CD34 + cell therapy significantly reduces adverse cardiac events, health care expenditures, and mortality in patients with refractory angina

Abstract Patients with refractory angina who are suboptimal candidates for further revascularization have improved exercise time, decreased angina frequency, and reduced major adverse cardiac events with intramyocardial delivery of CD34+ cells. However, the effect of CD34+ cell therapy on health care expenditures before and after treatment is unknown. We determined the effect of CD34+ cell therapy on cardiac‐related hospital visits and costs during the 12 months following stem cell injection compared with the 12 months prior to injection. Cardiac‐related hospital admissions and procedures were retrospectively tabulated for patients enrolled at one site in one of three double‐blinded, placebo‐controlled CD34+ trials in the 12 months before and after intramyocardial injections of CD34+ cells vs placebo. Fifty‐six patients were randomized to CD34+ cell therapy (n = 37) vs placebo (n = 19). Patients randomized to cell therapy experienced 1.57 ± 1.39 cardiac‐related hospital visits 12 months before injection, compared with 0.78 ± 1.90 hospital visits 12 months after injection, which was associated with a 62% cost reduction translating to an average savings of $5500 per cell therapy patient. Patients in the placebo group also demonstrated a reduction in cardiac‐related hospital events and costs, although to a lesser degree than the CD34+ group. Through 1 January 2019, 24% of CD34+ subjects died at an average of 6.5 ± 2.4 years after enrollment, whereas 47% of placebo patients died at an average of 3.7 ± 1.9 years after enrollment. In conclusion, CD34+ cell therapy for subjects with refractory angina is associated with improved mortality and a reduction in hospital visits and expenditures for cardiac procedures in the year following treatment.


| INTRODUCTION
As mortality from coronary artery disease declines, a growing number of patients experience refractory angina each year. 1 The European Society of Cardiology has defined refractory angina as "a chronic condition characterized by the presence of angina caused by coronary insufficiency in the presence of coronary artery disease which cannot be controlled by a combination of medical therapy, angioplasty, and coronary bypass surgery." 2 Patients with refractory angina are often ineligible for further surgical revascularization owing to comorbidities or advanced age with suboptimal coronary anatomy due to diffuse disease or chronic total occlusions. 3 The prevalence of refractory angina is unclear, with estimates varying from 300 000 to 1.7 million patients in the United States 1,4 and up to 200 000 new cases per year. 5 Because of the poor quality of life 6 and high resource use 7 associated with this patient population, the development of effective and cost-efficient therapies is critical.
There has been ongoing interest in therapeutic angiogenesis as a method of improving cardiac perfusion. 3,8 Preclinical studies have shown that intramyocardial transplantation of progenitor cells into ischemic tissue stimulates blood vessel growth. 9,10 In particular, cells expressing the surface protein CD34 + have demonstrated heightened efficacy in promoting neovascularization of myocardium. 11 Strong preclinical data led to the development and implementation of three double-blind, placebo-controlled trials of CD34 + cells with similar designs. 12-15 Recently, a patient-level meta-analysis of these trials demonstrated a significant improvement in exercise time, a reduction in angina and in major adverse cardiac events, 15 and an improvement in exercise capacity compared with subjects randomized to placebo. 15 Despite these promising results, the effect of CD34 + cell therapy on cardiac-related events, hospitalizations, and costs is unknown.
Although these patients are believed to have high health care costs, investigation into their health care expenditures is limited. 16 Therefore, we compared the number of cardiac hospital admissions and cardiovascular procedures in the 12 months prior to treatment vs the 12 months after treatment for patients randomized to injection of autologous CD34 + cells compared with placebo. We then conducted a cost analysis to determine whether CD34 + cell therapy was associated with a reduction in hospital expenditures within the first year after treatment. Neupogen; Amgen Inc., Thousand Oaks, California) followed by apheresis on day 5 of mononuclear cells enriched for CD34 + cells using a commercially available device. [12][13][14] Patients were randomly assigned to one of three doses of CD34 + cells (1 × 10 4 cells per kilogram, 1 × 10 5 cells per kilogram, or 5 × 10 5 cells per kilogram) or placebo delivered by intramyocardial injections with the NOGA Myostar catheter following electromechanical endocardial mapping using the NOGA system (Biologics Delivery Systems, Diamond Bar, California) to identify ischemic regions of myocardium prior to injection of CD34 + cells. A standard of care arm was implemented in the phase III trial only and was not included in this retrospective review. 14,17 Complete protocols for these trials have been previously described. [12][13][14]17 Cardiac-related hospital admissions and cardiovascular procedures were tabulated from electronic medical records for 12 months preceding injection of autologous CD34 + cells and for 12 months following injection. Hospital visits for cardiac rhythm abnormalities (including atrial fibrillation, supraventricular tachycardia, ablation procedures, and internal

