© The Author(s) 2024
Article reuse guidelines:sagepub.com/journals-permissionsDOI: 10.1177/17151635241249952
Heart failure with reduced ejection fraction is a chronic and progressive disease with high mortality and rehospitalization rates. We observed low adherence to guideline-directed medical therapy (GDMT) locally, leading us to develop an efficient yet effective tool to increase prescribing of GDMT.
L’insuffisance cardiaque à fraction d’éjection réduite est une maladie chronique et évolutive associée à des taux élevés de mortalité et de réhospitalisation. Nous avons observé localement une faible observance du traitement médical conforme aux lignes directrices (GDMT), ce qui nous a amenés à développer un outil à la fois efficace et efficient pour augmenter la prescription de GDMT.
Background: Heart failure with reduced ejection fraction (HFrEF) is a progressive disease with high rates of hospitalization and mortality. The Canadian Cardiovascular Society recommends treating patients with HFrEF with medications from 4 standard medication classes—this is known as guideline-directed medical therapy (GDMT). However, despite clear evidence and recommendations, GDMT agents are known to be underutilized in the HFrEF population.
Objective: To determine if the implementation of a prescriber-alert stewardship tool for hospitalized patients with HFrEF will increase the frequency of GDMT prescribing with all classes during hospitalization.
Methods: Utilization of GDMT in patients with HFrEF between admission and discharge pre- and post-implementation of a prescriber alert stewardship tool was compared. Patients admitted to a cardiology stepdown unit between January and April 2022 had a stewardship-alert tool placed on their chart for physician review, while those admitted during the same time frame 1 year prior did not.
Results: Following the use of a prescriber alert, there was a statistically significant increase in prescribing for β-blockers (38.1% to 95.2%; p < 0.001), mineralocorticoid receptor antagonists (9.5% to 66.7%; p < 0.001) and combination GDMT (9.5% to 52.4%; p = 0.004) from admission to discharge. A statistically significant increase in the prescribing of β-blockers (47.6% to 76.2%; p = 0.004) and angiotensin-converting enzyme inhibitors (21.4% to 40.5%; p = 0.008) was still observed without the use of the prescriber alert.
Conclusion: A pharmacist-led heart failure stewardship tool initiative increased uptake of GDMT in patients with HFrEF. Can Pharm J (Ott) 2024;157:181-189.
Heart failure is a progressive disease1 that affects more than 750,000 Canadians, with approximately 100,000 newly diagnosed patients each year.2 Patients with heart failure face a 50% mortality rate within 5 years of their diagnosis.3,4 Heart failure is the third most likely cause of hospitalization among Canadians, with estimates from the United States indicating 1 in 4 previously hospitalized patients will be rehospitalized within 30 days from their discharge.5,6 Each hospitalization for acute decompensated heart failure increases mortality in this already vulnerable population.7
Hospitalization of patients with heart failure serves as an opportunity to assess and optimize current medication regimens in this population. Fifty percent of patients admitted to hospital with heart failure have a reduced ejection fraction.8-10 Heart failure with reduced ejection fraction (HFrEF) is defined as a left ventricular ejection fraction of less than or equal to 40%.11 Per the 2021 Canadian Cardiovascular Society guidelines, patients with HFrEF, in the absence of contraindications, should be treated with a combination of 4 standard medication classes: angiotensin receptor neprilysin inhibitors (ARNIs), β-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and sodium glucose transport protein 2 inhibitors (SGLT2is).12 This is known as guideline-directed medical therapy (GDMT). If an ARNI is not available, an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) can be used as an alternative.12 Each medication class has a unique and complementary mechanism of action, with high-quality evidence for reducing cardiovascular mortality and heart failure hospitalization.11-18 The benefits of GDMT are cumulative and highest when the 4 agents are used in combination.8,11,19,20
It has been found that over 75% of patients not initiated on GDMT upon discharge continue to not be prescribed these medications within 1 year following hospital discharge.21-23 GDMT is estimated to prolong survival of patients with HFrEF for up to approximately 6 years when compared to conventional therapy (ACEi or ARB and BB) and clinical benefits of GDMT have been observed within just 30 days of initiation.18-20,24 Initiation and titration of each GDMT agent, either simultaneously or sequentially, is recommended to be completed as soon as possible after a diagnosis of HFrEF, with a goal of reaching target or maximally tolerated doses within 3 to 6 months after diagnosis.12
