USE OF FACTOR CONCENTRATES

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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE 4th GLOBAL FORUM OF THE
WFH 26th-27th, September, 2005 Alok
Srivastava Christian Medical CollegeVellore,
India
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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE Current paradigm CFC
replacement for joint bleeding CFC replacement
for surgery Concept of hemostatic vs
normal levels Can too much CFC
harm? Guidelines for management of hemophilia
3
Management of haemophilia Aims of therapy

• Prevent bleeding
• Prevent arthropathy

• Maintain full musculoskeletal function
• Maintain good quality of life
• -Full integration in society
• -No days lost from school or work

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LIFE EXPECTANCY OF PEOPLE WITH HEMOPHILIA

CONCENTRATES

HIV / HCV
PLASMA
NO THERAPY
Br J Haematol. 1982 Sep52(1)7-12
Br J Haematol. 1985
Apr59(4)593-602
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Relationship of Economic Capacity to Number of
Adult Hemophilia Patients
Data from 17 Randomly Selected Countries
Evatt and Robillard, Haemophilia
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Factor replacement therapy in haemophilia
Outcome at different doses (Sweden)
Nilsson IM, et al. J Intern Med 19922322532
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MANAGEMENT OF HEMOPHILIA CURRENT
PARADIGM Treatment Early recognition (?lt1
years of age) Primary prophylaxis for all -
?Before first bleed / ?After 1-2 bleeds
Large doses - 25-50 iu/kg/dose - 3x
weekly for H-A 2x weekly for H-B - ?Optimum
dose / schedule Aim to maintain factor level
gt1 at all times - Is this necessary /
possible?
Total yearly dose 3000-9000
IU/kg/yr National consumption 3-8
iu/capita Annual cost 50-150 k
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FACTOR REPLACEMENT IN HEMOPHILIA WHY DISCUSS
DOSE? Cost Competing health care needs /
Insurance caps General principles of
therapeutics
Compliance Children / CV Catheters Possible
side-effects of intensive doses ?
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The box-and-whisker plot shows the median value,
inter-quartile range (box) and extreme values
(whiskers) of the unconstrained factor VIII
(FVIII) demand when compared with observed FVIII
consumption for various countries (dots). The
median value is 6.1 units per capita, 25th and
75th percentiles are 4.5 and 8.6 units per
capita, and the extreme values are 2.7 (5th
percentile) and 13.6 units per capita (95th
percentile). The probability-weighted average is
6.9 units per capita.
Stonebreaker, et. al., Haemophilia (2004), 10,
18-26
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Clotting factor use Increasing trends
Courtesy M van den Berg
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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE Current paradigm CFC
replacement for joint bleeding CFC replacement
for surgery Concept of hemostatic vs
normal levels Can too much CFC
harm? Guidelines for management of hemophilia
13
Practice of Prophylaxis

• Balancing Costs ? Effects
• Should all joint bleeds be prevented or
• Can a limited number of bleeds be tolerized
• Without loss of function or HRQoL?

Van Creveldkliniek - University Medical Center -
The Netherlands - 2003
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STUDIES DESCRIBING OUTCOME OF LOWER DOSES OF
FACTOR REPLACEMENT FOR ACUTE HAEMARTHROSES
Srivastava BJH 2004 12712 - 25
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Factor replacement therapy in hemophilia
Outcome at different doses (the Netherlands)
Fischer K, et al. Haemophilia 2001744652
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Factor replacement therapy in hemophilia
Outcome at different doses
van den Berg HM, et al. Haemophilia
20039(suppl)2731
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Factor replacement therapy in hemophilia
Outcome at different doses
Sweden Sweden Netherlands Netherlands Netherlan
ds India Brazil Group 1 Group
2 1980 1990 2000 2004 2004 Age 21-35 13-20 20
.3 19.4 19.2 19 18.3 (1525) (1525) (1525)
(1526) (1525.6) Number 25 19 45 46 44 30 13
Age at start of 6.2 2.5 14.7 8.7 4.4 NA NA prophy
lactic treatment (313) (14.5) (12.217.8) (6.61
2) (2.46.2) on full NR NR 64 61 89 NA NA
prophylaxis Number of joint
bleeds/yr 5.2(0.516) 2.6(0.217) 7(2.815) 5(1.1
10.2) 2.2(0.96.5) 6.5(118) 10.4(138) Clinical
score 5.1(015) 1.2(07) NA NA NA 11(026) 10.5(
417) Patients with Petterssons score
(n) 25 19 27 40 44 30 13 Age (range) at
which NR NR 21.3 19.7 20.3 19 18.3 X-rays were
scored (2135) (1320) (16.922.8) (16.224.3) (17
.724.5) (1526) (1525.6) Petterssons
score 18(041) 4.8(022) 17(1133) 17(727) 8(016
) 18(048) 16.3(135) with Petterssons Score
of 0 NR NR 4 10 32 3 NR requiring
orthopaedic NR NR 27 22 9 10 23 surgery An
nual clotting factor 4003300 16005400 4111121 7
691667 15542425 25150 421538 usage
(IU/kg) (855) (1319) (2036) (627)
bleed score Only 10 had surgery, rest
yttrium synoviorthesis
Haemophilia 200410(suppl)2148
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Hypothetical correlation between joint scores and
dosage of factor replacement
Srivastava A. Br J Haematol 20041271225
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CORRELATION BETWEEN JOINT SCORES AND DOSAGE OF
FACTOR REPLACEMENT
100 75 50 20
Dose (iu/kg/yr)
No treatment
25-100
MUSFIH Study
100-500
Joint Score
500-1000
Critical level for total functional independence
1000-2000
2000-3500
gt 3500
5 10 15
20 25 30
Years
FISCHER Study
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Management of hemophilia Limitations of current
paradigms

