Use of Recombinant Factor VIIa in the Critically Ill: Fact & Fiction
Jill A. Rebuck, Pharm.D., BCPS Surgical ICU Pharmacist Clinician Clinical Assistant Professor of Surgery Fletcher Allen Health Care
Disclosures
• Novo Nordisk Pharmacy Advisory Board • Off-label indications will be discussed • Personal Biases:
– I believe in the negative effects of multiple blood transfusions! Serious side effects under-appreciated – I have visually watched rFVIIa work at the bedside in refractory bleeding cases (results in a lasting impression…)
Talk Outline
• Brief overview of rFVIIa • Therapeutic areas with randomized placebocontrolled trial (RCT) data:
– Focus on trauma and spontaneous ICH – patient case examples
• Anticoagulant reversal • Consensus guideline recommendations
rFVIIa Overview
•
•
•
• •
•
Current indications predominantly in hemophilia and congenital Factor VII deficiencies Intended to promote hemostasis via extrinsic coagulation cascade activation Dose: 90 µg/kg IV > every 2-3 hours for bleeding episodes or surgical interventions in hemophilia patients Half-life ~ 2.6 hours 1.2, 2.4, and 4.8 mg vials for reconstitution & IV bolus over 2 - 5 min Depending on the institution, either the blood bank or pharmacy is responsible for ensuring appropriate use
rFVIIa Effect on Hemostasis at Site of Injury
1. rFVIIa works at site of vascular injury, where TF is expressed & activated platelets are found 2. In pharmacological doses, rFVIIa binds directly to surface of activated platelets & activates FX to FXa, resulting in a burst of thrombin generation 3. rFVIIa enhances localized thrombin generation & fibrin clot formation, producing a stable fibrin clot
Hoffman M, et al. Thromb Haemost. 2001;85:958-965
Potential Influence of rFVIIa Efficacy ?
• • • • Hypothermia Acidic arterial pH Platelet count Number of PRBC units & blood products transfused pre-drug • Use in futility of care patients
Labeled Indication Adverse Effects: rFVIIa
• N/V, fever, hemorrhage, injection site pain, arthralgia, headache, high/low BP • Mild LFT changes, edema, skin rash • No anaphylaxis reactions reported
• theoretical risk as rFVIIa is produced by genetic engineering from hamster kidney cells
• Influence of classification as drug or blood product
Thrombotic Adverse Events
• 18 thrombotic events per> 700,000 standard doses (1996-2003 voluntary reporting)1 – N=15 predisposing factors – N=8 other coagulation factor replacements – AMI (7), DVT (5), PE (1), DIC (2), cerebrovascular thrombosis (2), CVA (1) • Increased risk: DIC, advanced atherosclerotic disease, crush injury, or septicemia2
– due to circulating TF or predisposing coagulopathy
1Wilson
SJ, et al. Expert Opin Drug Saf 2005;4:557-70 2NovoSeven PI, Dated 10/3/05
Bleeding: Major Cause of Death in Trauma
MOF 7% Other Unknown 2% 4% CNS 42%
N=289
Bleeding 39%
* Patients
Bleeding + CNS 6%
dying in hospital within 48 hrs MOF: multiple organ failure
Sauaia A et al. J Trauma 1995;38:185-93
Hemostasis Management in Trauma: Options
• Blood transfusion • Surgical hemostasis • Pharmacological hemostasis
– Rationale: reduce blood loss, prevent
exsanguination, reduce shock load, and prevent death
Impact of Blood Transfusions on Complications Post-Trauma
Relationship between units of transfused blood in the first 12 hours and the incidence of Multiple Organ Failure1
60
100
Association between 0-15 units of PRBCs and infection rate2
R2 = 0.7566 n=1,593
Incidence of MOF (%)
P<0.001
Incidence of Infection (%)
11-15 16-20 >20
50 40
