- Email: [email protected]
Prognostic indicators in venous ulcers
Prognostic indicators in venous ulcers Tania J. Phillips, MD,a Fidelis Machado, MD,b Richard Trout, PhD,c John Porter, MD,d Jeffrey Olin, MD,e Vincent Falanga, MD,a and The Venous Ulcer Study Group* Boston, Massachusetts; Princeton and Piscataway, New Jersey; Portland, Oregon; and Cleveland, Ohio Background: Venous ulcers can be difficult to heal, and prognostic factors for healing have not been fully elucidated. Objective: The objective of this study was to analyze the results of a large multicenter venous ulcer trial to retrospectively establish prognostic factors for venous ulcer healing. Methods: This study examined data from a previously published prospective randomized placebocontrolled trial of an oral medication versus placebo treatment for venous ulcers. Local leg ulcer care involved the use of a moisture-retentive dressing and sustained graduated compression with a paste bandage and a self-adherent wrap. The oral medication or placebo was administered on a daily basis with the same dressings and bandage system in both groups for 12 weeks. A total of 165 patients completed the full 12-week treatment period; 83 received ifetroban, 82 received placebo. Results: There was no statistically significant difference in outcome between the two groups. The study showed that consistent local ulcer treatment with a clearly defined system of care was associated with an unexpectedly high percentage (55%) of long-standing large venous ulcers (mean duration, 27 months; mean area, 15.9 cm2) being healed in both groups. Baseline ulcer area and duration of leg ulcer were found to be important in predicting outcome. Ulcers of short duration were found to be most likely to heal. Percent healing and ulcer area at week 3 were good predictors of 100% healing. Ulcers that had at least 40% healing by week 3 predicted more than 70% of the outcomes correctly. Conclusion: From this large study it was determined that baseline ulcer area and ulcer duration are significant predictors of 100% healing and time to heal. Percent healing and ulcer area at week 3 are good predictors of complete ulcer healing. Ulcers that are large, long-standing, and slow to heal after 3 weeks of optimal therapy are unlikely to heal rapidly, and might benefit from alternative therapies. (J Am Acad Dermatol 2000;43:627-30.)
T
reatment of chronic wounds is a difficult medical challenge that consumes significant health care resources.1 In the western world chronic venous insufficiency is the most common cause of leg ulcers.2 These ulcers are generally slow
From the Department of Dermatology, Boston University School of Medicinea; Convatec, Inc, Princetonb; statistical consultant, Piscatawayc; the Department of Vascular Surgery, Oregon Health Sciences Universityd; and the Department of Vascular Medicine, The Cleveland Clinic Foundation.e Sponsored by Bristol Myers Squibb, PRI. Accepted for publication March 28, 2000. Reprint requests: Fidelis Machado, MD, 200 Headquarters Park Dr, Skillman, NJ 08558. *Members of The Venous Ulcer Study Group are given at the end of this article. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107496 doi:10.1067/mjd.2000.107496
to heal and cause significant morbidity and impact on quality of life.2 Many new technologies are being explored for venous ulcer treatment3 that are especially helpful for difficult-to-heal ulcers.4 Prognostic indicators for ulcer healing are therefore important in helping to identify potentially slow healers who might benefit most from new treatment options. This study examined the data from a previously published clinical trial of a systemic agent (ifetroban) versus oral placebo plus optimal standards of local care in venous ulcers.5
MATERIAL AND METHODS This was a multicenter, double-blind, placebocontrolled, parallel group study. The inclusion criteria for the study included age older than or equal to 21 years and male subjects or postmenopausal or surgically sterile female subjects with one or more 627
628 Phillips et al
venous ulcers larger than 1 cm2 in area. A minimum ulcer duration of 2 months was required, and subjects were required to have no evidence of arterial insufficiency with an ankle brachial pressure index of greater than 0.8. Venous insufficiency was confirmed by duplex ultrasound or plethysmography. A total of 165 patients were randomized after a 4-week baseline observation period to receive placebo (n = 82) or oral medication (n = 83). Local management of the ulcer in both groups included providing a moist environment with a hydrocolloid dressing (DuoDerm CGF, Convatec) and sustaining graduated compression with an Unna boot (Unna Flex, ConvaTec) and a self-adherent wrap (Co-Flex). Highly exudative ulcers received a topical alginate dressing (Kaltostat), and wound cavities were filled with a hydrogel (DuoDerm Hydrogel, ConvaTec). Patients received the oral medication or placebo once a day for 12 weeks. During the study, wound progression was tracked by tracing the ulcer outline onto transparent sheets. Ulcer area was calculated by computerized planimetry by an independent laboratory. Potential prognostic indicators for ulcer healing were studied. These included gender, race, baseline ulcer area, duration of leg ulcer, ulcer location, skin condition, any symptom of infection, age, and compression compliance. The measures of ulcer healing that were examined were 100% healing of the target ulcer, time to healing of the target ulcer, and final area of the target ulcer. The data also analyzed the relationship between ulcer size and percent healing at week 3 with 100% healing of the target ulcer. Statistical methods The basic approach used with each of the measures of efficacy was the same. The initial phase of the analysis examined the possible effect of each prognostic variable on the efficacy variable. The final phase of the analysis examined the possible effect of the prognostic variables in a model including as many prognostic variables as were determined to be important. For each of these steps different statistical methods were used for each of the measures of efficacy. For 100% healing of the target ulcer, the first phase of the analysis was based on a chi-square analysis for the categoric variables and an ANOVA for the quantitative variables. The second phase of the analysis was based on a logistic regression model. For the time to healing of the target ulcer, the first phase of the analysis was based on life-table methods using both the log rank test and Wilcoxon test. The values for both tests are reported. For the second phase of the analysis, a Cox modeling approach was used. For the final area of the target ulcer, an ANCO-
J AM ACAD DERMATOL OCTOBER 2000
VA was used for all of the variables. An ANCOVA was used for the second phase of the analysis.
