rhFVII a and Cardiac surgery …Why the concern..? Farjah Hassan AlGahtani, assistant Professor of Medicine, Consultant Hematology Director of Transfusion Medicine and Blood bank, King Saud University.

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Post –operative Bleeding Most common complicationfollowing Cardiopulmonary bypass (CPB).  6% requiring surgical re-exploration .  Associted with consideralbe morbidty and mortality. 

Dacey et al Arch Surg 1998 Unsworth et al Ann Thorc Surgy 1995 2/9/2010

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Homeostasis Controlled Process.  Homeostasis plug is self- limited in size and duration. - Sufficient to arrest the loss of blood at the site. -Long enough to allow cellular repair processes. 

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Coagulopathy in Cardiac suergery Hypother mia

Hemodilution Platelet dysfunction DIC

Lethal Triad Metabolic acidosis

OThers

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rh Factor VIIa Structurally nearly identical to human plasma.  Approved in 1999 by FDA and European regulatory agencies.  Half-life = 2.5 hrs  Inhibition via Tissue factor pathway inhibitor 

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rFVII a Licensed;  Bleeding

episode in Hemophilia A or B with inhibitors to F VIII Or F IX.

 Recently (2004–2005), replacement therapy in factor VII (FVII) deficiency.  Platelet

dysfunction ; Glanzmann’s thrombasthenia.

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Off-Lable Uesd Intractable bleeding in Cardiac surgery  Reveres LMWH / OA i.e. associated with sever bleeding.  Orthotopic Liver transplantation.  Massive Transfusion.  U G Bleeding in cirrhosis.  Postpartum Heorrahage.  Religious objection to blood products. 

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Off-Label Use rFVIIa 

Prophylaxis; - Retro pubic prostectomy. -Single preoperative dose. - 50%-60% reduced blood loss, and Blood transfusion respectively. Lancet 2003;361:201-5

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rFVIIa in surgery

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RCTs of rFVIIa in surgery     

Tow Parallel RCDB trials Blunt / Penetrating Trauma rFVIIa Dose( 200,100 m cg /kg) VS Placebo in addition to standard treatment. Conclusion: Significant reduction in RBC transfusion . Total of 12 Thromboembolic adverse events( 6 rFVIIa and 6 Placebo ) During the two Trial.

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The Journal of TRAUMA, July 2005 Dutton, J Trauma 2004, 57:709-18

RCTs of rFVIIa in surgery     

Tow Parallel RCDB trials 1 75 % response rate Blunt / Penetrating Trauma 1 No change in survival rFVIIa Dose( 200,100 m cg /kg) VS Placebo in addition to standard treatment. Conclusion: Significant reduction in RBC transfusion . Total of 12 Thromboembolic adverse events( 6 rFVIIa and 6 Placebo ) During the two Trial. 1.Dutton, J Trauma 2004, 57:709-18 2. The Journal of TRAUMA, July 2005

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

Neurosurgery   



↓ mortality, ↑ functional outcome in ICH 1 ↑ thrombotic complications 1 4 more RCTs in ICH ongoing 2

Urology 

↓ transfusion requirements in retropubic prostatectomy (control group bled 2700ml)

 3Ortho 

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no benefit in pelvic / acetabular frx 4

F AlGahtan

1. Mayer, N Engl J Med 2005;352:777-85 2.Scarpelini, Curr Opinion Crit Care 2006,12:351-6 3. Friedrich, Lancet 2003;361:201-5 4.Raobaikady, Br J Anaesth 2005;94:586-91

Acute Intracerbral Hemorrahage RDBCT  399 pts divide into 4 arms ,Placebo Vs rFVIIa ( 40,80,160 mcg/kg.  Result; 1)- 50 % in the growth of hemorrahge relative reduction 2)- 38 % reduction in the mortality. The throboembolic side events in r FVII a arm , 2% fatal or disabling as will as Placebo 2% 

NEJM Feb 24,2005 2/9/2010

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Cardiac surgery 



Largest consumers of blood products Largest users of rFVIIa. Scarpelini, Curr Opinion Crit Care 2006,12:351-6

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Published experience cardiac surgery

Patients treated with rFVIIa since 2000

pts treated with rFVIIa

250

adults (n=361) kids (n=34)

200 150 100 50 0 1999 2000 2001 2002 2003 2004 2005 2006 2007 1

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1

4

5

year, publications

6

F AlGahtani

13

11

Mysteries 

Timing

Efficacy  Safety 



Dose



General safety profile

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Timing  Early

 Late

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(prophylactic) (rescue tx)

F AlGahtani

Timing - efficacy Early: Effective ?

Late: Less effective



Last-ditch” use is ineffective 1 70% mortality @ 1wk. Multiorgan failure



Bloodless surgery possible when rFVIIa first line hemostatic therapy in 2 Jehovah’s witnesses2, 1 redo Bentall3 and 9 pediatric cardiac surgeries4 1) 2)

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Clark, Vox Sang 2004;86:120-4 Tanaka et al. Anesthesiol 2003, 98:1513-5

3) Bishop et al. Ann Thorac Surg 2006, 81: 875-9 4) Tobias et al. J Intens Care Med 2004, 19:270-3

Early

Late

Effective ?

