The Association Between Hemoglobin A1c Levels and Inflatable Penile Prosthesis Infection: Analysis of US Insurance Claims Data.

Abstract

Background:

The association between elevated hemoglobin A1c (HbA1c) levels and the risk of postoperative infection after penile prosthesis surgery remains controversial.

Aim:

To examine the association between HbA1c levels and penile implant infections in men undergoing inflatable penile prosthesis (IPP) surgery for erectile dysfunction using a large insurance claims database.

Methods:

This was a retrospective review using Optum's de-identified Clinformatics Data Mart Database. Male subjects 18 years and older with available laboratory data undergoing IPP insertion between 2003 and 2018 were included. Administrative diagnosis and procedural codes were used to assess subsequent penile implant revision surgery status for either infectious or noninfectious causes. Associated conditions were controlled for such as smoking status, hyperlipidemia, hypertension, obesity status, and Peyronie’s disease.

Outcomes:

The main outcomes were risk of revision for infection and time to revision.

Results:

A total of 2,363 individuals underwent initial IPP insertion and had available HbA1c data with a mean HbA1c of 6.9%. The overall IPP infection revision rate was 3.9% and the highest rate of 12.1% was seen in the highest HbA1c group (>10%). After adjusting for demographic and health factors, a higher HbA1c level was associated with a higher risk of revision for infection, with every one point increase in HbA1c conferring an increased risk of infection requiring revision by 29% (95% CI 17-42%). When infections did occur, they happened sooner in men with HbA1c>10.0% with an average of 1.3 months versus 3.5 months in the HbA1c <6.0% group.

Clinical Implications:

These findings provide insight into the potential relationship between HbA1c levels and postoperative risk of infection after penile prosthesis surgery and may aid in clinical decision-making.

Strengths and Limitations:

Strengths include the large sample size, length of data coverage, and real-world analysis of surgeries done across the United States. Limitations include the reliance on insurance claims data, the retrospective study design, and lack of additional relevant clinical variables that may impact infection rates.

Conclusions:

While the overall risk of penile prosthesis infection remains modest, the current report notes an increased risk of infection for diabetic men with poor glycemic control.

Introduction

Diabetes Mellitus (DM) is a significant risk factor in the development of erectile dysfunction (ED), with diabetic men having over a three-fold increased risk of developing ED over nondiabetic men¹. The pathogenesis of ED in patients with DM is described as a potential combination of neuropathy, vasculopathy, endothelial dysfunction, and damage to the venoocclusive mechanism of the cavernosal smooth muscle². Men with DM have earlier onset of ED, are less responsive to oral pharmacologic therapy, and are more likely to proceed to more aggressive treatments^3-5.

Penile prosthesis surgery is a highly successful treatment option for men with severe ED. The technology provides a reliable way to restore erections in patients who fail first and second-line therapies⁶. Available in inflatable and malleable-type models, the three-piece inflatable penile prosthesis (IPP) models are performed more often, due to properties of optimal configurations of rigidity and flaccidity⁷. DM is a known risk factor for implant infections. In a statewide population cohort study, Lipsky et al. reported that diabetics have a 32% higher risk of infection requiring surgery after initial implantation when compared to nondiabetics after controlling for patient and surgeon characteristics¹. Recent studies have also linked worse glycemic control, as indicated by higher levels of hemoglobin A1c (HbA1c), to increased risk of penile prosthesis infection. A retrospective multi-center study by Habous et al. determined that a threshold HbA1c level of 8.5% predicted infection with a sensitivity of 80% and a specificity of 65% with a majority of the cohort having malleable protheses ⁸. However, a recent review concluded that there is insufficient evidence regarding HbA1c levels as a predictor of prosthesis infection⁹ and an international study by Osman et. al of 932 diabetic patients undergoing penile prosthesis insertion also failed to find such an associatiom¹⁰.

The present study seeks to examine the association of HbA1c levels and penile implant infections in diabetic men undergoing penile prosthesis surgery for ED using a large insurance claims database.

Materials and Methods

The present study utilized the Optum’s De-identified Clinformatics® Data Mart database (OptumInsight, Eden Prairie, MN), which is a commercial and Medicare Advantage claims database including patient enrollment, physician, facility data, pharmacy claims, and lab results for 77 million individuals in the United States. Laboratory test values were available for a subset of individuals and were queried using Logical Observation Identifiers Names and Codes (LOINC®). International Classification of Diseases 9th revision and 10^th revision, Clinical Modification (ICD-9-CM, ICD-10-CM) codes, Current Procedural Terminology (CPT) codes were used to identify the target study population and measure primary and secondary outcomes of the study. This study was deemed exempt by the Institutional Review Board of Stanford University.

