Hypertrophic scars and keloids are dermal fibroproliferative disorders unique to humans. They are a common occurrence following burns, trauma, inflammation, or surgery, but sometimes occur spontaneously.1 Lawrence et al2 reported hypertrophic scar development is common after a burn, with an incidence of up to 77%. The presence of hypertrophic scars and keloids varies with age, race, sex, anatomic location, and the inciting trauma. They are associated with further physical and psychological consequences such as restricted range of motion and contracture,3–5 which could lead to pruritus, disfigurement, pain, elevated anxiety levels, and lower quality of life.6–9 These scars are typically assessed using the Vancouver Scar Scale (VSS), which covers four parameters: height, pliability, vascularity, and pigmentation.10
Since the 1970s, pressure therapy has been used for both prophylaxis and treatment of hypertrophic scars and keloids. Subsequently, a variety of nonsurgical and surgical treatment modalities for hypertrophic scars and keloids have been developed. Nonsurgical modalities include silicone-based products, intralesional triamcinolone acetonide (TAC) injection, cryotherapy, intralesional verapamil, lasers, intralesional antimitotic drugs, radiotherapy, immunomodulators, onion extracts, and botulinum toxin A.11 Despite advancements, hypertrophic scars and keloids remain a difficult challenge for clinicians.
Locally injected TAC is the criterion standard in the management of keloids and second-line therapy for the management of hypertrophic scars.12,13 Typically, insoluble TAC (at a concentration of 10-40 mg/mL) is injected at 3- to 6-week intervals. The TAC may improve scar pliability, diminish scar volume and height, and reduce scar-related itching and pain by suppressing inflammatory cell migration and inhibiting fibroblast proliferation. However, it has a high frequency of adverse drug reactions (up to 63%) such as skin atrophy, telangiectasias, hypopigmentation, injection pain, ineffectiveness, and rebound effects.14
In contrast, verapamil is a calcium-channel blocker with in vitro antifibrotic activity that has been shown to decrease extracellular matrix production in scars and depolymerize actin filaments to modify fibroblast morphology with a consequent increased secretion of procollagenase.15–17 Sporadic reports have demonstrated positive effects of verapamil for keloid and hypertrophic scar treatment, but these studies were uncontrolled and had a limited number of participants. Verapamil may have fewer adverse drug reactions compared with TAC, allowing a longer treatment period and the possibility that it might be effective for patients who cannot receive TAC.18–20
With this in mind, the study authors conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to compare the efficacy and safety of intralesional verapamil with intralesional TAC for treating keloids and hypertrophic scars using VSS, symptom change, and adverse effects as primary outcomes.
This systematic review and meta-analysis is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement and was registered at International Prospective Register of Systematic Reviews (no. CRD42018109155).
The study authors selected relevant studies published through September 2018 by searching MEDLINE (via PubMed), EMBASE, Cochrane Library, and the China National Knowledge Infrastructure databases. Literature written in English and Chinese was considered. Studies were eligible for inclusion if they were RCTs done in patients with keloids and hypertrophic scars; compared intralesional verapamil to intralesional TAC; had at least 18 weeks’ duration of intervention; and reported VSS, symptom changes, and/or adverse effects as outcomes. There was no restriction on treatment history. An 18-week study duration was chosen to observe the long-term effects of the interventions.
The following Medical Subject Headings keywords with Boolean operators were used: “Keloid” OR “Keloids”; “Cicatrix, Hypertrophic” OR “Cicatrices, Hypertrophic” OR “Hypertrophic Cicatrices” OR “Hypertrophic Cicatrix” OR “Scars, Hypertrophic” OR “Hypertrophic Scar” OR “Hypertrophic Scars” OR “Scar, Hypertrophic”; “Verapamil” OR “Iproveratril” OR “Cordilox” OR “Dexverapamil” OR “Verapamil Hydrochloride” OR “Hydrochloride, Verapamil” OR “Finoptin” OR “Izoptin” OR “Isoptine” OR “Isoptin” OR “Lekoptin” OR “Calan” OR “Falicard;” and “Triamcinolone Acetonide” OR “Acetonide, Triamcinolone” OR “Cinonide” OR “Tricort-40” OR “Tricort 40” OR “Tricort40” OR “Kenalog” OR “Kenalog 40” OR “Azmacort” OR “Kenacort A.” These search strategies retrieved different records that were combined with the Boolean operator “AND” to obtain the first round of records.
The bibliographies of related systematic reviews and clinical guidelines were searched, as were the references for each identified study. The authors also did a manual search using the reference lists of key articles published in English and in the Chinese databases of journals, dissertations, and magazines for related articles.
