AHDB April 2014, Vol 7, No 2

The Peer-Reviewed Forum for Real-World Evidence in Benefit Design ™ April 2014

Volume 7, Number 2

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

EDITORIAL

Harnessing the Power of Big Data in Healthcare David B. Nash, MD, MBA CLINICAL

Considering Patient Preferences When Selecting Anti–Tumor Necrosis Factor Therapeutic Options ™

Gosia Sylwestrzak, MA; Jinan Liu, PhD; Judith J. Stephenson, SM; Alexander P. Ruggieri, MD, MHS; Andrea DeVries, PhD Stakeholder Perspective: In a Fix on Addressing Alternatives

By Albert Tzeel, MD, MHSA, FACPE

Infliximab Dosing Patterns in a Sample of Patients with Crohn’s Disease: Results from a Medical Chart Review Joseph Tkacz, MS; Jennifer H. Lofland, PharmD, MPD, PhD; Julie Vanderpoel, PharmD, MPA; Charles Ruetsch, PhD Stakeholder Perspective: Infliximab Dosing for Crohn’s Disease: Too Much of a Good Thing?

By Atheer A. Kaddis, PharmD BUSINESS

Rising Costs of COPD and the Potential for Maintenance Therapy to Slow the Trend Christopher M. Blanchette, PhD, MBA; Nicholas J. Gross, MD, PhD; Pablo Altman, MD, MBA Stakeholder Perspective: Chronic Obstructive Pulmonary Disease Remains a Growing Population Health Concern

By F. Randy Vogenberg, PhD, RPh

Y

www.AHDBonline.com ©2014 Engage Healthcare Communications, LLC

For your members with COPD (chronic obstructive pulmonary disease)

The only once-daily ICS/LABA (inhaled corticosteroid/long-acting beta2-agonist) for the maintenance treatment of COPD. Contact your GlaxoSmithKline Account Manager to schedule a presentation.

Indications • BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2 -adrenergic agonist (ICS/LABA) indicated for the longterm, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

• BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

Important Safety Information for BREO ELLIPTA WARNING: ASTHMA-RELATED DEATH • Long-acting beta2-adrenergic agonists (LABAs), such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. A placebo-controlled trial with another LABA (salmeterol) showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of all LABAs, including vilanterol.

• The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

CONTRAINDICATIONS • BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients.

WARNINGS AND PRECAUTIONS • BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. • BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. Acute symptoms should be treated with an inhaled, short-acting beta2 -agonist.

• BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medications containing LABAs, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs. Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

• Oropharyngeal candidiasis has occurred in patients treated with BREO ELLIPTA. Advise patients to rinse the mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

• An increase in the incidence of pneumonia has been observed in subjects with COPD receiving BREO ELLIPTA. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences these pneumonia events were fatal.

– In replicate 12-month studies of 3255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving BREO ELLIPTA 100/25 mcg (6% [51 of 806 subjects]), fluticasone furoate (FF)/vilanterol (VI) 50/25 mcg (6% [48 of 820 subjects]), and FF/VI 200/25 mcg (7% [55 of 811 subjects]) than in subjects receiving VI 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving VI or FF/VI 50/25 mcg.

There was fatal pneumonia in 1 subject receiving BREO ELLIPTA at the approved strength (100/25 mcg) and in 7 subjects receiving FF/VI 200/25 mcg (<1% for each treatment group).

• Physicians should remain vigilant for the possible development of pneumonia in patients with COPD, as the clinical features of such infections overlap with the symptoms of COPD exacerbations.

• Patients who use corticosteroids are at risk for potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. A more serious or even fatal course of chickenpox or measles may occur in susceptible patients. Use caution in patients with the above because of the potential for worsening of these infections.

• Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. Taper patients slowly from systemic corticosteroids if transferring to BREO ELLIPTA. • Hypercorticism and adrenal suppression may occur with very high dosages or at the regular dosage of inhaled corticosteroids in susceptible individuals. If such changes occur, discontinue BREO ELLIPTA slowly.

Important Safety Information for BREO ELLIPTA (cont’d) WARNINGS AND PRECAUTIONS (cont’d) • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• If paradoxical bronchospasm occurs, discontinue BREO ELLIPTA and institute alternative therapy.

• Vilanterol can produce clinically significant cardiovascular effects in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. BREO ELLIPTA should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

• Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter.

• Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts.

• Use with caution in patients with convulsive disorders, thyrotoxicosis, diabetes mellitus, ketoacidosis, and in patients who are unusually responsive to sympathomimetic amines.

• Be alert to hypokalemia and hyperglycemia.

ADVERSE REACTIONS • The most common adverse reactions (≥3% and more common than placebo) reported in two 6-month clinical trials with BREO ELLIPTA (and placebo) were nasopharyngitis, 9% (8%); upper respiratory tract infection, 7% (3%); headache, 7% (5%); and oral candidiasis, 5% (2%).

• In addition to the events reported in the 6-month studies, adverse reactions occurring in ≥3% of the subjects treated with BREO ELLIPTA in two 1-year studies included COPD, back pain, pneumonia, bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

DRUG INTERACTIONS • Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and cardiovascular adverse effects may occur.

• BREO ELLIPTA should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval, or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists, such as vilanterol, on the cardiovascular system may be potentiated by these agents.

• Use beta-blockers with caution as they not only block the pulmonary effect of beta-agonists, such as vilanterol, but may produce severe bronchospasm in patients with reversible obstructive airways disease.

• Use with caution in patients taking non–potassium-sparing diuretics, as electrocardiographic changes and/or hypokalemia associated with non–potassium-sparing diuretics may worsen with concomitant beta-agonists.

USE IN SPECIFIC POPULATIONS • Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Fluticasone furoate exposure may increase in these patients. Monitor for systemic corticosteroid effects.

Please see Brief Summary of Prescribing Information, including Boxed Warning, for BREO ELLIPTA on the following pages.

BREO ELLIPTA was developed in collaboration with

BRIEF SUMMARY BREOTM ELLIPTATM (fluticasone furoate and vilanterol inhalation powder) FOR ORAL INHALATION USE The following is a brief summary only; see full prescribing information for complete product information WARNING: ASTHMA-RELATED DEATH Long-acting beta2-adrenergic agonists (LABA) increase the risk of asthma-related death. Data from a large placebo-controlled US trial that compared the safety of another LABA (salmeterol) with placebo added to usual asthma therapy showed an increase in asthma-related deaths in subjects receiving salmeterol. This finding with salmeterol is considered a class effect of LABA, including vilanterol, an active ingredient in BREO ELLIPTA [see Warnings and Precautions (5.1)].

The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

1 INDICATIONS AND USAGE BREO ELLIPTA is a combination inhaled corticosteroid/long-acting beta2-adrenergic agonist (ICS/LABA) indicated for the long-term, once-daily, maintenance treatment of airflow obstruction in patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and/or emphysema. BREO ELLIPTA is also indicated to reduce exacerbations of COPD in patients with a history of exacerbations.

Important Limitations of Use: BREO ELLIPTA is NOT indicated for the relief of acute bronchospasm or for the treatment of asthma.

4 CONTRAINDICATIONS The use of BREO ELLIPTA is contraindicated in patients with severe hypersensitivity to milk proteins or who have demonstrated hypersensitivity to either fluticasone furoate, vilanterol, or any of the excipients [see Warnings and Precautions (5.11), Description (11) of full prescribing information].

5 WARNINGS AND PRECAUTIONS 5.1 Asthma-Related Death Data from a large placebo-controlled trial in subjects with asthma showed that LABA may increase the risk of asthma-related death.

Data are not available to determine whether the rate of death in patients with COPD is increased by LABA. A 28-week, placebo-controlled, US trial comparing the safety of another LABA (salmeterol) with placebo, each added to usual asthma therapy, showed an increase in asthma-related deaths in subjects receiving salmeterol (13/13,176 in subjects treated with salmeterol vs 3/13,179 in subjects treated with placebo; relative risk: 4.37 [95% CI: 1.25, 15.34]). The increased risk of asthmarelated death is considered a class effect of LABA, including vilanterol, one of the active ingredients in BREO ELLIPTA. No study adequate to determine whether the rate of asthma-related death is increased in subjects treated with BREO ELLIPTA has been conducted. The safety and efficacy of BREO ELLIPTA in patients with asthma have not been established. BREO ELLIPTA is not indicated for the treatment of asthma.

5.2 Deterioration of Disease and Acute Episodes BREO ELLIPTA should not be initiated in patients during rapidly deteriorating or potentially life-threatening episodes of COPD. BREO ELLIPTA has not been studied in patients with acutely deteriorating COPD. The initiation of BREO ELLIPTA in this setting is not appropriate.

BREO ELLIPTA should not be used for the relief of acute symptoms, i.e., as rescue therapy for the treatment of acute episodes of bronchospasm. BREO ELLIPTA has not been studied in the relief of acute symptoms and extra doses should not be used for that purpose. Acute symptoms should be treated with an inhaled, short-acting beta2-agonist. When beginning treatment with BREO ELLIPTA, patients who have been taking oral or inhaled, short-acting beta2-agonists on a regular basis (e.g., 4 times a day) should be instructed to discontinue the regular use of these drugs and to use them only for symptomatic relief of acute respiratory symptoms. When prescribing BREO ELLIPTA, the healthcare provider should also prescribe an inhaled, short-acting beta2-agonist and instruct the patient on how it should be used.

Increasing inhaled, short-acting beta2-agonist use is a signal of deteriorating disease for which prompt medical attention is indicated. COPD may deteriorate acutely over a period of hours or chronically over several days or longer. If BREO ELLIPTA no longer controls symptoms of bronchoconstriction; the patientâ&#x20AC;&#x2122;s inhaled, shortacting, beta2-agonist becomes less effective; or the patient needs more short-acting beta2-agonist than usual, these may be markers of deterioration of disease. In this setting a re-evaluation of the patient and the COPD treatment regimen should be undertaken at once. Increasing the daily dose of BREO ELLIPTA beyond the recommended dose is not appropriate in this situation.

5.3 Excessive Use of BREO ELLIPTA and Use With Other Long-Acting Beta2Agonists BREO ELLIPTA should not be used more often than recommended, at higher doses than recommended, or in conjunction with other medicines containing LABA, as an overdose may result. Clinically significant cardiovascular effects and fatalities have been reported in association with excessive use of inhaled sympathomimetic drugs.

Patients using BREO ELLIPTA should not use another medicine containing a LABA (e.g., salmeterol, formoterol fumarate, arformoterol tartrate, indacaterol) for any reason.

5.4 Local Effects of Inhaled Corticosteroids In clinical trials, the development of localized infections of the mouth and pharynx with Candida albicans has occurred in subjects treated with BREO ELLIPTA. When such an infection develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while treatment with BREO ELLIPTA continues, but at times therapy with BREO ELLIPTA may need to be interrupted. Advise the patient to rinse his/her mouth without swallowing following inhalation to help reduce the risk of oropharyngeal candidiasis.

5.5 Pneumonia An increase in the incidence of pneumonia has been observed in subjects with COPD receiving the fluticasone furoate/vilanterol combination, including BREO ELLIPTA 100 mcg/25 mcg, in clinical trials. There was also an increased incidence of pneumonias resulting in hospitalization. In some incidences

these pneumonia events were fatal. Physicians should remain vigilant for the possible development of pneumonia in patients with COPD as the clinical features of such infections overlap with the symptoms of COPD exacerbations. In replicate 12-month trials in 3,255 subjects with COPD who had experienced a COPD exacerbation in the previous year, there was a higher incidence of pneumonia reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 6% [48 of 820 subjects]; 100 mcg/25 mcg: 6% [51 of 806 subjects]; or 200 mcg/25 mcg: 7% [55 of 811 subjects]) than in subjects receiving vilanterol 25 mcg (3% [27 of 818 subjects]). There was no fatal pneumonia in subjects receiving vilanterol or fluticasone furoate/vilanterol 50 mcg/25 mcg. There was fatal pneumonia in 1 subject receiving fluticasone furoate/vilanterol 100 mcg/25 mcg and in 7 subjects receiving fluticasone furoate/vilanterol 200 mcg/25 mcg (less than 1% for each treatment group).

5.6 Immunosuppression Persons who are using drugs that suppress the immune system are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In such children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If a patient is exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If a patient is exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. (See the respective package inserts for complete VZIG and IG prescribing information.) If chickenpox develops, treatment with antiviral agents may be considered. Inhaled corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculosis infections of the respiratory tract; systemic fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex.

5.7 Transferring Patients From Systemic Corticosteroid Therapy Particular care is needed for patients who have been transferred from systemically active corticosteroids to inhaled corticosteroids because deaths due to adrenal insufficiency have occurred in patients with asthma during and after transfer from systemic corticosteroids to less systemically available inhaled corticosteroids. After withdrawal from systemic corticosteroids, a number of months are required for recovery of hypothalamic-pituitary-adrenal (HPA) function. Patients who have been previously maintained on 20 mg or more of prednisone (or its equivalent) may be most susceptible, particularly when their systemic corticosteroids have been almost completely withdrawn. During this period of HPA suppression, patients may exhibit signs and symptoms of adrenal insufficiency when exposed to trauma, surgery, or infection (particularly gastroenteritis) or other conditions associated with severe electrolyte loss. Although BREO ELLIPTA may control COPD symptoms during these episodes, in recommended doses it supplies less than normal physiological amount of glucocorticoid systemically and does NOT provide the mineralocorticoid activity that is necessary for coping with these emergencies. During periods of stress or a severe COPD exacerbation, patients who have been withdrawn from systemic corticosteroids should be instructed to resume oral corticosteroids (in large doses) immediately and to contact their physicians for further instruction. These patients should also be instructed to carry a warning card indicating that they may need supplementary systemic corticosteroids during periods of stress or severe COPD exacerbation. Patients requiring oral corticosteroids should be weaned slowly from systemic corticosteroid use after transferring to BREO ELLIPTA. Prednisone reduction can be accomplished by reducing the daily prednisone dose by 2.5 mg on a weekly basis during therapy with BREO ELLIPTA. Lung function (mean forced expiratory volume in 1 second [FEV1]), beta-agonist use, and COPD symptoms should be carefully monitored during withdrawal of oral corticosteroids. In addition, patients should be observed for signs and symptoms of adrenal insufficiency, such as fatigue, lassitude, weakness, nausea and vomiting, and hypotension. Transfer of patients from systemic corticosteroid therapy to BREO ELLIPTA may unmask allergic conditions previously suppressed by the systemic corticosteroid therapy (e.g., rhinitis, conjunctivitis, eczema, arthritis, eosinophilic conditions). During withdrawal from oral corticosteroids, some patients may experience symptoms of systemically active corticosteroid withdrawal (e.g., joint and/or muscular pain, lassitude, and depression) despite maintenance or even improvement of respiratory function.

5.8 Hypercorticism and Adrenal Suppression Inhaled fluticasone furoate is absorbed into the circulation and can be systemically active. Effects of fluticasone furoate on the HPA axis are not observed with the therapeutic dose of BREO ELLIPTA. However, exceeding the recommended dosage or coadministration with a strong cytochrome P450 3A4 (CYP3A4) inhibitor may result in HPA dysfunction [see Warnings and Precautions (5.9), Drug Interactions (7.1)]. Because of the possibility of significant systemic absorption of inhaled corticosteroids in sensitive patients, patients treated with BREO ELLIPTA should be observed carefully for any evidence of systemic corticosteroid effects. Particular care should be taken in observing patients postoperatively or during periods of stress for evidence of inadequate adrenal response. It is possible that systemic corticosteroid effects such as hypercorticism and adrenal suppression (including adrenal crisis) may appear in a small number of patients who are sensitive to these effects. If such effects occur, BREO ELLIPTA should be reduced slowly, consistent with accepted procedures for reducing systemic corticosteroids, and other treatments for management of COPD symptoms should be considered.

5.9 Drug Interactions With Strong Cytochrome P450 3A4 Inhibitors Caution should be exercised when considering the coadministration of BREO ELLIPTA with long-term ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) because increased systemic corticosteroid and increased cardiovascular adverse effects may occur [see Drug Interactions (7.1), Clinical Pharmacology (12.3) of full prescribing information].

5.10 Paradoxical Bronchospasm As with other inhaled medicines, BREO ELLIPTA

can produce paradoxical bronchospasm, which may be life threatening. If paradoxical bronchospasm occurs following dosing with BREO ELLIPTA, it should be treated immediately with an inhaled, short-acting bronchodilator; BREO ELLIPTA should be discontinued immediately; and alternative therapy should be instituted.

5.11 Hypersensitivity Reactions Hypersensitivity reactions may occur after administration of BREO ELLIPTA. There have been reports of anaphylactic reactions in patients with severe milk protein allergy after inhalation of other powder products containing lactose; therefore, patients with severe milk protein allergy should not take BREO ELLIPTA [see Contraindications (4)].

5.12 Cardiovascular Effects Vilanterol, like other beta2-agonists, can produce a clinically significant cardiovascular effect in some patients as measured by increases in pulse rate, systolic or diastolic blood pressure, and also cardiac arrhythmias, such as supraventricular tachycardia and extrasystoles. If such effects occur, BREO ELLIPTA may need to be discontinued. In addition, beta-agonists have been reported to produce electrocardiographic changes, such as flattening of the T wave, prolongation of the QTc interval, and ST segment depression, although the clinical significance of these findings is unknown. In healthy subjects, large doses of inhaled fluticasone furoate/vilanterol (4 times the recommended dose of vilanterol, representing a 12-fold higher systemic exposure than seen in patients with COPD) have been associated with clinically significant prolongation of the QTc interval, which has the potential for producing ventricular arrhythmias. Therefore, BREO ELLIPTA, like other sympathomimetic amines, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension.

5.13 Reduction in Bone Mineral Density Decreases in bone mineral density (BMD) have been observed with long-term administration of products containing inhaled corticosteroids. The clinical significance of small changes in BMD with regard to long-term consequences such as fracture is unknown. Patients with major risk factors for decreased bone mineral content, such as prolonged immobilization, family history of osteoporosis, postmenopausal status, tobacco use, advanced age, poor nutrition, or chronic use of drugs that can reduce bone mass (e.g., anticonvulsants, oral corticosteroids) should be monitored and treated with established standards of care. Since patients with COPD often have multiple risk factors for reduced BMD, assessment of BMD is recommended prior to initiating BREO ELLIPTA and periodically thereafter. If significant reductions in BMD are seen and BREO ELLIPTA is still considered medically important for that patient’s COPD therapy, use of medicine to treat or prevent osteoporosis should be strongly considered. In replicate 12-month trials in 3,255 subjects with COPD, bone fractures were reported by 2% of subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: 2% [14 of 820 subjects]; 100 mcg/25 mcg: 2% [19 of 806 subjects]; or 200 mcg/25 mcg: 2% [14 of 811 subjects]) than in subjects receiving vilanterol 25 mcg alone (less than 1% [8 of 818 subjects]).

5.14 Glaucoma and Cataracts Glaucoma, increased intraocular pressure, and cataracts have been reported in patients with COPD following the long-term administration of inhaled corticosteroids. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. In replicate 12-month trials in 3,255 subjects with COPD, similar incidences of ocular effects (including glaucoma and cataracts) were reported in subjects receiving the fluticasone furoate/vilanterol combination (50 mcg/25 mcg: less than 1% [7 of 820 subjects]; 100 mcg/25 mcg: 1% [12 of 806 subjects]; 200 mcg/25 mcg: less than 1% [7 of 811 subjects]) as those receiving vilanterol 25 mcg alone (1% [9 of 818 subjects]).

5.15 Coexisting Conditions BREO ELLIPTA, like all medicines containing sympathomimetic amines, should be used with caution in patients with convulsive disorders or thyrotoxicosis and in those who are unusually responsive to sympathomimetic amines. Doses of the related beta2-adrenoceptor agonist albuterol, when administered intravenously, have been reported to aggravate preexisting diabetes mellitus and ketoacidosis.

5.16 Hypokalemia and Hyperglycemia Beta-adrenergic agonist medicines may produce significant hypokalemia in some patients, possibly through intracellular shunting, which has the potential to produce adverse cardiovascular effects. The decrease in serum potassium is usually transient, not requiring supplementation.

Beta-agonist medications may produce transient hyperglycemia in some patients. In 4 clinical trials of 6- and 12-month duration evaluating BREO ELLIPTA in subjects with COPD, there was no evidence of a treatment effect on serum glucose or potassium.

6 ADVERSE REACTIONS LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthma-related death. BREO ELLIPTA is not indicated for the treatment of asthma. [See Boxed Warnings and Warnings and Precautions (5.1).] Systemic and local corticosteroid use may result in the following: Increased risk of pneumonia in COPD [see Warnings and Precautions (5.5)]; Increased risk for decrease in bone mineral density [see Warnings and Precautions (5.13)].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice. The clinical program for BREO ELLIPTA included 7,700 subjects with COPD in two 6-month lung function trials, two 12-month exacerbation trials, and 6 other trials of shorter duration. A total of 2,034 subjects have received at least 1 dose of BREO ELLIPTA 100 mcg/25 mcg, and 1,087 subjects have received higher doses of fluticasone furoate/vilanterol. The safety data described below are based on the confirmatory 6-month and 12-month trials. Adverse reactions observed in the other trials were similar to those observed in the confirmatory trials.

6-Month Trials: The incidence of adverse reactions associated with BREO ELLIPTA in Table 1 is based on 2 placebo-controlled, 6-month clinical trials (Trials 1 and 2; n = 1,224 and n = 1,030, respectively). Of the 2,254 subjects, 70% were male and 84% were Caucasian. They had a mean age of 62 years and an average smoking

history of 44 pack years, with 54% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 48% (range: 14% to 87%), the mean postbronchodilator FEV1/forced vital capacity (FVC) ratio was 47% (range: 17% to 88%), and the mean percent reversibility was 14% (range: -41% to 152%). Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/ vilanterol 200 mcg/25 mcg, fluticasone furoate 100 mcg, fluticasone furoate 200 mcg, vilanterol 25 mcg, or placebo.

