**3. Results**

#### *3.1. Characteristics of the Study Population*

The search of the Registry led to the identification of 29 subjects with a definite diagnosis of HHT who had received AT. Of these, three were deceased at the time of study, for reasons unrelated to AT. In particular, one patient died from severe liver cirrhosis, one from progressive heart failure, and one su ffered sudden cardiac death. In the first patient, the indication to AT was AF. He was treated with anticoagulants for a short period of time and then therapy was stopped due to worsening of liver failure. The second patient had AF, but he underwent left atrial appendage closure and therefore was initially treated with anticoagulants and later with aspirin. He tolerated both treatments well. In the third patient, the indication to AT was surgical VTE prophylaxis, for which he was treated with prophylactic doses of enoxaparin for 1 month, without complications.

The 26 remaining patients accepted to participate and were included in the study. The demographical and clinical characteristics of the study population are presented in Table 1. There were 14 males and 12 females with a mean age of 59.3 ± 17.0 years. Nine patients had HHT1 due to *ENG* mutations, while 15 patients had HHT2 due to mutations of *ACVRL1*, consistent with the proportion of the two types of HHT previously found in Italy [17]. A genetic confirmation of the diagnosis was not available in 2 patients, but both fulfilled the Curaçao criteria for a 'definite' diagnosis of HHT. All patients (100.0%) had epistaxis. Twenty-three patients (88.5%) had mucocutaneous

telangiectases. There were 10 patients with pulmonary AVMs (pAVMs) (on a total of 22 who had been screened by CT scan of the chest), 5 patients with hepatic AVMs (on a total of 24 who had been screened by either abdominal ultrasound, CT scan, and/or MRI), and 2 patients with cerebral AVMs (on a total of 20 who had been screened by either CT scan and/or MRI of the brain and spinal cord). Ten patients (38.5%) had a history of GI bleeding due to the presence of GI AVMs (on a total of 15 who had been screened by endoscopic procedures).


**Table 1.** Characteristics of the study population.

AT: antithrombotic therapy; HHT: Hereditary Hemorrhagic Telangiectasia; AVMs: arteriovenous malformations; SD: standard deviation.

#### *3.2. Antithrombotic Therapy (AT): Indications, Type, Dosage, Duration, and Reasons for Therapy Discontinuation*

The 26 HHT patients included in this study received a total of 30 AT courses. As shown in Table 2, there were 19 courses of anticoagulant therapies and 11 courses of antiplatelet therapies. The drugs used were the following: enoxaparin (6 courses), fondaparinux (4 courses), vitamin K antagonists (VKA) (4 courses), direct oral anticoagulants (DOACs) (5 courses), acetylsalicylic acid (ASA) (9 courses), clopidogrel (1 course), and indobufen (1 course).

The indications for treatment are also presented in Table 2. We found that anticoagulant drugs were prescribed to our patients for the following reasons: AF (*n* = 6), heart valve bioprosthesis (*n* = 2), pulmonary embolism (PE) (*n* = 1), cerebral vein thrombosis (CVT) (*n* = 1), superficial vein thrombosis (SVT) (*n* = 3), retinal artery occlusion (RAO) in a patient with Horton's diseases (*n* = 1), secondary prevention after stroke in a patient with pAVMs (*n* = 1), surgical VTE prophylaxis (*n* = 4). The reasons for prescribing antiplatelet medications were: secondary prevention after stroke in patients with pAVMs (*n* = 3), secondary prevention after stroke or transient ischemic attack (TIA) (*n* = 3), secondary prevention after a myocardial infarction (MI) (*n* = 2), prevention of cardiovascular (CV) events in Horton's disease (*n* = 1), primary CV prevention (*n* = 2).

Information regarding dosage and duration of any single AT course is presented in Table 3, along with data regarding the genetic type of HHT and the reasons for possible cessation of therapy. The total time of exposure to AT courses was 554 months. The total time of exposure to antiplatelet courses was 385 months. The total time of exposure to anticoagulant courses was 169 months. In three cases, AT was discontinued by the patient, without medical advice.

*J. Clin. Med.* **2020**, *9*, 1699


**Table 2.** Type and number of AT courses and reasons for prescription.

AT: antithrombotic therapy; VKA: vitamin K antagonist; DOAC: direct oral anticoagulant; ASA: acetylsalicylic acid; AF: atrial fibrillation; PE: pulmonary embolism; CVT: cerebral vein thrombosis; SVT: superficial vein thrombosis; VTE: venous thromboembolism; TIA: transient ischemic attack; pAVMs: pulmonary arteriovenous malformations; RAO: retinal artery occlusion; MI: myocardial infarction; CV: cardiovascular.


SVT: superficial vein thrombosis; PE: pulmonary embolism; DOAC: direct oral anticoagulant; RAO: retinal artery occlusion; CVT: cerebral vein thrombosis; VTE: venous thromboembolism;

ASA: acetylsalicylic acid; TIA: transient ischemic attack; MI: myocardial infarction; CV: cardiovascular.

