June 2016 FAQs

What evidence is available for efficacy and stability of high dose mitomycin C concentrations?

Introduction

Intravesical mitomycin C (MMC) therapy is used for the treatment of non-muscle-invasive urinary bladder cancer, also known as superficial bladder cancer.¹ Urinary bladder cancer is the sixth most common cancer, with approximately 74,000 new cases diagnosed in 2015 in the United States. In addition, an estimated 16,000 deaths occurred in 2015 as a result of bladder cancer.

Tumors that cause superficial bladder cancer are classified as either low or high grade.¹ Transurethral resection of the bladder tumor (TURBT) is considered the standard treatment for low grade tumors. Following TURBT, the National Comprehensive Cancer Network (NCCN) bladder cancer guidelines recommend to administer a single dose of immediate intravesical chemotherapy within 24 hours of TURBT. This immediate intravesical chemotherapy may be followed with 6 weeks of adjuvant therapy depending on prognosis and risk factors for recurrence. The most common intravesical chemotherapy agent to be used for low grade tumors is MMC. For high grade tumors, intravesical MMC is also an option for adjuvant therapy after resection, yet it is not a first-line treatment option. In addition, patients with high grade tumors may undergo longer maintenance therapy. According to the American Urological Association (AUA) 2007 guidelines for management of noninvasive bladder cancer, intravesical MMC may be used as adjuvant or maintenance therapy for low grade superficial bladder cancer.² However, optimal maintenance schedules and length of therapy have not been determined and the side-effects and cost of therapy may be limiting factors for some patients. For high-grade tumors, the AUA guidelines recommend intravesical BCG for adjuvant and maintenance therapy over MMC. The NCCN guidelines currently do not recommend intravesical chemotherapy for maintenance therapy.¹

Intravesical Mitomycin C Dose

According to the AUA guidelines, the dose of MMC varies from 20 to 60 mg per instillation, with the most common dose as 40 mg in 40 mL of normal saline or sterile water administered weekly for 8 weeks, then monthly for 1 year.² Various drug resources also report a wide range of doses, with weekly doses ranging from 20 to 60 mg MMC in normal saline or sterile water, with concentrations ranging from 0.5 to 2 mg/mL.^3,4 The NCCN guidelines do not specify what dose of intravesical MMC should be used.¹

The range of doses and concentrations for intravesical MMC therapy varies in the literature. The Agency of Healthcare Research and Quality (AHRQ) recently published a comparative effectiveness review on the diagnosis and treatment of non-muscle-invasive bladder cancer.⁵ The most common doses of intravesical MMC reported were 40 mg in 50 mL of normal saline, 40 mg in 40 mL of sterile water, and 20 mg in 40 mL of normal saline, with concentrations ranging from 0.16 mg/mL to 1 mg/mL.  A summary of 8 trials that specifically compares dosages, duration, and timing of MMC administration is provided in the review. Of these, only one trial by Au and colleagues used a dose with the concentration of 2 mg/mL; the majority of the trials evaluated a concentration of 1 mg/mL with either 40 mg of MMC in 40 mL or 20 mg of MMC in 20 mL. In addition, the AUA guidelines mention an optimal method for intravesical MMC but state that this method is still uncertain.² The “optimized” regimen was evaluated in the phase III trial by Au and colleagues summarized in the AHRQ review.  The focus of this review will be efficacy and stability of concentrations greater than 1 mg/mL of intravesical MMC for superficial bladder cancer.

Au Trial

Many review articles and the AUA guidelines cite an optimized regimen that is based off one clinical trial from 2001 by Au and colleagues.⁶ This was a phase III international, multicenter, prospective trial that compared the efficacy of an optimized regimen with a standard regimen in the setting of superficial bladder cancer in patients with a high risk of recurrence. This optimized regimen was use to enhance intravesical drug delivery and consisted of multiple adjustments to the standard regimen. After reviewing various pharmacokinetic studies, the authors theorized that inadequate delivery of MMC to tumor cells is two-fold. During the 2-hour instillation of MMC, the concentration of MMC becomes diluted due to residual urine and production of urine during treatment. Also, MMC is unstable in acidic environments, such as urine, which may result in decreased MMC delivery during treatment.  The optimized regimen used in this trial attempted to address these concerns for inadequate MMC delivery and evaluate the regimen’s efficacy.

Patients were enrolled within 34 days of TURBT and were excluded if they had previous treatment with MMC in the past 56 weeks.⁶ Patients were followed quarterly for the first 2 years, biannually in years 3 to 5, and then annually.  The primary endpoint was time to recurrence, which was defined as the length of time from randomization to first evidence of tumor recurrence; this was analyzed using intent-to-treat and per-protocol analyses.

