Effectiveness of Pharmacist Care for Patients With Reactive Airways Disease: Title and subTitle BreakA Randomized Controlled Trial FREE

Reactive airways diseases, including asthma and chronic obstructive pulmonary disease (COPD), are prevalent, morbid, and costly long-term conditions.^{1 - 8} Although exacerbations are potentially preventable by appropriate drug therapy,^{9 - 10} patients often have difficulty following prescribed regimens. Pharmacists may be able to enhance patients' compliance and outcomes by engaging in pharmaceutical care activities (eg, monitoring symptoms, providing medication counseling, helping resolve drug-related problems, facilitating communication with physicians).^{11 - 12} Pharmaceutical care is promising because: (1) pharmacists have the knowledge and skills to identify and resolve patients' medication-related problems; (2) patients often have several physicians but frequently patronize a single pharmacy; (3) pharmacists are often the last health professional whom patients see before taking their medication; and (4) pharmacists are trusted by patients.¹³

Literature reviews suggest that enthusiastic reports about the effectiveness of pharmaceutical care are often plagued by serious methodological flaws.^{14 - 17} Although inpatient pharmaceutical care may be effective,^{18 - 19} there is less evidence of its effectiveness in outpatient settings and no rigorous studies have been performed in community pharmacies.^{14 - 17} As the largest provider of prescription services in the United States,²⁰ community pharmacies provide an important venue for improving patients' lives via pharmaceutical care. However, substantial barriers to implementing such programs exist.^{21 - 23 ,25}

We conducted a randomized controlled trial to assess the effectiveness of pharmaceutical care for adults with reactive airways disease. Primary outcomes were patients' peak expiratory flow rate (PEFR), health-related quality of life (HRQOL), medication compliance, and breathing-related emergency department (ED) or hospital visits. Secondary outcomes were patient satisfaction with care and with their pharmacist.

The study, approved by the Indiana University-Purdue University at Indianapolis institutional review board, was conducted in 36 Indianapolis CVS drugstores. The 36 drugstores were divided into 12 clusters of 3 geographically proximal drugstores ("triplets"). The 3 drugstores within each triplet were matched on percentage of Medicaid-insured adults with reactive airways disease (to control for customers' socioeconomic status) and number of prescriptions filled (high vs low volume). Within each triplet, we used a random-number chart to assign drugstores to 1 of 3 study groups. Each patient was followed up for a year. Face-to-face interviews at baseline, 6, and 12 months were conducted to assess primary and secondary outcomes (Figure 1).

Pharmaceutical Care Program. A detailed description of the pharmaceutical care program appears elsewhere.²⁶ Briefly, the program included (Table 1) the following.

Pharmacist Training. Investigators representing several backgrounds presented: (1) an overview of pharmaceutical care and its application to reactive airways disease; (2) an orientation to the study computer and available patient-specific data; (3) explanation for interpreting and using these data for pharmaceutical care; (4) appropriate techniques for measuring PEFR; (5) study materials, resources, and handouts when interacting with patients; and (6) strategies to implement the program.

Computer Display of Patient-Specific Data. When a study patient filled any prescription (not only breathing medications), the drugstore computer alerted pharmacists to review patient-specific data contained in a separate study computer behind the counter. To safeguard patients' confidentiality, access to patient-specific data required pharmacists' individualized passwords. Study computers contained: (1) contact information for patients and 1 to 2 physicians caring for their breathing problem; (2) graphical display of all PEFR data gathered during monthly interviews; (3) dates and locations of recent ED visits and hospitalizations; and (4) breathing medications (including compliance rates and refill histories). These data were obtained during monthly telephone interviews. Pharmacists were encouraged to document their pharmaceutical care activities at the bottom of the screen.

Written Patient Educational Materials. We developed 1-page handouts corresponding to specific problems associated with clinical data stored in the study computer. Handouts, designed to be easily understood by patients, used mnemonic devices and color coding to facilitate distribution by pharmacists.

Resource Guide. Attached to the study computer, guides contained laminated pages with practical suggestions to help pharmacists implement the program in a busy practice.

Pragmatic Strategies to Facilitate Pharmaceutical Care. To reinforce pharmacist training and facilitate program implementation, we: (1) encouraged pharmacists to page the on-call investigator with questions; (2) had an investigator make personal visits to each intervention drugstore every 1 to 2 months; (3) distributed periodic newsletters containing information about reactive airways disease and suggestions on implementing the program; (4) faxed weekly lists of recent patient activity (eg, medication refill, ED or hospital visit) and pharmacists' documented activities; and (5) provided pharmacists with telephone appointment scheduling cards to facilitate interactions with patients at a mutually convenient time. During the final year of the study, we paid pharmacists $50 per month for high rates of compliance with the pharmaceutical care protocol (viewing data on the study computer for ≥90% of patients and documenting actions for ≥75% of patients).

