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.