Nebulizers

CMS Manual System, Pub. 100-03, Medicare National Coverage Determinations Manual, Chapter 1, Section 200.2, Section 280.1

For any item to be covered by Medicare, it must 1) be eligible for a defined Medicare benefit category, 2) be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member, and 3) meet all other applicable Medicare statutory and regulatory requirements.

The purpose of a Local Coverage Determination (LCD) is to provide information regarding “reasonable and necessary” criteria based on Social Security Act § 1862(a)(1)(A) provisions.

In addition to the “reasonable and necessary” criteria contained in this LCD there are other payment rules, which are discussed in the following documents, that must also be met prior to Medicare reimbursement:

• The LCD-related Standard Documentation Requirements Article, located at the bottom of this policy under the Related Local Coverage Documents section.

• The LCD-related Policy Article, located at the bottom of this policy under the Related Local Coverage Documents section.

• Refer to the Supplier Manual for additional information on documentation requirements.

• Refer to the DME MAC web sites for additional bulletin articles and other publications related to this LCD.

For the items addressed in this LCD, the “reasonable and necessary” criteria, based on Social Security Act § 1862(a)(1)(A) provisions, are defined by the following coverage indications, limitations and/or medical necessity.

Payment may be made for supplies that are necessary for the effective use of durable medical equipment. Such supplies include those drugs and biologicals which must be put directly into the equipment in order to achieve the therapeutic benefit of the durable medical equipment or to assure the proper functioning of the equipment. However, the coverage of such drugs or biologicals does not preclude the need for a determination that the drug or biological itself is reasonable and necessary for treatment of the illness or injury or to improve the functioning of a malformed body member.

A small volume nebulizer (A7003, A7004, A7005), and related compressor (E0570) are considered for coverage when it is reasonable and necessary to administer the following FDA-approved inhalation solutions listed below (refer to the Group 3 Codes in the LCD-related Policy Article for applicable diagnoses):

1. It is reasonable and necessary to administer albuterol (J7611, J7613), arformoterol (J7605), budesonide (J7626), cromolyn (J7631), formoterol (J7606), ipratropium (J7644), levalbuterol (J7612, J7614), metaproterenol (J7669), or revefenacin (J7677) for the management of obstructive pulmonary disease (refer to the Group 8 Codes in the LCD-related Policy Article for applicable diagnoses); or

2. It is reasonable and necessary to administer dornase alfa (J7639) to a beneficiary with cystic fibrosis (refer to the Group 9 Codes in the LCD-related Policy Article for applicable diagnoses); or

3. It is reasonable and necessary to administer tobramycin (J7682) to a beneficiary with cystic fibrosis or bronchiectasis (refer to the Group 10 Codes in the LCD-related Policy Article for applicable diagnoses); or

4. It is reasonable and necessary to administer pentamidine (J2545) to a beneficiary with HIV, pneumocystosis, or complications of organ transplants (refer to the Group 4 Codes in the LCD-related Policy Article for applicable diagnoses); or

5. It is reasonable and necessary to administer acetylcysteine (J7608) for persistent thick or tenacious pulmonary secretions (refer to the Group 7 Codes in the LCD-related Policy Article for applicable diagnoses).

6. It is reasonable and necessary to administer hypertonic saline (J7131) to a beneficiary with cystic fibrosis, bronchiectasis, or ciliary dyskinesia (refer to Group 15 Codes in the LCD-related Policy Article for applicable diagnoses); or

7. It is reasonable and necessary to administer ensifentrine (J7601) as an add-on therapy for the management of chronic obstructive pulmonary disease (see Group 16 Codes in the LCD-related Policy Article) in beneficiaries who are on dual long-acting beta-agonist (LABA) and long-acting muscarinic-agonist (LAMA) therapy, or triple LABA+LAMA and inhaled corticosteroid (ICS) therapy, and experience one of the following (see the POLICY SPECIFIC DOCUMENTATION REQUIREMENTS in the LCD-related Policy Article):   

• Continued COPD exacerbations; or
• Persistent dyspnea.

Use of ensifentrine (J7601) without either dual LABA/LAMA maintenance therapy or triple LABA/LAMA/ICS maintenance therapy will be considered not reasonable and necessary. 

Compounded inhalation solutions (J7604, J7607, J7609, J7610, J7615, J7622, J7624, J7627, J7628, J7629, J7632, J7634, J7635, J7636, J7637, J7638, J7640, J7641, J7642, J7643, J7645, J7647, J7650, J7657, J7660, J7667, J7670, J7676, J7680, J7681, J7683, J7684, J7685, and compounded solutions billed with J7699) will be denied as not reasonable and necessary.

If none of the drugs used with a nebulizer are covered, the compressor, the nebulizer, and other related accessories/supplies will be denied as not reasonable and necessary.

A large volume nebulizer (A7007, A7017), related compressor (E0565 or E0572), and water or saline (A4217 or A7018) are considered for coverage when it is reasonable and necessary to deliver humidity to a beneficiary with thick, tenacious secretions, who has cystic fibrosis, bronchiectasis, a tracheostomy, or a tracheobronchial stent (refer to the Group 5 Codes in the LCD-related Policy Article for applicable diagnoses). Combination code E0585 will be covered for the same indications.

An E0565 or E0572 compressor and filtered nebulizer (A7006) are considered for coverage when it is reasonable and necessary to administer pentamidine to beneficiaries with HIV, pneumocystosis, or complications of organ transplants (refer to the Group 1 Codes in the LCD-related Policy Article for applicable diagnoses).

A small volume ultrasonic nebulizer (E0574) and related accessories are considered for coverage when it is reasonable and necessary to administer treprostinil inhalation solution to beneficiaries with pulmonary hypertension only (refer to the Group 11 Codes in the LCD-related Policy Article for applicable diagnoses). Claims for code E0574 used with other inhalation solutions will be denied as not reasonable and necessary.

Treprostinil inhalation solution (J7686) is considered for coverage when either criteria 1-3; or, criterion 4 are met:

1. The beneficiary has a diagnosis of pulmonary artery hypertension (refer to the Group 11 Codes in the LCD-related Policy Article for applicable diagnoses); and

2. The pulmonary hypertension is not secondary to pulmonary venous hypertension (e.g., left sided atrial or ventricular disease, left sided valvular heart disease) or disorders of the respiratory system other than interstitial lung disease (see criterion 4) (e.g., chronic obstructive pulmonary disease, obstructive sleep apnea or other sleep disordered breathing, alveolar hypoventilation disorders); and

3. The beneficiary has primary pulmonary hypertension or pulmonary hypertension which is secondary to one of the following conditions: connective tissue disease, human immunodeficiency virus (HIV) infection, cirrhosis, anorexigens or congenital left to right shunts. If these conditions are present, the following criteria (a-d) must be met:

   1. The pulmonary hypertension has progressed despite maximal medical and/or surgical treatment of the identified condition; and

   2. The mean pulmonary artery pressure is > 25 mm Hg at rest or > 30 mm Hg with exertion; and

   3. The beneficiary has significant symptoms from the pulmonary hypertension (i.e., severe dyspnea on exertion, and either fatigability, angina, or syncope); and

   4. Treatment with oral calcium channel blocking agents has been tried and failed, or has been considered and ruled out.

4. The beneficiary has a diagnosis of pulmonary hypertension associated with interstitial lung disease (refer to Group 11 Codes in the LCD-related Policy Article for applicable diagnoses) and the following criteria (a-e) are met:

   1. The presence of interstitial lung disease has been confirmed by a high-resolution CT scan of the chest; and

   2. The mean pulmonary artery pressure is ≥ 25 mm Hg; and

   3. The pulmonary capillary wedge pressure or left ventricular end-diastolic pressure is ≤ 15mm Hg; and

   4. The pulmonary vascular resistance is ≥ 3 Wood Units at rest; and

   5. The beneficiary has significant symptoms of pulmonary hypertension (e.g., dyspnea on exertion, fatigability)

If the above criteria are not met, code E0574 and the related drug treprostinil (J7686) will be denied as not reasonable and necessary.

