Manuscript Draft - University of East Anglia
Dibotermin alfa is a cost-effective substitute for autologous iliac crest bone graft in single level lumbar interbody spine fusion This is an original research article.Axel Svedbom1,2, Daniel Paech1, Catherine Leonard3, David Donnell4, Fujian Song5, Bronek Boszcyk6, Dominique A. Rothenfluh7, Andrew Lloyd8, Benny Borgman9Mapi, Level 6, Hus D, Klarabergsviadukten 90, Stockholm, 11164, SwedenUnit of Dermatology and Venereology, Department of Medicine, Karolinska Institute, 171 76 Stockholm, SwedenMedtronic Ltd, Building 9, Croxley Green Business Park, Watford, WD18 8WW, UKMedtronic BioPharma B.V., Earl Bakkenstraat 10, 6422 PJ Heerlen, NetherlandsNorwich Medical School, University of East Anglia, Norwich, Norfolk, NR4 7TJ, UKNottingham University Hospital, Centre for Spinal Studies and Surgery, D Floor, West Block, Queens Medical Centre, Derby Road, Nottingham, NG7 2UH, UKNuffield Orthopaedic Centre, Oxford University Hospitals NHS Trust, Windmill Rd., Oxford, OX3 7HE, UKBladon Associates Ltd., 3 Kings Meadow, Oxford OX2 0DB, UK. Medtronic International Trading SARL, Route du Molliau 31, CP 1131 Tolochenaz, SwitzerlandCorresponding author:Mr. Axel SvedbomMapi, Klarabergsviadukten 90, Hus D 111 64, Stockholm, SwedenPhone: +46 731 506 046E-mail: axel.svedbom@Key words: rhBMP-2, bone morphogenetic protein-2, ICBG, spinal fusion, autograft, lumbar arthrodesis, health utility Short titleThe cost-effectiveness of dibotermin alfa for use in spinal fusionAbstractObjectivesTo evaluate the cost-effectiveness of dibotermin alfa compared with autologous iliac crest bone graft (ICBG) for patients undergoing single level lumbar interbody spinal fusion in a UK hospital setting. MethodsAn individual patient data (IPD) meta-analysis of six randomised controlled clinical trials and two single arm trials compared dibotermin alfa on an absorbable collagen implantation matrix (ACIM) (n=456) and ICBG (n=244) on resource use, re-operation rates, and SF-6D (Short form 6-dimension) health utility (total N=700). Failure-related second surgery, operating time, post-operative hospital stay, and quality-adjusted life years (QALYs) derived from the IPD meta-analysis were included as inputs in an economic evaluation undertaken to assess the cost-effectiveness of dibotermin alfa/ACIM versus ICBG for patients undergoing single level lumbar interbody spinal fusion fusion. A four year time horizon and the United Kingdom (UK) National Health Service (NHS) and Personal Social Services (PSS) perspective was adopted in the base case, with sensitivity analyses performed to gauge parameter uncertainty. ResultsIn the base case analysis, patients treated using dibotermin alfa/ACIM (12 mg pack) accrued 0.055 incremental QALYs at an incremental cost of ?737, compared with patients treated with ICBG. This resulted in an Incremental Cost-Effectiveness Ratio (ICER) of ?13,523, indicating that at a willingness-to-pay threshold of ?20,000, dibotermin alfa/ACIM is a cost-effective intervention relative to ICBG from the NHS and PSS perspective. ConclusionsIn a UK hospital setting, dibotermin alfa/ACIM is a cost-effective substitute for ICBG for patients who require lumbar interbody arthrodesis.INTRODUCTIONAge-related degeneration of the spinal intervertebral discs can result in deterioration of their composition and operation, resulting in low back pain. Persistent low back pain is associated with impairment of physical and mental health and is a significant economic burden ADDIN EN.CITE <EndNote><Cite><Author>L</Author><Year>2009</Year><RecNum>361</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>361</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">361</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Manchikanti L</author><author>Singh V</author><author>Datta S</author><author>Cohen SP</author></authors></contributors><titles><title>Comprehensive review of epidemiology, scope and impact of spinal pain</title><secondary-title>Pain physician</secondary-title></titles><periodical><full-title>Pain physician</full-title></periodical><pages>E35-70</pages><volume>12</volume><number>4</number><reprint-edition>In File</reprint-edition><keywords><keyword>epidemiology</keyword><keyword>Pain</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>3033</label><urls></urls></record></Cite></EndNote>1. In the UK, the direct health costs of back pain were estimated to be ?1.6 billion in 1998 ADDIN EN.CITE <EndNote><Cite><Author>N</Author><Year>2000</Year><RecNum>362</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>362</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">362</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maniadakis N</author><author>Gray A</author></authors></contributors><titles><title>The economic burden of back pain in the UK</title><secondary-title>Pain</secondary-title></titles><periodical><full-title>Pain</full-title></periodical><pages>95-103</pages><volume>84</volume><number>1</number><reprint-edition>In File</reprint-edition><keywords><keyword>Back Pain</keyword><keyword>Pain</keyword></keywords><dates><year>2000</year><pub-dates><date>2000</date></pub-dates></dates><label>3034</label><urls></urls></record></Cite></EndNote>2. However, the addition of informal care and employment-related costs substantially increases the estimated total cost of back pain (range from ?6.6 billion to ?12.3 billion), and it is one of the most costly diseases for which an economic assessment has been conducted in the UK ADDIN EN.CITE <EndNote><Cite><Author>N</Author><Year>2000</Year><RecNum>362</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>362</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">362</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Maniadakis N</author><author>Gray A</author></authors></contributors><titles><title>The economic burden of back pain in the UK</title><secondary-title>Pain</secondary-title></titles><periodical><full-title>Pain</full-title></periodical><pages>95-103</pages><volume>84</volume><number>1</number><reprint-edition>In File</reprint-edition><keywords><keyword>Back Pain</keyword><keyword>Pain</keyword></keywords><dates><year>2000</year><pub-dates><date>2000</date></pub-dates></dates><label>3034</label><urls></urls></record></Cite></EndNote>2.Conservative approaches to treating disc degeneration include physical therapy, chiropractic therapy and pharmaceutical therapy (e.g. anti-inflammatories and pain medication). If pain persists despite conservative therapy, surgical approaches such as spinal fusion may be consideredPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaGlsbGlwczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
PFJlY051bT40NzwvUmVjTnVtPjxEaXNwbGF5VGV4dD48c3R5bGUgZmFjZT0ic3VwZXJzY3JpcHQi
PjM8L3N0eWxlPjwvRGlzcGxheVRleHQ+PHJlY29yZD48cmVjLW51bWJlcj40NzwvcmVjLW51bWJl
cj48Zm9yZWlnbi1rZXlzPjxrZXkgYXBwPSJFTiIgZGItaWQ9ImY5dDUyZmU1YXNzdnptZXhzMm54
NWR0NmZhZXZmOXd3ZXN3dCIgdGltZXN0YW1wPSIxNDM5OTcwNTY1Ij40Nzwva2V5PjwvZm9yZWln
bi1rZXlzPjxyZWYtdHlwZSBuYW1lPSJKb3VybmFsIEFydGljbGUiPjE3PC9yZWYtdHlwZT48Y29u
dHJpYnV0b3JzPjxhdXRob3JzPjxhdXRob3I+UGhpbGxpcHMsRi5NLjwvYXV0aG9yPjxhdXRob3I+
U2xvc2FyLFAuSi48L2F1dGhvcj48YXV0aG9yPllvdXNzZWYsSi5BLjwvYXV0aG9yPjxhdXRob3I+
QW5kZXJzc29uLEcuPC9hdXRob3I+PGF1dGhvcj5QYXBhdGhlb2ZhbmlzLEYuPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+RGVwYXJ0bWVudCBvZiBPcnRob3Bh
ZWRpYyBTdXJnZXJ5LCBSdXNoIFVuaXZlcnNpdHkgTWVkaWNhbCBDZW50ZXIsIENoaWNhZ28sIElM
LCBVU0EuIGZyYW5rLnBoaWxsaXBzQHJ1c2hvcnRoby5jb208L2F1dGgtYWRkcmVzcz48dGl0bGVz
Pjx0aXRsZT5MdW1iYXIgc3BpbmUgZnVzaW9uIGZvciBjaHJvbmljIGxvdyBiYWNrIHBhaW4gZHVl
IHRvIGRlZ2VuZXJhdGl2ZSBkaXNjIGRpc2Vhc2U6IGEgc3lzdGVtYXRpYyByZXZpZXc8L3RpdGxl
PjxzZWNvbmRhcnktdGl0bGU+U3BpbmUgKFBoaWxhIFBhIDE5NzYuKTwvc2Vjb25kYXJ5LXRpdGxl
PjwvdGl0bGVzPjxwZXJpb2RpY2FsPjxmdWxsLXRpdGxlPlNwaW5lIChQaGlsYSBQYSAxOTc2Lik8
L2Z1bGwtdGl0bGU+PC9wZXJpb2RpY2FsPjxwYWdlcz5FNDA5LUU0MjI8L3BhZ2VzPjx2b2x1bWU+
Mzg8L3ZvbHVtZT48bnVtYmVyPjc8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5vdCBpbiBGaWxl
PC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPkFkdWx0PC9rZXl3b3JkPjxrZXl3
b3JkPkFnZWQ8L2tleXdvcmQ+PGtleXdvcmQ+QW5hbHlzaXMgb2YgVmFyaWFuY2U8L2tleXdvcmQ+
PGtleXdvcmQ+QmFjayBQYWluPC9rZXl3b3JkPjxrZXl3b3JkPkNocm9uaWMgUGFpbjwva2V5d29y
ZD48a2V5d29yZD5DbGluaWNhbCBUcmlhbHMgYXMgVG9waWM8L2tleXdvcmQ+PGtleXdvcmQ+Q29o
b3J0IFN0dWRpZXM8L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5
d29yZD5kaWFnbm9zaXM8L2tleXdvcmQ+PGtleXdvcmQ+RGlzYWJpbGl0eSBFdmFsdWF0aW9uPC9r
ZXl3b3JkPjxrZXl3b3JkPmV0aW9sb2d5PC9rZXl3b3JkPjxrZXl3b3JkPkV2aWRlbmNlLUJhc2Vk
IE1lZGljaW5lPC9rZXl3b3JkPjxrZXl3b3JkPkZvbGxvdy1VcCBTdHVkaWVzPC9rZXl3b3JkPjxr
ZXl3b3JkPkh1bWFuczwva2V5d29yZD48a2V5d29yZD5JbnRlcnZlcnRlYnJhbCBEaXNjIERpc3Bs
YWNlbWVudDwva2V5d29yZD48a2V5d29yZD5Mb3cgQmFjayBQYWluPC9rZXl3b3JkPjxrZXl3b3Jk
Pkx1bWJhciBWZXJ0ZWJyYWU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9kczwva2V5d29yZD48a2V5
d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5QYWluPC9rZXl3b3JkPjxrZXl3b3Jk
PlBhaW4gTWVhc3VyZW1lbnQ8L2tleXdvcmQ+PGtleXdvcmQ+UGF0aWVudCBTYXRpc2ZhY3Rpb248
L2tleXdvcmQ+PGtleXdvcmQ+cHN5Y2hvbG9neTwva2V5d29yZD48a2V5d29yZD5SYW5kb21pemVk
IENvbnRyb2xsZWQgVHJpYWxzIGFzIFRvcGljPC9rZXl3b3JkPjxrZXl3b3JkPlJlb3BlcmF0aW9u
PC9rZXl3b3JkPjxrZXl3b3JkPlNldmVyaXR5IG9mIElsbG5lc3MgSW5kZXg8L2tleXdvcmQ+PGtl
eXdvcmQ+U3BpbmFsIEZ1c2lvbjwva2V5d29yZD48a2V5d29yZD5TcGluZTwva2V5d29yZD48a2V5
d29yZD5zdGF0aXN0aWNzICZhbXA7IG51bWVyaWNhbCBkYXRhPC9rZXl3b3JkPjxrZXl3b3JkPnN1
cmdlcnk8L2tleXdvcmQ+PGtleXdvcmQ+VHJlYXRtZW50IE91dGNvbWU8L2tleXdvcmQ+PC9rZXl3
b3Jkcz48ZGF0ZXM+PHllYXI+MjAxMzwveWVhcj48cHViLWRhdGVzPjxkYXRlPjQvMS8yMDEzPC9k
YXRlPjwvcHViLWRhdGVzPjwvZGF0ZXM+PGxhYmVsPjUwPC9sYWJlbD48dXJscz48cmVsYXRlZC11
cmxzPjx1cmw+aHR0cDovL3d3dy5uY2JpLm5sbS5uaWguZ292L3B1Ym1lZC8yMzMzNDQwMDwvdXJs
PjwvcmVsYXRlZC11cmxzPjwvdXJscz48ZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+MTAuMTA5Ny9C
UlMuMGIwMTNlMzE4Mjg3N2YxMSBbZG9pXTwvZWxlY3Ryb25pYy1yZXNvdXJjZS1udW0+PC9yZWNv
