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Original Research |

Off-Label Use of Recombinant Factor VIIa in U.S. Hospitals: Analysis of Hospital Records

Aaron C. Logan, MD, PhD; Veronica Yank, MD; and Randall S. Stafford, MD, PhD
[+] Article and Author Information

From Stanford Prevention Research Center and Stanford University School of Medicine, Stanford, California.


Disclaimer: The authors of this report are responsible for its content. Statements in the report should not be construed as endorsement by the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

Acknowledgment: The authors thank C. Vaughan Tuohy, Dena M. Brevata, Kristan Staudenmayer, Robin Eisenhut, Vandana Sundaram, Donal McMahon, David Johnston, Christopher Stave, James Zehnder, Ingram Olkin, Kathryn M. McDonald, and Douglas K. Owens for their contributions to an associated comparative effectiveness review commissioned by the Agency for Healthcare Research and Quality.

Grant Support: By the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services, under contract 290-02-0017. Dr. Stafford also was supported by a National Heart, Lung, and Blood Institute mentoring award (RSS, K24HL086703).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-2334.

Reproducible Research Statement:Study protocol: Available from www.ahrq.gov. Statistical code: Available from Dr. Stafford (e-mail, rstafford@stanford.edu). Data set: Available for purchase from Premier Perspectives (www.premierinc.com).

Requests for Single Reprints: Randall S. Stafford, MD, PhD, Stanford Prevention Research Center, Stanford University, Medical School Office Building X312, 251 Campus Drive, Stanford, CA 94304-5411; e-mail, rstafford@stanford.edu.

Current Author Addresses: Dr. Logan: Division of Blood and Marrow Transplantation, Stanford University School of Medicine, 265 Campus Drive, Lokey Stem Cell Research Building, Room G3045, Stanford, CA 94305.

Drs. Yank and Stafford: Stanford Prevention Research Center, Stanford University, Medical School Office Building X312, 251 Campus Drive, Stanford, CA 94304-5411.

Author Contributions: Conception and design: A.C. Logan, V. Yank, R.S. Stafford.

Analysis and interpretation of the data: A.C. Logan, V. Yank, R.S. Stafford.

Drafting of the article: A.C. Logan, R.S. Stafford.

Critical revision of the article for important intellectual content: A.C. Logan, V. Yank, R.S. Stafford.

Final approval of the article: A.C. Logan, V. Yank, R.S. Stafford.

Provision of study materials or patients: R.S. Stafford.

Statistical expertise: R.S. Stafford.

Obtaining of funding: R.S. Stafford.

Administrative, technical, or logistic support: R.S. Stafford.

Collection and assembly of data: A.C. Logan, R.S. Stafford.


Ann Intern Med. 2011;154(8):516-522. doi:10.7326/0003-4819-154-8-201104190-00002
Text Size: A A A

Background: Recombinant factor VIIa (rFVIIa) is approved for treatment of bleeding in patients who have hemophilia with inhibitors but has been applied to a wide range of off-label indications.

Objective: To estimate patterns of off-label rFVIIa use in U.S. hospitals.

Design: Retrospective database analysis.

Setting: Data were extracted from the Premier Perspectives database (Premier, Charlotte, North Carolina), which contains discharge records from a sample of academic and nonacademic U.S. hospitals.

Patients: 12 644 hospitalizations for patients who received rFVIIa during a hospital stay.

Measurements: Hospital diagnoses and patient dispositions from 1 January 2000 to 31 December 2008. Statistical weights for each hospital were used to provide national estimates of rFVIIa use.

Results: From 2000 to 2008, off-label use of rFVIIa in hospitals increased more than 140-fold, such that in 2008, 97% (95% CI, 96% to 98%) of 18 311 in-hospital uses were off-label. In contrast, in-hospital use for hemophilia increased less than 4-fold and accounted for 2.7% (CI, 1.9% to 3.5%) of use in 2008. Adult and pediatric cardiovascular surgery (29% [CI, 21% to 33%]), body and brain trauma (29% [CI, 19% to 38%]), and intracranial hemorrhage (11% [CI, 7.7% to 14%]) were the most common indications for rFVIIa use. Across all indications, in-hospital mortality was 27% (CI, 19% to 34%) and 43% (CI, 26% to 59%) of patients were discharged to home.