A controlled dose inhalation drug delivery system (K0730) is considered for coverage when it is reasonable and necessary to administer iloprost (Q4074) to beneficiaries with pulmonary hypertension only (refer to the Group 14 Codes in the LCD-related Policy Article for applicable diagnoses). Claims for code K0730 for use with other inhalation solutions will be denied as not reasonable and necessary.

Iloprost (Q4074) is considered for coverage when all of the following criteria 1-3 are met:

1. The beneficiary has a diagnosis of pulmonary artery hypertension (refer to the Group 14 Codes in the LCD-related Policy Article for applicable diagnoses); and

2. The pulmonary hypertension is not secondary to pulmonary venous hypertension (e.g., left sided atrial or ventricular disease, left sided valvular heart disease) or disorders of the respiratory system (e.g., chronic obstructive pulmonary disease, interstitial lung disease, obstructive sleep apnea or other sleep disordered breathing, alveolar hypoventilation disorders); and

3. The beneficiary has primary pulmonary hypertension or pulmonary hypertension which is secondary to one of the following conditions: connective tissue disease, human immunodeficiency virus (HIV) infection, cirrhosis, anorexigens or congenital left to right shunts. If these conditions are present, the following criteria (a-d) must be met:

   1. The pulmonary hypertension has progressed despite maximal medical and/or surgical treatment of the identified condition; and

   2. The mean pulmonary artery pressure is > 25 mm Hg at rest or > 30 mm Hg with exertion; and

   3. The beneficiary has significant symptoms from the pulmonary hypertension (i.e., severe dyspnea on exertion, and either fatigability, angina, or syncope); and

   4. Treatment with oral calcium channel blocking agents has been tried and failed, or has been considered and ruled out.

If the above criteria are not met, code K0730 and the related drug iloprost (Q4074) will be denied as not reasonable and necessary.

A large volume ultrasonic nebulizer (E0575) offers no proven clinical advantage over a pneumatic compressor and nebulizer and will be denied as not reasonable and necessary.


ACCESSORIES:

Accessories are separately payable if the related aerosol compressor and the individual accessories are reasonable and necessary. The following table lists the compressor/generator, which is related to the accessories described. Other compressor/generator/accessory combinations are considered not reasonable and necessary.

This array of accessories represents all possible combinations, but it may not be appropriate to bill any or all of them for one device.

The following table lists the usual maximum frequency of replacement for accessories. Claims for more than the usual maximum replacement amount will be denied as not reasonable and necessary.

 INHALATION DRUGS AND SOLUTIONS:

The following table represents the maximum milligrams/month of inhalation drugs that are reasonable and necessary for each nebulizer drug.

Claims for more than these amounts of drugs will be denied as not reasonable and necessary.

When albuterol, levalbuterol, or metaproterenol are prescribed as rescue/supplemental medication for beneficiaries who are taking formoterol or arformoterol, the maximum milligrams/month that are reasonably billed are:

Claims for more than these amounts of drugs will be denied as not reasonable and necessary.

When a "concentrated form" of an inhalation drug is covered, separate saline solution (A4216 or A4218 [metered dose]) used to dilute it will be separately reimbursed. Saline dispensed for the dilution of concentrated nebulizer drugs must be billed on the same claim as the drug(s) being diluted. If the unit dose form of the drug is dispensed, separate saline solution (A4216 or A4218 [metered dose]), will be denied as not reasonable and necessary. Water or saline in 500 or 1000 ml quantities (A4217 or A7018) are not appropriate for use by beneficiaries to dilute inhalation drugs and will therefore be denied as not reasonable and necessary if used for this purpose. These codes are only reasonable and necessary when used in a large volume nebulizer (A7007, A7017, or E0585).

Albuterol, levalbuterol, and metaproterenol are all short-acting bronchodilators with beta-adrenergic stimulatory effect. It is not reasonable and necessary for a beneficiary to use more than one of these at a time. The use of more than one of these drugs at the same time will be denied as not reasonable and necessary.

Albuterol, levalbuterol, or metaproterenol is covered if it is used as a rescue/supplemental medication in addition to the long-acting beta-adrenergic agonist drug, formoterol or arformoterol.

Formoterol and arformoterol are long-acting bronchodilators with beta-adrenergic stimulatory effect. It is not reasonable and necessary for a beneficiary to use more than one of these at a time. The use of more than one of these drugs at the same time will be denied as not reasonable and necessary.

Revefenacin (J7677) is a long-acting muscarinic antagonist. Concurrent use of long-acting and short-acting muscarinic antagonists, such as ipratropium (J7644) is not reasonable and necessary. Therefore, if a long-acting muscarinic antagonist is used, the short-acting muscarinic antagonist will be denied as not reasonable and necessary.

Code J7620 describes the FDA-approved unit dose combination of albuterol base 2.5 mg and ipratropium bromide 0.5 mg in unit dose vials. The medical necessity for administering additional albuterol sulfate (J7611, J7613), levalbuterol (J7612, J7614) and/or ipratropium bromide (J7644) has not been established. Claims for J7611, J7612, J7613, J7614, and J7644 billed in addition to J7620 will be denied as not reasonable and necessary.

Charges for the drugs, diluent, and dispensing fees may only be billed by the entity that actually dispenses the drug to the Medicare beneficiary and that entity must be permitted under all applicable federal, state, and local laws and regulations to dispense drugs. Only entities licensed in the state where they are physically located may submit a claim for nebulizer drugs. Practitioners may submit a claim for drugs if all of the following conditions are met: the practitioner is 1) enrolled as a durable medical equipment, prosthetics, orthotics and supplies (DMEPOS) supplier with the National Supplier Clearinghouse, and 2) dispensing the drug(s) to the Medicare beneficiary, and 3) authorized by the State to dispense drugs as part of the practitioner’s license. Claims submitted by entities not licensed to dispense drugs will be denied for lack of medical necessity.

GENERAL

A Standard Written Order (SWO) must be communicated to the supplier before a claim is submitted. If the supplier bills for an item addressed in this policy without first receiving a completed SWO, the claim shall be denied as not reasonable and necessary.

For Durable Medical Equipment, Prosthetics, Orthotics and Supplies (DMEPOS) base items that require a Written Order Prior to Delivery (WOPD), the supplier must have received a signed SWO before the DMEPOS item is delivered to a beneficiary. If a supplier delivers a DMEPOS item without first receiving a WOPD, the claim shall be denied as not reasonable and necessary. Refer to the LCD-related Policy Article, located at the bottom of this policy under the Related Local Coverage Documents section.

For DMEPOS base items that require a WOPD, and also require separately billed associated options, accessories, and/or supplies, the supplier must have received a WOPD which lists the base item and which may list all the associated options, accessories, and/or supplies that are separately billed prior to the delivery of the items. In this scenario, if the supplier separately bills for associated options, accessories, and/or supplies without first receiving a completed and signed WOPD of the base item prior to delivery, the claim(s) shall be denied as not reasonable and necessary.

An item/service is correctly coded when it meets all the coding guidelines listed in CMS HCPCS guidelines, LCDs, LCD-related Policy Articles, or DME MAC articles. Claims that do not meet coding guidelines shall be denied as not reasonable and necessary/incorrectly coded.

