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Consensus perspectives on prophylactic therapy for haemophilia: summary statement.

Berntorp, Erik; Astermark, Jan; Björkman, S; Blanchette, V. S.; Fischer, K.; Giangrande, P. L.F.; Gringeri, A.; Ljung, Rolf; Manco-Johnson, M. J.; Morfini, M.; Kilcoyne, R. F.; Petrini, P.;Rodriguez-Merchan, E. C.; Schramm, W.; Shapiro, A.; M Van Den Berg, H.; Hart, C.Published in:Haemophilia

DOI:10.1046/j.1365-2516.9.s1.17.x

2003

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Citation for published version (APA):Berntorp, E., Astermark, J., Björkman, S., Blanchette, V. S., Fischer, K., Giangrande, P. L. F., Gringeri, A., Ljung,R., Manco-Johnson, M. J., Morfini, M., Kilcoyne, R. F., Petrini, P., Rodriguez-Merchan, E. C., Schramm, W.,Shapiro, A., M Van Den Berg, H., & Hart, C. (2003). Consensus perspectives on prophylactic therapy forhaemophilia: summary statement. Haemophilia, 9(Suppl 1), 41278. https://doi.org/10.1046/j.1365-2516.9.s1.17.x

Total number of authors:17

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Consensus perspectives on prophylactic therapy forhaemophilia: summary statement

E. BERNTORP, J. ASTERMARK, S. BJORKMAN,* V. S. BLANCHETTE,� K. FISCHER,�P. L. F. GIANGRANDE,§ A. GRINGERI,– R. C. LJUNG,** M. J. MANCO-JOHNSON,��M. MORFINI,�� R. F. KILCOYNE,§§ P. PETRINI,–– E. C. RODRIGUEZ-MERCHAN,***

W. SCHRAMM,��� A. SHAPIRO,��� H. M. VAN DEN BERG� and C. HART§§§

Department of Coagulation Disorders, Malmo University Hospital, Malmo, Sweden, *Hospital Pharmacy, Malmo

University Hospital, Malmo, Sweden, �Division of Haematology/Oncology, The Hospital for Sick Children, Toronto,

Ontario Canada, �Van Creveldkliniek, University Medical Center Utrecht, Utrecht, The Netherlands, §Oxford

Haemophilia Centre, The Churchill Hospital, Headington, Oxford, UK, –Haemophilia and Thrombosis Centre,

Department of Internal Medicine, IRCCS Maggiore Hospital and University of Milan, Milan, Italy, **Departments

of Paediatrics and Coagulation Disorders, Malmo University Hospital, Malmo, Sweden, ��Mountain States Regional

Hemophilia and Thrombosis Center, Aurora, CO, USA, ��Hemophilia Center, Azienda Ospedaliera Careggi, Florence,

Italy, §§University of Colorado Health Sciences Center, Denver, CO, USA, ––Department of Paediatric/Coagulation

Disorders, Karolinska Hospital, Stockholm, Sweden, ***Haemophilia Centre, and Service of Traumatology and

Orthopaedics, La Paz University Hospital, Madrid, Spain, ���Klinikum der Universitat Munchen, International

Hemophilia Centre, Munchen, Germany, ���Indiana Hemophilia and Thrombosis Center, Inc. Indianapolis, IN, USA,

§§§InforMEDical, Inc., Narberth, PA, USA

Summary. Participants in an international confer-ence on prophylactic therapy for severe haemophiliadeveloped a consensus summary of the findingsand conclusions of the conference. In the consensus,participants agreed upon revised definitions forprimary and secondary prophylaxis and also maderecommendations concerning the need for an inter-national system of pharmacovigilance. Consider-ations on starting prophylaxis, monitoringoutcomes, and individualizing treatment regimenswere discussed. Several research questions were

identified as needing further investigation, includingwhen to start and when to stop prophylaxis, optimaldosing and dose interval, and methods for assessmentof long-term treatment effects. Such studies shouldinclude carefully defined cohorts, validated ortho-paedic and quality-of-life assessment instruments,and cost-benefit analyses.

