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کنسانتره فاکتور VIIa نو‌ترکیب در برابر کنسانتره مشتق از پلاسما، برای درمان اپیزود‌های خونریزی حاد در افراد مبتلا به هموفیلی و مهار‌کننده‌ها

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Referencias

Astermark 2007 {published data only}

Astermark J, Donfiled SM, DiMichele DM, Gringeri A, Gilbert SA, Waters J, et al. A randomized comparison of bypassing agents in hemophilia complicated by an inhibitor: the FEIBA NovoSeven Comparative (FENOC) study. Blood 2007;109(2):546‐51. CENTRAL
Carllson KS, Astermark J, Donfield SM, Berntorp E. Health‐Economic analysis of alternative bypassing agent in haemophilia complicated by an inhibitor ‐ the FEIBA NovoSeven comparative study (FENOC). Blood 2006;108:457. CENTRAL

Young 2008 {published data only}

Young G, Shaffer FE, Rojas P, Seremetis S. Single 270 mcg/kg ‐dose rFVIIa versus standard 90 mcg/kg ‐ dose rFVIIa and APCC for home treatment of joint bleeds in haemophilia patients with inhibitors: a randomized comparison. Haemophilia 2008;14(2):287‐94. CENTRAL

Chuansumrit 2000 {published data only}

Chuansumrit A, Isarangkura P, Angchaisuksiri P, Sriudomporn N, Tanpowpong K, Hathirat P, et al. Controlling acute bleeding episodes with recombinant factor VIIa in haemophiliacs with inhibitor: continuous infusion and bolus injection. Haemophilia 2000;6(2):61‐5. CENTRAL

de Paula 2012 {published data only}

de Paula EV, Kavakli K, Mahlangu J, Ayob Y, Lentz SR, Morfini M, et al. Recombinant factor VIIa analog (vatreptacog alfa [activated]) for treatment of joint bleeds in hemophilia patients with inhibitors: a randomized controlled trial. Journal of Thrombosis and Haemostasis 2012;10(1):81‐9. CENTRAL

Kavakli 2006 {published data only}

Kavakli K, Makris M, Zulfikar B, Erhardtsen E, Abrams ZS, Kent G. Home treatment of haemarthroses using a single dose regimen of recombinant activated factor seven in patients with haemophilia and inhibitors. A multi‐center, randomized, double‐blind, cross‐over trial. Thrombosis and Haemostasis 2006;95(4):600‐5. CENTRAL

Ljung 2013 {published data only}

Ljung R, Karim FA, Saxena K, Suzuki T, Arkhammar P, Rosholm A, et al. 40K glycoPEGylated, recombinant FVIIa: 3‐month, double‐blind, randomized trial of safety, pharmacokinetics and preliminary efficacy in hemophilia patients with inhibitors. Journal of Thrombosis and Haemostasis 2013;11(7):1260‐8. CENTRAL

Lusher 1998 {published data only}

Lusher JM, Roberts HR, Davignon G, Joist JH, Smith H, Shapiro A, 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(6):790‐8. CENTRAL

Mahlangu 2012 {published data only (unpublished sought but not used)}

Mahlangu JN, Coetzee MJ, Laffan M, Windyga J, Yee TT, Schroeder J, et al. Phase I, randomized, double‐blind, placebo‐controlled, single‐dose escalation study of the recombinant factor VIIa variant BAY 86‐6150 in hemophilia. Journal of Thrombosis and Haemostasis 2012;10(5):773‐80. CENTRAL

NCT00108758 {unpublished data only}

NCT00108758. Exploratory, multicenter, randomized, double‐blind, uncontrolled trial evaluating the efficacy of activated rFVII (Novoseven) in secondary bleeding prophylaxis in congenital hemophilia A or B patients with inhibitors. clinicaltrials.gov/show/ NCT00108758 (accessed 23 October 2013). CENTRAL

NCT01561391 {unpublished data only}

NCT01561391. Safety and efficacy of activated human recombinant FVIIa in patients with inhibitors during and after major surgery. clinicaltrials.gov/show/NCT01561391(accessed 5 December 2012) (accessed 5 December 2012). CENTRAL

Pruthi 2007 {published data only}

Pruthi RK, Matthew P. Valentino LA, Sumner MJ, Seremetis S, Hoots WK. Haemostatic efficacy and safety of bolus and continuous infusion of recombinant factor VIIa are comparable in haemophilia patients with inhibitors undergoing major surgery. Results from an open label, randomized multicenter trial. Thrombosis and Haemostasis 2007;98(4):726‐32. CENTRAL