Proof of delivery (POD) is a Supplier Standard and DMEPOS suppliers are required to maintain POD documentation in their files. Proof of delivery documentation must be made available to the Medicare contractor upon request. All services that do not have appropriate proof of delivery from the supplier shall be denied as not reasonable and necessary.

REFILL REQUIREMENTS

For DMEPOS items and supplies provided on a recurring basis, billing must be based on prospective, not retrospective use. For DMEPOS products that are supplied as refills to the original order, suppliers must contact the beneficiary, and document an affirmative response, prior to dispensing the refill and not automatically ship on a pre-determined basis, even if authorized by the beneficiary. This shall be done to ensure that the refilled item remains reasonable and necessary, existing supplies are expected to end, and to confirm any changes or modifications to the order. Contact with the beneficiary or designee regarding refills must take place no sooner than 30 calendar days prior to the expected end of the current supply. For delivery of refills, the supplier must deliver the DMEPOS product no sooner than 10 calendar days prior to the expected end of the current supply. This is regardless of which delivery method is utilized.

For all DMEPOS items that are provided on a recurring basis, suppliers are required to have contact with the beneficiary or caregiver/designee and document an affirmative response, prior to dispensing a new supply of items. Suppliers must not deliver refills without a refill request and an affirmative response from a beneficiary. Items delivered without a valid, documented refill request will be denied as not reasonable and necessary.

Suppliers must not dispense a quantity of supplies exceeding a beneficiary's expected utilization. Suppliers must stay attuned to changed or atypical utilization patterns on the part of their clients. Suppliers must verify with the treating practitioners that any changed or atypical utilization is warranted.

Regardless of utilization, a supplier must not dispense more than a three (3) - month quantity at a time.

DRUG WASTAGE

Claims for drugs billed to Medicare must use drug dosage formulations and/or unit dose sizes that minimize wastage. Medicare provides payment for the amount of a single use vial or other single use package of drug or biological discarded, in addition to the dose administered. (See the MODIFIERS section of the Nebulizers LCD-related Policy Article.)

Ensifentrine

Clinical Background

Chronic obstructive pulmonary disease (COPD) is a composite of progressive lung diseases including emphysema and chronic bronchitis. Approximately 12% of adults over the age of 65 have diagnosed COPD.¹ Cigarette smoking is the leading cause of COPD. It may also be caused by chronic marijuana use,² vaping, and exposure to air pollutants from traffic, second-hand smoke, or indoor fuels used for heating and cooking.^3,4 Approximately 25-30% of people with COPD have never smoked.⁵ Individuals may be predisposed to developing COPD due to biological factors, such as systemic inflammation, or genetic conditions, such as alpha-1 antitrypsin deficiency.^6,7 A family history of COPD is an independent risk factor for the development of COPD, severity of disease, and frequency of exacerbations.^4,8 People who experience more frequent acute exacerbations experience a faster progression of their COPD and worse health status compared with those with few acute exacerbations.⁹ Severe COPD is a disability that limits individuals from participating in activities of daily life.^10,11 People with COPD are at higher risk of developing other chronic health conditions, including respiratory tract infections, lung cancer, heart disease, musculoskeletal frailty, and depression.^6,12 Patients with other comorbidities (e.g., pulmonary hypertension, cardiovascular disease, lung cancer) typically have a poorer prognosis.⁶

Chronic Obstructive Pulmonary Disease is characterized by inflammation and mucus plugging of the airways and structural changes of the alveoli, resulting in poor gas exchange and airflow obstruction.⁶ Pulmonary function testing is the mainstay of diagnosis and longitudinal monitoring for disease progression. Obstruction to airflow limits the volume of air that can be exhaled in one second (FEV₁) and results in hyperinflation of the lungs and a decrease in forced vital capacity (FVC). A diagnosis is made when the ratio of the forced expiratory volume in one second compared with the forced vital capacity (FEV₁/FVC) is less than 0.7.¹³ Diffusion of carbon dioxide from the circulation into the alveoli is impaired due to damage of the alveolar basement membranes and obstruction to exhalation, resulting in chronically elevated levels of carbon dioxide. Disease severity is determined by the reduction in FEV₁, as established by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification system:

• GOLD 1 (mild disease): FEV₁ ≥80 percent predicted
• GOLD 2 (moderate disease): FEV₁ between 50 and 80 percent predicted
• GOLD 3 (severe disease): FEV₁ between 30 and 50 percent predicted
• GOLD 4 (very severe disease): FEV₁ <30 percent predicted

The Global Initiative for Chronic Obstructive Lung Disease also provides severity and symptom-specific therapy recommendations. For patients with milder, less frequent symptoms (<1 moderate exacerbations/year), initial management includes maintenance bronchodilator therapy with either a long-acting muscarinic antagonist (LAMA), a long-acting beta-agonist (LABA), or a combined LAMA+LABA bronchodilator medication. A short-acting beta-agonist (SABA) is used for acute exacerbations. In patients with more severe disease, first-line therapy includes LABA+LAMA dual bronchodilator therapy and a SABA for acute dyspnea. An inhaled corticosteroid (ICS) treatment is added to the maintenance regimen in patients with high levels of eosinophils. The decision to initiate ICS therapy must be weighed against the increased risk of developing pneumonia.⁶ Patients who continue to experience frequent exacerbations while on first-line maintenance therapy may benefit from the addition of methylxanthine (Phosphodiesterase (PDE) 3 inhibitor), roflumilast (Phosphodiesterase (PDE) 4 inhibitor), azithromycin, or dupilumab (a human interleukin-4 and interleukin-13 monoclonal antibody). Patients who continue to experience significant dyspnea while on maintenance bronchodilator monotherapy may require escalation to LABA-LAMA therapy; those on dual long-acting bronchodilator therapy may benefit from a change in their inhaler device, participation in a pulmonary rehabilitation program, or the addition of ensifentrine (a dual PDE3 PDE4 inhibitor).¹³

Product Description

Ensifentrine (Ohtuvayre; Verona Pharma) is a dual inhibitor of PDE3 and PDE4 that results in bronchodilation, decreased inflammation, and improved ciliary function via activation of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The medication is inhaled via a standard jet nebulizer twice daily. In June 2024, the US Food and Drug Administration approved ensifentrine for maintenance treatment of COPD in adults.¹⁴ This was the first ever market approval worldwide.

Evidence Analysis: Ensifentrine

Clinical Questions

The formulation of specific questions for the assessment recognizes that the effect of an intervention depends substantially on how it is delivered, to whom it is applied, the alternatives with which it is being compared, and the setting where it is used. To appraise the net health outcomes of ensifentrine, the DME MACs sought to address the following two key questions (KQ):

• KQ1: Is the evidence sufficient to conclude that ensifentrine combined with standard maintenance therapy will result in a net health benefit for Medicare beneficiaries with COPD?
• KQ2: Is the evidence sufficient to conclude that ensifentrine used as a stand-alone maintenance treatment will result in a net health benefit for Medicare beneficiaries with COPD comparable or superior to the available standard of care?

Literature Search

In its industry guidance for COPD drug development, the FDA recommends a minimum of three months follow-up to determine improvements in airflow obstruction, a minimum of six months to evaluate symptom relief, and a minimum of one year to assess exacerbation prevention.¹⁵ Consequently, we restricted our selection criteria to include RCTs with an endpoint measuring lung function improvement over at least three months or other outcomes with a minimum duration of six months. For harm outcomes, we included RCTs with a 4-week minimum duration.

The following additional PICO elements guided the literature search and study screening:

Exclusion criteria comprised non-English articles and non-peer-reviewed literature, including conference abstracts.