CPT codes were used to identify US adults who underwent either a malleable/self-contained or IPP implantation from 2003 to 2018 who also had HbA1c values available within 1 year of implantation. ICD-9-CM and ICD-10-CM codes were used to describe associated conditions including smoking status, hyperlipidemia, DM, hypertension, obesity status, and Peyronie’s disease (PD). Incidence of subsequent prosthetic revision surgery was then queried by CPT codes (Supplementary Table 1), and these were further subdivided into revisions for either non-infected or infected devices. Infected revisions were defined by either a CPT code explicit for the condition (54411, 54417), or a revision CPT code that was associated with an infection-related ICD-9-CM or ICD-10-CM code (Supplementary Table 1). We excluded patients with any of the following: (1) age younger than 18 years old; (2) Prior penile prosthesis surgery to focus on initial penile implants (3) absence of HbA1c values within 1 year of implantation.

Descriptive statistics were used to report baseline demographics and clinical characteristics of individuals who received inflatable prostheses and malleable/self-contained prostheses, as well as of the cohorts who went on to revision for either infected or non-infected devices. Serum HbA1c levels were stratified: <6.0%, 6.0-6.9%, 7.0-7.9%, 8.0-10.0%, and >10.0%. Time to either infected or non-infected revision was calculated from the first implant surgery until revision event, or censored at last enrollment time for those without a revision. Cox proportional hazards models were constructed to assess the association of HbA1c strata with risk of implant revision (with or without infection), adjusting for age, year, obesity, smoking, hypertension, hyperlipidemia, and PD. Kaplan-Meier curves were generated. P < .05 was considered significant. Analyses were performed with SAS (version 9.4; SAS, Cary, North Carolina).

Results

In all 2,719 individuals underwent initial penile prosthesis insertion and had available HbA1c levels, of which 2,363 (86.9%) received an IPP, and 356 (13.1%) received malleable/self-contained penile implants. The malleable cohort had <11 revision cases which precluded further detailed statistical analyses given data use agreements for rare outcomes. Individuals in the IPP cohort had a mean age of 65.2 years, a mean HbA1c of 6.9%, and an average follow-up of 2.3 years. 57.8% of diabetic men who underwent inflatable penile prostheses had available A1c values. Demographic data and characteristics of the IPP cohort are detailed in Table 1. 70.3% of patients undergoing IPP had a diagnosis of DM, 24.0% had concomitant PD, and 89.4% suffered from hypertension.

Table 1:

IPP Patient Characteristics. (p-value for comparison between revision groups)

	Inflatable Penile Prostheses	Revision with infection	Revision without infection	p-value
n	2363	93	131
Characteristic	Mean (STD)	Mean (STD)	Mean (STD)
Mean Age, years	65.2 (9.1)	62.6 (10.0)	63.9 (10.0)	0.3379
Smoking Status	869 (36.8)	37 (39.8)	43 (32.8)	0.284
Dyslipidaemia or Hyperlipidemia	1246 (52.7)	40 (43.0)	54 (41.2)	0.7892
Diabetes	1660 (70.3)	74 (79.6)	94 (71.8)	0.1832
Hypertension	2113 (89.4)	86 (92.5)	115 (87.8)	0.2548
Obesity Diagnosis	784 (33.2)	26 (28.0)	40 (30.5)	0.6767
Peyronie's Disease	568 (24.0)	17 (18.3)	22 (16.8)	0.7726
HbA1c, %, mean (SD; range)	6.9 (1.6) (4.1 - 14.8)	7.9 (2.2) (5.3 - 14.7)	6.7 (1.3) (4.7 - 10.9)	<.0001
Follow-up, years, mean (SD; range)	2.3 (2.1) (0 - 10.4)	2.4 (1.9) (0.2 - 8.3)	3.4 (2.6) (0.3 - 10.0)	0.0079

Of the IPP cases, 224 (9.4%) patients underwent subsequent revision surgery and 93 (41.5%) of the revision cases were for an infectious cause for an overall IPP infection rate of 3.9% (Table 2). The highest infection revision rate of 12.1% was seen in the highest HbA1c group (i.e. >10%), whereas the lowest infection revision rate (2.3%) was seen in the lowest HbA1c group (i.e.<6.0%). In addition to a higher rate of revisions due to infections, those revisions also happened earlier in men with higher HbA1c levels. After adjusting for demographic and health factors, a higher HbA1c level was associated with a significantly higher risk of revision for infection (Table 3, Figure 1a). For example, the risk of a revision for an IPP infection was 2.7 times higher (95% CI 1.42 – 5.13) in men with HbA1c between 8.0 and 10.0%, and 4.88 times higher (95% CI 2.42 – 9.84) in men with HbA1c greater than 10.0% compared to the low-risk HbA1c<6.0% group.

