Impact of a Comprehensive COPD Therapeutic Interchange Program on 30-Day Readmission Rates in Hospitalized Patients

The authors evaluate the impact of a comprehensive therapeutic interchange program (CTIP) in hospitalized patients with COPD and demonstrate that using a pharmacist-led CTIP of COPD inhalers does not worsen patient outcomes and may provide pharmacy cost savings.

Abstract

Purpose

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States. The economic effect of COPD management is substantial, and the prevalence of the disease continues to rise with the growth of older populations. The purpose of this study was to evaluate the clinical and financial impact of a comprehensive therapeutic interchange program (CTIP) in hospitalized patients with COPD. The primary outcome was a 30-day readmission rate, with the following secondary outcomes: 30-day mortality and pharmacy-inhaled medication cost per patient.

Methods

This study was a multi-center, retrospective, electronic chart review of patients with a diagnosis of COPD admitted to two hospitals from July 1, 2016 to June 30, 2017. Our intervention group was admitted to a 550-bed tertiary care hospital and was managed with a pharmacist-led CTIP for inhaled products used in COPD. Our control group was admitted to a 545-bed tertiary care hospital, which did not have a CTIP in place.

Results

2,885 hospitalized patients with a diagnosis of COPD were included in the analysis (1,350 in the intervention group and 1,535 in the control group). Univariable analysis demonstrated that the intervention group was associated with a lower 30-day readmission rate (5.8% vs. 8.3%; P = 0.012) and a lower average pharmacy-inhaled medication cost ($221 vs. $311; P = < 0.01). There was no statistical difference in 30-day mortality.

Conclusion

This study demonstrates that the use of a pharmacist-led CTIP of COPD inhalers does not worsen patient outcomes and may provide pharmacy cost savings. The cohort managed with a CTIP was statistically associated with a lower 30-day readmission rate and lower pharmacy-inhaled medication costs without any difference in 30-day mortality.

BACKGROUND

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States, and nearly 6.4% of Americans reported that they have been diagnosed with the disease.^1–2 This number is likely an underestimate as a result of the more than 50% of adults with low pulmonary function who reported that they were not aware that they had COPD.³ The prevalence of COPD is expected to increase over the next 30 years because of the aging population.⁴ The direct economic costs attributable to COPD and asthma have been estimated at $53.7 billion, with the cost for prescription medicines at $20.4 billion and hospital inpatient stays at $13.1 billion.⁵

Pharmacological therapy for COPD is used to reduce symptoms, reduce the frequency and severity of exacerbations, and improve exercise tolerance and health status.⁶ According to the Global Initiative for Chronic Obstructive Lung Disease 2017 report, bronchodilators, anticholinergics, inhaled corticosteroids, and combination products are the mainstays for inhaled COPD pharmacological treatment.⁶ The choice within each class depends largely on multiple patient-specific factors, including availability, cost, delivery mechanism, clinical response, and side effects.⁶

There are over 20 inhaled medications approved by the Food and Drug Administration (FDA) that can be used for the pharmacological management of COPD. Because of the many different inhaler options, patients who are admitted to the hospital with a COPD diagnosis are maintained on various pharmacologic regimens to manage their disease outside the hospital. This creates a problem for inpatient pharmacies in maintaining a cost-effective inventory and for respiratory therapists or nurses in administering treatment with the appropriate technique.

Therapeutic interchange is defined by the American Society of Health-System Pharmacists as “an authorized exchange of therapeutic alternatives in accordance with previously established and approved written guidelines or protocols within a formulary system.”⁷ Interchanges can be used as a method of pharmaceutical cost management and are a way to standardize hospital therapy. They also offer one proposed way for managing the variety of different COPD inhalers that patients may present with on their home medication list.

What is unknown is how therapeutic interchange programs for COPD medications produce clinical effectiveness while also taking into account pharmacy costs. The aim of this study was to evaluate the clinical and financial impact of a CTIP in hospitalized patients with COPD.

METHODS

Study Design

The study groups consisted of two hospital systems within the same health care enterprise system. Our intervention group was admitted to a 550-bed tertiary hospital and managed with a pharmacist-led CTIP for inhaled products used in COPD, and our control group was admitted to a 545-bed tertiary care hospital, which did not have a CTIP in place. Our intervention group utilizes a pharmacist-led CTIP, approved by the local pharmacy and therapeutics (P&T) committee, for all known inhaled products used for COPD management during the study period (Table 1). These products will be interchanged at time of verification for one of the nine approved respiratory products. Our control group did not have CTIP for any inpatient medications. The study was approved by the institutional review board with a waiver of informed consent and HIPAA authorization, and was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki and its later amendments.