A sensitive search of peer-reviewed publications indexed in PubMed was conducted on September 20, 2024. We used a combination of text and Medical Subject Headings (MeSH) terms such as "pulmonary disease, chronic obstructive," "RPL554," “ensifentrine” or “ohtuvayre.” The search returned 38 records. Based on title and abstract screening, 23 records were excluded, most of which were post-hoc analyses of the ENHANCE trials published as conference abstracts. Fifteen potentially relevant records were retrieved for full-text screening. Of these records, 10 were definitively excluded and 6 articles corresponding to 4 unique studies met the inclusion criteria. These studies included two phase II RCTs with 4-week follow-up^16-19 and two phase III RCTs with ≥ 24-week follow-ups.^20-24

Results

Phase III Trials

Summary

FDA approval of ensifentrine was based on evidence from two replicate phase III double-blind, placebo-controlled trials, which together enrolled 1,553 patients with moderate to severe COPD (ENHANCE-1, N = 760 and ENHANCE-2, N = 789).^20,22,24 The trials were conducted in the US, Canada, South Korea, and 14 European countries. In both trials, participants were randomized in a 5:3 ratio to receive either 3 mg of ensifentrine or a placebo twice a day through a standard jet nebulizer. The primary endpoint, average FEV₁ area under the curve (AUC)_0–12 h, was selected to assess bronchodilatory effects over 12 hours. This measurement uses the trapezoidal method to calculate the AUC at predefined time points: predose and 30 min and 1, 2, 4, 6, 8, and 12 h postdose. Key secondary outcomes included respiratory symptoms and QoL measured over 24 weeks. Adverse events, including exacerbations, were recorded for all participants up to Week 24 and for a subset of participants in ENHANCE-1 up to Week 48.

Participants were current or former smokers between 40 and 75 years of age with a FEV₁/FVC ratio of less than 0.70 and FEV₁ between 40% and 80% of the predicted normal. Patients receiving dual or triple maintenance therapy were excluded. Across the two trials, 39% of participants were on no maintenance therapy, 61% on LABA or LAMA with or without ICS, and 18.5% on ICS alone. Most participants were white (92.5%).

Both trials met their primary endpoint of improving lung function as measured by the average FEV₁ increase at 12 weeks (ENHANCE-1: 87 mL; 95% CI, 55-119; ENHANCE-2: 94 mL, 95% CI, 65-124). Importantly, ensifentrine was associated with 36% (ENHANCE-1) and 43% (ENHANCE-2) reductions in the annualized rates of moderate or severe COPD exacerbations (ENHANCE-1: rate ratio [RR] 0.64; 95% CI, 0.40-1.00; ENHANCE-2: RR, 0.57; 95% CI 0.38-0.87) as well as significant delays in time to first exacerbation (24 week endpoint: ENHANCE-1, hazard ratio [HR], 0.62; 95% CI, 0.39-0.97; ENHANCE-2, HR, 0.58; 95% CI, 0.38-0.87). Similar results were reported for the 48-week ENHANCE-1 extension. However, exacerbation reduction in ENHANCE-1 was marginally significant at both 24- and 48-week endpoints (P = .05 and P = .052, respectively), which suggests some degree of heterogeneity in participants’ responses to treatment.

Compared with placebo, the Evaluating Respiratory Symptoms Scale (E-RS)²⁵ scores were reduced further in favor of ensifentrine at Week 24 in both trials. However, the between group difference was statistically significant in ENHANCE-2 only and did not reach the MCID (≥ 2-point improvement) in either of the two trials.

The St. George’s Respiratory Questionnaire (SGRQ),²⁶ an airway disease-specific QoL tool, was used in both trials to assess perceived well-being and overall health. Compared to placebo, scores were reduced further in favor of ensifentrine at Week 24 in both trials. However, the difference was statistically significant in ENHANCE-1 only. In both trials, the differences between the ensifentrine and placebo groups were below the 4-point improvement MCID.

In a subsequent publication,^21,24 the investigators reported on the effect of ensifentrine on dyspnea related to daily activities over 24 weeks using pooled data from the ENHANCE trials. Transition Dyspnea Index (TDI),²⁷ an interview-based measurement of breathlessness, was used to measure changes in dyspnea severity from baseline. Responses were evaluated post-hoc by subgroups, including sex, age group, history of chronic bronchitis, exacerbation history, smoking status, presence of background medication, baseline eosinophil levels, and morning trough FEV₁ improvement. At Week 24, significantly more patients in the ensifentrine group were TDI responders compared with the placebo group (OR, 1.82; 95%CI, 1.43-2.32; P < .001). This outcome was consistent across all analyzed subgroups (all p < .02) except for the LABA + ICS subgroup.

In a second pooled analysis, the investigators explored the efficacy and safety of ensifentrine in patients receiving LAMA (N = 285) or LABA + ICS (N = 272) specifically. In both groups, ensifentrine was associated with statistically significant lung function improvements, reduced exacerbation rates, and reduced dyspnea.²⁸ These results should be interpreted with caution due to the post-hoc nature of the analyses.

Treatment-emergent adverse event (TEAE) rates, including severe TEAEs’ were similar in the ensifentrine and placebo groups in both ENHANCE trials over 24 and 48 weeks. Notable examples of TEAE’s leading to withdrawal from the trial include COPD exacerbations, COVID-19 infection, and non-COVID-19 pneumonia. Gastrointestinal adverse events observed with oral PDE4 inhibitors such as roflumilast²⁹ were low and comparable in both groups.

Risk of Bias/Limitations

Robust methodologies underpinned both ENHANCE-1 and ENHANCE-2. For the objective endpoints (FEV₁ and exacerbation rates), the results were judged to be at low risk of bias for each domain of the Cochrane risk-of-bias tool, version 2,³⁰ except for the Missing Outcome Data domain in ENHANCE-2. This trial had withdrawal rates exceeding 20%, largely due to Coronavirus Disease-19 (COVID).²⁶ The authors reported that a greater proportion of participants with severe COPD withdrew from the placebo group than from the ensifentrine group. Thus, there may have been an imbalance in disease severity between the two groups, resulting in a bias in the exacerbation rate ratio against the active intervention.

Both trials excluded patients on dual (LABA/LAMA) or triple (LABA/LAMA/ICS) maintenance therapy. Therefore, it remains unclear whether ensifentrine improves outcomes in such patients.

Additional RCTs

Two additional RCTs with a 4-week duration met our inclusion criteria for harm evaluation. Both were phase II multicenter double-blind multidose studies of comparable sizes (82 participants randomized to ensifentrine 3 mg in both). In Singh 2020 (NCT03443414),^17,18 participants were instructed not to take any long-acting bronchodilators during the trial following a 7-14-day washout run-in period. In Ferguson 2021 (NCT03937479),¹⁶ all participants were treated with tiotropium (LAMA), and no other long-acting bronchodilators were allowed. Statistically significant improvements in lung function (average FEV₁ and peak FEV₁) were reported in both trials. According to FDA recommendations for the conduct of COPD trials, however, a 4-week study period is an insufficient duration for efficacy evaluation.¹⁵ As in the phase III trials, treatment-emergent adverse event (TEAE) rates, including severe TEAEs, were similar in both the ensifentrine and placebo groups.

