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.