North American Study for the Treatment of Recurrent Epistaxis with Doxycycline: The NOSTRIL trial

Abstract

Background Hereditary hemorrhagic telangiectasia (HHT) is a vascular bleeding disorder characterized by mucocutaneous telangiectasias and visceral arteriovenous malformations. A frequently debilitating symptom is spontaneous recurrent epistaxis. Objective To evaluate whether doxycycline therapy improves epistaxis in HHT by using a prospective, randomized, placebo‐controlled crossover study design. Patients/Methods Twenty‐two eligible patients between December 2017 and July 2020 at a single center were randomized to one of two study arms: doxycycline treatment followed by placebo, or vice versa. Primary outcomes measured differences in epistaxis severity between treatments. Changes in quality of life, laboratory markers of bleeding, and number of monthly blood transfusions or iron infusions were assessed as secondary endpoints. Additional post hoc endpoints included frequency and duration of dripping epistaxis and gushing epistaxis. A post hoc longitudinal analysis assessed effects of doxycycline over time. Results/Conclusions Doxycycline was safe and well tolerated. However, there was no reduction in the three primary outcome measures, nosebleed frequency (p = .16), nosebleed duration (p = .05), and Epistaxis Severity Score (p = .19). Quality of life, hemoglobin level, and number of blood transfusions and iron infusions did not differ between groups. Post hoc analysis demonstrated reduction in instances of gushing (p = .02) with doxycycline, although this finding is of unclear clinical significance. Post hoc longitudinal analysis showed reduction in frequency (mean estimate of coefficient = −0.19, standard error = 0.07, p = .01) and duration (mean estimate of coefficient = −2.33, standard error = 1.08, p = .03) of epistaxis over time. Post hoc findings suggest possible benefit of doxycycline but should be interpreted with caution given the overall negative study. Further investigation is needed with a larger sample size and a longer treatment duration.

Randomized, double-blind, placebo-controlled, crossover trial of oral doxycycline for epistaxis in hereditary hemorrhagic telangiectasia

“…Unfortunately, we stopped trial recruitment earlier than planned, at approximately half the proposed sample size, due to recruitment restrictions during COVID times, underpowering our study. Our observations to date suggest that oral doxycycline may not be an effective drug for the treatment of epistaxis in most patients with HHT, and are in agreement with another recent clinical trial of 22 patients [25]. We confirmed that WED collection by daily diary was feasible, with an excellent completion rate of 98.8%.…”

“…In human brain VM tissue, there is evidence of increased expression of MMP-9 [21] and VEGF [22] and another tetracycline, minocycline, has attenuated brain hemorrhage in the mouse [23]. Recently, a small retrospective case series reported sustained reduction in epistaxis in seven HHT patients treated with oral doxycycline [24], though a very recent clinical trial (performed during the same period as our trial) of 2 months of doxycycline in HHT patients showed no benefit [25]. Doxycycline also has the advantages of a proven safety track record for long-term use, oral administration and low cost.…”

Most-Cited Patient-Reported Outcome Measures Within Otolaryngology—Revisiting the Minimal Clinically Important Difference

“…120 Although this approach is rarely used in the determination of the MCID, the value of 0.71 has been used as the MCID of the ESS in multiple high-stakes clinical trials that have changed the management of HHT. [141][142][143] Nevertheless, when there is a discrepancy between the MCID calculated via the anchor-based approach and the MCID calculated via the distributionbased approach, a clinically important statistical dilemma arises as to which MCID to report. Authors could use a conservative approach in reporting or recommending the use of only the MCID with the largest magnitude as was done with the MD Anderson Dysphagia Inventory (MDADI) and Tinnitus Handicap Index.…”

A precision medicine approach to hereditary hemorrhagic telangiectasia and complex vascular anomalies

“…[20][21][22][23][24][25] Doxycycline, an oral tetracycline antibiotic, has antiangiogenic potential owing to its ability to inhibit matrix metalloproteinases; however, a recent randomized, controlled trial of doxycycline for bleeding in HHT was unambiguously negative, finding no improvement in any of the primary or secondary endpoints for doxycycline over placebo. 26 Because antiangiogenic therapy in HHT typically requires long-term administration to maintain effectiveness and thalidomide may cause potentially irreversible peripheral neuropathy (a risk that increases with longer durations of treatment), 27 the authors only consider use of thalidomide when other agents are ineffective, contraindicated, or inaccessible. The phase II, multicenter US PATH-HHT study (NCT03910244) is presently evaluating the efficacy of a modern thalidomide derivative, pomalidomide, in up to 159 patients with HHT.…”

“…There are two oral, targeted antiangiogenic agents with multiple published studies describing effectiveness and safety in treating bleeding in HHT: pazopanib 18,19 and thalidomide 20‐25 . Doxycycline, an oral tetracycline antibiotic, has antiangiogenic potential owing to its ability to inhibit matrix metalloproteinases; however, a recent randomized, controlled trial of doxycycline for bleeding in HHT was unambiguously negative, finding no improvement in any of the primary or secondary endpoints for doxycycline over placebo 26 . Because antiangiogenic therapy in HHT typically requires long‐term administration to maintain effectiveness and thalidomide may cause potentially irreversible peripheral neuropathy (a risk that increases with longer durations of treatment), 27 the authors only consider use of thalidomide when other agents are ineffective, contraindicated, or inaccessible.…”