REVIEW ARTICLE. Pharmacist Care of Patients With Heart Failure

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1 REVIEW ARTICLE Pharmacist Care of Patients With Heart Failure A Systematic Review of Randomized Trials Sheri L. Koshman, BScPharm, PharmD, ACPR; Theresa L. Charrois, BSc(Pharm), MSc; Scot H. Simpson, BSP, PharmD, MSc; Finlay A. McAlister, MD, MSc, FRCPC; Ross T. Tsuyuki, BSc(Pharm), PharmD, MSc, FCSHP Background: While the role of multidisciplinary teams in the treatment of patients with heart failure (HF) is well established, there is less evidence to characterize the role of individual team members. To clarify the role of pharmacists in the care of patients with HF, we performed a systematic review evaluating the effect of pharmacist care on patient outcomes in HF. Methods: We searched PubMed, MEDLINE, EMBASE, International Pharmaceutical Abstracts, Web of Science, Scopus, Dissertation Abstracts, CINAHL, Pascal, and Cochrane Central Register of Controlled Trials for controlled studies from database inception to August. We included randomized controlled trials that evaluated the impact of pharmacist care activities on patients with HF (in both inpatient and outpatient settings). Summary odds ratios (s) with 95% confidence intervals (CIs) were calculated using a random-effects model for rates of allcause hospitalization, HF hospitalization, and mortality. Results: A total of 12 randomized controlled trials (2060 patients) were identified. Extent of pharmacist involvement varied among studies, and each study intervention was categorized as pharmacist-directed care or pharmacist collaborative care using a priori definitions and feedback from primary study authors. Pharmacist care was associated with significant reductions in the rate of all-cause hospitalizations (11 studies [2026 patients]) (, 0.71; 95% CI, ) and HF hospitalizations (11 studies [1977 patients]) (, 0.69; 95% CI, ), and a nonsignificant reduction in mortality (12 studies [2060 patients]) (, 0.84; 95% CI, ). Pharmacist collaborative care led to greater reductions in the rate of HF hospitalizations (, 0.42; 95% CI, ) than pharmacist-directed care (, 0.89; 95% CI, ). Conclusions: Pharmacist care in the treatment of patients with HF greatly reduces the risk of all-cause and HF hospitalizations. Since hospitalizations associated with HF are a major public health problem, the incorporation of pharmacists into HF care teams should be strongly considered. Arch Intern Med. 2008;168(7): Author Affiliations: Division of Cardiology, Faculty of Medicine and Dentistry (Drs Koshman and Tsuyuki and Ms Charrois), Faculty of Pharmacy and Pharmaceutical Sciences (Ms Charrois and Drs Simpson and Tsuyuki), and Division of General Internal Medicine, Faculty of Medicine and Dentistry (Dr McAlister), University of Alberta, Edmonton, Canada. HEART FAILURE (HF) IS ASsociated with significant morbidity and mortality. 1 Although the global burden of illness attributed to HF is already high, it is expected to continue to rise, given increased survival rates after acute myocardial infarction and an aging population. 1 Despite dramatic improvements in treatment over the last decade, a diagnosis of HF still portends a poor prognosis. 1 Mortality rates have changed little, and within 1 year of initial hospitalization for HF, up to 50% of patients will be rehospitalized and up to 40% will die. 2 To a large extent, HF is a medically managed disease. Medications such as angiotensin-converting enzyme inhibitors and blockers are well established in the treatment of HF, reducing mortality and hospitalizations. 3 However, despite pharmacotherapy, outcomes for patients with HF remain poor owing to the underuse of these agents. 4 Therefore, there has been an increasing focus on alternative models of care for these patients. Two recent systematic reviews demonstrated that multidisciplinary strategies for the management of HF reduce all-cause mortality, all-cause hospitalizations, and HF hospitalizations. 5,6 Although both reviews included some studies with pharmacist involvement, many HF clinics do not have a pharmacist team member, and the specific contribution of pharmacists within these multidisciplinary interventions was difficult to isolate owing to a paucity of detail in the published reports. Therefore, we conducted a systematic review to evaluate the impact of pharmacist care on the management of patients with HF and, in particular, contacted the primary study authors of multidisciplinary intervention trials that incorporated a pharmacist in an attempt to define the precise role of the pharmacist in these interventions. 687

