Advertisement

Use of Guideline-Directed Medical Therapy in Patients Aged 80 Years or Older with Heart Failure with Reduced Ejection Fraction

Open AccessPublished:January 06, 2023DOI:https://doi.org/10.1016/j.cjco.2023.01.002

      Abstract

      Background

      Guideline-directed medical therapy (GDMT) reduces morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF). Use of GDMT is recommended in all adults with HFrEF, but is potentially underutilized in patients with advanced age. This study sought to characterize use of GDMT in octogenarians/nonagenarians with HFrEF and identify barriers to initiation/up-titration.

      Methods

      This retrospective cohort study included patients aged 80-99 years at three heart failure clinics in the Lower Mainland of British Columbia, Canada. Patients with a left ventricular ejection fraction (LVEF) ≤40% and heart failure hospitalization <12 months were included. Data were collected between September 2019–August 2021 for up to 24 months from the initial clinic visit.

      Results

      Ninety-one patients were included. Mean age was 85 years and LVEF was 30%. About 50% of patients had New York Heart Association class II symptoms. Throughout the study follow-up period, approximately 91% of patients were on a beta-blocker, 72% on a renin-angiotensin system (RAS) inhibitor, 31% on a mineralocorticoid receptor antagonist (MRA), and 4% on a sodium-glucose cotransporter 2 (SGLT2) inhibitor. Target dose was achieved in 19% of patients on a beta-blocker, 7% on a RAS inhibitor, 11% on an MRA, and 100% on a SGLT2 inhibitor. Frequent barriers to GDMT initiation/up-titration were renal dysfunction, hypotension, and hyperkalemia.

      Conclusions

      Use of RAS inhibitors and beta-blockers in patients aged 80-99 years with HFrEF was reasonable, while use of MRAs and SGLT2 inhibitors was low. Achievement of target doses of GDMT was rare owing to common adverse effects.

      Key Words

      Introduction

      Heart failure (HF) places a significant burden on the healthcare system. An estimated 50,000 Canadians are newly diagnosed with HF each year and more than 2.8 billion dollars (CAD) are spent annually on HF-related complications.

      Heart & Stroke. Heart Failure, https://www.heartandstroke.ca/heart-disease/conditions/heart-failure. Accessed September 19, 2022.

      Within the Fraser Health region of British Columbia, Canada, the incidence of HF in men and women aged ≥80 years of age is 41 per 1000 persons, compared to 10 per 1000 among those 65-79 years of age.

      British Columbia Centre for Disease Control. Chronic Disease Dashboard, http://www.bccdc.ca/health-professionals/data-reports/chronic-disease-dashboard. Accessed September 19, 2022.

      The prevalence of HF in octogenarians and nonagenarians is projected to steadily rise, as this population is expected to increase by 54% over the next decade.

      Statistics Canada. Table 17-10-0057-01: Projected population, by projection scenario, age and sex, as of July 1 (x 1,000), https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1710005701. Accessed September 19, 2022.

      The 2021 Canadian Cardiovascular Society/Canadian Heart Failure Society heart failure guidelines update recommend four standard therapies for all patients (regardless of age) with heart failure with reduced ejection fraction (HFrEF) in the absence of contraindications.
      • 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.
      The four guideline-directed medical therapies (GDMT) include: (i) one of an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor; (ii) a beta-blocker; (iii) a mineralocorticoid receptor antagonist (MRA); and (iv) a sodium-glucose cotransporter 2 (SGLT2) inhibitor. These therapies have been demonstrated in landmark clinical trials to reduced HF-related hospitalizations and mortality, as well as improve symptoms and quality of life.

      The SOLVD Investigators. 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.