Table 2:

Breakdown of IPP revision rates by HbA1c.

Hemoglobin A1c (%)	% Revision without infection	%Revisions with infection
Overall n=224	5.5%	3.9%
<6.0	5.9%	2.3%
6.0-6.9	5.4%	3.2%
7.0 - 7.9	7.8%	3.9%
8.0 – 10.0	3.8%	6.6%
>10.0	2.27%	12.1%

^*Data use agreement precludes listing of n values for this table.

Table 3:

Multivariate Cox Proportional Hazards Model of Time to Revision stratified by Infection versus Noninfection (adjusted for patient age, year of implant, obesity status, smoking status, hypertension, hyperlipidemia, and Peyronie’s Disease) and times to revision for both infected and non-infected revisions.

	IPP Revision with Infection	IPP Revision without infection	Time to Revision (Infected)	Time to Revision (Non-infected)
Hemoglobin A1c (%)	HR (adj)	HR (adj)	months (median, range)	months (median, range)
<6.0	ref	ref	3.54 (0.48 - 19.20)	6.60 (0.36 - 88.32)
6.0-6.9	1.40 (0.75 - 2.60)	0.87 (0.56 - 1.34)	2.52 (0.84 - 31.92)	7.68 (0.12 - 70.56)
7.0 - 7.9	1.76 (0.88 - 3.51)	1.22 (0.76 - 1.95)	2.04 (0.72 - 39.72)	10.32 (1.32 - 95.76)
8.0 – 10.0	2.70 (1.42 - 5.13)	0.58 (0.31 - 1.11)	3.00 (0.12 - 16.32)	14.52 (2.52 - 101.28)
>10.0	4.88 (2.42 - 9.84)	0.34 (0.11 - 1.12)	1.26 (0.24 - 14.04)	7.44 (2.16 - 10.80)

Figure 1a:

Kaplain-Meier Curve of Infected Revisions after IPP stratified by Hba1c%

When HbA1c was assessed as a continuous variable, the hazard ratio for infection requiring revision was 1.29 (95% CI 17-42%), indicating that each one point increase in HbA1c, increased the risk of an infection requiring revision by 29%. In addition, when infections did occur, they happened sooner in men with HbA1c>10.0%. For example, the median time to revision for infection in men with HbA1c<6.0% was 3.5 months versus only 1.3 months in the HbA1c>10.0% group (Table 3). In contrast, revisions for non-infected reasons were not associated with HbA1c levels (Table 3, Figure 1b).

Figure 1b:

Kaplain-Meier Curve of Non-Infected Revisions after IPP stratified by Hba1c%

Discussion

In a large, national cohort of men undergoing inflatable penile implantation, the current report found that as HbA1c levels increase, the need for surgical management of prosthetic infection increases and those revisions occur sooner. In contrast, the risk of IPP revision for other causes is not associated with degree of blood sugar control. Infection is one of the most dreaded complications in prosthetic urology, and can lead to subsequent explantation, penile shortening, patient morbidity and dissatisfaction, and increased healthcare costs. Because revision surgery has a two- to five-fold increased chance of infection over virginal implant surgery, the best opportunity for an infection-free outcome lies in optimizing the first ^11,12 Advancements in both technology and surgical techniques have all had a common goal of increasing implant longevity and decreasing the risk of implant infection, but proper preoperative evaluation and patient selection must take place as well.

Early series that examined the relationship between DM and implant infection were been largely inconclusive. A 1995 Wilson et. al retrospective series of 1,337 inflatable penile prostheses found a non-significant difference in infection rates in diabetics (3%) versus nondiabetics (1%)¹³. A series by Montague et al of 491 IPPs inserted from 1986 to 1999 also did not find a statistical difference in infection between diabetics (2.2%) and nondiabetics (2%)¹⁴. Importantly, these studies did not take into account metrics of glycemic control. Bishop et al’s 1992 series examined the infection risk in 90 patients after stratifying by HbA1c levels and found that diabetic patients, especially those with HbA1c>l1.5%, had an increased rate of periprocedural infection¹⁵.

