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Evaluation of Resource Utilization and Treatment Patterns in Patients with Actinic Keratosis in the United States
VALUE IN HEALTH 19 (2016) 239–248
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Evaluation of Resource Utilization and Treatment Patterns in Patients with Actinic Keratosis in the United States Carl V. Asche, PhD1,2,*, Panagiotis Zografos, MS3, Jenny M. Norlin, PhD4, Bill Urbanek, MS3, Carl Mamay, BS, MBA3, Charles Makin, BSPharm, MS, MBA, MM5, Sandra Erntoft, PhD4, Chi-Chang Chen, MsPharm, PhD5, Dionne M. Hines, MPH, PhD5, Daniel Mark Siegel, MD, MS6,7 1
Center for Outcomes Research and the Department of Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA; Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA; 3 LEO Pharma, Inc., Parsippany, NJ, USA; 4LEO Pharma A/S, Ballerup, DK; 5IMS Health, RWE-HEOR Plymouth Meeting, PA, USA; 6 Department of Dermatology, SUNY Downstate, Brooklyn, NY, USA; 7Long Island Skin Cancer and Dermatologic Surgery, a division of ProHealthCare Associates, Smithtown, NY, USA 2
AB STR A CT
Objective: To compare health care resource utilization and treatment patterns between patients with actinic keratosis (AK) treated with ingenol mebutate gel (IngMeb) and those treated with other fielddirected AK therapies. Methods: A retrospective, propensity-score– matched, cohort study compared refill/repeat and adding-on/switching patterns and outpatient visits and prescriptions (health care resource utilization) over 6 months in patients receiving IngMeb versus those receiving imiquimod, 5-fluorouracil, diclofenac sodium, and methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT). Results: The final sample analyzed included four matched treatment cohort pairs (IngMeb and comparator; n ¼ 790–971 per treatment arm). Refill rates were similar except for imiquimod (15% vs. 9% for imiquimod and IngMeb, respectively; P o 0.05). MAL/ALA-PDT treatment repetition rates were higher than IngMeb refill rates (20% vs. 10%; P o 0.05). Topical agent add-on/ switch rates were comparable. PDT had higher switch rates than did IngMeb (5% vs. 2%; P o 0.05). The IngMeb cohort had a significantly lower proportion of patients with at least one AK-related outpatient
visit during the 6-month follow-up than did any other cohort: versus imiquimod (50% vs. 66%; P o 0.0001), versus 5-fluorouracil (50% vs. 69%; P o 0.0001), versus diclofenac sodium (51% vs. 56%; P ¼ 0.034), and versus MAL/ALA-PDT (50% vs. 100%; P o 0.0001). There were significantly fewer AK-related prescriptions among patients receiving IngMeb than among patients in other cohorts. Conclusions: Results based on the first 6 months after treatment initiation suggested that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with higher refill rates, and PDT, which was associated with significantly more frequent treatment sessions and higher switching rates. IngMeb was also associated with significantly fewer outpatient visits than were other field-directed therapies. Keywords: actinic keratosis, health care resource utilization, treatment patterns.
Introduction
range between 11% and 26% [4,11]. Among persons 40 years or older in Australia, the prevalence has been estimated to be up to 60% [11]. Clinically, AK may appear as a single lesion, as multiple lesions, or as field cancerization [1,4,5,12]. Field cancerization refers to an affected area that involves visible as well as nonvisible subclinical lesions [13–15]. At present, three approaches are used to treat AK: lesion-directed treatments, field-directed treatments, or a combination of both [4,16]. Cryosurgery with liquid nitrogen is the most commonly used treatment. Cryosurgery may efficiently treat single lesion, but it fails to treat field cancerization and has high recurrence rates. Thus, it is often used in combination with other treatment modalities [16]. Although lesion-directed treatments may be simple and quick, they may be painful and may leave permanent
Actinic keratoses (AK) are keratotic cutaneous lesions that may progress to invasive squamous cell carcinoma (SCC). AK lesions commonly occur in sun-exposed skin, such as on the head, neck, hands, and lower legs [1–3]. Risk factors for AK include fair skin, older age, baldness, immunodeficiency, and high cumulative ultraviolet radiation exposure [4–6]. AK is a common skin condition whose incidence is increasing [4]. There are few population-based studies of AK prevalence, and estimates vary widely [5,7–10]. Differences are likely due to variations in ultraviolet exposure, risk factors of included populations, and the methods used to estimate the prevalence. In the United States, the prevalence of AK has been estimated to
& 2016 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
* Address correspondence to: Carl V. Asche, Center for Outcomes Research, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61656. E-mail: [email protected]. 1098-3015$36.00 – see front matter & 2016 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR). http://dx.doi.org/10.1016/j.jval.2015.11.014
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scars or dyspigmented areas [4,17–19]. Field-directed therapies, including patient-applied topical agents and photodynamic therapy (PDT), target visible lesions as well as the surrounding fieldcancerized area with subclinical lesions [20]. Although PDT is highly effective and minimally invasive, it may be very painful for patients. Furthermore, the high cost of photosensitizing topical agents used with PDT and the need for multiple administrations make it relatively costly and time-consuming [4]. Patient-applied topical field therapies are starting to be more widely used as physicians increasingly recognize the importance of field cancerization when selecting treatment. Multiple agents are available including 5% or 0.5% fluorouracil (5-FU) topical, 3% diclofenac sodium (diclofenac), 5% or 2.5% or 3.75% imiquimod (imiquimod). Although all these agents have been shown to be effective in achieving therapeutic goals, they have drawbacks including long treatment times, photosensitivity, pain, severe erythema, and inflammation [4]. 5-FU is to be applied once or twice daily for 2 to 4 weeks. Imiquimod 5% is applied twice weekly for 16 weeks or 3 times a week for shorter periods, whereas the 2.5% and 3.75% formulations are used daily for 2 weeks with a 2-week rest period followed by a repeat 2-week treatment cycle. Diclofenac requires a twice-daily application for 60 to 90 days [4,16]. Lengthy dosing durations of treatments have been associated with high nonpersistence and nonadherence rates in patients with AK [21], which may affect the real-world effectiveness negatively. Reasons for early discontinuation may be related to the treatment being too time-consuming, too expensive, or causing a severe reaction [16]. Treatment and follow-up of AK represents a substantial burden in dermatological health care because AK lesions are common and have the potential to progress to SCC [5,18,22,23]. Because it is not possible to predict which lesions will progress to malignancy, most guidelines and consensus reports recommend that all AKs be treated [1,4,5,7,24–26]. It is estimated that AK treatment annually accounts for $1.2 billion in direct health care spending in the United States, primarily driven by office visits and associated procedures, which constitute 92% of direct costs [27]. Few studies have focused on the costs of AK treatments available at present [24,28–33]. New therapies continue to emerge in this rapidly evolving area of dermatology. Goals for this next generation of AK therapies include shortening dosing duration and dosing frequency, increasing tolerability (i.e., reducing adverse effects), and maintaining high efficacy and acceptable associated costs [4,23]. Ingenol mebutate gel (IngMeb) is approved for the topical fielddirected treatment of AK lesions. Compared with other topical agents that require daily applications for weeks or months, IngMeb has a significantly shorter dosing duration of treatment (2 or 3 days). Furthermore, studies suggest that IngMeb has a positive risk/benefit profile—producing well-defined adverse events (AEs) for a short treatment duration compared with other available topical agents [16,34]. Randomized clinical trials show the efficacy and safety of topical agents in AK treatment. Studies about the real-world usage of IngMeb and comparators are however limited. The objective of this study was to compare real-world treatment and health care resource utilization (HRU) between patients with AK treated with IngMeb and patients treated with other field therapies, including prescription refills, switching/augmenting to other AK therapies, and follow-up physician visits during a 6-month postindex period.