Table 1. Adverse Reactions With ≥3% Incidence and More Common Than Placebo With BREO ELLIPTA in Subjects With Chronic Obstructive Pulmonary Disease

Adverse Event

a

BREO ELLIPTA 100 mcg/25 mcg (n = 410) %

Vilanterol 25 mcg (n = 408) %

Fluticasone Furoate 100 mcg (n = 410) %

Placebo (n = 412) %

9

10

8

8

Infections and infestations Nasopharyngitis Upper respiratory tract infection Oropharyngeal candidiasisa

7

5

4

3

5

2

3

2

Nervous system disorders Headache

7

9

7

5

Includes terms oral candidiasis, oropharyngeal candidiasis, candidiasis, and oropharyngitis fungal.

12-Month Trials: Long-term safety data is based on two 12-month trials (Trials 3 and 4; n = 1,633 and n = 1,622, respectively). Trials 3 and 4 included 3,255 subjects, of which 57% were male and 85% were Caucasian. They had a mean age of 64 years and an average smoking history of 46 pack years, with 44% identified as current smokers. At screening, the mean postbronchodilator percent predicted FEV1 was 45% (range: 12% to 91%), and the mean postbronchodilator FEV1/FVC ratio was 46% (range: 17% to 81%), indicating that the subject population had moderate to very severely impaired airflow obstruction. Subjects received 1 inhalation once daily of the following: BREO ELLIPTA 100 mcg/25 mcg, fluticasone furoate/vilanterol 50 mcg/25 mcg, fluticasone furoate/vilanterol 200 mcg/25 mcg, or vilanterol 25 mcg. In addition to the events shown in Table 1, adverse reactions occurring in greater than or equal to 3% of the subjects treated with BREO ELLIPTA (N = 806) for 12 months included COPD, back pain, pneumonia [see Warnings and Precautions (5.5)], bronchitis, sinusitis, cough, oropharyngeal pain, arthralgia, hypertension, influenza, pharyngitis, diarrhea, peripheral edema, and pyrexia.

7 DRUG INTERACTIONS 7.1 Inhibitors of Cytochrome P450 3A4 Fluticasone furoate and vilanterol, the individual components of BREO ELLIPTA, are both substrates of CYP3A4.

Concomitant administration of the potent CYP3A4 inhibitor ketoconazole increases the systemic exposure to fluticasone furoate and vilanterol. Caution should be exercised when considering the coadministration of BREO ELLIPTA with longterm ketoconazole and other known strong CYP3A4 inhibitors (e.g., ritonavir, clarithromycin, conivaptan, indinavir, itraconazole, lopinavir, nefazodone, nelfinavir, saquinavir, telithromycin, troleandomycin, voriconazole) [see Warnings and Precautions (5.9) and Clinical Pharmacology (12.3) of full prescribing information].

7.2 Monoamine Oxidase Inhibitors and Tricyclic Antidepressants Vilanterol, like other beta2-agonists, should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors, tricyclic antidepressants, or drugs known to prolong the QTc interval or within 2 weeks of discontinuation of such agents, because the effect of adrenergic agonists on the cardiovascular system may be potentiated by these agents. Drugs that are known to prolong the QTc interval have an increased risk of ventricular arrhythmias.

7.3 Beta Adrenergic Receptor Blocking Agents Beta-blockers not only block the pulmonary effect of beta-agonists, such as vilanterol, a component of BREO ELLIPTA, but may produce severe bronchospasm in patients with reversible obstructive airways disease. Therefore, patients with COPD should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

7.4 Non–Potassium-Sparing Diuretics The electrocardiographic changes and/ or hypokalemia that may result from the administration of non-potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by betaagonists, especially when the recommended dose of the beta-agonist is exceeded.

Although the clinical significance of these effects is not known, caution is advised in the coadministration of beta-agonists with non–potassium-sparing diuretics.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects: Pregnancy Category C. There are no adequate and well-controlled trials with BREO ELLIPTA in pregnant women. Corticosteroids and beta2-agonists have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Because animal studies are not always predictive of human response, BREO ELLIPTA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Women should be advised to contact their physicians if they become pregnant while

taking BREO ELLIPTA. Fluticasone Furoate and Vilanterol: There was no evidence of teratogenic interactions between fluticasone furoate and vilanterol in rats at approximately 9 and 40 times, respectively, the maximum recommended human daily inhalation dose (MRHDID) in adults (on a mcg/m2 basis at maternal inhaled doses of fluticasone furoate and vilanterol, alone or in combination, up to approximately 95 mcg/kg/day). Fluticasone Furoate: There were no teratogenic effects in rats and rabbits at approximately 9 and 2 times, respectively, the MRHDID in adults (on a mcg/ m2 basis at maternal inhaled doses up to 91 and 8 mcg/kg/day in rats and rabbits, respectively). There were no effects on perinatal and postnatal development in rats at approximately 3 times the MRHDID in adults (on a mcg/m2 basis at maternal doses up to 27 mcg/kg/day). Vilanterol: There were no teratogenic effects in rats and rabbits at approximately 13,000 and 160 times, respectively, the MRHDID in adults (on a mcg/m2 basis at maternal inhaled doses up to 33,700 mcg/kg/day in rats and on an AUC basis at maternal inhaled doses up to 591 mcg/kg/day in rabbits). However, fetal skeletal variations were observed in rabbits at approximately 1,000 times the MRHDID in adults (on an AUC basis at maternal inhaled or subcutaneous doses of 5,740 or 300 mcg/kg/ day, respectively). The skeletal variations included decreased or absent ossification in cervical vertebral centrum and metacarpals. There were no effects on perinatal and postnatal development in rats at approximately 3,900 times the MRHDID in adults (on a mcg/m2 basis at maternal oral doses up to 10,000 mcg/kg/day).

Nonteratogenic Effects: Hypoadrenalism may occur in infants born of mothers receiving corticosteroids during pregnancy. Such infants should be carefully monitored.

8.2 Labor and Delivery There are no adequate and well-controlled human trials that have investigated the effects of BREO ELLIPTA during labor and delivery. Because beta-agonists may potentially interfere with uterine contractility, BREO ELLIPTA should be used during labor only if the potential benefit justifies the potential risk.

8.3 Nursing Mothers It is not known whether fluticasone furoate or vilanterol are excreted in human breast milk. However, other corticosteroids and beta2-agonists have been detected in human milk. Since there are no data from controlled trials on the use of BREO ELLIPTA by nursing mothers, caution should be exercised when it is administered to a nursing woman.

8.5 Geriatric Use Based on available data, no adjustment of the dosage of BREO ELLIPTA in geriatric patients is necessary, but greater sensitivity in some older individuals cannot be ruled out. Clinical trials of BREO ELLIPTA for COPD included 2,508 subjects aged 65 and older and 564 subjects aged 75 and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger subjects.

8.6 Hepatic Impairment Fluticasone furoate systemic exposure increased by up to 3-fold in subjects with hepatic impairment compared with healthy subjects. Hepatic impairment had no effect on vilanterol systemic exposure. Use BREO ELLIPTA with caution in patients with moderate or severe hepatic impairment. Monitor patients for corticosteroid-related side effects [see Clinical Pharmacology (12.3) of full prescribing information].

8.7 Renal Impairment There were no significant increases in either fluticasone furoate or vilanterol exposure in subjects with severe renal impairment (CrCl<30 mL/min) compared with healthy subjects. No dosage adjustment is required in patients with renal impairment [see Clinical Pharmacology (12.3) of full prescribing information].

10 OVERDOSAGE No human overdosage data has been reported for BREO ELLIPTA. BREO ELLIPTA contains both fluticasone furoate and vilanterol; therefore, the risks associated with overdosage for the individual components described below apply to BREO ELLIPTA. 10.1 Fluticasone Furoate Because of low systemic bioavailability (15.2%) and an absence of acute drug-related systemic findings in clinical trials, overdosage of fluticasone furoate is unlikely to require any treatment other than observation. If used at excessive doses for prolonged periods, systemic effects such as hypercorticism may occur [see Warnings and Precautions (5.8)]. Single- and repeat-dose trials of fluticasone furoate at doses of 50 to 4,000 mcg have been studied in human subjects. Decreases in mean serum cortisol were observed at dosages of 500 mcg or higher given once daily for 14 days.

10.2 Vilanterol The expected signs and symptoms with overdosage of vilanterol are those of excessive beta-adrenergic stimulation and/or occurrence or exaggeration of any of the signs and symptoms of beta-adrenergic stimulation (e.g., angina, hypertension or hypotension, tachycardia with rates up to 200 beats/ min, arrhythmias, nervousness, headache, tremor, seizures, muscle cramps, dry mouth, palpitation, nausea, dizziness, fatigue, malaise, insomnia, hyperglycemia, hypokalemia, metabolic acidosis). As with all inhaled sympathomimetic medicines, cardiac arrest and even death may be associated with an overdose of vilanterol.

Treatment of overdosage consists of discontinuation of BREO ELLIPTA together with institution of appropriate symptomatic and/or supportive therapy. The judicious use of a cardioselective beta-receptor blocker may be considered, bearing in mind that such medicine can produce bronchospasm. Cardiac monitoring is recommended in cases of overdosage.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility BREO ELLIPTA: No studies of carcinogenicity, mutagenicity, or impairment of fertility were conducted with BREO ELLIPTA; however, studies are available for the individual components, fluticasone furoate and vilanterol, as described below.

Fluticasone Furoate: Fluticasone furoate produced no treatment-related increases in the incidence of tumors in 2-year inhalation studies in rats and mice at inhaled doses up to 9 and 19 mcg/kg/day, respectively (approximately equal to the MRHDID in adults on a mcg/m2 basis). Fluticasone furoate did not induce gene mutation in bacteria or chromosomal damage in a mammalian cell mutation test in mouse lymphoma L5178Y cells in vitro. There was also no evidence of genotoxicity in the in vivo micronucleus test in rats. No evidence of impairment of fertility was observed

in male and female rats at inhaled fluticasone furoate doses up to 29 and 91 mcg/kg/ day, respectively (approximately 3 and 9 times, respectively, the MRHDID in adults on a mcg/m2 basis).

Vilanterol: In a 2-year carcinogenicity study in mice, vilanterol caused a statistically significant increase in ovarian tubulostromal adenomas in females at an inhalation dose of 29,500 mcg/kg/day (approximately 8,750 times the MRHDID in adults on an AUC basis). No increase in tumors was seen at an inhalation dose of 615 mcg/kg/ day (approximately 530 times the MRHDID in adults on an AUC basis). In a 2-year carcinogenicity study in rats, vilanterol caused statistically significant increases in mesovarian leiomyomas in females and shortening of the latency of pituitary tumors at inhalation doses greater than or equal to 84.4 mcg/kg/day (greater than or equal to approximately 45 times the MRHDID in adults on an AUC basis). No tumors were seen at an inhalation dose of 10.5 mcg/kg/day (approximately 2 times the MRHDID in adults on an AUC basis). These tumor findings in rodents are similar to those reported previously for other beta-adrenergic agonist drugs. The relevance of these findings to human use is unknown. Vilanterol tested negative in the following genotoxicity assays: the in vitro Ames assay, in vivo rat bone marrow micronucleus assay, in vivo rat unscheduled DNA synthesis (UDS) assay, and in vitro Syrian hamster embryo (SHE) cell assay. Vilanterol tested equivocal in the in vitro mouse lymphoma assay.

No evidence of impairment of fertility was observed in reproductive studies conducted in male and female rats at inhaled vilanterol doses up to 31,500 and 37,100 mcg/kg/day, respectively (approximately 12,000 and 14,000 times, respectively, the MRHDID in adults on a mcg/m2 basis).

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide and Instructions for Use) 17.1 Asthma-Related Death Patients should be informed that LABA, such as vilanterol, one of the active ingredients in BREO ELLIPTA, increase the risk of asthmarelated death. BREO ELLIPTA is not indicated for the treatment of asthma.

17.2 Not for Acute Symptoms BREO ELLIPTA is not meant to relieve acute symptoms of COPD and extra doses should not be used for that purpose. Acute symptoms should be treated with a rescue inhaler such as albuterol. The physician should provide the patient with such medicine and instruct the patient in how it should be used. Patients should be instructed to notify their physicians immediately if they experience any of the following: Symptoms get worse; Need for more inhalations than usual of their rescue inhaler; Significant decrease in lung function as outlined by the physician. Patients should not stop therapy with BREO ELLIPTA without physician/provider guidance since symptoms may recur after discontinuation.

17.3 Do Not Use Additional Long-Acting Beta2-Agonists When patients are prescribed BREO ELLIPTA, other medicines containing a LABA should not be used.

17.4 Risks Associated With Corticosteroid Therapy Local Effects: Patients should be advised that localized infections with Candida albicans occurred in the mouth and pharynx in some patients. If oropharyngeal candidiasis develops, it should be treated with appropriate local or systemic (i.e., oral) antifungal therapy while still continuing therapy with BREO ELLIPTA, but at times therapy with BREO ELLIPTA may need to be temporarily interrupted under close medical supervision. Rinsing the mouth without swallowing after inhalation is advised to help reduce the risk of thrush.

Pneumonia: Patients with COPD who have received BREO ELLIPTA have a higher risk of pneumonia and should be instructed to contact their healthcare providers if they develop symptoms of pneumonia (e.g., fever, chills, change in sputum color, increase in breathing problems).

Immunosuppression: Patients who are on immunosuppressant doses of corticosteroids should be warned to avoid exposure to chickenpox or measles and, if exposed, to consult their physicians without delay. Patients should be informed of potential worsening of existing tuberculosis, fungal, bacterial, viral, or parasitic infections, or ocular herpes simplex.

Hypercorticism and Adrenal Suppression: Patients should be advised that BREO ELLIPTA may cause systemic corticosteroid effects of hypercorticism and adrenal suppression. Additionally, patients should be instructed that deaths due to adrenal insufficiency have occurred during and after transfer from systemic corticosteroids.

Reduction in Bone Mineral Density: Patients who are at an increased risk for decreased BMD should be advised that the use of corticosteroids may pose an additional risk.

Ocular Effects: Long-term use of inhaled corticosteroids may increase the risk of some eye problems (cataracts or glaucoma); regular eye examinations should be considered.

17.5 Risks Associated With Beta-Agonist Therapy Patients should be informed of adverse effects associated with beta2-agonists, such as palpitations, chest pain, rapid heart rate, tremor, or nervousness.

BREO and ELLIPTA are trademarks of GlaxoSmithKline.

BREO ELLIPTA was developed in collaboration with

Š2013, GlaxoSmithKline. All rights reserved.

Revised 05/2013 Š2013 GlaxoSmithKline group of companies.

All rights reserved. Printed in USA. MH3770R0 October 2013

BRE:1BRS

April 2014

Volume 7, number 2 The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

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Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Directors, Client Services Joe Beck jbeck@the-lynx-group.com Zach Ceretelle zceretelle@the-lynx-group.com Ron Gordon rgordon@the-lynx-group.com Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Senior Associate Editor Lilly Ostrovsky Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Senior Production Manager Lynn Hamilton Founding Editor-in-Chief Robert E. Henry

Table of Contents EDITORIAL

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Harnessing the Power of Big Data in Healthcare David B. Nash, MD, MBA

CLINICAL

71 Considering Patient Preferences When Selecting Anti–Tumor Necrosis Factor Therapeutic Options Gosia Sylwestrzak, MA; Jinan Liu, PhD; Judith J. Stephenson, SM; Alexander P. Ruggieri, MD, MHS; Andrea DeVries, PhD 80

Stakeholder Perspective: In a Fix on Addressing Alternatives

By Albert Tzeel, MD, MHSA, FACPE

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Infliximab Dosing Patterns in a Sample of Patients with Crohn’s Disease: Results from a Medical Chart Review Joseph Tkacz, MS; Jennifer H. Lofland, PharmD, MPD, PhD; Julie Vanderpoel, PharmD, MPA; Charles Ruetsch, PhD 93 Stakeholder Perspective: Infliximab Dosing for Crohn’s Disease: Too Much of a Good Thing?

By Atheer A. Kaddis, PharmD Continued on page 68

Mission Statement American Health & Drug Benefits is founded on the concept that health and drug benefits have undergone a transformation: the econo­metric value of a drug is of equal importance to clinical outcomes as it is to serving as the basis for securing coverage in formularies and benefit designs. Because benefit designs are greatly affected by clinical, business, and policy conditions, this journal offers a forum for stakeholder integration and collaboration toward the im­provement of healthcare.

This publication further provides benefit design de­cision makers the integrated industry information they require to devise formularies and benefit designs that stand up to today’s special healthcare delivery and business needs.

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The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Associate Director, Content Strategy & Development John Welz Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Trevean Digital Programmer Michael Amundsen Meeting & Events Planner Linda Sangenito Senior Project Managers Andrea Boylston Jini Gopalaswamy Project Coordinators Deanna Martinez Jackie Luma IT Specialist Carlton Hurdle Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications

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Table of Contents

(Continued)

BUSINESS

98 Rising Costs of COPD and the Potential for Maintenance Therapy to Slow the Trend Christopher M. Blanchette, PhD, MBA; Nicholas J. Gross, MD, PhD; Pablo Altman, MD, MBA 106 Stakeholder Perspective: Chronic Obstructive Pulmonary Disease Remains a Growing Population Health Concern

By F. Randy Vogenberg, PhD, RPh

American Health & Drug Benefits, ISSN 1942-2962 (print); ISSN 1942-2970 (online), is published 9 times a year by Engage Healthcare Communications, LLC, 1249 South River Rd, Suite 202A, Cranbury, NJ 08512.

Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. American Health & Drug Benefits and The Peer-Reviewed Forum for Real-World Evidence in Benefit Design are trademarks of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the Publisher. Printed in the United States of America.

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Harnessing the Power of Big Data in Healthcare David B. Nash, MD, MBA Editor-in-Chief, American Health & Drug Benefits Jefferson School of Population Health, Philadelphia, PA

T

he Internet age has afforded anyone with a cell phone, laptop, or other electronic device access to more information than most people are able to manage comfortably. Conversely, those devices, which are such an indispensable part of modern life, also provide unprecedented, ongoing access to countless pieces of personal information. Those ubiquitous membership cards and key tags for the local supermarket, Fitbit tracking your physical activity, and the app that leads you to the shoe sale in the department store as you are walking past it are all part of the enormous enterprise of collecting, analyzing, and interpreting disparate pieces of information that fall under the umbrella of “big data.”

By now, most people are aware of the many uses of big data and the virtual impossibility of going “off the grid.”

Websites such as youarewhatyoulike.com are able to generate personality profiles in less than a second by comparing readily available personal information on Facebook with a vast trove of data on other users. Even older, established companies, such as 107-year-old United Parcel Service (UPS), are using sophisticated information to improve their systems and services. UPS makes use of special telematics sensors in more than 46,000 company trucks to track speed, direction, braking, and drivetrain performance.

In addition to tracking daily performance, this tidal wave of data allows the company to redesign each driver’s route so that the company was able to cut 85 million miles off of its pickup and delivery routes and save 8.4 million gallons of fuel in 2011.1 Appropriate analysis of big data can help us find relationships among variables that we may not otherwise recognize. Just think what we could do in healthcare if we could harness the power of big data.

Experts believe that a convergence of 3 factors has given rise to the notion of big data. These factors include tools that can treat almost any digital signal as useful data, increasing the means to gather such information, and ever-cheaper analytic power. Recent articles in leading management journals, such as Korn Ferry Briefings,1 the Harvard Business Review,2 and McKinsey Quarterly,3 have all highlighted the explosive growth of big data.

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In his article in Harvard Business Review, Thomas H. Davenport, MA, PhD, described the traditional types of analytics as “descriptive, which reports on the past; predictive, which uses models based on past data to predict the future; and prescriptive, which uses models to specify optimal behaviors and actions.”2 Dr Davenport stressed the importance of prescriptive analytics, because it allows for large-scale testing of modeling, and offers opportunities to embed analytics into processes to help improve employee performance.

Can we find some healthcare equivalence regarding the use of big data? I think many such examples already exist, especially in the area of so-called mHealth (mobile health). For example, large managed care organizations, such as Aetna and UnitedHealth Group, have already jumped into the mHealth arena.

Appropriate analysis of big data can help us find relationships among variables that we may not otherwise recognize. Just think what we could do in healthcare if we could harness the power of big data.

Aetna acquired iTriage, which allows patients to check symptoms, find doctors, make appointments, and do medical shopping—all online. UnitedHealth Group, the nation’s largest insurer, is working with a few innovative mHealth companies, such as CareSpeak Com­ munications, and has provided the Health4Me app.

Health4Me helps patients find the most convenient healthcare provider using global positioning system (GPS) location, supplies current and personalized data on claims, and enables members to compare services and treatments based on quality and cost.4 Imagine if one could compile data on millions of patients using the Health4Me app. We could perhaps predict the next flu outbreak and be prepared in certain zip codes to tackle these challenges.

Other health researchers claim that mHealth could actually lower healthcare costs and increase quality by4:

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• “Facilitating communication with populations traditionally difficult to reach • “Personalizing and targeting messages that better engage patients, allowing them to make better care decisions • “Providing real-time lifestyle data through specific apps, such as those that can track physical activity for vulnerable populations, such as smokers; GPS locations of asthma sufferers; and instant blood glucose readings for diabetic patients.”

Finally, I believe we can integrate clinical, medical, and public health electronic systems to potentially enable providers, payers, and other stakeholders to better coordinate care for the entire community. When we connect big data and mHealth, are we practicing a new type of medicine, a sort of Population Health 2.0? Population Health 2.0 may be very important for any organization, such as an accountable care organization (ACO) that bears economic risk for clinical decision-making. I certainly would want to know as much as possible about any population I would have to manage, especially one in which every clinical decision has an economic consequence.

I believe we can integrate clinical, medical, and public health electronic systems to potentially enable providers, payers, and other stakeholders to better coordinate care for the entire community. When we connect big data and mHealth, are we practicing a new type of medicine, a sort of Population Health 2.0?

Many have made the analogy that big data brings the concept of “moneyball” to healthcare. Let me enumerate some of the potential challenges we face in which big data may be helpful in making decisions based on performance data rather than mere guesses.

Perhaps we can use predictive analytics to reduce the risk of readmission for key patient groups, such as those with asthma, congestive heart failure, coronary disease, and the like. Hospitals now have a clear financial incentive to reduce patient readmissions. By studying certain key clinical characteristics, we can elaborate which of those characteristics are clearly predictive of readmission. Some clinical software already exists to help us

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implement this type of predictive analytic work. Imagine connecting all potential readmission patients with some mHealth applications.