Less effective

↓ PRBC prior 1

↑ PRBC prior

↓ PRBC total 1

↑ PRBC total

Early resolution of surgical bleeding 2 ↑ safety

Delayed resolution of surgical bleeding ↓ safety

1

↓ systemic TF? 1

↑ systemic TF?

almost no experience

some experience

$$$$$$$$$

$$$

1) 2)

Karkouti 2006 Can J Anesth 53:502-8 Walsham, Anaesth Intensive Care 2006; 34:13-20

Dose

Low dose (1.2mg = 10-20 µg/kg) Intermediate dose (2.4mg = 30-50 µg/kg) High dose (4.8mg or more = 70-90 µg/kg)

1) 2)

Dose/Timing Early

Late

Low 1.2 mg Medium ≥ 2.4 mg High ≥ 4.8 mg

Romagnoli 3 Karkouti 4

Karkouti 1,4

Diprose 2 Karkouti 4

Karkouti 1,4

Karkouti 2005, Transfusion 45:26-34 Diprose 2005, Br J Anaesth 95:596-602

3) Romagnoli, Anesth Analg 2006, 102:1320-6 4) Karkouti 2006 Can J Anesth 53:502-8

Karkouti 2005, Case control, late, n=102     

Case control study 51 pts, 51 controls matched for propensity to bleed 2.4 mg rFVIIa for controlled blood loss (x44) 4.8 mg rFVIIa for uncontrolled blood loss (x7) Endpoints:   

Product use before & after rFVIIa Chest tube drainage before & after rFVIIa Adverse events Karkouti 2005, Transfusion 45:26-34

Karkouti 2005, Case control, late, n=102



Adverse events in rFVIIa group: Longer ICU stay  Longer hospital stay  ↑ renal dysfunction (but not failure, not controlled for aprotinin tx, or transfusion requirements) 

Karkouti 2005, Transfusion 45:26-34

Conclusions 





Intermediate dose (2.4mg) as rescue treatment seems effective in 80% of pts Most treatment failures (need for reexploration even after 2nd dose) are due to surgical bleeding Safety profile appears favorable.

Karkouti 2005, Transfusion 45:26-34

Use of activated recombinant factor VII for severe coagulopathy  post ventricular assist device or orthotopic heart transplant  hemostasis in patients undergoing orthotopic heart transplant (OHT) and/or VAD implantation.  Methods: A retrospective review was conducted from Jan 03 to Aug 05 for patients who receivedrFVIIa for the management of intractable bleeding unresponsive to standard hemostatic bloodcomponent therapy. Blood loss and the quantity of blood products, prior to, and for at least 12  hours after, administration of rFVIIa were recorded.  Results: Mean patient age was 53, (38–64 yrs), mean dose of rFVIIa administered was 78.3 μg/kg  (24–189 μg/kg) in 1–3 doses. All patients received the drug either intraoperatively or within 6 hours of arrival in ICU. Mean transfusion requirements and blood loss were significantly reduced  after rFVIIa administration (PRBC's; 16.9 ± 13.3 to 7.1 ± 6.9 units, FFP; 13.1 ± 8.2 to 4.1 ± 4.9 units, thromboembolic cause. One patien developed a lower extremity arterial thrombus, and another deep vein thrombosis. 

Journal of Cardiothoracic Surgery 2007,

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2:32 F AlGahtani 2/9/2010

Conclusion: - there was a significant decrease in transfusion requirement and blood lossafter rFVIIa. -Although, 5/17 developed thromboembolic complications, these patients may have been at higher risk based on the multiple modality therapy used to manage intractable bleeding. Nevertheless, the exact role of rFVIIa with respect to

development of thromboembolic complications cannot be clearly determined. Further investigation is needed

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Journal of Cardiothoracic Surgery 2007, 2:32 F AlGahtani

Safety Profile of rFactor VIIa;   



the number of TEs reported to the US FDA over a 5-year period (1999–2004) ( AERS database). Atotal of 431 AE reports only 168 TE. The arterial spectrum of TE events comprised 54% of the reports and included non-ICH strokes (21%), MIs (21%), and other arterial TEs (18.6%). The venous TEs (40.4%) included deep venous thromboses (23%), pulmonary embolism (17.5%), and device associated thrombi (5.5%). O’Connell et al JAMA, January 2006

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Risks for Thromboembolic Complications 

  

Several of these have occurred when rFVIIa has been combined therapeutically or in close time approximation with other procoagulant replacement products (e.g., activated prothrombin complex concentrates) History of Coronary atherosclerotic heart disease, Stroke, Cancer. Infection DIC O’Connell ,JAMA 2006

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Risks of rFVIIa  Incidence

of adverse events 13%.

 Incidence

of serious adverse events