Real-world data opens up new opportunities in the treatment of blood clotting disorders

08.05.2023 17:16

At a satellite symposium supported by Novo Nordisk on the occasion of the GTH annual meeting, experts presented the importance of real-world data (RWD) for the treatment of blood clotting disorders using various examples. Real-world data, among other things, led to the approval of NovoSeven®, a recombinant factor VIIa (rFVIIa), for severe postpartum hemorrhage (sPPH) and to the inclusion of the new approval in the guidelines.

For patients with hemophilia B, analysis of data from a Canadian registry confirmed improved bleeding control after switching from factor IX (FIX) prophylaxis to long-acting rFIX Refixia®. 7,8 When assessing the success of therapy, not only bleeding control but also joint health is important. The real-world study pathfinderReal in patients with hemophilia A is now intended to evaluate the effects of prophylaxis with the long-acting rFVIII Esperoct®9 on joint health.

“In real-world studies, data is collected in the direct treatment of patients outside of controlled clinical trials. After appropriate analysis, evidence, so-called real-world evidence (RWE), can be obtained from the data generated,” explained Prof. Dr. Hermann Eichler, Director of the Institute for Clinical Hemostaseology and Transfusion Medicine at Saarland University. In contrast to controlled studies, in real-world studies the population examined is significantly more heterogeneous and therefore more closely reflects the scenario that occurs in normal treatment contexts. In addition, there is no randomization and the therapy is not laid down in a defined study protocol. RWE could be retrospective or prospective, longitudinal or cross-sectional. They were based on newly generated (primary) data, e.g. B. from non-interventional studies, or on existing (secondary) data, e.g. B. from registers. An example of a primary RWE data source is the multinational online survey (10) of 46 patients with hemophilia A and 16 caregivers about their experiences with Esperoct®. According to Eichler, the analysis of the surveys showed, among other things, that 91 % of the participants who had previously used another product were more satisfied with Esperoct® than with the previous therapy - mainly due to the lower injection frequency and the effectiveness of Esperoct®. (10) “Important secondary data sources are registries such as the German Hemophilia Register (DHR), which also monitors and examines the new therapy options,” emphasized Eichler.

Severe postpartum bleeding – current guidelines and possible treatment with NovoSeven®.

“Postpartum hemorrhage (PPH) is a birth emergency and the most common form of severe birth-related hemorrhage,” explained Dr. Bettina Faridi, senior physician specializing in obstetrics and prenatal medicine, Bonn University Hospital. Severe PPH (sPPH) is defined as blood loss of more than 1,500 ml within 24 hours of birth, regardless of the route of delivery (vaginal or cesarean section). (11) The incidence of PPH and sPPH is estimated to be 6–11 % and 1–3 % of all births worldwide, respectively, with large regional differences. (12) sPPH is one of the main causes of maternal mortality worldwide. (13)

The most common causes of PPH are ideopathic atony, uterine distension, administration of tocolytics and fibroids, but perineal tears/incisions, uterine rupture, placental retention and primary and secondary coagulopathies are also possible, says Faridi. (14) Since blood loss in PPH is often underestimated, the current guidelines recommend collecting bandages, swabs, etc. and calculating the amount of blood. In addition, attention must be paid to clinical signs: symptoms such as: B. Hypotension, tachycardia, pallor, clouding of consciousness and oligo-anuria, the blood loss can often be over 1.5 liters and there is a risk of severe hemorrhagic shock. From 2 liters of blood loss, the coagulation system is activated and life-threatening consumption coagulopathy occurs.

In the case of sPPH, the cause must be found quickly and the appropriate measures taken. However, it is important to stabilize coagulation at the same time. First, tranexamic acid, fresh-frozen plasma, erythrocyte and platelet concentrates are given. If coagulation remains unstable, desmopression and, in accordance with the current guideline, NovoSeven® would be used. (6) Ms. Dr. Faridi explained the approval of NovoSeven® for sPPH based on a randomized controlled open-label study (15) and real-world data. (2-5) In the clinical trial of women with sPPH in whom uterotonics failed to control bleeding, patients who received NovoSeven® injection (n = 42) required fewer surgical procedures to control bleeding than the 42 patients treated with standard of care (52 % vs. 93 %). (15) The safety profile of NovoSeven® was also confirmed in the real-world studies, Faridi reported. (2-5)