Prescriptive analytics would be useful in the comparison of primary care physician resource utilization, especially as it relates to conformance with pay-for-performance criteria. Simply put, we already have the capability of creating detailed physician practice profiles, and we also know which pay-for-performance criteria yield the highest payment from organizations such as our local managed care plans; using prescriptive analytics, we can then readily discern which primary care physician essentially “does it better.” We can also then benchmark this high-performing group against lower-performing groups in an attempt to “raise all boats” and to improve our overall pay-for-performance reward in each contract period.

The advent of ACOs presents a huge opportunity to use population health analytics to study the population at risk. For example, we could harness available data from the Dartmouth Atlas, the Robert Wood Johnson Foundation’s Community Tracking Study, the Pennsylvania Health Care Cost Containment Council, and other data sets by focusing on the zip codes represented by the patients in specific cohorts. I am confident that we could uncover some key population health trends that would allow us to focus our resources in the communities we serve to improve health status.

Leading organizational theorists believe that when we organize big data in this way, we may need to reorganize the leadership structure and appoint a chief data or a chief analytics officer.3 Although I am not immediately advocating the creation of a chief analytics officer in your hospital or health plan, I believe we could indeed be witnessing these types of positions in the next 3 to 5 years. A recent article in the Wall Street Journal notes that “everyone” is trying to recruit a big data expert right now.5 What is your view of big data in healthcare? Is your ACO or health plan linking mHealth and the big data conversation? Do you have a chief analytics officer? As always, I am interested in your views, and you can reach me at david.nash@jefferson.edu. n References

1. Berreby D. Making sense of big data: needles of insight, haystacks of numbers. Korn Ferry Briefings. Winter 2014:49-53.

2. Davenport TH. Analytics 3.0. Harvard Bus Rev. December 2013:65-71.

3. Brown B, Court D, Willmott P. Mobilizing your C-suite for big-data analytics.

McKinsey Q. 2013:77-87.

4. Levin-Epstein M. Mobile health: real game-changer. Manag Care. 2013;22:30-35.

5. Willhite J. Getting started in ‘big data.’ CFO Report. February 4, 2014. http://blogs. wsj.com/cfo/2014/02/04/getting-started-in-big-data/. Accessed February 22, 2014.

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Original Research

Considering Patient Preferences When Selecting Anti–Tumor Necrosis Factor Therapeutic Options Gosia Sylwestrzak, MA; Jinan Liu, PhD; Judith J. Stephenson, SM; Alexander P. Ruggieri, MD, MHS; Andrea DeVries, PhD Background: Anti–tumor necrosis factor (TNF) medications for the treatment of chronic inflammatory conditions represent a large and growing expenditure for health plans. Over the past few years, there has been an increase in options for patients receiving anti-TNFs, including choice of agent, route of administration, and location for receiving the medication.

Objective: To examine patient preferences regarding available anti-TNF agents and mode of administration options.

Methods: This cross-sectional survey and claims study was based on administrative claims in the HealthCore Integrated Research Database. Patients were identified for this study if they were receiving infliximab (the intravenous [IV] group) or adalimumab, golimumab, etanercept, or certolizumab pegol (the subcutaneous [SC] group) between March 2012 and August 2012 and were diagnosed with conditions for which these agents are indicated by the US Food and Drug Administration. The survey questionnaire was developed specifically for this study. Participants were asked about their use of anti-TNF agents, locations of administration, preferences for IV or SC therapy, interest in anti-TNF home therapy options, and their physician’s role in their decision-making process. A validated instrument, the Treatment Satisfaction Questionnaire for Medication (TSQM) version II, was used to assess treatment satisfaction by the patients.

Results: A total of 6000 patients were included in the final list of patients, and the study was stopped when the targeted number of 500 surveys were completed. The IV group consisted of 202 (40%) patients, and the SC group consisted of 298 (60%) patients. Patients in the SC group had a higher preference for the administration route they were using compared with patients in the IV group: 89.9% of the SC group preferred the SC route of administration, whereas 71.8% of the IV group preferred the IV route (P <.001).

The global treatment satisfaction scores were similar in both groups (81.9 in the IV group, 80.1 in the SC group; P = .247). The reported likelihood of patients discussing alternative anti-TNF options with their physician was low (45.5% in the IV group vs 49.7% in the SC group; P = .366).

Conclusions: When asked to make a hypothetical choice between IV and SC administration, patients had stronger preferences for SC routes than for IV routes. There was a strong correlation between the route of administration in use and the preference, indicating high level of satisfaction with the current treatment used, which was confirmed with the TSQM version II results. An opportunity for patient education exists, because conversations with physicians about alternative anti-TNF therapies and administration appear to be lacking.

T

he use of anti–tumor necrosis factor (TNF) medications for the treatment of chronic inflammatory conditions, such as rheumatoid arthritis (RA), Crohn’s disease, or psoriasis, represents a large and growMs Sylwestrzak is Research Manager, Payer and Provider Research, HealthCore, Inc.; Dr Liu is Senior Research Analyst, Payer and Provider Research, HealthCore, Inc.; Ms Stephenson is Senior Scientist, Survey-Based Research, HealthCore, Inc.; Dr Ruggieri is Managing Medical Director, Health Care Management, WellPoint, Inc.; Dr DeVries is Director, Payer and Provider Research, HealthCore, Inc.

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2014;7(2):71-81 www.AHDBonline.com Disclosures are at end of text

ing healthcare expenditure. For example, a 2013 sales forecast for adalimumab, the most frequently used injectable anti-TNF, projected continued growth in annual sales from $9.2 billion to $11.2 billion in 2016,1 and infliximab, an intravenous (IV) infusion anti-TNF, generated more than $7 billion in revenue in 2012.2 Parallel with the increased use of the anti-TNFs, there has been emerging evidence that the anti-TNFs have similar effectiveness and safety profiles,3-6 giving patients more options in terms of medication route and frequency of administration. Infliximab, the first anti-TNF approved by the US Food and Drug Administration (FDA),7

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Key Points The anti-TNF agents for chronic inflammatory conditions constitute a large and growing expenditure for health plans. ➤ These agents increasingly include more choices, various administration routes, and different service sites for receiving them. ➤ Patient preference is integral to the selection of therapeutic agents and routes of administration, which can increase treatment success. ➤ For this study, surveys completed by 500 patients discuss their anti-TNF use, preferences for mode of administration, interest in home therapy, and their physician’s role in treatment decisions. ➤ A high correlation was seen between current route of administration and patient preference, with 89.9% of patients using SC therapy preferring the SC route and 71.8% of those using IV agents preferring the IV route. ➤ Fewer than 50% of respondents discussed alternate anti-TNF options with their physicians, despite their desire for better communication. ➤ This study confirms findings of earlier studies but also provides updated information related to alternatives to IV infusions for a large set of indications. ➤

is available only as an IV infusion and requires administration by a medical provider every 4 to 8 weeks.8 Patients receiving infliximab have several options regarding where the infusion is administered, all of which include administration by a healthcare professional, including at a medical facility, such as a physician’s office; an infusion center; an outpatient department of a hospital; or at home by a home health agency nurse, all of which are typically covered by insurance plans.

Subcutaneous (SC) anti-TNFs, including etanercept, adalimumab, certolizumab pegol, and golimumab, offer the convenience of self-injection, but they need to be administered on a more frequent schedule, from twice weekly to once monthly, depending on the agent and its FDA indication.9-12 Since the 2013 FDA approval of its IV formulation, golimumab is the only anti-TNF agent available as both SC and IV medications.11 In the current healthcare environment of offering a wide variety of treatment options with similar clinical effectiveness but differing routes of administration and dosing regimens, there is an opportunity for patient preferences to play a greater role in the selection of agents.

IV treatment may appeal more to patients who desire greater physician control over medication administration, who feel the need for a physician’s presence for a

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sense of safety, or who have difficulty complying with a self-injecting regimen.13 By contrast, despite a more frequent dosing regimen, SC administration offers patients more flexibility and convenience, because their medication can be administered during the time selected by the patient, with no need for medical appointments. Self-administration also eliminates the need to travel to the physician’s office or to other facilities, which usually needs to occur during business hours, thus making it an attractive option for individuals who are more active or who are in the workforce.13 Previous research on mode of administration preferences among anti-TNF users is scarce; especially lacking are US-based studies and studies examining a wide variety of indications. A small British study of preferences among 109 patients with RA showed that 48% of patients preferred to administer their medication themselves, whereas 41% preferred having the hospital staff administer the treatment.13 A different single-center British study of 100 patients with RA reported that patients receiving anti-TNF therapy and those not yet receiving biologic therapies preferred SC injection as their first choice over intramuscular or IV administration; they also preferred administration at home rather than in an outpatient or inpatient setting.14 A 2009 Italian study of 802 patients with RA showed that both IV and SC anti-TNFs were well accepted, with patients evenly split in terms of their preferences for the route of administration.15 Finally, a recent study of 107 patients with RA in Denmark reported that IV administration was preferred by 85% of patients who are currently receiving IV therapies, and SC routes were preferred by 71% of patients who are currently receiving SC therapies.16 We identified only a single US-based study on the topic: a 2008 analysis of 50 patients with irritable bowel disorder reported a slightly greater percentage (54.3%) of patients expressing preference for the SC route of delivery, and all patients who had experienced both routes also preferring SC administration.17 Our study was designed to evaluate a large, geographically and clinically diverse, sample of US patients in 2012 who were using anti-TNFs regarding their preferences for route and place of administration, treatment satisfaction, and information sources related to their choice of therapy. This information is especially timely, because there are currently many more anti-TNFs available than before.

Methods Study Design This prospective observational study assessed the outcomes of 2 groups of patients: those receiving an IV in-

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fusion anti-TNF (ie, infliximab) and those receiving an SC anti-TNF (ie, adalimumab, golimumab, etanercept, or certolizumab pegol).

The study consisted of a cross-sectional patient survey, with all survey-related materials approved by a central Institutional Review Board before the start of the survey.

Eligible patients were included if they were fluent in English, could communicate by telephone, and consented to the study. Patients were contacted by telephone between November 29, 2012, and December 19, 2012, and either completed a 30-minute survey by telephone with the interviewer or via the Internet. Patient-level data were handled in compliance with the Health Insurance Portability and Accountability Act of 1996.

The survey questionnaire was developed specifically for the study and included questions about patients’ demographic and socioeconomic characteristics, use of anti-TNF agents, site of administration, preferences for IV or SC therapy, interest in anti-TNF home therapy, and their information sources about anti-TNFs. A sample questionnaire with selected questions from the survey is listed in the Appendix (available at www.AHDBonline.com). A validated patient-reported outcome instrument, the Treatment Satisfaction Questionnaire for Medication (TSQM) version II, was used to assess treatment satisfaction.

Patient Eligibility The HealthCore Integrated Research Database was used as a sampling frame to identify the eligible patient population, consisting of patients who were using an anti-TNF medication and who had been diagnosed with 1 or more of the FDA-approved indications for anti-TNF agents. Specific patient inclusion criteria included (1) at least 1 claim for infliximab, adalimumab, golimumab, etanercept, or certolizumab pegol between March 2012 and August 2012, and at least 1 medical claim with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code of Crohn’s disease, RA, plaque psoriasis, psoriatic arthritis, or ankylosing spondylitis during the 6-month period before the initiation of the anti-TNF agent; (2) age ≥18 years; (3) health plan membership at the time of patient sample list creation; (4) nonmissing telephone number and/or address; and (5) not being on the HealthCore do not call list.

The survey population was further restricted to a maximum of 6000 patients, selected at random, with an overrepresentation of patients taking infliximab and patients with a diagnosis of Crohn’s disease (regardless of whether they used infliximab or an SC medication).

Patients who received infliximab were oversampled to facilitate comparisons between the main groups of interest (IV and SC), and patients with Crohn’s disease were oversampled to facilitate subgroup analysis by condition.

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Outcomes Patient preferences and treatment satisfaction. Patients were asked to rank their preference for the route of administration of anti-TNFs, with options of expressing strong preference for an injectable, slight preference for an injectable, slight preference for an infusion, or strong preference for an infusion. All patients were asked this question, regardless of whether they had an experience with single or multiple routes of administration. We used a forced-choice method to elicit definitive opinion, because we were interested in providing the most actionable data for decision makers. For similar reasons, patients were asked to choose whether they would like to take their anti-TNF medications at home using a Likert scale with an even number of responses.18 For the assessment of anti-TNF treatment satisfaction, we used an 11-item validated satisfaction questionnaire, the TSQM version II, which allows for comparisons across various medication types and therapeutic areas. Four subscale scores were obtained, including effectiveness, side effects, convenience, and global satisfaction with treatment.19 The subscale scores each ranged from 0 to 100, with higher scores representing greater satisfaction with the effectiveness, lack of side effects, convenience, and global satisfaction of the respondents with their anti-TNF medications.

Information sources related to choice of therapy.

Patients were also asked whether their doctor had discussed prescribing for them any anti-TNF medication other than what they were currently taking. The patients who reported having such discussions were further asked whether the physician expressed preferences for one drug over another, and if so, whether the physician explained the reasons for that preference.

In addition, patients were asked to report where they usually received information about anti-TNF therapies, to report the mode by which they were most interested in receiving information, and to rank their interest in receiving additional information, on a scale from 1 to 5, where 1 was completely not interested and 5 was extremely interested.

Statistical Methods Sample size. The final list of patients eligible for the survey consisted of 6000 patients. All available patients with a claim for infliximab (N = 2095), as well as all patients with a diagnosis of Crohn’s disease (N = 1914) were retained in the study sample; the remaining patients who met the initial inclusion criteria (N = 2948) were randomly selected from the larger patient population of patients receiving anti-TNFs. The targeted number of completed surveys was set at 500, with the survey phase ending after reaching the targeted number.

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Data analysis. This was a descriptive study. For each of the 2 anti-TNF groups (ie, IV and SC), summary statistics, including mean and standard deviation, were provided for continuous variables; counts and percentages were provided for categorical variables. The differences between the 2 groups were compared using a t-test for continuous variables and a χ2 test for categorical variables. Statistical analyses were conducted with SAS version 9.1 software (SAS Institute; Cary, NC). All statistical tests were 2-sided and were performed at a 5% level of significance.

Results Of the 6000 patients included in the final patient list, 1370 patients had been contacted at the point when the target numbers of 500 complete surveys and 7 partial surveys were reached, resulting in a cooperation rate (ie, the percentage of respondents agreeing to be interviewed of the eligible patients contacted) of 37%.

Among respondents with completed surveys, the IV group consisted of 202 patients (40%) and the SC group consisted of 298 patients (60%).

Patient Characteristics Patients’ characteristics are listed in Table 1. The patient age distribution was different between the groups; IV users were more likely to be in the younger age-group (30.7% in the IV group vs 21.5% in the SC group) and in the older age-group (16.3% in the IV group vs 5.4% in the SC group), whereas SC patients were more likely to be of working age (73.2% in the SC group vs 53% in the IV group; P <.001).

As expected, because autoimmune diseases are more common in women, the respondents were more likely to be women (69.3% in the IV group and 67.1% in the SC group; P = .606). Respondents had similar distributions of household income. An overwhelming majority of respondents were white—more than 90% of patients in each group. In addition, similar proportions of both groups had a college or university degree (43.1% in the IV group, 46.3% in the SC group; P = .736).

A higher percentage of respondents in the SC group were employed full time outside the home than in the IV group (59.4% in the SC group vs 48% in the IV group; P = .039). The IV group was more likely to be composed of patients with Crohn’s disease (38.6% vs 25.8% in SC group; P = .004) and was less likely to include patients with RA (45.5% vs 50.7% in the SC group; P = .007) and those with plaque psoriasis (5.9% vs 16.8% in the SC group; P = .001).

The majority of patients reported using anti-TNFs for at least 1 year, but the IV group had a higher percentage of patients in the longest treatment category (84.2% in

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the IV group vs 74.8% in SC group; P = .011; Table 1). In addition, 48 (23.8%) patients in the IV group had previously used an SC anti-TNF and 61 (20.5%) patients in the SC group had previously used an IV anti-TNF.

Outcome Measures Patient preferences and treatment satisfaction. Noticeably, there was high correspondence between the expressed preference and the administration route for the medications that patients were currently taking (Table 2). This pattern was present regardless of the indication, and it held for patients who had previously used a different administration route (results are available on request). However, patients in the SC group reported a higher preference for the route of administration they were currently using compared with the IV group: 89.9% of patients in the SC group reported either a slight or strong preference for an SC anti-TNF, whereas only 71.8% of patients in the IV group had a slight or strong preference for infusions (P <.001).

We observed differences in preference regarding the location where patients received their treatment (facility-based vs home services). When asked whether they would like to be able to take anti-TNF medication at home, 46.1% of patients in the IV group reported either somewhat agreeing or strongly agreeing, indicating significant interest in being able to receive the medication outside of medical facilities (Table 3). In the SC group, a very high proportion (96.3%) of patients expressed preference for receiving medications at home. Although 46.1% of patients receiving IV medications liked the home administration option, only 1.5% were using it (results are available on request).

The results from the validation instrument TSQM version II indicated treatment satisfaction to be high and similar between the groups (Table 4). In terms of specific subscale scores, patients in the IV group reported higher effectiveness scores than in the SC group (82.4 ± 16 and 78.8 ± 19.3, respectively; P = .025) but lower convenience scores (75.6 ± 15.6 compared with 79 ± 14.8, respectively; P = .015). There were no significant differences between the 2 groups on the side effects subscale scores or on the global satisfaction subscale scores.

Information sources related to choice of therapy.

Slightly less than half of the respondents reported that they had had a discussion with their physician about alternative anti-TNF medications (45.5% of the IV group and 49.7% of the SC group; P = .366; Table 5). Those rates fluctuated depending on the condition, but differences between groups did not reach statistical significance in either of the condition-specific subgroups (results are available on request).

Among the patients who had a discussion with their

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Table 1 Patient Characteristics of Anti-TNF Usersa Characteristics

Intravenous anti-TNF users, N (%) (N = 202)

Subcutaneous anti-TNF users, N (%) (N = 298)

Age, yrs

P value <.001

18-39

62 (30.7)

64 (21.5)

40-64

107 (53)

218 (73.2)

â&#x2030;Ľ65

33 (16.3)

16 (5.4)

Mean

49.8 (16)

49.4 (12.2)

Sex

.761 .606

Female

140 (69.3)

200 (67.1)

Male

62 (30.7)

98 (32.9) .736

Education High school graduate/equivalent or less

53 (0.3)

65 (0.2)

Some college, technical school, or trade school, but no degree

37 (18.3)

57 (19.1)

Completed technical or community college

25 (12.4)

37 (12.4)

College/university degree or higher

87 (43.1)

138 (46.3)

White

185 (91.6)

279 (93.6)

Other

17 (8.4)

19 (6.4)

9 (4.5)

8 (2.7)

<$50,000

87 (43.1)

101 (33.9)

$50,000-$100,000

68 (33.7)

119 (39.9)

>$100,000

33 (16.3)

64 (21.5)

Race .387

Ethnicity Hispanic or Latino Total household income in the past 12 mo

.083

Current employment status Employed full time outside the home

.284

.039 97 (48)

177 (59.4)

Employed part time outside the home, full-time homemaker, or full-/part-time student

40 (19.8)

54 (18.1)

Disabled, retired, unemployed

64 (31.7)

67 (22.5)

Experience with anti-TNF agents Current anti-TNF medication use Infliximab

202 (100)

Certolizumab pegol

24 (8.1)

Adalimumab

140 (47)

Etanercept

125 (42)

Golimumab

9 (3)

Indication Crohnâ&#x20AC;&#x2122;s disease

78 (38.6)

77 (25.8)

.004

Rheumatoid arthritis

92 (45.5)

151 (50.7)

.007

Plaque psoriasis

12 (5.9)

50 (16.8)

.001

Psoriatic arthritis

23 (11.4)

50 (16.8)

.076

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Table 1 Patient Characteristics of Anti-TNF Usersa (Continued) Intravenous anti-TNF users, N (%) Characteristics (N = 202)

Subcutaneous anti-TNF users, N (%) (N = 298)

P value

Ankylosing spondylitis

15 (7.4)

17 (5.7)

.191

Others

15 (7.4)

14 (4.7)

.200

Duration of current anti-TNF therapy

.011

<2 mo

1 (0.5)

6 (2)

2 mo to <6 mo

5 (2.5)

25 (8.4)

6 mo to <1 yr

26 (12.9)

44 (14.8)

â&#x2030;Ľ1 yr

170 (84.2)

223 (74.8)

Previous anti-TNF medication use Intravenous (infliximab) Yes

61 (20.5)

No

236 (79.2)

Subcutaneous (adalimumab, certolizumab pegol, etanercept, golimumab)

.133

Yes

48 (23.8)

73 (24.5)

No

151 (74.8)

225 (75.5)

Numbers may not add to totals because missing values are not reported.

TNF indicates tumor necrosis factor.

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Table 2 Patient Preferences for Route of Administration of Anti-TNF Agentsa

IV anti-TNF users N (%)

Patient preference Overall

SC anti-TNF users N (%)

P value <.001

N = 202

N = 298

Strong preference for SC anti-TNF drug

37 (18.3)

211 (70.8)

Slight preference for SC anti-TNF drug

15 (7.4)

57 (19.1)

Slight preference for IV anti-TNF drug

35 (17.3)

9 (3)

Strong preference for IV anti-TNF drug

110 (54.5)

15 (5)

Patients who had previously used a different route of administration

N = 48

N = 61

Strong preference for SC anti-TNF drug

11 (22.9)

38 (62.3)

Slight preference for SC anti-TNF drug

6 (12.5)

12 (19.7)

Slight preference for IV anti-TNF drug

3 (6.3)

5 (8.2)

Strong preference for IV anti-TNF drug

28 (58.3)

6 (9.8)

<.001

Numbers may not add to totals because missing values are not reported.

IV indicates intravenous; SC, subcutaneous; TNF, tumor necrosis factor.

a

physician about an alternative anti-TNF, approximately 66% of patients (63% in the IV group and 69.6% in the SC group) reported that the physicians did not express a preference for one medication over another (Table 5).

