Wound Healing Pharmaceuticals: What the EBM Tells Us

Robert G. Smith DPM., MSc., R.Ph., C.Ped

PharmCon

2008 Pharmcon is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education

Learning Objectives

Appreciate the selection of the most appropriate wound healing product with regard to a presenting wound type as supported by relevant clinical evidence based data.

Develop a wound care product formulary for use in a clinical practice supported by available evidence based medicine.

Appreciate the clinical data regarding medicinal alternative wound care products as found in the literature

Prevalence of Diabetes Mellitus

Total:

20.8 million people —7 percent of the population —have diabetes.

Diagnosed:

14.6 million people

Undiagnosed:

million people 6.2 Approximately 15% of patients with diabetes will have a foot ulcer and those who develop an ulcer, 6% will be hospitalized due to infection or other ulcer related complications

Three Major Problems of an Open Wound

Hemorrhage Mechanical Disruption of Tissues Infection

Lower Extremity Wounds

Diabetic Venous Ischemic Combination

Wound Types

Acute Wounds: Wounds that heal with an orderly and timely restoration of anatomic and functional integrity Chronic Wounds: Wounds that appear to be stagnated in the inflammatory or proliferative phase. Accumulation of excess extracellular matrix components or matrix metalloproteinases (collageases elastase)

Wound Care Product History

Early accounts from 1650 BC described standard treatments to include grease, honey, and lint.

The Egyptians and Greeks introduced various metallic salt compounds, astringents, and antiseptics.

Joseph Lister addressed wound sepsis leading to the use of specific chemical therapies to manage wounds.

Winter’s 1962 observations of the benefits of a moist wound environment regarding scar formation

Central Dressing Selection Theme

Selection based on experience not scientific knowledge Studies focused on dressings as related to wound type and cost factors Morrison 1987 Gwyther 1988 Luker & Kenrick 1992 Flanagan 1992 Benbow 1994 Bell 1994 Bux & Malhi 1996 Vermeulen et 2006

Evidence Base Medicine

Evidence-based medicine is conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients. (Waldman 2006) Since wound care products are pharmaceuticals -evidence is drug data, what the drugs are, how they are used, and the latest recommendations for common and uncommon conditions.

Evidence Base Medicine Five Step EBM Model (Akobeng 2005)

A. Convert information needs into answerable questions. B. Find the best evidence which will answer the questions. (Decide where to search) C. Critical appraising of the evidence for its validity and usefulness. (Relevant) D. Applying the results of the appraisal into clinical practice.

E. Evaluating performance (Final outcome on patient care)

Evidence Base Medicine Category of Evidence

Ia – Evidence from meta analysis of RCTs Ib – Evidence from at least once RCT IIa – Evidence from at least one controlled study without randomization IIb – Evidence from at least one other type of quasi experimental study III – Evidence from non-experimental descriptive studies IV- Evidence from committee reports or opinions or clinical experience of respected authories

Evidence Base Medicine- Strength of Recommendations

A – Directed based on category I evidence.

B – Directed based on category II evidence or extrapolated Directed based on category III or extrapolated recommendation from category I or II evidence.

C – Directed based on category III or extrapolated recommendation from category I or II evidence.

D -Directed based on category IV or extrapolated recommendation from category I, II, III evidence.

Evidence Based Medicine in Wound Care

Much information available on evidence based medicine, including numerous useful books, publications, journal articles, and websites.

The search for evidence based medicine in wound care is still in the developmental stages.

Much of the work in wound care has been left to interpretation by wound care teams.

Searching for Evidence-Based Medicine Related to Wound Care Pharmaceuticals Review Ryan et al 2003 OWM 49 (11) 67-75 Search Pub Med www.pubmed.gov

Dates for literature 1980-2007 Limitations: Clinical Trials Meta-Analysis Randomized Control Trials Mesh Terms “Product Class” “Diabetic” “Foot” “Ulcers” 400 Literature Citations

Wound Care Products

Alignates Hydrocolloids Antiseptics Enzymatic Products Foams Gauze Hydrogels Antimicrobial or “biocides” Alternative Medicinals

ALGINATES

These products are produced from naturally occurring calcium and sodium salts of alginic acid found in a family of brown seaweed.

Alginates are rich in either mannuronic acid or guluronic acid, the relative amount of each influence the amount of exudate absorbed and the shape the dressing will retain.