30 20
80 60 40 20 0
10 0 0 0-5 6-10
0
2
4
6
8
10
12
14
Transfused units
Transfused PRBC units
1. Moore FA et al. Arch Surg 1997;132:620-4 2. Claridge JA et al. Am Surg 2000;68:566-72
rFVIIa in Traumatic Coagulopathy:
Largest Case Series
• N=81 patients unresponsive to conventional therapy1: – N=46 acute traumatic haemorrhage • Median 100 mcg/kg IV dose (range: 80-144); 1.23 average doses/pt. • 61/81 responded to rFVIIa & further assessed for blood product utilization • No thromboembolic events
Before rFVIIa 60
Volume of blood product (units)
After rFVIIa
*
50 40
*
30 20 10 0 RBC Plasma Platelets
**
**
Total
1
> 10 units PRBC, 8 units FFP, & platelets with continued ongoing bleeding
*
P<0.00001;
P<0.0001
Dutton RP, et al. J Trauma 2004;57:709-19
rFVIIa: Treatment of Bleeding in Severely Injured Trauma Patients
• Double-blind, multi-national RCT of rFVIIa efficacy/safety • N=277 trauma patients who required 6+ units PRBC within 4hrs of admission – stratified for penetrating and blunt injuries • Key Exclusion:GSW head, GCS < 8 if + head CT, base deficit > 15, severe acidosis pH < 7; time > 12h post-injury
Boffard KD, et al. J Trauma 2005;59:8-18
rFVIIa Trauma RCT: Study Design
rFVIIa N=139
trauma arrival ER randomize transfusion (units RBC) 0 6 8
Placebo N=138
48 hrs 30 days
0, 1, 3 200+100+100 mcg/kg
• Transfusion requirements & volume replacement • Days in ICU • Survival • Adverse Events • Multiple organ failure (MOF), ARDS, Serious adverse events
Boffard KD, et al. J Trauma 2005;59:8-18
Major Traumatic Bleeding
• Blunt Trauma Patients(N=143):
– rFVIIa resulted in:
• 2.6 units less PRBC at 48-hr (P=0.02) • less massive transfusion (14% vs. 33%, P =0.03) 56% relative risk reduction; NNT 5.4 • No difference in blood components vs. placebo
• Penetrating Trauma Patients (N=134)
– rFVIIa had less pronounced benefit:
• 1 unit less PRBC requirement (P=0.10) • reduced massive transfusion (7% vs. 19%, P =0.08)
Boffard KD, et al. J Trauma 2005;59:8-18
Blunt Trauma Results N=143
Outcome ARDS (30d) MOF (30d) rFVIIa 4% 7% Placebo 16% 12% 13 (0-29) 8 (0-29) 30% P 0.03 NS NS NS NS
Vent-free days 17 (0-29) ICU-free days 30d mortality 12 (0-29) 25%
Boffard KD, et al. J Trauma 2005;59:8-18
rFVIIa Safety in Trauma: Thromboembolic Events
Placebo rFVIIa (400mcg IV total) 6% 5% 4% 3% 2% 1% 0% Blunt Penetrating
Similar safety profile:
Placebo (6 total):
– 2 PE, 1 SC vein thrombosis, 1 cerebral infarction, 1 DVT, & 1 mesenteric vein thrombosis
rFVIIa (6 total):
– 1 each jugular vein/arterial limb thrombosis, cerebral infarction, DVT, intestinal infarction, & phlebothrombosis
Boffard KD, et al. J Trauma 2005;59:8-18
Patient Case: rFVIIa Benefit ?
• 25y M s/p multiple stab wounds to extremities & abdomen admitted to your ICU after 24 units of PRBC, 2 units FFP, & 1 pack platelets • 37y F severe automobile collision 12 hours earlier now with abdominal CT finding of major splenic laceration requiring OR
• 51y M s/p skiing accident (vs. tree) 4 hr PTA now in your ICU with ongoing bleeding after 6 units PRBC, 4 units FFP, with no surgical source of bleeding identified
Early Hemorrhage Growth in Patients with ICH
• N=103 patients scanned within < 3 hrs of onset • 38% significant hematoma growth
– (> 33% increase in volume) – 26% in 1hr of baseline scan – 12% between 1-20hr scan
• ICH growth associated with clinical deterioration on NIHSS
2.0 hours after onset
6.5 hours after onset
NIHSS, National Institutes of Health Stroke Scale. Brott T et al. Stroke. 1997;28:1-5.
