4 Discussion
We present the first systematic review and meta-analysis of subgroups of epistaxis patients taking OACs by means of data analysis of 466 DOAC and 924 VKA patients. According to our findings, DOAC epistaxis patients appear to have a more favourable outcome when compared to VKA epistaxis patients because they spend notably less time in hospital and have significantly less posterior epistaxis, which is more difficult to control. The heterogeneity and bias of the data used was low, allowing for a pooled analysis.
In order to compare the hospital dynamics and evaluate the disease severity of the two groups of patients, we extracted data from eight included studies with regard to the number of days spent in hospital, the rates of posterior epistaxis, the admission rates for stationary treatment, the intervention rates (including surgery and embolization), and recurrence rates. These indicators were chosen in accordance with the applicable general epistaxis guidelines in the United Kingdom1 and United States4 as well as the epistaxis guidelines applicable in France for patients taking OACs 2. In relation to OAC patients, the guidelines underline the fact that epistaxis patients have a less favourable outcome when taking OACs25, however no comparisons between DOAC and VKA subgroups of patients are noted, strengthening the need for our meta-analysis.
After performing the meta-analysis, statistically significant differences were found for pooled values of days spent in hospital and the rate of posterior epistaxis: all other listed investigated criteria showed no statistically significant differences. All results in this meta-analysis were dichotomous with exception of posterior epistaxis where all the analysed studies demonstrated more posterior epistaxis in VKA patients. This fact caught our attention and led us to search for an understanding and an explanation.
The general rate of posterior epistaxis is 5 – 10%26. It is more common in older patients and is more difficult to control than anterior epistaxis1. The rates of posterior epistaxis in DOAC patients in the included studies were very low with 2 studies reporting an absence of posterior epistaxis in the DOAC group8,13, whereas 4 out of 6 studies reported a posterior epistaxis rate of > 10% in the VKA group of patients. The included studies did not demonstrate a significantly advanced age in the VKA group thus eliminating this factor as an explanation for the discrepancy. One possible explanation is that DOACs and VKAs have different mechanisms of action with respect to the expression of tissue factor (TF) in nasal mucosa and nasal blood vessels adventitia. TF is a coagulation cofactor present on the plasma membrane of certain cells not in circulating blood and its expression is tissue dependent27. Evidence suggests that the upregulation of TF expression in epithelial mucosa as well as varying TF expressions in the blood vessel adventitia are dependent on vessel calibre27. Bearing in mind that posterior epistaxis occurs mostly on the postero-lateral aspect of the middle and inferior turbinate and/or meatus whilst anterior epistaxis occurs in the area of the Kiesselbachii’s plexus28, we speculate that there is a difference in TF expression in these two areas.
Kawabori et al. investigated patterns of intracerebral haemorrhaging in patients taking OACs and did not find a difference in the bleeding site between DOAC and VKA patients. However blood volume was significantly lower in the DOAC group29. In this study, no specific brain vessel was identified as predestined to cause bleeding in the DOAC cohort, contrary to the findings of our meta-analysis of epistaxis. It is interesting to note that the significantly higher rate of posterior epistaxis in the VKA group did not translate into a significantly higher rate of interventions, including operations and/or embolizations.
A possible explanation of the worse outcome in VKA patients could be an inappropriate medication intake. With respect to the papers analysed in the meta-analysis, we were able to extract data on the INR values of VKA patients from 5 of the 8 analysed papers. The reported INR values were generally in the therapeutic range of 2.6 - 37,13,20,22,23. However, Glikson and Send reported that up to one third of their VKA patients were out of their therapeutic INR range20,22. The rate of VKA discontinuation was up to 61% in one study13. Various studies demonstrated a strong connection between out-of-range INR and major bleeding events30,31. The need for INR monitoring could to some extent be a reasonable explanation for the longer hospital stays in the VKA group.
The recurrence rates found in this meta-analysis were high in both groups, ranging from 10 – 35%, and with no significant inter-group difference. It is important to identify strategies to avoid recurrence, bearing in mind the age and comorbidities of the patients. The CH2ADS2-VASc is the favoured risk stratification score for atrial fibrillation patients. A correlation between the CH2ADS2-VASc Score and epistaxis recurrence has been shown. Furthermore, when the CH2ADS2-VASc Score reaches or surpasses 7, the recurrence probability surpasses 50% in OAC epistaxis patients13. A recent study demonstrated that after the implementation of an education plan there were significantly less emergency department visits by epistaxis patients taking warfarin32. Such strategies should also be considered in DOAC patients. In addition, non-medical alternatives to OACs for patients with atrial fibrillation, such as percutaneous closure of the left atrial appendage (LAA), should be examined33. This alternative should be carefully considered after consultation with cardiologists, especially in patients with a CH2ADS2-VASc Score ≥ 7.
Future prospective studies are needed to verify the results of this meta-analysis. In addition, a more accurate understanding of the tendency toward anterior epistaxis in DOAC patients as well as a correlation between out-of-range INR and disease severity is needed.
This study has several limitations that are noteworthy: First of all, we were only able to include 8 studies in the meta-analysis, which could be explained by the fact that DOACs have only been available for a decade. All 8 studies were retrospective and therefore subject to potential bias. We accessed bias according to the MINORS Score and the average value was 14.4, whilst the maximum result was 24. Not all studies reported all of the criteria we sought to investigate and as a result the meta-analysis pro criteria included 5 to 7 studies. Additionally, we cannot guarantee the validity of the results reported, thus possibly affecting the final synthesis.