Table 1.

CTIP Inhaled Medications

Generic	Brand	Manufacturer	Dosing	Therapeutic Substitution Generic, brand name, manufacturer, dosing
LAMA/LABA Combination Inhalers
Tiotropium bromide/olodaterol	Stiolto Respimat	Boehringer Ingelheim	2 inhalations once daily	Umeclidinium/vilanterol, Anoro Ellipta, GlaxoSmithKline, 62.5/25 mcg: 1 inhalation once daily
Glycopyrrolate/formoterol fumarate	Bevespi Aerosphere	AstraZeneca	2 inhalations once daily
Indacaterol/glycopyrrolate	Utibron Neohaler	Sunovion	1 inhalation b.i.d.
ICS/LABA Combination Inhalers
Fluticasone propionate/salmeterol	Advair HFA, Advair Diskus, Advair Airduo	GlaxoSmithKline	45/21 mcg: 2 inhalations b.i.d. 55/14 mcg: 1 inhalation b.i.d. 100/50 mcg: 1 inhalation b.i.d. 115/21 mcg: 2 inhalations b.i.d. 113/14 mcg: 1 inhalation b.i.d. 250/50 mcg: 1 inhalation b.i.d.	Fluticasone furoate/vilanterol, Breo Ellipta, GlaxoSmithKline, 100/25 mcg: 1 inhalation once daily
Budesonide/formoterol	Symbicort	AstraZeneca	80/4.5 mcg: 2 inhalations b.i.d.
Mometasone/formoterol	Dulera	Merck	100/5 mcg: 2 inhalations b.i.d.
Fluticasone propionate/salmeterol	Advair HFA, Advair Diskus, Advair Airduo	GlaxoSmithKline	230/21 mcg: 2 inhalations b.i.d. 232/14 mcg: 1 inhalation b.i.d. 500/50 mcg: 1 inhalation b.i.d.	Fluticasone furoate/vilanterol, Breo Ellipta, GlaxoSmithKline, 200/25 mcg: 1 inhalation once daily
Budesonide/formoterol	Symbicort	AstraZeneca	160/4.5 mcg: 2 inhalations b.i.d.
Mometasone/formoterol	Dulera	Merck	200/5 mcg: 2 inhalations b.i.d.
LAMA Inhalers
Tiotropium	Spiriva Respimat	Boehringer Ingelheim	2.5 mcg: 2 inhalations once daily	Umeclidinium, Incruse Ellipta, GlaxoSmithKline, 62.5 mcg: 1 inhalation once daily
Tiotropium	Spiriva Handihaler	Boehringer Ingelheim	18 mcg: 1 inhalation once daily
Aclidinium	Tudorza Pressair	AstraZeneca	400 mcg: 1 inhalation b.i.d.
Glycopyrrolate	Seebri Neohaler	Sunovion	15.6 mcg: 1 inhalation b.i.d.
LABA Inhalers
Salmeterol	Serevent Diskus	GlaxoSmithKline	50 mcg	Formoterol nebulization, Mylan, 20 mcg, same frequency as Serevent Diskus
Arformoterol	Brovana	Sunovion	15 mcg	Formoterol nebulization, Mylan, 20 mcg, same frequency as Brovana
Indacaterol	Arcapta Neohaler	Sunovion	75 mcg: 1 inhalation once daily	Formoterol nebulization, Mylan, 20 mcg: 1 nebulization b.i.d.
Olodaterol	Striverdi Respimat	Boehringer Ingelheim	2.5 mcg: 2 inhalations once daily	Formoterol nebulization, Mylan, 20 mcg: 1 nebulization b.i.d.
SABA Inhalers
Albuterol	ProAir HFA	Teva	90 mcg: 2 inhalations every 4–6 hours	Albuterol nebulization, Nephron, 2.5 mg/3 mL, same frequency as albuterol inhaler
	Proventil HFA	Merck
	Ventolin HFA	GlaxoSmithKline
Levalbuterol	Xopenex HFA	Sunovion	45 mcg: 2 inhalations every 4–6 hours as needed	Levalbuterol nebulization, Teva, 1.25 mg, same frequency as Xopenex
ICS Inhalers
Beclomethasone	QVAR Redihaler	Teva	80–240 mcg/day	Budesonide nebulization, Nephron, 0.25 mg: 1 nebulization 1–2 times/day
			241–480 mcg/day	Budesonide nebulization, Nephron, 0.5 mg: 1 nebulization b.i.d.
			> 481 mcg/day	Budesonide nebulization, Nephron, 1 mg: 1 nebulization b.i.d.
Budesonide	Pulmicort	AstraZeneca	180–600 mcg/day	Budesonide nebulization, Nephron, 0.25 mg: 1 nebulization 1–2 times/day
			601–1,200 mcg/day	Budesonide nebulization, Nephron, 0.5 mg: 1 nebulization b.i.d.
			> 1,201 mcg/day	Budesonide nebulization, Nephron, 1 mg: 1 nebulization b.i.d.
Ciclesonide	Alvesco	Colvis	160 mcg/day	Budesonide nebulization, Nephron, 0.25 mg: 1 nebulization 1–2 times/day
			320 mcg/day	Budesonide nebulization, Nephron, 0.5 mg: 1 nebulization b.i.d.
			640 mcg/day	Budesonide nebulization, Nephron, 1 mg: 1 nebulization b.i.d.
Fluticasone	Flovent	GlaxoSmithKline	88–264 mcg/day	Budesonide nebulization, Nephron, 0.25 mg: 1 nebulization 1–2 times/day
			265–660 mcg/day	Budesonide nebulization, Nephron, 0.5 mg: 1 nebulization b.i.d.
			> 661 mcg/day	Budesonide nebulization, Nephron, 1 mg: 1 nebulization b.i.d.
Mometasone	Asmanex	Merck	= 200 mcg/day	Budesonide nebulization, Nephron, 0.25 mg: 1 nebulization 1–2 times/day
			220–440 mcg/day	Budesonide nebulization, Nephron, 0.5 mg: 1 nebulization b.i.d.
			> 440 mcg/day	Budesonide nebulization, Nephron, 1 mg: 1 nebulization b.i.d.
SABA/SAMA Combination Inhalers
Albuterol/ipratropium	Combivent Respimat	Boehringer Ingelheim	2.5/0.5 mg: 1 inhalation four times daily	Albuterol/ipratropium nebulization, Nephron, 3/0.5 mg, same frequency as Combivent Respimat
SAMA Inhalers
Ipratropium	Atrovent HFA	Boehringer Ingelheim	17 mcg: 2 inhalations four times daily	Ipratropium nebulization, Nephron, 500 mcg, same frequency as Atrovent HFA