Methods This retrospective cohort study was designed to compare treatment patterns and HRU in US adults who received IngMeb for AK
with treatment patterns and HRU in those receiving imiquimod, 5-FU, diclofenac, or methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT). The study used data from the IMS PharMetrics (Plymouth Meeting, PA, USA) health insurance claims database drawn from July 1, 2011, to June 30, 2013. The database captures pharmacy and medical claims for more than 75 million patients from 96 health plans across the United States. Database records were generally representative of the commercially insured US population. Approval from an institutional review board and informed patient consent were not required because data were de-identified and certified to be compliant with the Health Insurance Portability and Accountability Act of 1996. The patient selection period was from January 1, 2012, to December 31, 2012. Index therapy was defined as the first AK treatment of interest observed during the patient selection period, and the date of the first prescription fill for index therapy served as the index date. Baseline patient characteristics were established using data from the 6-month preindex period, and outcomes were assessed during the 6-month postindex period. Patients selected to be in the study population had to meet each of the following inclusion criteria: had received AK treatment (more than one prescription fill for a topical agent of interest or had evidence of MAL/ALA-PDT or cryosurgery) during the selection period; evidence of one or more AK diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification code 702.0) preindex; were 18 years of age or older on the index date; and were continuously enrolled in a health insurance plan for 6 months or more preindex and 6 months or more postindex. Patients meeting any of the following criteria were excluded from the study: younger than 18 years; pregnancy during the study period; evidence of using topical AK therapies or MAL/ALA-PDT in the preindex period; evidence of cryosurgery more than 4 weeks preindex; evidence of more than one AK therapy on the index date (except cryosurgery); or evidence of basal cell carcinoma or squamous cell carcinoma (SCC) during the preindex period. Patients with basal cell carcinoma were excluded because some included therapies that may have been used to treat these conditions and it was necessary to ensure that prescribed therapies were directed at AK lesions. Patients with SCC were excluded to ensure that patients had similar severity levels, because SCC is associated with severe AK. Patients who received field-directed therapy were assigned to one of five mutually exclusive treatment cohorts: IngMeb, imiquimod, 5-FU, diclofenac, or MAL/ALA-PDT (cryosurgery-only patients were not included in the present analysis). Patients were matched with propensity scores to ensure comparability within the cohorts (described later). Baseline combination cryosurgery (defined as receipt of cryosurgery within 4 weeks preindex or 2 weeks postindex) was permitted. As with other study patients, the index date for combination therapy patients was defined as the date of the first prescription fill for a topical AK agent. Outcomes included the following: the proportion of patients refilling the index therapy; time from index therapy to the first refill of the index therapy; proportion of patients adding or switching topical agents in the follow-up period (only the first switch postindex was considered and additional switches were not assessed); time from index date to initiation of a second topical agent; proportion of patients receiving cryosurgery beyond 2 weeks after index therapy with a topical agent (receipt of cryosurgery within 2 weeks after index topical treatment was considered combination therapy); and time from index treatment to subsequent cryosurgery beyond the first 2 weeks after treatment initiation. For purposes of this study, the first follow-up visit after index treatment was assumed to be a routine progress check and subsequent follow-up visits indicated inadequate treatment response. Switching to, or adding, another topical
VALUE IN HEALTH 19 (2016) 239–248
agent or initiating MAL/ALA-PDT after index topical agent might indicate that the AK lesion was not cleared by the initial therapy. Overall AK-attributable HRU for each treatment cohort was assessed over the 6-month postindex period. HRU was considered to be related to AK if it was associated with AK diagnosis, treatment, or management of AK treatment–related AE. Variables of interest for assessing HRU were AK-related outpatient visits (proportion of patients with one or more physician visits and total number of physician visits) and AK-related pharmacy prescriptions (total number of prescriptions filled for index therapy and total number of prescriptions filled for other medications related to AK management including AEs associated with treatment). Medications for AK-related AEs included painkillers, topical steroids, emollient or lipid-barrier creams, and silver sulfadiazine. These medications were considered attributable to an AK-related AE if they were administered during the overall index treatment period or within 2 weeks after completion of index treatment. The overall treatment period for each cohort was determined by the total days’ supply of filled index therapy prescriptions plus an allowed 2-week gap between prescriptions. Propensity score matching was used to balance the patients’ demographic and clinical characteristics between the cohorts. The IngMeb cohort served as the control to which other cohorts were matched on a one-to-one basis and compared [35,36]. Data on variables for the propensity score models were collected during the preindex period and included age, sex, physician specialty, health plan payer type, health plan product type, geographic region, Charlson comorbidity index score (Dartmouth-Manitoba adaptation), preindex total health care costs, time since AK diagnosis, and combination therapy with cryosurgery during the preindex 4-week period to the postindex 2-week period [37,38]. Patients were matched by their propensity scores using the nearest neighborwithin-caliper method. The resulting matched groups for comparison were as follows: IngMeb versus imiquimod, IngMeb versus 5FU, IngMeb versus diclofenac, and IngMeb versus MAL/ALA-PDT. The matched groups were used for all outcome analyses (unsuccessfully matched patients were excluded from analyses). Descriptive data were produced for the aggregate study population and each treatment cohort. Categorical measures were presented as the frequency and percentage of total patients in each category. Continuous variables were presented as the mean ⫾ SD and median. Statistically significant differences between patient strata were estimated using P values (o0.05) from chi-square or Fisher exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Kaplan-Meier survival analyses were used to compare time to therapy switch/augmentation or a second follow-up visit (whichever occurred first) between AK therapies. Those who did not experience one of these events were censored at the end of follow-up. Log-rank tests were used for comparisons. Cox proportional hazard models were constructed to evaluate any differences in the risk for augmenting/switching therapy or having a second follow-up visit between IngMeb and the comparator therapies. The risk of switching/augmenting therapy or having a second follow-up visit was evaluated using adjusted hazard ratios (HRs) with 95% confidence intervals as estimated by the Cox proportional hazards model. The main effect was AK treatment (IngMeb vs. comparison treatment), and independent variables included age, sex, geographic region, comorbidities, Charlson comorbidity index score, time from AK diagnosis to treatment initiation, cryosurgery at index date, and preindex total health care costs [37]. Baseline characteristics retained in the predictive models after stepwise selection (using a 0.25 significance criterion) included age, sex, geographic region, presence of comorbid lipid disorders, Charlson comorbidity index score, time from diagnosis to treatment initiation, use of topical agent plus cryosurgery (combination therapy) at index date, and preindex total health care costs.
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Results The database yielded 668,327 names of patients who had received at least one AK therapy (including topical agents, PDT, or cryosurgery) between January 1, 2012, and December 31, 2012. After applying inclusion and exclusion criteria, 39.7% of the patients remained in the unmatched sample, of whom 985 had received IngMeb (Fig. 1). Steps producing the greatest sample attrition included requiring an AK diagnosis in the preindex period (20% eroded) and requiring continuous health plan enrollment in the preindex and postindex periods (34% eroded). The most commonly prescribed topical AK treatment was 5-FU (3.6%). Many patients received combination therapy (cryosurgery in addition to another treatment) at index date, ranging from 26% of patients receiving MAL/ALA-PDT to 49% of patients receiving diclofenac. Patients who received only cryosurgery (93.4%) were not included in the analysis presented here, but were retained for a separate analysis. The four matched treatment cohort pairs (IngMeb and comparator) are presented in Table 1. The mean age of patients in all matched treatment cohorts was approximately 57 years, and men comprised more than 50% of each group. Nearly half the patients in each treatment cohort resided in the south (Z47%), and most were covered by a commercial preferred provider organization health plan (Z98%) (Table 1). For all matched cohorts, the most prevalent comorbidity was skin disorders (Z28%; common conditions included dyschromia, chronic dermatitis, eczema, rosacea, etc.) as dermatologists (Z75%) were the most frequently visited physician (Table 1). Most patients (Z62%) in the matched treatment cohorts received treatment for AK within 7 days of diagnosis (Table 1). Refill rates for index therapy were similar between IngMeb and other topical agents except imiquimod, which had a significantly higher refill rate than did IngMeb (15% vs. 9%; P o 0.05) (Table 2). IngMeb refill rates were also significantly lower than repeat administration of PDT (10% vs. 20%; P o 0.05) (Table 2). Refill rates for 5-FU and diclofenac were not significantly different from those of IngMeb (Table 2). Time-to-first refill comparisons revealed shorter refill times for IngMeb than for other therapies. Among patients with refill, the median time to first refill for IngMeb was 20 to 21 days, whereas for other cohorts it ranged from 30 to 55 days. Overall, few patients added or switched to topical agents during the first 6 months after index treatment (Table 2). More patients receiving MAL/ALA-PDT switched to a topical agent than did matched subjects receiving IngMeb (5% vs. 2%; P ¼ 0.01). No differences in proportions of patients adding or switching topical agents were found between IngMeb and the other topical agents except 5-FU. Fewer patients receiving 5-FU added or switched topical agents than did matched subjects receiving IngMeb, but sample sizes were small (n ¼ 6 vs. n ¼ 22). Among patients who added or switched to a topical agent, the median time to add/ switch ranged from 55 to 58 days for patients receiving IngMeb at index date to 58 to 90 days for those receiving other therapies. Across the matched treatment cohorts, 31% to 42% of patients received combination cryosurgery at baseline (i.e., cryosurgery in addition to index therapy). The proportions of patients receiving add-on cryosurgery in the postindex period were similar between patients receiving IngMeb and the matched topical cohorts and ranged from 15% to 17% (Table 2). Patients receiving IngMeb, however, showed significantly less add-on cryosurgery than did matched patients receiving MAL/ALA-PDT (25% vs. 17%; P o 0.0001). Among patients who added cryosurgery, the median time to add-on ranged from approximately 2 months (54–63 days) for patients receiving IngMeb or MAL/ALA-PDT to approximately 3 months (86–95 days) for patients receiving other topical agents.
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Total Paents with AK therapy (topical agents, PDT or cryosurgery) N = 668,327 (100%)
Unmatched Sample Aer Inclusion/Exclusion Criteria N = 265,093 (39.7%)
Unmatched Topical agent/PDT Cohorts IngMeb n = 985 (0.4%) 5 Fluorouracil n = 9,415 (3.6%) Imiquimod n = 3,036 (1.1%) Diclofenac n = 1,151 (0.4 %) MAL/ALA-PDT n = 2,984 (1.1 %)
1:1 Propensity Score Matched Treatment Cohorts IngMeb vs. Imiquimod n = 952 (96.6%) IngMeb vs. 5 Fluorouracil n = 982 (99.7%) IngMeb vs. Diclofenac n= 790 (80.2%) IngMeb vs. MAL/ALA-PDT n = 882 (89.5%)
*Paents who received cryosurgery only (n = 247,522) were not included in the analysis presented in this paper, but were retained for a separate analysis; IngMeb = Ingenol Mebutate gel; 5-FU = 5-Fluorouracil; 5% imiquimod and 2.5% or 3.75% imiquimod; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acid-photodynamic therapy
Fig. 1 – Patient population attrition during study sample selection. Patients who received cryosurgery only (n ¼ 247,522) were not included in the analysis presented in this article, but were retained for a separate analysis. AK, actinic keratosis; diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
The proportions of patients receiving topical agents who added MAL/ALA-PDT in the postindex period were very low (r1%) but were similar across cohorts. The first office visit after receiving index therapy was assumed to be a routine follow-up visit for treatment evaluation. Overall, most of the patients (Z52%) did not have a follow-up visit during the study period; patients receiving MAL/ALA-PDT had the highest rate of follow-up office visit during the 6 months (48%). Among patients who made a follow-up visit, the median time to this first visit was significantly shorter for patients receiving IngMeb than for those receiving imiquimod (35 vs. 55 days; P o 0.0001) or diclofenac (35 vs. 83 days; P o 0.0001). Overall, few patients receiving topical treatments for AK returned for a second physician visit during the postindex follow-up period. The proportions of patients with a second visit were similar between IngMeb and all other topical agents (6%– 9%). A relatively high proportion (17%) of patients receiving MAL/ ALA-PDT at the index visit returned for second visits (Table 2). The median time from the index visit to the second visit, among those who made at least two visits, was similar among cohorts except for patients receiving IngMeb versus diclofenac (70 vs. 104 days; P ¼ 0.002). Kaplan-Meier curves for time to therapy augmentation/switch or a second follow-up visit (whichever occurred first) were evaluated for each therapy of interest and compared with those for IngMeb (Fig. 2). No differences in the cumulative probabilities of these events were observed between IngMeb and the other topical agents, with approximately 8% of patients in each group adding/switching topical agents or having a second physician visit during follow-up (Fig. 2). Nevertheless, augmentation/switch or a second follow-up visit occurred significantly less often among patients receiving IngMeb than among the matched cohorts receiving MAL/ALA-PDT (8% vs. 19%; P o 0.0001) (Fig. 2). The risk of these events occurring in patients receiving IngMeb was no different than for the three other topical agents of interest: imiquimod (HR 0.97; P ¼ 0.836), 5-FU (HR 0.90; P ¼ 0.491), and diclofenac (HR 1.03; P ¼ 0.873). Patients receiving
IngMeb, however, had a 59% lower risk of experiencing one of these events than did patients receiving MAL/ALA-PDT. Factors that were significantly associated with the risk of augmenting/ switching therapy or having a second follow-up visit in patients receiving MAL/ALA-PDT were as follows: Midwest residence versus Northeast residence (HR 1.77; P ¼ 0.006) and delaying treatment for more than 1 week after diagnosis (HR 1.45; P ¼ 0.005). The mean number of AK-related outpatient visits and the proportion of patients with at least one AK-related office visit (including the index visit or the first follow-up visit) were significantly lower for IngMeb than for any other therapy (Fig. 3A; Table 2). Overall, most of the patients received only one prescription for index therapy during the postindex period (i. e., only the index prescription) and had very few prescriptions for other AK-related therapies in the 6-month follow-up period (Fig. 3B).