Limitation: Accuracy and completeness of the discharge diagnoses and patient medication records in the database sample cannot be verified.

Conclusion: Off-label use of rFVIIa in the hospital setting far exceeds use for approved indications. These patterns raise concern about the application of rFVIIa to conditions for which strong supporting evidence is lacking.

Primary Funding Source: Agency for Healthcare Research and Quality.

Figures

Grahic Jump Location
Figure 1.
Estimated annual in-hospital cases of recombinant factor VIIa use for hemophilia and off-label indications.

Cases signify the number of hospitalizations during which recombinant factor VIIa was used. All cases for each year are depicted. The width of each segment represents the number of cases for each category, as indicated by differential shading. Hemophilia includes hemophilia A and B, and trauma includes body and brain trauma. ICH = intracranial hemorrhage.

Grahic Jump Location
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Appendix Figure.
Estimated annual in-hospital cases using recombinant factor VIIa for adult and pediatric cardiovascular surgery (top) and for trauma and ICH (bottom).

ICH = intracranial hemorrhage.

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Figure 2.
Use of rFVIIa at academic and nonacademic institutions from 2000 to 2008.

GI = gastrointestinal; rFVIIa = recombinant factor VIIa.

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References

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Logan et al. and Yank et al. articles do not put rFVIIa use into proper context
Posted on April 18, 2011
Anne Phillips
No Affiliation
Conflict of Interest: None Declared

In the April 19th issue of Annals, Logan et al. and Yank et al. present a summary of their AHRQ-sponsored assessment [1]. Novo Nordisk is concerned that these articles do not put rFVIIa use into proper context. The majority of rFVIIa use is in hemophilia with inhibitors in the outpatient setting.

In 1972, Ulla Hedner discovered that coagulation factor VII was able to bypass factor VIII/IX-mediated clotting in patients with hemophilia complicated by alloantibodies. Due to the limited availability of plasma FVII and the risk of transmitting infectious agents Novo Nordisk agreed to develop a recombinant FVIIa in 1985. After the conduct of several successful clinical trials, rFVIIa was approved by EMA in 1996 and the FDA in 1999 for use in hemophilia patients with inhibitors, and subsequently in acquired hemophilia, congenital factor VII deficiency, and to prevent bleeding during surgery in those patients.

The use of rFVIIa outside of hemophilia is relatively recent. In 1999, Israeli hematologists, faced with a 19-year-old soldier with a gunshot wound to the vena cava and coagulopathy refractory to treatment and surgery, successfully used rFVIIa to sufficiently correct the coagulopathy which allowed for surgical repair [2].

Logan et al. reviewed the analysis of the PREMIER database of selected hospitals to assess the percentage of off-label use of rFVIIa without mentioning a key fact noted in the full AHRQ report. "The majority of use of rFVIIa occurs in the outpatient setting, and the majority of outpatient use is for on-label indications related to hemophilia."[1] Thus, their analysis describes only a small portion of overall rFVIIa use.

Yank et al. reviewed studies reported in the literature and data provided to AHRQ by Novo Nordisk to assess the benefits and risks of rFVIIa in critical bleeding. Their conclusions on rFVIIa-associated mortality and safety do not differ from the recent Cochrane review, other meta-analyses, or the analysis from the Novo Nordisk safety database published by Levi et al. last year [3,4,5].

Novo Nordisk has proactively modified the rFVIIa package insert several times in the past years in collaboration with regulatory agencies to warn about the potential risk of arterial thromboembolic events outside of labeled indications and does not promote the use of rFVIIa outside of approved indications.

NovoSeven RT has been used for more than a decade across the world to improve the lives of patients and to treat bleeding episodes and prevent bleeding during surgery in patients with hemophilia with inhibitors, acquired hemophilia, and congenital factor VII deficiency.