Patients (n=230) were randomized using stratified block randomization based on specific prognostic criteria.⁶ In the optimized regimen group (n=111), patients underwent 6 weekly intravesical treatments of 40 mg MMC in 20 mL of sterile water, resulting in a concentration of 2 mg/mL. In addition, patients in the optimized group refrained from drinking fluids for 8 hours before treatment and during treatment to decrease the amount of residual urine in the bladder. To alkalinize the urine in the optimized group, patients were instructed to take 1.3 grams of sodium bicarbonate the night before, the morning of, and 30 minutes before treatment. Lastly, investigators used an ultrasound device in this group to measure the post void residual urine volume. Once this volume was less than 10 mL, MMC was administered and retained in the bladder for 2 hours.  For the standard regimen group (n=119), patients underwent 6 weekly intravesical treatments of 20 mg MMC in 20 mL of sterile water (1 mg/mL), also retained for 2 hours in the bladder . Other than the bladder being emptied with a Foley catheter, no additional interventions were made in the standard group to decrease the amount of residual urine in the bladder or alkalinize the urine.

For baseline demographics, the majority of the patients were white males who had not previously had prior intravesical therapy.⁶ The only significant difference between the 2 groups was median age; the median age in the standard arm and optimized arm was 65 and 68 years, respectively. For the results of the intent-to-treat analysis, the patients in the standard treatment arm had a median time to recurrence of 11.8 months (95% confidence interval [CI] 7.2 to 16.4), compared to the optimized treatment group with a median time to recurrence of 29.1 months (95% CI 14.0 to 44.2, p=0.005).  The number of patients who were recurrence-free at 5 years after therapy was 24.6% (95% CI 14.9% to 34.3%) for the standard arm and 41% (95% CI 30.9% to 51.1%) for the optimized treatment group. Similar statistically significant results were seen in the per-protocol analysis.  For adverse effects, the only significant difference between the groups was an increase in dysuria in the optimized arm.

The authors concluded that a 6-week course of a higher concentration of MMC (2 mg/mL), dehydration before instillation, urinary alkalinization, and confirmation of complete bladder drainage prior to instillation improved recurrence-free survival and prolonged median time to recurrence.

Other Mitomycin C Trials

There have been few studies since the Au trial that have used this optimized regimen for treating superficial bladder cancer, including the higher concentration of 2 mg/mL of MMC. A descriptive study from 2010 reported outcomes from using sequential gemcitabine and MMC intravesical therapy to prevent recurrence in patients with superficial bladder cancer refractory or intolerant to BCG treatment in whom cystectomy was not possible or refused. ⁷ These patients received intravesical gemcitabine followed by intravesical MMC at a dose of 40 mg in 20 mL of sterile water every week for 6 weeks, and then continued monthly for maintenance. Of the 10 patients in this study, 6 of these patients responded to this treatment. The authors concluded that for patients who are refractory to first-line therapies, this combination of intravesical gemcitabine and MMC is a potential option and is well-tolerated. Other than the higher dose, there were no other adjustments to MMC therapy that followed the Au regimen.

In another study from 2013, urinary alkalinization with immediate single MMC instillation was used to see if it improved recurrence rates and relapses for patients with low grade tumors and at low risk for recurrence.⁸ There were 3 groups in this study: standard (n=11), optimized (n=15), and a retrospective control group (n=23). Both the standard and optimized alkalization arms used a dose of 40 mg of MMC in 40 mL of sterile saline which was instilled in the bladder for 2 hours within the first 6 hours of TURBT. Patients in the optimized treatment arm received 1.3 grams of sodium bicarbonate the night before, the morning of, and 30 minutes prior to MMC treatment. The retrospective control group consisted of patients with low risk of recurrence who undergone TURBT, but did not receive early single instillation of MMC. In the standard treatment arm, 100% of the patients remained recurrence-free at years 1, 3, and 5. For the optimized treatment arm, 86.7%, 79.4%, and 79.4% were recurrence-free at years 1, 3, and 5, respectively, while 91.3%, 82.6%, and 82.6% in the control group were recurrence-free at years 1, 3, and 5, respectively.  In the optimized group, the mean time to recurrence was 34.8 months (95% CI 28.5 to 41.1), compared to 51.8 months (95% CI 44.3 to 59.2) in the retrospective control group  (p=0.645). Between all the groups, there were no statistical differences. The authors concluded that they could not demonstrate an improvement in recurrence-free survival rates or time to recurrence when using a urinary alkalinization method for single, immediate instillation of MMC after TURBT. It should be noted that there are a few differences in this trial compared to the Au trial.  In this trial, the authors evaluated a single MMC instillation in low-risk patients compared to a longer treatment period in high risk patients in the Au study. In addition, this trial used a lower concentration of MMC.

Overall, there is limited literature beyond the Au trial to support the use of higher concentrations of MMC for intravesical instillation.