RESULTS There was no difference in healing rates between active therapy and placebo groups. In the placebo group, 54.4% healed, whereas 55.4% healed in the active medication group. These data have been reported previously.5 Patient demographics and ulcer baseline characteristics showed no statistically significant differences between placebo and the active therapy group. The data were therefore pooled and analyzed to look at possible prognostic indicators for ulcer healing in this protocol. Baseline variables including gender, race, ulcer location, skin conditions, infection, age, compression compliance, baseline ulcer area, and leg ulcer duration were assessed to determine their impact on 100% ulcer healing, time to complete healing, or area of the index ulcer at the end of the study. 100% Ulcer healing For the primary efficacy variable of 100% healing of the index ulcer, smaller baseline area and ulcers with a shorter duration were found to be more likely to heal. In subjects with baseline ulcer area of less than 5 cm2, 72% healed. In subjects with baseline ulcer area of greater than 5 cm2, 40% healed. Ulcer duration was another significant prognostic indicator. For ulcers of less than 1 year’s duration, 64% healed. For ulcers of duration between 1 and 3 years, 48% healed. However, with ulcers of greater than 3 years’ duration, only 24% healed. For ulcers that were 2 years or more in duration, the rate of 100% healing was reduced by approximately one half when compared with ulcers of a shorter duration. Time to healing For the variable of time to 100% healing of the index ulcer, ulcer location, baseline ulcer area, and duration of leg ulcer were found to be important in predicting this efficacy outcome. For ulcers of duration less than 1 year, the mean time to healing was 8.1 weeks. For ulcers of 1 to 3 years’ duration, mean time to healing was 8.4 weeks, and for ulcers greater than 3 years’ duration, mean time to healing was 10.9 weeks. For ulcers with baseline area of less than 5 cm2, mean time to healing was 7.5 weeks, whereas ulcers with baseline areas larger than 5 cm2 had mean time to healing of 9.8 weeks. Area of the index ulcer at the end of the study For this variable, compression compliance and baseline ulcer area were found to be important pre-
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
dictors. Subjects with smaller baseline area and higher percent compliance tended to have smaller wounds at the end of the study. Predictors of healing at 3 weeks Percent of healing (reduction in ulcer area) and ulcer area at week 3 were good predictors of complete ulcer healing. Using 44.1% healing at week 3 as the criteria, approximately 77% of the outcomes could be predicted correctly. This break point yielded the best predictability and maximized the overall prediction rate. Subject gender, race, age, skin condition, and infection had no prognostic implications.
