Evaluating Treatment Options for COPD

AJMC®: How is COPD definitively diagnosed in clinical practice, and how does this disease create a clinical burden on patients and caregivers?

Dr Rali: COPD diagnosis requires both clinical context and objective testing. Most commonly, patients will present with symptoms like chronic cough or shortness of breath, and we discover risk factors like smoking when taking a medical history. From there, we can confirm diagnosis with pulmonary function tests. Often, we will also test for enzyme deficiencies early in the diagnostic procedure, because the results of those inform treatment options.

In terms of burden, COPD is a chronic disease that affects multiple organ systems, not just the lungs. Patients often face complications involving bone health, cardiovascular disease, sleep apnea, weight loss, and hormonal changes. The liability for caregivers, accordingly, is to engage in long-term, comprehensive care that goes beyond prescribing medication to benefit the lungs. An optimal approach would be to treat COPD as a systemic disease and provide patients with holistic care. In practice, this is difficult, because patients experience depression and anxiety, particularly when faced with lifestyle changes like smoking cessation.

As with other chronic diseases, caring for patients with COPD requires trust building and longitudinal care. This includes helping patients identify support systems outside the clinical setting. Cumulatively, the effect is a substantial burden to both patients and caregivers as they navigate ongoing treatment and lifestyle changes.

AJMC®: Beyond the clinical burden, how does COPD create an economic burden for patients and the health care system?

Dr Rali: Exacerbations are the primary driver of COPD-related costs. Once a patient experiences an exacerbation, they are at high risk for recurrent episodes, often requiring hospitalization and sometimes ICU (intensive-care unit)-level care. A single day in the ICU can cost $10,000 to $15,000, not including physician charges, and prolonged hospitalizations may result in downstream needs, such as tracheostomy, long-term ventilator dependence, or placement in a nursing facility.

Given the risks of recurrent exacerbation episodes, costs can accumulate rapidly at both the institutional and patient levels. In that case, one of the goals for early intervention and effective disease management is not only to improve patient outcomes, but also to prevent costly exacerbation events.

AJMC®: What are the first-line treatment options for patients newly diagnosed with COPD?

Dr Rali: A top priority is patient education to help them understand that COPD is a chronic condition that will require long-term management. From there, initial care should focus on 3 goals: controlling symptoms, preventing exacerbations, and slowing further lung damage.

When initiating treatment, we start by classifying patients into GOLD groups A, B, or E, which consider both symptom burden and exacerbation history. We can use either the COPD Assessment Test (CAT) or modified Medical Research Council (mMRC) dyspnea scale to assess symptoms, and we will collect a patient’s full medical history to count exacerbations. Based on this, treatment may range from as-needed bronchodilators for low-risk patients to dual or triple therapy for those with greater symptom burden, frequent exacerbations, or high eosinophil counts. Two or more exacerbations in a year or 1 or more exacerbations that led to hospitalization indicate a high-risk patient, and we will use this information along with pulmonary function tests to select an initial inhaler to prescribe.

To slow further lung damage, we counsel patients to cease smoking. This includes making sure they do not transition from smoked tobacco products to electronic vaping products.

Lastly, we use a holistic approach to address comorbidities and ensure patients are adequately protected through [preventive] care. This includes making sure patients are up to date with their vaccinations, screening for lung cancer, and determining whether there are concomitant health problems like heart issues, osteoporosis, or sleep apnea [among others]. Overall, even when a patient first presents to my clinic, their care is individualized depending on their history and disease progression.

AJMC®: How do you assess treatment efficacy in patients newly diagnosed with COPD, and what guides treatment adjustment over time?

Dr Rali: After initiating therapy, follow-up visits every 3 to 6 months are necessary to judge whether symptoms have improved and to monitor exacerbation frequency. In the absence of improvement, we will confirm inhaler technique or consider adjusting therapy, escalating to dual or triple therapy, if indicated. We must attend particularly to exacerbations, because several events may be considered as such but likely will not come immediately to patients’ minds when [we collect] a medical history between follow-up visits. Urgent-care visits, prednisone prescriptions, and antibiotic use may all qualify, although patients often perceive these as routine events or viral illness. Recognizing exacerbations for what they are avoids underestimating disease activity.

