Discussion
This open, prospective, observational, multicenter study is the first
multicenter study primarily focusing on the potential effect of
β-blockers and ACEI on systemic AE during VIT and the severity of SSR.
It is by far the largest study, with 388 insect-venom-allergic patients
under antihypertensive drugs, and the first study with appropriate
sample size estimation to calculate the patients’ risk. It therefore
provides robust evidence that taking β-blockers or ACEI does not
increase the risk of systemic AE or aggravate sting reactions in
patients with insect venom allergy.
Previously published reports evaluating the influence of β-blockers on
AE have already shown that β-blocker medication was not associated with
a higher prevalence of (more severe) systemic
AE;12,23-25 however, although usually hundreds of
patients were included, the low number of patients under β-blocker
therapy provided only statistically fragile evidence. We could now show
that in 181 patients, taking β-blockers did not increase the risk for
systemic AE, and if AE occurred, they were not more severe.
ACEI also appeared to be safe with VIT25, and although
one small study reported more severe AE in patients taking ACEI, no
significant difference in the number of treatment doses of epinephrine
was observed.26
Another study reported an even lower frequency of AE in patients taking
antihypertensive treatment, although not statistically
significant.27 This is in agreement with our results;
VIT was safe in patients taking ACEI.
Whether β-blockers and ACEI are able to aggravate anaphylaxis is still a
controversial issue. A systematic review and meta-analysis revealed that
evidence of an increased risk of more severe anaphylaxis in patients who
take β-blockers and ACEI was tenuous owing to the heterogeneous control
of confounding variables.28 Importantly, higher age is
an established risk factor for more severe sting
reactions.8-10 Previous data had already suggested
that older patients are more likely to take β-blockers and ACEI and that
older age was the relevant predictor for severe
anaphylaxis16,17 or SSR.9 We were
able to demonstrate in 219 patients taking β-blockers and in 240
patients taking ACEI that higher age, but not taking antihypertensive
drugs, was a major risk factor for severe anaphylaxis.
It was also hypothesized that AE could be refractory to emergency
treatment and that epinephrine may cause paradoxical treatment effects
due to concomitant β-blocker therapy.29 Recent data
suggest that patients with β-blockers do not require increased doses of
epinephrine.30 In our study, epinephrine was rarely
used to treat AE, indicating that VIT was very safe. In detail, in 19
patients, epinephrine was administered to treat low to moderate adverse
reactions. It is, however, important to note that only two patients
taking β-blockers required epinephrine: One had a Grade I reaction and
was taking β-blockers and ACEI, the other had a Grade II reaction and
was only taking a β-blocker. Importantly, these patients tolerated
emergency treatment well and responded quickly. Therefore, the
beneficial effects of β-blockers by far outweigh the hypothetical
negative effects.
Treatment with ACE-inhibitors or β-blockers during VIT was considered as
contraindicated for years; therefore, ACEI and β-blocker therapy was
usually stopped and only maintained in patients with severe
cardiovascular diseases. These highly selective samples of patients may
have biased previous study results. Over recent years, guidelines have
become less restrictive, resulting in more patients taking
antihypertensive drugs with VIT. This may explain why older studies
sometimes reported a higher risk for AE12, while more
recent data suggested that taking ACEI and β-blockers is
safe.25 The situation is similar in terms of the
effectiveness of VIT: While one study reported a higher risk of VIT
failure in a small number of highly selected
patients7, others did not detect such a
risk.27,31 In our study, the effectiveness of VIT was
comparable in patients with or without antihypertensive drugs.
Interestingly, none of the patients who relapsed took ACEI.
Limitations of the study: The number of patients who experienced more
severe AE during VIT requiring epinephrine treatment was very low. Only
two patients taking β-blockers received epinephrine and no conclusion
can be drawn as to whether epinephrine was less effective or caused
paradoxical effects in patients taking β-blockers.
The effect of age on the severity of SSR may have been underestimated in
our study. Only patients aged 35 to 85 years were included because it
was assumed that 24% of this age group would take β-blockers or ACEI.
We still observed an age effect. However, we could not compare severity
of SSR between our age group and younger patients.
Monitoring VIT effectiveness by sting challenge was optional for study
centers and the evaluation was primarily based on the reported outcome
of field stings. Therefore, results should be interpreted with caution,
as patients may not have correctly identified the stinging insect.
This study provides robust evidence that β-blockers and ACEI do not
increase the frequency of systemic AE during VIT. The number of AE was
even lower compared with patients not taking antihypertensive treatment
(5.6% and 7.4%, respectively; OR: 0.74; CI: 0.43–1.22); moreover,
β-blockers and ACEI did not aggravate the severity of insect sting
reactions.