Control Groups. Patients in the pharmaceutical care group received a peak flow meter, instruction about its use, and monthly calls from research personnel to obtain current PEFR results. We were concerned that these activities could be an active treatment by increasing patients' self-monitoring. So, the peak flow meter monitoring control group also received a peak flow meter, instructions about its use, and monthly calls to elicit PEFRs. However, PEFR data were not provided to the pharmacist. Patients in the usual-care group received neither peak flow meters nor instructions in their use; during monthly telephone interviews, PEFR rates were not elicited. Pharmacists in both control groups also had a 4-hour training session although the topics were different and they received no components of our pharmaceutical care program (Table 1).

Customers were eligible if they (1) filled a prescription for methylxanthines, inhaled corticosteroids, inhaled or oral sympathomimetics, inhaled parasympathetic antagonists, or inhaled cromolyn sodium during the preceding 4 months; (2) reported having COPD or asthma as an active problem; (3) were 18 years or older; (4) received 70% or more of their medications from a single study drugstore; (5) reported no significant impairment in vision, hearing, or speech that precluded participation; (6) did not reside in an institution (eg, nursing home); and (7) provided written informed consent.

The recruitment protocol²⁷ was designed to maximize customers' confidentiality (Figure 1). Patients were enrolled between July 1998 and December 1999. In July 1998, drugstore programmers queried their database to identify all customers 18 years or older who, during the preceding 4 months, filled a prescription for 1 of the above breathing medications at any study pharmacy. Corporate personnel mailed letters to these individuals stating that: (1) they were working with Indiana University School of Medicine (IUSM) to develop programs to improve the health of its customers; (2) IUSM was evaluating these programs by talking to customers; (3) customers would be paid up to $60 for participating in the evaluation; and (4) they could page an investigator with questions about the project. Subjects were asked to sign and return a form providing permission in order to release their names to IUSM investigators or that they were uninterested in participating. A drugstore employee attempted to telephone persons who failed to return a signed form to verify that they received the letter, determine their interest in participating, and offer to send them another form. Only after receiving a signed form indicating a person's willingness to be contacted was the name released to the IUSM project manager.

The project manager then conducted a telephone screening interview to describe the study, review patient eligibility, and, for eligible patients, arrange a face-to-face baseline interview (Figure 1). All interviewers completed training on the study protocol, interviewing techniques, asthma and COPD, proper peak flow meter technique. Interviewers were instructed to ensure that the proper peak flow meter technique was used during face-to-face interviews.

Interviewers, blinded to study group assignment, obtained informed consent and conducted baseline interviews. After completing an interview, the laptop computer used to administer interviews revealed the patient's study group assignment. At that time, interviewers distributed a Personal Best peak flow meter (Health Scan Product, Inc, Cedar Grove, NJ) and reviewed proper meter technique for patients in the pharmaceutical care program and peak flow monitoring control groups. Following the baseline interview, we sent letters notifying physicians treating the patient's breathing problem and advised them that the patient was participating in a study in which a pharmacist might receive PEFR, medication compliance, and health services utilization data. The letter stressed that the pharmacist would make no treatment decisions but may educate patients about their breathing problem and reinforce compliance with the physician's prescribed treatment regimen.

Patients were censored from the study if they died, were placed in a nursing home, moved away permanently from Indianapolis, their insurance no longer covered using these drugstores, or they lost telephone access. For patients not censored, we attempted to conduct in-person follow-up interviews at 6 and 12 months to assess outcomes by individuals blinded to study group. Patients in all 3 groups received a $20 gift certificate for each interview completed.

Monthly telephone interviews were conducted with all patients to ascertain ED or hospital use, breathing medications not contained in the pharmacists' database (ie, over-the-counter, prescriptions from other drugstores, samples), and frequency with which they had spoken to a pharmacist about their breathing medications during the previous month. In addition, patients receiving peak flow meters were asked to use their meters and report their PEFR while on the telephone. Patients are capable of reliably recording PEFR readings.^{28 - 31}

Peak expiratory flow rate, the maximum velocity of exhalation that can be generated by patients, correlates highly with parameters of pulmonary function and clinical outcomes of patients with asthma and COPD.^{32 - 36} For this study, we transformed PEFRs into the percentage of maximum predicted value based on patients' sex, age, and height.³⁷