Not surprising, physicians were by far the most common source of information for both groups, with approx-

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imately 90% of patients listing their physician as 1 of the 3 sources from which they learned about their anti-TNFs (Table 6).

Patients receiving infusions reported a higher level of interest in obtaining additional information. On a 5-point scale, 49.5% of patients receiving infusions indicated they were interested or extremely interested in

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Table 3 Patient Preference for At-Home Administrationa IV anti-TNF users, N (%) Patient preference (N = 202)

SC anti-TNF users, N (%) (N = 298)

Would you like to take anti-TNF medication at home?

P value <.001

Strongly disagree

78 (38.6)

7 (2.4)

Somewhat disagree

31 (15.4)

3 (1)

Somewhat agree

46 (22.8)

6 (2)

Strongly agree

47 (23.3)

281 (94.3)

Numbers may not add to totals because missing values are not reported.

IV indicates intravenous; SC, subcutaneous; TNF, tumor necrosis factor.

a

Table 4 Treatment Satisfaction of Anti-TNF Usersa IV anti-TNF users, mean (SD) SC anti-TNF users, mean (SD) (N = 202) (N = 298) Effectiveness score

P value

82.4 (16)

78.8 (19.3)

.025

Side effects score

94.3 (16.2)

95.1 (12.8)

.585

Convenience score

75.6 (15.6)

79 (14.8)

.015

81.9 (15)

80.1 (18.6)

.247

Global satisfaction score

Numbers may not add to totals because missing values are not reported.

IV indicates intravenous; SC, subcutaneous; SD, standard deviation; TNF, tumor necrosis factor.

a

Table 5 Patient Perceptions of the Physicianâ&#x20AC;&#x2122;s Role in Choice of Anti-TNF Agenta IV anti-TNF users, N (%) SC anti-TNF users, N (%) Patient perceptions (N = 202) (N = 298) Has your doctor ever discussed an alternative or different anti-TNF agent than the one you are currently taking?

.366

Yes

92 (45.5)

148 (49.7)

No

110 (54.5)

150 (50.3)

92

148

30 (32.6)

39 (26.4)

Yes, he/she prefers an alternative anti-TNF medication

4 (4.3)

6 (4.1)

No, he/she has not expressed a preference

58 (63)

103 (69.6)

Has your doctor ever expressed a preference for one anti-TNF agent over another?

Yes, he/she prefers the anti-TNF medication I am currently using

P value

How much did your doctorâ&#x20AC;&#x2122;s recommendation influence your choice of current anti-TNF medication?

.564

.073

1-did not influence at all

11 (5.5)

2

9 (4.5)

9 (3)

3

10 (5)

28 (9.4)

4

25 (12.4)

59 (19.8)

5-influenced very much

146 (72.3)

189 (63.4)

11 (3.7)

Numbers may not add to totals because missing values are not reported.

IV indicates intravenous; SC, subcutaneous; TNF, tumor necrosis factor.

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Table 6 Education Needs of Patients Receiving Anti-TNF Agentsa IV anti-TNF SC anti-TNF users, N (%) users, N (%) Education needs (N = 202) (N = 298) P value Usual source of information about anti-TNF medications Doctor

189 (93.6)

267 (89.6)

.124

Nurse

113 (55.9)

99 (33.2)

<.001

Radio/TV/Internet

107 (53)

143 (48)

.193

Magazines/newspapers/ books

80 (39.6)

93 (31.2)

.024

Friends/family members

41 (20.3)

48 (16.1)

.291

Online support

35 (17.3)

63 (21.1)

.394

Health plan

34 (16.8)

67 (22.5)

.193

Pharmacist

33 (16.3)

129 (43.3)

<.001

In-person support

30 (14.9)

30 (10.1)

.162

Other

13 (6.4)

32 (10.7)

.058

Level of interest in receiving more information about anti-TNF medications 1-completely not interested

.008

42 (20.8)

69 (23.2)

2

19 (9.4)

59 (19.8)

3

41 (20.3)

61 (20.5)

4

46 (22.8)

45 (15.1)

5-extremely interested

54 (26.7)

64 (21.5)

Numbers may not add to totals because missing values are not reported.

IV indicates intravenous; SC, subcutaneous; TNF, tumor necrosis factor.

a

additional information compared with 36.6% of patients receiving SC agents (P = .008).

Discussion In this study, patients receiving SC anti-TNF agents reported a higher preference for the medication they were currently taking compared with those receiving IV agents.

The fact that the preferences among medication users largely corresponded with the route of administration of the drug that patients were taking suggested that they were satisfied with the treatment. The high satisfaction was confirmed by the results of the TSQM version II. The IV users reported higher satisfaction with effectiveness, whereas SC users were more satisfied with convenience.

In addition, a significant portion (46%) of IV patients expressed interest in receiving their medication at home.

Many such patients would have several options available, either using a home health agency nurse to receive the infusion at home (<2% of those in the IV group in our study reported actually using that option) or switch-

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ing to an SC anti-TNF when clinically appropriate.

However, to consider the alternatives available to them, patients need to be informed about different options in terms of agents, administration routes, or locations for treatment. These results demonstrate that although communication with physicians appears to be of high importance in choice of agent and the interest in receiving information about options was substantial, fewer than half of the respondents ever discussed any alternative anti-TNF options with their physician. This highlights a major opportunity for patient education.

Such education may be especially important considering that the infusion option has been on the market much longer than other options, and many patients, who usually continue to use an anti-TNF treatment for multiple years, initiated the therapy when alternatives such as infusion administration at home or self-injections were not available.

Although SC administration offers more patient control and convenience by eliminating the need to travel to a physicianâ&#x20AC;&#x2122;s office, it does require a patient to be able to self-inject, and the dosing regimens usually require more frequent administration than IV medications.

Some patients may prefer infusions based on the perception of safety because of the presence of medical personnel, and may find the less frequent dosing regimen more appealing. In fact, the 2014 Danish study of patients with RA reported that the most frequent reason among patients for choosing infusions was a wish for safety; among those preferring SC administration, it was a wish to minimize the time of transportation and treatment.16 In our study, patients in the IV group were more likely to be in the younger and older age-groups, whereas those in the SC group were more likely to be of working age and to work outside the home. In line with earlier findings, this indicates that lifestyle may play a role in the selection of a specific mode of administration: patients who are working, active, and/or independent are more likely than others to select the option offering better administration flexibility and convenienceâ&#x20AC;&#x201D;the self-administrated anti-TNFs. Our findings of patients preferring their current route of administration, high treatment satisfaction, and high interest in receiving therapy at home are in line with existing research14-17; however, we were able to assess a larger and more geographically diverse sample of patients and include multiple indications.

Inclusion of multiple indications allowed us to perform subgroup analysis by condition, revealing that regardless of the condition, the SC treatment option appears to be more preferred (results are available on request). In addition, because our study interviewed respondents in 2012, it provides updated information for

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the time period in which alternatives to IV infusion treatment have become more frequently used across different indications.

Despite the availability of options that could better address patient preferences, barriers to the more common use of alternatives (in addition to patientsâ&#x20AC;&#x2122; lack of knowledge) exist in the healthcare system. For example, among both clinicians and payers, the route of administration ranks low in reported importance in the choice of biologics. According to one analysis, clinicians ranked the route of administration fourth after efficacy, safety, and personal experience.20 Payers also ranked the route of administration fourth after efficacy, contracting, and safety.20 In addition, financial incentives can favor the choice of an infusion anti-TNF in both commercial and Medicare markets.21,22 Infusions are typically covered under medical benefits, which often have more favorable deductibles and out-of-pocket maximums for patients, whereas injections tend to be provided under pharmacy coverage with relatively higher copays or coinsurance.23 Patient preference is integral to the decision regarding the selection of therapeutic agents and routes of administration, given the potential to increase treatment success. Convenience and ease of administration have been linked to improved adherence to medication regimen.19 This is an important consideration for anti-TNF therapy, where consistent adherence is very important and is often challenging, with as many as approximately 25% of all users nonadherent to their medication regimen.24 Finally, focuses on quality of life and patient convenience, where similar efficacy and safety for medications have been demonstrated, fall in line with a trend toward the inclusion of quality measures that incorporate patient satisfaction in addition to clinical outcome. For patients using anti-TNF agents, the provision of information on all appropriate agents, routes of administration, and site of infusion service options may engender greater patient trust, sense of shared decision-making, and patient satisfaction.

Limitations Our survey cooperation rate was 37%. Although the cooperation rate is representative of the rates obtained for similarly structured surveys of health plan members where a concern about member abrasion was implemented by a maximum of 5 contact attempts and no attempts to convert refusals, the results may not be representative of the target population.

The results may not be generalizable to individuals who have noncommercial health insurance or no insurance.

Many patients received only 1 type of therapy, and this would have hindered their ability to provide a fully informed decision on their preferred route of administration.

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The questions regarding preference for administration method used a 4-point Likert scale, which might contribute to a bias among patients holding ambiguous attitudes; however, the nonresponse rate for these questions was minimal (ie, <2.5%).

Finally, we did not ask patients about their health status, which might affect preferences.

Conclusions This survey established that in a commercially insured population of patients using anti-TNF agents, patients receiving SC agents had a higher preference for the medication they were currently taking compared with those receiving infusion therapies. Patients receiving infusions reported higher effectiveness than those using SC agents but lower convenience; however, the magnitudes of the differences were not high, and global satisfaction was similar. A significant proportion of patients in the infusion group expressed interest in receiving their medication at home. These results suggest that the newer options of self-injectable administration and/or home-based infusions, when clinically appropriate, can be attractive alternatives for many patients. Despite that, we found that fewer than 50% of patients ever discussed alternative anti-TNFs with their physician and home-based options were used infrequently. This finding points out a need for greater communication to patients about the options that are available to them.

Acknowledgments The authors gratefully acknowledge Amanda Rodriguez, HealthCore, for providing valuable input during the questionnaire design phase and for facilitating the data collection. They also thank Jade Dinh, HealthCore, for supporting the data collection process and Cheryl Jones, HealthCore, for her assistance in the preparation of the manuscript. Finally, the authors would like to recognize Curt Le, WellPoint, for his contribution to the definition of the study objectives and design.

Funding Source Funding for this study was provided by WellPoint. No external source of funding was involved. The authors had complete control over the study planning and results.

Author Disclosure Statement Ms Sylwestrzak, Dr Liu, Ms Stephenson, and Dr deVries are employees of HealthCore, which is a wholly-owned WellPoint subsidiary; and Dr Ruggieri is an employee of WellPoint.

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2. Phillips DJ. After top-seller Remicade: analysis of J&J’s future. YCharts Analysis.

December 3, 2013. http://ycharts.com/analysis/story/after_topseller_remicade_analysis_ of_jandjs_future. Accessed January 28, 2014.

3. Zorzi F, Zuzzi S, Onali S, et al. Efficacy and safety of infliximab and adalimumab in Crohn’s disease: a single centre study. Aliment Pharmacol Ther. 2012;35:1397-1407.

4. Kestens C, van Oijen MG, Mulder CL, et al; for the Dutch Initiative on Crohn and Colitis (ICC). Adalimumab and infliximab are equally effective for Crohn’s disease in patients not previously treated with anti-tumor necrosis factor-α agents.

Clin Gastroenterol Hepatol. 2013;11:826-831.

5. Wiens A, Venson R, Correr CJ, et al. Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis.

Pharmacotherapy. 2010;30:339-353.

6. Atteno M, Peluso R, Costa L, et al. Comparison of effectiveness and safety of infliximab, etanercept, and adalimumab in psoriatic arthritis patients who experienced an inadequate response to previous disease-modifying antirheumatic drugs. Clin Rheumatol. 2010;29:399-403.

7. US Food and Drug Administration. Information on tumor necrosis factor (TNF) blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi). www.fda. gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ ucm109340.htm. Accessed March 27, 2014.

8. Remicade (infliximab) [prescribing information]. Horsham, PA: Janssen Biotech; November 2013.

9. Enbrel (etanercept) solution [prescribing information]. Thousand Oaks, CA: Immunex Corporation; 2013.

10. Humira (adalimumab) injection [prescribing information]. North Chicago, IL: Abbott Laboratories; September 2013.

11. Simponi (golimumab) injection [prescribing information]. Horsham, PA: Janssen Biotech, Inc; November 2013.

12. Cimzia (certolizumab pegol) injection [prescribing information]. Smyrna, GA: UCB, Inc; 2013.

13. Chilton F, Collett RA. Treatment choices, preferences and decision-making by

patients with rheumatoid arthritis. Musculoskeletal Care. 2008;6:1-14.

14. Williams EL, Edwards CJ. Patient preferences in choosing anti-TNF therapies-R1. Letter. Rheumatology (Oxford). 2006;45:1575-1576.

15. Scarpato S, Antivalle M, Favalli EG, et al; for the RIVIERA co-authors. Patient preferences in the choice of anti-TNF therapies in rheumatoid arthritis. Results from a questionnaire survey (RIVIERA study). Rheumatology (Oxford). 2010;49:289-294.

16. Huynh TK, Østergaard A, Egsmose C, Madsen OR. Preferences of patients and health professionals for route and frequency of administration of biologic agents in the treatment of rheumatoid arthritis. Patient Prefer Adherence. 2014;8:93-99.

17. Pitchumoni S, Scherl EJ, Bosworth BP, et al. Patient preferences for subcutaneous versus intravenous formulations of anti-TNF agents for treatment of inflammatory bowel disease. Gastroenterology. 2008;134(4 suppl 1). Abstract W1242.

18. Allen IE, Seaman CA. Statistics roundtable: Likert scales and data analyses. Qual Prog. 2007;40:64-65.

19. Atkinson MJ, Kumar R, Cappelleri JC, Hass SL. Hierarchical construct validity of the treatment satisfaction questionnaire for medication (TSQM version II) among outpatient pharmacy consumers. Value Health. 2005;8(suppl 1):S9-S24.

20. Greenapple R. Trends in biologic therapies for rheumatoid arthritis: results from a survey of payers and providers. Am Health Drug Benefits. 2012;5(2):83-92.

21. Zhang J, Xie F, Delzell E, et al. Trends in the use of biologic agents among rheumatoid arthritis patients enrolled in the US Medicare program. Arthritis Care Res. 2013;65:1743-1751.

22. Polinski JM, Mohr PE, Johnson L. Impact of Medicare Part D on access to and cost sharing for specialty biologic medications for beneficiaries with rheumatoid arthritis. Arthritis Rheum. 2009;61:745-754.

23. DeVries A, Liu J, Sylwestrzak G, Ruggieri A. Comparison of cost sharing for anti-TNF agents in a commercially insured Crohn’s disease population. J Manag Care Pharm. 2014;20(4-a suppl). Abstract K2.

24. Lopez A, Billioud V, Peyrin-Biroulet C, Peyrin-Biroulet L. Adherence to anti-TNF therapy in inflammatory bowel diseases: a systematic review. Inflamm Bowel Dis. 2013;19:1528-1533.

Stakeholder Perspective In a Fix on Addressing Alternatives

By Albert Tzeel, MD, MHSA, FACPE Regional Medical Director, Senior Products, North Florida, Humana

I

“

f it ain’t broke, don’t fix it.” This popular phrase, which is attributed to Bert Lance, Director of the Office of Management and Budget under President Jimmy Carter, purports to promote the concept of leaving well enough alone. Change should be made as a result of a specific need for having said change made and not merely for the sake of the change itself. When it comes to medical care, some may even argue that it aligns quite well with Hippocrates’ admonition to physicians of “primum non nocere” (ie, first, do no harm).

PATIENTS: And so it is in this vein that we look at the study by Sylwestrzak and colleagues that evaluated patient preference in the selection of anti–tumor necrosis factor (TNF) therapeutic options. The authors note that patient preference is key to the selection of therapeutic agents and to the routes of administration. The results of the survey show that nearly 90% of patients receiving subcutaneous (SC) therapy preferred that

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method of administration, whereas nearly 72% of patients receiving anti-TNF agents via intravenous (IV) infusion preferred that route. Yet, despite this significant difference, both groups were satisfied with their medication’s route of administration. Finally, the study showed that the group receiving IV medication was more interested in receiving additional information about alternative treatment options.

These points lead us to ask 2 important questions: (1) is it “broke?” and (2) if it isn’t broken, should we fix it anyway? The implication of the first question, according to the study authors, is that, yes, a problem exists. A significantly greater proportion of members were more satisfied with SC treatments than those receiving IV treatments, and more patients who received IV treatments wanted their physicians to discuss alternative routes of medication administration with them. However, given that there was no discernible difference in the

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patient global satisfaction scores, can we really say that a problem exists, especially when the IV group noted significantly higher effectiveness scores?

It is difficult to answer that question, because preference for therapy may be confounded by satisfaction with therapy, and satisfaction with therapy may be a function of health status, which the authors acknowledge they did not ask about. Then, the outcomes noted may be more a function of the so-called endowment effect.1 To paraphrase the endowment effect, the mere fact that a patient is receiving a given treatment (or, in behavioral economics terms, is the “owner” of said treatment) makes it more likely that the patient values the treatment that he or she has more than an alternative treatment. Furthermore, because the patient does not “own” the alternative treatment, it is considered less valuable or less worthwhile. This, again, begs the questions of whether it is broken, and whether a problem exists.

PAYERS: We find our answer here: the group receiving IV medication was more interested in receiving additional information about alternative treatment options.

Other studies have shown that mere exposure to an object (ie, “the exposure effect”) promotes preference but does not promote valuing the object more, whereas the endowment effect increases the value one attributes to an object but not necessarily a preference for that object.2 Because the IV group expressed a desire for more information on alternatives, while still ascribing value to IV treatment effectiveness, one could argue that the presence of an endowment effect does not mitigate the authors’ conclusions; moreover, it may even serve to strengthen them.

As payers and members/patients work to strengthen their partnership in improving health and well-being, both groups should bear in mind that communication regarding potential alternatives promotes such a goal.

Whether the situation is broken becomes irrelevant; in the spirit of continuous improvement, we can always fix it to make it better. n 1. Ariely D. The endowment effect. September 20, 2012. http://danariely.com/tag/ the-endowment-effect/. Accessed April 8, 2014.

2. Tom G, Nelson C, Srzentic T, King R. Mere exposure and the endowment effect on consumer decision making. J Psychol. 2007;141:117-125.

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VISIT THE NEW ONLINE RESOURCE FOR THE ENTIRE MULTIPLE MYELOMA CARE TEAM

“Better informed teams provide better care.”

Matthew P. Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth Murray, UT

Value-BasedCare IN Myeloma

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RESOURCE CENTER FOR PAYERS, PROVIDERS, AND THE ENTIRE CANCER CARE TEAM

Value-Based Care in Myeloma delivers exclusive interviews and perspectives related to cost, quality, and access issues.

Special sections for VA-based clinicians, advanced practice nurses, and pharmacists will also focus on the unique challenges in the management of multiple myeloma.

www.ValueBasedMyeloma.com Value-Based Care in Myeloma is a publication of Engage Healthcare Communications, a member of The Lynx Group. © 2014 All rights reserved.

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Original Research

Infliximab Dosing Patterns in a Sample of Patients with Crohn’s Disease: Results from a Medical Chart Review

Joseph Tkacz, MS; Jennifer H. Lofland, PharmD, MPH, PhD; Julie Vanderpoel, PharmD, MPA; Charles Ruetsch, PhD Background: Infliximab, a monoclonal antibody tumor necrosis factor-alpha inhibitor, is an effective therapy that is indicated for the treatment of patients with Crohn’s disease. Although dose escalation from 5 mg/kg to 10 mg/kg is allowed according to the prescribing label of infliximab, conflicting results exist regarding the rate at which this escalation may occur, which may affect payers and providers.

Objective: The goal of this exploratory study was to characterize and quantify the rate of infliximab dose escalation in a sample of patients with Crohn’s disease.

Methods: Administrative claims data from patients with Crohn’s disease in a large mid-Atlantic managed care organization were collected and used to target and recruit providers into a chart review study of infliximab dosing. Data from the charts of 161 patients with Crohn’s disease who were receiving infliximab between 2006 and 2010 were extracted. Patients were grouped into an infliximab dose-escalation group or a dose-stable group based on these data. The evidence of any infliximab dose ≥7.5 mg/kg or evidence of a mean maintenance interval of 42 days or less resulted in the placement of a patient in the dose-escalation group, with the balance of patients comprising the stable-dose group.

Results: A total of 925 infliximab infusions were captured from 161 patients. Of the 161 patients identified, 110 had at least 4 infusions, and 4 had missing data; therefore, only 106 (66%) patients were qualified for the final infliximab dosing analysis. A total of 18 (17%) of these patients had evidence of infliximab dose escalation (dose-escalation group), and the remaining 88 (83%) patients had a consistent 5-mg/kg dose and schedule (stable-dose group). Of the 18 patients in the dose-escalation group, 9 (50%) had a decrease in maintenance interval, whereas 12 (66.7%) patients had an increase in their dosage. A total of 3 (16.7%) patients had both an increase in dose and a reduction in maintenance interval.

Conclusions: Infliximab has been shown to be a cost-effective treatment for patients with Crohn’s disease. The rate of infliximab dose escalation in this study was within the lower range of published estimates for this medication. Studies using larger sample sizes are needed to validate the findings of the current study. In addition, studies that are focused on quantifying and describing the nature of infliximab dose escalation may be useful in the development of successful patient–treatment matching algorithms.

C

rohn’s disease is a chronic relapsing form of inflammatory bowel disease and is characterized by inflammation of the gastrointestinal tract.1 It is estimated that 1.4 million persons in the United States and 2.2 million persons in Europe have inflammatory bowel disease.2 The most recent and advanced approach to the treatment of Crohn’s disease is biologic therapy designed to neutralize the proinflammatory effects of the cytokine tumor necrosis factor (TNF)-alpha.3 Mr Tkacz is Staff Scientist, Health Analytics, LLC, Columbia, MD; Dr Lofland is Associate Director, HECOR, Janssen Scientific Affairs, Horsham, PA; Dr Vanderpoel is Director, HECOR, Janssen Scientific Affairs, Horsham, PA; Dr Ruetsch is President, Health Analytics, LLC, Columbia, MD.

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Stakeholder Perspective, page 93 Am Health Drug Benefits.

