- Email: [email protected]
Inhibitor treatment: State of the art
Inhibitor Treatment: State of the Art Amy Shapiro The treatment of hemophilic patients with inhibitors presents many challenges. Recombinant activated factor VII (rFVIIa; NovoSeven威, Novo Nordisk, Copenhagen, Denmark) is a new therapeutic option for this patient population. Optimization of dosing regimens may be achieved by considering (1) individual pharmacokinetics (especially in the pediatric population); (2) high-dose bolus regimens; (3) continuous infusion (CI) including high-dose CI; (4) early treatment with NovoSeven in the course of a bleeding event; and (5) use of NovoSeven as a prophylactic therapy. The literature involving these issues is reviewed here. Institution of early therapy has been shown to decrease total NovoSeven requirement while increasing efficacy. Pediatric patients may require a higher dose of NovoSeven due to the higher clearance rate and shorter half-life demonstrated by this population. Therefore, the patient’s age and/or individual pharmacokinetics and clearance rate should be considered when calculating doses and CI rates. High-dose NovoSeven has been shown to be effective in some patient populations without increased reported adverse events. Despite its short half-life, prophylactic use of NovoSeven has been reported in a small number of patients, with an apparent decrease in bleeding episodes experienced. There has been significant interest in administration of NovoSeven by CI, particularly in patients requiring prolonged treatment, and it has been shown to be successful, although the optimal target factor VII activity has yet to be established and some authors have recommended the use of concomitant antifibrinolytics. Dis Mon 2003;49:22-38 0037-1963/01/3804-1205$35.00/0 doi:10.1053/shem.2001.29506 22
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pproximately 30% of children with severe hemophilia A and 1% to 3% of those with severe hemophilia B develop inhibitor antibodies to factor VIII (FVIII) or factor IX (FIX), respectively.18 Several options exist for the management of these patients. These include immune tolerance therapy (ITI) to eradicate the inhibitors and various strategies for the prevention or ontrol of bleeding. Previous therapies have included prothrombin complex concentrates (PCCs), activated PCCs, and porcine FVIII. The advent of recombinant factor VIIa (rFVIIa; NovoSeven威, Novo Nordisk, Copenhagen, Denmark) has increased available treatment options. In many patients with inhibitors, NovoSeven is now the treatment of choice. Over the last decade, NovoSeven has been used with a high success rate in hemophilic patients with inhibitors, both for the management of bleeding episodes and for cover during surgical or physiotherapy interventions. Optimal dosing and administrative strategies are still being evaluated. Optimization of a patient’s regimen includes consideration of: (1) individual pharmacokinetics (especially in the pediatric population); (2) use of high-dose bolus regimens; (3) use of continuous infusion (CI), including high-dose CI; (4) institution of early treatment with NovoSeven in the course of a bleeding event; and (5) use of NovoSeven as a prophylactic therapy. These current trends in the use of NovoSeven for the treatment of hemophilic patients with inhibitors will be discussed.
A
Individual Pharmacokinetics The pharmacokinetics of NovoSeven have been shown to vary widely between individual patients (Fig 1).15,30,32 In particular, infants and children have been shown to have higher clearance rates of NovoSeven, with a shorter half-life compared to adults.9 Following bolus doses of 114 to 196 g/kg in six children (three with hemophilia A and three with hemophilia B) aged 5 to 12 years, mean clearance was found to be roughly doubled in children compared to adults, with a shorter mean residence time and a greatly reduced half-life (Table 1). Data from case reports of children treated with NovoSeven CI provide further evidence of variations in pharmacokinetics compared with adult values.16,24 In a 15-year-old hemophilic patient who was scheduled to receive NovoSeven CI postoperatively, plasma factor VII (FVII) levels after three initial bolus doses of 120 g/kg every 2 hours ranged from 29 to 31 U/mL at 10 minutes postinjection, from 9.5 to 15.5 U/mL at 1 hour postinjection, and from 3.7 to 7.2 U/mL at 2 hours postinjection.16 In vivo recovery of FVIIa was 0.5%/IU/kg and the half-life was estimated to be DM, January 2003
23
FIG 1. Clearance of NovoSeven (measured by a one-stage clotting assay) obtained by pharmacokinetic evaluation of seven cases. Reprinted with permission from Schulman et al: Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinol 9:S97-S101, 1998 (suppl 1).32
no more than 1 hour; both of these values were described as “less than expected.”16 In another case report of a 6-year-old child with severe hemophilia A with a weight of 23 kg, preoperative clearance of NovoSeven was found to be 34.6 mL/h/kg (similar to reported adult levels2), volume of distribution 40.6 mL/kg, and mean residence time 1.17 hours (similar to levels reported in children).9,24 During NovoSeven CI at doses ranging from 7.6 g/kg/h to 4.3 g/kg/h over 5 days, clearance rates varied between 15.2 and 34.0 mL/h/kg, with a downward trend compared to preoperative values. In some cases, and especially in the pediatric population, increased bolus and maintenance doses may therefore be necessary to achieve optimal hemostasis.
High-Dose NovoSeven Bolus Regimens Bolus dosing of NovoSeven remains the standard method of administration in the majority of patients, especially in patients treated at home and those with mild to moderate bleeds who only require a limited 24
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TABLE 1. Pharmacokinetics of NovoSeven in Six Hemophilic Children Compared to Previously Measured Adult Values
Children (mean age, 8 yr; range, 5-12) Adults
Mean Clearance (mL/h/kg)
Mean Residence Time (h)
Plasma Half-Life (h)
67.0
1.94
1.32
32.8
3.33
2.72
Based on data from Hedner et al.9
number of doses, and for the optimal management of specific patients, or bleeding episodes, depending on each unique clinical situation. The most common bolus dose of NovoSeven is 90 g/kg with dosing intervals dependent on the patient’s clinical circumstances. Some patients, particularly pediatric patients, appear to benefit from higher dose regimens. As NovoSeven is hemostatically active at a local level, it appears to have a wide safety margin. High-dose regimens may optimize thrombin generation or the thrombin burst, and may allow for prolongation of the dosing interval. Doses up to 300 g/kg have been administered without reported adverse event.18 Several investigators have reported the use of higher than standard bolus doses of NovoSeven in pediatric patients, without adverse effects or clinical signs of disseminated intravascular coagulation (DIC).4,10 Cooper et al in the United States described the use of high-dose NovoSeven for cover during major orthopedic manipulations and rehabilitation in a 12-year-old boy with severe hemophilia B and a high-titer inhibitor.4 He had previously responded poorly to conventional therapy and had become wheelchair-bound with greater than 30 degrees flexion contracture of the knees. Joint bleeding was eventually controlled with high doses of NovoSeven (240 to 300 g/kg). For this reason, the authors selected a NovoSeven dose of 240 g/kg, given at increasing intervals (every 6 hours, every 8 hours, every 12 hours, and every 24 hours), to maintain hemostasis during hospitalization and rehabilitation after successful release of contractures. During a 4- to 6-week period of vigorous physical therapy during which time the patient was dosed prophylactically, they reported only a single elbow bleed, which resulted from an improper use of crutches. Importantly, there was no evidence of accumulation of FVII activity, nor of any clinical thrombosis or increase in inhibitor titer. Jime´nez-Yuste et al in Spain have also reported the safe and effective use of high-dose NovoSeven for three bleeds and two Port-A-Cath placements in three pediatric patients with hemophilia and high-titer DM, January 2003
25
TABLE 2. Response to Various NovoSeven Treatment Protocols in Hemophilia Patients Undergoing Surgical Intervention or Treatment for Bleeding Events
Type of Case Surgical Major bleeds Hemarthrosis
Protocol*
N
Median Dose NovoSeven (g/kg)
Response (%)
II I I I II III
10 2 8 57 72 29
1074 2940 1746 270 360 300
100 100 65 70 72 82
Protocol I (standard-dose CI): 90 g/kg bolus followed by 14-16 g/kg CI for 2 days, and a clearance-adjusted rate thereafter to maintain FVII:C trough levels ⬎ 10 IU/mL; protocol II (high-dose CI): 180 g/kg bolus followed by 30 g/kg CI to maintain FVII:C trough levels ⬎ 20 IU/mL; protocol III: single high-dose (300 g/kg) bolus. Data from Kenet et al.13 *
inhibitors.10 In each case, NovoSeven was given every 2 hours, starting with 150 to 160 g/kg for the first dose, followed by 120 to 140 g/kg for the second dose, and 90 g/kg for the third and any subsequent doses. Compared to previous experiences with lower-dose NovoSeven in pediatric patients, the authors considered the high-dose treatment to be more effective for the prevention or control of bleeding, and possibly to reduce the number of doses required. They observed an increase in D-dimers in all patients but there were no clinical signs of DIC or other adverse events. A large study by Kenet et al13 involved 149 cases treated with CI NovoSeven for surgery or bleeding and included standard-dose CI (protocol I), high-dose CI (protocol II), and single high-dose bolus arms (protocol III), all defined in the footnote to Table 2.13 They found that both CI rotocols were effective for surgical cover in 100% of cases but that, in patients with bleeding events, the high-dose CI regimen and the single high-dose bolus were associated with a slightly higher and more rapid response rate compared with the lower-dose CI. The authors also stated that protocol III (single high-dose bolus infusion) provided a slightly better response rate in hemarthroses and in improved quality of life compared with other dosing regimens.