Santagostino 2006 {published data only}

Santagostino E, Mancuso ME, Rocino A, Mancuso G, Scaraggi F, Mannucci PM. A prospective randomized trial of high and standard dosages of recombinant factor VIIa for treatment of hemarthroses in hemophiliacs with inhibitors. Journal of Thrombosis and Haemostasis 2006;4(2):367‐71. CENTRAL

Seremetis 1994 {published data only}

Seremetis SV. The clinical use of factor VIIa in the treatment of factor VIII inhibitor patients. Seminars in Hematology 1994;31(2 Suppl 4):53‐5. CENTRAL

Shapiro 1998 {published data only}

Cooper HA, Gilchrist GS, Hoots WK, Shapiro A. Comparison of two doses of recombinant factor VIIa for producing hemostasis during and after surgery in patients with hemophilia A or B and inhibitors and patients with acquired inhibitors. [abstract]. Blood 1997;90(10 Suppl 1 Pt 1):600a. CENTRAL
Cooper HA, Hoots WK, Shapiro A. Comparison of two doses of recombinant factor Vlla (rFVlla) for producing hemostasis during and after surgery in patients (PTS) with hemophilia A or B and inhibitors and PTS with acquired inhibitors [abstract]. Thrombosis and Haemostasis 1997;Suppl:167‐8. CENTRAL
Shapiro AD, Gilchrist GS, Hoots WK, Cooper HA, Gastineau DA. Prospective, randomised trial of two doses of rFVIIa (NovoSeven) in haemophilia patients with inhibitors undergoing surgery. Thrombosis and Haemostasis 1998;80(5):773‐8. CENTRAL

Villar 2004 {published data only}

Villar A, Aronis S, Morfini M, Santagostino E, Auerswald G, Thomsen HF, et al. Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A. Haemophilia 2004;10(4):352‐9. CENTRAL

Athale 2014

Athale AH, Marcucci M, Iorio A. Immune tolerance induction for treating inhibitors in people with congenital haemophilia A or B. Cochrane Database of Systematic Reviews 2014, Issue 4. [DOI: 10.1002/14651858.CD010561.pub2]

Becker 1993

Becker MP, Balagtas CC. Marginal modelling of binary cross‐over data. Biometrics 1993;49(4):997‐1009.

Dimichele 2002

Dimichele D. Inhibitors: resolving diagnostic and therapeutic dilemmas. Haemophilia 2002;8(3):280‐7.

DiMichele 2007

DiMichele D. Inhibitor development in haemophilia B: an orphan disease in need of attention. British Journal of Haematology 2007;138(3):305‐15. [DOI: 10.1111/j.1365‐2141.2007.06657.x]

Elbourne 2002

Elbourne DR, Altman DG, Higgins JPT, Curtin F, Worthington HV, Vail A. Meta‐analysis involving cross‐over trials: methodological issues. International Journal of Epidemiology 2002;31(1):140‐9.

Ewenstein 1997

Ewenstein BM, Takemoto C, Warrier I, Lusher J, Saidi P, Eisele J, et al. Nephrotic syndrome as a complication of immune tolerance in hemophilia B. Blood 1997;89(3):1115‐6.

Goodeve 2003

Goodeve AC, Peake IR. The molecular basis of hemophilia a: genotype‐phenotype relationships and inhibitor development. Seminars in Thrombosis and Hemostasis 2003;29(1):23‐30.

Hay 2000

Hay CRM, Baglin TP, Collins PW, Hill FGH, Keeling DM. The diagnosis and management of factor VIII and IX inhibitors: a guideline from the UK Haemophilia Centre Doctors' Organization (UKHCDO). British Journal of Haematology 2000;111(1):78‐90.

Hedner 2000

Hedner U. Recombinant coagulation factor VIIa: from the concept to clinical application in hemophilia treatment in 2000. Seminars in Thrombosis and Hemostasis 2000;26(4):363‐6.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta‐analyses. British Medical Journal 2003;327(7414):557‐60.

