Currentblue cross blue shield - south dakotaPolicy 08.01.28

Stem Cell Therapy for Peripheral Arterial Disease

Defines Wellmark/Blue Cross Blue Shield stance on the use of stem cell injections or infusions (autologous or allogeneic) to treat peripheral arterial disease (PAD), including critical limb ischemia, for plan members.

Policy Summary

Payerblue cross blue shield - south dakota

PolicyStem Cell Therapy for Peripheral Arterial Disease

Policy CodePolicy 08.01.28

Change TypeAnnual review — no material change indicated

Effective DateJun 1, 2018

Next Review Date

Key ActionDo not authorize stem cell injections or infusions for PAD/CLI outside of clinical trials; document prior revascularization attempts or ineligibility if submitted for review.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

insufficientevidence conclusion

19 RCTsRCTs in Rigato review

213PLX-PAD phase III

through Mar 2025maintenance timeline

Coverage Determination

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Investigational / Not covered as medically necessary

Policy coverage stance

Investigational treatment: Treatment of PAD (including but not limited to CLI) with injection or infusion of stem cells (concentrated bone marrow, expanded in vitro, stimulated peripheral blood, autologous or allogeneic) is considered investigational because evidence is insufficient to show improvement in net health outcomes.

Based on small randomized trials, systematic reviews, and meta-analyses showing no consistent benefit for survival, amputation-free survival, or reduction in major amputation; larger, well-designed RCTs are needed.

Coverage rationale and evidence-based criteria

Evidence-summary driven stance for stem cell therapies in PAD/CLI:

Overall evidence summary: Randomized controlled trials of intramuscular and intra-arterial autologous bone marrow–derived cell therapies have shown mixed results: some trials report improvements in secondary outcomes (ulcer healing, ABI, pain-free walking distance) but primary endpoints such as major amputation, amputation-free survival, or targeted ABI increases were not consistently met.

See Prochazka, JUVENTAS, PROVASA, RESTORE-CLI, PACE.

Quality and heterogeneity: Systematic reviews and pooled analyses identify substantial heterogeneity in cell types, cell dose/volume, routes of administration (intramuscular vs intra-arterial), and trial quality; many studies are small, pilot or phase 2 and at risk of bias, limiting generalizability of positive secondary findings.

Meta-analyses of low-bias trials have not shown significant benefit for overall survival or amputation outcomes.

When therapy may be considered investigational or unproven: Because high-quality evidence demonstrating durable, clinically meaningful improvements in major clinical endpoints is lacking, stem cell–based and colony-stimulating–factor mobilization therapies for PAD/CLI are considered investigational for routine coverage; short-term or physiologic improvements observed in some trials do not establish net health benefit.

JUVENTAS and PROVASA did not meet primary endpoints; PACE (PLX-PAD) showed no AFS benefit; RESTORE-CLI showed reductions in some treatment failures but no significant difference in amputation rates.

Populations studied: Most randomized trials enrolled patients with severe or no-option CLI who had failed or were not candidates for revascularization; other trials examined intermittent claudication for growth-factor mobilization approaches.

See enrollment criteria and populations in Prochazka, JUVENTAS, PROVASA, Poole, Horie.

General coverage conclusion

Evidence summary and coverage inference

Evidence does not demonstrate consistent clinically meaningful benefit: Randomized trials (RESTORE-CLI, PACE, GM-CSF/G-CSF trials) show mixed or non-significant results for key clinical endpoints: RESTORE-CLI reported reduction in some treatment failures but no significant difference in amputation rates; PACE (PLX-PAD) showed no improvement in amputation-free survival; GM-CSF/G-CSF mobilization trials produced inconsistent functional and clinical endpoint improvements.

These findings support classifying cell-based and colony-stimulating–factor mobilization therapies as investigational or not medically necessary for routine care outside of clinical trials.

Treatment of peripheral arterial disease (PAD), including but not limited to critical limb ischemia (CLI), with injection or infusion of stem cells (concentrated bone marrow, expanded in vitro, stimulated peripheral blood autologous cells, or allogeneic sources) is classified as investigational because the evidence is insufficient to demonstrate an improvement in net health outcomes.

Off-the-shelf placental-derived mesenchymal stromal cell–like therapy (PLX-PAD) and expanded allogeneic mesenchymal stromal cell products have not demonstrated a significant improvement in key clinical endpoints (for example, no significant improvement in amputation-free survival in the phase III PACE trial) and therefore are not supported for routine coverage absent stronger evidence.

Regenerative medicine approaches for chronic limb‑threatening ischemia — including cell and gene therapies — should be limited to rigorously conducted randomized clinical trials, per Global Vascular Guidelines, and are not recommended for routine clinical use outside trial settings.