Rationale for NovoSeven CI There has been significant interest in the administration of NovoSeven by CI, particularly in patients requiring prolonged treatment. As NovoSeven has a short half-life of approximately 2.7 hours,15 necessitating 2to 3-hourly administration of bolus doses,31 CI theoretically may provide 26
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more reliable hemostatic coverage compared with bolus dose regimens. It has also been suggested that CI may be of benefit for bleeds in tissues with poor expression of tissue factor (eg, skeletal muscle), which may therefore require higher and more constant plasma evels of NovoSeven.29 CI is also considered more convenient than bolus dosing, as the syringes need to be changed only every 6 to 24 hours.16,21 There is also potential for cost savings, as lower dose requirements with NovoSeven CI have been documented in a number of studies,3,12,21,22,33 and particularly as there is an apparent decrease in clearance over time during prolonged infusion,9,16,24,31 allowing gradual tapering of doses.
Dosing With CI NovoSeven CI treatment is instituted after an initial bolus dose, usually of 90 to 120 g/kg, which generates the initial thrombin burst, thus ensuring adequate hemostasis.33 Repeat bolus dosing during CI may be required in some patients,33 that, in conjunction with the level of FVII activity targeted or required for hemostasis, may actually lead to increased utilization of NovoSeven compared with some bolus dosing regimens. Parallel saline infusion is also advised when NovoSeven CI is administered via a peripheral vein in order to reduce the risk of local thrombophlebitis.31 The concomitant use of unfractionated heparin (UFH) for this purpose is not recommended as the addition of UFH to infusion bags has been reported to result in a 50% loss of rFVIIa activity within 4 hours of storage.31 No such loss of activity has been reported with low-molecular-weight heparin (LMWH),31 but this agent has been associated with the formation of precipitates, that appear to contain FVIIa and may, therefore, decrease the FVIIa content of the infusion.16 In order to determine the optimal infusion rate needed to maintain the usual targeted FVII:C level of approximately 10 U/mL, individual clearance rates should be calculated whenever possible.31,33 These are calculated according to the following equation:33 Infusion rate 共IU/kg/h兲 ⫽ Clearance 共mL/kg/h兲 ⫻ stead y-state concentration 共IU/mL兲 A sample calculation is shown in Fig 2.
Experience With CI Data from 20 published reports of the use of NovoSeven CI for the management of 281 cases (187 bleeding events and 94 interventions) DM, January 2003
27
FIG 2. Sample calculation of individual NovoSeven infusion rate. Reprinted with permission from Schulman et al: Continuous infusion of recombinant factor VIIa in hemophilic patients with inhibitors: Safety, monitoring and cost effectiveness. Semin Thromb Hemost 26:421-424, 2000.33
suggest that CI is effective in controlling or preventing bleeding in the majority of patients (Table 3).1,3,5-7,11,13,16,21,23-25,27,29,30,31,34-37
Standard-Dose CI A study of NovoSeven CI reported by Schulman included 29 bleeding events and 26 interventions.30 The targeted FVII:C level was approximately 10 U/mL. Effective hemostasis was achieved in 91% of patients overall; 96% of cases when concomitant administration of antifibrinolytics was provided and in 66% of cases when antifibrinolytics were not administered.30 Significantly fewer hemorrhagic complications were observed in patients receiving antifibrinolytics compared with those who did not (2/46 v 3/9, respectively; P ⫽ .033). In a European study performed by Ludlam et al, all patients received a standard NovoSeven bolus dose of 90 g/kg and were then allocated to receive either a standard CI maintenance dose of 16.5 g/kg/h to achieve a target FVII:C level of 10 U/mL, or a high CI maintenance dose of 50 g/kg/h to achieve a target FVII:C level of 30 U/mL. Data from the high-dose arm of the study have not been published yet. Patients in the lower-dose arm were infused for a median of 13.5 days (range, 1 to 26 days).34 At this dosing level, effective hemostasis was achieved in one of two minor procedures and two of six major operations. Excessive bleeding was reported in three of the lower-dose patients, even though FVII:C levels were maintained at approximately 10 U/mL. The authors concluded that NovoSeven CI given at an infusion rate of 16.5 g/kg/h 28
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did achieve the target FVII:C level but that this level did not provide reliable hemostasis. The largest study of NovoSeven CI, reported by Kenet, also included a high-dose bolus NovoSeven treatment arm and is described in more detail above.13 Among the remaining 77 compiled reported cases of NovoSeven administered as an initial bolus with subsequent CI, dosing levels varied (bolus dose range, 75 to 150 g/kg; CI dose range, 4.7 to 50 g/kg/h; target FVII:C, 10 to 30 U/mL; actual FVII:C, 5.2 to 59 U/mL). Overall, CI NovoSeven was reported to be effective in 63 of 77 (82%) cases, partially effective in five of 77 (6%), and ineffective in nine of 77 (12%).1,3,5-7,11,16,21,23-25,27,29,31,34-37
Bolus Versus CI NovoSeven Three reports have compared bolus dosing and CI NovoSeven.3,7,29 Two of these were case reports of single patients, each of which was successfully switched from NovoSeven bolus dosing to CI7,29 due to lack of efficacy of bolus dosing (120 g/kg bolus switched to 16.7 g/kg/h, gradually decreasing to 4.7 g/kg/h CI29, and 90 g/kg bolus switched to 20 g/kg/h CI7). The third report, by Chuansumrit et al in Thailand, reported a prospective open study in hemophilic patients, in which NovoSeven was found to be effective in two of three cases treated with CI (90 g/kg bolus followed by 16.5 g/kg/h CI) and in three of six cases treated with bolus dosing (80 to 150 g/kg).3 Treatment was partially effective in the other three patients in the bolus dosing group and was ineffective in the third patient treated with CI. The authors noted that lack of efficacy was associated with delay in starting NovoSeven therapy, as described below.
High-Dose CI The large study reported by Kenet et al,13 which included standard-dose CI, high-dose CI, and single high-dose bolus arms, was described earlier and in Table 2.13 Briefly, it appeared that the high-dose regimens (high-dose CI and single high-dose bolus) achieved more rapid, improved responses in patients with bleeding events, while both CI regimens were 100% successful in patients undergoing surgery. In an Italian study reported by Santagostino et al, in which 18 patients with high-titer inhibitors were given a NovoSeven bolus dose (range, 90 to 150 g/kg) followed by a CI maintenance dose (range, 10 to 50 g/kg/h), the investigators found that somewhat higher CI rates appeared to be associated with a slightly better response rate.27 This means that 14 of 14 cases were successfully treated with a mean infusion rate of 16.5 to DM, January 2003
29
TABLE 3. Summary of Published Experience With CI NovoSeven
Reference, Year
No. of Patients
Gringeri et al, 19916 Schulman et al, 199631 Stieltjies et al, 199735 Mauser-Bunschoten et al, 199821
A: 1 A: 1C: 1 1 (age?) A: 7
Me´nart et al, 199823 Montoro et al, 199824 Rocino et al, 199825 Schulman, 199830
A: 1? C: 1 2 (age?) 36 (age?)