• Assessment of outcome limitations
• Clinical score ? Significance and correlation
  with overall function
• Radiological score
• Plain X ray Low sensitivity and ?clinical
  significance
• MRI scale More sensitive
• ?Clinical significance of changes
• ?Practicality of application outside studies

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Management of hemophilia Limitations of current
paradigms

• Assessment of outcome limitations
• Need for other outcome measures
• Quality of life
• Often complex
• Language-dependent
• Affected by psychosocial issues
• Overall musculoskeletal function

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Clinimetric instruments to assess functional
health status in patients with haemophilia a
literature review1

• 19662001
• 34 different clinimetric instruments used
• 24 original/9 modified/1 unclassified
• None validated for haemophilia
• Measuring body structure/function
• Abilities 12 (none measured performance)
• Participation 4

Selecting a performance measure of physical
activities in combination with a validated
self-assessment measurement may maximise the
description and evaluation of physical
functioning
1.De Kleijn P, et al. Haemophilia 2002841927
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• An important development
• Subjective scoring
• Dichotomy between subjective and actual abilities
  
• Language
• Needs to be supported by a performance-based
  scoring system

van Genderen FR, et al. Haemophilia 20041056571
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• A performance-based system to assess activities
  that
• Are considered to be important by patients and
  therapists
• Can be measured objectively in a clinic
• Can be performed safely

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Clotting factor concentrates given to prevent
bleeding and bleeding-related complications in
people with hemophilia A or B (Review) Stobart K,
Iorio A, Wu JK The Cochrane Database of
Systematic Reviews 2005, Issue 2. Art. No.
CD003429.pub2. DOI 10.1002/14651858.CD003429.pub2
.
Types of Participants In one study the
participants were people with severe hemophilia B
(factor IX less than 1) (Morfini 1976). In two
other trials the participants were people with
severe hemophilia A (factor VIII less than 1)
(Aronstam 1976 Aronstam 1977). The fourth study
included people with clinically severe
hemophilia, where one participant had a
pharmacological moderate level of factor VIII
(1.5), but behaved clinically as a person with
severe hemophilia A (Carlsson 1997). The age
range of participants was from 5 to 45 years. All
participants were male, and none had inhibitors.
The studies varied in sample size with 9, 4, 14,
and 10 participants respectively (Aronstam 1976
Aronstam 1977 Carlsson 1997 Morfini 1976).
A U T H O R S ' C O N C L U S I O N
S Implications for practice There is insufficient
evidence from RCTs to assess whether the use of
prophylactic clotting factor concentrate is
effective in decreasing the frequency of joint
bleeds. Implications for research Large
randomized clinical trials of good quality are
necessary to evaluate the effectiveness of
clotting factor concentrate prophylaxis for
people with hemophilia A or B.
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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE Current paradigm CFC
replacement for joint bleeding CFC replacement
for surgery Concept of hemostatic vs
normal levels Can too much CFC
harm? Guidelines for management of hemophilia
27
SURGERY IN HEMOPHILIA Hematologic management of
hemophilia A for surgery (Kasper CK, Boylen AL,
Ewing NP. JAMA 19852531279-83) 163 patients
underwent 350 procedures (1967-1983) 23
hemorrhagic complications
Concurrent factor level gt40
in 72 cases lt30 in 15 cases 0.6
mortality Protocol for factor
replacement Pre-op 80-120 Post-op gt30 (10
days, wound healing)
Mean level (1st week) Mean total dose
1967-72 39(trough) 600 iu/kg 1980-83 73(tr
ough) 2000 iu/kg No change in bleeding
complications over this period
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PUBLISHED PROTOCOLS FOR FACTOR REPLACEMENT FOR
SURGERY
a. Malmo, Sweden (Lofqvist et al, 1996)