Discussion Data collected from the first 6 months after initial treatment suggested that IngMeb is comparable with other topical AK agents in clinical practice in terms of refill rates, second followup visits, and adding/switching to another topical drug. Overall, about 10% of patients refilled their index therapy and this proportion was similar between IngMeb and other topical agents except imiquimod, which had a somewhat higher refill rate (9% vs. 15%; P o 0.05). The low rates of adding/switching to topical agents, as well as the few second follow-up visits, could suggest that all treatments were, in general, effective and well-tolerated during the first 6 months of treatment. MAL/ALA-PDT, however, was associated with a significantly higher rate of adding/switching topical agents than was IngMeb (5% vs. 2%; P ¼ 0.01) and had higher rates of add-on cryosurgery (25% vs. 17%; P o 0.0001). Furthermore, a higher proportion of patients receiving MAL/ALA-PDT received repeat administrations
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Table 1 – Demographic and clinical characteristics of the matched AK treatment cohorts * . Characteristic
Age (y) Mean ⫾ SD
IngMeb vs. imiquimod
IngMeb vs. 5-FU
IngMeb vs. 3% diclofenac sodium
IngMeb vs. MAL/ALA-PDT
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
IngMeb (n ¼ 882)
PDT (n ¼ 882)
56.81 ⫾ 8.53 57
56.97 ⫾ 8.47
56.99 ⫾ 8.60
56.79 ⫾ 8.50
56.88 ⫾ 8.72
57.03 ⫾ 8.59
58
57.29 ⫾ 8.51 58
57
57
58
56.91 ⫾ 8.87 57.5
443 (45) 539 (55)
434 (44) 548 (56)
355 (45) 435 (55)
354 (45) 436 (55)
418 (47) 464 (53)
427 (48) 455 (52)
208 (21) 207 (21) 468 (48) 99 (10)
194 216 470 102
143 164 409 74
(18) (21) (52) (9)
146 (19) 177 (22) 391 (50) 76 (10)
175 198 430 79
(20) (22) (49) (9)
175 (20) 190 (22) 433 (49) 84 (10)
67 (7) 851 (87) 64 (7)
63 (6) 868 (88) 51 (5)
49 (6) 700 (89) 41 (5)
61 (8) 681 (86) 48 (6)
66 (8) 755 (86) 61 (7)
63 (7) 766 (87) 53 (6)
969 (99)
967 (99)
783 (99)
779 (99)
869 (99)
868 (98)
9 (1) 4 (0)
11 (1) 4 (0)
5 (1) 2 (0)
10 (1) 1 (0)
9 (1) 4 (1)
11 (1) 3 (0)
758 (77) 187 (19) 32 (3) 5 (1) 0.4 ⫾ 0.88
764 (78) 188 (19) 25 (3) 5 (1) 0.38 ⫾ 0.85 0
623 (79) 145 (18) 17 (2) 5 (1) 0.36 ⫾ 0.84
619 (78) 144 (18) 20 (3) 7 (1) 0.38 ⫾ 0.88
681 (77) 167 (19) 29 (3) 5 (1) 0.4 ⫾ 0.9
0
0
0
683 (77) 167 (19) 26 (3) 6 (1) 0.4 ⫾ 0.89 0
Median 58 Sex, n (%) Female 441 (46) 424 (45) Male 511 (54) 528 (56) Geographic region, n (%) Northeast 207 (22) 185 (19) Midwest 198 (21) 204 (21) South 449 (47) 465 (49) West 98 (10) 98 (10) Health plan type, n (%) HMO 68 (7) 58 (6) PPO 823 (86) 842 (88) Other 63 (7) 52 (6) Payer type, n (%) Commercial/ 941 (99) 936 (98) self-insured Medicare risk 9 (1) 12 (1) Unknown 2 (0) 4 (0) CCI score, n (%) 0 738 (78) 730 (77) 1–2 181 (19) 183 (19) 3–4 28 (3) 30 (3) 5þ 5 (1) 9 (1) Mean ⫾ SD 0.39 ⫾ 0.42 ⫾ 0.95 0.87 Median 0 0 Top 10 preindex comorbidities, n (%) Hypertension 243 (26) 250 (26) Hyperlipidemia 232 (24) 236 (25) URTI 170 (18) 158 (17) Eye disorders 123 (13) 109 (11) Musculoskeletal 141 (15) 106 (11) disorders Skin disorders 324 (34) 279 (29) Joint pain 100 (11) 110 (12) Lipid disorders 97 (10) 105 (11) CVD 82 (9) 82 (9) Pain 90 (10) 99 (10) Physician specialty, n (%) Dermatology 723 (76) 717 (75) Family 61 (6) 60 (6) medicine/ general practice Other 168 (18) 175 (18) Index combination therapy, n (%) 352 (37) 362 (38) Cryosurgery þ topical agent Preindex total health care costs ($) Mean ⫾ SD 3886 ⫾ 4297 ⫾ 8266 7165 Median 1669 1565
0 253 245 177 126 146
(26) (25) (18) (13) (15)
(27) (25) (17) (12) (13)
200 (25) 192 (24) 138 (18) 96 (12) 117 (15)
204 172 148 100 112
(25) (24) (18) (13) (15)
217 (25) 196 (22) 141 (16) 94 (11) 119 (14)
336 (34) 107 (11) 97 (10) 90 (9) 93 (10)
273 (28) 134 (14) 103 (11) 70 (7) 99 (10)
272 (34) 86 (11) 76 (10) 76 (10) 71 (9)
256 (32) 84 (11) 94 (12) 75 (10) 97 (12)
307 (35) 96 (11) 82 (9) 78 (9) 85 (10)
314 (36) 113 (13) 97 (11) 81 (9) 80 (9)
751 (77) 61 (6)
761 (78) 60 (6)
607 (77) 45 (6)
597 (76) 48 (6)
662 (75) 59 (7)
679 (77) 50 (6)
170 (17)
161 (16)
138 (18)
145 (18)
161 (18)
153 (17)
360 (37)
348 (35)
322 (41)
331 (42)
284 (32)
275 (31)
4015 ⫾ 7700
4556 ⫾ 9786 1703
3981 ⫾ 7919
4240 ⫾ 9438
3886 ⫾ 7562
1659
1648
1684
266 249 167 118 127
(20) (22) (48) (10)
(26) (22) (19) (13) (14)
222 213 159 111 128
4139 ⫾ 9148 1643.09 1579.04 continued on next page
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VALUE IN HEALTH 19 (2016) 239–248
Table 1 – continued Characteristic
IngMeb vs. imiquimod
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
Time from diagnosis to treatment initiation, n (%) 0–7 d 636 (67) 649 (68)
IngMeb vs. 5-FU
IngMeb vs. 3% diclofenac sodium IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
IngMeb vs. MAL/ALA-PDT
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
IngMeb (n ¼ 882)
646 (66)
647 (66)
554 (70)
557 (71)
544 (62)
8–30 d
204 (21)
189 (20)
222 (23)
226 (23)
146 (19)
148 (19)
224 (25)
31–60 d 61–120 d 121–180 d Mean ⫾ SD
39 (4) 50 (5) 23 (2) 14.96 ⫾ 30.94 3
37 (4) 52 (6) 25 (3) 14.97 ⫾ 31.4
40 (4) 51 (5) 23 (2) 14.99 ⫾ 30.62 3
38 (4) 45 (5) 26 (3) 14.29 ⫾ 30.67 1
35 (4) 35 (4) 20 (3) 14.04 ⫾ 30.49
28 (4) 40 (5) 17 (2) 13.43 ⫾ 29.8 2
40 (5) 51 (6) 23 (3) 16.5 ⫾ 31.97
Median
2
2.5
4
PDT (n ¼ 882)
546 (62) 204 (23) 50 (6) 54 (6) 28 (3) 17.48 ⫾ 33.4 3
Note: No statistically significant differences were observed between ingenol mebutate gel and comparison therapies. AK, actinic keratosis; CCI, Charlson comorbidity index; CVD, cardiovascular disease; diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; HMO, health maintenance organization; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy; PPO, preferred provider organization; URTI, upper respiratory tract infection. * A separate exploratory analysis of cryosurgery was performed. Results are not presented.
