Medical devices, including implants used for total hip arthroplasty (THA) and total knee arthroplasty (TKA) are regulated by the US Food and Drug Administration (FDA). The pathways to market vary based on the device classification; from low risk class I to high risk class III. Each device comes with a set of approved indications, called “on-label” indications, set by the FDA. These indications for use were developed when the device was first being tested for approval. Implant labeling has not co-evolved with surgical indications, as most orthopaedic implants are cleared through the 510(k) process, which conserves the labeling of the predicate device. Surgeons have the ability to override these indications, and the use of medical devices outside of their approved indications has become common in arthroplasty.
With the increased off-label use of arthroplasty devices and the growing apprehension regarding potential liability for off-label use of medical devices, concerns regarding their safety and longevity have intensified. While surgeons can legally use devices for off-label indications as long as it is in the best interest of the patient, the scrutiny regarding off-label use of orthopaedic implants has increased, largely in the wake of the Synthes federal criminal case regarding off-label use of Norian. While not the typical off-label marketing case, the Norian disaster shook peoples’ faith in the medical community. Some courts have ruled to allow disclosure of off-label status of a drug or device as a factor to consider in medical malpractice trials.1 A 2012 article in Fortune was fairly unflattering towards orthopaedic surgeons, highlighting them as “jocks of the surgical world” who have been quoted as saying they “simply don’t have time to pore over labels,” resulting in the regular use of devices in unapproved ways.
The reality is that patients have changed since the original labeling of many orthopaedic devices, particularly in terms of obesity. While indications for THA and TKA have expanded over the last 35 yr, implant labeling has largely remained stagnant, with conditions including obesity, developmental dysplasia, and many others (Table 1) still considered as contraindications. Previous research has studied the outcomes of certain specific off-label indications, but no study has examined the outcomes and longevity of off-label procedures as a whole. Some off-label indications have been found to increase the risk of aseptic hip arthroplasty revision, such as developmental dysplasia.2 However, others have found similar outcomes between obese and nonobese patients or alternative versus traditional bearings.3–5 The general question as to whether or not off-label use for THA and TKA results in inferior clinical and functional patient outcomes remains unanswered.
The purpose of this study was to determine the prevalence of off-label use of primary TKA and THA implants at a large academic tertiary hospital and to compare the outcomes associated with on-label and off-label use in terms of revision rate, activity level, functional, and general health status. We hypothesized that patients who undergo total joint arthroplasty for off-label indications achieve similar postoperative outcomes in terms of revision rate, function, and general health outcomes as those who undergo the operation for product labeled indications.
MATERIALS AND METHODS
This retrospective review was approved by our Institutional Review Board. Patients who underwent primary TKA or THA (CPT codes 27447 and 27130, respectively) at a large academic tertiary referral center between January 1, 2010 and June 30, 2010 were considered (n=705) (Figure 1). All revision, hemiarthroplasty, resurfacing and bilateral procedures were excluded (n=259). A retrospective convenience sample (n=276) was selected based on available baseline data.
Demographic, procedural, and implant data were obtained from the Electronic Health Record (EHR). Functional levels were collected from the EHR and were evaluated during the preoperative medical clearance visit. These scores range from class I to class IV, with lower scores indicating ordinary physical activity and higher scores indicating physical discomfort with activity.6 Details regarding revision surgeries, University of California Los Angeles (UCLA) activity scores, Short form-12 (SF-12), Knee Injury and Osteoarthritis Outcome Score (KOOS) or Hip Disability and Osteoarthritis Outcome Score (HOOS) were collected via questionnaires administered either over the phone or through the mail.
On-label versus off-label
The labeled indications from product inserts from multiple joint arthroplasty manufacturers (including Zimmer, Warsaw, IN; Stryker, Mahwah, NJ; Depuy, Warsaw, IN; Smith & Nephew, Andover, MA) were compiled (Table 1). After data collection, each device used in primary hip or knee surgery was categorized as “on-label” or “off-label” depending on the labeled indications, contraindications, warnings, and precautions for that particular device. Any surgery with a patient or device use that did not meet an indication for total joint arthroplasty or that met a contraindication, warning, or precaution was considered off-label.
Outcomes including revision rate, UCLA activity score, and SF-12, KOOS, and HOOS scores were adjusted for age and sex by fitting a logistic model and analyzed using the Wald chi-square test (SPSS, Chicago, IL).