ICH Volume: Powerful Determinant of 30-day Outcome
Condition at 30 days (Oxford Handicap Scale)
Good recovery with volume > 30 mL does not occur
Broderick JP, et al. Stroke 1993;24:987-93
Dose-Ranging rFVIIa Study: Preventing Early Hematoma Growth in Acute ICH
Mayer SA, et al. NEJM 2005
Efficacy of rFVIIa in Acute ICH
< 3 hours ≤ 60 mins
Placebo N = 100
24 hours
90 days
2° Efficacy • Mortality • mRS • Barthel Index • E-GOS • NIHSS • GCS • Euro-QOL
CT
Baseline
CT
24 h
CT
72 h
Patients presenting with stroke-like symptoms
rFVIIa 40 mcg/kg N = 100 Baseline CT scan rFVIIa 80 mcg/kg N = 100 rFVIIa 160 mcg/kg N = 100
1° Efficacy Percent change in ICH volume at 24 hours
20 Countries 73 Trial Sites
Safety • Adverse events until discharge • Serious adverse events until day 90 • Exacerbation of edema
Mayer SA, et al. NEJM 2005;352:777-85
ICH Study: Exclusion Criteria
– GCS 3 - 5 (deep coma) – hematoma evacuation planned < 24hrs – hx: thrombocytopenia, coagulopathy, sepsis, crush injury, DIC, known oral anticoagulant use
Sx thrombotic or vaso-occlusive disease
• angina, claudication, DVT, CVA, MI
Secondary ICH related to: – aneurysm – arteriovenous malformation – trauma Mayer SA, et al. NEJM 2005;352:777-85
Baseline Characteristics
Placebo
40 108 63%
67 ± 12
80 92 61%
65 ± 12
160 103 67%
64 ± 13
mcg/kg
Subjects Male Age (yrs))
White Asian ICH volume (mL)
96 53%
68 ± 12
81% 15%
24 ± 22
77% 19% 22 ± 22
86% 10% 23 ± 24
80% 15% 26 ± 30
Treated < 3 hr after symptom onset
72%
62%
76%
71%
Mayer SA, et al. NEJM 2005;352:777-85
Results: Treatment Intervals
Treatment intervals
– Mean onset-to-CT interval114 ± 35 min – Mean CT-to-trial drug interval 54 ± 21 min – Mean onset-to-trial drug interval 167 ± 32 min 54 min 114 min
Onset-to-CT
0 1 hr
CT-to-Trial Drug
2 hrs
167 min
3 hrs
Mayer SA, et al. NEJM 2005;352:777-785
Estimated 24hr Mean % ICH Change
Percent change in ICH volume: Baseline 24 hours
35
% Increase from BL
30
25
29%
20
15
16%
10
14% 11%
14%
5
0
Placebo
40 mcg/kg P=0.07
80 mcg/kg P=0.05
160 mcg/kg
P=0.02
Combined rFVIIa Groups P=0.01
Mayer SA, et al. NEJM 2005;352:777-85
90 day Mortality: Acute ICH
Combined P rFVIIa Value* Groups
Placebo 40mcg/k 80mcg/ 160mcg/ g kg kg
29% RR
18% 38%
18% 38%
*Combined
19% 34%
18% 38%
0.02
rFVIIa vs placebo
Mayer SA,, et al. N Engl J Med 2005;352:777-85
Modified Rankin Scale (Day 90):“Left Shift”
0–1 no significant disability
160 mcg/kg
80 mcg/kg 40 mcg/kg
2–3 slight to moderate disability
4–5 moderately severe to severe disability
0% 20% 40% 60% 80% 100%
Placebo
6 dead
Mayer SA, et al. NEJM 2005;352:777-85
Modified Rankin Scale (Day 90)
• Unfavorable outcome is associated with Score of 4-6
Placebo
40 mcg/kg 80 mcg/kg 160 mcg/kg
Score
4– 6
69%
P = 0.02
55%
P = 0.008
49%
P = 0.02
54%
NNT*
7.1
5.0
6.7
*NNT to avoid 1 death or severe disability outcome
Mayer SA , et al. NEJM 2005;352:777-85
Barthel Index at Day 90
Placebo
40 mcg/kg 55 P = 0.07
80 mcg/kg 68 P = 0.01
160 mcg/kg 55 P = 0.02
Median
25
• Barthel Index: 100 = independent in Activities of Daily Living, 0 = completely dependent
• Dead patients were assigned a Barthel Index score of 0
Mayer SA , et al. NEJM 2005;352:777-85
Serious Thromboembolic Events: ICH rFVIIa Study
Placebo 40 mcg/kg 80 mcg/kg 160 mcg/kg Combined rFVIIa
2%
6%
4%
10 %
7%
P= 0.12 vs. placebo
• Independent safety board; all events within 90 days captured • 23 patients experienced 26 serious thromboembolic events
Mayer SA, et al. NEJM 2005;352:777-85
Arterial & Fatal Thromboembolic Events: rFVIIa ICH Trial
•
Arterial thromboembolic events occurred significantly (P = 0.01) more frequently with rFVIIa (5%) vs.placebo (0%)
–
cerebral infarction (9) & myocardial ischemic events (7)
•
Thromboembolic SAEs that were fatal or disabling occurred in 2% of rFVIIa-treated patients compared with 2% in the placebo group
Mayer SA,, et al. NEJM 2005;352:777-85
Patient Case: rFVIIa Benefit?