Systematic Reviews, Meta-Analyses, and Health Technology Assessments

The Institute for Clinical and Economic Review (ICER) recently released a comprehensive evidence report on ensifentrine.³¹ Since the designs and populations of ENHANCE-1 and ENHANCE-2 were similar, meta-analyses were used to pool outcome data from the two trials. The ensifentrine pooled placebo-adjusted estimate for the increase in average FEV₁, 92.3 mL, was statistically significant (95% CI, 66.2-118.4; P <.001; I²=0%). Compared to placebo, ensifentrine was associated with a statistically significant 40% decrease in the annualized rate of moderate-to-severe exacerbations (rate ratio [RR], 0.60; 95% CI, 0.41-0.79; P <.001; I²=0%). On week 24, ensifentrine was associated with a 40% placebo-adjusted delay in time to first exacerbation (HR, 0.60; 95% CI, 0.41-0.78; P <.0001; I²=0%). Compared to placebo the reduction in E-RS scores in the ensifentrine group was statistically significant but short of the MCID (-0.69; 95% CI: -1.38 to -0.01; P =.047; I²=0%). Regarding QoL, the SGRQ pooled estimate was not statistically significant and did not exceed the MCID (MD: 1.51; 95% CI, -3.13 to 0.12; P =.069; I²=22%).

ICER noted the uncertainty about the magnitude of benefits in patients with dual or triple maintenance therapy since they were excluded from the trial. Based on the results in patients on no or single therapy and the comparable incidence of serious TEAEs in the ensifentrine and placebo groups, the ICER investigators gave a B+ net health benefit rating, concluding that there is “high certainty that ensifentrine added to maintenance therapy results in at least a small net health benefit and may result in substantial net health benefit compared with maintenance therapy alone.”

Two systematic reviews with meta-analyses, both including the two ENHANCE trials and the two earlier phase II trials, were published shortly after the ICER review.^32,33 Their analyses echoed those of ICER, concluding that ensifentrine improves lung function and patients' health status. One of the reviews utilized the GRADE approach, assigning “moderate certainty” evidence to most critical outcomes.³²

Clinical Guidelines

The Global Initiative for Chronic Obstructive Lung Disease incorporated ensifentrine in its updated 2025 guidelines.¹³ Specifically, the organization assigned a “level A” to the evidence regarding lung function and dyspnea, while evidence related to health status was assigned a “level B.”

For patients with persistent breathlessness or exercise limitation on bronchodilator monotherapy, the organization recommends the use of two long-acting bronchodilators. If the addition of a second long-acting bronchodilator does not improve symptoms, the organization suggests either:

• Switching inhaler device or molecule
• Implementing or escalating non-pharmacological treatments
• Considering adding ensifentrine if available

For patients who need to be treated for both dyspnea and exacerbations, GOLD recommends adding roflumilast, azithromycin or dupilumab but not ensifentrine.

On February 2, 2024, we searched the following organization sites for guidelines published or updated after the FDA approval of ensifentrine. No guidelines matching these criteria were found on the following society sites:

• American Thoracic Society (ATS)
• American College of Chest Physicians (CHEST)
• American Academy of Family Physicians (AAFP)

Hypertonic Saline

Clinical Background

Muco-obstructive lung diseases are characterized by the presence of large amounts of viscous mucous in the airways. Alterations in mucus composition, hypersecretion, and/or deficits in ion-fluid transport result in thick, highly concentrated mucous leading to airway obstruction and inflammation, chronic cough, and persistent bacterial infections.³⁴ While all diagnoses within this category share the clinical pattern of copious, thick airway mucous and airway obstruction, the prevalence of these diseases vary with regard to the number and demographics of the people affected.

Cystic fibrosis (CF) is the second-most common autosomal recessive genetic disease in the United States.³⁵ It is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The CFTR gene regulates the secretion and absorption of chloride and bicarbonate in epithelial tissues; mutation in the CFTR gene results in dysregulation of anion secretion and hyperviscous mucous.³⁶ Cystic fibrosis affects approximately 40,000 people in the United States.³⁷ Patients from the Southern and Western United States experience higher mortality and hospitalization rates than CF patients in other parts of the country.³⁵ There are sex-related differences in both diagnosis and outcomes. Females are diagnosed later in life than males with the disease, and experience a lower quality of life while living with CF. The median life-expectancy is approximately 40 years.³⁶ Life expectancy for people living with CF has increased over the past several decades. Although the median age of death in 2023 was 37 years, people with CF born between 2019 and 2023 are predicted to have a mean survival age of 61 years due to new advances in treatment with the introduction of CFTR modulator tri-therapy called elexacaftor-tezacaftor-ivacaftor (ETI).^38,39 Approximately 50% of patients taking ETI no longer expectorate sputum, negating the need for daily airway clearance therapies.^35,36 Notably, adherence to respiratory therapy and chest physiotherapy is lower in older CF patients and those with advanced disease.⁴⁰ Adherence to treatment with daily hypertonic saline is reported to be approximately 36%; by contrast, adherence to daily inhaled rhDNAse therapy is reported to be 62% due to the ease of therapy.^41,42

Bronchiectasis is the result of an inability to clear the products of an immune response (neutrophils and other inflammatory mediators) to an airway infection. The most common etiologies of bronchiectasis are immunodeficiency, autoimmune disease, and focal airway obstruction due to tumor or foreign body. Environmental or occupational exposure to mold and other respiratory pollutants are factors associated with bronchiectasis and poorer disease management.^43,44 The thick, viscous sputum of bronchiectasis differs from that of CF due to a high concentration of DNA, inflammatory mediators, and mucin. A diagnosis of bronchiectasis is made based upon clinical symptoms of daily cough with tenacious sputum, frequent exacerbations, and the presence of bronchial dilation on radiographic imaging. Although bronchiectasis may be diagnosed in patients of any age, the prevalence increases with age; a 2018 Medicare survey reported an annual prevalence of 701 per 100,000 beneficiaries over the age of 65 years.⁴⁵ The prevalence and incidence have been increasing over time.⁴⁶ Non-cystic fibrosis bronchiectasis (NCFB) is more common in adults over 75 years and in females.⁴⁵

Primary ciliary dyskinesia (PCD) is caused by a congenital defect in the airway cilia that results in an inability to effectively clear mucous. Over 50 different genetic mutations have been identified that cause PCD. Common clinical manifestations of PCD include recurrent respiratory infections, rhinosinusitis, hearing loss,³⁷ infertility, and differences in organ laterality. The prevalence of PCD is approximated at 1:7500 individuals across all races and ethnicities, with an average age at diagnosis of 5 years. Fewer than 200,000 people in the United States are estimated to have PCD⁴⁸; however, the disease is likely underrecognized⁴⁹ due to lack of access to diagnostic tools and a heterogeneity of clinical phenotypes. A recent genetic study (Hannah et al 2022) found the frequency of PCD varies by ancestry (1 in 9906 in people of African descent vs. 1 in 10,388 in European vs. 1 in 14,606 in people of East Asian descent vs. 1 in 16,309 in Latinos).⁴⁹

Product Description

Hypertonic saline is a crystalloid solution of sodium chloride dissolved in water at a higher concentration of sodium than is normally present in blood. The high sodium concentration draws water into the airways and thins mucus, making it easier to expectorate and clear from the airways. It may also reduce airway inflammation in patients with muco-obstructive diseases.

Inhaled hypertonic saline is available in concentrations of 3% - 7% and is administered via a nebulizer device, with a mouthpiece preferred over a mask. The usual dose is 4ml once or twice per day.⁵⁰ It is often combined with other inhaled mucous thinning medications and chest physiotherapy in a once or twice daily regimen.

Nebulizers are covered under the durable medical equipment (DME) benefit.⁵¹

Food & Drug Administration Designation

The FDA regulates hypertonic saline vials for inhalation under 21 CFR 868.5630 (Nebulizers).