than did the IngMeb cohort (20% vs. 10%; P o 0.05). These findings also corroborate with results from the time-to-event models (Kaplan-Meir curves and Cox proportional hazards models) in which treatment change (switch/add-on) and second follow-up visit were combined into a single/composite end point. IngMeb had significantly shorter times to refill and a shorter time-to-first follow-up visit than did other therapies. This probably reflects the fact that a course of IngMeb treatment, which lasts 2 or 3 days, is completed faster than that of other topical agents, which require daily applications for several weeks or months. Because patients may have had multiple areas that required treatment [1–5], the shorter dosing duration allowed physicians to treat other areas sooner, potentially producing faster resolution of all lesions. A possible explanation for the overall low rates of adding/ switching therapies during the first 6 months after index treatment may reflect the need for a treatment holiday after course of treatments with long dosing durations and persistent skin reactions. Combination cryosurgery at baseline (31%–42% of patients) as well as subsequent cryosurgery during the 6-month period (15%– 25% of patients) were common. It is possible that subsequent cryosurgery after index therapy with topical agents targeted different lesions or was part of a treatment plan addressing multiple lesions that called for a combination of therapies. A recently published randomized clinical trial has shown that IngMeb field-directed treatment subsequent to cryosurgery has higher AK clearance rates than cryosurgery alone and improves the sustained clearance over time [20]. In the relatively short follow-up period of 6 months after index therapy, patients had low AK-attributable HRU. Nevertheless, the proportion of patients in the IngMeb cohort had significantly fewer AK-related outpatient visits compared with that in any other cohort. Despite this, median 6-month total health care costs appeared to be higher for patients prescribed IngMeb than for those prescribed most other comparators (median costs were $686–$691 and $352–$732 for IngMeb and other topical agents/PDT, respectively). This was predominantly
due to higher IngMeb prescription cost (it was new to the market) and the follow-up period being too short for reduced office visit to have full impact on total treatment cost. Future studies with longer follow-up periods are warranted to provide a more comprehensive comparative cost comparison. It is also worth noting that since this study was conducted, the percentage increases in acquisition costs for other topical agents were much higher than for IngMeb [39]. The present wholesale acquisition price (per package) for IngMeb reflects a 16% change since 2013 (from $638.14 to $738.73), whereas there has been a 32% to 509% change for 5-FU, depending on formulation strength (from $252.77 to $334.00, $397.00 to $597.00, and $410.29 to $2497.65 for 5%, 1%, and 0.5% cream, respectively), a 113% change for diclofenac (from $776.70 to $1651.18), and a 32% to 94% change for imiquimod (from $411.59 to $799.23 and from $784.18 to $1037.08 for 3.75% and 5%, respectively). Availability of generic imiquimod in 2015 will likely decrease the average imiquimod acquisition cost. Nevertheless, when comparing total drug cost, it is also important to take into account the different durations of therapy associated with each topical agent. In addition, although the comparative total drug cost may be subject to frequent variation because of price changes and availability of generics, utilization metrics tied to professional services, such as the lower number of office visits that appear to be associated with the use of IngMeb in this analysis, may demonstrate greater stability over time. A strength of the study is that the study population included only patients with AK who were newly initiating treatment (i.e., index therapy was their first AK treatment in 6 months). It is also likely that most patients studied were newly diagnosed, because patients with preindex SCC were excluded and because most received the AK diagnosis during the preindex period (r1 month before index therapy). Moreover, patients were matched with propensity scores, including key clinical and demographic characteristics, to ensure that patients in the different cohorts were similar. There are, however, inherent limitations in using health care claims data because they are collected for billing/reimbursement rather than for research purposes. Consequently, there may be confounding variables that were not captured in the database
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Table 2 – Actinic keratosis treatment patterns. Treatment decision
Refill index therapy Patients, n (%) Mean ⫾ SD (d)
IngMeb vs. imiquimod
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
84 (9) 34.92 ⫾ 38.88 21
139 (14.6) 55.35 ⫾ 44.43
IngMeb vs. 5-FU
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
87 (9) 81 (8) 33.97 ⫾ 45.25 ⫾ 38.16 43.5 Median (d) 40 21 30 P value o0.0001* 0.6283 Add or switch topical agents within 6 mo after index therapy Patients, n (%) 22 (2) 19 (2) 22 (2) 6 (1) Mean ⫾ SD (d) 68.4 ⫾ 78.3 ⫾ 51.6 68.4 ⫾ 41.9 64.7 41.9 ⫾ 58.4 Median (d) 58 71 58 58 P value 0.6358 0.0023* Add cryosurgery within 6 mo after index therapy Patients, n (%) 162 (17) 151 (16) 168 (17) 148 (15) Mean ⫾ SD (da)
Median P value Second follow-up visit With second visit, n (%) Mean ⫾ SD (days to second visit) Median (days to second visit) P value Outpatient visits 41 visit, n (%) Mean ⫾ SD (no. of visits) Median (no. of visits) P value
62.79 ⫾ 39.19
90.17 ⫾ 44.27
62.98 ⫾ 38.72
88.08 ⫾ 46.73
89
54.5
85.5
54 0.4964
IngMeb vs. diclofenac
IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
71 (9) 33.97 ⫾ 37.12 20
76 (10) 67.21 ⫾ 49 55 0.4848
17 (2) 54.1 ⫾ 25.9
IngMeb vs. MAL/ ALA-PDT IngMeb (n ¼ 882)
84 (10) 179 (20) 33.85 ⫾ 54.56 ⫾ 38.52 29.56 20.5 45 o0.0001*
22 (3) 83.1 ⫾ 51.1
21 (2) 67.0 ⫾ 42.4
41 (5) 77.6 ⫾ 47.4
90
57
67
55 0.4175 133 (17) 62.62 ⫾ 39.07 53
0.2194
PDT (n ¼ 882)
0.0097* 129 (16)
151 (17)
222 (25)
95.17 ⫾ 46.53
63.32 ⫾ 39.26
75.41 ⫾ 46.97
95
55
63 o0.0001*
0.7867
66 (7)
86(9)
66 (7)
86(9)
56 (7)
49 (6)
60 (7)
149(17)
82.5 ⫾ 40.0
90.1 ⫾ 44.9
82.7 ⫾ 41.4
96
76
76.2 ⫾ 36.7 70
100.2 ⫾ 40.9
71
75.7 ⫾ 42.4 67
82.8 ⫾ 41.6 82
87.8 ⫾ 43.6 84
0.1206
0.2327
473 (50)
627 (65.9)
487 (50)
1.27 ⫾ 1.89
1.73 ⫾ 2.26
1.27 ⫾ 1.88
0
1
0
o0.0001*
0.002* 674 (68.6) 1.65 ⫾ 1.83 1
o0.0001*
104
400 (51) 1.29 ⫾ 1.85 1
0.4774
442 (55.9)
440 (50)
1.51 ⫾ 2.03
1.26 ⫾ 1.88 0
1 0.0342*
882 (100) 2.83 ⫾ 2.17 2
o0.0001*
Diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALAPDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy. * Indicates statistically significant difference (P o 0.05).
such as the severity (number, location, size, and characteristics of lesions) of the AK at baseline, physician treatment practice, whether particular lesions recurred, or differences in patient out-of-pocket or co-pay costs. Furthermore, the compared therapies had different dosing regimens. First, some agents were labeled for use in areas of approximately 25 cm2 (IngMeb, diclofenac, imiquimod 5%), whereas other agents may have been used for full face or balding scalp (imiquimod 2.5% or 3.75%) or lacked a specification of the size of the treated area in the label (5FU). It is, however, unknown to what extent these topical agents were limited to the 25 cm2 area in everyday clinical practice. Second, the higher refill rates of MAL/ALA-PDT may have reflected the inherent differences in the therapies because the repeat administrations of MAL/ALA-PDT may have been part of the initial treatment plan, or it may have been driven by economic rather than clinical factors. Third, although all patients
were followed for 6 months postindex, one can argue that the time period for which treatment patterns could be captured were not equal among treatment cohorts because the recommended dosing duration varied significantly between topical agents— ranging from 2 or 3 days for IngMeb to up to 4 months for imiquimod. IngMeb was relatively new to the market at the time of this study. Thus, the follow-up period was limited to 6 months, which reduced the possibility to observe differences between therapies over a longer term. Furthermore, during the study time frame, there were restrictions in coverage of IngMeb therapy, which could have affected rates of switching as patients had to bear more costs. Findings from retrospective, observational studies, as the present, can demonstrate associations but cannot indicate causality. Although this research provided new knowledge about
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Probability of Not Having a Treatment Failure
VALUE IN HEALTH 19 (2016) 239–248
100% 90% 80% 70% 60% 50%
Imiquimod (n = 952) IngMeb (n = 952)
40% 30% 20% 10% 0% 0
Probability of Not Having a Treatment Failure
Log-Rank Test: Chi-SquareDF 0.0144 1
30
60
90 Days
120
150
180
P-value 0.9044
100% 90% 80% 70% 60% 50%
5 Fluorouracil (n = 982) IngMeb (n = 982)
40% 30% 20% 10% 0% 0
Probability of Not Having a Treatment Failure
Log-Rank Test: Chi-SquareDF 0.5486 1
30
60
90 Days
120
150
180
P-value 0.4589
100% 90% 80% 70% 60% 50%
3% diclofenac sodium (n = 790) IngMeb (n = 790)
40% 30% 20% 10% 0% 0
30
60
90 Days
120
150
180
Probability of Not Having a Treatment Failure
Log-Rank Test:Chi-SquareDF P-value 0.0307 1 0.861 100% 90%
0.9161
80%
0.8073
70% 60% 50%
MAL-PDT/ALA-PDT (n = 882)
40%
IngMeb (n = 882)
30% 20% 10% 0% 0
30
60
90 Days
120
150
180
Log-Rank Test: Chi-SquareDF P-value 43.2132 1 <.0001
IngMeb = Ingenol Mebutate gel; 5-FU = 5-Fluorouracil; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acidphotodynamic therapy
Fig. 2 – Kaplan-Meier survival curves for time to augment/switch therapy or have a second follow-up visit: ingenol mebutate gel versus imiquimod, MAL/ALA-PDT, 5-FU, and diclofenac. Diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
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VALUE IN HEALTH 19 (2016) 239–248
(A) Mean Number of -Month Post-index AK-related Outpaent Visits 3
p<0.0001
2.5 p<0.0001
2
p<0.0001
p<0.0342
1.5
IngMeb Comparator
1
0.5
0 IngMeb vs. Imiquimod
IngMeb vs. 5-FU
IngMeb vs. Diclofenac
IngMeb vs. MAL/ALA-PDT
(B) Mean Number of 6-Month Post-index Prescripon Fills for AK-related Medicaons 0.4 p<0.0001
p<0.0001
p<0.0025
0.35 0.3 0.25
p<0.498
0.2
IngMeb Comparator
0.15 0.1 0.05 0 IngMeb vs. Imiquimod
IngMeb vs. 5-FU
IngMeb vs. Diclofenac
IngMeb vs. MAL/ALA-PDT
AK = acnic keratosis; IngMeb = Ingenol Mebutate gel; 5% imiquimod and 2.5% or 3.75% imiquimod; 5-FU = 5-Fluorouracil; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acid-photodynamic therapy
Fig. 3 – Health care resource utilization. (A) Mean number of 6-month postindex AK-related outpatient visits. (B) Mean number of 6-month postindex prescription fills for AK-related medications. AK, actinic keratosis; diclofenac, 3% diclofenac sodium; 5FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
treatment patterns and HRU among patients receiving topical field treatment for AK, it is unknown to what extent the results of this study can be generalized to other populations and settings. Thus, future studies should further examine AK treatment patterns and HRU in larger samples, over a longer follow-up period, and for different populations (e.g., Medicare beneficiaries).
additional populations and with a longer follow-up period is needed to confirm and extend these findings. Source of financial support: This study was funded by LEO Pharma A/S.
