Acne often persists into adulthood, particularly for female patients.1 For those with persistent moderate-to-severe disease requiring treatment with systemic agents, it is important to identify which options can provide a durable treatment effect over time. Spironolactone is emerging as a potential alternative to oral antibiotics.2,3 However, little is known about long-term outcomes with spironolactone for those who have an initial positive response and how it compares to other alternatives.
To understand the drug usage survival of spironolactone compared to oral antibiotics for acne, a retrospective analysis using the OptumInsight™ Clinformatics™ DataMart (OptumInsight, Eden Prairie, MN) was performed between January 1, 2010 and December 31, 2016 among female patients ages 12–40 with at least two diagnosis codes for acne. Prescriptions for spironolactone and oral antibiotics were identified by their National Drug Codes. The primary outcome was drug usage survival (duration of therapy) for patients who received treatment for at least 12 months. In addition, multivariate Cox proportional hazard models were used to evaluate for differences in drug usage survival for spironolactone compared to oral antibiotics. Statistical analyses were performed in Stata 15 (StataCorp, College Station, Texas). The study was deemed exempt by the Institutional Review Board at the University of Pennsylvania.
Among 4,321 female patients treated with spironolactone, the mean course duration 697.8 days (SD 333.3) compared to 604.4 days (SD 261) among 7,517 female patients treated with oral tetracycline-class antibiotics (p<0.001, Table 1). After controlling for age at diagnosis, age at treatment, history of polycystic ovarian syndrome, and history of combined oral contraceptive or topical retinoid use, compared to those treated with oral tetracycline-class antibiotics, the hazard ratio for treatment discontinuation was 0.74 (0.71–0.77) for spironolactone (Table 1, Figure 1). Similar findings were observed in sensitivity analyses including patients who received treatment for at least 6 months.
Table 1.
Subject characteristics and hazard ratios for treatment discontinuation
| Spironolactone (n=4321) | Tetracyclines (n=7517) | Other Antibiotics (n=1606) | ||
| Median age at diagnosis, y (IQR) | 27 (18–32) | 16 (14–22) | 16 (14–23) | |
| Median age at treatment, y (IQR) | 29 (22–35) | 18(15–24) | 19 (16–25) | |
| Mean course duration, d (SD) | 697.8 (333.3) | 604.4 (261.0) | 612.1 (261.7) | |
| 12–20 years old at start of therapy | 653.6 (296.1)* | 594.4 (245.5) | 599.1 (238.7) | |
| 21–30 years old at start of therapy | 679.1 (313.0)* | 587.6 (239.6) | 596.1 (251.1) | |
| 31–40 years old at start of therapy | 730.9 (359.3)* | 664.1 (328.9) | 688.6 (342.2) | |
| Cox proportional hazards model | ||||
| Age at Start of Therapy, y | ||||
| Treatment | Overall | 12–20 | 21–30 | 31–40 |
| Tetracyclines | 1 [Reference] | 1 [Reference] | 1 [Reference] | 1 [Reference] |
| Spironolactone | 0.74 (0.71 – 0.77) | 0.77 (0.71 – 0.83) | 0.69 (0.64 – 0.75) | 0.77 (0.71 – 0.83) |
| Other antibiotics | 0.96 (0.91 – 1.02) | 0.98 (0.91 – 1.05) | 0.97 (0.86 – 1.10) | 0.89 (0.77 – 1.03) |
| History of combined oral contraceptive use | 1.04 (1.00 – 1.08) | 1.07 (1.01 – 1.13) | 1.01 (0.92 – 1.10) | 1.03 (0.95 – 1.11) |
| History of bottomical retinoid use | 1.05 (1.00 – 1.10) | 1.03 (0.95 – 1.12) | 1.09 (1.00 – 1.19) | 1.05 (0.98 – 1.13) |
| History of polycystic ovarian syndrome | 0.95 (0.88 – 1.02) | 0.94 (0.84 – 1.06) | 0.85 (0.75 – 0.97) | 1.08 (0.96 – 1.21) |
| Age at start of therapy | ||||
| 12–20 years old | 1 [Reference] | |||
| 21–30 years old | 1.02 (0.95 – 1.09) | |||
| 31–40 years old | 0.86 (0.78 – 0.96) | |||
| Age at diagnosis | ||||
| <20 years old | 1 [Reference] | |||
| 21–30 years old | 0.93 (0.86 – 1.00) | |||
| >31 years old | 0.91 (0.81 – 1.01) | |||
p<0.001
Compared to tetracyclines, Student’s t-test, unpaired
Other antibiotics includes azithromycin, amoxicllin, trimethoprim-sulfamethoxazole, and cephalexin.
Figure 1. Kaplan-Meier survival curve for spironolactone versus oral antibiotics.
Note: time zero is defined as when the patient has been stable on therapy for one year. Other antibiotics includes azithromycin, amoxicillin, trimethoprim-sulfamethoxazole, and cephalexin.
These findings suggest that spironolactone may have superior drug usage survival compared to oral antibiotics for the treatment of female patients with acne. In addition, prior studies have suggested that spironolactone may have similar effectiveness to oral antibiotics for acne and can decrease the duration of therapy with antibiotics in this patient population.3,4 Since female patients often have persistent acne into adulthood and given concerns regarding antibiotic overuse among acne patients, it is possible that using spironolactone as a first-line agent before oral antibiotics could improve outcomes for female patients with acne.5
This study has several limitations given its retrospective, observational design. It is important to recognize that spironolactone and oral antibiotics may be prescribed to different patient populations; however, similar findings are observed when stratified by age and after controlling for potential modifying factors such as history of polycystic ovarian syndrome and concomitant medication use. Since guidelines recommend limiting the duration of treatment with oral antibiotics to 3–6 months, patients receiving oral antibiotics may have discontinued therapy due to these recommendations. However, by limiting the analysis to patients who had already been on therapy for at least 12 months (and hence are not being treated in accordance with guidelines), this risk of bias is reduced. While it is not possible to determine whether medication discontinuation occurred due to lack of efficacy, cost, side-effects, resolution of acne, or other factors, the extended drug usage survival of spironolactone suggests that in routine clinical practice, spironolactone may have good long-term effectiveness and tolerability. Future prospective studies are needed to identify the optimal treatment approaches for female patients with moderate-to-severe acne.
Acknowledgments
Funding statement: Funded in part through NIAMS 1P30AR069589-01. Dr. Barbieri is supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health under award number T32-AR-007465 and receives partial salary support through a Pfizer Fellowship in Dermatology Patient Oriented Research grant to the Trustees of the University of Pennsylvania.
The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication
Footnotes
Conflict of Interest: The authors have no conflicts of interest to disclose.
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