Two independent investigators reviewed study titles and abstracts, and studies that satisfied the inclusion criteria were retrieved for full-text assessment. Trials selected for detailed analysis and data extraction were analyzed by two investigators with an agreement value (ĸ) of 96.5%; disagreements were resolved by a third investigator.
The risk of bias in each included study was assessed by two review authors independently according to the Cochrane Handbook for Systematic Reviews of Interventions based on seven items: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. Different opinions were resolved by discussion with a third author. Further, for disagreements regarding risk-of-bias judgments, discussion was conducted until a consensus was reached.
Data Extraction and Analysis
Independent variables included publication year, country of publication, type of assessment, age of participants, ratio of men and women, number of patients in each group, follow-up period, therapeutic regimen, and VSS scores such as scar pigmentation, vascularity, pliability, and height. Researchers also extracted the total numbers of participants with symptom improvement or adverse effects. Although the trials identified were all 18 weeks or longer, different articles chose different time points for data collection, and 3 weeks was the only observation point common to all articles; therefore, these observations are discussed in the results.
The study authors analyzed VSS scores as continuous variables and reported absolute differences between arithmetic means for verapamil treatment and intralesional TAC treatment. The authors calculated an overall odds ratio (OR) to analyze the proportion of participants with symptom changes and/or adverse effects. They also calculated pooled estimates of the mean differences (MDs) and corresponding 95% confidence intervals (CIs) in VSS scores between the two treatments using a random-effects model (DerSimonian-Laird method) to account for the additional uncertainty associated with interstudy variability in the effect of the two drugs. For categorical outcomes, investigators calculated the pooled estimates of the OR and 95% CI with a random-effects model. This comparison represented the most important clinical question pertaining to the role of intralesional verapamil treatment and reduced the heterogeneity of the treatment-induced changes in outcomes in the comparator arm seen in the overall analysis.
The ORs, MD, and 95% CIs were calculated with Review Manager version 5.3 (The Cochrane Collaboration, Copenhagen, Denmark). The I2 test for heterogeneity and random-effects model were applied, and P < .05 was considered to indicate statistical significance.
The study authors identified 40 studies, including 10 from PubMed, 14 from EMBASE, 7 from the Cochrane Library, and 9 from the China National Knowledge Infrastructure database; 8 duplicate studies were removed. During the title and abstract screen, 25 studies were excluded because they did not meet the inclusion criteria, and the remaining 7 articles were retrieved for full-text review. Three studies missing data were also excluded. Ultimately, four trials published between 2008 and 2018 were included (Table).21–24
Vancouver Scar Scale Scores
Three trials21–23 compared verapamil with TAC using the VSS broken down by scar height, pliability, vascularity, and pigmentation. The fourth (Qu et al24) did not list the four parameters separately and was excluded in the assessment of these outcomes.
The meta-analysis of three trials for measures of scar height demonstrated significant heterogeneity (I2 = 95%, P < .00001). The pooled result from the random-effects model did not demonstrate significant differences in scar height between the verapamil group and the TAC group at 3 weeks (MD, 0.30; 95% CI, −0.22 to 0.83; Figure 1A). Further, if research from Abedini et al23 is excluded, the meta-analysis of the other two trials21,22 did not demonstrate significant heterogeneity (I2 = 0%, P = .81) or significant differences between the verapamil group and the TAC group (MD, 0.05; 95% CI, −0.10 to 0.21).
This outcome demonstrated statistically significant heterogeneity (I2 = 96%, P < .00001). The results showed a statistically significant difference in scar pliability; the effects of TAC were superior to the effect of verapamil at 3 weeks (MD, 0.72; 95% CI, 0.02–1.43; Figure 1B). However, if Abedini et al23 is excluded, the meta-analysis of the remaining two trials21,22 did not demonstrate significant heterogeneity (I2 = 48%, P = .17) for measures of scar pliability and showed similar outcomes between the verapamil group and the TAC group (MD, 0.37; 95% CI, 0.13–0.61).
The statistical heterogeneity for this variable was not significant (I2 = 0%, P = .99), but there was a statistically significant difference between the verapamil group and the TAC group at 3 weeks (MD, 0.21; 95% CI, 0.08–0.35; Figure 1C) in favor of TAC.
The statistical heterogeneity for this variable was significant (I2 = 54%, P = .11), but there was no statistical difference between verapamil and TAC at 3 weeks (MD, 0.05; 95% CI, -0.14–0.25; Figure 1D).