• Design: Sterile, preservative-free Sodium Chloride Inhalation Solutions supplied in single use vials.
• Indication for use: Sodium Chloride Inhalation Solution, USP is used in conjunction with a nebulizer. The contents of these vials are for the induction of sputum production where sputum production is indicated (For ≥3% concentrations only)
• Patient Population: Any patient population where sputum production is indicated.⁵²

Hypertonic saline solutions fall under the regulatory category of "approved" drugs based on long-standing medical use before the modern FDA drug approval process was established. Current products on the market are approved via the 510(k) pathway via predicate nebulized hypertonic saline products. Three products with varied sodium chloride concentrations (3.5%, 6%, 7%, and 10%) received clearance and served as predicates for the clearance of subsequent products through the 510(k) pathway.⁵³

Summary of Evidence: Hypertonic Saline

Cystic Fibrosis

Primary studies

Nebulized hypertonic saline is commonly utilized by both adults and children with cystic fibrosis (CF) across numerous countries worldwide. Widespread use has been reported in many European countries, where it is typically covered by health insurance.⁵⁴ Extensive utilization has also been reported in the US. In a survey conducted among US adults and parents of children with CF, 88.5% of respondents indicated they or their children used hypertonic saline daily.⁵⁵

Three landmark randomized controlled trials (RCTs) are commonly cited in support of the use of HS in patients with CF.^56-58 With the addition of an infant trial that did not reach its primary and secondary endpoints,⁵⁹ these studies are the largest double-blind RCTs of HS in CF currently available.

Since no inhaled agent is completely inert, conducting a true placebo-controlled study of nebulized HS is not feasible.⁵⁹ Nebulized isotonic saline (IS) has been established as an appropriate control in clinical trials of HS.^60,61 It has been utilized as a substitute for a placebo in most blinded RCTs of HS, regardless of the indication.

In 2006, Elkins et al published the findings of a multicenter double-blind, parallel-group trial that investigated the long-term effects of HS in a mixed group of children (aged over 6 years) and adults with CF.⁵⁷ One hundred sixty-four participants were randomized 1:1 to twice-daily administration of either HS (7%) or IS (0.9%) over 48-weeks. The mean age was approximatively 18±9 years in both groups and the mean percent of predicted forced expiratory volume (ppFEV₁)⁶² at baseline was 73 ± 21% in the HS group and 76 ± 21% in the control group. The 48-week rate of change from baseline in lung function (primary outcome measured as a composite of spirometric parameters) did not differ significantly between groups. However, the mean number of exacerbations requiring intravenous antibiotics per patient over 48 weeks was significantly reduced in the HS group compared to the control group (RR 0.56; 95%CI, 0.14-0.86; P=0.02). Similarly, the mean number of days participants experienced exacerbations decreased by an additional 11 days in the HS group compared to the control one (95% CI, -3 to -19 days; P=0.02). Moreover, participants in the HS group experienced significantly fewer days of missed school or work (7, IQR 0 to 21 days vs 24, IQR 12 to 48, P<0.001). Treatment-related adverse events (TRAEs) were significantly more frequent in the HS group (15.5% vs .2%; P=0.001). The most common TRAEs included cough, chest tightness, and pharyngitis.

In 2016, Dentice et al published the results a double-blind RCT evaluating the efficacy of HS in adults experiencing exacerbations.⁵⁸ One hundred thirty-two adults hospitalized with CF exacerbations were randomized to inhale either 7% HS or 0.12% hypotonic saline three times a day. The primary outcome, length of stay, was 12 days in the treatment group and 13 days in the control group. The mean one-day difference was below the minimal 2 day expected and did not reach statistical significance (95%CI, 0-2, p=0.07). However, patients in the HS group were significantly more likely to regain their pre-exacerbation ppFEV₁ levels (75% vs 57%, p<0.05), and experienced significantly greater reduction in congestion and dyspnea severity (0-100 scale: mean difference [MD],10; 95% CI 3-18 and MD, 8; 95%CI 1-16, respectively).

In 2019, Ratjen et al published the findings of a multicenter double-blind, parallel-group trial involving 150 children with CF aged 3 to 6 years.⁵⁶ Participants were randomized 1:1 to twice-daily administration of either 7% HS or 0.9% IS over 48-weeks. The primary outcome measure was the change in lung clearance index (LCI2.5) from baseline to week 48. The LCI2.5 measures the number of breaths required to reduce the exhaled nitrogen concentration to one fortieth of the starting concentration during a maximum breath washout test. At 48 weeks, HS was associated with a small statistically significant improvement (i.e., decrease) in LCI2.5 compared with IS (MD, –0.63 LCI2.5 units, 95%CI, –1.10 to –0.15, p=0.01). There was no difference between groups in the frequency of adverse events. Reported serious adverse events (SAEs) included cough (3% with HS vs 4% with IS), gastrostomy tube placement or rupture (3% vs 1%), upper gastrointestinal disorders (1% vs 3%), distal intestinal obstruction syndrome (1% vs 1%), and decreased pulmonary function (0 vs 1%). None of these SAEs were judged to be treatment-related.

A parallel study with an identical design conducted by the same team investigated whether HS reduces structural lung disease by comparing chest computed tomography (CT) scans from baseline to 48 weeks.⁶³ Chest CTs were scored using the Perth-Rotterdam Annotated Grid Morphometric Analysis for Cystic Fibrosis (PRAGMA-CF), which measures the percentage of total lung volume occupied by abnormal airways.⁶⁴ Baseline and 48 week chest CTs were available for 49 participants in the HS group and 55 in the IS group. Mean PRAGMA-CF % disease at 48 weeks was significantly lower in the HS group compared to the IS group (MD, 0.67, 95% CI 0.26–1.08; p=0.009).

The largest double-blind trial involving infants with CF was published in 2012.⁵⁹ It enrolled 321 infants and young children aged 4 to 60 months across 30 centers. The trial failed to reach its primary endpoint–a decrease in exacerbations–or any secondary endpoints (height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores). Participants had been randomized to 7% HS or 0.9% IS inhaled twice daily for 48 weeks. There were no significant differences between groups in the proportion of participants experiencing SAEs. The most common SAE in both groups was cough or increased cough, occurring in 8% of participants in the HS group and 10% in the IS group.

The Cystic Fibrosis Foundation (CFF) recently sponsored a large multicenter study examining whether the treatment burden of patients with CF on ETI could be safely reduced by discontinuing either HS or dornase alfa (DA).⁶⁵ The study, named SIMPLIFY, encompassed two non-inferiority open label RCTs, each independently evaluating the effect of discontinuing versus continuing HS (Trial A) or DA (Trial B). The six-week study enrolled collectively more than 800 participants aged 12 and older between 2020 and 2022. The overall average ppFEV₁ was 96.9%. At six weeks, discontinuing either HS or DA did not result in clinically meaningful changes in ppFEV₁ and LCI2.5 among participants with relatively good lung function. However, within the small group of adults with ppFEV₁, 60 to 70% more respiratory adverse events were reported in those randomized to stop any of the two inhaled medications. The authors concluded that greater caution should be applied when considering changes to daily therapy in individuals with more advanced CF pulmonary disease.

Systematic Reviews

A recent Cochrane systematic review (SR) concluded that the evidence regarding the efficacy of HS in improving lung function in the overall patient population with CF aged 12 and over is uncertain. However, the authors deemed the evidence sufficient to conclude that HS is an effective adjunct to physiotherapy during acute exacerbations of lung disease in adults.⁶⁶

Similarly, Zhang et al found no statistical difference in ppFEV₁ between HS and non-HS groups in a recent meta-analysis that included 12 studies involving participants with CF of all ages. However, the meta-analysis of the outcome data from the two studies reporting on mucociliary clearance (MCC in 90 minutes) showed a significant improvement in favor of HS (MD, 10.5; 95% CI 6.5-14.4). Additionally, the meta-analysis of the data from the five studies reporting on quality of life (QoL) also showed a significant improvement in the HS group compared to the IS group (standardized mean difference [SMD], 0.44, 95% CI 0.02-0.87).⁶⁷

Practice Guidelines

Cystic Fibrosis Foundation

Infants

For infants with CF under 2 years of age, 7 percent hypertonic saline may be used in symptomatic infants. Certainty: Low, Benefit: Moderate, Consensus recommendation.⁶⁸ Last reviewed July 2021.

