BackgroundAtrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major risk factor for ischaemic stroke. Anticoagulation reduces the risk of stroke in older people with AF, but it is also associated with an increased risk of bleeding. Historically, warfarin was the main oral anticoagulant available but was under-utilised in older people due to concerns about applicability of the trials to older people, perceived elevated bleeding risk, complex dosing regimens and multiple drug and food interactions. Direct oral anticoagulants (DOACs), which were shown to be non-inferior to warfarin in preventing stroke and associated with a lower risk of intracranial haemorrhage, have provided an alternative option since being licensed in the UK in 2012. DOACs offered potential advantages over warfarin due to their fixed dosing regimens and limited drug interactions. However, older people were under-represented in the pivotal DOAC trials and clinicians have continued to express concern over the applicability of their findings and risks of anticoagulation in older people. To help guide clinicians' and patients' decision-making, robust, applicable evidence of the safety and effectiveness of anticoagulants in older people was needed.AimThe aim of this PhD was to evaluate the prescribing, effectiveness, and safety of DOACs for older people with AF. The objectives were to evaluate the evidence comparing DOACs with warfarin when prescribed for stroke prevention in patientsaged ≥75 years in clinical practice, to investigate changes in anticoagulant prescribing following the introduction of DOACs, and to compare the safety and effectiveness of DOACs with warfarin in older people.MethodsThis thesis comprises three empirical elements, including a:• Systematic review and meta-analyses• Retrospective cohort study of anticoagulant utilisation• Retrospective cohort study comparing effectiveness and safety outcomes between warfarin, DOACs, and non-exposed periodsFor the systematic review, searches were conducted using Medline, Embase, Scopus, and Web of Science from 1/1/2009 to 3/1/2018. Studies were eligible for inclusion if they compared a DOAC with a vitamin K antagonist, and presented outcome data for participants aged 75 years and over with atrial fibrillation. Quality assessment of the included studies was conducted independently by two reviewers using a modifed Newcastle-Ottawa scale. Adjusted hazard ratios and their 95% confidence intervals were pooled in the meta-analyses using both fixed and random effects models. The searches were run again in 2022 to identify additional studies published from 2018 onwards, these were not incorporated into the meta-analysis as this had already been published but were reviewed for quality.Both cohort studies used data extracted from the Clinical Practice Research Datalink (CPRD). The CPRD contains anonymised electronic primary care health record data for approximately 7% of the UK population. Clinical data, including: diagnoses,test results and referral data were extracted for patients aged ≥75 years with AF. Prescription data was also extracted to estimate anticoagulant exposure and to account for the confounding effect of concomitant medications.ResultsSystematic review and meta-analysesDOACs were as effective as warfarin in preventing stroke (Hazard Ratio (HR) 0.86, 95% Confidence Interval (CI) 0.75-0.99), they were associated with a lower risk of intracranial haemorrhage (HR 0.56, 95% CI 0.48-0.67), but a higher risk ofgastrointestinal bleeding (HR 1.46, 95% CI 1.31-1.63). No significant difference in major bleeding (HR 0.96, 95% CI 0.84-1.09) or mortality (HR 0.92, 95% CI 0.77-1.10) was observed. The 22 included studies were not designed specifically to study outcomes in older people and several methodological limitations were identified. The repeated search identified a further 16 studies comparing DOACs with warfarin in people aged ≥75 with AF, however, most exhibited the same limitations identified in the original studies.Anticoagulant utilisationRates of anticoagulant prescribing to older people increased following the introduction of DOACs. Anticoagulants, however, remained less likely to be prescribed to the oldest-old, patients with dementia, and those with a history of falls. Patients aged ≥90 years were 40% less likely (Risk difference (RD) -0.4, 95% CI -0.41 to -0.39) to be prescribed an anticoagulant than those aged 75-79 years. People with dementia and those with a history of falls were 34% (RD -0.34, 95% CI -0.35 to -0.33) and 17% (-0.17, 95% CI -0.18 to -0.16) respectively less likely to receive an anticoagulant compared with patients without these co-morbidities. These differences persisted following the introduction of DOACs.Effectiveness and safety outcomesDOACs as a group were not significantly different to warfarin in terms of effectiveness or safety, bar a marginal increase in the risk of gastrointestinal bleeding (HR 1.19, 95% CI 1.03-1.38). However, the analyses of individual DOACs showed differences in safety outcomes. Apixaban was associated with a lower risk of non-major bleeding (HR 0.73, 95% CI 0.64-0.85) than warfarin. The risks of major (HR 0.84, 95% CI 0.69-1.01) and gastrointestinal bleeding (HR 0.84, 95% CI 0.68-1.05) were lower with apixaban than warfarin but did not reach statistical significance. Rivaroxaban was associated with a higher risk of major (HR 1.34, 95% CI 1.15-1.55), non-major (HR1.29, 95% CI 1.16-1.44), and gastrointestinal (HR 1.46, 95% CI 1.23-1.73) bleeding than warfarin. These results suggest that the choice of DOAC could be important depending on individual patient risk. Periods where patients were not exposed to anticoagulation were associated with a substantially elevated risk of stroke (HR 3.08, 95% CI 2.38-3.99), myocardial infarction (HR 1.93, 95% CI 1.38-2.70), and death (HR 3.54, 95% CI 3.22-3.89), highlighting the risks of stopping anticoagulation treatment in older patients.ConclusionsReassuringly, DOACs as a whole appear to have similar levels of safety and effectiveness as warfarin. However, these data show that safety outcomes differ between DOACs and that periods without anticoagulation carry significant risk of ischaemic events. These findings have important implications for clinical practice, policy, and future research. Clinicians should be reassured that DOACs are a safe and effective treatment. Guideline authors should take note of these findings and consider whether the evidence base is now sufficient to recommend individual DOACs rather than DOACs as a class. Future research should evaluate the safety and effectiveness of anticoagulation in groups where anticoagulation is still under-utilised due to the perceived higher risk of bleeding, such as the oldest old, and those with a history of falls, frailty or dementia.
|Date of Award||22 Jun 2022|
|Sponsors||Dunhill Medical Trust|
|Supervisor||Anita McGrogan (Supervisor), Margaret Watson (Supervisor) & Tomas James Welsh (Supervisor)|