For coding and claims reporting, the policy references specific procedure CPT T‑codes for intramuscular autologous bone marrow cell therapy (0263T, 0264T, 0265T); use these codes and specify the appropriate type and place of service on claims.

Overall, stem cell therapy for PAD and CLI is considered investigational and is not supported as medically necessary due to insufficient and inconsistent evidence of clinically meaningful benefit in major outcomes such as limb salvage and survival.

Intra‑arterial or intramuscular administration of stem cell therapies for PAD/CLI has not consistently met primary endpoints (for example, major amputation reduction or ABI improvement) in randomized trials (JUVENTAS, PROVASA, RESTORE‑CLI, PACE) and therefore is not supported for routine coverage outside of clinical studies.

Cell‑based therapies and colony‑stimulating‑factor mobilization approaches (e.g., GM‑CSF/G‑CSF) for PAD/CLI show mixed and inconsistent results across randomized trials and meta-analyses; there is no consistent evidence of meaningful benefit in key clinical endpoints such as amputation‑free survival.

This portion of the document does not state a coverage determination for autologous bone marrow cell therapy specifically; refer to other sections of the policy for detailed medical necessity decisions and coding instructions related to autologous bone marrow cell procedures.

Coding and Procedure Codes

See Codes tablemixed

No codes listed

Procedure CPT T-codesCPT

0263T	Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure including unilateral or bilateral bone marrow harvest.
0264T	Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; complete procedure excluding bone marrow harvest.
0265T	Intramuscular autologous bone marrow cell therapy, with preparation of harvested cells, multiple injections, one leg, including ultrasound guidance, if performed; unilateral or bilateral bone marrow harvest only by separate physicians.

HCPCS / OtherHCPCS

No codes listed

Bone marrow volume required — large quantity (e.g., 240-500 mL) for adequate precursor cells

Required bone marrow volumeLarge quantity of bone marrow is required to obtain adequate numbers of functionally active autologous precursor cells (example range: 240–500 mL).

Purpose of large volumeHarvesting 240–500 mL is intended to supply sufficient monocytes, hematopoietic and mesenchymal progenitor cells for therapeutic preparations (concentrated bone marrow aspirate/BM-MNC).

ABI clinically significant change — increase > 0.1 mm Hg

Clinically significant ABI changeAn increase greater than 0.1 (0.10) in the Ankle–Brachial Index (ABI) is considered clinically significant.

ABI normative rangeNormative ABI range reported as approximately 0.96–1.2 mm Hg for reference context.

ABI use in trialsABI is used as an objective ischemia metric in trials and as an outcome measure alongside amputation-free survival and wound healing.

Normal transcutaneous oxygen pressure — 70–90 mm Hg

Normal transcutaneous oxygen pressure (TcPO2)Normal TcPO2 range is 70–90 mm Hg.

Measurement methodTcPO2 is measured with an oxymonitor and used as an objective ischemia metric in clinical trials.

Role in outcomesTranscutaneous oxygen pressure is listed among trial outcomes alongside ABI, Rutherford criteria, ulcer healing, and pain-free walking.

Prior Authorization, Documentation, and Billing Guidance

Prior Authorization

Prior Approval / Coverage Headline

Prior approval is Not applicable for this policy. However, treatment of PAD/CLI with stem cell or related cell/growth-factor therapies is considered investigational; requests may be denied on that basis.

Investigational treatments for PAD/CLI may be managed by denial if requested without trial or compelling evidence.

Prior Authorization

Prior Authorization for Stem Cell Therapies

Prior authorization may be required when billing for stem cell therapies. Documentation should demonstrate severe PAD/CLI and that the patient failed or was ineligible for guideline-based revascularization or standard therapies.

Document objective limb ischemia measures (ABI, ankle/toe pressures, TcPO2) and prior revascularization history or documented ineligibility.
Trials cited typically enrolled patients who had failed or were not candidates for revascularization.

Prior Authorization

Prior Authorization for Cell / Growth-Factor Therapies

When requesting coverage for cell- or growth-factor–based therapies (including expanded MSCs or growth-factor mobilization), include high-quality clinical trial evidence (randomized, controlled data) and specific outcome measures used in trials.

Provide randomized-trial–level documentation of efficacy (e.g., RESTORE-CLI, JUVENTAS, PROVASA, PACE) and relevant endpoints such as amputation-free survival and wound healing.
If only exploratory or phase II data are available, note that phase III trials have not consistently shown benefit for key endpoints.

Billing Rule

Prior Authorization for Listed CPT T-codes

For billing and prior authorization processes, report services with the specific CPT T-codes listed in the policy and follow payer-specific prior authorization pathways; policy maintenance runs through March 2025.