R EF E R EN C ES
Conclusions Findings from this study indicated that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with significantly higher refill rates, and PDT, which was associated with significantly higher retreatment/switch rate. Overall, patients using IngMeb had fewer office visits, which may have reduced the AK treatment burden for patients and the overall health care system. Further study in
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Evaluation of Resource Utilization and Treatment Patterns in Patients with Actinic Keratosis in the United States Carl V. Asche, PhD1,2,*, Panagiotis Zografos, MS3, Jenny M. Norlin, PhD4, Bill Urbanek, MS3, Carl Mamay, BS, MBA3, Charles Makin, BSPharm, MS, MBA, MM5, Sandra Erntoft, PhD4, Chi-Chang Chen, MsPharm, PhD5, Dionne M. Hines, MPH, PhD5, Daniel Mark Siegel, MD, MS6,7 1
Center for Outcomes Research and the Department of Medicine, University of Illinois College of Medicine at Peoria, Peoria, IL, USA; Department of Pharmacy Systems, Outcomes and Policy, University of Illinois at Chicago College of Pharmacy, Chicago, IL, USA; 3 LEO Pharma, Inc., Parsippany, NJ, USA; 4LEO Pharma A/S, Ballerup, DK; 5IMS Health, RWE-HEOR Plymouth Meeting, PA, USA; 6 Department of Dermatology, SUNY Downstate, Brooklyn, NY, USA; 7Long Island Skin Cancer and Dermatologic Surgery, a division of ProHealthCare Associates, Smithtown, NY, USA 2
AB STR A CT
Objective: To compare health care resource utilization and treatment patterns between patients with actinic keratosis (AK) treated with ingenol mebutate gel (IngMeb) and those treated with other fielddirected AK therapies. Methods: A retrospective, propensity-score– matched, cohort study compared refill/repeat and adding-on/switching patterns and outpatient visits and prescriptions (health care resource utilization) over 6 months in patients receiving IngMeb versus those receiving imiquimod, 5-fluorouracil, diclofenac sodium, and methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT). Results: The final sample analyzed included four matched treatment cohort pairs (IngMeb and comparator; n ¼ 790–971 per treatment arm). Refill rates were similar except for imiquimod (15% vs. 9% for imiquimod and IngMeb, respectively; P o 0.05). MAL/ALA-PDT treatment repetition rates were higher than IngMeb refill rates (20% vs. 10%; P o 0.05). Topical agent add-on/ switch rates were comparable. PDT had higher switch rates than did IngMeb (5% vs. 2%; P o 0.05). The IngMeb cohort had a significantly lower proportion of patients with at least one AK-related outpatient
visit during the 6-month follow-up than did any other cohort: versus imiquimod (50% vs. 66%; P o 0.0001), versus 5-fluorouracil (50% vs. 69%; P o 0.0001), versus diclofenac sodium (51% vs. 56%; P ¼ 0.034), and versus MAL/ALA-PDT (50% vs. 100%; P o 0.0001). There were significantly fewer AK-related prescriptions among patients receiving IngMeb than among patients in other cohorts. Conclusions: Results based on the first 6 months after treatment initiation suggested that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with higher refill rates, and PDT, which was associated with significantly more frequent treatment sessions and higher switching rates. IngMeb was also associated with significantly fewer outpatient visits than were other field-directed therapies. Keywords: actinic keratosis, health care resource utilization, treatment patterns.
Introduction
range between 11% and 26% [4,11]. Among persons 40 years or older in Australia, the prevalence has been estimated to be up to 60% [11]. Clinically, AK may appear as a single lesion, as multiple lesions, or as field cancerization [1,4,5,12]. Field cancerization refers to an affected area that involves visible as well as nonvisible subclinical lesions [13–15]. At present, three approaches are used to treat AK: lesion-directed treatments, field-directed treatments, or a combination of both [4,16]. Cryosurgery with liquid nitrogen is the most commonly used treatment. Cryosurgery may efficiently treat single lesion, but it fails to treat field cancerization and has high recurrence rates. Thus, it is often used in combination with other treatment modalities [16]. Although lesion-directed treatments may be simple and quick, they may be painful and may leave permanent
Actinic keratoses (AK) are keratotic cutaneous lesions that may progress to invasive squamous cell carcinoma (SCC). AK lesions commonly occur in sun-exposed skin, such as on the head, neck, hands, and lower legs [1–3]. Risk factors for AK include fair skin, older age, baldness, immunodeficiency, and high cumulative ultraviolet radiation exposure [4–6]. AK is a common skin condition whose incidence is increasing [4]. There are few population-based studies of AK prevalence, and estimates vary widely [5,7–10]. Differences are likely due to variations in ultraviolet exposure, risk factors of included populations, and the methods used to estimate the prevalence. In the United States, the prevalence of AK has been estimated to
& 2016 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
* Address correspondence to: Carl V. Asche, Center for Outcomes Research, University of Illinois College of Medicine at Peoria, One Illini Drive, Peoria, IL 61656. E-mail: [email protected]. 1098-3015$36.00 – see front matter & 2016 Published by Elsevier Inc. on behalf of International Society for Pharmacoeconomics and Outcomes Research (ISPOR). http://dx.doi.org/10.1016/j.jval.2015.11.014
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scars or dyspigmented areas [4,17–19]. Field-directed therapies, including patient-applied topical agents and photodynamic therapy (PDT), target visible lesions as well as the surrounding fieldcancerized area with subclinical lesions [20]. Although PDT is highly effective and minimally invasive, it may be very painful for patients. Furthermore, the high cost of photosensitizing topical agents used with PDT and the need for multiple administrations make it relatively costly and time-consuming [4]. Patient-applied topical field therapies are starting to be more widely used as physicians increasingly recognize the importance of field cancerization when selecting treatment. Multiple agents are available including 5% or 0.5% fluorouracil (5-FU) topical, 3% diclofenac sodium (diclofenac), 5% or 2.5% or 3.75% imiquimod (imiquimod). Although all these agents have been shown to be effective in achieving therapeutic goals, they have drawbacks including long treatment times, photosensitivity, pain, severe erythema, and inflammation [4]. 5-FU is to be applied once or twice daily for 2 to 4 weeks. Imiquimod 5% is applied twice weekly for 16 weeks or 3 times a week for shorter periods, whereas the 2.5% and 3.75% formulations are used daily for 2 weeks with a 2-week rest period followed by a repeat 2-week treatment cycle. Diclofenac requires a twice-daily application for 60 to 90 days [4,16]. Lengthy dosing durations of treatments have been associated with high nonpersistence and nonadherence rates in patients with AK [21], which may affect the real-world effectiveness negatively. Reasons for early discontinuation may be related to the treatment being too time-consuming, too expensive, or causing a severe reaction [16]. Treatment and follow-up of AK represents a substantial burden in dermatological health care because AK lesions are common and have the potential to progress to SCC [5,18,22,23]. Because it is not possible to predict which lesions will progress to malignancy, most guidelines and consensus reports recommend that all AKs be treated [1,4,5,7,24–26]. It is estimated that AK treatment annually accounts for $1.2 billion in direct health care spending in the United States, primarily driven by office visits and associated procedures, which constitute 92% of direct costs [27]. Few studies have focused on the costs of AK treatments available at present [24,28–33]. New therapies continue to emerge in this rapidly evolving area of dermatology. Goals for this next generation of AK therapies include shortening dosing duration and dosing frequency, increasing tolerability (i.e., reducing adverse effects), and maintaining high efficacy and acceptable associated costs [4,23]. Ingenol mebutate gel (IngMeb) is approved for the topical fielddirected treatment of AK lesions. Compared with other topical agents that require daily applications for weeks or months, IngMeb has a significantly shorter dosing duration of treatment (2 or 3 days). Furthermore, studies suggest that IngMeb has a positive risk/benefit profile—producing well-defined adverse events (AEs) for a short treatment duration compared with other available topical agents [16,34]. Randomized clinical trials show the efficacy and safety of topical agents in AK treatment. Studies about the real-world usage of IngMeb and comparators are however limited. The objective of this study was to compare real-world treatment and health care resource utilization (HRU) between patients with AK treated with IngMeb and patients treated with other field therapies, including prescription refills, switching/augmenting to other AK therapies, and follow-up physician visits during a 6-month postindex period.
Methods This retrospective cohort study was designed to compare treatment patterns and HRU in US adults who received IngMeb for AK
with treatment patterns and HRU in those receiving imiquimod, 5-FU, diclofenac, or methyl aminolevulinate or aminolevulinic acid photodynamic therapy (MAL/ALA-PDT). The study used data from the IMS PharMetrics (Plymouth Meeting, PA, USA) health insurance claims database drawn from July 1, 2011, to June 30, 2013. The database captures pharmacy and medical claims for more than 75 million patients from 96 health plans across the United States. Database records were generally representative of the commercially insured US population. Approval from an institutional review board and informed patient consent were not required because data were de-identified and certified to be compliant with the Health Insurance Portability and Accountability Act of 1996. The patient selection period was from January 1, 2012, to December 31, 2012. Index therapy was defined as the first AK treatment of interest observed during the patient selection period, and the date of the first prescription fill for index therapy served as the index date. Baseline patient characteristics were established using data from the 6-month preindex period, and outcomes were assessed during the 6-month postindex period. Patients selected to be in the study population had to meet each of the following inclusion criteria: had received AK treatment (more than one prescription fill for a topical agent of interest or had evidence of MAL/ALA-PDT or cryosurgery) during the selection period; evidence of one or more AK diagnoses (International Classification of Diseases, Ninth Revision, Clinical Modification code 702.0) preindex; were 18 years of age or older on the index date; and were continuously enrolled in a health insurance plan for 6 months or more preindex and 6 months or more postindex. Patients meeting any of the following criteria were excluded from the study: younger than 18 years; pregnancy during the study period; evidence of using topical AK therapies or MAL/ALA-PDT in the preindex period; evidence of cryosurgery more than 4 weeks preindex; evidence of more than one AK therapy on the index date (except cryosurgery); or evidence of basal cell carcinoma or squamous cell carcinoma (SCC) during the preindex period. Patients with basal cell carcinoma were excluded because some included therapies that may have been used to treat these conditions and it was necessary to ensure that prescribed therapies were directed at AK lesions. Patients with SCC were excluded to ensure that patients had similar severity levels, because SCC is associated with severe AK. Patients who received field-directed therapy were assigned to one of five mutually exclusive treatment cohorts: IngMeb, imiquimod, 5-FU, diclofenac, or MAL/ALA-PDT (cryosurgery-only patients were not included in the present analysis). Patients were matched with propensity scores to ensure comparability within the cohorts (described later). Baseline combination cryosurgery (defined as receipt of cryosurgery within 4 weeks preindex or 2 weeks postindex) was permitted. As with other study patients, the index date for combination therapy patients was defined as the date of the first prescription fill for a topical AK agent. Outcomes included the following: the proportion of patients refilling the index therapy; time from index therapy to the first refill of the index therapy; proportion of patients adding or switching topical agents in the follow-up period (only the first switch postindex was considered and additional switches were not assessed); time from index date to initiation of a second topical agent; proportion of patients receiving cryosurgery beyond 2 weeks after index therapy with a topical agent (receipt of cryosurgery within 2 weeks after index topical treatment was considered combination therapy); and time from index treatment to subsequent cryosurgery beyond the first 2 weeks after treatment initiation. For purposes of this study, the first follow-up visit after index treatment was assumed to be a routine progress check and subsequent follow-up visits indicated inadequate treatment response. Switching to, or adding, another topical