Vermylen et al, 199837
2 (age?)
Lorenzo et al, 199916 Scaraggi et al, 199929 Baudo et al, 20001
Chuansumrit et al, 20003
No. of Procedures
Disease 1 hem A 2 hem A 1 hem A 6 hem A 1 hem? 1 hem A 1 hem A 2 hem A 27 hem A 3 hem B 2 Glanz. 2 FXI def. 2 FVII def. 2 hem?
1 intervention 4 interventions 1 intervention 4 bleeds 5 interventions 1 intervention 1 intervention 2 interventions 29 bleeds 26 inteventions
C: 1 (15 yr) A: 1 A: 4
1 1 3 1
1 1 2 2
2 hem?
3 bleeds
d’Oiron et al, 20005
A: 1 C: 1 A: 3
3 Glanz
3 interventions
Grossmann et al, 20007 Smith et al, 200134
A: 1 A: 8
1 VWD 8 hem A or B
Tagariello et al, 200036 Jime´nez-Yuste et al, 200011
A: 2 A: 1
2 hem A 1 FVII def.
1 bleed 8 interventions (2 major, 6 minor) 2 interventions 1 intervention
Kenet et al, 200013
Not specified
Hem?
137 bleeds 12 interventions
Santagostino et al, 200027
18 (age?)
15 hem? 3 acq inhib
10 bleeds 13 interventions
hem A hem A hem A hem?
3 interventions
intervention bleed bleeds interventions
*
Actual (rather than target) FVII:C. Patient was switched from CI FVIII to CI rFVIIa. Abbreviations: A, adults; age?, age unspecified; C, children; hem, hemophilia; hem?, not specified whether hemophilia A or B; Glanz, Glanzmann’s thrombasthenia; def., deficiency; VWD, von Willebrand disease; acq inhib, acquired inhibition; N/A, not applicable.
†
30
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TABLE 3. Continued
RFVIIa, CI (g/kg/h)
Target or Actual* FVII:C (U/mL)
38 — 20 30-6
g10* 10 — —
12 h 3.5-14 d 12 h 1-14 d
20 — 22.0-6.8 —
⬎8 20-10 — 10
? 5d 10-34 d Total 368 d
29 -6
10
20 16.7-4.7 20 -10
10.4-6.3† — 24.0-5.2*
90
16.5
—
70-110
30 -9
25 -13*
3-15 d
90 90
20 16.5
— 10
4d 1-26 d
120 13.3
42 -11 3.3 -1.7
56-8* —
12-29 d 4d
—
⬎10 ⬎20
⬎2 d
RFVIIa, Initial Bolus (g/kg) 75 90 90 90 0† 90 90-120 N/A
90
120 120 90-100
I) 90 II) 180
90-150
50 -10
59-6*
Duration of CI
13-14 d 7 d post-op ⫹ 4 boluses for joint mobilization 17 d 4-18 d
64-702 h
Median, 6 d (range, 134)
CI Effective No Yes No 8 Yes 1 Partial Yes Yes Yes Yes in 91-96 1 No
Yes
Yes Yes 2 Yes 1 Partial 1 No 2 Yes 1 No 2 Yes 1 Partial Yes 3 Yes 4 No Yes Yes I & II Yes in 100% interventions and 65-72% bleeds
22 Yes 1 No
20.0 g/kg/h, compared with six of eight cases treated with infusion rates less than 16.5 g/kg/h. In one patient undergoing a pacemaker implantation, NovoSeven treatment was initially considered ineffective at a DM, January 2003
31
TABLE 4. CI NovoSeven Regimens in Two Patients Undergoing Total Hip Replacement Patient No.
Age (yr)
Bolus Dose rFVIIa (g/kg)
1
32
120⫻2
2
29
120*⫻4
CI Dose rFVIIa (g/kg/h) 30, 22, 18, 11, 18, 11, 42, 30, 21,
d d d d d d d d d
1 2-3 4-5 6-8 8-13 14-29 1-4 5-8 9-12
Plasma FVII: C Range Peak-Trough (U/mL)
Total rFVIIa Dose (mg/kg)
Breakthrough Bleeding on rFVIIa
24-8
9.93
d 8, major bleed at site of surgery
56-13
9.32
None
Dose not specified in text; assumed to be 120 g/kg, as for patient no. 1. Data from Tagariello et al.36.
*
FVII:C level of 6 U/mL, but more accurate surgical hemostasis resolved the problem. It is possible that patients with significant trauma or bleeding in soft tissues may require maintenance FVII:C levels of greater than 10 U/mL. In a case report of two adult hemophilic patients treated with NovoSeven CI following total hip arthroplasty, both patients received a similar total dose of NovoSeven but better hemostatic control was achieved in the patient treated with a more intensive regimen (Table 4, Fig 3).36 In patient no. 2, mobilization was started on day 8 but he did not experience any bleeding until day 14, the day after CI NovoSeven was stopped. This bleed at the site of the wound was treated successfully with two bolus doses of NovoSeven (90 g/kg) 2 hours apart.
Timing of Treatment Current treatment strategies emphasize the benefits of early use of NovoSeven. There is now good evidence that the earlier NovoSeven treatment is initiated after the onset of a bleeding episode, the better the response rate, and the fewer the doses required, with subsequent cost savings.17,26 Lusher17 has reviewed the effect of NovoSeven timing on response rate and total dose given in hemophilia patients with inhibitors included in the compassionate use,2,8,19 dose-finding,20 and US home treatment14 studies. Only episodes of peripheral extremity hemorrhage were included in the review. A comparison of the results demonstrated a much higher success rate with early compared with delayed NovoSeven treatment, with fewer doses required to control the bleeding (Table 5). The extensive delay before NovoSeven treatment in the compassionate32
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FIG 3. Plasma FVII:C and rFVIIa dose in two adult patients with severe hemophilia A and inhibitors treated with 2 different rFVIIa regimens (see Table 4) during total hip replacement. Reprinted with permission from Tagariello et al.36
use study occurred because the protocol stated that NovoSeven could only be given when all other therapeutic options had failed. Lusher commented that delayed NovoSeven treatment was also associated with greater morbidity, prolonged hospitalizations and enormous additional and unnecessary cost.17 In an Italian study of NovoSeven home treatment (90 g/kg every 3 ⫹ 1 hours) for 53 bleeding episodes (45 hemarthroses and eight hematomas), reported by Santagostino et al, the response was rated by the patient as effective (hemorrhage stopped or substantially decreased), partially effective (bleeding reduced), or ineffective (unchanged or worse).26 Treatment was considered to be effective in 36 (80%) of 45 hemarthroses, and in six (75%) of eight hematomas (Table 6). Again, there was a clear DM, January 2003
33
TABLE 5. Overall Comparison of Results of Treatment With NovoSeven for Peripheral Intramuscular Hemorrhages From Three Databases
No. of Bleeding Episodes
Study Compassionate use2,8,19 Dose-finding20
111 a) 14 b) 15
US home treatment14
116
Mean Time Interval (onset of bleeding to first % Achieving Mean No. treatment Excellent or Doses of with Effective rFVIIa rFVIIa) Response Given
rFVIIa Dosage (g/kg/dose) and Interval 60-120, every 2⫾4h a) 70 every 2.5 ⫾ 0.5 h b) 35 every 2.5 ⫾ 0.5 h 90 every 3 h
5d
63.1
13.6
9h
72
3.6
9h
53
3.5
1.2th
92
2.3
17
Data from Lusher et al.
TABLE 6. Response to Home Treatment With NovoSeven in 53 Bleeding Episodes Response to rFVIIa Treatment Bleeding Episode
No.