**Table 3.** Dosage, duration of treatment, compliance to AT, and reasons for therapy discontinuation.

*J. Clin. Med.* **2020**, *9*, 1699

#### *3.3. AT: E*ff*ectiveness and Safety*

The e ffectiveness of anticoagulant therapy was high. In particular, patients receiving anticoagulant therapy for AF did not experience embolic stroke or systemic embolism during treatment. Patients treated with anticoagulants for PE, SVT, or CVT did not display thrombotic recurrences during treatment. There were no thrombotic complications during the two courses of anticoagulant therapy prescribed for heart valve bioprosthesis. The patient with pAVM who was treated with acenocoumarol after stroke did not experience new ischemic events during treatment. The patient with Horton's disease that had RAO and was treated with enoxaparin lost vision on the a ffected eye, but therapy was started many days after onset of symptoms. Finally, patients receiving thromboprophylaxis for surgery did not have thrombotic events while on treatment.

The e ffectiveness of antiplatelet therapy was also high. In particular, patients with and without pAVMs who started therapy with ASA after stroke or MI did not experience new ischemic events during treatment. The same happened to the patient treated with indobufen after TIA. Finally, the two patients receiving ASA for primary CV prevention and the patient with Horton's disease receiving clopidogrel did not experience ischemic events while on treatment.

Safety data are reported in Table 4. In total, there were three major bleedings. Of these, two were GI bleedings that occurred in the same patient during two di fferent treatment courses with the DOAC rivaroxaban. This patient had already experienced GI bleeding before starting anticoagulation and bleeding while on rivaroxaban occurred after 6 months of treatment in one occasion and after 27 months of the treatment in another occasion. The other case of major bleeding consisted of severe hematuria in a patient treated with warfarin for AF. In the whole population, the incidence rate of major bleeding was 6.5 per 100 patients per year. In the population of patients taking anticoagulants, the incidence rate of major bleeding was 21.6 per 100 patients per year. There were no CRNM bleedings and no minor bleedings di fferent from epistaxis. Likewise, there were no di fferences in the mean hemoglobin levels measured in the three months that preceded AT and those measured during AT (11.1 ± 2.5 vs. 10.8 ± 2.2 respectively, 95% CI −0.90–0.31, *p* = 0.3256) (Table 4 and Figure 1).



AT: antithrombotic therapy; CRNM: clinically relevant non-major; Hb: hemoglobin; SD: standard deviation.

**Figure 1.** Distribution of hemoglobin (Hb) levels before and during AT.

## **4. Discussion**

This study presents data on the way AT is managed in the real-world in patients with HHT. One interesting point of discussion is the variety of medical conditions requiring AT that we found in subjects with HHT. While some of these conditions, such as secondary CV prevention, and surgical thromboprophylaxis, are relatively common for most physicians, other, such as AF, PE, CVT, RVO, Horton's disease, and stroke in subjects with pAVMs, may be more challenging and require specialized expertise to be properly managed. For instance, in the case of AF, we found that four di fferent anticoagulants were used, which reflects the complexity of the therapeutic choices that can be made in these patients. When the chosen anticoagulant was a DOAC, we found that a low dose was always prescribed: rivaroxaban 15 mg o.d., dabigatran 110 mg b.i.d., and apixaban 2.5 mg b.i.d. It is important to note that precise rules exist for the prescription of low doses of DOACs in patients with AF, based on age, body weight, and kidney function [18,19]. We retrospectively assessed whether the prescription of reduced doses in our patients was respectful of these rules and found that in three cases (two therapeutic courses with rivaroxaban and one therapeutic course with apixaban) prescriptions were o ff-label. It is known that the prescription of inappropriately low doses of DOACs may increase the risk of stroke and systemic embolism and therefore it should be avoided [20]. It is possible to speculate that the physicians that prescribed these DOACs were more concerned with the hemorrhagic, rather than the thrombotic, risk of their patients and this led to the inappropriate use of low-dose anticoagulant medications. However, it should be noted that, in the population that we analyzed, the e ffectiveness of these therapies were high and no thrombotic events were registered. Of course, this may be due to the limited number of patients and therefore it is not enough to justify the use of off-labeled doses of DOACs in HHT patients.

Attention should also be paid to the way secondary prevention was managed in patients with pAVMs that had an ischemic stroke. In three cases, it was prescribed an antiplatelet medication, while in another patient it was prescribed the anticoagulant acenocoumarol. This is odd, since the most recent recommendations on the medical treatment of stroke in subjects with pAVMs (produced by the British Thoracic Society) state that, as in the general population, ischemic strokes in patients with pAVM should be treated with antiplatelet agents, while anticoagulants should be used if other indications, such as AF or VTE, coexist [21].

Regarding safety, our study shows that 90% of AT courses was completed without the occurrence of significant hemorrhagic events and that only 10% of them was complicated by episodes of major bleeding. Importantly, there were no episodes of fatal bleeding. Additionally, hemoglobin levels, which are an objective outcome, did not change between before and after starting AT. However, when the incidence of major bleeding was calculated, based on time of exposure to AT, it resulted to be as high as 6.5/100 patients/year. Importantly, the incidence of major bleeding raised to 21.6/100 patients/year when only patients taking anticoagulants were considered. On the other hand, there were no episodes of major bleeding among HHT subjects treated with antiplatelet medications, although the total exposure time to antiplatelet therapy (385 months) was approximately twice the total exposure time to anticoagulant therapy (169 months).

