What is the Appropriate Role for Hyperbaric Therapy in the Diabetic - PDF document

4/8/19 What is the Appropriate Role for Hyperbaric Therapy in the Diabetic Foot? Geoffrey C. Gurtner, MD, FACS Johnson and Johnson Professor of Surgery Professor of Materials Science (By Courtesy) Professor of Bioengineering (By Courtesy) Stanford University No Financial Conflicts to Disclose 1

4/8/19 …but I do use hyperbaric oxygen for DFUs Stanford Advanced Wound Care Center • (AWCC) Two hyperbaric chambers • About 1% of DFU patients undergo HBO • No experience or interest prior to 2015 when • center opened Hyperbaric Oxygen Therapy for Diabetic Foot Ulcers • Increasingly controversial • Multiple recent meta-analyses and studies • Rapidly changing guidance from different groups • Scandals at major wound care chains • Increased scrutiny from third party payors including Medicare 2

4/8/19 Controversy is Understandable • Lots of stakeholders with differing motivations and incentives • Lack of clear mechanism of action for HBO • Unscrupulous and unsupported cash pay business for a variety of indications (autism, sports injuries, etc.) Many Unregulated and Unsupported Uses • HBOT has been shown ineffective for multiple sclerosis, dementia, allergies, autism, cancer, stroke, rheumatoid arthritis, HIV/AIDS, etc. • Continues to be marketed aggressively to consumers in cash-pay scenarios 3

4/8/19 For Diabetic Foot Ulcers • HBO therapy is considered an “advanced treatment modality” • Clinical rationale for HBO therapy to counteract “tissue hypoxia” • HBO therapy has been used for chronic wounds for over 50 years, with varying reimbursement …Not a New Technology • 1662: British physician Henshaw first utilized compressed air for hyperbaric therapy in a chamber called “Domicilium” • 1789: Toxic effects of oxygen was first reported, thereby increasing the hesitation to use HBOT 1662: Henshaw's Domicilium • 1917: German inventors, Bernhard and Dräger, applied pressurized oxygen to treat decompression illness from diving accidents • 1928: Kansas City physician Cunningham built the largest hyperbaric chamber, five-story, able to accommodate 40 patients at a 1928: Cunningham’s Steel Ball Hospital time 4

4/8/19 …Not a New Technology • 1956: Dutch cardiac surgeon Boerema (father of modern hyperbaric medicine) used pure oxygen operating rooms during cardiac surgery • 1968: Kulonen first reported use of HBO in chronic wounds Ite Boerema Operating in Pure Oxygen • 1970s: Research revealed that some elements of tissue repair are extremely oxygen- dependent, including bacterial killing by macrophages. • 2002 CMS (Medicare) rules to cover HBO for diabetic foot www.cms.gov 2002 ulcers Clinical Indications Indications per Undersea & Hyperbaric Medical Society • Professional Society: Undersea Air or Gas Embolism & Hyperbaric Medical Society Carbon Monoxide Poisoning (UHMS) Cyanide Poisoning Clostridial Myositis and Myonecrosis (Gas Gangrene) • Discrepancies between Crush Injury, Compartment Syndrome and Other Acute “accepted”, “covered”, and Traumatic Ischemia “off-label” indications Decompression Sickness * Arterial Inefficiencies: Central Retinal Artery Occlusion • Some UHMS-approved * Arterial Inefficiencies: Enhancement of Healing In indications are not FDA Selected Problem Wounds * Severe Anemia approved, and seen as an “off- * Intracranial Abscess label” use of HBOT Necrotizing Soft Tissue Infections • Most conditions for which Osteomyelitis (Refractory) Delayed Radiation Injury (Soft Tissue and Bony Necrosis) HBOT is utilized have few Compromised Grafts and Flaps successful alternatives. * Acute Thermal Burn Injury * Idiopathic Sudden Sensorineural Hearing Loss * Indications not included on the CMS list 5

4/8/19 Mechanism of Action? • The cellular, biochemical, and physiological mechanisms by which HBOT achieves beneficial results are not fully understood • Most benefits of HBOT are explained by the simple physical relationships determining gas concentration, volume, and pressure • Increased oxygen tension in arterial blood improves cellular oxygen supply by raising the tissue-cellular diffusion gradient • Other biologic effects: Fibroblast activation • Down-regulation of inflammation • Up-regulation of growth factors • Neovascularization • Potentiation of antibiotics, and antibacterial • effects Mechanisms of Action – Ongoing Stanford Study • Perfusion effects of HBOT on chronic wounds was evaluated via ICG angiography. We examined potential predictive attributions of wound perfusion in predicting response to HBOT and healing. • Increased percent change in perfusion from HBOT session 1 to 2 correlated 100% with wounds that went on to heal within 30 days of HBOT completion. Pre-HBOT 1 Pre-HBOT 1 Post-HBOT 1 Post-HBOT 1 Control Patient 6