2 3115 Unique citations identified and screened 2997 Articles excluded after review of title and abstract 118 Full articles retrieved for more detailed evaluation 103 Articles excluded with reason 81 Not RCT 10 Not desired population 3 Inadequate pharmacist services 3 No outcomes of interest 6 Other 12 Articles included in meta-analysis 7 Pharmacist-directed care 5 Pharmacist collaborative care Figure 1. Flow diagram of studies assessed and included in meta-analysis. RCT indicates randomized controlled trial. METHODS DATA SOURCES We searched, with assistance from a librarian, the following electronic databases from their inception until August : PubMed, MEDLINE, EMBASE, International Pharmaceutical Abstracts, Web of Science, Scopus, Dissertation Abstracts, CINAHL, PASCAL, and the Cochrane Central Register of Controlled Trials. Language restrictions were not applied. Search items included pharmacy-related terms (pharmacist, pharmaceutical care, pharmaceutical services, clinical pharmacy services, hospital pharmacy, community pharmacy, and pharmacy) and HF-related terms (heart failure, congestive heart failure, heart disease, cardiomyopathy, and ventricular dysfunction). Also, bibliographies of identified studies were hand searched. STUDY SELECTION Two of us (S.L.K. and T.L.C.) independently screened the citations from the literature search for eligibility. Studies were included if they tested (in randomized controlled trials) the impact of pharmacist care on patients with HF (compared with no pharmacist care) on the outcomes of all-cause hospitalizations, HF hospitalizations, and all-cause mortality. Secondary outcomes included healthrelated quality-of-life measures and medication adherence. We contacted all primary study authors and asked them to fill out a standardized questionnaire to better define the role that the pharmacist played in each multidisciplinary team and to verify outcome definitions and published results. Publications were excluded if they were not randomized, if they did not have adequate description of the pharmacist s intervention and the author could not be contacted, or if they did not report the outcomes of interest. Disagreements were resolved by consensus. Based on information provided in the article or from corresponding author responses to our questionnaire, we classified pharmacist interventions using a priori defined categories: pharmacistdirected care (pharmacist-initiated and managed intervention) or pharmacist collaborative care (member of a multidisciplinary team). DATA EXTRACTION AND QUALITY ASSESSMENT Data extraction was performed by 2 of us (S.L.K. and T.L.C.) independently using a standardized data collection form. Outcomes from individual studies were assigned according to the intention-totreat principle. We documented allcause hospitalizations and HF hospitalizations according to the definitions used by the authors of the individual studies. Hospitalization rates (all-cause or HF) were defined as the number of patients in each group who were hospitalized at least once for that diagnosis (only the first hospitalization was counted for patients with multiple hospitalizations). Randomized controlled trials were assessed for quality using the Jadad score and evaluated as to whether allocation concealment was adequately described. 7 DATA ANALYSIS Data analysis was performed using Cochrane Review Manager software (RevMan 4.2.7; Nordic Cochrane Centre, Copenhagen, Denmark). A random-effects model was used to estimate the pooled odds ratios (s) and 95% confidence intervals (CIs) for rates of HF hospitalizations, all-cause hospitalizations, and mortality. Heterogeneity between studies was evaluated using the Higgins I 2 test. Data for secondary outcomes are reported descriptively, and, where possible, pooled s (random-effects model) and weighted mean differences were calculated. Sensitivity analyses were defined a priori to include analysis based on quality of studies (determined according to Jadad scores) and type of pharmacist intervention (pharmacist-directed vs collaborative care). Two approaches were used to identify potential sources of heterogeneity. First, an indirect comparison of pharmacistdirected care vs pharmacist collaborative care was done using the method of Song et al. 8 Second, we used the process described by Tobias 9 to assess the influence of a single study