When the need to escalate therapy arises, symptom phenotypes can guide the process. For example, patients with non-eosinophilic COPD sometimes present with chronic cough and poor pulmonary function test results; these patients are likely to be on dual LAMA/LABA (long-acting muscarinic antagonist/long-acting b₂-agonist) therapy, and we could consider adding roflumilast if their disease is a chronic bronchitis variant or azithromycin if the exacerbation rate is more of a concern. Pulmonary rehabilitation is another option that we tend to recommend for any patient in GOLD group B or E. These programs can assist patients who experience chronic dyspnea by offering breathing muscle training, nutritional support, and strategies to manage breathlessness during daily living. Together, these considerations ensure that treatment adjustments are tailored to both symptoms and risk profiles.

AJMC®: What are the second-line therapy options in COPD, and when do you decide to use these therapies?

Dr Rali: Anything beyond inhalers is generally what we would consider a second-line COPD medication. This includes oral agents such as roflumilast and azithromycin. Roflumilast is particularly useful in patients with the chronic bronchitis phenotype, more advanced lung function impairment, and frequent exacerbations—especially if they have been hospitalized for COPD. Azithromycin is best suited for patients who continue to have frequent exacerbations despite optimized inhaler therapy, particularly if they are nonsmokers.

When selecting between these options, we consider the patient’s comorbidities and tolerability. For example, roflumilast may not be well tolerated in patients with depression or certain gastrointestinal conditions, making azithromycin the better option. With azithromycin, it is important to remember that it is prescribed as a long-term anti-inflammatory agent rather than as an anti-infective. Because of that intended long-term use, adverse events to monitor for include hearing loss and cardiac events, which can be anticipated and managed with appropriate baseline and follow-up testing. We also rule out concomitant Mycobacterium avium complex infection before starting therapy, since azithromycin could drive resistance in that setting. Dosing is often 3 times weekly to start, with escalation to daily use if symptoms persist and the drug is well tolerated.

Both roflumilast and azithromycin can be considered add-on therapies to inhaled triple therapy for exacerbation prevention. Beyond these oral agents, new options include the biologics dupilumab and mepolizumab, which were recently approved as add-on therapy for patients with eosinophilic COPD, and ensifentrine, a novel inhaled medication with a dual PDE3/PDE4 mechanism. For select patients, surgical lung volume reduction procedures may also be considered.

AJMC®: How long should patients remain on second-line therapies before assessing response, and how do you evaluate disease progression in COPD?

Dr Rali: Follow-up will generally be within 3 to 6 months or before 5 months in patients with advanced COPD. During follow-up, we review exacerbation history, assess symptoms with CAT and mMRC, and monitor quality of life. Simultaneously, we ensure patients are complying with their inhaler regimen and that they have proper technique, correcting those issues if needed. We don’t usually perform pulmonary function tests at each follow-up visit, but they should be repeated at least once every 12 to 18 months and always before escalating treatment.

Second-line, advanced treatment options are often prescribed to reduce patients’ exacerbation rates, and if we can reduce exacerbations, patients’ quality of life will improve. If patients remain symptomatic or [experience exacerbation] despite these measures, we consider escalating therapy, including biologics or ensifentrine, as indicated. Some specific benchmarks we can use to monitor treatment success are CAT score below 10, mMRC score below 2, and no recent history of exacerbations.

AJMC®: As you escalate COPD therapy, how do you decide between roflumilast, azithromycin, or dupilumab, and where does ensifentrine fit into escalating treatment?