Abbreviations: b.i.d.: twice daily; mcg: microgram; mg: milligram; ICS: inhaled corticosteroid; LABA: long-acting beta agonist; LAMA: long-acting muscarinic antagonist; SABA: short-acting beta agonist; SAMA: short-acting muscarinic antagonist

Study Population

Electronic medical records were identified with the presence of COPD on diagnosis at time of discharge, as determined by International Classification of Diseases, 10^th Revision (ICD-10) code starting with J44: J44.0 (COPD, with acute lower respiratory infection), J44.1 (COPD with acute exacerbation), or J44.9 (COPD, unspecified). COPD did not have to be the primary reason for admission. The intervention group had 1,350 patients and the control group had 1,535 patients included in the analysis. Patients under the age of 18 were excluded from analysis. Only the index hospitalization was included in the analysis, and subsequent readmissions were not included.

Data Collection

In addition to 30-day mortality, readmission rates, and pharmacy inhaler and nebulized-product costs, the following information was collected for each patient: length of stay, age, sex, payer, comorbidities, and case-mix index (CMI). The severity of illness was determined by the CMI. The charge report for the patient population included only inhalers and/or unit-dosed nebulized products that were administered. All pharmacy costs for inhalers and unit-dose nebulized products were determined by the average wholesale price (AWP) in June 2018. Only patients with pharmacy charges for inhalers and unit-dose nebulized products were included in the cost analysis. Baseline characteristics related to comorbidities were determined by ICD-10 codes associated with those conditions.

OUTCOMES

We performed a retrospective, cohort analysis from July 1, 2016 through June 30, 2017. The primary outcome was 30-day readmission rate. The secondary outcomes were 30-day mortality rates and pharmacy cost for inhaled products.