cmQ+PC9DaXRlPjwvRW5kTm90ZT5=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5QaGlsbGlwczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+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ADDIN EN.CITE.DATA 3. Fusion of the vertebrae of the affected lumbar segment prevents motion and thereby reduces pain. Bone growth at the fusion site is facilitated with bone grafts or substitutes, which may be bone harvested from the patient undergoing the procedure (autograft, usually from the iliac crest), bone from another individual (allograft), or synthetic alternatives. Autologous iliac crest bone graft (ICBG) is considered the gold standard ADDIN EN.CITE <EndNote><Cite><Author>H</Author><Year>2014</Year><RecNum>383</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>383</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">383</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Singh H</author><author>Levi AD</author></authors><tertiary-authors><author>Patel VV</author></tertiary-authors></contributors><titles><title>Bone Graft and Bone Substitute Biology</title><secondary-title>Spine Surgery Basics</secondary-title></titles><pages>147-152</pages><reprint-edition>Not in File</reprint-edition><keywords><keyword>Spine</keyword><keyword>surgery</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><publisher>Springer-Verlag Berlin Heidelberg</publisher><label>3055</label><urls></urls></record></Cite></EndNote>4. However, harvesting ICBG can result in pain and complications related to the donor site ADDIN EN.CITE <EndNote><Cite><Author>Koyonos</Author><Year>2014</Year><RecNum>384</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>384</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">384</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Koyonos,R</author></authors><secondary-authors><author>Patel VV</author></secondary-authors></contributors><titles><title>Lumbar Degenerative Spondylolisthesis</title><secondary-title>Spine Surgery Basics</secondary-title></titles><pages>221-227</pages><reprint-edition>Not in File</reprint-edition><keywords><keyword>Spondylolisthesis</keyword><keyword>Spine</keyword><keyword>surgery</keyword></keywords><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><publisher>Springer-Verlag Berlin Heidelberg</publisher><label>3056</label><urls></urls></record></Cite></EndNote>5, with infection, seroma, haematoma, postoperative pain, scar sensitivity, and meralgia paraesthetica all reported ADDIN EN.CITE <EndNote><Cite><Author>MK</Author><Year>2007</Year><RecNum>363</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>363</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">363</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sen MK</author><author>Miclau T</author></authors></contributors><titles><title>Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions?</title><secondary-title>Injury</secondary-title></titles><periodical><full-title>Injury</full-title></periodical><pages>S75-80</pages><volume>38</volume><number>Suppl 1</number><reprint-edition>In File</reprint-edition><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>3035</label><urls></urls></record></Cite></EndNote>6. Additionally, some patients may have limited bone available for harvesting ADDIN EN.CITE <EndNote><Cite><Author>MK</Author><Year>2007</Year><RecNum>363</RecNum><DisplayText><style face="superscript">6</style></DisplayText><record><rec-number>363</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">363</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Sen MK</author><author>Miclau T</author></authors></contributors><titles><title>Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions?</title><secondary-title>Injury</secondary-title></titles><periodical><full-title>Injury</full-title></periodical><pages>S75-80</pages><volume>38</volume><number>Suppl 1</number><reprint-edition>In File</reprint-edition><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>3035</label><urls></urls></record></Cite></EndNote>6. Consequently, alternatives to ICBG have been developed. In Europe, dibotermin alfa/ACIM (rhBMP-2; InductOs* implantation matrix, Medtronic BioPharma B.V.) is the only commercially available medicinal product licensed for use as a substitute for autogenous bone graft in the treatment of lumbar interbody fusion in adults with disc degeneration ADDIN EN.CITE <EndNote><Cite><Author>BioPharma</Author><Year>2014</Year><RecNum>388</RecNum><DisplayText><style face="superscript">7</style></DisplayText><record><rec-number>388</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">388</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>Medtronic BioPharma</author></authors></contributors><titles><title>InductOs Summary of Product Characteristics</title></titles><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>3060</label><urls><related-urls><url><style face="underline" font="default" size="100%">, the safety and efficacy of dibotermin alfa/ACIM had not been established with spinal implants other than the LT-CAGE* device, implantation at locations other than L4-S1 in the lower lumbar spine, and using surgical techniques other than anterior open or anterior laparoscopic approaches. However, In December 2014, the indication for dibotermin alfa/ACIM in lumbar interbody spinal fusion was broadened. Dibotermin alfa/ACIM is indicated for single-level lumbar interbody spine fusion (L1-S1) as a substitute for autogenous bone graft in adults with disc degeneration who have had at least six months of non-operative treatment for this condition using any approved interbody fusion device implanted using the appropriate surgical technique. To date, economic evidence of lumbar interbody fusion using dibotermin alfa/ACIM compared with ICBG is limited, particularly in a European setting. A study performed in the US found that the cost of dibotermin alfa/ACIM may be entirely offset by reductions in the use of other medical resourcesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BY2tlcm1hbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BY2tlcm1hbjwvQXV0aG9yPjxZZWFyPjIwMDI8L1llYXI+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ADDIN EN.CITE.DATA 8, 9. An economic evaluation performed in the UK in 2007 found unfavourable cost-effectiveness of dibotermin alfa/ACIM compared with ICBG ADDIN EN.CITE <EndNote><Cite><Author>KR</Author><Year>2007</Year><RecNum>50</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970565">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garrison KR</author><author>Donell S</author><author>Ryder J,</author><author>Shemilt I</author><author>Mugford M</author><author>Harvey I,</author><author>Song F.</author></authors></contributors><titles><title>Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review</title><secondary-title>Health Technol Assess</secondary-title></titles><periodical><full-title>Health Technol Assess</full-title></periodical><pages>1-150</pages><volume>11</volume><number>30</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Bone Morphogenetic Proteins</keyword><keyword>Spinal Fusion</keyword></keywords><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>54</label><urls></urls></record></Cite></EndNote>10. Since the UK analysis ADDIN EN.CITE <EndNote><Cite><Author>KR</Author><Year>2007</Year><RecNum>50</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970565">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garrison KR</author><author>Donell S</author><author>Ryder J,</author><author>Shemilt I</author><author>Mugford M</author><author>Harvey I,</author><author>Song F.</author></authors></contributors><titles><title>Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review</title><secondary-title>Health Technol Assess</secondary-title></titles><periodical><full-title>Health Technol Assess</full-title></periodical><pages>1-150</pages><volume>11</volume><number>30</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Bone Morphogenetic Proteins</keyword><keyword>Spinal Fusion</keyword></keywords><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>54</label><urls></urls></record></Cite></EndNote>10 was conducted, additional trials and pooled analyses have been conducted comparing dibotermin alfa/ACIM and ICBG. Two independent systematic reviews were published in 2013 examining the safety and effectiveness of dibotermin alfa/ACIM for spinal fusion based on individual patient data (IPD) from Medtronic sponsored trials and other published studiesPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVt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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVjTnVt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ADDIN EN.CITE.DATA 11, 12. Although the reviews were comprehensive and methodologically rigorous, the research questions warranted the inclusion of a wide range of clinical trials, including some that used unlicensed investigational products (giving doses several times higher than the approved dose) and others that recruited patients outside of the currently approved indication for dibotermin alfa/ACIM (e.g. applying the product outside the lumbar spine). Therefore a need was identified for meta-analysis of all IPD derived from clinical trials relating to the safety and efficacy of the current dibotermin alfa/ACIM indication.The results of the IPD meta-analysis, which were the evidentiary basis for the broadening of the indication for dibotermin alfa/ACIM, have instigated the need to re-evaluate the cost-effectiveness of dibotermin alfa/ACIM versus ICBG. The objective of this study was to utilise the findings of the IPD meta-analysis to estimate the cost-effectiveness of dibotermin alfa/ACIM compared with ICBG in patients undergoing single level lumbar interbody spinal fusion fusion.MATERIAL AND METHODSThis economic evaluation is reported according to the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) Statement ADDIN EN.CITE <EndNote><Cite><Author>D</Author><Year>2013</Year><RecNum>389</RecNum><DisplayText><style face="superscript">13</style></DisplayText><record><rec-number>389</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">389</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Husereau D</author><author>Drummond M</author><author>Petrou S</author><author>Carswell C</author><author>Moher D</author><author>Greenberg D</author><author>Augustovski F</author><author>Briggs AH</author><author>Mauskopf J</author><author>Loder E</author></authors></contributors><titles><title>Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.