2014;7(2):87-93 www.AHDBonline.com Disclosures are at end of text

In addition to infliximab, the other anti-TNFs approved by the US Food and Drug Administration (FDA) for the treatment of Crohn’s disease include adalimumab and certolizumab pegol.4,5 The focus of the current study, however, is on infliximab, which has been shown to be an effective treatment for Crohn’s disease.6-8 According to the FDA’s approved indication of infliximab for Crohn’s disease, infliximab induction consists of 5-mg/kg infusions at weeks 0, 2, and 6, followed by continued 5-mg/kg infusions every 8 weeks, with the option to escalate the dosing to 10 mg/kg on the same infusion schedule.9 As discussed in several reviews, dose escalation of infliximab has been reported in patients with Crohn’s disease.10,11 The dose escalation of infliximab has been defined as either an increase in dosage or a decrease in the dosing

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Key Points Infliximab is a TNF blocker that is indicated for the treatment of patients with Crohn’s disease; 2 other TNF blockers are approved by the FDA for this condition.

➤

Understanding dose escalation rates for therapies such as infliximab is important for controlling costs, managing patient expectations, spurring provider intervention, and optimizing treatment efficacy.

➤

This study used claims data from a large midAtlantic managed care organization and medical charts to quantify the rate of dose escalation in patients diagnosed with Crohn’s disease between 2006 and 2010.

➤

Of the 166 patients identified with infliximab claims, 106 were eligible for the analysis; of these, only 17% had evidence of dose escalation, a rate that is lower than previously published estimates.

➤

Patient eligibility for infliximab therapy should be determined early in the treatment to enhance treatment efficacy and avoid unnecessary costs of ineffective therapies.

which Chao and Mulani have raised some doubt about.20 Several investigations have demonstrated the rate of loss of response requiring dose escalation to be between 30% and 40%,6,13,21,22 whereas Waters and colleagues reported that 79% of patients who are new users of infliximab maintained a stable 5-mg/kg dose during the first year.23 Understanding the expected rate of dose escalation for medications such as infliximab is critical for controlling costs, managing patient expectations, spurring provider intervention, and optimizing treatment efficacy. Dose escalation will increase ingredient medication costs and may affect the treatment experience of patients. An enhanced overall understanding of the rates of infliximab dose escalation and the characteristics of patients requiring escalation may allow health plans and physicians to begin modeling algorithms that better match patients to therapy and reduce the incidence of treatment failure. Therefore, the goal of the present study was to characterize and to quantify the rate of infliximab dose escalation in a sample of patients with Crohn’s disease.

➤

Studies using a larger sample size are needed to validate the findings in this exploratory analysis.

➤

interval,12,13 because either approach results in an increase in the amount of infliximab that is infused during a period of multiple infusions. Studies have demonstrated the safety14 and the efficacy12 of increased infliximab doses (ie, >5 mg/kg every 8 weeks), and each method is likely to be equally effective15; however, for convenience, patients may prefer increased dosages versus decreased dosing intervals.16 Various studies indicate that increasing the dose of infliximab is a safe and cost-effective treatment pathway for patients with Crohn’s disease.17,18 Infliximab has been shown, in a recent cost analysis, to be the most cost-­ effective biologic for patients with Crohn’s disease who do not respond to standard therapy,17 and increasing its dose may actually result in more quality-adjusted lifeyears than switching to another biologic.18 Furthermore, switching from infliximab to adalimumab could result in the loss of tolerance and efficacy,19 which suggests that increasing the dose of infliximab to an effective level may be the more successful approach to treatment, especially in chronic diseases such as Crohn’s disease.

Conflicting results have been reported on the rate of infliximab dose escalation. Gisbert and Panés stated that the annual risk for the loss of infliximab response that requires dose escalation is 13% per patient-year,11 a rate

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Methods Patient data were collected retrospectively from administrative claims and from medical charts. The claims data were secured first and were used to identify the gastroenterology providers who may be willing to supply medical charts for review. The Essex Institutional Review Board approved this study.

Medical and Pharmacy Claims Data A large mid-Atlantic managed care organization participated in this study as the health plan partner and agreed to provide claims data for its population of patients with Crohn’s disease during the calendar years 2006 through 2010. To be included in the data extraction, a member had to have a primary or a secondary diagnosis code for Crohn’s disease (International Classification of Diseases, Ninth Revision, Clinical Modification code 555.X). Three tables comprised the final database—professional, facility, and pharmacy claims. The data from a total of 27,931 unique members with Crohn’s disease were extracted.

Chart Review Data Professional and facility claims were aggregated by physician tax identification number to identify the providers with the largest panels of patients with Crohn’s disease. Targeted providers were then solicited by telephone for recruitment into the study. Interested sites had to confirm their participation with the health plan partner and their general panel size of patients with Crohn’s disease who were also members of the health plan. All providers were offered an initial incentive of $500 for

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agreeing to participate in the study, as well as an additional $50 for every chart that was identified as eligible for review. The following inclusion and exclusion criteria were imposed on patient charts: • A diagnosis of Crohn’s disease between 2006 and 2010 • Treatment with infliximab • Age ≥18 years • Absence of any terminal illnesses • Absence of a thought disorder (eg, schizophrenia, schizotypal) • Absence of an organic brain disorder and syndromes (eg, head trauma, moderate-to-severe developmental disability with cognitive impairment) • For female patients, the absence of pregnancy.

To aid in the chart data extraction, an electronic case report form was developed that included fields for demographics, diagnoses, medications, diagnostic tests, surgical procedures, and corresponding dates. Infliximab-­ specific variables included the dose (mg/kg), weight (kg), administered quantity (mg), and the date of infusion. A total of 5 research staff members comprised the chart review team, with each being trained on the Health Insurance Portability and Accountability Act privacy laws and general research ethics.

As a result of variability in the medical charts composition across practices, inter-rater reliability among chart reviewers was calculated on the initial visit to each provider’s office. Any item disagreements were addressed and were corrected before additional charts were reviewed by the team. Overall, 8 gastroenterology practices and infusion centers in the mid-Atlantic area agreed to participate in the study. Charts were reviewed for a total of 161 patients with Crohn’s disease who were being treated with infliximab.

Infliximab Dosing Given the variances in the number of captured infusions and in the length of their current treatment with infliximab, only patients with at least 4 infusions were retained for the main analysis in the study. Patients were grouped and were compared according to their dosing pattern into the dose-stable or dose-escalation group.

Each patient’s first episode of infliximab care, as it appeared in his or her chart, was examined for dose-escalation episode. Any lapse in therapy of 180 days or longer constituted a second episode of care,13 and such infusions were dropped from the analyses. For individual infusions for which the dose was missing, illegible, or unavailable (ie, total <5%), the dose was computed based on the administered quantity of infliximab and the patient’s weight values. If both the administered quantity and the weight were unavailable in such cases, the dose was coded as missing.

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Table 1 Overall Patient Characteristics Patients in Characteristic analysis, N

Mean

Standard deviation

161

37.99

13.24

Total infusions, N

161

5.29

2.54

Starting dose, mg/kg

155

5.39

1.21

Ending dose, mg/kg

146

5.59

1.48

Maintenance interval, days

134

59.28

17.84

Length of therapy, days

148

254.84

149.07

Age, yrs

N (%)

Male

160

75 (46.9)

Captured patients at induction

161

27 (16.8)

Patients with evidence of a lapse in therapy

161

25 (15.5)

Infliximab dose escalation is typically defined as either an increase in dosing from 5 mg/kg to 10 mg/kg or a decrease in the maintenance interval from every 8 weeks to every 6 weeks.12,13 For the present study, evidence of any infliximab dose ≥7.5 mg/kg or a mean maintenance interval of 42 days or less resulted in the placement of a patient in the dose-escalation group. Maintenance infusions were determined based on physician notes, and, when unavailable, were determined by the pattern of infusion intervals during each patient’s episode of care.

The patients who did not meet the dose-escalation criteria were placed in the stable-dose group.

Data Analysis For the complete infliximab sample, descriptive statistics (including means, standard deviations, frequencies, and percentages) were presented for the infliximab treatment-specific outcomes derived from the charts. Next, bivariate analyses were performed comparing stable-dose patients with dose-escalated patients. Chi-square tests of equality of proportions were used for categorical variables, and independent t-tests were used for scale variables.

Results A total of 925 infliximab infusions were captured from 161 patients. A total of 73 (7.9%) infusions were captured during a second episode of care and were dropped from the analyses. Descriptive statistics on the entire sample (N = 161) are listed in Table 1. The mean patient age (in rounded numbers) was 38 ± 13 years, and 75 (47%) patients were male. Within the study period, the patients’ first episode of infliximab care included a mean of 5.3 ± 2.5 infusions (range, 1-8), for a mean length of care of 255 ± 149 days. The mean medication

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Table 2 Infliximab Dosing Analysis Dosing pattern Stable dosing Dose escalation (N = 88) (N = 18) Characteristic Mean SD Mean SD P value Age, yrs

38.11

12.1

Total infusions, N

6.78

Starting dose, mg/kg Ending dose, mg/kg Maintenance interval, days Length of therapy, days

39

14.41

.785

1.5

6.72

1.53

.876

5.03

0.28

6.39

1.96

<.001

5.08

0.35

7.78

2.25

<.001

60.21 333.2

12.8

46.3

12.35

<.001

106.67

257.22

97.46

.006

N (%)

N (%)

P value

Male

47 (53.4)

4 (22.2)

.016

Captured patient at induction

12 (13.6)

4 (22.2)

.354

Evidence of lapse in therapy

5 (5.7)

2 (11.1)

.398

Evidence of dose escalation Increased dosage

—

—

12 (66.7)

—

To 7.5 mg/kg

—

—

4 (22.2)

—

To 10 mg/kg

—

—

8 (44.4)

—

Decreased interval

—

—

9 (50)

—

Either type of dose escalation

—

—

18 (100)

—

SD indicates standard deviation.

interval during the maintenance phase of treatment was 59 ± 18 days. A total of 25 (15.5%) patients showed a lapse in their infliximab treatment, defined as a gap between any 2 infusions of 180 days. Induction infusions were identified in 27 (16.8%) samples, indicating that the majority of the captured infusion data were during the patients’ maintenance phase of treatment.

Table 2 shows the results from the infliximab-dosing analysis. Overall, 110 patients received at least 4 infusions, but 4 patients had missing dose and interval data, resulting in a total of 106 patients of the 166 patients (ie, 66%) who were qualified for the dosing analysis. Patients in both groups received a mean of 6.7 infusions.

A total of 18 (17%) patients showed evidence of dose escalation. Of the 18 patients, 9 (50%) showed a decrease in maintenance interval, whereas 12 (66.7%) showed an increase in their dosage to either 7.5 mg/kg (N = 4; 22.2%) or to 10 mg/kg (N = 8 [44.4%]). Three patients (16.7%) showed both an increase in dose and a

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reduction in maintenance interval.

Patients in the infliximab dose-escalation group had a significantly shorter length of therapy (257 vs 333 days, respectively; t[104] = 2.79; P = .006) and were significantly less likely to be male (22% vs 53%, respectively; χ2[1, N = 106] = 5.82; P = .016) compared with the stable-dose patients. The majority of patients in both dose groups were in the maintenance phase of treatment (86.4% vs 77.8%, respectively; χ2[1, N = 106] = 0.86; P = .354).

Discussion The aim of the present study was to examine dosing patterns in a sample of patients with Crohn’s disease who were treated with infliximab. Existing reports of infliximab dose-escalation rates vary and complicate the estimates of costs and efficacy. Overall, the rate of infliximab dose escalation observed in the present study was within the lower range of published estimates.10 Studies focused on quantifying and describing the nature of infliximab dose escalation may be useful in the development of successful patient treatment-matching algorithms, which may ultimately help to minimize the amount of time and the expenditure lost from ineffective treatments.

A total of 8 gastroenterology sites were recruited to participate in a chart review study. These sites were targeted by an analysis of Crohn’s disease patient service and pharmacy utilization data; member patient data were provided by a large mid-Atlantic managed care organization. In all, the charts of 161 patients with Crohn’s disease who received infliximab were reviewed. As a whole, the sample appeared to be receiving infliximab treatment in accordance with the FDA-approved prescribing information, with a mean starting dose of 5.29 mg/kg and a mean maintenance interval just more than 8 weeks (59 days).

Of these 161 patients receiving infliximab, 106 patients met the inclusion criteria for the dosing analysis, the majority of whom (85%; N = 90) were in the maintenance phase of treatment. A total of 17% of the patients receiving infliximab showed evidence of dose escalation.

Patients who had dose escalation were more likely to be female and had significantly shorter lengths of therapy compared with the patients in the stable-dose group.

These results are consistent with differences in sex that have been reported in patients with Crohn’s disease and the skewing of the complications of Crohn’s disease toward female patients.24,25 There was no difference between the dose-escalation and dose-stable groups with regard to the number of patients showing a lapse in therapy or regarding the proportion of patients who were captured during induction.

Although the rate of dose escalation of infliximab observed in the present study was within the lower range of published estimates, comparison across studies is diffi-

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cult. Gisbert and Panés found that the risk of infliximab dose escalation was 13% per patient-year, although the authors acknowledge that patient follow-up periods varied markedly across studies.11 Other investigators have reported rates of 1-year infliximab postinduction loss of response requiring dose escalation to be between 30% and 40%.6,13,21,22 The design of the current study was distinct from previous investigations in several ways, including the focus on a single health plan, the 5-year measurement window, and the capture of infusion episodes at various time points over the maintenance phase of treatment. This study did validate previous research showing a greater proportion of increased dosages as opposed to decreased intervals (66.7% vs 50%, respectively) among the dose-escalation population16; however, the level to which physician preferences affect these results remains unknown.

Although medication ingredient costs will certainly increase with dose escalation, compliance with infliximab has already been shown to be associated with reduced emergency department and inpatient hospital utilizations, which are primary concerns to payers and to patients.26 As the SWITCH trial has previously demonstrated, some proportion of patients receiving infliximab will benefit more from persisting with and optimizing their current treatment dose than from switching to another biologic.19 This type of evidence can facilitate the development of management algorithms that maximize the cost-benefit of therapies for the treatment of Crohn’s disease.

A pilot study conducted in southern Ohio focused on the site of care of infliximab demonstrated that the collaborative efforts of the health plan, provider, and specialty pharmacy were able to formulate an intervention that reduced out-of-pocket patient costs and maintained continuity of care.27 Obviously, the first step in the current effort is to better quantify the rate of dose escalation.

It may also be worth reexamining the concept of dose escalation, because many patients who require higher doses of infliximab during the course of treatment may be better described as “dose optimized” if treatment effectiveness is achieved and maintained at the higher dose.

This may also serve to remove the negative connotations associated with dose escalation.

A study by Schnitzler and colleagues that examined infliximab interventions that are aimed at keeping the disease under control demonstrated that more than 70% of patients receiving an increased dose or reinduction of infliximab were eventually able to return to the standard 5-mg/kg dose.28 In addition, approximately 60% of patients with both an increased dose and shortened interval were able to return to the standard 5-mg/kg dose and 8-week maintenance interval.28 This evidence suggests that the dose escalation of infliximab may be useful prac-

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tice in the treatment of disease flares, and that reinitiating the standard dose is possible.

Several studies have previously examined factors to facilitate the maintenance of infliximab dose response; however, further testing is needed. Being a nonsmoker29 and having higher C-reactive protein levels30 may each increase the likelihood of maintained response and remission.

In the present study, being female was associated with dose escalation. Although the implication of this result is presently unclear, it is consistent with other reports of worse disease in female patients.24,25 A previous study found that young age and concomitant immunosuppressive treatment were both predictors of short-term response to infliximab.31 Ultimately, as previously stated, the goal is to successfully identify patients, early in treatment, who may be suitable for infliximab therapy to avoid the high costs associated with and to prevent the prolonged use of ineffective treatment. The formation of antibodies against infliximab is associated with a reduced duration of response to treatment.32 As of the writing of this manuscript, a study that is aimed at predicting nonresponse and loss of response to infliximab at the initial diagnosis is in the recruitment phase.33 In addition, the emerging field of pharmacogenomics has already produced early models for the prediction of infliximab response using genotypic markers.34,35

Limitations There are several limitations to the current study. As previously noted, the majority of the patient data extracted from charts did not include induction infusions, making it unfeasible to know how long patients were receiving therapy before the dose escalation. The identification of patients at their initial infusion would have assuaged this confound, but this approach was impractical, because of the need to temporally match patient charts to the claims file, and because of the use of multiple infusion centers by some patients.

In addition, although it was not the goal of the present study, the collection of greater clinical data could have allowed for an examination of the relationship between disease symptoms and dose escalation.

The majority of patient data were retrieved from medical charts, but more than 33% of patient data were restricted to the infusion worksheets within the chart, which was limited specifically to indicators of treatment with infliximab.

Also, the results of the studies that incorporate insurance claims data may only pertain to the insured population and may not apply to uninsured patients.

Finally, the dosing group sample sizes, particularly those of the dose-escalation group (N = 18), were very small, raising concerns of power and the level to which

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this small sample is representative of the larger population of patients with Crohn’s disease who receive infliximab therapy.

Conclusion The rate of infliximab dose escalation in the present study was within the lower range of published estimates.

Although additional studies utilizing larger sample sizes are needed to validate the current findings, the methodology of using administrative claims to identify sites for medical chart reviews proved to be a useful technique.

Overall, the ultimate goal is to develop successful patient treatment-matching algorithms to avoid wasteful spending, to prevent the prolonged use of ineffective treatment, and to identify which cases would be best served by dose optimization versus by switching to an alternate therapeutic medication. The incorporation of patient demographics, treatments, service utilization, and even genetic data is crucial for the advancement of these efforts.

The type of evidence presented in this study is crucial for the development and modification of reimbursement policies for advanced therapeutics, including biologic agents. Specifically, this type of evidence can facilitate the development of management algorithms that maximize the cost-benefit of therapies for the treatment of Crohn’s disease. In an attempt to further reduce waste, managed care organizations may seek to reduce the number of failed trials of expensive therapeutics and begin modeling algorithms that better match patients to a therapy and reduce the probability of treatment failure. The involvement of all stakeholders is crucial to this effort.

Funding Source Funding for this study was provided by Janssen Scientific Affairs, which did not participate in the management or the analysis of the data.

Author Disclosure Statement Mr Tkacz received research support from Janssen Scientific Affairs, Dr Lofland is an employee of and has stock in Johnson & Johnson, Dr Vanderpoel is an employee of Janssen Scientific Affairs and has stock in Janssen Scientific Affairs and Johnson & Johnson, and Dr Ruetsch received research support from Janssen Scientific Affairs.

References

1. Baumgart DC, Sandborn WJ. Crohn’s disease. Lancet. 2012;380:1590-1605. Erratum in: Lancet. 2013;381:204.

2. Loftus EV Jr. Clinical epidemiology of inflammatory bowel disease: incidence, prevalence, and environmental influences. Gastroenterology. 2004;126:1504-1517.

3. Thomson AB, Gupta M, Freeman HJ. Use of the tumor necrosis factor-blockers for Crohn’s disease. World J Gastroenterol. 2012;18:4823-4854.

4. Cimzia (certolizumab pegol) lyophilized powder or solution [prescribing information]. Smyrna, GA: UBC, Inc; November 2012.

5. Humira (adalimumab) injection, solution [prescribing information]. North Chicago, IL: Abbott Laboratories; December 2011.

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6. Hanauer SB, Feagan BG, Lichtenstein GR, et al; for the ACCENT I Study Group.

Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet. 2002;359:1541-1549.

7. Lichtenstein GR, Yan S, Bala M, et al. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn’s disease. Gastroenterology. 2005;128:862-869.

8. Panés J, Gomollón F, Taxonera C, et al. Crohn’s disease: a review of current treatment with a focus on biologics. Drugs. 2007;67:2511-2537.

9. US Food and Drug Administration. Infliximab product approval informationlicensing action. www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsare DevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/ ucm093327.htm. Accessed September 7, 2012.

10. Ben-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn’s disease. Aliment Pharmacol Ther. 2011;33:987-995.

11. Gisbert JP, Panés J. Loss of response and requirement of infliximab dose intensification in Crohn’s disease: a review. Am J Gastroenterol. 2009;104:760-767.

12. Lin KK, Velayos F, Fisher E, Terdiman JP. Durability of infliximab dose intensification in Crohn’s disease. Dig Dis Sci. 2012;57:1013-1019.

13. Regueiro M, Siemanowski B, Kip KE, Plevy S. Infliximab dose intensification in Crohn’s disease. Inflamm Bowel Dis. 2007;13:1093-1099.

14. Chaparro M, Martínez-Montiel P, Van Domselaar M, et al. Intensification of infliximab therapy in Crohn’s disease: efficacy and safety. J Crohns Colitis. 2012;6:62-67.

15. Kopylov U, Mantzaris GJ, Katsanos KH, et al. The efficacy of shortening the dosing interval to once every six weeks in Crohn’s patients losing response to maintenance dose of infliximab. Aliment Pharmacol Ther. 2011;33:349-357.

16. Katz L, Gisbert JP, Manoogian B, et al. Doubling the infliximab dose versus halving the infusion intervals in Crohn’s disease patients with loss of response. Inflamm Bowel Dis. 2012;18:2026-2033.

17. Tang DH, Armstrong EP, Lee JK. Cost-utility analysis of biologic treatments for moderate-to-severe Crohn’s disease. Pharmacotherapy. 2012;32:515-526.

18. Kaplan GG, Hur C, Korzenik J, Sands BE. Infliximab dose escalation vs. initiation of adalimumab for loss of response in Crohn’s disease: a cost-effectiveness analysis. Aliment Pharmacol Ther. 2007;26:1509-1520.

19. Van Assche G, Vermeire S, Ballet V, et al. Switch to adalimumab in patients with Crohn’s disease controlled by maintenance infliximab: prospective randomised SWITCH trial. Gut. 2012;61:229-234.

20. Chao J, Mulani P. What is the rate of loss of response to infliximab therapy in Crohn’s disease? Am J Gastroenterol. 2009;104:2353-2354; author reply 2354-2355.

21. de Ridder L, Rings EH, Damen GM, et al. Infliximab dependency in pediatric Crohn’s disease: long-term follow-up of an unselected cohort. Inflamm Bowel Dis. 2008;14:353-358.

