Undertaking multi-centre randomised controlled trials in primary care: learnings and recommendations from the PULsE-AI trial researchers.

BACKGROUND: Conducting effective and translational research can be challenging and few trials undertake formal reflection exercises and disseminate learnings from them. Following completion of our multicentre randomised controlled trial, which was impacted by the COVID-19 pandemic, we sought to reflect on our experiences and share our thoughts on challenges, lessons learned, and recommendations for researchers undertaking or considering research in primary care. METHODS: Researchers involved in the Prediction of Undiagnosed atriaL fibrillation using a machinE learning AlgorIthm (PULsE-AI) trial, conducted in England from June 2019 to February 2021 were invited to participate in a qualitative reflection exercise. Members of the Trial Steering Committee (TSC) were invited to attend a semi-structured focus group session, Principal Investigators and their research teams at practices involved in the trial were invited to participate in a semi-structured interview. Following transcription, reflexive thematic analysis was undertaken based on pre-specified themes of recruitment, challenges, lessons learned, and recommendations that formed the structure of the focus group/interview sessions, whilst also allowing the exploration of new themes that emerged from the data. RESULTS: Eight of 14 members of the TSC, and one of six practices involved in the trial participated in the reflection exercise. Recruitment was highlighted as a major challenge encountered by trial researchers, even prior to disruption due to the COVID-19 pandemic. Researchers also commented on themes such as the need to consider incentivisation, and challenges associated with using technology in trials, especially in older age groups. CONCLUSIONS: Undertaking a formal reflection exercise following the completion of the PULsE-AI trial enabled us to review experiences encountered whilst undertaking a prospective randomised trial in primary care. In sharing our learnings, we hope to support other clinicians undertaking research in primary care to ensure that future trials are of optimal value for furthering knowledge, streamlining pathways, and benefitting patients.

Detecting transthyretin amyloid cardiomyopathy (ATTR-CM) using machine learning: an evaluation of the performance of an algorithm in a UK setting.

OBJECTIVE: The aim of this study was to evaluate the potential real-world application of a machine learning (ML) algorithm, developed and trained on heart failure (HF) cohorts in the USA, to detect patients with undiagnosed wild type cardiac amyloidosis (ATTRwt) in the UK. DESIGN: In this retrospective observational study, anonymised, linked primary and secondary care data (Clinical Practice Research Datalink GOLD and Hospital Episode Statistics, respectively, were used to identify patients diagnosed with HF between 2009 and 2018 in the UK. International Classification of Diseases (ICD)-10 clinical modification codes were matched to equivalent Read (primary care) and ICD-10 WHO (secondary care) diagnosis codes used in the UK. In the absence of specific Read or ICD-10 WHO codes for ATTRwt, two proxy case definitions (definitive and possible cases) based on the degree of confidence that the contributing codes defined true ATTRwt cases were created using ML. PRIMARY OUTCOME MEASURE: Algorithm performance was evaluated primarily using the area under the receiver operating curve (AUROC) by comparing the actual versus algorithm predicted case definitions at varying sensitivities and specificities. RESULTS: The algorithm demonstrated strongest predictive ability when a combination of primary care and secondary care data were used (AUROC: 0.84 in definitive cohort and 0.86 in possible cohort). For primary care or secondary care data alone, performance ranged from 0.68 to 0.78. CONCLUSION: The ML algorithm, despite being developed in a US population, was effective at identifying patients that may have ATTRwt in a UK setting. Its potential use in research and clinical care to aid identification of patients with undiagnosed ATTRwt, possibly enabling earlier diagnosis in the disease pathway, should be investigated.

Identification of undiagnosed atrial fibrillation using a machine learning risk prediction algorithm and diagnostic testing (PULsE-AI) in primary care: cost-effectiveness of a screening strategy evaluated in a randomized controlled trial in England.

