Diagnostic Testing Approaches for Activated Protein C Resistance and Factor V Leiden: A Comparison of Institutional and National Provider Practices

Abstract

Objectives

To analyze the economic impact of testing for activated protein C resistance (APC-R) due to factor V Leiden (FVL) mutation with APC-R with reflexive FVL genotyping (algorithmic approach) or genotyping alone.

Methods

OptumLabs Data Warehouse (OLDW) data were used to assess testing approaches. Insurance claims for APC-R and FVL in 2013 were compared with the Mayo Clinic database. Centers for Medicare & Medicaid Services diagnostic fee schedules were used to assign costs.

Results

Of 19.3 million OLDW-covered individuals, 74,242 (0.385%) received 75,608 tests: APC-R, 2,265 (2.9%); FVL genotyping, 70,619 (90.1%); and both APC-R and FVL, 2,724 (7.0%). In total, 1,317 tests were performed at Mayo Clinic: APC-R with reflex FVL (1,256; 95.4%) and FVL alone (61; 4.6%). Costs per evaluated individual and per total population (person/year) in OLDW and algorithmic approach were $83.77 vs $36.38 and $0.32 vs $0.14, respectively.

Conclusions

The cost-optimized algorithmic approach reduces health care costs.

Materials and Methods

Venous thromboembolism (VTE) is a multifactorial disease with a global incidence of 0.75 to 2.69 cases per 1,000 people per year.¹ Acquired risk factors for VTE are common,² and activated protein C resistance (APC-R) due to factor V Leiden (FVL) mutation is currently the most commonly recognized hereditary risk factor among the white population.³ Activated factors V (Va) and VIII (VIIIa) are inactivated by activated protein C (APC), thus limiting thrombin generation and development of thrombosis.^4,5 The c.1691G>A; pArg534Gln mutation of the factor V gene (F5), commonly known as FVL, affects the cleavage site for APC and confers resistance to inactivation by APC, termed APC-R. Given the incidence of VTE in the general population and the prevalence of APC-R in the white population, laboratory testing to identify APC-R and/or FVL is frequently ordered.

Laboratory evaluation for APC-R can be approached in two ways: the first consists of initial plasma-based screening to detect the presence or absence of APC-R; reflexive DNA-based FVL genotyping is reserved for those with abnormal APC-R.^6,7 The second option consists of direct genotyping, without assessing the presence or absence of APC-R; this latter approach is likely the most commonly pursued strategy. Studies demonstrating relative costs of each approach have been published,^8-10 but population-based analysis of financial implications of current routine clinical practice is not available. Herein we analyzed the testing patterns from data obtained from the OptumLabs Data Warehouse (OLDW), compared ordering patterns with an algorithmic approach implemented at our institution, and determined the potential cost savings with the latter approach.

We conducted a retrospective analysis of administrative claims data from OLDW, which includes more than 100 million privately insured and a number of Medicare Advantage enrollees throughout the United States.¹¹ The database contains longitudinal data from geographically diverse regions across the United States, with greatest representation from the South and Midwest. The database contains professional, facility, and outpatient medication service claims for covered individuals enrolled in the health plans.¹² The data include enrollee information (insurance plan, sex, age race/ethnicity, dates of eligibility) and medical claims (including International Classification of Diseases, 9th Revision, Clinical Modification [ICD-9-CM] diagnosis codes; ICD-9 procedure codes; Current Procedural Terminology, version 4 [CPT-4] procedure codes; Healthcare Common Procedure Coding system procedure codes; sites of service codes; and provider specialty codes). Because this portion of the study involved analysis of preexisting, de-identified data, the Mayo Clinic Institutional Review Board deemed it exempt from institutional review board approval.

We identified all claims for FVL and an APC-R clot-based assay performed between January 2013 and December 2013 (calendar year 2013). If a test was performed multiple times in one day, we only counted it as one per day. To determine if the two tests were performed alone or in combination, we looked out 14 days from the initial test. We restricted the cohort to patients with continuous medical enrollment for the entire 2013 calendar year. Descriptive summary of testing patterns is reported.

Results

Study Setting, Design, and Patient Population

After institutional review board approval, we searched the Mayo Clinic Laboratory Information systems for all results of the APC-R and FVL mutation tests performed for patients seen in the Mayo Clinic (Rochester, MN) over the same time period (calendar year 2013). These tests were ordered on patients seen in the primary care clinics and multiple different specialties within the Mayo Clinic campus. The data were cross-referenced with a Special Coagulation Laboratory database that maintains information on all patients seen at the Mayo Clinic on whom special coagulation testing is performed.

Assay Method

The OLDW includes claims identified by CPT-4 codes for laboratory tests performed but does not include data on performing laboratory or assay method.

For the Special Coagulation Laboratory at the Mayo Clinic in Rochester, blood samples were collected in 3.2% sodium citrate tubes (Becton Dickinson, Franklin Lakes, NJ) centrifuged to prepare platelet-poor plasma as per Clinical & Laboratory Standards Institute guidelines¹³ and either assayed within 4 hours of specimen collection or frozen at –70°C until assay performance. The APC-R assay was performed using the COATEST APC Resistance V kit (Chromogenix/Instrumentation Laboratory, Bedford, MA) following the manufacturer’s instructions.