Despite high-quality evidence for GDMT in patients with HFrEF, it is not well utilized in practice, which may be contributing to high hospitalization and mortality rates among this patient population.11-18,25 The prospective observational CHAMP-HF trial evaluated the usage of combination HFrEF therapy including an ARNI or ACEi or ARB, BB and MRA and found that the highest documented absolute contraindication for all medications was less than 2%.25 Despite the low percentage of patients having a contraindication to GDMT, the study found that only 22% of eligible patients were prescribed a dose of each of the 3 therapies, and only 1% of patients were prescribed all 3 agents at target doses.25
Inspired by the CHAMP-HF trial, a local quality improvement chart audit of HFrEF discharges was completed in 2019 at a regional tertiary care centre by a member of this study team (R.M.J.), which demonstrated that only 23% of patients with HFrEF (28/120) were discharged on triple therapy of ARNI or ACEi or ARB, BB and MRA, despite explicit guideline recommendations indicating this combination as the standard of care at the time.11 As a result of the known gap in GDMT prescribing identified in the 2019 quality improvement project, the current study was designed to test the hypothesis that implementation of an HFrEF prescriber-alert stewardship tool would increase prescribing of GDMT during hospitalization and prior to discharge in relation to standard of care with no stewardship tool being used.
This study was designed as a single-centre, quantitative study that assessed change in HFrEF GDMT prescribing from hospital admission to discharge pre- and post-implementation of a prescriber-alert stewardship tool using retrospective data collection of patient outcomes (Appendix 1, available in Supplemental Materials). Prescribers providing care to patients between January and April 2022 comprised the post-stewardship tool group, whereas those providing care to patients between January and April 2021 were included in the pre-stewardship tool group. For inclusion in the study, patients had to be at least 19 years of age, be admitted to the cardiology stepdown unit, have documented HFrEF (a left ventricular ejection fraction of less than or equal to 40%) and be discharged within the above predefined time frames. As we were interested in evaluating the change in prescription of GDMT from admission to discharge within patients with HFrEF and due to the progressive nature of the disease and potential for changes to medication prescription between hospitalizations, all hospitalizations of patients were treated independently and included within the analysis. Each hospitalization was approached as a new opportunity to review the patient GDMT and to perform the heart failure stewardship initiative. Patients with incomplete discharges (e.g., patients who left against medical advice, died, were transferred to another hospital or were not yet discharged within the respective time frames) were excluded from this study. The stewardship tool initiative was implemented in January 2022 after approval by the Horizon Health Network Human Research Protection Program (File #101436).
The stewardship tool initiative proceeded as follows: on weekdays, a pharmacist member of the stewardship initiative team assessed each patient within the cardiology stepdown unit for inclusion eligibility, and a patient-specific stewardship tool was completed for those patients meeting eligibility criteria. The prescriber-alert stewardship tool was developed by pharmacist team members and reflects the 2021 Canadian Cardiovascular Society guidelines for HFrEF treatment. The stewardship tool noted the patient’s current HFrEF GDMT regimen in comparison to guideline recommendations to highlight gaps in their therapy and provided the prescriber an opportunity to cosign for pharmacy to help facilitate medication coverage. The tool did not make patient-specific recommendations or change previous medication orders and was reviewed by inpatient cardiologists prior to implementation to ensure it was comprehensive and easy to use (Appendix 1). If the stewardship tool was not addressed by a physician after 5 days, another stewardship tool was affixed to the patient chart. For physician-cosigned stewardship tools, an assessment was then completed by the pharmacist, which included identifying and documenting patient medication coverage (e.g., no medication coverage, private coverage, provincial coverage, etc.) and outlining patient-specific criteria that were required to have each agent covered, as applicable. The pharmacist would also identify if the patient already had coverage for agent-specific GDMT. Medication assessments were placed on the patient chart and documented electronically for physician review.
The primary end point of this study was to determine if there was an increase in the proportion of eligible patients with HFrEF being discharged on individual agents and combination GDMT (triple or quadruple therapy) in the post- compared to the pre-stewardship tool groups. Secondary end points included assessing the frequency of pharmacist consultations, noting potential barriers to prescribing GDMT such as medication access, identifying physician specialties prescribing GDMT and determining the proportion of patients with a documented reason for not starting GDMT (e.g., abnormal values for potassium, estimated glomerular filtration rate, systolic blood pressure and heart rate).
