Populations	Interventions	Comparators	Outcomes
Individuals: · With dry eye symptoms consistent with meibomian glad dysfunction	Interventions of interest are: · Eyelid thermal pulsationPopulations	Comparators of interest are: · Standard treatment with warm compresses and eyelid massage	Relevant outcomes include: · Symptoms · Morbid events · Functional outcomes

Background

Dry Eye Syndrome

Dry eye syndrome (DES), dry eye disease, or dysfunctional tear syndrome, either alone or in combination with other conditions, is a frequent cause of ocular irritation that leads patients to seek ophthalmologic care. DES is considered a significant public health problem. It is estimated to affect between 14% and 33% of the population worldwide.^1,2, The prevalence of DES increases with age, especially in postmenopausal women. It is estimated that DES affects more than 7 million Americans older than 40 years of age,^1, and approximately 1 to 4.3 million Americans between 65 and 84 years of age.^3, Prevention and treatment of DES are expected to be of greater importance as the population ages.

Treatment

Current treatment options for Meibomian gland dysfunction include physical expression to relieve the obstruction, administration of heat (warm compresses) to the eyelids to liquefy solidified meibomian gland contents, eyelid scrubs to relieve external meibomian gland orifice blockage, and medications (eg, antibiotics, topical corticosteroids) to mitigate infection and inflammation of the eyelids.^4,5, These treatment options, however, have shown limited clinical efficacy. For example, physical expression can be very painful given the amount of force needed to express obstructed glands. Warm compress therapy can be time-consuming and labor intensive, and there is limited evidence that medications relieve MGD.^5, While the symptoms of DES often improve with treatment, the disease usually is not curable and may lead to substantial patient and physician frustration. Dry eyes can be a cause of visual morbidity and may compromise results of corneal, cataract, and refractive surgery. Inadequate treatment of DES may result in increased ocular discomfort, blurred vision, reduced quality of life, and decreased productivity.

Regulatory Status

In 2011, the LipiFlow® Thermal Pulsation System (TearScience; assigned the generic name of eyelid thermal pulsation system) was cleared by the U.S. Food and Drug Administration (FDA).^6, FDA classified the LipiFlow® System as class II (special controls) to provide a “reasonable assurance of safety and effectiveness” of the device. The LipiFlow® System was identified by FDA “as an electrically powered device intended for use in the application of localized heat and pressure therapy to the eyelids. The device is used in adult patients with chronic cystic conditions of the eyelids, including meibomian gland dysfunction (MGD), also known as evaporative dry eye or lipid deficiency dry eye.” FDA product code: ORZ.

Related Policies

• None

For members enrolled in a Fully Integrated Dual Eligible Special Needs Plan (FIDE-SNP): (1) to the extent the service is covered under the Medicare portion of the member’s benefit package, the above Medicare Coverage statement applies; and (2) to the extent the service is not covered under the Medicare portion of the member’s benefit package, the above Medicaid Coverage statement applies.

[RATIONALE: This policy was created in 2013 and has been updated regularly with searches of the MEDLINE database. The most recent literature update was performed through February 26, 2019.

Evidence reviews assess the clinical evidence to determine whether the use of a technology improves the net health outcome. Broadly defined, health outcomes are length of life, quality of life, and ability to function - including benefits and harms. Every clinical condition has specific outcomes that are important to patients and to managing the course of that condition. Validated outcome measures are necessary to ascertain whether a condition improves or worsens; and whether the magnitude of that change is clinically significant. The net health outcome is a balance of benefits and harms.

To assess whether the evidence is sufficient to draw conclusions about the net health outcome of a technology, 2 domains are examined: the relevance and the quality and credibility. To be relevant, studies must represent one or more intended clinical use of the technology in the intended population and compare an effective and appropriate alternative at a comparable intensity. For some conditions, the alternative will be supportive care or surveillance. The quality and credibility of the evidence depend on study design and conduct, minimizing bias and confounding that can generate incorrect findings. The randomized controlled trial (RCT) is preferred to assess efficacy; however, in some circumstances, nonrandomized studies may be adequate. RCTs are rarely large enough or long enough to capture less common adverse events and long-term effects. Other types of studies can be used for these purposes and to assess generalizability to broader clinical populations and settings of clinical practice.

Dry Eye Syndrome

Clinical Context and Purpose

The purpose of eyelid thermal pulsation in patients who have dry eye syndrome (DES) is to provide a treatment option that is an alternative to or an improvement on existing therapies.