      The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
      • Køber L.
      • Torp-Pedersen C.
      • Carlsen J.E.
      • et al.
      A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
      • Cohn J.N.
      • Tognoni G.
      Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
      • Pfeffer M.A.
      • Swedberg K.
      • Granger C.B.
      • et al.
      Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
      • McMurray J.J.
      • Packer M.
      • Desai A.S.
      • et al.
      Angiotensin-neprilysin inhibition versus enalapril in heart failure.
      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).
      • Committees
      CIBIS-II Investigators
      The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
      • Packer M.
      • Bristow M.R.
      • Cohn J.N.
      • et al.
      The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
      • Zannad F.
      • McMurray J.J.
      • Krum H.
      • et al.
      Eplerenone in patients with systolic heart failure and mild symptoms.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      However, the average age of patients in these clinical trials was approximately 61-65 years of age, with very limited inclusion of patients aged ≥80 years.
      Despite the lack of representation in these clinical trials, efficacy of GDMT is often extrapolated to octogenarians and nonagenarians. However, there is limited real-world evidence regarding actual use in this patient population. There are several barriers to using GDMT in older adults.
      • Butrous H.
      • Hummel S.L.
      Heart failure in older adults.
      • Man J.P.
      • Jugdutt B.I.
      Systolic heart failure in the elderly: optimizing medical management.
      • Azad N.
      • Lemay G.
      Management of chronic heart failure in the older population.
      Due to pharmacodynamic changes, older patients are at higher risk of common adverse effects of GDMT including hypotension, bradycardia, renal impairment, and electrolyte disturbances, as well as drug-drug interactions due to polypharmacy. Further, age-related comorbidities, such as frailty and cognitive impairment, may be actual or perceived barriers to initiation or up-titration of GDMT. Conversely, appropriate use of GDMT in non-frail patients aged ≥80 years may be underutilized due to an overestimation of the risk of harm, or underestimation of the benefit on symptoms and quality of life. Other factors, such as increased pill burden or financial concerns, may negatively affect medication utilization and adherence in older adults regardless of frailty or comorbidity. Despite these concerns, many patients aged ≥80 years with HFrEF may be undertreated with GDMT due to a potential overestimation of the risk of therapy or underestimation of the benefit of therapy.
      • Butrous H.
      • Hummel S.L.
      Heart failure in older adults.
      The objective of this study was to evaluate and characterize the utilization of GDMT, as well as identify barriers to initiation and up-titration of GDMT, in a cohort of in octogenarians and nonagenarians with HFrEF who were receiving care from specialized heart failure clinics.

      Methods

      Study Design

      This was a retrospective cohort study of all patients receiving care from one of three specialized heart failure clinics within the Fraser Health region of British Columbia. The clinics are based at the Royal Columbian Hospital in New Westminster, the Jim Pattison Outpatient Care and Surgery Centre in Surrey, and the Abbotsford Regional Hospital and Cancer Centre in Abbotsford, British Columbia. Each heart failure clinic is an outpatient secondary care cardiac clinic located in a hospital or ambulatory care centre. These multidisciplinary clinics provide specialized care to patients referred for a clinical diagnosis of new or worsening heart failure irrespective of ejection fraction. Each clinic is staffed by a rotating group of cardiologists, as well as other healthcare professionals such as nurses, nurse practitioners, pharmacists, dietitians, and social workers. The purpose of the clinics is to provide evidence-based care to patients with heart failure to reduce mortality and hospitalizations, and improve symptoms and quality of life. This study was approved by the University of British Columbia Clinical Research Ethics Board and Fraser Health Research Ethics Board via a harmonized review (H21-02568).

      Study Population

      Included were patients aged 80-99 years with a left ventricular ejection fraction (LVEF) of 40% or less. Patients were also required to have been hospitalized with a primary diagnosis of an acute heart failure exacerbation within the 12 months prior to being seen in the heart failure clinic, and were required to have two or more visits at the heart failure clinic. Patients with heart failure with preserved ejection fraction (LVEF >40%) were excluded. Patients were identified based on International Classification of Diseases 10th Revision code I50 (heart failure) and electronic health record coding in Meditech (Westwood, MA).