Descriptive statistics were reported for all patient demographics and outcomes. Continuous variables were described using mean and standard deviation, while categorical variables were described using frequencies and percentages. Patient characteristics were stratified by stewardship cohort and presented descriptively. The proportion of patients on a 3-agent therapy (pre-stewardship tool, past guidelines) or 4-agent therapy (stewardship tool, updated guidelines) were reported as a frequency and percentage. McNemar tests were used to assess a change in medication prescribing from admission to discharge for both the pre-stewardship tool and post-stewardship tool groups, and α = 0.05 was used for all analyses. Power analysis to estimate the sample size required for our McNemar analysis was performed using GPower (3.1.9.7) and indicated a sample size of 42 patients in both the pre-stewardship tool and post-stewardship tool cohorts (odds ratio = 3.45 [medium effect size], α = 0.05, power = 0.8, proportion of discordant pairs = 0.5, 1-tailed test). Statistical analysis was performed using IBM SPSS Statistics version 27.
In this study, 42 patients formed the pre-stewardship tool group, while 21 patients were included in the post-stewardship tool group. Baseline characteristics were consistent in both groups for age, ejection fraction, reason for admission and diabetes status (Table 1). A cardiologist was involved in patient care for 88% and 95% of admitted patients in the pre- and post-stewardship tool groups, respectively (Table 1). In the pre- and post-stewardship tool groups, the cardiologist was the physician making changes to GDMT 52% and 76% of the time, respectively, but was the discharging physician for only 14% and 24% of patients, respectively (Table 1).
In the pre-stewardship tool group, prescription rates at discharge varied by agent from as low as 7.1% for ARNI to as high as 76.2% for β-blockers (Figure 1). There was an increase in prescribing of β-blockers from admission to discharge (from 47.6% to 76.2%; p = 0.004; Figure 1). As ACEis and ARBs can be used in place of ARNI when not available, we also investigated a change in prescribing of these agents from admission to discharge. When looking at the use of these agents together, we did not observe a statistically significant change in prescription from admission to discharge (p = 0.344, Figure 1), but individually, we observed an increase in prescribing from admission (21.4%) to discharge (40.5%) for the ACEi in the pre-stewardship tool group (21.4% to 40.5%, p = 0.008). There was no statistically significant change in prescribing from admission to discharge for ARNI, ARB, MRA, SGLT2i or combination GDMT in the pre-stewardship tool group (p > 0.05 for all analyses; Figures 1 and 2).
In the post-stewardship tool group, β-blockers remained the agent with the highest rate of prescription at discharge (95.2%; Figure 1), with ARNI being the lowest individual agent prescribed (19%; Figure 1). There were increases in the rates of prescribing for β-blockers (p < 0.001; 38.1% to 95.2%), MRA (p < 0.001; 9.5% to 66.7%) and combination-GDMT (p = 0.004; 9.5% to 52.4%) from admission to discharge (Figures 1 and 2). There was no statistically significant change in ARNI, ACEi or ARB, or SGLT2i prescribing in the post-stewardship tool group (p > 0.05 for all analyses; Figure 1). In the pre- and post-stewardship tool group, 23.8% (10/42) and 52.4% (11/21) of patients, respectively, were discharged on combination GDMT (Figure 2). One patient in the pre-stewardship tool group and 2 in the post-stewardship tool group were discharged on gold-standard quadruple therapy (ARNI, BB, MRA, SGLT2i) (Table 2).
The absence of documented reasons for not initiating individual GDMT varied by agent, with nearly 60% of patients in the pre-stewardship group having no documented reason for not initiating ARNI or SGLT2i agents, with this number remaining over 20% for the same agents post-stewardship tool implementation (Table 3). Identifiable reasons for not being prescribed GDMT were agent-specific and determined by investigators based on clinical experience and judgment. Reasoning included abnormal lab work, such as a systolic blood pressure less than 100 mmHg, estimated glomerular filtration rate less than 30 mL/min, a serum potassium greater than 5 mmol/L and having an allergy or intolerance to the agent (Appendix 2). Pharmacists were involved with 7.1% and 66.7% of enrolled patients in the pre- and post-stewardship tool groups, respectively (Table 1). Eight patients in the post-stewardship tool group did not have medication coverage for an ARNI, and 1 did not have medication coverage for an SGLT2i (Table 1). Medication coverage was not known for 57.1% of patients in the pre-stewardship tool group (Table 1).
