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Pharmacy‐based interdisciplinary intervention for patients with chronic heart failure: results of the PHARM‐CHF randomized controlled trial

Medication non‐adherence is frequent and is associated with high morbidity and mortality in patients with chronic heart failure (CHF). We investigated whether an interdisciplinary intervention improves adherence in elderly CHF patients.


Introduction
Heart failure (HF) is an increasingly prevalent condition, limiting functional capacity associated with impaired quality of life and mortality imposing a high burden on health care systems. 1 Guideline-directed pharmacotherapy decreases morbidity and mortality in patients with HF with reduced ejection fraction. Guidelines recommend the use of diuretics for symptom relief and appropriate management of co-morbidities in patients with HF with preserved or mid-range ejection fraction. 2 Non-adherence to pharmacotherapy, however, affects 20-50% of all patients, and affects morbidity and mortality in patients with chronic HF (CHF). 3 -5 Patients with CHF often receive additional drugs for co-morbidities leading to polypharmacy with an increased risk of drug-related problems (DRPs). 6,7 DRPs are potentially preventable by interdisciplinary advise involving physicians and pharmacists. These efforts appear to be successful when the pharmacist acts as part of a multidisciplinary team. 8 However, there are no pharmacy-based randomized controlled trials (RCT) aiming to improve medication adherence in elderly CHF patients by structured, regular and long-term patient contacts. HF is associated with impaired quality of life (QoL), but few RCTs have provided evidence with regard to interventions improving QoL. 9 PHARM-CHF investigated whether an interdisciplinary intervention consisting of regular contacts with the local pharmacy and weekly dosing aids improves medication adherence and QoL in elderly patients with CHF, and whether it affects hospitalizations and mortality.

Study design and participants
PHARM-CHF was an investigator-initiated, prospective multicentre, randomized controlled study. The study design has been published previously. 10 In brief, patients aged 60 years and older with CHF defined by HF symptoms, currently treated with a diuretic, and a hospitalization for HF within the last 12 months or increased B-type natriuretic peptide or N-terminal pro-B-type natriuretic peptide concentrations, were recruited by study physicians. After choosing the attending community pharmacy, patients were randomized via a secure web interface tool (www.pharm-chf.de) in a 1:1 ratio to the intervention (pharmacy care) or control group (usual care). The PHARM-CHF trial was conducted according to the principles stated in the current version of the Declaration of Helsinki, International Conference on Harmonization (ICH) Good Clinical Practice (GCP), and to local and national regulations. Documented approvals from independent ethics committees were obtained for all participating centres and written informed consent from all patients. The study is registered with ClinicalTrials.gov, identifier: NCT 01692119.

Study protocol
Details on study visits, data collection, intervention, and standardization were previously described. 10 In brief, the intervention consisted of the following components: first, medication review (Type 2a according  in the community pharmacy at baseline with the aim of generating a consolidated medication plan. This included the following: • compilation of the patient's entire medication (based on the physician's medication list, documented drug dispensing in the pharmacy, and patient interview in the pharmacy), • check for DRPs such as drug interactions and double medications using a standardized check-list, and • contact with the physician to discuss problems and risks if necessary.
Based on the subsequently consolidated medication plan, the patient received a weekly dosing aid together with a printout of the medication plan. The type of the dosing aid (dosette, pill-box) was at the discretion of the pharmacist and in agreement with the patient. Pharmacy care continued by (bi-)weekly visits to the local pharmacy including: • updating the medication plan if necessary, • receiving the supply of medicines in dosing aids filled by the pharmacist for 1 or 2 weeks, • counselling regarding medication, adherence, potential side effects, signs and symptoms of decompensation, • measurement of blood pressure and pulse rate, • in case of newly detected DRP and/or significant changes in vital signs, contact with the physician.
Patients in the usual care group continued to visit pharmacies of their choice to fill prescriptions without further intervention. Usual care mainly consisted of dispensing prescribed medication, including counselling by the pharmacist or pharmacy technician on the safe and appropriate use of the drug. Medication review, measuring blood pressure and pulse rate or providing medication in a weekly dosing aid are neither part of usual care nor reimbursed.