Keywords: haemophilia, diagnosis, treatment,guidelines

Introduction

Consensus Perspectives on Prophylactic Therapy forHemophilia, held in London 20–21 September 2002,was a small international conference convened toreview the field of haemophilia prophylaxis. Over the2-day course of the conference, invited participantsfrom Sweden, the Netherlands, Germany, Italy,Spain, the UK, the USA and Canada reviewed theexperience with prophylaxis in their own countries

as well as globally. The format of the conferencecombined brief presentations with extended periodsof open discussion. The overall goal was to summar-ize what is known regarding the indications, benefits,costs, and optimal regimens for haemophilia pro-phylaxis, as well as to identify issues in need offurther research.

Defining prophylaxis

Prophylaxis is defined as treatment by intravenousinjection of factor concentrate in anticipation of andin order to prevent bleeding. Thus defined, prophy-laxis may range from a single dose prior to surgery orother anticipated bleeding, to long-term prophylaxis

Correspondence: Erik Berntorp, Department of Coagulation Dis-orders, Malmo University Hospital, SE-205 02 Malmo, Sweden.

Tel.: +46 (0) 40 33 23 92; fax: +46 (0) 40 33 62 55;

e-mail: [email protected]

Haemophilia (2003), 9, (Suppl. 1), 1–4

� 2003 Blackwell Publishing Ltd 1

begun in infancy and continued into adulthood.Primary prophylaxis is started prior to the develop-ment of joint damage, whereas secondary prophy-laxis is started after the onset of joint damage orother significant bleeding (e.g. intracranial bleeds).

Conference participants discussed the definitionsof primary and secondary prophylaxis developed bythe European Paediatric Network for the Manage-ment of Haemophilia (Second Workshop of theEuropean Paediatric Network for HaemophiliaManagement, 17–19 September 1998, Vitznau/Switzerland). Several changes were proposed,primarily to eliminate confusion over the properclassification of some patients, for example, a childwho begins therapy at age 3 but before the first jointbleed. It was felt that the revised definitions encom-passed more clearly the differing treatment modelsfollowed in Europe, where prophylaxis is usuallystarted by age 2 regardless of bleeding tendency, andin North America, where prophylaxis is often initi-ated after the first bleed. Conference participants feltthat there was no evidence to indicate how manyjoint bleeds may be tolerated before irreversibledamage (i.e. arthropathy) occurs. Therefore, untilmore data are available, they considered that pro-phylaxis started after multiple joint bleeds should beclassified as secondary prophylaxis. The reviseddefinitions are shown in Table 1.

Conference participants emphasized the import-ance of categorizing patients correctly in order toprovide meaningful data for analysing and compar-ing outcomes. For example, if patients are notreceiving prophylaxis for 46–52 weeks a year, or iftreatment is initiated after more than one joint bleed,then that cohort should be reported as managed bysecondary, not primary, prophylaxis.

Benefits and risks of prophylaxis

There are now over three decades of experiencewith long-term prophylaxis. Observational studiesstrongly suggest that continuous prophylaxis issuperior to on-demand treatment in delaying or

preventing the development of arthropathy and alsoin controlling bleeding frequency. Despite the lackof controlled studies, long-term prophylaxis shouldbe the standard for treating children with severehaemophilia in developed countries with strongeconomies and health care resources.

The primary goal of prophylaxis is the preventionof arthropathy, and this is the major outcomereported in long-term studies. Other long-term out-comes such as school performance may also beaffected by the number of bleeding events experi-enced. As important but less well studied is thepotential of prophylaxis to prevent intracranial andother serious bleeds. This could clearly improve boththe child’s school performance and, later in life, theadult’s contributions to society.

Frequent infusions of replacement therapy maynever be risk-free. While the modern record forsafety with recombinant products is excellent, con-tinued vigilance is required as new pathogens con-tinue to emerge, such as variant Creutzfeldt-Jakobdisease or West Nile virus. Based upon surveillancedata, there has been no increased incidence in thedevelopment of inhibitors with the adoption ofrecombinant products or with the more widespreaduse of full prophylaxis. The incidence of inhibitorsdoes not appear to be influenced by product purity;it seems more likely that a genetic predisposition isresponsible for the development of inhibitors.

However, under-reporting of complications andadverse effects likely occurs throughout Europe andNorth America. Clinicians, as well as patients,caregivers and other healthcare personnel, must bemore involved in pharmacovigilance by documentingall adverse effects, whether expected or unexpected.Conference participants recommended the develop-ment of a coherent international pharmacovigilancesystem using cooperative national registries.