Stability

According to its product label, MMC reconstituted with sterile water to a concentration of 0.5 mg/mL is stable for 14 days refrigerated or 7 days at room temperature.⁹

The highest concentration of MMC in the literature with stability data is 1 mg/mL.¹⁰ When MMC was stored at concentrations of 1 mg/mL, a precipitate formed in 24 hours when refrigerated. In addition, when 1 mg/mL MMC was stored at 21° C and exposed to fluorescent light, there was 6% loss in 24 hours and a precipitate formed in 4 days. When it was stored at a slightly higher temperature of 25° C and protected from light, there was a 6% loss in 24 hours and 10% loss in 7 days, and no precipitate formed.

One study from 1990 looked at the stability of MMC in solutions for intravesical instillation.¹¹ It concluded that 30 mg or 40 mg in 50 mL of sterile water is stable for 4 days at room temperature and in the dark. When refrigerated at 4° C, 30 mg MMC in 50 mL of sterile water was stable for 4 days, while 40 mg MMC in 50 mL of sterile water was stable for 1 day. In addition, concentrations greater than 0.8 mg/mL are more likely to precipitate when refrigerated and at room temperature. The authors concluded that this phenomenon makes it “practically impossible” to conduct the stability study with higher concentrations.

For higher concentrations of 2 mg/mL of MMC, there are no studies available on its stability. In the British Columbia Cancer agency’s cancer drug manual, it states that MMC concentrations of 2 mg/mL should be prepared freshly for intravesical use and should not be refrigerated to prevent precipitation.¹² The drug manual cited personal communication with the author from the optimized phase III trial previously mentioned.

Conclusion

The most current NCCN guidelines do not provide insight on what dose or concentration of MMC should be used for the treatment of superficial bladder cancer. Only one trial has been completed to support the use of 2 mg/mL of MMC, though the significant results may be multi-factorial. Few studies have tried to replicate parts of the optimized regimen the Au trial used, and none have provided significant differences. Stability data of MMC supports higher concentrations are less stable and result in precipitation earlier than lower concentrations. Overall, there is limited data available on concentrations higher than 1 mg/mL for the efficacy and stability of MMC for intravesical instillation. Since there are limited data available for the stability of higher concentrations of MMC, USP 797 requirements should be followed if higher than 1 mg/mL concentrations of MMC are prepared for intravesical instillation.

References

1.         Bladder cancer: version 1.2016. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology website. http://www.nccn.org/professionals/physician_gls/pdf/bladder.pdf. Published April 4, 2016. Accessed April 10, 2016.

2.         Bladder cancer: guideline for the management of nonmuscle invasive bladder cancer: (stages Ta, T1, and Tis): 2007 update. American Urological Association website. https://www.auanet.org/common/pdf/education/clinical-guidance/Bladder-Cancer.pdf. Updated February 12, 2014. Accessed March 23, 2016.

3.         Micromedex Solutions [database online]. Greenwood Village, CO: Truven Health Analytics; 2016. http://www.micromedexsolutions.com/micromedex2/librarian/. Accessed March 23, 2016.

4.         LexiComp Online [database online]. Hudson, OH: Lexicomp; 2016. http://online.lexi.com/lco/action/home. Accessed May 16, 2016.

5.         Chou R, Buckley D, Fu R, et al. Emerging Approaches to Diagnosis and Treatment of Non-Muscle-Invasive Bladder Cancer. In. AHRQ Comparative Effectiveness Reviews. Rockville (MD): Agency for Healthcare Research and Quality (US); 2015.

6.         Au JL, Badalament RA, Wientjes MG, et al. Methods to improve efficacy of intravesical mitomycin C: results of a randomized phase III trial. J Natl Cancer Inst. 2001;93(8):597-604.

7.         Breyer BN, Whitson JM, Carroll PR, Konety BR. Sequential intravesical gemcitabine and mitomycin C chemotherapy regimen in patients with non-muscle invasive bladder cancer. Urol Oncol. 2010;28(5):510-514.

8.         Ersoy H, Yaytokgil M, Karakoyunlu AN, Topaloglu H, Sagnak L, Ozok HU. Single early instillation of mitomycin C and urinary alkalinization in low-risk non-muscle-invasive bladder cancer: a preliminary study. Drug Des Devel Ther. 2013;7:1-6.

9.         Mitomycin [package insert]. Durham, NC: Accord Healthcare, Inc; 2013.

10.       McEvoy G. Handbook on Injectable Drugs. 18th ed. Bethesda, MD: American Society of Health-System Pharmacists; 2015.

11.       Beijnen JH, van Gijn R, Underberg WJ. Chemical stability of the antitumor drug mitomycin C in solutions for intravesical instillation. J Parenter Sci Technol. 1990;44(6):332-335.

12.       Mitomycin. British Columbia Cancer Agency Drug Manual website. http://www.bccancer.bc.ca/drug-database-site/Drug%20Index/Mitomycin_monograph_1Apr2016.pdf.

