Introduction: Atrial fibrillation (AF) increases the risk of stroke by up to five-fold and costs the UK economy £2 billion per year. Direct-acting oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) are offered to eligible individuals to reduce their thromboembolic risk, yet are not suitable for all patients, for instance due to significant drug–drug interactions. Off-label use of subcutaneous low molecular weight heparins (LMWHs) may constitute an alternative option for stroke prevention in such patients. The aim of this systematic review was to ascertain whether or not the monotherapy of existing LMWHs was as safe and effective in the prevention of stroke in adult patients with AF compared to DOACs or VKAs.
Methods: The study was conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (protocol reference: CRD42022378257). Literature searches were carried out on MEDLINE and Embase in November 2022. Longitudinal studies reported in English were included if they investigated the safety and/or effectiveness of LMWHs compared to DOACs or VKAs for the prevention of stroke in participants with AF aged ≥18 years. Study characteristics and clinical outcomes (risk of stroke/transient ischaemic attack [TIA]/systemic embolic events [SEEs], all-cause mortality and major bleeding) were extracted and analysed in Microsoft Excel using descriptive statistics. Study quality was assessed using the Newcastle-Ottawa scale for observational studies.
Results: Seven eligible studies involving 3,145 participants (3 prospective cohorts; 49.6% female) were included in the review. Of these studies, 3/7 involved patients with active cancer, and 1/7 involved either patients with a COVID-19 infection, those receiving haemodialysis, older persons or stroke survivors, respectively. A total of 790/3,145 (25.1%) participants were given LMWH monotherapy (506/790 [64.1%] were prescribed a therapeutic dose). Stroke/TIA/SEEs were an outcome in 5/7 studies, whereas major bleeding and all-cause mortality were reported by 7/7 and 3/7 manuscripts, respectively. In patients with active cancer, LMWHs were associated with a seven-fold greater risk of stroke/SEEs compared to DOACs. LMWH were also associated with a two-fold increased risk of recurrent strokes/TIAs and major bleeding compared to DOACs or VKAs post-acute stroke. There was a non-significant trend towards increased risk of bleeding with LMWH compared to DOACs or VKAs in all other studies. One study reported a 1.5-fold greater mortality amongst active cancer patients prescribed LMWH compared to those receiving DOACs.
Conclusions/Implications: Data presented here does not support routine use of LMWH for stroke prevention AF, however are limited by heterogeneity of studies retrieved. LMWHs were associated with increased risk of major bleeding compared to either DOACs or VKAs, although this trend was only significant in stroke survivors. Several studies highlighted the inferiority of LMWH monotherapy compared to oral anticoagulants with regards to stroke/TIA/SEEs and all-cause mortality outcomes. Future studies should consider exploring the effects of varying LMWH doses on clinical outcomes in AF, particularly amongst specific population groups that may benefit from them as an alternative option. ❑