Disease-specific HRQOL was assessed during the baseline and 6- and 12-month interviews using asthma- and COPD-specific measures developed to detect clinically important changes within randomized trials.^{38 - 40} Both questionnaires use analogous 7-point Likert formats to produce an overall assessment, as well as disease-specific subscales for COPD (dyspnea, fatigue, emotional function, mastery) and asthma (activity limitations, symptoms, emotional function, environmental stimuli). Scores range from 1 (worst) to 7 (best) function; differences of 0.5 units are considered clinically important. Patients were administered the COPD questionnaire if they met American Thoracic Society criteria (age >45 years and smoking history ≥10 pack-years).^{41 - 42} Otherwise, patients completed the asthma questionnaire.

Medication compliance with breathing medications over the previous month was assessed using 2 validated measures: a single-item indicator⁴³ (proportion of noncompliance), and a 4-item scale⁴⁴ ranging from 0 (low) to 4 (high) noncompliance. Self-report has been found to be valid when inquiries are made in a nonthreatening manner.^{43 - 45}

Breathing-related ED or hospital visits were obtained from patient reports during monthly interviews and the Indianapolis Network for Patient Care, an integrated network linking data from Indianapolis' major hospitals, neighborhood health centers, and public health and homeless clinics.⁴⁶ We contacted the site of care to verify the visit. To determine whether an ED or hospital visit was breathing-related, a physician and pharmacist, blinded to patient's study group, independently reviewed reports for each episode. Disagreements were adjudicated by the raters.

Patient satisfaction with care was assessed using a validated 4-item global measure.^{47 - 48} Items were modified to ask about satisfaction for their breathing-related problems. Scores range from 4 (lowest) to 20 (highest) satisfaction. Patient satisfaction with pharmacists was measured with an 11-item scale that has been used among patients with reactive airways disease.⁴⁹ Scores (average of the 11 items) range from 1 (lowest) to 5 (highest) satisfaction.

A log file captured each time the intervention pharmacists had accessed a patient's record from the study computer or had documented their actions on the study computer. The frequency with which pharmacists documented their actions was used to estimate the dose of the intervention.

All analyses were conducted with SAS Version 8 (SAS Institute, Cary, NC). The success of randomization was assessed by comparing baseline characteristics of study groups using χ² tests for categorical variables and analysis of variance for continuous variables. When assumptions for these parametric tests were not met, we used the Fisher exact and Kruskal-Wallis tests, respectively. When between-group baseline differences were significant (P<.05), we controlled for those variables in all subsequent analyses. We used χ² tests and t tests to compare baseline characteristics of patients who did and did not complete 12-month interviews. During the study period, 2 drugstores (both control) were closed. In both cases, all study patients transferred to another study drugstore. Patients' original study group was retained for all analyses.

Consistent with our hypotheses, we compared the pharmaceutical care group with each of the 2 control groups using an intent-to-treat analysis. Sample size was based on our ability to detect a 10% difference in breathing-related ED or hospital visits (25% vs 15%) between the pharmaceutical care group and each control group with 80% power and α = .025 (using Bonferroni correction⁵⁰ for 2 pairwise comparisons). For an estimated 15% attrition, we enrolled approximately 1100 patients.

To test for differences in intervention group means for continuous outcomes measured at 6 and 12 months, we used repeated measures analysis of variance models, with baseline scores as covariates. This model makes no assumption about outcome measures in intervention groups' being linear over time. Random effects corresponding to the design variables (ie, triplet and pharmacy) were included. However, because variation due to pharmacy was consistently nonsignificant, we excluded the effect of pharmacy from the final models. For binary outcomes (compliance, proportion with a breathing-related ED or hospital visit), we used logistic regression. For compliance, we used a repeated measures approach. For breathing-related ED or hospital visits, we weighted each person's contribution by the amount of time in the study. Because HRQOL had different items depending on disease group (asthma vs COPD), separate models were constructed. For all other outcomes, interaction effects of disease with intervention group were investigated. If the interaction was not significant, we analyzed COPD and asthma patients together, including disease group as a covariate. Separate models were analyzed for patients with COPD and for patients with asthma if the interaction was significant. Treatment by time interactions were also tested and, if significant, tests of intervention effect were done separately for 6- and 12-month outcomes. We also examined temporal trends by comparing 6- and 12-month outcomes to baseline measures, accounting for multiple comparisons using Holms procedures.⁵¹ If the overall effect of intervention group was significant from tests described above, change from baseline was analyzed separately for each intervention group. For all repeated measures analyses, compound symmetry variance-covariance structure was used to specify the correlation between responses for the same individual. For all pairwise comparisons, we reported unadjusted P values.