Statistical Analysis

Pearson’s Chi-squared tests were used for categorical variables. T-tests and Wilcoxon rank-sum tests were used for statistical analysis of parametric and non-parametric continuous variables, respectively. Data are percentages with the mean ± standard deviation (SD). Data were assessed by univariable analysis, with a P-value of ≤ 0.05 being considered as statistically significant. Data were analyzed with JMP software, version 12.2.0 (Cary, North Carolina).

RESULTS

We reviewed 2,885 patients’ index hospitalization with the presence of COPD diagnosis at time of discharge (1,350 in the intervention group and 1,535 in the control group). The acuity of these two hospital systems, as determined by fiscal year 17 average CMI, was 2 and 1.58 for our intervention and control groups, respectively. Baseline characteristics between the groups were similar; however, the intervention group had a statistically higher rate of asthma, depression, and hypertension, and a higher severity of illness, as illustrated by CMI (2.3 vs. 1.6; P = < 0.01). Overall, Medicare was the primary payer for both groups, but there were statistically significant differences in the primary payer between the two groups. The intervention group had a statistically significant, greater number of patients on Medicare (79% vs. 75.1%; P = 0.01) and Medicaid (8.5% vs. 5.9%; P = < 0.01), but the control group had a statistically significant, greater number of patients with private insurance (14.7% vs. 9.2%; P = < 0.01) and self-paid patients (1.3% vs. 0.4%; P = 0.01). A full summary of baseline characteristics can be found in Table 2.

Table 2.

Characteristics of Patients Discharged With the Presence of COPD Diagnosis

	Intervention (n = 1,350)	Control (n = 1,535)	P value
Male, n (%)	708 (52)	824 (54)	0.52
Female, n (%)	642 (48)	711 (46)
Age (years ± SD)	71 ± 11.2	70 ± 11.8	0.18
Case-mix index (score ± SD)	2.3 ± 0.73	1.6 ± 0.43	< 0.01
Comorbid conditions
Asthma (%)	9.7	7.4	0.03
CKD (%)	16.3	17.9	0.26
Depression (%)	20.1	12.4	< 0.01
Diabetes Mellitus (%)	23.9	23.4	0.76
Heart Failure (%)	22.9	22.9	1.0
Hypertension (%)	48.1	41.2	< 0.01
Ischemic Heart Disease (%)	25.5	23.1	0.14
Insurance type
Medicaid (%)	8.5	5.9	< 0.01
Medicare (%)	79.0	75.1	0.01
Private (%)	9.2	14.7	< 0.01
Self (%)	0.4	1.3	0.01
Veterans a_airs (%)	2.8	2.9	0.85

CKD: chronic kidney disease; COPD: chronic obstructive pulmonary disease; SD: standard deviation

Univariable analysis demonstrated that the patients in the intervention group, who utilized a CTIP, had a statistically significant, lower 30-day readmission rate (5.8% vs. 8.3%; P = 0.012). The difference in 30-day mortality was not statistically significant (Table 3). In the intervention group and the control group, 1,006 (75%) patients and 1,194 (78%) patients, respectively, received at least one inhaler and/or unit-dose nebulized products. The intervention group was statistically associated with a lower average pharmacy-inhaler cost per patient ($221 vs. $311; P = < 0.01). However, the intervention group was associated with a statistically significant, longer length of stay (6.2 days vs. 4.6 days; P = < 0.01). A full summary of clinical outcomes and pharmacy-inhaler and nebulized-product costs per patient can be found in Tables 3 and 4, respectively.

Table 3.

Association of Formulary Substitution With Clinical Outcomes

	Intervention (n = 1,350)	Control (n = 1,535)	P value
30-day readmission rates (%)	5.8	8.3	0.012
30-day mortality (%)	9.9	8.4	0.17
Hospital length of stay (days ± SD)	6.2 ± 9.2	4.6 ± 4.5	< 0.01

SD: standard deviation

Table 4.

Pharmacy Inhaler and Nebulized Products Cost

	Intervention (n = 1,006)	Control (n = 1,194)	P value
Pharmacy cost for inhalers and unit-dose nebulized products per patient ($ ± SD)	221 ± 380	311 ± 352	< 0.01

SD: standard deviation; $: U.S. dollar

DISCUSSION

Therapeutic interchanges are implemented as a method for pharmaceutical cost management and a way to standardize therapy. There are no studies comparing patient outcomes and pharmacy costs in a facility with a CTIP for COPD inhalers with a facility that does not utilize formulary interchanges.

