Successful Treatment of Recalcitrant, Diabetic Heel Ulcers with Topical
Becaplermin (rhPDGF-BB) Gel

Introduction Diabetic foot ulceration is a major complication of diabetes mellitus.1–5 Among the 10 to 15 million diabetic patients, two to three percent will develop foot ulcers each year, and approximately 15 percent will develop foot ulcers during their lifetimes.4,6–8 The four percent of the US population with diagnosed diabetes mellitus constitute 46 percent of the approximately 162,500 annual hospitalizations for foot ulcers.4,7 Foot ulcers precede 85 percent of all nontraumatic, lower-limb amputations, and half of all nontraumatic, lower-limb amputations in the US are performed in persons with diabetes.2,7,9,10 It is estimated that patients with diabetes mellitus have as much as a 30- to 40-times higher risk of lower-limb amputations compared to the nondiabetic population.8 The costs attendant with the large numbers of diabetic foot ulcers and amputations are staggering. The average cost for a single episode of a foot ulcer has been reported to be $4,595.00.7,11 The costs for treating foot ulcers can amount to $1.2 billion annually, excluding the costs of surgery, rehabilitation, prostheses, and lost income.8 The average costs for revascularization surgery or amputation can approach $40,000.00 per patient.8 In addition, diabetic patients who require lower-limb amputations are at great risk for requiring amputation of the contralateral limbs in less than two years.12 Heel ulcers may be considered to have the poorest prognosis among diabetic foot ulcers. Edmonds, et al., reported that heel ulcers tend to be ischemic and that these ischemic heel ulcers heal less than 50 percent of the time.13 This is compared to a 86-percent healing rate when ischemia was not present and a 74-percent healing rate when ischemia was present in ulcers other than on the heel. Although the forefoot ulcer in the diabetic patient is usually of neuropathic etiology, heel ulcers are more likely to have a mixed neuropathic and ischemic etiology. Atherosclerosis has a predilection for different vessels in diabetic patients versus nondiabetic patients. The tibial and peroneal arteries are more likely to be involved, while the dorsalis pedis and plantar arteries are frequently spared.7,14 This puts the heel at risk for decreased perfusion. Also, the footpad under the heel can become atrophied in people with neuropathy, reducing the heel’s cushioning ability.14,15 Recent advances in the treatment of diabetic foot ulcers have occurred. The use of topically applied recombinant growth factors or bioengineered dressings has increased the healing rates of foot ulcers. Becaplermin (rhPDGF-BB) and recombinant transforming growth factor beta-2 (rhTGF-b2) have been reported to improve healing rates in neuropathic diabetic foot ulcers.16–18 Two bioengineered skin substitutes have also shown the ability to accelerate healing of diabetic foot ulcers.19,20 However, there are inherent problems when applying these new therapies to the heel ulcer. It is difficult to maintain a skin substitute dressing in place on the convex heel without shearing occurring. The biology of topically applied growth factors may be impaired if the heel ulcer has a significant degree of ischemia. The only recombinant growth factor approved by the United States Food and Drug Administration for the treatment of diabetic foot ulcers is becaplermin (rhPDGF-BB)*. Wu, et al., demonstrated that PDGF receptors are markedly decreased in ischemic wounds.21 They also showed that in young animals with ischemic wounds, topical PDGF did not reverse wound healing deficits. Later work from the same laboratory suggested that topically applied TGF-b1 failed to stimulate wound healing in an aged ischemic ulcer model.22 Because of these theoretical considerations, several recent clinical trials of topically applied growth factors have been limited to forefoot neuropathic ulcers, excluding heel ulcers. The purpose of this study was to evaluate the usefulness of becaplermin (rhPDGF-BB) in the treatment of a series of recalcitrant diabetic heel ulcers. Methods Ten patients (9 men, 1 woman) with a mean age of 71 years (range 51–83) presented to the multidisciplinary wound service with diabetic heel ulcers. The ulcers had been present from 39 to 296 days (mean 125 days). All patients had significant diabetic neuropathy. Five patients had end-stage renal disease, and four patients were receiving dialysis. The HbA1c was less than nine percent for all patients. When ankle brachial indices (ABI) were less than 0.8 or either pedal pulse was absent, arteriography and vascular consultation were obtained (7/10). We have found toe pressures and TcpO2 to be unreliable prognosticators in patients with heel ulcers. Revascularization procedures to the posterior tibial artery were performed on three patients, three patients were determined not to be reconstructible, and one patient refused vascular reconstruction. Patients who were either