DISCUSSION Adequate compression is regarded as the “gold standard” for venous ulcer treatment. What is the expected healing rate of venous ulcers with compression therapy? Nelzen, Bergqvist, and Lindhagen6 performed a 5-year prospective cohort study to determine prognosis of patients with chronic venous ulcers. They found that only 44% of patients with venous ulcers healed without recurrence. Moffat et al7 performed an uncontrolled study of 4-layer compression bandages in the treatment of venous ulcers. Overall, there was 69% healing at 12 weeks, but only 42% healing was achieved for ulcers larger than 10 cm2, and 57% healing was achieved for ulcers of longer than 6 months’ duration. Very small ulcers (0.1 cm2) of short duration (1 week) were included in this study and achieved a much higher healing rate. In another study of the same bandaging technique, of 438 patients with 514 ulcers, fewer than 30% of ulcers larger than 10 cm2 were healed by 12 weeks. For ulcers over 6 months in duration, approximately 22% were healed at 12 weeks.8 Fletcher, Cullum, and Sheldon9 recently performed a systematic review of compression treatment for venous ulcers. Twenty-four randomized controlled trials were reviewed, and it was found that many trials had inadequate sample size, poor methodology, and overall weak research evidence. It was concluded that high compression systems are more effective than low compression systems, but insufficient reliable evidence exists to indicate which compression system is the most effective. In our study, mean ulcer size was large (>14 cm2) with long ulcer duration (>27 months). In this group of difficult-to-heal ulcers, good local wound care and compression healed 55% of venous ulcers. Several groups have investigated prognostic factors for venous ulcer healing, but the majority of these studies have been based on fewer than 100 patients and lacked power. In concurrence with our data, Stewart and Leaper10 found that ulcer dura-
Phillips et al 629
tion and area correlated with healing. Kitka et al11 found a significant correlation with ulcer area, whereas in another study,12 no significant predictors were found. Our observations confirm the findings of Skene et al,13 who analyzed data from 200 patients with leg ulceration. They found that in the presence of graduated compression, healing occurred more rapidly in patients with a smaller initial ulcer area and brief duration of ulcer. Young patient age and absence of deep venous insufficiency were also good prognostic factors. Margolis, Berlin, and Strom14 also found that large wound area and long duration were indicators of a poor prognosis, along with history of venous surgery, hip or knee replacement, ankle brachial pressure index of less than 0.8, and fibrin present on more than 50% of the wound surface. Our data confirmed the above reports and showed that for patients with baseline ulcer area of less than 5 cm2, healing occurred in 72%. For patients with ulcers larger than 5 cm2, healing occurred in 40%. From our data and other reports, ulcer duration also correlates with healing. For ulcer duration up to 1 year, 65% healed completely, whereas ulcers with a duration of 1 to 2 years had a similar healing rate (61%). For ulcers with more than 2 years in duration, healing rates fell dramatically to 29% (23 years) and 24% (>3 years). Compression compliance was significantly related to outcome. It is known that compliance with compression treatment is critical in influencing venous ulcer healing as well as recurrence. Moffat et al7 reported a recurrence rate of one third of venous ulcers by 1 year, despite the use of compression hosiery in venous ulcer patients previously healed with multilayer compression bandages. Samson et al15 reported recurrence rates of 79% in venous ulcer patients who were not compliant with compression therapy versus only 4% recurrence in those who were compliant with the use of good compression stockings. A prospective study demonstrated that patients who complied with the treatment regimen had faster healing and fewer recurrent ulcers than did less compliant patients.16 A retrospective chart review of 113 patients older than 15 years showed that noncompliance with compression stockings significantly decreased initial ulcer healing (P < .0001). All patients who were noncompliant had recurrent ulceration by 36 months, whereas recurrence in compliant patients was only 15%.17 Is it possible to observe ulcers over a brief period of optimal therapy and predict which ones will heal? Several authors have attempted this using different parameters. Planimetric healing rates have been calculated by several groups by means of the Gilman
630 Phillips et al
formula: D = ∆A/P, where D = linear advance of the wound margin toward the wound center, ∆A = change in wound area, and P = average of the wound perimeter. Using this formula, the healing rate over 4 weeks could predict ulcer healing.18 Others have reported similar findings.18-20 Tallman et al21 modified the Gilman formula to calculate the mean adjusted healing rate over 3 weeks in 15 ulcers. This was predictive of ulcer healing. In a much larger study of 136 patients, baseline adjusted healing rates by 4 weeks helped to predict ulcer healing. Patients who achieved complete wound closure within 24 weeks had a mean initial heal rate of greater than 0.1 cm per week compared with less than 0.05 cm per week in nonhealers.22 In the present study, the percentage healing at week 3 was a good predictor of complete ulcer healing. With 44% healing at week 3 used as the criterion, approximately 77% of outcomes could be predicted correctly. This might be a helpful formula to predict ulcer outcome and perhaps to determine which ulcers might require more aggressive therapy. Another group reported that greater than 30% healing after 2 weeks of therapy with moist occlusive dressings and compression predicted healing.23 This study used a once-weekly office-based management of venous ulcers, which is inexpensive and produced a high healing rate of 55% in large, chronic venous ulcers. The identification of potentially slow healers using percentage healing at week 3 might justify more expensive therapeutic measures such as growth factors or skin substitutes. From this large study, it was determined that baseline ulcer area and leg ulcer duration are significant prognostic variables for 100% ulcer healing and time to healing. The percentage healing at week 3 was a good predictor of complete ulcer healing. Ulcers that are large, of long duration, and slow to heal after 3 to 4 weeks of optimal therapy might benefit from alternative therapeutic measures. The Venous Ulcer Study Group consisted of the following investigators: Donald Belsito, MD, John Blebea, MD, Lloyd Clever, DO, Anthony Comerota, MD, G. Richard Curl, MD, Herbert Dardik, MD, James Dennis, MD, Bo Eklof, MD, PhD, Vincent Falanga, MD, Duyen Faria, DO, Jay Fisher, MD, Thomas Garland, Jr, MD, David Gilespie, MD, Mitchell Goldman, MD, Adelaide Herbert, MD, James Hoballah, MD, John Hugill, MD, William Krupski, MD, Benjamin Levy, MD, Joann Lohr, MD, Mark Meissner, MD, James O. Menzoian, MD, William Mullcian, MD, Jeffrey Olin, MD, Louis Palo, MD, Tania Phillips, MD, John Porter, MD, John Ricotta, MD, Robert Scheinfeld, MD, Anton Sidawy, MD, Ronald Snyder, MD, Stephen Storfer, MD, Jonathon Towne, MD, Robert Weiss, MD, and Thomas Whitsett, MD.