Study endpoints
The primary efficacy endpoint was medication adherence, defined as a significant difference between the pharmacy care and usual care groups using pharmacy claims data during the 365 days following randomization for three HF medication classes [beta-blockers, angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA)] prescribed at baseline. Adherence was calculated using the proportion of days covered (PDC), which is the ratio of number of days in the period covered by a medicine (numerator) to the total number of days in the observation period (denominator).
The main secondary efficacy endpoint was the proportion of patients classified as adherent (mean PDC ≥ 80%). We further analysed the PDC for each drug class (beta-blockers, ACEi/ARB, MRA), and the percentages of patients with a PDC ≥ 80% for each drug class for the periods of 365 as well as 730 days post-randomization.
Data collection, use of information and calculating the PDC were the same in both groups and for all time-periods analysed. Health insurance companies and data processing centres provided claims data of prescribed drugs, dispensed at community pharmacies. These data included information on the active ingredient(s), the dosage per unit (strength), the package size, and the dispensing date. For all patients, the information on the daily dose documented by the study physician in the electronic case report form was used. Medication switches, stockpiling, hospital stays, medication fills prior to randomization, and death were considered. To measure baseline adherence, the PDC for the period 183 days before randomization was analysed. In case of inpatient days, the proportion was adjusted by excluding days from both the numerator and denominator assuming that patients did not deplete their medication on their medication supply on those excluded days. If a patient switched medications within a class (including ACEi/ARB), the patient's medication supply was replaced with the new medication supply. If a patient died, all days following the death were censored. Existing medication at randomization and medication dispensed during 14 days after randomization were considered if at least one additional dispensing occurred during the 365-day follow-up. Existing medication at randomization was captured, but only the days during the 365-day follow-up contributed to the final proportion.
Other secondary efficacy endpoints included QoL, depression, and Patient Global Assessment (PGA). QoL was measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ) at baseline, and after 12 and 24 months. Depression was assessed using the 9-item Patient Health Questionnaire (PHQ-9). 12 Patients were characterized (dichotomized) as non-depressed (< 10 points) and as suspected to currently have depression (≥ 10 points).
The primary composite safety endpoint was days lost due to unplanned cardiovascular hospitalizations (blindly adjudicated) or all-cause death. Secondary safety endpoints were percentage of days lost due to unplanned cardiovascular hospitalizations or death of any cause, all-cause mortality or unplanned cardiovascular hospitalizations as recurrent event, unplanned cardiovascular hospitalizations, unplanned hospitalizations for HF, days lost due to hospitalizations of any cause or death, unplanned all-cause hospitalizations, and all-cause mortality. 10

Sensitivity analyses
Pre-specified subgroup analyses were performed for age, sex, New York Heart Association class, level of illness burden, diabetes, depression, heart rate, HF medication, time between last HF hospitalization and randomization, and QoL as previously defined.

Statistical analyses
Assuming a mean PDC before randomization of approximately 70%, a sample size of 176 patients (88 per group) was calculated to detect a 10% [standard deviation (SD) 22%] improvement of the mean PDC between the intervention and the usual care group with a power of 85% and an alpha of 5%. 10 The primary and secondary efficacy and safety analyses were performed as described. Baseline characteristics are summarized as number of patients (%) for categorical variables and as mean (SD) or median [interquartile range (IQR)] for continuous variables. For continuous variables such as the PDC or the MLHFQ score, changes in means of both study groups at 12 and 24 months were compared by ANCOVA models adjusted for the baseline value. Odds ratios (OR) for a PDC ≥ 80% between groups were calculated via logistic regression, adjusting for the baseline PDC. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA). PDC calculations were performed using Microsoft SQL 2016.