on pooled results. RESULTS DESCRIPTION OF STUDIES AND TYPES OF INTERVENTIONS Of the 3115 citations identified in our search, 12 randomized controlled trials (RCTs) (2060 patients) met the eligibility criteria for our analysis (Figure 1 and Table 1). All primary study investigators were contacted to clarify the published data, and 11 of 12 provided further data. Based on information from the articles and corresponding authors, we determined that 7 studies compared pharmacist-directed interventions with usual care, and 5 studies compared pharmacist collaborative care with usual care Details about study settings, patient demographics, intervention frequency, end point ascertainment, and usual care for each trial are provided in Table 1. The pharmacist-specific interventions in these studies typically involved education on both HF and evidencebased HF medications, including selfmonitoring, medication management, and facilitation of compliance. Details on the specific educational interventions offered by the pharmacists (as reported by each of the primary study authors) are also provided in Table 1. ROLE OF THE PHARMACIST Eleven of the 12 trial authors responded to our survey to define the exact role of the pharmacist in each multidisciplinary team. Seven trialists identified the pharmacist as the key driver of the intervention (pharmacist-directed care), with their responsibilities including medication and HF education, self-monitoring, recommendations to physicians, and adherence aids (Table 1) Four trialists identified the pharmacist as one of the members of the multidisciplinary team (pharmacist collaborative care). 17,18,20,21 We received no response from 1 study author; however, 688

3 Table 1. Key Features of Included Studies Source Varma et al, 10 Bouvy et al, Tsuyuki et al, Sadik et al, Holland et al, 14 López Cabezas, Murray et al, 16 Stewart et al, Gattis et al, 18 Rainville, 19 Gwardy-Sridhar et al, Triller and Hamilton, 21 Study Design (Jadad Score 7 ) Sample Size Study Population (Country) RCT (2) 83 Patients aged 65 y with heart failure who either were hospitalized or attended an outpatient clinic; the majority were in NYHA class II (Northern Ireland) RCT (3) 152 Patients with HF using loop diuretics; the majority were in NYHA class II/III (the Netherlands) RCT (3) 276 Patients hospitalized with HF; the majority were in NYHA class II (Canada) RCT (2) 208 Patients with HF; the majority were in NYHA class II (United Arab Emirates) RCT (3) 293 Patients admitted to the ED with HF as an ongoing condition; the majority were in NYHA III class (United Kingdom) RCT (2) 134 Patients hospitalized for HF, the majority were in NYHA class I-II (Spain) RCT (3) 314 Patients with HF from a single primary care group practice; the majority were in NYHA II class (United States) RCT (1) 97 Patients discharged from hospital with HF and high-risk clinical features for readmission; the majority were in NYHA class II (Australia) RCT (2) 181 Patients with HF being evaluated in a cardiology clinic; the majority were in NYHA class II (United States) RCT (1) 34 Patients aged 50 y discharged from hospital with HF; the majority were in NYHA class III (United States) RCT (2) 134 Patients admitted to hospital with HF and an LVEF of 40%; the majority had an LVEF of 20% (Canada) RCT (1) 154 Patients discharged from hospital with a primary or secondary diagnosis of HF and receiving home care (United States) Mean Age of Patients, y Key Components of Pharmacist Intervention (Setting) Pharmacist Directed 76 Med recommendations, HF Med education, self-monitoring, liaison with GP or community pharmacist, written information (outpatient clinic) 70 Med education, compliance assessment, liaison with GP (community pharmacy) 72 Patient support program, including HF Med education, self-monitoring, Med organizer, Med recommendations, written information (outpatient clinic) 58 Med recommendations, HF Med education, self-monitoring, written information (outpatient clinic) 77 HF Med education, adherence aid, diary, Med recommendations (home visit) 76 HF diet and Med education (in hospital) 62 Med history, Med education, assessment of Med compliance (outpatient clinic) Pharmacist Collaborative Care With HF Team 75 Med compliance assessment, Med organizer, Med education, referral to community pharmacist (home visit) Team members: nurse 67 Med recommendations, education on Med (outpatient clinic) Team members: physician, nurse, social worker, nutritionist, and physical therapist 