J AM ACAD DERMATOL OCTOBER 2000
REFERENCES 1. Olin JW, Beusterein K, Childs MB, Seavey C, McHugh L, Griffiths RI. Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vasc Med 1999;4:1-7. 2. Phillips TJ, Dover JS. Leg ulcers. J Am Acad Dermatol 1991; 25:965-89. 3. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1997;134:293-300. 4. Phillips TJ. New skin for old: developments in biologic skin substitutes. Arch Dermatol 1998;134:344-9. 5. Lyon R, Veith FJ, Bolton L, Machado F, et al. Clinical benchmark for healing of chronic venous ulcers. Am J Surg 1998;178:172-5. 6. Nelzen O, Bergqvist D, Lindhagen A. Long-term prognosis for patients with chronic leg ulcers: a prospective cohort study. Eur J Vasc Endovasc Surg 1997;13:500-8. 7. Moffat CJ, Franks PJ, Olroyd M, et al. Community clinics for leg ulcers and impact on healing. Br Med J 1992;305:1389-92. 8. Thomson B, Hooper P, Powell R, Warin AP. Four layer bandaging and healing rates of venous leg ulcers. J Wound Care 1996;5: 213-6. 9. Fletcher A, Cullum N, Sheldon A. A systematic review of compression treatment for venous leg ulcers. Br Med J 1997;315:576-9. 10. Stewart AJ, Leaper DJ. Treatment of chronic ulcers in the community: a comparison of Scherinsorb and Iodosorb. Phlebology 1987;2:115-21. 11. Kikta MJ, Schuler JJ, Meyer JP, Durham TR, Eldrup-Jorgensen T, Schwarcz TH, et al. A prospective randomized trial of Unna’s boots vs hydroactive dressings in the treatment of venous stasis ulcers. J Vasc Surg 1988;7:478-83. 12. Colgan MP, Dormandy JA, Jones PW, et al. Oxypentifylline treatment of venous ulcers of the leg. Br Med J 1990;300:972-3. 13. Skene AI, Smith JM, Dore CJ, Charlett A, Lewis JD. Venous leg ulcers: a prognostic index to predict time to healing. Br Med J 1992;305:1119-21. 14. Margolis DJ, Berlin JA, Strom B. Risk factors associated with the failure of a venous ulcer to heal. Arch Dermatol 1999;135:920-6. 15. Samson RH, Showalter DP. Stockings in the prevention of recurrent venous ulcers. Dermatol Surg 1996;22:373-6. 16. Erickson CA, Lanza DJ, Karp DL, et al. Healing of venous ulcers in an ambulatory program: the role of chronic venous insufficiency and patient compliance. J Vasc Surg 1995;22:629-36. 17. Mayberry JC, Moneta GL, Taylor LM, Porter JM. Fifteen years’ results of ambulatory compression therapy. Surgery 1991;109: 575-81. 18. Margolis DM, Gress EA,Wood CR, Lazarus GS. Planimetric rate of healing in venous ulcers of the leg treated with pressure bandage and hydrocolloid dressing. J Am Acad Dermatol 1993; 28:418-21. 19. Percoraro RE, Ahroni JH, Boyko EJ, et al. Chronology and determinants of tissue repair in diabetic lower extremity ulcers. Diabetes 1991;40:1305-13. 20. Cordts PR, Hanrahan LM, Rodriguez AA, et al. A prospective randomized trial of Unna’s boot vs DuoDerm CGF plus compression in the management of venous leg ulcers. J Vasc Surg 1992;15:480-6. 21. Tallman P, Muscare E, Carson P, Eaglstein W, Falanga V. Initial rate of healing predicts complete healing of venous ulcers. Arch Dermatol 1997;133:1231-4. 22. Sabolinski M, Falanga V. Heal rates at four weeks in venous ulcers treated with compression predict complete healing by 24 weeks [abstract]. American Academy of Dermatology, 57th Annual Meeting, March 19-24, 1999, New Orleans, LA. 23. VanRijswijk L and the Multicenter Leg Ulcer Study Group. Fullthickness leg ulcers: patient demographics and predictors of healing. J Fam Pract 1993;36:625-32.