Of the 276 patients, 225 patients responded to the survey (81.5% follow-up) with an average follow up of 2.4 yr (±0.2). Of these, implants were used off-label in 1524 (67.6%) of the procedures at our institution. Patients in the on-label group were slightly older than off-label patients (P=0.1), and had a higher percentage of women relative to the off-label group (P=0.21) (Table 2). Since obesity was an off-label indication, body mass index (BMI) was higher in off-label patients (mean BMI= 34.1) than on-label (mean BMI=25.9; P<0.0001). There were no differences between the two groups with regards to primary diagnosis or average number of comorbidities (P=0.21 and 0.7, respectively (Table 3). The groups were different in terms of functional class, with better functional scores observed more in the on-label group (P=0.0002).
After adjusting for age and sex, the revision rate for on-label (three of 73; 4.2%) compared with off-label (eight of 1524; 0.52%) was not significantly different (P=0.99). Similarly, no significant difference was observed between groups in terms of UCLA activity score, with on-label patients demonstrating a mean score of 5.9 and off-label patients having a mean score of 5.8 (P=0.68). These scores fall between “sometimes participates in moderate activities such as swimming or could do unlimited housework or shopping” and “regularly participates in moderate activities.” The majority of patients (n=110; 72.4%) had a single reason for being considered off-label (Table 4). Obesity was the most prevalent off-label indication (n=118; 77.6%). Age and sex adjusted changes in preoperative and postoperative SF-12 and KOOS or HOOS scores were not significantly different between groups (Table 5).
Off-label use of joint replacement is a common practice in orthopaedics. The increased prevalence of their use and the concern for surgeon liability warrant outcome studies for these procedures. Though many specific contraindications to joint arthroplasty have been studied, no study to date has looked at off-label uses as a whole. These results indicate that there are no differences in early failure rates for total joint arthroplasty between on-label and off-label indications, even after adjusting for age and sex. Revision rates were similar between the two groups, as were UCLA activity score and the preoperative to postoperative improvements observed with SF-12 and HOOS or KOOS.
The on-label patients were slightly older, perhaps because younger patients may get surgery for more off-label reasons such as congenital dysplasia, and obese patients get joint replacement at a younger age.7 The majority (68.4%) of procedures in our sample were performed for off-label indications, most of which were for obesity. Reported prevalence rates of obesity are 39% for THA patients8 and 55% for TKA patients.9 Considering the rising weight of Americans, it is reasonable to expect that the off-label use in obese patients will also rise. Obesity has been linked to increased postoperative morbidity, higher readmission rates, and decreased implant longevity.10 Other reports have shown no difference in mid-term (i.e. 11-year) survival, but significantly lower functional outcomes as measured by Harris Hip score and range of motion.11
The use of implants in alcoholic patients also is considered off-label use. A recent study by Harris et al.12 reported that for every point increase in the AUDIT-C score (a validated alcohol-misuse screening instrument) to above 1, the patient has a 29% increase in risk for postoperative complications. Pneumonia, stroke, pulmonary embolism, deep vein thrombosis, and deep infection were among the complications reported. While the current study did not directly compare complications, revision rate, and general health comparisons did not reflect any differences between the groups.
Kim et al.13 reported comparable Harris Hip Scores for THA patients with dysplasia, low dislocation and high dislocation types, and concluded that improvements in design and cementing techniques allow for acceptable results in these patients. This highlights the core issue of on-label and off-label use of arthroplasty implants, which is the fact that these indications have not co-evolved with the advances in techniques, products, and instrumentation used to medically and surgically treat patients.
There were several limitations to this study. The nonprobability technique of convenience sampling has inherent problems, and makes it impossible to estimate the amount of sampling error. We were limited to these patients due to the fact that they had sufficient baseline data. Additionally, the severity of comorbidities such as rheumatoid arthritis or obesity were not collected. Data pertaining to mild disease may not be generalizable to more severe cases. While it is important to recognize the potential bias with this sample, this pilot study as a first look at an important question helps to set a foundation for a larger study. The relatively low numbers available also render the study vulnerable to type-II error.
This pilot study suggests that certain off-label procedures may have similar short-term outcomes as on-label procedures. Further studies with higher numbers of patients would help to clarify whether there are additional issues to consider with off-label use. While these findings may not be generalizable to all off-label procedures, they may help ease tensions and concern for commonly encountered cases of off-label use. Further research is needed to determine whether or not off-label use of orthopaedic implants has any effect on the patients’ clinical and functional outcome.
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Keywords:Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved
total hip arthroplasty; total knee arthroplasty; off-label; indications; functional outcomes