The question addressed in this policy is; does the use of eyelid thermal pulsation in patients who have DES improve net health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients

The relevant population(s) of interest are patients with DES. DES is often classified into the aqueous-deficient subtype or the evaporative subtype, although classification is not mutually exclusive. DES is a multifactorial disease of the ocular surface that may require a combination approach to treatment. Meibomian gland dysfunction (MGD), characterized by changes in gland secretion with or without concomitant gland obstruction, is recognized as the most common cause of evaporative dry eye and may also play a role in aqueous-deficient dry eye.

Interventions

The treatment being considered is the use of eyelid thermal pulsation. The LipiFlow Thermal Pulsation System is a device developed to relieve MGD. This device heats the palpebral surfaces of both the upper and lower eyelids, while applying graded pulsatile pressure to the outer eyelid surfaces. The LipiFlow System is composed of a disposable ocular component and a handheld control system. Following application of a topical anesthetic, the heated inner portion of the LipiFlow eyecup is applied to the conjunctival surface of the upper and lower eyelids. The outer portion of the device covers the skin surface of the upper and lower eyelids. The device massages the eyelids with cyclical pressure from the base of the meibomian glands in the direction of the gland orifices, thereby expressing the glands during heating

Comparators

The following practices are currently being used to treat DES; current treatment options for MGD include physical expression to relieve the obstruction, administration of heat (warm compresses) to the eyelids to liquefy solidified meibomian gland contents, eyelid scrubs to relieve external meibomian gland orifice blockage, and medications (eg, antibiotics, topical corticosteroids) to mitigate infection and inflammation of the eyelids.

Outcomes

The general outcomes of interest are symptoms, change in disease status, functional outcomes and quality of life.

Timing

Follow-up of at least 6 months would be desirable to assess outcomes.

Setting

Thermal pulsation is provided in the outpatient setting.

Study Selection Criteria

Methodologically credible studies were selected using the following principles:

a. To assess efficacy outcomes, comparative controlled prospective trials were sought, with a preference for RCTs;
b. In the absence of such trials, comparative observational studies were sought, with a preference for prospective studies.
c. To assess longer term outcomes and adverse events, single-arm studies that capture longer periods of follow-up and/or larger populations were sought.

Comparative studies of eyelid thermal pulsation for the treatment of dry eye syndrome include 3 RCTs and 1 nonrandomized comparative study of the LipiFlow System (see Table 1). In the multicenter RCT by Lane et al (2012), controls crossed over to treatment after 2 weeks; therefore, only the 2-week follow-up is available (see Table 2).^7, Results at 2 weeks showed statistically significant improvements in the primary and secondary outcome measures. Trial limitations included the short-term follow-up (2 weeks) for the primary comparative outcomes, lack of masking, and lack of intention-to-treat analysis. In addition, the control intervention did not include massage along with the warm compress, which is a common treatment for meibomian gland dysfunction.

An RCT by Finis et al (2014), which reported on outcomes prior to crossover at 3 months, found a significant effect of treatment compared with controls for the primary outcome measure (Ocular Surface Disease Index [OSDI] score), but not for any other outcome measures.^8, The clinical significance of the 11.6-point improvement in OSDI score is unclear because final OSDI scores at 3 months (34.6 for LipiFlow, 40.0 for control) would still be classified as severe dry eye disease.

In a 2-stage multicenter RCT, Blackie et al (2016) evaluated treatment effects of the LipiFlow System for patients with meibomian gland function and dry eye symptoms.^9, The first stage involved the open-label evaluation of treatment effects over the short term. Trialists compared the single, in-office, LipiFlow treatment with conventional treatments consisting of warm compress and eyelid hygiene control therapy, conducted twice daily for 3 months. Significant treatment effects relative to controls were observed for OSDI scores and meibomian gland secretion score (higher scores reflect less dysfunction) (see Table 2). The second stage involved an observational crossover study to evaluate the long-term effects (from 3 to 12 months) of a single session using the LipiFlow System or in combination with other conventional treatments when considered necessary. Sustained treatment effects for the single LipiFlow treatment compared with the combination treatment subgroups were observed over the long-term for OSDI scores, but not for Meibomian gland secretion score. Trial limitations included lack of masking and lack of massage combined with warm compression, the usual treatment approach. The clinical significance of the 17- to 22-point improvement in OSDI scores observed across treatment and controls may be relatively small because final OSDI scores indicated that patients in both groups improved from severe disease to mild disease (treatment) or moderate disease (controls). The lack of blinding might also have led to an overestimation of the treatment effect of LipiFlow.