      Data Collection

      Data on eligible patients were collected retrospectively from their electronic health record (Meditech) from September 1, 2019 to August 31, 2021 (up to 24 months of follow-up). The following data were collected: age, sex, weight, LVEF, etiology of HF, New York Heart Association (NYHA) classification, medical comorbidities (hypertension, coronary artery disease, atrial fibrillation, stroke, chronic kidney disease, and diabetes mellitus), and relevant vitals and laboratory values. Data on use of the four standard GMDT were collected at each visit (drug name, dose, route, and frequency of administration), as well as any documented barriers to the use or up-titration of GDMT. The barriers to initiation or up-titration of GDMT were based on any freeform documented reason in the patient’s electronic health record. These barriers did not have specific definitions or criteria, as the goal was to capture any perceived barriers to use or up-titration of GDMT. All data were collected by one researcher (MG) using a standardized data collection form.

      Objectives

      The primary objective of this study was to determine proportion of patients aged 80-99 years with HFrEF who were prescribed three of the four standard GDMT: a renin-angiotensin system (RAS) inhibitor (e.g., angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, or angiotensin receptor-neprilysin inhibitor), beta-blocker, and MRA over the study follow-up period. Sodium-glucose cotransporter 2 inhibitors were excluded from the primary objective, as they were only recently endorsed by heart failure guidelines. Additional objectives included the proportion of patients on each of the four standard GDMT including SGLT2 inhibitors, as well as the proportion of patients on the target dose of each agent. The target dose for each medication was based on the recommended doses provided in the 2021 Canadian Cardiovascular Society/Canadian Heart Failure Society heart failure guidelines update.
      • 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.
      Data on any documented barriers to initiation or up-titration of the four GDMT (e.g., adverse drug reactions, contraindications, non-adherence, potential harm perceived to outweigh the potential benefit) were also collected.

      Statistical Analysis

      Descriptive statistics were used to report patient characteristics and medication utilization. Categorical values were reported as frequencies with percentages, and continuous variables were reported as means with standard deviations or medians with interquartile ranges based on the distribution. All analyses were performed with Microsoft Excel (Redmond, WA).