Effective (%)
Partially Effective (%)
Failure (%)
Hemarthroses In nontarget joints In target joints Hematomas Type of hemorrhage Spontaneous Post-traumatic Total
45 21 24 8
36 (80) 18 (86) 18 (75) 6 (75)
4 (9) 2 (9) 2 (8) 2 (25)
5 (11) 1*(5) 4†(17) 0
41 12 53
34 (83) 8 (67) 42 (79)
3 (7) 3 (35) 6 (11)
4 (10) 1 (8) 5 (10)
*
Bleeding recurrence at the same site within 48 hours of the first rFVIIa injection. Three ineffective treatment courses and one bleeding recurrence at the same site within 48 hours of the first dose. Data from Santagostino et al.26
†
correlation between early NovoSeven administration, treatment efficacy, and the number of doses required (Table 7). Data regarding treatment timing and efficacy of NovoSeven based on type of bleeding event were not presented.26 In a study by Chuansumrit et al (described earlier), a correlation between NovoSeven efficacy and earlier initiation of treatment was reported.3 Among the six cases included in a bolus dosing group (80 to 150 g/kg), treatment was effective in three episodes treated within 1, 6, 34
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TABLE 7. Efficacy of NovoSeven Treatment (90 g/kg self-administered every 3 ⫾ 1 h up to a maximum of four doses) in Relation to Time of Administration and Number of Doses Required in 53 Bleeding Episodes
Median time of NovoSeven treatment from bleeding onset (h) Median no. NovoSeven doses required
Effective (n ⴝ 42)
Partially Effective/Failed (n ⴝ 11)
P Value
0.6
2.7
.02
3
.007
1.5 26
Data from a home treatment study by Santagostino et al.
Reprinted with permission.
and 36 hours of bleeding onset and partially effective in three episodes treated within 36, 44, and 72 hours, respectively. Moreover, patients who received NovoSeven 1 or 6 hours after the onset of bleeding required only one or three doses, respectively, compared with the other patients, who each received four doses.
Prophylaxis for Bleed Prevention Although the short half-life of NovoSeven would seem to preclude its use as a prophylactic therapy for bleed prevention, it has been used in a small number of difficult patients in this manner, with reported success. Saxon and Jory in Australia described the prophylactic use of NovoSeven 90 g/kg/day in a 5-year-old boy with severe hemophilia A and high-titer inhibitors.28 During the previous year, the child had experienced repeated joint bleeds, for which he received treatment with NovoSeven on each occasion, as well as rest and splinting for a minimum of 3 days. The joint bleeds included six left ankle hemarthroses during one 7-week period, that were treated with a mean of 4.7 doses of 90 g/kg NovoSeven per bleeding episode. Four weeks later, 10 right ankle hemarthroses and nine severe periarticular bleeds occurred over a 9-week period, each of which was treated with a mean of 4.0 doses of NovoSeven. As the bleed frequency in this patient was increasing, and as he had developed calf muscle wasting resulting in severely restricted mobility, the authors decided to initiate daily NovoSeven prophylaxis (240 g/kg/d). As a result, the frequency of bleeding episodes was dramatically decreased, as well as the number of treatments per bleed, and the child’s mobility was improved. Based on the information presented in this report, calculations for total doses administered revealed that, during the previous periods of ankle hemarthroses (totaling 16 weeks), the mean number of NovoSeven doses per week was 8.4 (giving a total of ⬃134 doses). In contrast, only DM, January 2003
35
8.5 additional doses of NovoSeven were required during the 11-week prophylactic period (giving a total of ⬃86 doses, or ⬃7.8 per week). This treatment strategy may therefore have been cost-effective in this child. In the report described above,4 Cooper et al administered high-dose NovoSeven (240 g/kg every 6 hours, every 8 hours, every 12 hours, and every 24 hours) for cover during surgery for release of severe knee contractures in a 12-year-old boy. Prophylactic NovoSeven was given once daily at a dose of 240 g/kg during a subsequent 4- to 6-week period of physical therapy.4 During this time, there was just one bleed (in the elbow joint, as result of improper use of crutches), and no evidence of accumulation of NovoSeven activity, clinical thrombosis, or increase in inhibitor titer.
Summary State-of-the-art treatment of hemophilic patients with inhibitors using NovoSeven includes: institution of early therapy; consideration of the patient’s age and/or individual pharmacokinetics and clearance rate; type of bleeding episode experienced or procedure to be undertaken; delivery method (bolus v CI); and dose level and infusion interval. Attention to these issues may allow optimization of a patient’s individual outcome. The ability to choose rationally and monitor dosing and treatment regimens would be improved by the development of a laboratory parameter that correlated with clinical efficacy. The evelopment of such a test to be utilized with NovoSeven is clearly necessary to advance both development of rational dosing guidelines and our understanding of why some patients fail, and to limit cost while maximizing efficacy. Increased knowledge of the parameters that impact the pharmacokinetics of NovoSeven in individual patients would also be of benefit to the clinician. Expanded pharmacokinetic studies, particularly in the pediatric population, would be useful in the development of optimal treatment guidelines.
References 1.
4.
Baudo F, Redaelli R, Caimi TM, et al. The continuous infusion of recombinant activated factor VIIa (rFVIIa) in patients with factor VIII inhibitors activates the coagulation and fibrinolytic systems without clinical complications. Thromb Res 2000;99:21-24. Bech RM. Recombinant factor VIIa in joint and muscle bleeding episodes. Haemostasis 1996;26(suppl 1):135-138. Chuansumrit A, Isarangkura P, Angchaisuksiri P, et al. Controlling acute bleeding episodes with recombinant factor VIIa in haemophiliacs with inhibitor: continuous infusion and bolus injection. Haemophilia 2000;6:61-65. Cooper HA, Jones CP, Campion E, et al. Successful use of high dose rFVIIa in a
36
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15. 16. 17. 18. 19. 20.
21.
high titre inhibitor patient with haemophilia B during major orthopaedic manipulations and rehabilitation to release fixed flexion contractions of both knees. Haemophilia 2000;6(abstr 45):297-298. d’Oiron R, Me´ nart C, Trzeciak MC, et al. Use of recombinant factor VIIa in 3 patients with inherited type I Glanzmann’s thrombasthenia undergoing invasive procedures. Thromb Haemost 2000;83:644-647. Gringeri A, Santagostino E, Mannucci PM. Failure of recombinant activated factor VII during surgery in a hemophiliac with high-titer factor VIII antibody. Haemostasis 1991;21:1-4. Grossmann RE, Geisen U, Schwender S, et al. Continuous infusion of recombinant factor VIIa (NovoSeven) in the treatment of a patient with type III von Willebrands disease and alloantibodies against von Willebrand factor. Thromb Haemost 2000; 83:633-634. Hedner U, Glazer S, Falch J. Recombinant activated factor VII in the treatment of bleeding episodes in patients with inherited and acquired bleeding disorders. Transfus Med Rev 1993;7:78-83. Hedner U, Kristensen H, Berntorp E, et al. Pharmacokinetics of rFVIIa in children. Haemophilia 1998;4:355. Jime´ nez-Yuste V, Villar A, Foncillas MA, et al. Are higher doses needed of recombinant activated factor VII in haemophiliac paediatric patients with inhibitor? Haemophilia 2000;6(abstr):298. Jime´ nez-Yuste V, Villar A, Morado M, et al. Continuous infusion of recombinant activated factor VII during caesarean section delivery in a patient with congenital factor VII deficiency. Hemophilia 2000;6:588-590. Kenet G, Lubetsky A, Gitel S, et al. Treatment of bleeding episodes in patients with hemophilia and an inhibitor: Comparison of two treatment protocols with recombinant activated factor VII. Blood Coag Fibrinol 2000;11:S35-S38. Kenet G, Lubetzky A, Luboshitz J, et al. Treatment of inhibitor patients with rFVIIa: Continuous infusion protocols as compared to a single, large, dose. Haemophilia 2000;76(abstr 44):297. Key NS, Aledort LM, Beardsley D, et al. Home treatment of mild to moderate bleeding episodes using recombinant factor VIIa (Novoseven) in haemophiliacs with inhibitors. Thromb Haemost 1998;80:912-918. Lindley CM, Sawyer WT, Macik BG, et al. Pharmacokinetics and pharmacodynamics of recombinant factor VIIa. Clin Pharmacol Ther 1994;55:638-648. Lorenzo JI, Montoro JM, Aznar JA. Postoperative use of rFVIIa by continuous infusion in a haemophilic boy. Haemophilia 1999;5:135-138. Lusher JM. Early treatment with recombinant factor VIIa results in greater efficacy with less product. Eur J Haematol 1998;63:7-10. Lusher JM. Inhibitor antibodies to factor VIII and factor IX: Management. Semin Thromb Hemost 2000;26:179-188. Lusher JM, Ingerslev J, Roberts HR, et al. Clinical experience with recombinant factor VIIa. Blood Coagul Fibrinol 1998;9:119-128. Lusher JM, Roberts HR, Davignon G, et al. A randomized, double-blind comparison of two dosage levels of recombinant factor VIIa in the treatment of joint, muscle and mucocutaneous haemorrhages in persons with haemophilia A and B, with and without inhibitors. RFVIIa Study Group. Haemophilia 1998;4:790-798. Mauser-Bunschoten EP, de Goede-Bolder A, Wielenga JJ, et al. Continuous infusion
DM, January 2003
37
22.