Preschool Children

Hypertonic saline and dornase alfa may be selectively offered based on individual circumstances. Grade: C, Certainty: Moderate, Benefit: Moderate.⁴¹ Last reviewed July 2021.

Children Aged Six Years and Older, and Adults

For individuals with CF, 6 years of age and older, the CF Foundation recommends the chronic use of inhaled hypertonic saline to improve lung function and quality of life and reduce exacerbations. Moderate Certainty of Net Benefit, estimate of net benefit Moderate, Recommendation “B” (the committee recommends clinicians routinely provide the therapy).^70,71 Last reviewed 2021.

CFF Otolaryngology Care Multidisciplinary Consensus Recommendations

Per CFF guidelines, individuals with CF benefit from the use of nebulized dornase alfa and nebulized hypertonic saline. Based on these recommendations, individuals with CF who undergo endoscopic sinus surgery should have access to perioperative airway clearance therapy, nebulized dornase alfa, and nebulized hypertonic saline perioperatively. These therapies could be beneficial to avoid exacerbation in the perioperative period when pain medication and sedation is necessary.⁷² Published in 2022.

National Institute for Health and Care Excellence (NICE, UK)

Cystic fibrosis: diagnosis and management NICE guideline [NG78]. Last reviewed, 2024.

NICE recommends HS as a second choice if there is an inadequate response to dornase alfa.⁷³

• 1.6.18. Offer rhDNase (dornase alfa) as the first choice of mucoactive agent.
• 1.6.19. If clinical evaluation or lung function testing indicates an inadequate response to rhDNase, consider both rhDNase and hypertonic sodium chloride or hypertonic sodium chloride alone. Last reviewed, 2024.

Non-Cystic Fibrosis Bronchiectasis

Primary Studies

A recent registry study revealed HS is commonly used by US patients with non-cystic fibrosis bronchiectasis (NCFB). The study evaluated the utilization of HS and positive expiratory pressure (PEP) devices in this population by analyzing patient data from the United States Bronchiectasis and Nontuberculous Mycobacterial (NTM) Lung Disease Research Registry (BRR). From an initial pool of 4670 patients diagnosed with NCFB, the records of 1113 patients using other forms of chest therapy and 1362 patients with conflicting data were excluded. Among the remaining 2195 patients, one-third used HS daily, with or without concomitant PEP.⁷⁴

The largest RCT in adults with NCFB, which included 40 participants, was published in 2012. No significant differences were found in the number of exacerbations, hospital admissions, lung function tests, and QoL between the 6% HS and 0.9% IS groups after 12 months of use. One participant in the HS group experienced chest tightness while inhaling, which improved after treating an underlying acute exacerbation.⁷⁵

In a cross-over RCT involving 28 adult patients, published around the same period, ppFEV₁ and FVC improved significantly more in the 7% HS group compared to the 0.9% IS group after three months of daily use (change from baseline: 15.1% vs 1.8% p<0.01 and 11.2% vs 0.7%, p<0.01, respectively). Quality of life, as measured by the St. George's Respiratory Questionnaire (SGRQ), also improved significantly more with HS compared to IS (change from baseline: 6.0 points vs 1.2-point, p<0.05).⁷⁶

A triple-arm, double-blind, randomized crossover trial published in 2018 compared three solutions: 0.1% hyaluronic acid added to 7% HS (HS +HA), 7% HS alone (HS), and 0.9% isotonic saline (IS). Twenty- three adult participants received each solution in single sessions separated by a 7-day washout period. Sessions one and two included 30 minutes of airway clearance techniques. The primary outcome measure, sputum weight, was recorded at each session and at 24-hour follow-ups. Quality of life, assessed using the Leicester Cough Questionnaire (LCQ), and lung function were measured both before and after each treatment. Sputum collected over the 24-hour follow-ups tended to be lighter in weight in the HS and HA+HS groups compared with the IS group (HS vs IS: -1.7g, 95%CI -4.2g to 0.0g; HA+HS vs IS -1.1g, 95%CI -3.6g to 0.7g). However, the differences were not statistically significant. The most common adverse events reported by participants were coughing and throat irritation. These symptoms were especially prevalent after inhaling HS, and to a lesser extent, after inhaling HA+HS. Three small sputum samples containing blood were observed from two participants: one during the use of the IS solution, and the other during the use of both the HS and IS solutions.⁷⁷ As with all the other RCTs of HS involving patients with NCFB, these favorable or unfavorable results should be interpreted carefully because of the study’s small size.

The only RCT evaluating HS in pediatric patients with NCFB was a crossover trial involving 52 children aged five to 15 years. Participants were randomized to receive either 200 µg of inhaled salbutamol followed by 3% HS nebulization or 200 µg of inhaled salbutamol alone for 8 weeks. After a 30-day washout period participants were crossed over to the other arm. Participants receiving 3% HS showed significantly greater improvement in ppFEV₁ compared to patients receiving salbutamol alone (pre-crossover: 14.2% vs 5%, p<0.01; post-crossover: 10.8% vs 3.5%, P<0.01). The first group of HS recipients experienced significantly fewer exacerbations than the control group, though this difference was not significant post-crossover. While the study was welcomed due to the paucity of research in pediatric patients with NCFB, it has been questioned for its lack of blinding and absence of within-subject analytical comparison.⁷⁸

Systematic Reviews

In 2020, Xie et al published an SR with meta-analyses assessing the effects of inhaled HS vs IS in treating adult patients with NCFB. The review included the three RCTs mentioned above plus a small pilot RCT published in 2005.⁷⁹ Compared to IS, HS showed no significant impact on FV1 (SMD, 0.12; 95% CI, -0.06 to 0.30; P=0.18), FVC (SMD, 0.10; 95% CI, -0.09 to 0.28; p=0.30), sputum expectoration (SMD, -0.03; 95% CI, -2.73 to 2.68; P=0.99), or Leicester Cough Questionnaire (LCQ) scores (SMD, 0.15; 95% CI, -0.89 to 0.58; p=0.68).⁸⁰

Practice Guidelines

While several US guidelines for managing bronchiectasis associated with CF are available, there are no US guidelines yet for managing NCFB although one is currently being developed.⁸¹ Other regions, including Europe, have published guidelines for NCFB management, but the recommendations are based on evidence of low quality or limited in scope.⁸¹

The European Respiratory Society guidelines for the management of children and adolescents with bronchiectasis suggests not using HS routinely in pediatric populations (conditional recommendation, very low quality of evidence) with some exceptions. The guideline states that 6–7% HS may be considered in selected patients with high daily symptoms, frequent exacerbations, difficulty in expectoration and/or poor QoL. The panel judged that HS could improve QoL and facilitate expectoration if well tolerated. Children should be old enough to tolerate the intervention. The panel also considered that short-acting β2-agonists should be used prior to inhaling HS and the first dose administered under medical supervision.⁸²

The European Respiratory Society guidelines for the management of adults with bronchiectasis suggest offering long-term (≥3 months) mucoactive treatment, including HS but not DA, in adult patients with bronchiectasis who have difficulty in expectorating sputum and poor quality of life and where standard airway clearance techniques have failed to control symptoms (weak recommendation, low quality of evidence). The society issued a strong recommendation against offering DA to adult patients with bronchiectasis.⁸³

