Pharmacist care and the management of coronary heart disease: a systematic review of randomized controlled trials

Background Secondary prevention is important for reducing both mortality and morbidity of patients with coronary heart disease (CHD). Pharmacists can provide medication and also work on disease management for patients with CHD. This review has been carried out to evaluate the role of pharmacist care on mortality, morbidity, and the CHD management. Methods The PubMed, MEDLINE, EMBASE, Web of Science and Cochrane Central Register of Controlled Trials databases were searched for randomized controlled trials (RCTs) to evaluate the impact of pharmacist care interventions on patients with CHD (in both community and hospital settings). Primary outcomes of interest were mortality, cardiovascular events and hospitalizations. Secondary outcomes were medication adherence, blood pressure control, and lipid management. Results Five RCTs (2568 patients) were identified. The outcomes were mortality, cardiovascular events, and hospitalizations in one study (421 patients), medication adherence in five studies, blood pressure in two studies (1914 patients), and lipid management in three studies (932 patients). The interventions of pharmacists included patient education, medication management, feedback to health care professionals, and disease management. There was no significant effect of pharmacist care on mortality, recurrent cardiac events or hospitalization of CHD patients. Significant positive effects of pharmacist care were shown on medication adherence in three studies, on blood pressure control in one study and on lipid management in one study. Conclusion In this study, we concluded that pharmacists have a beneficial role in the care of CHD patients, although the evidence supporting positive impacts on mortality and morbidity remains uncertain due to the unavailability of data in these areas. Further research is needed to discern the contribution of pharmacist care on hard endpoints of CHD.


Background
Coronary heart disease (CHD) is one of the leading causes of morbidity and mortality in the world [1]. With reference to increased survival rates after acute myocardial infarction and also due to an increase of the aging population, the burden of CHD increases gradually [1]. Secondary prevention is important because cardiovascular events occur at a high rate after an acute vascular event [2]. For example, about one fifth of patients were rehospitalized for ischemic heart disease or died within a year after the first acute coronary syndrome (ACS) [3].
Randomized studies have demonstrated the efficacy of lifestyle changes (e.g. smoking cessation, physical activity), and the use of medications such as aspirin, β-blockers, angiotensin-converting enzyme (ACE) inhibitors and statins to reduce death, reinfarction, or stroke in patients with CHD [4,5]. The nonadherence to medications for secondary prevention of CHD is associated with an increased risk of subsequent cardiovascular events and mortality [6][7][8][9][10]. Physicians and healthcare providers should make necessary efforts to engage the patient's active participation in prescribed medical regimens and lifestyle changes to improve the prognosis of CHD.
Pharmacists, in addition to medication dispensing, can provide medication education and disease management for patients, to improve medication adherence to achieve the goals of desired therapeutic outcomes, and to improve safe medication use. Previous systematic reviews have demonstrated that interventions provided by pharmacists are beneficial in the management of major cardiovascular disease (CVD) risk factors in outpatients (e.g. lowering blood pressure and cholesterol levels or smoking cessation) [11], and in reducing the risk of hospitalizations in patients with heart failure [12]. The contributions from pharmacists in CHD secondary prevention have not been systematically reviewed so far, and hence we have carried out this study to evaluate the role of pharmacist care on mortality, morbidity, and the management of CHD.

Data sources and searches
A systematic literature search for randomized controlled trials (RCTs) on MEDLINE, PubMed EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials, from their inception until July 2012 was conducted (with an update performed in September 2013). Language restrictions were not applied. Search terms were pharmacy-related terms ('pharmacist' OR 'pharmaceutical care' OR 'pharmaceutical services' OR 'pharmacy services' OR 'hospital pharmacy' OR 'community pharmacy' OR 'pharmacy') AND CHD-related terms ('coronary heart disease (CHD)' OR 'coronary disease' OR 'myocardial infarction (MI)' OR 'angina pectoris' OR 'revascularization' OR 'coronary artery bypass grafting (CABG)' OR 'percutaneous transluminal coronary angioplasty (PTCA)' OR 'percutaneous coronary intervention (PCI)' OR 'coronary artery stenting') AND trial-related terms ('randomized controlled trial (RCT)' OR 'clinical trial' OR 'comparative study'). Additionally, the bibliographies of all relevant articles were reviewed.

Study selection
Two authors (HX and HC) independently screened the citations from the literature search to determine eligibility ( Figure 1). Studies were included if they (1) had a randomized control design; (2) evaluated the impact of pharmacist care on patients with CHD (compared with usual care); and (3) had at least one of the outcomes of interest. Usual care for CHD involved routine care performed by a nurse, physician, and dispensing pharmacist. Pharmacist care in this study refers to enhanced pharmacist care provided by a clinical pharmacist, hospital pharmacist, community pharmacist, or pharmacy pharmacist. This study involves both pharmacist-directed care and pharmacist collaborative care. Primary outcomes of interest for this study were mortality, cardiovascular events and hospitalizations. Mortality included both cardiovascular and non-cardiovascular mortality. Cardiovascular events included non-fatal myocardial infarction, stroke, and coronary and carotid revascularization. Hospitalizations referred to the total number of cardiac-related or any-cause hospital admissions in the follow-up period. Secondary outcomes were medication adherence, blood pressure control, and lipid management.
Publications were excluded if they were not randomized, did not have adequate description of the pharmacist's intervention, did not directly apply to patients with CHD, were not conducted on patients all with CHD, or if they did not report the targeted outcomes. Disagreements were resolved by discussion.