As a secondary analysis, we used data from the pharmaceutical care program group only to determine if there were a dose-response relationship with our primary outcomes by repeating analyses with an additional continuous predictor for dose: the number of times the pharmacist documented his/her actions on the study computer.

Letters were mailed to 14 195 persons meeting initial eligibility criteria: 3019 returned forms (2195 were interested; 824 refused). Of those not returning a form, follow-up telephone calls identified 756 additional persons interested in participating. Of 2951 interested patients screened by the project coordinator, 1202 were ineligible, 492 refused, and 136 could not be contacted. After excluding 8 pilot study participants, 1113 were enrolled. Table 2 presents baseline characteristics for 453 patients with COPD and 660 patients with asthma. We completed interviews with 947 patients (85.1%) at 6 months and patients 898 patients (80.7%) at 12 months. Completion rates did not differ significantly by disease or study group. Patients not completing 12-month interviews were more likely to report a hospital or ED visit during the month prior to enrollment (9.8% vs 5.9%, P = .04), less education (13.1 vs 13.6 years, P = .04) and, for COPD patients only, lower HRQOL. Unadjusted outcome data across time are presented in Table 3.

Study groups were comparable at baseline (P>.05), except for race (both diseases) and PEFR (COPD only). To account for these differences, we controlled for race in all analyses and for baseline PEFR among COPD patients only. Except for satisfaction with health care, for which the intervention group by time interaction was significant, intervention effects were reported across 6 and 12 months together. Disease groups were tested in the same model for all outcomes except breathing-related ED or hospital visits, for which the effect of the intervention groups differed significantly by disease.

Across 6 and 12 months, there was a significant (P = .006) overall difference in PEFR among the 3 study groups (Table 4). Specifically, the pharmaceutical care group had higher PEFR than usual care (P = .02) but was not different from the peak flow meter monitoring group (P = .28). Time contrasts showed significant (P<.01) increases in PEFR in the pharmaceutical care group from baseline to 12 months and in the peak monitoring group from baseline to both 6 and 12 months.

There were no significant between-group differences in overall HRQOL for patients with either asthma (P = .23) or COPD (P = .31, Table 4). To increase statistical power, we combined patients with asthma and with COPD, using overall HRQOL as the dependent variable and disease as covariate; the treatment group difference remained nonsignificant (P = .12). For each disease group, we observed statistically significant (P<.002) within-group improvement over 12 months in overall HRQOL. This same pattern was observed for all HRQOL subscales in both diseases.

Similarly, there were no significant between-group differences in medication compliance using the proportion noncompliant (P = .22) or 4-item scale (P = .57); there were significant (P<.001) within-group declines in noncompliance at 6 and 12 months.

There was a significant interaction (P = .02) between disease and study group for the proportion of patients with a breathing-related ED or hospital visit over 12 months. Although there was no difference (P = .34) across study groups for COPD patients (Table 4), asthma patients in the pharmaceutical care group were more likely to have a breathing-related ED or hospital visit than those receiving usual care (odds ratio [OR], 2.16; 95% confidence interval [CI], 1.76-2.63; P<.001). There was no difference between the pharmaceutical care and peak flow meter control groups (P = .32).

Across 6 and 12 months, pharmaceutical care group patients reported greater satisfaction with their pharmacist than did patients in either the usual care (P = .02) or peak flow monitoring (P = .001) control group. Moreover, the pharmaceutical care group reported greater satisfaction with their health care compared with the usual care group at 6 months (P = .01); this difference was not sustained at 12 months (P = .14). There was no difference in satisfaction with health care between the pharmaceutical care and peak flow monitoring groups at 6 months (P = .08) or 12 months (P = .14). During monthly interviews, 49.3% of patients in the pharmaceutical care group reported having discussions with their pharmacists about their breathing problems while 24.3% of patients in the peak flow meter monitoring and 24.2% in the usual care control groups reported having discussions with their pharmacists (P<.001). Patients in the pharmaceutical care group reported a mean (SD) rate of speaking to their pharmacist during the previous month 1.17 (1.77) times compared with 0.51 (1.19) times in the peak flow monitoring and compared with 0.40 (0.89) in the usual care group (P<.001). Frequency of interactions with the pharmacist was correlated with patient satisfaction with their pharmacist (r = 0.12; P<.001).