Use CPT codes 0263T, 0264T, 0265T as applicable.
Follow payer-specific prior authorization processes and note policy renewal/maintenance through March 2025.

Denial Risk

Insufficient Efficacy Evidence

Evidence from phase III trials is insufficient to demonstrate improvement in key clinical endpoints (for example, amputation-free survival). Several randomized trials failed to show reduced major amputation rates compared with placebo or standard care.

Phase III and randomized trials (e.g., JUVENTAS, PROVASA, PACE) did not show consistent AFS or major amputation benefit.
RESTORE-CLI showed some secondary outcome differences but no AFS benefit at 12 months.

Denial Risk

Coding-related Denial Risk

Services not reported with the listed CPT T-codes or without clear place/type of service and clinical documentation may be denied. Ensure claims include the appropriate CPT and place of service.

Report intramuscular autologous bone marrow cell therapy with CPT 0263T, 0264T, 0265T.
Specify Type of Service (Therapy) and Place of Service (Outpatient/Inpatient) as appropriate; missing or miscoded claims risk denial.

Documentation Required

Suggested Clinical Outcome Documentation

Document clinical outcomes that trials use to assess benefit for PAD/CLI when submitting requests: amputation-free survival, Rutherford criteria, ABI, transcutaneous oxygen pressure (TcPO2), ulcer healing, and pain-free walking.

Include baseline and follow-up measures for ABI (noting a clinically significant change >0.1), ankle/toe pressures, TcPO2 (normal 70–90 mm Hg), Rutherford classification, wound size/healing, and pain-free walking distance or treadmill time.

Documentation Required

Required Clinical Outcome Documentation

When requesting coverage or prior authorization, include required clinical outcome and trial-related documentation: objective measures of limb ischemia, prior treatments (revascularization attempts or documented ineligibility), and trial endpoints (AFS, wound healing, amputation rates).

Objective ischemia measures: ABI, ankle and toe systolic pressures, TcPO2.
History of conservative care and revascularization procedures; documentation if revascularization was attempted and failed or deemed infeasible.
Outcome data from trials if applicable: amputation-free survival, limb salvage/amputation rates, ulcer healing metrics, pain scores, and revascularization rates.

Billing Rule

Required Claim Coding Details

Required claim coding details: use CPT codes 0263T, 0264T, 0265T and specify the type and place of service. Failure to use these codes or to indicate appropriate place/type of service may result in claim denials.

CPT 0263T — Intramuscular autologous bone marrow cell therapy, complete procedure including harvest.
CPT 0264T — Intramuscular autologous bone marrow cell therapy excluding bone marrow harvest.
CPT 0265T — Bone marrow harvest only.
Specify Type of Service: Therapy; Place of Service: Outpatient or Inpatient as appropriate.

Step Therapy

Step Therapy Note

No formal step therapy program is specified in this policy. The policy emphasizes that cell/gene therapies are investigational and should follow guideline-based care pathways before consideration.

There are no listed step-therapy requirements, but requests should document adherence to guideline-based care where applicable.

Step Therapy

Step Requirement: Attempt Standard Therapy First

Step requirement: standard therapies should be attempted first. Revascularization and conservative management (including rehabilitation and wound care) should be attempted or documented as contraindicated before considering investigational cell therapies.

Document attempts at or ineligibility for surgical or endovascular revascularization.
If revascularization was attempted and failed, include operative/interventional reports and dates.

Step Therapy

Step After Guideline-Based Care

If considered at all, cell- or gene-based therapies are to be evaluated only after guideline-based care (including revascularization when feasible) has been attempted; randomized trials and guideline-based care represent the appropriate comparators.

Trials typically enrolled patients who were not candidates for revascularization or who had failed prior procedures; document how the patient compares to trial populations when using those data.

Key Definitions and Terms

Critical limb ischemia (CLI) — definition and characteristics

DefinitionCritical limb ischemia (CLI) is the end stage of lower‑extremity peripheral arterial disease (PAD) in which severe obstruction of blood flow causes ischemic rest pain, non-healing ulcers, or gangrene and confers a significant risk for limb loss.

Clinical characteristicsCLI is characterized by ischemic rest pain, tissue loss (ulcers or gangrene), and often reduced ankle or toe systolic pressures used as objective ischemia metrics.

Relevant outcomes/timeframeKey outcomes include amputation rates, amputation-free survival, wound healing, and pain-free walking, typically assessed at 3, 6, and 12 months postintervention.

Arteriogenesis vs angiogenesis — brief definition contrast

Arteriogenesis (brief)Arteriogenesis: enlargement of preexisting collateral arterioles driven by increased shear stress and recruitment/migration of bone marrow–derived monocytes to the perivascular space.