70 Med recommendations, HF Med education, Med organizer, self-monitoring (in-hospital and telephone follow-up) Team members: nurse and physician 66 HF Med education, written and audio video information (in hospital) Team members: nurse or educator 80 Med assessment, Med recommendations, Med education (home visit) Team members: nurse Usual Care Description No counseling, no education, no self-monitoring, no liaison with GP or community pharmacist No structured interview, no follow-up General heart disease pamphlet provided No counseling, no education, no self-monitoring No counseling, no education, no home visit No counseling, no education Regular pharmacy dispensing services, no education materials Preexisting postdischarge care, regular home support if needed No Med recommendation, followed by physician, physician assistant, or nurse practitioner Nurse review of diet plan and Med, computerized Med sheets Received written and audio video information, no pharmacist education No description End Point Measurement (Intervention Frequency) 12 mo (every 3 mo) 6 mo (every mo) 6mo(2and4wk, then every mo) 12 mo (every 3 mo) 6mo(2and 6-8 wk) 12 mo (2, 6, and 12 mo) 12 mo (at prescription refills 9 mo) 6mo(1wk) 6 mo (2, 12, and 24 wk) 12 mo (3, 7, 30, 90, and 365 d) 12 mo (2 d) 6 mo (1, 2, and 3 wk) Abbreviations: ED, emergency department; GP, general practitioner; HF, heart failure; LVEF, left ventricular ejection fraction; Med, medication; NYHA, New York Heart Association; RCT, randomized controlled trial. 689

4 Study or Subcategory Mortality, No./Total No. Treatment Control Weight, % Pharmacist-directed care Varma et al, 10 7/42 Bouvy et al, /74 Tsuyuki et al, /140 Sadik et al, /104 López Cabezas et al, /70 Holland et al, 14 30/149 Murray et al, 16 9/ Total events: 83 (treatment), 90 (control) Test for heterogeneity: χ2 = 8.37 (P =.21), I 2 = 28.3% 6 Test for overall effect: Z = 0.38 (P =.70) 7/41 16/78 12/136 2/104 19/64 24/144 10/ ( ) 0.61 ( ) 1.33 ( ) 1.00 ( ) 0.35 ( ) 1.26 ( ) 1.45 ( ) 0.92 ( ) Pharmacist collaborative care Stewart et al, /49 Gattis et al, 18 3/90 Rainville, 19 1/17 Gwadry-Sridhar et al, /67 Triller and Hamilton, 21 17/ Total events: 34 (treatment), 46 (control) Test for heterogeneity: χ2 4 = 4.34 (P =.36), I 2 = 7.9% Test for overall effect: Z = 1.37 (P =.17) 12/48 5/91 4/17 11/67 14/ ( ) 0.59 ( ) 0.20 ( ) 0.59 ( ) 1.28 ( ) 0.69 ( ) Total Total events: 117 (treatment), 136 (control) Test for heterogeneity: χ 2 = (P =.25), I 2 = 19.3% 11 Test for overall effect: Z = 1.10 (P =.27) ( ) Favors Treatment Favors Control Figure 2. Forest plot of total mortality. CI indicates confidence interval;, odds ratio (random-effects model). Study or Subcategory Hospitalization Rate, No./Total No. Treatment Control Weight, % Pharmacist-directed care Varma et al, 10 14/42 Bouvy et al, /74 Tsuyuki et al, /140 Sadik et al, /104 López Cabezas et al, /70 Holland et al, 14 76/149 Murray et al, 16 45/ Total events: 253 (treatment), 310 (control) Test for heterogeneity: χ2 = (P =.03), I 2 = 56.3% 6 Test for overall effect: Z = 1.49 (P =.14) 27/41 13/78 51/136 29/104 31/64 73/144 86/ ( ) 1.38 ( ) 1.21 ( ) 0.62 ( ) 0.52 ( ) 1.01 ( ) 0.72 ( ) 0.77 ( ) Pharmacist collaborative care Stewart et al, /49 Gattis et al, 18 8/90 Gwadry-Sridhar et al, /67 Triller and Hamilton, 21 42/ Total events: 110 (treatment), 139 (control) Test for heterogeneity: χ2 3 = 4.57 (P =.21), I 2 = 34.4% Test for overall effect: Z = 2.17 (P =.03) 31/48 23/91 40/67 45/ ( ) 0.29 ( ) 0.78 ( ) 0.85 ( ) 0.60 ( ) Total Total events: 363 (treatment), 449 (control) Test for heterogeneity: χ 2 = (P =.03), I 2 = 49.6% 10 Test for overall effect: Z = 2.43 (P =.02) ( ) Favors Treatment Favors Control Figure 3. Forest plot of all-cause hospitalization rate. CI indicates confidence interval;, odds ratio (random-effects model). it was clear from the article that the pharmacist worked in conjunction with a clinical nurse specialist and was therefore identified as providing collaborative care. 19 METHODOLOGICAL QUALITY OF INCLUDED STUDIES The studies were of variable methodological quality. Because of the nature of the interventions, none of the studies was double-blind. Only 6 of the 12 RCTs adequately described allocation concealment. 12,14-17,20 Jadad scores are listed in Table

