Peripheral artery disease (PAD) affects approximately 8.5 million Americans over the age of 40 years and 202 million people worldwide.1 Patients with diabetes and PAD represent a high-risk subgroup with worse clinical outcomes.2,3 PAD may lead to critical limb ischemia (CLI), limb amputations, and disability which increases the financial burden on the patient and healthcare system.1,4
The Trial to Assess Chelation Therapy (TACT) showed that in patients with a history of myocardial infarction, treatment with ethylenediamine tetra-acetic acid (edetate disodium) improved cardiovascular outcomes compared to placebo.5,6 The greatest effect was observed in the subgroup of patients with diabetes and PAD, with a 41% relative risk reduction in combined major adverse cardiovascular events.7 Subsequent case reports8,9 and a small open-label pilot study in patients with diabetes and CLI suggested that treatment with edetate disodium was associated with a decrease in lower extremity amputations, improvement in wound healing, and quality of life.10
However, treatment studies of edetate disodium have focused on clinical efficacy and have not addressed costs of care. The cost of edetate disodium treatment in the United States is unknown and has been roughly estimated to be $400 million annually for ischemic heart disease,11 paid primarily by patients, not third-party insurers. Treatment of CLI is estimated to be $4.2 billion for hospitalization and $12 billion for annual costs of incident cases.12,13 Therefore, a therapy that might reduce the cost of care for CLI patients is of interest. The aim of the current study was to analyze the cost of care one year prior (pre-treatment) and one year after (post-treatment) the start of edetate disodium infusion in patients with diabetes and CLI.
Materials and Methods
This is a cost analysis of 7 patients with diabetes participating in an open-label study investigating the role of edetate disodium chelation in CLI. The initial study evaluated the efficacy of edetate disodium, the progression of lower extremity wounds, and quality of life during 30 weeks of chelation therapy in 10 patients.
The charts reviewed are from the patients who completed per protocol intention to treat 40 infusions of edetate disodium, which are 7 out of 10 participants of the original study. The other 3 patients received less than 20 edetate disodium infusions, 2 patients (3 infusions, and 11 infusions) elected for major amputation secondary to ischemic pain and one stopped treatment due to social issues.
The original study included 10 total patients. Only patients completing per protocol intention to treat 40 infusions of edetate disodium treatment were included in this analysis. Selection criteria have been previously published.10
Data from hospitalization and outpatient visits was collected from the electronic medical records. The study was reviewed and approved by the Mount Sinai Medical Center Institutional Review Board. All patients signed informed consent for the edetate disodium open-label study. Charts were reviewed between 2014 and 2018. Index date was the start of edetate disodium therapy, and charts were reviewed a year before and a year after the index date.
The cost of treatment in patients with PAD includes office visits (cardiology, cardiovascular surgery/interventional radiology, podiatry), imaging (lower extremity arterial ultrasound, lower extremity angiogram, computed tomography of lower extremities, magnetic resonance imaging of lower extremities) and procedures (wound care, endovascular and surgical revascularization, and lower extremity amputation). For standardization of costs, the Healthcare Common Procedure Coding System (HCPCS) and national Medicare reimbursements were used.14
The focus of the current study was to assess the cost of treatment in patients before and after the initiation of edetate disodium chelation treatment. Thus, the cost of chelation therapy was not factored into the analysis. The evaluation of the treatment cost of the items mentioned is similar to studies assessing the expenditure of patients with CLI.
Categorical variables are descriptively summarized using percentages and continuous variables using mean, median, interquartile range, and standard deviation variables. To compare costs of treatment before and after edetate disodium infusions, the cost difference and percentage change was calculated for each participant and for all the population. The mean and median change were calculated from the continuous variables, favoring the median as a measure of central tendency due to the small number of patients and to reduce the effect of outliers. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute., Cary, NC).
Previous results and patient characteristics have been published.10 The study included 4 (57%) male, mean age ± standard deviation of 76 ± 8.3 years and baseline urine creatinine 0.92 ± 0.24 mg/dL. Past medical history included 2 (29%) with a smoking history, 6 (86%) with a history of coronary artery disease, and 4 (57%) with non-healing ulcers or dry gangrene. Patient characteristics are described in Table 1.