More recent data on prosthetics suggest an association between infectious risk and glucose control. Indeed, it is well-established in the orthopedic literature that patients with poorly controlled DM are at significantly increased risk of periprocedural infections while patients with well-controlled DM have similar outcomes to nondiabetic patients^16,17. Examining penile prostheses, a 2017 retrospective multi-institutional study by Habous et. al attempted to discern an HbA1c level above which the risk of penile implant infection increases. Their review of 902 penile implants performed in the post-antibiotic coating era of 2009-2015 found on Receiver Operating Characteristic (ROC) curve analysis that an HbA1c threshold of 8.5% was the best predictor of infection with a sensitivity of 80% and specificity of 65%⁸. Unfortunately, a large majority of the implants (76%) were malleable, and no sub-analysis on the IPPs were performed, which limits application to inflatable penile implant surgery.

This relationship between DM and penile prosthesis infection is complicated by the parallel evolution of penile implant technology over time. Once antibiotic-coating innovations were applied to implants in the early 2000’s by both American Medical Systems (AMS) in 2001 and Coloplast in 2002¹⁸, infection rates decreased significantly independent of patient factors. A series of 39,000 AMS IPPs demonstrated that non-impregnanted implants had twice the risk of undergoing revision due to infection¹⁹. This relationship was confirmed a year later by Mandava et. al’s meta-Analysis of 14 clinical case studies including both AMS and Coloplast IPPs²⁰. However, independent of antibiotic coating status, a recent 2018 analysis of a New York statewide administrative database, reviewed almost 15,000 initial IPPs performed between 1995 and 2014 and found DM to be an independent risk factor of IPP infection regardless of whether the implant had antibiotic coating or not¹. An August 2020 meta-analysis of 6 studies, including 2,610 patients, found the relationship between HbA1c and penile prosthesis infection to be inconclusive⁹.

More recently, in a contemporary, international, multi-center retrospective study of 923 penile implant surgeries done between 2003 and 2018 at 18 high-volume institutions, Osman et. al report that neither preoperative HbA1c nor blood glucose levels were associated with postoperative infection rates¹⁰. The authors reported similar HbA1c levels among the men with and without prosthesis infections, with a median HbA1c level of 7.1%, an overall infection rate of 3.8% and revision rate of 7.1%. However, as the cohort consisted of high volume implanters, the applicability to implanters with more diverse surgical volumes is uncertain. The current report details a real-world analysis of procedures done throughout the US by a wide variety of providers.

Thus, clarity regarding the relationship between HbA1c and IPP infection risk in the modern post-antibiotic coating era continues to be lacking. This present study attempts to guide clinicians with an actionable HbA1c cutoff for preoperative patient counseling and risk assessment for an infection-related revision. While this study’s initial goals were to assess the risk in both malleable and IPP surgeries, limited numbers of revisions in the malleable cohort precluded further statistical analyses. Our findings on the IPP cohort demonstrate that HbA1c levels greater than 8.0% portend a higher risk of subsequent infection-related revision. The time to revision for infected prostheses is also shorter in patients with HbA1c greater than 10.0%. Among patients requiring non-infected revisions, worse glycemic control was not associated with either a difference in time to revision or risk for revision.

There are several limitations of this study that warrant discussion. Because this was an analysis of a population-based administrative claims database, the accuracy of the results rely on valid and proper coding of diagnoses and procedures²¹. Administrative claims data are also susceptible to selection bias depending on applied enrollment criteria²².Although the study uses a large sample of patients from across the United States, the population is insured and may limit generalizability to the rest of the United States or self-paying individuals. Certain factors are not available in the dataset that could have been potential confounders including surgeon experience, duration of surgery, surgical approach, perioperative or postoperative antibiotics, and implant manufacturer. It is possible that patients classified as having a first implant had a remote history of penile prosthesis implantation outside of database enrollment period. While HbA1c as a marker of glycemic control was utilized, additional detail regarding types of diabetic medications, duration of diabetes, or severity of diabetes as evidenced by end-organ damage were not available. In addition, microbiological data such as wound culture at time of infection, or preoperative urine culture evaluations were not available. The resulting analysis could only report on IPP outcomes due to limited numbers of malleable/self-contained patients. Not all patients had HbA1c levels available in the dataset and those individuals were not included in the analysis.

Appropriate patient selection and preoperative assessment and optimization of patient comorbidities are important to successful surgical outcomes. Specifically to diabetic management, preoperative interventions aimed at lowering HbA1c were shown to be sustainable in the postoperative period as well²³. While the overall risk of penile prosthesis infection remains modest, the current report notes an increased risk of infection for diabetic men with poor glycemic control. Thus, preoperative HbA1c assessment may provide important information regarding a man’s risk of acquiring a penile prosthesis infection and may also provide an opportunity for patient counseling and improved care.

Conclusions

While the overall risk of penile prosthesis infection remains modest, the current report notes an increased risk of infection for diabetic men with poor glycemic control.