22. Hyams J, Crandall W, Kugathasan S, et al. Induction and maintenance infliximab therapy for the treatment of moderate-to-severe Crohn’s disease in children.

Gastroenterology. 2007;132:863-873; quiz 1165-1166.

23. Waters H, Vanderpoel J, McKenzie S, et al. Stability of infliximab dosing in inflammatory bowel disease: results from a multicenter US chart review. J Med Econ.

2011;14:397-402.

24. Gupta N, Bostrom AG, Kirschner BS, et al. Gender differences in presentation and course of disease in pediatric patients with Crohn disease. Pediatrics. 2007;120: e1418-e1425.

25. Wagtmans MJ, Verspaget HW, Lamers CB, van Hogezand RA. Gender-related differences in the clinical course of Crohn’s disease. Am J Gastroenterol. 2001;96:1541-1546.

26. Carter CT, Waters HC, Smith DB. Impact of infliximab adherence on Crohn’s disease-related healthcare utilization and inpatient costs. Adv Ther. 2011;28:671-683.

27. Johnson R, Freeman EN. Addressing costs and continuity of care through innovative solutions for infused therapies: a collaborative experience with infliximab. Am Health Drug Benefits. 2011;4(1):39-46.

28. Schnitzler F, Fidder H, Ferrante M, et al. Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort.

Gut. 2009;58:492-500.

29. Zorzi F, Zuzzi S, Onali S, et al. Efficacy and safety of infliximab and adalimumab in Crohn’s disease: a single centre study. Aliment Pharmacol Ther. 2012;35:1397-1407.

30. Reinisch W, Wang Y, Oddens BJ, Link R. C-reactive protein, an indicator for maintained response or remission to infliximab in patients with Crohn’s disease: a post-hoc analysis from ACCENT I. Aliment Pharmacol Ther. 2012;35:568-576.

31. Vermeire S, Louis E, Carbonez A, et al; for the Belgian Group of Infliximab Expanded Access Program in Crohn’s Disease. Demographic and clinical parameters influencing the short-term outcome of anti-tumor necrosis factor (infliximab) treatment in Crohn’s disease. Am J Gastroenterol. 2002;97:2357-2363.

32. Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the longterm efficacy of infliximab in Crohn’s disease. N Engl J Med. 2003;348:601-608.

33. ClinicalTrials.gov. Predictors of non-response and loss of response in IBD patients treated with anti-TNF. http://clinicaltrials.gov/ct2/show/NCT01605188. Accessed September 12, 2012.

34. Hlavaty T, Ferrante M, Henckaerts L, et al. Predictive model for the outcome of infliximab therapy in Crohn’s disease based on apoptotic pharmacogenetic index and clinical predictors. Inflamm Bowel Dis. 2007;13:372-379.

35. Hlavaty T, Pierik M, Henckaerts L, et al. Polymorphisms in apoptosis genes predict response to infliximab therapy in luminal and fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2005;22:613-626.

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Vol 7, No 2

Infliximab Dosing Patterns in Patients with Crohn’s Disease

Stakeholder Perspective Infliximab Dosing for Crohn’s Disease: Too Much of a Good Thing?

By Atheer A. Kaddis, PharmD Senior Vice President, Sales and Business Development, Diplomat Specialty Pharmacy, Flint, MI

PAYERS/PROVIDERS: Are you familiar with the phrase “Start low and go slow”? During my pharmacist training and into my professional career, this has been the mantra for initiating drug therapy for the treatment of patients with all forms of disease states. Most medications require some form of titration to achieve the optimal dose for effective treatment. This is the recommended approach to the dosing of infliximab for the treatment of Crohn’s disease.

After the initial initiation phase with infliximab, which utilizes dosing of 5 mg/kg at 0, 2, and 6 weeks, the maintenance dose is 5 mg/kg every 8 weeks. The catch is that some patients may benefit from dosing up to 10 mg/ kg every 8 weeks. Pretty straightforward, correct? Well, not exactly. The issue is that the majority of payers are experiencing a higher-than-expected number of patients who are receiving infliximab at doses of more than 5 mg/ kg every 8 weeks, and some patients are receiving higher doses at less frequent intervals, such as every 6 weeks.

In their article in this issue, using medical chart reviews, Tkacz and colleagues found that approximately 17% of patients with Crohn’s disease within one health insurance plan had some form of infliximab dose escalation, and that this prevalence of dose escalation was at the lower end of the dose escalation that had been reported in previously published studies.

PAYERS/PATIENTS: This should be great news to payers, providers, and especially for patients; however, we do have to realize the following issue. According to the Centers for Medicare & Medicaid Services, the payment limit for infliximab—based on the average sales price plus 6%—for the time period of April 1, 2014, through June 30, 2014, is $713.47 per 100 mg.

For a patient weighing 80 kg, the average drug cost for an infliximab infusion that is dosed at 5 mg/kg would be $2853.88 (with an annual drug cost of $17,123.28). For a patient population of 100 patients, the annual drug cost would be $1,712,328. Now, take into account 17% of patients receiving infliximab at a dose of 7.75 mg/kg, and the annual cost of infliximab becomes $1,872,430, an annual increase of $160,102. If this same methodology was applied to a patient population of 1000 patients, the annual drug costs for infliximab would exceed $1.6 million. The point is that, although 17% may appear low by itself, the implications of this seemingly low dose-­escalation rate can be very significant to payers, as well as to patients.

We have to find ways to better manage patients with Crohn’s disease in a more cost-effective manner. Taking drug cost into account will help us to better manage the disease effectively, without sacrificing the quality of care for the patient. n

VISIT OUR ENHANCED USER-FRIENDLY WEBSITE American Health & Drug Benefits is an independent, peer-reviewed journal founded in 2008 Examines drug and other healthcare intervention value for payers, purchasers, providers, patients, manufacturers, regulators, distributors, and evaluators Provides up-to-date information on new drugs approved by the FDA

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The median age of patients in the VISTA† trial was 71 years (range: 48-91).

Indication and Important safety Information for VELCADE® (bortezomib) InDICAtIon VELCADE (bortezomib) is indicated for the treatment of patients with multiple myeloma.

ContrAInDICAtIons VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WArnIngs, prECAutIons, AnD Drug IntErACtIons ▼ Peripheral neuropathy: Manage with dose modification or discontinuation. Patients with preexisting severe neuropathy should be treated with VELCADE only after careful risk-benefit assessment. ▼ Hypotension: Use caution when treating patients taking antihypertensives, with a history of syncope, or with dehydration.

▼ Cardiac toxicity: Worsening of and development of cardiac failure have occurred. Closely monitor patients with existing heart disease or risk factors for heart disease. ▼ Pulmonary toxicity: Acute respiratory syndromes have occurred. Monitor closely for new or worsening symptoms. ▼ Posterior reversible encephalopathy syndrome: Consider MRI imaging for onset of visual or neurological symptoms; discontinue VELCADE if suspected. ▼ Gastrointestinal toxicity: Nausea, diarrhea, constipation, and vomiting may require use of antiemetic and antidiarrheal medications or fluid replacement. ▼ Thrombocytopenia or Neutropenia: Monitor complete blood counts regularly throughout treatment. ▼ Tumor lysis syndrome: Closely monitor patients with high tumor burden. ▼ Hepatic toxicity: Monitor hepatic enzymes during treatment.

In treating multiple myeloma

What is the value of ® VELCADE (bortezomib)? ▼ Overall survival advantage ▼ Defined length of therapy ▼ Medication cost If you DEfInE VALuE As An oVErALL surVIVAL ADVAntAgE: VELCADE (bortezomib) combination delivered a >13-month overall survival advantage A t 5-year median follow-up, VELCADE+MP* provided a median overall survival of 56.4 months vs 43.1 months with MP alone (HR=0.695 [95% CI, 0.57-0.85]; p<0.05)† At 3-year median follow-up, VELCADE+MP provided an overall survival advantage over MP that was not regained with subsequent therapies

If you DEfInE VALuE As DEfInED LEngth of thErApy: Results achieved using VELCADE twice-weekly followed by weekly dosing for a median of 50 weeks (54 planned)1

If you DEfInE VALuE As MEDICAtIon Cost: Medication cost is an important factor when considering overall drug spend. The Wholesale Acquisition Cost for VELCADE is $1568 per 3.5-mg vial as of January 2014 When determining the value of a prescription drug regimen, it may be worth considering medication cost, length of therapy, and dosing regimens. This list is not all-inclusive; there are additional factors to consider when determining value for a given regimen

▼ Embryo-fetal risk: Women should avoid becoming pregnant while being treated with VELCADE. Advise pregnant women of potential embryo-fetal harm. ▼ Closely monitor patients receiving VELCADE in combination with strong CYP3A4 inhibitors. Avoid concomitant use of strong CYP3A4 inducers.

ADVErsE rEACtIons Most commonly reported adverse reactions (incidence ≥20%) in clinical studies include nausea, diarrhea, thrombocytopenia, neutropenia, peripheral neuropathy, fatigue, neuralgia, anemia, leukopenia, constipation, vomiting, lymphopenia, rash, pyrexia, and anorexia.

Please see Brief Summary for VELCADE on the next page of this advertisement.

For Reimbursement Assistance, call 1-866-VELCADE (835-2233), Option 2, or visit VELCADEHCP.com.

Reference: 1. Mateos M-V, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial.

J Clin Oncol. 2010;28(13):2259-2266. *Melphalan+prednisone. † VISTA TRIAL: a randomized, open-label, international phase 3 trial (N=682) evaluating the efficacy and safety of VELCADE administered intravenously in combination with MP vs MP in previously untreated multiple myeloma. The primary endpoint was TTP. Secondary endpoints were CR, ORR, PFS, and overall survival. At a prespecified interim analysis (median follow-up 16.3 months), VELCADE+MP resulted in significantly superior results for TTP (median 20.7 months with VELCADE+MP vs 15.0 months with MP [p=0.000002]), PFS, overall survival, and ORR. Further enrollment was halted and patients receiving MP were offered VELCADE in addition. Updated analysis was performed.

Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy.

CONTRAINDICATIONS: VELCADE is contraindicated in patients with hypersensitivity (not including local reactions) to bortezomib, boron, or mannitol, including anaphylactic reactions. VELCADE is contraindicated for intrathecal administration. Fatal events have occurred with intrathecal administration of VELCADE. WARNINGS AND PRECAUTIONS: Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory; however, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain, or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. In the Phase 3 relapsed multiple myeloma trial comparing VELCADE subcutaneous vs intravenous, the incidence of Grade ≥2 peripheral neuropathy events was 24% for subcutaneous and 39% for intravenous. Grade ≥3 peripheral neuropathy occurred in 6% of patients in the subcutaneous treatment group, compared with 15% in the intravenous treatment group.

Starting VELCADE subcutaneously may be considered for patients with pre-existing or at high risk of peripheral neuropathy.

Patients experiencing new or worsening peripheral neuropathy during VELCADE therapy may require a decrease in the dose and/or a less dose-intense schedule. In the VELCADE vs dexamethasone phase 3 relapsed multiple myeloma study, improvement in or resolution of peripheral neuropathy was reported in 48% of patients with ≥Grade 2 peripheral neuropathy following dose adjustment or interruption. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma.

Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 8%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics.

Cardiac Toxicity: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have occurred during VELCADE therapy, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing, heart disease should be closely monitored. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of any treatment-related cardiac disorder was 8% and 5% in the VELCADE and dexamethasone groups, respectively.

The incidence of adverse reactions suggestive of heart failure (acute pulmonary edema, pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock) was ≤1% for each individual reaction in the VELCADE group. In the dexamethasone group, the incidence was ≤1% for cardiac failure and congestive cardiac failure; there were no reported reactions of acute pulmonary edema, pulmonary edema, or cardiogenic shock. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established.

Pulmonary Toxicity: Acute Respiratory Distress Syndrome (ARDS) and acute diffuse infiltrative pulmonary disease of unknown etiology, such as pneumonitis, interstitial pneumonia, and lung infiltration have occurred in patients receiving VELCADE. Some of these events have been fatal.

In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease.

In the event of new or worsening cardiopulmonary symptoms, consider interrupting VELCADE until a prompt, comprehensive, diagnostic evaluation is conducted.

Posterior Reversible Encephalopathy Syndrome (PRES): Posterior Reversible Encephalopathy Syndrome (PRES; formerly termed Reversible Posterior Leukoencephalopathy Syndrome (RPLS)) has occurred in patients receiving VELCADE. PRES is a rare, reversible, neurological disorder, which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing PRES, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing PRES is not known.

Gastrointestinal Toxicity: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting, sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur.

Fluid and electrolyte replacement should be administered to prevent dehydration. Interrupt VELCADE for severe symptoms.

Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern, with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice-weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline.

The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study of VELCADE vs dexamethasone, the incidence of bleeding (≥Grade 3) was 2% on the VELCADE arm and <1% on the dexamethasone arm. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. Gastrointestinal and intracerebral hemorrhage has been reported in association with VELCADE. Transfusions may be considered.

Tumor Lysis Syndrome: Tumor lysis syndrome has been reported with VELCADE therapy.

Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment.

Monitor patients closely and take appropriate precautions.

Hepatic Toxicity: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic reactions include hepatitis, increases in liver enzymes, and hyperbilirubinemia. Interrupt VELCADE therapy to assess reversibility. There is limited re-challenge information in these patients.

Embryo-fetal: Pregnancy Category D. Women of reproductive potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses.

ADVERSE EVENT DATA: Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose administered intravenously twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously-treated multiple myeloma (N=1008) and previously-treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported (≥10%) adverse reactions were nausea (49%), diarrhea NOS (46%), fatigue (41%), peripheral neuropathies NEC (38%), thrombocytopenia (32%), vomiting NOS (28%), constipation (25%), pyrexia (21%), anorexia (20%), anemia NOS (18%), headache NOS (15%), neutropenia (15%), rash NOS (13%), paresthesia (13%), dizziness (excl vertigo 11%), and weakness (11%). Eleven percent (11%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (4%) and neutropenia (2%). A total of 26% of patients experienced a serious adverse reaction during the studies. The most commonly reported serious adverse reactions included diarrhea, vomiting, and pyrexia (3% each), nausea, dehydration, and thrombocytopenia (2% each), and pneumonia, dyspnea, peripheral neuropathies NEC, and herpes zoster (1% each).

In the phase 3 VELCADE+melphalan and prednisone study in previously untreated multiple myeloma, the safety profile of VELCADE administered intravenously in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse reactions in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (48% vs 42%), neutropenia (47% vs 42%), peripheral neuropathy (46% vs 1%), nausea (39% vs 21%), diarrhea (35% vs 6%), neuralgia (34% vs <1%), anemia (32% vs 46%), leukopenia (32% vs 28%), vomiting (26% vs 12%), fatigue (25% vs 14%), lymphopenia (23% vs 15%), constipation (23% vs 4%), anorexia (19% vs 6%), asthenia (16% vs 7%), pyrexia (16% vs 6%), paresthesia (12% vs 1%), herpes zoster (11% vs 3%), rash (11% vs 2%), abdominal pain upper (10% vs 6%), and insomnia (10% vs 6%).

In the phase 3 VELCADE subcutaneous vs intravenous study in relapsed multiple myeloma, safety data were similar between the two treatment groups. The most commonly reported adverse reactions in this study were peripheral neuropathy NEC (37% vs 50%), thrombocytopenia (30% vs 34%), neutropenia (23% vs 27%), neuralgia (23% vs 23%), anemia (19% vs 23%), diarrhea (19% vs 28%), leukopenia (18% vs 20%), nausea (16% vs 14%), pyrexia (12% vs 8%), vomiting (9% vs 11%), asthenia (7% vs 16%), and fatigue (7% vs 15%). The incidence of serious adverse reactions was similar for the subcutaneous treatment group (20%) and the intravenous treatment group (19%). The most commonly reported SARs were pneumonia and pyrexia (2% each) in the subcutaneous treatment group and pneumonia, diarrhea, and peripheral sensory neuropathy (3% each) in the intravenous treatment group.

DRUG INTERACTIONS: Bortezomib is a substrate of cytochrome P450 enzyme 3A4, 2C19 and 1A2. Co-administration of ketoconazole, a strong CYP3A4 inhibitor, increased the exposure of bortezomib by 35% in 12 patients. Monitor patients for signs of bortezomib toxicity and consider a bortezomib dose reduction if bortezomib must be given in combination with strong CYP3A4 inhibitors (eg, ketoconazole, ritonavir). Co-administration of omeprazole, a strong inhibitor of CYP2C19, had no effect on the exposure of bortezomib in 17 patients. Co-administration of rifampin, a strong CYP3A4 inducer, is expected to decrease the exposure of bortezomib by at least 45%. Because the drug interaction study (n=6) was not designed to exert the maximum effect of rifampin on bortezomib PK, decreases greater than 45% may occur. Efficacy may be reduced when VELCADE is used in combination with strong CYP3A4 inducers; therefore, concomitant use of strong CYP3A4 inducers is not recommended in patients receiving VELCADE. St. John’s wort (Hypericum perforatum) may decrease bortezomib exposure unpredictably and should be avoided. Co-administration of dexamethasone, a weak CYP3A4 inducer, had no effect on the exposure of bortezomib in 7 patients. Co-administration of melphalan-prednisone increased the exposure of bortezomib by 17% in 21 patients. However, this increase is unlikely to be clinically relevant.

USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: The safety and effectiveness of VELCADE in children has not been established.

Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out.

Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, VELCADE should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer’s prescribing information.

Patients with Hepatic Impairment: The exposure of bortezomib is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients.

Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Please see full Prescribing Information for VELCADE at VELCADEHCP.com.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners.

Millennium Pharmaceuticals, Inc., Cambridge, MA 02139 Copyright © 2013, Millennium Pharmaceuticals, Inc. All rights reserved. Printed in USA V-12-0306a

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The Peer-Reviewed Forum for REAL-World Evidence in Benefit Design ™

For Payers, Purchasers, Policymakers, and Other Healthcare Stakeholders

Call for Papers Neurology Theme Issue American Health & Drug Benefits is publishing a Neurology Theme Issue in September 2014.

Take part in the conversation on the human brain and the focus on brain research. The aging of the US population and the growing clinical and economic burden associated with neurologic disorders have placed the field of neurology at the forefront of medical research and drug development.

American Health & Drug Benefits is a peer-reviewed journal reaching providers, payers, and policy decision makers in the United States. All articles submitted for publication in this journal undergo the journal’s rigorous peer-review process and acceptance is dependent on that review.

Readers are invited to submit original research, case reports, or systematic reviews on any topic related to the field of neurology.

Topics of particular interest include: ORIGINAL RESEARCH

REVIEW ARTICLES

• Case studies/case series

• Alzheimer’s disease: diagnosis, treatment

• Comparative effectiveness analyses

• Dementia update

• Cost-effective analyses

• Developments in neurology

• Drug therapy for a neurologic disorder

• Economic burden of neurologic disorders

• Health economics research outcomes

• Emerging therapies

• New therapies for multiple sclerosis,

• Epilepsy: new developments

seizures, migraine

• Migraine management

• Patient-reported outcomes

• Multiple sclerosis management

• Pharmacoeconomic analyses

• Pain medicine

• Quality-of-life issues in neurology • Review articles on neurologic conditions • Survey results

• Parkinson’s disease • Practice guidelines • Sleep disorders • Stroke/cerebrovascular disease

Submission Deadline: June 25, 2014 Articles must follow the Information for Authors at www.AHDBonline.com Submit articles to editorial@engagehc.com Vol 7, No 2

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Review Article

Rising Costs of COPD and the Potential for Maintenance Therapy to Slow the Trend Christopher M. Blanchette, PhD, MBA; Nicholas J. Gross, MD, PhD; Pablo Altman, MD, MBA

Stakeholder Perspective, page 106 Am Health Drug Benefits.

2014;7(2):98-106 www.AHDBonline.com Disclosures are at end of text

Background: Chronic obstructive pulmonary disease (COPD) affects an estimated 14% of adults in the United States between the ages of 40 and 79 years. This progressive disease is characterized by persistent airflow limitation. The management of patients with COPD is focused on reducing risk factors, relieving symptoms, and preventing exacerbations.

Objective: To examine the peer-reviewed literature on the impact of maintenance therapy on the direct treatment costs of patients with COPD in the United States.

Methods: PubMed was searched for articles written in English that were published between 2000 and 2013, using the search terms “COPD,” “economics,” “exacerbation,” “maintenance,” and related terms.

Articles reporting the results of longitudinal studies of the costs associated with the management of patients with COPD, the costs associated with hospitalizations for acute exacerbations of COPD, and randomized clinical trials evaluating the effects of maintenance therapy on the incidence of COPD exacerbations were included in this review.

Results: The search identified a total of 277 articles, and 11 of these articles were deemed appropriate for inclusion in this review. The direct healthcare costs for patients with COPD increased by 38% between 1987 and 2007, and continued to increase by approximately 5% annually between 2006 and 2009. The costs associated with hospital admissions for patients with COPD accounted for the largest absolute increase ($2289 per admission in constant 2007 US dollars). Recent estimates suggest that the aggregate costs associated with the treatment of acute exacerbations are between $3.2 billion and $3.8 billion, and that annual healthcare costs are 10-fold greater for patients with COPD associated with acute exacerbations than for patients with COPD but without exacerbations. The results of 2 large clinical trials of maintenance therapy, including a long-acting cholinergic antagonist or a long-acting beta-2 agonist, showed a 16% to 17% reduction in the incidence of exacerbations compared with placebo. Nevertheless, maintenance therapy remains underutilized, with only 30% to 35% of patients with COPD in private and public health insurance plans receiving prescriptions for maintenance therapy.

Conclusions: The treatment of acute exacerbations of COPD remains the major driver of increasing healthcare costs associated with this condition. The appropriate use of maintenance therapy has been shown to reduce the incidence of exacerbations and has the potential to reduce overall costs associated with the management of patients with COPD.