VALUE IN HEALTH 19 (2016) 239–248
agent or initiating MAL/ALA-PDT after index topical agent might indicate that the AK lesion was not cleared by the initial therapy. Overall AK-attributable HRU for each treatment cohort was assessed over the 6-month postindex period. HRU was considered to be related to AK if it was associated with AK diagnosis, treatment, or management of AK treatment–related AE. Variables of interest for assessing HRU were AK-related outpatient visits (proportion of patients with one or more physician visits and total number of physician visits) and AK-related pharmacy prescriptions (total number of prescriptions filled for index therapy and total number of prescriptions filled for other medications related to AK management including AEs associated with treatment). Medications for AK-related AEs included painkillers, topical steroids, emollient or lipid-barrier creams, and silver sulfadiazine. These medications were considered attributable to an AK-related AE if they were administered during the overall index treatment period or within 2 weeks after completion of index treatment. The overall treatment period for each cohort was determined by the total days’ supply of filled index therapy prescriptions plus an allowed 2-week gap between prescriptions. Propensity score matching was used to balance the patients’ demographic and clinical characteristics between the cohorts. The IngMeb cohort served as the control to which other cohorts were matched on a one-to-one basis and compared [35,36]. Data on variables for the propensity score models were collected during the preindex period and included age, sex, physician specialty, health plan payer type, health plan product type, geographic region, Charlson comorbidity index score (Dartmouth-Manitoba adaptation), preindex total health care costs, time since AK diagnosis, and combination therapy with cryosurgery during the preindex 4-week period to the postindex 2-week period [37,38]. Patients were matched by their propensity scores using the nearest neighborwithin-caliper method. The resulting matched groups for comparison were as follows: IngMeb versus imiquimod, IngMeb versus 5FU, IngMeb versus diclofenac, and IngMeb versus MAL/ALA-PDT. The matched groups were used for all outcome analyses (unsuccessfully matched patients were excluded from analyses). Descriptive data were produced for the aggregate study population and each treatment cohort. Categorical measures were presented as the frequency and percentage of total patients in each category. Continuous variables were presented as the mean ⫾ SD and median. Statistically significant differences between patient strata were estimated using P values (o0.05) from chi-square or Fisher exact tests for categorical variables and Wilcoxon rank-sum tests for continuous variables. Kaplan-Meier survival analyses were used to compare time to therapy switch/augmentation or a second follow-up visit (whichever occurred first) between AK therapies. Those who did not experience one of these events were censored at the end of follow-up. Log-rank tests were used for comparisons. Cox proportional hazard models were constructed to evaluate any differences in the risk for augmenting/switching therapy or having a second follow-up visit between IngMeb and the comparator therapies. The risk of switching/augmenting therapy or having a second follow-up visit was evaluated using adjusted hazard ratios (HRs) with 95% confidence intervals as estimated by the Cox proportional hazards model. The main effect was AK treatment (IngMeb vs. comparison treatment), and independent variables included age, sex, geographic region, comorbidities, Charlson comorbidity index score, time from AK diagnosis to treatment initiation, cryosurgery at index date, and preindex total health care costs [37]. Baseline characteristics retained in the predictive models after stepwise selection (using a 0.25 significance criterion) included age, sex, geographic region, presence of comorbid lipid disorders, Charlson comorbidity index score, time from diagnosis to treatment initiation, use of topical agent plus cryosurgery (combination therapy) at index date, and preindex total health care costs.
241
Results The database yielded 668,327 names of patients who had received at least one AK therapy (including topical agents, PDT, or cryosurgery) between January 1, 2012, and December 31, 2012. After applying inclusion and exclusion criteria, 39.7% of the patients remained in the unmatched sample, of whom 985 had received IngMeb (Fig. 1). Steps producing the greatest sample attrition included requiring an AK diagnosis in the preindex period (20% eroded) and requiring continuous health plan enrollment in the preindex and postindex periods (34% eroded). The most commonly prescribed topical AK treatment was 5-FU (3.6%). Many patients received combination therapy (cryosurgery in addition to another treatment) at index date, ranging from 26% of patients receiving MAL/ALA-PDT to 49% of patients receiving diclofenac. Patients who received only cryosurgery (93.4%) were not included in the analysis presented here, but were retained for a separate analysis. The four matched treatment cohort pairs (IngMeb and comparator) are presented in Table 1. The mean age of patients in all matched treatment cohorts was approximately 57 years, and men comprised more than 50% of each group. Nearly half the patients in each treatment cohort resided in the south (Z47%), and most were covered by a commercial preferred provider organization health plan (Z98%) (Table 1). For all matched cohorts, the most prevalent comorbidity was skin disorders (Z28%; common conditions included dyschromia, chronic dermatitis, eczema, rosacea, etc.) as dermatologists (Z75%) were the most frequently visited physician (Table 1). Most patients (Z62%) in the matched treatment cohorts received treatment for AK within 7 days of diagnosis (Table 1). Refill rates for index therapy were similar between IngMeb and other topical agents except imiquimod, which had a significantly higher refill rate than did IngMeb (15% vs. 9%; P o 0.05) (Table 2). IngMeb refill rates were also significantly lower than repeat administration of PDT (10% vs. 20%; P o 0.05) (Table 2). Refill rates for 5-FU and diclofenac were not significantly different from those of IngMeb (Table 2). Time-to-first refill comparisons revealed shorter refill times for IngMeb than for other therapies. Among patients with refill, the median time to first refill for IngMeb was 20 to 21 days, whereas for other cohorts it ranged from 30 to 55 days. Overall, few patients added or switched to topical agents during the first 6 months after index treatment (Table 2). More patients receiving MAL/ALA-PDT switched to a topical agent than did matched subjects receiving IngMeb (5% vs. 2%; P ¼ 0.01). No differences in proportions of patients adding or switching topical agents were found between IngMeb and the other topical agents except 5-FU. Fewer patients receiving 5-FU added or switched topical agents than did matched subjects receiving IngMeb, but sample sizes were small (n ¼ 6 vs. n ¼ 22). Among patients who added or switched to a topical agent, the median time to add/ switch ranged from 55 to 58 days for patients receiving IngMeb at index date to 58 to 90 days for those receiving other therapies. Across the matched treatment cohorts, 31% to 42% of patients received combination cryosurgery at baseline (i.e., cryosurgery in addition to index therapy). The proportions of patients receiving add-on cryosurgery in the postindex period were similar between patients receiving IngMeb and the matched topical cohorts and ranged from 15% to 17% (Table 2). Patients receiving IngMeb, however, showed significantly less add-on cryosurgery than did matched patients receiving MAL/ALA-PDT (25% vs. 17%; P o 0.0001). Among patients who added cryosurgery, the median time to add-on ranged from approximately 2 months (54–63 days) for patients receiving IngMeb or MAL/ALA-PDT to approximately 3 months (86–95 days) for patients receiving other topical agents.
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Total Paents with AK therapy (topical agents, PDT or cryosurgery) N = 668,327 (100%)
Unmatched Sample Aer Inclusion/Exclusion Criteria N = 265,093 (39.7%)
Unmatched Topical agent/PDT Cohorts IngMeb n = 985 (0.4%) 5 Fluorouracil n = 9,415 (3.6%) Imiquimod n = 3,036 (1.1%) Diclofenac n = 1,151 (0.4 %) MAL/ALA-PDT n = 2,984 (1.1 %)
1:1 Propensity Score Matched Treatment Cohorts IngMeb vs. Imiquimod n = 952 (96.6%) IngMeb vs. 5 Fluorouracil n = 982 (99.7%) IngMeb vs. Diclofenac n= 790 (80.2%) IngMeb vs. MAL/ALA-PDT n = 882 (89.5%)
*Paents who received cryosurgery only (n = 247,522) were not included in the analysis presented in this paper, but were retained for a separate analysis; IngMeb = Ingenol Mebutate gel; 5-FU = 5-Fluorouracil; 5% imiquimod and 2.5% or 3.75% imiquimod; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acid-photodynamic therapy
Fig. 1 – Patient population attrition during study sample selection. Patients who received cryosurgery only (n ¼ 247,522) were not included in the analysis presented in this article, but were retained for a separate analysis. AK, actinic keratosis; diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
The proportions of patients receiving topical agents who added MAL/ALA-PDT in the postindex period were very low (r1%) but were similar across cohorts. The first office visit after receiving index therapy was assumed to be a routine follow-up visit for treatment evaluation. Overall, most of the patients (Z52%) did not have a follow-up visit during the study period; patients receiving MAL/ALA-PDT had the highest rate of follow-up office visit during the 6 months (48%). Among patients who made a follow-up visit, the median time to this first visit was significantly shorter for patients receiving IngMeb than for those receiving imiquimod (35 vs. 55 days; P o 0.0001) or diclofenac (35 vs. 83 days; P o 0.0001). Overall, few patients receiving topical treatments for AK returned for a second physician visit during the postindex follow-up period. The proportions of patients with a second visit were similar between IngMeb and all other topical agents (6%– 9%). A relatively high proportion (17%) of patients receiving MAL/ ALA-PDT at the index visit returned for second visits (Table 2). The median time from the index visit to the second visit, among those who made at least two visits, was similar among cohorts except for patients receiving IngMeb versus diclofenac (70 vs. 104 days; P ¼ 0.002). Kaplan-Meier curves for time to therapy augmentation/switch or a second follow-up visit (whichever occurred first) were evaluated for each therapy of interest and compared with those for IngMeb (Fig. 2). No differences in the cumulative probabilities of these events were observed between IngMeb and the other topical agents, with approximately 8% of patients in each group adding/switching topical agents or having a second physician visit during follow-up (Fig. 2). Nevertheless, augmentation/switch or a second follow-up visit occurred significantly less often among patients receiving IngMeb than among the matched cohorts receiving MAL/ALA-PDT (8% vs. 19%; P o 0.0001) (Fig. 2). The risk of these events occurring in patients receiving IngMeb was no different than for the three other topical agents of interest: imiquimod (HR 0.97; P ¼ 0.836), 5-FU (HR 0.90; P ¼ 0.491), and diclofenac (HR 1.03; P ¼ 0.873). Patients receiving
IngMeb, however, had a 59% lower risk of experiencing one of these events than did patients receiving MAL/ALA-PDT. Factors that were significantly associated with the risk of augmenting/ switching therapy or having a second follow-up visit in patients receiving MAL/ALA-PDT were as follows: Midwest residence versus Northeast residence (HR 1.77; P ¼ 0.006) and delaying treatment for more than 1 week after diagnosis (HR 1.45; P ¼ 0.005). The mean number of AK-related outpatient visits and the proportion of patients with at least one AK-related office visit (including the index visit or the first follow-up visit) were significantly lower for IngMeb than for any other therapy (Fig. 3A; Table 2). Overall, most of the patients received only one prescription for index therapy during the postindex period (i. e., only the index prescription) and had very few prescriptions for other AK-related therapies in the 6-month follow-up period (Fig. 3B).