OBJECTIVE: The PULsE-AI trial sought to determine the effectiveness of a screening strategy that included a machine learning risk prediction algorithm in conjunction with diagnostic testing for identification of undiagnosed atrial fibrillation (AF) in primary care. This study aimed to evaluate the cost-effectiveness of implementing the screening strategy in a real-world setting. METHODS: Data from the PULsE-AI trial - a prospective, randomized, controlled trial conducted across six general practices in England from June 2019 to February 2021 - were used to inform a cost-effectiveness analysis that included a hybrid screening decision tree and Markov AF disease progression model. Model outcomes were reported at both individual- and population-level (estimated UK population ≥30 years of age at high-risk of undiagnosed AF) and included number of patients screened, number of AF cases identified, mean total and incremental costs (screening, events, treatment), quality-adjusted-life-years (QALYs), and incremental cost-effectiveness ratio (ICER). RESULTS: The screening strategy was estimated to result in 45,493 new diagnoses of AF across the high-risk population in the UK (3.3 million), and an estimated additional 14,004 lifetime diagnoses compared with routine care only. Per-patient costs for high-risk individuals who underwent the screening strategy were estimated at £1,985 (vs £1,888 for individuals receiving routine care only). At a population-level, the screening strategy was associated with a cost increase of approximately £322 million and an increase of 81,000 QALYs. The screening strategy demonstrated cost-effectiveness versus routine care only at an accepted ICER threshold of £20,000 per QALY-gained, with an ICER of £3,994/QALY. CONCLUSIONS: Compared with routine care only, it is cost-effective to target individuals at high risk of undiagnosed AF, through an AF risk prediction algorithm, who should then undergo diagnostic testing. This AF risk prediction algorithm can reduce the number of patients needed to be screened to identify undiagnosed AF, thus alleviating primary care burden.

Identification of undiagnosed atrial fibrillation using a machine learning risk-prediction algorithm and diagnostic testing (PULsE-AI) in primary care: a multi-centre randomized controlled trial in England.

Aims: The aim of the PULsE-AI trial was to assess the effectiveness of a machine learning risk-prediction algorithm in conjunction with diagnostic testing for identifying undiagnosed atrial fibrillation (AF) in primary care in England. Methods and results: Eligible participants (aged ≥30 years without AF diagnosis; n = 23 745) from six general practices in England were randomized into intervention and control arms. Intervention arm participants, identified by the algorithm as high risk of undiagnosed AF (n = 944), were invited for diagnostic testing (n = 256 consented); those who did not accept the invitation, and all control arm participants, were managed routinely. The primary endpoint was the proportion of AF, atrial flutter, and fast atrial tachycardia diagnoses during the trial (June 2019-February 2021) in high-risk participants. Atrial fibrillation and related arrhythmias were diagnosed in 5.63% and 4.93% of high-risk participants in intervention and control arms, respectively {odds ratio (OR) [95% confidence interval (CI)]: 1.15 (0.77-1.73), P = 0.486}. Among intervention arm participants who underwent diagnostic testing (28.1%), 9.41% received AF and related arrhythmia diagnoses [vs. 4.93% (control); OR (95% CI): 2.24 (1.31-3.73), P = 0.003]. Conclusion: The AF risk-prediction algorithm accurately identified high-risk participants in both arms. While the proportions of AF and related arrhythmia diagnoses were not significantly different between high-risk arms, intervention arm participants who underwent diagnostic testing were twice as likely to receive arrhythmia diagnoses compared with routine care. The algorithm could be a valuable tool to select primary care groups at high risk of undiagnosed AF who may benefit from diagnostic testing.

Costs and Healthcare Resource Use Associated with Risk of Cardiovascular Morbidity in Patients with Chronic Kidney Disease: Evidence from a Systematic Literature Review.

INTRODUCTION: The management of chronic kidney disease (CKD) costs in excess of $114 billion in the USA and £1.45 billion in the UK annually and is projected to increase alongside the increasing disease prevalence. The aim of this review was to evaluate the risks of cardiovascular (CV) morbidity, CV mortality or all-cause mortality based on KDIGO (Kidney Disease: Improving Global Outcomes) 2012 categorisations and estimate the additional costs and healthcare resource utilisation associated with CV morbidity linked to CKD severity in US and UK settings. METHODS: A systematic literature review was conducted of studies reporting on the risk of CV morbidity, CV mortality or all-cause mortality characterised by CKD severity (published between January 2000 and September 2018). Additional costs and bed days associated with CKD severity in the USA and UK were estimated on the basis of median hazard ratios for CV morbidity risk at each CKD and albuminuria stage. RESULTS: Twenty-nine studies reported risk of adverse clinical outcomes based on KDIGO categorisations. Compared to stage 1 (or without) CKD, patients with stage 5 CKD and macroalbuminuria experienced a relative risk increase of 11.77-12.46 across all outcomes. Additional costs and bed days associated with stage 5 CKD and macroalbuminuria (versus stage 1 (or without) CKD) per 1000 patient years were US$3.93 million and 803 bed days and £435,000 and 1017 bed days, in the USA and UK, respectively. CONCLUSION: Risks of adverse clinical outcomes increase with CKD and albuminuria severity and are associated with substantial additional costs and resource utilisation. Thus, early diagnosis and proactive management of CKD and its complications should be a priority for healthcare providers to alleviate the burden of CV morbidity and its management on healthcare resources.