The present results are among the first published findings on the topic of STP under LTP and prodromal symptoms under LTP in patients with bradykinin-mediated angioedema. The authors are aware of two other studies by colleagues from Berlin, Germany and Milan, Italy on the topic of STP under LTP with lanadelumab [10, 11]. The study from Milan involved only dental prodecures. No publications are currently available on the evaluation of prodromal symptoms under LTP. Both topics directly affect the daily management recommendations for patients with HAE or AAE.

One point for discussion is the chosen methodology. Ideally, a prospective, randomized evaluation would be advantageous but is hardly feasible for ethical reasons. The number of included patients must be considered in the context of the low incidence of this rare disease - it is estimated that 1,500 to 2,000 patients in Germany are diagnosed with HAE. One of the two studies to date on STP under LTP is the real-life evaluation of patients on LTP with lanadelumab by Buttgereit and colleagues from Charité Berlin, which evaluated data from 22 patients for this question [11]. A retrospective Italian study published by Zanichelli and colleagues analyzed 20 HAE and AAE patients with a total of 75 dental and oral procedures: 27 procedures were preceded by STP only, 13 were performed in patients regularly taking LTP without STP, 33 procedures were under both LTP and STP, and two procedures took place without either STP or LTP. Two attacks were reported: one in an HAE patient without any treatment and one in an AAE-C1INH patient without LTP but with prior STP [10]. In the present study, it was also the AAE-C1INH-patient who suffered from the only laryngeal attack after surgery with intubation, although STP was given. Since it is known that in AAE-C1INH patients the catabolism of C1INH is faster, these patients seem to have an increased risk of developing post-interventional edema and should therefore take STP (which is off-label in AAE) and be supervised afterwards accordingly.

As already mentioned, one patient with AAE-C1INH and two patients with HAE-nC1INH with confirmed mutations were also included in the present analysis. This inclusion can be debated, as the clinical courses of AAE-C1INH and HAE-C1INH, as well as HAE-nC1INH and HAE-C1INH, show clear differences. Additionally, the therapy for AAE-C1INH and HAE-nC1INH is off-label. However, since all patients and disease patterns showed a good response (defined as positive results in AECT, AE-QoL and reduced frequency of HAE attacks) to LTP and breakthrough attacks can occur under therapy in all three disease patterns, it was decided to include these patients in the evaluation. This approach is consistent with the Berlin evaluation by Buttgereit et al. and the Milan evaluation by Zanichelli et al. [11].

The topic of a new definition of prodromal symptoms under LTP is a newly discussed issue at congresses on bradykinin-mediated angioedema. In principle, attacks in HAE patients should be treated as early as possible, as the pharmacokinetics of the medications result in a better therapeutic response with earlier treatment. In the present evaluation, the frequency and intensity of prodromal symptoms was in most of the patients significantly reduced under LTP, although the nature of the symptoms remained the same. Approximately half of the prodromal symptoms were followed by an HAE attack. A prospective study including 119 HAE attacks associated with prodromal symptoms (but without information about their current treatment) concluded that many patients experience a prodrome before at least one of their attacks, and 64% can predict an oncoming attack by having a prodrome [7]. Thus, the “warning function” of prodromal symptoms remains under LTP. Since no attack followed approximately half of the prodromal symptoms and the overall frequency was significantly reduced in our results, general recommendations for acute therapy cannot be given based solely on the occurrence of a prodromal symptom. However, the patients appear to be more relaxed about prodromal symptoms under LTP, as evidenced by the reduced use of on-demand medication.

In the following, the present results are compared with the evaluation from Berlin [11]: the spectrum of interventions, with a predominance of dental procedures, is comparable. In the Berlin study, only patients under lanadelumab treatment were evaluated, which also constituted most patients in the present evaluation. The approach and outcomes of dental procedures are similar in both studies. Each study showed that patients rarely used STP for over 100 dental interventions. Nevertheless, both the Berlin study and the present study reported only one swelling incident after dental procedures, corresponding to a rate of less than 1%. These results are also supported by the study from Milan, although it is not directly comparable due to the different forms of therapy (STP versus STP and LTP versus LTP alone versus none) [10].

Patients in the Berlin study were overall more restrictive in using STP: only two patients used situational prophylaxis, compared to the present evaluation where STP was used in 8 out of 9 surgical operations and 3 out of 9 endoscopies. Almost paradoxically, the results for breakthrough attacks differ. Despite not using STP for these interventions, there were no swellings in the evaluation by Buttgereit and colleagues, while in the present study, 5 out of 10 surgical interventions resulted in breakthrough attacks—all of which were under STP. Gastro- and colonoscopies did not lead to any angioedema attacks in the Berlin study, whereas in the present study, two mild attacks (both in the same patient) occurred during a total of 7 endoscopies, each without prior STP administration [11].

Stress is one of the most common triggers for an HAE attack. Since (dental) medical procedures typically mean stress for patients, this is an important consideration for healthcare providers managing HAE and AAE patients. Creating a stress-free environment by having acute medication ready and assuring the patient of the provider’s capability to handle any potential attack is crucial. Communication between HAE centers and local healthcare providers is essential for this.

In summary, the data from the present study, combined with the data from Berlin and Milan, do not support the necessity of mandatory STP under LTP in HAE patients. For dental procedures, the mandatory use of STP in HAE patients on effective LTP should be reconsidered, provided acute treatment is available and other trigger factors are absent. Breakthrough attacks were particularly rare during dental procedures and endoscopies, despite minimal STP use. The results of other surgical interventions should be interpreted with caution, given the overall small number of procedures per center. In addition to that, the situation seems to be different in AAE-C1INH patients. However, these results alone, contrary to initial expectations, show that many HAE patients remained attack-free without STP, and those who experienced swelling did so even under STP. It is not possible to interpret from the present data what impact LTP had, as it is unclear how the course would have been without LTP.

The discussion should include the goal of reducing STP. Fortunately, C1INH preparations have very few side effects, so one can argue that STP provides protective effects with minimal risk. Nevertheless, any unnecessary medication administration is a relief for the patient and simplifies pre-interventional management. Additionally, economic factors are relevant: HAE treatment medications are expensive and should be used judiciously. Reducing STP is another argument for LTP, which generally provides a significant quality of life improvement for severely affected patients.

However, the authors emphasize that the conclusion that reducing STP under effective LTP is possible should not endanger any HAE or AAE patient. For example, increased stress from not applying STP could lead to more breakthrough attacks. Treatment decisions should be made through shared decision-making, with the presence of effective and sufficient acute therapy as the foundation of any therapeutic approach.