      Results

      A total of 91 patients were included in this study. Reasons for excluding patients are outlined in Figure 1. Among the excluded patients, a high proportion had heart failure with preserved ejection fraction (161/241, 67%). Patient characteristics are included in Table 1. Mean age was 85.2 ± 3.9 years, with a mean LVEF of 30.4%. Most patients had NYHA class II or III symptoms. A majority of patients (53.8%) had HFrEF secondary to myocardial ischemia. Data were available for 75 patients (82% of the overall population) at 1-3 months, 66 patients (73% of the overall population) at 4-6 months, and 54 patients (59% of the overall population) at 7-24 months.
      Figure thumbnail gr1
      Figure 1Study flow diagram, HF, heart failure; HFC, heart failure clinic; LVEF, left ventricular ejection fraction
      Table 1Baseline characteristics (N=91)
      Age, yr85.2 ± 3.9
      Male sex55 (60.4)
      Weight, kg72.8 ± 19.7
      Systolic BP, mmHg120.4 ± 18.2
      Diastolic BP, mmHg66.5 ± 11.1
      Heart rate, bpm72.3 ± 14.6
      Serum creatinine, μmol/L145.0 ± 81.2
      eGFR, mL/min/1.73 m243.5 ± 19.5
      Serum sodium, mmol/L138.1 ± 4.0
      Serum potassium, mmol/L4.2 ± 0.6
      Hemoglobin A1c, %6.4 ± 1.1
      LVEF, %30.4 ± 6.7
      Etiology of heart failure
      Ischemic49 (53.8)
      Non-ischemic32 (35.2)
      Mixed ischemic and non-ischemic8 (8.8)
      Unknown2 (2.2)
      NYHA classification
      I4 (4.4)
      II45 (49.4)
      III39 (42.9)
      IV3 (3.3)
      Comorbidities
      Hypertension77 (84.6)
      CAD59 (64.8)
      CKD59 (64.8)
      Atrial fibrillation58 (63.7)
      Diabetes mellitus37 (40.7)
      Stroke20 (22.0)
      Values presented as mean ± standard deviation or number (percentage)
      BP, blood pressure; CAD, coronary artery disease; CKD, chronic kidney disease, eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association
      Overall medication utilization is included in Figure 2. At the initial clinic visit, 23 patients (25%) were prescribed the three primary GDMT (i.e., RAS inhibitor, beta-blocker, and MRA). The highest utilization was beta-blockers at 92%, while no patients were on an SGLT2 inhibitor. Over the entire study period, the proportion of patients prescribed a beta-blocker and MRA remained fairly consistent at 89-92% and 31-32%, respectively. Though there was an initial increase in the proportion of patients prescribed a RAS inhibitor up to the 6-month follow-up visit (79%), this decreased during the 7- to 24-month period (67%). The proportion of patients prescribed SGLT2 inhibitor increased to 7% by the end of the study period.
      Figure thumbnail gr2
      Figure 2Proportion of patients on each of the guideline-directed medical therapies
      The proportion of patients on the target dose of each of the GDMT is included in Figure 3. There was a low overall achievement of target doses of GDMT. The proportion of patients achieving target dosing of a RAS inhibitor was variable. It increased from a baseline of 11% up to a peak of 17% during the 4- to 6-month period, but then declined to 7% in the 7- to 24-month period. The proportion of patients on a target dose of a beta-blocker and MRA was stable at approximately 19% and 11%, respectively, throughout the study period. All patients that were prescribed an SGLT2 inhibitor were on the target dose.
      Figure thumbnail gr3
      Figure 3Proportion of patients on the target dose of each of the guideline-directed medical therapies
      Barriers to initiation and up-titration of GDMT are detailed in Table 2. Patients could have had more than one barrier. Almost half of patients (48%) had renal dysfunction. The other most common documented barriers were hypotension and hyperkalemia.
      Table 2Barriers to initiation or up-titration of guideline-directed medical therapies (N=91)
      Barriern%
      Renal dysfunction4448.4
      Hypotension3639.6
      Hyperkalemia2224.2
      Dizziness1718.7
      Hospitalization1516.5
      Orthostatic hypotension1415.4
      No blood work or vitals available1415.4
      Bradycardia1213.2
      Patient request1213.2
      Falls risk1112.1
      Non-adherence1112.1
      Frailty1011.0
      Cough77.7
      Syncope66.6
      LVEF improved55.5
      Fatigue55.5
      Gastrointestinal disorder22.2
      Allergy11.1
      Amyloidosis11.1
      Angioedema11.1
      Aortic stenosis11.1
      Second-degree AV block11.1
      Urinary retention11.1
      AV, atrioventricular; LVEF, left ventricular ejection fraction