Primary Ciliary Dyskinesia

Primary Studies

The only randomized trial of hypertonic saline (HS) in primary ciliary dyskinesia (PCD) we identified was a double-blind crossover trial published in 2017. Twenty-two adult participants were randomized to either 7% HS or 0.9% IS twice daily for 4 weeks. After a 4-week washout period, participants switched solutions for another 4 weeks. The primary outcome was the change in QoL as measured by the SGRQ. Secondary outcome measures included SGRQ sub scores, the QoL Questionnaire-Bronchiectasis (QOL-B), lower respiratory tract symptoms, exacerbations, spirometry results, inflammatory markers in the body and sputum, adherence, and adverse events. There were no significant differences in SGRQ total score change from baseline at 4 weeks between the HS and IS groups (−2.6, IQR -9.0, -1.5 points; −0.3, IQR, -8.1, -6.1 points, respectively). Most secondary outcomes were either not statistically significant or did not meet the minimum clinically important difference. Adverse events were more frequent with HS, though they were generally mild. These included throat irritation, cough, and chest tightness.⁸⁴ These negative results should be interpreted with caution due to the small size of the study’s sample.

Practice Guidelines

PCD Foundation

Based on evidence obtained from NCFB studies, the 2016 PCD Foundation Consensus Recommendations suggest HS may be used after physicians instruct patients in proper equipment sterilization.⁸⁵

European Respiratory Society

The European Respiratory Society (ERS) last consensus statement for the treatment of PCD was a pediatric guideline issued in 2006. It stated that nebulized HS may theoretically be effective in increasing mucus clearance in patients with PCD. Noting the quasi absence of clinical research in PCD, ERS is currently developing a set of core outcomes for clinical research in the condition.⁸³

Conclusion: Ensifentrine

Ensifentrine is an FDA-approved inhaled therapy for COPD that results in both bronchodilation and reduced inflammation via inhibition of the PDE-3 and PDE-4 enzymes. In two phase III double-blind, placebo-controlled trials, ensifentrine was associated with significant improvements in lung function, exacerbation rates, and respiratory symptoms in patients with moderate-to-severe COPD. The rates of adverse events in the ensifentrine groups were similar to those observed with placebo. However, the background therapy regimens used in the trials do not reflect the current standards of care for treatment for moderate to severe COPD, which include dual LABA+LAMA therapy or triple LABA+LAMA+ICS therapy. A significant portion of patients in the Phase III trials (30-45%) were not on any background maintenance therapy, and additional information on these individual participants is not available. Therefore, the true magnitude of benefit gained by patients already on optimal guideline-directed inhaler therapy is uncertain.

Compared to well-established maintenance therapies with over four decades of evidence, long-term (>48 weeks) data on ensifentrine is limited. Head -to-head comparisons of ensifentrine versus current first-line standard of care therapies are not yet available, limiting the conclusions that can be made about its effectiveness as a stand-alone treatment or as escalation therapy in lieu of dual LABA+LAMA therapy for frequent exacerbations.

A 2024 comprehensive evidence report from the Institute for Clinical and Economic Review (ICER) indicated that the addition of ensifentrine to maintenance therapy is likely to offer at least a small, but potentially significant, net health benefit compared to maintenance therapy alone. The ICER report also highlights that while participants taking dual LAMA+LABA or triple LAMA+LABA+ICS background therapy were excluded from the Phase III trials, short-term data from a Phase IIb study suggest that ensifentrine may improve lung function in patients with COPD when added on to LAMA+LABA therapy.

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) clinical guidelines published in 2025 recommend the addition of ensifentrine as escalation therapy for patients on dual LABA+LAMA maintenance therapy with persistent dyspnea, citing inconsistent effects of ensifentrine on quality of life measures and difficulty with incorporating the medication into current treatment algorithms given the lack of studies designed to assess its impact when added to standard maintenance regimens of dual LABA+LAMA or triple LABA+LAMA+ICS therapy.

Ensifentrine is generally considered by subject matter experts as an add-on therapy rather than as monotherapy or as an initial therapeutic option for COPD. This is due to the current limitations of Phase III trials, a lack of long-term data, and the availability of other therapeutic options such as long-acting bronchodilators (LABA+LAMA) and ICS+long-acting bronchodilator combinations that have long been established as first-line options and the standard of care.

Based on the best available literature, there is consistent evidence to suggest that ensifentrine may be an effective therapeutic option for Medicare beneficiaries over 18 years of age with COPD with continued exacerbations or with persistent dyspnea while on dual LABA+LAMA maintenance therapy or LABA+LAMA+ICS triple therapy. There is insufficient evidence to conclude that ensifentrine used as a stand-alone maintenance treatment will result in a net health benefit for Medicare beneficiaries with COPD comparable or superior to the currently available standard of care.

Conclusion: Hypertonic Saline

Nebulized hypertonic saline is FDA-approved for the induction of sputum production in patients of all ages. The effective osmolality of the solution promotes the movement of water into the airways and thins mucus, making it easier to expectorate. Nebulized hypertonic saline therapy may also reduce airway inflammation.

The small sample sizes of most of the available clinical trials limit the conclusions that may be drawn about the clinical impact of hypertonic saline therapy for muco-obstructive diseases. However, the consensus from the available practice guidelines is that hypertonic saline may offer moderate benefit to patients experiencing acute respiratory exacerbations or who have not received benefit from first-line therapies. The reported side effects of HS use were minor and serious adverse events were uncommon.

Based upon the best available literature in combination with existing specialty society guidelines, there is evidence to support that hypertonic saline used as part of an airway clearance therapy regimen may result in a net health benefit for Medicare beneficiaries with cystic fibrosis, non-cystic fibrosis bronchiectasis or primary ciliary dyskinesia.

It is reasonable and necessary to administer hypertonic saline via nebulizer for the management of cystic fibrosis, non-cystic fibrosis bronchiectasis or primary ciliary dyskinesia.

DOCUMENTATION REQUIREMENTS

Section 1833(e) of the Social Security Act precludes payment to any provider of services unless "there has been furnished such information as may be necessary in order to determine the amounts due such provider.” It is expected that the beneficiary's medical records will reflect the need for the care provided. The beneficiary's medical records include the treating practitioner's office records, hospital records, nursing home records, home health agency records, records from other healthcare professionals and test reports. This documentation must be available upon request.

GENERAL DOCUMENTATION REQUIREMENTS

In order to justify payment for DMEPOS items, suppliers must meet the following requirements:

• SWO

• Medical Record Information (including continued need/use if applicable)

• Correct Coding

• Proof of Delivery

Refer to the LCD-related Standard Documentation Requirements article, located at the bottom of this policy under the Related Local Coverage Documents section for additional information regarding these requirements.

Refer to the Supplier Manual for additional information on documentation requirements.

Refer to the DME MAC web sites for additional bulletin articles and other publications related to this LCD.

POLICY SPECIFIC DOCUMENTATION REQUIREMENTS

Items covered in this LCD have additional policy-specific requirements that must be met to justify Medicare reimbursement.

Refer to the LCD-related Policy article, located at the bottom of this policy under the Related Local Coverage Documents section for additional information.

Miscellaneous

Appendices

Utilization Guidelines

Refer to Coverage Indications, Limitations and/or Medical Necessity

N/A

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2. Vasconez-Gonzalez J, Delgado-Moreira K, Lopez-Molina B, Izquierdo-Condoy JS, Gamez-Rivera E, Ortiz-Prado E. Effects of Smoking Marijuana on the Respiratory System: A Systematic Review. Subst Abus. Jul 2023;44(3):249-260. doi:10.1177/08897077231186228
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