Angiogenesis (brief)Angiogenesis: capillary growth mediated by hypoxia-induced release of chemokines and cytokines (e.g., VEGF) leading to sprouting of small endothelial tubes from existing capillary beds.

Clinical implicationArteriogenesis produces larger collateral vessels potentially able to compensate for occluded arteries, whereas angiogenesis yields small capillaries less able to replace large-artery flow.

Critical limb ischemia (alternate entry) — CLI clinical metrics and characterization

CLI clinical metricsCLI is characterized by rest pain, non-healing ulcers or gangrene and is evaluated using objective ischemia measures such as ABI, ankle or toe systolic pressures, and transcutaneous oxygen pressure (TcPO2).

Functional and outcome measuresTrials assess outcomes including amputation-free survival, Rutherford criteria for limb status, ulcer healing, and pain-free walking distance/time.

Typical follow-up intervalsFollow-up at 3, 6, and 12 months is commonly used to monitor CLI treatment outcomes; longer-term follow-up is also of interest.

Concentrated bone marrow aspirate / BM-MNC — definition of therapeutic preparation

DefinitionConcentrated bone marrow aspirate (BM-MNC) refers to therapeutic preparations derived from autologous bone marrow that contain monocytes, hematopoietic and mesenchymal progenitor cells concentrated for intramuscular or intra-arterial delivery to stimulate neovascularization.

Intended mechanismThese preparations aim to induce arteriogenesis/angiogenesis through delivery of progenitor cells and cytokines to ischemic tissue.

Clinical trial contextRandomized and nonrandomized studies have evaluated intramuscular and intra-arterial concentrated bone marrow aspirate in CLI, with mixed results on primary endpoints like major amputation and ABI improvement.

ixmyelocel-T / expanded autologous bone marrow-derived cells — definition and trial context

Definitionixmyelocel-T consists of cultured and expanded monocytes and mesenchymal stem cells derived from a patient’s bone marrow aspirate (an expanded autologous bone marrow–derived cell product).

Trial contextIxmyelocel-T was evaluated in the RESTORE-CLI randomized, double‑blind, placebo‑controlled trials in patients with CLI who were not candidates for revascularization (phase II: 72 patients reported).

Reported outcomesRESTORE-CLI reported reductions in some treatment-failure components (e.g., wound surface area increase, de novo gangrene) but no significant difference in amputation rates at 12 months.

PLX-PAD — off-the-shelf placental-derived MSC-like therapy definition

DefinitionPLX-PAD is an off‑the‑shelf placental-derived mesenchymal stromal cell–like therapy administered via intramuscular injections.

Trial contextPLX-PAD was evaluated in the phase III PACE trial in patients with CLI unsuitable for revascularization (213 participants); no significant improvement in amputation-free survival was observed.

Safety/efficacy noteIn PACE, rates of revascularization and complete wound healing were comparable between PLX-PAD and placebo; adverse events were common and consistent with the CLI population.

GM-CSF / G-CSF mobilization — colony-stimulating factors mobilization definition

DefinitionGM‑CSF and G‑CSF mobilization refers to use of colony‑stimulating factors to mobilize progenitor cells into the peripheral blood for collection or to increase circulating progenitor cells, with subsequent administration (e.g., intramuscular transplantation) as a therapeutic strategy in PAD.

Trial evidenceRandomized trials of GM‑CSF and G‑CSF have produced mixed results: some functional outcomes (walking time, questionnaire scores) improved in select studies, but ABI and many clinical endpoints did not consistently improve.

Population studiedTrials have included patients with intermittent claudication and varying PAD severity; some analyses suggest benefit in subgroups with large progenitor cell increases.

Autologous bone marrow cell therapy — intramuscular autologous bone marrow cell therapy procedure definition

Procedure descriptionAutologous bone marrow cell therapy (intramuscular) involves harvest and preparation of a patient’s bone marrow‑derived cells followed by multiple intramuscular injections into the affected leg; these procedures are represented by CPT T‑codes 0263T–0265T.

Components and codingCPT 0263T describes the complete procedure including harvest; 0264T excludes the bone marrow harvest; 0265T describes the bone marrow harvest only when performed by separate physicians.

Therapeutic intentThe intramuscular injections deliver concentrated or prepared autologous marrow cells intended to promote neovascularization and improve limb outcomes in CLI or severe PAD.

OpenPayer

Stem Cell Therapy for Peripheral Arterial Disease

Coverage Determination

Coding and Procedure Codes

Prior Authorization, Documentation, and Billing Guidance

Clinical Background and Context

Key Definitions and Terms

Policy History and Maintenance