Discussion Data collected from the first 6 months after initial treatment suggested that IngMeb is comparable with other topical AK agents in clinical practice in terms of refill rates, second followup visits, and adding/switching to another topical drug. Overall, about 10% of patients refilled their index therapy and this proportion was similar between IngMeb and other topical agents except imiquimod, which had a somewhat higher refill rate (9% vs. 15%; P o 0.05). The low rates of adding/switching to topical agents, as well as the few second follow-up visits, could suggest that all treatments were, in general, effective and well-tolerated during the first 6 months of treatment. MAL/ALA-PDT, however, was associated with a significantly higher rate of adding/switching topical agents than was IngMeb (5% vs. 2%; P ¼ 0.01) and had higher rates of add-on cryosurgery (25% vs. 17%; P o 0.0001). Furthermore, a higher proportion of patients receiving MAL/ALA-PDT received repeat administrations
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VALUE IN HEALTH 19 (2016) 239–248
Table 1 – Demographic and clinical characteristics of the matched AK treatment cohorts * . Characteristic
Age (y) Mean ⫾ SD
IngMeb vs. imiquimod
IngMeb vs. 5-FU
IngMeb vs. 3% diclofenac sodium
IngMeb vs. MAL/ALA-PDT
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
IngMeb (n ¼ 882)
PDT (n ¼ 882)
56.81 ⫾ 8.53 57
56.97 ⫾ 8.47
56.99 ⫾ 8.60
56.79 ⫾ 8.50
56.88 ⫾ 8.72
57.03 ⫾ 8.59
58
57.29 ⫾ 8.51 58
57
57
58
56.91 ⫾ 8.87 57.5
443 (45) 539 (55)
434 (44) 548 (56)
355 (45) 435 (55)
354 (45) 436 (55)
418 (47) 464 (53)
427 (48) 455 (52)
208 (21) 207 (21) 468 (48) 99 (10)
194 216 470 102
143 164 409 74
(18) (21) (52) (9)
146 (19) 177 (22) 391 (50) 76 (10)
175 198 430 79
(20) (22) (49) (9)
175 (20) 190 (22) 433 (49) 84 (10)
67 (7) 851 (87) 64 (7)
63 (6) 868 (88) 51 (5)
49 (6) 700 (89) 41 (5)
61 (8) 681 (86) 48 (6)
66 (8) 755 (86) 61 (7)
63 (7) 766 (87) 53 (6)
969 (99)
967 (99)
783 (99)
779 (99)
869 (99)
868 (98)
9 (1) 4 (0)
11 (1) 4 (0)
5 (1) 2 (0)
10 (1) 1 (0)
9 (1) 4 (1)
11 (1) 3 (0)
758 (77) 187 (19) 32 (3) 5 (1) 0.4 ⫾ 0.88
764 (78) 188 (19) 25 (3) 5 (1) 0.38 ⫾ 0.85 0
623 (79) 145 (18) 17 (2) 5 (1) 0.36 ⫾ 0.84
619 (78) 144 (18) 20 (3) 7 (1) 0.38 ⫾ 0.88
681 (77) 167 (19) 29 (3) 5 (1) 0.4 ⫾ 0.9
0
0
0
683 (77) 167 (19) 26 (3) 6 (1) 0.4 ⫾ 0.89 0
Median 58 Sex, n (%) Female 441 (46) 424 (45) Male 511 (54) 528 (56) Geographic region, n (%) Northeast 207 (22) 185 (19) Midwest 198 (21) 204 (21) South 449 (47) 465 (49) West 98 (10) 98 (10) Health plan type, n (%) HMO 68 (7) 58 (6) PPO 823 (86) 842 (88) Other 63 (7) 52 (6) Payer type, n (%) Commercial/ 941 (99) 936 (98) self-insured Medicare risk 9 (1) 12 (1) Unknown 2 (0) 4 (0) CCI score, n (%) 0 738 (78) 730 (77) 1–2 181 (19) 183 (19) 3–4 28 (3) 30 (3) 5þ 5 (1) 9 (1) Mean ⫾ SD 0.39 ⫾ 0.42 ⫾ 0.95 0.87 Median 0 0 Top 10 preindex comorbidities, n (%) Hypertension 243 (26) 250 (26) Hyperlipidemia 232 (24) 236 (25) URTI 170 (18) 158 (17) Eye disorders 123 (13) 109 (11) Musculoskeletal 141 (15) 106 (11) disorders Skin disorders 324 (34) 279 (29) Joint pain 100 (11) 110 (12) Lipid disorders 97 (10) 105 (11) CVD 82 (9) 82 (9) Pain 90 (10) 99 (10) Physician specialty, n (%) Dermatology 723 (76) 717 (75) Family 61 (6) 60 (6) medicine/ general practice Other 168 (18) 175 (18) Index combination therapy, n (%) 352 (37) 362 (38) Cryosurgery þ topical agent Preindex total health care costs ($) Mean ⫾ SD 3886 ⫾ 4297 ⫾ 8266 7165 Median 1669 1565
0 253 245 177 126 146
(26) (25) (18) (13) (15)
(27) (25) (17) (12) (13)
200 (25) 192 (24) 138 (18) 96 (12) 117 (15)
204 172 148 100 112
(25) (24) (18) (13) (15)
217 (25) 196 (22) 141 (16) 94 (11) 119 (14)
336 (34) 107 (11) 97 (10) 90 (9) 93 (10)
273 (28) 134 (14) 103 (11) 70 (7) 99 (10)
272 (34) 86 (11) 76 (10) 76 (10) 71 (9)
256 (32) 84 (11) 94 (12) 75 (10) 97 (12)
307 (35) 96 (11) 82 (9) 78 (9) 85 (10)
314 (36) 113 (13) 97 (11) 81 (9) 80 (9)
751 (77) 61 (6)
761 (78) 60 (6)
607 (77) 45 (6)
597 (76) 48 (6)
662 (75) 59 (7)
679 (77) 50 (6)
170 (17)
161 (16)
138 (18)
145 (18)
161 (18)
153 (17)
360 (37)
348 (35)
322 (41)
331 (42)
284 (32)
275 (31)
4015 ⫾ 7700
4556 ⫾ 9786 1703
3981 ⫾ 7919
4240 ⫾ 9438
3886 ⫾ 7562
1659
1648
1684
266 249 167 118 127
(20) (22) (48) (10)
(26) (22) (19) (13) (14)
222 213 159 111 128
4139 ⫾ 9148 1643.09 1579.04 continued on next page
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VALUE IN HEALTH 19 (2016) 239–248
Table 1 – continued Characteristic
IngMeb vs. imiquimod
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
Time from diagnosis to treatment initiation, n (%) 0–7 d 636 (67) 649 (68)
IngMeb vs. 5-FU
IngMeb vs. 3% diclofenac sodium IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
IngMeb vs. MAL/ALA-PDT
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
IngMeb (n ¼ 882)
646 (66)
647 (66)
554 (70)
557 (71)
544 (62)
8–30 d
204 (21)
189 (20)
222 (23)
226 (23)
146 (19)
148 (19)
224 (25)
31–60 d 61–120 d 121–180 d Mean ⫾ SD
39 (4) 50 (5) 23 (2) 14.96 ⫾ 30.94 3
37 (4) 52 (6) 25 (3) 14.97 ⫾ 31.4
40 (4) 51 (5) 23 (2) 14.99 ⫾ 30.62 3
38 (4) 45 (5) 26 (3) 14.29 ⫾ 30.67 1
35 (4) 35 (4) 20 (3) 14.04 ⫾ 30.49
28 (4) 40 (5) 17 (2) 13.43 ⫾ 29.8 2
40 (5) 51 (6) 23 (3) 16.5 ⫾ 31.97
Median
2
2.5
4
PDT (n ¼ 882)
546 (62) 204 (23) 50 (6) 54 (6) 28 (3) 17.48 ⫾ 33.4 3
Note: No statistically significant differences were observed between ingenol mebutate gel and comparison therapies. AK, actinic keratosis; CCI, Charlson comorbidity index; CVD, cardiovascular disease; diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; HMO, health maintenance organization; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy; PPO, preferred provider organization; URTI, upper respiratory tract infection. * A separate exploratory analysis of cryosurgery was performed. Results are not presented.
