comparative effectiveness of recombinant factor viia for off-label uses vs. usual care in the...

Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Uses vs. Usual Care in the

Hospital SettingPrepared for:

Agency for Healthcare Research and Quality (AHRQ)www.ahrq.gov

Introduction to recombinant activated factor VII (rFVIIa)

Process for developing the comparative effectiveness review (CER)

Results on rFVIIa off-label use in the hospital

Results of rFVIIa comparative effectiveness Gaps in knowledge

Outline of Study

Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.

Approved by the FDA for use in patients with hemophilia A or B with inhibitors, acquired hemophilia, and congenital factor VII deficiency.

Increasingly used off-label beyond hemophilia-related indications to prevent excessive bleeding for a range of surgical and medical conditions.

In the past decade, off-label use of rFVIIa in the hospital has significantly increased. The three most common uses are for spontaneous intracranial hemorrhage, bleeding secondary to trauma, and adult cardiac surgery.

Introduction to Recombinant Activated Factor VII (rFVIIa)


The Coagulation Cascade: rFVIIa Mechanism of Action

TF = tissue factor

Since 1999, the FDA has approved four separate applications that have gradually expanded the scope of rFVIIa use in hemophilia: Hemophilia A or B with inhibitors for bleeding episodes

(March 25, 1999) Bleeding and surgery in congenital factor VII deficiency (July

11, 2005) Surgery and invasive procedures in hemophilia A or B with

inhibitors (August 12, 2005) Bleeding and surgery in acquired hemophilia (October 13,

2006)

FDA–Approved Indications for rFVIIa


Chronic prophylactic use in hemophilia A and B

Episodic use for: Other isolated, congenital, or acquired clotting factor

defects Disease states where impaired coagulation is but one

manifestation Anticoagulant therapy-associated bleeding problems

Consumptive coagulopathy from substantial blood loss

Prophylactic use for anticipated blood loss Traumatic, surgical, or spontaneous bleeding

in noncoagulopathic patients

Off-Label Uses of rFVIIa


The publicly nominated topic was reviewed and selected based on need, importance, and feasibility.

Experts and stakeholders guided the development of the clinical questions that were made available for public comment.

A specialized Technical Expert Panel assisted the research process and development of the draft report.

The CER Development Process (1)


Methods for literature review, data collection, and meta-analysis followed version 1.0 of the Methods Reference Guide for Effectiveness and Comparative Effectiveness Reviews.

The draft CER was subject to public comment and peer review.

The complete final report is available online.

The CER Development Process (2)


Framework for Analyzing Outcomes for

Off-Label rFVIIa Use in the Hospital Setting

Prophylactic Useof rFVIIa

(repeat dosing possible)

Treatment Useof rFVIIa


End-Stage Useof rFVIIa


Overall Use of rFVIIa

ICH and Trauma

Cardiac, Liver, and Prostate Surgery

Clinical Situationwith Bleeding

Potential

Major Bleeding

No Bleeding orMinor Bleeding

Deterioration

Improvement

Overview of rFVIIa real-world use and description of comparative studies

The benefits and harms of rFVIIa for: Spontaneous intracranial hemorrhage Bleeding from body trauma Bleeding from brain trauma Adult cardiac surgery Pediatric cardiac surgery Liver transplantation Prostatectomy

Clinical Questions Addressed by the Comparative Effectiveness Review


Direct outcomes: Clinical endpoints: death, functional status, ARDS Adverse effects: thromboembolism (PE, DVT, MI, stroke)

Indirect outcomes: Health care process/resource use: transfusion requirements,

length of ICU/hospital stay, operating room time Intermediate/surrogate: hematoma expansion, blood

loss/chest tube output, surgical re-exploration, coagulation tests

Outcomes of Interest for Off-Label rFVIIa Usein the Hospital Setting


Risk of bias Consistency Directness Precision

Four Domains Used To AssessRelevant Studies


The strength of evidence was classified into four broad categories:

Rating the Strength of Evidence From the CER

High ●●● Further research is very unlikely to change the confidence in the estimate of effect.

Moderate ●●○

Further research may change the confidence in the estimate of effect and may change the estimate.

Low ●○○ Further research is likely to change the confidence in the estimate of effect and is likely to change the estimate.

Insufficient Evidence either is unavailable or does not permit estimation of an effect.


Overview of In-Hospital, Off-Label vs. On-Label rFVIIa Use From the Premier Database (2000-2008)

In 2008, 97% of rFVIIa in-hospital use was off-label.