5 Study or Subcategory Hospitalization Rate, No./Total No. Treatment Control Weight, % Pharmacist-directed care Bouvy et al, /74 Tsuyuki et al, /140 Sadik et al, /104 López Cabezas et al, /70 Holland et al, 14 33/149 Murray et al, 16 11/ Total events: 127 (treatment), 143 (control) Test for heterogeneity: χ2 5 = 4.80 (P =.44), I 2 = 0% Test for overall effect: Z = 0.82 (P =.41) 10/78 38/136 26/104 22/64 26/144 21/ ( ) 0.93 ( ) 0.59 ( ) 0.61 ( ) 1.29 ( ) 0.81 ( ) 0.89 ( ) Pharmacist collaborative care Stewart et al, /49 Gattis et al, 18 1/90 Rainville, 19 4/17 Gwadry-Sridhar et al, /67 Triller and Hamilton, 21 32/ Total events: 56 (treatment), 95 (control) Test for heterogeneity: χ2 4 = 5.86 (P =.21), I 2 = 31.7% Test for overall effect: Z = 3.03 (P =.002) 18/48 11/91 10/17 17/67 39/ ( ) 0.08 ( ) 0.22 ( ) 0.34 ( ) 0.69 ( ) 0.42 ( ) Total Total events: 183 (treatment), 238 (control) Test for heterogeneity: χ 2 10= (P =.08), I 2 = 40.1% Test for overall effect: Z = 2.32 (P =.02) ( ) Favors Treatment Favors Control Figure 4. Forest plot of heart failure hospitalization rate. CI indicates confidence interval;, odds ratio (random-effects model). PRIMARY OUTCOMES Mortality All 12 RCTs (2060 patients) reported all-cause mortality (Figure 2). One study 15 showed a significant difference in all-cause mortality between intervention and control. The pooled estimate of the 12 RCTs showed a nonsignificant reduction in mortality for pharmacist care compared with control (, 0.84; 95% CI, ; I 2, 19%). All-Cause Hospitalization Rates Eleven RCTs (2026 patients) reported all-cause hospitalization rates (ie, the number of patients hospitalized at least once). The pooled for all-cause hospitalization rates demonstrated a significant benefit of pharmacist care (, 0.71; 95% CI, ) (Figure 3). There was, however, heterogeneity in these results (I 2, 50%). HF Hospitalization Rates Of the 11 RCTs (1977 patients) reporting HF hospitalization rates, 3 demonstrated statistically significant reductions with pharmacist care, and the pooled-effect estimate revealed a significant benefit with pharmacist care (, 0.69; 95% CI, ) (Figure 4). There was alsosomeheterogeneityintheseresults (I 2, 40%). SECONDARY END POINTS Health-related quality-of-life data are presented in Table 2. Healthrelated quality of life was measured in 7 studies; 6 studies used diseasespecific measures, 10,11,13,14,16,20 and 5 studies used generic measures. 11,13-15,20 The way in which data were reported and the small number of studies using health-related quality of life precluded pooling of data. Adherence was measured as an outcome in 7 studies (Table 3) ,15,16,20 Methods for measuring adherence varied substantially among studies. Of the 3 studies that collected adherence data using community pharmacy refill records, 10,12,20 only 1 found significant differences (favoring the intervention) between study groups. 10 However, this study had adherence data available for only 28% of the total study population. Of the 3 studies that reported adherence using patient selfreport, 10,13,16 1 reported significant differences (favoring intervention). 13 Two studies used an electronic monitoring system to measure adherence, and both studies demonstrated that patients in the control group had lower adherence. 11,16 SENSITIVITY ANALYSES Indirect Comparison of Pharmacist-Directed Care and Collaborative Care The indirect comparisons of pharmacist-directed interventions and collaborative pharmacist care showed no significant difference between the 2 types of intervention in their effects on mortality or rate of all-cause hospitalizations (P=.40 and P=.40, respectively). In terms of HF hospitalization rates, the effects of these interventions were significantly different, with pharmacist collaborative care being associated with a greater risk reduction (P=.02). Assessing Influence of Single Studies on Primary End Points Using the method defined by Tobias, 9 we looked at each primary end point to determine whether re- 691

6 Table 2. Summary of Reported Health-Related Quality-of-Life (HRQL) Measures in Included Studies Source HRQL Measure Used Outcome Bouvy et al, MLHF Both groups improved No difference between groups COOP/WONCA Intervention worsened and control improved Significant difference between groups in favor of control Gwadry-Sridhar et al, moval of any 1 study would dramatically affect the results. The pooled did not change more than 8% after removal of each study for the end points of HF hospitalizations and allcause hospitalizations. For mortality, the removal of the study by López Cabezas et al 15 increased the by 15%; however, the result was still nonsignificant (P=.75). Study Quality MLHF The results for the sensitivity analyses based on study quality are presented in Table 4. Only 4 studies (n=1035) had Jadad scores that were higher than 3. 