T
reatment of chronic wounds is a difficult medical challenge that consumes significant health care resources.1 In the western world chronic venous insufficiency is the most common cause of leg ulcers.2 These ulcers are generally slow
From the Department of Dermatology, Boston University School of Medicinea; Convatec, Inc, Princetonb; statistical consultant, Piscatawayc; the Department of Vascular Surgery, Oregon Health Sciences Universityd; and the Department of Vascular Medicine, The Cleveland Clinic Foundation.e Sponsored by Bristol Myers Squibb, PRI. Accepted for publication March 28, 2000. Reprint requests: Fidelis Machado, MD, 200 Headquarters Park Dr, Skillman, NJ 08558. *Members of The Venous Ulcer Study Group are given at the end of this article. Copyright © 2000 by the American Academy of Dermatology, Inc. 0190-9622/2000/$12.00 + 0 16/1/107496 doi:10.1067/mjd.2000.107496
to heal and cause significant morbidity and impact on quality of life.2 Many new technologies are being explored for venous ulcer treatment3 that are especially helpful for difficult-to-heal ulcers.4 Prognostic indicators for ulcer healing are therefore important in helping to identify potentially slow healers who might benefit most from new treatment options. This study examined the data from a previously published clinical trial of a systemic agent (ifetroban) versus oral placebo plus optimal standards of local care in venous ulcers.5
MATERIAL AND METHODS This was a multicenter, double-blind, placebocontrolled, parallel group study. The inclusion criteria for the study included age older than or equal to 21 years and male subjects or postmenopausal or surgically sterile female subjects with one or more 627
628 Phillips et al
venous ulcers larger than 1 cm2 in area. A minimum ulcer duration of 2 months was required, and subjects were required to have no evidence of arterial insufficiency with an ankle brachial pressure index of greater than 0.8. Venous insufficiency was confirmed by duplex ultrasound or plethysmography. A total of 165 patients were randomized after a 4-week baseline observation period to receive placebo (n = 82) or oral medication (n = 83). Local management of the ulcer in both groups included providing a moist environment with a hydrocolloid dressing (DuoDerm CGF, Convatec) and sustaining graduated compression with an Unna boot (Unna Flex, ConvaTec) and a self-adherent wrap (Co-Flex). Highly exudative ulcers received a topical alginate dressing (Kaltostat), and wound cavities were filled with a hydrogel (DuoDerm Hydrogel, ConvaTec). Patients received the oral medication or placebo once a day for 12 weeks. During the study, wound progression was tracked by tracing the ulcer outline onto transparent sheets. Ulcer area was calculated by computerized planimetry by an independent laboratory. Potential prognostic indicators for ulcer healing were studied. These included gender, race, baseline ulcer area, duration of leg ulcer, ulcer location, skin condition, any symptom of infection, age, and compression compliance. The measures of ulcer healing that were examined were 100% healing of the target ulcer, time to healing of the target ulcer, and final area of the target ulcer. The data also analyzed the relationship between ulcer size and percent healing at week 3 with 100% healing of the target ulcer. Statistical methods The basic approach used with each of the measures of efficacy was the same. The initial phase of the analysis examined the possible effect of each prognostic variable on the efficacy variable. The final phase of the analysis examined the possible effect of the prognostic variables in a model including as many prognostic variables as were determined to be important. For each of these steps different statistical methods were used for each of the measures of efficacy. For 100% healing of the target ulcer, the first phase of the analysis was based on a chi-square analysis for the categoric variables and an ANOVA for the quantitative variables. The second phase of the analysis was based on a logistic regression model. For the time to healing of the target ulcer, the first phase of the analysis was based on life-table methods using both the log rank test and Wilcoxon test. The values for both tests are reported. For the second phase of the analysis, a Cox modeling approach was used. For the final area of the target ulcer, an ANCO-
J AM ACAD DERMATOL OCTOBER 2000
VA was used for all of the variables. An ANCOVA was used for the second phase of the analysis.
