Untreated bleeds: Unveiling the subtleties and challenges of bleeding event counts and patient experience in clinical trials for bleeding disorders

• DOI: 10.1002/rth2.12832
• Publication Date: 2022-11-03T02:55:18Z
• Authors: Beth B. Warren
• Keywords: 03 medical and health sciences; 0302 clinical medicine; hemophilia; Commentary; pain; Diseases of the blood and blood-forming organs; joint diseases; prophylaxis; RC633-647.5; bleeding

Emicizumab, the bispecific human antibody that mimics factor VIII by bringing together activated IX and X, has significantly improved care for persons with hemophilia A (HA), providing a subcutaneous means of prophylaxis is given less frequently than intravenous infusions. The HAVEN studies,1.Oldenburg J. Mahlangu J.N. Kim B. et al.Emicizumab in inhibitors.N Engl J Med. 2017; 377: 809-818https://doi.org/10.1056/NEJMoa1703068Crossref PubMed Scopus (585) Google Scholar, 2.Young G. Liesner R. Chang T. al.A multicenter, open‐label phase 3 study emicizumab children inhibitors.Blood. 2019; 134: 2127-2138https://doi.org/10.1182/blood.2019001869Crossref (163) 3.Mahlangu Oldenburg Paz‐Priel I. patients who have without 2018; 379: 811-822https://doi.org/10.1056/NEJMoa1803550Crossref (354) 4.Pipe S.W. Shima M. Lehle al.Efficacy, safety, pharmacokinetics every 4 weeks people haemophilia (HAVEN 4): multicentre, open‐label, non‐randomised study.Lancet Haematol. 6: e295-e305https://doi.org/10.1016/s2352-3026(19)30054-7Abstract Full Text PDF (0) Scholar which demonstrated efficacy safety emicizumab, differed from most previous studies not only mechanism; they presented bleeding event data both treated untreated bleeds. In this issue RPTH, Callaghan al.5.Callaghan M.J. Asikanius E. al.Untreated bleeds non‐interventional intra‐patient comparison after initiating emicizuma 1‐3.Res Pract Thromb Haemost. 2022; e12782Abstract (2) present all available details 1–3, including adults HA inhibitors 1), 2), 3). studies, as disorder was based on participant/caregiver report events. Bleeding medication administration were recorded separately, whether bleed or determined investigator linking treatment episodes to episodes. Although count events seems at first be straightforward proposition, practicality it can quite challenging. As an illustration, consider epistaxis, should easy because blood seen coming nose. Imaginary participant Q gushing nosebleed. holds pressure 20 min, stopping nosebleed temporarily, but hour later starts again. At point, she takes oral antifibrinolytic (which does want do tastes terrible) continues hold pressure. stops, goes sleep. She wakes up few hours covering her pillow. really get out bed infuse needles hurt might vein try, expensive, last dose. wonders what will happen if insurance company month approve next refill. What joint keeps working week cannot factor? Should save dose even worse bleed? After much internal debate many short recurrent nosebleeds, decides treat factor. How counted event? each period one bleed, whole episode If just fully capture patient's miserable experience another whose stops completely briefly holding On other hand, counting epistaxis multiple would inflate count. Now similar situation bleeding. Fortunately, published definition, used studies.5.Callaghan 2014 ISTH guidelines define “aura” combination swelling/warmth, pain, loss range motion joint, note improvement symptoms clotting rest help distinguish arthropathy pain bleeding.6.Blanchette V.S. Key N.S. Ljung L.R. Manco‐Johnson van den Berg H.M. Srivastava A. Definitions hemophilia: communication SSC ISTH.J 2014; 12: 1935-1939https://doi.org/10.1111/jth.12672Abstract (410) new musculoskeletal defined occurring more 72 h initial moderate excellent response treatment, meaning least prior worsening pain. study, aura could applied younger participants, 72‐h rule When person experiences differential diagnosis includes bleeding, arthritis related damage, (eg, patellofemoral syndrome Achilles tendonitis). Determining gets layered over decisions about outlined Q's epistaxis. addition, concluding consistent may take days, requiring monitoring how changes activity, responds often professional clinical evaluation. ultrasound determination waiting delay especially participants living farther site. entering diary actually easily changed diary. solved making diaries flexible, increase potential accidental alterations. Finally, days weeks. 2‐week long 2‐h similarly annualized rates, reflect very different experiences. studies' analytic inclusion extremely important, work al. RPTH crucial understanding types go untreated. It also illustrates remains unknown identification likely challenging improve rates continue decrease (Figure 1). Children started before recognize associated activities cause nonbleeding Furthermore, barriers infusion are increase, infusions become habit families. number future increase. critical include outcomes beyond events, physical exam, magnetic resonance imaging (MRI), quality‐of‐life scores. Previous shown that, although MRI scores generally correlate, possible low rate higher levels damage vice versa,7.Warren B.B. Thornhill D. Stein al.Young adult childhood severe A: results Joint Outcome Continuation Study.Blood Adv. 2020; 4: 2451-2459https://doi.org/10.1182/bloodadvances.2019001311Crossref (36) further emphasizing importance long‐term outcomes. HAVEN‐7 follows infants age 12 months, those evaluations (clinicaltrials.gov, NCT04431726). addition longer‐term measures, trials need identify estimate likelihood bleed. This add burden statistical analyses balanced inconvenience additional logging participants. alternative patient‐centric outcome, variation complicate analysis randomization. Future delve deeper understand treatments influence true patient experience. commentary supported NIH 1K23HL151886.