Despite robust guideline recommendations and concrete evidence documenting that use of GDMT for patients with HFrEF reduces mortality and heart failure hospitalizations, the proportion of patients being treated appropriately is suboptimal.11-18,25 In this study, a patient-specific prescriber-alert stewardship tool resulted in an increase in the rate of individual (BB and MRA) and combination-GDMT prescribing from admission to discharge in admitted patients with HFrEF, while the pre-stewardship tool group only showed increases in prescribing for 2 individual agents (BB and ACEi).
Interventions for the improvement and optimization of GDMT prescription in patients with HFrEF have shown success in elevating both individual and combined therapy prescription upon hospital discharge26,27 or at 30-day follow-up for outpatients.28 Using our prescriber-alert tool, we observed similar improvements to β-blockers and overall GDMT prescription, as seen in inpatient and outpatient settings using alternative interventions,27,28 while also observing improvement to MRA prescription that was reported for hospital inpatients.26,27 Our tool was patient-specific and provided the prescriber an opportunity to consult pharmacy, making the alert more targeted, a strategy that previous HFrEF stewardship programs were also able to successfully use.26-28 In contrast to more resource-intensive initiatives, this stewardship tool can easily be implemented by non-pharmacist health care providers, does not require electronic patient charts to execute and was not found to be time-consuming to implement. We believe part of the success of this stewardship tool was due to the fact it was reviewed by cardiology peers with feedback incorporated prior to implementation of the tool and was designed in a way that allowed for physicians to maintain their prescribing autonomy by simply “nudging” the prescribers. Finally, we received positive verbal feedback from nursing and physician colleagues regarding the usefulness of our stewardship tool following its implementation.
Among GDMT, β-blockers and ACEi or ARBs have traditionally been the most frequently prescribed agents for patients with HFrEF.25 Evidence for decreasing mortality and heart failure hospitalization for β-blockers, ACEi and ARBs has been available for several years, and the previous 2017 Canadian HFrEF guideline recommendations have reflected the abundance of evidence in their recommendation.11-13,29-32 Thus, it is not surprising to see increases in prescribing from admission to discharge for β-blockers and ACEi without the use of our stewardship tool. ACEi prescribing did not see an increase in prescribing from admission to discharge in our stewardship tool group. This may be due to the nearly 20% of patients discharged with an ARNI prescription, a first-line treatment for patients with HFrEF and a subsequent discontinuation of their ACEi or ARBs to avoid duplicate therapy within the same class of medication.12
Unlike β-blockers and ACEi or ARBs, MRAs and ARNIs are known to be underprescribed.25 In the CHAMP-HF trial, less than 33.1% and 12.8% of patients were found to be treated with an MRA and ARNI, respectively.25 Our stewardship tool resulted in more than 60% of patients being discharged on an MRA, with 19% of patients in the stewardship tool group discharged on an ARNI. This nonsignificant increase to ARNI prescription may have been impacted by the 38% of patients found to not have medication coverage for an ARNI, representing a potentially significant barrier to prescribing. In terms of combination GDMT, more than 50% of patients in the post-stewardship tool were discharged on either triple or quadruple GDMT therapy, representing nearly a 30% increase in GDMT from the pre-stewardship cohort. Although there has been an improvement in the prescribing of both individual and combination GDMT with the use of our stewardship tool, only just over half of our patients are being discharged on life-prolonging combination GDMT, and large gaps in HFrEF therapy still exist. Future stewardship initiatives must focus on continuing to elevate GDMT uptake for all eligible patients.
Hospitalization is an attractive time for initiation and titration of HFrEF GDMT, as clinical benefits of GDMT can be seen within days or weeks after starting treatment.18,19,24 Failure to start GDMT while the patient is hospitalized is associated with a high likelihood the patient will still not be on GDMT 1 year from discharge and, given the known benefits of these medications, may put the patient at an increased risk of rehospitalization and death.11-18,21 Our study captured patients with HFrEF admitted for heart failure and non-heart failure reasons, which allowed for reassessment of GDMT regardless of the reason for admission and aimed to take advantage of the patient’s admission to hospital for GDMT initiation.