Knight 2009

Knight C, Dano AM, Kennedy‐Martin T. A systematic review of the cost‐effectiveness of rFVIIa and APCC in the treatment of minor/moderate bleeding episodes for haemophilia patients with inhibitors. Haemophilia 2009;15(2):405‐19. [DOI: 10.1111/j.1365‐2516.2008.01969.x]

Kreuz 2002

Kreuz W, Ettingshausen CE, Zyschka A, Oldenberg J, Saguer IM, Ehrenforth S, et al. Inhibitor development in previously untreated patients with hemophilia A: a prospective long‐term follow‐up comparing plasma‐derived and recombinant products. Seminars in Thrombosis and Hemostasis 2002;28(3):285‐90.

Lloyd Jones 2003

Lloyd Jones M, Wight J, Paisley S, Knight C. Control of bleeding in patients with haemophilia A with inhibitors: a systematic review. Haemophilia 2003;9(4):464‐520.

Mannucci 2001

Mannucci PM, Tuddenham EG. The hemophilias ‐ from royal genes to gene therapy. New England Journal of Medicine 2001;344(23):1773‐9.

Rizza 2001

Rizza CR, Spooner RJ, Giangrande PL, UK Haemophilia Centre Doctors' Organization (UKCDO). Treatment of haemophilia in the United Kingdom 1981‐1996. Haemophilia 2001;7(4):349‐59.

Thomas 1977

Thomas T, Williams H, Williams Y, Hunt J. FEIBA in haemophiliacs with factor VIII inhibitor. BMJ 1977;1(6052):52.

Treur 2009

Treur MJ, McCracken F, Heeg B, Joshi AV, Botteman MF, De Charro F, et al. Efficacy of recombinant activated factor seven vs activated prothrombin complex concentrates for patients suffering from haemophilia complicated with inhibitors: a Bayesian meta‐regression. Haemophilia 2009;15(2):420‐36. [DOI: 10.1111/j.1365‐2516.2008.01956.x]

UKHCDO 2003

United Kingdom Haemophilia Doctors' Organisation. Guidelines on the selection and use of therapeutic products to treat haemophilia and other hereditary bleeding disorders. Haemophilia 2003;9(1):1‐13.

White 2001

White GC, Rosendaal F, Aledort LM, Lusher JM, Rothschild C, Ingerslev J, et al. Definitions in hemophilia. Recommendation of the scientific subcommittee on factor VIII and factor IX of the scientific and standardization committee of the International Society on Thrombosis and Haemostasis. Thrombosis and Haemostasis 2001;85(3):560.

Yee 1999

Yee TT, Pasi KJ, Lilley PA, Lee CA. Factor VIII inhibitors in haemophiliacs: a single‐centre experience over 34 years, 1964‐97. British Journal of Haematology 1999;104(4):909‐14.

Iorio 2010

Iorio A, Matino D, D'Amico R, Makris M. Recombinant Factor VIIa concentrate versus plasma derived concentrates for the treatment of acute bleeding episodes in people with haemophilia and inhibitors. Cochrane Database of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/14651858.CD004449.pub3]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Astermark 2007

Methods

Open‐label cross‐over multicentre RCT.

Participants

Individuals with severe haemophilia A with inhibitors not undergoing ITI. A total of 66 individuals were enrolled, but 14 withdrew prior to treatment or were treated only once. Diaries for a further 4 participants were not adequately completed.

Age: mean 27.5 years (range 8 ‐ 55 years).

Mean inhibitor titre 8.6 BU/ml (range 0 ‐ 1800).

96 episodes in 48 participants.

Interventions

aPCC (FEIBA®) 75 ‐ 100 IU/kg (target 85 IU/kg) as a single IV bolus.

Activated rFVII (NovoSeven®) 90 ‐ 120 mcg/kg (target 105 mcg/kg) as IV bolus repeated after 2 hours.

Both treatments were administered a mean of 2 hours after bleeding onset.

Outcomes

Subjective evaluation of treatment efficacy based on a four level scale (effective, partially effective, poorly effective, not effective); efficacy was defined as effective or partially effective by participant rating at 6 hours (primary) and at various times from 2 ‐ 48 hours (secondary).

Subjective evaluation of stop of bleeding (binary outcome).

Additonal treatments and the occurrence of re‐bleeding were recorded.

Notes

Use of analgesics was allowed and its distribution in the treatment group was evaluated.

A significantly different number of knee (higher in Novoseven®‐treated participants) and elbow (higher in aPCC‐treated participants) bleeding events were recorded. The analysis technique used to balance for the uneven distribution of knee bleeds is unclear and not sufficiently detailed.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation in association with the first bleeding event was performed in a block of participants equally divided into two.