</title><secondary-title>European Journal of Health Economics</secondary-title></titles><periodical><full-title>European Journal of Health Economics</full-title></periodical><pages>367-372</pages><volume>14</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Health</keyword><keyword>standards</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>3061</label><urls></urls></record></Cite></EndNote>13.Meta-analysisAn IPD meta-analysis was undertaken comparing dibotermin alfa/ACIM and ICBG on resource use, re-operation rates, and SF-6D (Short form 6-dimension) health utility. Eligible studies were company-sponsored trials using dibotermin alfa/ACIM for single-level lumbar interbody fusion. There were no restrictions on surgical approach, lumbar segment treated, composition of interbody fusion device, dose of dibotermin alfa or pack size, technique used to harvest autograft bone, or the site of autograft harvest. All patients were 19–70 years of age and had symptomatic degenerative disc disease between L1 and S1. Prior to surgery, all had experienced low back pain for at least six months that was recalcitrant to nonoperative treatment modalities (such as physical therapy, bed rest, and anti-inflammatory medication). Patients were included in these studies if their plain radiographic findings documented single-level disc disease, and they had undergone at least one additional confirmatory neuroradiographic study, such as MRI, CT-enhanced myelography, or discography. All patients were considered candidates for a single-level lumbar interbody fusion. Minimum duration of follow up was 24 months. For all clinical studies, protocols were approved by an independent ethics committee, all patients provided written informed consent prior to study commencement, and studies were performed in accordance with the Declaration of Helsinki and other applicable regulatory requirements ADDIN EN.CITE <EndNote><Cite><Author>Association</Author><Year>2013</Year><RecNum>392</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>392</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">392</key></foreign-keys><ref-type name="Patent">25</ref-type><contributors><authors><author>World Medical Association</author></authors></contributors><titles><title>WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects</title></titles><keywords><keyword>Research</keyword></keywords><dates><year>2013</year></dates><label>3064</label><urls></urls><custom2>1/10/2013</custom2></record></Cite></EndNote>14.A total of eight trials met the inclusion criteria for the IPD meta-analysis. Six comparative randomised controlled trials (RCTs) were included: 3100N3-117PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2RlbjwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+PFJl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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Cb2RlbjwvQXV0aG9yPjxZZWFyPjIwMDA8L1llYXI+PFJl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ADDIN EN.CITE.DATA 15, 3100N3-303PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 16, C-9703PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS
ZWNOdW0+Mzk8L1JlY051bT48RGlzcGxheVRleHQ+PHN0eWxlIGZhY2U9InN1cGVyc2NyaXB0Ij4x
Nzwvc3R5bGU+PC9EaXNwbGF5VGV4dD48cmVjb3JkPjxyZWMtbnVtYmVyPjM5PC9yZWMtbnVtYmVy
Pjxmb3JlaWduLWtleXM+PGtleSBhcHA9IkVOIiBkYi1pZD0iZjl0NTJmZTVhc3N2em1leHMybng1
ZHQ2ZmFldmY5d3dlc3d0IiB0aW1lc3RhbXA9IjE0Mzk5NzA1NjUiPjM5PC9rZXk+PC9mb3JlaWdu
LWtleXM+PHJlZi10eXBlIG5hbWU9IkpvdXJuYWwgQXJ0aWNsZSI+MTc8L3JlZi10eXBlPjxjb250
cmlidXRvcnM+PGF1dGhvcnM+PGF1dGhvcj5CdXJrdXMsSi5LLjwvYXV0aG9yPjxhdXRob3I+VHJh
bnNmZWxkdCxFLkUuPC9hdXRob3I+PGF1dGhvcj5LaXRjaGVsLFMuSC48L2F1dGhvcj48YXV0aG9y
PldhdGtpbnMsUi5HLjwvYXV0aG9yPjxhdXRob3I+QmFsZGVyc3RvbixSLkEuPC9hdXRob3I+PC9h
dXRob3JzPjwvY29udHJpYnV0b3JzPjxhdXRoLWFkZHJlc3M+SHVnaHN0b24gU3BpbmUgU2Vydmlj
ZSwgVGhlIEh1Z2hzdG9uIENsaW5pYywgQ29sdW1idXMsIEdlb3JnaWEgMzE5MDgtOTUxNywgVVNB
LiBqa2I2NkBrbm9sb2d5Lm5ldDwvYXV0aC1hZGRyZXNzPjx0aXRsZXM+PHRpdGxlPkNsaW5pY2Fs
IGFuZCByYWRpb2dyYXBoaWMgb3V0Y29tZXMgb2YgYW50ZXJpb3IgbHVtYmFyIGludGVyYm9keSBm
dXNpb24gdXNpbmcgcmVjb21iaW5hbnQgaHVtYW4gYm9uZSBtb3JwaG9nZW5ldGljIHByb3RlaW4t
MjwvdGl0bGU+PHNlY29uZGFyeS10aXRsZT5TcGluZSAoUGhpbGEgUGEgMTk3Ni4pPC9zZWNvbmRh
cnktdGl0bGU+PC90aXRsZXM+PHBlcmlvZGljYWw+PGZ1bGwtdGl0bGU+U3BpbmUgKFBoaWxhIFBh
IDE5NzYuKTwvZnVsbC10aXRsZT48L3BlcmlvZGljYWw+PHBhZ2VzPjIzOTYtMjQwODwvcGFnZXM+
PHZvbHVtZT4yNzwvdm9sdW1lPjxudW1iZXI+MjE8L251bWJlcj48cmVwcmludC1lZGl0aW9uPk5v
dCBpbiBGaWxlPC9yZXByaW50LWVkaXRpb24+PGtleXdvcmRzPjxrZXl3b3JkPmFkbWluaXN0cmF0
aW9uICZhbXA7IGRvc2FnZTwva2V5d29yZD48a2V5d29yZD5BZHVsdDwva2V5d29yZD48a2V5d29y
ZD5hZHZlcnNlIGVmZmVjdHM8L2tleXdvcmQ+PGtleXdvcmQ+QWdlZDwva2V5d29yZD48a2V5d29y
ZD5CYWNrIFBhaW48L2tleXdvcmQ+PGtleXdvcmQ+Qm9uZSBNb3JwaG9nZW5ldGljIFByb3RlaW4g
Mjwva2V5d29yZD48a2V5d29yZD5Cb25lIE1vcnBob2dlbmV0aWMgUHJvdGVpbnM8L2tleXdvcmQ+
PGtleXdvcmQ+Qm9uZSBUcmFuc3BsYW50YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+Q29sbGFnZW48
L2tleXdvcmQ+PGtleXdvcmQ+Y29tcGxpY2F0aW9uczwva2V5d29yZD48a2V5d29yZD5EaXNrZWN0
b215PC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgQ2FycmllcnM8L2tleXdvcmQ+PGtleXdvcmQ+ZHJ1
ZyBlZmZlY3RzPC9rZXl3b3JkPjxrZXl3b3JkPkRydWcgSW1wbGFudHM8L2tleXdvcmQ+PGtleXdv
cmQ+ZXRpb2xvZ3k8L2tleXdvcmQ+PGtleXdvcmQ+RmVtYWxlPC9rZXl3b3JkPjxrZXl3b3JkPkh1
bWFuczwva2V5d29yZD48a2V5d29yZD5JbGl1bTwva2V5d29yZD48a2V5d29yZD5pbnN0cnVtZW50
YXRpb248L2tleXdvcmQ+PGtleXdvcmQ+SW50ZXJ2ZXJ0ZWJyYWwgRGlzYyBEaXNwbGFjZW1lbnQ8
L2tleXdvcmQ+PGtleXdvcmQ+TG93IEJhY2sgUGFpbjwva2V5d29yZD48a2V5d29yZD5MdW1iYXIg
VmVydGVicmFlPC9rZXl3b3JkPjxrZXl3b3JkPk1hbGU8L2tleXdvcmQ+PGtleXdvcmQ+bWV0aG9k
czwva2V5d29yZD48a2V5d29yZD5NaWRkbGUgQWdlZDwva2V5d29yZD48a2V5d29yZD5Pc3Rlb2dl
bmVzaXM8L2tleXdvcmQ+PGtleXdvcmQ+UGFpbjwva2V5d29yZD48a2V5d29yZD5Qcm9zcGVjdGl2
ZSBTdHVkaWVzPC9rZXl3b3JkPjxrZXl3b3JkPlF1ZXN0aW9ubmFpcmVzPC9rZXl3b3JkPjxrZXl3
b3JkPnJhZGlvZ3JhcGh5PC9rZXl3b3JkPjxrZXl3b3JkPlJlY29tYmluYW50IFByb3RlaW5zPC9r
ZXl3b3JkPjxrZXl3b3JkPlNwaW5hbCBGdXNpb248L2tleXdvcmQ+PGtleXdvcmQ+U3BpbmU8L2tl
eXdvcmQ+PGtleXdvcmQ+c3VyZ2VyeTwva2V5d29yZD48a2V5d29yZD5Ub21vZ3JhcGh5LFgtUmF5
IENvbXB1dGVkPC9rZXl3b3JkPjxrZXl3b3JkPlRyYW5zZm9ybWluZyBHcm93dGggRmFjdG9yIGJl
dGE8L2tleXdvcmQ+PGtleXdvcmQ+dHJhbnNwbGFudGF0aW9uPC9rZXl3b3JkPjxrZXl3b3JkPlRy
ZWF0bWVudCBPdXRjb21lPC9rZXl3b3JkPjwva2V5d29yZHM+PGRhdGVzPjx5ZWFyPjIwMDI8L3ll
YXI+PHB1Yi1kYXRlcz48ZGF0ZT4xMS8xLzIwMDI8L2RhdGU+PC9wdWItZGF0ZXM+PC9kYXRlcz48
bGFiZWw+NDI8L2xhYmVsPjx1cmxzPjxyZWxhdGVkLXVybHM+PHVybD5odHRwOi8vd3d3Lm5jYmku
bmxtLm5paC5nb3YvcHVibWVkLzEyNDM4OTkwPC91cmw+PC9yZWxhdGVkLXVybHM+PC91cmxzPjxl
bGVjdHJvbmljLXJlc291cmNlLW51bT4xMC4xMDk3LzAxLkJSUy4wMDAwMDMwMTkzLjI2MjkwLkRE
IFtkb2ldPC9lbGVjdHJvbmljLXJlc291cmNlLW51bT48L3JlY29yZD48L0NpdGU+PC9FbmROb3Rl
PgB=
ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 17, C-9806PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWlkPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5IYWlkPC9BdXRob3I+PFllYXI+MjAwNDwvWWVhcj48UmVj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ADDIN EN.CITE.DATA 18, P00-01PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDA1PC9ZZWFyPjxS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ADDIN EN.CITE.DATA 19and C-9804 (data on file). This efficacy dataset (six RCTs) comprised 536 patients, including 292 patients receiving dibotermin alfa/ACIM and 244 receiving ICBG. Two additional studies of dibotermin alfa/ACIM (3100N3-304 ADDIN EN.CITE <EndNote><Cite><Author>Burkus</Author><Year>2003</Year><RecNum>40</RecNum><DisplayText><style face="superscript">20</style></DisplayText><record><rec-number>40</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970565">40</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burkus,J.K.</author><author>Heim,S.E.</author><author>Gornet,M.F.</author><author>Zdeblick,T.A.</author></authors></contributors><auth-address>Spine Service, The Hughston Clinic, Columbus, Georgia, USA. JKB66@</auth-address><titles><title>Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device</title><secondary-title>J.Spinal Disord.Tech.</secondary-title></titles><periodical><full-title>J.Spinal Disord.Tech.</full-title></periodical><pages>113-122</pages><volume>16</volume><number>2</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Analysis of Variance</keyword><keyword>Bone Substitutes</keyword><keyword>Bone Transplantation</keyword><keyword>Clinical Trials as Topic</keyword><keyword>Collagen</keyword><keyword>epidemiology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>instrumentation</keyword><keyword>Male</keyword><keyword>methods</keyword><keyword>Pain</keyword><keyword>Reoperation</keyword><keyword>Spinal Diseases</keyword><keyword>Spinal Fusion</keyword><keyword>Spine</keyword><keyword>statistics & numerical data</keyword><keyword>surgery</keyword><keyword>therapeutic use</keyword><keyword>Transplantation,Autologous</keyword></keywords><dates><year>2003</year><pub-dates><date>4/2003</date></pub-dates></dates><label>43</label><urls><related-urls><url> and P01-07 (data on file)) were included in safety and supplementary efficacy analyses. Study 3100N3-304 was not included in the efficacy dataset because the comparator was a concurrent control taken from another study, and Study P01-07 was not included because there was no comparator. In total, the safety dataset (eight trials) comprised 700 patients, including 456 patients receiving dibotermin alfa/ACIM and 244 receiving ICBG. The primary analysis dataset included all patients who received the study implants and completed surgical procedures. Primary statistical comparisons were based on the observed data, and missing data (due to lost-to follow-up or invalid radiographic assessments) were not imputed. A two-stage approach ADDIN EN.CITE <EndNote><Cite><Author>GB</Author><Year>2012</Year><RecNum>372</RecNum><DisplayText><style face="superscript">21</style></DisplayText><record><rec-number>372</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">372</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Stewart GB</author><author>Altman DG</author><author>Askie LM</author><author>Duley L</author><author>Simmonds MC</author><author>Stewart LA</author></authors></contributors><titles><title>Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice</title><secondary-title>PLoS One</secondary-title></titles><periodical><full-title>PLoS One</full-title></periodical><pages>e46042</pages><volume>7</volume><number>10</number><reprint-edition>In File</reprint-edition><keywords><keyword>analysis</keyword><keyword>methods</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>3044</label><urls></urls></record></Cite></EndNote>21 was used for all outcomes in the meta-analysis except health utility. In the two-stage analyses, first the effects of dibotermin alfa/ACIM compared with ICBG were estimated separately within each of the included trials, after which the results across trials were combined using random-effects meta-analysis ADDIN EN.CITE <EndNote><Cite><Author>JJ</Author><Year>2009</Year><RecNum>373</RecNum><DisplayText><style face="superscript">22</style></DisplayText><record><rec-number>373</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">373</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Deeks JJ</author><author>PT Higgins</author><author>DG Altman</author></authors><secondary-authors><author>Higgins JPT</author><author>Green S</author></secondary-authors></contributors><titles><title>Analysing data and undertaking meta-analysis</title><secondary-title>Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.2 (Updated September 2009)</secondary-title></titles><reprint-edition>In File</reprint-edition><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><publisher>The Cochrane Collaboration</publisher><label>3045</label><urls></urls></record></Cite></EndNote>22. Heterogeneity across individual trials was assessed using the I2 and Q statistics ADDIN EN.CITE <EndNote><Cite><Author>JP</Author><Year>2003</Year><RecNum>374</RecNum><DisplayText><style face="superscript">23</style></DisplayText><record><rec-number>374</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">374</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Higgins JP</author><author>Thompson SG</author><author>Deeks JJ</author><author>Altman DG</author></authors></contributors><titles><title>Measuring inconsistency in meta-analyses</title><secondary-title>BMJ</secondary-title></titles><periodical><full-title>BMJ</full-title></periodical><pages>557-560</pages><volume>327</volume><number>7414</number><reprint-edition>In File</reprint-edition><dates><year>2003</year><pub-dates><date>2003</date></pub-dates></dates><label>3046</label><urls></urls></record></Cite></EndNote>23. For health utility, linear mixed-effects models were used on the pooled IPD. The models compared outcomes in the intervention and control groups after adjusting for individual study effects, assuming random intercepts, fixed slopes, and heterogeneous residual variance across studies. The analyses were performed separately at 3, 6, 12 and 24 months follow-up. In addition, health utility analyses were stratified by (i) radiographic fusion status at two years; and (ii) failure related reoperation status at two years. Mean difference was the primary effect measure for continuously distributed outcomes, and for binary outcomes, odds ratio, risk ratio and risk difference were reported. Statistical tests were two-tailed, and considered statistically significant when the p value was less than 0.05. Stata/IC 13 was used to conduct statistical analyses.Markov ModelA Markov model was developed in Microsoft Excel and Visual Basic Applications (VBA), which sought to estimate the cost-effectiveness of dibotermin alfa/ACIM relative to ICBG for patients who had at least six months of non-operative treatment and required a lumbar interbody spinal fusion fusion procedure. The model target patient population was aligned with the population included in the IPD meta-analysis and the indication for dibotermin alfa/ACIM. The mean (± standard deviation) age of patients included in the meta-analysis (all eight trials) was 43.4 ± 10.4 years and 43.3 ± 9.5 years for dibotermin alfa/ACIM and ICBG, respectively. The proportion of males was similar in each treatment (46.5% and 46.3% for dibotermin alfa/ACIM and ICBG, respectively). The setting for the study was a United Kingdom (UK) hospital. For the base case analysis, the UK National Healthcare System (NHS) and Personal Social Services (PSS) perspective was adopted. The cost-effectiveness of dibotermin alfa/ACIM was also assessed from a societal perspective in sensitivity analysis, including indirect costs due to lost work productivity. The model cycle length was six months and the base case model time horizon was four years. The primary outcome measure was cost per quality-adjusted life years (QALYs) gained. A two health state model structure was implemented. The improvements in health utility from baseline to two years for respective treatment were derived from the meta-analysis of SF-6D ADDIN EN.CITE <EndNote><Cite><Author>J</Author><Year>2002</Year><RecNum>370</RecNum><DisplayText><style face="superscript">24</style></DisplayText><record><rec-number>370</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">370</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Brazier J</author><author>Roberts J</author><author>Deverill M</author></authors></contributors><titles><title>The estimation of a preference-based measure of health from the SF-36</title><secondary-title>Journal of Health Economics</secondary-title></titles><periodical><full-title>Journal of Health Economics</full-title></periodical><pages>271-292</pages><volume>21</volume><reprint-edition>In File</reprint-edition><keywords><keyword>Health</keyword></keywords><dates><year>2002</year><pub-dates><date>2002</date></pub-dates></dates><label>3042</label><urls></urls></record></Cite></EndNote>24 data, with extrapolation of health benefit beyond two years modelled. SF-6D was considered an appropriate measure of health utility as it is a generic, preference-based measure, as recommended by the National Institute of Health and Care Excellence ADDIN EN.CITE <EndNote><Cite><Author>NICE</Author><Year>2013</Year><RecNum>367</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>367</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">367</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>NICE</author></authors></contributors><titles><title>Guide to the methods of technology appraisal 2013</title></titles><keywords><keyword>methods</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>3039</label><urls><related-urls><url><style face="underline" font="default" size="100%">. Beyond the meta-analysis period (two years), health utility for patients treated with dibotermin alfa/ACIM was assumed to remain constant. In the base case analysis, the health utility difference between dibotermin alfa/ACIM and ICBG was assumed to decline to zero over a period of two years (“the offset period”). A four year base case time horizon was considered adequate to capture all relevant costs, the proportion of patients requiring a second surgery, and difference in health utility over time. It was assumed that patients were only re-operated once during the modelled time horizon, two years after their initial surgery. Costs and effects were discounted 3.5% per year for all patients, consistent with published guidelines ADDIN EN.CITE <EndNote><Cite><Author>NICE</Author><Year>2013</Year><RecNum>367</RecNum><DisplayText><style face="superscript">25</style></DisplayText><record><rec-number>367</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">367</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>NICE</author></authors></contributors><titles><title>Guide to the methods of technology appraisal 2013</title></titles><keywords><keyword>methods</keyword></keywords><dates><year>2013</year><pub-dates><date>2013</date></pub-dates></dates><label>3039</label><urls><related-urls><url><style face="underline" font="default" size="100%">. All costs are reported in 2014 pounds sterling (?). Model inputsInputs derived from the IPD meta-analysis included operative parameters (operation time, post-operative hospital stay) ( REF _Ref410034338 \h \* MERGEFORMAT Table 1), failure-related second surgery ( REF _Ref410833245 \h \* MERGEFORMAT Table 3), the proportion of patients returning to work ( REF _Ref419272884 \h \* MERGEFORMAT Figure 1), and QALYs based on SF-6D ( REF _Ref417402424 \h \* MERGEFORMAT Figure 2). The mean difference in operative time was 0.38 hours (approximately 23 minutes) (p<0.001), and the mean difference in post-operative hospital stay was 0.28 days (approximately 7 hours) (p=0.013), for patients treated with dibotermin alfa/ACIM versus ICBG (Table 1, six RCTs). The rate of failure-related secondary surgery at 24 months was 6.58% for dibotermin alfa/ACIM and 11.07% for ICBG (p=0.04; REF _Ref420355895 \h \* MERGEFORMAT Table 2; all eight trials).Of those who were classified as working prior to surgery, 83.5% of patients treated with dibotermin alfa/ACIM and 73.4% of ICBG patients returned to work within 24 months (RR [95% CI]: 1.14 [1.02 to 1.27]; p=0.02; REF _Ref419272884 \h \* MERGEFORMAT Figure 1, six RCT). In the societal perspective analysis, the proportion of patients who did not return to work was multiplied by the average six monthly earnings in the UK to calculate the cost of lost productivity (i.e. the human capital approach) ADDIN EN.CITE <EndNote><Cite><Author>A</Author><Year>2011</Year><RecNum>390</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>390</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">390</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larg A</author><author>Moss JR</author></authors></contributors><titles><title>Cost-of-illness studies: a guide to critical evaluation</title><secondary-title>Pharmacoeconomics</secondary-title></titles><periodical><full-title>Pharmacoeconomics</full-title></periodical><pages>653-671</pages><volume>29</volume><number>8</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cost of Illness</keyword></keywords><dates><year>2011</year><pub-dates><date>2011</date></pub-dates></dates><label>3062</label><urls></urls></record></Cite></EndNote>26. After 24 months, the proportion of patients who returned to work was assumed to remain the same as at 24 months.Based on only randomized trials, the mean difference in mean change in SF-6D at 24 months for patients treated with dibotermin alfa/ACIM versus ICBG was 0.027 (p=0.03; REF _Ref417402424 \h \* MERGEFORMAT Figure 2, six RCT). Based on these SF-6D data, the difference in QALYs gained at 24 months between dibotermin alfa/ACIM and ICBG was 0.040 (p=0.06). Unit costsResource use and unit costs were collected from publicly available sources and previously published literature ( REF _Ref410833245 \h \* MERGEFORMAT Table 3). The cost of dibotermin alfa/ACIM was ?1,720 (excluding value added tax), with the price per 12 mg pack varied in sensitivity analyses. The surgical interventions had two additional cost components; the length of time in the operating room and the length of stay in hospital. The cost of one hour of operating room time was ?1,125, as reported by the Information Services Division, Scotland ADDIN EN.CITE <EndNote><Cite><Author>2014</Author><Year>2014</Year><RecNum>375</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">375</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>ISD Scotland National Statistics: December 2014</author></authors></contributors><titles><title>Net cost per theatre hour used</title><secondary-title>ISD Scotland</secondary-title></titles><periodical><full-title>ISD Scotland</full-title></periodical><section>2014</section><reprint-edition>In File</reprint-edition><dates><year>2014</year></dates><label>3047</label><urls><related-urls><url><style face="underline" font="default" size="100%">. The cost of a hospital bed day was ?308.50, based on the UK National Reference Cost for a revision procedure (HC03Z) ADDIN EN.CITE <EndNote><Cite><Author>Health</Author><Year>2014</Year><RecNum>376</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">376</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>UK