RESULTS There was no difference in healing rates between active therapy and placebo groups. In the placebo group, 54.4% healed, whereas 55.4% healed in the active medication group. These data have been reported previously.5 Patient demographics and ulcer baseline characteristics showed no statistically significant differences between placebo and the active therapy group. The data were therefore pooled and analyzed to look at possible prognostic indicators for ulcer healing in this protocol. Baseline variables including gender, race, ulcer location, skin conditions, infection, age, compression compliance, baseline ulcer area, and leg ulcer duration were assessed to determine their impact on 100% ulcer healing, time to complete healing, or area of the index ulcer at the end of the study. 100% Ulcer healing For the primary efficacy variable of 100% healing of the index ulcer, smaller baseline area and ulcers with a shorter duration were found to be more likely to heal. In subjects with baseline ulcer area of less than 5 cm2, 72% healed. In subjects with baseline ulcer area of greater than 5 cm2, 40% healed. Ulcer duration was another significant prognostic indicator. For ulcers of less than 1 year’s duration, 64% healed. For ulcers of duration between 1 and 3 years, 48% healed. However, with ulcers of greater than 3 years’ duration, only 24% healed. For ulcers that were 2 years or more in duration, the rate of 100% healing was reduced by approximately one half when compared with ulcers of a shorter duration. Time to healing For the variable of time to 100% healing of the index ulcer, ulcer location, baseline ulcer area, and duration of leg ulcer were found to be important in predicting this efficacy outcome. For ulcers of duration less than 1 year, the mean time to healing was 8.1 weeks. For ulcers of 1 to 3 years’ duration, mean time to healing was 8.4 weeks, and for ulcers greater than 3 years’ duration, mean time to healing was 10.9 weeks. For ulcers with baseline area of less than 5 cm2, mean time to healing was 7.5 weeks, whereas ulcers with baseline areas larger than 5 cm2 had mean time to healing of 9.8 weeks. Area of the index ulcer at the end of the study For this variable, compression compliance and baseline ulcer area were found to be important pre-
J AM ACAD DERMATOL VOLUME 43, NUMBER 4
dictors. Subjects with smaller baseline area and higher percent compliance tended to have smaller wounds at the end of the study. Predictors of healing at 3 weeks Percent of healing (reduction in ulcer area) and ulcer area at week 3 were good predictors of complete ulcer healing. Using 44.1% healing at week 3 as the criteria, approximately 77% of the outcomes could be predicted correctly. This break point yielded the best predictability and maximized the overall prediction rate. Subject gender, race, age, skin condition, and infection had no prognostic implications.
DISCUSSION Adequate compression is regarded as the “gold standard” for venous ulcer treatment. What is the expected healing rate of venous ulcers with compression therapy? Nelzen, Bergqvist, and Lindhagen6 performed a 5-year prospective cohort study to determine prognosis of patients with chronic venous ulcers. They found that only 44% of patients with venous ulcers healed without recurrence. Moffat et al7 performed an uncontrolled study of 4-layer compression bandages in the treatment of venous ulcers. Overall, there was 69% healing at 12 weeks, but only 42% healing was achieved for ulcers larger than 10 cm2, and 57% healing was achieved for ulcers of longer than 6 months’ duration. Very small ulcers (0.1 cm2) of short duration (1 week) were included in this study and achieved a much higher healing rate. In another study of the same bandaging technique, of 438 patients with 514 ulcers, fewer than 30% of ulcers larger than 10 cm2 were healed by 12 weeks. For ulcers over 6 months in duration, approximately 22% were healed at 12 weeks.8 Fletcher, Cullum, and Sheldon9 recently performed a systematic review of compression treatment for venous ulcers. Twenty-four randomized controlled trials were reviewed, and it was found that many trials had inadequate sample size, poor methodology, and overall weak research evidence. It was concluded that high compression systems are more effective than low compression systems, but insufficient reliable evidence exists to indicate which compression system is the most effective. In our study, mean ulcer size was large (>14 cm2) with long ulcer duration (>27 months). In this group of difficult-to-heal ulcers, good local wound care and compression healed 55% of venous ulcers. Several groups have investigated prognostic factors for venous ulcer healing, but the majority of these studies have been based on fewer than 100 patients and lacked power. In concurrence with our data, Stewart and Leaper10 found that ulcer dura-
Phillips et al 629
