The Impact of Clostridium Histolyticum Collagenase on the Prevalence and Management of Peyronie's Disease in the United States

Peyronie's disease (PD) is characterized by fibrous penile plaque formation in the tunica albuginea, leading to penile deformities that may interfere with sexual function [1]. When left untreated, the disease has a variable course with some patients spontaneously improving, and others progressing to significant disability. The prevalence of PD has been estimated to be between 0.5% and 20.3% [2, 3], though there is concern these may be underestimates given the potentially embarrassing nature of the condition. While diabetes and erectile dysfunction have been postulated as medical comorbidities [3, 4], PD has been linked to depression, low self-esteem, and emotional distress [5].

A number of therapies for PD exist. Of these, only intralesional verapamil, intralesional collagenase clostridium histolyticum (CCH), tunical plication, plaque incision/excision, and penile prosthesis are currently recommended by American Urological Association (AUA) guidelines [1]. In particular, there has been significant interest in use of CCH given the weak evidence for efficacy of verapamil [1, 6, 7] and the invasive nature of surgical procedures. Indeed, phase III studies showing significant improvements in penile curvature and PD symptoms with CCH led to approval from the United Stated Food and Drug Administration in 2013 [8]. Given the impressive results of initial CCH trials, there has been a substantial increase in PD research. In 2015 and 2016, there were 103 and 102 “Peyronie's Disease” PubMed articles indexed, compared with 68, 86, 68, and 64 in the 4 years prior. However, if any changes in the rates of diagnosis and management of PD have occurred in tandem remains unknown.

Despite its potential as a therapy, CCH has been associated with significant adverse events. An analysis of the data from both phase III clinical trials of CCH found that 84.2% of patients in the CCH group had an adverse event, compared to 36.3% in the placebo arm. Though most adverse events were mild or moderate (79.0%), 3 corporal ruptures and 3 severe hematomas occurred in the CCH group [8]. Subsequent studies have reported that 34% of urologists administering CCH have encountered a corporal rupture [9], and in one series, 4.9% of patients treated with CCH developed this complication. In the later study, 20% of cases were managed non-operatively [10]. However, to date, there have been no studies looking at population-level data to assess if corporal rupture rates have increased in the era of CCH use or compared CCH corporal rupture rates to other injection agents used in practice.

The primary goal of this study was to use a national insurance claims database to define the prevalence of PD, utilization of AUA recommended treatments for PD, and cost of treating PD in actual practice and examine how CCH availability has affected these. Further, we assessed the rates of corporal rupture and repair in men with PD and association with CCH availability and use.

To our knowledge, this is the first study to examine how CCH has affected AUA-recommended management of PD in actual practice. We found that the reported prevalence of men with PD did not change after CCH entered the market. However, we did find that more men with PD received treatment due to a clinically and statistically significant increase in penile injection utilization. Though the cost of treating PD per man increased over the entire study period, this was most pronounced after CCH became available. Given the significant increase in penile injections during this period and substantial cost associated with CCH use [14], the sharp rise is likely due to CCH use. We found that risk of corporal rupture in men with PD is low, and the overall prevalence of corporal rupture did not change after CCH entered the market.

In our population, the prevalence of PD remained at approximately 0.3% before and after CCH entered the market. Our reported prevalence of 0.3% is lower than recently published estimates, though it is close to a 0.5% prevalence reported in a previous population-based study [2, 3]. While this is in part due to the younger age of our study population (average age, 57–60, annually), it likely reflects that PD is an underdiagnosed condition in population-based samples. In general, our findings are congruent with the accepted understanding that PD prevalence increases with age (as high as 0.48% in the 60–69 year-old age group). However, the prevalence in patients over 70 years old declined substantially. Whether this represents underdiagnosis or is directed by patient and provider desires requires further study.

Though we expected the prevalence of diagnosed PD to potentially increase after the approval of a new, minimally invasive treatment, this did not occur. However, we did note a gradual increase in prevalence of PD over the early years of our study. Though this may be related to slowly increasing awareness of PD in the community, it may also be true rise in incidence of PD over these years, mirroring the rise in incidence of associated comorbidities such as obesity, erectile dysfunction, and diabetes [15].

The annual percent of patients with PD receiving treatment increased significantly after CCH entered the market. This was associated with a significant increase in penile injections that offset overall declines in rates of surgical treatments for PD. Rates of PD treatment with AUA-recommended therapies has not been previously reported to our knowledge. However, it has been estimated that 59% to 72% of urologists initiate some therapy (including those outside AUA recommendations) for patients with PD, upon presentation [16, 17]. CCH availability was associated with a significant increase in annual cost of PD treatment per man. Though cost of PD treatment rose of the entire study period, the most pronounced increases were seen in the years after CCH became available. Unfortunately, we lack the required clinical data to comment on if this increase in cost is justified by improved patient outcomes. Future studies should assess if CCH is a cost-effective way to manage PD.

Corporal rupture is the most severe adverse event associated with CCH use. The proposed mechanism of action (enzymatic degradation of collagen) and occurrence of corporal rupture only in the CCH arm of the clinical trials validated concerns [8]. However, when considering all men with PD as a group, there was no change in the rate of corporal rupture before and after CCH became available. Though we did not find conclusive evidence that CCH significantly increases the risk of corporal rupture in men with PD, up to 34% of urologists using CCH have reported experience with a corporal rupture. It is possible that such events are not reliably captured using administrative claims data as non-specific codes (such as those for “penile hematoma”) may also have been used [9].

We acknowledge several limitations. The data used for our study does not include clinical outcomes of patients, so the efficacy of CCH in practice could not be assessed. Similarly, clinical data, such as severity of penile deformity/curvature, is not included. The number of corporal ruptures identified was small, limiting our ability to make definitive conclusions. Our study design cannot control for variations in diagnosis and coding behaviors between individual physicians. Though diverse, our study population is an insured population, and our findings may not be representative of uninsured patients, who many represent an undertreated group in general. However, our study uses of a large, well-maintained database that includes patients from various geographic and demographic strata in the United States. The coding data used for study inclusion are very specific to the conditions and treatments of interest. Finally, use of this type of database allows for evaluation of actual practice patterns and outcomes beyond the scope of clinical trials or institutional chart review.

This study investigates the effect of CCH availability on PD prevalence and treatment. While no change in PD prevalence occurred after CCH entered the market, a significant increase in the proportion of men with PD who received treatment, specifically with penile plaque injections, was found. In contrast, significantly less men underwent surgical repair for PD. At the same time, there was a significant increase in annual cost of PD treatment. Investigation into rates of corporal rupture found no change in men with PD as a whole after CCH entered the market.