OptumLabs data warehouse testing pathway results based on defined testing events for 2013. APC-R, activated protein C resistance; FVL, factor V Leiden. ^a2,724 each for a total of 5,448 test orders.

APC-R Algorithm/Profile

Discussion

Statistical Analysis

The data were entered into Microsoft Excel (Microsoft, Redmond, WA) and descriptive statistics were calculated. Laboratory test costs of APCR and FVL were obtained from the Centers for Medicare & Medicaid Services (CMS) 2014 Clinical Diagnostic Laboratory Fee Schedule for appropriate CPT codes (85307 and 81241, respectively).¹⁵ We used the national limit from the fee schedule, which is a percentage of the median of all local fee schedule amounts for each test. These costs were then used to calculate total costs for testing in our OLDW and Mayo Clinic cohorts. The total costs were used to measure cost per patient and extrapolated to determine the cost potential savings per 100,000 standardized population.

Of the 100 million cumulative patients in the database, 19.3 million unique individuals met our study criteria of continuous coverage over the study period (calendar year 2013). After application of our testing criteria, which included grouping of tests into testing episodes, defined as a 14-day window after the initiation of a performed test to determine if a patient had only one of the tests or both, and the criteria of continuous enrollment for 2013, it was revealed that of a total of 19.3 million unique individuals with continuous coverage in 2013, a total of 78,332 tests were performed on 74,242 (0.385%) unique individuals. Approximately 15% were 60 years or older, and in approximately 15%, age was not available; 56% of the total study sample were female.

Frequency of testing consisted of the APC-R test alone (2,265; 2.9%), FVL testing alone (70,619; 90.1%), and both APC-R and FVL tests (2,724; 7.0%), resulting in an approximate ratio of APC-R to FVL of 1:15. Of those having both the APC-R and FVL tests, more than half (54.6%) of the APC-R tests were followed up with FVL, and only a small number of FVL tests were followed up by APC-R (0.2%) Figure 2.

Over the study period, 379,762 unique individuals received care at the Mayo Clinic in Rochester, for whom a total of 1,317 (0.347%) tests for assessment of APC-R/FVL were ordered and performed. The APCR-R was performed on a total of 1,256 (95.4%) patients, whereas the FVL assay alone was performed on 61 (4.6%), resulting in an APCR-R to FVL test ratio of approximately 20:1. Of the 1,256 APCR-R tests, 38 (3.0%) had the FVL ordered and performed simultaneously; review of clinical notes revealed no documentation of the rationale for ordering both the assays simultaneously. During the study period, the performing laboratory did not have systems in place to prevent duplicate test performance.

For those having the APCR-R, 1,023 (81.0%) of 1,256 patients had a normal APC-R ratio, and thus FVL was not indicated or performed; all 38 patients who had the APCR-R and FVL ordered simultaneously had a normal APC-R ratio and were wild type (negative) for the FVL mutation.

Of the 1,256 undergoing APCR-R, in three patients with a reduced APC-R, reflexive FVL testing was cancelled once results of previous FVL testing performed elsewhere were brought to the attention of the laboratory; the APC-R ratio was indeterminate in 119 patients, thus prompting reflexive FVL testing; and 114 (9.1%) had an abnormally low APC-R ratio indicative of the presence of APC resistance. Reflexive FVL testing, to genotype this cohort, demonstrated that 109 (96.0%) of 114 were heterozygous. One (0.9%) of 114 was homozygous; this patient, who was wild type, was a recipient of an ortho- topic liver transplant and presumably received an allograft from a patient who was a FVL carrier, resulting in a discrepancy between the APC ratio and the FVL result.

The 61 patients receiving FVL testing as the only test (34/61; 55.8%) were wild type, 26 (42.6%) of 61 were heterozygous, and one (1.6%) of 61 was homozygous. In 50 of these orders, there was no mention of ordering rationale in the medical record; six patients were taking anticoagulants that interfered with the APC-R assay, and in seven patients, confirmation of zygosity was the indication Figure 3.

OLDW

Using the 2014 CMS Clinical Diagnostic Fee Schedule for CPT codes,¹⁵ standard reimbursement rates were applied to create cost scenarios for the testing patterns seen in the OLDW and the Mayo Clinic Special Coagulation Laboratory Database. Comparisons of the cost per evaluated individual and also the cost per individual in the total population were compared, and the savings opportunity when using an APC-R profile testing approach was calculated.

Mayo Clinic Special Coagulation Laboratory Database

Given that the intent of this analysis was to demonstrate the cost savings using the APCR-R profile, the cost of testing in the Mayo Clinic Special Coagulation Laboratory Database (outlined in Table 1) was restricted to those patients who only had the APCR-R profile ordered. As mentioned above, 38 patients had the APCR-R profile and FVL tests ordered, and 61 patients had the FVL testing ordered.

