Discussion
In this systematic review and meta-analysis of observational studies, we found no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD compared with OLNRD of NOACs.
The effect of OLRD of NOACs
Although all point estimates in our meta-analysis lie above 1, indicating a possible harmful effect, it cannot be concluded from our meta-analysis that OLRD of NOACs overall in fact is harmful, not to mention beneficial. However, it should be realised that NOACs differ. First, plasma levels may be more stable for some NOACs than for others due to once daily (rivaroxaban and edoxaban) versus two times daily (dabigatran and apixaban) dosing. Second, NOACs vary in the percentage by which the dose should be reduced (50% for apixaban and edoxaban; 25%–33% for dabigatran and rivaroxaban). Finally, some NOACs have more extensive dose reduction criteria than others, which might suggest that OLNRD of NOACs with more extensive dose reduction criteria is more tailored to the individual patient and that OLRD of these NOACs might cause more harm. This may explain why data in our study suggest a harmful effect of OLRD specifically for apixaban (of the apixaban studies, almost all HRs for stroke/thromboembolism, bleeding and all-cause mortality are above 1). However, we cannot confirm this, because there were not sufficient studies meeting our inclusion criteria for meta-analysis stratified by the four different NOACs.
Comparison with existing literature
In a recent meta-analysis, Caso et al compared OLRD to on-label dosing (ie, both on-label reduced and on-label non-reduced). This showed that OLRD increased the risk of all-cause mortality (HR 1.28 (95% CI 1.10 to 1.49)) with a null effect on major bleeding (HR 1.04 (95% CI 0.90 to 1.19)).18
In another previous meta-analysis, the authors also compared OLRD to, again, on-label dosing and used less stringent inclusion criteria, which allowed them to include more studies and examine each NOAC separately. This showed that OLRD of rivaroxaban may increase the risk of stroke/thromboembolism (HR 1.31 (95% CI 1.05 to 1.63)) compared with on-label dosing of rivaroxaban, whereas OLRD of apixaban may increase the incidence of all-cause mortality (HR 1.21 (95% CI 1.05 to 1.40)) compared with on-label dosing of apixaban. They reported no differences in outcomes when comparing OLRD versus on-label dosing of dabigatran and edoxaban.16
A third meta-analysis combined the four NOACs in their analyses and showed higher risk of stroke/systemic embolism (risk ratio (RR) 1.24 (95% CI 1.14 to 1.35)) without a reduction in bleeding risk (RR 1.18 (95% CI 0.91 to 1.53)) and a higher risk of all-cause mortality (RR 1.58 (95% CI 1.25 to 1.99)) in patients with OLRD compared with on-label dosing. However, this meta-analysis largely lacked measures to prevent confounding. Moreover, it also compared OLRD to on-label dosing (ie, both on-label reduced and on-label non-reduced) instead of comparing OLRD to OLNRD as we did.17
In contrast to these previous studies, we did not find an increased risk for all-cause mortality in patients with OLDR. The most obvious explanation could be the comparison we choose. Unlike previous meta-analyses, we restricted our included studies to those comparing OLRD to OLNRD. This is the most clinically relevant comparison, as it represents the patient groups—those without an indication for dose reduction—in whom clinicians face a dosing dilemma most often.
Strengths and limitations
This selection of studies comparing OLDR only with OLNRD is the major strength of our study. Second, we tried to minimise the influence of confounding by indication as best as possible by including only studies meeting predefined criteria, including applying propensity scoring methods. Finally, we conducted a very comprehensive and thorough search which resulted in a large sample size.
Limitations of our study are: (1) the inclusion of a predominantly Asian population who has shown to have different pharmacokinetics, meaning that our results cannot be generalised on a one-to-one basis to, for example, the Western population; (2) the fact that we could not include enough studies to stratify by NOAC in the meta-analysis; (3) risks of misclassification within studies (eg, when an NOAC dose has been changed by a cardiologist but is not yet recorded in the general practitioner’s file, while the latter has been requested by the study) and significant heterogeneity between studies (eg, in the duration of follow-up (with a median ranging from 4 to 24 months in our meta-analyses)) which is both inherent to using data from observational studies and(4) conducting our research at study level rather than at patient level (as we did not have data on individual patient level).
Clinical implications and areas for future research
Choosing an NOAC dose is all about balancing stroke risk against bleeding risk. Our results indicate that the risk of stroke may not be increased while the risk of bleeding may not be decreased in patients that are prescribed OLRD of NOACs compared with patients with OLNRD of NOACs. This may be considered as an argument to adhere to prescription guidelines in most, if not all, patients. However, our results may also indicate that OLRD of NOACs may not be harmful in specific cases. Physicians, in close discussion with their patients, may use our findings to decide on the treatment regimen in the specific situation of each patient. Future research may focus on these situations and, and perhaps more importantly, on differences between NOACs.
In conclusion, this systematic review and meta-analysis shows that there is no statistically increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs compared with patients with OLNRD of NOACs. Future research may focus on differences between NOACs.