Summary of clinical response
From the 7 patients completing the 40 planned infusions of edetate disodium, 5 had complete wound resolution (Figures 1 and 2). There were no new active wound infections during treatment with edetate disodium. No antibiotic therapy was used during chelation treatment. No patient underwent minor or major amputation and only 1 required lower extremity revascularization during the infusion phase of the study. No major cardiovascular adverse event or death were observed. The pilot study showed a median improvement of 76.5% in the SF-36 pain score and an increase of 351% in the PAD Questionnaire quality of life.10
The pre-treatment annual cost of care ranged from $953 to $120,310, compared to post-treatment cost of $463 to $48,005. The total pre-treatment cost for all 7 patients was $238,766 (median $15,933 and interquartile range $43,247 to $7,537). The total post-treatment cost was $69,375 (median $1,295 and interquartile range $9,047 to $758). The difference between the pre-treatment and post-treatment cost was $169,391 (Table 2 and Figure 3).
As expected, lower extremity procedures comprised most of the expenditures. Revascularization and amputation limited to the pre-treatment infusions were observed in 6 patients. However, 1 patient did undergo lower extremity endovascular revascularization pre- and post-treatment. In all 7 patients, the post-treatment cost was lower than the pre-treatment.
Highest costs of care were observed with worse disease severity. For the 7 patients, the highest cost of care was present in patients with non-healing ulcers or dry gangrene ($100,073 and $121,605) (Table 2).
This post-hoc analysis suggests, in this very small pilot study setting, that edetate disodium-based treatments may reduce cost of care in patients with diabetes and CLI. Costs of treatment show a median percentage reduction of 85% after the start of edetate disodium. Admittedly, as we will discuss below, this does not include the cost of the edetate disodium-based infusions, as the cost is highly variable in the community.
The average cost of standard treatment after the diagnosis of CLI has been estimated to be $35,700 per patient-year.13 The cost of treatment is reduced in patients with less severe PAD ($12,701) although still higher compared to that of the general population.4,15 In the current study, pre-treatment CLI patients had a similar mean cost of care ($34,109) compared to patients with a new diagnosis of CLI.
After the start of edetate disodium, mean (median) costs of care per patients decreased from $34,109 ($15,933) to $9,911 ($1,295). Although not directly comparable, other studies have shown adjusted costs per patient-year from $49,200 to $55,700 after revascularization or amputation.13
The highest expenditures in patients with PAD or CLI are hospital inpatient care and to a lesser extent outpatient hospital-based visits.4,13,15,16 In the present study, the main factor affecting the difference in costs is a decrease in lower extremity procedures including revascularization and amputations.
Patients with more advanced disease ascertained by WIfI score had higher costs of care. A previous study demonstrated an average per-patient cost of $78,300 for rest pain, $91,200 for ulcer, and $116,400 for gangrene.13 The greatest treatment cost pre-treatment was in patients with gangrene.
The relevance of cost-effective therapies for CLI is highlighted by increasing costs and high morbidity and mortality. Total inpatient costs have increased by 50% from 2001 to 2007 ($579 to $870 million).17 Death or major amputation occurs in up to 29% after initial diagnosis, with a lower median survival compared to heart failure, stroke, or most cancers.13 This small sample size of 7 patients shows a possible decrease in interventions and amputations after initiation of edetate disodium therapy and a downstream reduction in cost of care.
No major cardiovascular adverse events or death were noted in patients enrolled in the pilot study, suggesting that edetate disodium treatment may be safe. In the CLI pilot study, 353 intravenous infusions of edetate disodium were administered to all patients, with no serious adverse events encountered.10 The TACT trial administered 55,222 infusions, with no statistically significant serious or non-serious adverse events in the edetate disodium arm compared to the placebo group.6
Cost of edetate disodium treatment
In the Miami community, the cost of a single edetate disodium-based infusion, similar to that which was used in the 7 patients pilot study, ranges from $200 to $400 per treatment; or $8,000 to $16,000 for 40 infusions. The sample is too small, and the variability in cost too great to comment on whether this therapy might reduce health care cost. Still, if edetate disodium treatment prevents amputations or leads to a reduction in pain, the cost-effectiveness of the therapy might be quite favorable.
This post-hoc analysis has many limitations. Most importantly this is a very small study. The design is post-hoc. There is no independent control group. At best, the conclusions must be considered hypothesis generating. A larger sample size study is needed for further analysis of the cost effectiveness of edetate disodium treatment in patients with diabetes and CLI.
Edetate disodium-based therapy may be an effective adjunct pharmacotherapy in the treatment of CLI. The present cost analysis suggests that this therapy may decrease costs of care in patients with diabetes and critical limb ischemia.
Currently ongoing studies, TACT2 and TACT3a, will further help in analyzing the cost effectiveness of edetate disodium therapy (www.tact2.org).
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Clinical Trials registration: NCT03424746
Manuscript submitted May 17, 2020, final version accepted May 22, 2020.
Address for correspondence: Gervasio A. Lamas MD, Columbia University Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Road, Suite # 2070A, Miami Beach, FL 33140.
Dr. Francisco Ujueta can be reached via email at:
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