Alginate Dressings (RCTs)

Donaghue et al (1998) Evaluation of collagen-alginate dressing in diabetic foot ulcers.

75 patients (2:1 ratio) for the collagen alginate vs gauze 80.6% reduction wound area vs 61.1% Complete healing was achieved in 24 (48%) vs 9 (36%) after 8 weeks

Alginate Dressings (RCTs)

Bales et al (2001) Exploring the use of an alginate dressing for diabetic foot ulcers.

Non-comparative, two center study not a RCT 41 patients in two sites 6 weeks or until ulcer healed 11 of 39 patients (28.2%) healed

Antiseptics

Antiseptics are disinfectants used on body surfaces to reduce the number of normal flora and pathogenic contaminants Antiseptics function as non specific microbial inhibitors without a specific cellular target.

Smith A Critical Discussion of the Use of Antiseptics in Acute Traumatic Wounds

J Am Podiatr Med Assoc 2005 95: 148-153

Antiseptic Concerns (Level “D”)

Brennan & Leaper microcirculatory Cooter attractive agent Lineaweaver Fibroblast retards epithlialization Kozol-Neutrophils “NO SAFE [ ]

Tap Water Irrigation

A review of the reference material used to support this declaration of water’s negative effects could not be substainated.

Only one reference could be found declaring tap water contact with living cells at the wound’s edge caused cell break down with resulting tissue damage and pain discomfort.

Clinical Trials on Tap Water

Hall reviewed the medical literature regarding the effect of tap water verses normal saline on infection rates in acute traumatic wounds. No association with the use of tap water and an increase rate of infection.

Angeras et al conducted a randomized study comparing the use of tap water with saline to cleanse acute traumatic soft tissue injuries.

Lower rate of infection in those wounds where tap water had been used to cleanse wounds; 5.4% with tap water compared to 10.3% with the saline group.

Bansal et al and Valente et al compared tap water and saline wound irrigation of simple lacerations in pediatric patients.

Bansal et al performed a blinded investigation while Valente et al conducted an unblinded non randomized investigation.

Despite positive post irrigation cultures were found in Bansal et al’s investigation and clinical determination of infection in Valente et al’s study determined these findings were not significantly different between the normal saline solution and tap water groups.

Antiseptics in Practice

The level of dilution that caused no damage to fibroblasts at the same time maintaining bactericidal activity was a 1/1000 concentration for povidone iodine and 1/100 concentration for sodium hypochlorite. While hydrogen peroxide and acetic acid solutions lose their bactericidal activity before they lose their tissue toxicity during dilution. Interestingly, the dilutions utilized in the cell culture experiments are below the strengths used in clinical practice.

Enzymatic Debriders

Collagenase-Based Products Papain-Based Products Papain-Urea Chlorophyllin Copper Complex

Collagenase-Based Products

Collagenase, is an enzymatic debriding agent derived from

Clostridium histolyticum

to the metallopeptidase family.

belonging It specifically hydrolyzes peptide bonds and digests all triple helical collagen and will not degrade any other proteins lacking the triple helix. This is a unique feature of bacterial collagenase; since none of the other available proteases can digest collagen.

Collagenase-Based Products

The enzyme liquefies necrotic tissue without damaging granulation tissue. Collagenase digests the lower portion of an escar working from the bottom up giving the appearance of working more slowly.

Collagenase has been shown to be gentle to viable cells and might promote angiogenesis and epithelialization.

Papain-Based Products

Papain is a nonspecific proteolytic enzyme derived from the fruit of the papaya tree (Carica papaya).

Papain breaks down fibrinous material in necrotic tissue and requires the presence of sulfhydryl groups, such as cysteine, for its activity.

It does not digest collagen, and it requires specific activators that are present in necrotic tissue in order to be stimulated.

Papain-Based Products

Papain-urea preparations produce more exudate digesting eschar from the top which may irritate the surrounding skin.

Papain-urea products should be applied daily with a moisture retentive dressing.

Hydrogen peroxide solution may inactivate papain as well as salts of heavy metals such as lead, silver, and mercury have been shown to inactivate papain.

Papain-Urea-Chlorophyllin Copper Complex

Chlorophyllin, an anti-agglutinin, has been added to preparations of papain/urea in an attempt to reduce the pain.

Brett summarizes that there are favorable clinical results that reveal papain-urea chlorophyllin copper complex’s proteolytic action thoroughly cleanses lesions of all necrotic tissue debris and then maintains optimal circulation so that affected tissue will benefit from both hematological and nutritive elements.