Department of Health</author></authors></contributors><titles><title>National Reference Costs 2011-12</title></titles><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>3048</label><urls></urls></record></Cite></EndNote>28. A general cost for second surgery (?11,262) was obtained from the National Schedule of Reference Costs, based on code HRG03Z ADDIN EN.CITE <EndNote><Cite><Author>Health</Author><Year>2015</Year><RecNum>117</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970566">117</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>UK Department of Health</author></authors></contributors><titles><title>National Tariff 2014-15 HRG Category 4 Code: HR03Z</title></titles><keywords><keyword>injuries</keyword><keyword>Decompression</keyword></keywords><dates><year>2015</year><pub-dates><date>1/1/2015</date></pub-dates></dates><label>121</label><urls></urls></record></Cite></EndNote>29. Average six monthly earnings (?12,454) were calculated from the average weekly wages reported by the Office of National Statistics ADDIN EN.CITE <EndNote><Cite><Author>Statistics</Author><Year>2014</Year><RecNum>295</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>295</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970567">295</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>Office for National Statistics</author></authors></contributors><titles><title>Average Weekly Earnings</title><secondary-title>Office for National Statistics</secondary-title></titles><periodical><full-title>Office for National Statistics</full-title></periodical><section>12/17/2014</section><reprint-edition>In File</reprint-edition><dates><year>2014</year></dates><label>303</label><urls><related-urls><url><style face="underline" font="default" size="100%">. In the base case, it was assumed that there were no other differences in costs related to the interventions. The effect of including outpatient visit costs (?2,796) for patients requiring a failure-related secondary surgery was evaluated in a sensitivity analysis. ADDIN EN.CITE <EndNote><Cite><Author>A</Author><Year>2015</Year><RecNum>216</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>216</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970566">216</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Lloyd A</author><author>Casey A</author></authors></contributors><titles><title>Counting the cost of failed spinal fusion for relief of low back pain; Does primary fusion with bone morphogenetic protein make economic sense from a primary payer and societal perspective?</title><secondary-title>Journal of Spinal Disorders and Techniques</secondary-title></titles><periodical><full-title>Journal of Spinal Disorders and Techniques</full-title></periodical><volume>Epub ahead of print</volume><reprint-edition>Not in File</reprint-edition><keywords><keyword>Spinal Fusion</keyword><keyword>Low Back Pain</keyword><keyword>Back Pain</keyword><keyword>Pain</keyword></keywords><dates><year>2015</year><pub-dates><date>2015</date></pub-dates></dates><label>225</label><urls></urls></record></Cite></EndNote>31Model outcomesThe primary health outcome was the QALY. An incremental cost effectiveness ratio (ICER) was calculated as (Cost dibotermin alfa/ACIM - Cost ICBG) / (QALY dibotermin alfa/ACIM – QALY ICBG).Sensitivity analysesA probabilistic sensitivity analysis (PSA) was also conducted. The model was run 10,000 times as a Monte Carlo simulation, using randomly drawn sets of inputs. The possible inputs were defined by assigning a statistical distribution around the mean value of each parameter, reflecting the extent and nature of dispersion around the mean ( REF _Ref291855076 \h \* MERGEFORMAT Table 4). For each model run, values were sampled at random from each distribution, and the decision tree was rolled back to obtain a (cost, effectiveness) pair. Each pair is represented as a point plotted on the cost-effectiveness plane and results can be summarised using a cost-effective acceptability curve (CEAC). In addition to the base case analysis, several one-way sensitivity analyses were conducted to test the impact of parameter uncertainty on the model result ( REF _Ref405972786 \h \* MERGEFORMAT Table 5). RESULTSAs demonstrated in the IPD meta-analysis, use of dibotermin alfa/ACIM was associated with less health care resource use compared with ICBG with respect to operating room time (Table 1), hospital bed days (Table 1), failure-related secondary surgeries ( REF _Ref410034338 \h \* MERGEFORMAT Table 1). In addition, dibotermin alfa/ACIM was associated with less blood loss than ICBG (Table 1), albeit this outcome was not incorporated into the model. A higher proportion of dibotermin alfa patients than ICBG patients had returned to work by 24 months (83.5% and 73.4%, respectively, REF _Ref419272884 \h \* MERGEFORMAT Figure 1). The cost savings resulting over four years (?983) did not entirely offset the additional cost of dibotermin alfa/ACIM, as overall the dibotermin alfa/ACIM treatment strategy remained more expensive than ICBG (incremental cost ?737). Patients treated with dibotermin alfa/ACIM achieved higher mean health utility following surgery relative to ICBG ( REF _Ref417402424 \h \* MERGEFORMAT Figure 2) and therefore over four years, accrued an additional 0.055 QALYs. These findings resulted in an incremental cost per QALY gained of ?13,523. Change in patient health utility following primary surgery is one of the key determinants of cost-effectiveness. QALY results stratified by radiographic fusion status and failure-related secondary surgery status at two years were investigated to provide additional insight into a probable link between clinical outcomes and health utility; albeit not incorporated cost-effectiveness model. The IPD meta-analysis showed that patients who experienced radiographic fusion on average accrued 0.112 additional QALYs over two years compared to patients who did not experience radiographic fusion (p<0.01; REF _Ref420440572 \h \* MERGEFORMAT Figure 3). Similarly, patients who did not experience failure-related secondary surgery accrued 0.134 additional QALYs over two years compared to patients who experienced radiographic fusion (p<0.001; REF _Ref420440587 \h \* MERGEFORMAT Figure 4).The incremental cost-effectiveness ratios generated by each of the 10,000 PSA simulations are shown in REF _Ref292372176 \h \* MERGEFORMAT Figure 5. Almost all simulations fell in the north eastern quadrant, indicating that with very low uncertainty, dibotermin alfa/ACIM is expected to be more expensive, but also more effective for patients in terms of QALYs, than ICBG. The CEAC is shown in REF _Ref297111685 \h \* MERGEFORMAT Figure 6. The graph shows that there is a high probability of dibotermin alfa/ACIM being cost-effective when compared with ICBG for a willingness to pay interval above ?15,000 per QALY gained. At a willingness-to-pay threshold of ?20,000 per QALY gained, the probability that dibotermin alfa/ACIM was cost-effective was 71.8%.One-way sensitivity analyses were performed to determine the change in cost per QALY after varying key inputs in the model ( REF _Ref405972786 \h \* MERGEFORMAT Table 5). Overall, the tornado diagram shows that the ICER remained stable while varying a range of inputs in deterministic sensitivity and scenario analyses ( REF _Ref413847752 \h \* MERGEFORMAT Figure 7). The result was most sensitive to the perspective of the evaluation; the health utility offset period and the cost of dibotermin alfa/ACIM. However, the ICER did not exceed ?20,000 per QALY gained in any analysis. There was no change in the ICER when a 5 year time horizon was modelled.DISCUSSIONThis study estimated the cost-effectiveness of dibotermin alfa/ACIM compared with ICBG for single-level lumbar interbody spinal fusion in adults treated for disc degeneration in the UK. A new IPD meta-analysis showed that, compared with ICBG, patients treated with dibotermin alfa/ACIM experienced significantly shorter operative time and post-operative hospital stay, and at 24 months had a significantly lower rate of failure-related secondary surgery, and a significantly higher return to work rate. A Markov cohort model, populated with clinical and health utility data from the IPD meta-analysis and UK-specific cost data, showed that although the overall cost of lumbar interbody spinal fusion using dibotermin alfa/ACIM exceeded that of ICBG, patients treated with dibotermin alfa achieved higher health utility over the model time horizon. Based on these results, the base case ICER was below the commonly applied threshold range of ?20,000 per QALY gained, indicating that dibotermin alfa/ACIM is cost-effective for use in lumbar interbody fusion in the UK. The assumptions regarding change in patient health utility over time were considered conservative from a dibotermin alfa/ACIM cost-effectiveness perspective. Beyond two years, health utility for patients treated with dibotermin alfa/ACIM was assumed to remain constant, however, there is evidence showing a sustained increase in SF-6D score for patients over five years ADDIN EN.CITE <EndNote><Cite><Author>SD</Author><Year>2012</Year><RecNum>369</RecNum><DisplayText><style face="superscript">32</style></DisplayText><record><rec-number>369</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">369</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Glassman SD</author><author>Polly DW</author><author>Dimar JR</author><author>Carreon LY</author></authors></contributors><titles><title>The Cost Effectiveness of Single-Level Instrumented Posterolateral Lumbar Fusion at Five Years After Surgery</title><secondary-title>Spine(Phila Pa 1976)</secondary-title></titles><periodical><full-title>Spine(Phila Pa 1976)</full-title></periodical><pages>769-774</pages><volume>37</volume><number>9</number><reprint-edition>In File</reprint-edition><keywords><keyword>surgery</keyword></keywords><dates><year>2012</year><pub-dates><date>2012</date></pub-dates></dates><label>3041</label><urls></urls></record></Cite></EndNote>32. In addition, the base case analysis assumed the mean health utility in the ICBG arm increased to the same level as dibotermin alfa/ACIM over two years. This also appears conservative, given that a decrease in mean health utility was observed between 12 and 24 months for patients treated with ICBG in the IPD meta-analysis.Change in patient health utility following primary surgery is one of the key determinants of cost-effectiveness. Evidence from the IPD meta-analysis showed that patients treated with dibotermin