rFVIIa use in QLD

2. rFVIIa use in QLD 2003 Since the “early days”, off license rFVIIa use in Queensland has tended to be at lower dose than the 90mcg/kg extrapolated from licensed indications. Guideline for off license use of rFVIIa at Princess Alexandra Hospital developed by Director of Haematology in August 2003. PAH is the lead site in Qld for clinical research, evidence based protocol driven care. Other Qld Health sites use PAH Qld Health intranet site in the absence of local clinical guidelines Haematologists were gatekeepers, so dose recommendation reinforced at authorisation stage & blood bank would query higher dose requests

3. rFVIIa use in QLD 2006 Statewide guideline for off license rFVIIa use in Queensland Public Hospitals. Supercedes PAH guideline Author Clinical Pharmacologist, consultation with clinical stakeholders Gatekeeper role maintained at individual institutions (frequently with stronger interest in budget than haemostasis) Evidence base for protocol .…

5. Are outcomes of cardiac surgery patients treated with lower dose rFVIIa different to those treated with standard or higher dose? • Patients >15 years • Sept 2005 – Nov 2008 • Cardiac surgery context • Dose categories based on initial dose used • Low <81 mcg/kg • Medium 81-100 mcg/kg • High >100 mcg/kg *Isbister et al 2008 IMJ (38):156-165

6. Dose categories Medium dose chosen to encompass median dose of ~90mcg/kg, allowing for practice of rounding up to nearest 1.2 mg ampoule High Med Low

7. Statistical Analysis • Outcome measures • Response in bleeding to treatment • Mortality • TAEs • Univariate and Multivariate analyses • A multilevel model was used as patients were clustered by hospital to account for institutional dosing practices

8. Results • 859 cases met criteria • 55 cases missing dose data • 804 cases analysed • 253 (31.47%) low dose • 368 (45.77%) medium dose • 183 (22.76%) high dose

9. Patients Characteristics

10. Patient Characteristics No significant difference in Age, Gender, Hb, medications prior, platelets units prior, blood components after, case complexity, pH or temperature

11. Case Complexity by Dose

12. Response & 28-Day Mortality Clinician defined Responder = bleeding stopped or decreased, Non-responder = bleeding unchanged or increased

13. Thromboembolic Adverse Events

14. Regression model covariates

15. Regression models Size of Dose? – not significant in either model Mortality n=344, wald chi2 164.68, p <0.001 Response n=319, wald chi2 180.47, p <0.001

16. Summary of Results 1 • Pretreatment differences between groups: • Weight 79.2 / 79.5 / 69.2 p <0.001 • RBC 6 / 6 / 7 p 0.031 • Cryo 5 / 8 / 8 p <0.001 • INR 1.4 / 1.6 / 1.5 p 0.015 • Fibrinogen 2.3 / 2.1 / 2.0 p 0.029 • Outcomes in relation to dose • Effect on bleeding no difference • 28 day mortality no difference • Adverse events PE in low dose group

17. Summary of Results 2 • Regression Models • Mortality • Procedure type (CABG + Valve)p 0.014 • Baseline platelet count p <0.001 • RBC transfused prior to rFVIIa p 0.046 • pH p <0.001 • Response to initial dose • RBC transfused pre rFVIIa p 0.005 • pH p 0.002

18. Conclusions • No difference in response to bleeding or 28 day mortality outcome in cardiac surgery patients treated with low, medium & high dose rFVIIa • No difference in TIA, CVA, DVT or arterial thrombosis between groups, but PE (4 cases) exclusively seen in low dose group

19. Are Groups Truly Comparable? • As there is no randomisation, even if all pretreatment variables were statistically matched, comparability could be debated (? unknown confounders) • Significant differences in key parameters have been highlighted • Are these differences clinically significant?

20. Can the dose question be addressed by a randomised trial? • Eligibility criteria • Consent • Trigger for rFVIIa use • Randomisation • Incomplete data collection

21. Probably the only trial... • “Whilst nobody should be accused of providing substandard care when opting not to give rFVIIa for major bleeding, a trial of rFVIIa when conventional surgical, interventional and blood product support measures have failed is certainly worth a try.” • Spahn DR, Tucci MA, Makris M • Editorial BJA, May 2005

22. Acknowledgements Thanks to • Local Investigators and Data Collectors at Participating Hospitals • Dr Louise Phillips • Dr Cameron Willis • Dr Amanda Zatta The Haemostasis Registry is funded by an unrestricted Educational Grant from Novo Nordisk Pharmaceuticals Pty Ltd

23. Statistical Analysis Baseline patient characteristics (including age, weight, gender, place of administration, pH, temperature, case complexity and medications, products administered and coagulation parameters prior to rFVIIa) were compared between groups using χ2 for categorical data, one-way ANOVA for normally distributed continuous data and the non-parametric Kruskal Wallis test for non-normally distributed continuous variables. Response in bleeding to treatment (a clinical judgment made at the time of administration), mortality and TAEs were compared by dosage group using χ2. Multivariate analyses modelled the relationship between covariates (described in Table 4) and response to treatment and mortality using a backward step-wise approach. A multilevel model was used as patients were clustered by hospital to account for institutional dosing practices. Values p<0.05 were considered statistically significant. All analyses were conducted using Stata v. 9.2 (Stata Corp, Texas USA).