• 24y F who sustained severe traumatic ICH due to motor vehicle collision 1 hr ago admitted to your emergency dept. (ED)
• 48y F diagnoses with spontaneous ICH upon presentation to your ED 1.5 hours after symptom onset
• 66y M found unconscious by friend, transported initially to outside hospital x 2 hours for intraventricular blood per head CT scan, arrived in your ED 75 minutes ago
rFVIIa: Excessive Anticoagulant Reversal
• No RCT data currently available; case series suggestive of beneficial effects
– predominantly with doses < 40 mcg/kg IV x 1
• 15 - 20 mcg/kg IV sufficient for warfarin reversal1,2 • 90 mcg/kg IV in normal volunteers s/p fondaparinux3 or idraparinux4
– result in thrombin generation & PT/PTT correction
J, et al. J Neurosurg 2003;98:737-40; 2Deveras RA, et al. Ann Intern Med 2002;137:884-8; 3Bijsterveld NR, et al. Circulation 2002;106:2550-2554; 4Bijsterveld NR, et al. Br J Haematol 2004;124:653-8
1Lin
rFVIIa: Drug Expense
• Acquisition cost: $0.94/mcg (FAHC)
– 90 mcg/kg dose for 70 kg patient = 6300 mcg • $5,640 (rounding down to nearest vial size)
• Practical considerations for reducing cost:
– multidisciplinary guidelines to ensure appropriate use &maximize efficacy likelihood – rounding to nearest vial size (1.2, 2.4, 4.8mg) – only prepare 1 dose at a time, even if multiple are ordered (3 hr stability once reconstituted)
Recommendations for rFVIIa in Actively Bleeding Trauma Patients (1)
Patient must meet ALL of the following criteria: • Failure of aggressive conventional therapies • Active bleeding with attempt at surgical control • > 6 units PRBC infused & at least 2-4 more are expected to control bleeding • Platelet count > 50,000; if not, ensure platelets are infused concurrently • Appropriate FFP,other blood or reversal products given based on patients condition • Attempts at correcting metabolic acidosis/ normothermia • Non-futile care
Rebuck JA, et al. FAHC Guidelines, Approved June 2005
Recommendations for rFVIIa in Actively Bleeding Trauma Patients (2)
• Prescribing approval by surgical attending pre-dose • Max 40 mcg/kg IVP over 2 min stat for excessive anticoagulation reversal • 90 mcg/kg IVP over 2 min stat for all other ongoing, active bleeding • 2nd dose in 15 minutes if necessary (do not order at same time as original dose) • Pharmacy will round down to nearest 1200 mcg vial size (no minimal effective dose has been established) • Follow-up: Each use of rFVIIa reviewed & summary data provided to Trauma and P+T Committees PRN
Rebuck JA, et al. FAHC Guidelines, Approved June 2005
rFVIIa Off-Label Consensus Guidelines
• Multi-disciplinary panel
– Co-sponsored by SABM and UHC (July 2004) – Published November 2005 in pharmacy journal
• Dosing Regimens: – non-stat anticoagulant reversal: 20-40 mcg/kg – All other scenarios: 41-90 mcg/kg • Rated rFVIIa use as appropriate (A), uncertain (U), or inappropriate (I) based on available data
Shander A, et al. P+T 2005;30:644-58
rFVIIa Off-Label Consensus Guidelines: Closed-Space Bleeding
• Non-traumatic ICH – < 4hr since Sx onset (no warfarin/LWMH): • taking warfarin/LMWH – > 4hr since Sx onset (no warfarin/LMWH) • taking warfarin/LMWH • Isolated traumatic brain injury – No expanding bleed (no warfarin/LMWH) • taking warfarin/LMWH – Expanding bleed evidence (no warfarin/LMWH) • taking warfarin/LWMH
Shander A, et al. P+T 2005;30:644-58
A A I U
I U U A
rFVIIa Off-Label Consensus Guidelines: Closed-Space Bleeding