11,12,14,16 The studies with Jadad scores that were lower than 2 had consistently more positive results than studies with Jadad scores that were higher than 3. In terms of allocation concealment, the results were similar when studies with adequate allocation concealment were compared with those with inadequate allocation concealment for the outcomes of all-cause hospitalizations and mortality. Both groups improved Significant difference between groups in favor of intervention SF-36 Sadik et al, MLHF Significant difference between groups in favor of intervention SF-36 Significant difference between groups in favor of intervention in 6 of 8 domains Varma et al, 10 López Cabezas, Holland et al, 14 Murray et al, 16 MLHF EQ-5D MLHF EQ-5D Chronic HF Questionnaire Both groups improved Intervention improved and control worsened Intervention worsened and control improved Intervention had no change and control worsened Both groups improved Abbreviations: COOP/WONCA, Dartmouth Primary Care Cooperative Research Network/World Organization of National Colleges, Academies and Academic Associations of General Practitioners/Family Physicians; EQ-5D, EuroQoL-5 Dimensions form; HF, heart failure; MLHF, Minnesota Living With Heart Failure questionnaire; SF-36, 36-Item Short-Form Health Survey. COMMENT This systematic review confirms the benefits of pharmacist care in reducing hospitalization in patients with HF. Interventions that include some element of pharmacist care reduced the rates of both all-cause hospitalization and HF hospitalization by almost one-third. Because HF is one of the leading causes of hospitalization, 22 we recommend the addition of a pharmacist to the HF team. Other studies have confirmed that a substantial proportion of HF exacerbations can be attributed to medication misadventures, highlighting the potential importance of pharmacists on the HF team. 23 These results are consistent with an earlier systematic review of multidisciplinary care in HF 5 but extends this earlier work by including data from 8 trials that were not included in the earlier review and by focusing specifically on the impact of the pharmacist within the setting of the multidisciplinary team (as defined by the primary authors of each of these trials). There are several plausible explanations for our findings of reductions in HF hospitalizations and allcause hospitalizations but no change in mortality. Given that the majority of events examined were hospitalizations and our sample size was relatively small, it is unlikely that we would be able to show a decrease in mortality as a result of low statistical power. Also, the duration of follow-up in these studies ranged from 2 days to 12 months, with the majority of follow-ups lasting only 6 months or less, likely too short to see an impact on mortality. Given the significant heterogeneity in many of the primary outcomes, we sought to determine the potential sources. First, we analyzed the data in predefined categories (pharmacist-directed care or pharmacist collaborative care). When these categories were compared, we found no difference in the type of intervention and outcomes for mortality and all-cause hospitalizations. For HF hospitalizations, pharmacist collaborative care did appear to be more beneficial than pharmacist-directed care. This finding is not surprising given that medication management and patient education would complement care given by nurses, physicians, and other health care professionals. Second, we compared the data using the method described by Tobias 9 to examine the influence of single studies on each outcome. No particular study influenced the pooled when taken out of the analysis. Finally, we evaluated results by study quality and, not surprisingly, found that lowerquality studies reported greater beneficial effects with the tested interventions. The Jadad score is well recognized for randomized controlled trials; however, it may not be the best for practice research, where blinding is not possible. In the absence of alternative quality scores, this sensitivity analysis should be interpreted as hypothesis generating only. There are a number of limitations that warrant discussion. There were notable differences in pharmacist activities between studies, making it difficult to define precisely which intervention provides the best outcomes (even after contact with 692