Physician comfort may represent a barrier to prescribing GDMT in this patient population. We identified that most changes being made to GDMT were done by a cardiologist, but very few patients were subsequently discharged by a cardiologist. The frequency of family physicians and hospitalists making changes to GDMT was low despite the Canadian guidelines encouraging GDMT prescribing by nonspecialists.12 Cardiologists were more involved in the stewardship tool group, which may have also led to increased prescribing of GDMT among the stewardship group. Increasing education to nonspecialist prescribers regarding the benefits of initiating GDMT for hospitalized patients with HFrEF may increase the prescribing of GDMT and would be an important area for future quality improvement projects.
GDMT agents, specifically ARNI and SGLT2i, are higher-cost medications and require a special authorization form to be filled out by the prescriber to obtain access for patients under the provincial formulary.33-35 Our stewardship tool provided prescribers the opportunity to cosign for a pharmacy assessment of patient-specific medication coverage to remove this barrier for prescribing, where applicable. More than half of patients in the pre-stewardship tool group’s medication coverage was not known, and thus the prescriber may not have been aware that their patient might be able to access ARNIs and SGLT2is with little added cost. Patient medication coverage was known for each patient in the stewardship tool group, making it easier for prescribers to understand the barriers, or lack thereof, for medications such as ARNIs and SGLT2is.
This study had several limitations. First, the study was only completed on the cardiology stepdown unit of a single hospital; therefore, patients with HFrEF admitted to different hospital units were not captured. The true incidence of patients with HFrEF being admitted to units other than the cardiology stepdown unit remains unknown. Second, patients with incomplete discharge were excluded (e.g., those transferred to another facility for further investigations), and therefore the effects of our stewardship tool remain unknown in this population. Third, impacts from the global COVID-19 pandemic decreased the number of admissions and increased the length of hospitalization in the stewardship tool group due to heightened infection prevention and control requirements for managing the impacts of this virus. A decrease in admissions to the stepdown unit may have reduced our sample size, and longer hospitalizations may have impacted GDMT prescribing behaviours. We also recognize that our reduced sample size in the stewardship tool group may have impacted the power of our statistical analyses; therefore, future work should look at replicating this study on a larger scale and across multiple sites to improve our understanding of the use of GDMT prescriber alerts.
This study demonstrated that a pharmacist-led heart failure stewardship tool initiative significantly increased prescribing of guideline-directed medical therapy in patients with HFrEF. This low-resource intervention can be easily implemented into clinical practice to increase prescribing of life-prolonging GDMT in patients with HFrEF.
From Horizon Health Network, Moncton (MacDonald, Johnston) and Saint John (Flewelling), New Brunswick. Contact GemmaMacDonald@ihis.org.
Author Contributions: All authors approved the final version of the article.
Declaration of Conflicting Interests: The authors declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.
Funding: The authors received no financial support for the research, authorship and/or publication of this article.
Supplemental Material: Supplemental material for this article is available online.
ORCID iDs: Gemma-Dawn A. MacDonald https://orcid.org/0009-0008-8055-6522Andrew J. Flewelling https://orcid.org/0000-0002-2739-8595
Gheorghiade M, De Luca L, Fonarow GC, Filippatos G, Metra M, Francis GS. Pathophysiologic targets in the early phase of acute heart failure syndromes. Am J Cardiol 2005;96:11G-7G.
Heart and Stoke Foundation of Canada. Falling short: how Canada is failing people with heart failure and how we can change that. 2022. https://www.heartandstroke.ca/-/media/pdf-files/canada/2022-heart-month/hs-heart-failurereport-2022-final.pdf (accessed 30 Mar. 2024).
Benjamin EJ, Blaha MJ, Chiuve SE, et al. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. Circulation 2017;135:e146-603.
Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA 2004;292:344-50.
Canadian Institute for Health Information. Top 5 reasons for hospital stays in Canada. February 2023. Available: https://www.cihi.ca/en/hospital-stays-incanada (accessed Mar. 16, 2023).
Krumholz HM, Merrill AR, Schone EM, et al. Patterns of hospital performance in acute myocardial infarction and heart failure 30-day mortality and readmission. Circ Cardiovasc Qual Outcomes 2009;2:407-13.
Setoguchi S, Stevenson LW, Schneeweiss S. Repeated hospitalizations predict mortality in the community population with heart failure. Am Heart J 2007;154:260-66.