tion and area correlated with healing. Kitka et al11 found a significant correlation with ulcer area, whereas in another study,12 no significant predictors were found. Our observations confirm the findings of Skene et al,13 who analyzed data from 200 patients with leg ulceration. They found that in the presence of graduated compression, healing occurred more rapidly in patients with a smaller initial ulcer area and brief duration of ulcer. Young patient age and absence of deep venous insufficiency were also good prognostic factors. Margolis, Berlin, and Strom14 also found that large wound area and long duration were indicators of a poor prognosis, along with history of venous surgery, hip or knee replacement, ankle brachial pressure index of less than 0.8, and fibrin present on more than 50% of the wound surface. Our data confirmed the above reports and showed that for patients with baseline ulcer area of less than 5 cm2, healing occurred in 72%. For patients with ulcers larger than 5 cm2, healing occurred in 40%. From our data and other reports, ulcer duration also correlates with healing. For ulcer duration up to 1 year, 65% healed completely, whereas ulcers with a duration of 1 to 2 years had a similar healing rate (61%). For ulcers with more than 2 years in duration, healing rates fell dramatically to 29% (23 years) and 24% (>3 years). Compression compliance was significantly related to outcome. It is known that compliance with compression treatment is critical in influencing venous ulcer healing as well as recurrence. Moffat et al7 reported a recurrence rate of one third of venous ulcers by 1 year, despite the use of compression hosiery in venous ulcer patients previously healed with multilayer compression bandages. Samson et al15 reported recurrence rates of 79% in venous ulcer patients who were not compliant with compression therapy versus only 4% recurrence in those who were compliant with the use of good compression stockings. A prospective study demonstrated that patients who complied with the treatment regimen had faster healing and fewer recurrent ulcers than did less compliant patients.16 A retrospective chart review of 113 patients older than 15 years showed that noncompliance with compression stockings significantly decreased initial ulcer healing (P < .0001). All patients who were noncompliant had recurrent ulceration by 36 months, whereas recurrence in compliant patients was only 15%.17 Is it possible to observe ulcers over a brief period of optimal therapy and predict which ones will heal? Several authors have attempted this using different parameters. Planimetric healing rates have been calculated by several groups by means of the Gilman
630 Phillips et al
formula: D = ∆A/P, where D = linear advance of the wound margin toward the wound center, ∆A = change in wound area, and P = average of the wound perimeter. Using this formula, the healing rate over 4 weeks could predict ulcer healing.18 Others have reported similar findings.18-20 Tallman et al21 modified the Gilman formula to calculate the mean adjusted healing rate over 3 weeks in 15 ulcers. This was predictive of ulcer healing. In a much larger study of 136 patients, baseline adjusted healing rates by 4 weeks helped to predict ulcer healing. Patients who achieved complete wound closure within 24 weeks had a mean initial heal rate of greater than 0.1 cm per week compared with less than 0.05 cm per week in nonhealers.22 In the present study, the percentage healing at week 3 was a good predictor of complete ulcer healing. With 44% healing at week 3 used as the criterion, approximately 77% of outcomes could be predicted correctly. This might be a helpful formula to predict ulcer outcome and perhaps to determine which ulcers might require more aggressive therapy. Another group reported that greater than 30% healing after 2 weeks of therapy with moist occlusive dressings and compression predicted healing.23 This study used a once-weekly office-based management of venous ulcers, which is inexpensive and produced a high healing rate of 55% in large, chronic venous ulcers. The identification of potentially slow healers using percentage healing at week 3 might justify more expensive therapeutic measures such as growth factors or skin substitutes. From this large study, it was determined that baseline ulcer area and leg ulcer duration are significant prognostic variables for 100% ulcer healing and time to healing. The percentage healing at week 3 was a good predictor of complete ulcer healing. Ulcers that are large, of long duration, and slow to heal after 3 to 4 weeks of optimal therapy might benefit from alternative therapeutic measures. The Venous Ulcer Study Group consisted of the following investigators: Donald Belsito, MD, John Blebea, MD, Lloyd Clever, DO, Anthony Comerota, MD, G. Richard Curl, MD, Herbert Dardik, MD, James Dennis, MD, Bo Eklof, MD, PhD, Vincent Falanga, MD, Duyen Faria, DO, Jay Fisher, MD, Thomas Garland, Jr, MD, David Gilespie, MD, Mitchell Goldman, MD, Adelaide Herbert, MD, James Hoballah, MD, John Hugill, MD, William Krupski, MD, Benjamin Levy, MD, Joann Lohr, MD, Mark Meissner, MD, James O. Menzoian, MD, William Mullcian, MD, Jeffrey Olin, MD, Louis Palo, MD, Tania Phillips, MD, John Porter, MD, John Ricotta, MD, Robert Scheinfeld, MD, Anton Sidawy, MD, Ronald Snyder, MD, Stephen Storfer, MD, Jonathon Towne, MD, Robert Weiss, MD, and Thomas Whitsett, MD.