Prepared by:
Brittany Lee
PharmD Candidate Class of 2017
College of Pharmacy
University of Illinois at Chicago

June 2016

The information presented is current as of May 2016.  This information is intended as an educational piece and should not be used as the sole source for clinical decision making.

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What evidence supports or refutes the use of medical grade honey for wound healing?

Natural products have been used throughout history for a number of medical applications. Natural remedies have provided valuable treatment options in ancient societies, and some remain in use today. One such natural remedy that has been available for centuries is honey. Honey was first used as a topical agent to promote wound healing by the ancient Egyptians.¹ Egyptians commonly applied honey covered with adhesive wrap at the site of wounds. Honey continues to be used today as a topical agent for wounds because of its various therapeutic properties, including antimicrobial, anti-inflammatory, antioxidant, and immune-stimulant, as well as its role in promoting wound regeneration.²     

Mechanism of honey

The array of honey’s medicinal properties makes it an appealing agent for use in wound healing. Honey has been shown to have antimicrobial activity against bacteria and fungi.² Honey exerts its antimicrobial activity through direct and indirect elimination. Direct elimination of microbes occurs through: hydrogen peroxide production, the high osmolarity of the substance acting as a barrier, the acidity of honey creating an unfavorable environment for growth, and non-peroxide activity and antioxidants. Honey also stimulates lymphocyte, antibody, cytokine, and nitric oxide production as part of its indirect antimicrobial activity. With the prevalence of antibiotic resistance continuing to trend upward, honey may be beneficial as, to date, there is no evidence of microbial resistance to honey.³  

Honey has a number of other mechanisms that may be useful in wound healing. Its high osmotic pressure and protease activation by hydrogen peroxide contribute to wound debridement.² Honey reduces the inflammatory response by free radical reduction which also minimizes scarring. The moist environment and anti-inflammatory properties provided by the application of honey are thought to aid in the reduction of pain when undergoing dressing changes. ⁴ The phenolic component of honey decreases the release of reactive oxygen species resulting in an antioxidant effect. Finally, honey is also beneficial in the healing process through angiogenesis and reepithelialization, which reduces the need for skin graft and minimizes scarring.⁵  

Types of honey

There are a variety of honeys available due to different species of bees and plants in various geographical locations.⁴ The differences among various honey types allows for differences in antibacterial potency and mechanism of antimicrobial activity.^5,6

MEDIHONEY was one of the first medical grade honeys available, and it is currently licensed in the United States as a medical device.⁷ MEDIHONEY is derived from the Leptospermum species of plant in New Zealand, also known as the Manuka plant. Leptospermum species have proven their antibacterial activity through in vitro testing.⁶ A variety of MEDIHONEY products are available including gel, paste, adhesive, and non-adhesive dressings.

The primary antibacterial activity for most honey products is due to hydrogen peroxide production.⁸ This process becomes activated when honey is diluted with the wound exudate. Unfortunately, wound exudate and serum contain enzyme catalases that can break down hydrogen peroxide. Manuka honey has an additional mechanism of antibacterial activity; therefore, it is less affected by these catalases. Manuka exerts its antibacterial effect through methylglyoxal.^2,5,8 The methylglyoxal component of Manuka honey is theorized to be necessary for honey to be useful in the treatment of biofilms such as those produced by Staphylococcus aureus.

Wounds

Wounds can be separated into 2 categories, acute and chronic. Acute wounds include lacerations and burns. Lacerations are usually treated with a local anesthetic, irrigation with normal saline, and either local or systemic antimicrobial treatment.⁹ The treatment of burns depends on the depth, surface area, and location. The majority of burns are treated by cooling, topical nonsteroidal anti-inflammatory agents, topical antimicrobial medication, or absorptive occlusive dressing.¹⁰ Topical antimicrobial agents include silver sulfadiazine (SSD), bacitracin, and mupirocin. There is no evidence suggesting one of these agents is superior to the other.⁹ Absorptive occlusive dressings available include hydrocolloid, collagen dressing, and silicone mesh dressing. The American Burn Association does not recommend one agent over another.¹⁰  

Chronic wounds include diabetic foot ulcers and venous leg ulcers. Poorly controlled diabetic patients can develop wounds secondary to neuropathy and peripheral vascular disease. Diabetic foot ulcers should be debrided, and can be treated with a topical or systemic antimicrobial depending on the severity and presence of systemic symptoms.¹¹ Venous leg ulcers are defined as open skin lesions of the foot or leg in areas affected by venous hypertension.¹² Treatment of venous leg ulcers is similar to diabetic foot ulcers. The ulcer should be cleaned, wound exudate controlled, and surface bacteria managed.