      Discussion

      This study demonstrated that the use of GDMT in patients aged ≥80 years was variable depending on the agent, but low overall. Throughout the study period, only up to roughly one-third of patients were prescribed the three primary GDMT, specifically a RAS inhibitor, beta-blocker, and MRA. This was primarily due to low utilization of MRAs at approximately 31%. The highest utilization of any of the GDMT was beta-blockers at approximately 90%, while the use of RAS inhibitors was also relatively high at >65% with variability across the study period. Not unexpectedly, the use of SGLT2 inhibitors was low, as it was only recently added to GDMT. Appropriate use of GDMT should be considered a priority in older patients with HFrEF to reduce adverse HF-related outcomes—irrespective of a patient’s advanced age—as it has been shown to reduce the risk of HF hospitalization, which may be more consequential to some older persons versus a mortality benefit. This is germane to the present study, as all included patients had a previous HF hospitalization. Conversely, as articulated in a review by Butrous and Hummel
      • Butrous H.
      • Hummel S.L.
      Heart failure in older adults.
      , “The conventional viewpoint that elderly patients with HF value symptom control and quality of life over longevity is not always true”, as there is evidence to support that some older patients may value the survival benefit of GDMT.
      Our study population was similar to the CHECK-HF study, which examined the use of the three primary GDMT (RAS inhibitor, beta-blocker, and MRA) in 2009 patients aged 80 years or older with HFrEF at 34 outpatient clinics in the Netherlands in 2013-16.
      • Linssen G.C.M.
      • Veenis J.F.
      • Kleberger A.
      • et al.
      Medical treatment of octogenarians with chronic heart failure: data from CHECK-HF.
      At baseline, the average age was 84 years, 42% were female, mean LVEF was 30%, mean estimated glomerular filtration rate (eGFR) was 45 mL/min/1.73 m2, and about half the population had NYHA class II symptoms. Similar to our study, the three primary GDMT agents were prescribed to about 30% of patients in the CHECK-HF study. The use of RAS inhibitors was similar in the present study compared to CHECK-HF (67-79% versus 73%), whereas the use of beta-blockers was higher in the present study versus CHECK-HF (89-92% versus 78%). This may have been due to a higher number of patients in the present study with atrial fibrillation (64% versus 34%). Conversely, the use of MRAs was lower (31-32% versus 52%) despite similar baseline renal function in both populations.
      The CHAMP-HF study included 3518 patients from 150 primary care and cardiology clinics in the United States between 2015-17.
      • Greene S.J.
      • Butler J.
      • Albert N.M.
      • et al.
      Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry.
      This study did not specifically enroll older patients, as the mean age was 66 years. Use of drug therapy was reported based on eligibility (e.g., treated, with a contraindication, or untreated without a contraindication). The use of RAS inhibitors and MRAs among eligible patients was similar in the present study at 73% and 33%, while the use of beta-blockers was lower at 67%. Fewer than 30% of patients prescribed a RAS inhibitor or beta-blocker were on the target dose, which is comparable to the present study, while 77% were on the target dose of an MRA versus roughly 32% in the present study. Despite a lower mean age, only 22% of the cohort were on all three of the primary GDMT (RAS inhibitor, beta-blocker, and MRA), which is less than the present study. In adjusted logistic regression models, older age, renal insufficiency, lower blood pressure, and a recent HF hospitalization were independently associated with lower medication utilization and dose, which supports the relatively low overall use of GDMT in the present study. Both the CHECK-HF and CHAMP-HF studies support that the current use of GDMT in older persons has remained relatively unchanged since these studies were conducted in 2013-17.
      To our knowledge, this was the first study to evaluate the use of SGLT2 inhibitors in octogenarians and nonagenarians with HFrEF. However, the overall utilization was low at 7%. This may have been due to slow uptake in practice, as the first SGLT2 inhibitor trial conducted specifically in HFrEF patients was initially published in November 2019.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      As well, the population in the present study was older (85 years vs 66-67 years) with lower baseline renal function (eGFR 44 mL/min/1.73 m2 vs 62-66 mL/min/1.73 m2) versus patients in the DAPA-HF and EMPEROR-Reduced trials.
      • McMurray J.J.V.
      • Solomon S.D.
      • Inzucchi S.E.