Data extraction and risk of bias assessment
Data extraction was independently performed by 2 authors (HX and YH) using a standardized data extraction form. Details about study design, participants, interventions, outcomes, risk of bias data and results were extracted. Risk of bias tools were applied as described in the Cochrane Handbook for Systematic Reviews of Intervention [13]. Factors that were considered included the following: the quality of random sequence generation and allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias) and other bias (e.g. extreme baseline imbalance, fraudulence etc.). For each item, the quality characteristics of each study were rated as (1) low risk of bias; (2) unclear; and (3) high risk of bias.

Description of studies and types of interventions
The interventions delivered by pharmacists included (1) patient education (defined as education or counseling about therapy, medication compliance, lifestyle, social support etc.) in five studies [14][15][16][17][18]; (2) medication management (defined as medication review from medical records or patient interview; providing tools to improve medication compliance; assessment of medication compliance; monitoring of medication therapy such as assessment, adjustment, change of medications etc.) in five studies [14][15][16][17][18]; (3) feedback to health care professionals in three studies [14,15,18]; and (4) disease management (defined as assessment of targets for medication therapy such as blood pressure and lipid, and lifestyle such as smoking, obesity etc.) in four studies [15][16][17][18].

Methodological quality of included studies
The studies were of variable methodological quality. Three studies provided evidence of adequate random sequence generation [14,16,17] and only two studies reported adequate concealment [14,15]. Because of the nature of the interventions, none of the studies blinded study participants to the pharmacist intervention, but two studies provided evidence of blinding assessment of outcome data [14,15]. High risks of bias existed in selection, performance and detection in the cluster RCT study [18].

Primary outcomes Mortality, cardiac events, and hospitalizations
Only one study reported all-cause mortality, the occurrence of fatal/nonfatal coronary events (acute MI, PCI, and CABG), and any-cause hospitalization as a secondary outcome of that study [17]. The study demonstrated that there was no difference in all-cause mortality, coronary events, or any-cause hospitalization between pharmacist care and the control group.

Secondary outcomes Medication adherence
All the five studies reported about medication adherence. Methods of medication adherence assessment and main outcomes of each study are shown in Table 2. Medication adherence was assessed by prescription in five studies [14,[16][17][18], by patient self-reported in two studies [14,15], and by pill and package count in one study [16]. Adherence to aspirin and β-blocker were reported in two studies [14,15], lipid-lowering drug in five studies [14][15][16][17][18], and an ACE inhibitor in one study [15]. None of the studies demonstrated a statistically significant difference between pharmacist care and control in adherence to aspirin and an ACE inhibitor. Medication adherence was significantly increased in the intervention group than in the control group, for a β-blocker in one study [14], and for lipidlowering drug in two studies [16,18].

Blood pressure (BP) control
Two studies reported the number of patients who achieved BP control target values [15,17]. One study demonstrated a statistically significant increase in BP control rate for pharmacist care compared with control [17] (Table 3).

Lipid management
Three studies reported the number of patients who achieved low-density lipoprotein cholesterol (LDL-C) control target levels [16][17][18]. Two studies demonstrated a statistically significant increase in LDL-C control rate for pharmacist care compared with control [16,18] (Table 3).
Two studies reported changes in lipid profiles in accordance with certain previous studies [16,18] and both of these studies reported a greater reduction in LDL-C levels with pharmacist care compared to controls.

Discussion
Our systematic review, identified five RCTs (2568 patients) assessing the effects of pharmacist care in the secondary prevention of CHD. The 'dose', 'duration',  method and outcome of pharmacist intervention varied across the studies. Our study did not show any survival benefits, or reduction in cardiac events and hospitalizations from pharmacist care in patients with CHD. However, it shows that the pharmacist can help to improve medication adherence, blood pressure and lipid control. This review did not confirm the benefits of pharmacist intervention on mortality and morbidity of CHD. There are two possible explanations. First, as there are only a few trials available, with insufficient numbers of participants, there may not be adequate statistical power to detect clinical differences. Only one study used 'hard endpoints' (such as mortality, cardiac events and hospitalizations) as secondary outcomes of the study, and the sample size was not estimated based on these [17]. Second, the design of this study was quite different from the others, where all of the patients received a disease management program from a clinical pharmacy specialist and had achieved target cholesterol values before randomization. The aim of this study was to evaluate whether patients with CHD discharged from the management program could maintain their lipid profile levels. Thus, even patients in the control group also received intensive pharmacist care before the study. Unfortunately, we could not find any other study comparing the pharmacist care to the 'real' usual care for mortality, cardiac events and hospitalizations of patients with CHD. Further research is needed regarding the contribution of pharmacist care on mortality and morbidity of CHD.
Although there are no reports on the benefits of pharmacist intervention in mortality and morbidity of CHD, this review details the potential benefits of pharmacists on CHD care processes. Pharmacist care showed positive effects on medication adherence [14,16,18], blood pressure control [17] and lipid management [16,18]. Since medication nonadherence is associated with an increased  rate of subsequent cardiovascular events and mortality [6][7][8][9][10], improvements in medication adherence will lead to clinically important reductions in recurrent myocardial infarctions and death.

Conclusion
Due to the unavailability of data and the limited number of the studies, we could not carry out a quantitative meta-analysis. However, through qualitative analysis of the available data, we were able to evaluate the impact of pharmacist care on patients with CHD. However, the hypothesis that pharmacist care is beneficial for CHD care, with respect to mortality and morbidity, should be verified.