The primary literature and guidelines regarding treatment of acute and chronic wounds do not recommend one localized therapy over another. Many of the recommendations are based on small, observational studies or expert opinion. The American Burn Association has a guideline published in 2001 about burn care. The guideline provides recommendations on the overall management of burn patients, but fails to discuss different treatment options.¹⁰  The Wound Healing Society published a guideline on the treatment of diabetic foot ulcers stressing the importance of maintaining a moist environment, but does not provide recommendations on the use of particular agents.¹¹ The management of venous leg ulcers guideline also fails to recommend 1 type of antimicrobial or dressing over another.¹² None of these references mention the use of honey as an option for wound treatment.

Honey – safety and efficacy

A 2015 Cochrane review compared honey with other topical agents for the treatment of wounds.¹³ Twenty-six trials in acute wounds, chronic wounds, or both types of wounds were included. The type of honey was specified as monofloral (including Manuka) in 10 of the trials; the type of honey was unspecified in the remaining trials. There were multiple methods of honey application including impregnated gauze, alginate dressings, or topical honey covered by dressings as well as a number of comparators: SSD, antiseptics, excision, and various dressings. The results are summarized in the table below.

Table. Evidence for honey in wound healing.¹³

The authors concluded that it is difficult to draw conclusions on the efficacy of honey for wounds due to the high heterogeneity of the trials and, in general, the low quality of the evidence.¹³ However, honey may be superior to conventional treatment for partial thickness burns and may heal postoperative wounds more quickly than antiseptics.

The majority of studies in the above review were conducted in patients with burns.¹³ It appears from the available evidence that the use of honey in these patients may result in quicker healing and fewer adverse events when compared with SSD. A 2015 systematic review specifically evaluated studies comparing honey to SSD in patients with burns.¹⁴ The authors included 6 studies and found honey to be more effective than SSD for wound healing, similar to the 2015 Cochrane analysis.

Another 2015 systematic review evaluated medical grade honey for chronic venous leg ulcers.¹⁵ The authors found 5 relevant studies: 2 randomized controlled trials, 1 case series, and 1 cohort study. The largest trial included 368 patients and did not find honey to be more effective than standard wound therapy (calcium alginate dressings) with 12-week healing rates of 55.6% and 49.7% (p=0.258), respectively.¹⁶ The study did associate honey with an increase in adverse events, primarily pain. An open-label trial in 108 patients found honey to be effective for improving healing compared with hydrogel dressings.¹⁷ At 12 weeks, 44% of patients treated with medical grade honey healed compared with 33% with standard therapy (p=0.037). Although there are numerous reasons these trials may have found conflicting results, the authors proposed that it could be due to differences in standard therapy, the types of patients studied, or the honey formulation (although both studies used Manuka honey).¹⁵ Both observational studies found honey to be effective, but any conclusions from these studies are largely limited by their small sample size and lack of a control group. The authors concluded that it was impossible to recommend for or against the use of honey in chronic venous leg ulcers based on this evidence.

Additional evidence has been published since the above reviews. Amaya published a multicenter, retrospective chart review in pediatric and neonatal wounds treated with MEDIHONEY products (gel, calcium alginate, or HCS-hydrogel colloidal sheets).¹⁸  A total of 115 patients were treated. The majority of patients were either premature neonates or infants 0 to 6 months of age. The mean treatment duration was 18.7 days. The majority of patients (77.7%) had successful debridement and wound closure. Few patients required surgical debridement (1.7%) or alternate dressing types (6.6%). No adverse events were reported. Although this study supports the safety and efficacy in the neonatal population, its retrospective nature makes it difficult to draw firm conclusions.

Conclusion

Honey has a variety of therapeutic properties that make it an appealing agent for use in wound care. The trials conducted on the use of honey in wounds have variable results and are often low quality evidence. It is difficult to draw conclusions based on these studies due to the small number of patients and the use of different honey formulations; however, it appears that honey may be effective for certain wound types, especially partial thickness burns.

Prior to using honey for the treatment of wounds, careful selection of a honey product should be considered. It is important to select only medical grade honey products as honey can be contaminated with Clostridium botulinum. The medical grade honeys undergo gamma irradiation which eradicates the organism.^7,19 Additionally, Manuka honey appears to confer greater benefits compared to other honey types and is the preferred honey type for wound healing.

References

1. Shah JB. The history of wound care. J Am Col Certif Wound Spec. 2011;3(3):65-66.
2. Oryan A, Alemzadeh E, Moshiri A. Biological properties and therapeutic activities of honey in wound healing: a narrative review and meta-analysis. J Tissue Viability. 2016;25(2):98-118.

3.      McLoone P, Warnock M, Fyfe L. Honey: a realistic antimicrobial for disorders of the skin. J Microbiol Immunol Infect. 2016;49(2):161-167.