      • et al.
      Dapagliflozin in patients with heart failure and reduced ejection fraction.
      • Packer M.
      • Anker S.D.
      • Butler J.
      • et al.
      Cardiovascular and renal outcomes with empagliflozin in heart failure.
      Therefore, clinicians may have been more reluctant to initiate SGLT2 inhibitors in patients aged ≥80 years, as they were not well represented in these trials. Finally, publicly funded insurance coverage for SGLT2 inhibitors specifically for HFrEF only came available in the province in 2022 (after the data collection period), though coverage was available for patients with diabetes.
      The barriers to initiation and up-titration of GDMT identified in the present study were expected given the age of the population. This may have explained the low use of MRAs, as many of the documented barriers are common adverse effects, such as renal dysfunction, hypotension, and hyperkalemia. Some of the barriers, such as frailty, falls risk, and non-adherence, are common among older persons, but can be mitigated through formal assessments and interventions by healthcare professionals specializing in the care of older patients. Therefore, this represents an unmet need among older patients who attend specialized heart failure clinics, and supports the development of cardiac clinics specifically designed for patients with advanced age or frailty that are staffed by clinicians with specialized training in both cardiology and geriatrics. Of note, most of the data collection period overlapped with the COVID-19 pandemic. Thus, the up-titration of GDMT may have been halted due to patients’ inability to attend clinic visits or have routine blood work drawn.
      The concept of guideline-recommended target doses in older patients is controversial, as most of the patients included in the clinical trials were younger (mean age 61-65 years). Therefore, it is questionable whether achievement of these target doses is clinically appropriate in those aged 80 years or older. Based on our results, we advocate use of lower doses of each of the four GDMT to maximize the benefit of reducing HF-related hospitalizations among patients aged ≥80 years. Our study identified that there remain opportunities to improve utilization of MRAs and SGLT2 inhibitors in this patient population. As such, clinicians should potentially consider a lower dose of a RAS inhibitor to facilitate concomitant use of an MRA and SGLT2 inhibitor. Further, clinicians should accept that most older patients with HFrEF may only be able to achieve a maximally tolerated dose of each GDMT (as opposed to the target dose), and that achievement of target doses should only be pursued in select patients who tolerate each medication without evidence of adverse effects, primarily hypotension and renal impairment. The risk of hypotension and bradycardia is of particular concern to older persons, as these may contribute to falls and other sequalae.
      This study characterized the real-world use of GDMT in a contemporary cohort of patients aged ≥80 years with HFrEF at three specialized heart failure clinics. However, it included a small sample size, as a high proportion of screened patients had heart failure with preserved ejection fraction (161/332, 49%). Thus, the results of this study are only generalizable to patients with HFrEF, which represents only a fraction of patients 80 years of age or older with heart failure. It was not designed to assess the use of MRAs and SGLT2 inhibitors in patients with heart failure with preserved ejection fraction. We did not collect data on frailty, as patients seen in these clinics are not routinely assessed for frailty using a validated tool. Further, we did not specifically collect data on dementia or cognitive impairment at baseline. The study design did not permit the determination of any association between GDMT use and clinical outcomes, such as mortality or HF hospitalization. Yet, a cohort study of 2045 older patients with HFrEF in Korea identified that use of a RAS inhibitor and beta-blocker, as compared to no therapy, was associated with a 48% relative lower risk of all-cause mortality among patients aged ≥80 years.
      • Seo W.W.
      • Park J.J.
      • Park H.A.
      • et al.
      Guideline-directed medical therapy in elderly patients with heart failure with reduced ejection fraction: a cohort study.
      There was also a potential for underreporting of barriers to initiation or up-titration of therapy in the present study, as it relied on the completeness of the documentation in the electronic health record. The usage and dosing of diuretic therapy, in combination with RAS inhibitors and MRAs, may have contributed to some of the barriers (e.g., hypotension, renal dysfunction), but was not collected as part of this study.