Murphy SP, Ibrahim NE, Januzzi JL Jr. Heart failure with reduced ejection fraction: a review. JAMA 2020;324:488-504.
Shah KS, Xu H, Matsouaka RA, et al. Heart failure with preserved, borderline and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol 2017;70:2476-86.
Virani SS, Alonso A, Benjamin EJ, et al. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 2020;141:e139-596.
Ezekowitz JA, O’Meara E, McDonald MA, et al. 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of heart failure. Can J Cardiol 2017;33:1342-433.
McDonald M, Virani S, Chan M, et al. CCS/CHFS heart failure guidelines update: defining a new pharmacologic standard of care for heart failure with reduced ejection fraction. Can J Cardiol 2021;37:531-46.
Shibata MC, Flather MD, Wang D. Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure. Eur J Heart Fail 2001;3:351-7.
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.
McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993-1004.
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
Packer M, Anker SD, Butler J, et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Circulation 2021;143:326-36.
Brownell NK, Ziaeian B, Fonarow GC. The gap to fill: rationale for rapid initiation and optimal titration of comprehensive disease-modifying medical therapy for heart failure with reduced ejection fraction. Card Fail Rev 2021;7:e18.
Vaduganathan M, Claggett BL, Jhund PS, et al. Estimating lifetime benefits of comprehensive disease-modifying pharmacological therapies in patients with heart failure with reduced ejection fraction: a comparative analysis of three randomised controlled trials. Lancet 2020;396:121-8.
Rao VN, Murray E, Butler J, et al. In-hospital initiation of sodium-glucose cotransporter-2 inhibitors for heart failure with reduced ejection fraction. J Am Coll Cardiol 2021;78:2004-12.
Carnicelli AP, Lippmann SJ, Greene SJ, et al. Sacubitril/valsartan initiation and postdischarge adherence among patients hospitalized for heart failure. J Card Fail 2021;27:826-36.
Curtis LH, Mi X, Qualls LG, et al. Transitional adherence and persistence in the use of aldosterone antagonist therapy in patients with heart failure. Am Heart J 2013;165:979-86.e1.
Krum H, Roecker EB, Mohacsi P, et al. Effects of initiating carvedilol in patients with severe chronic heart failure: results from the COPERNICUS Study. JAMA 2003;289:712-8.
Greene SJ, Butler J, Albert NM, et al. Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry. J Am Coll Cardiol 2018;72:351-66.
Sparks ER, Beavers JC. Evaluation of a pharmacist-driven aldosterone antagonist stewardship program in patients with heart failure. J Pharm Pract 2019;32:158-62.
Bhatt AS, Varshney AS, Nekoui M, et al. Virtual optimization of guideline-directed medical therapy in hospitalized patients with heart failure with reduced ejection fraction: the IMPLEMENT-HF pilot study. Eur J Heart Fail 2021;23:1191-201.
Ghazi L, Yamamoto Y, Riello RJ, et al. Electronic alerts to improve heart failure therapy in outpatient practice: a cluster randomized trial. J Am Coll Cardiol 2022;79:2203-13.
MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999;353:2001-7.
Cohn JN, Tognoni G. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001;345: 1667-75.
SOLVD Investigators;Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991;325: 293-302.
CIBIS-II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999;353:9-13.
CADTH Common Drug Review. CADTH reimbursement recommendation—empagliflozin (Jardiance). November 2022. Available: https://www.cadth.ca/sites/default/files/DRR/2022/SR0726%20Jardiance%20-%20Final%20CADTH%20Recommendation.pdf (accessed 15 Mar. 2023).
CADTH Common Drug Review. CADTH Canadian drug expert committee recommendation—dapagliflozin (Foxiga). January 2021. Available: https://www.cadth.ca/sites/default/files/cdr/complete/SR0642%20Forxiga%20-%20CDEC%20Final%20Recommendation%20January%2021%2C%202021_revised_redacted_for%20posting.pdf (accessed 30 Mar. 2023).
CADTH Common Drug Review. CADTH Canadian drug expert committee recommendation—sacubitril/valsartan (Entresto). March 2021. Available: https://www.cadth.ca/sites/default/files/cdr/complete/SR0644%20Entresto%20-%20%20CDEC%20Final%20Recommendation%20March%2026%2C%202021%20%28Redacted%29_for%20Posting.pdf (accessed 30 Mar. 2023).