T

he clinical and economic burden of chronic obstructive pulmonary disease (COPD) is significant and is increasing. COPD is now the third leading cause of death in the United States, after heart disease and cancer.1 COPD reached this rank in 2008, more than a decade earlier than projected by the Global Burden of Dr Blanchette is Research Associate Professor, Department of Public Health Sciences, College of Health & Human Services, University of North Carolina at Charlotte, and Director, Health Economics & Outcomes Research, Otsuka America Pharmaceutical, Inc, Charlotte, NC; Dr Gross is President and CEO, University Medical Research, LLC, Farmington, CT; Dr Altman was Medical Director, Medical Affairs, Mylan Specialty LP, Basking Ridge, NJ, at the time of writing.

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Disease Study.2 In the United States, mortality due to COPD is the only one among the 5 leading causes of death that showed an increasing rate between 2010 and 2011.3 In 2011, 6.3% of US adults (an estimated 15 million) contacted by the Behavioral Risk Factor Surveillance System (BRFSS) reported being told by their physician that they had COPD.4 This estimate is likely to be low.

Spirometric testing performed for the National Health and Nutrition Examination Survey (NHANES; 20072010) indicated that an estimated 14% of US adults aged 40 to 79 years met the diagnostic criteria for COPD.5 The roughly 2-fold greater prevalence of COPD that is cited by NHANES is considered a better estimate than the BRFSS prevalence, because COPD is underdiagnosed in its earlier stages.6

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Along with the growing prevalence, the death rate for COPD is also rising.1 Between the years 1980 and 2000, the overall death rate attributed to COPD increased by 67%, from 40.7 deaths to 66.9 deaths per 100,000 persons aged ≥25 years.6 Although the death rate for COPD has remained relatively constant through 2005, when it was 64.3 deaths per 100,000 persons aged ≥25 years, the absolute number of annual deaths continues to increase, as a result of the aging of the US population.7 Because the prevalence and severity of COPD increase with age, the impact on the healthcare system will likely continue to expand.8 COPD is a progressive disease and to date cannot be cured.9 Exacerbations of COPD, which are typically defined as an acute worsening of symptoms that results in a change in treatment and often hospitalization, are a major contributor to the high costs associated with the management of patients with COPD10,11 and are a significant risk factor for COPD-related mortality.12 The use of inhaled long-acting bronchodilators has been shown to reduce the incidence of COPD exacerbations,13 but their use remains suboptimal.14,15 The goal of this article is to summarize the current information about the prevalence and healthcare costs associated with COPD in the United States. In the remainder of this review we discuss the rising costs associated with COPD and expand on the evidence that maintenance therapy can improve outcomes and may reduce overall costs. In addition, obstacles that impede appropriate COPD management are also discussed.

Methods Although this article is not a systematic review, detailed searches of the medical literature were conducted.

To assess the changing economic impact of COPD in the United States, and, in particular, the contribution of exacerbations to the total cost and the influence of the use of maintenance medication on exacerbations, we conducted several searches on PubMed. The searches were conducted to identify studies that reported on the economic impact of COPD, estimated at 2 or more time periods; pharmacoeconomic studies of the costs of treatment of COPD exacerbations; and randomized, double-blind studies of the impact of maintenance therapy on COPD exacerbations.

The primary search terms were (“Pulmonary Disease, Chronic Obstructive/economics”[Majr] OR ((chronic obstructive [ti] OR COPD [ti])) AND (cost*[ti] OR economic*[ti])). The results for this search were further refined by combining results with additional search terms (eg, “AND exacerbation*”, “AND maintenance”). Only articles describing original research or meta-analyses that were written in English and were

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Key Points The prevalence and severity of COPD, a progressive and costly condition, increase with age; although this disease has no cure, appropriate management can improve patient outcomes, improve quality of life, and reduce overall costs. ➤ The treatment of acute exacerbations of COPD remains the major cost driver in this patient population, reaching between $3.2 billion and $3.8 billion in aggregate. ➤ The annual healthcare costs are 10-fold greater for patients with acute exacerbations of COPD than for patients with COPD without exacerbations. ➤ The results of 2 clinical trials of maintenance therapy showed a 16% to 17% reduction in the incidence of exacerbations compared with placebo. ➤ Maintenance therapy remains underutilized for COPD and is used by only 30% to 35% of patients in private and public health plans. ➤ Earlier diagnosis and the earlier initiation of treatment can improve patient outcomes and lessen the financial burden associated with this disease. ➤

published in the year 2000 or later were considered for this review.

Results Search Results A total of 277 articles were identified by our search.

Of these, 11 articles were selected for this review (Table), including 2 articles that presented longitudinal analyses of the changing COPD-related healthcare costs,16,17 and 7 articles that estimated the costs associated with the treatment of COPD exacerbations.16-22 In addition, 2 large, randomized, double-blind studies of the impact of maintenance therapy on the incidence of exacerbations were identified and included,23,24 as well as a recent meta-analysis of 35 clinical studies of maintenance therapy lasting at least 4 weeks.13 One recent comprehensive systematic review of pharmacoeconomic studies of maintenance therapy related to COPD was also included.25 The New Demographic for Patients with COPD Smoking is a major risk factor for COPD. A meta-­ analysis that included 62 studies from 28 countries reported that the prevalence of COPD among smokers was 15.4% compared with 10.7% among nonsmokers.26 In the United States, smoking is estimated to be responsible for more than 77% of all deaths from COPD.27 There are currently 44 million smokers in the United States, ap-

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Table Studies Reporting Cost and Efficacy of Treatment of COPD Exacerbations in the United States Study Study design Key findings Trends in COPD-related healthcare costs Blanchette et al, 2012

Longitudinal, cross-sectional surveys

Dalal et al, 201117

Longitudinal study of COPD• From 2006 to 2009, total direct COPD-related related health service utilization healthcare costs increased by approximately 6% for patients with commercial annually among commercially insured patients and by insurance or Medicare Advantage approximately 5% in Medicare Advantage beneficiaries

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• Average direct per-patient medical costs for patients with COPD increased by 38% between 1987 and 2007, from $11,807 to $16,292 (2007 dollars) • In 2007, the largest cost was for inpatient admissions for COPD ($13,840)

Healthcare costs associated with acute COPD exacerbations Analysis of the Healthcare Cost and Utilization Project data

• In 2008, the aggregate cost for hospital admissions for acute COPD exacerbation was $3.8 billion

Perera et al, 201219

Analysis of the Healthcare Cost and Utilization Project data

• From 2006-2010, the aggregate cost for hospitalization for acute COPD exacerbation increased from $2.96 billion to $3.47 billion (2010 dollars)

Yu et al, 201120

Analysis of service claims and cost data from the Thomson Reuters MarketScan database

• In 2004-2008, the total COPD-related cost for patients with a severe exacerbation was $7014 per quarter • Cost associated with COPD patients who had no exacerbations was $658 per quarter (or $2632 annually)

Pasquale et al, 201221

Analysis of claims data from a large national healthcare company for a predominately Medicare population

• In 2007-2009, mean annual COPD-related healthcare cost was $12,765 for patients with a severe exacerbation • The cost for moderate exacerbation was $3356 • The cost for patients with no exacerbations was $1425

Dalal et al, 201122

Analysis of hospital administrative data from the Premier Perspective Database

• Between 2005 and 2008 the mean cost of a COPDrelated emergency room visit increased by 4.0%, to $647 • In the same period the mean cost of simple hospital admissions for COPD increased by 5.9%, to $7242 • Little change was seen in mean cost of complex hospital admission for COPD ($20,757 in 2008)

Wier et al, 2011

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Maintenance therapy for preventing acute COPD exacerbation Tashkin et al, 2008

4-year, randomized, double-blind, placebo-controlled study of inhaled tiotropium (18 µg daily) in COPD

Calverley et al, 200724

3-year, randomized, double-blind, • The relative risk for exacerbation requiring placebo-controlled study of inhaled hospitalization was 0.82 (95% CI, 0.69-0.96) in patients salmeterol (50 µg twice daily) plus receiving salmeterol alone compared with placebo inhaled fluticasone propionate (500 • Addition of fluticasone propionate to salmeterol was not µg twice daily), inhaled salmeterol different from salmeterol alone in reducing the risk for alone, inhaled fluticasone exacerbation requiring hospitalization (relative risk 1.02 propionate alone, or placebo [95% CI, 0.87-1.20] compared with salmeterol alone)

Puhan et al, 200913

Meta-analysis of randomized trials • 35 studies included 26,786 patients receiving placebo, of ≥4 weeks’ duration to test the inhaled long-acting beta-agonists, inhaled long-acting effect of inhaled drug regimens cholinergic antagonists, inhaled corticosteroids, or on COPD exacerbations inhaled combination therapy with long-acting betaagonists and inhaled corticosteroids • All regimens of inhaled therapy were equally effective compared with placebo at reducing the risk for exacerbation Continued

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• The relative risk for first exacerbation was 0.86 (95% CI, 0.81-0.91) in the group randomized to tiotropium compared with placebo • The risk of first hospitalization for an exacerbation was 0.86 (95% CI, 0.78-0.95) in patients receiving tiotropium compared with placebo

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Table Studies Reporting Cost and Efficacy of Treatment of COPD Exacerbations in the United States (Continued) Study Study design Key findings Cost-effectiveness of maintenance therapy of COPD Rutten-van Mölken, Goossens, 201225

Systematic literature review of economic evaluations of drug therapy for COPD

• Tiotropium, a long-acting cholinergic antagonist, reduced COPD-related healthcare costs in most, but not in all studies • Long-acting beta-2 agonists combined with inhaled corticosteroids improve outcomes, but with an increase in total COPD-related costs • The cost-effectiveness of COPD maintenance therapy is better in patients at high risk for exacerbation

CI indicates confidence interval; COPD, chronic obstructive pulmonary disease.

proximately 78% of whom smoke daily.28 Together with the approximately 50 million former US smokers, approximately 94 million Americans are at an increased risk for COPD.28 Women may be more susceptible to the adverse effects of smoking than men,29 which may account for the increasing COPD-related mortality among women. The death rate from COPD among US women has increased steadily, nearly tripling between 1980 and 20006; since 2000, more women than men have died of COPD.7,30 This influence of COPD in women has changed the demographic characteristics of COPD from a disease of elderly men to a condition with a 58% prevalence among women, with an average age <65 years.16 The younger age and the changing sex ratio of the COPD population, together with the expansion of Medicare Advantage, have sharply increased the likelihood that a patient with COPD will be enrolled in a private health plan in the United States. In 1987, the National Medical Expenditure Survey (NMES) showed that only 16.2% of patients with COPD had private insurance coverage.16 By 2007, that percentage had increased to 40.6% during a period of little overall growth in private health insurance coverage.16 Patients with COPD have an average of 3.7 to 9 chronic medical comorbidities, including lung disease (often lung cancer), that contribute to their utilization of healthcare at a rate twice that of age- and sex-matched patients without COPD.31,32 Many of these comorbidities are at least in part related to smoking.32 The 2007 Medical Expenditure Panel Survey (MEPS) showed that common comorbidities included hypertension (65% of patients), asthma (41%), diabetes (26%), coronary heart disease (20%), stroke (16%), and myocardial infarction (14%).16 Other often occurring conditions included peripheral arterial disease, obesity, osteoarthritis, osteoporosis/osteopenia, depression, and gastroesophageal reflux disease.33,34 Comorbidities associated with COPD can be worsened by deteriorating COPD; conversely, these co-

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morbidities can contribute to a more rapid COPD decline.35,36 Therefore, the treatment plans for patients with COPD should also include appropriate attention to these comorbidities.

Increasing Costs of COPD Of the 11 articles included in this article, 2 presented analyses of change in costs in US-based populations.

Blanchette and colleagues compared 2 cross-sectional, population-based surveys and analyzed data for patients aged ≥40 years with COPD (1987 NMES37; 2007 MEPS38), and found that the average direct per-patient medical costs (primarily based on payments by health insurance or federal plans)—including COPD-related and non–COPD-related costs—increased by 38% between 1987 and 2007, from $11,807 to $16,292 (constant 2007 US dollars).16 The largest absolute increase was for inpatient admissions, which increased by $2289 per admission. The prescription drug costs increased by 170% per patient, and the costs of emergency department services increased by 183% per visit.16 Dalal and colleagues compared the medical records of commercially insured and Medicare Advantage populations for the period from 2006 to 2009, and found that the direct COPD-related health service utilization (both medical and pharmacy claims) costs increased by approximately 6% annually in the commercially insured patients compared with an annual rate of 5% in the Medicare Advantage patients.17 Because the current prevalence of COPD is higher than it was projected 10 years ago, the overall costs associated with COPD are higher as well. Dalal and colleagues performed a retrospective claims-based analysis of commercially insured patients with COPD and estimated that in 2006, the direct COPD-associated medical and pharmacy costs were $15.7 billion (in 2008 US dollars).39 However, their estimate is likely low, because it does not reflect the impact of comorbidities on these costs. As mentioned earlier, the prevalence of comorbid-

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ities among patients with COPD is high, and COPD often exacerbates other chronic conditions. Therefore, including the impact of COPD on coexisting conditions may better represent the actual cost of COPD. The study

by Blanchette and colleagues estimated that the allcause direct costs of patients with COPD in the United States were more than $75 billion in 2007.16 Analysis of the distribution and allocation structure of the current costs of COPD may allow the identification of opportunities to reduce acute care costs via better management of the disease.

A comparison of 1987 to 2007 cumulative expenditures for patients with COPD and the cumulative number of patients reveals nearly identical distributions, with only 20% of patients with COPD accounting for 74% of the total expenditures.16 This observation suggests that the nature of the underlying problem has not changed in those 20 years. Specifically, hospitalization costs have remained the greatest proportion of direct medical costs (85%) associated with COPD, and most of the total cost increase in that period is attributable to hospitalizations, largely resulting from COPD exacerbations.16 Of the articles identified by our search, 7 described the costs associated with hospitalizations for acute exacerbations of COPD in the United States. For example, Wier and colleagues analyzed data from the Healthcare Cost and Utilization Project for patients aged ≥40 years who were hospitalized with COPD in 2008.18 They estimated that the aggregate cost for hospital stays with COPD exacerbation as the primary diagnosis was $3.8 billion.18 A similar study using the same database reported that the aggregate costs for hospitalizations for acute COPD exacerbations increased from $2.96 billion in 2006 to $3.47 billion in 2010 (constant 2010 US dollars).19 Yu and colleagues conducted a retrospective analysis of the Thomson Reuters MarketScan administrative database and reported that the total COPD-related costs for patients with a severe exacerbation were $7014 per 90 days (or $28,056 annually) compared with $658 per 90 days in patients with no exacerbations.20 More than 90% of the costs in patients with severe exacerbations were for inpatient expenses.20 In a predominantly Medicare population, Pasquale and colleagues reported that the annual COPD-related healthcare costs were much higher in patients with a severe exacerbation ($12,765) than in patients with moderate exacerbations ($3356) or no exacerbations ($1425).21 In addition, 1 single article discussed the changes in emergency department or inpatient costs over time, showing that between 2005 and 2008, the inflation-adjusted mean costs for a COPD emergency department visit and for a simple COPD-related hospital admission increased by 4% and 5.9%, respectively.22 The researchers reported

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no change in the costs associated with COPD-related complex admissions during the same period.22

The Impact of Suboptimal COPD Management on Costs COPD is a progressive disease, and although it cannot be cured, appropriate management can slow its progression, reduce the frequency and severity of exacerbations, and improve symptoms and a patient’s quality of life.9,40 Despite the existence of several evidence-based guidelines for the diagnosis and treatment of COPD,9 the diagnosis and management of COPD remains suboptimal.15 This “clinical inertia,” which includes physician-, patient-, and system-related factors,15 may contribute to increased morbidity, which in turn contributes to rising COPD-related costs.

The diagnosis of COPD is usually based on clinical signs or symptoms and is often made at a late stage, when the disease is overt. Only 32% of patients with COPD have spirometry performed within 2 years before or 6 months after their diagnosis.41 As a result, COPD is diagnosed later than it would be if spirometry was routinely done, and the opportunities for earlier, and less expensive, interventions are lost. One study showed that 76% of patients with COPD were categorized as having either moderate or severe disease at first diagnosis.42 Before their diagnosis, patients with COPD use 50% to 60% more inpatient and emergency services than matched controls without COPD, and their average incremental annual costs are at least $2627 more than those without COPD.43 Those increased costs are most frequently incurred in the month before COPD diagnosis.43 The investigators speculated that some of these additional costs might have been avoided by earlier diagnosis and earlier initiation of treatment, but no evidence was presented.43 As noted, after delayed diagnosis, opportunities for early intervention are lost. A recent large survey of patients with COPD from 19 health plans (including private plans and private plans offering Medicare Advantage) showed that 66% of patients in commercial plans were not prescribed any maintenance pharmacotherapy, and 7% of patients were given only short-acting beta-­ agonists.44 Patients with Medicare Advantage coverage managed by private health plans fared not much better, with 71% prescribed no maintenance prescriptions and approximately 5% prescribed short-acting beta-agonists only.44 “High complexity” patients (ie, using comorbidities and procedures as markers for advanced COPD) were similarly undertreated despite their higher risk, with 59% and 69% of the patients in commercial and Medicare plans, respectively, receiving no maintenance therapy at all.44 In addition to the suboptimal use of

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eta-Analysis of the Effect of Inhaled Pharmacologic Maintenance Therapy in Patients with Stable COPD Figure M on the Risk of Exacerbation Treatments

Comparison with Placebo

Long-acting beta-agonists

0.77 (0.71-0.84)

Long-acting anticholinergics

0.71 (0.64-0.78)

0.91 (0.81-1.03)

Inhaled corticosteroids

0.78 (0.70-0.86)

1.00 (0.90-1.13)

1.10 (0.97-1.23)

Long-acting beta-agonists + inhaled corticosteroids

0.72 (0.65-0.80)

0.93 (0.84-1.04)

1.02 (0.90-1.16)

Long-acting beta-agonists

Long-acting anticholinergics

Inhaled corticosteroids

0.93 (0.82-1.05)

5 .75 1 1.33 2

5 .75 1 1.33 2

5 .75 1 1.33 2

5 .75 1 1.33 2

Odds ratio

Odds ratio

Odds ratio

Odds ratio

NOTE: These forest plots show the odds ratios (95% CI) indicating the odds of having at least 1 exacerbation in patients receiving a treatment from the row compared with the treatment from the corresponding column.

CI indicates confidence interval; COPD, chronic obstructive pulmonary disease.

Reprinted with permission from Puhan MA, et al. BMC Med. 2009;7:2.

COPD medications, other aspects of treatment guidelines were similarly underutilized. For example, fewer than 20% of the population had received a current influenza vaccination, and more than 80% of current smokers had not received any smoking cessation intervention.44 Smoking cessation is the most effective method of slowing the progression of COPD.9 Maintenance therapy with long-acting bronchodilators has been shown in 2 large, randomized, double-blind studies to significantly reduce the incidence of exacerbations and related hospitalization. In the Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT) trial, tiotropium (18 µg daily) reduced the relative risk of exacerbation by 14% compared with placebo during the 4-year study.23 A similar reduction in the risk of hospitalization was also observed. In the Towards a Revolution in COPD Health (TORCH) trial, the rate of exacerbations requiring hospitalization was reduced by 18% in the group treated with salmeterol (50 µg twice daily) alone compared with placebo.24 The addition of fluticasone propionate (500 µg twice daily) to the treat-

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ment regimen had no further benefit (ie, risk reduction of 17% compared with placebo).24 A recent meta-analysis by Puhan and colleagues supports this concept that inhaled maintenance therapy reduces the incidence of exacerbations in patients with stable COPD.13 In their meta-analysis, Puhan and colleagues reviewed 35 studies of inhaled maintenance therapies with durations of ≥4 weeks and concluded that, compared with placebo, long-acting beta-agonists (LABAs), long-acting anticholinergics, inhaled corticosteroids, or the combination of LABAs plus inhaled corticosteroids significantly reduced the odds of having at least 1 exacerbation (Figure). The authors concluded that each of these pharmacotherapies was equally effective in their ability to reduce the risk of exacerbation.13 In addition, a recent systematic review of long-acting bronchodilators reported that in more than 70% of the 51 studies included in that review, a minimally impor­ tant difference (defined as the smallest change perceived as important by patients) in health-related quality of life was reported.45

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The results of the TORCH and the UPLIFT trials changed the emphasis of pharmacotherapy from the palliation of symptoms to the prevention of exacerbations.46 Exacerbations of COPD contribute to disease progression and to loss of lung function, and mortality increases directly with severe exacerbation frequency, particularly if hospital admission is required. Patients who are hospitalized for 1 exacerbation annually have a significantly elevated mortality risk (hazard ratio [HR], 2.94; 95% confidence interval [CI], 1.82-4.72), and patients with ≥3 exacerbations in 5 years have a much higher mortality risk (HR, 4.31; 95% CI, 2.7-6.88) compared with patients with COPD who do not have exacerbations.12 The high cost of exacerbations suggests that their incidence rate is the primary element affecting treatment cost-effectiveness in COPD10,11; therefore, a reduction in the number of exacerbations is key to COPD management as well as for lowering overall costs. In a 9-year study of Medicare beneficiaries with COPD, the use of maintenance medication was significantly associated with a lower risk for hospitalization (odds ratio [OR], 0.70; 95% CI, 0.61-0.79) and rehospitalization (OR, 0.74; 95% CI, 0.630.87) compared with the cohort not using maintenance therapy.47 Of note, the group using maintenance therapy incurred significantly lower annual Medicare expenses (–$3916; 95% CI, –$4977 to –$2854). This was a retrospective study, and the 2 observation groups had many significant differences in baseline disease severity and other characteristics.47 Therefore, these results cannot be used to support the concept that adding maintenance therapy for nonusers would have reduced costs.