4/8/19 Clinical Levels of Evidence • Among current approved indications for HBOT, the highest level of evidence (Level I) exists for carbon monoxide poisoning . N Engl J Med. 2002 Oct 3;347(14):1057-67 • Other clinically proven indications include decompression illness , and gas embolism • Among potential indications for HBOT in the field of chronic wounds, the best evidence exists for ischemic, infected (Wagner Grade III or worse) DFUs • Many of the initial HBOT studies that demonstrated positive outcomes and physician adoption were performed in hospital settings ensuring compliance. These results have not translated to an outpatient clinic reality Economics & Cost - United States • Total Market Size: $2 Billion • North America leads the global HBOT market, comprising 32% of the share in 2016, primarily driven by the U.S. • Each HBOT session costs $100 to $1,000 depending on the type of treatment center and the State (cost for 30 “dives” could amount to $30,000 per patient) • Medicare’s total spending on HBOT, including all approved conditions, was $230 million in 2015 United States HBOT Devices Market by Application, 2016 (%) 7

4/8/19 2010 Cochrane Review • In DFU patients “HBOT significantly reduced the risk of major amputation and may improve the chance of healing at 1 year”… however, in view of limited sample sizes and methodological shortcomings, authors emphasized that “this result should be interpreted cautiously”. • Regarding the effect of HBOT on chronic wounds associated with other pathologies, the conclusion was that “the routine management of such wounds with HBOT is not justified by the evidence in this review”. 2015 Cochrane Review • In DFU patients “HBOT significantly improved the ulcers healed in the short term” (i.e. 6 weeks)… “but not the long term” (i.e. 1 year). Authors further emphasized that “trials had various flaws in design and/or reporting that means we are not confident in the results”. • Authors also concluded that “there was no statistically significant difference in major amputation rate”. 8

4/8/19 • 2010 - Löndahl et al . - RCT on DFUs. • Conclusion: Adjunctive HBOT facilitates healing. • Criticism: Only 55% of patients were available for analysis at 1-year follow-up. • Overall Verdict: Favorable • 2013 - Margolis et al . • Evaluation of 6,000 DFU patients with adequate arterial inflow. • Conclusion: HBOT neither reduced the amputation risk nor improved healing. • Criticism: • Poor study design • Selection bias • Many failed to receive “full” course of HBOT • Short follow-up period. • Authors’ Response: Retrospective studies have inherent limitations. • Overall Verdict: Unfavorable 9

4/8/19 • 2016 - Elraiyah et al . • Conclusion: Adjunctive HBOT was associated with increased healing and reduced major amputation. • Criticism: Low- to moderate-quality evidence. • Overall Verdict: Favorable Meta-analysis of healing rate and major amputation rate • 2016 - Fedorko et al . • Conclusion: Adjunctive HBOT neither facilitates healing nor reduces amputation. • Criticism: • Error in including Wagner Grade 2 • Reporting and confirmation bias • Under-powered. • Authors’ Response: Time restraints in patient recruitment and follow up was a major limitation. • Overall Verdict: Unfavorable 10

4/8/19 • 2018 - Santema et al . • Conclusion: Adjunctive HBOT didn’t improve healing or limb salvage. • Criticism: • Under-powered • Matching error • Selection bias • Authors’ Response: • Efficacy of HBOT is undetermined. Kaplan-Meier curves for complete • HBOT may help if administered “full-course”. wound healing (ITT analysis). • Overall Verdict: Unfavorable • 2018 - Ennis et al . • Retrospective study of over 600,000 Wagner Grades 3 and 4 DFUs. • Conclusion: HBOT can be effective for advanced ulcers. • Overall Verdict: Favorable mITT pop: modified intent-to-treat population level. mITT db pop: modified intent-to-treat diabetic population. wag 3/4/foot: Wagner Grade 3 or 4 on foot. wag 3/4/foot>1 HBO: Wagner Grade 3 or 4 on foot incomplete HBOT. wag 3/4/foot complete HBO: Wagner Grade 3 or 4 on foot completed HBOT treatment course. 11