Hemophilia B – PK comparison studies and real-world data speak for Refixia®

Since June 2018, the long-acting rFIX Refixia® has been available for the treatment and prevention of bleeding in patients aged 12 and over with hemophilia B. Dr. Carmen Escuriola Ettingshausen, director of the Rhein Main Hemophilia Center in Mörfelden, reported that mean FIX trough levels of 27 % can be achieved with a once-weekly administration of Refixia®. (16) In studies, Refixia® led to a significant reduction in bleeding and prevented further bleeding into target joints - with fewer injections compared to standard rFIX. (16,17) In addition, the pharmacokinetics (PK) study paradigmTM7 in a crossover design showed that the FIX activity 7 days after the administration of Refixia® was 6 times higher than after the injection of the also long-acting eftrenonacog alfa (rFIXFc) (C168h = 18.7 vs. 3.2 IU/dl). (18)

An analysis from the multicenter Canadian Bleeding Disorders Registry (CBDR) examined how switching FIX prophylaxis from a standard rFIX preparation or rFIXFc to Refixia® affects bleeding control in a real-life setting. Thirty-seven adult male hemophilia B patients for whom data were available for at least 6 months before and after switching therapy were included in the analysis. (7) 15 patients switched from standard rFIX to Refixia® and benefited from this with a reduction in the median annual bleeding rate compared to previous therapy (annualized bleeding rate [ABR] 5.72 vs. 1.67). 22 patients switched from rFIXFc to Refixia®, their ABR reduced from 1.54 to 0.77 during the observation period. This improvement in bleeding prevention also occurred for joint bleeding. In the group that switched from rFIXFc to Refixia®, 36 % patients remained bleeding-free with a median follow-up of 2.3 years. This means that there were more bleeding-free patients with Refixia® compared to FIXFc, despite a significantly longer follow-up time, emphasized Escuriola Ettingshausen. (7) In addition, after switching to Refixia®, the total annual consumption of FIX and the number of injections per year for prophylaxis decreased - regardless of which preparation was switched to Refixia®. (7)

“It has been shown that data can be generated from patient registers in a timely and meaningful manner in order to compare different therapies or therapeutic agents at short notice,” concludes Escuriola Ettingshausen.

“Assessing joint health is part of comprehensive care”

“It should not be forgotten that, in addition to the bleeding rate, joint health is an important parameter for assessing the success of therapy,” explained Dr. Katharina Holstein, specialist in internal medicine and hematology, coagulation clinic and hemophilia center, University Hospital Hamburg-Eppendorf. In hemophilia, bleeding into the joints is common, which over time can lead to arthropathies with pain, massive physical disability, reduced participation and a reduction in quality of life. “A situation that must be avoided at all costs,” warned Holstein. Early prophylactic therapy is essential to prevent bleeding and hemophilic arthropathy in particular
Prevent target joints. (19,20)

Recording joint health, especially with regard to the (early) detection of arthropathy, is part of comprehensive care, explained Holstein. Imaging procedures (sonography, MRI) and various scores are available for clinical examination. The Gilbert score is not very sensitive, but is suitable for assessing the course of older patients with advanced arthropathy. The Haemophilia Joint Health Score (HJHS), on the other hand, is more sensitive, even for detecting minor joint damage, and can be easily used in children and adolescents. The HJHS also shows a good correlation with, among other things, the cumulative number of bleedings and the radiologically proven damage. (21) However, the examinations for the HJHS require a relatively long time (elbows, knees, buttocks are systematically assessed on both sides), but with a little practice you will get faster.

Real-world study on joint health under prophylaxis with Esperoct®

Nun solle der Frage nach dem Einfluss einer Umstellung auf Prophylaxe mit Esperoct® auf die Gelenkgesundheit bei Patienten mit Hämophilie A nachgegangen werden. Laut Holstein habe die Studie pathfinderTM2 mit 186 Patienten mit schwerer Hämophilie A (FVIII-Aktivität < 1 %) für Esperoct® (50 I.E./kg alle 4 Tage22) eine effektive Blutungsprophylaxe gezeigt. Bei dieser Dosierung wurde ein mittlerer FVIII-Talspiegel im SteadyState von 3,1 %22 bis 5,5 % (23) (bei Patienten mit längerer Esperoct®-Behandlung) sowie eine niedrige mediane ABR von 0,8422 erreicht, so Holstein.
“In order to evaluate the effects of prophylaxis with Esperoct® on joint health, a real-world study comes into play again - the ongoing multi-national, prospective, non-interventional study pathfinderReal,” says Holstein. The recording of the clinical joint score using HJHS over 24 months from the start of the study is intended to provide data in a real-world setting on the effectiveness of prophylaxis with Esperoct® in adult patients with hemophilia A who were switched to Esperoct®. “With the HJHS, important data on the patient’s joint health can be collected with relatively little effort. “We should therefore collect the score regularly,” Holstein concluded.

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