Allocation concealment (selection bias)

High risk

Open‐label trial. A randomisation list specifying the order of treatment for enrolled participants was provided to each participating centre.

Blinding (performance bias and detection bias)
All outcomes

High risk

Blinding was not possible for physicians and participants because of difference between the 2 products (physical appearance and required volume for injection). Outcome assessment was not blinded.

Incomplete outcome data (attrition bias)
All outcomes

High risk

The trial was analysed on a per protocol basis.

Selective reporting (reporting bias)

Low risk

Outcome data reported in the methods and the results sections correspond.

Other bias

High risk

Use of analgesics allowed during the trial.

A significantly different number of knee (higher in participants treated with Novoseven®) and elbow (higher in participants treated with aPCC) bleeding events were recorded. The analysis technique used to balance for the uneven distribution of knee bleeds is unclear and not sufficiently detailed.

Young 2008

Methods

Open‐label cross‐over multicentre 3‐tier RCT.

The comparison between rFVIIa and aPCC was open label, while the comparison between the two different rFVIIa regimens was concealed.

Outcome assessor was blinded.

Participants

Individuals with severe haemophilia A and B with inhibitor (the number of participants with A and B was not separately specified). A total of 42 were randomised, with 21 completing all 3 arms of treatment.

Age: mean 19.5 years (range 1 ‐ 54 years).

Interventions

Activated rrF VII (NovoSeven®) 90 mcg/kg as IV bolus administered at 0, 3 and 6 hours.

Activated recombinant factor VII (NovoSeven®) 270 mcg/kg as single IV bolus (followed by 2 placebo infusions).

aPCC (FEIBA®) 75 IU/kg as a single IV bolus.

Outcomes

Primary outcomes

Number of participants requiring additional treatment.

Secondary outcomes

Subjective pain and mobility scale rating evaluated as global treatment response (composite end‐point) and separately.

Rate of adverse events.

Notes

The trial states that the analysis was performed on an intention‐to‐treat basis, but the data seems to have been analysed on‐treatment.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

6 treatment sequences were generated by the permutation of the 3 dosing regimens. The sequences were randomly assigned to the participants.

Allocation concealment (selection bias)

Unclear risk

The comparison between rFVIIa and aPCC was open label, while the comparison between the 2 different rFVIIa regimens was described as blinded without details about randomisation code concealment.

Blinding (performance bias and detection bias)
All outcomes

High risk

Participants and clinicians could not be blinded to comparison between both NovoSeven® treatments and the FEIBA® treatment due to differences in physical appearance and required volume for injection, but comparison of 2 NovoSeven® treatments was blinded (3 active versus 1 active and 2 placebo doses). Outcome assessment was blinded for the treatments.

Incomplete outcome data (attrition bias)
All outcomes

High risk

The trial states that the analysis was performed on an intention‐to‐treat basis, but the data seems to have been analysed on‐treatment.

Selective reporting (reporting bias)

Low risk

Outcome data reported in the methods and results sections correspond.

Other bias

Unclear risk

Use of analgesics allowed during the trial. Distribution of analgesics use among group was evaluated.

The trial was interrupted by the sponsor for unspecified reasons.

aPCC: activated prothrombin complex concentrates
BU: Bethesda units
ITI: immune tolerance induction
IV: intravenous
RCT: randomised controlled trial
rFVIIa: recombinant factor VIIa
vs: versus

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Chuansumrit 2000

Not a randomised or quasi‐randomised controlled trial.
Prospective, open‐label, uncontrolled, observational study.

de Paula 2012

Dosage‐finding trial: comparator is not an alternative therapy.

Kavakli 2006

Double‐blind cross‐over RCT comparing two different regimens of rFVIIa.

Ljung 2013

RCT comparing two different regimens of rFVIIa.

Lusher 1998

Dosage‐finding trial: comparator is not an alternative therapy.
Double‐blind RCT.

Mahlangu 2012

Dosage‐finding trial: comparator is not an alternative therapy.

NCT00108758

RCT comparing two different regimens of rFVIIa.

NCT01561391

RCT comparing two different regimens of rFVIIa.

Pruthi 2007

Open label randomised RCT comparing two different regimens of rFVIIa (90 mcg/kg boluses versus continuous infusion) in people with haemophilia undergoing major surgery.

Santagostino 2006

Open label cross‐over RCT comparing two different regimens of rFVIIa.

Seremetis 1994

Not a randomised or quasi‐randomised controlled trial.
Phase II safety and efficacy trial.

