146 CHAPTER 8 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 (e.g. when a 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 (e.g. in the duration of follow-up (with a median ranging from 4 to 24 months in our metaanalyses)) 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 a 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, 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.
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