      Conclusions

      The findings of this study provide insight on the use of GDMT in octogenarians and nonagenarians with HFrEF in clinical practice. Use of RAS inhibitors and beta-blockers was reasonably high and comparable to other studies, while use of MRAs and SGLT2 inhibitors was low. Achievement of target doses of GDMT was rare owing to common adverse effects, which is not unexpected considering that these target doses were utilized in clinical trials with a younger population. Optimization of GDMT in patients with advanced age remains challenging due to factors that affect this patient population, such as hypotension and renal impairment. Therefore, clinicians should consider achieving maximally tolerated doses of GDMT, as opposed to target doses, based on patient-specific factors. There remains a need for randomized controlled trials to evaluate the safety and efficacy of GDMT specifically in patients aged ≥80 years with HFrEF.

      Acknowledgements

      None.
      Funding Sources
      This study was unfunded. Funding for the publication fee was supported by internal start-up funding at the Faculty of Pharmaceutical Sciences at the University of British Columbia.
      Disclosures
      The author has no financial or other conflicts of interest related to this work.

      References

      1. Heart & Stroke. Heart Failure, https://www.heartandstroke.ca/heart-disease/conditions/heart-failure. Accessed September 19, 2022.

      2. British Columbia Centre for Disease Control. Chronic Disease Dashboard, http://www.bccdc.ca/health-professionals/data-reports/chronic-disease-dashboard. Accessed September 19, 2022.

      3. Statistics Canada. Table 17-10-0057-01: Projected population, by projection scenario, age and sex, as of July 1 (x 1,000), https://www150.statcan.gc.ca/t1/tbl1/en/tv.action?pid=1710005701. Accessed September 19, 2022.

        • 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: 531-546
      4. The SOLVD Investigators. 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.

      5. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure.
        Lancet. 1993; 342: 821-828
        • Køber L.
        • Torp-Pedersen C.
        • Carlsen J.E.
        • et al.
        A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group.
        N Engl J Med. 1995; 333: 1670-1676
        • Cohn J.N.
        • Tognoni G.
        Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
        N Engl J Med. 2001; 345: 1667-1675
        • Pfeffer M.A.
        • Swedberg K.
        • Granger C.B.
        • et al.
        Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme.
        Lancet. 2003; 362: 759-766
        • McMurray J.J.
        • Packer M.
        • Desai A.S.
        • et al.
        Angiotensin-neprilysin inhibition versus enalapril in heart failure.
        N Engl J Med. 2014; 371: 993-1004
        • 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: 2001-2007
        • Committees
        • CIBIS-II Investigators
        The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.
        Lancet. 1999; 353: 9-13
        • Packer M.
        • Bristow M.R.
        • Cohn J.N.
        • et al.
        The effect of carvedilol on morbidity and mortality in patients with chronic heart failure.
        N Engl J Med. 1996; 334: 1349-1355
        • Pitt B.
        • Zannad F.
        • Remme W.J.
        • et al.
        The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
        N Engl J Med. 1999; 341: 709-717
        • Zannad F.
        • McMurray J.J.
        • Krum H.
        • et al.
        Eplerenone in patients with systolic heart failure and mild symptoms.
        N Engl J Med. 2011; 364: 11-21
        • McMurray J.J.V.
        • Solomon S.D.
        • Inzucchi S.E.
        • et al.
        Dapagliflozin in patients with heart failure and reduced ejection fraction.
        N Engl J Med. 2019; 381: 1995-2008
        • Packer M.
        • Anker S.D.
        • Butler J.
        • et al.
        Cardiovascular and renal outcomes with empagliflozin in heart failure.
        N Engl J Med. 2020; 383: 1413-1424
        • Butrous H.
        • Hummel S.L.
        Heart failure in older adults.
        Can J Cardiol. 2016; 32: 1140-1147
        • Man J.P.
        • Jugdutt B.I.
        Systolic heart failure in the elderly: optimizing medical management.
        Heart Fail Rev. 2012; 17: 563-571
        • Azad N.
        • Lemay G.
        Management of chronic heart failure in the older population.
        J Geriatr Cardiol. 2014; 11: 329-337
        • Linssen G.C.M.
        • Veenis J.F.
        • Kleberger A.
        • et al.
        Medical treatment of octogenarians with chronic heart failure: data from CHECK-HF.
        Clin Res Cardiol. 2020; 109: 1155-1164
        • Greene S.J.
        • Butler J.
        • Albert N.M.
        • et al.
        Medical therapy for heart failure with reduced ejection fraction: the CHAMP-HF registry.
        J Am Coll Cardiol. 2018; 72: 351-366
        • Seo W.W.
        • Park J.J.
        • Park H.A.
        • et al.
        Guideline-directed medical therapy in elderly patients with heart failure with reduced ejection fraction: a cohort study.
        BMJ Open. 2020; 10e030514