than did the IngMeb cohort (20% vs. 10%; P o 0.05). These findings also corroborate with results from the time-to-event models (Kaplan-Meir curves and Cox proportional hazards models) in which treatment change (switch/add-on) and second follow-up visit were combined into a single/composite end point. IngMeb had significantly shorter times to refill and a shorter time-to-first follow-up visit than did other therapies. This probably reflects the fact that a course of IngMeb treatment, which lasts 2 or 3 days, is completed faster than that of other topical agents, which require daily applications for several weeks or months. Because patients may have had multiple areas that required treatment [1–5], the shorter dosing duration allowed physicians to treat other areas sooner, potentially producing faster resolution of all lesions. A possible explanation for the overall low rates of adding/ switching therapies during the first 6 months after index treatment may reflect the need for a treatment holiday after course of treatments with long dosing durations and persistent skin reactions. Combination cryosurgery at baseline (31%–42% of patients) as well as subsequent cryosurgery during the 6-month period (15%– 25% of patients) were common. It is possible that subsequent cryosurgery after index therapy with topical agents targeted different lesions or was part of a treatment plan addressing multiple lesions that called for a combination of therapies. A recently published randomized clinical trial has shown that IngMeb field-directed treatment subsequent to cryosurgery has higher AK clearance rates than cryosurgery alone and improves the sustained clearance over time [20]. In the relatively short follow-up period of 6 months after index therapy, patients had low AK-attributable HRU. Nevertheless, the proportion of patients in the IngMeb cohort had significantly fewer AK-related outpatient visits compared with that in any other cohort. Despite this, median 6-month total health care costs appeared to be higher for patients prescribed IngMeb than for those prescribed most other comparators (median costs were $686–$691 and $352–$732 for IngMeb and other topical agents/PDT, respectively). This was predominantly
due to higher IngMeb prescription cost (it was new to the market) and the follow-up period being too short for reduced office visit to have full impact on total treatment cost. Future studies with longer follow-up periods are warranted to provide a more comprehensive comparative cost comparison. It is also worth noting that since this study was conducted, the percentage increases in acquisition costs for other topical agents were much higher than for IngMeb [39]. The present wholesale acquisition price (per package) for IngMeb reflects a 16% change since 2013 (from $638.14 to $738.73), whereas there has been a 32% to 509% change for 5-FU, depending on formulation strength (from $252.77 to $334.00, $397.00 to $597.00, and $410.29 to $2497.65 for 5%, 1%, and 0.5% cream, respectively), a 113% change for diclofenac (from $776.70 to $1651.18), and a 32% to 94% change for imiquimod (from $411.59 to $799.23 and from $784.18 to $1037.08 for 3.75% and 5%, respectively). Availability of generic imiquimod in 2015 will likely decrease the average imiquimod acquisition cost. Nevertheless, when comparing total drug cost, it is also important to take into account the different durations of therapy associated with each topical agent. In addition, although the comparative total drug cost may be subject to frequent variation because of price changes and availability of generics, utilization metrics tied to professional services, such as the lower number of office visits that appear to be associated with the use of IngMeb in this analysis, may demonstrate greater stability over time. A strength of the study is that the study population included only patients with AK who were newly initiating treatment (i.e., index therapy was their first AK treatment in 6 months). It is also likely that most patients studied were newly diagnosed, because patients with preindex SCC were excluded and because most received the AK diagnosis during the preindex period (r1 month before index therapy). Moreover, patients were matched with propensity scores, including key clinical and demographic characteristics, to ensure that patients in the different cohorts were similar. There are, however, inherent limitations in using health care claims data because they are collected for billing/reimbursement rather than for research purposes. Consequently, there may be confounding variables that were not captured in the database
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Table 2 – Actinic keratosis treatment patterns. Treatment decision
Refill index therapy Patients, n (%) Mean ⫾ SD (d)
IngMeb vs. imiquimod
IngMeb (n ¼ 952)
Imiquimod (n ¼ 952)
84 (9) 34.92 ⫾ 38.88 21
139 (14.6) 55.35 ⫾ 44.43
IngMeb vs. 5-FU
IngMeb (n ¼ 982)
5-FU (n ¼ 982)
87 (9) 81 (8) 33.97 ⫾ 45.25 ⫾ 38.16 43.5 Median (d) 40 21 30 P value o0.0001* 0.6283 Add or switch topical agents within 6 mo after index therapy Patients, n (%) 22 (2) 19 (2) 22 (2) 6 (1) Mean ⫾ SD (d) 68.4 ⫾ 78.3 ⫾ 51.6 68.4 ⫾ 41.9 64.7 41.9 ⫾ 58.4 Median (d) 58 71 58 58 P value 0.6358 0.0023* Add cryosurgery within 6 mo after index therapy Patients, n (%) 162 (17) 151 (16) 168 (17) 148 (15) Mean ⫾ SD (da)
Median P value Second follow-up visit With second visit, n (%) Mean ⫾ SD (days to second visit) Median (days to second visit) P value Outpatient visits 41 visit, n (%) Mean ⫾ SD (no. of visits) Median (no. of visits) P value
62.79 ⫾ 39.19
90.17 ⫾ 44.27
62.98 ⫾ 38.72
88.08 ⫾ 46.73
89
54.5
85.5
54 0.4964
IngMeb vs. diclofenac
IngMeb (n ¼ 790)
Diclofenac (n ¼ 790)
71 (9) 33.97 ⫾ 37.12 20
76 (10) 67.21 ⫾ 49 55 0.4848
17 (2) 54.1 ⫾ 25.9
IngMeb vs. MAL/ ALA-PDT IngMeb (n ¼ 882)
84 (10) 179 (20) 33.85 ⫾ 54.56 ⫾ 38.52 29.56 20.5 45 o0.0001*
22 (3) 83.1 ⫾ 51.1
21 (2) 67.0 ⫾ 42.4
41 (5) 77.6 ⫾ 47.4
90
57
67
55 0.4175 133 (17) 62.62 ⫾ 39.07 53
0.2194
PDT (n ¼ 882)
0.0097* 129 (16)
151 (17)
222 (25)
95.17 ⫾ 46.53
63.32 ⫾ 39.26
75.41 ⫾ 46.97
95
55
63 o0.0001*
0.7867
66 (7)
86(9)
66 (7)
86(9)
56 (7)
49 (6)
60 (7)
149(17)
82.5 ⫾ 40.0
90.1 ⫾ 44.9
82.7 ⫾ 41.4
96
76
76.2 ⫾ 36.7 70
100.2 ⫾ 40.9
71
75.7 ⫾ 42.4 67
82.8 ⫾ 41.6 82
87.8 ⫾ 43.6 84
0.1206
0.2327
473 (50)
627 (65.9)
487 (50)
1.27 ⫾ 1.89
1.73 ⫾ 2.26
1.27 ⫾ 1.88
0
1
0
o0.0001*
0.002* 674 (68.6) 1.65 ⫾ 1.83 1
o0.0001*
104
400 (51) 1.29 ⫾ 1.85 1
0.4774
442 (55.9)
440 (50)
1.51 ⫾ 2.03
1.26 ⫾ 1.88 0
1 0.0342*
882 (100) 2.83 ⫾ 2.17 2
o0.0001*
Diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALAPDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy. * Indicates statistically significant difference (P o 0.05).
such as the severity (number, location, size, and characteristics of lesions) of the AK at baseline, physician treatment practice, whether particular lesions recurred, or differences in patient out-of-pocket or co-pay costs. Furthermore, the compared therapies had different dosing regimens. First, some agents were labeled for use in areas of approximately 25 cm2 (IngMeb, diclofenac, imiquimod 5%), whereas other agents may have been used for full face or balding scalp (imiquimod 2.5% or 3.75%) or lacked a specification of the size of the treated area in the label (5FU). It is, however, unknown to what extent these topical agents were limited to the 25 cm2 area in everyday clinical practice. Second, the higher refill rates of MAL/ALA-PDT may have reflected the inherent differences in the therapies because the repeat administrations of MAL/ALA-PDT may have been part of the initial treatment plan, or it may have been driven by economic rather than clinical factors. Third, although all patients
were followed for 6 months postindex, one can argue that the time period for which treatment patterns could be captured were not equal among treatment cohorts because the recommended dosing duration varied significantly between topical agents— ranging from 2 or 3 days for IngMeb to up to 4 months for imiquimod. IngMeb was relatively new to the market at the time of this study. Thus, the follow-up period was limited to 6 months, which reduced the possibility to observe differences between therapies over a longer term. Furthermore, during the study time frame, there were restrictions in coverage of IngMeb therapy, which could have affected rates of switching as patients had to bear more costs. Findings from retrospective, observational studies, as the present, can demonstrate associations but cannot indicate causality. Although this research provided new knowledge about
246
Probability of Not Having a Treatment Failure
VALUE IN HEALTH 19 (2016) 239–248
100% 90% 80% 70% 60% 50%
Imiquimod (n = 952) IngMeb (n = 952)
40% 30% 20% 10% 0% 0
Probability of Not Having a Treatment Failure
Log-Rank Test: Chi-SquareDF 0.0144 1
30
60
90 Days
120
150
180
P-value 0.9044
100% 90% 80% 70% 60% 50%
5 Fluorouracil (n = 982) IngMeb (n = 982)
40% 30% 20% 10% 0% 0
Probability of Not Having a Treatment Failure
Log-Rank Test: Chi-SquareDF 0.5486 1
30
60
90 Days
120
150
180
P-value 0.4589
100% 90% 80% 70% 60% 50%
3% diclofenac sodium (n = 790) IngMeb (n = 790)
40% 30% 20% 10% 0% 0
30
60
90 Days
120
150
180
Probability of Not Having a Treatment Failure
Log-Rank Test:Chi-SquareDF P-value 0.0307 1 0.861 100% 90%
0.9161
80%
0.8073
70% 60% 50%
MAL-PDT/ALA-PDT (n = 882)
40%
IngMeb (n = 882)
30% 20% 10% 0% 0
30
60
90 Days
120
150
180
Log-Rank Test: Chi-SquareDF P-value 43.2132 1 <.0001
IngMeb = Ingenol Mebutate gel; 5-FU = 5-Fluorouracil; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acidphotodynamic therapy
Fig. 2 – Kaplan-Meier survival curves for time to augment/switch therapy or have a second follow-up visit: ingenol mebutate gel versus imiquimod, MAL/ALA-PDT, 5-FU, and diclofenac. Diclofenac, 3% diclofenac sodium; 5-FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
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VALUE IN HEALTH 19 (2016) 239–248
(A) Mean Number of -Month Post-index AK-related Outpaent Visits 3
p<0.0001
2.5 p<0.0001
2
p<0.0001
p<0.0342
1.5
IngMeb Comparator
1
0.5
0 IngMeb vs. Imiquimod
IngMeb vs. 5-FU
IngMeb vs. Diclofenac
IngMeb vs. MAL/ALA-PDT
(B) Mean Number of 6-Month Post-index Prescripon Fills for AK-related Medicaons 0.4 p<0.0001
p<0.0001
p<0.0025
0.35 0.3 0.25
p<0.498
0.2
IngMeb Comparator
0.15 0.1 0.05 0 IngMeb vs. Imiquimod
IngMeb vs. 5-FU
IngMeb vs. Diclofenac
IngMeb vs. MAL/ALA-PDT
AK = acnic keratosis; IngMeb = Ingenol Mebutate gel; 5% imiquimod and 2.5% or 3.75% imiquimod; 5-FU = 5-Fluorouracil; Diclofenac = 3% Diclofenac Sodium; MAL/ALA-PDT = methyl aminolevulinate- or aminolevulinic acid-photodynamic therapy
Fig. 3 – Health care resource utilization. (A) Mean number of 6-month postindex AK-related outpatient visits. (B) Mean number of 6-month postindex prescription fills for AK-related medications. AK, actinic keratosis; diclofenac, 3% diclofenac sodium; 5FU, 5-fluorouracil; imiquimod, 5% or 2.5% or 3.75% imiquimod; IngMeb, ingenol mebutate gel; MAL/ALA-PDT, methyl aminolevulinate or aminolevulinic acid photodynamic therapy.
treatment patterns and HRU among patients receiving topical field treatment for AK, it is unknown to what extent the results of this study can be generalized to other populations and settings. Thus, future studies should further examine AK treatment patterns and HRU in larger samples, over a longer follow-up period, and for different populations (e.g., Medicare beneficiaries).
additional populations and with a longer follow-up period is needed to confirm and extend these findings. Source of financial support: This study was funded by LEO Pharma A/S.
R EF E R EN C ES
Conclusions Findings from this study indicated that most field-directed AK therapies had clinically comparable treatment patterns except imiquimod, which was associated with significantly higher refill rates, and PDT, which was associated with significantly higher retreatment/switch rate. Overall, patients using IngMeb had fewer office visits, which may have reduced the AK treatment burden for patients and the overall health care system. Further study in
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