alfa/ACIM experienced higher health utility gains than patients treated with ICBG. These benefits may be driven by the lower failure related reoperation rates observed with dibotermin alfa/ACIM compared with ICBG in the IPD meta-analysis ( REF _Ref420355895 \h \* MERGEFORMAT Table 2). Another potential driver is the higher radiographic fusion rates observed with dibotermin alfa/ACIM compared with ICBG ADDIN EN.CITE <EndNote><Cite><Author>Agency</Author><Year>2015</Year><RecNum>366</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">366</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>European Medicines Agency</author></authors></contributors><titles><title>InductOs EPAR Product Information</title></titles><dates><year>2015</year><pub-dates><date>2011</date></pub-dates></dates><label>3038</label><urls><related-urls><url>. Meta-analysis of the six comparative RCTs included in this study showed that dibotermin alfa/ACIM was associated with a higher fusion success rate at 24 months post-surgery compared with ICBG ADDIN EN.CITE <EndNote><Cite><Author>Agency</Author><Year>2015</Year><RecNum>366</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">366</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>European Medicines Agency</author></authors></contributors><titles><title>InductOs EPAR Product Information</title></titles><dates><year>2015</year><pub-dates><date>2011</date></pub-dates></dates><label>3038</label><urls><related-urls><url>: The odds ratio for fusion success with dibotermin alfa/ACIM compared to ICBG was estimated at 3.26 (95 % CI: 1.17, 9.08; p = 0.024) whereas the absolute difference in fusion success rate was estimated at 11.7 % (95 % CI: 8.0 %, 22.5 %; p = 0.035) ADDIN EN.CITE <EndNote><Cite><Author>Agency</Author><Year>2015</Year><RecNum>366</RecNum><DisplayText><style face="superscript">33</style></DisplayText><record><rec-number>366</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">366</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>European Medicines Agency</author></authors></contributors><titles><title>InductOs EPAR Product Information</title></titles><dates><year>2015</year><pub-dates><date>2011</date></pub-dates></dates><label>3038</label><urls><related-urls><url>. Radiographic fusion may result in improved health utility because it reduces the likelihood of the pain and disability associated with pseudarthrosis ADDIN EN.CITE <EndNote><Cite><Author>Herkowitz</Author><Year>1995</Year><RecNum>394</RecNum><DisplayText><style face="superscript">34</style></DisplayText><record><rec-number>394</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">394</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Herkowitz,H.N.</author><author>Sidhu,K.S.</author></authors></contributors><auth-address>Department of Orthopaedic Surgery, William Beaumont Hospital, Royal Oak, Mich</auth-address><titles><title>Lumbar Spine Fusion in the Treatment of Degenerative Conditions: Current Indications and Recommendations</title><secondary-title>J.Am.Acad.Orthop.Surg.</secondary-title></titles><periodical><full-title>J.Am.Acad.Orthop.Surg.</full-title></periodical><pages>123-135</pages><volume>3</volume><number>3</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Arthrodesis</keyword><keyword>Back Pain</keyword><keyword>complications</keyword><keyword>Decompression</keyword><keyword>instrumentation</keyword><keyword>Pain</keyword><keyword>Patients</keyword><keyword>Scoliosis</keyword><keyword>secondary</keyword><keyword>Spinal Stenosis</keyword><keyword>Spine</keyword><keyword>Spondylolisthesis</keyword><keyword>surgery</keyword></keywords><dates><year>1995</year><pub-dates><date>5/1995</date></pub-dates></dates><label>3067</label><urls><related-urls><url>. In this context it may be noted that the definition of radiographic fusion was stringent. Fusion was assessed using radiographs (CT scans). Fusion success required evidence of bridging trabeculae, no evidence of motion (<3-mm difference in translation and<5-degree difference in angular motion), and no evidence of radiolucency surrounding >50% of the interbody device. The notion that the differences in health utility between dibotermin alfa/ACIM and ICBG partially reflect differences in radiographic fusion and failure-related reoperation rates are provided in the analyses of health utility improvements from baseline stratified by those outcomes ( REF _Ref420440572 \h \* MERGEFORMAT Figure 3 and REF _Ref420440587 \h \* MERGEFORMAT Figure 4).The stability of the incremental cost per QALY (?13,523) was robust when tested in deterministic and probabilistic sensitivity analyses, with all ICERs below ?20,000 per QALY gained ( REF _Ref413847752 \h \* MERGEFORMAT Figure 7). The ICER was most sensitive to the utility offset period assumption, with analyses showing no utility offset would increase the ICER to ?19,356. Without an increase in the health utility offset period to three years, there was no change in the ICER for a 5 year time horizon, as all costs and effects were captured within four years. Analyses showed that a lower price of dibotermin alfa/ACIM would improve the cost-effectiveness, suggesting that a smaller pack size would improve the cost-effectiveness further, all else equal. The PSA indicated that dibotermin alfa/ACIM had a 88.9% chance of being cost-effective when the willingness to pay was ?30,000 and 71.8% chance of being cost-effective at a willingness-to-pay threshold of ?20,000 ( REF _Ref297111685 \h \* MERGEFORMAT Figure 6). Indirect costs associated with absenteeism due to low back pain are known to be substantial, and improvements in employment levels following spinal surgery have been suggested to provide long-term economic benefits ADDIN EN.CITE <EndNote><Cite><Author>R</Author><Year>2010</Year><RecNum>385</RecNum><DisplayText><style face="superscript">35</style></DisplayText><record><rec-number>385</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">385</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Fayssoux R</author><author>Goldfarb NI</author><author>Vaccaro AR</author><author>Harrop J</author></authors></contributors><titles><title>Indirect Costs Associated with Surgery for Low Back Pain—A Secondary Analysis of Clinical Trial Data</title><secondary-title>Population health management</secondary-title></titles><periodical><full-title>Population health management</full-title></periodical><pages>9-13</pages><volume>13</volume><number>1</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>analysis</keyword><keyword>secondary</keyword><keyword>surgery</keyword></keywords><dates><year>2010</year><pub-dates><date>2010</date></pub-dates></dates><label>3057</label><urls></urls></record></Cite></EndNote>35. When evaluated from a societal perspective, dibotermin alfa/ACIM provided incremental QALYs (0.055) at a cost differential of -?7,492 compared with ICBG, and was therefore the dominant treatment strategy. The cost savings were attributable to an increased proportion of patients who returned to work in the dibotermin alfa/ACIM group relative to the ICBG group, in combination with the faster return to work following surgery. The findings of the present study differ from the previously conducted cost-effectiveness evaluation of dibotermin alfa/ACIM versus ICBG, which generated an ICER of approximately ?120,000 per QALY gained ADDIN EN.CITE <EndNote><Cite><Author>KR</Author><Year>2007</Year><RecNum>50</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>50</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970565">50</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Garrison KR</author><author>Donell S</author><author>Ryder J,</author><author>Shemilt I</author><author>Mugford M</author><author>Harvey I,</author><author>Song F.</author></authors></contributors><titles><title>Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review</title><secondary-title>Health Technol Assess</secondary-title></titles><periodical><full-title>Health Technol Assess</full-title></periodical><pages>1-150</pages><volume>11</volume><number>30</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Bone Morphogenetic Proteins</keyword><keyword>Spinal Fusion</keyword></keywords><dates><year>2007</year><pub-dates><date>2007</date></pub-dates></dates><label>54</label><urls></urls></record></Cite></EndNote>10. That evaluation, however, was based on fewer clinical data, and a more restrictive dibotermin alfa/ACIM indication that relied on evidence from a single randomised clinical trialPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CdXJrdXM8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS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ADDIN EN.CITE.DATA 17. More comparative clinical and resource use data are now available from the current IPD meta-analysis, based on RCTs relevant to the current dibotermin alfa/ACIM indication. The current analysis showed a greater difference with respect to QALYs gained, secondary surgery rates related to treatment failure and resource use (length of hospital stay), favouring the dibotermin alfa/ACIM arm.One strength of the present economic evaluation is the low level of uncertainty in the model, which is due to robust data (clinical, resource use, health-related quality of life, and cost). Few assumptions were required for the economic analysis, and dibotermin alfa/ACIM remained cost-effective compared with ICBG when key model parameters and assumptions were varied in sensitivity analyses. These are the best quality data available to date for the comparison of dibotermin alfa/ACIM and ICBG in lumbar interbody spinal fusion surgery, and incorporated into this new economic analysis the outcomes indicate that dibotermin alfa/ACIM is cost effective in a UK setting. There were some limitations in the current analysis. It was assumed that there were no differences in other resources consumed related to the interventions. Potential differences may have existed with respect to the use of bone fillers, complication management, and physician care. Furthermore, no comparative data were available on health utility after two years of follow-up. Therefore the relative health utility trajectory for patients treated with dibotermin alfa/ACIM and ICBG beyond this period is uncertain.Long term comparative data on failure-related secondary surgery and patient return to work status are also limited. Data from a non-comparative six-year follow up study of 128 patients treated with dibotermin alfa/ACIM indicated that the rate of failure-related second surgery reduced from 6.7% during the first 24 months to 3.7% during the period 2-6 years; and the percentage