Mayo Clinic Special Coagulation Laboratory database testing pathway results for 2013. APC-R, activated protein C resistance; FVL, factor V Leiden. ^aFVL was ordered in addition to APC-R with reflex FVL and was unnecessary given the wild-type results.

Based on the pattern of testing, the cost per evaluated individual was $83.77 and $36.38 in the OLDW and Mayo Clinic, respectively; the cost-savings opportunity was $47.39 per evaluated individual. When the data were normalized, the total cost of testing per 100,000 individuals was $0.32 and $0.14 in the OLDW and Mayo Clinic populations, respectively, with a resulting cost savings opportunity of $0.18 per population individual and $18,245.02 per 100,000 Table 2 .

In general, laboratory tests can be broadly categorized as screening and diagnostic assays; the former are typically used to screen for the presence or absence of disease, whereas the latter provide confirmatory evidence (or lack thereof) of disease. The optimal choice of assay will vary with the performance characteristics of the assay (eg, sensitivity, specificity, and positive and negative predictive values), as well as population prevalence of disease; lower cost screening assays with high sensitivity are likely more cost-effective when population prevalence of disease is low, whereas a diagnostic test as an initial test may be more appropriate with a high population prevalence of disease.

References

Total Cost of Testing Scenarios

In this study, using administrative claims data representing a broad sample of privately insured people in the United States, we confirmed the ordering practice patterns reported from single-institution studies.²⁰ Although data from the OLDW do not provide the results of testing or the indications for testing, the comparative data from our institution confirm the modest prevalence of APC-R/FVL in the tested population and suggest that an algorithmic approach to APC-R/FVL testing is likely to be cost-effective. In addition to being more cost-effective, from a clinical standpoint, the APC-R is more clinically meaningful. Hepatocytes are the main source for circulating factor V, whereas FVL testing is performed on peripheral blood leukocyte genomic DNA. Thus, patients with FVL undergoing orthotopic liver transplantation or hematopoietic stem cell transplant may have discrepant APC-R and FVL results.^21-24 Thus, the APC-R may be a better reflection of increased risk of thrombosis than FVL genotype by itself and hence more useful in clinical decision making.⁹

From a cost standpoint, as we have demonstrated, the two testing approaches have very different financial implications. Costs for the APC-R profile are $36.38 per evaluated individual, which on a large scale and taken over the entire population cost approximately $0.14 per covered individual. By comparison, the testing pattern demonstrated in the OLDW results in a cost of $83.77 and $0.32 per evaluated individual and per population member, respectively, an approximately twofold higher payer cost. Our analysis is based only on patients undergoing testing with the APCR-R profile, whereas FVL was ordered in 38 and 61 patients in addition to the APCR-R and as an initial test, respectively. Based on an analysis of the actual practice, the cost per evaluated individual would increase to $40.82, and the annual savings per 100,000 covered lives would decrease to $15,715.05.

A small proportion (3.1%) of patients in the OLDW had both APC-R and FVL testing, and of those, 92.1% had both APC-R and FVL ordered on the same day. From the data available, it was not possible to determine whether those who had APC-R and FVL ordered the same day were sent to laboratories that offer the APC-R profile or whether both assays were ordered more for convenience of the patient, reducing the need for a return visit for follow-up FVL testing, or simply a lack of understanding of the information received from the assays. Our data and that of others demonstrate that in approximately 80% of tests, FVL testing is not needed.²⁵ Extrapolating the OLDW data, where approximately 0.385% of the covered population underwent APC-R/FVL evaluation, to a national level, we estimate that approximately one million individuals are tested for APC-R/FVL annually. In addition to appropriate patient selection, a cost-effective approach to testing is essential.

Limitations to this data analysis warrant discussion. This OLDW data set identifies only outpatient testing scenarios, and the symptomatology of the evaluated patients, including results of testing and population prevalence of APC-R/FVL in the evaluated individuals, remains unknown. In addition, the 14-day window may have precluded the inclusion of additional APC-R or FVL tests, but the impact on the cost analysis is not likely to be significant. In addition, while we have applied CMS reimbursement rates, commercial insurers may have different arrangements that can offer different financial conclusions to this analysis. In addition, this study does not address the impact of testing for APC-R/FVL on patient care, thus precluding a formal cost-effectiveness analysis.

What can be done to encourage proper test utilization for APC-R/FVL? Several parallel interventions may ensure long-term success. Educating ordering providers, although a daunting task given the diversity of ordering providers, is critical but unlikely to suffice. Recent “choosing wisely” initiatives from specialty societies are steps in the right direction.²⁶ The electronic orders systems can be programed to assist the provider in choosing the right test and help reduce duplicate orders. In addition, ceding control of optimal testing to the performing laboratory is an option that has been successful in our institution but may pose challenges to reference laboratories, and finally changing test reimbursement rates or noncoverage of tests is a more drastic option. The latter would likely increase out-of-pocket expenses for the patient.

In conclusion, we demonstrate the cost savings of an algorithmic approach using an optimized plasma-based assay for detection of APC resistance rather than the DNA-based FVL assay.