FVIII FIX
__________________________________________________
_____ PRE-OP
100 140 60 70 DAYS 2
7 30 40 30 40
DAYS 7 10 20
10 20 _______________________________
________________________
FVIII 50-70 IU/kg pre-op / 20-40 IU/kg q4-8h /
10-15 IU/kg q12h FIX 60-70
IU/kg pre-op / 40-60 IU/kg q12-24H / 10-20
IU/kg q24-48h b. Vellore, India (Srivastava et
al, 1998) FVIII FIX
_________________________________________
______________ PRE-OP
80 100 60 80
DAYS 2 4 20
40 15 30 DAYS 5
15 30 10 20
__________________________________________________
_____ Levels refer to peak and trough.
FVIII administered q12H and FIX q24H
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FACTOR REPLACEMENT FOR SURGERY ISSUES Bolus
/ continuous infusion? Levels maintained
post-op? Type of procedure BI interval
between dosage CI - adjusted dose or fixed
dose -?Kinetic data Duration of infusion
for major / minor surgery Use of adjuvants
tranexamic acid / fibrin glue Outcome
safety / efficacy / total dose
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FACTOR REPLACEMENT STRATEGIES FOR SURGERY IN
HEMOPHILIA ISTH SURVEY
(2002-2003)

(COUNTRY / NUMBER OF CENTERS
RESPONDING)
ANALYZED WITH DEVELOPING COUNTRIES TOTAL -
45 (12 OF THESE ARE IHTCs OF THE WFH)
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FACTOR REPLACEMENT FOR SURGERY IN HEMOPHILIA
CONSUMPTION FOR SURGERY PER PROCEDURE
DEVELOPED DEVELOPING JOINT REPLACEMENT
SURGERY (iu/kg) Mean SD 682.3 378.9
1117.5 362.3 Median 550 850
Range 300 - 1500 670 - 1500 OTHER
MAJOR SURGERY (iu/kg) Mean SD 688.5
304.4 690.5 398.6 Median 650
575 Range 300 - 1400 300 - 1300
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FACTOR REPLACEMENT FOR SURGERY IN HEMOPHILIA
Complications (Unexpected hemorrhage)
DEVELOPED DEVELOPING SIGNIFICANT
OPERATIVE () Mean SD 5.0 3.1 1.5
Median - 3.1 Range - 2
4.1 n 1 2
SIGNIFICANT POST-OP () Mean SD 6.5
7.5 5.2 2.8 Median 3.5
4.2 Range 1 20 3 8.3 n 6 3
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FACTOR REPLACEMENT FOR SURGERY IN HEMOPHILIA
Complications
DEVELOPED DEVELOPING WOUND INFECTION ()
Mean SD 3.5 4.4 4.2 4.2
Median 1.5 2.0 Range 1 10 1
10 n 4 6 POST-OP THROMBOSIS () Mean
SD 4.5 0.7 5.0 Median 4.5
- Range 4 5 - n
2 1 COMPLICATIONS REQUIRING RE-ADMISSION ()
Mean SD 3.7 3.1 2.7
2.1 Median 3.0 2.0 Range 1
10 1 - 5 n 7 3
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PROPOSED PROTOCOL BOLUS INFUSION
FACTOR REPLACEMENT FOR SURGERY AN ISTH SSC
STUDY(2005)

• DAYS
  FACTOR LEVEL
• Lower Dose Protocol
• Pre op 60 100
• Days 1-3 30 60
• Days 4 -6 20 40
• Day 7 onwards 15 30
• Higher Dose Protocol
• Pre op 60 100
• Days 1 -6 40 80
• Day 7 onwards 30 60
• 10 higher levels to be used joint replacement
  surgeries ??
• Centers to choose between the two options

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FACTOR REPLACEMENT FOR SURGERY AN ISTH SSC
STUDY(2005)PROPOSED PROTOCOL CONTINUOUS
INFUSION

• DAYS
  FACTOR LEVEL
• Lower Dose Protocol
• Pre op 60 100
• Days 1-3 40 50
• Days 4 -6 30 40
• Day 7 onwards 20 30
• Higher Dose Protocol
• Pre op 80 100
• Days 1 -6 50 60
• Day 7 onwards 30 40
• 10 higher levels to be used joint replacement
  surgeries ??
• Centers to choose between the two options