23.
24.
25.
26.
27.
28. 29.
30. 31. 32.
33.
34.
35.
36.
37.
38
of recombinant factor VIIa in patients with haemophilia and inhibitors. Experience in the Netherlands and Belgium. Neth J Med 1998;53:249-255. McPherson J, Sutcharitchan P, Lloyd J, et al. Experience with continuous infusion of recombinant activated factor VII in the Asia-Pacific region. Blood Coagul Fibrinol 2000;11(suppl 1):S31-S34. Me´ nart C, Cognet V, Petit PY, et al. Management of an anti-factor VIII inhibitor occurring during surgical procedure with continuous infusion of NovoSeven. Blood Coagul Fibrinol 1998;9:289-290. Montoro JB, Altisent C, Pico M, et al. Recombinant factor VIIa in continuous infusion during central line insertion in a child with factor VIII high-titre inhibitor. Haemophilia 1998;4:762-765. Rocino A, Miraglia E, Ziello L, et al. Successful continuous infusion (CI) rFVIIa treatment during surgery in two high responding inhibitor patients with hemophilia A. Haemophilia 1998;4(abstr):350. Santagostino E, Gringeri A, Mannucci PM. Home treatment with recombinant activated factor VII in patients with factor VIII inhibitors: The advantages of early intervention. Br J Haematol 1999;104:22-26. Santagostino E, Rocino A, Gringeri A, et al. Continuous infusion of recombinant activated factor VIIa (rFVIIa) for treatment of high titre inhibitor patients: The Italian experience. Haemophilia 2000;6(abstr 43):279. Saxon BR, Jory CB. Effective prophylaxis with daily rFVIIa (NovoSeven) in a child with high titre inhibitors and a target joint. Haemophilia 2000;6(abstr 49):299. Scaraggi FA, De Mitrio V, Marino R, et al. Treatment with recombinant activated factor VII in a patient with hemophilia A and an inhibitor: Advantages of administration by continuous infusion over bolus intermittent injections. Blood Coagul Fibrinol 1999;10:33-38. Schulman S. Safety, efficacy and lessons from continuous infusion with rFVIIa. rFVIIa-CI Group. Haemophilia 1998;4:564-567. Schulman S, Bech Jensen M, Varon D, et al. Feasibility of using recombinant factor VIIa in continuous infusion. Thromb Haemost 1996;75:432-436. Schulman S, d’Oiron R, Martinowitz U, et al. Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinol 1998;9(suppl 1):S97S101. Schulman S, rFVIIa-CI Group. Continuous infusion of recombinant factor VIIa in hemophilic patients with inhibitors: Safety, monitoring, and cost effectiveness. Semin Thromb Hemost 2000;26:421-424. Smith MP, Ludlam CA, Collins PW, et al. Elective surgery on factor VIII inhibitor patients using continuous infusion of recombinant activated factor VII: Plasma factor VII activity of 10 IU/mL is associated with an increased incidence of bleeding. Thromb Haemost 2001;86:949-953. Stieltjes N, Ounnoughene N, Vassilieff D, et al. Failure of recombinant factor VIIa to control surgical bleeding in a severe hemophilia A patient with an inhibitor and possible DIC. Thromb Haemost 1997;50(suppl, abstr):PS-202. Tagariello G, de Biasi E, Gajo GB, et al. Recombinant FVIIa (NovoSeven) continuous infusion and total hip replacement in patients with haemophilia and high titre of inhibitors to FVIII: Experience of two cases. Haemophilia 2000;6:581-583. Vermylen J, Peerlinck K. Optimal care of inhibitor patients during surgery. Eur J Haematol 1998;63(suppl):15-17. DM, January 2003
DM, January 2003
pproximately 30% of children with severe hemophilia A and 1% to 3% of those with severe hemophilia B develop inhibitor antibodies to factor VIII (FVIII) or factor IX (FIX), respectively.18 Several options exist for the management of these patients. These include immune tolerance therapy (ITI) to eradicate the inhibitors and various strategies for the prevention or ontrol of bleeding. Previous therapies have included prothrombin complex concentrates (PCCs), activated PCCs, and porcine FVIII. The advent of recombinant factor VIIa (rFVIIa; NovoSeven威, Novo Nordisk, Copenhagen, Denmark) has increased available treatment options. In many patients with inhibitors, NovoSeven is now the treatment of choice. Over the last decade, NovoSeven has been used with a high success rate in hemophilic patients with inhibitors, both for the management of bleeding episodes and for cover during surgical or physiotherapy interventions. Optimal dosing and administrative strategies are still being evaluated. Optimization of a patient’s regimen includes consideration of: (1) individual pharmacokinetics (especially in the pediatric population); (2) use of high-dose bolus regimens; (3) use of continuous infusion (CI), including high-dose CI; (4) institution of early treatment with NovoSeven in the course of a bleeding event; and (5) use of NovoSeven as a prophylactic therapy. These current trends in the use of NovoSeven for the treatment of hemophilic patients with inhibitors will be discussed.
A
Individual Pharmacokinetics The pharmacokinetics of NovoSeven have been shown to vary widely between individual patients (Fig 1).15,30,32 In particular, infants and children have been shown to have higher clearance rates of NovoSeven, with a shorter half-life compared to adults.9 Following bolus doses of 114 to 196 g/kg in six children (three with hemophilia A and three with hemophilia B) aged 5 to 12 years, mean clearance was found to be roughly doubled in children compared to adults, with a shorter mean residence time and a greatly reduced half-life (Table 1). Data from case reports of children treated with NovoSeven CI provide further evidence of variations in pharmacokinetics compared with adult values.16,24 In a 15-year-old hemophilic patient who was scheduled to receive NovoSeven CI postoperatively, plasma factor VII (FVII) levels after three initial bolus doses of 120 g/kg every 2 hours ranged from 29 to 31 U/mL at 10 minutes postinjection, from 9.5 to 15.5 U/mL at 1 hour postinjection, and from 3.7 to 7.2 U/mL at 2 hours postinjection.16 In vivo recovery of FVIIa was 0.5%/IU/kg and the half-life was estimated to be DM, January 2003
23
FIG 1. Clearance of NovoSeven (measured by a one-stage clotting assay) obtained by pharmacokinetic evaluation of seven cases. Reprinted with permission from Schulman et al: Experiences with continuous infusion of recombinant activated factor VII. Blood Coagul Fibrinol 9:S97-S101, 1998 (suppl 1).32
no more than 1 hour; both of these values were described as “less than expected.”16 In another case report of a 6-year-old child with severe hemophilia A with a weight of 23 kg, preoperative clearance of NovoSeven was found to be 34.6 mL/h/kg (similar to reported adult levels2), volume of distribution 40.6 mL/kg, and mean residence time 1.17 hours (similar to levels reported in children).9,24 During NovoSeven CI at doses ranging from 7.6 g/kg/h to 4.3 g/kg/h over 5 days, clearance rates varied between 15.2 and 34.0 mL/h/kg, with a downward trend compared to preoperative values. In some cases, and especially in the pediatric population, increased bolus and maintenance doses may therefore be necessary to achieve optimal hemostasis.