The most common off-label uses from 2000–2008 were: Adult cardiac surgery

(16.4%) Trauma to the body

(excluding brain trauma) (15.9%)

Spontaneous intracranial hemorrhage (10.5%)


24 randomized controlled trials and 31 comparative observational studies on rFVIIa use across several clinical indications: Cardiac surgery (12 studies) Trauma (9 studies) Intracranial hemorrhage (8 studies) Liver transplantation (8 studies) Other liver disease (5 studies)

Comparative Studies on Off-Label rFVIIa Use


Strength of evidence available from existing studies was compromised by: Small study size Use of indirect outcomes Heterogeneity in dosage/indication Applicability diminished by mismatch between existing

research and real-world patterns of indication and types of use

Characteristics of Comparative Studies on Off-Label rFVIIa Use


Mean Differences in Mortality and Thromboembolic Event Rates by Study and rFVIIa Indication

The area of each circle approximates the total sample size of each respective study; shaded circles represent studies on treatment use of rFVIIa and clear circles represent studies on prophylactic use of rFVIIa.


Evidence for rFVIIa Use for Spontaneous Intracranial

Hemorrhage vs. Usual Care

No effect of rFVIIa on mortality or rate of poor functional status. ●●○

Increased rate of arterial thromboembolic events for medium- (41–119 μg/kg) and high-dose (≥120 μg/kg) groups. ●●○

Associated with a decrease in the percent hematoma expansion. ●●○

Evidence suggests that neither benefits nor harms exceed each other for rFVIIa use in spontaneous intracranial hemorrhage.

Overview of Comparative Effectiveness of rFVIIa for Spontaneous Intracranial Hemorrhage


Relative Hematoma Expansion Is Reduced After rFVIIa Use in Spontaneous Intracranial Hemorrhage

Dose of rFVIIa for Spontaneous

Intracranial Hemorrhage

Relative change in hematoma volume

Standardized mean difference(95% CI)

Low (≤40 mg/kg)-0.157

(-0.302 to -0.012)

Medium (41-119 mg/kg)

-0.293 (-0.439 to -0.1)

High (≥120 mg/kg) -0.304

(-0.549 to -0.06)


Increased Risk of Arterial Thromboembolic Events With rFVIIa for Spontaneous Intracranial Hemorrhage vs. Usual Care

Dose of rFVIIa for Spontaneous Intracranial Hemorrhage

TE Events/Total Patients (%)

rFVIIa Usual Care

Risk Difference Summary Effect

Size (95% CI)

Estimated Effect on TE Events (Strength of

Evidence)

Low (≤40 mg/kg)24/415(5.8)

13/378(3.4)

0.025(-0.004 to 0.053)

No effect* (●●○)

Medium (41-119 mg/kg) 29/399

(7.3)13/378(3.4)

0.035(0.008 to 0.062)

Increase withrFVIIa (●●○)

High (≥120 mg/kg) 8/115(7.0)

0/107(0)

0.063(0.011 to 0.114)

Increase withrFVIIa (●●○)

*While this effect was not significantly different from zero, there may have been insufficient statistical power to detect a difference.CI = confidence interval; TE = thromboembolic.


Evidence of rFVIIa Use for Bleeding Secondary to Body

Trauma vs. Usual Care

Overview of rFVIIa Use in BleedingSecondary to Body Trauma

Outcome of Interest

Number of Studies(RCT/COS)

Number of SubjectsrFVIIa Usual

Care

EstimatedEffect of rFVIIa

Overall Strength of Evidence

Mortality(30 days)

2 139 138 No effect●○○

3 128 279Weakly favors

rFVIIaThromboembolic events

5 301 469 No effect ●○○

Units of RBCs transfused

2 139 138 Favors rFVIIa●○○

1 49 75 Favors usual care

ARDS 3 188 213Weakly favors

rFVIIa●○○

RCT = randomized controlled trials; COS = comparative observational studies; ARDS = acute respiratory distress syndrome; RBCs = red blood cells.


Evidence of rFVIIa Use forBleeding Secondary to Brain

Traumavs. Usual Care

Overview of rFVIIa for BleedingSecondary to Brain Trauma

Outcome of Interest

Number of

Studies Number of Subjects


Overall Strength

of Evidence

rFVIIa Usual Care

Mortality(15 days) 2 79 53 No effect ●○○

Thromboembolic events (72 hours) 2 79 53 No effect ●○○

Glasgow Coma Scale (15 days)

2 79 53 No effect ●○○

Hematoma volume change 1 61 36 No effect ●○○


Evidence of rFVIIa Use forAdult Cardiac Surgery vs. Usual

Care

Overview of rFVIIa for Adult Cardiac Surgery: Clinical Outcomes

Outcome of Interest

Number of

Studies Number of SubjectsEstimated

Effect of rFVIIa

Overall Strength

of Evidence

rFVIIa Usual care

Mortality(in-hospital) 10 455 385 No effect ●○○

Units of RBCs transfused

4 108 108 Weakly favors rFVIIa or no effect ●○○

ICU lengthof stay 5 147 148

Weak increase with rFVIIa

or no effect●○○

ICU = intensive care unit; RBCs = red blood cells.