J AM ACAD DERMATOL OCTOBER 2000
REFERENCES 1. Olin JW, Beusterein K, Childs MB, Seavey C, McHugh L, Griffiths RI. Medical costs of treating venous stasis ulcers: evidence from a retrospective cohort study. Vasc Med 1999;4:1-7. 2. Phillips TJ, Dover JS. Leg ulcers. J Am Acad Dermatol 1991; 25:965-89. 3. Falanga V, Margolis D, Alvarez O, et al. Rapid healing of venous ulcers and lack of clinical rejection with an allogeneic cultured human skin equivalent. Arch Dermatol 1997;134:293-300. 4. Phillips TJ. New skin for old: developments in biologic skin substitutes. Arch Dermatol 1998;134:344-9. 5. Lyon R, Veith FJ, Bolton L, Machado F, et al. Clinical benchmark for healing of chronic venous ulcers. Am J Surg 1998;178:172-5. 6. Nelzen O, Bergqvist D, Lindhagen A. Long-term prognosis for patients with chronic leg ulcers: a prospective cohort study. Eur J Vasc Endovasc Surg 1997;13:500-8. 7. Moffat CJ, Franks PJ, Olroyd M, et al. Community clinics for leg ulcers and impact on healing. Br Med J 1992;305:1389-92. 8. Thomson B, Hooper P, Powell R, Warin AP. Four layer bandaging and healing rates of venous leg ulcers. J Wound Care 1996;5: 213-6. 9. Fletcher A, Cullum N, Sheldon A. A systematic review of compression treatment for venous leg ulcers. Br Med J 1997;315:576-9. 10. Stewart AJ, Leaper DJ. Treatment of chronic ulcers in the community: a comparison of Scherinsorb and Iodosorb. Phlebology 1987;2:115-21. 11. Kikta MJ, Schuler JJ, Meyer JP, Durham TR, Eldrup-Jorgensen T, Schwarcz TH, et al. A prospective randomized trial of Unna’s boots vs hydroactive dressings in the treatment of venous stasis ulcers. J Vasc Surg 1988;7:478-83. 12. Colgan MP, Dormandy JA, Jones PW, et al. Oxypentifylline treatment of venous ulcers of the leg. Br Med J 1990;300:972-3. 13. Skene AI, Smith JM, Dore CJ, Charlett A, Lewis JD. Venous leg ulcers: a prognostic index to predict time to healing. Br Med J 1992;305:1119-21. 14. Margolis DJ, Berlin JA, Strom B. Risk factors associated with the failure of a venous ulcer to heal. Arch Dermatol 1999;135:920-6. 15. Samson RH, Showalter DP. Stockings in the prevention of recurrent venous ulcers. Dermatol Surg 1996;22:373-6. 16. Erickson CA, Lanza DJ, Karp DL, et al. Healing of venous ulcers in an ambulatory program: the role of chronic venous insufficiency and patient compliance. J Vasc Surg 1995;22:629-36. 17. Mayberry JC, Moneta GL, Taylor LM, Porter JM. Fifteen years’ results of ambulatory compression therapy. Surgery 1991;109: 575-81. 18. Margolis DM, Gress EA,Wood CR, Lazarus GS. Planimetric rate of healing in venous ulcers of the leg treated with pressure bandage and hydrocolloid dressing. J Am Acad Dermatol 1993; 28:418-21. 19. Percoraro RE, Ahroni JH, Boyko EJ, et al. Chronology and determinants of tissue repair in diabetic lower extremity ulcers. Diabetes 1991;40:1305-13. 20. Cordts PR, Hanrahan LM, Rodriguez AA, et al. A prospective randomized trial of Unna’s boot vs DuoDerm CGF plus compression in the management of venous leg ulcers. J Vasc Surg 1992;15:480-6. 21. Tallman P, Muscare E, Carson P, Eaglstein W, Falanga V. Initial rate of healing predicts complete healing of venous ulcers. Arch Dermatol 1997;133:1231-4. 22. Sabolinski M, Falanga V. Heal rates at four weeks in venous ulcers treated with compression predict complete healing by 24 weeks [abstract]. American Academy of Dermatology, 57th Annual Meeting, March 19-24, 1999, New Orleans, LA. 23. VanRijswijk L and the Multicenter Leg Ulcer Study Group. Fullthickness leg ulcers: patient demographics and predictors of healing. J Fam Pract 1993;36:625-32.