However, although summary analyses of clinical studies of inhaled pharmacologic maintenance therapy in COPD have concluded that the incidence of exacer­ bations is reduced by this therapy,13 estimates of the cost-­ effectiveness of maintenance therapy show considerable variation, including cost increases and decreases, and dependent on the patient population, the country being studied, the length of observation, and the pharmacoeconomic models used.25 A recent systematic review of maintenance therapy concluded that the cost-benefit is likely greatest in patients with a high risk for exacerbations.25 Furthermore, in other diseases, it has been difficult to demonstrate cost reduction after the implementation of prophylactic therapy.48

Obstacles to COPD Maintenance Therapy The reduction of COPD exacerbation frequency may not occur unless maintenance pharmacotherapy is more consistently adopted.15 In the period from 1987 to 2007, despite the advent of new and effective maintenance therapies, the average number of COPD medications per patient did not change.16 Drug costs have continued to

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increase and are sometimes seen as easy targets for cost reductions. However, prescribed drugs account for only 2.3% of the annual direct expenditures associated with COPD,16 and efforts to reduce this cost may have unintended consequences. For example, in British Columbia, efforts to reduce pharmacy costs by increasing the cost-sharing of prescription drugs for COPD led to the desired decrease in payer drug costs, but they also led to an increase in the net health plan expenditures caused by increased hospitalizations associated with lower adherence rates.49 The proper management of COPD critically depends on the effective delivery of inhaled medications to the lungs. Despite the apparent simplicity of handheld inhaler devices, including pressurized metered-dose inhalers and dry powder inhalers, misuse is common and may negatively influence inhaled drug administration.50 In practice, effective inhaler use depends on a number of factors, such as manual dexterity, cognitive function, and hand strength, that are sometimes impaired in the COPD population.50 In a meta-analysis by Brocklebank and colleagues, 77% of patients using a metered-dose inhaler made ≥1 error during administration.51 The correct use of metered-dose inhalers is reported to decline with advancing age,52 which is important in the aging patient population with COPD. This disease may also negatively influence the ability to properly use a dry powder inhaler because of the need to consistently provide adequate inspiratory airflow to disperse and deliver the drug properly.53,54 The use of a nebulizer to administer inhaled medications may improve drug delivery in patients who are unable to effectively use handheld inhalers. Nebulizers are well received by patients with COPD,55-57 because they require only tidal breathing,58 which facilitates adherence.59 The use of nebulized medication administration may benefit patients with COPD and muscle wasting and weakness, a common systemic effect of COPD that can make operating an inhaler difficult,50,60,61 or patients with borderline or mild cognitive impairment.62 In the United States, nebulized formulations of LABAs (ie, formoterol and arformoterol) and corticosteroids (ie, budesonide) for maintenance therapy of COPD are currently available.9,63 Patients with COPD who are unable to properly use metered-dose inhaler–, or dry-powder inhaler–delivered maintenance medications, may be best served by nebulized formulations of maintenance medications.

Conclusion In the past decade, pharmacotherapeutic advances in the management of COPD have brought the possibility of improving patient outcomes while lowering expenditures, largely through reducing the rate of exacerbations

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with the optimal use of maintenance medications. Extending the benefits of maintenance therapy to all patients with COPD must take into account the specific characteristics and capabilities of each patient and the need to administer the appropriate drug most effectively.64 Closer attention to the needs and abilities of patients with COPD to handle specific therapies can improve patient outcomes and reduce overall costs for patients and for payers. n Acknowledgments The authors wish to thank Zaid Smith, PhD, of PharmaWrite, LLC, Princeton, NJ, for providing medical writing and editorial assistance.

Funding Source Mylan Specialty LP provided funding support for the development of this manuscript.

Author Disclosure Statement Dr Blanchette has received grants from AstraZeneca, Auxilium, Eli Lilly, Endo, GlaxoSmithKline, and Merck. Dr Gross is a consultant to Boehringer Ingelheim and Mylan Specialty; has served as a board member for Alexza, Boehringer Ingelheim, Elevation, Mylan Specialty, and Pfizer; has received honoraria and lecture fees from Boehringer Ingelheim, Forest, and Mylan Specialty; is on the Speaker’s Bureau for AstraZeneca, Boehringer Ingelheim, and Forest; is a research grantee for Boehringer Ingelheim; is an advisor to Almirall, AstraZeneca, Elevation, Forest, Nycomed, and Skye; and has provided expert testimony for Alexza. Dr Altman was an employee of Mylan Specialty at the time of writing of this manuscript.

References

1. Miniño AM, Xu J, Kochanek KD. Deaths: preliminary data for 2008. Natl Vital Stat Rep. 2010;59:1-52.

2. Lopez AD, Shibuya K, Rao C, et al. Chronic obstructive pulmonary disease: current burden and future projections. Eur Respir J. 2006;27:397-412.

3. Hoyert DL, Xu J. National Center for Health Statistics. Deaths: preliminary data for 2011; October 2012. www.cdc.gov/nchs/data/nvsr/nvsr61/nvsr61_06.pdf. Accessed April 3, 2014.

4. Centers for Disease Control and Prevention (CDC). Chronic obstructive pulmonary disease among adults—United States, 2011. MMWR Morb Mortal Wkly Rep. 2012;61:938-943.

5. Tilert T, Dillon C, Paulose-Ram R, et al. Estimating the U.S. prevalence of chronic obstructive pulmonary disease using pre- and post-bronchodilator spirometry: the National Health and Nutrition Examination Survey (NHANES) 2007-2010. Respir Res. 2013;14:103.

6. Mannino DM, Homa DM, Akinbami LJ, et al. Chronic obstructive pulmonary disease surveillance—United States, 1971-2000. MMWR Surveill Summ. 2002;51:1-16.

7. Centers for Disease Control and Prevention (CDC). Deaths from chronic obstructive pulmonary disease—United States, 2000-2005. MMWR Morb Mortal Wkly Rep. 2008;57:1229-1232.

8. Blanchette CM, Berry SR, Lane SJ. Advances in chronic obstructive pulmonary disease among older adults. Curr Opin Pulm Med. 2011;17:84-89.

9. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease.

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Accessed April 3, 2014.

10. Hertel N, Kotchie RW, Samyshkin Y, et al. Cost-effectiveness of available treat-

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ment options for patients suffering from severe COPD in the UK: a fully incremental analysis. Int J Chron Obstruct Pulmon Dis. 2012;7:183-199.

11. Nielsen R, Johannessen A, Benediktsdottir B, et al. Present and future costs of COPD in Iceland and Norway: results from the BOLD study. Eur Respir J. 2009;34: 850-857.

12. Soler-Cataluña JJ, Martínez-García MA, Román Sánchez P, et al. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease.

Thorax. 2005;60:925-931.

13. Puhan MA, Bachmann LM, Kleijnen J, et al. Inhaled drugs to reduce exacerbations in patients with chronic obstructive pulmonary disease: a network meta-analysis. BMC Med. 2009;7:2.

14. Dalal AA, Shah MB, D’Souza AO, et al. Observational study of the outcomes and costs of initiating maintenance therapies in patients with moderate exacerbations of COPD. Respir Res. 2012;13:41.

15. Cooke CE, Sidel M, Belletti DA, Fuhlbrigge AL. Review: clinical inertia in the management of chronic obstructive pulmonary disease. COPD. 2012;9:73-80.

16. Blanchette CM, Dalal AA, Mapel D. Changes in COPD demographics and costs over 20 years. J Med Econ. 2012;15:1176-1182.

17. Dalal AA, Liu F, Riedel AA. Cost trends among commercially insured and Medicare Advantage-insured patients with chronic obstructive pulmonary disease: 2006 through 2009. Int J Chron Obstruct Pulmon Dis. 2011;6:533-542.

18. Wier LM, Elixhauser A, Pfuntner A, Au DH. Overview of hospitalizations among patients with COPD, 2008: statistical brief #106. February 2011. In: Healthcare Cost and Utilization (HCUP) Statistical Briefs. Rockville, MD: Agency for Healthcare Research and Policy (US); February 2006.

19. Perera PN, Armstrong EP, Sherrill DL, Skrepnek GH. Acute exacerbations of COPD in the United States: inpatient burden and predictors of costs and mortality.

COPD. 2012;9:131-141.

20. Yu AP, Yang H, Wu EQ, et al. Incremental third-party costs associated with COPD exacerbations: a retrospective claims analysis. J Med Econ. 2011;14:315-323.

21. Pasquale MK, Sun SX, Song F, et al. Impact of exacerbations on health care cost and resource utilization in chronic obstructive pulmonary disease patients with chronic bronchitis from a predominantly Medicare population. Int J Chron Obstruct Pulmon Dis. 2012;7:757-764.

22. Dalal AA, Shah M, D’Souza AO, Rane P. Costs of COPD exacerbations in the emergency department and inpatient setting. Respir Med. 2011;105:454-460.

23. Tashkin DP, Celli B, Senn S, et al; for the UPLIFT Study Investigators. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359: 1543-1554.

24. Calverley PM, Anderson JA, Celli B, et al; for the TORCH Investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007;356:775-789.

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26. Halbert RJ, Natoli JL, Gano A, et al. Global burden of COPD: systematic review and meta-analysis. Eur Respir J. 2006;28:523-532.

27. Centers for Disease Control and Prevention (CDC). Annual smoking-attributable mortality, years of potential life lost, and productivity losses—United States, 1997-2001. MMWR Morb Mortal Wkly Rep. 2005;54:625-628.

28. Schiller JS, Lucas JW, Ward BW, Peregoy JA. Summary health statistics for U.S. adults: National Health Interview Survey, 2010. Vital Health Stat 10. January 2012:1-207.

29. Sørheim IC, Johannessen A, Gulsvik A, et al. Gender differences in COPD: are women more susceptible to smoking effects than men? Thorax. 2010;65:480-485.

30. Heron M. Deaths: leading causes for 2010. Natl Vital Stat Rep. 2013;62:1-97.

31. Mapel DW, Hurley JS, Frost FJ, et al. Health care utilization in chronic obstructive pulmonary disease. A case-control study in a health maintenance organization.

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32. Barr RG, Celli BR, Mannino DM, et al. Comorbidities, patient knowledge, and disease management in a national sample of patients with COPD. Am J Med. 2009; 122:348-355.

33. Reid WD, Yamabayashi C, Goodridge D, et al. Exercise prescription for hospitalized people with chronic obstructive pulmonary disease and comorbidities: a synthesis of systematic reviews. Int J Chron Obstruct Pulmon Dis. 2012;7:297-320.

34. Patel AR, Hurst JR. Extrapulmonary comorbidities in chronic obstructive pulmonary disease: state of the art. Expert Rev Respir Med. 2011;5:647-662.

35. Antonelli Incalzi R, Fuso L, De Rosa M, et al. Co-morbidity contributes to predict mortality of patients with chronic obstructive pulmonary disease. Eur Respir J. 1997;10:2794-2800.

36. Holguin F, Folch E, Redd SC, Mannino DM. Comorbidity and mortality in COPD-related hospitalizations in the United States, 1979 to 2001. Chest. 2005;128: 2005-2011.

37. Strassels SA, Smith DH, Sullivan SD, Mahajan PS. The costs of treating COPD in the United States. Chest. 2001;119:344-352.

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42. Mapel DW, Dalal AA, Blanchette CM, et al. Severity of COPD at initial spirometry-confirmed diagnosis: data from medical charts and administrative claims. Int J Chron Obstruct Pulmon Dis. 2011;6:573-581.

43. Akazawa M, Halpern R, Riedel AA, et al. Economic burden prior to COPD diagnosis: a matched case-control study in the United States. Respir Med. 2008;102: 1744-1752.

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45. Braido F, Baiardini I, Cazzola M, et al. Long-acting bronchodilators improve health related quality of life in patients with COPD. Respir Med. 2013;107:1465-1480.

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52. Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J. 2002;19:246-251.

53. Lavorini F, Magnan A, Dubus JC, et al. Effect of incorrect use of dry powder inhalers on management of patients with asthma and COPD. Respir Med. 2008;102:593-604.

54. Broeders ME, Vincken W, Corbetta L; for the ADMIT Working Group. The ADMIT series—Issues in Inhalation Therapy. 7. Ways to improve pharmacological management of COPD: the importance of inhaler choice and inhalation technique.

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55. Barta SK, Crawford A, Roberts CM. Survey of patients’ views of domiciliary nebuliser treatment for chronic lung disease. Respir Med. 2002;96:375-381.

56. Lowe DO, Lummis H, Zhang Y, Sketris IS. Effect of educational and policy interventions on institutional utilization of wet nebulization respiratory drugs and portable inhalers. Can J Clin Pharmacol. 2008;15:e334-e343.

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Stakeholder Perspective Chronic Obstructive Pulmonary Disease Remains a Growing Population Health Concern

By F. Randy Vogenberg, PhD, RPh Partner and Principal, Institute for Integrated Healthcare, and Access Market Intelligence, Greenville, SC

PURCHASERS/PAYERS: Chronic obstructive pul­ monary disease (COPD) remains a growing population health issue from a clinical effectiveness perspective and from an economic efficiency perspective, given our lifestyles and the aging US population. In their current review, Blanchette and colleagues highlight key outcome drivers to address when considering health plan design elements or coverage frameworks to improve and sustain health status goals. For example, employer-sponsored plans should focus on plan designs that align with their business goals of productivity and reduced absenteeism, while providing benefit designs that are attractive for their employees, including patients with chronic conditions, such as COPD. Aligning health plan coverage through care management that optimizes maintenance therapies remains an elusive goal, yet this presents a significant opportunity to enhance patient outcomes and improve the plan’s financial performance. Blanchette and colleagues provide in-

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sight on how to address this challenge, which now needs to be followed up with action.

PATIENTS: The growth in high-deductible plans creates a potential economic barrier for patients with a chronic disease (such as COPD), who require long-term therapy. The underutilization of maintenance therapy by patients and the lack of incentives to change this behavior are barriers to be overcome, as well as plan-­ imposed barriers.

Finding the appropriate balance between meeting the treatment needs of patients and aligning plan designs to create opportunities to reward health status improvement remains a challenge. Building on the health reform focus on disease prevention, the challenge is how best to engage patients in the care of their chronic condition, and how best to inform healthcare providers about the optimal strategies that will have a positive impact on their patients to reinforce successes without penalty from using poor plan design. n

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editorial board Editor-in-Chief

David B. Nash, MD, MBA Dean, the Dr Raymond C. and Doris N. Grandon Professor, Jefferson School of Population Health Philadelphia, PA Deputy Editors

Joseph D. Jackson, PhD Program Director, Applied Health Economics and Outcomes Research, Jefferson University School of Population Health, Philadelphia Laura T. Pizzi, PharmD, MPH, RPh Associate Professor, Dept. of Pharmacy Practice, Jefferson School of Pharmacy, Philadelphia Aging and Wellness

Eric G. Tangalos, MD, FACP, AGSF, CMD Professor of Medicine Mayo Clinic, Rochester, MN CANCER RESEARCH

Al B. Benson, III, MD, FACP, FASCO Professor of Medicine, Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center Northwestern University, IL Past Chair, NCCN Board of Directors Samuel M. Silver, MD, PhD, FASCO Professor of Internal Medicine, Hematology/Oncology Assistant Dean for Research, Associate Director, Faculty Group Practice, University of Michigan Medical School EMPLOYERS

Arthur F. Shinn, PharmD, FASCP President, Managed Pharmacy Consultants, LLC, Lake Worth, FL F. Randy Vogenberg, RPh, PhD Principal, Institute for Integrated Healthcare Greenville, SC ENDOCRINOLOGY

James V. Felicetta, MD Chairman, Dept. of Medicine Carl T. Hayden Veterans Affairs Medical Center, Phoenix, AZ Quang Nguyen, DO, FACP, FACE Medical Director, Las Vegas Endocrinology Adjunct Associate Professor Endocrinology Touro University Nevada EPIDEMIOLOGY Research

Joshua N. Liberman, PhD Executive Director, Research, Development & Dissemination, Sutter Health, Concord, CA

Steven Miff, PhD Senior Vice President VHA, Inc., Irving, TX Terri S. Moore, PhD, RPh, MBA Senior Manager, Product Development URAC, Washington, DC Kavita V. Nair, PhD Professor and Director, Graduate Program Track in Pharmaceutical Outcomes Research Skaggs School of Pharmacy and Pharmaceutical Sciences University of Colorado, Aurora Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Andrew M. Peterson, PharmD, PhD Dean, Mayes School of Healthcare Business and Policy, Associate Professor, University of the Sciences, Philadelphia Sarah A. Priddy, PhD Director, Competitive Health Analytics Humana, Louisville, KY Timothy S. Regan, BPharm, RPh, CPh Executive Director, Strategic Accounts Xcenda, Palm Harbor, FL Vincent J. Willey, PharmD Associate Professor, School of Pharmacy, University of the Sciences, Philadelphia Paul Wilson Senior VP, Health Consumer Insights and Analytics, Blue Bell, PA David W. Wright, MPH President, Institute for Interactive Patient Care Bethesda, MD

PHARMACY BENEFIT DESIGN

Joel V. Brill, MD, AGAF, CHCQM Chief Medical Officer, Predictive Health, Phoenix, AZ Teresa DeLuca, MD, MBA Chief Medical Officer–Pharmacy Magellan Health Services Leslie S. Fish, PharmD Vice President of Clinical Programs Fallon Community Health Plan, MA John Hornberger, MD, MS Cedar Associates, LLC CHP/PCOR Adjunct Associate, Menlo Park, CA Michael S. Jacobs, RPh MSJ Associates, Sandy Springs, GA Matthew Mitchell, PharmD, MBA Director, Pharmacy Services SelectHealth, Murray, UT Paul Anthony Polansky, BSPharm, MBA PAPRx, LLC Gulph Mills, PA Christina A. Stasiuk, DO, FACOI Senior Medical Director Cigna, Philadelphia, PA POLICY & PUBLIC HEALTH

health & value promotion

Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks, Orlando, FL Thomas G. McCarter, MD, FACP Chief Clinical Officer Executive Health Resources, PA Albert Tzeel, MD, MHSA, FACPE Regional Medical Director Medicare Operations, North Florida Humana, Jacksonville MANAGED MARKETS

Kevin B. “Kip” Piper, MA, FACHE President, Health Results Group, LLC Washington, DC

Jeffrey A. Bourret, PharmD, MS, RPh, FASHP Senior Director, North America Medical Affairs Medical Lead, Specialty Payer & Channel Customer Strategy, Pfizer Inc. Richard B. Weininger, MD Chairman, CareCore National, LLC Bluffton, SC

HEALTH INFORMATION TECHNOLOGY

PATIENT ADVOCACY

GOVERNMENT

Kelly Huang, PhD Operating Partner, Spindletop Capital Austin, TX Victor J. Strecher, PhD, MPH Professor and Director for Innovation and Social Entrepreneurship, University of Michigan School of Public Health and Medicine HEALTH OUTCOMES RESEARCH

Russell Basser, MBBS, MD, FRACP Senior Vice President Global Clinical Research and Development CSL Behring, King of Prussia, PA Diana Brixner, RPh, PhD Professor & Chair, Dept. of Pharmacotherapy Executive Director, Outcomes Research Center, Director of Outcomes, Personalized Health Care Program, University of Utah, Salt Lake City Joseph E. Couto, PharmD, MBA Clinical Program Manager Cigna Corporation, Bloomfield, CT

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Mike Pucci Sr VP, Commercial Operations and Business Development, PhytoChem Pharmaceuticals Lake Gaston, NC Personalized medicine

Amalia M. Issa, PhD, MPH Director, Program in Personalized Medicine & Targeted Therapeutics, University of the Sciences, Philadelphia

RESEARCH & DEVELOPMENT

Christopher (Chris) P. Molineaux President, Pennsylvania BIO Malvern, PA Michael F. Murphy, MD, PhD Chief Medical Officer and Scientific Officer Worldwide Clinical Trials King of Prussia, PA SPECIALTY PHARMACY

PHARMACOECONOMICs

Josh Feldstein President & CEO, CAVA, The Center for Applied Value Analysis, Inc., Norwalk, CT Jeff Jianfei Guo, BPharm, MS, PhD Professor of Pharmacoeconomics & Pharmacoepidemiology, College of Pharmacy, Univ. of Cincinnati Medical Center, OH

www.AHDBonline.com

Joseph R. Antos, PhD Wilson H. Taylor Scholar in Health Care Retirement Policy, American Enterprise Institute Washington, DC Robert W. Dubois, MD, PhD Chief Science Officer National Pharmaceutical Council, Washington, DC Jack E. Fincham, PhD, RPh Professor of Pharmacy, School of Pharmacy University of Missouri, Kansas City, MO Walid F. Gellad, MD, MPH Assistant Professor of Medicine, University of Pittsburgh, Staff Physician, Pittsburgh VA Medical Center, Adjunct Scientist, RAND Health Paul Pomerantz, MBA CEO, American Society of Anesthesiologists Park Ridge, IL J. Warren Salmon, PhD Professor of Health Policy & Administration School of Public Health University of Illinois at Chicago Raymond L. Singer, MD, MMM, CPE, FACS Chief, Division of Cardiothoracic Surgery Vice Chair, Department of Surgery for Quality & Patient Safety and Outreach Lehigh Valley Health Network, PA

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Atheer A. Kaddis, PharmD Senior Vice President Sales and Business Development Diplomat Specialty Pharmacy, Flint, MI James T. Kenney, Jr, RPh, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA Michael Kleinrock Director, Research Development IMS Institute for Healthcare Informatics

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4TH ANNUAL CONFERENCE

MAY 6-9, 2014 LOEWS HOLLYWOOD HOTEL â&#x20AC;˘ LOS ANGELES, CA Government and Employers Co-Chairs Jayson Slotnik, JD, MPH

F. Randy Vogenberg, PhD, RPh

Vice President of Reimbursement Strategy & Innovation United BioSource Corporation

Principal Institute for Integrated Healthcare

Personalized Medicine and Payers Co-Chairs Michael A. Kolodziej, MD National Medical Director Oncology Solutions Aetna

Grant Lawless, RPh, MD, FACP Program Director Associate Professor University of Southern California

Oncology Practice Management, Advocacy, and Navigation Co-Chairs Linda Bosserman, MD, FACP

President Wilshire Oncology Medical Group

Vicki Kennedy, LCSW

Vice President, Program Development and Delivery Cancer Support Community

AVBCC Leadership Burt Zweigenhaft, BS President and CEO OncoMed

Gary M. Owens, MD

President Gary Owens Associates

www.AVBCConline.org

Craig K. Deligdish, MD Hematologist/ Oncologist Oncology Resource Networks

HELD IN PARTNERSHIP WITH

AVBCC2014chairs Asize_13114

NEW FOR 2014! Principles in Value and Market Access Educational sessions for Product Managers, Reimbursement Specialists, Account Managers, and Marketers focusing on access, reimbursement, proving product value, and international markets.