High-Dose NovoSeven Bolus Regimens Bolus dosing of NovoSeven remains the standard method of administration in the majority of patients, especially in patients treated at home and those with mild to moderate bleeds who only require a limited 24
DM, January 2003
TABLE 1. Pharmacokinetics of NovoSeven in Six Hemophilic Children Compared to Previously Measured Adult Values
Children (mean age, 8 yr; range, 5-12) Adults
Mean Clearance (mL/h/kg)
Mean Residence Time (h)
Plasma Half-Life (h)
67.0
1.94
1.32
32.8
3.33
2.72
Based on data from Hedner et al.9
number of doses, and for the optimal management of specific patients, or bleeding episodes, depending on each unique clinical situation. The most common bolus dose of NovoSeven is 90 g/kg with dosing intervals dependent on the patient’s clinical circumstances. Some patients, particularly pediatric patients, appear to benefit from higher dose regimens. As NovoSeven is hemostatically active at a local level, it appears to have a wide safety margin. High-dose regimens may optimize thrombin generation or the thrombin burst, and may allow for prolongation of the dosing interval. Doses up to 300 g/kg have been administered without reported adverse event.18 Several investigators have reported the use of higher than standard bolus doses of NovoSeven in pediatric patients, without adverse effects or clinical signs of disseminated intravascular coagulation (DIC).4,10 Cooper et al in the United States described the use of high-dose NovoSeven for cover during major orthopedic manipulations and rehabilitation in a 12-year-old boy with severe hemophilia B and a high-titer inhibitor.4 He had previously responded poorly to conventional therapy and had become wheelchair-bound with greater than 30 degrees flexion contracture of the knees. Joint bleeding was eventually controlled with high doses of NovoSeven (240 to 300 g/kg). For this reason, the authors selected a NovoSeven dose of 240 g/kg, given at increasing intervals (every 6 hours, every 8 hours, every 12 hours, and every 24 hours), to maintain hemostasis during hospitalization and rehabilitation after successful release of contractures. During a 4- to 6-week period of vigorous physical therapy during which time the patient was dosed prophylactically, they reported only a single elbow bleed, which resulted from an improper use of crutches. Importantly, there was no evidence of accumulation of FVII activity, nor of any clinical thrombosis or increase in inhibitor titer. Jime´nez-Yuste et al in Spain have also reported the safe and effective use of high-dose NovoSeven for three bleeds and two Port-A-Cath placements in three pediatric patients with hemophilia and high-titer DM, January 2003
25
TABLE 2. Response to Various NovoSeven Treatment Protocols in Hemophilia Patients Undergoing Surgical Intervention or Treatment for Bleeding Events
Type of Case Surgical Major bleeds Hemarthrosis
Protocol*
N
Median Dose NovoSeven (g/kg)
Response (%)
II I I I II III
10 2 8 57 72 29
1074 2940 1746 270 360 300
100 100 65 70 72 82
Protocol I (standard-dose CI): 90 g/kg bolus followed by 14-16 g/kg CI for 2 days, and a clearance-adjusted rate thereafter to maintain FVII:C trough levels ⬎ 10 IU/mL; protocol II (high-dose CI): 180 g/kg bolus followed by 30 g/kg CI to maintain FVII:C trough levels ⬎ 20 IU/mL; protocol III: single high-dose (300 g/kg) bolus. Data from Kenet et al.13 *
inhibitors.10 In each case, NovoSeven was given every 2 hours, starting with 150 to 160 g/kg for the first dose, followed by 120 to 140 g/kg for the second dose, and 90 g/kg for the third and any subsequent doses. Compared to previous experiences with lower-dose NovoSeven in pediatric patients, the authors considered the high-dose treatment to be more effective for the prevention or control of bleeding, and possibly to reduce the number of doses required. They observed an increase in D-dimers in all patients but there were no clinical signs of DIC or other adverse events. A large study by Kenet et al13 involved 149 cases treated with CI NovoSeven for surgery or bleeding and included standard-dose CI (protocol I), high-dose CI (protocol II), and single high-dose bolus arms (protocol III), all defined in the footnote to Table 2.13 They found that both CI rotocols were effective for surgical cover in 100% of cases but that, in patients with bleeding events, the high-dose CI regimen and the single high-dose bolus were associated with a slightly higher and more rapid response rate compared with the lower-dose CI. The authors also stated that protocol III (single high-dose bolus infusion) provided a slightly better response rate in hemarthroses and in improved quality of life compared with other dosing regimens.
Rationale for NovoSeven CI There has been significant interest in the administration of NovoSeven by CI, particularly in patients requiring prolonged treatment. As NovoSeven has a short half-life of approximately 2.7 hours,15 necessitating 2to 3-hourly administration of bolus doses,31 CI theoretically may provide 26
DM, January 2003
more reliable hemostatic coverage compared with bolus dose regimens. It has also been suggested that CI may be of benefit for bleeds in tissues with poor expression of tissue factor (eg, skeletal muscle), which may therefore require higher and more constant plasma evels of NovoSeven.29 CI is also considered more convenient than bolus dosing, as the syringes need to be changed only every 6 to 24 hours.16,21 There is also potential for cost savings, as lower dose requirements with NovoSeven CI have been documented in a number of studies,3,12,21,22,33 and particularly as there is an apparent decrease in clearance over time during prolonged infusion,9,16,24,31 allowing gradual tapering of doses.
Dosing With CI NovoSeven CI treatment is instituted after an initial bolus dose, usually of 90 to 120 g/kg, which generates the initial thrombin burst, thus ensuring adequate hemostasis.33 Repeat bolus dosing during CI may be required in some patients,33 that, in conjunction with the level of FVII activity targeted or required for hemostasis, may actually lead to increased utilization of NovoSeven compared with some bolus dosing regimens. Parallel saline infusion is also advised when NovoSeven CI is administered via a peripheral vein in order to reduce the risk of local thrombophlebitis.31 The concomitant use of unfractionated heparin (UFH) for this purpose is not recommended as the addition of UFH to infusion bags has been reported to result in a 50% loss of rFVIIa activity within 4 hours of storage.31 No such loss of activity has been reported with low-molecular-weight heparin (LMWH),31 but this agent has been associated with the formation of precipitates, that appear to contain FVIIa and may, therefore, decrease the FVIIa content of the infusion.16 In order to determine the optimal infusion rate needed to maintain the usual targeted FVII:C level of approximately 10 U/mL, individual clearance rates should be calculated whenever possible.31,33 These are calculated according to the following equation:33 Infusion rate 共IU/kg/h兲 ⫽ Clearance 共mL/kg/h兲 ⫻ stead y-state concentration 共IU/mL兲 A sample calculation is shown in Fig 2.
