a cohort of 253,963 AF patients accounted for 2,988,607 hospital admissions and 4,452,476 outpatient attendances. The mean cost per patient was estimated to be £3,071 (95% CI 3,033-3,109). Overall, hospital admissions and outpatient visits accounted for 71.7% and 3.7% of the total cost, respectively; social care accounted for 24.6% of the total costs. The cost increased with age and females incurred higher costs than males. Significant differences were observed among the urban/rural classifications, individual health boards and the socio-economic status. Conclusions This study has shown the importance of taking into account healthcare resource use incurred beyond hospitalisation. In addition to inpatient costs, outpatient and social care costs contribute considerably to the overall economic burden

Propensity score methods for comparative-effectiveness analysis: a case study of direct oral anticoagulants in the atrial fibrillation population

Objective: To explore methodological challenges when using real-world evidence (RWE) to estimate comparative-effectiveness in the context of Health Technology Assessment of direct oral anticoagulants (DOACs) in Scotland. Methods: We used linkage data from the Prescribing Information System (PIS), Scottish Morbidity Records (SMR) and mortality records for newly anticoagulated patients to explore methodological challenges in the use of Propensity score (PS) matching, Inverse Probability Weighting (IPW) and covariate adjustment with PS. Model performance was assessed by standardised difference. Clinical outcomes (stroke and major bleeding) and mortality were compared for all DOACs (including apixaban, dabigatran and rivaroxaban) versus warfarin. Patients were followed for 2 years from first oral anticoagulant prescription to first clinical event or death. Censoring was applied for treatment switching or discontinuation. Results: Overall, a good balance of patients’ covariates was obtained with every PS model tested. IPW was found to be the best performing method in assessing covariate balance when applied to subgroups with relatively large sample sizes (combined-DOACs versus warfarin). With the IPTW-IPCW approach, the treatment effect tends to be larger, but still in line with the treatment effect estimated using other PS methods. Covariate adjustment with PS in the outcome model performed well when applied to subgroups with smaller sample sizes (dabigatran versus warfarin), as this method does not require further reduction of sample size, and trimming or truncation of extreme weights. Conclusion: The choice of adequate PS methods may vary according to the characteristics of the data. If assumptions of unobserved confounding hold, multiple approaches should be identified and tested. PS based methods can be implemented using routinely collected linked data, thus supporting Health Technology decision-making

Risk of grade 3-4 diarrhea and mucositis in colorectal cancer patients receiving anti-EGFR monoclonal antibodies regimens: A meta-analysis of 18 randomized controlled clinical trials

The anti-Epidermal Growth Factor Receptor monoclonal antibodies (anti-EGFR MoAbs) are beneficial in the treatment of wild type (WT) KRAS colorectal cancer, but are burdened by serious toxicities. We conducted a systematic review and meta-analysis to determine incidence and relative risk (RR) of severe and life-threatening diarrhoea and mucositis in colorectal cancer patients and WT-KRAS subpopulation. PubMed and Embase were searched for trials comparing the same therapeutic regimens with or without anti-EGFR for colorectal cancer. Data on severe and life-threatening diarrhoea and mucositis were extracted from 18 studies involving 13,382 patients. Statistical analyses calculated incidence of AEs, RRs and 95% confidence intervals by using either random or fixed effects models. Patients receiving anti-EGFR MoAbs showed an increased risk of diarrhoea (RR: 1.66, CI 1.52–1.80) and mucositis (RR: 3.44, CI 2.66–4.44). The risk was similar among WT-KRAS patients. Prevention and risk reduction strategies of these AEs are mandatory to optimize clinical outcomes

How least developed to lower-middle income countries use health technology assessment: a scoping review

Health Technology Assessment (HTA) is a multidisciplinary tool to inform healthcare decision-making. HTA has been implemented in high-income countries (HIC) for several decades but has only recently seen a growing investment in low- and middle-income countries. A scoping review was undertaken to define and compare the role of HTA in least developed and lower middle-income countries (LLMIC). MEDLINE and EMBASE databases were searched from January 2015 to August 2021. A matrix comprising categories on HTA objectives, methods, geographies, and partnerships was used for data extraction and synthesis to present our findings. The review identified 50 relevant articles. The matrix was populated and sub-divided into further categories as appropriate. We highlight topical aspects of HTA, including initiatives to overcome well-documented challenges around data and capacity development, and identify gaps in the research for consideration. Those areas we found to be under-studied or under-utilized included disinvestment, early HTA/implementation, system-level interventions, and cross-sectoral partnerships. We consider broad practical implications for decision-makers and researchers aiming to achieve greater interconnectedness between HTA and health systems and generate recommendations that LLMIC can use for HTA implementation. Whilst HIC may have led the way, LLMIC are increasingly beginning to develop HTA processes to assist in their healthcare decision-making. This review provides a forward-looking model that LLMIC can point to as a reference for their own implementation. We hope this can be seen as timely and useful contributions to optimize the impact of HTA in an era of investment and expansion and to encourage debate and implementation