• Retroperitoneal Bleeding – Not taking warfarin/LMWH:
• no significant clotting factor replacement • attempted significant factor replacement Inappropriate Uncertain Inappropriate Appropriate
– Taking warfarin/LMWH:
• no significant clotting factor replacement • attempted significant factor replacement
20ml/kg or 6 units FFP or 6 units of platelets x2 if platelet count < 50,000 or 10 bags of cryoprecipitate x2 if fibrinogen was low or clotting factor replacement not feasible due to time/volume constraints
Shander A, et al. P+T 2005;30:644-58
rFVIIa Off-Label Consensus Guidelines: Rescue Therapy in Surgical Patients
• Cardiac Surgery
– No significant clotting factor replacement – Attempted significant clotting factor replacement Inappropriate Appropriate Inappropriate Appropriate
• Thoracic Aortic Surgery
– No significant clotting factor replacement – Attempted significant clotting factor replacement
• Abdominal Aortic Surgery
– No significant clotting factor replacement – Attempted significant clotting factor replacement Inappropriate Uncertain
Uncertain Appropriate
• Hepatic Resection or Liver Transplant
– No significant clotting factor replacement – Attempted significant clotting factor replacement
Shander A, et al. P+T 2005;30:644-58
rFVIIa Off-Label Consensus Guidelines: Rescue Therapy in Surgical Patients
Nontraumatic high blood loss orthopedic surgery • Spine
– No significant clotting factor replacement – Attempted significant clotting factor replacement Inappropriate Appropriate
• Large joint replacement
– No significant clotting factor replacement – Attempted significant clotting factor replacement Inappropriate Inappropriate
Shander A, et al. P+T 2005;30:644-58
rFVIIa Off-Label Consensus Guidelines: Other Uses
• Severe Multiple Trauma
– Ongoing bleeding and coagulopathy despite intervention and > 10 units of PRBC in 6 hours Appropriate
• Active GI Bleeding • Postpartum period and after hysterectomy
– No attempted significant factor replacement – Attempted significant factor replacement
Inappropriate
Inappropriate Appropriate
• Thrombocytopenia with severe bleeding refractory to conventional treatment
Uncertain
Shander A, et al. P+T 2005;30:644-58
rFVIIa Off-Label Consensus Guidelines: Other Uses
• Hepatic Failure with GI bleeding or pending invasive procedure
– No attempted significant factor replacement – Attempted significant clotting factor replacement Inappropriate Appropriate
• Prophylactic use before major surgery
Inappropriate
Shander A, et al. P+T 2005;30:644-58
Steps to Ensure Appropriate rFVIIa Use
• Multidiscipline consensus • Develop institutional-specific guidelines
– Pharmacy, Blood bank, Intensivists - Medicine & Surgery, specialty surgeons, GI/hepatology, Nursing
• Institution approval of guidelines • Continuously measure impact • Update guidelines frequently
Advantages of Implementing Appropriate Use rFVIIa Guidelines
•Minimize variability in prescribing • Increase likelihood of positive outcomes •Appropriate use based on clinical condition
• Enhance use in population that may benefit most from rFVIIa • Minimize use in population that has less propensity of rFVIIa benefit or heightened risk:benefit safety ratio
Future Directions
• Develop institutional rFVIIa guidelines to decrease variability & guide administration • Optimal dose unknown for most conditions • Critically evaluate literature to ensure patients most likely to benefit receive rFVIIa therapy
– Off-label use: benefit must outweigh risk