Prophylaxis in developing countries

Countries with low per capita income and manycompeting health care issues are often unable to

Table 1. Revised definitions of primary and secondary prophylaxis.

Model Revised definition

Primary prophylaxis determined by age Long-term continuous* treatment started before the age of 2 years and prior to

any clinically evident joint bleeding.

Primary prophylaxis determined

by first bleed

Long-term continuous* treatment started prior to the onset of joint damage

(presumptively defined as having had no more than one joint bleed) irrespective of age.

Secondary prophylaxis Long-term continuous* treatment not fulfilling the criteria for primary prophylaxis.

Short-term prophylaxis Short-term treatment to prevent bleeding.

On demand therapy Treatment given when bleeding occurs.

*with the intent of treating 52 weeks/year up to adulthood and receiving treatment a minimum of 46 weeks/year.

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provide adequate treatment for persons withhaemophilia. In these settings, care for personswith haemophilia must be focused on saving livesin the event of uncontrolled bleeding. The firstpriority must thus be to develop capability toprovide adequate on-demand treatment of bleedingepisodes.

A review of the safety data suggests that plasma-derived products meeting modern standards forsafety (including donor testing and documented viralinactivation methods) may be used for both on-demand and prophylactic treatment in countries inwhich recombinant products are not readily avail-able or affordable. However, a national system foradverse event reporting should be instituted to allowdetection and recall of implicated products.

Access to prophylaxis in developing countries maybe improved by research that will define more clearlythe minimum effective prophylactic regimen as wellas analyse the cost-effectiveness of such a regimencompared with on-demand treatment. These cost-effectiveness studies should include the affectedindividuals’ ability to participate as productivemembers of society.

Starting prophylaxis

A majority of conference participants felt thatcurrent evidence supports an early start for prophy-laxis at 1–2 years of age in all children with severehaemophilia A or B (factor levels <0.01 IU/mL or1% of normal). Nonetheless, it is recognized that thisapproach is not only costly, but may result in over-treatment of a minority of children who are notprone to haemarthroses despite low endogenouslevels of coagulant factor. An important researchissue therefore is the identification of markers thatmight distinguish this population of persons withsevere haemophilia.

There are few data available to support guidelineson the initial dosing interval. Conference participantsconsidered that starting with once-weekly dosing inthe youngest patients may be less stressful forchildren and parents than starting full prophylaxisat once. However, the goal should then be to increasethe dosing frequency gradually to full prophylaxis(every other day for haemophilia A or every third dayfor haemophilia B) by the time the child becomesmore active or begins to experience bleeding. Thelong-term outcome of this approach needs to beascertained, optimally, by prospective studies or,minimally, by ongoing follow-up.

Starting prophylaxis gradually with once-weeklyinjections has the presumed advantage of avoiding

use of a central venous access device, such as aPort-A-Cath, which is often necessary for frequentinjections in very young boys. The benefits and risksof central venous access devices were extensivelydiscussed, as were the alternative benefits and risksof once-weekly prophylaxis. The decision to insti-tute early full prophylaxis by means of an injectionport must take into consideration the child’s bleed-ing tendency, the family’s social situation, and theexperience of the specific haemophilia centre. Thereported complication rates for infection andthrombosis have varied considerably from centreto centre. Whether these differences are bestexplained by surgical technique, by monitoringand detection methods, or by other factors, iscurrently unknown. For children with inhibitorsneeding daily infusions for immune tolerance induc-tion, a central venous line is often unavoidable, andan increased incidence of infection is associatedwith this regimen.

A number of straightforward measures may beeffective in reducing the risk of infection. Theseinclude repeated education of patients and staff,effective surveillance routines, and careful choice ofthe individuals allowed to use the device. A cooper-ative multicentre study might be of value for identi-fying optimal techniques for placement, maintenanceand removal of the devices. In considering optionsfor early therapy, the currently understood risks andbenefits should be thoroughly discussed with theparents.

Duration of prophylaxis

There are no data available for forming a consensuson stopping prophylaxis in adult patients. Themature joint would appear to be less vulnerable thanthat of a growing child; nonetheless, adults withhaemophilia remain at risk for joint and other bleeds.Research is needed to examine costs and outcomes ofmore flexible lower-dose regimens in adults, partic-ularly those who are less active and thus at reducedrisk of traumatic bleeding.