The nonrandomized trial by Zhao et al (2016) compared 25 patients undergoing a single LipiFlow treatment with 25 patients using warm compresses and lid massage.^10, At 4 and 12 weeks, between-group outcomes were similar for symptom change, change in meibomian gland force evaluator, and tear break-up time. At 12 weeks, change in Schirmer test scores also did not differ significantly between groups.

Three other studies have evaluated long-term outcomes for some trial subjects who had undergone LipiFlow treatment. The study by Greiner (2013)^11, evaluated 18 of 30 subjects from 1 site of the Lane trial (described above).^7, Several outcomes remained significantly improved from baseline, but the improvements were of lower magnitude at 1 year than at 1 month. Finis et al (2014) evaluated 26 patients at 6 months after LipiFlow treatment.^12, Several outcome measures remained improved 6 months after treatment. Another study of 20 patients conducted by Greiner (2016) found that most outcomes remained significantly improved up to 3 years relative to baseline.^13,

Table 1. Summary of Key Characteristics of Comparative Studies

					Interventions
Study	Countries	Sites	Dates	Participants	Active	Comparator
Lane et al (2012)7,	U.S.	9	Mar-May 2009	·   69 LipiFlow ·   70 control	Single LipiFlow treatment	Daily warm compress for 2 wk
Finis et al (2014)8,	Germany	NR	Apr 2012-Jun 2013	·   20 LipiFlow ·   20 control	Single LipiFlow treatment	Twice daily lid warming and massage
Zhao et al (2016)10,	Singapore	1	Feb 2012-Mar 2013	·   25 LipiFlow ·   25 control	Single LipiFlow treatment	Twice daily lid warm compresses and massage
Blackie et al (2016)9,	U.S.	9	Feb-Oct 2012	·   101 LipiFlow ·   99 control	Single LipiFlow treatment	Twice daily warm compress and eyelid hygiene control therapy for 3 mo

Table 2. Summary of Key Results of Comparative Studies

Study	MGS Scorea	TBUT, sb	OSDI Scorec	SPEED Scored	Symptom Score, %	Schirmer Test, mm
Lane et al (2012)7,
LipiFlow	7.9	1.5	14.7	6.2
Controls	0.5	0.1	8.1	3.5
p	<0.001	<0.001	<0.001	<0.001
Finis et al (2014)8,
LipiFlow	3.0	2.0	11.6	2.3
Controls	2.5	0.2	0.1	1.2
p	NS	NS	0.029	NS
Zhao et al (2016)10,
LipiFlow		89.2%			-30.5%	1.0
Controls		63.0%			-15.9%	-3.95
p		0.625				0.55
Blackie et al (2016)9,
LipiFlow	11.6		-23.4
Controls	4.5		-17.8
p	<0.001		0.007

MGS: meibomian gland secretion; NR: not reported; OSDI: Ocular Surface Disease Index; SPEED: Standard Patient Evaluation for Eye Dryness; TBUT: tear break-up time.

^a The Meibomian Gland Evaluator device was developed by TearScience to evaluate gland secretion through gland expression to determine if meibomian glands are blocked.

^b Practice parameters from the American Academy of Ophthalmology (2013) has indicated that a tear break-up time of <10 s is considered abnormal.^3, Note that Zhao et al (2016) is reported in percent not seconds.

^c The OSDI assesses the patient’s frequency and severity of dry eye symptoms in specific contexts during the week prior to the examination. The minimal clinically important difference for the OSDI ranges from 4.5-7.3 for mild or moderate disease. The overall OSDI score defines the ocular surface as normal (0-12 points) or as having mild (13-22 points), moderate (23-32 points), or severe (33-100 points) disease.^14,

^d The SPEED questionnaire is a self-reported measure of the frequency and severity of dryness, grittiness, scratchiness, soreness, irritation, burning, watering, and eye fatigue within 3 months of examination. It was developed by TearScience and validated in a 2013 study funded by TearScience.^15, In this validation study, the mean SPEED score of symptomatic subjects was 21.0 and the mean of asymptomatic subjects was 6.25.