| RESULTS
A total of 37 patients who received autologous CD34 + cells were included in this study. The mean age was 57.9 ± 7.5 years, and 13.5% of patients were female. Baseline characteristics are shown in Table 1.
Patients randomized to CD34 + cell therapy experienced an average of 1.57 ± 1.39 cardiac-related hospital visits 12 months before injection compared with 0.78 ± 1.90 cardiac-related hospital visits 12 months after injection (P = .002, Table 2). Overall, the cell therapy group experienced a 50% reduction in hospital visits in the year following CD34 + cell therapy.
When considering interventional coronary procedures only, patients in the CD34 + group experienced an average of 1.2 ± 0.91 events (n = 18) 12 months before injection compared with 0.32 ± 0.75 events (n = 6) 12 months after injection (P < .0001). Overall, the cell therapy group experienced a 73% reduction in coronary procedures in the 12 months following their injection. The total median variable costs of all cardiac hospital visits and procedures significantly decreased by 62% in the cell therapy group following injection (P = .03, Mortality in the CD34 + group since enrollment was significantly less than in the placebo group. The total number of deaths in the CD34 + group was nine (24%), compared with eight (47%) in the placebo group. In the CD34 + group, five deaths were due to cardiovascular disease, two deaths were due to cancer, and cause of death was unavailable for two subjects. The average time between treatment with CD34 + cells and death was 6.5 ± 2.4 years. In contrast, placebo patients died an average of 3.7 ± 1.9 years after enrollment, resulting in a significantly shorter timespan compared with the CD34 + group (P = .02).
Although not the focus of this investigation, subjects randomized to the placebo group (n = 19) also experienced fewer hospitalizations and procedures in the year following injection, from 1.26 ± 0.87 hospital visits and procedures before injection to 0.63 ± 1.42 hospital visits after injection, although this decline was not significant because of the smaller sample size. However, postinjection placebo subjects did exhibit a significant 70% reduction in their health care expenditures, that translated to a significant cost savings of $3700 per subject, although less than the total cost savings per patient in the CD34 + treatment group (Table 4).

| DISCUSSION
In the 12 months following intramyocardial injection of CD34 + stem cells, significant reductions in cardiac-related ED visits and hospital admissions, interventional coronary procedures, and associated hospital expenditures were observed compared with the 12 months before injection.
The reduction in hospital visits following CD34 + therapy is consistent with results from a recent analysis of a European cell therapy trial 18  ineligibility for further revascularization rather than improvements in coronary artery disease. In contrast, we recently reported that up to 25% of "no-option" patients with refractory angina will still undergo revascularization less than 2 years following this diagnosis. 19 Importantly, ours is the first study to document a reduction in mortality in addition to the decrease in health care costs and adverse events with the CD34 + cell product and is the only cost study that included a placebo group. We observed that mortality was halved for those patients that received CD34 + compared with patients who received placebo. Furthermore, among patients who eventually died, those that received CD34 + cells lived twice as long as those who received placebo, supporting a true therapeutic benefit for this therapy.

DATA AVAILABILITY STATEMENT
The data from this study is not available as it is patient protected health information.