4. Manyi-Loh CE, Clarke AM, Ndip RN. An overview of honey: therapeutic properties and contribution in nutrition and human health. Afr J Microbiol Res. 2011;5(8):844-852.
5. Molan P. Potential of honey in the treatment of wounds and burns. Am J Clin Dermatol. 2001;2(1):13-19.
6. Simon A, Traynor K, Santos K, Blaser G, Bode U, Molan P. Medical honey for wound care—still the ‘latest resort?’ Evid Based Complement Alternat Med. 2009;6(2):165-173.
7. MEDIHONEY. Derma Sciences website. http://www.dermasciences.com/medihoney. Accessed May 12, 2016.
8. Mandal MD, Mandal S. Honey: its medicinal property and antibacterial activity. Asian Pac J Trop Biomed. 2011;1(2):154-160.
9. Singer AJ, Dagum AB. Current management of acute cutaneous wounds. N Engl J Med. 2008;359(10):1037-1046.
10. Practice guidelines for burn care. American Burn Association website. http://www.ameriburn.org/PracticeGuidelines2001.pdf. Accessed May 25, 2016.
11. Steed DL, Attinger C, Colaizzi T, et al. Guidelines for the treatment of diabetic ulcers. Wound Repair Regen. 2006;14(6):680-692.
12. O’Donnell TF Jr, Passman MA, Marston WA, et al. Management of venous leg ulcers: clinical practice guidelines of the Society for Vascular Surgery and the American Venous Forum. J Vasc Surg. 2014;60(2 Suppl):3S-59S.
13. Jull AB, Cullum N, Dumville JC, Westby MJ, Deshpande S, Walker N. Honey as a topical treatment for wounds. Cochrane Database Syst Rev. 2015;3:CD005083.
14. Lindberg T, Andersson O, Palm M, Fagerstrom C. A systematic review and meta-analysis of dressing used for wound healing: the efficiency of honey compared to silver on burns. Contemp Nurs. 2015;51(2-3):121-134.
15. Holland LC, Norris JM. Medical grade honey in the management of chronic venous leg ulcers. Int J Surg. 2015;20:17-20.
16. Jull A, Walker N, Parag V, Molan P, Rodgers A; Honey as Adjuvant Leg Ulcer Therapy trial collaborators. Randomized clinical trial of honey-impregnated dressings for venous leg ulcers. Br J Surg. 2008;95(2):175-182.
17. Gethin G, Cowman S. Manuka honey vs. hydrogel—a prospective, open label, multicenter, randomised controlled trial to compare desloughing efficacy and healing outcomes in venous ulcers. J Clin Nurs. 2009;18(3):466-474.
18. Amaya R. Safety and efficacy of active leptospermum honey in neonatal and paediatric wound debridement. J Wound Care. 2015;24(3):95;97-103.
19. Lee DS, Sinno S, Khachemoune A. Honey and wound healing: an overview. Am J Clin Dermatol. 2011;12(3):181-190.

Prepared by:
Meghan Glynn
PGY-1 Pharmacy Practice Resident
University of Illinois at Chicago

June 2016

The information presented is current as of May 25, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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What are the new 2016 ACC/AHA guideline recommendations for dual antiplatelet therapy?

Introduction

Dual antiplatelet therapy (DAPT) involves the use of a P2Y₁₂ inhibitor (clopidogrel, ticagrelor, or prasugrel) in combination with aspirin.¹ This therapy is utilized in order to prevent restenosis and stent thrombosis after percutaneous intervention (PCI) for silent ischemic heart disease (SIHD) or acute coronary syndrome (ACS). Additionally, DAPT is utilized for those who present with ACS and do not undergo revascularization, but rather are managed only medically. Traditionally, the recommended duration of DAPT was 1 month after bare metal stent (BMS) placement and 12 months after drug-eluting stent (DES) placement.² It was unclear what the risks and benefits of administering DAPT were for shorter or longer durations than 12 months of DAPT for DES. More recently, there have been a multitude of studies which evaluated outcomes in patients treated with DAPT for both shorter (3 to 6 months) and longer (18 to 48 months) durations than the previous 12 month recommendation. In March 2016, the American College of Cardiology and American Heart Association (ACC/AHA) Task Force released a focused update on the optimal duration of DAPT in patients with coronary artery disease in order to update recommendations based on recent data.¹ Previous guidelines were based on data available for first-generation DES, sirolimus- and paclitaxel-eluting stents. The first-generation stents are seldom used in current practice and have been replaced by “newer-generation” stents, which are everolimus- or zotarolimus-eluting. The newer stents have a lower risk for stent thrombosis and myocardial infarctions (MIs) than the previous generations.³ The updated guideline is applicable to patients who have received newer-generation stents.¹

Guideline summary

The recommendations provided within this guideline focuses on balancing a reduction in ischemic risk without an unreasonable increase in bleeding risk.¹ The newly-released guideline replaces previous DAPT recommendations for PCI, coronary artery bypass graft (CABG) surgery, stable ischemic heart disease, non-ST-elevation ACS (NSTE-ACS), ST-elevation myocardial infarction (STEMI), and perioperative management of patients undergoing noncardiac surgery.^2,4-8 The ACC/AHA updated guideline divides recommendations into 2 populations of patients: patients with SIHD and patients with ACS.¹ The ACS patient group includes both NSTE-ACS and STEMI. This is a change from previous guidance where NSTE-ACS was routinely presented separately from STEMI.²