Shapiro 1998

Dosage‐finding trial: comparator is not an alternative therapy.
Double‐blind RCT.

Villar 2004

Dosage‐finding trial: comparator is not an alternative therapy.

RCT: randomised controlled trial
rFVIIa: recombinant factor VIIa

Data and analyses

Open in table viewer
Comparison 1. aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment efficacy judgement Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 1.1

Comparison 1 aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses, Outcome 1 Treatment efficacy judgement.

Comparison 1 aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses, Outcome 1 Treatment efficacy judgement.

1.1 At 2 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 At 12 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 At 24 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.5 At 36 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.6 At 48 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

Open in table viewer
Comparison 2. rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 2.1

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 1 Mobility evaluation.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 1 Mobility evaluation.

1.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 2.2

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 2 Pain evaluation.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 2 Pain evaluation.

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 2.3

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 3 Need for rescue medication.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 3 Need for rescue medication.

Open in table viewer
Comparison 3. rFVIIa 270 ug/kg vs APCC 75 U/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 3.1

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

1.1 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 3.2

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 2 Pain evaluation.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 2 Pain evaluation.

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 3.3

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Open in table viewer
Comparison 4. rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 4.1

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

1.1 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 4.2

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 2 Pain evaluation.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 2 Pain evaluation.

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Analysis 4.3

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Comparison 1 aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses, Outcome 1 Treatment efficacy judgement.
Figuras y tablas -
Analysis 1.1

Comparison 1 aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses, Outcome 1 Treatment efficacy judgement.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 1 Mobility evaluation.
Figuras y tablas -
Analysis 2.1

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 1 Mobility evaluation.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 2 Pain evaluation.
Figuras y tablas -
Analysis 2.2

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 2 Pain evaluation.

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 3 Need for rescue medication.
Figuras y tablas -
Analysis 2.3

Comparison 2 rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses, Outcome 3 Need for rescue medication.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 1 Mobility evaluation.
Figuras y tablas -
Analysis 3.1

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 2 Pain evaluation.
Figuras y tablas -
Analysis 3.2

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 2 Pain evaluation.

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 3 Need for rescue medication.
Figuras y tablas -
Analysis 3.3

Comparison 3 rFVIIa 270 ug/kg vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 1 Mobility evaluation.
Figuras y tablas -
Analysis 4.1

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 1 Mobility evaluation.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 2 Pain evaluation.
Figuras y tablas -
Analysis 4.2

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 2 Pain evaluation.

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 3 Need for rescue medication.
Figuras y tablas -
Analysis 4.3

Comparison 4 rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg, Outcome 3 Need for rescue medication.

Table 1. aPCC 75‐100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses ‐ Treatment efficacy judgement

Study ID

Hours (pts number)

aPCC n (%)

rFVIIa n (%)

90% CI of the difference (%)

P value

Astermark 2007

2 (48)

36 (75.0)

29 (60.4)

‐0.73 to 29.9

0.482

6 (47)

38 (80.9)

37 (78.7)

‐11.42 to 15.67

0.059

12 (45)

38 (80.0)

38 (84.4)

‐18.08 to 9.19

0.101

24 (42)

40 (95.2)

36 (85.7)

‐1.29 to 20.33

0.202

36 (41)

41 (100)

37 (90.2)

2.13 to 17.38

0.129

48 (41)

40 (97.6)

35 (85.4)

2.05 to 22.34

0.325

The table reports the number and % of participants who judged the treatment efficacious for any treatment and any time point. The 90% CIs of the difference test the hypothesis of equivalence between the treatments. When considering the difference at 2 hours, it has to be taken into account that this time point is before the administration of the second rFVIIa bolus.

aPCC: activated prothrombin complex concentrates
CI: confidence interval
rFVIIa: recombinant factor VIIa

Figuras y tablas -
Table 1. aPCC 75‐100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses ‐ Treatment efficacy judgement
Table 2. aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses ‐ Bleeding stop

Study ID

Hours (number of participants)

aPCC (%)

rFVIIa (%)

90% CI of the difference (%)

P value

Astermark 2007

2 (47)

53.2

38.3

0.06 to 29.72

0.495

6 (46)

76.1

65.2

‐2.73 to 24.47

0.309

12 (45)

77.8

75.6

‐11.92 to 16.37

0.069

24 (42)

90.5

85.7

‐4.75 to 14.28

0.038

36 (41)