7 Table 3. Summary of Adherence and Compliance Measures in Included Studies Source Bouvy et al, Gwadry-Sridhar et al, Sadik et al, Tsuyuki et al, Varma et al, 10 López Cabezas, Murray et al, 16 Method of Measuring Adherence Medication event monitoring system (based on loop diuretic) Pharmacy refill records (cumulative medication acquisition) Self-reported Pharmacy refill records (based on ACE-Is) the primary study authors). There were also differences in terms of patient population and settings, which Results Intervention: 140/7656 d without use of diuretic Usual care: 337/6196 d without use of diuretic RR: 0.33 (95% CI, ) Noncompliance in intervention compared with control, RR : ACE-I/ARB: 0.78 ( ) -Blocker: 0.89 ( ) Digoxin: 0.79 ( ) Diuretic: 1.02 ( ) No. of patients who reported compliance with prescribed medications was significantly higher in control than in intervention (P.05) Intervention: 83.5% adherence Usual care: 86.2% adherence (P=.70) Pharmacy refill records Intervention: 10 patients were compliant; 3 were noncompliant Usual care: 3 patients were compliant; 7 patients were noncompliant (P=.04) Self-reported Intervention: at 12 mo, patients reported that they never skipped a dose or took an extra dose Usual care: at 12 mo, 1 patient reported omitting a dose on a daily basis Tablet counts Reliable (95%-100% of prescribed doses) at 12 mo Control: 73.9% Intervention: 85% Difference: NS Medication event monitoring system Self-reported Intervention period Intervention: 78.8% of doses taken Control: 67.9% of doses taken Difference: 10.9% (95% CI, 5.0%-16.7%) Postintervention period Intervention: 70.6% of doses taken Control: 66.7% of doses taken Difference: 3.9% (95% CI, 2.8% to 10.7%) No difference between groups Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CI, confidence interval; NS, nonsignificant; RR, relative risk Table 4. Sensitivity Analysis Based on Study Quality Outcome Based on Jadad Score 7 Mortality Score 2: 0.65 ( ) Score 3: 1.13 ( ) All-cause hospitalizations Score 2: 0.55 ( ) Score 3: 0.99 ( ) Heart failure hospitalizations Score 2: 0.52 ( ) Score 3: 1.05 ( ) Odds Ratio (95% Confidence Interval) Based on Allocation Concealment Inadequate: 0.87 ( ) Adequate: 0.82 ( ) Inadequate: 0.58 ( ) Adequate: 0.82 ( ) Inadequate: 0.59 ( ) Adequate: 0.80 ( ) included both hospitalized patients and ambulatory patients, making it difficult to elucidate which patient population would most likely benefit. It is also likely that there were different cointerventions across the studies that could not be accounted for. In addition to contributing to the current body of literature supporting the beneficial effects of multidisciplinary teams in the treatment of patients with HF, our findings further describe the beneficial role of the pharmacist in the treatment of patients with HF. Because HF results in more than hospitalizations each year in the United States, a 30% reduction would have a substantial impact. 24 From our results, we can infer that including a pharmacist in the care of patients with HF, particularly within a multidisciplinary team, is beneficial and should be strongly considered by health policy makers. Accepted for Publication: November 2,. Correspondence: Ross T. Tsuyuki, BSc(Pharm), PharmD, MSc, FCSHP, Division of Cardiology, EPICE Centre/COMPRIS, University of Alberta, 220 College Plaza, St NW, Edmonton, AB T6G 2C8 Canada (ross.tsuyuki@ualberta.ca). Author Contributions: Dr Koshman and Ms Charrois had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Koshman, Charrois, Simpson, McAlister, and Tsuyuki. Acquisition of data: Koshman and Charrois. Analysis and interpretation of data: Koshman, Charrois, Simpson, McAlister, and Tsuyuki. Drafting of the manuscript: Koshman and Charrois. Critical revision of the manuscript for important intellectual content: Simpson, McAlister, and Tsuyuki. Statistical analysis: Charrois, Simpson, and McAlister. Obtained funding: Tsuyuki. Administrative, technical, and material support: Koshman, Charrois, and Tsuyuki. Study supervision: McAlister and Tsuyuki. Financial Disclosure: None reported. Funding/Support: This study was supported by COMPRIS (Centre for Community Pharmacy Research and 693