postvascular reconstruction or were not candidates for reconstruction and had persistent heel ulcers were treated in the following manner. Pressure relief to the heel area was obtained with offloading by means of orthotic devices or total weight relief with crutches or wheelchair usage. Wounds were sharply debrided and brought into bacterial balance (105 or fewer bacteria/gram of tissue and no b-hemolytic streptococci) with the use of topical antimicrobials.23 Any clinical suspicion of osteomyelitis was ruled out by a negative bone biopsy. Following debridement, the wounds were photographed, the perimeter traced, and wound areas measured by digital planimetry. All 10 patients were treated with topical becaplermin (rhPDGF-BB) daily. The medication was applied by the patient or home healthcare provider in the morning and left in place for 12 hours. After 12 hours, a normal saline-soaked (0.9% NaCl) gauze was placed on the ulcer for 12 hours. Patients remained as outpatients throughout their treatment periods and were seen in the clinic at weekly intervals. Repeat debridement of necrotic tissue and/or excessive callus was performed as necessary. Ulcer photographs and tracings were performed monthly during clinic visits. The patients were followed to complete healing (100% wound closure). Once healed, offloading was converted to orthotic shoes. Results Eight of the ten patients’ heel ulcers completely healed, i.e., achieved 100-percent wound closure (Figures 1A–D) (Table 1). The time to healing was 13 days to four months. One patient failed to heal secondary to failure to comply with the offloading regimen and repetitive trauma to the ulcer site. The remaining patient in the series died secondary to renal and hepatic failure unrelated to his ulcer or ulcer treatment. At the time of his death, his ulcer had decreased 98 percent in area. The eight patients were followed since healing from one month to twenty-one months (mean 8 months) without recurrence of their heel ulcers. Discussion Foot ulceration in the patient with diabetes mellitus is a serious problem. More hospital beds are occupied by diabetic patients with foot ulceration than those with all the other complications of diabetes put together.13 Diabetic ulcers of the heel may be the most severe of diabetic ulcers. Although Apelquist, et al., report that heel ulcers can heal as well as those in other locations, this has not been the case in most series.24 The problem is the heel ulcer not only has the neuropathy attendant with most diabetic foot ulcers, but usually has a degree of ischemia as well.14 The ischemia not only plays a role in the etiology of the heel ulcer, but once the ulcer has formed, the blood supply necessary to heal it is several times more than the blood supply necessary for intact skin.14 Because of the role of ischemia both in the etiology and impaired healing of the diabetic heel ulcer, treatment of these ulcers has been difficult. Vascular reconstruction, when feasible, should be the primary therapeutic modality. Three of our patients had reconstruction but had persistent heel ulcers. Local or regional flap reconstruction can be used if the blood supply is adequate.25 More often, some type of amputation is required. Although these can be successfully limited in ulcers of the forefoot, most often major amputations are required for infected, gangrenous heel ulcers. If the problem is limited and sufficient skin is available for closure, partial calcanectomy is an option.8 Forefoot surgery usually leads to rehabilitation, while heel surgery more often leads to limb loss and significant functional disability.8 Cevera, et al., have stated that although a transmetatarsal amputation is a usable functional amputation, man cannot function without his heel.8 Since patients in this series did not have osteomyelitis in the calcaneus, partial calcanectomy was not performed, and election was made to maintain the heel. The discovery and approval of a topical growth factor for the treatment of diabetic foot ulcers was a giant step in decreasing the morbidity of these lesions. This advance of medical, nonoperative treatment is particularly valuable in ill patients, such as those with end-stage renal disease. The concern that it may not be effective in ischemic ulcers, such as diabetic heel ulcers, was real, based on experimental data.21,22 This series, although small, suggests that becaplermin (rhPDGF-BB) can be effective in treating diabetic heel ulcers. It promoted total healing of the ulcers and allowed the healing to remain intact for periods of up to 21 months. Although vascular reconstruction should always be performed when feasible in patients with heel ulcers, total healing may not always occur postreconstruction. In three of our patients, the ulcer persisted after vascular reconstruction, but responded to topical growth factor treatment. Based on our experience, it appears that topical becaplermin (rhPDGF-BB) can be a successful treatment for diabetic heel ulcers.