Results
The study was performed at 31 sites (general practitioners, internal medicine specialists, and both office-and hospital-based cardiologists) and 69 community pharmacies in nine different Federal States of Germany. 10 In total, 258 patients were recruited between October 2012 and January 2016, and 130 were randomized to the pharmacy care group and 128 into the usual care group. In this interdisciplinary study, randomization was performed by the physician without involvement of a pharmacist but the intervention was delivered by the pharmacy. Three patients in the pharmacy care and one patient in the usual care group were excluded because of major protocol violations (i.e. patients were not prescribed a diuretic as required). 10 Furthermore, due to the nature of the pharmacy care intervention, we defined the intention to treat (ITT) analyses as those who completed randomization by attending their pharmacy -a modified ITT (mITT). For various reasons, 17 patients randomized into the pharmacy care group by their physician did not present to a participating pharmacy. According to the pre-specified analytical plan in the study protocol, 10 these individuals were not included in the analyses. A comprehensive statistical comparison showed no relevant differences between these individuals compared to the 110 patients included in the pharmacy care cohort of the mITT population ( Figure 1). Patients in the mITT population had a mean (±SD) age of 74.1 ± 7.0 years (median 75.0, range 60-88) and 62% were male. The median number of drugs used was nine and the mean baseline PDC for three HF medication classes was 68%. Both groups had similar baseline characteristics (  For 35 patients [20 (18%) of the pharmacy care and 15 (12%) of the usual care group] we were unable to calculate a PDC. Reasons included criteria to calculate a PDC not fulfilled, withdrawal of informed consent (n = 11), or claims data not provided (n = 4). Compared to the 202 patients for whom a PDC was calculated, these individuals showed no relevant differences (online supplementary Table S1).

Secondary efficacy outcomes
For ACEi/ARB there was a non-significantly higher adherence within 365 and 730 days (adjusted difference at 365 days: 4.7%, 95% CI −0.8 to 10.2, P = 0.09). The proportion of patients with a PDC ≥ 80% within 365 days was significantly higher in the pharmacy care group (OR 2.9, 95% CI 1.1-7.5], P < 0.05; NNT 8.3) compared to usual care ( Table 2 and Figure 2B). Changes in medication adherence for MRA were not significant ( Table 2).

Sensitivity analyses
In all subgroups examined, 10 the treatment effect for the primary efficacy endpoint was preserved. A consistent improvement in 365-day medication adherence in patients receiving pharmacy care Changes in PHQ-9 and PGA scores were not statistically different between groups at 12 and 24 months compared to baseline.

Safety outcomes
During 365 days post-randomization, eight patients in each group died (7% and 6%, respectively). Until the end of the study, 20 (18%) and 27 (21%) patients died in the pharmacy care and usual care groups, respectively. There was no significant difference between the pharmacy care and usual care groups in the days lost due  to unplanned cardiovascular hospitalizations or death of any cause in the 365 days following randomization or any other of the morbidity or mortality endpoints. During follow-up until the end of the study, there was a numerically higher number of deaths in the usual care group ( Table 3). The Nelson-Aalen plot of time to first event (all-cause death or unplanned cardiovascular hospitalization) during 365 days post-randomization is shown in Figure 5.