As already mentioned in the Introduction section, two other studies have recently evaluated whether HHT subjects tolerate AT [11,12]. These studies and ours have many similarities. First, they include a similar number of HHT patients: 28 in the study by Shovlin et al. [11], 23 in the study by Riera-Mestre et al. [12], and 26 in our study. Additionally, all these studies have a retrospective design: Shovlin et al. utilized the databases of VASCERN-participating centers [11], Riera-Mestre et al. analyzed the RIETE Registry [12], and we studied the database of the HHT Center of our University Hospital. However, there are also important di fferences between our study and the other two. For instance, in the study of Riera-Mestre et al., the authors were not able to retrospectively assess Curaçao criteria and/or collect genetic data for all patients [12]. In contrast, in our study, all patients had a 'definite' diagnosis of HHT and a genetic confirmation of the disease was present in 24 out of 26 patients. Another di fference is that Shovlin et al. and Riera-Mestre et al. only studied

subjects treated with anticoagulants (and only with DOACs in the case of Shovlin et al.) [11,12], while we included individuals treated with antiplatelet medications. Additionally, the indications to treatment were di fferent between these three studies. In Shovlin's study, all patients were a ffected by either AF or VTE [11], while Riera-Mestre et al. only evaluated subjects with VTE [12]. In contrast, the patients investigated in our study had more heterogeneous indications to AT, which included stroke, MI, thromboprophylaxis, and other diseases. Regarding the results of these studies, Shovlin et al. found that epistaxis worsened in 24 cases and in 11 cases patients had to discontinue treatment, on a total of 28 patients [11]. However, all their subjects were treated exclusively with DOACs. In addition, they did not provide precise information on the medical regimen followed by patients and did not carry out a distinction between bleedings, in terms of severity [11]. On the other hand, Riera-Mestre et al. found two major bleedings and six non major bleedings during anticoagulant treatment, on a total of 23 patients [12]. Precise information on the medical regimen followed by patients was not provided in this case either. Numerically speaking, our results (three major bleedings on a total of 26 patients who received a total of 30 AT courses) appear similar to those reported by Riera-Mestre et al. However, as mentioned above, our population is di fferent, because it did not only include subjects with VTE who were treated with anticoagulants. Therefore, no direct comparisons can be made.

Other important reports available in the literature on this topic are those published by Edwards et al. in 2012 and Devlin et al. in 2013 [22,23]. A main di fference between these two studies and ours is that we were able to distinguish between major, CRNM, and minor bleedings, thus providing data not only on the number of hemorrhagic complications, but also on their severity and clinical impact, while this was not done in the study by Devlin et al. [23]. Additionally, the subjects studied by Devlin et al. did not always have a 'definite' diagnosis of HHT [23] and those investigated by Edwards et al. had lower rates of epistaxis, GI bleeding, anemia, and visceral AVMs compared to our patients [22].

Our study has some limitations. It has a small sample size and a retrospective nature. It is possible that some HHT subjects did not receive a prescription of AT despite the presence of a clinical indication, and this might be a selection bias of our study. Additionally, the di fference that we saw in the safety of antiplatelet drugs compared to anticoagulant therapies might depend on the small sample size, which also did not allow us to make distinctions between di fferent types of antiplatelet and anticoagulant medications. It is also possible that HHT subjects requiring anticoagulation are di fferent from those requiring antiplatelet therapy and that the increased rate of bleeding that we observed in subjects treated with DOACs depends on the intrinsic characteristics of the patients rather than on the drugs used. Finally, the small sample size did not allow us to investigate whether HHT1 and HHT2 patients have di fferent tolerability to AT, which is a very intriguing issue that deserves further investigation.

In conclusion, our study presents real-world data on HHT subjects treated with AT, providing novel information on the way antiplatelet and anticoagulant medications are used in this unique population, which has an intrinsically high hemorrhagic risk. Our results indicate that major bleeding may occur in HHT patients receiving AT, especially those treated with anticoagulants. Further studies are needed to better define the optimal use of these medications and fully assess the safety profile of various types of AT agents in HHT patients.

**Author Contributions:** Conceptualization, E.G., A.G., and R.P.; Methodology, E.G. and R.P.; Software, I.G. and A.P.; Validation, E.G. and R.P.; Formal Analysis, F.A., A.P. and I.G.; Investigation, F.A. and L.D.M.; Resources, F.A. and L.D.M.; Data Curation, F.A., A.P. and I.G.; Writing—Original Draft Preparation, E.G. and R.P.; Writing—Review & Editing, E.G., A.G., and R.P.; Visualization, E.G., R.P., A.P. and I.G.; Supervision, E.G. and R.P.; Project Administration, E.G., A.G., and R.P. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Conflicts of Interest:** The authors declare no conflict of interest.