Dr Rali: Roflumilast and azithromycin we tend to consider simultaneously, depending on whether patients have chronic bronchitis. They are most appropriate in patients without an eosinophilic phenotype. For patients with an eosinophilic phenotype, dupilumab is an appropriate option, particularly if these patients continue to exacerbate despite triple therapy or LAMA/LABA if they cannot tolerate inhaled steroids. One caveat to dupilumab is that it is a self-administered injection, so patients must be comfortable with that.

Ensifentrine can be considered for patients with persistent symptoms and exacerbations despite inhaled therapy. However, this medication is administered via nebulizer, and some formulations of LAMA/LABA/ICS (inhaled corticosteroids) may be nebulized, as well. In that scenario, again, you have to consider patients’ willingness to comply with the full treatment regimen, balancing efficacy with treatment burden and quality-of-life considerations.

There are also some managed care considerations, particularly with the newer medications dupilumab and ensifentrine, but these have not been fully fleshed out, since those approvals are more recent. In general, payers will require adequate documentation of persistent symptoms, exacerbation history, and use of guideline-directed therapies before approving advanced treatments. Currently, payers do not seem to be forcing selection of 1 newer therapy over another, but rather ensuring patients receive proper prescriptions based on the clinical trial data.

AJMC®: When evaluating patients for potential use of biologics, what clinical factors help guide your decision?

Dr Rali: Even before seeing a patient within the clinic, I can often review electronic medical records (EMRs) to determine whether the patient has an eosinophilic phenotype and would therefore be a candidate for biologics. That information exists from routine blood work done for other reasons.

Another factor that can be derived from an EMR is asthma history. About 10% to 15% of the general population has a history of asthma, and there is some clinical overlap of asthma and COPD. Although the dosing schedule differs between the 2 conditions, if I saw both on a patient’s EMR, that is another scenario that would make me consider the patient a candidate for biologics. Likewise, there is some overlap between the eosinophilic COPD phenotype and other upper airway syndromes, like allergic rhinitis or chronic rhinosinusitis. All of these I can generally derive from reviewing a patient’s medical chart to consider whether they are a candidate for biologic therapy. Of course, once we meet, I consider practical issues like the patient’s comfort with self-injection and the likelihood that they would adhere to the therapeutic regimen.

AJMC®: Another novel therapy, ensifentrine, was recently approved by the FDA for COPD. Where are you incorporating this therapy into your treatment algorithm?

Dr Rali: We’re still learning how best to position ensifentrine, but I most often prescribe it to patients who do not have a chronic bronchitis phenotype and either cannot tolerate inhaled corticosteroids or are steroid dependent and currently on triple therapy. In that context, ensifentrine offers a potential steroid-sparing option that may improve symptoms and reduce exacerbations.

Ensifentrine is a nebulized therapy taken twice daily, so I discuss with patients up front the commitment required. This is not something you can take on the go like an inhaler, so treatment adherence and patient preference are important considerations.

I also avoid it in patients with a history of bronchospasm or significant irritability to inhalers, since that raises concerns about tolerability. But for patients without that history, ensifentrine can move up in my treatment considerations as an add-on option to optimize outcomes.

AJMC®: What are the remaining unmet needs in the care of patients with COPD?

Dr Rali: We’ve made important progress establishing that the currently available biologics appear most beneficial to patients with eosinophilic COPD. There remains substantial unmet need for patients with non-eosinophilic disease. Before long, I expect we may see biologic therapies that target pathways beyond eosinophilic inflammation, similar to advances seen in asthma.

Another unmet need is dosing convenience. Dupilumab is administered every 2 weeks and mepolizumab every 4 [weeks], but I think longer-acting options—whether monthly, quarterly, or even every 6 months—would greatly improve adherence and reduce treatment burden while still maintaining efficacy in reducing exacerbations.

Finally, prevention remains critical. Many of my patients are smokers who transition to vaping, which is often mistakenly perceived as safer. In reality, vaping can be just as harmful for individuals with COPD, and more public health focus is needed to address this growing challenge.