Individualizing the regimen: pharmacokineticconsiderations

The standard goal of maintaining factor levels above1% of normal does not take variation in the clinicalseverity of haemophilia into account. Moreover, theuse of standardized dosing disregards the approxi-mately 3-fold variation in clearance and half-life ofthe coagulation factors among patients. Conferenceparticipants agreed that maintaining a specific trough

CONSENSUS SUMMARY STATEMENT 3

� 2003 Blackwell Publishing Ltd Haemophilia (2003), 9, (Suppl. 1), 1–4

level should not be an end in itself: the dosing regimenshould be based upon clinical outcome. The goalshould be to ascertain and use the minimum effectivedose for the individual patient. Pharmacokinetic dosetailoring has been demonstrated to improve the cost-effectiveness of prophylactic treatment. For thispurpose, the pharmacokinetics of the coagulationfactor in the patient needs to be determined, forexample, by means of a single-dose study at a suitabletime during prophylactic treatment or before electivesurgery. The plasma level of coagulation factoractivity should also be monitored as needed.

Monitoring, assessing, and reporting outcomes

Radiological assessment

Magnetic resonance imaging (MRI) is considered tobe more sensitive in the detection of early stage jointdisease than conventional radiography because itallows an assessment of soft tissue and provides abetter visualization of erosions. It is now beingstudied prospectively in the North American pro-phylaxis trial as a research tool for assessing thedevelopment and reversibility of cartilage damage,joint space narrowing, and bony changes such ascysts and erosions. In clinical practice, MRI would bereserved for investigating difficult cases, for example,diagnosing poor treatment response. Conferenceparticipants concurred that it is not cost-effectivefor routine monitoring. However, prior to invasivesurgical procedures such as synoviorthesis or syno-vectomy, an MRI study is highly advisable as anobjective demonstration of synovitis; whenever feasi-ble, these studies should be done by centres withexpertise in joint MRI studies. Standardization ofMR methods and grading systems is needed to allowmore valid comparisons of treatments and outcomes.The WFH Paediatric Committee is currently workingto establish internationally accepted scoring systemsfor both MRI and orthopaedic assessment.

Conference participants agreed that plain filmX-rays have no role in the early management ofchildren with haemophilia. Their proper use is formore advanced disease, to detect the typical findingsof haemophilic arthropathy (narrowing of the jointline, subchondral cysts, abnormalities in alignment,etc.).

Clinical assessment

Validated and reliable instruments are important tosetting treatment goals and assessing patient satis-faction and treatment outcome. Unfortunately, noexisting instrument avoids some level of subjectivityin interpretation. Two instruments, one specific andone general, are recommended for simultaneous usein scoring and monitoring joint disease: a specifichaemophilia outcomes instrument, the ColoradoPhysical Examination Instrument (Colorado PE-1and Colorado PE-0.5 for children, reprinted in thepaper by E. C. Rodriguez-Merchan included in theseproceedings), which improves upon the World Fed-eration of Haemophilia Physical Joint Examinationinstrument; and a general health status assessmentsuch as the SF-36 Health Survey.

Health-related quality-of-life (HR-QoL) is a cru-cial outcome for chronic diseases such as haemo-philia for which there is no cure. Formal assessmentof HR-QoL for differing treatment strategies couldbe very informative as a long-term outcome measure,and a validated HR-QoL instrument should beincluded in the design of clinical trials. Both genericand specific indices should be used, and utility scoresshould be included in economic analyses.

Cost-effectiveness of prophylaxis

The question as to whether the costs of long-termprophylaxis will be offset by reduced hospital-izations, improved quality of life, improved schoolperformance, and increased productivity in adult-hood needs to be further investigated by well-designed health economic studies. Cost comparisonswith other rare chronic diseases, using a variety ofperspectives and outcome measures, may aid inclarifying issues of health care resource allocation.Reductions in the cost of clotting factor concentrateswould certainly be important for increasing access toprophylaxis amongst persons with severe haemophi-lia worldwide. It is clear that prophylactic treatmentof severe haemophilia allows patients to lead func-tionally normal and productive lives. Important stepstowards proving not only the humanitarian but alsothe economic value of prophylactic treatment havebeen taken, and as these proceedings will show, thework goes on.

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Haemophilia (2003), 9, (Suppl. 1), 1–4 � 2003 Blackwell Publishing Ltd