Duration of Dual Antiplatelet Therapy

The new guideline provides both a recommended minimum duration of DAPT along with suggestions for either abbreviated or extended therapy.¹ These 2 recommendations are separated into: Class I recommendations (“should be given”; minimum treatment duration) and Class IIb recommendations (“may be considered”; alternative treatment duration that can be used for an individual based on their respective ischemic and bleeding risks).These recommendations are summarized in Table 1. A major change in this guideline was the reduction of the minimum duration of treatment for patients with SIHD treated with a DES from 12 to 6 months.

Table 1. Duration of dual antiplatelet therapy recommendations¹

Abbreviations: ACS=acute coronary syndrome; BMS=bare metal stent; DES=drug-eluting stent; PCI=percutaneous intervention; SIHD=silent ischemic heart disease.

^aClass I recommendation; defined as “should be given”

^bClass IIb recommendation; defined as “may be considered”

^cEach patient should be evaluated for their individual ischemic/bleeding risk, preferences, cost, etc to determine the ideal duration of DAPT.

^d14 day minimum duration based on currently available data which are limited to trials evaluating short-term treatment; 12 month duration recommendation is based on expert opinion due to lack of available data.

Ischemic and Bleeding Risk Evaluation

In order to help clinicians decide whether extended DAPT would be beneficial in an individual patient, the guidelines provide a scoring system to objectively measure the risk-benefit ratio of prolonged DAPT.¹ The factors and the scores associated with them as presented in the guideline are provided in Table 2. The DAPT score is calculated by adding up the points for the risk factors present. Scores ≥2 indicate that the benefits of prolonged DAPT may outweigh the risks; and scores <2 indicate that the risks of prolonged DAPT may outweigh the benefits.

Table 2. DAPT Score¹

Abbreviations: CHF=congestive heart failure; LVEF=left ventricular ejection fraction; MI=myocardial infarction; PCI=percutaneous coronary intervention.

Antiplatelet Therapy Choices

The guideline provides recommendations pertaining to which P2Y₁₂ inhibitor to choose based on the current available evidence.¹ In general, ticagrelor and prasugrel are more potent P2Y₁₂ inhibitors, but are also associated with a higher bleed risk.^9,10 Despite their increased potency, clopidogrel has more data for use in patients with PCI so it remains the first line P2Y₁₂ inhibitor in the majority of scenarios; clopidogrel is recommended in patients with SIDH after PCI or CABG and patients with ACS treated with thrombolytics.¹ In patients with ACS treated with PCI, enough evidence exists to support use of ticagrelor or prasugrel over clopidogrel. However, prasugrel should not be used in patients with prior history of stroke/transient ischemic attack due to an increased risk of intracranial hemorrhage. Lastly, ticagrelor is preferred over clopidogrel in patients with NSTE-ACS who were treated with medical therapy alone.

The guideline also endorses use of  aspirin doses ≤100 mg daily due to consistent data demonstrating lower bleeding risks with similar ischemic event protection compared to higher doses.¹ Specifically a daily aspirin dose between 75 mg and 100 mg is recommended.

Literature summary

As briefly discussed above, many randomized controlled trials  have evaluated ischemic, mortality, and bleeding outcomes in patients treated with varying durations of DAPT. A summary of these trials can be found in a previous UIC Drug Information Group FAQ from December 2015 here. Since publication of the December 2015 FAQ, one additional study has been published. The OPTIDUAL study sought to compare the effects of 48 months to 12 months of DAPT on net adverse clinical events in patients who had completed 12 months of DAPT after PCI with DES.¹¹ The authors defined net adverse clinical events as a composite outcome including all-cause mortality, non-fatal MI, stroke, or major bleeding. The primary outcome occurred at a rate of 5.8% in the prolonged DAPT group compared to 7.5% in the aspirin monotherapy group (hazard ratio, 0.75; 95% confidence interval [CI]: 0.5 to 1.28; p = 0.17) indicating no difference between groups for net adverse clinical events. However, it should be noted that due to slow enrollment, the OPTIDUAL trial was terminated early and thus was likely underpowered to detect a difference between groups.

