A Closer Look At The Evidence For Using Regranex
As I get my practice ready to compete in the upcoming years of the Merit-based Incentive Payment System (MIPS) and Medicare Access and CHIP Reauthorization Act (MACRA), I am reviewing the evidence of treatment protocols and products I use to heal lower extremity wounds. I am evaluating the products for the strength of evidence and cost, not just of the product but the cost to deliver the care (to the patient, insurance plan, my office, etc.) In other words, I’m looking at the cost to the entire system.
I won’t belabor the point on the number of patients with diabetes and the cost of amputations from a financial and human standpoint because we all have heard this repeatedly. There is evidence that shows that patients whose wounds do not heal, have a subsequent infection and end up with an amputation have a 30 to 50 percent mortality rate within a three- to five-year period.1 This information scares me personally as many of my family members and over 50 percent of my patients I see every day have diabetes.
I know the discussions that DPMs have when a wound continues to fail to respond to the treatment plan that they have initiated. The first comment I hear is how the patient is “non-compliant” or, in today’s language, “non-adherent.” I truly believe that most patients whom clinicians deem “non-complaint” don’t have a mean bone in their body and don’t set out to aggravate their doctor. I have found after interviewing patients a little more closely and with an open heart and mind, that patients have what they feel are legitimate reasons for their inability to do what you want them to do. We may need to find alternative and “out of the box” answers to their roadblocks. Often, I can find a solution that allows the patient to be more adherent.
So what does the previous discussion have to do with Regranex (Smith and Nephew)? One of the solutions to allowing patient to be more adherent is to close the wound faster. From my own personal experience with the medical system in the past year with my husband’s medical condition, solving the medical problem quickly allows people to return to their very busy lives. It also reduces the stress the entire family is experiencing when their loved one constantly has to visit doctors, needing procedures and needing constant medical care.
Until very recently, there were only three products on the market with Food and Drug Administration (FDA) approval with level 1 evidence in the world of wound healing. These are Regranex, Apligraf (Organogenesis) and Dermagraft (Organogenesis). More recently, Omnigraft (Integra LifeSciences) received an FDA approved indiation for diabetic foot ulcers.
Regranex Gel is the first and only FDA-approved recombinant platelet-derived growth factor (PDGF). As the package insert notes, Regranex Gel, 0.01% contains becaplermin, a human PDGF that is indicated for the treatment of lower extremity diabetic neuropathic ulcers that extend into the subcutaneous tissue or beyond, and have an adequate blood supply.2 Regranex Gel is indicated as an adjunct to and not a substitute for good ulcer care practices.
Regranex works at all phases of the wound healing cascade to promote chronic wound healing. Platelet-derived growth factor (PDFG) attracts macrophages and polymorphonuclear neutrophils in the initial phase of wound healing to remove necrotic or non-viable tissue. Then PDGF works to stimulate fibroblast proliferation to increase granulation tissue, increase the rate of reepithelialization and revascularization, and promote collagen production through the wound healing process.
You may have heard about the boxed warning issued with Regranex in 2008. However, if you review the boxed warning carefully, it does not indicate that Regranex causes cancer. It states there is an increased rate of mortality secondary to malignancy observed in patients treated with three or more tubes of Regranex Gel in a postmarketing retrospective cohort study (called the i3 Study), which was requested by a European Medicines Agency (EMA).3 The i3 Study failed to observe any increased risk for the incidence of cancer but did note the increased mortality when patients used three or more tubes. The FDA noted this evidence but was not persuaded to remove or modify the boxed warning.
Clinicians should consider Regranex Gel use based on benefits versus risks. One should not use it in patients with known malignancy, even at a site not near the wound, and should definitely not use it at the wound site. To date, no published data indicates the use of Regranex will have a direct carcinogenic effect.
A larger study evaluating cancer risk and the use of Regranex Gel in U.S. veterans with diabetes was recently completed.4 However, the details of the study have yet to be published.
In a recent study, Gilligan and colleagues found that patients treated with becaplermin and good wound care had substantially more closed wound weeks in comparison with good wound care alone (16.1 versus 12.5 weeks respectively).5 More patients receiving Regranex had healed wounds at one year in comparison with those receiving good wound care alone (48.1 percent versus 38.3 percent). The risk of amputation was lower in the Regranex cohort (6.8 percent versus 9.8 percent). The expected annual direct costs for diabetic foot ulcers (DFU) were $21,920 for those treated with Regranex and $24,640 for those treated with good wound care alone. Authors found Regranex to be “economically dominant” over good wound care alone, providing better outcomes at a lower cost in patients with DFUs.
Regranex does not have a time window for use and one can use it at the initial presentation of DFUs. In contrast, one can only use Apligraf for DFUs (that extend through the dermis without tendon, muscle, capsule or bone exposure) after three weeks of standard care have failed.2,6
I believe all of us who take care of chronic wounds feel that advanced therapies may be more beneficial when we start treatment earlier for those patients who are already at risk for developing chronic wounds. Accordingly, Regranex appears to be positioned to help us to start the healing process on wounds that meet the stated indications at an earlier time than other biologics.
As we prepare to be judged and paid by our outcomes, it may behoove us all to review the literature and re-evaluate our treatment protocols we have adopted.
Instead of the famous saying from the Jerry McGuire movie (“Show me the money!”), my anthem to the reps that visit my office is now “Show me the evidence.” It may improve the care I deliver and the outcomes I can get for my patients who have honored me by trusting me to take care of their wound(s).
References
1. Sen CK, Gordillo GM, Roy S, et al. Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regen. 2009; 17(6):763–71.
2. Regranex package insert, Smith and Nephew.
3. Ziyadeh N, Fife D, Walker AM, et al. A matched cohort study of the risk of cancer in users of becaplermin. Adv Skin Wound Care. 2011; 24(1):31–9.
4. Becaplermin use and cancer risk in a patient population of US veterans with diabetes. Available at https://clinicaltrials.gov/ct2/show/NCT01235260 .
5. Gilligan AM, Waycaster CR, Motley TA. Cost-effectiveness of becaplermin gel on wound healing of diabetic foot ulcers. Wound Repair Regen. 2015;23(3):353-60.
6. Apligraf package insert, Organogenesis.