8 Interdisciplinary Studies), http: // /index.html. Previous Presentations: This study was presented in part at the Canadian Cardiovascular Congress; October 23, 2006; Vancouver, British Columbia, Canada; and at Cardiac Sciences Research Day; June 9, 2006; University of Alberta, Edmonton, Canada. Additional Contributions: We thank the following authors of primary studies who answered our requests for further information: Marcel Bouvy, PhD; Miriam Fradette, BSc (Pharm); Wendy Gattis-Stough, PharmD; Femida Gwadry-Sridhar, PhD; Adel Sadik, PhD; Simon Stewart, PhD; Darren Triller, PharmD; Sam Varma, PhD; Carmen López Cabezas, PhD; Richard Holland, PhD; and Michael Murray, MPH. We also thank Ben Vandermeer for statistical assistance and our librarian, Marlene Dorgan. REFERENCES 1. The growing burden of heart disease and stroke in Canada. Heart and Stroke Foundation of Canada Web site. _En03.pdf. Accessed August 2,. 2. Howlett JG, Johnstone DE, Sketris I, et al. Identifying opportunities to address the congestive heart failure burden: the Improving Cardiovascular Outcomes in Nova Scotia (ICONS) study. Can J Cardiol. 2003;19(4): Arnold JM, Howlett JG, Dorian P, et al. Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update : prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Can J Cardiol. ;23(1): Bungard TJ, McAlister FA, Johnson JA, Tsuyuki RT. Underutilisation of ACE inhibitors in patients with congestive heart failure. Drugs. 2001;61 (14): McAlister FA, Stewart S, Ferrua S, McMurray JJ. Multidisciplinary strategies for the management of heart failure patients at high risk for admission: a systematic review of randomized trials. J Am Coll Cardiol. 2004;44(4): Holland R, Battersby J, Harvey I, Lenaghan E, Smith J, Hay L. Systematic review of multidisciplinary interventions in heart failure. Heart. 2005;91 (7): Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996; 17(1): Song F, Altman DG, Glenny AM, Deeks JJ. Validity of indirect comparison for estimating efficacy of competing interventions: empirical evidence from published meta-analyses. BMJ. 2003;326 (7387): Tobias A. Assessing the influence of a single study in the meta-analysis estimate. Stata Tech Bull. ;47: Varma S, McElnay JC, Hughes CM, Passmore AP, Varma M. Pharmaceutical care of patients with congestive heart failure: interventions and outcomes. Pharmacotherapy. ;19(7): Bouvy ML, Heerdink ER, Urquhart J, Grobbee DE, Hoes AW, Leufkens HG. Effect of a pharmacistled intervention on diuretic compliance in heart failure patients: a randomized controlled trial. J Card Fail. 2003;9(5): Tsuyuki RT, Fradette M, Johnson JA, et al. A multicenter disease management program for hospitalized patients with heart failure. J Card Fail. 2004;10(6): Sadik A, Yousif M, McElnay JC. Pharmaceutical care of patients with heart failure. BrJClin Pharmacol. 2005;60(2): Holland R, Brooksby I, Lenaghan E, et al. Effectiveness of visits from community pharmacists for patients with heart failure: HeartMed randomised controlled trial. BMJ. ;334(7603): López Cabezas C, Falces Salvador C, Cubi Quadrada D, et al. Randomized clinical trial of a postdischarge pharmaceutical care program vs regular follow-up in patients with heart failure. Farm Hosp. 2006;30(6): Murray MD, Young J, Hoke S, et al. Pharmacist intervention to improve medication adherence in heart failure: a randomized trial. Ann Intern Med. ;146(10): Stewart S, Pearson S, Horowitz JD. Effects of a homebased intervention among patients with congestive heart failure discharged from acute hospital care. Arch Intern Med. 1998;158(10): Gattis WA, Hasselblad V, Whellan DJ, O Connor CM. Reduction in heart failure events by the addition of a clinical pharmacist to the heart failure management team: results of the Pharmacist in Heart Failure Assessment Recommendation and Monitoring (PHARM). Arch Intern Med. ; 159(16): Rainville EC. Impact of pharmacist interventions on hospital readmissions for heart failure. Am J Health Syst Pharm. ;56(13): Gwadry-Sridhar FH, Arnold JM, Zhang Y, Brown JE, Marchiori G, Guyatt G. Pilot study to determine the impact of a multidisciplinary educational intervention in patients hospitalized with heart failure. Am Heart J. 2005;150(5): Triller DM, Hamilton RA. Effect of pharmaceutical care on outcomes for patients with heart failure. Am J Health Syst Pharm. ;64(21): Tsuyuki RT, McKelvie RS, Arnold JM, et al. Acute precipitants of congestive heart failure exacerbations. Arch Intern Med. 2001;161(19): Tsuyuki RT, Shibata MC, Nilsson C, Hervas-Malo M. Contemporary burden of illness of congestive heart failure in Canada. Can J Cardiol. 2003; 19(4): Koelling TM, Chen RS, Lubwama RN, L Italien GJ, Eagle KA. The expanding national burden of heart failure in the US: the influence of heart failure in women. Am Heart J. 2004;147(1):