Experience With CI Data from 20 published reports of the use of NovoSeven CI for the management of 281 cases (187 bleeding events and 94 interventions) DM, January 2003
27
FIG 2. Sample calculation of individual NovoSeven infusion rate. Reprinted with permission from Schulman et al: Continuous infusion of recombinant factor VIIa in hemophilic patients with inhibitors: Safety, monitoring and cost effectiveness. Semin Thromb Hemost 26:421-424, 2000.33
suggest that CI is effective in controlling or preventing bleeding in the majority of patients (Table 3).1,3,5-7,11,13,16,21,23-25,27,29,30,31,34-37
Standard-Dose CI A study of NovoSeven CI reported by Schulman included 29 bleeding events and 26 interventions.30 The targeted FVII:C level was approximately 10 U/mL. Effective hemostasis was achieved in 91% of patients overall; 96% of cases when concomitant administration of antifibrinolytics was provided and in 66% of cases when antifibrinolytics were not administered.30 Significantly fewer hemorrhagic complications were observed in patients receiving antifibrinolytics compared with those who did not (2/46 v 3/9, respectively; P ⫽ .033). In a European study performed by Ludlam et al, all patients received a standard NovoSeven bolus dose of 90 g/kg and were then allocated to receive either a standard CI maintenance dose of 16.5 g/kg/h to achieve a target FVII:C level of 10 U/mL, or a high CI maintenance dose of 50 g/kg/h to achieve a target FVII:C level of 30 U/mL. Data from the high-dose arm of the study have not been published yet. Patients in the lower-dose arm were infused for a median of 13.5 days (range, 1 to 26 days).34 At this dosing level, effective hemostasis was achieved in one of two minor procedures and two of six major operations. Excessive bleeding was reported in three of the lower-dose patients, even though FVII:C levels were maintained at approximately 10 U/mL. The authors concluded that NovoSeven CI given at an infusion rate of 16.5 g/kg/h 28
DM, January 2003
did achieve the target FVII:C level but that this level did not provide reliable hemostasis. The largest study of NovoSeven CI, reported by Kenet, also included a high-dose bolus NovoSeven treatment arm and is described in more detail above.13 Among the remaining 77 compiled reported cases of NovoSeven administered as an initial bolus with subsequent CI, dosing levels varied (bolus dose range, 75 to 150 g/kg; CI dose range, 4.7 to 50 g/kg/h; target FVII:C, 10 to 30 U/mL; actual FVII:C, 5.2 to 59 U/mL). Overall, CI NovoSeven was reported to be effective in 63 of 77 (82%) cases, partially effective in five of 77 (6%), and ineffective in nine of 77 (12%).1,3,5-7,11,16,21,23-25,27,29,31,34-37
Bolus Versus CI NovoSeven Three reports have compared bolus dosing and CI NovoSeven.3,7,29 Two of these were case reports of single patients, each of which was successfully switched from NovoSeven bolus dosing to CI7,29 due to lack of efficacy of bolus dosing (120 g/kg bolus switched to 16.7 g/kg/h, gradually decreasing to 4.7 g/kg/h CI29, and 90 g/kg bolus switched to 20 g/kg/h CI7). The third report, by Chuansumrit et al in Thailand, reported a prospective open study in hemophilic patients, in which NovoSeven was found to be effective in two of three cases treated with CI (90 g/kg bolus followed by 16.5 g/kg/h CI) and in three of six cases treated with bolus dosing (80 to 150 g/kg).3 Treatment was partially effective in the other three patients in the bolus dosing group and was ineffective in the third patient treated with CI. The authors noted that lack of efficacy was associated with delay in starting NovoSeven therapy, as described below.
High-Dose CI The large study reported by Kenet et al,13 which included standard-dose CI, high-dose CI, and single high-dose bolus arms, was described earlier and in Table 2.13 Briefly, it appeared that the high-dose regimens (high-dose CI and single high-dose bolus) achieved more rapid, improved responses in patients with bleeding events, while both CI regimens were 100% successful in patients undergoing surgery. In an Italian study reported by Santagostino et al, in which 18 patients with high-titer inhibitors were given a NovoSeven bolus dose (range, 90 to 150 g/kg) followed by a CI maintenance dose (range, 10 to 50 g/kg/h), the investigators found that somewhat higher CI rates appeared to be associated with a slightly better response rate.27 This means that 14 of 14 cases were successfully treated with a mean infusion rate of 16.5 to DM, January 2003
29
TABLE 3. Summary of Published Experience With CI NovoSeven
Reference, Year
No. of Patients
Gringeri et al, 19916 Schulman et al, 199631 Stieltjies et al, 199735 Mauser-Bunschoten et al, 199821
A: 1 A: 1C: 1 1 (age?) A: 7
Me´nart et al, 199823 Montoro et al, 199824 Rocino et al, 199825 Schulman, 199830
A: 1? C: 1 2 (age?) 36 (age?)
Vermylen et al, 199837
2 (age?)
Lorenzo et al, 199916 Scaraggi et al, 199929 Baudo et al, 20001
Chuansumrit et al, 20003
No. of Procedures
Disease 1 hem A 2 hem A 1 hem A 6 hem A 1 hem? 1 hem A 1 hem A 2 hem A 27 hem A 3 hem B 2 Glanz. 2 FXI def. 2 FVII def. 2 hem?
1 intervention 4 interventions 1 intervention 4 bleeds 5 interventions 1 intervention 1 intervention 2 interventions 29 bleeds 26 inteventions
C: 1 (15 yr) A: 1 A: 4
1 1 3 1
1 1 2 2
2 hem?
3 bleeds
d’Oiron et al, 20005
A: 1 C: 1 A: 3
3 Glanz
3 interventions
Grossmann et al, 20007 Smith et al, 200134
A: 1 A: 8
1 VWD 8 hem A or B
Tagariello et al, 200036 Jime´nez-Yuste et al, 200011
A: 2 A: 1
2 hem A 1 FVII def.
1 bleed 8 interventions (2 major, 6 minor) 2 interventions 1 intervention
Kenet et al, 200013
Not specified
Hem?
137 bleeds 12 interventions
Santagostino et al, 200027
18 (age?)
15 hem? 3 acq inhib
10 bleeds 13 interventions
hem A hem A hem A hem?
3 interventions
intervention bleed bleeds interventions
*
Actual (rather than target) FVII:C. Patient was switched from CI FVIII to CI rFVIIa. Abbreviations: A, adults; age?, age unspecified; C, children; hem, hemophilia; hem?, not specified whether hemophilia A or B; Glanz, Glanzmann’s thrombasthenia; def., deficiency; VWD, von Willebrand disease; acq inhib, acquired inhibition; N/A, not applicable.
†
30
DM, January 2003
TABLE 3. Continued
RFVIIa, CI (g/kg/h)
Target or Actual* FVII:C (U/mL)
38 — 20 30-6
g10* 10 — —
12 h 3.5-14 d 12 h 1-14 d
20 — 22.0-6.8 —
⬎8 20-10 — 10
? 5d 10-34 d Total 368 d
29 -6
10
20 16.7-4.7 20 -10
10.4-6.3† — 24.0-5.2*
90
16.5
—
70-110
30 -9
25 -13*
3-15 d
90 90
20 16.5
— 10
4d 1-26 d
120 13.3
42 -11 3.3 -1.7
56-8* —
12-29 d 4d
—
⬎10 ⬎20
⬎2 d
RFVIIa, Initial Bolus (g/kg) 75 90 90 90 0† 90 90-120 N/A
90
120 120 90-100
I) 90 II) 180
90-150
50 -10
59-6*
Duration of CI
13-14 d 7 d post-op ⫹ 4 boluses for joint mobilization 17 d 4-18 d
64-702 h
Median, 6 d (range, 134)
CI Effective No Yes No 8 Yes 1 Partial Yes Yes Yes Yes in 91-96 1 No
Yes
Yes Yes 2 Yes 1 Partial 1 No 2 Yes 1 No 2 Yes 1 Partial Yes 3 Yes 4 No Yes Yes I & II Yes in 100% interventions and 65-72% bleeds
22 Yes 1 No
20.0 g/kg/h, compared with six of eight cases treated with infusion rates less than 16.5 g/kg/h. In one patient undergoing a pacemaker implantation, NovoSeven treatment was initially considered ineffective at a DM, January 2003
31
TABLE 4. CI NovoSeven Regimens in Two Patients Undergoing Total Hip Replacement Patient No.
Age (yr)
Bolus Dose rFVIIa (g/kg)
1
32
120⫻2
2
29
120*⫻4
CI Dose rFVIIa (g/kg/h) 30, 22, 18, 11, 18, 11, 42, 30, 21,
d d d d d d d d d
1 2-3 4-5 6-8 8-13 14-29 1-4 5-8 9-12
Plasma FVII: C Range Peak-Trough (U/mL)
Total rFVIIa Dose (mg/kg)
Breakthrough Bleeding on rFVIIa
24-8
9.93
d 8, major bleed at site of surgery
56-13
9.32
None
Dose not specified in text; assumed to be 120 g/kg, as for patient no. 1. Data from Tagariello et al.36.