Enzymatic Clinical Trials

Study

Lee & Ambrus (1975) Parish & Collins (1979)

Enzymatic Agent

Collagenase Collagenase Rao et al (1975) Collagenase

Level of Evidence

B Vetra & Whittaker (1975) Collagenase B Hansbrough et al (1995) Collagenase B B B Muller et al (2001) Collagenase Pullen et al (2002) Collagenase A A

Enzymatic Clinical Trials

Konig (2005) Collagenase Marazzi et al (2006) Collagenase Gasser (1940) Papain Emulsion Miller (1956) Papain-Urea Morrison & Casali (1957) Papain-Urea-Chlorophyllin Katz el at (1956) B Papain-Urea-Chlorophyllin B Carter (1958) Papain-Urea-Chlorophyllin B A B B B Burke & Golden (1958) Papain-Urea-Chlorophyllin B Alvarez et al (2002) Collagenase Papain-Urea-Chlorophyllin A

CMS Statement 2008

FDA approved Santyl will not be affected Products contain papain/urea and chlorophyll complex are scheduled to be removed from 2008 Medicare Formulary Reference File

FOAMS

Foam dressings are manufactured as either polyurethane or silicone form with either hydrophilic or hydrophobic properties.

They transmit moisture vapor, O 2 , and thermal insulation.

Foams (RCTs)

Lohmann M et al (2004) Safety and performance of a new-adhesive foam dressing for the treatment of diabetic foot ulcers.

Open Non-comparative, prospective study 35 out of 37 patients completed study 6 weeks Relative wound area reduction from 100% to 40%

Gauze and Sponges

This cotton product has relative wide weave through which new tissue can grow.

Gauze dressings are manufactured in many forms.

Gauze and Sponges

Gold standard (Wet to Dry Gauze Dressing) Comparative studies with impregnated products Randomized Controlled Studies Often used for economic studies for cost analysis-Material cost for the dressing and labor expenses

Hydrocolloids

Hydrocolloids are hydrophilic colloid particles (sodium carboxymethycellulose, gelatin, pectin, elastomers, and adhesives) bound to polyurethane foams that are impermeable to bacteria and facilitating wound debribement

Hydrocolloids RCTs

Apelqvist et al (1990) Topical treatment of necrotic foot ulcers in diabetic patients: a comparative trial of DuoDerm and MeZinc An Open Randomized Controlled Trial 44 patients 14 of the 21 patients treated with MeZinc had their necrotic ulcers improve by at least 50% compared to 6 out of 21 of hydrocolloid dressing

Hydrocolloids RCTs

Varma et al (2006) Efficacy of Polyurethane Foam Dressing in Debrided Diabetic Lower Limb Wounds.

Patients randomly assigned to study or control group (conventional gauze dressing) 48 patients (24 patients in each group) There was a significant reduction in the time taken for wounds to heal 22.5 compared to 52 days.

Hydrogels

Hydrogels are non adherent, water based, or glycerin based amorphous, crossed-linked polymer gels.

Hydrogels can help reduce pain, decrease wound temperature and inflammation.

Hydrogels RCTs

Smith (2002) Debridement of diabetic foot ulcers.

Three Hydrogel RCTs suggested that hydrogels are significantly more effective than gauze or standard of care in healing diabetic foot ulcers.

Scanlon (2003) Review: debridement using hydrogel appears to be more effective than standard wound care for healing diabetic foot ulcers There is little good quality clinical evidence to indicate superiority of any one hydrogel over another

Broad-Spectrum Antimicrobials (Biocides) Cadexomer iodine Silver

Cadexomer Iodine

Iodine is a potent broad spectrum antiseptic agent.

Improved formulations of iodophors “carriers” release low levels of iodine over a longer period of time.

Over the recent years the clinical use of silver and polyhexamethylene biguanide products have been favorably embraced when compared to cadexomer Iodine

Cadexomer Iodine RCTs

Apelqvist et al (1996) An economic analysis of cadexomer iodine ointment and standard therapy.

Compare Clinical effect and economic cost of cadexomer iodine ointment and standard therapy.

12 week open randomized comparative study 25 patients Treatment with cadexomer iodine ointment show no clinical difference compared to standard therapy

Silver

Silver ions attack the cell membrane, the membrane transport system, the RNA, the DNA function, protein function, and inhibits bacterial mutation.