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FACTOR REPLACEMENT FOR SURGERY IN
HEMOPHILIA Is minor hemorrhage that does not
affect outcome acceptable in 5 cases? Or Should
the aim be to increase factor levels till there
is zero post-operative hemorrhage? Is that
always possible? Difference in cost of care
between these two approaches can be very
significant
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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE Current paradigm CFC
replacement for joint bleeding CFC replacement
for surgery Concept of hemostatic vs
normal levels Can too much CFC
harm? Guidelines for management of hemophilia
38
FACTOR REPLACEMENT IN HEMOPHILIA Is there data to
support high doses for hemostasis in
hemophilia? Concept of hemostatic vs normal level
Data suggesting that lower doses may be
sufficient 1.Clinical data of response from
early studies 2.Clinical profile of people with
mild hemophilia 3.Experience from other
coagulation factor deficiencies 4.Data from
thrombin generation assays Response at 30-40
level
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NORMAL LEVELS vs HEMOSTATIC LEVEL OF COAGULATION
FACTORS
The haemostatic level may be defined as the
lowest plasma concentration of a given
coagulation factor that is required for normal
hemostasis
FACTOR DEFICIENCY HAEMOSTATIC LEVEL
(U/dl) Fibrinogen 100 mg/dl
Prothrombin ? 20 40 Factor
V 15 25 Factor VII 10 20
Factor VIII 25 30 Factor IX 15
30 Factor X 10 20 Factor XI 10
20 Factor XIII 3 5 ?Indicates
insufficient data or significant disagreement
among published figures.
Wintrobes Clinical Hematology 10th Edition,
page - 1710
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Modified TGT on FVIII Def Plasma spiked with
KogenateFS
Nair S C (unpublished)
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USE OF FACTOR CONCENTRATES DOSE AND OUTCOME IN
HEMOPHILIA CARE Current paradigm CFC
replacement for joint bleeding CFC replacement
for surgery Concept of hemostatic vs
normal levels Can too much CFC
harm? Guidelines for management of hemophilia
42
GUIDELINES FOR MANAGEMENT OF
HEMOPHILIA WHY DO WE NEED THEM? Standardize
approach to treatment and documentation of
outcome Helps health care providers plan on a
national strategy Provide an introduction to
health care personnel not familiar with
hemophilia Prevent iatrogenic complications
PROVIDE WFH PERSONNEL AN INSTRUMENT TO WORK WITH
IN GAP COUNTRIES
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GUIDELINES FOR MANAGEMENT OF
HEMOPHILIA PROBLEMS How much to
include Define principles only -Good general
agreement Provide specifics -Dosage of
factor replacement -Contentious issue lack of
data
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GUIDELINES FOR MANAGEMENT
OF HEMOPHILIA (WFH) WORKING
GROUP ALOK SRIVASTAVA (Chair) PAUL
GIANGRANDE (VP-Med) ANGUS McCRAW (Chair, Lab
Sciences Committee) JEROME WEIDEL (Chair,
Musculoskeletal Committee) MAN CHIU
POON MARY CHUA SUPPORTED BY WFH
PUBLICATIONS DEPARTMENT ELIZABETH MYLES / ANNE
FOTHERINGHAM
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GUIDELINES FOR MANAGEMENT
OF HEMOPHILIA
(WFH) METHODOLOGY Collate information- -Publi
shed literature -National guidelines -Other
consensus documents Prepare draft document in
point format -For internal circulation April,
2004 Circulate to IHTCs / Twinned centers /
others major treatment centers /
WHO June, 2004 Formalize a final consensus
document September, 2004
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Desired Plasma Factor Level and Duration of
Administration (when there is no significant
resource constraint)
WFH, 2005
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Desired Plasma Factor Level and Duration of
Administration (when there is significant
resource constraint)
WFH, 2005
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FACTOR REPLACEMENT IN HEMOPHILIA DOSE
Choice often Depends
on Evidence
Resources Definition
of end points
Social
Expectations
MAXIMAL
? OPTIMAL
PRACTICAL
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WORLD POPULATION
CONSUMPTION OF FACTOR CONCENTRATES
40 OF THE WORLD USES lt2 OF THE FACTOR
CONCENTRATES
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MANAGEMENT OF HEMOPHILIA DO WE NEED A PARADIGM
SHIFT? Data needed on outcome at different
doses -Current doses not based on
evidence Outcome measurements need to be
redefined -Joint scores -Musculo-skeletal
function scores -Quality of life measures
End-points of care needs to be
defined -Likely to vary depending on
socio-economic factors
STUDIES NEEDED TO PROVIDE THESE DATA
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FACTOR REPLACEMENT IN HEMOPHILIA Need to
determine optimal doses 1.Patient perspective-
?Less infusions, better compliance, lower costs
(in time, if not money), ?less
complications 2.Physician perspective- Resources
could be utilized for needs of PWH other than
CFC 3.Industry- Better idea of real needs of the
market, not planning in a bubble?
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