*
FVII:C level of 6 U/mL, but more accurate surgical hemostasis resolved the problem. It is possible that patients with significant trauma or bleeding in soft tissues may require maintenance FVII:C levels of greater than 10 U/mL. In a case report of two adult hemophilic patients treated with NovoSeven CI following total hip arthroplasty, both patients received a similar total dose of NovoSeven but better hemostatic control was achieved in the patient treated with a more intensive regimen (Table 4, Fig 3).36 In patient no. 2, mobilization was started on day 8 but he did not experience any bleeding until day 14, the day after CI NovoSeven was stopped. This bleed at the site of the wound was treated successfully with two bolus doses of NovoSeven (90 g/kg) 2 hours apart.
Timing of Treatment Current treatment strategies emphasize the benefits of early use of NovoSeven. There is now good evidence that the earlier NovoSeven treatment is initiated after the onset of a bleeding episode, the better the response rate, and the fewer the doses required, with subsequent cost savings.17,26 Lusher17 has reviewed the effect of NovoSeven timing on response rate and total dose given in hemophilia patients with inhibitors included in the compassionate use,2,8,19 dose-finding,20 and US home treatment14 studies. Only episodes of peripheral extremity hemorrhage were included in the review. A comparison of the results demonstrated a much higher success rate with early compared with delayed NovoSeven treatment, with fewer doses required to control the bleeding (Table 5). The extensive delay before NovoSeven treatment in the compassionate32
DM, January 2003
FIG 3. Plasma FVII:C and rFVIIa dose in two adult patients with severe hemophilia A and inhibitors treated with 2 different rFVIIa regimens (see Table 4) during total hip replacement. Reprinted with permission from Tagariello et al.36
use study occurred because the protocol stated that NovoSeven could only be given when all other therapeutic options had failed. Lusher commented that delayed NovoSeven treatment was also associated with greater morbidity, prolonged hospitalizations and enormous additional and unnecessary cost.17 In an Italian study of NovoSeven home treatment (90 g/kg every 3 ⫹ 1 hours) for 53 bleeding episodes (45 hemarthroses and eight hematomas), reported by Santagostino et al, the response was rated by the patient as effective (hemorrhage stopped or substantially decreased), partially effective (bleeding reduced), or ineffective (unchanged or worse).26 Treatment was considered to be effective in 36 (80%) of 45 hemarthroses, and in six (75%) of eight hematomas (Table 6). Again, there was a clear DM, January 2003
33
TABLE 5. Overall Comparison of Results of Treatment With NovoSeven for Peripheral Intramuscular Hemorrhages From Three Databases
No. of Bleeding Episodes
Study Compassionate use2,8,19 Dose-finding20
111 a) 14 b) 15
US home treatment14
116
Mean Time Interval (onset of bleeding to first % Achieving Mean No. treatment Excellent or Doses of with Effective rFVIIa rFVIIa) Response Given
rFVIIa Dosage (g/kg/dose) and Interval 60-120, every 2⫾4h a) 70 every 2.5 ⫾ 0.5 h b) 35 every 2.5 ⫾ 0.5 h 90 every 3 h
5d
63.1
13.6
9h
72
3.6
9h
53
3.5
1.2th
92
2.3
17
Data from Lusher et al.
TABLE 6. Response to Home Treatment With NovoSeven in 53 Bleeding Episodes Response to rFVIIa Treatment Bleeding Episode
No.
Effective (%)
Partially Effective (%)
Failure (%)
Hemarthroses In nontarget joints In target joints Hematomas Type of hemorrhage Spontaneous Post-traumatic Total
45 21 24 8
36 (80) 18 (86) 18 (75) 6 (75)
4 (9) 2 (9) 2 (8) 2 (25)
5 (11) 1*(5) 4†(17) 0
41 12 53
34 (83) 8 (67) 42 (79)
3 (7) 3 (35) 6 (11)
4 (10) 1 (8) 5 (10)
*
Bleeding recurrence at the same site within 48 hours of the first rFVIIa injection. Three ineffective treatment courses and one bleeding recurrence at the same site within 48 hours of the first dose. Data from Santagostino et al.26
†
correlation between early NovoSeven administration, treatment efficacy, and the number of doses required (Table 7). Data regarding treatment timing and efficacy of NovoSeven based on type of bleeding event were not presented.26 In a study by Chuansumrit et al (described earlier), a correlation between NovoSeven efficacy and earlier initiation of treatment was reported.3 Among the six cases included in a bolus dosing group (80 to 150 g/kg), treatment was effective in three episodes treated within 1, 6, 34
DM, January 2003
TABLE 7. Efficacy of NovoSeven Treatment (90 g/kg self-administered every 3 ⫾ 1 h up to a maximum of four doses) in Relation to Time of Administration and Number of Doses Required in 53 Bleeding Episodes
Median time of NovoSeven treatment from bleeding onset (h) Median no. NovoSeven doses required
Effective (n ⴝ 42)
Partially Effective/Failed (n ⴝ 11)
P Value
0.6
2.7
.02
3
.007
1.5 26
Data from a home treatment study by Santagostino et al.
Reprinted with permission.
and 36 hours of bleeding onset and partially effective in three episodes treated within 36, 44, and 72 hours, respectively. Moreover, patients who received NovoSeven 1 or 6 hours after the onset of bleeding required only one or three doses, respectively, compared with the other patients, who each received four doses.
Prophylaxis for Bleed Prevention Although the short half-life of NovoSeven would seem to preclude its use as a prophylactic therapy for bleed prevention, it has been used in a small number of difficult patients in this manner, with reported success. Saxon and Jory in Australia described the prophylactic use of NovoSeven 90 g/kg/day in a 5-year-old boy with severe hemophilia A and high-titer inhibitors.28 During the previous year, the child had experienced repeated joint bleeds, for which he received treatment with NovoSeven on each occasion, as well as rest and splinting for a minimum of 3 days. The joint bleeds included six left ankle hemarthroses during one 7-week period, that were treated with a mean of 4.7 doses of 90 g/kg NovoSeven per bleeding episode. Four weeks later, 10 right ankle hemarthroses and nine severe periarticular bleeds occurred over a 9-week period, each of which was treated with a mean of 4.0 doses of NovoSeven. As the bleed frequency in this patient was increasing, and as he had developed calf muscle wasting resulting in severely restricted mobility, the authors decided to initiate daily NovoSeven prophylaxis (240 g/kg/d). As a result, the frequency of bleeding episodes was dramatically decreased, as well as the number of treatments per bleed, and the child’s mobility was improved. Based on the information presented in this report, calculations for total doses administered revealed that, during the previous periods of ankle hemarthroses (totaling 16 weeks), the mean number of NovoSeven doses per week was 8.4 (giving a total of ⬃134 doses). In contrast, only DM, January 2003
35
8.5 additional doses of NovoSeven were required during the 11-week prophylactic period (giving a total of ⬃86 doses, or ⬃7.8 per week). This treatment strategy may therefore have been cost-effective in this child. In the report described above,4 Cooper et al administered high-dose NovoSeven (240 g/kg every 6 hours, every 8 hours, every 12 hours, and every 24 hours) for cover during surgery for release of severe knee contractures in a 12-year-old boy. Prophylactic NovoSeven was given once daily at a dose of 240 g/kg during a subsequent 4- to 6-week period of physical therapy.4 During this time, there was just one bleed (in the elbow joint, as result of improper use of crutches), and no evidence of accumulation of NovoSeven activity, clinical thrombosis, or increase in inhibitor titer.
Summary State-of-the-art treatment of hemophilic patients with inhibitors using NovoSeven includes: institution of early therapy; consideration of the patient’s age and/or individual pharmacokinetics and clearance rate; type of bleeding episode experienced or procedure to be undertaken; delivery method (bolus v CI); and dose level and infusion interval. Attention to these issues may allow optimization of a patient’s individual outcome. The ability to choose rationally and monitor dosing and treatment regimens would be improved by the development of a laboratory parameter that correlated with clinical efficacy. The evelopment of such a test to be utilized with NovoSeven is clearly necessary to advance both development of rational dosing guidelines and our understanding of why some patients fail, and to limit cost while maximizing efficacy. Increased knowledge of the parameters that impact the pharmacokinetics of NovoSeven in individual patients would also be of benefit to the clinician. Expanded pharmacokinetic studies, particularly in the pediatric population, would be useful in the development of optimal treatment guidelines.
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