There were ample visits during which pharmacists had opportunities to implement the pharmaceutical care program for patients with both asthma (mean [SD], 19.4 [16.8] visits) and COPD (22.4 [17.7] visits). However, they only accessed data from the study computer about half the time (asthma, 10.3 [7.5] visits; COPD, 11.8 [10.5] visits) and documented actions only about half the time these records were accessed (asthma, 6.2 [5.8] visits; COPD, 6.2 [7.0] visits). Using documentation to assess dose of the intervention, we observed no statistically significant dose-response effect for PEFR or HRQOL. Notably, when pharmacists documented more pharmaceutical care actions, patients exhibited less noncompliance with their breathing medications (OR, 0.96; 95% CI, 0.92-0.99; P = .02) and had more breathing-related ED or hospital visits (OR, 1.06; 95% CI, 1.04-1.07; P<.001).

We examined the effectiveness of a pharmaceutical care program designed to improve patients' clinical status, HRQOL, and medication compliance. At 12 months, patients in the pharmaceutical care group had significantly higher PEFRs than those receiving usual care; however, our program offered no advantage compared with monitoring patients' PEFRs monthly. Moreover, patients participating in our program were significantly more satisfied with their pharmacists than the other 2 groups; they were also more satisfied with their health care than the usual care group. Although we observed a substantial improvement in both medication compliance and HRQOL among patients in the pharmaceutical care program at 6 months that was sustained at 1 year, similar improvement was observed in both control groups.

However, contrary to our hypothesis, asthma patients in the pharmaceutical care group had more breathing-related ED or hospital visits. Notably, we are observing care-seeking behavior and did not examine the appropriateness of visits although observed PEFRs suggest poor function. Interestingly, although our a priori hypotheses did not involve comparing the 2 control groups with each other, breathing-related ED or hospital visits in the peak flow monitoring control group (14.6%) was twice that of usual care (7.3%). Increased visits may have resulted from patients associating their PEFR values with symptoms, which could have resulted in more care seeking. That simple monitoring could have measurable effects on clinical outcomes is consistent with our previous study of regular telephone calls from non–health care professionals.⁵² These findings suggest that strategies to increase patient involvement in care of their chronic conditions (especially enhancing self-efficacy for monitoring) may increase health services utilization.

The most likely explanation for our findings was that despite our efforts to design a pragmatic program and reinforce its use, it was not used consistently. Notably, pharmacists only viewed data in the study computer half the time patients filled prescriptions, and they documented their actions only 50% of the time those data were viewed. There are several possible explanations for this. First, our intervention was cumbersome and required pharmacists to access data on a separate study computer. When this investigation began, it was not possible to integrate patient-specific data into the regular drugstore computer. Now, those options exist through the intranet. Second, implementation of the program may require release time or other incentives for the pharmacists. Third, although all pharmacists participated in our program, they were not universally enthusiastic about this expanded role. In retrospect, a better strategy may have been to identify 1 enthusiastic pharmacist per store to be responsible for implementing the program in his/her drugstore. Indeed, a recent randomized trial found that an intervention delivered by highly motivated and selected community pharmacists in Canada improved the process of cholesterol risk management; interestingly, unlike our results, patients were not more satisfied with this program.⁵³

Our investigation had several limitations. First, although our overall drop-out rate was relatively low (18%), those not completing 12-month interviews appeared to have worse breathing problems, worse HRQOL scores, and less education. These are characteristics of patients who might have benefitted most from our program. Indeed, the rate of breathing-related ED or hospital visits, particularly among patients with asthma, was lower than expected from our previous work.⁵⁴ Second, the recruitment protocol required to safeguard patient confidentiality resulted in our inability to contact more than half the patients, thus compromising generalizability. Third, several important questions are beyond the scope of this study: Was the observed increase in visits due to increases in ED or hospital use? Were the increased visits clinically appropriate? Was there an effect on the appropriateness of medication regimens? Could the increase in ED visits have accounted for improvements in PEFR (eg, by alterations in medications)? Finally, we cannot determine whether patients' knowledge that they were being observed influenced self-reported outcomes.

Pharmaceutical care can play an important role in patient care, as supported by a recent American College of Physicians position paper.⁵⁵ However, data from this study suggest that implementation of the pharmacy care program was poor, perhaps due to limited time or lack of incentives to use the resources provided, and resulted in limited benefits in terms of clinical end points. Given the poor implementation, it is not surprising that our program provided little benefit compared with peak flow monitoring alone. Additional research is needed to determine whether other approaches using pharmaceutical care will improve patients' outcomes. Such evaluations should be conducted in "real-world" community pharmacies using strategies that are pragmatic in busy retail pharmacies, even though randomized trials conducted in real world settings present methodological and pragmatic challenges.