Anne Phillips, MD Vice President, Clinical, Medical and Regulatory Affairs, Novo Nordisk Inc. Princeton, New Jersey

References:

1. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, Sundaram V, McMahon D, Stave CD, Zehnder JL, Olkin I, McDonald KM, Owens DK, Stafford RS. Comparative Effectiveness of Recombinant Factor VIIa for Off-Label Indications vs. Usual Care. Comparative Effectiveness Review No. 21. (Prepared by Stanford-UCSF Evidence-based Practice Center under Contract No. #290-02-0017) Rockville, MD: Agency for Healthcare Research and Quality. May 2010. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.

2. Kenet G, Walden R, Eldad A, and Martinowitz U. Treatment of traumatic bleeding with recombinant factor VIIa. Lancet 1999. 354(9193):1879.

3. Lin Y, Stanworth S, Birchall J, Doree C, Hyde C. Recombinant factor VIIa for the prevention and treatment of bleeding in patients without haemophilia. Cochrane Database Syst Rev. Available online 2011 Feb 16.

4. Hsia CC, Chin-Yee IH, McAlister MB. Use of Recombinant Activated Factor VII in Patients without Hemophilia: A Meta-Analysis of Randomized Control Trials. Ann Surg 2008:248:61-68.

5. Levi M, Levy JH, Andersen HF, Truloff D. Safety of Recombinant Activated Factor VII in Randomized Clinical Trials. N Engl J Med 2010;363: 1791-800.

Conflict of Interest:

Dr. Anne Phillips is an employee of Novo Nordisk Inc. (Princeton, NJ).

Trends in the Use of Factor VII in Cardiac Surgery
Posted on May 4, 2011
Awori J Hayanga
University of Washington
Conflict of Interest: None Declared

Logan et al provide appropriate insight into prevailing patterns of usage of Recombinant Factor VII [1]. Specifically, however, the authors report that usage in cardiac surgery constitutes the largest single off-label use and indeed hint at a possible over-usage. Any indictment of this usage, however, is best tempered by the fact that the majority of cardiac interventions today is indeed off-label. This is particularly true of percutaneous interventions [2].

FDA approval in isolation, therefore, does not govern all contemporary practice decisionmaking in cardiovascular healthcare delivery in the United States. This has been well demonstrated in the use of drug eluting stents [3]. In our institution's adult cardiac surgery practice, Factor VII is not a first line agent for hemostasis, is rarely used outside the context of catastrophic bleeding, and never as a "routine measure" to achieve hemostasis. Indeed, the prophylactic usage of Factor VII upon termination of cardiopulmonary bypass cited in the article has not been a widely accepted practice [4]. The criticism that there has been no survival benefit may also be countered by the implications of a decrease in transfusion requirements and the accepted survival benefit derived from withholding blood transfusion, particularly old blood. [5]

The increased usage of Factor VII is likely to continue unabated. This will likely be further fueled by an ever increasing number of elderly patients undergoing complex re-do procedures. The calls and demands for more rigorous evaluation into the off-label use of this potent hemostatic agent are growing louder but until these evaluative data become available, its utility, at least per anecdotal report, is unlikely to dissipate.

REFERENCES

1. Logan AC, Yank, V, Stafford RS. Off-Label Use of recombinant Factor VIIa in US Hospitals: Analysis of Hospital Records. Ann Intern Med: 2011;154:516- 522

2. Holmes DR Jr, Bell MR, Holmes DR 3rd, Berger PB, Bresnahan JF, Hammes LN, Grill DE, Garratt K Interventional cardiology and intracoronary stents--a changing practice: approved vs. nonapproved indications. Cathet Cardiovasc Diagn. 1997 Feb;40(2):133-8.

3. Impact of "off-label" utilization of drug-eluting stents on clinical outcomes in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2008 Feb 1;101(3):293-9. Epub 2007 Dec 21.

4. Roy P, Buch AN, Javaid A, Okabe T, Raya V, Pinto Slottow TL, Steinberg DH, Smith K, Xue Z, Gevorkian N, Satler LF, Kent KM, Suddath WO, Pichard AD, Lindsay J, Waksman R. Impact of "off-label" utilization of drug-eluting stents on clinical outcomes in patients undergoing percutaneous coronary intervention. Am J Cardiol. 2008 Feb 1;101(3):293- 9. Epub 2007 Dec 21.