Margaret Shanthi et al21 and Ahuja and Chatterjee22 did not use symptom change as an outcome and were excluded from these results. The effects of therapy on symptoms such as pruritus, pain, and burning were extracted from the remaining two studies,23,24 and the statistical heterogeneity was significant (I2 = 67%, P = .08). Compared with the TAC group, symptom change in the verapamil group was not significantly different (OR, 1.18; 95% CI, 0.12–11.55; Figure 2).
Three trials22–24 evaluated adverse effects, including pain, telangiectasia, and skin atrophy, to measure the safety of verapamil versus TAC for keloids and hypertrophic scars. However, Margaret Shanthi et al21 did not mention the adverse effects, and that study was excluded from this portion of the results.
The random-effects pooled results did not demonstrate differences between the verapamil group and the TAC group with regard to pain during treatment procedures (OR, 3.25; 95% CI, 0.28–37.89; Figure 3A). The analysis demonstrated significant heterogeneity (I2 = 87%, P = .0003). However, if the study of Abedini et al23 is excluded, the meta-analysis of the remaining two trials22,24 did not demonstrate significant heterogeneity (I2 = 0%, P = .82); both concluded there was similar pain incidence between the verapamil group and the TAC group (OR, 0.99; 95% CI, 0.29–3.42).
The random-effects pooled results did not demonstrate differences between the verapamil group and the TAC group regarding telangiectasia experienced during treatment procedures (OR, 0.19; 95% CI, 0.01–3.27; Figure 3B).
The results showed that patients have a lower risk of skin atrophy with verapamil versus TAC treatment (OR, 0.08; 95% CI, 0.01–0.46; Figure 3C).
Assessment of Risk of Bias of the Included Studies
The risk of bias in the included studies is shown in Figure 4. The studies included a number of methodological limitations. Because verapamil and TAC have different physical properties (TAC is an oily emulsion, whereas verapamil is a plain-colored solution), information on allocation concealment was not detailed, permitting bias.
The study results show that intralesional TAC is more effective than intralesional verapamil in improving scar pliability and vascularity in keloids and hypertrophic scars after 3 weeks of treatment (Figures 1–3). However, adverse drug reactions are more frequent with intralesional TAC than with intralesional verapamil. As such, these data support intralesional verapamil treatment as an alternative to TAC in treating keloids and hypertrophic scars.
Further, the between-study heterogeneity for scar height, pliability, and pain is reassuring. This likely reflected the differences in the region or nationality of the study facilities. In addition, it also likely reflected the differences in study design, including the paired split-scar design, with each patient being his/her own control. Abedini et al23 appeared to be the main source of heterogeneity in this meta-analysis.
This review can only comment on the short-term effects of the two drugs. One literature review not included in this analysis demonstrated that verapamil is not as effective as TAC in preventing keloid recurrence.25 Interestingly, Kant et al26 explored the efficacy and potential synergetic effects of combined TAC and verapamil for the treatment of hypertrophic and keloid scars. This retrospective study revealed that combined therapy resulted in significant overall scar improvement with a long-term stable result.26
None of the studies included in the current review included the mechanism of these two drugs. However, a Chinese study showed that verapamil could also prohibit proliferative scars by inhibiting transforming growth factor β1 and inducing apoptosis. Although the effect of verapamil in inducing apoptosis was stronger than TAC in that study, its ability to inhibit transforming growth factor β1 expression was weaker than TAC.27 Yang et al28 reported that verapamil inhibited hypertrophic scars in a dose-dependent manner through the quantitative gene expressions of decorin and collagenase.28
This analysis should be interpreted in light of its limitations, most of which are related to the original trials. First, in the majority of the included studies, the risk of bias was moderate. The overall trial quality was reduced because of a lack of concealed allocation or double-blind study designs. Second, the authors cannot comment on the long-term control of the scar tendency to hypertrophy because of these studies’ limited period of observation. Third, all studies included in the current review lacked a control group, which limits some conclusions about the effects of intralesional verapamil in keloids and hypertrophic scars. However, it was likely not possible to include control groups in the design of these studies because ethically, scars should be treated early. Finally, intralesional injections can be supplemented with silicone or even paper tape to increase their clinical effectiveness, which was not considered in this analysis.29
This study presents limited evidence from four individual RCTs that TAC is more effective than verapamil in improving scar pliability and vascularity in keloids and hypertrophic scars after 3 weeks of treatment. However, verapamil has fewer adverse drug reactions compared with TAC, allowing for a longer treatment period and the possibility of effectiveness in patients who cannot receive TAC. Studies with a longer follow-up period and those investigating the combination of verapamil with other therapeutic methods could be considered to better understand the treatment efficacy of verapamil for keloids and hypertrophic scars in the short and long term.
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