Discussion
Poor medication adherence represents a major problem but provides a major opportunity to improve outcomes in patients with HF at the same time. Convincing evidence for effective interventions to improve adherence from prospective, randomized studies is lacking. The PHARM-CHF intervention improved mean adherence to three HF medications combined and the proportion of adherent patients (PDC ≥ 80%). The intervention led to a clinically meaningful improvement in QoL and was safe with regard . The analysis of all events that occurred until the end of the study showed a slight numerically higher number of deaths in the usual care group. To our knowledge, PHARM-CHF is the first pharmacy-based RCT in ambulatory care of elderly HF patients investigating the impact of a multifaceted, interdisciplinary intervention. Although the overall intervention effect on the mean PDC across three HF medication classes was less than the assumed 10% for the sample size calculation, patients in the pharmacy care group had a threefold higher likelihood to achieve a PDC ≥ 80%, which is a broadly accepted threshold for being classified as adherent, compared to the usual care group. The effects were most pronounced for beta-blockers and to a lesser extent for ACEi/ARB. The number of patients receiving MRAs was too small to show a significant difference.
Several systematic reviews have sought to identify the most effective interventions for improving medication adherence. 8,13 Despite differences in methodologies, the main findings have been consistent: only multifaceted and continuous interventions, combining several different elements, have the potential to improve adherence. However, a number of previous studies in cardiovascular patients failed to demonstrate a significant effect on medication adherence. The HeartStrong RCT tested whether a system of medication reminders using financial incentives and social support applied for 12 months delays subsequent vascular events in patients following acute myocardial infarction compared with usual care. Medication adherence (mean PDC for statins, beta-blockers, and antiplatelet agents) was low and did not differ between the control (42%) and intervention cohorts (46%). 14 The two-arm pragmatic cluster-randomized controlled STIC2IT trial enrolled patients with suboptimal hyperlipidaemia, hypertension, or diabetes disease control, who were non-adherent to prescribed medications for these conditions (mean baseline PDC from pharmacy claims data was 57%). A multicomponent intervention using telephone-delivered behavioural interviewing by trained clinical pharmacists, text messaging, pillboxes, and mailed progress reports was compared  CI, confidence interval.
to usual care. The intervention was associated with a 10% increase in adherence, but did not change clinical outcomes. 15 A pharmacist care programme combining education and counselling with the preparation of medicines in time-specific punch cards increased medication adherence to 97% measured by pill count. This improvement was associated with improved blood pressure and lipid values. However, 6 months after randomization, medication adherence decreased to 69% among those patients assigned again to usual care. 16 In accordance with this study, a multifaceted intervention comprising pharmacist interventions, education, interdisciplinary care, and voice messaging increased medication adherence in the year after an acute coronary syndrome with a 15% difference in the proportion of patients with a mean PDC ≥ 80%. Mean PDC was 7% higher in the intervention group. 17 Herein, a greater proportion of patients on intervention were adherent to clopidogrel, statins, and ACEi/ARB therapies, but not to beta-blockers. In the HF population included in PHARM-CHF, adherence to beta-blockers was markedly improved, suggesting that clinical trials addressing adherence in specific patient populations are needed.
A 9-month intervention provided by one pharmacist at a single study site improved medication adherence by 11% (measured by electronic monitoring) but was no longer significantly different during the 3 months post-study phase of the trial. 18 These data confirm that poor adherence cannot be persistently 'cured'; it decreases after stopping the interventions to improve adherence, indicating a need for a continuous strategy.
Heart failure patients are often symptomatic and have a poor QoL. Alleviating symptoms and improving well-being is important. 2 However, very few RCTs have provided evidence with regard to improvements in QoL. A recent systematic review on disease management interventions for HF concluded that clinic-based interventions may result in little or no difference in QoL. 19 In PHARM-CHF, QoL improved in both groups by 12 20 This positive effect on QoL in the intervention group probably did not relate to medication adherence only as the control group was likewise adherent at 2 years (PDC ≥ 80%). We therefore assume an effect of constant support by study pharmacists and physicians, which may explain the increasing difference to the usual care group over time.

Limitations
The relevant improvement in medication adherence in the usual care group was unexpected and could have affected the difference to the effect of the intervention on the primary efficacy endpoint. By design, patients of the control arm were unknown to the pharmacies, minimizing contamination but at the same time limiting the availability of detailed information. We cannot therefore exclude the possibility of cross over with regard to general awareness, the use of dosing aids and/or physician interventions to optimizing pharmacotherapy in the usual care group. A certain degree of improved monitoring and care of patients during a RCT when compared to 'real-world' usual care is unavoidable. The effect of the intervention on the PDC as a continuous variable is quantitatively smaller than the effect on the proportion of patients with a PDC ≥ 80%. The 80% cut-point for PDC is widespread practice and was used because it is associated with improved clinical outcomes for several medications/diseases including HF. 5,21 -23 Unfortunately, we were unable to calculate a PDC for 35 patients. However, these individuals did not differ in any relevant characteristic available and the power to detect a 10% difference in mean adherence was preserved by the remaining number of participants. Notably, this study was not powered to explore the effects on morbidity and mortality.

Conclusion
A pharmacy-based interdisciplinary intervention improved mean adherence to three HF medication classes and the proportion of adherent patients, and led to clinically important improvements in QoL. For these important aims, pharmacy care represents a valuable addition to the comprehensive care for HF patients. Morbidity and mortality effects need to be scrutinized in an adequately powered RCT.

Supplementary Information
Additional supporting information may be found online in the Supporting Information section at the end of the article. Figure S1. Boxplots of adherence to beta-blockers within 365 days and 730 days compared to baseline (183 days prior to randomization). The treatment effects are shown with the 95% confidence intervals. The green horizontal line represents the cut-off for classifying a patient adherent (proportion of days covered ≥ 80%). Table S1. Characteristics of participants with or without calculation of proportion of days covered.