Discussion
This systematic review found that seven papers were suitable for meta-analysis with most addressing correct DOAC dosing and the remainder focusing on DOAC adherence. There were no papers to compare persistence. Despite an abundance of publications on the use of DOACs in AF, there is a lack of data currently available in the context of AF and CKD.
Correct DOAC dosing
Our analysis shows that 68% of patients with correct DOAC dosing is in line with other studies for overall correct DOAC dosing in AF.37 48 This has increased since the DOACs was initially introduced. Most systematic literature reviews in this area have focused on risk of bleeding and stroke38–40 on the assumption that real-world DOAC dosing mirrors the adherence and persistence typical of clinical trials. This is the first systematic literature review and meta-analysis which is specific to DOAC monitoring in CKD and AF. It was not possible to do subanalysis of the various dosing structures of standard and low doses of each DOAC as the studies did not divide it according to CKD groups 3–4 which covers the overarching grouping of CKD for which DOACs are licensed; the lower doses will generally be in those with CKD; some may be in those without CKD if they are older or have low body weights as in the case of apixaban according to guidelines. There were too few studies available to assess correct dosing by individual drug.
Adherence
The DOAC adherence was suboptimal but similar to other studies with AF overall.33 41 49 However, this is much lower than other chronic disease medications.50 Very few studies had adherence at CKD level and hence limited data is available. However, the findings of Shore et al34 showed good adherence to dabigatran.34 This was done very early on in 2014 when DOACs had recently been introduced, and hence patients may have been seen more often which increased adherence. In addition, the numbers of patients involved on dabigatran with CKD are much less due to stringent guidelines with respect to creatinine clearance. Eighty per cent to 85% of dabigatran is excreted by the kidneys via glomerular filtration, and hence it can only be used in moderate renal impairment unlike the factor Xa inhibitors (apixaban, rivaroxaban and edoxaban). There were no adequate studies on adherence in CKD and AF as we only had two studies to show a link between non-adherence and worsening kidney disease.
Adherence with two times per day dosing regimens is assumed to be lower than with once per day regimens in real-world settings and in patients with a high pill burden. Conversely, two times per day dosing is expected to deliver a more stable anticoagulant effect over the course of 24 hours. A meta-analysis of the four key efficacy RCTs of DOAC in AF revealed that two times per day dosing provided a better benefit–risk equation than once per day dosing. The economic impact of non-adherence is well documented with significantly higher annual adjusted per-patient medical costs (inpatient and outpatient).43
We found no associations between adherence and any determinants. Although it has been shown in other studies that increasing comorbidity (by CHA2DS2VASc) was associated with decreased likelihood of non-adherence.33 41 Age ≥75 years, diabetes, female gender and anaemia were also associated with reduced risk of non-adherence, while hypertension and vascular disease were associated with increased risk. Adherence was non-linearly associated with time since the introduction of DOACs, increasing for approximately 2 years (to early 2013) before starting to decrease, returning to its original level by early 2015 and then dropping below its original level.
Persistence
Beshir et al36 and Banerjee et al33 differed on the documentation of what persistence was with the former deeming individuals to be persistent if no gaps of >90 days appear in the prescription history in the year following the index date while the latter felt it was >60 days following the index date. Thus, only qualitative analysis was possible. The limited findings in both studies were consistent with those of other studies in AF overall that showed persistence in DOACs to be better than VKAs.30 32
Dhamane et al35 also deemed patients persistent with no gaps >60 days and said non-persistence was affected by CKD with HR 1.02 but no further details were given.35
Further analysis at drug level was not possible overall for comparison but Banerjee et al33 reported a higher risk of non-persistence among dabigatran users than rivaroxaban and warfarin users. The two times per day dosing of dabigatran was thought to be a possible explanation for these observations. However, patients receiving apixaban, which also has a two times per day dosing regimen, had a lower risk of non-persistence than those receiving rivaroxaban and warfarin. This suggests that factors other than the dosing regimen play a major role in the lower persistence associated with dabigatran.
No studies have shown the determinants of persistence in CKD and AF. However, in just AF, heart failure, vascular disease, CKD, prior bleeding and alcohol misuse were associated with increased risk of non-persistence, while hypertension and age >65 years were associated with reduced risk.33 41 Although the persistence rate of DOACs was higher than VKA, suboptimal persistence with DOAC therapy remains a great concern for patients with AF and CKD.
Limitations and strengths
Our study has several strengths. There is a high level of congruence between our findings and those reported in the existing literature. This is a timely systematic review that synthesises the evidence on extent of poor adherence to oral anticoagulants, its determinants, and clinical and economic outcomes, among patients with AF and CKD. We focused on mainly observational studies to evaluate the evidence on patients’ real-world medication-taking behaviour. We considered all oral anticoagulants, including the newer drugs (apixaban, rivaroxaban, dabigatran and edoxaban), and aimed to generate pooled adherence at the individual drug level.
Our study also had some limitations. First and foremost, there were very few studies specifically on combined CKD, AF and DOAC. Second, there was heterogeneity of the included studies, possibly due to variations in definitions of adherence, small numbers, as well as follow-up durations. We tried to conduct subgroup analyses to pool the same definitions, however, residual heterogeneity persisted. Third, there was no universal tool available to assess the risk of bias for systematic reviews of observational studies. We used the Newcastle-Ottawa Scale, a commonly used tool, however, due to the similar methodology for our included studies; this tool did not differentiate between study quality and rated all included studies at the level of good quality. Finally, the included studies used scripts prescribed than dispensed, which does not necessarily mean they were taken. It is therefore possible that adherence and persistence rates are even lower than from the papers.