Meta-analysis

The ACC/AHA task force conducted a meta-analysis in conjunction with the guideline development.¹² The meta-analysis included the results from 11 randomized controlled trials which compared either prolonged or shorter courses of DAPT after DES placement. There were a total of 33,051 patients enrolled in these 11 trials, the majority who received newer-generation DES. There was no difference in death, major hemorrhage, MI, or stent thrombosis when comparing DAPT for 12 months to DAPT for 3 to 6 months. However, the authors found that prolonged DAPT (18 to 48 months) was associated with decreased MI (odds ratio [OR], 0.67; 95% CI 0.47 to 0.95), decreased stent thrombosis (OR, 0.42; 95% CI, 0.24 to 0.74), but increased major hemorrhage (OR, 1.58; 95% CI, 1.2 to 2.09) compared to 6 to 12 months of DAPT. Additionally, this analysis aimed to determine whether DAPT for 18 to 48 months was associated with an increase in all-cause mortality compared to DAPT for 6 to 12 months. This was a significant analysis as an increase in all-cause mortality was reported in the DAPT trial, the largest study on prolonged DAPT to date.¹³ Thus, this meta-analysis aimed to answer whether the DAPT study result was a true or spurious finding. Unfortunately, the analysis reported conflicting results for this outcome.¹² When conducting a traditional, frequentist statistical approach, there was no difference in the rate of all-cause mortality found between groups (OR, 1.14; 95% CI, 0.92 to 1.42). However, analyzing the results using a Bayesian analysis, the authors reported that prolonged DAPT was likely associated with an increase in all-cause mortality (OR, 1.16; 95% Bayesian credible interval, 0.98 to 1.37; translated into a 95.7% probability that prolonged DAPT increases mortality with a 4.3% probability that there is no mortality difference). Lastly, the authors conducted a risk-benefit analysis and found that prolonged DAPT resulted in 3 fewer stent thromboses, 6 fewer MIs, and 5 more major bleeds per 1000 patients per year compared to standard 12 month therapy. Overall, the authors of the meta-analysis concluded that prolonging DAPT resulted in reduction of stent thrombosis and MI, but was complicated by more major bleeding. However, with the potential for increased all-cause mortality and the increasing safety of newer generation stents with less late stent thrombosis risk, the decision to prolong DAPT to 18 to 48 months must be considered carefully.

Conclusions

The 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients with Coronary Artery Disease introduces useful tools and recommendations to aid providers in making decisions regarding the optimal duration of DAPT for their patients.¹ The DAPT score provides an objective measure of patient specific risk factors regarding both ischemic and bleeding factors to help identify patients who may benefit from shorter or more prolonged durations of DAPT. It is clear from the recommendations made in these guidelines, that the decision to use shorter or longer duration DAPT is a patient specific decision that will be driven largely by a patient's risk factors for bleeding; and in those patients who are not at an increased bleeding risk, extended duration DAPT may be beneficial.

References

1. Levine GN, Bates ER, Bittl JA, et al. 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines [published online ahead of print March 23, 2016]. J Am Coll Cardiol. doi:10.1161/CIR.0000000000000404.
2. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. Circulation. 2011;124(23):e574-e651.
3. Navarese EP, Tandjung K, Claessen B, et al. Safety and efficacy outcomes of first and second generation durable polymer drug eluting stents and biodegradable polymer biolimus eluting stents in clinical practice: comprehensive network meta-analysis. BMJ. 2013;347:f6530.
4. Hillis LD, Smith PK, Anderson JL, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Developed in collaboration with the American Association for Thoracic Surgery, Society of Cardiovascular Anesthesiologists, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2011;58(24):e123-e210.
5. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2014;64(18):1929-1949.
6. O'Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;61(4):e78-e140.
7. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC guideline for the management of patients with non─ST-elevation acute coronary syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(24):e139-e228.
8. Fleisher LA, Fleischmann KE, Auerbach AD, et al. 2014 ACC/AHA guideline on perioperative cardiovascular evaluation and management of patients undergoing noncardiac surgery: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014;64(22):e77-e137. 
9. James SK, Roe MT, Cannon CP, et al; PLATO Study Group. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: a Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122(21):2131-2141.
10. Montalescot G, Wiviott SD, Braunwald E, et al; TRITON-TIMI investigators. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet. 2009;373(9665):723-731.
11. Helft G, Steg PG, Le Feuvre C, et al; OPTImal DUAL Antiplatelet Therapy Trial Investigators. Stopping or continuing clopidogrel 12 months after drug-eluting stent placement: the OPTIDUAL randomized trial. Eur Heart J. 2015;37(4):365-374.
12. Bittl JA, Baber U, Bradley SM, Wijeysundera DN. Duration of dual antiplatelet therapy: a systematic review for the 2016 ACC/AHA guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines [published online ahead of print March 22, 2016]. J Am Coll Cardiol. doi:0.1016/j.jacc.2016.03.512.
13. Mauri L, Kereiakes DJ, Yeh RW, et al; DAPT Study Investigators. Twelve or 30 months of dual-antiplatelet therapy after drug-eluting stents. N Engl J Med. 2014;371(23):2155-2166.

Prepared by:
Emily Kilber, PharmD
PGY1 Pharmacy Practice Resident
College of Pharmacy
University of Illinois at Chicago

June 2016

The information presented is current as April 20, 2016. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.