95.1

87.8

‐1.45 to 16.09

0.075

48 (41)

95.1

92.7

4.48 to 9.36

0.001

The table reports the number and % of participants who judged the treatment efficacious for any treatment and any time point. The 90% CIs of the difference test the hypothesis of equivalence between the treatments. When considering the difference at 2 hours, it has to be taken into account that this time point is before the administration of the second rFVIIa bolus.

aPCC: activated prothrombin complex concentrates
CI: confidence interval
rFVIIa: recombinant factor VIIa

Figuras y tablas -
Table 2. aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses ‐ Bleeding stop
Table 3. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Pain scale

Study ID

Outcome

rFVIIa 270 mcg/kg

(N = 24)

rFVIIa 90 mcg/kg x 3

(n = 22)

aPCC 75 IU/kg

(n = 22)

Young 2008

Positive treatment response (%)

45.8

54.5

27.3

The response was globally evaluated 9 hours after treatment. The positive response were defined as at least 3 positive assessments at 1, 3, 6 and 9 hours. The positive assessment was defined on the base of a 3‐level scale (more pain, no difference, less pain). There were no statistically significant differences between treatments (P = 0.219).

aPCC: activated prothrombin complex concentrates
rFVIIa: recombinant factor VIIa

Figuras y tablas -
Table 3. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Pain scale
Table 4. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Mobility scale

Study ID

Outcome

rFVIIa 270 mcg/kg

(N = 24)

rFVIIa 90 mcg/kg x 3

(n = 22)

aPCC 75 IU/kg

(n = 22)

Young 2008

Positive treatment response (%)

25.0

45.5

22.7

The response was globally evaluated 9 hours after treatment. The positive response were defined as at least 3 positive assessments at 1, 3, 6 and 9 hours. The positive assessment was defined on the base of a 3‐level scale (more mobility, no difference, less mobility). There were no statistically significant differences between treatments (P = 0.903).

aPCC: activated prothrombin complex concentrates
rFVIIa: recombinant factor VIIa

Figuras y tablas -
Table 4. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Mobility scale
Table 5. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Rescue medication use

Study ID

Outcome

rFVIIa 270 mcg/kg

(n = 24)

rFVIIa 90 mcg/kg x 3

(n = 22)

aPCC 75 IU/kg

(n = 22)

Young 2008

Participants requiring rescue medication n (%)

2 (8.3)

2 (9.1)

8 (36.4)

Participants with an insufficient treatment response within 6 hours of the first treatment administration were evaluated in the clinic or by phone to consider the use of rescue medication. Rescue medication was defined as additional haemostatic treatment within 9 hours post first administration of trial product. The difference between rFVIIa 270 mcg/kg vs aPCC was statistically significant (P = 0.032). The efficacy difference between the aPCC treatment group and the rFVIIa 90 x 3 mcg/kg did not reach statistical difference (P = 0.069).

aPCC: activated prothrombin complex concentrates
rFVIIa: recombinant factor VIIa

Figuras y tablas -
Table 5. aPCC 75 IU/kg vs rFVIIa 270 mcg/kg vs rFVIIa 90 mcg/kg x 3 doses ‐ Rescue medication use
Comparison 1. aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Treatment efficacy judgement Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

1.1 At 2 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 At 12 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 At 24 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.5 At 36 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.6 At 48 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

Figuras y tablas -
Comparison 1. aPCC 75 ‐ 100 IU/kg vs rFVIIa 90 ‐ 120 mcg/kg x 2 doses
Comparison 2. rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

1.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 2. rFVIIa 270 ug/kg vs rFVIIa 90 ug/kg x 3 doses
Comparison 3. rFVIIa 270 ug/kg vs APCC 75 U/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

1.1 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 3. rFVIIa 270 ug/kg vs APCC 75 U/kg
Comparison 4. rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg

Outcome or subgroup title

No. of studies

No. of participants

Statistical method

Effect size

1 Mobility evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

1.1 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

1.2 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2 Pain evaluation Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

2.1 At 1 hour

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.2 At 3 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.3 At 6 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

2.4 At 9 hours

1

Odds Ratio (Fixed, 95% CI)

0.0 [0.0, 0.0]

3 Need for rescue medication Show forest plot

1

Odds Ratio (Fixed, 95% CI)

Totals not selected

Figuras y tablas -
Comparison 4. rFVIIa 90 ug/kg x 3 doses vs APCC 75 U/kg