For individuals who have dry eye symptoms consistent with meibomian gland dysfunction who receive eyelid thermal pulsation, the evidence includes 3 RCTs, a nonrandomized comparison study, and longer term follow-up of patients from RCTs and observational studies. Relevant outcomes are symptoms, morbid events, and functional outcomes. The trials do not provide strong evidence of long-term efficacy. Two RCTs have demonstrated positive findings for most outcome measures over the short term (up to 3 months). Observational studies have shown sustained treatment effects for most outcomes up to 3 years. The nonrandomized study showed similar outcomes for eyelid thermal pulsation and standard treatment. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Practice Guidelines and Position Statements

In 2013, the American Academy of Ophthalmology published preferred practice patterns guidelines on dry eye syndrome.^3,A number of treatment options were recommended. The use of thermal pulsation treatment devices was not mentioned.

U.S. Preventive Services Task Force Recommendations

Not applicable.

Ongoing and Unpublished Clinical Trials

Some currently unpublished trials that might influence this review are listed in Table 3.

Table 3. Summary of Key Trials

NCT No.	Trial Name	Planned Enrollment	Completion Date
Ongoing
NCT02894658	LipiFlow Versus Warm Compresses in Parkinson’s Disease	25	Jan 2020 (suspended)

NCT: national clinical trial.

^a Denotes industry-sponsored or cosponsored trial.]
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Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

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Index:
Eyelid Thermal Pulsation for the Treatment of Dry Eye Syndrome
LipiFlow System
Dry Eye, Treatment with Eyelid Thermal Pulsation of
Meibomian Gland Dysfunction, Treatment with Eyelid Thermal Pulsation of

References:
1. Fiscella RG. Understanding dry eye disease: a managed care perspective. Am J Manag Care. Dec 2011;17(Suppl 16):S432-439. PMID 22435675

2. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. Apr 2007;5(2):75-92. PMID 17508116

3. American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern Guidlines. Dry Eye Syndrome. San Francisco, CA: American Academy of Ophthalmology; 2013.

4. Nichols KK, Foulks GN, Bron AJ, et al. The international workshop on meibomian gland dysfunction: executive summary. Invest Ophthalmol Vis Sci. Mar 2011;52(4):1922-1929. PMID 21450913

5. Blackie CA, Korb DR, Knop E, et al. Nonobvious obstructive meibomian gland dysfunction. Cornea. Dec 2010;29(12):1333-1345. PMID 20847669

6. Medical devices; ophthalmic devices; classification of the eyelid thermal pulsation system. Final rule. Fed Regist. Aug 19 2011;76(161):51876-51878. PMID 21894651

7. Lane SS, DuBiner HB, Epstein RJ, et al. A new system, the LipiFlow, for the treatment of meibomian gland dysfunction. Cornea. Apr 2012;31(4):396-404. PMID 22222996

8. Finis D, Hayajneh J, Konig C, et al. Evaluation of an automated thermodynamic treatment (LipiFlow(R)) system for meibomian gland dysfunction: a prospective, randomized, observer-masked trial. Ocul Surf. Apr 2014;12(2):146-154. PMID 24725326

9. Blackie CA, Coleman CA, Holland EJ. The sustained effect (12 months) of a single-dose vectored thermal pulsation procedure for meibomian gland dysfunction and evaporative dry eye. Clin Ophthalmol. Jul 26 2016;10:1385-1396. PMID 27555745

10. Zhao Y, Veerappan A, Yeo S, et al. Clinical trial of thermal pulsation (Lipiflow) in meibomian gland dysfunction with preteatment meibography. Eye Contact Lens. Nov 2016;42(6):339-346. PMID 26825281

11. Greiner JV. Long-term (12-month) improvement in meibomian gland function and reduced dry eye symptoms with a single thermal pulsation treatment. Clin Experiment Ophthalmol. Aug 2013;41(6):524-530. PMID 23145471

12. Finis D, Konig C, Hayajneh J, et al. Six-month effects of a thermodynamic treatment for MGD and implications of meibomian gland atrophy. Cornea. Dec 2014;33(12):1265-1270. PMID 25321941

13. Greiner JV. Effects of a single thermal pulsation system treatment on meibomian gland function and dry eye symptoms. Eye Contact Lens. Mar 2016;42(2):99-107. PMID 26222095

14. Miller KL, Walt JG, Mink DR, et al. Minimal clinically important difference for the Ocular Surface Disease Index. Arch Ophthalmol. Jan 2010;128(1):94-101. PMID 20065224

15. Ngo W, Situ P, Keir N, et al. Psychometric properties and validation of the Standard Patient Evaluation of Eye Dryness questionnaire. Cornea. Sep 2013;32(9):1204-1210. PMID 23846405

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

0207T