The longevity of silver ions in dressing material due to controlled release mechanisms insures that the wound environment is hostile to bioburden

Silver Dressing (RCTs)

Rayman et al (2005) clinical and safety of sustained silver-releasing foam dressing.

27 patients 6 weeks Cross over study using Biatain dressings Silver foam is safe and easy to use and effectively supports healing and good wound progress of diabetic ulcers

Alternative Medicinals

Honey- Molan (2006) reviews the literature to describe the evidence supporting honey as a wound dressing.

Phenytoin – Scheinfeld (2003) Descriptive review Estrogen- (2005) A review of medical literature Topical Insulin- (1999) 2 RCT double blind placebo control trial

Alternative Therapies

Honey- Honey consists of simple sugars and is both sterile and inhibits growth of both Gram-negative and Gram-positive organisms. Its antibiotic properties are attributed to its low pH, a thermolabile substance called inhibine, and its hygroscopic properties.

Molan summarized the clinical base evidence supporting the use of honey as a wound dressing. This review reported the findings of 17 randomized controlled trials involving 1965 participants, as well as 5 clinical trials of other forms involving 97 participants treated with honey.

Alternative Medicinals

The wound types treated with honey during these control trials were either superficial burns, partial thickness wounds, moderate burns, third degree burns, chronic leg ulcers, pressure ulcers, and surgical wounds.

These studies compared honey to either silver sulfadiazine, amniotic membrane, Vaseline gauze, an occlusive dressing, mupirocin, povidone-iodine, or a boiled potato peel.

Commercial products released in 2007

Alternative Medicinals

This review presents a large body of evidence supporting the use of honey as a wound dressing for a wide range of wounds because its antibacterial activity rapidly clears infection and protects the wound and it provides a moist healing environment without the risk of bacterial growth occurring. Also, honey rapidly debrides wounds and removes malodor and its anti inflammatory activity reduces edema and exudate and prevents or minimizes hypertrophic scarring.

Alternative Medicinals

Phenytoin – Muthukumarasamy et al (1991) Topical phenytoin in diabetic foot ulcers 100 patients (50 study) (50 control) Matched paired with sex, age, ulcer size, and depth Mean time to heal 21 days for DPH and 45 days with control dry sterile occlusive dressing

Alternative Medicinals

Phenytoin – Pai et al (2001) Topical phenytoin in diabetic ulcers: a double blind control trial 57 patients completed trial Marginal increase in reduction of mean ulcer area after 3 to 4 weeks Treatment was better in Wagner grade II ulcers

Developing a wound care product Formulary References

Preece J. Development of a wound management formulary for use in clinical practice. Professional Nurse 2004 20 (3) 27-29.

Posnett J. Making cost effectiveness the basis of product selection. J of Wound Care 2006 15 (1) S14-S15.

Fikar CR and Delinosi BD. Wound-care resources on the internet: a second update. JAPMA 2006 96 (3) 264-268.

Developing a Wound Care Product Formulary Criteria

Efficacy Effectiveness and Safety Quality of the Drug and Supply Chain Availability of Clinical expertise for questions Cost estimates to the institution, including costs of drug, hospitalization, and time Availability of the Drug

Developing a Wound Care Product Formulary

Do not assume that all products within a particular category are the same.

Always challenge product suppliers to provide evidence to support their claims.

The price of products used in the treatment process is relatively a minor part of the overall cost.

Available resources thus must be used in the most efficient way possible.

Developing a Wound Care Product Formulary

Final Product Inclusion Literature Review Best Evidence Evaluate On Clinical Basis Make a Short List Of 2-3 products Class

Challenge of Finding Evidence in Wound Management

Majority of products are categorized as medical devices.

They are deemed safe for use after successful investigations of safety based on Phase 1 and Phase 2 trials yield satisfactory outcomes Thus the motivation for designing and developing Phase 3 studies (RCTs) may be less in the field of wound healing compared to other areas of clinical medicine.

Strategy for over coming the Challenge

Development of the most appropriate design for establishing evidence should be a priority for all clinicians.

An international working group of respected leaders in the field should be formed to focus on this lack of evidence.

This group should be responsible for defining the tools to be used to develop protocols for the translation of RCTs into clinical practice.

Conclusions

While there are many wound care products (Pharmaceuticals) available on the market, robust evidence of comparative effectiveness of products is limited.

Although there is some reliable evidence on the management of venous leg ulcers, there is a lack of good quality data regarding the effectiveness of products on other wound types