of patients working at six months (63%) was higher than pre-operation (52%), which was sustained at six years (68%) ADDIN EN.CITE <EndNote><Cite><Author>JK</Author><Year>2009</Year><RecNum>386</RecNum><DisplayText><style face="superscript">36</style></DisplayText><record><rec-number>386</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">386</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Burkus JK</author><author>Gornet MF</author><author>Schuler TC</author><author>Kleeman TJ</author><author>Zdeblick TA</author></authors></contributors><titles><title>Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recombinant Human Bone Morphogenetic Protein-2</title><secondary-title>J Bone Joint Surg Am</secondary-title></titles><periodical><full-title>J Bone Joint Surg Am</full-title></periodical><pages>1181-1189</pages><volume>91</volume><number>5</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Arthrodesis</keyword><keyword>Bone Morphogenetic Protein 2</keyword></keywords><dates><year>2009</year><pub-dates><date>2009</date></pub-dates></dates><label>3058</label><urls></urls></record></Cite></EndNote>36. Nevertheless, further research is required to study the long-term costs and health benefits of dibotermin alfa/ACIM. It should also be noted that it has been suggested that the human capital approach may overestimate the costs of productivity losses ADDIN EN.CITE <EndNote><Cite><Author>Koopmanschap</Author><Year>1993</Year><RecNum>393</RecNum><DisplayText><style face="superscript">37</style></DisplayText><record><rec-number>393</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">393</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Koopmanschap,M.A.</author><author>Rutten,F.F.</author></authors></contributors><auth-address>Institute for Medical Technology Assessment, Erasmus University Rotterdam, The Netherlands</auth-address><titles><title>Indirect costs in economic studies: confronting the confusion</title><secondary-title>Pharmacoeconomics.</secondary-title></titles><periodical><full-title>Pharmacoeconomics.</full-title></periodical><pages>446-454</pages><volume>4</volume><number>6</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Absenteeism</keyword><keyword>Cost of Illness</keyword><keyword>Efficiency</keyword><keyword>Evaluation Studies as Topic</keyword><keyword>Health</keyword><keyword>Health Policy</keyword><keyword>Humans</keyword><keyword>Research</keyword><keyword>Value of Life</keyword></keywords><dates><year>1993</year><pub-dates><date>12/1993</date></pub-dates></dates><label>3065</label><urls><related-urls><url>, albeit a contentious issue ADDIN EN.CITE <EndNote><Cite><Author>A</Author><Year>2011</Year><RecNum>390</RecNum><DisplayText><style face="superscript">26</style></DisplayText><record><rec-number>390</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">390</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Larg A</author><author>Moss JR</author></authors></contributors><titles><title>Cost-of-illness studies: a guide to critical evaluation</title><secondary-title>Pharmacoeconomics</secondary-title></titles><periodical><full-title>Pharmacoeconomics</full-title></periodical><pages>653-671</pages><volume>29</volume><number>8</number><reprint-edition>Not in File</reprint-edition><keywords><keyword>Cost of Illness</keyword></keywords><dates><year>2011</year><pub-dates><date>2011</date></pub-dates></dates><label>3062</label><urls></urls></record></Cite></EndNote>26.CONCLUSIONSA robust economic analysis based on new comparative clinical, resource use and health utility data available from an IPD meta-analysis, illustrate the benefits of dibotermin alfa/ACIM relative to ICBG over a four year time horizon. Based on these findings, this economic evaluation concluded that dibotermin alfa/ACIM is cost-effective compared with ICBG in single level lumbar interbody fusion in adults being treated for disc degeneration in the UK, within currently accepted cost-effectiveness thresholds..TRANSPARENCYDeclaration of fundingThe study was sponsored by Medtronic BioPharma B.V.Declaration of financial/other relationshipsC Leonard, D Donnell and B Borgman are employees of Medtronic BioPharma B.V, the sponsor of the study.D Paech and A Svedbom are employees of Mapi. Medtronic BioPharma provided funding to Mapi for the independent health economic analyses and production of this manuscript.F Song is a consultant for UEA Consulting Limited. Medtronic BioPharma provided funding to UEA Consulting Limited for the independent statistical analyses in this manuscript.B Boszcyk is a paid consultant for NHS Research & Innovation Division. The NHS Research & Innovation Division received payment from the study sponsor for clinical review and guidance. AcknowledgmentsThe authors gratefully acknowledge Professor Michael Drummond (University of York) and Professor Alistair McGuire (London School of Health Economics) for helpful advice in the preparation of this manuscript.Reference List ADDIN EN.REFLIST 1.L Manchikanti, V Singh, S Datta, SP Cohen. Comprehensive review of epidemiology, scope and impact of spinal pain. Pain physician. 2009;12(4):E35-70.2.N Maniadakis, A Gray. The economic burden of back pain in the UK. Pain. 2000;84(1):95-103.3.Phillips F.M., Slosar P.J., Youssef J.A., Andersson G., Papatheofanis F. Lumbar spine fusion for chronic low back pain due to degenerative disc disease: a systematic review. Spine (Phila Pa 1976). 2013;38(7):E409-E22.4.H Singh, AD Levi. Bone Graft and Bone Substitute Biology. Spine Surgery Basics: Springer-Verlag Berlin Heidelberg; 2014. p. 147-52.5.Koyonos R. Lumbar Degenerative Spondylolisthesis. In: VV P, editor. Spine Surgery Basics: Springer-Verlag Berlin Heidelberg; 2014. p. 221-7.6.MK Sen, T Miclau. Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions? Injury. 2007;38(Suppl 1):S75-80.7.BioPharma Medtronic. InductOs Summary of Product Characteristics. 2014 2014. Report No.8.Ackerman S.J., Mafilios M.S., Polly D.W., Jr. Economic evaluation of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion: an evidence-based modeling approach. Spine (Phila Pa 1976). 2002;27(16 Suppl 1):S94-S9.9.Polly D.W., Jr., Ackerman S.J., Shaffrey C.I., Ogilvie J.W., Wang J.C., Stralka S.W., et al. A cost analysis of bone morphogenetic protein versus autogenous iliac crest bone graft in single-level anterior lumbar fusion. Orthopedics. 2003;26(10):1027-37.10.KR Garrison, S Donell, Ryder J, I Shemilt, M Mugford, Harvey I, et al. Clinical effectiveness and cost-effectiveness of bone morphogenetic proteins in the non-healing of fractures and spinal fusion: a systematic review. Health Technol Assess. 2007;11(30):1-150.11.R Fu, S Selph, M McDonagh, K Peterson, A Tiwari, R Chou. Effectiveness and Harms of Recombinant Human Bone Morphogenetic Protein-2 in Spine Fusion. Annals Intern Medicine. 2013;158:890-902.12.MC Simmonds, JVE Brown, MK Heirs, JPT Higgins, RJ Mannion, MA Rodgers, et al. Safety and Effectiveness of Recombinant Human Bone Morphogenetic Protein-2 for Spinal Fusion. Annals Internal Medicine. 2013;158:877-89.13.D Husereau, M Drummond, S Petrou, C Carswell, D Moher, D Greenberg, et al. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement. European Journal of Health Economics. 2013;14(3):367-72.14.Association World Medical, inventorWMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects2013.15.Boden S.D., Zdeblick T.A., Sandhu H.S., Heim S.E. The use of rhBMP-2 in interbody fusion cages. Definitive evidence of osteoinduction in humans: a preliminary report. Spine (Phila Pa 1976). 2000;25(3):376-81.16.Burkus J.K., Gornet M.F., Dickman C.A., Zdeblick T.A. Anterior lumbar interbody fusion using rhBMP-2 with tapered interbody cages. JSpinal DisordTech. 2002;15(5):337-49.17.Burkus J.K., Transfeldt E.E., Kitchel S.H., Watkins R.G., Balderston R.A. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine (Phila Pa 1976). 2002;27(21):2396-408.18.Haid R.W., Jr., Branch C.L., Jr., Alexander J.T., Burkus J.K. Posterior lumbar interbody fusion using recombinant human bone morphogenetic protein type 2 with cylindrical interbody cages. Spine J. 2004;4(5):527-38.19.Burkus J.K., Sandhu H.S., Gornet M.F., Longley M.C. Use of rhBMP-2 in combination with structural cortical allografts: clinical and radiographic outcomes in anterior lumbar spinal surgery. JBone Joint SurgAm. 2005;87(6):1205-12.20.Burkus J.K., Heim S.E., Gornet M.F., Zdeblick T.A. Is INFUSE bone graft superior to autograft bone? An integrated analysis of clinical trials using the LT-CAGE lumbar tapered fusion device. JSpinal DisordTech. 2003;16(2):113-22.21.GB Stewart, DG Altman, LM Askie, L Duley, MC Simmonds, LA Stewart. Statistical analysis of individual participant data meta-analyses: a comparison of methods and recommendations for practice. PLoS One. 2012;7(10):e46042.22.JJ Deeks, Higgins PT, Altman DG. Analysing data and undertaking meta-analysis. In: JPT H, S G, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 502 (Updated September 2009): The Cochrane Collaboration; 2009.23.JP Higgins, SG Thompson, JJ Deeks, DG Altman. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60.24.J Brazier, J Roberts, M Deverill. The estimation of a preference-based measure of health from the SF-36. Journal of Health Economics. 2002;21:271-92.25.NICE. Guide to the methods of technology appraisal 2013. 2013 2013. Report No.26.A Larg, JR Moss. Cost-of-illness studies: a guide to critical evaluation. Pharmacoeconomics. 2011;29(8):653-71.27.2014 ISD Scotland National Statistics: December. Net cost per theatre hour used. ISD Scotland [Internet]. 2014. Available from: UK Department of. National Reference Costs 2011-12. 2014 2014. Report No.29.Health UK Department of. National Tariff 2014-15 HRG Category 4 Code: HR03Z. 2015 1/1/2015. Report No.30.Statistics Office for National. Average Weekly Earnings. Office for National Statistics [Internet]. 2014. Available from: Lloyd, A Casey. Counting the cost of failed spinal fusion for relief of low back pain; Does primary fusion with bone morphogenetic protein make economic sense from a primary payer and societal perspective? Journal of Spinal Disorders and Techniques. 2015;Epub ahead of print.32.SD Glassman, DW Polly, JR Dimar, LY Carreon. The Cost Effectiveness of Single-Level Instrumented Posterolateral Lumbar Fusion at Five Years After Surgery. Spine(Phila Pa 1976). 2012;37(9):769-74.33.Agency European Medicines. InductOs EPAR Product Information 2015 [updated 2011]. Available from: H.N., Sidhu K.S. Lumbar Spine Fusion in the Treatment of Degenerative Conditions: Current Indications and Recommendations. JAmAcadOrthopSurg. 