Increased Risk of Thromboembolic Events With rFVIIa Use for Adult Cardiac Surgery

In-Hospital, Off-Label Use of

rFVIIa

TE Events/Total Patients

(%)rFVIIa Usual

Care

Risk Difference Summary Effect Size(95% CI)

EstimatedEffect on TE

Events

Overall Strength

of Evidence

Adult cardiac surgery

19/203

(9.4)

8/170(4.7)

0.053(0.01 to 0.096)

Increase withrFVIIa

●●○

CI = confidence interval; TE = thromboembolic.


Evidence of rFVIIa Use for Pediatric Cardiac Surgery, Liver

Transplantation, and Prostatectomy vs. Usual Care

Overview of rFVIIa Use for Liver Transplantation

Outcomesof Interest

Number of Studies Number of Subjects


Overall Strength of Evidence

rFVIIa Usual Care

Mortality(timeframe unclear)

4 201 102 No Effect ●○○

Thromboembolic events

4 201 102 No Effect ●○○

Units of RBCs transfusedin 24 hours

4 201 102 Weakly FavorsrFVIIa ●○○

Operating room time 2 30 36 No Effect ●○○

ICU length of stay 3 195 90 No Effect ●○○

ICU = intensive care unit; RBCs = red blood cells.Yank V, et al. AHRQ Comparative Effectiveness Review No. 21. Available at: http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=450.

Overview of rFVIIa Use forPediatric Cardiac Surgery

Outcomes of Interest

Number of

Studies Number of Subjects

EstimatedMagnitudeof Effect

Effect of rFVIIa Dosage

Overall Strength

of Evidence

Grade

rFVIIa Usual Care

Mortality 1 40 36 No data No data Insufficient

Thromboembolic events

1 40 36 Unknown Unknown Insufficient

Units of whole blood/RBCs transfused

1 40 36Weakly favors

rFVIIaUnknown Insufficient

Time to chest closure

1 40 36Increase with

rFVIIaUnknown InsufficientRBCs = red blood cells.


Overview of rFVIIa Use for Prostatectomy

Outcome of Interest

Number of

Studies

Number of Subjects

rFVIIa Usual Care


OverallStrength

of Evidence

Mortality(10 day) 1 24 12 Unknown Insufficient

Thromboembolic events 1 24 12 Unknown Insufficient

Units of RBCstransfused 1 24 12 Favors rFVIIa Insufficient

Operating room time 1 24 12 Favors rFVIIa Insufficient

RBCs = red blood cells.


Summary of Outcomes for Most Common Off-Label, In-Hospital Uses of rFVIIa

In-Hospital, Off-Label Uses

for rFVIIa Benefits

Strengthof

Evidence Harms

Strengthof

Evidence

Spontaneousintracranialhemorrhage

No effect on mortality or functional outcomes. Attenuation of hematoma expansion.

●●○

●●○

Increased risk for arterial thromboembolic events, particularly at doses >40 μg/kg of patient body weight.

●●○

Adult cardiac surgery

No significant effect on mortality, RBC transfusion rates, or ICU length of stay.

●○○ Increased risk for thromboembolic eventswhen compared to usual care.

●●○

Body trauma No consistent effects on mortality.Possible reduction in acute respiratory distress syndrome.

●○○

●○○

No effect on thromboembolic events.

●○○


Management of abdominal aortic aneurysm (with and without surgical intervention)

Pediatric cardiac surgery Vascular surgeries (not related to

abdominal aortic aneurysm) Surgical procedures beyond cardiac and

vascular surgery

Additional Off-Label Uses of rFVIIa Requiring Future Research: Surgery

Cancer-related conditions Gastrointestinal bleeding not related to liver

disease Hematopoietic stem cell transplantation Liver disease (other than transplantation) Neonatal conditions (beyond cardiac surgery) Obstetrical conditions Primary clotting disorders (other than

hemophilia) Pulmonary conditions (e.g., pulmonary

hemorrhage, pulmonary transplantation) Secondary clotting disorders (e.g.,

complications of warfarin anticoagulation)

Additional Off-Label Uses of rFVIIa Requiring Future Research: Medical

For the uses examined, current evidence does not show that off-label use of rFVIIa reduces mortality or improves other direct outcomes.

Thromboembolic events are increased by using rFVIIa to treat spontaneous intracranial hemorrhage and in adult cardiac surgery.

Conclusions From Available Evidence


comparative effectiveness of recombinant factor viia for off-label uses vs. usual care in the...

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