5. Diprose P, Herbertson MJ, O'Shaughnessy D, Gill RS. Activated recombinant factor VII after cardiopulmonary bypass reduces allogeneic transfusion in complex non-coronary cardiac surgery: randomized double-blind placebo-controlled pilot study. Br J Anaesth. 2005 Nov;95(5):596-602. Epub 2005 Sep 23

Conflict of Interest:

None declared

Response to letters regarding our two papers
Posted on May 31, 2011
Veronica Yank
Stanford University
Conflict of Interest: None Declared

May 31, 2011

To the Editors:

We appreciate the comments on our two analyses of off-label use of recombinant activated factor VII (rFVIIa). Our investigation of U.S. hospital data indicated that between 2000 and 2008 off-label use of rFVIIa increased more than 140-fold (1). In 2008, off-label uses for such conditions as cardiovascular surgery, intracranial hemorrhage, and trauma accounted for 97% of in-hospital use. Our second study, a systematic review of five in-patient off-label uses of rFVIIa, analyzed the results of 17 randomized clinical trials, 26 comparative observational studies, and 19 non-comparative observational studies (2). Taken together these studies showed no mortality reduction with rFVIIa use and, for some indications, an increase in thromboembolism.

Our first study examined only hospital data. We did not analyze outpatient usage in relationship to hospital cases. Nonetheless, off-label hospital usage of rFVIIa was sizeable, encompassing an estimated 17,800 cases in 2008. While we appreciate Dr. Phillips' assurances regarding Novo Nordisk's marketing of rFVIIa, we nevertheless observed increasing off- label use of this product in the absence of strong supporting evidence. In a broader context, pharmaceutical promotion is a common mechanism for the growth of off-label use of other drugs (3).

Dr. Hayanga points out that many interventions are used off-label, a point we also make in our systematic review of off-label rFVIIa use for adult cardiovascular surgery, intracranial hemorrhage, trauma, liver transplantation, and prostatectomy. He suggests that for adult cardiovascular surgery, the diminished transfusion requirements expected with rFVIIa use might produce a survival benefit, but this was not demonstrated in our analysis. The majority of patients in the studies we analyzed were adults undergoing complex cardiac procedures who received rFVIIa as treatment (not prophylaxis) for bleeding complications. For these patients, we observed that "red blood cell transfusion requirements were possibly reduced with rFVIIa," but noted that this tendency did not result in improved survival, but rather was accompanied by an increase in thromboembolic adverse events. Similar findings pertained to rFVIIa use for intracranial hemorrhage. Thus, an important insight from our review is that improvements in intermediate outcomes (e.g., cessation of bleeding, reduction in the use of transfusion products) did not translate into better patient survival. This may occur because a patient's underlying trajectory of clinical decline does not correlate with the changes in intermediate outcomes or because rFVIIa produces clinical harms that offset the possible gains represented by intermediate outcomes.

We are disheartened by Dr. Hayanga's view that increased usage of rFVIIa is likely to continue unabated. The rigorous evidence available to date would argue against such expansion without evidence of benefit to balance the documented harms. His comments suggest a more general need for better translation of clinical evidence into practice, particularly when such evidence differs from the conclusions physicians may draw from intermediate outcomes or anecdotal information.

Sincerely, Veronica Yank, MD Aaron C. Logan, MD, PhD Randall S. Stafford, MD, PhD

References

1. Logan AC, Yank V, Stafford RS. Off-label use of recombinant factor VIIa in U.S. hospitals: analysis of hospital records. Ann Intern Med 2011;154:516-522.

2. Yank V, Tuohy CV, Logan AC, Bravata DM, Staudenmayer K, Eisenhut R, Sundaram V, McMahon D, Olkin I, McDonald KM, Owens DK, Stafford RS. Systematic review: benefits and harms of in-hospital use of recombinant factor VIIa for off-label indications. Ann Intern Med 2011;154:529-40.

3. Fugh-Berman A, Melnick D. PLoS Med 2008;5:e210.

Conflict of Interest:

None declared

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