We noted a decreased rate of 30-day readmissions and decreased pharmacy-inhaled medication costs per patient in the intervention group. The control group had a decreased length of hospital stay, and no statistically significant difference in 30-day mortality was noted between the groups. Patients admitted in the two groups exhibited similar characteristics, with the exception that more patients had asthma, depression, hypertension, and a higher severity of illness in the intervention group. This is consistent with our intervention hospital system’s higher acuity during our study period.

Although there was a lower 30-day readmission rate in our intervention group, this may have been influenced by the longer length of stay. While we cannot exclude the possibility that the CTIP was responsible for the increased length of stay, there may have been other factors that affected the length of stay, such as the higher severity of illness found in our intervention group, issues with placement post-discharge, or other unmeasured confounding variables.

There are conflicting financial studies looking at the use of multidose inhalers (MDI) compared with nebulizers. One study found that pharmacy inhaler charges were lower when using MDI versus hand-held nebulizers.⁸ Another study found that there were savings in switching to nebulizer treatments from MDI.⁹ Neither of these studies evaluated patient outcomes. A study assessing the interchange of a combination of long-acting beta agonist (LABA)/long-acting muscarinic antagonist (LAMA) product for patients with COPD over a daily anticholinergic inhaler plus a twice-daily LABA, found that the interchange was not statistically associated with an increased 30-day readmission rate, but was associated with a lower cost of care.¹⁰

In addition to pharmacy costs, other aspects of health care are affected by formulary substitutions. In the intervention group, three primary inhalers were utilized (Figure 1) versus a more robust spread of inhalers in the control group (Figure 2). The three primary inhalers utilized in the intervention group were all once-daily inhalers. For the control group, two of the three most frequently dispensed inhalers are FDA-approved for twice-daily dosing. Using once-daily medications leads to fewer administrations needing to be delivered, and could save time. Moreover, doing so allows respiratory therapists or nurses to focus on the administration of these inhalers, instead of having to rotate through different inhaler types and administration techniques. A CTIP also could aid in inventory control. Being able to primarily use three inhalers allows for the acquisition of a smaller variety of inhalers, and avoids having to obtain inhalers from outside sources and having to label and identify the patient’s own inhalers for use inside the hospital.

Figure 1.

Intervention Group: Inhaler Distribution

Figure 2.

Control Group: Inhaler Distribution

The intervention group was associated with statistically fewer pharmacy costs for inhalers and unit-dose nebulized products. Another cost-saving measure, which was unaccounted for in this study and could come about through formulary substitution, is pharmacy reimbursements through rebates. This could lead to greater pharmacy department cost savings in some cases.

The results of this study may have some applicability to the therapeutic and financial effect of a CTIP on asthma patients. There is overlap with the inhaled and unit-dose medications. However, only 8.5% of our patient population had asthma, and additional research would need to be carried out to evaluate these effects. Furthermore, this study has internal validity, as demonstrated by the fact that the CTIP implemented by our intervention group did not harm patients and was associated with pharmacy cost savings. However, we cannot directly apply these findings to a CTIP that uses different inhaler interchanges.

There are several limitations to our study, which was conducted at a single health care system and was retrospective in nature. We relied on the use of ICD-10 codes for the diagnosis of COPD, as opposed to clinical diagnosis. An additional limitation is that patients’ discharge medication lists were not evaluated to see if patients were returned to their home inhaler. Although this limitation exists, the CTIP process at this health care system was to link the home and formulary-substituted products upon discharge. This provided transparency to the prescriber regarding what medication the patient was taking at home. Moreover, a previous study that looked at an automatic therapeutic substitution (ATS) at an academic center found that only 5% of patients were discharged on the ATS medication. ¹¹ Lastly, pharmacy costs were calculated from the AWP in June 2018. We cannot exclude the possibility that varying charges for the same product existed at certain points in time during our study. Also, these pharmacy costs do not include potential rebates and group purchasing rates.

CONCLUSION

This study demonstrates that the use of a CTIP of COPD inhalers through an approved therapeutic interchange policy does not worsen patient outcomes and may provide pharmacy cost savings. The automatic therapeutic formulary substitution was statistically associated with a decreased 30-day readmission rate (5.8% vs. 8.3%; P = 0.012) and decreased pharmacy costs for inhalers and unit-dose nebulized products ($221 vs. $311; P = < 0.01), but also with an increased length of hospital stay (6.2 days vs. 4.6 days; P = < 0.01). Randomized prospective trials are needed to validate whether a CTIP of COPD inhalers is safe and cost-effective.