1995;3(3):123-35.35.R Fayssoux, NI Goldfarb, AR Vaccaro, J Harrop. Indirect Costs Associated with Surgery for Low Back Pain—A Secondary Analysis of Clinical Trial Data. Population health management. 2010;13(1):9-13.36.JK Burkus, MF Gornet, TC Schuler, TJ Kleeman, TA Zdeblick. Six-Year Outcomes of Anterior Lumbar Interbody Arthrodesis with Use of Interbody Fusion Cages and Recombinant Human Bone Morphogenetic Protein-2. J Bone Joint Surg Am. 2009;91(5):1181-9.37.Koopmanschap M.A., Rutten F.F. Indirect costs in economic studies: confronting the confusion. Pharmacoeconomics. 1993;4(6):446-54.TABLESTable SEQ Table \* ARABIC 1: Operative parameters (IPD meta-analysis, based on six RCTs)Dibotermin alfa/ACIMICBGMixed effectsnMean (SE)nMean (SE)Mean difference (95% CI)p-valueOperative time (hours)?2921.70 (-0.04)2462.12 (-0.05)-0.38 (-0.52,-0.23)<0.001Postoperative hospital stay (days)2923.02 (0.08)2453.53 (0.23)-0.28 (-0.50,-0.06)0.01Blood loss (mL)293127.5 (8.9)248190.4 (13.7)-51.54(-74.64, 28.45)<0.001Abbreviations: ACIM: Absorbable collagen implantation matrix; CI: Confidence interval; ICBG: iliac crest bone graft; IPD: individual patient data; RCT: randomised controlled trial; SE: Standard error. Note that the number of patients in this analysis is slightly higher than in the analyses of outcomes during follow-up. The reason for this includes withdrawal of consent during study follow-up. Table SEQ Table \* ARABIC 2: Patients requiring failure-related secondary surgery up to 24 months (IPD meta-analysis)Dibotermin alfa/ACIMICBGMixed effectsnProportionnProportionRR (95% CI)p-valueAll eight studies 4566.58%24411.07%0.59 (0.36, 0.97)0.04Six RCT only 2927.19%24411.07%0.65 (0.37, 1.13)0.13Abbreviations: ACIM: Absorbable collagen implantation matrix; CI: Confidence interval; ICBG: iliac crest bone graft; IPD: individual patient data; RCT: Randomised controlled trial; RR: Relative riskTable SEQ Table \* ARABIC 3: Cost inputs for the base case economic economic evaluationVariableBase case valueSourceDibotermin alfa/ACIM product (12 mg pack)?1,720Medtronic NHS Acquisition CostHospital bed day?308.50National Reference Cost 2011/12: Code HR03Z, inflated to 2014 ADDIN EN.CITE <EndNote><Cite><Author>Health</Author><Year>2014</Year><RecNum>376</RecNum><DisplayText><style face="superscript">28</style></DisplayText><record><rec-number>376</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">376</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>UK Department of Health</author></authors></contributors><titles><title>National Reference Costs 2011-12</title></titles><dates><year>2014</year><pub-dates><date>2014</date></pub-dates></dates><label>3048</label><urls></urls></record></Cite></EndNote>28One hour of operating room time?1,125ISD Scotland National Statistics, average cost of one hour of theatre operating time, inflated to 2014 ADDIN EN.CITE <EndNote><Cite><Author>2014</Author><Year>2014</Year><RecNum>375</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>375</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970568">375</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>ISD Scotland National Statistics: December 2014</author></authors></contributors><titles><title>Net cost per theatre hour used</title><secondary-title>ISD Scotland</secondary-title></titles><periodical><full-title>ISD Scotland</full-title></periodical><section>2014</section><reprint-edition>In File</reprint-edition><dates><year>2014</year></dates><label>3047</label><urls><related-urls><url><style face="underline" font="default" size="100%"> surgery?11,262Final PBR Tariff 2014-15: Code HR03Z ADDIN EN.CITE <EndNote><Cite><Author>Health</Author><Year>2015</Year><RecNum>117</RecNum><DisplayText><style face="superscript">29</style></DisplayText><record><rec-number>117</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970566">117</key></foreign-keys><ref-type name="Report">27</ref-type><contributors><authors><author>UK Department of Health</author></authors></contributors><titles><title>National Tariff 2014-15 HRG Category 4 Code: HR03Z</title></titles><keywords><keyword>injuries</keyword><keyword>Decompression</keyword></keywords><dates><year>2015</year><pub-dates><date>1/1/2015</date></pub-dates></dates><label>121</label><urls></urls></record></Cite></EndNote>29Average salary for six months?12,454UK Office of National Statistics 2014 ADDIN EN.CITE <EndNote><Cite><Author>Statistics</Author><Year>2014</Year><RecNum>295</RecNum><DisplayText><style face="superscript">30</style></DisplayText><record><rec-number>295</rec-number><foreign-keys><key app="EN" db-id="f9t52fe5assvzmexs2nx5dt6faevf9wweswt" timestamp="1439970567">295</key></foreign-keys><ref-type name="Electronic Article">43</ref-type><contributors><authors><author>Office for National Statistics</author></authors></contributors><titles><title>Average Weekly Earnings</title><secondary-title>Office for National Statistics</secondary-title></titles><periodical><full-title>Office for National Statistics</full-title></periodical><section>12/17/2014</section><reprint-edition>In File</reprint-edition><dates><year>2014</year></dates><label>303</label><urls><related-urls><url><style face="underline" font="default" size="100%">: ACIM: Absorbable collagen implantation matrix; ISD: Information services division; mg: Milligrams; PBR: Payment by results; UK: United KingdomTable SEQ Table \* ARABIC 4: Variables and distributions used in probabilistic sensitivity analysis VariableBase case valueStandard ErrorDistributionα?QALY difference at 2 years0.040.02Normal0.050.02Difference in operating time-0.380.07Normal-0.380.07Difference in post-operative stay-0.280.11Normal-0.280.11Probability of second surgery Dibotermin alfa/ACIM0.070.01Beta30456Probability of second surgery ICBG0.110.01Beta27456Cost of second surgery11,262.002815.50*Gamma16.00703.88Hospital bed day308.5077.13*Gamma16.0019.28Cost of one hour operating room time1125.00281.25*Gamma16.0070.31Abbreviations: ACIM: Absorbable collagen implantation matrix; ICBG: iliac crest bone graft; mL: millilitres; QALY: Quality adjusted life year; * Assumed to be 25% of the mean.Table SEQ Table \* ARABIC 5: Model inputs changed in deterministic sensitivity analysesModel inputValueModel time horizon (years)Base case 4 yearsRCT period2 yearsUpper limit5 yearsModel perspectiveBase caseNHS & PSSAlternativeSocietalDiscount rates (%)Base case 3.5%No discount0%High discount5%Failure-related second surgery with dibotermin alfa/ACIM (%)Base case 6.58%Alternative (RCTs only)7.19%QALY difference at 2 yearsBase case0.0401Alternative (all trials) 0.0452Outpatient costs related to secondary surgeryBase caseNo costsAlternative?2,796Health utility offset period (years)Base case 2 yearsNo offsetNoneLonger offset3 yearsDifference in operating time (hours) Base case-0.377Lower bound 95% CI-0.519Upper bound 95% CI-0.234Difference in post-operative hospital length of stay (days)Base case-0.281Lower bound 95% CI-0.503Upper bound 95% CI-0.059Cost of dibotermin alfa/ACIM (?)Base case?1,72010% cost decrease?1,54810% cost increase ?1,892Abbreviations: ACIM: Absorbable collagen implantation matrix: CI: Confidence interval; ICBG: iliac crest bone graft; NA: Not applicable; NHS: National Health Service; PSS: Personal Social Services; QALY: Quality adjusted life year; RCT: Randomised controlled trial; SE: Standard errorFIGURE 1Figure SEQ Figure \* ARABIC 1. Proportion of patients who returned to work within two years post-surgery (IPD meta-analysis, based on six RCT)* p= 0.02Abbreviations: ACIM: Absorbable collagen implantation matrix: ICBG: iliac crest bone graft; IPD, individual patient data; RCT, randomised controlled trialFigure SEQ Figure \* ARABIC 2. Change from baseline in SF-6D (IPD meta-analysis, based on six RCT) and mean QALY difference during two years of follow-up post-surgery for patients treated with dibotermin alfa/ACIM and ICBG Abbreviations: ACIM: absorbable collagen implantation matrix; CI: Confidence interval; ICBG: Iliac crest bone graft; IPD: individual patient data; RCT: randomised controlled trial; SF-6D: Short form 6-dimension; QALY: Quality-adjusted life yearFigure SEQ Figure \* ARABIC 3. Change from baseline in SF-6D (IPD meta-analysis, based on all trials) and mean QALY difference during two years of follow-up post-surgery stratified by radiographic fusion status at two yearsAbbreviations: CI: Confidence interval; IPD: individual patient data; SF-6D: Short form 6-dimension; QALY: Quality-adjusted life yearFigure SEQ Figure \* ARABIC 4. Change from baseline in SF-6D (IPD meta-analysis, based on all trials) and mean QALY difference during two years of follow-up post-surgery stratified by radiographic fusion status at two yearsAbbreviations: CI: Confidence interval; IPD: individual patient data; SF-6D: Short form 6-dimension; QALY: Quality-adjusted life yearFigure SEQ Figure \* ARABIC 5. Scatterplot of incremental cost-effectiveness values generated by the PSA Abbreviations: PSA: Probability sensitivity analysis; QALYs: Quality adjusted life years-1654175101600ICBG00ICBGFigure SEQ Figure \* ARABIC 6: Cost-effectiveness acceptability curve for the base case analysis of dibotermin-alfa/ACIM and ICBG Abbreviations: ACIM: Absorbable collagen implantation matrix; ICBG: autologous iliac crest bone graftFigure SEQ Figure \* ARABIC 7: Tornado diagram showing the effect of altering base case model inputs in one way sensitivity analyses (incremental cost/QALY)Abbreviations: CI: Confidence interval; QALY: Quality adjusted life year; RCT: Randomised controlled trial ................
................
In order to avoid copyright disputes, this page is only a partial summary.
To fulfill the demand for quickly locating and searching documents.
It is intelligent file search solution for home and business.
Related download
- kq1 ahrq 2010 lippincott williams wilkins
- supplemental digital material
- treatment of the painful motion segment
- low back pain a pathway to prioritisation
- stop interspinous implant for lumbar spinal decompression
- manuscript draft university of east anglia
- microsoft word 1090 1 aidr lumbar final psd endorsed 21
- spinal cord decompression
- function after spinal treatment exercise and
- using comparative effectiveness review findings in
Related searches
- the return of east atlanta santa
- school city of east chicago
- city of east chicago indiana
- school city of east chicago indiana
- school of east chicago
- county map of east texas
- city of east grand rapids
- city of east grand rapids mi
- city of east chicago indiana website
- school city of east chicago homepage
- city of east cleveland
- covenant health of east tennessee patient portal