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

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

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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)

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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

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…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

  • 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

Hyperbaric Oxygen Therapy for Diabetic Foot Ulcers

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  • 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.)

Controversy is Understandable

  • 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

Many Unregulated and Unsupported Uses

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  • 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

For Diabetic Foot Ulcers

  • 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

  • 1917: German inventors, Bernhard

and Dräger, applied pressurized

  • xygen 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 time

1662: Henshaw's Domicilium 1928: Cunningham’s Steel Ball Hospital

…Not a New Technology

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  • 1956: Dutch cardiac surgeon

Boerema (father of modern hyperbaric medicine) used pure

  • xygen operating rooms during

cardiac surgery

  • 1968: Kulonen first reported use
  • f HBO in chronic wounds
  • 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 ulcers

Ite Boerema Operating in Pure Oxygen

www.cms.gov 2002

…Not a New Technology

Indications per Undersea & Hyperbaric Medical Society Air or Gas Embolism Carbon Monoxide Poisoning Cyanide Poisoning Clostridial Myositis and Myonecrosis (Gas Gangrene) Crush Injury, Compartment Syndrome and Other Acute Traumatic Ischemia Decompression Sickness * Arterial Inefficiencies: Central Retinal Artery Occlusion * Arterial Inefficiencies: Enhancement of Healing In Selected Problem Wounds * Severe Anemia * Intracranial Abscess Necrotizing Soft Tissue Infections Osteomyelitis (Refractory) Delayed Radiation Injury (Soft Tissue and Bony Necrosis) Compromised Grafts and Flaps * Acute Thermal Burn Injury * Idiopathic Sudden Sensorineural Hearing Loss * Indications not included on the CMS list

  • Professional Society: Undersea

& Hyperbaric Medical Society (UHMS)

  • Discrepancies between

“accepted”, “covered”, and “off-label” indications

  • Some UHMS-approved

indications are not FDA approved, and seen as an “off- label” use of HBOT

  • Most conditions for which

HBOT is utilized have few successful alternatives.

Clinical Indications

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  • 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

Mechanism of Action?

  • 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 Post-HBOT 1 Pre-HBOT 1 Post-HBOT 1

Control Patient

Mechanisms of Action – Ongoing Stanford Study

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  • 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

  • utpatient clinic reality

Clinical Levels of Evidence

  • 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 (%)

Economics & Cost - United States

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  • 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”.

2010 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”.

2015 Cochrane Review

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  • 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
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  • 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
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  • 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.
  • HBOT may help if administered “full-course”.
  • Overall Verdict: Unfavorable

Kaplan-Meier curves for complete wound healing (ITT analysis).

  • 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.
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  • Inherent “procedural” component.
  • FDA recognizes “complete wound

closure” as the only primary healing outcome.

  • Paucity of disease-modifying

genes and biomarkers

  • HBOT trials often include patients

with more advanced ulcers, seen in more heterogenous populations.

Challenges in Conducting Wound Healing Trials

  • The number of new investigational drugs for chronic wounds approved

by FDA in the past two decades has been “zero”!

  • The last investigational drug approved by FDA for healing chronic

wounds was rhPDGF-BB, approved in 1997 for neuropathic DFUs.

0%

The Likelihood for Approval (LOA) for drugs across various disease categories between 2006 and 2015

Result: No Successful Drug Trials in 20 Years

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  • 1. HBO has some biological effect
  • 2. There is level I data for a clinical effect in some conditions

(carbon monoxide poisoning)

  • 3. Trials in diabetic wound healing have a very high failure

rate

  • 4. The physics of the hyperbaric environment create

additional barriers to blinding, trial design and compliance

  • 5. It is unlikely that HBO will be useful for the vast majority
  • f diabetic foot ulcers
  • 6. However, predictive models may be able to identify

patients who are most likely to benefit so that this expensive therapy can be targeted to them

My Conclusions

  • 1. HBO For chronic Wagner 3DFUs (sometimes after

a trial of other “advanced wound therapies”)

  • 2. Usually at risk for ray or larger amputations
  • 3. Combined with antibiotics under supervision of

ID consultants

  • 4. Patient must be motivated to complete entire

course of therapy

  • 5. In these highly selected patients, on an anecdotal

basis, HBO seems to be beneficial

My Practice

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Questions?